Catalytic, Asymmetric Synthesis of β-Lactams

H N 3 4 S Ph O O 2 N 1 OH O Matt Windsor Gellman Group 10/19/06

Outline

• Background and Applications • Synthesis – Gilman-Speeter – Kinugasa – Staudinger • Potential Industrial Uses • Conclusions 2

Synthesis by Staudinger

• First to synthesize β-lactam core from diphenylketene and benzylideneaniline Ph   + O Ph Ph N Ph Ph Ph Ph O N Ph H 2 N Ph O Ph Ph N Ph NEt 3 H Ph Ph Cl O Ph Ph Cl O Ph Ph Staudinger, H.

Liebigs Ann. Chem. 1907 ,

356

, 51-123.

O 3

Discovery of Penicillin

• Discovered in 1928 • First used to treat patients in 1942 • Significantly lowered number of deaths and amputations caused by infected wounds in WWII Fleming, A.

Br. J. Exp. Pathol

.

1929

,

10

, 226-36.

http://en.wikipedia.org/wiki/Image:PenicillinPSA.gif

4

Penicillin’s Mode of Action

• Prevents crosslinking of bacteria’s cell wall polymer strands (peptidoglycan) http://en.wikipedia.org/wiki/Peptidoglycan 5

Mechanism of Activity

R 2 R 1 O Enz O H N R B R 2 R 1 O O Enz N R BH R 2 R 1 O Enz HN O R •  -lactams act as inhibitors of serine proteases: –  -lactamases – Prostate Specific Antigen – Thrombin – Human Cytomegalovirus – Elastase 6

Antibiotic Resistance

via



-Lactamases

•  -Lactamases able to remove acyl group, regenerate serine sidechain R 2 R 1 R 2 R 1 R 2 R 1 BH O Enz O H N R B O O Enz N R O O NH R Enz H O H B R 2 R 1 R 2 R Enz O H O NH OH R BH O NH OH O Enz R Sandanayak, V. P.; Prashad, A. S.

Curr. Med. Chem. 2002 ,

9

, 1145-1165.

1 7

Outline

• Background and Applications • Synthesis – Gilman-Speeter – Kinugasa – Staudinger • Potential Industrial Uses • Conclusions 8

Common Methodologies

• Enantiomerically pure substrates • Chiral auxiliaries PhtN O O N = PhtN Me 3 SiN OTIPS O Et 3 N Cl toluene, reflux; H 2 O 40% dr 85:15 O O N Ph O Cl N PhtN H H OTIPS NH Et O 3 N CH 2 Cl 2 , rt 53% PhtN O O N H H Ph O N O H H NH OTIPS Bandini, E.; Martelli, G.; Spunta, G.; Bongin, A.; Panunzio, M.

Muller, M.; Bur, D.; Tschamber, T.; Streith, J.

T etrahedron Lett. 1996 Helv. Chim. Acta. 1991 ,

74

,

37

, 4409-4412.

, 767-773.

9

Gilman-Speeter

Me Me O O PMP N R Ph Ph MeO OMe 0.2 eq LICA (2.2 eq) toluene Me Me O R N PMP R Ph PMP 1-Naphthyl 2-Naphthyl CMe=CHPh CH 2 CH 2 Ph Temp ( o C) Time (h)

ee

(%) yield (%) -20 -50 -50 -50 -78 -78 7 20 15 15 9 1 60 80 75 90 75 90 95 70 40 85 40 80 PMP = MeO LICA = Li N Tomioka, K.

et al. J. Am. Chem. Soc. 1997 ,

119

, 2060-2061.

10

Gilman-Speeter Selectivity

• Ternary complex: Li amide, chiral ligand, Li enolate ester • Screening of new, tridentate catalysts to replace amide base in complex O Ph Me O O Li Li

i

-Pr N O Me Ph O Ph Me O O Li Li Me X X= N, O X Ph Hussein, M. A.; Iida, A.; Tomioka, K.

T etrahedron

.

1999

,

55

, 11219-11228.

11

Comparison of Catalytic Ligand

O O PMP N R

1

or

2

LICA toluene O R N PMP CH 2 R Ph PMP 1-Naphthyl 2-Naphthyl CMe=CHPh CH 2 Ph Temp ( o C) -20 -50 -50 -50 -78 -78 Catalyst 1 2 1 2 1 2 1 2 1 2 1 2 Time (h) 7 1.5

20 3.5

15 1.5

15 2.5

9 5 1 0.5

ee

(%) yield (%) 60 89 80 90 75 84 90 88 75 82 90 65 95 99 70 99 40 99 85 99 40 90 80 99 Tomioka, K.

et al. J. Am. Chem. Soc. 1997 ,

119

, 2060-2061.

