Axially Chiral Allenes: Not a Laboratory Curiosity Any More!Predeus...Camphor-Derived Auxiliary for...
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Axially Chiral Allenes: Not a Laboratory Curiosity Any More! Alexander V. Predeus Michigan State University, 2004
Transcript of Axially Chiral Allenes: Not a Laboratory Curiosity Any More!Predeus...Camphor-Derived Auxiliary for...
Axially Chiral Allenes: Not aLaboratory Curiosity Any More!
Alexander V. PredeusMichigan State University, 2004
Chiral Allenes: General Information
a
•ad
a
•ed
a
•ab
b b b
H3C
•H
CH3
H
asymmetric asymmetric dissymmetric
propadiene-2,3
CH3
•H
H3CH
FW = 68.12 (C5H8) bp = 48oC [α]D +,-80o
Axially Chiral Allenes: Nomenclature
n-C4H9
•CH3
HHOOC
CH3
COOH
HCH3 > H > COOH > n-C4H9
H3C
•CH3
HH
CH3
H
H
CH3
CH3 > H > CH3 > H
aS (P)
aR (M)
n-C4H9
Some Facts About Chiral Allenes
• The rotation barrier to stereoisomerization of chiral allenes amounts to195 kJ/mol for 1,3-dialkylallenes and to > 125 kJ/mol for 1,3-diarylallenes, while the threshold for isolation of stereoisomers at 20oCis 83 kJ/mol.
• Higher cumulenes - pentatetraenes and heptahexaenes - have lowerrotation barrier. Thus, only few enantioenriched pentatetraenes and noheptahexaenes are known.
• Cumulated double bonds in allenes are strained. Upon undergoing anyaddition reaction it experiences a relief in strain of about 40 kJ/mol.
(C)n
R1
R2
R1
R2
n = 0,2,4,6...flat moleculeZ/E isomerism
n = 1,3,5,7...chiral moleculeoptical isomerism
Elsevier, C.J. In Houben-Weyl, series Methods of Organic Chemistry; Helmchen, G., Hoffmann, R.W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1995; Vol. E21a, p 537
Chiral Allenes: Historical Insight• 1875, Jacob van't Hoff - Prediction of the existence of two
enantiomeric forms for an asymmetrically substituted allene• 1935, Maitland and Mills - First experimental confirmation of van't Hoff's
hypothesis. Formation of slightly dextrorotatory sample of allene bydehydration of allylic alcohol with (+)-camphor-10-sulfonic acid.
• 1952, Celmer and Solomons - The discovery of mycomycin, the firstoptically active allene found in nature.
HO•
(+)-camphor-10-sulfonic acid
[α]D +437o (benzene),after several
crystallizations
Rossi, R; Diversi, P. Synthesis, 1973, 25
Some Naturally Occurring Chiral Allenes
O •
HOHO OH
• COOH
HO
H3C
neoxanthin
(+)-odyssic acidOEt
OBr
H •H
Br
H
(-)-isolaurallene
O
O
O (CH2)14CH3
O
O
O
O
CO
(CH2)4CH3
•H H
HOOC
(-)-mycomycin
Rossi, R; Diversi, P. Synthesis, 1973, 25; Hoffmann-Roder, A.; Krause, N.; Angew. Chem. Int. Ed. 2002, 41, No. 16, 2933 - 2935
Ring Opening of Cyclopropanes
