Toward the development of a general chiral auxiliary. Enantioselective alkylation and a new catalytic asymmetric addition of silyloxyfurans: Application to a total synthesis of (-)-rasfonin

Article abstract of DOI:10.1021/ja063532+

An enantioselective total synthesis of the apoptosis-inducing natural product, (-)-rasfonin, is described. Camphor lactam-mediated asymmetric alkylation reactions enabled the installation of three stereogenic centers with >95:5 diastereoselectivity. A modified Corey-Peterson olefination was employed in the construction of the (E,E)-diene system. A highly diastereoselective, asymmetric vinylogous Mukaiyama aldol addition was conducted using a chiral cationic oxazaborolidine catalyst. The pyranone core of the natural product was prepared via a DBU-promoted rearrangement of a furanol to its corresponding pyranol with concomitant [1,4]-silyl transfer. Copyright

Full text of DOI:10.1021/ja063532+

Published on Web 08/04/2006
Toward the Development of a General Chiral Auxiliary. Enantioselective
Alkylation and a New Catalytic Asymmetric Addition of Silyloxyfurans:
Application to a Total Synthesis of (-)-Rasfonin
Robert K. Boeckman, Jr.,* Joseph E. Pero, and Debra J. Boehmler
Department of Chemistry, UniVersity of Rochester, P.O. Box 270216, Hutchison Hall,
Rochester, New York 14627-0216
Received May 26, 2006; E-mail: rkb@rkbmac.chem.rochester.edu
Scheme 1. Retrosynthetic Analysis
In 2000, TT-1, an R-pyranone-containing natural product, was
isolated by Ishibashi et al. from the fungus Trichurus terrophilus.1
In the same year, Hayakawa and co-workers reported the isolation
of (-)-rasfonin from the fermented mycelium of Taleromyces
species 3656-A1.2 Through chemical and spectroscopic studies,1,2
TT-1 and (-)-rasfonin (1) were found to be identical and to possess
the depicted structure and absolute configuration consisting of two
principal alkyl appendages and a δ-lactone core.
(-)-Rasfonin (1) was named after the protein ras since its
biological activity is elicited in cells that are dependent on ras for
growth. The protein ras functions as a molecular switch for signal
Scheme 2. Preparation of Butenolide 16a
transduction pathways that control cell growth and differentiation,
as a stimulant for cell growth, as a suppressor of apoptosis
(programmed cell death), and, most significantly, as an oncogene
that is able to induce tumors in animals or cell cultures.2
Recent studies have indicated that (-)-rasfonin (1) can selectively
destroy ras-dependent cells with an IC50 of 0.16 µg/mL.2 Exposure
to higher concentrations of (-)-1 (1 µg/mL) resulted in a consider-
able number of cells exhibiting condensed chromatin and frag-
mented nuclei, the typical markers of apoptosis.2 A non-ras-
a Reagents and conditions: (a) LiHMDS, THF, 0 °C, then 8, -40 °C,
18 h; (b) LiBH4, MeOH, Et2O, 0 °C to rt, 2 h; (c) (COCl)2, DMSO, TEA,
-78 to 0 °C, 45 min; (d) toluene, reflux, 24 h; (e) DCE, 70 °C, 18 h; (f)
Et3SiH, Pd/CaCO3/PbO, acetone, 50 °C, 18 h; (g) LiHMDS, THF, -78
°C, then MeI, -78 to -40 °C, 18 h; (h) LAH, Et2O, rt, 18 h; (i) NMO,
TPAP, 4 Å MS, rt, 20 min; (j) BF3‚OEt2, CH2Cl2, -78 °C, 18 h.
dependent cell line was unaffected at concentrations of (-)-1 up
to 1.25 µg/mL.
Selective inducers of apoptosis in ras-dependent cells could
represent a novel class of cancer chemotherapeutics useful for
treatment of tumors expressing constitutively active, mutant ras.
Despite this potential, only one lengthy total synthesis of (-)-1
has been reported.3 That synthesis was principally intended to
confirm the structure and absolute configuration of (-)-1. Thus,
we sought to develop an alternative route to (-)-1 that would be
flexible enough for analogue preparation and more amenable to
scale-up.
In our retrosynthetic analysis, (-)-1 was envisioned to be derived
from diene acid 2 and pyranol 3 (Scheme 1). Rearrangement of
furanol 4 with concomitant [1,4]-silyl transfer would afford
intermediate 3. An asymmetric vinylogous Mukaiyama aldol
addition4 of siloxyfuran 5 to aldehyde 6 would give rise to the
butenolide precursor to furanol 4. Judicious use of the appropriate
enantiomers of the camphor lactam chiral auxiliaries should, in
theory, allow access to all stereoisomers of the two side chains in
high enantiomeric purity via the same reaction sequence for each.
Diastereoselective alkylation of (1S)-2-azaimide 7 (Scheme 2)
with tiglic iodide (8) afforded alkenyl imide 9 in 87% yield as a
single diastereomer.5 Reductive removal of the camphor lactam and
subsequent Swern oxidation6 furnished the sensitive aldehyde 10.
Homologation of 10 with phosphorane 13,7 in turn obtained in
90% yield by acylation of (1R)-11 with (triphenylphosphora-
nylidene)ketene,8 provided imide 14 in 80% yield with >95:5 E:Z
diastereoselectivity. No detectable epimerization of the proximal
stereogenic center was observed.
Regioselective reduction of the conjugated olefin in imide 14
