490 Davis et al.
N-sulfinyl auxiliary in (+)-26 gave the salt 27, which
was isolated in crude form and treated with ac-
etaldehyde to furnish the 4-oxopiperidine (+)-28 as
a single isomer, exclusively. The exclusive cis orien-
tation of the piperidine 2,6-substitutents is consis-
1,3
tent with transition state TS-1 because A strain
disfavors TS-2, which would lead to the trans isomer
(Scheme 7). Next hydrogenation removed the double
bonds and decarboxylation, using LiOH/MeOH, fur-
nished 4-oxopiperidine 30. Stereoselective reduction
of 30 with NaBH
and >97% ee.
4
gave (+)-241D (31) in 90% yield
Isoquinolines
The current interest in 3-substituted 1,2,3,4-
tetrahydroisoquinolines stems from their unique
structures and diverse biological properties. Typ-
ically these alkaloids are prepared by cyclization
of -arylethylamino derivatives using the Bischler–
Napieralski and Pictet–Spengler protocols. Because
nitrilium ion intermediates are involved, side reac-
tions can occur and there are difficulties in con-
trolling the regio- and stereoselective formation of
the isoquinoline ring. In the asymmetric synthe-
sis of isoquinolines, preparation of nonracemic -
arylethylamino derivatives is problematic.
As part of a program aimed at developing new
strategies for the asymmetric synthesis of tetrahy-
droisoquinolines we have been examining the reac-
tions of laterally lithiated species 32 with enantiop-
ure sulfinimines (Scheme 8) [7,14]. Cyclization of the
resulting sulfinamide 33 furnishes the isoquinolone
SCHEME 8 Synthesis of tetrahydroisoquinolines using lat-
erally lithiated anions.
the diastereoselectivity of this material by NMR. By
conversion into a known product, i.e. (� )-43, the
de of (+)-38 was determined to be >97%. Removal
of the sulfinyl auxiliary in 38 and cyclization with
tert-butyllithium afforded isoquinolone 40a. To
introduce the C-4 hydroxy group, we carried out
an oxaziridine-mediated hydroxylation of the C-4
anion of 40b using (camphorylsulfonyl)oxaziridine
(
� )-41. A single hydroxy diastereoisomer (+)-42
having the trans orientation was obtained. Protec-
tion, reduction, and deprotection of (+)-42 gave
(
3R,4S)-(� )-43 in 78% yield for the three steps [14].
34 or cyclic imine 35, which can be elaborated
A more direct route to hydroxy isoquinolines is
to the tetrahydroisoquinoline 36. Importantly, this
methodology has the potential for avoiding many
of the limitations of the Bischler–Napieralski and
Pictet–Spengler protocols as well as providing iso-
quinolines with substitution patterns not easily ac-
cessible by other means.
illustrated by the reaction of phthalide anions with
sulfinimines (Scheme 10) [14]. When an equimolar
mixture of 6-methoxyphthalide (44) and (S)-(+)-36
were treated with base, pseudoenantiomers 45a and
45b were obtained in good yield (Scheme 10). In-
terestingly, the selectivity proved to be counterion
dependent with LiHMDS affording a 10:1 ratio of
45a:45b while NaHMDS gave a 1:15 ratio. Chelation
and steric control arguments were suggested to ex-
plain the stereoselectivity and were supported by the
fact that LiHMDS-DMPU, known to disrupt metal
chelation, resulted in a 1:2 mixture of 45a:45b. Treat-
ment of these sulfinamides with NaH afforded iso-
quinolones 46a and 46b, which were elaborated in
two steps to 42.
4
-Hydroxy-3-phenyltetrahydroisoquinoline
Hydroxy isoquinolines are potential precursors of
hydroxyprotoberberines, a class of alkaloids that
exhibit diverse biological properties. A new route to
these types of isoquinolines is illustrated in the asym-
metric synthesis of 4-hydroxy-6-methoxy-N-methyl-
3
-phenyl-1,2,3,4-tetrahydroisoquinoline
(43)
(Scheme 9) [14]. The laterally lithiated amide anion
of 5-methoxy N,N-diethyl-o-toluamide (37), pre-
pared by reaction with LDA, was treated with sulfin-
1,3-Disubstituted Tetrahydroisoquinolines
imine (S)-(+)-3 affording sulfinamide (S
S
S)-(+)-38
The formation of atropodiastereoisomers in the ad-
dition of lateral lithiated amides to sulfinimines
(Scheme 9) makes it nearly impossible not only
in 90% yield. Because atropodiastereoisomers are
formed, it was not possible to accurately determine