H COOH
Ph HH Ph
1. SOCl22. NaN3
ΔH NCO
Ph HH Ph
1. NH32. HNO2
H N
Ph HH Ph
NH2
NO
OH
•PhH
PhLiOEt 41% ee
90% ee after 3 crystallizations
BrBrH
H CH3LiEt2O
H•
H89% yield, 88% ee
H
Ph HH Ph
N3
O
Walbrick, J.M.; Wilson, J.W., Jr.; Jones, W. M. J. Am. Chem. Soc. 1968, 90, 2895Cope, A.C.; Moore, W.R.; Bach, R.D.; Winkler, H.J.S. J. Am. Chem. Soc. 1970, 92, 1243
Synthesis of Chiral Allenes: [3,3]-Rearrangements
HO
R2 R1O
R2R1
R3
R4H
•R2R1
H
R3 R4CHO
CHOR4R3
H+
[3,3]; Δ
HO
C8H17HH3C C(OEt)3
C2H5COOH
H•C8H17
HCOOC2H5
+110oC
O
N
R1
OR
O N
O O
•
HR2
R3
RR1
OH
•
HR2
R3
R1
[H]R2R3
HO
Jones, E.R.H.; Loder, L.D.; Whiting, M.C. Proc. Chem. Soc. 1960, 180;Mori, K.; Nukada, T.; Ebata, T. Tetrahedron 1981, 37, 1343;Frederick, M.O.; Hsung, R.P.; Lambeth, R.H.; Mulder, J.A.; Tracey, M.R. Org. Lett. 2003, 5, 2663
Synthesis of Chiral Allenes: [2,3]-Rearrangements
O
OH
O
OPhS
O
•S(O)Ph
H
PhSCl, Et3N
CH2Cl2,-70oC
[2,3]-40oC
94% yield99% ee after crystallization
•HH3C
BuO
SnBu3
Bu
OH
H CH3
BuLi/THF 71%, 93% ee
Smith, G.; Stirling, C.J.M. J. Chem. Soc. C 1971, 1530Marshall, J.A.; Robinson, E.D.; Zapata, A. J. Org. Chem. 1989, 54, 5854
Copper-Mediated SN2’ Substitution
R3Y
R2R1
R2
•R4
R3-MY
R1R4M, anti
R1, R2, R3 - alkyl, aryl, HR4M - mixed lithium and magnesium cupratesR4 - Me, Et, i-Pr, t-Bu, Cy, Ph, allylY - PhCOO, Ac, OSO2R, OSOR, Br
70 - 98% yield> 95% chirality
transfer
R3O
HPh
H•
EtH
Ph[EtCuBr]-[MgBr]+
R3Ac
HPh
H•
PhH
75%, 99% ee
PhPhCu
S(O)Me81%
Elsevier, C.J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726
Halogen Effect in Copper-Mediated Substitution
H3CO
HBu
OCH3
M Bu
H
M
H Bu
OCH3
H
H
Bu
Bu
BuMgX / CuBrH
•H
BuBu
Bu•
HBu
H
X = I
X = Cl
95%, 96% ee
95%, 76% ee
anti
syn
Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J.F. J. Am. Chem. Soc. 1990, 112, 8042 - 8047
Two Possible Mechanisms of Copper-MediatedSubstitution
X
H R'H
CuLi
R R
H•
HR'
CuIII
RR
H•
HR'
R
X
H R'H
CuR Cu R
XHR'
H•
HR'
R
when X is a good leaving group, as OSO2R, OAc, etc.
when X is poor leaving group, as OMe
Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J.F. J. Am. Chem. Soc. 1990, 112, 8042 - 8047
Studies on the Nature of Halogen Effect
OMe
BuH
MeO BuH
CuBu
MeO BuH
LiBuBuCu 1. I2, - CuI
2. BuLi
MeO BuH
LiBu
MeO BuH
LiBu
MgI2
MgCl2
MeO BuH
MgIBu
MgI2
OHBu
MgClBuMg
Cl
Cl
Me H•
HBu
Bu
Bu• Bu
H
H(S), ee 65%
(R), ee 35%
anti
syn
Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J.F. J. Am. Chem. Soc. 1990, 112, 8042 - 8047
Synthesis of Chiral Allenes Using Organozinc Reagents
R1
SR2O
R3CuTHF
R3
R1
Cu
S(O)R2
Bu2Zn, LiBrthen
R4II
R3
R1 S(O)R2
R4ZnBu
R1
•R3 R4RT
SO
Tol
BuCuTHF
Bu
H
Cu
S
BuII
TolO
1.
