poly carbonyls GM04 02 - Scripps Research · SS S O HO HO O HO O HO O O HO HO O HO O HO HO O HO HO...
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Poly(ß-carbonyl)s Q. Michaudel Baran Group Meeting 04/02/2011 Poly(β-carbonyl)s, intermediates in polyketides biosynthesis This group meeting will mainly focus on poly(β-carbonyl)s with unsubstituted methylenes at the α-position: 1 O O n enzymatic transformations enzymatic transformations OH OH n polyacetates (often macrocyclic) aromatic polyketides fatty acids enzymatic transformations Polyketides rapid overview: * name coined in 1907 by John Norman Collie (polyketenes hypothesis) J. Chem. Soc. 1907, 91, 1806. * correct biosynthetic pathway proposed by A. Birch in the 1950s ("head-to-tail" condensation of acetate units * first polyketide synthase (PKS) was isolated in the 1970s * secondary metabolites of microorganisms (bacteria, fungi, etc.) * 20 marketed drugs out of some 7000 characterized polyketide structures, "hit rate" of 0.3 % Science 2009, 325, 161. OH O 4 OH Me OH O 6-methylsalicylic acid = 14 C Aus. J. Chem. 1955, 8, 539 A few examples of polyketides : O Me OH HO Me Me Me O O Me Me O O OH O HO NMe 2 Me O MeO Me OH Me erythromycin A roflamycoin OH OH Me OH O O emodin O O HO HO OH O OH O O HO O OH OH R daeschol A JACS doi.org/10.1021/ja110932p R = H, dalesconol A R = OH, dalesconol B (synthesized by S.A. Snyder Angew. Chem., Int. Ed. 2010, 49, 5146) O O O O O O OH MeO OMe HO CO 2 Me β−rubromycin (revised structure) see Renata group meeting 2008 O O O Me Me Me OH OH OH Me OH OH OH OH OH OH Me
Transcript of poly carbonyls GM04 02 - Scripps Research · SS S O HO HO O HO O HO O O HO HO O HO O HO HO O HO HO...
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
Poly(β-carbonyl)s, intermediates in polyketides biosynthesis
This group meeting will mainly focus on poly(β-carbonyl)s with unsubstituted methylenes at the α-position:
1
O O
n
enzymatic
transformations
enzymatic transformations
OH OH
n
polyacetates (often macrocyclic)
aromatic polyketides
fatty acidsenzymatic transformations
Polyketides rapid overview:
* name coined in 1907 by John Norman Collie (polyketenes hypothesis) J. Chem. Soc. 1907, 91, 1806.* correct biosynthetic pathway proposed by A. Birch in the 1950s ("head-to-tail" condensation of acetate units
* first polyketide synthase (PKS) was isolated in the 1970s* secondary metabolites of microorganisms (bacteria, fungi, etc.)* 20 marketed drugs out of some 7000 characterized polyketide structures,"hit rate" of 0.3 % Science 2009, 325, 161.
OH
O4
OH
Me
OH
O
6-methylsalicylic acid
= 14C
Aus. J. Chem. 1955, 8, 539
A few examples of polyketides:
OMeOH
HO
Me
Me
Me
O
O
Me
MeO
O
OH
OHO
NMe2
Me
O
MeOMe
OHMe
erythromycin A
roflamycoin
OHOH
Me OH
O
Oemodin
O
O
HO
HO
OH
OOH
O
O
HO
O
OH
OH
R
daeschol AJACS doi.org/10.1021/ja110932p
R = H, dalesconol AR = OH, dalesconol B(synthesized by S.A. Snyder Angew. Chem., Int. Ed. 2010, 49, 5146)
O
O
O O
OO
OHMeO
OMe
HOCO2Me
β−rubromycin(revised structure) see Renata group meeting 2008
O
O O
Me
Me
Me
OH OH OH
MeOH
OH OH OH OH
OH
Me
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
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Biosynthesis of polyketides:
KS ACP
CO2KS ACP
CoA-SH
KS ACP
KS ACP
CoA-SH
SHSH
SO
CoAS
O
CoA
OOH
SO
SO
OO
HS
O
O
SH
SO
O
SH
Cycle repeated n times
KSS
OO
n
KS: keto-synthase ACP: acyl carrier proteinKR: keto-reductaseDH: dehydrataseER: enoyl-reductase
KSS
O
R
S
OO
R ACP S
OOH
R ACP S
O
R ACP S
O
R ACP
KR ERDH
condensation
OO
R SX
O
npoly(β-carbonyl)s
OO
R
OH
SX
O
reduced poly(β-carbonyl)sR OH
O
nfatty acids
acyl transfer
For a review, see: D. A. Hopwood, Chem. Rev. 1997, 97, 2465.P. M. Dewick, Medicinal Natural Products, 2002, John Wiley & Sons, Ltd.
