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.