2.Bu2Zn, 2eq MgBr2
Bu
H STol
O
ZnBuBu
Bu
H STol
O
ZnBuBu
•BuBusyn
elimination
Varghese, J.P.; Zouev, I.; Aufauvre, L.; Knochel, P.; Marek, I. Eur. J. Org. Chem. 2002, 4151 - 4158
Approach based on Mitsunobu reaction
R1
R2
H OH
R1
R2
N HH2NSO2Ar
R2•
HR1
HArSO2NHNH2Ph3P, DEAD
-15oCAr = o-C6H4NO2
RT
Substrate Product Yield, %
Me2N CH3
H OH H•
HCH3
Me2N83
TMSOTBS
H OH H•TMS
HOTBS 91
TMSOH
H•TMS
HH 53 (88)
NC(H2C)3
H OH
OO
H3C CH3O
O
H3C CH3
•
NC(H2C)3
H
H
70
Myers, A.G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-4493
First successful catalytic synthesis of chiral allene
BrR NuH
Pd/(R)-binap (10 mol %)dba (2 eq to Pd)
base, 20oC•
R
Nu+
R = Ph, ferrocenyl, t-Bu, n-C8H17
Nu = C(NHAc)(COOEt)2, CMe(COOMe)2
PPh2PPh2
(R)-binap52 - 89% ee, 34-98% yield
base - CsOt-Bu
Osagawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 2089 - 2090
Scheme of Suggested Mechanism of Catalytic Reaction
Pd0(binap)
BrR
R PdBr
P P
R PdP P
PdP P
RBr
BrNu
R• H
H
Nu
R•
H
HNu
P P = binap
Osagawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 2089 - 2090
Other Catalytic Syntheses of Chiral Allenes
Br
NuH
Pd/(R)-segphos (10 mol %)
•
Nu
+
SiMe3
Nu
MeO HBu
t-BuCH(OMe)2TiCl4
O
R
ArTi(O-iPr)4Li
ClSiMe3+
[RhCl(C2H4)2]2 (R)-segphos
OSiMe3
•
R Ar
O
O
O
O
PPh2PPh2
(R)-segphos
Me3Si
87% eeaxially chiral
74%eecentrally chiral
up to 93% ee
R = n-Bu, Cy, 4-MeOC6H4Ar = Ph, 4-FC6H4, 4-MeOC6H4
Osagawara, M.; Ueyama, K.; Nagano, T.; Mizuhata, Y.; Hayashi, T. Org. Lett. 2002, 123, 2089 - 2090; Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2003, 123, 2089 - 2090
Nazarov Cyclization of Allenyl Ketones
•
TMS
OOMeO
H
(H2C)4
OEtn-C6H13
O
OEtn-C6H13
HO
TMS
MeO
O
OEtn-C6H13
HO
TMS
H
H
O
n-C6H13
HO
HCOOEt
H+loss ofMeOCH2
+
CCl3COOH
Hu, H.; Smith, D.; Cramer, R.E.; Tius, M.A. J. Am. Chem. Soc. 1999, 121, 9895-9896
Proposed Mechanism for Allenyl Ketone Cyclization
O H
C
R3
HO OMeR1
R2
O H
C
R3
HO OMeR1
R2
OHOR1
R2 R3H
H
OHOR1
H H
R3
R2
favored
disfavored
Hu, H.; Smith, D.; Cramer, R.E.; Tius, M.A. J. Am. Chem. Soc. 1999, 121, 9895-9896
Chiral Modification of Allene Nazarov Reaction
R
OMOM
•
R
OMOM
•
R
OMOMHOOC
•R OMOM
NO
OBuLi, THF, -78oC, 2h
BuLi, THF, -78oC, 30 min
then CO2(s)
Et3N, PPh3, CBr4
morpholine, CH2Cl2
•R OMOM
NO
O
H
OH
R
HO
MeH OTBS
OR
H
BzO
MeH OTBS
R = n-Bu or t-BuMOM = MeOCH2
racemate
(+) afterseparation
Li OTBS
Me1.PhCOCl, Et3N,CH2Cl22.sunshine,
PhH
chirality transfer:84% for n-Bu>95% for t-Bu
