Abstract
A new preparative route to Oppolzer’s glycylsultam,
the ‘NC’ component in the asymmetric [C+NC+CC] coupling
reaction leading to functionalized pyrrolidines, is described. The
synthesis features a novel application of the Delépine
reaction, providing a safe, efficient, and environmentally benign
route to this useful chiral reagent for pyrrolidine synthesis.
Key words
asymmetric synthesis - chiral auxiliaries - chiral
pool - Delépine reaction - Oppolzer’s
camphorsultam
References
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18 The modest yield of this reaction
was due to competitive addition of HBr to 1 that
resulted in an unstable compound tentatively identified as 7 on the basis of diagnostic peaks in its ¹ H
NMR spectrum: ¹ H NMR (300 MHz, CDCl3 ): δ = 8.15 (br
s, NH3
+ ), 5.28 (d, J = 14.2
Hz, 1 H), 3.94 (d, J = 14.2
Hz, 1 H). Attempts to suppress this side reaction were unsuccessful.
In a separate control experiment, compound 7 was
produced quantitatively by the action of HBr gas on 1 dissolved
in CDCl3 (Scheme
[³ 7 reverts back to camphorsultam 1 upon exposure to water.
Scheme 3
Figure 1
19 Monoalkylation of HMTA with the chiral
bromide 3 breaks its T
d
molecular symmetry, resulting
in AB quartets for both sets of diastereotopic HMTA methylene protons
in 4 . This Delépine salt was unstable,
but these key HMTA signals could be observed in the ¹ H
NMR spectrum: ¹ H NMR (300 MHz, CDCl3 ): δ = 5.90
(d, J = 11.1
Hz, 3 H), 5.82 (d, J = 11.1
Hz, 3 H), 4.76 (d, J = 13.0
Hz, 3 H), 4.54 (d, J = 13.0
Hz, 3 H).
20 The proposed structure of 8 (Figure
[¹ m /z [M - H]+ calcd
for C39 H59 N6 O9 S3 : 851.3500;
found: 851.2368) and the presence of an aminal carbon signal in
its ¹³ C NMR spectrum: ¹³ C
NMR (75 MHz, CDCl3 ): δ = 73.1.
21 Solutions of the free glycylsultam 6 were found to be susceptible to nucleophile-induced
deacylation to give back starting camphorsultam 1 .
The level of contamination ranged from 3 mol% on a 0.5-g
scale to 5 mol% on a 10-g scale of bromosultam 3 . However, a solid sample of 6 that had been kept at room temperature
for more than one month showed minimal decomposition.
