Total synthesis and determination of the absolute configuration of (-)-dolabriferol

Article abstract of DOI:10.1002/anie.201003735

A reaction cascade combining sulfur dioxide with a 1-oxy-1,3-diene and (E)-silyl enol ether formed the basis of a short total synthesis of (-)-dolabriferol (see scheme; TMS=trimethylsilyl). The absolute configuration of this natural product, which was first extracted from a gastropod mollusc in 1996, was established unequivocally.

Full text of DOI:10.1002/anie.201003735

Angewandte
Chemie
DOI: 10.1002/anie.201003735
Natural Product Synthesis
Total Synthesis and Determination of the Absolute Configuration of
(ꢀ)-Dolabriferol**
Sylvain Laclef, Maris Turks, and Pierre Vogel*
In 1996 Ciavatta et al.[1] isolated (ꢀ)-dolabriferol ((ꢀ)-1;
Scheme 1) from Dolabrifera dolabrifera, a gastropod mollusk
scarcely protected by a shell and collected off Cuba. The
structure and relative configuration of (ꢀ)-1 was established
Scheme 2. One-pot synthesis of a,b,g-syn,anti-stereotriads through
Scheme 1. (ꢀ)-Dolabriferol ((ꢀ)-1).
SO2-induced oxyallylation of (Z)-enoxysilanes.
by advanced NMR studies and by single-crystal X-ray
analysis, but the absolute configuration was not assigned.[1]
It is assumed that (ꢀ)-1 protects the shell-less mollusk from
predators. The natural product is made of two polypropionate
subunits linked by an ester function structural motif which is
also found in natural products such as baconipyrones A–D[2]
and siserrone A.[3] Up to now four reports have described the
attempted synthesis of (ꢀ)-1.[4–7]
a,b,g-anti,anti-stereotriads
in
a
one-pot
operation
(Scheme 3, Table 1). This allowed us to develop efficient
syntheses of the polypropionate subunits of (ꢀ)-1. We have
found also a route to combine them and to construct (ꢀ)-1,
thus realizing the first total synthesis of this natural product.
We also established its absolute configuration.
The reaction of diene (+)-7a and silyl enol ether 8a with
an excess of SO2/toluene in the presence of (CF3SO2)2NH
(Tf2NH, 20 mol%) provided a mixture of silyl sulfinates,
Using our reaction cascade (oxyallylation of alkenes),
which combines electron-rich dienes 2 and (Z)-enoxysilanes 4
through SO2 umpolung,[8,9] we have developed a one-pot
synthesis of a,b,g-syn,anti-stereotriads of type 6 (Scheme 2).
The starting dienes 2 are obtained readily from pent-3-one,
ethyl formate, and inexpensive enantiomerically enriched 1-
arylethanol as the source of chirality.[10] The latter is
transferred to the intermediate silyl sulfinates 5, which are
converted in situ into 6 in the presence of catalytic amounts
of Pd(OAc)2 and PPh3 with high stereoselectivity
(Scheme 2).[11,12]
We now have found that the same reaction cascade
applied to (E)-enoxysilanes generates the corresponding
[*] S. Laclef, Prof. Dr. P. Vogel
Scheme 3. One-pot synthesis of a,b,g-anti,anti-stereotriads through
SO2-induced oxyallylation of (E)-enoxysilanes. Reagents and condi-
tions: a) SO2, Tf2NH, CH2Cl2, ꢀ788C; b) Pd(OAc)2 (cat.), PPh3 (cat.),
iPrOH, MeCN, K2CO3. Tf=trifluoromethanesulfonyl.
Laboratoire de Glycochimie et de Synthꢀse Asymꢁtrique
Swiss Federal Institute of Technology (EPFL)
Batochime, 1015 Lausanne (Switzerland)
Fax: (+41)21-693-9375
E-mail: pierre.vogel@epfl.ch
Table 1: Results of SO2-induced oxyallylation cascade with (E)-enoxy-
Prof. Dr. M. Turks
silanes.
Faculty of Material Sciences and Applied Chemistry
Riga Technical University, Riga 1658 (Latvia)
Diene
R*
R3
R4
Yield
(9+10)
Ratio
9/10
[**] We thank the Swiss National Science Foundation (Bern) and the
Roche Research Foundation for financial support, Dr. M. L. Ciavatta
for copies of the 1H and 13C NMR spectra of natural (ꢀ)-1, and Dr. R.
Scopellitti and Dr. K. Schenk for X-ray diffraction studies.