Polyketide bioengineering:
Two general methods with PKSs:
* genetic modifications of enzymatic complexes: lead to "unnatural products" but often decrease productivity.
* recombination of intact modules from the repertoire of PKSs.
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
3
OH O
SNAc
M3 + TE
M2 (or M5 or M6) + TE
O
O
O
OH
O
O
methylmalonyl-CoA
methylmalonyl-CoA
Polyketides bioengineering:
LD M1 M2 M3 M4 M5 M6 TE
SO
SO
HO
LD: loading domainM: moduleTE: thioesterase
S S S S SO
HO
HO
O
HO
O
HO
O
O
HO
HO
O
HO
O
HO
HO
O
HO
HO
HO
O
OH
O
O
O
OH
OH
aglycone of erythromycin
Khosla, Science 1999, 284, 482
O
Me
OH
O
O
OHO
HO
OH O
HO
TW93c
O
OHO
HO
OH O
HO
TW93d
MeO
OH
OH
Ectopic expression of polyketide synthase, the minimal whiE (Moore et al.)
O O
Me
OH
HO
HO
HO OH
HO
O
OHOTW93h Proc. Natl. Acad. Sci.
U.S.A. 1999, 96, 3622
HO
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
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O
OH
O
S-EnCacyl carrier protein EncC
ligase EncN
ATP
HO SCoA
O O
HO S-EnC
O O7 eq. 7 eq.
ketosynthaseEncA-EncB,
ketoreductase EncD,transacylase FabD
NADPH
OH
O O OO
OO O
Ph
Enc-S
O
HO O
HO
OHO
Ph
O
HO O
OHOH
Ph
" favorskiiase"flavoprotein
EncM
wailupemycin G
wailupemycin F
COS-EnCO
HO
OO
PhOO
O
O
Favorskii-type rearrangement
COS-EnCO
HO
O
O
O
O
O
OPh
OH
HO
O
O
O
OH
OH
OPh
OH
O
H
MeO
O
O
O
OH
OH
OPh
OH
O
H
methyltransferaseEncK
SAM
MeO
O
O
O
OH
OH
OPh
OH
O
H
HO
ferredoxin,ferredoxin-NADP+
reductaseEncRSAM
NADP+
enterocin
5
5
Moore et al. Nat. Chem. Biol. 2007, 3, 557
See also Gulder group meeting 2007on biocatalysis.
~ 25% overall yield;formation of 10 C–C, 5 C–O,
and 7 stereocenters in one–pot
Total synthesis through in vitro reconstitution of complete biosynthetic pathways:
See also Harris' biosynthesis of griseofulvin
OO
OOMe
MeO
MeO
MeCl
J. Am. Chem. Soc. 1976, 98, 5380
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
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Chemistry of poly(β-carbonyl)s: the 'cyclase phase':
Poly(β–carbonyl)s are highly reactive (methylenes have a pKa around 13–14) and cyclize easily due to concomitant aromatization: for a review, see Harris et al., Tetrahedron 1977, 33, 2159.
Me Me
O O Me
OH
Me Me
O
NaOH
reflux
EtO OEt
O O
OH
HO OH
base
Ph
ONa ONa
Ph
O O
SH
O1. COS, Et2O
2. H+, H2O OPh O
OH
spont.
Me
O O
Me
O H+
or strong base
OH
HO Me
Takeshita, Tetrahedron Lett. 1977, 19, 1657.
Harris, Tetrahedron 1969, 25, 2687.
R OH
O O O O
O
O
ROH
O
O
HO
OH
OH
O
R
weak acid (pH 5)
OH– H+
R=Ph or Me R=Ph or Me
R=Ph or Me
R OH
O O O O
R=Ph or Meresorcyclic acid
HF (anhyd.)
