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alcohol and amine from the synthetic intermediate 10 are required
for the preparation of (À)-hygroline (1) and (À)-pseudohygroline
(2), while only lactam reduction from 10 is needed for the synthe-
sis of (À)-hygrine (3). After protecting the ketone as an acetal, the
reduction of the c-lactam with LiAlH4 was carried out for the prep-
aration of the pyrrolidine ring. After the reduction was completed,
the acetal protecting group was removed to give (À)-hygrine (3) in
55% overall yield, which was identified by comparison of the
known data.7a In the same manner we expected (À)-hygroline
(1) and (À)-pseudohygroline (2) to be formed by reductions for
both ketone and amide. However, what we found was that most
of the reduction conditions for both ketone and amide were not
satisfactory to obtain the final products in decent yield. Further-
more, the two diastereomers formed after the reduction of the
ketone were inseparable. The two diastereomeric mixtures of the
reduced hydroxy compounds 11 and 12 were separable after the
bulky t-butyldiphenylsilyl group was attached to the alcohol to
form compounds 13 and 14, respectively. Therefore, we decided
to reduce the ketone first with the hope to achieve stereoselectiv-
ity, so as to obtain one of the isomers as the major.
Some of the representative trials by hydride reduction were as
shown in Table 1. Most reduction conditions yielded 1:1 mixture
of diastereomers without any noticeable stereoselectivity, which
suggests that the pendant propan-2-one at the C2 position of the
pyrrolidine ring is freely rotatable (entries 1–3). With LiAl
(Ot-Bu)3H as the hydride source, the reaction afforded two diaste-
reomers with the ratio of 11 to 12 as 60:40 (entry 4). Most of the
reductions with NaBH4 were quite efficient and gave a high yield
with a small difference in the diastereomeric ratio according to
the additives (entries 5–7). With the addition of CoCl3, a slightly
excess amount of compound 11 was obtained at a ratio of 65:35
in 98% yield (entry 8). Much greater success was achieved with
the Corey–Bakshi–Shibata reduction11 with BH3ÁDMS in the pres-
ence of either (S)-oxazaborolidine or (R)-oxazaborolidine to yield
compound 11 or 12 as the major product in about 84–86% yield
(entries 9 and 10). This taught us that the stereochemical outcome
of the reduction is independent of the configuration of the C2
position in the pyrrolidine ring.
Scheme 2. Retrosynthesis of (À)-hygroline, (À)-pseudohygroline, and (À)-hygrine.
opening reaction of 2-methoxycarbonylethyl aziridine (5) with the
nitrile nucleophile (Scheme 2).
The synthesis started from the N-methylative aziridine ring
opening of 2-methoxycarbonylethylaziridine (5) with the nitrile
nucleophile shown in Scheme 3. The starting aziridine 5 was pre-
pared from commercially available (2R)-aziridine-2-carboxylate
(4) in high yield.8,9 The configuration ‘2R’ of the starting aziri-
dine-2-carboxylate ended at the C2 position of all targeted com-
pounds. The next step was a key reaction, the N-methylative
aziridine ring opening reaction of 5, applying the treatment of
MeOTf followed by NaCN in CH3CN to afford the product 6 where
methyl and nitrile groups were located at the nitrogen and at the
end of acyclic backbone respectively in 94% yield. Hydrolysis of
the nitrile in the compound
6 by c-HCl under reflux and
subsequent esterification with a catalytic amount of sulfuric acid
in MeOH yielded dimethyl 3-aminohexadicaboxylate (7) which
was easily converted to the common synthetic intermediate 8 by
the removal of the phenylethyl group in 87% yield.
Conversion of this ester (8) to the advanced common synthetic
intermediate 10 was successfully accomplished by the sequential
reactions of Weinreb amide formation and methylation with
MeMgBr.10 Two different reductions of ketone and lactam to
Scheme 3. Reagents and conditions: (a) CH3OTf, NaCN, CH3CN, 0 °C to rt, 94%; (b) (i) concd HCl, reflux; (ii) cat. H2SO4, CH3OH 87% in 2 steps; (c) Pd(OH)2/H2, CH3OH, rt, 93%;
(d) AlMe3, DMHAÁHCl, CH2Cl2, 0 °C to rt, 98%; (e) MeMgBr, THF, À78 °C to À45 °C, 96%; (f) Table 1; (g) t-BuPh2SiCl (TBDPSCl), Imidazole, DMAP, CH2Cl2, 0 °C to rt, 98% in 2
steps; (h) LiAlH4, THF, reflux, 89%; (i) (i) p-TsOH, HC(OMe)3, MeOH, 40 °C, (ii) LiAlH4, THF, reflux and then 6 M HCl, 55% in 2 steps.
Lee, Jaedeok
