S. M. Allin et al. / Tetrahedron Letters 42 (2001) 3943–3946
3945
CHO
(iii)
(i)
(ii)
(7b)
N
N
N
O
O
O
Me
(9)
Me
(10), [α]D = -261.2
Me
(8)
Scheme 4. (i) Dess–Martin periodinane, CH2Cl2; (ii) Rh(PPh3)2(CO)Cl, dppp, xylene, D, 2 h; (iii) H2/10% Pd–C, EtOH.
In order to rationalise the stereochemical outcome of
the cyclisation reactions described in this paper, we
have invoked the conformational models10 highlighted
in Fig. 1, in which activation of the bicyclic lactam
substrate by a Lewis acid leads to a formal N-acyli-
minium species as an intermediate.
attempted a Rh-catalysed decarbonylation but found
that the reaction proceeded to give enamide (9) in 64%
yield, with no sign of the desired compound (10). We
were subsequently able to convert enamide (9) into the
desired compound (10) in 89% yield by catalytic
hydrogenation.
In summary, we report a facile and highly stereoselec-
tive approach to the pyrroloisoquinoline ring system
from readily available non-racemic bicyclic lactam sub-
strates. We have also demonstrated that removal of the
pendant hydroxymethyl auxiliary is possible from a
product of cyclisation.
In conformation A (R=H), leading to the favoured
product 4a, the carbonyl moiety is ‘eclipsed’ in a 1,3-
fashion by the small hydrogen atom at the b-amino
alcohol chiral centre. The angular H-atom (R=H) at
the iminium carbon atom provides no significant steric
bulk to interfere with the steric positioning of the
benzyl or Lewis acid-complexed oxymethyl groups. In
this model, the Lewis acid-complexed oxymethyl group
is viewed as the larger substituent.10
Acknowledgements
The alternative conformation, B, which would lead to
the minor (unobserved) diastereoisomer (4b), has the
benzyl group positioned as the larger substituent. In
this scenario an unfavourable 1,3-interaction appears to
exist between the carbonyl group and the more bulky
Lewis acid-complexed oxymethyl group.
Loughborough University and GlaxoSmithKline Phar-
maceuticals (joint studentship to S.L.J.) for facilities
and financial support of this research. We also thank
Professor H. Heaney, W. R. Bowman and P. C. B.
Page for helpful comments made during the course of
this work and the preparation of this manuscript.
With substrate (6), the steric influence provided by the
angular methyl substituent (R=Me) at the iminium
carbon atom overrides the conformational effect noted
above and this leads to a major diastereoisomer of
opposite relative stereochemistry. One can envisage
interactions between this angular methyl group and the
benzyl substituent (A, R=Me). Bond rotation about
the extra-annular CꢀN bond leads to an alternative
conformation B (R=Me) with minimised steric inter-
ference from the iminium carbon substituent, which
furnishes the observed major product diastereoisomer
(7b) with retention of stereochemistry. We have not
ruled out the possible influence of chelation control
with a Lewis acid such as TiCl4 in conformations such
as A and B. Such an effect, that of changing the sense
and level of diastereoselectivity by increasing the rela-
tive size of this angular iminium substituent, has been
reported by Meyers, and was also rationalised using
similar Felkin–Anh like models.11
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To demonstrate the potential synthetic utility of this
new methodology we undertook a study aimed at
removal of the pendant hydroxymethyl substituent
(auxiliary) from a product of cyclisation (Scheme 4).
Our initial attempt involved alcohol oxidation of
pyrroloisoquinoline (7b), isolated as
a
single
diastereoisomer by column chromatography. The Dess–
Martin oxidation proceeded in 89% yield to provide
aldehyde (8) as a single diastereoisomer. Following a
method previously used in our laboratory, we
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