Advances in the chemistry of β-lactam and its medicinal ...szolcsanyi/education/files/Chemia... ·...
-
Upload
dinhnguyet -
Category
Documents
-
view
222 -
download
2
Transcript of Advances in the chemistry of β-lactam and its medicinal ...szolcsanyi/education/files/Chemia... ·...
at SciVerse ScienceDirect
Tetrahedron 68 (2012) 10640e10664
Contents lists available
Tetrahedron
journal homepage: www.elsevier .com/locate/ tet
Advances in the chemistry of b-lactam and its medicinal applications
Anushree Kamath a,b, Iwao Ojima a,b,*
a Institute of Chemical Biology & Drug Discovery (ICB&DD), Stony Brook University, Stony Brook, NY 11794-3400, USAbDepartment of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA
a r t i c l e i n f o
Article history:Received 11 May 2012Available online 7 August 2012
Keywords:b-Lactamb-Lactam synthon methodAsymmetric synthesisStaudinger cycloadditionEster enolate cyclocondensationNon-protein amino acidsPaclitaxelTaxoidNitrogen-heterocycles
* Corresponding author. Tel.: þ1 631 632 1339; faaddress: [email protected] (I. Ojima).
0040-4020/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2012.07.090
1. Introduction
b-Lactam or azetidin-2-one is an important structural motif ofthe penicillin, cephalosporin, carbapenem, and carbecephem clas-ses of antibiotics.1 Naturally occurring as well as synthetic mono-bactams, such as nocardicins and tabtoxin, are also known for theirunique antibacterial activities.2e4 Besides their importance as thekey structural component of b-lactam antibiotics, b-lactams havebeen attracting considerable interest in organic synthesis as ver-satile synthetic intermediates and chiral synthons.5e13 In addition,the b-lactam scaffold has found new pharmaceutical applicationsother than its use as antibiotics, such as LHRH antagonists,14 cho-lesterol absorption inhibitors,15 and anticancer agents.16e19 Thering strain of the b-lactam skeleton facilitates ring-opening re-actions,8,20,21,22 and this unique property has been exploited for thesynthesis of a variety of medicinally active compounds.
For the last couple of decades, a large number of b-lactam-basedsynthetic methods, collectively termed as ‘b-lactam synthonmethod’, has been developed. This method has provided highlyefficient routes to a variety of non-protein amino acids, oligopep-tides, peptidomimetics, and nitrogen-heterocycles, as well as bi-ologically active natural and unnatural products of medicinal
x: þ1 631 632 7942; e-mail
All rights reserved.
interest, such as indolizidine alkaloids, paclitaxel, docetaxel, tax-oids, cyptophycins, lankacidins, etc.5,7e13
In this report, we present an overview of the evolution of themethods for the synthesis of enantiopure b-lactams, and the ap-plications of the ‘b-lactam synthon method’ for the synthesis ofbiologically active compounds of medicinal interest. Examples ofthe use of the rigid b-lactam scaffold for drug design and discoveryare also described.
2. Asymmetric synthesis of b-lactams
The Staudinger keteneeimine [2þ2] cycloaddition and the chi-ral ester enolateeimine cyclocondensation are the two methods,which are most commonly used for the synthesis of b-lactams withexcellent enantiopurity. Thus, these two synthetic methods arediscussed in this section.
2.1. Staudinger keteneeimine [2D2] cycloaddition
In 1907, long before the antibacterial activity of penicillin wasdiscovered, Staudinger reported the first synthesis of a b-lactam,1,3,3,4-tetraphenylazetidin-2-one, through the [2þ2] cycloadditionof diphenylketene with a Schiff base derived from aniline andbenzaldehyde.23 Subsequently, the scope of this reaction has beenextended to alkyl-, amino-, halo-, alkoxy-, and siloxy-ketenes, aswell as imino esters. Because of its broad scope in substrate
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10641
structures and simplicity in experimental procedure, this reactionis regarded as one of the most reliable routes to b-lactams.1 How-ever, in spite of common practice in laboratory synthesis for de-cades, the mechanistic details of this reaction have been disputedand subjected to theoretical investigations since its inception.24,25
The most widely accepted mechanism is a two-step reaction pro-cess, which involves the nucleophilic attack of the imine nitrogenon the electrophilic central carbon of a ketene, generated in situfrom an acid chloride and a base, to form a zwitterionic in-termediate, followed by conrotatory ring closure to give the four-membered ring system (Fig. 1).24,25
R1Cl
O Base
O
R1
NO R3
R2R1
NO
H HR1
R3
R2
NO R3
R1 R2N
O
H HR1
R3
R2
NR3
R2
trans
cis
H
H
HH
H H
Fig. 1. Mechanism of Staudinger [2þ2] keteneeimine cycloaddition.
In the reactionof amonosubstitutedketenewith analdimine, twochiral centers are introduced to the cycloadduct. Thus, the reactionwould give either a single stereoisomer (i.e., cis or trans) of b-lactamor a mixture of cis- and trans-b-lactams, depending on the reactantsand reaction conditions.25,24 As Fig. 1 shows, cis-b-lactam should beformed from the zwitterionic intermediate bearing the (E)-iminemoiety, but if isomerization to the zwitterionic intermediate bearingthe (Z)-imine moiety takes place, the reaction should give trans-b-lactam.26e29 This mechanism also indicates that the reaction witha (Z)-iminewould give the corresponding trans-b-lactam selectively.Theoretical studies on the origin of the stereoselectivity suggest that
N
Me
Ph
Cl
ClN
O
O
O
Et3NN
N
O
OCl
Me
PhON
N
O
OCl
Me
PhO
9:11 2 3
Scheme 1.
the relative transition-state energy in the rate-determining step isdictated by electronic torque selectivity.30,31
The stereoselectivity of the reaction is influenced by reactionvariables such as temperature, solvent, base, additives, chiral pen-dant groups, order of addition of reagents, microwave irradiation,
N
Ph
CO2Bn
OR N3CH2COCl, Et3NCH2Cl2, -40 °C
N
4a: R = TPS4b: R = TBS4c: R = H
64% (for 4a)
Scheme
etc.32e34 For example, it has been shown that non-polar solventsfavor the formation of cis-b-lactamwhereas polar solvents facilitatetrans-b-lactam formation. The result was explained by the stabili-zation of the zwitterionic intermediate in a polar solvent, promotingisomerization to the energetically more stable intermediate bearingthe (Z)-imine moiety before conrotatory ring closure.32
Asymmetric keteneeimine [2þ2] cycloaddition can be per-formed using combinations of (i) a chiral imine with an achiralketene, (ii) a chiral ketene with an achiral amine or (iii) a chiralketene with a chiral imine.
2.1.1. Asymmetric [2þ2] cycloaddition of achiral ketenes and chiralimines. Chiral imines can be prepared either from chiral aminesor from aldehydes. However, the diastereoselectivity of the re-action is lower, in most cases, using a chiral imine from a chiralamine, as compared to that from a chiral aldehyde.35 Neverthe-less, chiral amine sources are widely used for the asymmetricsynthesis of b-lactams.9,36 For example, the reaction of phthali-midoacetyl chloride with chiral imine 1, derived from (R)-1-phenylethylamine, in the presence of triethylamine gave b-lac-tams 2 and 3 in 74% combined yield with high stereoselectivity(2/3¼9:1) (Scheme 1).36
Commercially available enantiopure esters of a-amino acids arecommon sources of chiral amines. For example, 3-azido-b-lactam5a (R¼triphenylsilyl¼TPS) was obtained in 64% yield and 19:1 dr(5a/6a) using imine 4a derived from (R)-O-TPS-threonine benzylester and cinnamaldehyde (Scheme 2).37 The stereoselectivity of
NO
H H3
Ph
+
CO2Bn
ORN
O
H HN3
Ph
CO2Bn
OR
5a
5b
5c
19:19:11:1
6a
6b
6c
2.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410642
this reaction was found to depend critically on the bulkiness of thehydroxyl protecting group. Thus, the reaction of 4b (R¼tert-butyl-dimethylsilyl¼TBS) gave 5b with 9:1 dr (5b/6b) and that of 4c(R¼H) afforded a 1:1 mixture of 5c and 6c.37
Alternatively, one of the most effective routes for a large-scalesynthesis of b-lactams with high enantiopurity is to use chiralimines derived from chiral aldehydes such as a-oxyaldehydes andsugar-derived aldehydes (Scheme 3).35,38e40 For example, the[2þ2] cycloaddition of various ketenes with chiral imines 9 of D-glyceraldehyde acetonide (8), derived from D-mannitol via 7,afforded cis-b-lactams 10 exclusively in 45e70% yield.41,42 Theacetonide moiety of b-lactams 10 was deprotected to the corre-sponding b-lactam diols, which were oxidized by ruthenium te-troxide, followed by diazomethane esterification, to afford the 4-carbomethoxy-b-lactams.41 The b-lactam diols were also con-verted into the corresponding 4-formyl-b-lactam 11, which areversatile synthetic intermediates for further manipulations.13,42e44
HOOH
OH
OHOH
OHD-mannitol
OO
NR1
R2CH2COCl, Et3N
acetone, rt OO
CH2Cl2, -78 °C-rt
R1NH2, Et3N
ZnCl2
9
CH2Cl2, rt
R1 = PMP, Bn, CH2CO2Me; R2 = N3, MeO, PhO
Scheme
H2N OH
Me
CO2H
H2N OT
Me
CO2Me
NO
Ox
OTBS
OO
Me
MeO2C
(R)-threonine
O O
NTBSO
CO2Me
Me
i) 3 N HCl, MeOHreflux, 100%
ii) TBSCl, imidazoleDMF, 94%
OxCH2COCl, TEA
OxCH
+
12
14
16
1:2.9
CH2Cl2, 61%
H2N OH
Me
CO2H
(S)-threonine
CH
Scheme
When a chiral aldimine derived from a chiral aldehyde as well asa chiral amine was used, clear double asymmetric induction wasobserved, i.e., a matching pair gave the corresponding b-lactam asa single stereoisomer, while a mismatching pair afforded the b-lactam with only modest stereoselectivity. As Scheme 4 illustrates,the reaction of chiral aldimine 13, derived from (R)-threonine andchiral aldehyde 8 via 12, with a ketene, generated in situ fromdiphenyloxazolylacetyl chloride and triethylamine, gave a 1:2.9mixture of b-lactams 14 and 15 (i.e., mismatching pair reaction),while the reaction using chiral aldimine 16, derived from (S)-threonine and 8, afforded b-lactam 17 exclusively in 69% yield fortwo steps (i.e., matching pair reaction).45
2.1.2. [2þ2] Cycloaddition of chiral ketenes and achiral imines. Theketeneeimine [2þ2] cycloaddition using chiral ketenes has beenvery successful for the asymmetric synthesis of 3-amino-b-lactams.Enantiopure oxazolidinones derived from (S)- and (R)-phenylglycine
OO
O
OH
OH
OO
CH2Cl2, rt
NR1O
R2OO
NaIO4, Na2CO3
7
10
H
8
NR1O
R2 HO
11
i. H3O+
ii. NaIO4
, BnO, PhthN
3.
BS
O O
OHC
O O
NTBSO
Me
CO2Me
NO
Ox
OTBS
OO
Me
MeO2C
NO
Ox
OTBS
Me
OO
MeO2C
MgSO4, CH2Cl2quant.
O N
O
Ph Ph
Ox =
2COCl, TEA
8
13
15
17
2Cl2, 69%
4.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10643
are excellent chiral auxiliaries for this reaction and have been ex-tensively utilized.8,9,46 For example, (S)-4-phenyloxazolidinon-3-ylacetyl chloride (18) with N-benzylaldimines 20 gave b-lactams21 with 95:5 to 97:3 dr in 80e90% yield (Scheme 5).46 This meth-odology has been successfully applied to the solid-phase synthesis ofa library of b-lactams.47,48 Even a fused nitrogen aromatic com-pound, phenanthridine (22) was found to react with ketene 19 toafford fused tetracyclic trans-b-lactam 23 exclusively in 53% yield,wherein 22 apparently reacted as a (Z)-imine (Scheme 5).49
ON
O
Ph
R N PhEt3N
N
RN
PhO
O
Ph
O
CH2Cl2, -78 oC
R = Ph, CH=CH-Ph, CH=CH-C6H4-OMe-3, CH=CH-(2-Furyl)
80-90%
dr = 95:5 - 97:318
20
21
N+
Et3N
CH2Cl2rt53%
NO
H HN
O
Ph
O
22 23
N
O
Ph
O
19
O
H
ClO
ON
O
Ph
18
ClO
Scheme 5.
It has been shown that the [2þ2] cycloaddition of polyaromaticimines and ketenes, generated from acetoxy, phenoxy, and phtha-limidoacetyl chloride and an amine base, exclusively gives trans-b-lactams, which makes a sharp contrast to the normal reactionpattern, yielding cis-b-lactams from the same ketene sources anddiarylaldimines.16,17 In a similar manner, the reaction of a chiralketene, generated from alkoxyacetic acid 24 bearing an a-glycosidegroup, with chresenylaldimine 25 gave a 45:55 mixture of 26 and27 in 70% combined yield (Scheme 6). These two b-lactams werereadily separated by column chromatography and the hydrolysis ofthe sugar chiral auxiliary afforded the corresponding enantiopuretrans-3-hydroxy-4-phenyl-b-lactams.18
R =
O
OH
AcO
AcO NR
N
Ph
O R
O
O
AcOOAc
N
Ph
O R
O
O
AcOOAc
+ +
24 2526 27
OH
O
N ClI
Et3N, CH2Cl2
45: 55
Me
+-
Scheme 6.
2.1.3. Synthesis of enantiopure b-lactams via enzymatic kinetic res-olution. Enzymatic kinetic optical resolution of racemic b-lactamsprovides a practical route to enantiopure b-lactams. This methodhas been successfully applied to the synthesis of 3-hydroxy-b-lac-tams required for the semisynthesis of paclitaxel, docetaxel, andtaxoids.43,50e55 Hydrolytic enzymes such as PS Amano lipase andthe esterase in pig liver acetone powder (PLAP) have been shown to
give excellent results for the optical resolution of racemic cis-3-acetoxy-b-lactams. For example, the kinetic resolution of racemiccis-3-acetoxy-4-phenyl-b-lactam 29, obtained from 28, with PSAmano lipase afforded (3R,4S)-3-acetoxy-b-lactam 30 with >99.9%ee and (3S,4R)-3-hydroxy-b-lactam 31 with >99.0% ee in goodyields (Scheme 7).54
This protocol has also been successfully employed for the kineticoptical resolution of cis-3-acetoxy-4-isobutenyl-b-lactam.43,50,55
Although kinetic optical resolution does not have good ‘atom econ-
omy’, it should be noted that themethod is still quite economical andeasily scalable. In addition, both enantiomers serve as useful chiralbuilding blocks in organic synthesis, especially for the synthesis ofnon-protein amino acids, peptides, and peptidomimetics.