1-(PhCHMe)
(+)-7a
(+)-7b
(ꢀ)-7c
(ꢀ)-7d
1R
1R
1S
1S
iPr
tBu
Ph
H
H
Me
Me
71%
76%
67%
72%
9aa/10aa=3:1
9ba/10ba=5:1
9cb/10cb >95:5
9 db/10 db=9:1
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003735.
Me
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Communications
which were desulfinylated by iPrOH/MeCN/K2CO3 in the
presence of Pd(OAc)2/PPh3 (10 mol%). The resulting 3:1
mixture of stereotriads 9aa and 10aa (71% yield) was
separated readily by flash chromatography on silica gel
(Scheme 3, Table 1). The reaction of (+)-7b and 8a gave a
5:1 mixture of pivalates 9ba/10ba in 76% yield. Single-crystal
X-ray diffraction of 10ba established its structure unambig-
uously. The reaction of diene (ꢀ)-7c with 8b resulted in the
stereotriad 9cb which was isolated as a single diastereomer in
67% yield. The combination of (ꢀ)-7d and 8b led to a readily
separable 9:1 mixture of 9 db and 10 db in 72% yield.
The diastereoselectivities observed for the reaction cas-
cades in Schemes 2 and 3 are consistent with the preferred
transition states shown in Scheme 4. The hetero-Diels–Alder
addition of Lewis acid activated SO2 to the least hindered face
of the diene results in the formation of a zwitterionic species,
which is quenched by the nucleophilic attack of the silyl enol
ether to give the corresponding silyl sulfinate (e.g. 5), which
leads preferentially to stereotriads 6 starting with (Z)-silyl
enol ethers 4, and to diastereomers 9 starting with (E)-silyl
enol ethers 8 after palladium-catalyzed desilylation and
desulfinylation.
Scheme 5. Conversion of stereotriads into semiprotected subunits of
(ꢀ)-dolabriferol. Reagents and conditions: a) O3, CH2Cl2, ꢀ788C;
b) Me2S, H2O, RT, 61% (over two steps); c) Me2AlCl, Bu3SnH, CH2Cl2,
ꢀ788C, 90%; d) MeLi·LiBr, DME/Et2O, ꢀ788C; e) H2O/NH4Cl, RT,
91% (over two steps); f) Pd(OH)2, AcOEt, RT, 72%; g) Pd(OH)2,
MeOH, RT, 69%. Bz=benzoyl.
Scheme 4. Hypothetical transition structures for the oxyallylation
reaction.
Ozonolysis of pure (+)-9aa gave the carboxylic subunit
(+)-11 of (ꢀ)-1 in 61% yield. Reduction of ketone (ꢀ)-9cb
with NaBH4, l-selectride, LiBH4, or DIBAL-H was not highly
diastereoselective. Fortunately, the Evansꢀ method[13] using
Bu3SnH and Me3AlCl gave the pure alcohol (ꢀ)-12 (90%
yield), which was converted into (ꢀ)-13 (91% yield). Hydro-
genolysis of the phenethyl ether (H2/Pd(OH)2 in EtOAc)
produced the hemiacetal subunit (ꢀ)-14 (72% yield)
(Scheme 5). Its structure was established by 1H and
13C NMR analysis and confirmed by single-crystal X-ray
diffraction. The corresponding methyl acetal (ꢀ)-15 was
obtained in 69% yield by carrying out the hydrogenolysis in
MeOH.
Scheme 6. Synthesis of (ꢀ)-dolabriferol and stereomer (+)-25.
Reagents and conditions: a) Me2AlCl, Bu3SnH, CH2Cl2, ꢀ788C, 89%;
b) Allyl chloroformate, pyridine, THF, RT, 91%; c) TiCl4, CH2Cl2,
ꢀ788C, 69%; d) (+)-11, 2,4,6-trichlorobenzoyl chloride, NEt3, DMAP,
toluene, ꢀ788C, 71%; e) Bu3SnOMe, 708C, 0.1 torr; f) KF, H2O, RT;
g) CF3COOH, anisole, CH2Cl2, RT, 96% (over three steps); h) Pd-
(OAc)2, Et2NH, TPPTS, CH3CN/H2O, RT, 99%. DMAP=4-dimethylami-
nopyridine, TPPTS=3,3’,3’’-phosphinidynetris(benzenesulfonic acid)
trisodium salt.
