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Absolute Asymmetric Synthesis [AAS] by Photochemistry on Solid-State
Qihui Jin
Supergroup MeetingSept. 28, 2005
What is an absolute asymmetric synthesis?
Absolute asymmetric synthesis: An asymmetric synthesis starting froman achiral reagent andin the absence of any external chiral agent
Achiral Chiral
Chiral Crystal
spontaneous chiral crystallization
photochemical reaction
Chiral Crystal
A crystal lacking both a center of symmetry and a glide plane is defined as chiral. Such a chiral crystal must belong to a chiral space group.
Space group: 230 Chiral Space Group: 65
Table: The 10 most common space groups:
Order Space group % Order Space group %1 P21/c 36.0
13.711.66.76.6
6 Pbca 4.32 PĪ 7 Pnma 1.93 P212121 8 Pna21 1.84 P21 9 Pbcn 1.25 C2/c 10 P1 1.1
achiral crystal
chiral crystalchiral compound
achiral compound
8%
enantiomorph
Sakamoto, M. In Molecular and Suparamolecular Photochemistry: vol 11, Chiral Photochemistry; Inoue, Y.; Ramamurthy, V. Eds; Marcel Dekker: New York; 2004, p415-461
Asymmetric Induction by Chiral Quartz
l- and d-quartzFlack, H. D. www.flack.ch/howard/cristallo/publcns.html
N
N
CHO
t-Bu
i-Pr2Zn
l-Quartz
N
Nt-Bu
OH
84-97% ee93-97%
N
N
CHO
t-Bu
i-Pr2Zn
d-Quartz
N
Nt-Bu
OH
80-97% ee90-97%
Soai, K.; Osanai, S.; Kadowaki, K.; Yonekubo, S.; Shibata, T.; Sato, I. J. Am. Chem. Soc. 1999, 121, 11235.
Forming Desired Chiral Crystal
Spontaneous Chiral Crystallization: Equal chance to form D or L Crystal
32 different crystallizations of NaClO3
14 L 18 DP213
L D
Kondepudi, D. K.; Kaufman, R. J.; Singh, N. Science 1990, 250, 975.
The First Absolute Asymmetric Synthesis Using Crystals
O
Me Me
O
Me Me
O
Me Me
BrBr
Br Br
6% ee 0% ee
Br2, liquidBr2, gas
space group P212121
Penzien, K.; Schmidt, G. M. J. Angew. Chem. Int. Ed. Engl. 1969, 8, 608
Absolute Asymmetric Photochemistry on Solid-State
• Unimolecular– Di-π-Methane Photorearrangement– Electrocyclization– [2+2], [4+4]– Hydrogen Abstraction Followed by Cyclization– Migration and Radical Pair
• Intermolecular– Single Component Crystal– Cocrystal
• Racemic-to-Chiral
Di-π-Methane Photorearrangement
hν
P212121
PriO2C
CO2Pri
PriO2C
CO2Pri
>95% ee
CO2PriiPrO2CCO2Pri
PriO2C
Evans, S. V.; Garcia-Garibay, M.; Omkaram, N,; Scheffer, J. R.; Trotter, J.; Wireko, F. J. Am. Chem. Soc. 1986, 108, 5648.
Di-π-methane photorearrangement
1
2 3 4
51
23
45
1
2
54
3
1
24
3
5
Zimmerman, H. E.; Armesto, D. Chem. Rew. 1996, 96, 3065.
Di-π-Methane Photorearrangement
CNNC
OO
CNCN
O
CN
CN
O
NC
NC
O
CN
CN
ab
P212121
O
NC
NC
87% ee
44% eehν
-21 oC
a
b
1 : 1.3
16% conv.
Roughton, A. L.; Muneer, M.; Demuth, M.; Klopp, I.; Kruger, C. J. Am. Chem. Soc. 1993, 115, 2085.
Photo Electrocyclization
N
Ph
Ph
O
O
MeN
Ph
Ph
O
O
Mesolution
N
Ph
Ph
O
O
Mehν
N
O
O
Me
HPh Ph
N
O
O
Me
Ph
HPhPh
1,5-H shift
Toda, F.; Tanaka, K. Superamol. Chem. 1994, 3, 87.
HN O
O
hν O
HN
O
OMe OMe
P212121
H
H
90% ee
27% convesion
Wu, L.-C.; Cheer, C. J.; Olovsson, G.; Scheffer, J. R.; Trotter, J.; Wang, S.-L.; Liao, F.-L. Tetrahedron Lett. 1997, 38, 3135.