OPh OH
O
O
O Me
O
–CO2
HCl or H2SO4
OR OH
O
O
MeOH R=Ph or Me
Ac2O
O O
OH
R
OR=Ph or Me
1. COS
2. H+
KOH
MeOH HO
OH
OMe
O
R
KOH
H2O HO
OH
OMe
O
R HO
OH
R
O
OHmajor
R=Ph or Me
R=Ph or Me
R=Ph
R=Ph or Me
R=Ph or Me
R OH
O O O O
R OH
O O O O
R OH
O O O O
R
ONa ONa ONa
R=Ph or Me
R OMe
O O O O
R=Ph or Me
35%
Ph
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
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OH
O O O O
HO
OH
OH
O
MeMe
Me
HO
OH
OH
O
MeMe
OH
O O O O
Me
O O
Me
O LDA
LDA
CO 2
CO2
1:1 ratio
Me Me
O O O O
HO
OH
Me
O
Me
spontaneous
Me Ph
O O O O
HO
OH
Ph
O
Me
base
HO
OH
Me
O
Ph62% 7%
Ph
O O O O
OH
O
NaHCO3 or weak acid OH
OHHO
Ph O O
KOH
HO
OH O
OH
OPh
67%
19
C4/C9
C3/C8 +
(C4/C9)
OH
OHHO
Ph O O
minor
OHO
Ph
O
OH
Ph
O O O O
OH
O
91 O O
OH
Ph
O OAc2O
Ph
O O O O
Ph
O
HO
OH O
Ph
OPh
Ph
OHHO
Ph O Osilica gel
KOH
91
C4/C9
C3/C8
Ph
O O O O O
Ph
O
111
Ph
HO
OH O Osilica gel
Ph
OPh
HO
OH OH O
Ph
not detected
C3/C8 C1/C10
HO
OH OPh
KOH
PhHO
OH O O O
PhO O
Ph70%
minorC2/C7 +C1/C6
Ph
HO
OH Ph O
OH PhHO
O
HOPh
O
O
K2CO3 or CF3CO2H C1/C10
348
34 8
1
10
1
10
3 872
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
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Me
ONa ONa ONa
Me
O O O O
MeOO Me OMe
OOO
OO OO
O
O
Me
O
Me
HO
H+, 87%
O
Me
Me
O
O
H2SO4 conc. 80%
iPr2NH, PhH,
reflux, 80%
Me
HO
OH O OO
MeO
OAc2O pyr.Me
AcO
OAc O OO
MeO
O
1.HCl/Me2CO 1:40, rt, 55%
1.
2. H+
HO
OH OH O
Me
Me
30–45%
barakol6-hydroxymusizin
2. 4M KOHrt, 70%
Starting with a formal heptaketone, see also synthesis of:
O
O
OH OH
HO Me
emodin
O
O
Me
Me
OH
HO
eleutherinol
J. Am. Chem. Soc. 1975, 97, 3270
OCl OMeNHOMe
NN
O O
MeMe
MeO OMeNH
quant.quant.
N
NN
O O
MeMe
MeO OMeN
O
O O O
O
OtBu
OOtBu
OLi OLi
OtBu
CO2tBu
CO2tBu
OH OH
67%
Tip: tBu ester is less likelyto undergo self-condensation than Me ester (27% yield)
1. Me2SO4, K2CO32. TFA3. CH3COCl92% (3 steps)
OMe OMe O
O
O
OLi
OtBu
then CDI30%
OMe OMe O
O
OtBu
O
NOOLiLi
70%
OMe OMe OH
OtBuO
NO OHOH OH OH
OH
OH
NH2
OHI/P/AcOH
reflux74%
pretetramide
Synthesis of pretetramides, biosynthetic precursors of tetracycline and 6-demethyltetracycline (Harris et al.): J. Am. Chem. Soc. 1988, 110, 6172
J. Am. Chem. Soc. 1988, 110, 6180J. Am. Chem. Soc. 1988, 110, 6186
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
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CO2Me
CO2Me
OMe OLi OLi
OMe(7 eq)
OMe O
OMe
O O
O
OMe
O O30%
OMe OH OH O
OMe
OMe
O
OMe OMe OMe O
OMe
ONH2
O1. MeI, K2CO3
80%
2. OLi
NTMS
Li
Tip #2: made with 2 eq. of LDA, soluble in THF, thermally stable,more nucleophilic than bis-TMS monoanion and reacts at the C-position instead of the N-position.J. Org. Chem. 1984, 49, 2015.
