Radical cyclisation with high diastereofacial selectivity: Asymmetric synthesis of (+)-12b-epidevinylantirhine

Article abstract of DOI:10.1039/a700834a

Radical cyclisation of the chiral α,β-unsaturated ester 1, carried out in the presence of MAD, gives six-membered cyclic acetal 2 diastereoselectively, which is transformed into (+)-12b-epidevinylantirhine 7.

Full text of DOI:10.1039/a700834a

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Radical cyclisation with high diastereofacial selectivity: asymmetric
synthesis of (؉)-12b-epidevinylantirhine
Masataka Ihara,* Akira Katsumata and Keiichiro Fukumoto
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-77, Japan
Table 1 Diastereofacially selective radical cyclisation of 1
Radical cyclisation of the chiral á,â-unsaturated ester 1,
carried out in the presence of M AD, gives six-membered
cyclic acetal 2 diastereoselectively, which is transformed
into (؉)-12b-epidevinylantirhine 7.
Yield of
Entry Conditions
3 (%)a
De (%)b
1
2
3
4
5
Bu3SnH, AIBN, benzene, reflux,
3.5 h
(Me3Si)3SiH, AIBN, benzene, reflux,
4 h
Bu3SnH, Et3B, toluene, Ϫ40 ЊC,
1.5 h
Bu3SnH, Et3B, Me3Al, toluene,
Ϫ40 ЊC, 2 h
Bu3SnH, Et3B, MAD, toluene,
Ϫ40 ЊC, 1.5 h
70
65
44
51
38
13
13
31
67
Radical cyclisation is well recognised as one of the most vers-
atile methods for the creation of new carbon–carbon bonds.1
Previously, we demonstrated the stereoselective formation of
six-membered ring compounds with excellent 1,2-asymmetric
induction.2 As an extension of this work, a diastereofacially
selective radical cyclisation of a chiral α,β-unsaturated ester has
been investigated. We now report the highly selective outcome,
as well as an asymmetric synthesis of (ϩ)-12b-epidevinyl-
antirhine, a cleaved product of geissoschizol.3
The substrate 1 was prepared from 3-tert-butyldimethyl-
silyloxypropanol4 using standard procedures; oxidation with
pyridinium dichromate (PDC), Wittig reaction using (Ϫ)-8-
phenyl-p-menthan-3-yl (triphenylphosphoranylidene)acetate,5
deprotection with Bu4NF in the presence of acetic acid and
acetal formation with ethyl vinyl ether and N-bromosuccin-
imide (NBS).6 Radical cyclisation of 1 was carried out under
various conditions. Since purification of cyclic acetal 2 was dif-
ficult, the crude product was converted into the lactone 3
(Scheme 1). The overall yield for the three steps and the dia-
>98
a
Overall yield for three steps from 1. b De was calculated based on the
1H NMR spectrum of 3.
O
O
NH
OH
O
N
H
i
H
H
Ph-MenO2C
Ph-MenO2C
4
5
EtO
O
EtO
O
*
O
O
*
i
ii, iii
ii, iii
Br
Ph-MenO2C
Ph-MenO2C
Ph-MenO2C
3
1
2
N
N
O
N
H
N
H
iv–vi
H
Ph
Ph-Men =
H
H
HO
Ph-MenO2C
Scheme 1 Reagents and conditions: i, see Table 1; ii, 10% HClO4, THF,
20 ЊC, 12 h; iii, Ag2CO3–Celite, benzene, reflux, 1 h
7
6
Scheme 2 Reagents and conditions: i, tryptamine, toluene, 110 ЊC, 7.5
h, 72%; ii, MeSO2Cl, Et3N, benzene, 20 ЊC, 1 h; iii, KH, 18-crown-6,
MeOCH2CH2OMe, 20 ЊC, 1.5 h, 69% for 2 steps; iv, POCl3, MeCN,
reflux, 1.5 h; v, NaBH4, MeOH, 0 ЊC, 1 h; vi, DIBAL, toluene, 0 ЊC, 0.5
h, 35% for 3 steps
stereoisomeric excess (de), determined by 1H NMR spec-
troscopy (300 MHz in C6D6) of 3, are shown in Table 1.
Heating with Bu3SnH (entry 1) and (Me3Si)3SiH (entry 2) in
the presence of azoisobutyronitrile (AIBN) resulted in poor
diastereoselectivities (13% de), while reaction with Bu3SnH and
Et3B7 at Ϫ40 ЊC gave 31% de (entry 3). The diastereoselectivity
was improved by addition of a Lewis acid.8 A moderate selectiv-
ity, 67% de, was obtained by reaction in the presence of 4.0
equiv. of Me3Al (entry 4). However, no formation of the other
stereoisomer was observed (>98% de) in the 1H NMR spectrum
of 3, prepared by reaction in the presence of 2.0 equiv. of
reaction of 6, followed by reduction of the resulting iminium
salt with NaBH4, produced stereoselectively the indolo[2,3-
a]quinolizine as a single stereoisomer, which was further
reduced with DIBAL to provide (ϩ)-7, [α]D21 ϩ12.3 (c 0.50 in
MeOH). The relative stereochemistry was deduced from the 1H
NMR spectroscopic data.3a The selective formation of the
single isomer by the above reduction with NaBH4 is explainable
by stereoelectronic effects.10 The R configuration at the 12b pos-
ition was suggested by the circular dichroism (CD) spectrum,
[θ] Ϫ3.14 × 103 (269 nm in MeOH).11 This indicates that the
radical cyclisation proceeds via the s-trans conformation 8, and
is restricted by the presence of the Lewis acid.
methylaluminium
bis(2,6-di-tert-butyl-4-methylphenoxide)
(MAD)9 (entry 5).
The stereochemistry of the predominant isomer 4 was estab-
lished by transformation into (ϩ)-12b-epidevinylantirhine 7
(Scheme 2). Treatment of the product 4, obtained using MAD
(Table 1, entry 5), with tryptamine in hot toluene afforded 5,
which was cyclised to 6 in two steps. The Bischler–Napieralski
It is expected that the above six-membered ring compounds 2
J. Chem. Soc., Perkin Trans. 1, 1997
991

