New entries for regio-and enantiopure syntheses of pyrrolidene systems fused to carbohydrate templates

Facile syntheses of polysubstituted dihydro-and alkylidene tetrahydropyrrols using β - dimethylhydrazone esters and epoxy pyranosides are described


Introduction
Polysubstituted tetrahydro-and dihydropyrroles with rich stereochemical functionalities are important targets either as a single entity 1 or as substructures of many biological active molecules 2,3 .Therefore, their synthesis has attracted the interest of many laboratories 3 .
A long-term objective of our research program has been to develop practical laboratory strategies for elaborating the epoxy pyranoside moiety 4 .Highlights of this program have included the development of new synthetic tactics for bis-cyclopentanoids, 4a furanoids, 4b oxazines or pyridazines 4c .
The chemistry of β-ketoester and/or 1,3-diketones continues to play a major role in synthetic design 5 .Unfortunately, the major problem of O-vs C-alkylation of such species plagues this important C-C bond-forming process.In this regard, we have elaborated new synthons derived from carbohydrates and β-ketoesters 4b,6 .
ARKAT USA, Inc.  Extending our work on β-ketoesters-DMH tactics for the construction of polyfunctionalized azacycles, we treated the epoxy triflate 11 with the monoanion of 12 (formed by condensing asymmetric DMH wit tert-butyl acetoacetate in EtOH) to produce the polysubstituted dihydopyrrolidene 14 in 86% yield (Scheme 3).Interestingly, the ring-closure is taking place via N-alkylation, whereby the nitrogen nucleophile can assume colinearity for the intramolecular S N 2 nucleophlic ring opening of the oxirane ring.On the other hand, compound 13 is not observed (Scheme 3).It seems that the double C-alkylation process is not feasible due to stereoelctronic considerations.The 1 H NMR spectrum of 14 shows a doublet of doublet (J=5.1, 9.5 Hz) assigned to the heteroatom ring proton (H-3).A salient feature of the 1 H NMR spectrum of the ARKAT USA, Inc.
dihydropyrrolidene 14 is the two singlets at 2.57 and 2.16 ppm, assigned to the N(CH 3 ) 2 and CH 3 -7 protons, respectively.Interestingly, in the 13 C NMR of 14, we were unable to detect a N(CH 3 ) resonance, although the 1 H NMR, FD, FAB and EI analysis indicate the presence of this residue.This phenomenon may be due to the dihydropyrrolidene framework coupled with long spin-lattice relaxation time of N-N(CH 3 ) 2 rotamers.Furthermore, the 1 H/ 13 C COSY spectrum of 14 indicates that the broad singlet at 2.57 ppm, assigned to N(CH 3 ) 2 in the 1 H NMR, is connected to the region around 43 ppm in the 13 C NMR spectrum.The presence of the signals at 163.2 and 100.2 ppm (assigned for C-7 and C-6, respectively) in the 13 C NMR spectrum of 14 further confirm the dihydropyrrolidene skeleton.The versatility and feasibility of our new methodology is expanded at present time to produce different dihydropyrrolidene systems with different functionality and stereochemistry.
In conclusion, the chemistry described here, represents new and economic entries to polyfunctionalized pyrrolidene systems, fused to pyranoside skeletons with the further aim to expand this strategy to other targets.Furthermore, the integration of our new synthons to the synthesis of natural molecules is under way in our laboratories.

Experimental Section
General Procedures.All chemicals were purchased from Sigma-Aldrich and used as received. 1H NMR spectra were recorded in CD 3 OD or CDCl 3 on a Bruker Aspect AM-400 spectrometer operating at 400 MHz using 1% TMS as an internal standard.Splitting patterns are given follows: s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet.Chemical shifts are reported in δ (ppm) and coupling constants are given in Hz.FD mass spectra (FDMS) were determined on a Finnigan MAT-312 spectrometer.The progress of all reactions was monitored using 2 x 5 cm glass plates precoated with silica gel 60 F 254 to a thickness of 0.25 mm.The chromatograms were visualized under ultraviolet light (where appropriate) sprayed with an orcinol/H 2 SO 4 /FeCl 3 solution and heated to develop.Optical rotations were obtained with an LEP AZ polarimeter (Zeiss, Jena) at 546 nm.All melting points are uncorrected.

Procedure for dihydropyrrole syntheses
To a suspension of 3.3 mmol of NaH, 65% dispersion in paraffin oil, in THF (10 ml) under argon at 0 º C the β-dimethylhydrazone ester 12 (3.0mmol) was added over a period of 10 min.The mixture was stirred for 1 h at the same temperature, followed by the addition of 11 (1 mmol) in THF (2 ml) at 0 °C and kept for 5 h at room temperature.The reaction was quenched with a saturated solution of NH 4 Cl (5 ml), extracted with EtOAc (2 x 20 ml), dried over anhydrous Na 2 SO 4 and concentrated under vacuum to afford crude 14.The crude product was further purified on a short silica gel column using EtOAc/CH 2 Cl 2 (5-10%) as eluent to afford compound 14 in 95% yield.Selected data of 14:
t BuO t BuO t BuO O t BuO Scheme 1. ARKAT USA, Inc.