2.1.4. Catalytic asymmetric reactions for b-lactam synthesis. A cat-alytic process applicable to the asymmetric [2þ2] keteneeiminecycloaddition has been developed.56 Cobalticenium tetracarbonylcobaltate (32) contains both a nucleophilic Co(CO)4 anion anda Cp2Co cation that could act in a concerted manner. Thus, in the[2þ2] cycloaddition of diphenylketene (34), generated from 33 andNaH, with N-tosylimino ester 36 via dicobalt species 35, dicobalt
complex 32 showed a good catalyst activity, giving b-lactam 37 inup to 85% yield in 5 min at room temperature (Scheme 8).57 Itshould be noted that, in this process, the electronic demand of thetwo reactants is reversed from that in the normal keteneeimine[2þ2] cycloaddition process. Thus, in this process, the imine com-ponent is made highly electrophilic by incorporating an electron-withdrawing group into the imine nitrogen and a carbalkoxy
Cl
OAcO
Ph NPMP
Et3N (2 eq)
CH2Cl2 -78 °C-rt
NO PMP
AcO Ph
29
racemic
PS Amano, pH 8
10% CH3CN50 °C
NO PMP
AcO Ph
30
> 99.9% ee(3R,4S)
NO PMP
HO Ph
31
> 99.0% ee(3S,4R)
+
28
Scheme 7.
ClO
PhPh PhPh
Cp2CoO Co(CO)4
NTs
HEtO2C
NO
PhPh CO2Et
Ts
Co Co(CO)4
33 35 37
36
85%
32NaHPh Ph
Obenzotrif luoridert, 5 min
34
Scheme 8.
38, M(OTf)x(10 mol% each)
96-98% ee9:1-60:1 dr
M = In, Al, Zn,La, Sc
ClO
R
NTs
HEtO2C
NO
CO2Et
Ts4036
+
39
toluene, -78 °C
R
R = Et, vinyl, N3, Br, Ph, Bn,OAc, OPh, OBn, CH2OPh
92-98%
Scheme 10.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410644
substituent to the imine carbon. The electrophilic ketene compo-nent is transformed into a nucleophilic zwitterionic enolatethrough the addition of a nucleophilic catalyst to the central carbonof the ketene component. Then, the nucleophilic attack of thezwitterion on the a-carbon of the imine leads to the CeC bondformation, followed by cyclization to give b-lactam 37 and re-generates the catalyst 32. This reaction mechanism logically led tothe realization of the fact that a catalyst for this reaction does nothave to be a metal ion or charged and thus nucleophilic organo-catalysts should be effective as well.58 It was also hypothesized andproven that an organocatalyst, containing a nucleophilic center(e.g., tertiary amine) as well as an electrophilic center (e.g.,hydrogen-bonding acceptor), would rigidify the key intermediateand the transition state to yield b-lactams with higher diaster-eoselectivity than that without the electrophilic center.58
In order to accomplish the catalytic asymmetric synthesis of b-lactams based on this process, a number of optically active cinchonaalkaloids were screened as potential chiral organocatalysts, andbenzoylquinine (38) was found to give best results. Thus, the re-action of acid chlorides 39 with imine 36 in the presence of 38 ascatalyst (10 mol %) and a proton sponge gave b-lactams 40 with95e99% ee and 96:4 to 99:1 dr in 36e65% yield (Scheme 9).58
ClO
R
NTs
HEtO2C
NO
CO2Et
Ts4036
+
39
PhO
ON
MeH
N
MeO
38
38 (10 mol%)proton sponge
toluene, -78 °C
R
R = Et, vinyl, N3, Br, Ph, Bn,OAc, OPh, OBn, CH2OPh
95-99% ee96:4-99:1 dr
36-65%
Scheme 9.
In order to improve the chemical yield, metal salts were ex-plored as effective co-catalysts to further activate imines.59 Then, itwas found that the use of triflates of Sc(III), Al(III), Zn(II), and In(III)(10 mol %) with 38 (10 mol %) gave b-lactams 40 in excellent yieldand enantioselectivity (96e98% ee) as well as high diaster-eoselectivity (9:1 to 60:1 dr) (Scheme 10). Among the metal salts
examined, In(OTf)3 gave the best results followed by Zn(OTf)2,while Al(OTf)3 and Sc(OTf)3 were less effective.59
It has been shown that fused DMAP/ferrocene-based ‘planar-chiral’ nucleophilic catalysts, such as 41, are effective for theasymmetric synthesis of b-lactams through keteneeimine [2þ2]cycloaddition. For example, the reaction of symmetrical ketenes 42with electron-deficient N-tosylaldimines 43 catalyzed by 41(0.1 mol %) gave b-lactams 44 in 76e93% yield and 81e94% ee,while the reaction of unsymmetrical ketenes 42 (R¼Ph, R1¼i-Bu orEt) with 43 under the same conditions afforded b-lactams 44 in88e98% yield with 8:1 to 15:1 dr and 89e98% ee (Scheme 11).60
Recently, N-heterocyclic carbenes (NHCs) have been shownto serve as excellent catalysts for the asymmetric synthesis ofb-lactams through keteneeimine [2þ2] cycloaddition.61,62 Forexample, NHC 45a derived from (S)-pyroglutamic acid catalyzedthe reactions of various arylketenes 46 with N-Boc-arylaldi-mines 47 to give the corresponding b-lactams 48 in moderate-
H
NTs
R2 41 (0.1 eq)
tolune or CH2Cl2rt, 12 h
NTsO
R2RR1
N
Fe
N Me Me
Me
MeMe
+
41R = Ph, Et, -(CH2)6-R1 = i-Bu, Et
R2 = Ph, furanyl, cyclopropyl,cyclohexyl,(E)-phenylethenyl
42 43 44
R R1
O
Scheme 11.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10645
to-good yields and excellent enantioselectivity61 (Scheme 12).Another NHC 45b was used as a catalyst for the reaction ofarylketenes 49 with azodicarboxylate 50, which afforded aza-b-lactams 51 in fairly good-to-excellent yields and 33e91% ee(Scheme 12).62
NNN
PhOTBS
BF4
O
Ar1 Et
NBoc
Ar2
Ar1 = Ph, 4-MeOC6H4,4-ClC6H4
Cs2CO3 (10 mol%), THF, rt
91-99% ee
PhPh
NO Boc
Ar1 Ar2
R H+
46 47 48
45aH
Ar2 = Ph, 4-NO2C6H4,4-Cl-C6H4, 2-furyl2-BrC6H4, 2,4-Cl2C6H3
NNN
PhOTMS
BF4
O
Ar1 RNNCO2R'
R'O2C
R= Me, Et, n-Pr, i-Pr, n-BuAr1 = Ph, 4-MeOC6H4,
4-ClC6H4, Bn
Cs2CO3 (10 mol%)CH2Cl2/toluene, rt
33-91% ee
PhPh
NN
O CO2R'
Ar1R CO2R'
+
49 50 51
45b
H
R' = Me, Et, i-Pr, t -Bu
53-78%
60 - 95%
Scheme 12.
C-2 symmetric imidazolinium catalyst 52 and chiral tri-azolium catalyst 53 have been used in the reaction of diphe-nylketene (34) with N-tosylaldimines 54 to give thecorresponding b-lactams 55 in high yields and 55e75% ee(Scheme 13).63 It has also been shown that chiral imidazoli-niumdithiocarboxylates, e.g., 56, act as efficient organocatalystsfor Staudinger [2þ2] cycloaddition reactions of arylketenes 57with N-tosylaldimine 58, giving the corresponding b-lactams 59as a mixture of E and Z isomers (59-E/59-Z¼25:75 to 11:89) in96e99% yield with 83e96% ee for 59-Z (major) and 48e83% eefor 59-E (minor) (Scheme 14).64
55
R = Ph, 2-naphthyl, 2-furyl, 4-BrC6H4
O
PhPh
N
R
TsN
O
Ph RPh
54
55-75%
52 or 53 (10 mol%)KHMDS (9 mol%)
79-96%
Et2O, rt
34
+
Scheme
The b-lactam synthesis through Rh-catalyzed carbene insertioninto a CeH bond is another catalytic process that is applicable tocatalytic asymmetric synthesis. The construction of the b-lactamring based on the intramolecular CeH insertion of carbene speciesgenerated from a-diazo amides, initially by photoirradiation and
then by Rh2(OAc)4 catalysis, was used for the synthesis of carba-penems, especially thienamycin.65,66 Then, the Rh2(OCOR)4-cata-lyzed process was successfully employed in the intramolecular CeHinsertion reaction of a-diazoacetamides to yield the correspondingb-lactams. For example, the reaction of N-tert-butyl-N-arylmethyl-a-diazoacetamides 60 catalyzed by Rh2(OAc)4 gave the trans-b-lactams 62 exclusively via a Rh-carbenoid species 61 in 90e98%yield (Scheme 15).67,68
The catalytic asymmetric synthesis of b-lactams through Rh-catalyzed intramolecular CeH insertion reactions of a-diazo-acetamides has been investigated using dimeric Rh(II) complexes
O
NNN
PhBF4N N BnBnTs
H
52 53
BF4
ee
13.
R = Me, EtAr = Ph, 2-Naph, 2-thiophenyl, 4-ClC6H4, 4-CNC6H4, 4-FC6H4, 4-CF3C6H4
O
Ph R
N
Ar
Ns-p+
NO Ns-p
Ph ArR H
57 58
N NMe Me
SS
56
56 (10 mol%)
toluene, rt NO Ns-p
PhArRH
+
59-E 59-Z
F3C CF3
96-99%
Scheme 14.
R1
N2
O
NR3
R2
R1
RhL4
O
NR3
R2
NR3O
6260 61
R1= COMe; R2 = t-BuR3 = Ph, p-NO2C6H4, m-BrC6H4, 3,4-(MeO)2C6H3
R2R1Rh2(OAc)2benzenereflux 90-98%
Scheme 15.
N2
O
NBu-t
R
NBu-tO
6463
RMeO2CRh2(S-PTPA)4
94-98%
MeO2CCH2Cl2, 16-22 oC
N ON2
MeO2C
O OR R
Rh2(PT-(S)-AA)4
85-94%
CH2Cl2, 0oC N
O
66
MeO2C
R R65
H H
N ON2
MeO2C
O O
Rh2(PT-(S)-AA)4
85-94%
CH2Cl2, 0oC N
O
68
MeO2C
67
H H
NHO
OTBS
H HTBSO
1β-thienamycin
69
Scheme 16.
N
Ph
Pr-i
Me CO (20 atm)[Rh(CO)2Cl]2
benzene90 oC, 48 h
NO
Ph Me
Pr-i7170 81%
N
Ph
adamantyl
CO (20 atm)[Rh(CO)2Cl]2
benzene90 oC, 48 h
NO
Ph
adamantyl7372 89%
CO (20 atm)
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410646
with chiral carboxylate ligands. For example, the reaction of a-methoxycarbonyl-a-diazoacetamides 63 catalyzed by Rh2(S-PTPA)4(S-PTPA¼N-naphthoylphenyl-(S)-phenylalaninate) afforded cis-b-lactams 64 in excellent yield and 56e74% ee (Scheme 16).69 Thisreaction system was successfully applied to the asymmetric syn-thesis of bicyclic b-lactams, which served as key intermediates forthe synthesis of enantiopure carbapenems.70 Thus, the reaction ofa-methoxycarbonyl-a-diazoacetamides 65 catalyzed by Rh2(N-naphthoyl-(S)-AA)4 (AA¼Phe, Ala, Val, PhGly, t-BuGly) afforded b-lactams 66 in 85e94% yield and 83e96% ee (Scheme 16). The bestresult (94% yield and 96% ee) was obtained with a-diazoacetamide65a (R, R¼e(CH2)5e) and Rh2(PTA)4 (PTA¼N-naphthoyl-Ala). Ina similar manner, b-lactam 68 (88% ee, 83% yield), a key in-termediate in the synthesis of 1b-methylthienamycin, was obtainedby the reaction of diazoacetamide 67 catalyzed by Rh2(PTA)4, whichwas successfully converted into the enantiopure advanced key in-termediate 69 in several steps (Scheme 16).70
Regio- and stereospecific carbonylation of chiral aziridines cata-lyzed by [Rh(CO)2Cl]2 gives the corresponding b-lactams in highyields. For example, the reactions of 70 and 72 afforded 71 and 73 in81 and 89% yields, respectively (Scheme 17).71 This carbonylationprocesswas found to proceed stereospecifically at the carbonbearinga phenyl substituent with complete retention of configuration. Thisprocess was successfully applied to the kinetic resolution of racemic2-phenylaziridine 74 in the presence of (�)-menthol (3 equiv) and[Rh(COD)Cl]2 (5 mol %) as catalyst at 90 �C and 20 atm CO for 24 h togive (S)-b-lactam 75with 99.5% ee (25% yield) and (R)-74with 85% ee(56% yield) (Scheme 17).71 It is of interest to note that Co2(CO)8 wasfound to catalyze the regio- and stereospecific carbonylation of chiralaziridines aswell, but with complete inversion of configuration at themore substituted carbon with alkyl or phenyl substituents.72 Thisprocess exhibited its exceptional stereochemical integrity in the for-mation of extremely strained trans-bicyclic b-lactams, 8-aza-7-oxo-[4.2.0]bicyclooctanes, from cis-cyclohexeneaziridines.72 However,this process has not been applied to asymmetric synthesis.
N
Ph
Pr-i
[Rh(COD)Cl]2(-)-menthol (3 equiv)
benzene90 oC, 24 h
NO
Ph
Pr-i(S)-75rac-74
N
Ph
Pr-i
(R)-74
+
Scheme 17.
2.2. Asymmetric synthesis of b-lactams through ester enola-teeimine cyclocondensation
The chiral lithium enolates generated in situ from N,N-bis(silyl)glycinates 76 reacted with N-PMP-arylaldimines 77 to give trans-3-
Table 1Asymmetric synthesis of 3-TIPSO-b-lactams 82 through chiral ester enolateeiminecyclocondensation
Entry R1 R2 R3 b-Lactam Yield (%) ee (%)
1 Ph TMS H 82a 85 962 4-MeOC6H4 TMS H 82b 80 963 3,4-(MeO)2C6H3 TMS H 82c 80 984 Ph PMP PMP 82d 89 985 4-FC6H4 PMP PMP 82e 81 986 4-CF3C6H4 PMP PMP 82f 84 997 2-Furyl PMP PMP 82g 78 928 (E)-PhCH]CH2 PMP PMP 82h 85 969 2-FuryleCH]CH2 PMP PMP 82i 72 9410 c-C6H11CH2 PMP PMP 82j 85 9011 Me2CHCH2 PMP PMP 82k 85 9212 Me2C]CH PMP PMP 82l 60 94
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10647
amino-b-lactams 78 exclusively in fairly good yields and excellentenantiopurity.73 Among the various chiral ester auxiliariesscreened, (�)-menthyl and (�)-2-phenylcyclohexyl were found tobe highly effective for this reaction. For example, the reaction of 76a(R*¼(�)-menthyl) and 76b (R*¼(�)-2-phenylcyclohexyl) with N-PMP-benzaldimine (77a) in the presence of LDA in THF at �78 �Cafforded (3R,4R)-b-lactam 78a with >99% ee in 65 and 58% yields,respectively (Scheme 18).73 Under the same conditions, the re-actions of 76a with other N-PMP-arylaldimines 77bee (Ar¼4-FC6H4, 4-CF3C6H4, 4-MeOC6H4, 3,4-(MeO)2C6H3) gave the corre-sponding b-lactams 78bee with >99% ee, albeit with smallamounts of cis-b-lactams 78d,e being obtained in the case of 77dand 77e.73
a: Ar = Ph,b: Ar = 4-FC6H4c: Ar = 4-CF3C6H4d: Ar = 4-MeOC6H4e: Ar = 3,4-(OMe)2C6H3
i. LDA, THF, -78 °Cii. Ar-CH=N-PMP (77)
iii. H2O NO
H2N Ar
PMP76 78
a: R* = (-)-menthyl,b: R* = (-)-2-Ph-cyclohexyl
N
O OR*
Si
Si
Scheme 18.