Ph MeO

1

Ph OMe Ph Me 2 N

2

Ph O MeO 12

Kinugasa: Background

• First reaction to give exclusively

cis

-lactam • Stoichiometeric use of copper under nitrogen Kinugasa, M.; Hashimoto, S.

King, L. K.; Irwin, W.

J. Chem. Soc., Chem. Comm. 1973 J. Chem. Soc. Perkin Trans. 1 1976 , 466-467.

, 2382-2386.

13

First Catalytic Kinugasa Reaction

• Significant isomerization to

trans

lactam under basic conditions • Imine byproduct Ph H Ph O N Ph O O N N

i

-Pr 10% CuI, py.

i

-Pr DMF Ph N Ph Ph O 45% yield 40%

ee

Ph N Ph Miura, M.; Enna, M.; Okuro, K.; Nomura, M.

J. Org. Chem. 1995 ,

60,

4999-5004.

14

Isomerization from

cis

to

trans

Ph N Ph R O H B Ph N Ph R O BH Ph N Ph R O Ph O N Ph 10% CuI, py.

2 hours DMF Ph N Ph R O R R

cis

:

trans

CO 2 Me Ph CH 2 OH 0:100 46:54 80:20 Isomerization rate depends on R: Ester > aryl > alkyl King, L. K.; Irwin, W.

J. Chem. Soc. Perkin Trans. 1 1976 , 2382-2386.

15

New Kinugasa Mechanism

Ye, M.-C.; Zhou, J.; Tang, Y.

J. Org. Chem. 2006 ,

71

, 3576-3582.

16

Bulky Base Prevents Isomerization

R H 1 R 2 O N Ph R 1 R 2 Ph Ph Ph Ph Cy PhCO PhCH 2 Cy 1-cyclo hexenyl PhCO

cis

:

trans ee

(%) Yield (%) 95:5 93:7 91:9 71:29 90:10 77 89 72 73 92 69 57 42 43 45 1% CuCl Ligand Cy 2 NMe MeCN, 0 o C R 1 O R 2 N Ph Me Me Me Me Me Me Fe Me Me Fe N Me Me Me N Me Ligand Cy = Lo, M. M.-C.; Fu, G. C.

J. Am. Chem. Soc. 2002 ,

124

, 4572-4573.

17

O N Ar

Tricyclic Systems

CuBr (5%) ligand (5.5%) O (C 6 H 11 ) 2 NMe (0.5 eq) MeCN, 0 o C Ar =

p

-carboethoxyphenyl Ar N ligand = Me Ph Me Me Me O Fe P Me Me N Me

i-

Pr O Ar N 88%

ee

74% yield O Ar N O Ar N 90%

ee

46% yield O O O Ar N O O Ar N 90%

ee

64% yield S 85%

ee

53% yield 91%

ee

68% yield Rhintain, R.; Fu, G.C.

Angew. Chem. Int. Ed. 2003 ,

42

, 4082-4085.

18

Quaternary Center Hypothesis

• Introduce electrophile and get quaternary center • Addition should be

trans

to C-4 substituent H R 3 O R 1 N R 2 H + R 3 [Cu]O R 1 Electrophile = E + N R 2 ??

E R 3 O R 1 N R 2 Rhintain, R.; Fu, G.C.

Angew. Chem. Int. Ed. 2003 ,

42

, 4082-4085.

19

Initial Quaternary Conditions

• Standard reaction conditions gave negligible amount of product O N O OEt 3.0 eq I CuBr (5%) ligand (5.5%) Cy 2 NMe MeCN, 0 o C O N trace O OEt Rhintain, R.; Fu, G.C.

Angew. Chem. Int. Ed. 2003 ,

42

, 4082-4085.

20

Development of New Proton Sink

• Replaced R 3 N base • New system generates acetophenone – Poor proton donor compared to trialkylammonium salt O N O OEt 3.0 eq I CuBr (5%) ligand (5.5%) OTMS (2.0 eq) Ph KOAc (1.0 eq) MeCN, r.t.

O N 85%

ee

76% yield O OEt Rhintain, R.; Fu, G.C.

Angew. Chem. Int. Ed. 2003 ,

42

, 4082-4085.

21

Air Stable Kinugasa Catalyst

• Cu(II) reagent stable under air • Cu(I) catalytic species Ph Ph O N Ph Cu(ClO 4 ) 2 6H 2 O (10%) TOX (12%) CH 3 CN Cy 2 NH (1 eq) air, 15 o C yield = 63% (

cis

+

trans

) N O O N N O Ph Ph O N Ph 13:1

cis

:

trans

79%

ee

[Cu] trisoxazoline (TOX) TOX-[Cu] (Down onto Cu complex) Ye, M.-C.; Zhou, J.; Tang, Y.

J. Org. Chem. 2006 ,

71

, 3576-3582.

