New asymmetric construction of the benzylic quaternary stereogenic centre: An enantiocontrolled access to (-)-α-cuparenone

Article abstract of DOI:10.1039/a702667f

An efficient and enantiocontrolled formal total synthesis of (-)-α-cuparenone has been accomplished by employing a new asymmetric construction methodology for formation of the benzylic quaternary stereogenic centre.

Full text of DOI:10.1039/a702667f

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New asymmetric construction of the benzylic quaternary stereogenic centre: an
enantiocontrolled access to (2)-a-cuparenone
Takamitsu Kosaka, Toshikazu Bando and Kozo Shishido*
Institute for Medicinal Resources, University of Tokushima, Sho-machi 1, Tokushima 770, Japan
An efficient and enantiocontrolled formal total synthesis of
(2)-a-cuparenone has been accomplished by employing a
new asymmetric construction methodology for formation of
the benzylic quaternary stereogenic centre.
prepared from 11 by a standard method, with lithium
trimethylsilylacetylide produced the alkynylsilane 13 in 69%
yield.
The stage was now set to explore the crucial construction of
the quaternary stereogenic centre via the [1,5] C–H insertion
reaction of the alklidene carbene. For this purpose, we intended
to use the procedure developed by Ochiai,4d,e,g since the product
obtained by this method is vinyl sulfone, which would be
Development of the methodology for assembling an asymmet-
ric quaternary stereogenic centre has been a challenging and
important target in organic synthesis.1 Particularly, construction
of benzylic quaternary centres has become of special interest2
since it is involved in many biologically significant molecules.
Here we present a new and efficient strategy for the asymmetric
construction of the benzylic quaternary carbon centre by
illustrating an enantiocontrolled formal total synthesis of
(2)-a-cuparenone 1.3 Our basic strategy is shown in Scheme 1.
But
O
OH
OH
OH
O
i
ii
OAc
5
6
7
iii–vii
O
1
viii
We envisaged that a pivotal construction of the benzylic
quaternary carbon in 2 might be realized by employing the
diastereoselective [1,5] C–H insertion reaction of alkylidene
carbene 3,4 in which the benzylic tertiary asymmetric centre
should be generated via a lipase-mediated asymmetric acetyla-
tion5 of the prochiral diol 4. It is well known that the C–H
insertion reaction proceeds with complete retention of config-
uration.4b,c
R
8 R = OH
SiMe3
9 R = OSO2Me
10 R = CN
11 R = CH2OH
12 R = CH2Br
13
ix
Treatment of 2-tert-butyl-4,5-dihydro-5-(4-methylphenyl)-
1,3-dioxepine 5,6a prepared by the Heck reaction6 between
4-methyliodobenzene and 2-tert-butyl-4,7-dihydro-1,3-diox-
epine,7 under ozonolytic cleavage conditions followed by
reductive workup with NaBH4 provided the prochiral 1,3-diol 6
in 84% yield (Scheme 2). It should be noted that the procedure
is efficient and superior to the conventional method.8 With the
prochiral diol in hand, we examined the optimum conditions for
asymmetric acetylation using some lipases.9 Of these, porcine
pancreatic lipase (PPL)-catalysed transesterification in diethyl
ether using vinyl acetate as an acetyl donor at room temperature
proved to be the best choice and (R)-monoacetate 7, [a]D + 15.6
(c 1.28, CHCl3) {lit.,9 for the (S)-isomer; [a]D 2 16.2 (c 1.20,
CHCl3)}, was obtained in 84% yield. The enantiomeric excess
was 99% as determined by 1H NMR analysis of its MTPA ester
derivative. Removal of the hydroxy moiety in 7 by tosylation
and subsequent reduction with NaBH4 in Me2SO9 furnished the
alcohol 8, which was mesylated to give 9 in 88% yield from 7.
Sequential cyanation, DIBAL-H reduction–acidic workup, and
further reduction with NaBH4 gave one-carbon elongated
alcohol 11 in 75% overall yield. Reaction of the bromide 12,
••
H
x
SO2Ph
–
BF4
+
IPh
14
15
SO2Ph
xi
16
17
xii
1
O
18
Scheme 2 Reagents and conditions: i, O3 then NaBH4, CH2Cl2, 278 to
0 °C, 84%; ii, vinyl acetate, PPL, Et2O, room temp., 84%; iii, TsCl, Et3N,
DMAP, CH2Cl2, room temp., then NaBH4, Me2SO, 60 °C, 73%; iv, MsCl,
Pri2NEt, CH2Cl2, room temp., 88%; v, KCN, 18-crown-6, Me2SO, 60 °C,
90%; vi, DIBAL-H, hexane–CH2Cl2 (1:1), 278 °C then 1 m HCl, NaBH4,
MeOH, 75%; vii, Ph3P, CBr4, CH2Cl2, 240 °C, 94%; viii, BunLi,
HC·CSiMe3, THF, HMPA, 278–0 °C, 69%; ix, (PhIO)n, BF3·OEt2,
CH2Cl2, 0 °C; x, PhSO2Na, H2O, 0 °C, 83% for 2 steps; xi, Na–Hg (5%),
MeOH, sonication, room temp., 70%; xii, PDC, ButOOH, Celite, benzene,
10 °C–room temp., 72%
OH
••
H
*
R
R
**
OH
2
3
4
Scheme 1
Chem. Commun., 1997
1167