It has also been shown that the chiral ester enolateeiminecyclocondensation is a highly efficient method for the asymmetricsynthesis of 3-hydroxy-b-lactams with excellent enantiopurity.7,8
In contrast to the rigid bissilylamino moiety in glycinates 76, theO-protected hydroxyl group is very flexible in hydroxyacetates 79.Thus, both the chiral auxiliaries and the O-protecting groups werescreened to find the optimal chiral ester enolate 80 for this pro-cess. Then, the combination of TIPS and (�)- or (þ)-2-phenylcyclohexyl groups was found to achieve the best results.It should be noted that, in contrast to the reactions of 76, cis-b-lactams 82 were formed exclusively in this process. Chiral enolate80 was generated from (�)-2-phenylcyclohexyl TIPSO-acetate 79with LDA in THF at �78 �C for 2 h. N-TMS-arylaldimines 81(R2¼TMS) were added to the enolate solution and reacted at�78 �C and then gradually warmed to room temperature to give(3R,4S)-3-TIPSO-4-aryl-b-lactams 82 with 96e98% ee in 80e85%yield (Scheme 19).74,75 It is worthy of note that (3R,4S)-3-TIPSO-4-phenyl-b-lactam 82a (Table 1) serves as a key intermediate for thehighly efficient semisynthesis of paclitaxel and docetaxel (videinfra).74,76
TIPSOCH2COOR*
LDA THF, -78 °C
79
R* = (-)-2-pheny
NR1R2 N
LiO
R2
THF
THF
OR1
OO
H O
Li
E-80
(i -Pr)3Si
TS
81(THF)3
Scheme
Although N-TMS-imines 81 (R2¼TMS) are efficient to produceb-lactams 82 (R3¼H) with free NH directly, those imines are lim-ited to arylaldimines due to the instability of N-TMS-alkylaldi-mines. Thus, N-PMP-imines 81 (R2¼PMP) were employed tosuccessfully expand the scope of this reaction. Table 1 summarizesrepresentative results, including those for N-TMS-imines 81(R2¼TMS).74,75,77
An asymmetric estereenolate cyclocondensation process me-diated by a ternary chiral ether ligandelithium amide complexwas developed. The reaction of lithium enolate 83, generated fromthe corresponding 3-pentyl alkanoate (2 equiv) and LDA(2.2 equiv), with N-PMP-aldimine 84 in the presence of (1S,2S)-1,2-dimethoxy-1,2-diphenylethane (86) (2.6 equiv) and additionallithium amide, e.g., LiN(Pr-i)Cy and LiNCy2, (2.2 equiv) gave b-lactam 85 in 12e85% yield and 26e90% ee (Scheme 20).78 Theyield and enantioselectivity depend on the structure of the lith-ium amide used. For example, the reaction of 83a (R1¼Me) with84a (R2¼Ph) using LiN(Pr-i)Cy afforded 85a in 85% yield and 88%ee, while the same reaction using LiN(Bu-t)Cy gave 85a in 22%yield and 55% ee.
3. Synthesis of amino acids, dipeptides and their derivativesby means of b-lactam synthon method
3.1. Asymmetric synthesis of non-protein amino acids
Non-protein amino acids are amino acids, which are not pro-duced from protein amino acids by post-translational modificationand these amino acids do not have a specific transfer-RNA andcodon triplet, and thus the main chains of proteins do not havethese amino acid residues.79 Since various non-protein amino acidsare important components of medicinally important compounds,
NO
R1TIPSO
82
R3
R*OLi
lcyclohexyl
R*
H
OSi(Pr-i)3N
O LiR2R*O
(i-Pr)3SiO R1
19.
Et2CHO OLi
R1R1 R2
NPMP
MeO OMe
Ph Ph
+ toluene-20 ~ -78 oC
N
R2
O
R1
R1
PMP83 84
86
85
a R1 = Meb R1, R1= (CH2)5
R2 = Ph, PMP, 1-Naph, 2-Naph, PhCH=CH, PhCH2CH2
LiNRR'
Scheme 20.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410648
the efficient synthesis of non-protein amino acids with highenantiopurity has significance in medicinal chemistry and organicsynthesis.
3.1.1. Synthesis of a,b-diamino acids, azetidines, and poly-amines. a,b-Diamino acids are often components of peptidic anti-biotics such as lavendomycin and glumamycin.80 It has been shownthat a,b-diamino acids are readily obtained through the hydrolysis ofenantiopure 3-amino-b-lactams, which were prepared by chiral es-ter enolate cyclocondensation or asymmetric [2þ2] keteneeiminecycloaddition reactions (vide supra).7,9 Thus, the hydrolysis of 3-amino-b-lactam (3S,4R)-87 and its epimer, (3R,4R)-87, using 6 Mhydrochloric acid gave the corresponding a,b-diamino acids (2S,3R)-88 and (2R,3R)-88, respectively, as hydrochlorides in quantitativeyields (Scheme 21). The epimerization of (3S,4R)-87 to (3R,4R)-87was readily realized through imine formation, deprotonation, and
NHO
RH2N
(S,R)-87
i. PhCHii. LiHM
iii. H2OCO2H
HH2NR
NH2H
H3O+
(S,R)-88
HH2NR
NH2H
OH
(S,R)-89
LAH
Scheme
NO R
X ArAlH2Cl
X = N3, Bn
* *NR
X' A* *
Et2O, r.t.
90 91
N
O Ph
Ph
O
NHO
MeNO
PhO Ph
AlH2ClEt2O
N
NH
MeN
PhO Ph
93 94
33%
X' = NH2, B
Scheme
protonation.7 Moreover, (3R,4S)-87 can be prepared just by switch-ing the chiral auxiliary to the other enantiomer in the asymmetricketeneeimine [2þ2] cycloaddition or from the other enantiomerobtained in the enzymatic optical resolution (vide supra). Thus,(3S,4S)-87, (2R,2S)-88, and (2S,2S)-88 can be prepared in the samemanner. Furthermore, a,b-diamino acids 88 were reduced to thecorresponding a,b-diamino alcohols 89 in high yields using LiAlH4(Scheme 21). Thus, this protocol provides facile access to all fourdiastereoisomers of a,b-diamino acids 88 and amino alcohols 89.7,8
Azetidine is a very challenging amine to synthesize, but the se-lective reduction of b-lactams using monochloroalane (AlH2Cl) ordichloroalane (AlHCl2) provides one of the most straightforwardand efficient routes to enantiopure azetidines.75,81 The reduction ofenantiopure 4-aryl-b-lactam 90 with monochloroalane (AlH2Cl) inether gave the corresponding 2-arylaziridine 91 in high yieldwithout epimerization. Then, the hydrogenolysis of 91 at the NeC2bond afforded the enantiopure diamine or amino alcohol 92 inquantitative yield (Scheme 22).75 In the same manner, the mono-chloroalane reduction of tetrapeptide synthon bis-b-lactam 93 gavebisazetidine 94 in moderate yield, which was converted into poly-amino ether 95 in quantitative yield via hydrogenolysis. It should benoted that the reductive cleavage of the two azetidinemoieties of 94were much faster than debenzylation in this case (Scheme 22).9,82
3.1.2. Synthesis of a-alkyl-a-amino acids and their dipeptides. Va-rious a-alkyl-a-amino acids are known to act as potent substrate-based inhibitors of decarboxylases and aminotransferases.80 Inaddition, the strategic incorporation of a-alkyl-a-amino acid resi-dues into physiologically active peptides can introduce conforma-tional constraints to stabilize 3D peptide structures.80 The access to
ODS
NHO
RH2N
(R,R)-87
CO2H
NH2HR
NH2H
H3O+
(R,R)-88
NH2HR
NH2H
(R,R)-89
OH(R)
LAH
21.
rH2/Pd-C Ar NHR
Y
*
Y = NH2, OH92
O Ph
Ph NHNH HN
O
Ph
O
Ph
Me
Ph
H2 / Pd-CMeOH, RT
quant.
95
n
Ph
22.
N
PhO Ph
O
1) LDA/THF2) RX
THF, -78 C
R= Bn, Et
Me
CO2Bu-t
N
PhO Ph
O Me
CO2Bu-t
R
H2, Pd/C
H2N COOH
MeR
+
101 102
103
104
PhO CO- CO2Bu-t
MeRPh
H3OPh
+
NH
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10649
enantiopure a-alkyl-a-amino acids is not easy because conven-tional enzymatic resolution cannot be applied effectively. Fortu-nately, the b-lactam synthon method provides highly efficientroutes to a-alkyl-a-amino acids with high enantiopurity throughextremely stereoselective alkylation of 3-amino-b-lactams.
Two protocols have been developed for asymmetric alkylations,i.e., (i) the alkylation of the C-3 position of a b-lactam (Type 1) and(ii) the alkylation of the side chain ester enolate (Type 2) (Fig. 2).7,9
As Fig. 2 illustrates, in the Type 1 alkylation, an electrophile attacksthe b-lactam enolate at the C-3 position from the back side of the C-4 aryl group, while, in the Type 2 alkylation, an electrophile attacksthe C10 position of the lithium enolate, forming a chelate with theb-lactam oxygen, from the opposite side of the C-4 aryl group.
N
X
O R
Ar NO
X Ar
R1
OOR2
Li
E+
Li
Type1 Type 2
E+
Fig. 2. Type 1 and Type 2 asymmetric alkylations.
PhO COOH
Scheme 24.
A typical example of the Type1 alkylation is shown in Scheme23.The stereoselective methylation of b-lactam 96 (X¼H or MeO) withMeI and LiHMDS gave 3-methyl-b-lactam 97 with >99.5% de inexcellent yield. Birch reduction of 97 gave the corresponding amideof a-methyl-a-amino acid 98 (>99.5% ee) in high yield.7,83 Acidichydrolysis of 98a (X¼H) and 98b (X¼MeO) should afford (S)-a-methylphenylalanine and (S)-O,O-dimethyl-a-methyldopa with>99.5% ee, respectively. It should be noted, however, that similarType 1 alkylations of a bicyclic trans-b-lactam99, which didnothavea 4-aryl group, gave 3-alkyl-b-lactams 100with>97% de in 51e80%yields, wherein the electrophiles attacked the C3 position of the b-lactam moiety of 99 from the front face with retention of configu-ration (Scheme 23).84
N
N
O Me
O O
Ph
X
X
N
N
O Me
O O
Ph
X
XMe
X
X
CONH2H2NMe
i. LiHMDSii. MeI
97
Li, NH3,THF, t-BuOH
98
a: X = Hb: X = OMe
THF, -78 oC
96
N
N
O
O
O
i. KHMDSii. RXO
Ph
N
N
O
O
OO
PhR
R = Me, allyl, Bu99 100
THF, -78 °C
H
Scheme 23.
The Type 2 alkylation was first examined with enantiopureb-lactam ester 101with 1.0 equiv of LDA and alkyl halides (BnBr andEtBr). As Scheme 24 shows, deprotonation took place exclusively atC10 of the ester moiety, leaving C3 of the b-lactam moiety intact.
Thus, the alkylation proceeded at C10 exclusively to give 102 (>98%de), which was subjected to hydrogenolysis on Pd/C to give N-acyl-a-alkyl-a-amino acid ester 103 and subsequent acidic hydrolysisafforded a-alkyl-(R)-alanine 104 (>98% ee) in excellent yield(Scheme 24).7,9,83 The results indicated that the Type 2 alkylationprocess should be applicable for the asymmetric synthesis of di-peptides or depsipeptide fragments bearing an a-alkyl-a-aminoacid residue at the C-terminus.
The Type 2 alkylation was successfully applied to the sequentialasymmetric double alkylation of chiral b-lactam ester 105 (>99%de, >99% ee) to give phenylalanyl-a-alkylalanines, (S,S)-108 (via(R)-106 and (S)-107) and (S,R)-108 (via (S)-106 and (R)-107) in goodoverall yields and >99% de, and . In this process, the double al-kylation took place exclusively at C10 and the absolute configura-tion of C10 was controlled by changing the order of addition of thetwo alkyl halides (Scheme 25).9,85
The highly efficient triple alkylation of 105 was also achievedthrough sequential Type 2 double alkylation and Type 1 alkylations(Scheme 26)9,85 For example, sequential double alkylation of b-lactam 105 with methyl iodide and allyl bromide proceeded in thesame manner as that in Scheme 25, giving 107b (>99% de), whichwas followed by the third (Type 1) alkylation with methyl iodide toafford 109 (>99% de) uneventfully in 80% yield for three steps.Then, triply alkylated b-lactam 109 was converted into (S)-a-methylphenylalanyl-(R)-a-allylalanine, 110 in 62% yield throughdeprotection, Birch reduction, and separation on a Dowex column(Scheme 26).
3.1.3. Asymmetric synthesis of a-hydroxy-b-amino acids and theirdipeptides. a-Hydroxy-b-amino acids (isoserines) are key structuralmotifs in numerous therapeutically important substances. (2R,3S)-3-Amino-2-hydroxy-5-methylhexanoic acid (norstatine) and itsanalogues, for example, are readily found in peptide-based in-hibitors of enzymes such as renin,86,87 HIV-I protease,88 andangiotensin-converting enzyme (ACE),89 as well as in a variety ofnatural products.90 (2R,3S)-3-Phenylisoserines are indispensableconstituents of paclitaxel and docetaxel, which are two of the mostwidely used anticancer drugs in chemotherapy.91,92 Therefore, ex-tensive efforts have been made to develop efficient methods for thesyntheses of isoserines with excellent enantiopurity. The b-lactamsynthon method has made a significant contribution to solve thissynthetic challenge.
