Total Synthesis of (–)-Dendrobine

Kreis, L. M.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51, 1-5.

Kara George RosenkerWipf Group Current Literature

31 March 2011

Me

NMe

OO

H i-Pr

(!)-Dendrobine

MeO2C

MeMe

OMe

H NH

Me

Me

CHO

MeO2C

MeMe

O

Cascade sequence

Linchpin amineNHBnMe

Kara Rosenker @ Wipf Group Page 1 of 15 3/31/2012

(–)-Dendrobine: Isolation and Biological Activity

Most abundant sesquiterpene bases isolated from the ornamental orchid “JinchaiShihu” (Dendrobium nobile Lindl.)

Principle component of the Chinese medicinal tonic “Chin Shih Hu” and exhibitsantipyretic, hypertensive, and convulsant activity

Intriguing structure containing seven contiguous stereocenters Has served as a target to examine novel tactics and strategies for chemical

synthesis 12 syntheses to dateSuzuki, H.; Keimatsu, I.; Ito, K. Pharm. Soc. Jpn. 1932, 52, 1049-1060.Suzuki, H.; Keimatsu, I.; Ito, K. Pharm. Soc. Jpn. 1934, 54, 802-812.Inubushi, Y.; Sasaki, Y.; Tsuda, Y.; Yasui, B.; Konika, T.; Matsumoto, J.; Katarao, E.; Nakano, J. Tetrahedron, 1964, 20, 2007-2023.Inubushi, Y.; Sasaki, Y.; Tsuda, Y.; Nakano, J. Tetrahedron Lett. 1965, 6, 1519-1523.Chen, K. K.; Chen, A. L.; J. Biol. Chem. 1935, 111, 653-658.Chen, K. K.; Chen, A. L.; J. Pharmacol. 1935, 55, 319-325.

Me

NMe

OO

H i-Pr

(!)-Dendrobine

Kara Rosenker @ Wipf Group Page 2 of 15 3/31/2012

Dendrobine: Previous Syntheses

Racemic Total Syntheses Yamada, K. et al. JACS, 1972, 94, 8278. 24 steps, 0.99% yield Inubushi, Y. et al. J. Chem. Soc. Chem. Commun.1972, 1252. 20 steps, 0.06% yield Kende, A. S. et al. JACS 1974, 96, 4332. 15 steps, 1.1% yield Roush, W. R. JACS 1978, 100, 3599. 24 steps, 0.66% yield Livinghouse, T. et al. JACS 1992, 114, 4089. 10 steps, 6.15% yield

Racemic Formal Syntheses Martin, S. F. et al. JOC 1991, 56, 642. (Inubushi) 14 steps, 0.12% yield Padwa, A. et al. Org. Lett. 2000, 2, 3233. (Kende) 19 steps, 0.4% yield

Enantioselective Total Syntheses Sha, C.-K. et al. JACS 1997, 119, 4130. 20 steps, 2.0% yield Cassayre, S. Z. et al. JACS 1999, 121, 6072. 13 steps, 1.8% yield

Enantioselective Formal Syntheses Trost, B. M. et al. JACS 1991, 113, 670. (Roush) 26 steps, 1.98% yield Mori, M. et al. JOC 1994, 59, 5633. (Kende) 21 steps, 0.78% yield Corey, E. J. et al. JACS 2004, 126, 13708. (Kende) carried out Kende’s key Diels-

Alder step in an enantionselective fashion

Kara Rosenker @ Wipf Group Page 3 of 15 3/31/2012

Title Paper: Retrosynthetic Strategy

Strategy is based on a key cascade reaction with an amine functioning as the linchpin Installs both the quaternary C11 center and the stereocenter at C3

Lukas, K. M.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51, 1-5.

Me

CHO

MeO2C

MeMe

OMeO2C

MeMe

OMe

NMe

R

Me

NMe

OO

H i-Pr

(!)-Dendrobine

Cascade sequence

C10-N bond formationreductive lactonization

Stereoselective protonation

Enamine conjugate addition

3

11

MeMe

BzO OOTBS

MeLi

(CH2)4OTBDPS

OTBS

OHOTBDPS

4HO

Me MeO

OTBDPS

O

Me

Me OTBS4

Ireland-ClaisenRearrangement

10

Kara Rosenker @ Wipf Group Page 4 of 15 3/31/2012

Asymmetric Michael Reactions

Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.