22

Kinugasa Stereochemical Model

Ph Cy 2 (1.0 eq) NH (1.0 eq) N L Cu N O O N O N O N L Cu N O O O N Ye, M.-C.; Zhou, J.; Tang, Y.

J. Org. Chem. 2006 ,

71

, 3576-3582.

23

More Evidence for New Mechanism

• Intermediate stabilized by electron withdrawing group (EWG) Ph H Ph O N R Cu(CLO 4 ) 2 6H 2 O (10%) TOX (12%) CH 3 CN Cy 2 NH (1 eq) air, 0 o C Ph O Ph N R Ph O Ph N R R C 6 H 5

p

-MeC 6 H 5

p

-MeOC 6 H 5

p

-BrC 6 H 6

p

-EtO 2 CC 6 H 4 yield (%) 56 36 36 70 98

cis

:

trans

15:1 19:1 31:1 13:1 10:1

ee

(%) 82 82 84 74 70 O Ye, M.-C.; Zhou, J.; Tang, Y.

J . Org. Chem. 2006 ,

71

, 3576-3582.

N Ph Ph EWG 24

Staudinger Mechanism

O • • One of the most common methods toward  lactams

cis

-Lactam predominant product in most reactions (can isomerize to get

trans

) • High background rate (spontaneous) Ph Ph N Ph O N Ph Ph Ph O Ph N Ph Ph 25

Reaction Control

• In order to control reaction, had to first prevent spontaneous cyclization • Requires development of electron-deficient imine • Catalyst needed for reaction to proceed O R 1 R 2 Nucleophilic Catalyst (Nu) Nu O R 1 R 2 R 3 N R 4 electron deficient imine -Nu R 3 N R 4 O R 2 R 1 Wack, H.

et al. Org. Lett. 1999 ,

1

, 1985-1988.

26

Lectka’s Imine

O Ph Ph O Ph Ph Ts N CO 2 Et No Reaction 5% catalyst benzotrifluoride Cp (CO) 4 2 Co Co O Ph Ph Ts N CO 2 Et 85% yield Ts N EtO 2 C O Ph Ph Co Co(CO) 4 Ts= O S O Catalyst Wack, H.

et al. Org. Lett. 1999 ,

1

, 1985-1988.

27

Diastereoselective Catalyst

• Rigidify transition state by using catalyst that is H bond donor and acceptor • Selectivity lost in H-bonding solvent O O 1. Catalyst THF, r.t.

Ts N O Me N H Et N Et Ph Me Ts N Cl O 2.

CO 2 Et EtO 2 C Ph proposed ketene adduct Ph Me NEt 3 yield= 83% dr (

ci s:trans

) = 55:45 Cl O O N Et Et yield = 77% dr (

cis

:

trans

) = 34:66 Cl Taggi, A. E.

et al. J. Am. Chem. Soc. 2000 ,

122

, 7831-7832.

O N H Et N Et yield = 80% dr (

cis

:

trans

) = 3:97 28

Enantioselective Catalyst

• Cinchona alkaloids used previously as enantioselective catalyst OMe N O O H N O NH Et Et N Cl Benzoylquinine (BQ) Calter, M. A.

Jarvo, E.

J. Org. Chem. 1996 , et al. J. Am. Chem. Soc. 1999

61

, , 8006-8007.

121

; 11638-11643

.

29

Staudinger Stereochemical Model

N O O N O O O NR 3 CO 2 Et O NR 3 Ts N O EtO 2 C NR 3 Ph Ts N Ph CO 2 Et Ph N Ts Anti orientation

ci s

-assembly Gauche orientation

trans-

assembly Anti-orientation

trans-

assembly Taggi, A. E.

et al. J. Am. Chem. Soc. 2002 ,

124

, 6626-6635.

30

Ketene Generation

• Commonly use trialkylamine to dehydrohalogenate acyl chloride • Base can act as nucleophile to catalyze reaction racemically • Need non-nucleophilic, but strong thermodynamic base O O Cl R 3 N R 3 N byproducts H R Me 2 N R NMe 2 O Cl Proton Sponge (PS) No Reaction R Taggi, A. E.

et al. J. Am. Chem. Soc. 2000 ,

122

, 7831-7832.

31

Shuttle Deprotonation

• Use weaker but faster base, have PS remove HCl and precipitate • BQ plays role of kinetically active base Ts N O BQ O Cl R OMe EtO 2 C R N O O H N BQ BQ O H R NTs CO 2 Et O BQ HCl H R Me 2 N NMe 2 PS PS Ts N O CO 2 Et BQ R H PS HCl Taggi, A. E.

et al. J. Am. Chem. Soc. 2000 ,

122

, 7831-7832.

