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Synthesis 2009(8): 1261-1264  
DOI: 10.1055/s-0028-1088021
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Efficacious Preparation of Oppolzer’s Glycylsultam via the Delépine Reaction

Alper Isleyen, Carolyn Gonsky, Robert C. Ronald, Philip Garner*
Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Fax: +1(509)3358867; e-Mail: ppg@wsu.edu;
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Publication History

Received 10 September 2008
Publication Date:
16 March 2009 (online)

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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

5

Although Oppolzer did not actually report a synthesis of the parent glycylsultam, we feel that it is appropriate to refer to it as ‘Oppolzer’s glycylsultam’ for descriptive reasons.

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 ¹H NMR spectrum: ¹H 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] ). Byproduct 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 ¹H NMR spectrum: ¹H 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] ) was supported by its exact mass (HRMS: m/z [M - H]+ calcd for C39H59N6O9S3: 851.3500; found: 851.2368) and the presence of an aminal carbon signal in its ¹³C NMR spectrum: ¹³C 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.