Acidic hydrolysis of 3-TIPSO-b-lactams 112 with excellent enan-tiopurity, obtained from1-PMP-b-lactam 111, provides a ready accessto norstatine (113a, R¼isobutyl) and isoserines 113 (Scheme 27).7,93
The ring opening of b-lactams at the N1eC2 bond is substantiallyaccelerated when an electron-withdrawing group, e.g., acyl, carbal-koxy, carbamoyl, sulfonyl, etc., is introduced into the N1 position. Forexample, the ring-opening coupling of N-Boc-3-hydroxy-b-lactams
(R1, R2 = MeI, BnBr, CH2=CHCH2I)
NO
CO2t-Bu
R1H
PhNO
O
Ph
i. LiHMDS
ii. R2X NO
CO2t -Bu
R2R1
PhNO
O
Ph
NO
CO2t-Bu
PhNO
O
Ph
NO
CO2t -Bu
R2H
PhNO
O
Ph
NO
CO2t-Bu
R1R2
PhNO
O
Ph
H2N CO-NH CO2H
R1R2HPh
H2N CO-NH CO2H
R2R1HPh
i. LiHMDS
i. LiHMDS
ii. R1X
i. LiHMDS
i. TFA
ii. Li/NH3iii. Dowex
i. TFA
ii. Li/NH3iii. Dowex
Priority: R1 > R2
105
(R)-106 (S)-107
(S)-106 (R)-107
(S,S)-108
(S,R)-108
ii. R1X
ii. R2X
Scheme 25.
NO
CO2t-Bu
PhNO
O
Ph
105
i. LiHMDS,THF, -78 °C
ii. MeI NO
CO2t -Bu
MeH
PhNO
O
Ph
106a
i. LiHMDS,THF, -78 °C
ii. CH2=CHCH2BrN
OCO2t-BuMe
PhNO
O
Ph
107b
i. LiHMDS,THF, -78 °C
ii. MeI NO
CO2t-BuMe
PhNO
O
Ph
109
Mei. TFA, 20 °Cii. Li/NH3/THFt -BuOH, -78 °C
iii. Dowex 50X-2H2N CO-NH CO2H
MeMePh
(S,R)-11080% for 3 steps
62% for 3 steps
Scheme 26.
NO
RTIPSO
PMPNH
O
RTIPSO6 M HCl
rt HCl.H2NCO2H
R
OH111 112 113
R = i-Bu, cyclohexylmethyl, 2-phenylethenyl, phenyl, 4-fluoromethyl,4-(trifluoromethyl)phenyl, 2-furyl, 2-(2-furyl)ethenyl, crotyl, isobutenyl etc.
CAN
Scheme 27.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410650
114 with various amino acid esters 115 proceeded smoothly to givethe corresponding dipeptides 116, bearing an isoserine residue at theN terminus, in high yields without epimerization or racemizationunder mild conditions without any coupling agent (Scheme 28).Proline methyl ester as well as the Wang resin-bound amino acidswere also successfully employed for this coupling.7,94 The high effi-ciency and atom economy in this ring-opening coupling process isone of themost salient features of the b-lactam synthonmethod. It isalsoworthy of note that enantiopure N-Boc-3-siloxy-b-lactamswerereadily converted into the corresponding hydroxyethylene isosteresand dihydroxyethylene isosteres, which are key components in var-ious enzyme inhibitors, mimicking tetrahedral intermediates.95,96
It has been shown that the incorporation of fluorine(s) intoa medicinally active compound often improves its pharmacological
properties, such as increased membrane permeability, enhancedhydrophobic binding, and stability against metabolic oxidationamong other merits.43,97,98 As fluorine is absent in living tissue, theincorporation of fluorine(s) into biologically relevant molecules asmarker(s) provides a valuable means to monitor protein structuresand dynamics as well as drugeprotein interactions in vitro andin vivo by 19F NMR. Accordingly, efficient and convenient methodsfor the synthesis of fluorine-containing compounds of biologicaland medical interest are in high demand.
The b-lactam synthon method has provided convenient and effi-cient routes to fluorine-containing a-hydroxy-b-amino acid de-rivatives and congeners. Enantiopure 3-TIPSO-4-Rf-b-lactams(Rf¼fluorine-containing substituent) were prepared through (i)functional-group transformationsof4-isobutenyl-b-lactams, (3R,4S)-
NO Boc
R1HO
H2N CO2R3
R2
+CH2Cl2
BocHN
O
NH
CO2R3
R2R1
R1 = Ph, i-Bu, C6H11CH2, PhCH=CHR2 = Bn, i-Bu, i-Pr, indolylmethylR3 = Me, t -Bu, Wang resin
114 115 116
rt OH
Scheme 28.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10651
82l or (3S,4R)-82l, and (ii) keteneeimine [2þ2] cycloaddition fol-lowed by enzymatic resolution using PSAmano lipase.13 For instance,the ozonolysis of (3R,4S)-82l afforded the corresponding 4-formyl-b-lactam (3R,4R)-11f (R1¼PMP; R2¼TIPSO) in high yield, which wasreacted with diethylaminosulfur trifluoride (DAST) and CBr2F2/Zn togive 4-difluoromethyl-b-lactam (3R,4R)-117 and 4-difluorovinyl-b-lactam (3R,4R)-118, respectively, with >99.9% ee in high yields(Scheme 29).13,44,99 (3R,4R)- and (3S,4S)-1-PMP-4-trifluoromethyl-b-lactamswith>99%eewereobtained throughenzymatic resolutionofracemic cis-3-acetyl-4-CF3-b-lactam prepared through ketene-eimine [2þ2] cycloaddition.13,43 Enantiopure 1-PMP-3-TIPSO-4-Rf-b-lactams 119, thus obtained, were deprotected by cerium ammo-nium nitrate (CAN) to give NH-free b-lactams 120, which were con-verted into the corresponding 1-acyl-, 1-carbalkoxy-, and 1-arenesulfonyl-b-lactams 121 in good yields through reactions withacyl chlorides, chloroformates, and arenesulfonyl chlorides in thepresence of an appropriate base (Scheme 30; only one enantiomer isshown for simplicity).13
NO PMP
TIPSO
(3R,4S)-82l
i. O3, CH2Cl2, -78 °C
ii. Me2S, -78 °C ~ rtN
O PMP
TIPSO O
(3R,4R)-11fHMPT, THF-78 °C-reflux N
O PMP
TIPSO
(3R,4S)-118
F
F
NO PMP
TIPSO
(3R,4R)-117
DASTCH2Cl2
F
F
73-100%
78-86%
68-88%
CBr2F2, Zn
Scheme 29.
MeCN/H2O-10 °C
NHO
TIPSO Rf
120
NO PMP
TIPSO RfCAN
NO
TIPSO Rf
R121
Rf = CHF2, CF3, CH=CF2; R = CO2Bn, CO2Bu-t, SO2Tol-p, COC6H4-F-4
119
R-X
base
Scheme 30.
Methanolysis of b-lactams 121 in the presence of triethylamineand 4-dimethylaminopyridine (DMAP) at room temperature affor-ded the corresponding b-Rf-a-siloxy-b-amino acidmethyl esters 122in modest-to-quantitative yields (Scheme 31).13 Furthermore, thering-opening coupling of b-lactams 121with various a- and b-amino
acid esters gave the corresponding dipeptides, 123 and 124, bearingfluoroisoserine residues, in 50e100% yields (Scheme 31)13 [Note:Scheme 31 only shows the reactions of (3R,4R)-121 for simplicity, but(3S,4S)-121 reacted in a similar manner.].
The Type 1 alkylation of 3-siloxy-b-lactams 125 proceeded withexcellent diastereoselectivity to give 3-alkyl-3-siloxy-b-lactams126 with >99% de, which were converted into NH-b-lactams viaCAN deprotection, followed by acidic hydrolysis to afford the cor-responding a-alkyl-a-hydroxy-b-amino acids 127 in excellentyields (Scheme 32).13,100 b-Lactams 126were also converted into 1-Boc-b-lactams 128 via NH-b-lactams via CAN deprotection andsubsequent reaction with Boc-anhydride.13,100 The facile meth-anolysis of 1-Boc-b-lactams 128 proceeded at room temperature togive N-Boc-a-alkyl-a-hydroxy-b-amino acid methyl esters 129 inexcellent yields (Scheme 32).100 1-Boc-3-hydroxy-b-lactams 130were prepared by deprotection of b-lactams 128 with HF/pyridineand subjected to ring-opening coupling with (S)-LeueOMe to givethe corresponding dipeptides 131 in high yields (Scheme 33).100
4. Applications of b-lactam synthon method for the synthesisof medicinally active compounds
4.1. Synthesis of paclitaxel, docetaxel, and new-generationtaxoids
Paclitaxel (Taxol�; Fig. 3), a complex diterpene isolated from thebark of Taxus brevifolia (Pacific yew), is a leading FDA-approveddrug for the treatment of advanced ovarian cancer (1992), breastcancer (1994), AIDS-related Karposi’s sarcoma (1997), non-small-cell lung cancer (1999), and other cancers (Fig. 3).91,101,102 Doce-taxel (Fig. 3), the first semisynthetic analogue (‘taxoid’) of pacli-taxel, was also approved by the FDA in 1996 against breast cancerand has been extensively used for the treatment of various cancerssuch as those of lung, ovarian, prostate, and others.91,92,102
Paclitaxel and docetaxel are cytotoxic drugs, which act as mi-totic spindle poisons by accelerating tubulin polymerization in
Rf = CHF2, CF3R = Cbz, Boc, Ts, 4-F-C6H4COAA = Gly, (S)-Phe, (S)-Val, (S)-Leu, (S)-Met
NO R
TIPSO RfDMAP, Et3N
MeOH, rtNH
RRf
OTIPSOMe
O
121122
NH
RRf
OTIPS
NH
O
CO2Me
R2
NH
RRf
OTIPS
NH
OCO2Et
α-AA-OMe.HCl
β-Ala-OEt.HCl
123
124
58-100%
NMM, CH2Cl2, rt
NMM, CH2Cl2, rt
50-100%
Scheme 31.
NO PMP
PO R i. LDA, THF-78 °C
ii. R1X NO PMP
PORR1 i. CAN,
MeCN/H2O
ii. 6 N HCl HCl H2N OH
O
HO R1
R
125 126 127
P = Et3Si, PhMe2SiR = i -butenyl, Ph, i-Bu, CF3R1 = Me, allyl
NO
RPO
Boc
MeOH, Et3N
rtBocHN
CO2MeR
HO
129128
>99% de
i. CAN, MeCN/H2Oii. Boc2O, Et3N, DMAP, CH2Cl2
R1
R1
Scheme 32.
NO Boc
RHOH2N CO2Me
+CH2Cl2
BocHN
O
NH
CO2Me
R
reflux, 36 h
R = Ph, isobutenyl; R1 = Me, allyl130 131
R1
R1HO87-92%
Scheme 33.
O
O
OH
NH
OOH
OHO O
O
O
O
OO
O
O
OH
NHO
OH
OHHO O
O
O
O
O
OO
O
paclitaxel (Taxol®) docetaxel
Fig. 3. Chemical structures of paclitaxel and docetaxel.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410652
microtubules, but stabilize them and arrest cell mitosis at the G2/Mphase, leading to apoptosis.103e106 Although the total synthesis ofpaclitaxel has been accomplished as outstanding hallmark of aca-demic research by six research groups via very long steps,107e112 thesemisynthesis of paclitaxel from 10-deacetylbaccatin III, 132(P¼R1¼H), a renewable natural product abundantly isolated fromthe leaves of Taxus baccata (European yew) and Taxus wallichiana(Himalayan yew), has been found to be the practical approach forthe manufacturing of this drug.7,74,113e115
The b-lactam synthon method has played a crucial role in thehighly efficient semisynthesis of paclitaxel and docetaxel. For in-stance, paclitaxel was synthesized through ring-opening coupling of(3R,4S)-1-benzoyl-3-EEO-4-phenyl-b-lactam 132a (R¼Ph) with 7-TES-baccatin 133a (R1¼Ac, P¼Et3Si) at the C13 position, affording134a, followed by deprotection of the 1-ethoxyethyl (EE) and TESgroups with 0.5% HCl in ethanol in high overall yield (Scheme 34).7 b-Lactam 132a and this ring-opening coupling protocol were alsoemployed to complete the total synthesis of paclitaxel.107e110 In
NO
EEO
O
RHO O
OH
OR2R1O O
O
O
OO
+LiHMDS, THF
O
O
OEE
NHO
OH
OR2R1O O
O
O
R
O
OO
a: R1 = Ac, R2 = SiEt3b: R1 = R2 = Troc
a: R = Phb: R = t-BuO
133132
-30 °C, 30 min
134
a: R = Ph, R1 = Ac, R2 = SiEt3b: R = t -BuO, R1 = R2 = Troc
134a
134b
0.5% HCl, EtOH
Zn/AcOH/MeOH
paclitaxel
docetaxel
89-92%
90%
93-95%
Scheme 34.
Table 2Selected examples of new-generation taxoids
OR3O OH
OOAcHO
OO
O
R1
O
OH
NH
X
O
R2
Y
Taxoid R1 R2 R3 X Y
Paclitaxel Ph Ph Ac H HDocetaxel Ph t-BuO H H HSBT-1213 Me2C]CH t-BuO EtCO H HSBT-1214 Me2C]CH t-BuO c-PrCO H HSBT-1216 Me2C]CH t-BuO Me2NCO H HSBT-11033 Me2CHCH2 t-BuO EtCO MeO HSBT-121303 Me2C]CH t-BuO EtCO MeO HSBT-121313 Me2C]CH t-BuO EtCO MeO MeOSBT-121602 Me2C]CH t-BuO Me2NCO Me HSBT-12823-3 CF3 t-BuO Me2NCO Cl HSBT-12854 F2C]CH t-BuO Me2NCO H HSBT-12855-1 F2C]CH t-BuO MeOCO MeO H
Table 3Cytotoxicity (IC50, nM) of selected new-generation taxoids against human cancer celllines
Taxoid MCF-7a HT-29b CFPAC-1c DLD-1d LCC6-MDRe NCI/ADRf
Paclitaxel 1.7 12 68 300 346 550Docetaxel 1.0 d d d 120 723SBT-1213 0.18 0.37 4.6 3.9 d 4.0SBT-1214 0.20 0.73 0.38 3.8 d 3.9SBT-1216 0.13 0.052 0.66 5.4 d 7.4SBT-11033 0.36 d d d d 0.61SBT-121303 0.36 d 0.89 d 0.90 0.79SBT-121313 0.30 3.6 0.025 13 d d
SBT-121602 0.08 0.003 0.31 0.46 d d
SBT-12823-3 0.17 0.45 d d d 1.9SBT-12854 0.18 0.46 0.35 0.25 d 4.3SBT-12855-1 0.11 d d d d 0.92
a Breast cancer cell line (Pgp�).b Colon cancer cell line (Pgp�).c Pancreatic cancer cell line.d Colon cancer cell line (Pgpþ).e Breast cancer cell line (Pgpþ).f Ovarian cancer cell line (Pgpþ).
