Memory of Chirality: A Strategy for Asymmetric Synthesis

David J. Richard

September 14, 2005 Two Forms of Chirality

Absolute (Static) Chirality

H NH2 Ph OH

O - Absolute chirality - orientation of functional groups at a stereocenter

Dynamic (Conformational) Chirality

H H H CO2H HO C H Ph OH 2 Ph Ph H H O

- Dynamic chirality - chirality present only when C-C single bond rotation is restricted

H3C CH3

CH3 H3C

Barrier of rotation = 18 kcal/mol Memoryof Chirality in Enolate Chemistry

- In 1981, Seebach and Wasmuth made the following observation:

O LDA Ot-Bu O t-BuO THF, t-BuO t-BuO Ot-Bu OLi Ot-Bu HN CH3 O HN then MeI O N O O O OLi 15%, 60% ee

- No mechanism was established; however, one hypothesis was that reaction occurred through an axially chiral intermediate

- Mixed aggregates involving the chiral enolate below were later implicated

O t-BuO Ot-Bu OLi HN

O

Seebach, D.; Wasmuth, D. Angew. Chem., Int. Ed. Engl. 1981, 20, 971. Seebach, D.; Sting, A. R.; Hoffman, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708. Memoryof Chirality: Definition

Problem: Can stereochemical information be retained during a process in which the sole stereogenic center of a substrate is destroyed?

NHR H NHR1 1 R NHR1 Ph OCH3 Ph OCH Ph OCH3 3 * O OM O > 0% ee

Memory of chirality (MOC) has been defined as a process in which:

"the chirality of the starting material is preserved in a reactive intermediate for a limited time"

Fuji, K.; Kawabata, T. Chem.-Eur. J. 1998, 4, 373-378.

This process has also been described as follows:

"A 'memory of chirality' reaction can be defined as a formal substitution at an sp3 stereogenic center that proceeds stereospecifically, even though the reaction proceeds by trigonalization of that center, and despite the fact that no other permanently chiral elements are present in the system." Zhao, H.; Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1-17.

Additional Review: Kawabata, T.; Fuji, K. Top. Stereochem. 2003, 23,175-205. Enolate Alkylation: Design of aMemory of Chirality System

O OM Base R1 R1 R3 R3 H R 2 R2

R1 OM MO R1 A A R2 R2 B B

M M

R1 O O R1

R2 R3 R3 R2

- Fuji and co-workers proposed two strategies for the establishment of conformationally chiral enolates - axially chiral enolates or planar chiral enolates

Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113, 9694. Stereoselectivity by Memoryof Chirality: General Considerations

Fast Fast Substrate* (M)-Intermediate (R)-Product A C

Very Slow Very Slow B Very Slow

Fast (P)-Intermediate (S)-Product

A Reaction at stereogenic center (e.g., enolate formation) generates conformationally chiral intermediate

B Conformationally chiral intermediate must not readily racemize

C Reaction must occur with high stereospecificity

-Critical issue: reaction kinetics Enolate Alkylation Utilizing Memory of Chirality (MOC)

Ph O KH KO O CH3 OCH 3 18-crown-6 OCH3 MeI OCH3 EtO EtO EtO Toluene EtO EtO EtO 93% ee 54%, 73% ee

H3C O Et CH Ph O O 2 O O OCH 3 OCH3 OCH3 OCH3 EtO EtO EtO EtO

EtO EtO EtO EtO

65% ee 67% ee 48% ee 70% ee

- O-methylated product also isolated in 65% ee by chiral HPLC

- Half-life of racemization determined to be 53 minutes at room temperature

Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113,9694. Asymmetric Syntheses of Amino Acid Derivatives

O OM Base R1 R1 OR4 OR4 H N R2 N R2 R3 R3

R3 M

R1 OM R2 N O R2 N OR4 R1 OR4

R3

Axial Chirality Planar Chirality

M R2 N O R3 R1 OR4

Central Chirality

Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K. J. Am. Chem. Soc. 1994, 116, 10809. Asymmetric Alkylation of Amino Acid Esters

LiTMP O O THF Ph OEt Ph OEt N - 78 C, H3C N CH3 H C Boc 3 Boc then CH3I

40%, 82% ee

KHMDS O O Toluene-THF (4:1) Ph OEt Ph OEt O N MOM N CH3 H C Boc - 78 C, 3 Boc then CH3I 96 %, 81% ee

O BocN O O MOMN OEt N OEt OEt MOM N CH 3 MOM N CH3 MOM N CH3 Boc Boc Boc

78%, 78% ee 83%, 93% ee 88%, 76% ee

Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K. J. Am. Chem. Soc. 1994, 116, 10809. Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155. Mechanism of Memoryof Chirality Effect

