A stereoselective construction of a bicyclo[m.n.1] ring system from enol-lactones

Article abstract of DOI:10.1039/a806808i

A stereoselective one-pot transformation of simple enol-lactone derivatives into the corresponding more complex compounds having the bicyclo[m.n.1] ring system was investigated. Under improved reduction conditions using DIBAL-H, the enol-lactones efficien

Full text of DOI:10.1039/a806808i

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A stereoselective construction of a bicyclo[m.n.1] ring system from
enol-lactones
Chisato Mukai,* Kohei Kagayama and Miyoji Hanaoka*
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920,
Japan. E-mail: cmukai@kenroku.kanazawa-u.ac.jp; fax: ϩ81-76-234-4410
Received (in Cambridge) 1st September 1998, Accepted 23rd September 1998
A stereoselective one-pot transformation of simple enol-
OTBDMS
lactone derivatives into the corresponding more complex
compounds having the bicyclo[m.n.1] ring system was
investigated. Under improved reduction conditions using
DIBAL-H, the enol-lactones efficiently provided the
bicyclo[m.n.1] derivatives via tandem reduction of the
lactone moiety, aldol reaction and subsequent reduction of
CO2H
d
a, b, c
S
CHO
S
HO
6
7
TBDMSO
O
O
the resulting carbonyl functionality.
e, f, g
h, i
The bicyclo[m.n.1] ring system has been found to be a core
skeleton of many natural compounds such as Taxol,1
crispolide2 and utilin B.3 The development of an efficient and
stereoselective method for construction of the bicyclo[m.n.1]
ring system, therefore, would be an important theme for
organic as well as medicinal chemistry. We envisioned, on the
basis of literature precedents,4,5 that simple enol-lactone deriv-
atives like 1 would be easily transformed into the corresponding
more complex bicyclo[m.n.1]ones 5 on the basis of the follow-
ing scheme: the lactone moiety of 1 would be reduced to the
lactol 2 when exposed to a suitable reducing agent. The lactol
derivative 2 thus formed would be in an equilibrium with
the aldehyde–enolate species 3 through C–O bond cleavage.
The aldehyde–enolate derivative 3 can be regarded as a well-
recognized intermediate leading to the final product 5 in the
aldol reaction where the Lewis acidic metal (M) should
be coordinated with both oxygen atoms of the enolate and
aldehyde moieties. The reaction would be anticipated to pro-
ceed via the six-membered chair-like transition state6 such as 4
resulting in the stereoselective formation of 5 with the stereo-
chemistry depicted in Scheme 1. In this paper, we describe
preliminary results on this successful conversion, as shown in
Scheme 1.
S
S
8
9
O
O
O
j
10
11
Scheme 2 Reagents and conditions: a, propane-1,3-dithiol, BF3ؒOEt2,
CH2Cl2, rt; b, LAH, THF, rt; c, TBDMSCl, imidazole, DMF, rt, 73%;
d, LDA, cyclohexenone, THF, Ϫ78→0 ЊC, 73%; e, Raney–Ni (W-2),
EtOH, reflux, f, PyؒSO3, Et3N, DMSO, rt; g, TBAF, THF, rt, 48%; h,
PDC, CH2Cl2, rt; i, 10% NaOH aq., MeOH, 74%; j, mCPBA, CH2Cl2,
rt, 68%.
(TBDMS) group to afford 7. The Michael reaction7 between 7
and cyclohexenone was carried out under the standard con-
ditions to give 8, which was converted into 9 by successive
exposure to Raney–Ni,8 oxidation with pyridine–sulfur trioxide
and DMSO,9 and desilylation. Oxidation of 9 with PDC gave
the corresponding aldehyde, whose aldol reaction with 10%
sodium hydroxide provided 10. Treatment of 10 with mCPBA
furnished the required enol-lactone 11.
The first attempt at the transformation of 11 into the corre-
sponding 8,9-benzobicyclo[4.3.1]dec-8-ene derivative was made
using diisobutylaluminum hydride (DIBAL-H) as a reducing
agent. Upon treatment with DIBAL-H (3 equiv.) in Et2O at
Ϫ78 ЊC, 11 underwent consecutive reduction of the lactone
moiety, aldol reaction, and reduction of the resulting carbonyl
functionality leading to the formation of 12 in 37% yield along
with its isomer 13 (13%) (Scheme 3). Although the total yield
MO
O
H
M
O
O
O
O
MH
m–3
H
m–3
m–3
H
n–2
n–2
n–2
1
2
3
M
O
HO
O
O
RO
RO
m–3
H
H
H
m–3
H
H
H
OR
OR
DIBAL-H
n–2
+
11
n–2
CH2Cl2
0 °C
4
5
H
H
n
2
m 3
12 : R = H (81%)
14 : R = Ac
13 : R = H (4%)
15 : R = Ac
Scheme 1
16 : R = p-Br-C6H4CO
For the initial evaluation of this strategy, the enol-lactone 11
was prepared in several straightforward steps from 2-carb-
oxybenzaldehyde 6 (Scheme 2). Protection of the aldehyde
moiety of 6 with propane-1,3-dithiol was followed by reduction
with lithium aluminum hydride (LAH) and protection of the
resulting primary hydroxy group with a tert-butyldimethylsilyl
Scheme 3
(50%) and stereoselectivity were rather lower, transformation
of the simpler 11 into the more complex 12 and 13 could be
attained in one operation. When this reaction was conducted in
J. Chem. Soc., Perkin Trans. 1, 1998, 3517–3518
3517

