Stereoselective synthesis of a chiral synthon, 2,2,5-trisubstituted tetrahydropyran, based on simultaneous 1,3- and 1,6-asymmetric induction via nucleophilic acetal cleavage reaction of the bicyclic acetal: A total synthesis of (-)-malyngolide

Article abstract of DOI:10.1039/a703242k

A chiral 2,2,5-trisubstituted tetrahydropyran is synthesised efficiently via facial and group selective nucleophilic acetal cleavage reaction of a bicyclic acetal, wherein simultaneous 1,3- and 1,6-asymmetric induction from a sulfinyl chirality is accompl

Full text of DOI:10.1039/a703242k

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Stereoselective synthesis of a chiral synthon, 2,2,5-trisubstituted
tetrahydropyran, based on simultaneous 1,3- and 1,6-asymmetric induction via
nucleophilic acetal cleavage reaction of the bicyclic acetal: a total synthesis of
(2)-malyngolide
Naoyoshi Maezaki,a Yuˆki Matsumori,a Takeshi Shogaki,a Motohiro Soejima,a Tetsuaki Tanaka,a Hirofumi
Ohishib and Chuzo Iwata*a
a Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565, Japan
b Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-11, Japan
A chiral 2,2,5-trisubstituted tetrahydropyran is synthesised
efficiently via facial and group selective nucleophilic acetal
cleavage reaction of a bicyclic acetal, wherein simultaneous
1,3- and 1,6-asymmetric induction from a sulfinyl chirality is
accomplished with high diastereoselectivity; this chiral
synthon is successfully applied to a total synthesis of
(2)-malyngolide.
and apply this chiral synthon to a total synthesis of (2)-ma-
lyngolide.
Upon treatment with a mixture of the bicyclic acetal 22 and
allyltrimethylsilane with TiCl4, nucleophilic acetal cleavage
reaction took place at 278 °C to produce allylated alcohol 3a
along with the three diastereomeric isomers 3b–d‡
(67:10:17:6) (Table 1). Selectivity was increased by lowering
the reaction temperature; CH2Cl2 was the most suitable solvent.
The best result was obtained when TiCl4 (5 equiv.) was added
to a mixture of substrate and allyltrimethylsilane (10 equiv.) in
CH2Cl2 at 2100 °C. In this case, the ratio of 3a and its three
other isomers was 84 :6:7:3.
The development of a methodology for remote asymmetric
induction is one of the most challenging problems in organic
synthesis.1,2 In addition, the simultaneous installation of chiral
centres separated by more than two carbons is a very difficult
task. We have previously reported a novel asymmetric de-
symmetrisation of a prochiral 1,3-diol via diastereoselective
acetal cleavage reaction.2 The results prompted us to develop a
methodology for simultaneous 1,3- and 1,6-asymmetric induc-
tion via a nucleophilic acetal cleavage reaction,3 wherein a
chiral sulfinyl group controls both the diastereotopic C–O bond
cleavage and diastereofacial nucleophilic addition, thereby
yielding chiral 2,2,5-trisubstituted tetrahydropyrans with two
chiral centres at the C2 and C5 positions (Scheme 1).† The
resulting tetrahydropyran derivative 1 is considered as a useful
chiral synthon for various natural products, i.e. (2)-dactyloxene
A,4 (+)-pseudomonic acid C5 and (2)-malyngolide.6
The absolute configuration of the major product 3a was
inferred from the relative configuration determined by single
crystal X-ray analysis of the p-nitrobenzoate§ and the known
absolute configuration of the sulfoxide.¶
The reaction was rationalised as follows: TiCl4 coordinates
between the sulfinyl oxygen and one of the acetal oxygens to
form the chelation intermediates A or B, in which the bulky
tolyl group located at equatorial position (Fig. 1). The
intermediate A is more favourable than B, since the electro-
positive sulfur atom is located between electronegative oxygens
and is anti to the bulky 7-methylene group in the intermediate
A.7 The C–O bond coordinated by TiCl4 is weakened or cleaved
to produce transition state C or tight ion pair intermediate D,
respectively. Allyltrimethylsilane reacts with the bicyclic acetal
from the backside of the breaking C–O bond via an SN2-type
substitution (transition state C) or an SN1-like mechanism
(intermediate D)8 to give the (2S,5S)-isomer 3a diaster-
eoselectively as a potential multifunctional chiral synthon.
