Enantioselective Total Synthesis of (+)-Salvileucalin B

Leiv, S.; Nani, R. R.; Reisman, S.E. JACS. 2010, ASAP

Tropylium Ion Mediated alpha-cyanation of AminesAllen, J. M.; Lambert, T. H. JACS. 2010, ASAP

OO

O

H

OO

i-Bu2NMe

H

Me

BF4–

KCN, MeCN23 °C, 3 hrs

i-Bu2NMe

CN

Me

+ KBF4

+

HH

81% yield

Sarah E. Reisman

1997 - 2001: B.A. Connecticut College, New London, CT

2001 - 2006: Ph.D. Yale University (John Wood/Total Synthesis)

2006 - 2008: NIH Postdoctoral Fellow, Harvard University (Jacobsen, asymmetric catalysis)

2008 - current: Assistant Professor at Caltech University

Research Interests

Natural product synthesis - Emphasis on the development of catalytic asymmetric methods that facilitate the construction of complex molecules.

Current areas of research - Synthesis of alkaloid natural products, catalytic asymmetric methods for the synthesis of arylated indolines, and the development of catalysts for enantioselective electrophilic chlorination.

(+)-Salvileucalin B

• Isolated in 2008 by Takeya and co-workers from Salvia leucantha

• Exhibits cytotoxicity again A459 (Human Lung) and HT-29 (Human Colon) cells with IC50 of 5.23 and 1.88 µg/mL

• Norcaradiene core embedded within a caged polycyclic skeleton

• Five stereogenic centers, with 3 all carbon quaternary centers

• First reported enantioselective total synthesis

• The key step involves a intramolecular copper catalyzed arene cyclopropanation •18 steps longest linear sequence

OO

O

H

OO

OO

O

H

OO

OO

O

H

OO

Retrosynthetic Approach to (+)-Salvileucalin B

OO

O

H

OO

salvileucalin B

O

O

H

OO

IntramolecularArene

CyclopropanationO

O

H

O

N2

CN

O

H*R

O O

Metal-CatalyzedCycloisomerization

*R

O

TMS

+OTBS

+O

OHC

Construction of TriyneO

H*R

O O

O

*R

TMSO

O

H

TBSO

Me2Zn,8 (40 mol %)PhMe, 70 °C;

3-furaldehyde0 °C to 23 °C 85 % yield

O

NH

Me

PhOH

Ph

8

TBSO

OH

O

93% ee

1) NaH, DMF, 23 °C2) 1M HCl, MeOH

Br

3) MsCl, Et3N, THF, 23 °C, then LiBr 80% yield, 3 steps

Br

O

O

LHMDS, LiCl,THF, –78 °C to 23 °C;

NMe

O

TMS

Me

OH

Ph

then , –78 °C 90% yield

O

NMeMe

PhOH

TMS

O

O> 10: 1 dr

Synthesis of (+)-Salvileucalin B

O

*R

TMSO

O

H

1) TBAF, DCM, 23 °C2) RuCp*(Cod)Cl (8 mol %), DCM, 45 °C3) n-Bu4NOH, t-BuOH/H2O, 90 °C 74% yield, 3 steps

O

O

H

HO2C

1) (COCl)2, cat. DMF then CH2N2, THF

2) AgTFA, MeOH, Et3N THF, —30 °C to 23 °C 69% yield, 2 steps

O

O

H

CO2Me

Arndt—Eistert homologation

1) NaCH2CN THF, –78 °C to 23 °C2) (imid)SO2N3, pyr 78% yield, 2 steps

O

O

H

O

N2

CN

O

O

H

CNO

Cu(hfacac)2(10 mol %)

DCM, 120 °Cµwave, 1 min

65% yield

O

F3C CF3

O

hexafluoroacetylacetonate

NaHMDS, –78 °C;then Tf2NPh

90% yield

O

O

H

CNOTf

Continued Synthesis of (+)-Salvileucalin B

O

O

H

CNOTf

DIBALDCM, –40 °C;then aq. AcOH

O

O

H

OTf

O

H

retro-Claisenrearrangment

O

O

H

OTf

O

H

DIBALDCM, –40 °C;then aq. AcOH57% yield, 2 steps

O

O

H

OTf OH

Pd2(dba)3 (5 mol %)dppf (10 mol %), CO

DIPEA, THF, 23 °C98% yield

O

O

H

OO

CrO3,

DCM, —35 °C51% yield

NNH

Me

MeO

O

H

OO

O

O

O

H

OO

O

H1:2 ratio

Tristan H. Lambert

1994 - 1998: B.S. University of Wisconsin at Platteville; Dwight Klaassen

1998 - 2004: Ph.D. UC-Berkeley and Caltech (David MacMillan/Methodology)

2004 - 2006: NIH Postdoctoral Fellow, Sloan-Kettering Cancer Center; (Danishefky, total synthesis)

2006 - current: Assistant Professor at Columbia University

Research InterestsAromatic Ions - The use of aromatic ions as catalysts/promoters for new synthetic methodologies

Multicatalysis - The use of catalysis to assemble complex molecules in a single pot.

Reaction Design - new transition metal catalyzed cycloadditions

Iminium Ion in Synthesis

• Traditional carbonyl-amine condensations are limited in terms of scope

• Iminium ion formation by amine oxidation typically carried out under harsh conditions (transition metals, DDQ, PhI(OAc)2, or singlet oxygen).

• Trityl and tropylium ions are known to oxidize amines by hydride abstraction; synthetic utility under explored.

• Tropylium ion - 6π electron aromatic cation, shelf stable, commercially available

NRR

R1

Nu— N RR

R1 Nu

H

BF4

i-Bu2NMe

H

Me MeCN23 °C, 30 min

i-Bu2NMe

Me

b.p. = 116 °C

+

HH

100% conv.

BF4

Alpha-cyanation of Amines

i-Bu2NMe

H

Me

BF4–

KCN, MeCN23 °C, 3 hrs

i-Bu2NMe

CN

Me

+ KBF4

+

HH

81% yield

KCN added before oxidation

BF4– KCNHNC

Not observed

i-Bu2NMe

H

Me

BF4–

KCN, MeCN18-crown-623 °C, 3 hrs

No oxidation observed

i-Bu2NMe

H

Me

BF4–

TMSCN, MeCN23 °C, 3 hrs

No oxidation observed

Key is low solubility of KCN

in MeCN

Substrate Scope

R1N

R2R3

BF4–

KCN, MeCN

R1N

R2R3

CN

N

Me

CN

80 °C, 12 h71% yield

Me

MeMe

N

N

H

H

CN

23 °C, 3 h90% yield1 g scale

N

i-Bu Me

Me

23 °C, 0.25 h73% yield

CNBn

N

Bn

80 °C, 12 h42% yield

CN

Ni-Bu Me

Me

120 °C, 12 h78% yield

5.9:1 regioselectivity

CN

Ni-Bu Me

Me

120 °C, 12 h77% yield

> 20:1 regioselectivity

CN

O2N

Ni-Bu Me

Me

100 °C, 12 h43% yield

3.7:1 regioselectivity

CN

MeO

Proposed Mechanistic Pathway

N

R

RH

R

hydridetransfer

Tp+BF4—

HH

N

R

R

R

N

R

RH

R

electrontransfer

N

i-Bu Me

Me

H

R+

• electron donor-acceptor complex

• might explain poor benzylic oxidations

One Final Transformation

NH

Ph

Ph

secondary amine

BF4–

120 °C MeCN NPhPh 73% yield

oxidativeaza-cope

rearrangement

Steric ecumbrance by the gem-diphenyl group prevents alkylation of secondary amine