Total synthesis of buergerinin F via effective construction of the asymmetric quaternary carbons using an enantioselective aldol reaction

Article abstract of DOI:10.1039/b507401k

An efficient method for the synthesis of (+)-buergerinin F is established via the enantioselective aldol reaction of a tetra-substituted ketene silyl acetal with crotonaldehyde, followed by intramolecular Wacker-type ketalization. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b507401k

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Total synthesis of buergerinin F via effective construction of the
asymmetric quaternary carbons using an enantioselective aldol
reaction{
Isamu Shiina,* Yo-ichi Kawakita, Ryoutarou Ibuka, Kazutoshi Yokoyama and Yu-suke Yamai
Received (in Cambridge, UK) 26th May 2005, Accepted 17th June 2005
First published as an Advance Article on the web 14th July 2005
DOI: 10.1039/b507401k
An efficient method for the synthesis of (+)-buergerinin F is
established via the enantioselective aldol reaction of a tetra-
substituted ketene silyl acetal with crotonaldehyde, followed by
intramolecular Wacker-type ketalization.
Buergerinin F (1), a potentially antiphlogistic and febrifuge agent,
was isolated in 2000 from the root of Scrophularia buergeriana
together with buergerinin G (2) by Zhu et al.1 Its structure consists
of a peculiar trioxatricyclo[5.3.1.01,5]undecane skeleton, including a
carbons.
ketal moiety with asymmetric quaternary carbons. The relative
Scheme 1 Enantioselective construction of asymmetric quaternary
stereochemistries of 1 and 2 were first shown by NOE correlations
Retrosynthetic analysis of 1 is shown in Scheme 2. An optically
and X-ray crystallography, and the absolute configurations of 1
active linear compound 4 might be used as an intermediate for the
and 2 were recently determined through the total synthesis starting
construction of the framework 3 by the intramolecular Wacker-
from thymidine by Lowary et al.2 Independently, we planned to
type cyclization. A highly oxygenated aldol 5, a precursor of 4
synthesize 1 via the asymmetric aldol reaction of a tetrasubstituted
including the asymmetric quaternary carbon at C-5, could be
ketene silyl acetal with a simple achiral aldehyde, followed by the
synthesized by an enantioselective aldol reaction between the
intramolecular ketalization of the precursory dihydroxy alkene
tetrasubstituted ketene silyl acetal
6 and crotonaldehyde.
using an abnormal intramolecular Wacker-type ketalization. In
this communication,3 determination of the stereochemistry of 1
and its asymmetric total synthesis using our chiral induction
technology4 for providing optically active compounds are
described.
According to the above hypothesis, the a,c-dioxy ester 7 derived
from a simple a-hydroxy-c-butyrolactone was chosen as the
starting material.
First, the benzylation of the racemic a-hydroxy-c-butyrolactone
was carried out and successive cleavage of the lactone ring
followed by silylation of the resulting primary alcohol, produced
the a,c-dioxy ester 7 in a good yield (Scheme 3). The desired ketene
Recently, we reported an effective method for the construction
of asymmetric quaternary carbons using the enantioselective aldol
reaction;5 namely, in the presence of Sn(II) triflate coordinated
with a chiral diamine, tetrasubstituted ketene silyl acetals react
with achiral aldehydes to produce the corresponding optically
active aldols with a highly functionalized structure (Scheme 1).
These successful results prompted us to develop an enantioselective
method for the construction of the basic skeleton of 1, which
possesses an asymmetric quaternary carbon at C-5.
Department of Applied Chemistry, Faculty of Science, Tokyo University
of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
E-mail: shiina@ch.kagu.tus.ac.jp; Fax: (+81)-3-3260-5609
{ Electronic supplementary information (ESI) available: experimental
section. See http://dx.doi.org/10.1039/b507401k
Scheme 2 Retrosynthetic analysis of buergerinin F.
4062 | Chem. Commun., 2005, 4062–4064
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Scheme 3 Reagents and conditions: (a) NaH, BnBr, THF, DMF, 0 uC to
rt (83%); NaOMe, MeOH, rt; TBSCl, imidazole, DMF, 0 uC to rt (80%,
two steps); (b) LDA, TMSCl, THF, 278 uC to rt (97%, E/Z 5 92:8); (c)
Sn(OTf)2, nBu2Sn(OAc)2, (S)-1-methyl-2-(1-naphthylaminomethyl)pyrro-
lidine, EtCN, 278 uC (74%, 5/epi-5 5 .99:1, 94% ee for 5).