32

Synthesis with Unique Ketenes

• Oxygen substituted ketenes can not be synthesized with chiral auxiliaries O Cl R Ts N CO 2 Et BQ (10%) PS (1.0 eq) -78 to -25 o C toluene Ts N EtO 2 C O R R Ph Et OAc OBn

ee

(%) dr (

cis

:

trans

) yield (%) 96 99 98 95 99:1 99:1 >99:1 99:1 65 57 61 56 Taggi, A. E.

et al. J. Am. Chem. Soc. 2000 ,

122

, 7831-7832.

33

Will a Lewis Acid (LA) Increase Yield?

• Intermediate reacting promiscuously • Need to activate imine or make intermediate more chemoselective • Four scenarios: coordinate to imine ( A ), enolate ( B ), both ( C ) or catalyst ( D ) Ts LA LA N O BQ Ts N O LA O BQ EtO O OEt Ph Ph O BQ

A B C

Ph Lewis Acid (LA) BQ LA BQ Dead system

D

France, S.

et al. Org. Lett. 2002 ,

4

, 1603-1605.

34

Indium as Lewis Acid

• Increase in yield, small loss in diastereoselectivity O Cl R Ts N CO 2 Et In(OTf) 3 (10%) BQ (10%) PS (1.0 eq) -78 to -25 o C toluene Ts N EtO 2 C O R R Ph OAc OBn Without In(OTf) 3 yield (%) With In(OTf) 3 yield (%) 65 61 56 95 92 98 France, S.

et al. Org. Lett. 2002 ,

4

, 1603-1605.

35

Variation of the Imine Substituent

• Range of ketene and imine substituents in very good yield,

ee

O Ph

i

-Bu Ts N R 10% Catalyst toluene, rt N 2 atm.

O N Ts Ph

i

-Bu R R O Ph Ph yield (%) 97 88 95

ee

(%) dr (

cis

:

trans

) 98 11:1 98 98 10:1 10:1 Me 2 N N Me Me Fe Me Catalyst Me Me Hodous, B. L.; Fu, G. C.

J. Am. Chem. Soc. 2001 ,

124

, 1578-1579.

36

Control of

cis

or

trans

Product

•

cis/trans

selection depends on N-protecting group!

Ph O Me Tf = O S CF O Tf N Ar 10% Catalyst toluene N 2 atm.

yield 76-89% O N Tf Ph Me Ar dr (

trans

:

cis

) 4:1 to 49:1

ee

65-99% 3 N N Me Me Fe Me Catalyst Me Me Lee, E. C.

et al. J. Am. Chem. Soc. 2005 ,

127

, 11586-11587.

37

trans

Products From Anionic Catalyst

• Negative charge, bulky counterion are key • No alkyl groups, work ongoing O Cl R 1 Ts N N NR 4 SO 3 N 10% Ph CO 2 Et PS (1.0 eq) toluene Ts N O CO 2 Et R 1 Up to 50:1 trans:cis dr Yield: 46-70% Weatherwax, A.; Abraham, C. J.; Lectka, T.

Org. Lett. 2005 ,

7

, 3461-3463.

38

Summary of Substrate Scope

N-1 Possible Substituents at: C-3 C-4 Gilman-Speeter PMP (can be deprotected) Di-methyl aryl alkyl, vinyl 3 4 O 2 1 N Kinugasa aryl aryl alkyl, vinyl aryl Staudinger Ts, Tf (can be deprotected) aryl, alkyl, oxy (OR) CO 2 Et , aryl, vinyl 39

Outline

• Background and Applications • Synthesis – Rhodium Catalyzed – Gilman-Speeter – Kinugasa – Staudinger • Potential Industrial Uses • Conclusions 40

Industrial Uses: Zetia

 OH OH F O Zetia  N F • Inhibitor of intestinal cholesterol absorption • Combined with Merck statin (ZOCOR ) and sold as Vytorin Wu, G.; Wong, Y.; Chen, X.; Ding, Z.

J . Org. Chem. 1999 ,

64

, 3714-3718.

41

Industrial Uses: Zetia

 Wu, G.; Wong, Y.; Chen, X.; Ding, Z.

J. Org. Chem. 1999 ,

64

, 3714-3718.

42

Industrial Uses: Taxol

Holton, R. A. Method for Preparation of Taxol Using Beta Lactam. U.S. Patent 5,175,315, Dec. 29, 1992.

43

Conclusions

• Field still in its infancy • Primarily limited by substrate specificity – Enolate for Gilman-Speeter – Imine for Staudinger – Nitrone for Kinugasa • Better catalysts to maximize selectivity, yield 44

Shout Outs

• Professor Sam Gellman • Gellman Group • Practice Talk Attendees – Lauren Boyle – Maren Buck – Julee Byram – Alex Clemens – Richard Grant Claire Poppe Chris Shaffer Becca Splain Katherine Traynor 45