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(1 H, m), 4.16–4.24 (1 H, m, 6-H), 4.31–4.38 (1 H, m, 6-H), 4.81
LA
O
H
(1 H, ddd, J 4.4, 10.7, 10.7, 3Ј-H), 7.09–7.31 (5 H, m, Ph)
(HRMS: found Mϩ Ϫ CMe2Ph, 253.1490. C14H21O4 requires
253.1440).
Ph
O
.
Acknowledgements
O
OEt
This work was, in part, supported by the Mitsumaru Pharma-
ceutical Co., Ltd, whose support is gratefully acknowledged.
8
and 4, possessing newly created stereogenic centres with three
References
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Experimental
(؉)-(1ЈR,3ЈR,4ЈS)-8Ј-Phenyl-p-menthan-3Ј-yl (4S)-2-oxo-
3,4,5,6-tetrahydro-2H-pyran-4-ylacetate 4
To a mixture of 1 (42.6 mg, 0.089 mmol) and Bu3SnH (0.036
cm3, 0.133 mmol) in dry toluene (20 cm3) at 20 ЊC was added 0.5
 MAD in toluene (0.186 cm3, 0.093 mmol), and the mixture
was stirred for 30 min at Ϫ40 ЊC. After addition of 1.0  Et3B
in hexane (0.093 cm3, 0.093 mmol) at Ϫ40 ЊC, the mixture was
stirred for 1.5 h at the same temperature. After evaporation of
the solvents, followed by dilution with Et2O, the resulting mix-
ture was washed with 10% HCl, saturated aqueous NaHCO3
and brine, dried (MgSO4) and the solvent evaporated. A mix-
ture of the residue and 10% HClO4 (2 cm3) in THF (4 cm3) was
stirred for 12 h at 20 ЊC. After dilution with Et2O, the organic
layer was washed with saturated aqueous NaHCO3 and brine
and dried (MgSO4). Evaporation of the solvents gave the crude
cyclic hemiacetals, which were taken up into dry benzene (10
cm3). After addition of Ag2CO3–Celite (17:15 w/w, 890 mg,
0.887 mmol), the mixture was heated for 1 h under reflux. Fil-
tration through Celite, followed by evaporation of the filtrate,
afforded a residue which was subjected to column chroma-
tography on silica gel. Elution with hexane–AcOEt (3:1 v/v)
provided 4 (12.6 mg, 38%) as an oil; [α]D24 ϩ3.9 (c 1.05 in CHCl3);
νmax/cmϪ1 1735 and 1725 (C᎐O); δ (300 MHz, CDCl ) 0.88 (3
᎐
H
3
H, d, J 6.6, 7Ј-H3), 0.93–1.01 (1 H, m), 1.10–1.26 (1 H, m), 1.18
(3 H, s, 8Ј-Me), 1.29 (3 H, s, 8Ј-Me), 1.33–1.59 (4 H, m), 1.62–
1.76 (2 H, m), 1.80–1.90 (3 H, m), 1.94–2.13 (3 H, m), 2.53–2.65
Paper 7/00834A
Received 5th February 1997
Accepted 7th February 1997
992
J. Chem. Soc., Perkin Trans. 1, 1997