An enantioselective total synthesis of (+)- and (-)-saudin. Determination of the absolute configuration

Article abstract of DOI:10.1021/ja017194i

A short efficient enantioselective synthesis of both (+)- and (-)-saudin, a naturally occurring hypoglycemic diterpene, is described. This synthesis establishes the absolute configuration of natural (-)-saudin for the first time. The key steps include the

Full text of DOI:10.1021/ja017194i

Published on Web 12/14/2001
An Enantioselective Total Synthesis of (+)- and (-)-Saudin. Determination of
the Absolute Configuration
Robert K. Boeckman, Jr.,* Maria del Rosario Rico Ferreira, Lorna H. Mitchell, and Pengcheng Shao
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627-0216
Received September 28, 2001
Saudin (1) was isolated from Clutya Richardiana in 19851 and
Scheme 1
has been shown to possess in vivo noninsulin dependent hypogly-
cemic activity.2 The highly oxidatively modified labdane diterpene
presents a compact caged bis-ketal skeleton with five contiguous
stereogenic centers, three of which are quaternary or fully substi-
tuted. Several approaches,3 including a concise total synthesis of
(()-saudin,4 have been reported.
Herein we report the first enantioselective total synthesis of (+)-
Scheme 2
and (-)-saudin and the determination of its absolute configuration.
The core of our synthetic strategy is a Lewis acid mediated
stereoselective Claisen rearrangement to establish the correct relative
stereochemistry between the two quaternary centers (C13 and C16)
as well as the required functionalization for further elaboration
a Ethyl vinyl ketone, PhMe, 50 °C; then aqueous HCl, room temperature.
(Scheme 1).
b Pyrrolidine, AcOH, PhMe, ∆ (62% from 2-methyl ethylacetoacetate).
Enone (-)-6 was obtained from (S)-R-methylbenzyl carbamate
2 by Michael addition to ethyl vinyl ketone catalyzed by ZnCl2
and aldol-dehydration of the resulting diketone 3, which afforded
(-)-4 with high regioselectivity (18:1). After saponification and
reesterification, (-)-6 was isolated in 95% ee and 50% yield overall
from ethyl 2-methyl acetoacetate (Scheme 2).5 Derivatives 3-6 are
known in the literature only in racemic form6 but their analogues,
obtained in a similar way using methyl vinyl ketone as the Michael
aceptor, are described in optically pure form5a,7 and the sense of
the chiral induction is well established.8 Furthermore, we have
corroborated the absolute configuration of (-)-4 at C13 by
transformation of known (+)-79 into (-)-4.
c Aqueous KOH, MeOH, reflux. d K2CO3, (CH3)2SO4, acetone, ∆ (80% from
4).
Figure 1. Transition states for the Claisen rearrangement.
Scheme 3
O-alkylation of the thermodynamic enolate prepared from 6 with
allylic triflate 8 (prepared in 3 steps from the TBDPS ether of
3-butyn-1-ol) afforded Claisen rearrangement precursor 9.9b Thermal
Claisen rearrangement of 9 at 90 °C afforded a mixture of 10 and
11 (4:1) in which the undesired stereoisomer 10 predominated. This
stereochemical outcome can be rationalized via a preferred chairlike
transition state 12 (Figure 1) in which rearrangement occurs from
the face of the half-chair cyclic enol ether ring allowing stereo-
electronically favored axial bond formation at the ring stereogenic
center.
To overcome this preference, we reasoned it would be necessary
to induce a conformational change in the cyclohexenol ring.
Reaction via a boatlike conformation would then allow stereoelec-
tronically favored axial bond formation from the R face affording
the required stereoisomer 11. We chose to accomplish this using a
bidentate Lewis acid promoter. Gratifyingly, treatment of 9 at -65
°C with excess TiCl4, in the presence of Me3Al as proton scavenger
afforded adducts 10 and 11 (1:10), where 11 was now the major
product, along with ca. 10% of 6 (Scheme 3).10 The reversal in
facial selectivity can be rationalized by invoking bidentate coor-
dination by Ti(IV) of both the oxygen of the vinyl ether and the
ester enforcing the boatlike conformation 13 in which rearrangement
a KHMDS, THF-HMPA -78 °C to room temperature; then 8, -78 °C
(65%). b TiCl4, Me3Al, 4 Å MS, CH2Cl2, -65 °C (65%).
takes place via the chairlike transition state preferentially axial on
the less hindered R face (Figure 1).11
Deprotection of silyl ether 11 with TBAF resulted in spontaneous
formation of a mixture of hemiketals (∼1:1), which were directly
converted to a single methyl ketal 14. Hydroboration with 9-BBN
occurred exclusively at the less hindered, monosubstituted olefin
and the resulting primary alcohol 15 was efficiently converted to
carboxylic acid 16.12
Acid 16 was epoxidized with mCPBA to afford a single
diastereomeric epoxy lactone 17 after acidic workup. Addition of
3-lithiofuran13 to δ lactone 17 exhibited complete chemoselectivity
