1942
M. A. Brodney et al. / Tetrahedron Letters 48 (2007) 1939–1943
silane/TFA reduction (so-called ionic reduction condi-
O
OH
N
OH
NaCNBH3
pH 2.0-2.5
tions) afforded cis-product 13. For enamide 8, the bulk-
ier phenyl substituent hinders reduction from the same
face of the molecule as the phenyl group. This results
in negligible reduction of the enamide under ionic
hydrogenation conditions. Under more forcing condi-
tions (i.e., sodium cyanoborohydride at pH 2–2.5) ena-
mide and ketone reductions both occur, but from the
concave face of the molecule to give the trans ring-fused
product 18a.
Ph
Ph
Ph
+
aq. MeOH
rt
H
H
N
N
Boc
Boc
Boc
18a (62 - 75%)
18b-d
8
Scheme 7.
was significantly improved (Scheme 7). The effect of pH
on conversion rate and stereoselectivity was studied with
the optimal conditions for the formation of the major
isomer 18a being pH 2–2.5 (the pH was controlled by
addition of 2 M HCl) at room temperature. Attempts
to further improve the stereoselectivity by lowering the
temperature to 0 ꢁC resulted in unacceptably low con-
version rates. Under the optimal conditions, HPLC
analysis indicated that the major isomer 18a represented
80% of the product mixture and could be isolated in 75%
yield after chromatography on silica. A larger scale
preparation yielded 20 g of analytically pure 18a in
62% yield after chromatography and recrystallization.
In summary, the synthesis of hexahydroindolin-5-ones
via IMDAF chemistry has been developed so as to be
amenable for large-scale chemistry. Our preliminary
results for the reduction of the hexahydroindolin-5-ones
show that the ring-junction substituent plays an impor-
tant role in the reduction of the enamide moiety. The
smaller methyl substituent favours formation of the cis
ring-fused product, whereas the larger phenyl substitu-
ent results in favoured reduction to the trans ring-fused
product.
Acknowledgements
The stereochemistry of major alcohol 18a was unequiv-
ocally determined by single crystal X-ray structure
analysis (Fig. 2). The crystal structure clearly shows a
trans-relationship between the ring-junction phenyl
and hydrogen groups and a cis-relationship between
the phenyl group and the alcohol group.19
This work was funded by Pfizer Global Research and
Development. The authors thank Dr. Roger Mulder
for assistance with collection and analysis of NMR data.
Supplementary data
We have found that the ring-junction substituent in 4
(methyl) or 8 (phenyl) has a marked effect on the ena-
mide reactivity and the stereoselectivity of the reduction
of the enamide moiety in N-Boc-hexahydroindolin-5-
ones. The molecular models of compounds 4 and 8 indi-
cate that they are bowl-shaped with the 3a-substituent
situated on the convex side of the hexahydroindolinone
framework. The shape of the molecule would favour
reduction of the enamide from the same face of the mole-
cule as the substituent. Thus for enamide 4, triethyl-
Experimental procedures and analytical data for all new
compounds. X-ray experimental procedures for com-
pounds 15b and 18a. Supplementary data associated
with this article can be found, in the online version, at
References and notes
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Figure 2. ORTEP diagram of alcohol 18a, illustrating the trans
relationship of the ring-junction proton H6 and phenyl substituent.