- One possibility - mixed aggregate mechanism

OEt Ot-Bu MOM Ph O O N K N O O Ph MOM Ot-Bu OEt

- Ruled out by competition experiments

- Silyl enol ether prepared - exhibits rotational barrier of 16.8 kcal/mol by VT NMR experiments

OEt OEt

Ph OTBS Ph OTBS N O N O MOM MOM Ot-Bu Ot-Bu

- Half-life of approximately 7 days at -78 C

- Variable reaction times explored for enolate deprotonation - rotational barrier calculated as 16.0 kcal/mol

Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155. Mechanism of Memoryof Chirality Effect

Ot-Bu Ot-Bu O O O O O OOt-Bu O Ph O OEt Ph O N N N O Ph N OK O O K H H CH3 O N O O TMS TMS CH3I Major product

CH3I OO O O Ph O O Ph O OEt H3C O N N O Ph N OK K t-BuO N O H HO O O t-BuO N O Ot-Bu TMS TMS O Minor product

- Additional evidence: di-Boc and oxazolidinone analogs showed no enantioselectivity

Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155. Effect of Adjacent Stereocenters

O O

OEt OEt N N Boc MOM Boc MOM

KHMDS -78 C

OK OK EtO EtO CH2OCH3 CO2t-Bu N N CO2t-Bu CH2OCH3

CH3I

O O

OEt OEt MOM N N MOM Boc Boc

93%, 93% de 91%, 86% de

Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39,2155. Asymmetric Alkylation - Intramolecular Cyclization

O KHMDS EtO2C Ph OEt Ph DMF BocN N Br Boc -60 C 94%, 98% ee

EtO2C EtO2C EtO2C Ph Ph Ph BocN BocN BocN

84%, 97% ee 61%, 95% ee 31%, 83% ee

- Other six-membered rings were produced in excellent ee (94-97%)

O Ot-Bu O Ot-Bu O O OEt EtO C N Ph 2 N OK Ph BocN H Br

Br Favored conformation

Kawabata, T.; Kawakami, S.; Majumdar,S.J. Am. Chem. Soc. 2003, 125, 13012. Additional Applications of Memory of Chirality Strategy

S S

NaOCH3 N N CO2CH3 CO CH Et3N, CH3OH = 65% O 2 3 O NH CH3OH N2 N O O - NMR studies of SM indicate presence of three rotamers 35%

N S H CO O N 3 N H3CO O O N O N CO CH H 2 3 N N O NH O O N S S O

Observed

S N N N O H N O N CO2CH3 S CO Me 2 S O NH N N O N O O O MeO

Not observed

Beagley, B.; Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R. J.; Vohra, S. J. Chem. Soc., Perkin Trans. I 1993, 1761-1770. Extension of Methodology: Cyclization of Sulfoxides

O O S S

Et3N N N CO2CH3 CO CH O 2 3 O NH CH3OH N2 N O O

61%

O O O O S S S S Et N N 3 N N CO2CH3 N CO2CH3 CO CH O 2 3 + O CO2CH3 O NH O NH N CH3OH 2 N2 N N O O O O

65% 35% 63% 37%

Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R. J.; Vohra, S. J. Chem. Soc., Perkin Trans. I, 1999, 1067-1072. Additional Applications - Aldol Cyclization and Azetidinone Closure

S S S

N KCN N CO2iPr + N CO2iPr O CO2i-Pr OH O O MeOH OH O 49% 19%

Ph CO2t-Bu Ph Cs2CO3

N CO2t-Bu Cl PMB CH3CN N O O PMB

53%, 56% ee

- Enantioselectivity highly substrate dependent (0-50% ee)

- No specific models proposed - however, existence of axial chirality proposed

Brewster, A. G.; Frampton, C. S.; Jayatissa, J.; Mitchell, M. B.; Stoodley, R. J. Chem. Commun. 1998, 299. Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.; Garcia-Lopez, M. T.; Gonzalez-Muniz, R. J. Org. Chem. 2001, 66, 3538. Memoryof Chirality in Benzodiazepines

Cl Cl Ph LDA Ph - With N-Me amide: 0% ee HMPA N N n-BuLi, - Alkylation with other electrophiles (Me, allyl, 2- Ni-Pr Ni-Pr PhC H CH , 4-MeC H CH ) all proceed with 94- then BnBr 6 4 2 6 4 2 O O 99% ee Ph -78 C 74%, 97% ee

Cl Cl

H

H3C t (inversion) = H C N N 0.0 kcal/mol 1/2 3 970 hours @ -78 C N N i-Pr i-Pr O O - Factors which lead to attack of electrophile on concave face yet to be determined

Ph Ph N N O H Ni-Pr Ni-Pr + 17.5 kcal/mol H C CH3 3

Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam, P.C.-H. J. Am. Chem. Soc. 2003, 125, 11482. Memoryof Chirality in Radical Chemistry

