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CU Synthesis Lit Group Presents Career in Review:

Stephen F. Martin

September 7, 2007 Kristy Tran ­ Leighton Group

Career Snapshot

1968 1970 1972 1972-73 1973-74 1974-1980 1980-1986 1986-Present 2000-Present BS, University of Mexico (Prof. R. N. Castle ) MA, Princeton University (Prof. E. C. Taylor) Ph. D, Princeton University (Prof. E. C. Taylor) Post-Doc, University of Munich (R. Gompper ) Post-Doc, MIT, (G. Buchi) Assistant Professor, University of Texas Associate Professor, University of Texas Professor, University of Texas M. June and J. Virgil Waggoner Regents Chair in Chemistry, University of Texas

ISIS Web of Knowledge statistics as of August 11, 2007 Total Publications: 240 Total Citations: 6118

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 2

Five Most Cited Papers

1. Martin, SF Methodology for the construction of quaternary carbon centers Tetrahedron 36 (4): 419-460 1980 Times Cited: 385 Martin SF, Dodge JA Efficacious modification of the Mitsunobu reaction for inversions of sterically hindered secondary alcohols Tetrahedron Letters 32 (26): 3017-3020 JUN 24 1991 Times Cited: 265 Deiters A, Martin SF Synthesis of oxygen- and nitrogen-containing heterocycles by ring-closing metathesis Chemical Reviews 104 (5): 2199-2238 MAY 2004 Times Cited: 252 Doyle MP, Austin RE, Bailey AS, et al. Enantioselective Intramolecular Cyclopropanations of Allylic and Homoallylic Diazoacetates and Diazoacetamides Using Chiral Dirhodium(II) Carboxamide Catalysts Journal of the American Chemical Society 117 (21): 5763-5775 MAY 31 1995 Times Cited: 155 Martin SF Synthesis of Aldehydes, Ketones, and Carboxylic Acids from Lower Carbonyl Compounds by C-C Coupling Reactions Synthesis(9): 633-665 1979 Times Cited: 153

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 3

2.

3.

4.

5.

Undergraduate Career

Synthesis of Imidazo [4,5-d]-pyridazines

OCOCH3 N N N N

O HN N N N N N

SBn N N H N N

NH(CH)nNR2 N N H

O HN N SBn HN NH2 N

O SBn SBn HN N

O Cl Cl HN N

O NH2 HN NH2 N

S N N H N N

SCH3 N N H N N

NHNH2 N N H

N N N N N

N N H

SBn N N N N N H HN N

S N N N H N N

N N H

NH(CH2)nNR2 N N N N N H N N

SMe N N N H N N

NH2 N N N H

NHNH2 N N N N N H

(a) Martin, S.F. and Castle, R. N.; J. Het. Chem. 1969, 6, 93.

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 4

Graduate Career

7 Publications and 1 Patent A facile method for alkylation and alkenylation of heterocycles JACS 1972, 94, 2874.

OH 2 equiv CH=PR'3 2 equiv n-BuLi Het X DME Het R(H) R2 PR'3 O R3 Het R3

MeO MeO 74% OMe N OMe

Het R

R2

Me

Bn

N 72%

Me

N 79%

Et

N 75%

n-Bu

N 58%

Me

N 82%

A facile synthesis of Quinine and related Cinchona alkaloids JACS 1972, 94, 6128.