We planned to apply this chiral synthon to the synthesis of a
marine antibiotic, (2)-malyngolide.6 Although various synthe-
Here we describe a novel method of synthesising 2,2,5-tri-
substituted tetrahydropyran based on simultaneous 1,3- and
1,6-asymmetric induction with high diastereoselectivity via
group and facial selective nucleophilic acetal cleavage reactions
R
6
R
HO
HO
O
Acetalisation
O
6
O
S
1
S
1
Ar
O
Ar
Table 1 Nucleophilic acetal cleavage reaction of the bicyclic acetal 2
O
3
3
1,3 and 1,6 asymmetric induction
5
O
HO
Nucleophile (R')
Lewis acid
2
S
O
+ 3b + 3c + 3d
O
Tol
O
Me
S
R
H
HOCH2
O
Tol = p-MeC6H4
Tol
O
5
2
3a (2S,5S)
Me
2
S
O
Ar
O
b
Yield
(%)a
Ratio
Me
R'
1
Me
Conditons (equiv.)
3a:3b:3c:3d
(–)-dactyloxene A
TiCl4 (5), Me3Si(allyl) (5), CH2Cl2, 220 °C
TiCl4 (5), Me3Si(allyl) (5), CH2Cl2, 278 °C
TiCl4 (5), Me3Si(allyl) (5), CH2Cl2, 2100 °C
TiCl4 (5), Me3Si(allyl) (5), PhMe, 278 °C
TiCl4 (5), Me3Si(allyl) (5), THF, 278 °C
91
93
92
63
0
19:26:48:7
67:10:17:6
79: 6: 9:6
66:10:16:8
—
OH
(CH2)8CO2H
OH
Me
Me
O
O
2
Me
5
O
O
C9H19
OH
O
TiCl4 (5), Me3Si(allyl) (10), CH2Cl2, 2100 °C 90
84: 6: 7:3
HO Me
(+)-pseudomonic acid C
(–)-malyngolide
a
b
Isolated yield. The ratio was determined by 500 MHz 1H NMR
Scheme 1
spectroscopic measurements.
Chem. Commun., 1997
1755

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In summary, we have synthesised 2,2,5-trisubstituted tetra-
hydropyran 1 as a multifunctional chiral synthon based on facial
and group selective acetal cleavage reactions, in which highly
diastereoselective 1,3- and 1,6-asymmetric induction was
observed. The utility of this chiral synthon was demonstrated by
its application to the total synthesis of (2)-malyngolide.
This work was supported by a Grant-in-Aid (No. 08772018)
for Encouragement of Young Scientists from the Ministry of
Education, Science, Sports and Culture, Japan.
7
O
4
2
6 O
Tol
O
1
O
TiCl4
S
TiCl4
S
O
O
Tol
Nu
A
B
Nu
δ+
+
O
O
–
O
O
δ–
Footnotes and References
TiCl4
S
TiCl4
S
O
Tol
* E-mail: iwata@phs.osaka-u.ac.jp
O
Tol
† Relative and absolute configurations at the C2 and the C5 positions in the
chiral synthon 1 can be controlled by the sulfinyl chirality. Furthermore,
inversion of the stereochemistry at the C2 position in 1 (RA = allyl) is also
possible, since both allyl and sulfinyl groups can be converted into variety
of functional groups.
‡ The absolute configurations of 3b–d were determined as (2S,5R), (2R,5S),
and (2R,5R), respectively. Structural determination of these compounds will
be reported elsewhere.