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10653
a similarmanner, docetaxelwasobtained inhighoverall yieldvia ring-opening coupling of (3R,4S)-1-Boc-3-EEO-4-phenyl-b-lactam 132b(R¼t-BuO) with 7,10-diTroc-baccatin 133b (R1¼P¼Cl3CCH2OCO), giving 134b, followed by deprotectionwith Zn/acetic acid/methanol (Scheme 34).7,76 b-Lactams 132a and 132b were derivedfrom (3R,4S)-3-TIPSO-4-phenyl-b-lactam 82a or 82d (see Table 1)prepared by chiral ester enolateeimine cyclocondensation (see Sec-tion 2.2)74,75 or (3R,4S)-3-acetoxy-4-phenyl-b-lactam 30 (see Scheme7) prepared by keteneeimine [2þ2] cycloaddition followed by enzy-matic optical resolution.54
This highly efficient ring-opening coupling process, ‘Oji-maeHolton coupling’, opened an avenue for the synthesis andstructureeactivity relationship (SAR) studies on a variety of pacli-taxel congeners, ‘taxoids’.76,77,115e119 The standard procedure forthe coupling quickly evolved to the use of 1-acyl- or 1-carbalkoxy-3-TIPSO-b-lactams and LiHMDS as the base.7
Extensive SAR studies on taxoids have led to the discovery ofhighly potent new-generation taxoids, which have modifications atC30, C10 and/or C2 and possess 2e3 orders of magnitude higherpotencies than paclitaxel and docetaxel against multidrug resistant(MDR) as well as paclitaxel-resistant cancer cell lines. Selected new-generation taxoids exhibit much better efficacy than paclitaxel anddocetaxel against human tumor xenografts in animal mod-els.77,117e119 Selected new-generation taxoids are listed in Table 2 andtheir in vitro activities against several cancer cell lines in Table 3.
In order to investigate the bioactive conformation of paclitaxel,conformationally restricted macrocyclic paclitaxel congeners weredesigned and synthesized by using a combination of the b-lactamsynthon method and an intramolecular Heck reaction or Ru-catalyzed ring-closing metathesis (RCM).119e121
For example, a 30NeC2-linked novel macrocyclic taxoid 138wassynthesized using an intramolecular Heck reaction in the macro-cyclization step (Scheme 35).121 Enantiopure 1-(3-iodobenzoyl)-3-TESO-4-phenyl-b-lactam 135 was prepared from (3R,4S)-3-TIPSO-4-phenyl-b-lactam 82a (see Table 1). The ring-opening coupling of135 with 2-(2-vinylbenzoyl)-7-TES-baccatin (136) under the stan-dard conditions gave the iodo-vinyl-taxoid 137 in high yield. Theintramolecular Heck reaction of 137 catalyzed by a Pd(0)eAsPh3complex at 55 �C, followed by deprotection afforded the 19-membered exo-methylene-macrocyclic taxoid 138 in 56% yield.The macrocyclic taxoid 138 exhibited a very good IC50 value of67 nM against LCC6-WT human breast cancer cell line.121
30NBz-C14b-linked novel macrocyclic taxoids, SB-T-2053 andSB-T-2054, were synthesized using Ru-catalyzed intramolecularcoupling reactions of taxoid-dienes 141. Taxoid-dienes 141a and
HO OOH
OTESAcO O
OAcOO
NO O
TESO
O OOH
OTESAcO O
OAcOO
O
HNOTIPSO
O OOH
OHAcO O
OAcO
OHO
ONH
O
136135 137
138
I
+
77%
56% for 2 steps
LiHMDS
THF, -40 °C30 min
i. Pd2(dba)3AsPh3, Et3N,MeCN, 55 °C
ii. HF-Py, MeCN
I
Scheme 35.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410654
141bwere synthesized though ring-opening coupling of (3R,4S)-1-(2-allylbenzoyl)-3-TESO-4-phenyl-b-lactam 139a and (3R,4S)-1-(2-vinyl)-4-phenyl-3-TESO-b-lactam 139b with 7-TES-14b-allylox-ybaccatin III (140), respectively, in high yields under the standardconditions (Scheme 36).120
HO
OAcO OTES
OOAcOBz
HHOO
NO
TESO
XO
139
+LiH-30 -
a:
b:
14
141a
141b
HNO
i. Cl2Ru(=CHPh)(PCy3)2CH2Cl2, rt
ii. HF/Py, Py, MeCN
HNO
i. Cl2Ru(=CHPh)(PCy3)2CH2Cl2, rt
ii. HF/Py, Py, MeCN
140
72
79% for 2 steps
57% for 2 steps
Scheme
The RCM of 141a using the first-generation Grubbs Ru catalyst atroom temperature, followed by deprotection of the silyl groups,gave the expected 15-membered macrocyclic taxoid SB-T-2053 inhigh yield (Scheme 36).120,122 However, the attempted RCM of 141bdid not occur and an unanticipated novel coupling took place to
O
OAcO OTES
OOAc
OBzH
OHO
O
OTES
141
HN
O
X
MDS, THF> 0 oC, 2.5 h
X = CH2X = none
SBT-2053
O
OAcO OH
OOAcOBz
HHOO
O
OH
SBT-2054
O
OAcO OH
OOAcOBz
HHOO
O
OH
-82%
36.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10655
give the 15-membered macrocyclic taxoid SB-T-2054, in which thedouble bond of the linkage was conjugated to the benzoyl moiety,in good yield after deprotection (Scheme 36).120 This novel couplingreaction is mediated by the Ru complex, but not catalytic, and likelyto involve Rueallyl complexes as key intermediates.120 Thesemacrocyclic taxoids were examined for their activities in tubulinpolymerization and microtubule stabilization as well as their po-tencies against six human cancer cell lines. It was found that bothSBT-2053 and SBT-2054 possessed virtually the same activity asthat of paclitaxel in the tubulin polymerization/depolymerizationassay. Moreover, SBT-2054 was found to be as potent as paclitaxelin the cytotoxicity assay, which is the closest conformationally re-stricted paclitaxel congener to date, mimicking the binding struc-ture of paclitaxel in microtubules.120,123
4.2. Synthesis of cryptophycins by means of N-acyl-b-lactammacrolactonization
Cryptophycins are macrocyclic cytotoxins produced by cyano-bacteria, which exhibit potent tumor-selective antitumor activitiesby binding microtubules and disrupting cellular mitosis (Fig. 4).These compounds are particularly active against MDR cancer celllines. Synthetic cryptophycin-52 (Cr-52) is currently under clinicaldevelopment for treatment against solid tumors and has shown anexceptionally potent cytotoxicity against the MCF-7 breast cancercell line (IC50¼0.037 nM).124 Dechlorocryptophycin-52 also exhibitsgood activity in the tubulin assembly assay (IC50¼3 mM; for Cr-1,IC50¼2.5 mM) and excellent cytotoxicity against the MCF-7 cellline (IC50¼0.3 nM).124
O
OO
O
O
NH
O
HN
O
R R1OMe
X
cryptophycin-1: R = Me, R1 = H, X = Clcryptophycin-24: R = H, R1 = H, X = H (arenastatin A)cryptophycin-52: R = R1 = Me, X = Cldechlorocryptophycin-52: R = R1 = Me, X = H
Fig. 4. Cryptophycins.
An efficient synthesis of the macrolide core of cryptophycins hasbeen achieved by using the N-acyl-b-lactam macrolactonizationprotocol.125,126 The key steps in the total synthesis of cryptophycin-24 (arenastatin A) are illustrated in Scheme 37, which representsthe synthetic strategy for this class of compounds.126 The key b-lactam 144 was prepared in 53% yield for three steps through thecoupling of the Northern/Western fragment 142 with N-(p-MeOePhe)-b-lactam 143, the Eastern fragment. The macro-lactonization of 144 proceeded through cyanide-initiated b-lactamring opening using Bu4NCN and subsequent lactonization to givethe 16-membered macrocycle 145 in 68% yield. The attempted di-rect ring-opening coupling using NaH and NaHMDS as base wasunsuccessful, presumably due to the instability of 144 under basicconditions. The introduction of the C30-phenyl moiety through theHeck reaction gave the desired product, but only in modest yield.Epoxidation of the resulting styryl double bond with dime-thyldioxirane (DMD) gave cryptophycin-24 as a 2:1 (b/a) di-astereomeric mixture, which was separated by reverse-phaseHPLC. This strategy was also employed for the total synthesis ofdechlorocryptophycin-52.126
4.3. Synthesis of b-turn mimetics of enkephalin via b-lactammacrocyclization
In connection with the investigations into the binding confor-mation of enkephalins,127 endogenous opioid pentapeptides, tospecific opiate receptors, conformationally constrained non-peptide b-turn mimetics 146 (Fig. 5) were designed and synthe-sized using a b-lactam macrocyclization protocol.128
The synthesis of the novel 4/1 b-turn mimic 146a (X¼NH) isillustrated in Scheme 38 as a typical example.128 b-Lactam 147, an(S)-Tyr-Gly-Gly mimic synthon, was prepared from (3S,4S)-1-TBS-3-but-3-enyl-4-(4-TBSO-benzyl)-b-lactam, which was obtainedthrough highly stereoselective alkylation of (4S)-1-TBS-4-(4-TBSO-benzyl)-b-lactam, via NaIO4 oxidation and peptide coupling witha glycinate. (S)-Tyr-(S)-LeueOMe hydrazide 148 was prepared bycoupling LeueOMewith (S)-BocNHNH-TyreOH, whichwas derivedfrom (R)-Tyr and BocNHNH2 via diazonium species. The coupling of147 with 148 was carried out by converting 147 into the corre-sponding acid chloride, followed by reaction with 148 in thepresence of AgCN to give the b-lactam key intermediate 149a in49% yield. Then, the Boc group was removed from 149a with tri-fluoroacetic acid (TFA) and the subsequent b-lactam macro-cyclization, followed by silicon group deprotection, gave Leu-enkephalin mimic 146a in 94% yield for three steps.128
4.4. Stereoselective synthesis of indolizidine alkaloids via b-lactam ring-expansion
Indolizidine alkaloids are among the most abundant naturallyoccurring alkaloid natural products and possess various biologicalactivities ofmedicinal interest. For example, indolizidine (�)-205A, analkaloid from poison dart frogs extracts, as well as castanospermineand swainsonine, extracted from plant sources have been extensivelystudied for their syntheses and biological activities.129e131
The b-lactam synthon method was applied to the construction ofthe indolizidine skeleton through ring-expansion of piperidinyl-b-lactams 153 (Scheme 40).132 The preparation of b-lactams 153 is il-lustrated in Scheme 39. An aza-DielseAlder reaction of b-lactam 150withDanishefsky’s diene151 gave a 3:1mixture of cycloadducts152aand 152b, which were separated by column chromatography.132 b-Lactam 152a was reduced successively with L-Selectride and NaBH4to give a 3:2mixture of epimeric alcohols,whichwere protectedwithTBS and separated by chromatography to afford piperidinyl-b-lac-tams 153a and 153b. It is interesting to note that the same reduc-tioneprotection sequence for b-lactam 152b gave153c exclusively.133
The ring-expansion reaction of three piperidinyl-b-lactams,153a, 153b, and 153c, catalyzed by sodium methoxide proceededsmoothly at 0 �C to afford the corresponding epimeric indolizi-dines, 154a, 154b, and 154c, respectively, in quantitative yields(Scheme 40).133 Although the preparation of piperidinyl-b-lactamsneeds improvements, the ring-expansion process is highly efficientand this methodology can be applied to the construction of otherizidine alkaloid skeletons.
5. Synthesis of three- to eight-membered nitrogen-heterocycles from b-lactams
As any of the four bonds in the b-lactam ring can be selectivelycleaved by varying either the reaction conditions and/or the sub-strate, the b-lactam ring system can be used for the construction ofN-containing heterocycles of different ring sizes. Various examplesof intramolecular ring-expansions leading to functionalizedenaminones, g-lactams and lactones as well as peptide- and non-peptide-based macrocycles through intra- or intermolecular nu-cleophilic attack have been reported in literature.11,134e136
146
HONH2
X N
OO NH
CO2H
NH
OO
X = NH, NH-CMe2CH2, NHCMe2(CH2)2, NH-CMe2CH=CHCH2
Fig. 5. Conformationally constrained non-peptide b-turn mimics.
OO
OTBS
O
OtBu
NO O
H3NCl
i) TFA, CH2Cl2, ii) HBTU, DIPEA, MeCN, iii) BF3 Et2O, CHCl3, 53% over 3 steps,iv) PhI, Pd(OAc)2, MeCN, sealed tube, 80-85 °C, 37%, v) DMD, acetone, 76%
OO
OH N O
HN
O
O
Bu4NCNCH2Cl2
OO
O
O
NH
O
HN
OO
OO
O
O
NH
O
HN
O
cryptophycin-24
142
+
143144
145
68%
i, ii, iii
iv, v
OMe OMe
OMe
MeO
Scheme 37.
i) 147, (COCl)2, CH2Cl2, 0 oC; ii) 148, AgCN3 h; iv) Et3N, CH2Cl2, 0 °C, 1 h; iv) TBAF, TH
fo
NO
TBS
O
NH O
NBocHN
O
HN CO2Me
149a
TBSO
,
NOTBS
O
NH
HO2CO
TBS
+
147
Scheme
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410656
5.1. Formation of aziridines through ring contraction of b-lactams
The reductive cleavage of the N1eC2 bond of 4-(2-chloroisopropyl)-b-lactam 155 with LiAlH4 gave b-hydrox-yethylaziridine 156 in modest-to-fairly good yield through a tan-dem reductionecyclization process (Scheme 41).137
Treatment of 2-aryl-3,3-dichloroazetidines 158, derived from b-lactams 157 by monochloroalane reduction, with sodium meth-oxide inmethanol gave aziridine ketals 159 in 60e90% yield for twosteps (Scheme 42). This reaction is likely to involve 2-azetines 160and highly strained azabicyclo[1.1.0]cyclobutanes 161, as key in-termediates. The ring contraction of 161 through CeN bondcleavage generates aziridine oxonium salts 162, which react withmethoxide ion to give 159 (Scheme 42).138
, benzene; iii) TFA, CH2Cl2, -10 oC,F, rt, 2 h
ii, iii, iv
146a
94%r 3 steps
HONH2
NHN
OO NH
CO2H
NH
OO
HNBocHN
O
HN CO2Me i, ii
49%for 2 steps
148
38.
NO
MeO HH OTMS
OMeN
O
MeON
O
H
HH
NO
MeON
O
H
HHN-PMP
MeCN-20 °C, 16 h
ZnI2
150 152a 152b
+
3:1151
+
i, ii, iii, iv
i) L-selectride, -78 °C, 1h.ii) NaBH4, MeOH, 0 °C.iii) TBSCl, imidazole, DMF, rt, 16 h.iv) CAN, AcCN-H2O, -35 °C, 30 min
NO
MeONH
OTBS
H
HH
TolN
O
MeONH
OTBS
H
HH
Tol
+
i, ii, iii, iv
NO
MeONH
OTBS
H
HH
Tol
152a
153a 153b
152b
153c
TolPMP PMP
Tol Tol
57%
21%for 4 steps
3:2
22%for 4 steps
Scheme 39.