Harrington, P.E.; Tius, M.A. Org. Lett. 2000, Vol. 2, No. 16, 2447-2450
Camphor-Derived Auxiliary for AsymmetricCyclopentannelation
OO
• LiH
NO
OR1
R2
OR2
HOR1
92-96% eeR1, R2 - aryl,alkyl, bromine
+
OO
DIBAL
OHO
CH2Br
+Bu4HSO4
PhMe/H2O NaOH OO
1.BuLi, 2eqTHF, 2h2.t-BuOH OO
• HH
Harrington, P.E.; Murai, T.; Chu, C.; Tius, M.A. J. Am. Chem. Soc. 2002, 124, 10091-10100
Preparation of Optically Active Allenylsilane
O O
CHO
Ph
O O
Ph
SiMe3
TBSO OH
SiMe3
H
•
SiMe3H
HO
1.N2CHP(O)(OMe)2 1.H+/MeOH2.TBSCl
1.ArSO2N2H3Ph3P, DEAD
2.HF/MeCN/H2O
t-BuOK2.BuLi, TMSCl
Shepard, M.S.; Carreira, E.M. J. Am. Chem. Soc. 1997, 119, 2597 - 2605
Asymmetric Photocycloaddition with anOptically Active Allenylsilane
O •
SiMe3H
X
OH
X
SiMe3 OH
X
light
OH
X
Y
O
HX = O, NBoc85-92% ee
Y = O, S89-100%ee
F-
[2+2]
Shepard, M.S.; Carreira, E.M. J. Am. Chem. Soc. 1997, 119, 2597 - 2605
Ti(II)-mediated Asymmetric Allenyne Cyclization
•* R1
R2
Ti(Oi-Pr)2
•* R1
R2
Ti(Oi-Pr)2
*Ti(Oi-Pr)2
R1
R2
*Ti(Oi-Pr)2
R2
R1
a ba b
• SiMe2Ph
SiMe3
PhMe2Si
SiMe3
Ti(Oi-Pr)2
PhMe2Si
SiMe3
DD
Ti(Oi-Pr)2 D+
Urabe, H.; Takeda, T.; Hideura, D.; Sato, F. J. Am. Chem. Soc. 1997, 119, 11295-11305
Cyclization of 1,2-Dien-7-ynes
• SiMe2Ph
SiMe3
PhMe2Si
SiMe3
Ti(Oi-Pr)2
PhMe2Si
SiMe3
Ti(Oi-Pr)2 H+
HHH
• H
SiMe3
Me3Si
SiMe3
SiMe3
Ti(Oi-Pr)2
H+
SiMe3H
then CO Ti(Oi-Pr)2O
Me3Si
SiMe3
H Ti(Oi-Pr)2O O
HSiMe3
Urabe, H.; Takeda, T.; Hideura, D.; Sato, F. J. Am. Chem. Soc. 1997, 119, 11295-11305
Cyclization of 1,2-Dien-6-ynes
•H
Ti
SiMe3
H
C5H11
•C5H11
SiMe3
H
H
R2R1 XH
SiMe3
C5H11
Ti(Oi-Pr)2
C5H11
SiMe3
SiMe3
C5H11
Ti(Oi-Pr)2
H
H
SiMe3
C5H11
Ti(Oi-Pr)2
H
H
OR2R1 N
PrPh
or
Ti(Oi-Pr)21.
2. R1R2C=XR1 = H,R2 = C8H17,X = O, 80%ee R1 = Me,R2 = Me,X = O, 80% eeR1 = Ph,R2 = H,X = NPr, 81% ee
< 83% ee
Urabe, H.; Takeda, T.; Hideura, D.; Sato, F. J. Am. Chem. Soc. 1997, 119, 11295-11305
Allenic Pauson-Khand Type Cycloaddition
C8H17
O
C8H17
HHO
• HC8H17
O
SiMe3
C8H17
H
(S)-BINAL-H91%, 95% ee
C8H17
HMsOMsCl, NEt3
SiMe3
Cp2ZrCl2, BuLiTHF, CO (20 psi)2h; 39%, 85% ee
(CH2)3MgClMe3Si
LiBr, CuBr, 90% (2 steps)95% ee
• HDPS
O
H
HDPS
O
H
HDPS
+Mo(CO)6DMSO
toluene, 95oC 80%, E/Z 8 : 1
DPS = Me2PhSi
TMS
95% ee 63% ee
Brummond, K.M.; Kerekes, A.D.; Wan, H. J. Org. Chem. 2002, 67, 5156-5163
The Use of Chiral Allenes as Ligands for Catalysis
Sato, I.; Matsueda, Y.; Kadowaki, K.; Yonekubo, S.; Shibata, T.; Soai, K. Helv. Chim. Acta, 2002, 85, 3383 - 3387.