affording only keto alcohol 18 (Scheme 4), as the other potentially
electrophilic sites are apparently too hindered or unreactive to be
competitive. Hydroxy ketone 18 was directly acetylated affording
19 in 81% overall yield (Scheme 4).
The C9 tertiary oxygen center was installed by Lewis acid
promoted opening of epoxide 19 with inversion via nucleophilic
participation of the side chain ketone carbonyl followed by ring
* Address correspondence to this author. E-mail: rkb@rkbmac.chem.rochester.edu.
9
190 VOL. 124, NO. 2, 2002 J. AM. CHEM. SOC.
10.1021/ja017194i CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
Scheme 6
a TBAF, AcOH, THF, room temperature, then TsOH, CH(OMe)3, MeOH,
room temperature. b 9-BBN, THF, reflux; then NaBO3, H2O, room
temperature (87% from 11). c DMSO, (COCl)2, Et3N, CH2Cl2, -60 to 0
°C, then NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O, room tem-
perature. d mCPBA, NaHCO3, CH2Cl2, room temperature, then aqueous HCl,
THF, room temperature (73% from 15). e 3-Tributylstannyl furan, n-BuLi,
THF, -78 °C, then Ac2O, DMAP, py, CH2Cl2, room temperature (81%
from 17).
configuration of natural (-)-saudin can finally be assigned as 28
as shown in Scheme 6.
Using (R)-(+)-R-methylbenzylamine as the chiral auxiliary, we
then employed the above-described sequence to achieve the first
enantioselective total synthesis of (-)-saudin (28). Synthetic (-)-
25
saudin (28) has [R]D -14 (c 0.460, CHCl3) and spectroscopic
properties identical with those of the natural product.1
Scheme 5
Acknowledgment. We thank the NIGMS of the National
Institutes of Health for a research grant (GM-30345) in support of
these studies. We thank Professor J. S. Mossa for an authentic
sample of natural (-)-28.
Supporting Information Available: Experimental procedures,
analytical data, and copies of 1H NMR spectra for intermediates 9, 11,
14, 16, 17, 19, 20, 23, 24, and synthetic (+)-1 and natural (-)-28 (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
a BF3‚Et2O, CH3CN, room temperature (90%). b K2CO3, MeOH, H2O,
0 °C. c DMSO, (COCl)2, Et3N, CH2Cl2, -60 to 0 °C, then NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O, room temperature. d NaOAc,
(CF3CO)2O, CH2Cl2, room temperature (67% from 19). e LiTMP, THF, -78
°C, then HMPA, MeI, -50 °C (75% of 24/25). f LDA, THF, 0 °C (88%/
70% combined of 24 from 23). g 2 N aqueous KOH, reflux, then TMSOTf,
C2H4Cl2, room temperature (70% from 24).
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closure to bicyclic ketal 20.14 After saponification of acetate 20,
the resulting alcohol 21 was oxidized to carboxylic acid 22 (Scheme
5). Direct conversion of 21 to 22 could also be performed with
catalytic TEMPO-NaOCl using NaClO2 as co-oxidant,15 but the
yield was lower (65%) owing to concomitant oxidation of the furan
ring.
Introduction of the C4 secondary methyl group was initiated by
conversion of acid 22 to the crystalline enol lactone 23 via the
mixed trifluoroacetic anhydride (Scheme 5).16 When LDA was
employed as base, deprotonation of 23 and addition of CH3I led to
24 and 25 in variable ratio and yield depending upon reaction
conditions. Unreacted 23 along with significant amounts of dialky-
lated 26 were obtained even when an excess of base was used. It
seemed likely that these difficulties resulted from proton exchange
between 24 and 25 and the enolate derived from 23 perhaps
facilitated by diisopropylamine.17
Fortunately, deprotonation of enol lactone 23 with the hindered
strong base Li-TMP then addition of HMPA and CH3I afforded
monoalkylated products 24 and 25 (1:1.5) and only traces of 26.
Methyl diastereomers 24 and 25 were separated by chromatography
and the axial stereoisomer 25 was equilibrated to 24 by treatment
with a substoichiometric amount of LDA affording 24 in a
combined 70% yield.
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J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564-2566.
(16) The structure and relative stereochemistry of 23 was confirmed by single-
crystal X-ray analysis. Details will be published separately.
(17) Caine, D. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford 1991; Vol. 3, p 1 and references therein.
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5574-5576.
Although attempts to assemble the bis ketal system from 22 were
unsuccessful, conversion of 24 to the bis ketal system occurred
smoothly by hydrolysis of 24 followed by treatment of the resulting
bis carboxylic acid 27 with TMSOTf18 affording (+)-1 in 70% yield
(Scheme 5). The spectroscopic properties of (+)-1 were identical
with those of an authentic sample of natural (-)-saudin, except
25
for the sign of the optical rotation: [R]D +14 (c 0.460, CHCl3),
including melting point (mp 204-206 °C). Thus, the absolute
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