H Cl MeO N 2 equiv CH2=PPh3 MeO N MeO N PPh3 H OH N Quinine N COMe

OMe N

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 5

Synthesis of (±)-Reserpine: Retrosynthesis

MeO

N H H H MeO2C

N H O O OMe OMe OMe OMe Oxidative Cyclization

MeO

N H H MeO2C

N H O O OMe OMe OMe OMe

(±)-Reserpine

R1 N O O O OR3 Intramolecular Diels-Alder H

R1 N O

R1 N H H MeO2C OR2 OMe

OR3

(a) JACS 1985, 107, 4074 (b) JACS 1987, 109, 6124

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 6

Synthesis of (±)-Reserpine: Intramolecular DielsAlder

Cl O O O Et3N, DCM, -30 to 5°C, 1.5h, 89% MOMO H

O 1) n-BuLi; , THF, -78°C to rt, 20h, 81%

OH

1) p-TsCl, Py, DCM, 0°C, 12h, 90% 2) PhCH2NH2, cat NaI, DMSO, rt, 20h, 85%

NHBn

MOMO

2) H2 (45 psi), Pd/CaCO3/PbO, EtOAc, rt, 15 min, 96% MOMO

H N O MOMO H H

-CO2 O MOMO H

H NO

O MOMO H

O

H N O

Bn O N Xylenes reflux, 24h, 93% O O MOMO O

H

H

Bn N O

H MOMO

(a) JACS 1985, 107, 4074 (b) JACS 1987, 109, 6124

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 7

Synthesis of (±)-Reserpine: Refunctionalization of E ring

Bn N Bn O MCPBA, H MOMO DCM, 0°C, 6h, 88% H MOMO O N O 1) BuCH(Et)COOH/BuCH(Et)COOLi, DME, reflux, 12h, 90% 2) MeI, Ag2O, 98% H O MOMO OMe Bn N O O Et n-Bu

Epoxide opening with other bases and conditions gave a mixture of isomers Forcing conditions required for selective hydrogenation of double bond

Bn N O H H MeO2C OMe O O Et n-Bu iii. CH2N2, MeOH/Et2O (1:3), 0°C 75% over three steps H O MOMO OMe H2/1800 psi, 20% Pd(OH)2/C, MeOH, 24h, rt, 90%

i. p-TsOH, MeOH, 45°C, 20h ii. PDC, DMF, rt, 18h

Bn N O H O Et n-Bu

(a) JACS 1985, 107, 4074 (b) JACS 1987, 109, 6124

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 8

Total Synthesis of (±)-Reserpine

Bn N O H H MeO2C OMe O O Et n-Bu THF, -70 to -20°C, 2h, 79% AlH3 H MeO2C OMe O Bn N H O Et n-Bu H N H H MeO2C OMe OMe O O OMe OMe 3) H2/15 psi, 20% Pd(OH)2/C, AcOH, rt, 15h, 94% 1) p-TsOH, MeOH, 85°C, 72h, 81% 2) 3,4,5-trimethoxylbenzoylchloride, Py, DMAP, DCM, rt, 24h, 91%

MeO

N H H MeO2C

N H O O OMe OMe OMe OMe MeO N H Br

DMSO, i-Pr2NEt, rt, 60h, 69%

(a) JACS 1985, 107, 4074 (b) JACS 1987, 109, 6124

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 9

Total Synthesis of (±)-Reserpine

N H H MeO2C OMe OMe O O OMe OMe iii. Zn, 7% HClO4 (aq)/Acetone/THF (1:1:1) reflux, 20 min i. Hg(OAc)2 (10 equiv), 5% HOAc (aq) , 85°C, 1.5h ii. H2S

MeO

N H

MeO H MeO O MeO MeO OMe O OMe 18% -H 4% -H N H H N

N H H H MeO2C

N H O O OMe OMe OMe OMe

H CO2Me

(±)-Reserpine 35% -H (±)-Isoresperine + 8% -H

(a) JACS 1985, 107, 4074 (b) JACS 1987, 109, 6124

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 10

The vinylogous Mannich reaction in alkaloid synthesis

Mannich Reaction N OR N O

Bn N

O Intramolecular hetero Diels-Alder

Bn N

O

5:1 H Me H O

Vinylogous Mannich Reaction N OR Z N O Z

2

O

N H H

( )n N OR Z N H O Z

3

N

O H Me H N O H O

O MeO2C Tetrahydroalstonine 13 steps, 18% yield from commercially available starting materials

H

Me

H MeO2C

( )n N O OR N O O

H

H

Stereoselctivity in C2-C3 bond formation is uncertain. A more consice and efficient route to yohimboid alkaloids may be found using vinylogous mannich reactions (VMR).

(a) Acc. Chem. Res. 2002, 35, 895

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 11

The vinylogous Mannich reaction in alkaloid synthesis

A more concise and efficient route using vinylogous Mannich reaction

COCl N H H OTMS MeO2C O 2 Steps N O N H H H N [H] O H O Me

N H

N

Tetrahydroalstonine 4 steps, from Tryptamine

N H H H MeO2C

N H O Me

Other variants of the vinylogous Mannich/intramolecular hetero Diels-Alder reaction

COCl O O N H N OMe OTMS MeO2C N H H N O O O Benzoquinone MeO2C Oxogambirtannine N H N O

(a) Acc. Chem. Res. 2002, 35, 895. (b) JACS 1991, 113, 6161.