OEt LiDBB R - 78 C

THF, then Cr(CO)3 Cr(CO) RX 3

R = TMSCl; 72%, 87% ee R = PhCH2Br; 37%, 87% ee R = CH3OC(O)Cl; 67%, 86% ee R = (CH3)2NC(O)Cl; 57%, 84% ee

OEt H H R + 1 e Fast Fast CH3 CH3 CH3

Cr(CO)3 Cr(CO)3 Cr(CO)3 Cr(CO)3 Cr(CO)3

Configurationally Stable Slow

CH3

H

Cr(CO)3

Schmalz, H.-G.; Koning, C. B. D.; Bernicke, D.; Siegel, S.; Pfletschinger, A. Angew. Chem. Int. Ed. 1999, 38, 1620. Reaction of Pyranyl Radicals

hv

O 1M PhSH O Ph Ph -78 C H O O S N 92%, 88% ee

LiDBB Li (6.4M)/NH3 THF THF O O O O Ph Ph Ph Ph CN -78 C, -78 C, CO2H CN H then CO2 then NH4Cl 48% ee 90% ee

- Memory of original chiral center retained due to ring conformational preference

- Furanyl radicals exhibit no enantioselectivity

Buckmelter, A. J.; Kim, A. I.; Rychnovsky, S. D. J. Am. Chem. Soc. 2000, 122, 9386. Radical Cyclization of Cyclodecenyl Systems

S O Toluene S N O H N O 51%, 68% ee hv CO2Bn BnO2C CO2Bn O -15 C CO2Bn H

CO2Bn

CO2Bn CO2Bn - Barrier to ring inversion H H provides stereocontrol CO2Bn

H

H CO2Bn CO Bn 2 CO2Bn - Lower temp. provides no improvement of ee CO2Bn H H

N S S N H H CO Bn 2 CO2Bn CO Bn 2 CO2Bn H H Dalgard, J. E.; Rychnovsky,S.D.Org. Lett. 2004, 6, 2713-2716. Radical Cyclization of Haloacrylanilides

O O Bu3SnH N NCH3 Et3B I

O2 rt

84% ee

O O

NCH3 N Bu3SnH Et B I 3

O2 rt

82% ee

- Chirality of atropisomer is maintained in radical - cylization proceeds faster than isomerization

Curran, D. P.; Liu, W.; Chen, C. H.-T. J. Am. Chem. Soc. 1999, 121, 11012-11013. Radical Cyclization to Substituted Pyrrolidines

hv O CO2CH3 CO CH Benzene 2 3 OEt OH OH H3CO2C N + Ts N O CO2Et N CO Et Ts Ts 2

40%, 96% ee 7%, 94% ee

CO2CH3 CO2CH3 OH 5 kcal/mol OEt N OH N CO Et Ts O Ts 2

H3CO2C EtO HO N O Ts

Helically chiral diradicals

- When reaction is performed in the presence of a triplet sensitizer, no diastereoselectivity or enantionselectivity is observed

Giese, B.; Wettstein, P.; Stahelin, C.; Barbosa, F.; Neuburger, M.; Zehnder, M.; Wessig, P. Angew. Chem. Int. Ed. 1999, 38, 2586-2587. Sinicropi, A.; Barbosa, F.; Basosi, R.; Giese, B.; Olivucci, M. Angew. Chem. Int. Ed. 2005, 44, 2390-2393. Cyclization via Photodecarboxylation

O O hv

N Acetone N OH H O O H O 2 N 13 kcal/mol N CO2K O

45%, 86% ee

- Via triplet diradical

Griesbeck, A.G.;Kramer, W.; Lex, J. Angew. Chem. Int. Ed. 2001, 40, 577. MOC via a Carbocationic Intermediate

O NaOCH3 O

CH3OH N CO2H N OCH3 Graphite O anode O Pt cathode

69%, 39% ee

O NaOCH3 O

CH3OH N CO2H N OCH3 Graphite O anode O

Ph Pt cathode Ph

69%, 39% ee

CH3OH

O O O CO2H N N N OCH3 O O O

Ph

Matsumura, Y.; Shirakawa, Y.; Satoh, Y.; Umino, M.; Tanaka, T.; Maki, T.; Onomura, O. Org. Lett. 2000, 2, 1689. Conclusions

- Memory of chirality represents an emerging strategy in the field of stereoselective synthesis

- This method takes advantage of the dynamic, conformational chirality present in systems with restricted rotation about single bonds

- Requires no external sources of chirailty

- Highly time, temperature, and substrate dependent

- Primary application has been in the area of enolate chemistry - limited number of examples involving radical and carbocationic intermediates