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CH2Cl2 at 0 ЊC instead of in Et2O at Ϫ78 ЊC, 11 produced 12
in 81% yield in a highly stereoselective manner (13 was obtained
in 4% yield).10 A similar result [12 (73%) and 13 (4%)] was
obtained on exposure of 11 to DIBAL-H in CH2Cl2 in the
presence of ZnCl2.11 Other Lewis acidic metal hydride reagents
like BH3ؒTHF, BH3ؒSMe2 and 9-BBN were also employed for
this transformation, but no improvement in yield or stereo-
selectivity could be achieved.12 The structure of these com-
pounds was determined on the basis of the spectral data of 12
and 13 as well as their diacetyl derivatives 14 and 15. In particu-
lar, the stereochemical outcome was unambiguously established
as described in Scheme 3 by X-ray crystallographic analysis of
the bis-p-bromobenzoate 1613 derived from 12.
mmol) at 0 ЊC under a nitrogen atmosphere. The reaction mix-
ture was stirred at the same temperature for 2 h and quenched
by addition of water. The reaction mixture was diluted with
ethyl acetate, and washed with water and brine, dried over
MgSO4, and concentrated to dryness. Chromatography of the
residue with hexane–ethyl acetate (5:1) afforded 12 (67.2 mg,
81%) and 13 (3.4 mg, 4%). Compound 12 was converted to the
corresponding acetate 14 for detailed analysis: the acetate 14
was a colourless oil (Found: C, 70.9; H, 7.4. C18H22O4 requires
C, 71.5; H, 7.3%); νmax/cmϪ1 1725 (CO); δH 7.53 (1H, d, J 7.5,
aromatic H), 7.18 (1H, apparent t, J 7.5, aromatic H), 7.11 (1H,
apparent t, J 7.5, aromatic H), 7.02 (1H, d, J 7.5, aromatic H),
5.42 (1H, dd, J 5.0, 7.0, 10-H), 5.34 (1H, apparent t, J 9.0, 2-H),
3.77 (1H, d, J 7.0, 1-H), 3.24 (1H, dd, J 7.5, 17.5, 7-H), 2.75
(1H, d, J 17.5, 7-H), 2.49 (1H, m, 6-H), 2.20–2.02 (2H, m), 2.17
(3H, s, Ac), 2.06 (3H, s, Ac), 1.92–1.85 (1H, m), 1.82–1.78 (1H,
m), 1.50–1.44 (1H, m) and 1.19–1.11 (1H, m); δC 170.5, 170.4,
136.3, 135.0, 130.2, 128.9, 126.6, 126.3, 79.7, 74.4, 43.7, 36.4,
34.6, 34.0, 33.2, 29.7, 21.4 and 20.1; CI-MS m/z 303 (Mϩ ϩ 1,
1.1%), 243 (100) and 183 (16).
The next phase of our study now involved the application
of these conditions (3 equiv. of DIBAL-H, CH2Cl2) to other
enol-lactone derivatives. Treatment of the enol-lactone 1714
with DIBAL-H in CH2Cl2 at 0 ЊC gave stereoselectively the
bicyclo[4.3.1]decane-7,10-diol 20 in 55% yield (Scheme 4). In
O
DIBAL-H
HO
HO
R1
O
Acknowledgements
O
OH
DIBAL-H
R1
R2
R2
R1
+
We are very grateful to Dr S. Hosoi of this Faculty and
Dr M. Shiro, Rigaku Corporation, for X-ray crystallographic
analysis.
R2
CH2Cl2
0 °C
R1 = R2 = H
R1 = H, R2 = Me
R1 = Me, R2 = H
R1 = R2 = H
R1 = H, R2 = Me
R1 = Me, R2 = H
R1 = R2 = H
R1 = H, R2 = Me
R1 = Me, R2 = H
17 :
18 :
19 :
20 :
21 :
23 :
25 :
References
22 :
24 :
1 (a) M. C. Wani, H. L. Taylor, W. E. Wall, P. Coggon and A. T.
McPhail, J. Am. Chem. Soc., 1971, 93, 622; (b) S. Blechert, D.
Guenard, The Alkaloids, ed. A. Brossi, Academic Press, New York,
1990, vol. 39, p. 195.
2 (a) G. Appendino, P. Gariboldi and G. M. Nano, Phytochemistry,
1982, 21, 1099; (b) G. Chiari, G. Appendino and G. M. Nano,
J. Chem. Soc., Perkin Trans. 2, 1986, 263.
O
HO
O
OH
DIBAL-H
R1
R1
R2
CH2Cl2
0 °C
R2
3 W. M. Daniewski, M. Gumulka, W. Danikiewicz, P. Gluzinski,
J. Krajewski, E. Pankowska, E. Bloszyk, U. Jacobsson, T. Norin and