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3 For recent representative chiral syntheses of (2)-a-cuparenone; (a)
A. I. Meyers and B. A. Lefker, J. Org. Chem., 1986, 51, 1541; (b)
M. M. Gharpure and A. S. Rao, Synth. Commun., 1989, 19, 1813; (c)
H. Nemoto, H. Ishibashi, M. Nagamochi and K. Fukumoto, J. Org.
Chem., 1992, 57, 1707; (d) J. L. Canet, A. Fadel and J. Salau¨n, J. Org.
Chem., 1992, 57, 3463, and references are cited therein. For
(+)-a-cuparenone, (e) T. Honda, N. Kimura and M. Tsubuki, Tetra-
hedron Asymmetry, 1993, 4, 21; (f) J. B. Schwarz and A. I. Meyers,
J. Org. Chem., 1995, 60, 6511; (g) K. Maruoka, M. Oishi and
H. Yamamoto, J. Am. Chem. Soc., 1996, 118, 2289.
4 For cyclopentene annulation via [1,5] C–H insertion of alkylidene
carbene; (a) J. Wolinsky, G. W. Clark and P. C. Thorstenson, J. Org.
Chem., 1976, 41, 745; (b) J. C. Gilbert, D. H. Giamalva and
U. Weerasooriya, J. Org. Chem., 1983, 48, 5251; (c) J. C. Gilbert,
D. H. Giamalva and M. E. Baze, J. Org. Chem., 1985, 50, 2557; (d)
M. Ochiai, M. Kunishima, Y. Nagao, K. Fuji, M. Shiro and E. Fujita,
J. Am. Chem. Soc., 1986, 108, 8281; (e) M. Ochiai, M. Kunishima,
S. Tani and Y. Nagao, J. Am. Chem. Soc., 1991, 113, 3135; (f) S. Ohira,
K. Okai and T. Moritani, J. Chem. Soc., Chem. Commun., 1992, 721; (g)
M. Ochiai, K. Uemura and Y. Masaki, J. Am. Chem. Soc., 1993, 115,
2528; (h) S. Ohira, T. Moritani, T. Ida and M. Yamato, J. Chem. Soc.,
Chem. Commun., 1993, 1299; (i) R. R. Tykwinski, P. J. Stang and
N. E. Persky, Tetrahedron Lett., 1994, 35, 23; (j) M. Kunishima,
K. Hioki, S. Tani and A. Kato, Tetrahedron Lett., 1994, 35, 7253; (k)
D. F. Taber and R. P. Meagley, Tetrahedron Lett., 1994, 35, 7909; (l)
S. Kim and C. M. Cho, Tetrahedron Lett., 1994, 35, 8405; (m)
D. F. Taber, A. Sahli, H. Yu and R. P. Meagley, J. Org. Chem., 1995,
60, 6571; (n) D. F. Taber, R. P. Meagley and D. J. Doren, J. Org. Chem.,
1996, 61, 5723.
convenient for further transformations. Thus, treatment of 13
with iodosylbenzene in the presence of boron trifluoride–
diethyl ether in CH2Cl2 at 0 °C followed by treatment with
aqueous sodium tetrafluoroborate provided the iodonium tetra-
fluoroborate 14, which was immediately exposed to aqueous
sodium benzenesulfinate at 0 °C to give the cyclized vinyl
sulfone 16,† via the alkylidene carbene intermediate 15, in 83%
overall yield from 13 as the sole product. The absolute
configuration at the newly-generated quaternary centre was
