Transcript Direct Catalytic, Enantioselective Synthesis of β
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