F. Szafranski, Phytochemistry, 1993, 33, 1534.
R1 = R2 = H
R1 = R2 = H
27 :
26 :
4 A few precedents5 on the transformation of enol-lactones to the
bicyclo[m.n.1] skeletons possessing the angular substituents by
treatment with Li(OBut)AlH3 or LAH have been reported.
5 (a) J. Martin, W. Parker and R. A. Raphael, J. Chem. Soc. (C), 1964,
289; (b) G. I. Fujimoto and J. Pavlos, Tetrahedron Lett., 1965, 4477;
(c) J. Martin, W. Parker, B. Shroot and T. Stewart, J. Chem. Soc. (C),
1967, 101; (d) W. Carruthers and M. I. Qureshi, J. Chem. Soc. (C),
1970, 2238.
R1 = H, R2 = Me
R1 = Me, R2 = H
R1 = H, R2 = Me
R1 = Me, R2 = H
28 :
30 :
29 :
31 :
Scheme 4
this case, the 10-oxo derivative 21, presumably a precursor of
20, could be isolated in 26% yield. The conversion of 21 to 20
was easily realized by DIBAL-H reduction. Similar results were
obtained when the methyl congeners 18 and 1914 were submit-
ted to the reduction conditions to afford the corresponding
diols 22 (44%) and 24 (53%) together with the 10-oxo deriv-
atives 23 (38%) and 25 (41%), respectively. In addition, the
exclusive formation of the bicyclo[3.3.1]nonane-2,9-diol skel-
eton15 was established using the previous procedure: thus, 27
(67%), 29 (78%) and 31 (70%) were obtained as the sole
products when 26, 28 and 30,14 respectively, were exposed to
DIBAL-H in CH2Cl2 at 0 ЊC.
In conclusion, we have improved on a method for the
stereoselective construction of bicyclo[4.3.1]decane-7,10-diol
derivatives and bicyclo[3.3.1]nonane-2,9-diol from the corre-
sponding enol-lactones by simple treatment with DIBAL-H in
CH2Cl2. Further studies in line with this program are now in
progress.
6 (a) D. A. Evans, J. V. Nelson and T. R. Taber, Top. Stereochem.,
1982, 13, 1; (b) C. H. Heathcock, Asymmetric Synthesis, ed. J. D.
Morrison, Academic Press, New York, 1984, vol. 3, p. 111.
7 (a) P. Ostrowski and V. V. Kane, Tetrahedron Lett., 1977, 3549;
(b) A. Wadi and F. Lopez-Calahorra, Tetrahedron Lett., 1992, 33,
3679.
8 M. D. Rozwadowska and D. Matecka, Tetrahedron, 1988, 44, 1221.
9 J. R. Parikh and W. E. Doering, J. Am. Chem. Soc., 1967, 89, 5505.
10 A variety of attempts was made to obtain the corresponding 10-oxo
compound selectively by changing the molar ratio between 11 and
DIBAL-H. However, no trace of the 10-oxo derivative could be
detected in the reaction mixture.
11 A. Solladié-Cavallo, J. Suffert, J. A. Joule and G. Solladié, Tetra-
hedron Lett., 1990, 31, 5549.
12 LAH was found not to be a suitable reducing agent (see ref. 5).
13 X-Ray crystallographic analysis of 16 disclosed that compound 12
should have the structure described as (1R*,2R*,6S*,10S*)-2,10-
dihydroxy-8,9-benzobicyclo[4.3.1]dec-8-ene. Details of the X-ray
analysis together with full experimental details will be reported
elsewhere.
14 The starting enol-lactones were prepared according to the literature
precedents (see ref. 5).
15 The corresponding 9-oxo derivatives could never be detected in
more than trace quantities.
Experimental
Typical method for transformation of the enol-lactone 11 into the
bicyclo[4.3.1] derivative 12
To a solution of 11 (81.0 mg, 0.38 mmol) in CH2Cl2 (4.0 cm3)
was added DIBAL-H in hexane (1.00 mol dmϪ3; 0.95 cm3, 0.95
Communication 8/06808I
3518
J. Chem. Soc., Perkin Trans. 1, 1998, 3517–3518