N

EWG

ONEWG Nu

Enamine Enolate Iminium

R1N

R2

R1N

R2

R1N

R5EWG

R3 R4

R3R5

EWGR4R1

O

R5EWG

R3 R4

R2

R2

R1O

R2

NH

H

H2O H

H2O

Catalytic activation:

Enamine-Catalyzed Michael Reaction

Kara Rosenker @ Wipf Group Page 5 of 15 3/31/2012

Asymmetric Michael Reactions

Fonseca, M. T. H.; List, B. Angew. Chem. 2004, 116, 4048-4050.Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028-16029.

First catalytic asymmetric intramolecular Michael reaction of aldehydes

Complementary catalytic asymmetric intramolecular Michael reaction of aldehydes

H

O R3O

R1 R2

R3

OH

O

R1 R2

R1 = H, CO2Me, -S(CH2)3S- R2 = H, CO2Me, -S(CH2)3S- R3 = Me, Ph

93-100%97- >99% ee

(8:1 dr - >19:1 dr)

S

NH2 HN

O

CF3CO2

10 mol%

acetone, 0 °C, 1-4 h

H

O

X

RO NH2

NO

Bn

10 mol%

THF, rt, 15-24 h XR

OH

OCl

R = H, Me, PhX = CH2, NTs

85-99%80-97% ee

(8:1 dr - 49:1 dr)

Kara Rosenker @ Wipf Group Page 6 of 15 3/31/2012

Asymmetric Michael Reactions

Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028-16029.

Complementary catalytic asymmetric intramolecular Michael reaction of aldehydes

S

NH2 HN

O

CF3CO2

10 mol%

CH3CN, 0 °C, 3-5 h

O

H

O

RH

R

O

H

O

89-100%90-95% ee

(10:1 dr - 24:1 dr)

R= Me, n-Bu, Bn, allyl

No examples of a Michael reaction involving β-substitued enones to generatequaternary centers

MeO2C

MeMe

OMe

H NH

Me

Me

CHO

MeO2C

MeMe

O

Cascade sequence

Linchpin amineNHBnMe

Kara Rosenker @ Wipf Group Page 7 of 15 3/31/2012

Fragment Synthesis

OH OTBDPS

1. TBDPSCl, im. DCM, 0 °C to rt

2. BuLi, MeI, -78 °C to rt

88% (2 steps)

1. Cp2ZrCl2, DIBAL THF, 0 °C to 60 °C

2. I2, -78 °C81% (2 steps)

Me

MeI

OTBDPS

Costa, J. S.; Dias, A. G.; Anholeto, A. L.; Monteiro, M. D.; Patocinio, V. L.; Cosat, P. R. R. J. Org. Chem., 1997, 62, 4002 - 4006.

EtO2C

OO

MeMe

MeMeO

O

MeMeEtO2C

1. i-PrNO2, TBAF THF, rt

2. Bu3SnH, AIBN tol., 110 °C

76% (2 steps)

1. LiAlH4, THF, 0 °C2. BzCl, DMAP, Et3N DCM, 0 °C to rt

3. AcOH, H2O, 50 °C4. TBSCl, DMAP, im. DCM, 0 °C to rt

5. HF!pyridine, THF 0 °C to rt

6. (COCl)2, DMSO, Et3N -78 °C to rt

73% (4 steps)

MeMe

BzO OTBSOTBS

82% (2 steps)

MeMe

BzO OOTBS

Kara Rosenker @ Wipf Group Page 8 of 15 3/31/2012

Synthesis of Key Intermediate

OOTBDPS

O

Me

Me OTBS4

88%

1. LDA, TMSCl, !

2. TMSCHN2

95% (2 steps)Me Me

OTBS

Me

TBDPSO 4

1. HF"pyridine, THF 0 °C to rt

2. PCC, Celite DCM, rt

MeO2C

Me Me

O

Me

MeO2C

OHC

67% (2 steps)

OTBSMeLi

(CH2)4OTBDPS

OHOTBDPS

4

B, 0 °C; then EtMgBr

81% (anti/syn = 2.2:1)

MeMe

BzO OOTBS

HO

Me Me

B

TEMPO, PhI(OAc)2

DCM, 0 °C to rt

pyrrolidine, C5H6

4 Å mol. sieves, 80 °C MeO2C

MeMe

O

!CHOMe

Me Me

O

MeN

EtO2C

65% (d.r. = 2:1)