§ The X-ray crystal structure of compound 3a confirms the relative
configuration at C2 and C5 although the quality of the data is not adequate
for publication. These assignments are supported by the conversion of 3a
into (2)-malyngolide.
¶ The absolute configuration of the sulfoxide moiety in 3a was based on the
optical rotation of the known methyl p-tolyl sulfoxide (ref. 12), from which
3a was derived (ref. 2). Since all synthetic intermediates after introduction
of the sulfinyl group (including 2 and 3a) possess positve optical rotations,
their absolute configurations on sulfur are assumed to be retained during the
transformations [by the empirical rule (ref. 13)].
D (SN1-type)
C (SN2-type)
Fig. 1
Me
O
MsO
O
i, ii
iii–vi
S
S
2
Tol
O
Tol
O
OMOM
MOM = CH2OMe
4
5
Scheme 2 Reagents and conditions: i, TiCl4, allyltrimethylsilane, CH2Cl2,
2100 °C; ii, MsCl, DMAP, CH2Cl2, 0 °C (73% in 2 steps); iii, LiBEt3H,
THF, room temp. (97%); iv, PdCl2(PhCN)2, benzene, 80 °C (60%, 90%
based on recovery of material); v, O3, MeOH, 278 °C then NaBH4, room
temp. (93%); vi, MOMCl, Pri2NEt, CH2Cl2, room temp. (77%)
ses of malyngolide have been reported,9 most of synthetic
routes lack stereocontrol at the C2 methyl group. A few methods
overcome this problem by constructing the two chiralities one
by one.9a,c,e,f After the nucleophilic acetal cleavage reaction of
2, the major diastereomeric isomer 3a, which possesses three
appropriately installed side-chains for the synthesis of (2)-ma-
lyngolide, was isolated as a mesylate 4 (73% yield from 2).
After reduction of the mesylate moiety with Super Hydride®, a
catalytic amount of PdCl2(PhCN)2 was used to isomerise the
allyl group to a prop-1-enyl group.10 Ozonisation was followed
by a reductive work-up, and protection as a methoxymethyl
(MOM) ether was undertaken to yield 5 (Scheme 2).
The p-tolylsulfinyl group was converted into the alcohol 6 via
Pummerer rearrangement followed by reduction with LiBH4.
After Dess–Martin oxidation,11 eight carbon elongation at the
hindered position was successfully accomplished with a Wittig
reagent followed by hydrogenation of the olefin to produce
compound 7 in good yield. Finally, the tetrahydropyran ring
was oxidised to the d-lactone with RuO4, and the MOM ether
was removed with Me3SiBr to give (2)-malyngolide without
epimerisation at the methyl group (Scheme 3). The spectro-
scopic data and specific rotation [[a]D 212.5 (CHCl3)] were
consistent with the reported data [[a]D 213.0 (CHCl3)].6
1 For selected recent references to 1, n-asymmetric induction (n > 4), see
N. Magnus and P. Magnus, Tetrahedron Lett., 1997, 38, 3491 and
references cited therein; H. Fujioka, H. Kitagawa, N. Matsunaga, Y.
Nagatomi and Y. Kita, Tetrahedron Lett., 1996, 37, 2245; T. Sato, M.
Kido and J. Otera, Angew. Chem., Int. Ed. Engl., 1995, 34, 2254; K.
Mikami and A. Yoshida, Tetrahedron Lett., 1994, 35, 7793; H.-C.
Zhang, M. J. Costanzo and B. E. Maryanoff, Tetrahedron Lett., 1994,
35, 4891; W. R. Roush and C. K. Wada, J. Am. Chem. Soc., 1994, 116,
2151; G. A. Molander and K. L. Bobbitt, J. Am. Chem. Soc., 1993, 115,
7517; R. J. Mears and A. Whiting, Tetrahedron Lett., 1993, 34, 8155.
