Enantioselective Total Synthesis of (+)-Salvileucalin B
Leiv, S.; Nani, R. R.; Reisman, S.E. JACS. 2010, ASAP
O
O
O
H
O
O
Tropylium Ion Mediated alpha-cyanation of Amines
Allen, J. M.; Lambert, T. H. JACS. 2010, ASAP
BF4–
H
H
CN
Me
i-Bu2N
Me
i-Bu2N
Me
KCN, MeCN
23 °C, 3 hrs
H
+
Me
81% yield
+ KBF4
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
O
O
O
H
H
O
O
• 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
Retrosynthetic Approach to (+)-Salvileucalin B
O
O
O
O
O
O
Intramolecular
Arene
Cyclopropanation
O
H
H
H
N2
O
O
O
O
O
CN
salvileucalin B
Metal-Catalyzed
Cycloisomerization
O
TMS
OHC
OTBS
O
+
+
*R
O
*R
H
O
O
O
Construction of Triyne
*R
H
O
Me2Zn,
8 (40 mol %)
PhMe, 70 °C;
TBSO
3-furaldehyde
0 °C to 23 °C
85 % yield
O
Ph
OH
O
TBSO
OH
93% ee
1) NaH,
DMF, 23 °C Br
2) 1M HCl, MeOH
O
O
Br
3) MsCl, Et3N, THF,
23 °C, then LiBr
80% yield, 3 steps
O
Me
N
H
Ph
8
TMS
O
Me
O
NMe
then , –78 °C
90% yield
Ph
OH
O
> 10: 1 dr
O
*R
H
O
O
TMS
LHMDS, LiCl,
THF, –78 °C to 23 °C;
Me
Ph
OH
O
N
Me
TMS
Synthesis of (+)-Salvileucalin B
O
*R
H
O
O
TMS
3) n-Bu4NOH,
t-BuOH/H2O, 90 °C
74% yield, 3 steps
O
O
1) TBAF, DCM, 23 °C
2) RuCp*(Cod)Cl
(8 mol %), DCM, 45 °C
O
H
1) (COCl)2, cat. DMF
then CH2N2, THF
O
H
2) AgTFA, MeOH, Et3N
THF, —30 °C to 23 °C
69% yield, 2 steps
HO2C
CO2Me
Arndt—Eistert homologation
1) NaCH2CN
THF, –78 °C to 23 °C
2) (imid)SO2N3, pyr
78% yield, 2 steps
O
O
H
NaHMDS, –78 °C;
then Tf2NPh
90% yield
O
H
CN
OTf
O
O
CN
O
Cu(hfacac)2
(10 mol %)
DCM, 120 °C
µwave, 1 min
65% yield
H
N2
O
O
O
F3C
O
CF3
hexafluoroacetylacetonate
CN
Continued Synthesis of (+)-Salvileucalin B
O
O
O
O
H
DIBAL
DCM, –40 °C;
then aq. AcOH
retro-Claisen
rearrangment
O
H
O
H
O
O
CN
OTf
OTf
OTf
H
DIBAL
DCM, –40 °C;
then aq. AcOH
57% yield, 2 steps
O
O
O
H
O
O
H
O
O
N
H
Me
O
H
Pd2(dba)3 (5 mol %)
dppf (10 mol %), CO
O
H
DIPEA, THF, 23 °C
98% yield
O
O
O
O
N
DCM, —35 °C
51% yield
1:2 ratio
O
O
O
Me
CrO3,
H
H
OTf
OH
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 Interests
Aromatic 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
R
N
R
Nu—
R
N
R1
R1
R
H
Nu
• 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
BF4
H
BF4
H
Me
i-Bu2N
Me
i-Bu2N
Me
MeCN
23 °C, 30 min
H
+
Me
100% conv.
b.p. = 116 °C
Alpha-cyanation of Amines
BF4–
H
H
CN
Me
i-Bu2N
Me
i-Bu2N
KCN, MeCN
23 °C, 3 hrs
Me
H
Key is low
solubility of KCN
in MeCN
+
Me
81% yield
+ KBF4
KCN added before oxidation
NC
BF4–
KCN
H
Not observed
BF4–
H
Me
i-Bu2N
No oxidation observed
KCN, MeCN
18-crown-6
23 °C, 3 hrs
Me
BF4–
H
Me
i-Bu2N
Me
No oxidation observed
TMSCN, MeCN
23 °C, 3 hrs
Substrate Scope
BF4–
R1
R3
N
KCN, MeCN
R2
R3
N
R2
CN
CN
Me
N
i-Bu
CN
R1
Me
Me
N
i-Bu
O2N
120 °C, 12 h
78% yield
5.9:1 regioselectivity
Me
H
CN
23 °C, 3 h
90% yield
1 g scale
i-Bu
MeO
Me
N
Me
100 °C, 12 h
43% yield
3.7:1 regioselectivity
N
N
Me
N
120 °C, 12 h
77% yield
> 20:1 regioselectivity
H
Me
CN
Me
N
i-Bu
Me
23 °C, 0.25 h
73% yield
Bn
Me
80 °C, 12 h
71% yield
CN
CN
Me
N
Bn
80 °C, 12 h
42% yield
CN
Proposed Mechanistic Pathway
H
R
H
R
N
hydride
transfer
R
R
R
Tp+BF4—
N
H
R
electron
transfer
R
R
N
H
R
R+
• electron donor-acceptor complex
H
Me
N
i-Bu
Me
• might explain poor benzylic oxidations
One Final Transformation
BF4–
Ph
Ph
73% yield
Ph
N
H
secondary amine
120 °C MeCN
Ph
N
oxidative
aza-cope
rearrangement
Steric ecumbrance by the gem-diphenyl group prevents alkylation of secondary amine