[2+2] Cycloaddition
N
OMe Ph
PhS
N
OMe Ph
PhSNS
O
Ph
Me
Phhν
70% yield, 40% eeP212121
-45 oC
Sakamoto, M.; Hokari, N.; Takahashi, M.; Fujita, T.; Watanabe, S.; Iida, I.; Nishio, T. J. Am. Chem. Soc. 1993, 115, 818.Sakamoto, M.; Takahashi, M.; Mino, T.; Fujita, T. Tetrahedron 2001, 57, 6713.
hν
P21
-78 oCN
OPh
OMeS S
N
O
Ph
OMeH
N
O
Ph
H
SOMe
S
O
H
NMeOPh
84% yield, 20% ee
Sakamoto, M.; Takahashi, M.; Arai, T.; Shimizu, M.; Yamaguchi, K.; Mino, T.; Watanabe, S.; Fujita, T. Chem. Commun. 1998, 2315.
[2+2] Cycloaddition
N
O
O
O
Ph
hνN
O
OPh
O
Me
N
O
OPh
O
Me
+
syn anti
MeMe
PhPhPhMe H
H Me15 oC
60:1100%
91% ee
Sakamoto, M.; Takahashi, M.; Arai, T.; Fujita, T.; Watanabe, S.; Iida, I.; Nishio, T.; Aoyama, H. J. Org. Chem. 1993, 58, 3476.
ON
O
O
Ph
hνN
O
OPh
O
Me
N
O
OPh
O
Me
+
syn anti
PhPhPhMe H
H Me0 oC
15:1
Me
40% yield, 0% ee
+N
Ph
O
O
O
20% yield, 88% ee
Ph*
ON
O
O
Ph
Me
Ph
Sakamoto, M.; Takahashi, M.; Fujita, T.; Watanabe, S.; Nishio, T.; Iida, I.; Aoyama, H. J. Org. Chem. 1997, 62, 6298.
[4+4] Cycloaddition
NR
OON
O
O
Rhν
R Yield, % ee, %
quantitative
quantitative
82
>99
P212121
P21
Kohmoto, S.; Ono, Y.; Masu, H.; Yamaguchi, K.; Kishikawa, K.; Yamamoto, M. Org. Lett. 2001, 3, 4153.
H Abstraction and Cyclization
N
S
hν
81% yield, 81% eeP21
0 oCPh
NS
Ph
PhH Ph
H
N
S
Ph
PhH
Sakamoto, M.; Takahashi, M.; Kamiya, K.; Yamaguchi, K.; Fujita, T.; Watanabe, S. J. Am. Chem. Soc. 1996, 118, 10664.
N
S
Phhν
P212121
Ph N
S
PhN
S
PhMe
PhMe
0 oC
44% yield, 55% ee
HH
HH
PhH
NS
PhMe
PhMe
N
S
Ph
PhHPri
H
Zwitterion
conrotatoryHN
S
PhPri
Sakamoto, M.; Takahashi, M.; Arai, W.; Nino, T.; Yamaguchi, K.; Watanabe, S.; Fujita, T. Tetrahedron 2000, 56, 6795.
H Abstraction and Cyclization
OPh Ph OHPh PhPh
OH
hνH
H HPh
H
P212121
OHPh PhH
b
a
a
bPh
OHPh
H
40-50 oC
6% yield, 86% ee
Irngartinger, H.; Fettel, P. W.; Siemund, V. Eur. J. Org. Chem. 1998, 2079.
H Abstraction and Cyclization
MeO
Cl
Me
HO
Arhν
8 oC8% conv.
>80% ee
Evans, S. V.; Garcia-Garibay, M.; Omkaram, N,; Scheffer, J. R.; Trotter, J.; Wireko, F. J. Am. Chem. Soc. 1986, 108, 5648.
Migration of Radical Pair
OO
S(o-Tol)
Ph
O
S(o-Tol)
PhO
O
O
Ph S(o-Tol)
P212121 65% yield, 30% ee
hν
0 oC
Sakamoto M.; Takahashi, M.; Moriizumi, S.; Yamaguchi, K.; Fujita, T.; Watanabe, S. J. Am. Chem. Soc. 1996, 118, 8183.