OLi
NTMS
Lipretetramide
11% overall yield
51% (+17% SM)HBr, HOAc86%
OMe
O
OLDA (2 eq.)
then ClCO2Methen MeI
70% (one pot)
OMe
MeOO
O
CO2MeMe
OLi OLi
OtBu
OMe O OH O
OtBu
OtBu
O
57%
HO Me
1. TFA, Et3SiH
2. Me2SO4, K2CO366% (2 steps)
OMe OMe OMe O
OMe
OMe
O
Me
1. KOH, MeOH 85%
2. NaH thenOLi
NTMS
Li
3. CH2N2 25% (2 steps)4. HBr, HOAc, 50%
OH OH OH
OH
OH
NH2
O
6-methylpretetramideMe
See also bio-inspired synthesis of alternariol and lichexanthone
and bio-inspired synthesis of eleutherinJ. Am. Chem. Soc. 1977, 99, 1631
Tetrahedron Lett. 1977, 24, 2069
Summary of the 'cyclase phase':
* Regio- and chemoselective cyclizations conditions of poly(β-carbonyl)s in the literature are scarce and all of them involve simple reagents
* The main issue is the synthesis of long poly(β-carbonyl) chains due to their high instability in acidic, basic or oxidative conditions.
* Poly(β-carbonyl)s with terminal ketones are more eager to cyclize than esters or carboxylic acids, as well as those with terminal methyl groups than terminal phenyl groups.
* Some total synthesis of natural products use partially protected poly(β-carbonyl)s, but fully deprotected poly(β-carbonyl)s are never isolated.
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
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Ph Ph
O O O O O O
Ph OEt
ONa O
n=2,32
OLi OLi
n=2,3
1. n-BuLi2. H+
Ph Ph
O O O O O O
Ph
OLi OLi OLi OLi OEt
ONa O
Ph1.
2. additional base3. H+
19%
n=2, 15%n=3, 3%
Chemistry of poly(β-carbonyl)s: the 'elongation phase':
J. Am. Chem. Soc. 1973, 95, 6865
R
OLi OLi
N
OMeO
MeR
OLi O
Me
O N MeOLi
Me
H+
R
O O
Me
O
nnnn=1-3
R=Ph n=0 0% n=1 86% (56% isolated yield) n=2, 80% (75%) n=3, 88% (55%)R=Me n=2 96% (60%)
Direct condensation of poly(β-carbonyl)s (Harris and coworkers):
Tetrahedron Lett. 1983, 24, 1851
Me Me
O O O OBirch, J. Chem. Soc. 1963, 2209.
OMe
Me
made in 15 steps (14 longest linear)!!
Li, NH3
86% OMe
Me
O3 then H2, Pd/C42%
OMe
O O O O O
Me
O
Aromatic compounds as synthons for 1,3-dicarbonyl derivatives:For a review, see Chem. Soc. Rev., 2009, 38, 3082
Me
Me
Birch
reduction
Me
Me
ozonolysis
* Yields drop with increasing chain length.
* Octaketone is the longest chain reported.
J. Org. Chem., 1985, 50, 1319
Me OH
CO2HO
O
Me1. Li, NH3, 85%
2. Ac2O, Et3N92%
1. O3then Me2S60%O
O
O
O
O
O
Me
Tetrahedron Lett. 1993, 34, 4957.
made in 7 steps
"Comparison of the UV spectrum of [this molecule] with the spectra of other polyketide structures (Table I) was especially informative."
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
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MeO R
O
1: R=CH2SO2PH2: R=OCOtBU
1
1. NaH, 2
2. Zn, 64%
MeO
O O
OMe
J. Am. Chem. Soc., 1993, 115, 3360.
1. RuCI2[(R)-BINAP]Et3N 10%, H2 100 atm, 59%2.(EtO)2CHCH3, H+, 90%3. Li/NH3; O3, 60%
O O
MeO
O O O O
OMe
Me
O O O O O O
Me Me Me MeMe Me
1. RuCI2[(R)-BINAP]Et3N 10%, H2 100 atm2.(EtO)2C(CH3)2, H+
3. DIBAL-H, vinyl Grignard4. EtO)2C(CH3)2, H+
30% (4 steps)
(+)-mycoticin A.
MeOO OOH
OMe
racemic made in 5 steps fromO Br and Ar Li
1. TIPSOTf, Et3N
2. Li/NH33. O3, then PPh3 64% (3 steps)
O O
MeO
OH OTIPSOH O O
OMe
O OTBS
MeO
OTBSOTIPS OTBS OTBS O
OMe
1. MeOBEt2, NaBH4
2. TBSOTf, Et3N90% (2 steps)
J. Am. Chem. Soc., 1992, 114, 1090.
R1
R2
+
R1
R2
R1
R2
+
R1
Δ CoBr2(diimine)
Zn, Fe, ZnI2, rt
* A major drawback: only few substituents can tolerated Birch reduction and ozonolysis conditions. An alternative to avoid Birch reduction is to use [4+2] or 1,4-hydrovinylation to make the polyene.