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 12

The vinylogous Mannich reaction in alkaloid synthesis: (±)-Akuammicine

COCl N H H OTMS H N O H O Ph Me 1. p-TsOH aq. THF 2. (Ph3P)3RuCl2, Et3N O Me NaOMe, MeOH then (COCl)2, 0°C Cl N H N H Me CO2Me tert-BuOCl N H H H MeO2C N Me3OBF4, DBPy; then, NaBH4 N O N H H H O N O H O Me N H N

N H H H MeO2C

Me

Me

Deformylgeissoschizine

H Cl N H N Rearrange H CO2Me then tautomerize Me N H

N

H CO2Me

Me

52% from Deformylgeissoschizine

Akuammicine

(a) Acc. Chem. Res. 2002, 35, 895. (b) JACS 1996, 118, 9804.

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 13

The vinylogous Mannich reaction in alkaloid synthesis: (±)-Strychine

BnO N

COCl N H H OTMS H

N

O H OBn O

6 Steps

N H H H MeO2C

N

O

N H

OTBS

1. SnCl4, tert-BuOCl 2. LiHMDS, 3. HCl, MeOH 22%

H H N O H

N Overman's Conditions H O N H

H

N

H CO2Me OH

H Strychnine

(a) Acc. Chem. Res. 2002, 35, 895. (b) JACS 2001, 123, 8003. (c) Overman, LE JACS 1993, 115, 9293.

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 14

Nitrogen heterocycles by olefin metathesis

R2

x(

)

n(

N ) R1 R3

R4

Catalyst Olefin metathesis

x(

)

n(

Cl

PCy3 Ru

Ph A i-Pr Ph Ph B N (F3C)2MeCO Mo (F3C)2MeCO C i-Pr Ph Me Me

N

Cl

) R1

R

2

PCy3 PCy3 Ru Cl PCy3

Olefin metathesis allows for the facile synthesis of fused nitrogen heterocycles, including medium sized rings!

Cl

N O

N O

N O

N O

N O

OBn C, N F3COC Benzene, 50°C 77% N F3COC

OBn

OH

OH OH

OHC

N

O

NH

FR-900482

(a) TL 1994, 35, 6005 (b) Chem. Rev. 2004, 104, 2199. (c) JACS 2000, 122, 10781.

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 15

Total Synthesis of (±)-Manzamine

N H N N

N H OH N

H

CHO H OH Ring Closing N Metathesis R1 N O OR2

CO2Me OH R3 NBoc

Manzamine A Intramolecular Diels-Alder

CO2Me CO2H N TBDPSO Boc R1 CO2Me Br NH R1 N O OR2 NBoc

(a) JACS 1999, 121, 866 (b) JACS 2002, 124, 8584

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 16

Total Synthesis of (±)-Manzamine

1) (Boc)2O 2) TBDPS-Cl HO-(CH2)5-NH2 3) Acrolein, H+, 69% R N CHO Br CO2Me PPh3 Boc DCM, 91% R N Boc CO2Me Br

R = (CH2)5OTBDPS

TMS-OTf, 2,6-Lutidine, then p-TsOH, 85%

CO2Me Br

R

NH2

p-TsO

(a) JACS 1999, 121, 866 (b) JACS 2002, 124, 8584

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 17

Total Synthesis of (±)-Manzamine

a) LHMDS; CO2, -78°C b) NaBH4, 0°C, then H+ N TBDPSO Boc O c) Na2CO3 95% ("one pot") N TBDPSO A= Boc CO2Me Br N O NBoc Br CO2Me R NH2 p-TsO R CO2H (COCl)2 (2.5 equiv) OH then A, Et3N, 79%

R = (CH2)5OTBDPS

OTBDPS

H N O

CO2Me H R NBoc N O NBoc CO2Me Sn (Ph3P)4Pd PhMe,

R

OTBDPS

OTBDPS

(a) JACS 1999, 121, 866 (b) JACS 2002, 124, 8584

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 18

(±)-Manzamine: Synthesis of RCM Precursor

H N O CO2Me H CrO3, 3,5-dimethylpyrazole, DCM, rt, 48h, 63% NBoc R H N O CO2Me H O NBoc 3) Ph3P=CH2, -78 to 0°C 47% O 1) HCl, MeOH 2) DMSO, (COCl)2, Et3N N H CO2Me H O NBoc