As already reported,[14] the direct esterification of ana-
logues of (+)-11 and (ꢀ)-14 failed.[15,16] In order to reduce
possible steric interference between these compounds, we
envisioned the esterification of a suitably protected acyclic
precursor of the hemiacetal (ꢀ)-14 (Scheme 6). The enol
acetate (+)-9db was reduced to (+)-20 (89% yield). Protec-
tion as the allyl carbonate (+)-21 (91% yield) followed by
treatment with TiCl4/CH2Cl2 provided (ꢀ)-22 (69% yield).
Esterification between (ꢀ)-22 and (+)-11 using Patersonꢀs
protocol[17] gave a 9:1 mixture of the desired diastereoisomers
(+)-23 and a diastereoisomer resulting from the concurrent
based-induced (NEt3, DMAP, toluene) isomerization of
(+)-11. Selective removal of the acetyl group of (+)-23 was
realized by treatment in pure Bu3SnOMe at 708C followed by
KF/H2O workup. Subsequent treatment with CF3COOH
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[2] D. C. Manker, D. J. Faulkner, T. J. Stout, J. Clardy, J. Org. Chem.
removed the phenylethyl ether giving (+)-24 (96% yield).
Final deprotection and formation of the cyclic acetal
(Pd(OAc)2, HNEt2, TPPTS) gave (ꢀ)-dolabriferol (ꢀ)-1;
99% yield), the 1H and 13C NMR spectra of which were
identical to those of natural (ꢀ)-1. Furthermore, single-crystal
X-ray analysis of synthetic (ꢀ)-1 confirmed its structure. As
the absolute configurations of the starting dienes 7 and of
synthetic intermediates are known, our synthesis of
(ꢀ)-1 establishes its absolute configuration to be
(2R,3S,4S,5S,6S,2’R,3’R,4’S).[18]
Polypropionate stereotriads syn,anti-6 and anti,anti-9 are
obtained in one-pot operations starting from inexpensive
dienes and enoxysilanes in both their enantiomeric forms. The
cyclic hemiacetal subunit (ꢀ)-14 is obtained in four steps
starting from diene (ꢀ)-7c, and the carboxylic acid unit
(+)-11 is prepared in only two steps. Esterification of
stereotriad (ꢀ)-22 with (+)-11 has permitted the first total
synthesis of (ꢀ)-dolabriferol (10 steps, 7.9% overall yield
based on dienes) and has established its absolute configu-
ration.[19] Stereomers of (ꢀ)-1 can be obtained using the same
chemistry. For instance, esterification of (ꢀ)-22 with (ꢀ)-11
derived from diene (ꢀ)-7a has led to (+)-25 in good yield.
The evaluation of the biological activities of (ꢀ)-1 and of its
stereoisomers and analogues can now be envisioned.
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Alvarez, J. A. Sordo, Acc. Chem. Res. 2007, 40, 931.
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[11] X. G. Huang, C. Craita, P. Vogel, J. Org. Chem. 2004, 69, 4272.
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[13] D. A. Evans, B. D. Allison, M. G. Yang, C. E. Masse, J. Am.
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[14] T. Lister, Ph.D. thesis, Flinders University, Adelaide, Australia,
2006.
[15] Failed: Keckꢀs modification of the Steglich protocol and
Yamagushiꢀs esterification along with its Yonemitsu and Pater-
son modifications.
[16] a) G. E. Keck, E. P. Boden, J. Org. Chem. 1985, 50, 2394; b) B.
Neises, W. Steglich, Angew. Chem. 1978, 90, 556; Angew. Chem.
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Katsuki, M. Yamagushi, Bull. Chem. Soc. Jpn. 1979, 52, 1989;
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Received: June 18, 2010
Published online: September 23, 2010
[17] I. Paterson, D. Y.-K. Chen, J. L. Acena, A. S. Franklin, Org. Lett.
2000, 2, 1513.
Keywords: asymmetric synthesis · natural products ·
polypropionates · SO2 umpolung · stereotriads
.
25
25
[18] ½aꢁD ¼ꢀ25 (c = 0.2, CHCl3); Lit.[1]: ½aꢁD ¼ꢀ29.4 (c = 0.7, CHCl3).
[19] I. M. Socorro, J. M. Goodman, J. Chem. Inf. Model. 2006, 46, 606.
[1] M. L. Ciavatta, M. Gavagnin, R. Pulliti, G. Cimino, E. Martinez,
J. Ortea, C. A. Mattia, Tetrahedron 1996, 52, 12831.
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