NO
MeONH
OTBS
H
HH
TolN
O
MeONH
OTBS
H
HH
TolN
O
MeONH
OTBS
H
HH
Tol153a 153b 153c
i) MeONa, MeOH, rt, 0 °C.
N
O
N
O
N
O
OTBSTol-HN Tol-HN Tol-HN
MeO MeO MeOOTBSOTBS
H H H
i i i
154a 154b 154c
quant. quant. quant
Scheme 40.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10657
5.2. Formation of pyrrolidines through one-carbon ring-ex-pansion of b-lactams
The reaction of (2R,3R)-3-alkoxy-4-formyl-b-lactams 11 (seeScheme 3) with t-BuMe2SiCN (TBSCN) catalyzed by molecular io-dine gave 5-cyanopyrrolidin-2-ones 163 in moderate-to-high yieldwith high syn selectivity (86e100%) (Scheme 43).139,140 The syn/antiselectivity depends mostly on the N-substituents and PMP gave thebest results, i.e., 100% syn selectivity. This skeletal rearrangementinvolves the C3eC4 bond cleavage, acyliminium ion formation, andcyanide addition. This mechanism was supported by a DFT calcu-lation using 4-formyl-b-lactam 11 (R1¼Me, R2¼Ph) and TMSCN.
Other nucleophiles such as allyltrimethylsilanes and prop-argylsilane can be used in this unique reaction.139
The ring-expansion reaction of enantiopure 4-(arylimino)-b-lactams 164, which were readily derived from 4-formyl-b-lactams11 with arylamines, in the presence of a catalytic amount of tet-rabutylammonium cyanide (Bu4NCN) proceeded smoothly in ace-tonitrile at room temperature to give the corresponding 5-aryliminopyrrolidin-2-ones 165 without racemization in 44e70%yields via N1eC4 bond breakage (Scheme 43).141 The acidic hy-drolysis of 165a (R1¼Me; R2¼PMP; R3¼PMP) gave succinimide 166in 64% yield. It is worth mentioning that the same reaction se-quence in one pot from 4-formyl-b-lactam 11 afforded succinimide
N NO R2 R2
MeO OMeClCl
R1
R1
i. AlH2Cl, Et2O, 34 °C, 6 h
R1 = H, Me, F, OMeR2 = i-Pr, c-hexyl
60 - 90% for 2 steps
NR2
R1
Cl
NR2
R1
C lMeO
NR2
R1
MeOSN2
NR2 R1
OMe
ii. NaOMe, 2 M MeOHreflux, 90 h
MeOH
157 159
NR2
R1
ClCl
160 161
162
AlH2Cl
158
OMe
OMe
Scheme 42.
NO
R2O
R1
Cl OR2
NR1
HO H
NO
R2O
R1
Cl
AlH3
NO
R2O
R1
Cl
AlH3
[H]
LiAlH4
Et2O, 0 °C, 2 h
R1 = i-Pr, Bn, allyl, c-hexylR2 = Bn, Me
43 - 62%155156
Scheme 41.
NO R2
R1ONR3
NO
R1O
R
TBACN(20 mol %)
CH3CN, rt
44-70%for 2 steps
NO
R
R1OTBSCN,I2 (10 mol %)
MeCN, rt46-89%
H H
16
syn
H
H
R1 = Me, Bn; R2 = allyl, Bn, PMP;R3 = PMP, p-MeC6H4, p-ClC6H4, p-Me2NC
11
NO R2
R1OO
H HH
PMP-NH2molecular sievesMeCN
164
Scheme
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410658
166 in 50e55% yields, which were better than the overall yields inthe original three-step process (Scheme 41).141
5.3. Formation of six-membered nitrogen-heterocycles viatwo-carbon ring-expansion of b-lactams
Reduction of 4-(2-TBSO-ethyl)-b-lactams 167 with mono-chloroalane, followed by TBS deprotection and mesylation, gave 2-(2-TBSO-ethyl)azetidines 168 in three steps. The subsequent reactionof 168 with sodium acetate in acetonitrile, followed by basic hy-drolysis, gave cis-3-alkoxy/phenoxy-4-hydroxypiperidines 170 inmoderate overall yields through two-carbon ring-expansion(Scheme 44).142 This ring-expansion process involves the ammo-nium ion of 1-azabicyclo[2.2.0]hexane 169 as the key intermediate,which can explain the 3,4-cis stereochemistry of 170 as the result ofexo-attack of acetate ion to cleave the 1e4 bond.142 Closely relatedreactions using 3-alkoxyl-4-(2-bromo-1,1-dimethylethyl)-b-lactamsafforded 3,3-dimethyl-4-X-5-alkoxypiperidines (X¼Br, OAc, OH, CN,N3) in high-to-excellent yields.143,144 The reaction of 168 (R1¼i-Pr)with LiBr in acetonitrile gave cis-3-alkoxy-4-bromopiperidine 171,which was converted into piperidin-3-one 172 via the enol-ether infairly good yield for two steps (Scheme 44).142
Two-carbon ring-expansion of b-lactams 173 through theN1eC4 bond cleavage via 175 to form 176, followed by 1,6-conjugate addition of a malonate to 176, lactamization via 177,and deprotection of the resulting 178, gave glutarimides 174(Scheme 45). trans-4-hydroxyphenyl-b-lactams 173 were reactedwith tert-butyl methyl malonate in the presence of potassium tert-butoxide to give 1,3,4,5-substituted glutarimides 174 in 54e77%yield, as illustrated in Scheme 45.145 The relative stereochemistry ofthe 3, 4, and 5 positions depends on the nature of R1 and R2. Thus,the reactions of trans-b-lactams 173a (R1¼benzyl; R2¼Ph) and 173b(R1¼cyclohexylmethyl; R2¼Ph) exclusively gave transetrans gluta-rimides 174a and 174b, respectively, while that of 173c (R1¼Me;R2¼CH2CO2Me) afforded 174c as a 2:1 mixture of transetrans andcisetrans isomers.145
The reaction of 4-acyloxy-b-lactams 179with an acid chloride andDBU afforded 1,3-oxazin-6-ones 180 in modest-to-good yields(Scheme 46).146 The mechanism of this unique process is likely toinvolve the formation of highly strained N-acylazetone 181, whichrapidly undergoes electrocyclic ring opening to generate N-acylimi-doylketene 182. Then, the cyclization of 182 gave 1,3-oxazin-6-one
NR3
2
OTBS
CN2
5
-163
6H4
20% HCl
N OO
R1O
R2
H
166
NO
OTBS
CN
R2
R1O
anti-163
H
rt
(100:0~86:14)
+
43.
N
R1
O R2
O
O
R1
O
HNR2
CO2ButMeO2C
H
HO
R1
O
NR2
O
OMe
N
O
O
CO2But
R1
HO
R2
OBut
OMe
TFA
N
R1
O R2
OH
N
O
O
CO2H
R1
HO
R2
1). t-ButOK,t-butyl methyl malonateDMF
2). TFA
OButO
R1 = Me, Bn, CH2-c-hexyl; R2 = Ph, CH2CO2Me
173 174
175
176177
178
54-77%
Scheme 45.
N
R2O
OTBS
R1O167
i) AlH2Cl, Et2O, rt, 0 °C, 2 h; ii) TBAF, THF, 0 °C to rt, (48-50% for 2 steps);iii) MsCl, Et3N, DMAP, CH2Cl2, 0 °C (85-90%); iv) NaOAc, MeCN, heat, 15 h(55-66%); v) K2CO3, MeOH (56-70%); vi) LiBr, MeCN, heat, 15 h (47-65%);vii) NaH, DMSO, 150 °C, 15 h (56-60%); viii) 2 M HCl, H2O, 40 °C, 40 h (78-85%).
N
R2O
OMs
R1
R1 = i-Pr, c-Hex;R2 = Bn, Ph
i, ii, iii
N
OHR2O
R1
N
BrR2O
N
O
(R1 = i-Pr)
168
170
171 172
iv, v
vi
vii, viii
N
R2O H
O R1+
Nu-
169
Scheme 44.
NHO
O COR1
NO
O COR1
O
R2N
OO
R2
HDBU
O
N
OR2
O
N
O R2
R2CO2Cl, DBU
CH2Cl2, 25 °C, 5 h
R1 = Me, PhR2 = Ph, 4-Cl-Ph, 2-furyl, t-Bu, Et, 4-Br-Ph, (E)-Ph-CH=CH
40-76%179 180
181 182
Scheme 46.
NO
MeOMeO X
R1
PMP
R2
NO
MeOMeO X
R1
PMP
R2SnLn
N
X R1
R2
PMP
O
O
N
X R1
R2
PMP
MeO
O
MeO
N
X R1
R2
PMP
MeO
O
MeOSnLn
SnCl2*2H2O
CH2Cl2, rt
R1 = H, Me, Ph; R2 = H, Me; X = O, N-PMP
75-99%183 184
SnCl2*2H2OSnCl2*2H2O -2 MeOH
Scheme 47.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10659
180.147 A theoretical study on this reaction based on ab initio and DFTanalysis has confirmed that two pseudopericyclic reactions are in-volved. The first key reaction is a retro-[4-exo-dig] cyclization togenerate 183 instead of a thermal conrotatory electrocyclic ringopening, followed by another exothermic pseudopericyclic reactionto form 180 inplace of a six-electron disrotatoryelectrocyclization.146
The C3eC4 bond cleavage of 4-formyl-b-lactam 183a (X¼O) and4-arylimino-b-lactam 183b (X¼ArN) was mediated by stannouschloride and the subsequent six-membered ring formation gave1,4-dihydrooxane 184a (X¼O) and pyrazine-2,3-dione 184b(X¼ArN), respectively, in good-to-excellent yield (Scheme 47).22
5.4. Formation of eight-membered rings through [3,3] sig-matropic rearrangement of b-lactams
The [3,3] sigmatropic (Cope) rearrangement of 3,4-dialkenyl-b-lactams 185 proceeded at 120 �C in a sealed tube using toluene assolvent to give the eight-membered lactams, tetrahydroazocinones186, in 60e100% yield (Scheme 48).148 This rearrangement involvesthe cleavage of the C3eC4 bond of the b-lactam.
N
R2
O
R1
R3N
R2
O
R1
R3N
R2
R1
O R3
toluene
120 oCsealed tube
R1 = H, Me; R2 = CN, Ph, COMe, CO2MeR3 = PMP, Bn, (R)-CH(Me)Ph
60-100%
185 186
Scheme 48.
This sigmatropic rearrangement was found to be completely ste-reospecific. Thus, the reactions of enantiopure (3S,4R)-b-lactam 185aand (3R,4S)-b-lactam 185a, bearing an (R)-1-phenylethyl group atN1,gave (6S)-186a and (6R)-186a in 75 and 83% yields, respectively, asa single product in each case. The observed excellent stereospecificitywasattributed to theboat-like conformationsof thesediastereomericb-lactams, as illustrated in Scheme 49.148
N
PhR
O
(6S)-186a
N
RPh
HH
PhMeHO
H
N
H
PhMeH
O RH
Ph
H
N
PhR
O
(3R,4S)-185a
(3S,4R)-185a
Me
Me
H
HPh
Ph
(6R)-186a
75%
83%
R = H, Me
Scheme 49.
O
O
OH
NO
HO
OBn
F
OH
NO
O
F
OBn
F
ezetimibe
192 194
9:1 t rans/ cis
196
i) LDA; 2) 4-BnO-C6H4CH=NC6H4-F-4 (193); iii) LiCl; iv) NaIO4;v) (TMSO)(4-F-C6H4)C=CH2 (195); vi) p-TsOH; vii) H2,(Ph3P)3RhCl; viii) CBS reduction; ix) H2, Pd-C, EtOH
i, ii (193) iv, v (195)
iii vi
vii, viii, ix
64% 68%
39%
Scheme 51.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410660
6. Use of b-lactam skeleton as a uniquely rigid scaffold fordrug discovery
6.1. b-Lactam cholesterol absorption inhibitors
Atherosclerotic coronary heart disease (CHD) is the major causeof death in the United States, and it has been shown that CHD isassociated with elevated serum cholesterol levels, to which cho-lesterol from dietary or intestinal sources is themajor contributor.15
Accordingly, the serum cholesterol level should be effectivelycontrolled by blocking the intestinal sources of cholesterol. Then,the cholesterol absorption in the intestine can be blocked byinhibiting acyl-CoA:cholesterol O-acyltransferase (ACAT).15 Thus,ACAT inhibitors have been extensively studied, including b-lactams,which led to the discovery of ezetimibe, a trans-b-lactam, as a po-tent and highly efficacious cholesterol absorption inhibitor.15
Ezetimibe was approved by the FDA for the treatment of hyper-cholesterolemia in 2002 and combination therapies with statinshave been extensively studied as well.
In a patented asymmetric synthesis of ezetimibe (Scheme 50),a key intermediate, (S)-hydroxypentanoyl-(S)-oxazolidinone 189(99:1 dr), was prepared by the CoreyeBakshieShibata (CBS)asymmetric reduction of 188 in excellent yield. Oxazolidinone
F
O
OH
O
F
O
NFOH
N
O
O
O
Ph
HN
TMSO
187
188
190
191
i) pivaloyl chloride, Et3N; ii) (S)-4-phenyloxazolidinone; iiTMSCl, DiPEA, TiCl4, CH2Cl2, -25 oC; v) bis-TMS-acetamdil. H2SO4.
i, ii
iv
92%
65%
Scheme
188 was obtained through coupling of d-keto acid 187 and(S)-phenyloxazolidinone in excellent yield. The asymmetricenolateeimine cyclocondensation of 189 with imine 190 (via insitu silylation and TMS-enolate formation) afforded b-aminoamide 191 with high stereoselectivity. The N-silylation followedby TBAF-catalyzed cyclization of 191 gave ezetimibe in highyield.15,149
Another synthesis of ezetimibe includes a one-step highly dia-stereoselective formation of trans-b-lactam 194 through enolateeimine cyclocondensation of (S)-hydroxy-g-lactone 192 with 4-BnOeC6H4CH]NC6H4eF-4 (193) (Scheme 51). The sodium peri-odate oxidation of the diol moiety of 194 to the corresponding 3-formyl-b-lactam, which was subjected to Mukaiyama aldol con-densation with (TMSO)(4-FeC6H4)C]CH2 (195), followed by desi-lylation, to give the b-lactam 196. Hydrogenation of the doublebond, followed by asymmetric CBS reduction of the ketone moiety
N
O
O
O
F
N
O
O
OOH
OTMS
F
F
NO
OH
F
OH
F
189
ezetimibe
i) MeCBS (3 mol%), BH3-THF, THF; iv)ide, t-BuOMe, TBAF.3H2O; vi) aq. i -PrOH,
iii
v, vi
95%98% de
91.5%
50.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10661
and removal of the benzyl protection by hydrogenolysis, affordedezetimibe with >99% ee in good overall yield.150
6.2. b-Lactam-based combretastatin mimics
Combretastatins are naturally occurring diarylstilbenes, isolatedfrom the stem of Combretum caffrum (South African bushwillowtree).151,152 These compounds exhibit strong cytotoxicity and areknown to share the same tubulin-binding site as colchicine.153
Among these, the highly potent combretastatin A-4 was selectedfor drug development and its phosphate derivative, combretastatinA-4-phosphate, a water-soluble prodrug, is currently in clinicaltrials for the treatment of thyroid cancer (Fig. 6).152,154 As the cis-olefin moiety of combretastatin A-4 is prone to isomerization,which causes a loss of activity, the rigid b-lactam ring system wasused to develop a series of b-lactam-based structurally stablecombretastatin mimics, some of which exhibited promising activ-ities (Fig. 6).19
MeO
MeO
MeO
RMeO
combretastatin A-4 (R = OH)combretastain A-4P (R = OPO3Na2)
NO
RHO
OMe
MeOOMe
OMe
β-lactam-based combretastatin A-4 mimics
197a (R = H )197b (R = OH)197c (R = NH2)
Fig. 6. Combretastatin A-4, its derivative and b-lactam-based mimics.