silyl acetal 6 was easily generated from 7 by a conventional
method, and a nearly quantitative conversion yield was observed
1
by H NMR analysis of the crude mixture. Although the E- and
Z-isomers were formed in a 92:8 ratio,6 we used this mixture for
the next reaction without further purification because similar
stereoselectivities were attained regardless of the geometric
difference between the two enolates during the course of our
continuous studies on the asymmetric aldol reactions.4,5 Actually,
excellent diastereo- and enantioselectivities were attained in the
asymmetric aldol reaction of the mixture of 6 with crotonaldehyde
using the chiral Lewis acid that consisted of Sn(OTf)2, (S)-1-
Scheme 4 Reagents and conditions: (a) PhMe2CMe2SiOTf, pyridine, 0 uC
(83%); DIBAL, CH2Cl2, 218 uC (92%); (b) LDBB, THF, 278 uC (45%,
9/99 5 45:55); (c) Ac2O, DMAP, pyridine, rt (98%); 0.1 M HCl, THF, rt
(43% for 10 and 45% for 109 from a mixture of 9 and 99); (d) PdCl2, DMF,
0 uC (91%); (e) PdCl2, DMF, 0 uC to rt (60% of 119 plus 38% of recovered
109).
n
methyl-2-(1-naphthylaminomethyl)pyrrolidine and Bu2Sn(OAc)2
to give the coupling product 5 in satisfactory yield. The HPLC
analysis of 5 referenced to the corresponding racemic sample
showed the enantiomeric excess of 5 to be 94%. The relative
stereochemistry of 5 had not yet been clarified at this stage,
however, the absolute configuration at C-5 in 5 was determined as
R using Mosher’s method modified by Kusumi.7 This stereo-
selectivity gave good agreement with the empirical rule of our
asymmetric synthesis using the chiral Sn(II) complex.
at all and only the 1,2,3-triol 13 was obtained in high yield.
Though the protection of 13 with acetic anhydride and
triethylamine gave the mono-acetylated diol 14 in 71% yield along
with the formation of a mixture of undesired acetates in 14% yield,
the by-products were easily converted to the starting material 13 in
quantitative yields. The successive silylation and desilylation of 14
afforded synthetic intermediate 10 without producing its C-1
epimer 109. The dihydroxy alkene 10 was transformed into the
corresponding ketal 11 by the Wacker-type cyclization using a
catalytic amount of palladium dichloride, which was in turn
selectively deprotected to form a primary alcohol 15 in good yield.
The one carbon elongation at the C-4 position in 15 and
cyclization to construct the 5-membered ether ring were then
examined. The successive oxidation8 of 15 and Wittig olefination
of the resulting aldehyde, followed by deprotection of the silyl
group, afforded the corresponding secondary alcohol 16. After
screening several cyclization reactions involving oxymercuration
and oxypalladation to produce a tricyclic compound from 16, it
was found that the iodine-promoted ether ring formation rapidly
proceeded to afford the desired 17 in high yield. The NOE
relationships and conformational analysis showed the relative
stereochemistry of 17 to be as illustrated in Scheme 5.
As shown in Scheme 4, the major aldol 5 was converted to a
primary alcohol 8 in good yield by protection with cumyldi-
methylsilyl triflate in pyridine and subsequent reduction with
DIBAL. The debenzylation of 8 using lithium di-tert-butyl-
biphenylide (LDBB) took place smoothly but a mixture of the
desired diol 9 and its epimer 99 were produced. The successive
treatment of the mixture with acetic anhydride and DMAP in
pyridine and with 0.1 M HCl in THF gave the separate diols 10
and 109. The intramolecular Wacker-type ketalization of 10 and
109 using an excess amount of palladium dichloride produced the
corresponding bicyclic ketals 11 and 119 in good and moderate
yields, respectively. The NOE experiment of 11 and 119 showed
that each configuration is (1R,5R) and (1S,5R) as depicted in
Scheme 4. Because 11, derived from 5 via 10, has the same relative
stereochemistry as 1, it was proved that 10, in which the C-1
configuration is R, should be used as the precursor of 1.
Next, we tried to exclusively synthesize the desired stereoisomer
10 from 5 as described in Scheme 5. The optically active 5 was
directly treated with Red-Al1 to form the corresponding 1,3-diol
12, and then the debenzylation of 12 was carried out using LDBB.
In this case, the unwanted epimerization at C-1 did not take place
Finally, treatment of the iodide 17 with potassium tert-butoxide
and consecutive hydrogenation catalyzed by palladium on
charcoal, gave the target molecule in good yield. The 1H and
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Thus, an efficient method for the synthesis of (+)-buergerinin F
(1) was established via the enantioselective aldol reaction of a
tetrasubstituted ketene silyl acetal with a simple achiral aldehyde,
followed by Wacker-type ketalization and then iodocyclization.
