Novel nitrile oxide cycloaddition approach towards papuamine: stereoselective
synthesis of a potentially useful trans-hydrindane intermediate
Arabinda Saha and Anup Bhattacharjya*
Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Calcutta 700 032, India
In a potentially useful approach to the marine alkaloid
papuamine 1, a known trans-hydrindane intermediate 17
has been synthesised in racemic form using a model
sequence of reactions involving a nitrile oxide cycloaddition
as a key step.
is critically dependent on the fidelity of the sequence
4 ? 3 ? 2. We herein report an unusually simple but efficient
synthesis of a racemic trans-hydrindane intermediate 17, which
is the racemate of an intermediate used3 for papuamine, via the
model sequence of conversions 14 ? 15 ? 17 involving a
highly stereoselective, intramolecular, nitrile oxide cycloaddi-
tion and subsequent reduction of the isoxazoline ring (Scheme
2).
The diol 7, which was easily obtained from (±)-6 by reduction
with LiAlH4, was monobenzoylated and the resulting alcohol
8† was oxidised6 with PCC to the aldehyde 9. Wittig
methylenation of 9 gave the olefinic ester 10, which on
deprotection furnished the alcohol 11. Oxidation of 11 by PCC
led to the aldehyde 12, which was converted to the nitro
compound 13 via a known protocol7 involving reaction with
nitromethane, acetylation and reduction with sodium borohy-
dride without purification of any of the intermediate products.
The conversion of 6 to 12 was effected via the above route in
order to adapt this strategy for preparing enantiomerically pure
intermediates required for the synthesis of optically active
papuamine. The construction of the crucial trans-hydrindane
skeleton was then achieved by the treatment of 13 with phenyl
isocyanate leading to the formation of the nitrile oxide 14,
which underwent cycloaddition to furnish the isoxazoline 15‡
as the exclusive product. The gross structure of 15 was
Papuamine 1, a unique C2-symmetric pentacyclic alkaloid, was
isolated from the marine sponge Haliclona sp.1,2 The presence
of two disubstituted trans-hydrindane units of identical chirality
and a central diazadiene ring makes papuamine a challenging
target for synthesis. A crucial task in such a synthesis is the
stereoselective construction of the disubstituted trans-hydrin-
dane unit incorporating four chiral centres. Three recent
syntheses3–5 of optically active papuamine have solved this
problem either by reductive amination of suitably substituted
trans-hydrindanone derivatives3,4 or by utilising a highly
stereoselective iminoene reaction.5 We envisaged a novel and
expedient strategy (Scheme 1) towards 1 involving the
intramolecular cycloaddition of the bis-nitrile oxide 4 to give a
bis-isoxazoline derivative 3, which could be elaborated to the
papuamine skeleton by reductive cleavage to 2 followed by the
incorporation of a C3-unit. The future success of this approach
H
N
H
N
H
H
H
H
H
H
H
H
H
H
O
H
H
H
1
OR
OH
OR
H
i
iii
O
H
H
H
NHR
RHN
H
H
H
O
H
H
X
OR RO
7 R = H
8 R = Bz
9 R = Bz, X = O
10 R = Bz, X = CH2
11 R = H, X = CH2
6
H
H
ii
iv
H
v
2
vi
N
N
H
H
H
H
NO2
CHO
+
–
O
O
O
H
C
N
viii
vii
H
H
H
H
H
H
3
14
13
12
+
N
–
–
+
N
C
O
O
C
H
NHR
OH
H
H
N
H
O
H
ix
H
H
H
H
H
H
4
15
16 R = H
17 R = Boc
x
NO2
O2N
H
Scheme 2 Reagents and conditions: i, LiAlH4, THF, 90%; ii, NaH (1
equiv.), then BzCl (1 equiv.), 82%; iii, PCC, neutral alumina, CH2Cl2, 96%;
iv, Ph3PMe+I2, BuLi, THF, 70%; v, NaOH, MeOH, H2O, 96%; vi, PCC,
neutral alumina, CH2Cl2, 92%; vii, CH3NO2, KF, then Ac2O, then NaBH4,
EtOH (68% overall); viii, PhNCO, C6H6, 72%; ix, LiAlH4, Et2O, 88%; x,
Boc2O, EtOAc, 90%
H
H
5
Scheme 1
Chem. Commun., 1997
495
Saha, Arabinda