Combretastatin A-4 mimic 197a was synthesized via the Refor-matsky reactionof phenylbromoacetate198 and imine199, followedby desilylation (Scheme 52).19 Mimics 197b and 197c were synthe-sized through the Staudinger keteneeimine cycloaddition reactionof ketenes generated from 200a and 200bwith imine 199, formingb-lactams 201a and 201b, respectively, followed by desilylationand reductive removal of the benzyl or Cbz group (Scheme 52).19
OH
OY
N
OMeMeO
MeOBr
O
O
+
200a: Y = BnO200b: Y = NHCbz
NO
YTB
M
201a: Y201b: Y
i) (Cl3CO)2C=O, NEt3, CH2Cl2, reflux; ii) TBAF,
i
199
198
199
+
Scheme
The reported chemical yields for these mimics are modest, at best,for some reason. The IC50 values of thesemimicswere determined tobe 9.6, 0.8, and 4.5 nM, respectively, indicating that they are as po-tent as, or more potent than, combretastatin A-4 against the MCF-7human breast cancer cell line.19 Although these mimics have beenfound to be potent and promising, a substantial improvement in thesyntheses is necessary for their further development as drugcandidates.
6.3. b-Lactam-based novel vasopressin V1a antagonists
Vasopressin and oxytocin are neurohypophysical hormones,which bind to specific receptors of the G protein-coupled receptor(GPCR) superfamily.155 Vasopressin V1a, V1b and oxytocin receptorsactivate phospholipase C, which leads to secretion of inositol 1,4,5-triphosphate and diacylglycerol that mobilize intracellular calciumand activation of protein kinase C.155 Besides their functions inthe cardiovascular system, vasopressin antagonists have been
recommended for some CNS applications.156 Although numerousvasopressin V1 receptor antagonists have been developed, none ofthem had been reported to penetrate the central nervous system(CNS) efficiently, until novel b-lactam-based antagonists such as202a (SRX246) were discovered.
Based on its structural similarities to ketoconazole, a knownantagonist of the luteinizing hormone releasing hormone (LHRH)
OMe
OTBS197a
SOOMe
eOOMe
OMe
= BnO= NHCbz
THF, 0 oC; iii) H2, Pd-C, EtOH/EtOAc (1/1) rt
ii, iii 197b (Y = OH)197c (Y = NH2)
i. Zn, TMSClbenzenemicrowave
ii. TBAFTHF, 0 oC
52.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410662
receptor, LY307174 (IC50¼45 nM for human V1a receptor) wasidentified as the lead structure for extensive SAR studies (Fig. 7).14
After systematic SAR studies, two highly potent compounds, 202a(SRX246) and 202b (SRX251) (Fig. 7 and Scheme 53) were discov-ered, which exhibited Ki values of 0.3 and 0.66 nM, respectively.When administered orally, these two compounds reached ca. 100-fold higher brain levels in rats than their in vitro receptor affinities.Thus, these two compounds are currently under drug developmentfor human clinical evaluation.14
OO
NN
O
N
N
O
NO
N
O
O
O
O
O
O
Ketoconazole LY307174
NO
N
O
HNH
O
O
N
N
O
SRX246 (202a)
Fig. 7. Rational design of b-lactam-based LHRH receptor antagonists.
OBu-t
O
OH
ONH-Cbz
OBu-t
ON
ONH2
PhCHO
iiit-BuO
O
N
ON
Ph
O N
Ph
O
COCl
N
v
N PhO O
Ph
CO2HO
1,4'-dipiperidineN
NPh
O O
Ph
ONH
NF3C
Me
203 204 205
206
202
a:
b:
i) R1R2NH, HOBT, EDC.HCl, CH2Cl2; ii) H2, Pd/C; iii) MgSO4, CH2Cl2; iv) 18, NEt3, CH2Cl2; v) HCO2H;vi) 1,4'-dipiperidine, HOBT, EDC.HCl, CH2Cl2
>90%
R1
R2
70%R1 R1
18
64-69%
iv
R1R2N>90%
viO
R1R2N N
O
N
ii
R1R2NH2i
O
R1R2N =
(SRX246)
(SRX251)
Scheme 53.
The synthetic routes to 202a and 202b are illustrated in Scheme53.14 A key intermediate b-lactams 206 was synthesized using theasymmetric Staudinger keteneeimine cycloaddition of (R)-phe-nyloxazolidinylacetyl chloride (18; see Scheme 5) with function-alized imines 205 in the presence of a base, which proceededwith excellent stereoselectivity. Imine 205 was prepared from
(R)-N-CbzeAspeOBu-t (203) via coupling with an amine [a: (S)-1-phenylethylamine; b: N-methyl-(3-trifluoromethyl)phenylmethyl-amine] to give amides 204, followed by removal of benzylprotection and imine formation with cinnamaldehyde. The asym-metric Staudinger cycloaddition of 18 with 205 in the presence oftriethylamine, followed by treatment with formic acid gave b-lac-tam 206 in 64e69% yield. The amide coupling of 206a and 206bwith 1,40-dipiperidine afforded 202a (SRX246) and 202b (SRX251),respectively, in >90% yield (Scheme 53).14
7. Conclusions
This Tetrahedron Report has summarized the recent advances inthe synthesis of b-lactams with high enantiomeric purity, thechemistry of b-lactams, the b-lactam synthon method, and its ap-plications to the synthesis of non-protein amino acids, their
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e10664 10663
derivatives and peptides as well as biologically active natural andunnatural compounds of medicinal interest. In addition, the dis-covery and development of novel b-lactams with anticancer ac-tivity, cholesterol absorption inhibitory activity and CNS activity byexploiting the rigid and unique b-lactam scaffold are described.Traditionally, the organic chemistry and medicinal chemistry of b-lactams have been directly related to b-lactam antibiotics. However,it is obvious that the potential of b-lactams has been explored ex-tensively in an impressive breadth, which has created an entirelynew field of chemical and medicinal research. Thus, it is safe to saythat this field of research will continue to expand and flourish.
References and notes
1. Georg, G. I. The Organic Chemistry of b-Lactams; VCH: New York, NY, 1992; andreferences cited therein.
2. Aoki, H.; Sakai, H.; Kohsaka, M.; Konomi, T.; Hosoda, J. J. Antibiot. 1976, 29,890e901.
3. Hashimoto, M.; Komori, T.; Kamiya, T. J. Am. Chem. Soc. 1976, 98, 3023e3025.4. Imada, A.; Kitano, K.; Kintaka, K.; Muroi, M.; Asai, M. Nature 1981, 289,
590e591.5. Ojima, I.; Shimizu, N.; Qiu, X.; Chen, H.-J. C.; Nakahashi, K. Bull. Soc. Chim. Fr.
1987, 649e658.6. Hatanaka, N.; Abe, R.; Ojima, I. Chem. Lett. 1981, 10, 1297e1298.7. Ojima, I. Acc. Chem. Res. 1995, 28, 383e389.8. Ojima, I. In Advances in Asymmetric Synthesis; Hassner, A., Ed.; JAI: Greenwich,
CT, 1995; pp 95e146.9. Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377e386.
10. Deshmukh, A. R.; Bhawal, B. M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B.A.; Jayanthi, A. Curr. Med. Chem. 2004, 11, 1889e1920.
11. Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11, 1921e1949.12. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiardide, M. Curr. Med. Chem. 2004, 11,
1837e1872.13. Ojima, I.; Kuznetsova, L.; Ungureanu, I. M.; Pepe, A.; Zanardi, I.; Chen, J. In
Fluorine-containing Synthons; Soloshonok, V., Ed.; ACS Symposium Series;American Chemical Society/Oxford University Press: Washington, DC, 2005;Vol. 911, pp 544e561.
14. Guillon, C. D.; Koppel, G. A.; Brownstein, M. J.; Chaney, M. O.; Ferris, C. F.; Lu,S.-F.; Fabio, K. M.; Miller, M. J.; Heindel, N. D.; Hunden, D. C.; Cooper, R. D. G.;Kaldox, S. W.; Skelton, J. J.; Dressman, B. A.; Clay, M. P.; Steinberg, M. I.; Bruns,R. F. Bioorg. Med. Chem. 2007, 15, 2054e2080.
15. Burnett, D. Curr. Med. Chem. 2004, 11, 1873e1887.16. Banik, I.; Becker, F. F.; Banik, B. K. J. Med. Chem. 2003, 46, 12e15.17. Banik, B. K.; Becker, F. F.; Banik, I. Bioorg. Med. Chem. 2004, 12, 2523e2528.18. Banik, B. K.; Banik, I.; Becker, F. F. Eur. J. Med. Chem. 2010, 45, 846e848.19. O’Boyle, N.; Carr, M.; Greene, L.; Bergin, O.; Nathwani, S.; McCabe, T.; Lloyd, D.;
Zisterer, D.; Meegan, M. J. Med. Chem. 2010, 53, 8569e8584.20. Del Buttero, P. ,M. G.; Roncoroni, M. Tetrahedron Lett. 2006, 47, 2209e2211.21. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiardide, M. Amino Acids 1999, 16,
321e343.22. Alcaide, B.; Martin-Cantalejo, Y.; Rodriguez-Lopez, J.; Sierra, M. J. Org. Chem.
1993, 58, 4767e4770.23. Staudinger, H. Justus Liebigs Ann. Chem. 1907, 356, 51e123.24. Venturini, A.; Gonzalez, J. Mini-Rev. Med. Chem. 2006, 3, 185e194.25. Cossio, F. P.; Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008, 41, 925e936.26. Dumas, S.; Hegedus, L. S. J. Org. Chem. 1994, 59, 4967e4971.27. Georg, G. I.; Ravikumar, V. T. In Organic Chemistry b-Lactams; Georg, G. I., Ed.;
VCH: New York, NY, 1993; pp 295e368.28. Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad, D. C. J. Am. Chem. Soc.
1991, 113, 5784e5791.29. Cossio, F. P.; Ugalde, J. M.; Lopez, X.; Lecea, B.; Palomo, C. J. Am. Chem. Soc.
1993, 115, 995e1004.30. Lopez, R.; Sordo, T. L.; Sordo, J. A.; Gonzalez, J. J. Org. Chem. 1993, 58,
7036e7037.31. Cossio, F. P.; Arrieta, A.; Lecea, B.; Ugalde, J. M. J. Am. Chem. Soc. 1994, 116,
2085e2093.32. Wang, Y.; Liang, Y.; Jiao, L.; Du, D.-M.; Xu, J. J. Org. Chem. 2006, 71, 6983e6990.33. Li, B.; Wang, Y.; Du, D.-M.; Xu, J. J. Org. Chem. 2007, 72, 990e997.34. Linder, M. R.; Podlech, J. Org. Lett. 2001, 3, 1849e1851.35. Palomo, C.; Oiarbide, M.; Esnal, A.; Landa, A.; Miranda, J.; Linden, A. J. Org.
Chem. 1998, 63, 5838e5846.36. Aszodi, J.; Bonnet, A.; Teusch, G. Tetrahedron 1990, 46, 1579e1586.37. Bose, A.; Manhas, M.; van der Veen, J.; Bari, S.; Wagle, D. Tetrahedron 1992, 48,
4831e4844.38. Hubschwerlen, C.; Schmid, G. Helv. Chim. Acta 1983, 66, 2206e2209.39. Banik, B.; Manhas, M.; Kaluza, Z.; Barakat, J.; Bose, A. Tetrahedron Lett.1992, 33,
3603e3606.40. Chincholkar, P.; Puranik, V. G.; Deshmukh, A. R. A. S. Tetrahedron 2007, 63,
9179e9187.41. Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.; Kurys, B. E.; Strohmeyer,
T. W.; Hegde, V. R.; Manhas, M. S.; Bose, A. K. J. Org. Chem. 1988, 53,4227e4236.
42. Li, L.; Thomas, S. A.; Klein, L. L.; Yeung, C. M.; Maring, C. J.; Grampovnik, D. J.;Lartey, P. A.; Plattner, J. J. J. Med. Chem. 1994, 37, 2655e2663.
43. Kuznetsova, L.; Ungureanu, I.; Pepe, A.; Zanardi, I.; Wu, X.; Ojima, I. J. FluorineChem. 2004, 125, 487e500.
44. Ojima, I.; Kuznetsova, L. V.; Sun, L. In Current Fluoroorganic Chemistry. NewSynthetic Directions, Technologies, Materials and Biological Applications; Solo-shonok, V., Mikami, K., Yamazaki, T., Welch, J. T., Honek, J., Eds.; ACS Sym-posium Series; American Chemical Society/Oxford University Press:Washington, DC, 2007; Vol. 949, pp 288e304.
45. Niu, C.; Miller, M. J. Tetrahedron Lett. 1995, 36, 497e500.46. Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1985, 26, 3783e3786.47. Ruhland, B.; Bhandari, A.; Gordon, E.; Gallop, M. J. Am. Chem. Soc. 1996, 118,
253e254.48. Delpiccolo, C.; Mata, E. Tetrahedron: Asymmetry 2002, 13, 905e910.49. Alcaide, B.; Rodriguez-Vicente, A. Tetrahedron Lett. 1999, 40, 2005e2006.50. Chen, J.; Kuznetsova, L.; Ungureanu, I.; Ojima, I. In Enantioselective Synthesis of
Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V., Eds.; John Wiley: New York,NY, 2005; pp 447e476.