N
NR
CHO
+
(i-Pr)2Zn
N
NR
N
NR
OH
OH
(R), 97% ee
(S), 98% ee
H•
HPh
Ph
H•
PhH
Ph
CyMe
CyMe
portionwise additionaldehyde and (i-Pr)2Zn
portionwise additionaldehyde and (i-Pr)2Zn
(S)
(R)
Synthesis of (-)-Malyngolide Using Chiral Allene
CHO
OBnO
Me
CH2OBn
O• n-C9H19
H
CO2HMe OBn
OO n-C9H19
Me
OBn OO n-C9H19
Me
OBn
10% cat.EtCOBr
i-Pr2NEt,CH2Cl2, -50oC, 85%
n-C9H19MgBr10% CuBr, THF
-78oC; 92%
10% AgNO35% i-Pr2NEt
80oC, CH3CN80%
H2, Pd/C [α]D -12.4o
(lit. -13.0o)
94% ee91:9 cis:trans
NN NAl
Me
Bn
F3CO2S SO2CF3
i-Pr i-PrCatalyst =
87%
(-)-malyngolidenaturally occuringantibiotic94% ee, 100% de54% overall yield
Wan, Z.; Nelson, S.G. J. Am. Chem. Soc. 2000, 122, 10470-10471
Chiral Allenic Stannanes: Preparation
Me
OR
OMsR MeH
Bu3Sn•
HMe
R1. LiAlH4Chirald
2.MsCl, Et3N
Bu3SnLi,CuBr2*SMe2
Bu3Sn•
HMe
C7H15
C7H15
Me
OH
i-PrCHO, BF3*Et2O> 99% syn
Chirald akaDarvon alcohol =
PhH2C H
HO CH2NMe2Ph Me
Marshall, J.A.; Wang, X.-j.; J. Org. Chem. 1991, 56, 3211
Chiral Allenic Stannanes: Preparation of FourPossible Naturally Occurring Chiral Triads
Bu3Sn•
HMe
Me
OH
AcO
MeOBn
OAcMe
OH
MeOBn
OAcMe
OH
MeOBn
OAcMe
OH
MeOBn
OAc
OHCOBn
Me
BF3*Et2O(Felkin - Ahn)
OBnMe
OHC
OBnMe
OHC
OBnMe
OHC
MgBr2*Et2O(chelation)
SnCl4(chelation)
SnCl4(Felkin - Ahn)
(S)
(R)
(R)
(R)
(R)
Marshall, J.A.; Perkins, J.F.; Wolf, M.A. J. Org. Chem. 1995, 60, 5556
Mechanism for syn,syn- and syn,anti- ProductsFormation
O
HC
MeH
SnBu3R
Me
HBnOH2C
BF3
Me
OH
MeOBn
OAc
O
HC
MeH
SnBu3R
Me
OH
MeOBn
OAc
BnOMg
Br Br
HMe
Felkin-Ahncontrol
chelationcontrol
Marshall, J.A.; Wang, X.-j.; J. Org. Chem. 1992, 57, 1242
Transmetallations with SnCl4
Bu3Sn•
HMe
AcO
Me
OHOAc
(R)
•HMe
AcO
OH
Me
OHOAc
(R)
(R)
i-PrCHO, BF3*Et2OCH2Cl2, -78oC
SnCl4, CH2Cl2-78oC, 10 minthen i-PrCHO
SnCl4, CH2Cl20oC to -78oC, then i-PrCHO
(S)
Marshall, J.A.; Perkins, J.F. J. Org. Chem. 1994, 59, 3509
Mechanism for SnCl4 Reactions
H•R
Bu3SnMe
RSnCl3H
Me
H•R
Cl3SnMe
H• SnBu3
RMe
OHF3B
R
Me
OH
(R)
R
H MeSn
Cl Cl
Cl O
H • HMe
R
OH
SnCl Cl
Cl O
H•
R
Me HR
Me
OH
(R)
SnCl4anti
SnCl4syn
i-PrCHO
i-PrCHO
i-PrCHO
(R)
(R)
(S)
Marshall, J.A.; Perkins, J.F. J. Org. Chem. 1994, 59, 3509
The Use of Propargylic Stannanes
MeSn(Bu)Cl2
H
C7H15
H•
Bu3SnMe
C7H15(S) (R)BuSnCl3CH2Cl2, -40oC
MeCl2(Bu)Sn
H
C7H15(R)
• C7H15H
Me
OH O
Me
H HC7H15
• C7H15H
Me
OHBnO
Me
• C7H15H
Me
OHBnO
Me
O
Me
H HC7H15
Me
BnO
O
Me
H HC7H15
Me
BnO
i-PrCHO
OBnMe
OHC
OBnMe
OHC
AgNO3acetone
AgNO3
AgNO3
acetone
acetone
Marshall, J.A.; Yu, R.H.; Perkins, J.F. J. Org. Chem. 1995, 60, 5550
Conclusions
• Axially chiral allenes are very diverse and interesting syntheticallyuseful class of compounds. Numerous chiral allenes can be foundin nature.
• There are many effective methods of nonracemic chiral allenepreparation. Only a few effective asymmetric catalytic reactionsare known.
• Allenes are successfully used in many synthetic transformations,but rarely exploited as ligands for catalytic asymmetric reactions.They have been extensively used in natural product synthesis.Naturally occurring chiral allenes also have been synthesized.
Acknowledgements
My sincere and warm gratitude to:
• Prof. William D. Wulff• Prof. Babak Borhan• Laboratory coworkers, especially Victor Prutyanov, Vijay
Gopalsamuthiram, and Keith Korthals• Banibrata Ghosh (Bani)