R

OTBDPS R = (CH2)5OTBDPS

OTBDPS R = (CH2)5OTBDPS 1) xs DiBAL-H 2) Dess-Martin Periodinane, 53%

Allylic oxidation was troublesome and best achieved with Salmond's protocol

H N O

CH(OMe)2 H H O N O 2) CH2=CHCH2CH2Li -78 to -20°C, 55% 1) MeOH, HC(OMe)3, H+ N O

CHO H O NBoc

(a) JACS 1999, 121, 866 (b) JACS 2002, 124, 8584 (c) Salmond JOC 1978, 43, 2057

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 19

Total Synthesis of (±)-Manzamine

H N O CH(OMe)2 H O N O P(Cy)3 Cl Ru CHPh Cl P(Cy)3 DCM, reflux, 3h 67% H N N O O CH(OMe)2 1) KOH, MeOH, 2) COCl ( )3 , Et3N, 75% N N H CH(OMe)2 OH

O

P(Cy)3 Cl Ru CHPh Cl P(Cy)3 DCM, reflux, 30 min then 1N HCl 26% N H OH N N Manzamine A Ircinal A H CHO OH H 1) DiBAL-H 2) Dess-Martin Periodinane, 56% N N CHO OH

N H N N

O

(a) JACS 1999, 121, 866 (b) JACS 2002, 124, 8584 (c) JOC, 1992, 57, 2480

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 20

Quaternay carbon centers: geminal acylationalkylation

O (OEt)2 P R3 N Ph Ph 1. n-BuLi 2. R1COR2 R1 R

2

N R

3

LiR4

Li R1 R

2

Ph N R R

3 4

1. E 2. H3O R

R1

2

O R3

E

Carbonyl is the most general and accessible functional group. Protocol gives a quaternary carbon center from ketones in a two-step/one-pot reaction.

O O O O 2 Steps O CHO O Me O 1. (OEt)2 O P Li THF, -78°C to reflux 2. n-BuLi O N Ph O O Li N Me O Ph n-Bu H 1. ZnCl, Me O N CO2Me OCOMe CHO N Me Me CO2Bn O O

2. ClCO2Me, 3. HCl aq. O

AcOH, MeOH O O OH O H MeO H N Me MeO H N O N Me CO2Bn O OH OH O OCOMe O O

(±)-Pretazettine

(±)-Haemanthidine

(a) JACS 1980, 102, 5866 (b) JOC 1987, 52, 1962. (c) JACS 1984, 106, 6431 (d) Review: Tetrahedron 1980, 36, 419.

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 21

A modified Mitsunobu

Mitsunobu Reaction

OH R1 R2 RCO2H, Ph3P, EtO2CN=NCO2Et R1 OCOR R2

Modified Mitsunobu Reaction

OH Me H ArCO2H, Ph3P, DEAD Me O OTBS OTBS PhH Me Ar

O O H O Me

OTBS

OTBS Ar = PhAr = p-O2NC6H4OH

27% 86%

OH

OH

n-C6H13

OH

OMe

Me Ar = PhAr = p-O2NC6H4Ar = p-MeOC6H427% 84% 17%

Me Ar = PhAr = p-O2NC6H419% 73%

Ar = PhAr = p-O2NC6H4-

58% 99%

Ar = PhAr = p-O2NC6H4-

35% 50%

Me OH Me

Me Me

O Ar = PhAr = p-O2NC6H462% 89%

HO Ar = PhAr = p-O2NC6H467% 70%

(a) TL 1991, 32, 3017

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 22

Alkoxide-accelerated sigmatropic rearrangements: Taxane diterpenes

Me HO Me OH OH OH Me Me Me OH Me Me Me O OH OH OR RO

O O CH2=CHMgBr 81%, 1.6:1 mixture of ds OH KH THF, 25°C, 10h 83% O

OR

OH

OH

O

Me Me O O O

OMe

OMe

O

O

(a) Evans JACS 1975, 97, 4765 (b) JOC, 1982, 47, 3190

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 23

Enantioselective intramolecular cyclopropanations

MeO2C MeO2C N O O N Rh Rh O O N N CO2Me MeO2C N CO2Me MeO2C O O N Rh Rh O O N N CO2Me CO2Me