deduced to be R, which was confirmed by the following
conversion. Removal of the benzenesulfonyl moiety in 16 using
Na–Hg under sonication10 afforded 17 in 70% yield. Finally,
oxidation of the allylic methylene in 17 with pyridinium
dichromate (PDC) in the presence of tert-butylhydroperoxide
1
and Celite11 produced the enone 18, whose H NMR data and
optical rotation, [a]D + 101 (c 1.28, EtOH) {lit.3a [a]D + 114 (c
1.36, EtOH)}, were identical with those reported. Since the
compound 18 has already been converted into
(2)-a-cuparenone 1 by a two-step sequence,3a the present
synthesis constitutes a formal total synthesis of 1.
In summary, we have developed an efficient and un-
precedented methodology for assembling benzylic quaternary
stereogenic centres and demonstrated the formal total synthesis
of (2)-a-cuparenone as an application of the procedure.
We are grateful to Professor Masahito Ochiai and Mr Takuya
Sueda, University of Tokushima, for valuable discussions.
5 H. M. Sweers and C.-H. Wong, J. Am. Chem. Soc., 1986, 108, 6421;
Y.-F. Wang and C.-H. Wong, J. Org. Chem., 1988, 53, 3127;
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Footnotes
* E-mail: shishido@ph.tokushima-u.ac.jp
† Selected spectroscopic data for 16; pale yellow oil; [a]D +34.6 (c 0.38,
CHCl3); dH(200 MHz, CDCl3) 1.45 (3 H, s), 2.14–2.21 (2 H, m), 2.31 (3 H,
s), 2.54–2.73 (2 H, m), 6.82 (1 H, s), 7.09 (4 H, s), 7.55–7.61 (3 H, m),
7.91–8.43 (2 H, m); dC(100 MHz, CDCl3) 20.9 (CH3), 26.6 (CH3), 30.0
(CH2), 41.0 (CH2), 52.9 (C), 124.5 (CH 3 2), 128.0 (CH 3 2), 129.2 (CH
3 2), 129.3 (CH 3 2), 133.5 (CH), 136.2 (C), 139.5 (C), 143.2 (C), 143.8
(C), 149.5 (CH); m/z (EI) 312 (M+); HRMS (EI) calc. for C19H20O2S,
312.1184. Found: 312.1169. Anal. calc. for C19H20O2S: C, 73.04; H, 6.45.
Found: C, 72.89; H, 6.49%.
7 H. Frauenrath, Synthesis, 1989, 721.
8 P. A. Levene and G. M. Meyer, Org. Synth., 1943, Coll. Vol. II, 288.
9 G. Guanti, E. Narisano, T. Podgorski, S. Thea and A. Williams,
Tetrahedron, 1990, 46, 7081.
10 R. E. Dabby, J. Kenyon and R. F. Mason, J. Chem. Soc., 1952, 4881.
11 N. Chidambaram and S. Chandrasekaran, J. Org. Chem., 1987, 52,
5048.
References
1 K. Fuji, Chem. Rev., 1993, 93, 2037.
2 T. Takemoto, M. Sodeoka, H. Sasai and M. Shibasaki, J. Am. Chem.
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Received in Cambridge, UK, 18th April 1997; Com.
7/02667F
1168
Chem. Commun., 1997