The synthesis of 1 proceeds in 14 steps and 33% overall yield from
crotonaldehyde with an achiral nucleophile. The absolute stereo-
chemistry of 1, including the asymmetric quaternary carbons, was
additionally confirmed by the enantioselective synthesis. Since it is
already known that 1 can be converted to 2 by oxygenation using
RuCl3/NaIO4,2 the present report is related to the formal synthesis
of buergerinin G (2). An advanced investigation of an alternative
synthesis of 2 is now in progress in this laboratory.
This study was partially supported by a Research Grant from
the Kurata-Hitachi Foundation and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and
Culture, Japan. The author thanks the Shin-Etsu Chemical Co.,
Ltd. (Japan), for kindly providing tert-butylchlorodimethylsilane
as a bulk sample.
Notes and references
1 S. Lin, S. Jiang, Y. Li, J. Zeng and D. Zhu, Tetrahedron Lett., 2000, 41,
1069–1071.
2 J.-S. Han and T. L. Lowary, J. Org. Chem., 2003, 68, 4116–4119.
3 I. Shiina, Y. Kawakita and R. Ibuka, Asymmetric Total Synthesis of
Buergerinin F, Abstracts of Papers, 83rd National Meeting of the
Chemical Society of Japan, Tokyo, 2003, vol. 2, 2C401.
4 (a) T. Mukaiyama and S. Kobayashi, in Stereocontrolled Organic
Synthesis, ed. B. M. Trost, Blackwell Scientific Publications, Oxford,
1994, pp. 37–65; (b) I. Shiina, in Modern Aldol Reactions, ed.
R. Mahrwald, Wiley-VCH, Weinheim, 2004, vol. 2, pp. 105–165; (c)
S. Kobayashi, H. Uchiro, Y. Fujishita, I. Shiina and T. Mukaiyama,
J. Am. Chem. Soc., 1991, 113, 4247–4252; (d) S. Kobayashi, H. Uchiro,
I. Shiina and T. Mukaiyama, Tetrahedron, 1993, 49, 1761–1772; (e)
T. Mukaiyama, I. Shiina, H. Uchiro and S. Kobayashi, Bull. Chem. Soc.
Jpn., 1994, 67, 1708–1716.
Scheme 5 Reagents and conditions: (a) Red-Al1, toluene, 245 to 0 uC
(99%); (b) LDBB, THF, 278 uC (quant.); (c) Ac2O, Et3N, CH2Cl2, 0 uC
(71%); (d) PhMe2CMe2SiOTf, toluene, pyridine, 0 uC (93%); 1 M HCl,
THF, 0 uC (98%); (e) PdCl2, CuCl, O2, DME, rt (88%); K2CO3, MeOH, rt
t
˚
(quant.); (f) PhSNH Bu, NCS, K2CO3, MS 4A, CH2Cl2, rt (quant.);
Ph3PCH3+I2, KHMDS, toluene, THF, 278 uC to rt (quant.); TBAF,
THF, 0 uC (quant.); (g) I2, NaHCO3, CH3CN, 0 uC to rt (80%); (h)
tBuOK, DMSO, rt (quant.); H2, Pd/C, AcOEt, rt (quant.).
5 (a) T. Mukaiyama, I. Shiina, J. Izumi and S. Kobayashi, Heterocycles,
1993, 35, 719–724; (b) I. Shiina and R. Ibuka, Tetrahedron Lett., 2001, 42,
6303–6306; (c) I. Shiina, H. Oshiumi, M. Hashizume, Y. Yamai and
R. Ibuka, Tetrahedron Lett., 2004, 45, 543–547.
6 The geometry of the major isomer was determined by NOE experiment.
7 (a) I. Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa, J. Am. Chem.
Soc., 1991, 113, 4092–4096; (b) T. Kusumi, J. Synth. Org. Chem. Jpn.,
1993, 51, 462–470.
13C NMR spectra of the obtained 1 showed that the synthetic
sample has the same relative stereochemistry as the naturally
occurring buergerinin F. Other properties of 1, including its optical
rotation, were identical with those of buergerinin F isolated by
Zhu et al.;9 therefore, it was shown that the naturally occurring 1
has the (1R,5S,8S) configuration as Lowary et al. reported.2
8 T. Mukaiyama, J. Matsuo, D. Iida and H. Kitagawa, Chem. Lett., 2001,
846–847.
9 [a]D23 +38u (c 0.41, CHCl3) [ref. [a]D18 +41u (c 0.43, CHCl3)1 [a]D +39u (c 0.9,
CHCl3)2].
4064 | Chem. Commun., 2005, 4062–4064
This journal is ß The Royal Society of Chemistry 2005