R2
In that case, R can be an aromatic group, that allows to make polyketones with a terminal aromatic group with the Birch/ozonolysis sequence.
Me
Me2 +
CoBr2(dppe)
Zn, ZnI2, rt90%
Me
Me
Me
Me
Me
Me
O3 then Me2S95%
O
OMe
OMe
OSynthesis, 2002, 609.
Isoxazole as synthons for 1,3-dicarbonyl derivatives:
N O
R1 R2 R1 R2
R1 R2
NH2 O
O O
HCl/H2O
Et3O+BF4-
* H2, Raney Ni* Mo(CO)6, H2O, Δ* Na/NH3, tBuOH (1eq)* SmI2, MeOH
NaOH
See also Mitsos group meeting 2004 on isoxazoles
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
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An oxidative ring opening has also been reported recently:
N O
R1 R3
R2
Me3OBF4
DCM, rt, 10h
N O
R1 R3
R2
Meaq. NaOCl
MeCN, 0°C, 10 min
N O
R1 R3
R2
Me
O
BF4 BF4
R1
O O
R3
R2 OH
R1 and R3 = Me, Ph...R2 = H, Me, CO2Et...
MeO2C
ON
ON
ON
O
H2, Raney Ni
MeOH, pH 7
MeO2C
ONH2
OH2N
OH2N
O
NH
NN
N
Ni+
ClO4–
Ni(II) octamethylcorphin
Made in 5 steps from known starting materials
Isoxazole opening in total synthesis:
J. Am. Chem. Soc. 1975, 97, 5940
Other notable total syntheses:
garuganin IIIJ. Org. Chem. 1993, 58, 6725geiparvarinTetrahedron Lett. 1985, 26, 5319vitamin B12J. Am. Chem. Soc. 1986, 108, 1039tetracyclineJ. Am. Chem. Soc. 2005, 127, 8292
Polyisoxazoles as hidden poly(β-carbonyl)s:
Me
NOH NCS, DMF
or Cl2 Me
NOH
Cl
OMe
ET3N, 70%
N O
Me OMe
HCl aq. refluxthen HONH3Cl70%
N O
Me H
NOH
H
N O
Me
ON
N O
NO
Me
J. Heterocyclic Chem. 1977, 14, 667
* Bis-, tris- and tetraisoxazoles have been synthesized by Aurrichio et al.
* Cleavage of bisisoxazoles have been reported by the same team:
N OPh
NOMe
H2
Ph Me
O ONH2 NH2 H+
Ph Me
O OOH OH
60%(2 steps)
Ph
OOH
HO Me
Me
OOH
HO Ph8 : 2
+
N OPh
NOMe
controlledhydrogenation
then H+
N OPh
O
Me
OH
H2, Raney Ni then H+
Me
OOH
HO Ph60% (4 steps)
Raney Ni
Tetrahedron Lett. 1974, 33, 2793
Angew. Chem. Int. Ed. 2008, 47, 7446
Poly(ß-carbonyl)sQ. Michaudel Baran Group Meeting04/02/2011
12
To conclude, a biomimetic synthesis of (–)–zearalenone: Tetrahedron 2010, 6331
O
MeOH
HO
O
O
biomimetic key disconnection"classic" key disconnections
CO2H
1) CDI, THF, rt2) EtOAc, LDATHF, –78°C to 0°C
3) HOCH2CH2OH, p-TsOH, HC(OEt)3, PhMe, rt 70%
CO2Et
O
O
580°C,0.18 mbar
FVP
OEtOO
O
1) KOH, EtOH, 45°C,2) EDC HCl, CH2Cl2, rt
NH
NN
70%
NOO
O
N N
LiHMDS, ZnCl2,THF, –78°C to 0°C 63%
O O
Me O
Me Me
OOO OO
O
Me Me
Me
OH OO
+
Grubbs II (10 mol%)DCM, 40°C
75%, > 20:1 E/ZMe
OH OO OOO OO
O
Me Me
1.PhMe110°C
Me
OH OO OOO O
Me
OO
OO
O
OO O
Me
O O
O
O
O
O
2. p-TsOH, H2O,Me2CO
3. Cs2CO3,MeOH4. AcOHthen aq. HCl
O
MeOH
HO
O
O
46% over 4 steps!
(–)–zearalenone
O
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