[Rh2(5S-MEPY)4]

[Rh2(5R-MEPY)4]

O R3 R1 R2 O N2

[Rh2(5S-MEPY)4] CH2Cl2

R3 O H O

R2 R1

29 to 88 % 65 to >94 %ee

· 2,2 disubstituted olefins gives poor enantioselectivity · Z olefins give greater levels of enantioselectivity than E isomers

H O H O 75 % 95 %ee

H H O

H H O

Me Me O

Me H H O 72 % 7 %ee H O

H H O

Ph H O

H H O

H Ph

89 % 98 %ee

70 % >94 %ee

78 % >68 %ee

(a) JACS 1991, 113, 1423 (b) JACS 1995, 117, 5763

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 24

Enantioselective intramolecular cyclopropanations

O Me O n-BuLi, Me3SI, THF, 84% Me OH O O Me O O p-TsN3, Et3N, CH3CN; Me then, LiOH·H2O, 97% O N2 O

DMAP, NaOAc, THF, 93%

[Rh2(5R-MEPY)4] CH2Cl2, 99% 1:1 dr, 94%ee OHC Me H 1. (COCl)2, DMF, CH2Cl2, H HO2C Me H H OBn MeO2C CO2Me Pd(PPh3)4, PPh3, NaH, THF, 71% OBn O H O H Me

MeO2C MeO2C

2. LiAlH(Ot-Bu)3, THF, -78°C 84% over two steps OBn MeO2C MeO2C

[Rh(CO)2Cl]2,PhMe 110°C, 85% OH CHO MeO2C MeO2C H Me Me Me H Me OH OH Me Me H Me O O

Tremulenolide A and Tremulenediol A

(a) OL 2005, 7, 4345

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 25

MeO

N H H H MeO2C

N H O O OMe OMe

Natural Product Synthesis

N

OMe

O

H

O O OH OH MeO N MeO N Me OH O H H H

(+)-Tirandamycic Acid JOC 1984. 49, 2512 HO O

N H OH

O

O

OMe

N N

(±)-Reserpine JACS 1985, 107, 407 JACS 1987, 109, 6124

HO O O O

HO H O O Lycorine JOC 1982, 47, 3634 N H

Manzamine A JACS 2002, 124, 8584 JACS 1999, 121, 866 TL 1994, 35, 691

Me Ph

OH

(±)-Haemanthidine JOC 1987, 52, 1962 JACS 1984, 106, 6431

(±)-Pretazettine

O

JOC 1987, 52, 1962 JACS 1984, 106, 6431

MeO2C

O H

NH

(+)-Phyllanthocin JOC 1987, 52 3706

OH OCONH2 OH OHC N O NH

HO

H O H OH O

N H H H MeO2C

N H O Me

(+)-Anatoxin-a OL 2004, 6, 1329

N H H H N

Solandelactone E

(±)-Tetrahydroalstonine TL 1997, 38, 7641 JACS 1988, 110, 5925

N H H H N Me O

MeO2C OH Geissoschizine (±) JACS 1988, 110, 5925 (+) OL 1999, 1, 79 (+) JACS 2003, 125, 4541

FR-900482 TL 1995, 36, 1169

Me O O H N H H O

JACS 2007, 129, 510

Me O

OH O H

OH OH O Me

MeO2C (±)-Cathenamine

N H MeO N H H

(+)-Croomine JACS 1996, 118, 3299

Me OH O Galtamycinone TL 2003, 44, 1075

JACS 1988, 110, 5925

H Me N H

O

Me

Me OH

O O

Aspidospermine

O

Me

H

N Me H HN Setoclavine JACS 2001, 123, 5918

NHMe H

O O

OH OH O

JACS 1980, 102, 3294

OH OH H O HO2C OH (+)-KDO JOC 1991, 56, 6600

O

Me

O Me

HN Rugulovasines A = -H Rugulovasines B = -H JACS 2001, 123, 5918

(±)-Dendrobine

OH

HO N

HO

H

H

JOC 1991, 56, 642

H

MeO

H

N

Tremulenolide A and Tremulenediol A OL 2005, 7, 4535

(±)-Crinine TL 1987, 28, 503

(±)-Bulphanisine TL 1987, 28, 503

CU Synthesis Lit Group ­ CIR:SF Martin ­ Tran 26

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