3

11

Kara Rosenker @ Wipf Group Page 9 of 15 3/31/2012

Intramolecular Enamine Michael Addition: Cyclization Studies

Preliminary cyclization studiesrevealed good stereocontrol at

C11, and no stereocontrol at C3

Me Me

O

Me1. BnMeNH, 4 Å MS tol. 80 °C

2. H2, Pd/C, 4 Å MS MeOH, 0 °C to rt MeO2C

MeMe

OMe

MeO2C

68% (2 steps)

311OHC

H NH

Me

Cyclization with N-methylbenzyl-amine gave same d.r. (2:1)

Cyclization and subsequentreduction provided a d.r.>10:1

and allows for introduction of thedesired pendant amine

pyrrolidine, C5H6

4 Å mol. sieves, 80 °CMeO2C

MeMe

O

!CHOMe

65% (d.r. = 2:1)

3

11

Me Me

O

Me

MeO2C

OHC

BnMeNH, C5H6

4 Å mol. sieves

(d.r. = 2:1)

Me Me

O

Me

MeO2C

OHC

MeO2C

MeMe

O

!CHOMe3

11

Kara Rosenker @ Wipf Group Page 10 of 15 3/31/2012

Intramolecular Enamine Micahel Addition: Cyclization Studies

Me Me

O

Me1. Me2NH, 4 Å MS tol. 80 °C

2. H2, Pd/C, 4 Å MS MeOH, 0 °C to rt MeO2C

MeMe

OMe

MeO2C

311OHC

H NMe2

98% (2 steps)

The cyclization cascade can also be applied to other amines

Me Me

O

Me1. BnNH(CH2)2OTBDPS 4 Å MS, tol. 80 °C

2. H2, Pd/C, 4 Å MS MeOH, 0 °C to rt MeO2C

MeMe

OMe

MeO2C

311OHC

H NH

55% (2 steps)

OTBDPS

Kara Rosenker @ Wipf Group Page 11 of 15 3/31/2012

Cascade Sequence: Mechanistic Proposals

CO2Me

i-Pr

O

NMe

Bn H

MeO Mei-Pr

CO2Me

BnMeN

endo

Me Me

O

Me

MeO2C

NMeBn

MeO2C

MeMe

OMe

NMeBnO Mei-Pr

CO2Me

NMeBn

stereoselectiveC=C reduction

MeO2C

MeMe

OMe

H NH

Me

concave protonation

convexprotonation O Mei-Pr

CO2Me

BnMeN

[H]

O Mei-PrCO2Me

H NMeBn

[H]

[H]

A

B

C

D

provides diastereomer

Kara Rosenker @ Wipf Group Page 12 of 15 3/31/2012

Cascade Sequence: Pathway D Favored

pyrrolidine, C5H6

4 Å mol. sieves, 80 °CMeO2C

MeMe

O

!CHOMe3

11

Me Me

O

Me

MeO2C

OHC

65% (d.r. 2:1)

(d.r. 5:1)

Me Me

O

Me

MeO2C

NMeBn

MeO2C

MeMe

OMe

NMeBn

MeO2C

MeMe

OMe

H NH

Me

convexprotonation O Mei-Pr

CO2Me

BnMeN

[H]

D

Kara Rosenker @ Wipf Group Page 13 of 15 3/31/2012

Completion of (–)-Dendrobine

18 linear steps, 4.0% overall yield NH

O3

HBr3

PHT: pyrrolidone hydrotribromide

MeO2C

MeMe

OMe

310

H NH

Me

MeO2C

MeMe

OMe

H NMe

Br

MeO2C

MeMe

OMe

H NH

Me

Br

MeO2C

MeMe

OMe

N

H

Me

10PHT, THF, rt;

then DMAP

63%

NaBH4, i-PrOH

rt to 50 °C

Me

NMe

OO

H i-Pr

(!)-Dendrobine65%

Awang, D. V. C.; Wolfe, S. Canadian J. Chem. 1969, 47, 706-709.McKenzie, T. C. J. Org. Chem. 1974, 39, 629-631.

Kara Rosenker @ Wipf Group Page 14 of 15 3/31/2012

Conclusions

Asymmetric total sythesis of (–)-dendrobine was achieved in 18 linear steps,4.0% overall yield

Key features of the synthesis include: Efficient construction of the central cyclohexane core by an Ireland-Claisen

rearrangement A conjugate enamine addition/hydrogenation sequence to install the quaternary

center as well as the pendant methyl amino group Regioselective ketone bromination followed by pyrrolidine formation

The first report of an enamine conjugate addition to a β-disubstituted enoneto generate a quaternary stereocenter

Kara Rosenker @ Wipf Group Page 15 of 15 3/31/2012