2 N. Maezaki, M. Murakami, M. Soejima, T. Tanaka, T. Imanishi and C.
Iwata, Chem. Pharm. Bull., 1996, 44, 1146; C. Iwata, N. Maezaki, M.
Murakami, M. Soejima, T. Tanaka and T. Imanishi, J. Chem. Soc.,
Chem. Commun., 1992, 516. Related work: N. Maezaki, A. Sakamoto,
M. Soejima, I. Sakamoto, Y. X. Li, T. Tanaka, H. Ohishi, K. Sakaguchi
and C. Iwata, Tetrahedron: Asymmetry, 1996, 7, 2787 and references
cited therein.
3 T. Harada and A. Oku, Synlett, 1994, 95; A. Alexakis and P. Mangeney,
Tetrahedron: Asymmetry, 1990, 1, 477.
4 F. J. Schmitz, F. J. McDonald and D. J. Vanderah, J. Org. Chem., 1978,
43, 4220.
5 D. R. Williams, J. L. Moore and M. Yamada, J. Org. Chem., 1986, 51,
3916; J. P. Clayton, P. J. O’Hanlon, N. H. Rogers and T. J. King,
J. Chem. Soc., Perkin Trans. 1, 1982, 2827; J. P. Clayton, P. J. O’Hanlon
and N. H. Rogers, Tetrahedron Lett., 1980, 21, 881.
6 J. H. Cardllina II and R. E. Moore, J. Org. Chem., 1979, 44, 4039.
7 E. Juaristi, in Introduction to Stereochemistry and Conformational
Analysis, Wiley, New York, 1991, ch. 16, p. 271.
Me
i, ii
8 K. Ishihara, A. Mori and H. Yamamoto, Tetrahedron, 1990, 46, 4595.
9 (a) D. Enders and M. Knopp, Tetrahedron, 1996, 52, 5805 and
references cited therein; (b) H. P. Zeng, J. Y. Su and L. M. Zeng, Yaoxue
Xuebao, 1994, 29, 680; (c) M. Asaoka, S. Hayashibe, S. Sonoda and H.
Takei, Tetrahedron, 1991, 47, 6967; (d) K. Machiya, I. Ichimoto, K.
Tonari, M. Kirihara and H. Ueda, Agric. Biol. Chem., 1985, 49, 1767; (e)
H. Hagiwara and H. Uda, J. Chem. Soc., Perkin Trans. 1, 1985, 1157; (f)
T. Kogure and E. L. Eliel, J. Org. Chem., 1984, 49, 576.
5
OH
O
OMOM
6
iii–v
Me
vi, vii
(–)-malyngolide
10 J. K. Cha and R. J. Cooke, Tetrahedron Lett., 1987, 28, 5473; P. Golborn
and F. Scheinmann, J. Chem. Soc., Perkin Trans. 1, 1973, 2870.
11 R. E. Ireland and L. Liu, J. Org. Chem., 1993, 58, 2899; D. B. Dess and
J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
12 U. de la Camp and H. Hope, Acta Crystallogr., Sect. B, 1970, 26,
846.
C9H19
OMOM
O
7
Scheme 3 Reagents and conditions: i, Ac2O, AcONa, 130 °C (90%; 2:1
diastereomeric ratio); ii, LiBH4, THF, room temp. (97%); iii, Dess–Martin
periodinate, CH2Cl2, 0 °C (88%); iv, Ph3P+ (C8H17)Br2, KHMDS, THF, 0
°C (94%); v, H2, 10% Pd–C, MeOH, room temp. (86%); vi, RuCl3·3H2O,
NaIO4, CCl4–MeCN–H2O (57%, 80% based on recovery of material); vii,
Me3SiBr, CH2Cl2, 230 °C (85%)
13 K. Mislow, M. M. Green, P. Laur, J. T. Melillo, T. Simmons and A. L.
Ternay, Jr., J. Am. Chem. Soc., 1965, 87, 1958.
Received in Cambridge, UK, 12th May 1997; 7/03242K
1756
Chem. Commun., 1997