OO
N
Ph
P212121
MePh
OO
N
Ph
MePh
OR R R
ON
MePh
OR
O
Ph N Me
Ph
hν
Ph
R = H 0 oC, 100% yield, 83% eeR = Me 50 oC, 25% yield, 87% ee
Sakamoto M.; Seikine, N.; Miyoshi, H.; Mino, T.; Fujita, T. J. Am. Chem. Soc. 2000, 122, 10210.
Intermolecular [2+2]
CN
CO2Me
O2CEt
Et
CN
CO2Me
O2CEt
Et CN
CO2Me
O2CEt
Et
CN
CO2Me
O2CEt
Ethν
100% ee
+ trimer + oligomers
Addadi, L.; van Mil, J.; Lahav, M. J. Am. Chem. Soc. 1982, 104, 3422.
Intermolecular [2+2]
hνCO2EtN
EtO2C NCO2Et
N
N
EtO2C
-40 oC
45% yield, 95% ee
P21
Hasegawa, M.; Chung, C.-M.; Muro, N.; Maekawa, Y. J. Am. Chem. Soc. 1990, 112, 5676.
Intermolecular [2+2]: Cocrystal
Ar
Ph
Ar
Th
Ar
Ph
15%
Ar = 2,6-ClC6H3
Th = 2-thienyl
hν
Ar
Ph
Ar
Th
Ar
Th
Ar
Ph+
29% conv.
70% ee
Elgavi, A.; Green, B. G.; Schmidt, G. M. J. J. Am. Chem. Soc. 1973, 95, 2058.
hν
NS
NNS
N
NC CN
CNNC
P21
NS
NNS
N
CNNC
NCNC H*
95% ee
91%
Suzuki, T.; Fukushima, T.; Yamashita, Y.; Miyashi, T. J. Am. Chem. Soc. 1994, 116, 2793.
Cocrystal For AAS
Koshima, H.; Ding, K.; Chisaka, Y.; Matsuura, T. J. Am. Chem. Soc. 1996, 118, 12059.
P212121
hν
N
HO O
PhPh
N
O O
PhPh
NPh
Ph
PhPh
37% yield, 35% ee
RT
Frozen Molecular Chirality Memorized by Chiral Crystallization
N
O
O
O
Ph
N
O
O
O
Ph(S) (R)
18.24-18.36Kcal/mol
at 233-253K
N
O
O
O
Ph
hνN
O
OPh
OH
N
O
OPh
OH
+
A B
T, °C Conditions Yield, % A : B A, ee, % B, ee, %
15 Solid State 100
-
-
-
95:5 >99 -
0 THF 67:33 0 0
−20 THF 68:32 51 31
−60 THF 81:19 87 79
Sakamoto, M.; Iwamoto, T.; Nono, N.; Ando, M.; Arai, W.; Mino, T.; Fujita, T. J. Org. Chem. 2003, 68, 942.
Chirality Retention: From Solid-State to Homogenous Solution
P PPh Ph
PPPhPh
S[R,R] R[S,S]
P PPh Ph
S[R,R]
PdCl2(CH3CN)2
DCM, -78oC16h
P P
S[R,R]-(+)-Cat
PtCl Cl
Ph Ph
OAc
PhPhNaCH(CO2Me)2+
1% S[R,R]-(+)-Cat
THF, 25 oC93%
PhPh
CO2MeMeO2C
80% ee
Tissot, O.; Gouygou, M.; Dallemer, F.; Daran, J.-C.; Balavoin, G. G. A. Angew. Chem. Int. Ed. 2001, 40, 1076.
Racemic-to-Chiral: Optical Activity Generated by Crystallization
CO2H
CO2H
HO
HO
HO2C
HO2C
OH
OH
L-(+)-tartaric acid D-(-)-tartaric acid
Louis Pasteur, 1947
Spontaneous Solid-State Resolution:
S-(+) R-(-)
half-life 15 min at 50 oC
Pincock, R. E.; Wilson, K. R. J. Am. Chem. Soc. 1970, 93, 1291.
Optical Enrichment of a Racemic Chiral Crystal by X-ray Irradiation
N
NCo
N
N Me
Me
Me
MeOH O
O HO
N
CNMe
H
N
NCo
N
N Me
Me
Me
MeO HO
OH O
N
NC HMe
P212121
(R) (S)
D enantiomorph
Volumn of reaction cavity: R 7.49 ΧS 11.57 Χ
Required volume for the racemization: 11.5 Χ
Osano, Y. T.; Uchida, A.; Ohashi, Y. Nature 1991, 352, 510.