51. Brieva, R.; Crich, J. Z.; Sih, C. J. J. Org. Chem. 1993, 58, 1068e1075.52. Banik, B. K.; Manhas, M. S.; Bose, A. K. J. Org. Chem. 1994, 59, 4714e4716.53. Patel, R. N. (Bristol-Myers Squibb Co., USA.). Eur. Pat. Appl. 634492 A1, 1995.54. Holton, R. A.; Vu, P. PCT Int. Appl. WO 2001/029245, Florida State University,
USA, 2001.55. Kuznetsova, L. V.; Pepe, A.; Ungureanu, I. M.; Pera, P.; Bernacki, R. J.; Ojima, I. J.
Fluorine Chem. 2008, 129, 817e828.56. France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37,
592e600.57. Wack, H.; Drury, W.; Taggi, A.; Ferraris, D.; Lectka, T. Org. Lett. 1999, 1,
1985e1988.58. Taggi, A.; Hafez, A.; Wack, H.; Young, B.; Drury, W.; Lectka, T. J. Am. Chem. Soc.
2000, 122, 7831e7832.59. France, S.; Wack, H.; Hafez, A.; Taggi, A.; Witsil, D.; Lectka, T. Org. Lett. 2002, 4,
1603e1605.60. Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578e1579.61. Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett. 2008, 10, 277e280.62. Huang, X.; Chen, X.; Ye, S. J. Org. Chem. 2009, 74, 7585e7587.63. Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A. D. Org. Biomol. Chem.
2008, 6, 1108e1113.64. Sereda, O.; Blanrue, A.; Wilhelm, R. Chem. Commun. 2009, 1040e1042.65. Ponsford, R. J.; Southgate, R. J. Chem. Soc., Chem. Commun. 1979, 846e847.66. Brown, P.; Southgate, R. Tetrahedron Lett. 1986, 27, 247e250.67. Doyle, M. P.; Shanklin, M. S.; Oon, S.-M.; Pho, H. Q.; van der Heidet, F. R.; Veal,
W. R. J. Org. Chem. 1988, 53, 3384e3386.68. Doyle, M. P.; Oon, S. M.; van der Heide, F. R.; Brown, C. B. Bioorg. Med. Chem.
Lett. 1993, 3, 2409e2414.69. Watanabe, N.; Anada, M.; Hashimoto, S.; Ikegami, S. Synlett 1994, 1031e1033.70. Anada, M.; Watanabe, N.; Hashimoto, S. Chem. Commun. 1998, 1517e1518.71. Calet, S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989, 111, 931e934.72. Piotti, M. E.; Alper, H. J. Am. Chem. Soc. 1996, 118, 111e116.73. Ojima, I.; Habus, I. Tetrahedron Lett. 1990, 31, 4289e4292.74. Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y.; Sun, C.; Brigaud, T. Tetrahe-
dron 1992, 48, 6985e7012.75. Ojima, I.; Habus, I.; Zhao, M. J. Org. Chem. 1991, 56, 1681e1683.76. Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk, S. D. Tetrahedron
Lett. 1993, 34, 4149e4152.77. Ojima, I.; Slater, J. S.; Kuduk, S. D.; Takeuchi, C. S.; Gimi, R. H.; Sun, C.-M.; Park,
Y. H.; Pera, P.; Veith, J. M.; Bernacki, R. J. J. Med. Chem. 1997, 40, 267e278.78. Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tamioka, K. J. Am. Chem. Soc. 1997,
119, 2060e2061.79. Dunnill, P. Nature 1966, 210, 1265e1267.80. Jung, M. Chemistry and Biochemistry of Amino Acids; Chapman and Hall: New
York, NY, 1985.81. Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988e4035.82. Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Abe, R. J. Org. Chem. 1991, 56,
5263e5277.83. Ojima, I.; Chen, H. J.; Qiu, X. Tetrahedron 1988, 44, 5307e5318.84. Colson, P.-J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918e5924.85. Ojima, I.; Chen, H. J.; Nakahashi, K. J. Am. Chem. Soc. 1988, 110, 278e281.86. Thaisrivongs, S.; Pals, D. T.; Kroll, L. T.; Turner, S. R.; Han, F. S. J. Med. Chem.
1987, 30, 976e982.87. Iizuka, K.; Kamijo, T.; Kubota, T.; Akahane, K.; Umeyama, Y.; Kiso, Y. J. Med.
Chem. 1988, 31, 701e704.88. Huff, J. R. J. Med. Chem. 1991, 34, 2305e2314.89. Okino, T. M.; Matsuda, H.; Murakami, M.; Yamaguchi, K. Tetrahedron Lett. 1993,
34, 501e504.90. Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117e128.91. Rowinsky, E. K. Annu. Rev. Med. 1997, 48, 353e374.92. Kingston, D. G. I. J. Nat. Prod. 2009, 72, 507e515.93. Ojima, I.; Park, Y. H.; Sun, C. M.; Zhao, M.; Brigaud, T. Tetrahedron Lett. 1992, 33,
5739e5742.94. Ojima, I.; Sun, C. M.; Park, Y. H. J. Org. Chem. 1994, 59, 1249e1250.95. Ojima, I.; Wang, T.; Ng, E. W. Tetrahedron Lett. 1998, 39, 923e926.96. Palomo, C.; Aizpurua, J. M.; Cuevas, C. J. Chem. Soc., Chem. Commun. 1994,
1957e1958.97. Kukhar, V. P.; Soloshonok, V. A. Fluorine Containing Amino Acids: Synthesis and
Properties; Wiley: Chichester, UK, 1994.
A. Kamath, I. Ojima / Tetrahedron 68 (2012) 10640e1066410664
98. Ojima, I. Biomedical Frontiers of Fluorine Chemistry; American Chemical Soci-ety: Washington, DC, 1996.
99. Ojima, I.; Lin, S.; Slater, J. C.; Wang, T.; Pera, P.; Bernacki, R. J.; Ferlini, C.;Scambia, G. Bioorg. Med. Chem. 2000, 8, 1576e1585.
100. Ojima, I.; Wang, T.; Delaloge, F. Tetrahedron Lett. 1998, 39, 3663e3666.101. Suffness, M. Taxol: Science and Applications; CRC: New York, NY, 1995.102. Rowinsky, E. K.; Onetto, N.; Canetta, R. M.; Arbuck, S. G. Semin. Oncol. 1992, 19,
646e662.103. Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277, 665e667.104. Schiff, P. B.; Horwitz, S. B. Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 1561e1565.105. Jordan, M.; Wilson, L. Nat. Rev. Cancer 2004, 4, 253e265.106. Jordan, M. A. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 1e17.107. Holton, R.A.;Kim,H.-B.; Somoza,C.; Liang, F.; Biediger, R. J.; Boatman, P.D.; Shindo,
M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.;Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc.1994, 116, 1599e1600.
108. Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.;Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J.Nature 1994, 367, 630e634.
109. Danishefsky, S.; Masters, J.; Young, W.; Link, J.; Snyder, L.; Magee, T.; Jung, D.;Isaacs, R.; Bornmann, W.; Alaimo, C.; Coburn, C.; Di Grandi, M. J. Am. Chem. Soc.1996, 118, 2843e2859.
110. Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Houze, J.B.; Krauss, N. E.; Lee,D.;Marquess,D. G.;McGrane, P. L.;Meng,W.;Natchus,M.G.;Shuker, A. J.; Sutton, J. C.; Taylor, R. E. J. Am. Chem. Soc. 1997, 119, 2757e2758.
111. Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sa-koh, H.; Nishimura, K.; Tani, Y.; Hasegawa,M.; Yamada, K.; Saitoh, K. Chem.dEur. J.1999, 5, 121e161.
112. Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama, H.;Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 12980e12981.
113. Denis, J.-N.; Greene, A. E.; Gu�enard, D.; Gu�eritte-Voegelein, F.; Mangatal, L.;Potier, P. A. J. Am. Chem. Soc. 1988, 110, 5917e5919.
114. Gu�enard, D.; Gu�eritte-Vogelein, F.; Potier, P. Acc. Chem. Res. 1993, 26, 160e167.115. Holton, R. A.; Biediger, R. J.; Boatman, P. D. In Taxol�: Science and Applications;
Suffness, M., Ed.; CRC: New York, NY, 1995; pp 97e121.116. Georg, G. I.; Boge, T. C.; Cheruvallath, Z. S.; Clowers, J. S.; Harriman, G. C. B.;
Hepperle, M.; Park, H. In Taxol�: Science and Applications; Suffness, M., Ed.;CRC: New York, NY, 1995; pp 317e375.
117. Ojima, I.; Slater, J. C.; Michaud, E.; Kuduk, S. D.; Bounaud, P.-Y.; Vrignaud, P.;Bissery,M.-C.; Veith, J.; Pera, P.; Bernacki, R. J. J. Med. Chem.1996, 39, 3889e3896.
118. Ojima, I.; Chen, J.; Sun, L.; Borella, C. P.; Wang, T.; Miller, M. L.; Lin, S.; Geng, X.;Kuznetsova, L.; Qu, C.; Gallager, D.; Zhao, X.; Zanardi, I.; Xia, S.; Horwitz, S. B.;Mallen-St. Clair, J.; Guerriero, J. L.; Bar-Sagi, D.; Veith, J. M.; Pera, P.; Bernacki,R. J. J. Med. Chem. 2008, 51, 3203e3221.
119. Ojima, I.; Das, M. J. Nat. Prod. 2009, 72, 554e565.120. Sun, L.; Geng, X.; Geney, R.; Li, Y.; Simmerling, C.; Li, Z.; Lauher, J. W.; Xia, S.;
Horwitz, S. B.; Veith, J. M.; Pera, P.; Bernacki, R. J.; Ojima, I. J. Org. Chem. 2008,73, 9584e9593.
121. Geng, X.; Miller, M.; Lin, S.; Ojima, I. Org. Lett. 2003, 5, 3733e3736.122. Geney, R.; Sun, L.; Pera, P.; Bernacki, R. J.; Xia, S.; Horwitz, S. B.; Simmerling, C.
L.; Ojima, I. Chem. Biol. 2005, 12, 339e348.123. Sun, L.; Simmerling, C.; Ojima, I. ChemMedChem 2009, 4, 719e731.124. Eggen, M. J.; Georg, G. I. Med. Res. Rev. 2002, 22, 85e101.125. Eggen, M.; Nair, S.; Georg, G. Org. Lett. 2001, 3, 1813e1815.
126. Vidya, R.; Eggen, M. J.; Nair, S. K.; Georg, G. I.; Himes, R. H. J. Org. Chem. 2003,68, 9687e9693.
127. Hughes, J.; Smith, T. W.; Kosterlitz, H. W.; Fothergill, L. A.; Morgan, B. A.;Morris, H. R. Nature 1975, 258, 577e579.
128. Gardner, B.; Nakanishi, H.; Kahn, M. Tetrahedron 1993, 49, 3433e3448.129. Michael, J. P. Nat. Prod. Rep. 2004, 21, 625e649.130. Cenci di Bello, I.; Fleet, G.; Namgoong, S. K.; Tadano, K.; Winchester, B. Bio-
chem. J. 1989, 259, 855e861.131. Olden, K.; Breton, P.; Grzegorzewski, K.; Yasuda, Y.; Gause, B. L.; Oladipa, A.;
Oredipe, A.; Newton, S. A.; White, S. L. Pharmacol. Ther. 1991, 50, 285e290.132. Alcaide, B.; Almendros, P.; Alonso, J. M.; Moustafa, F. A.; Torres, M. R. Synlett
2001, 1531e1534.133. Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Chem.dEur. J. 2003, 9,
3415e3426.134. Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem.dEur. J. 2002, 8, 3646e3652.135. Alcaide, B.; Aly, M.; Rodriguez, C.; Rodriguez-Vicente, A. J. Org. Chem. 2000, 65,
3453e3459.136. Banfi, L.; Guanti, G.; Rasparini, M. Eur. J. Org. Chem. 2003, 1319e1336.137. Van Brabandt, W.; Dejaegher, Y.; Van Landeghem, R.; De Kimpe, N. Org. Lett.
2006, 8, 1101e1104.138. Dejaegher, Y.; Mangelinckx, S.; De Kimpe, N. J. Org. Chem. 2002, 67,
2075e2081.139. Alcaide, B.; Almendros, P.; Cabrero, G.; Callejo, R.; Ruiz, M.; Arno, M.;
Domingo, L. Adv. Synth. Catal. 2010, 352, 1688e1700.140. Alcaide, B.; Almendros, P.; Cabrere, G.; Ruiz, M. P. Chem. Commun. 2008,
615e618.141. Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. Org. Lett. 2005, 7, 3981e3984.142. Mollet, K.; Catak, S.; Waroquier, M.; van Speybroeck, V.; D’hooghe, M.;
De Kimpe, N. J. Org. Chem. 2011, 76, 8361e8375.143. Van Brabandt, W.; Van Landeghem, R.; De Kimpe, N. Org. Lett. 2006, 8,
1105e1108.144. Mollet, K.; Broeckx, L.; D’hooghe, M.; De Kimpe, N. Heterocycles 2011, 84,
431e447.145. Cabell, L. A.; McMurray, J. S. Tetrahedron Lett. 2002, 43, 2491e2493.146. Alajarin, M.; Sanchez-Andrada, P. J. Org. Chem. 2001, 66, 8470e8477.147. Alajarin, M.; Vidal, A.; Sanchez-Andrada, P.; Tovar, F.; Ochoa, G. Org. Lett. 2000,
2, 965e968.148. Almendros, P.; Aragoncillo, C.; Cabrero, G.; Callejo, R.; Carrascosa, R.; Luna, A.;
del Campo, T. M.; Pardo, M. C.; Quiros, M. T.; Redondo, M. C.; Rodriguez-Ra-nera, C.; Rodriguez-Vicente, A.; Ruiz, M. P. Arkivoc 2010, 74e92.
149. Tiruvettipuram, K. T.; Fu, X.; Tann, C. H.; McAllister, T. L.; Chiu, J. S.; Colon, C.(Schering Corporation). U.S. Patent 6,207,822 B1, 2001.
150. Wu, G.; Wong, Y. S.; Chen, X.; Ding, Z. J. Org. Chem. 1999, 64, 3714e3718.151. Watt, J. M.; Gerdina, M. The Medicinal and Poisonous Plants of Southern and
Eastern Africa; E. & S. Livingstone: Edinburgh and London, UK, 1962.152. Cooney, M.; Ortiz, J.; Bukowski, R.; Remick, S. Curr. Oncol. Rep. 2005, 7, 90e95.153. Cragg, G.; Kingston, D.; Newman, D. Anticancer Agents from Natural Products;
CRC: Boca Raton, FL, 2005.154. Young, S. L.; Chaplin, D. J. Expert Opin. Investig. Drugs 2004, 13, 1171e1182.155. Neumann, I. D.; Landgraf, R. Advances in Vasopressin and Oxytocin: from Genes
to Behaviour to Disease; Elsevier: Oxford, 2008.156. Tribollet, E.; Barberis, C.; Jard, S.; Dubois-DAuphin, M.; Dreifuss, J. J. Brain Res.
1988, 442, 105e118.