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