with Lindlar catalyst and triethylsilane9 followed by auxiliary-
controlled diastereoselective methylation provided adduct 15 in 84%
yield over two steps and >95:5 dr. Reductive removal of the
auxiliary, followed by Ley oxidation,10 afforded aldehyde 6 with
complete retention of stereochemical fidelity.
The pivotal vinylogous Mukaiyama aldol addition was first
attempted using BF3‚OEt2. Reaction of 5 and 6 afforded butenolide
product 16 in 95% yield with 11.7:1 threo:erythro diastereoselec-
tivity. The (R,R)-threo:(S,S)-threo diastereomeric ratio was only
1.3:1, verifying the expected lack of substrate control of diaste-
reofacial selectivity in addition to the aldehyde.
Considering the excellent threo:erythro relative diastereoselec-
tivity provided by BF3‚OEt2, we envisioned use of a chiral boron
Lewis acid for the requisite Mukaiyama aldol reaction. The chiral
cationic oxazaborolidines used by Corey for asymmetric Diels-
Alder reactions appeared attractive.11 The easy preparation and
modification and high reactivity of these catalysts rendered them
promising candidates for catalysis of the key vinylogous Mukaiyama
aldol reaction.12
Our results (Table 1) are in accord with Corey’s report.11
Increasing the steric bulk of the boron substituent (18a f 18b) led
to significantly higher asymmetric induction. Utilization of the
9
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J. AM. CHEM. SOC. 2006, 128, 11032-11033
10.1021/ja063532+ CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Catalysis of the Vinylogous Mukaiyama Aldol by 18
Scheme 4. Completion of the Total Synthesis of (-)-Rasfonin (1)a
yield
entry
18
R
R
′
(%)
threo:erythroa
threo dra
1
2
3
a
b
c
Me
o-tol
o-tol
H
H
Me
75
78
81
4:1
11:1
20:1
3:1
6:1
>20:1
1
a Diastereomeric ratio was measured by H NMR.
a Reagents and conditions: (a) TiCl4, DIPEA, CH2Cl2, 0 °C, then
BOMCl, 0 °C, 24-48 h; (b) O3, CH2Cl2:MeOH (95:5), pH 7 phosphate
buffer, -78 °C, then DMS, -78 to rt, 18 h; (c) BH3‚THF, THF, 0 °C, 2.5
h; (d) (MeO)(Me)NH‚HCl, AlMe3, THF, -78 to 0 °C, 1.5 h; (e) BnBr,
TBAI, Ag2O, CH2Cl2, rt, 4 h; (f) DIBAL-H, Et2O, -78 °C, 3 h; (g) s-BuLi,
THF, -78 to -20 °C, 1 h, aq. workup, then TFA, THF, 0 °C, 1 h, then
H2O, 18 h; (h) n-BuLi, THF, 0 °C to rt, 18 h; (i) BCl3‚DMS, CH2Cl2, -78
°C to rt, 1 h; (j) TBSCl, imidazole, CH2Cl2, rt, 18 h; (k) LiOH‚H2O, THF,
H2O, MeOH, rt, 40 h; (l) 2,4,6-trichlorobenzoyl chloride, TEA, toluene, rt,
1 h, then 20, toluene, DMAP, rt, 5 h; (m) CSA, CH2Cl2, MeOH, 0 °C, 2 h.
Scheme 3. Synthesis of Pyranone 20a
a Reagents and conditions: (a) DIBAL-H, Et2O, -78 °C, 10 min; (b)
DBU, THF, 0 °C, 20 h; (c) MnO2, CH2Cl2, rt, 24 h; (d) 1 N HCl, THF, rt,
25 min.
centers via asymmetric alkylation. To the best of our knowledge,
we report the first use of cationic chiral oxazaborolidine catalyst
18c in the key assembly of butenolide 17 via an asymmetric
vinylogous Mukaiyama aldol addition, whose scope we are currently
seeking to expand.
more-hindered oxazaborolidine 18c afforded butenolide 17 in 81%
yield with 20:1 threo:erythro relative diastereoselectivity. To our
delight, the (R,R)-threo:(S,S)-threo diastereomeric ratio exceeded
20:1. A putative transition state (Table 1) based on Corey’s model11
for association of the aldehyde with 18a-c suggests that the
B-substituent controls orientation of the siloxyfuran (erythro:threo
or C1-C2 diastereoselection), and the bulky ring aryl groups control
the alkyl group orientation of the aldehyde (C2-C3 diastereose-
lection).
Reduction of 17 with DIBAL-H furnished lactol 4 quantitatively
(Scheme 3). Sequential treatment of 4 with DBU and oxidation
gave an equilibrium mixture (1:1) of 17 and 19. Recycling recovered
17 afforded 19 in 58% overall yield. Desilylation then provided
alcohol 20 in 94% yield.
Acknowledgment. We thank the National Science Foundation
(CHE-0305790) for support of these studies.
Supporting Information Available: Experimental procedures and
analytical and spectroscopic (1H NMR, 13C NMR, IR) data for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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The key chiral center in diene acid 2 was installed via a TiCl4-
catalyzed asymmetric alkylation of 3-azaimide 21 with BOMCl
(Scheme 4), providing 22 in 81% yield and >95:5 diastereoselec-
tivity.13 Terminal olefin cleavage by ozonolysis/BH3‚THF reduction
furnished imido alcohol 23 in 76% overall yield. After protection
of the alcohol as the benzyl ether, 23 was transformed by standard
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via Yamaguchi coupling of alcohol 20 with diene acid 2.17
Desilylation with CSA afforded (-)-rasfonin (1) in 84% yield.1-3
The present total synthesis is shorter (longest linear sequence of
16 steps) and higher yielding (12.7% overall yield) than the only
reported route.3 The flexibility of camphor lactams as auxiliaries
was exemplified during the installation of the side chain stereogenic
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