Application of a 5-endo -trig cyclisation in the total synthesis of (+)- preussin

The synthesis of 2,5-syn disubstituted pyrrolidines from N -SES protected aziridines is described. The key step in the methodology is a 5-endo -trig cyclisation. Application of this reaction in the synthesis of (+)-preussin is reported.


Introduction
The pyrrolidine ring system has been identified as an important pharmacophore in many natural products and drug candidates. 1 Representative examples of compounds isolated from nature containing a pyrrolidine ring are the antifungal agent (+)-preussin, 1, 2 and the pheromone (+)monomorine I, 2.  As a consequence of the widespread occurrence of highly functionalised pyrrolidine containing compounds, there are a number of different methods for their construction. 4We have been evaluating the use of the 5-endo-trig cyclisation (formally disfavoured according to Baldwin's guidelines) 5 for the formation of 2,5-syn disubstituted pyrrolidines. 6,7This methodology is mediated by a sulfone group, which directs two carbon-carbon bond-forming reactions to construct the pyrrolidine framework prior to cyclisation (Scheme 1).n-BuLi Scheme 1. 5-Endo-trig cyclisations to 2,5-syn-disubstituted pyrrolidines.
First, enantiomerically pure N-diphenylphosphinyl (N-Dpp) aziridines, derived from amino acids, were treated with the anion of methylsulfonylbenzene 3. Double deprotonation of the resulting ring-opened products 4 was followed by introduction of a second electrophile, a nonenolisable acyl halide, to afford a β-keto sulfones (not shown).Further functionalisation gave the vinylic sulfones 5 (in some cases this was a transient species) as a mixture of Eand Zisomers.Finally, cyclisation was achieved under basic conditions to give the 2,5-syn pyrrolidines 6 stereoselectively (syn:anti ≥10:1).Using this route a variety of N-Dpp pyrrolidines were prepared efficiently in 6 steps from N-Dpp aziridines.However, there were limitations in this methodology.The N-Dpp aziridines were particularly slow to form (often the cyclisation would take 1-2 weeks to achieve acceptable yields) and also only non-enolisable acid halides could be used in the second carbon-carbon bond-forming reaction.
To circumvent these issues, we investigated the replacement of the Dpp protecting group, via a two-step sequence, to give the benzoyl (Bz) derivative 7. Double deprotonation of 7 now permitted the reaction with other electrophiles such as aldehydes (alkyl or aryl), which, after subsequent modification provided vinylic sulfones 8 suitable for 5-endo-trig cyclisation.This adaptation of the methodology expanded the range of R 2 groups that could be incorporated into the pyrrolidine products 9.The synthetic utility of this revised protecting group strategy was demonstrated in the efficient enantioselective synthesis of (+)-monomorine I. 8 Although the variety of 2,5-syn pyrrolidines accessible using the 5-endo-trig methodology had been improved, the necessary switch of protecting groups a (Dpp to Bz) following the ringopening of the aziridine increased the number of synthetic steps.We were therefore keen to evaluate other aziridine protecting groups in order to simplify the methodology.This paper describes the use of the 2-(trimethylsilanyl)ethanesulfonyl (SES) protecting group in the synthesis of pyrrolidines and an application of the 5-endo-trig reaction in the total synthesis of (+)-preussin.

Results and Discussion
The aziridine protecting group should allow easy formation of the aziridine, activate the aziridine to nucleophilic attack, and, following ring-opening, must be readily removed under conditions that would not affect other functionality in the molecule.To satisfy these criteria, several new protecting groups were investigated, including Boc and 4-nitrobenzenesulfonyl.The optimum group was found to be the SES protecting group developed by Weinreb et al. 9,10 The N-SES protected aziridines were accessed readily from amino alcohols 10 according to the sequence outlined in Scheme 2. First, the amino alcohols 10a-c were protected as the corresponding N-SES derivatives 11a-c using SES-Cl at low temperature.For the preparation of the valine-and serine-derived aziridines 12a and 12b, cyclodehydration was then performed using an adaptation of the procedure reported by Wessig and co-workers 11 using toluenesulfonyl chloride and potassium hydroxide.Unfortunately, under these reaction conditions the tosyl intermediate for the cyclohexyl derivative (not shown) failed to cyclise.However, in this case aziridine formation to provide 12c could be achieved using a modified Mitsunobu reaction according to a procedure by Tsunoda et al. 12 Aziridines 12a-c were accessed via these routes (Table 1).With the aziridines in hand, our attention turned to the synthesis of the pyrrolidines.n-Butyllithium-promoted deprotonation of arylsulfonyl methane (Ar = 4-benzyloxyphenyl or phenyl) was followed by the addition of the aziridine at low temperature.As expected, ringopening of the aziridine was facile and adducts 14a-e were isolated in good yield (79-92%).The intermediates 14a-e were then treated with two equivalents of n-butyllithium to effect a double deprotonation and this was followed by the sequential addition of an aldehyde and benzoyl chloride to provide the vinylic sulfones 15a-e (as predominantly the E-isomer in ratios >3:1, as evidenced by 1 H nmr spectroscopy).The advantage of the SES protecting group over the Bz and Dpp groups was demonstrated in the final step.In a one-pot procedure using excess tetrabutylammonium fluoride (TBAF) at either room temperature or reflux, deprotection and cyclisation occurred to provide the target pyrrolidines 16a-e as shown in Scheme 3. We found that cesium fluoride could also effect the deprotection-cyclisation, although the yields were higher when TBAF was used.This modification of the original 5-endo-trig protocol provided the unprotected pyrrolidines (Table 2), ready for immediate modification.We were also encouraged that spirocyclic compounds (e.g.16e) were accessible using this chemistry as the rapid assembly of compounds containing multiple ring systems could be envisaged.
Scheme 3. Reagents and conditions: i. n-BuLi, THF:TMEDA (4:1), -78 ºC, then aziridine, -78 ºC to rt; ii.n-BuLi, THF:TMEDA (4:1), -78 ºC, then aldehyde R 2 CHO, -78 ºC, then BzCl, -78 ºC to rt; iii.TBAF, THF, rt or reflux.During the synthesis of 16a, we observed that if the TBAF deprotection-cyclisation step was stopped prematurely then spectroscopic evidence for the formation of allylic sulfone 17 could be obtained.Fortunately, in the presence of excess quantities of TBAF, 17 was completely consumed in the reaction and only the pyrrolidine 16a was isolated.Presumably the reaction medium is sufficiently basic that the equilibrium is driven towards the pyrrolidine via the vinylic species 15a.This finding suggested that allylic sulfones might also be substrates for the 5-endotrig cyclisation.

Scheme 4
In three synthetic steps (five chemical transformations) from readily accessible N-SES protected aziridines, highly functionalised pyrrolidines suitable for further modification were accessed in good overall yields (28-33%).We were keen to demonstrate the synthetic utility of our adapted 5-endo trig methodology, and the natural product (+)-preussin, 1 [13][14][15] appeared to be an excellent target with its 2,5-syn disubstituted pyrrolidine core.
Our initial retrosynthetic analysis is illustrated in Scheme 4. We envisaged that the hydroxyl group in 1 could be accessed by reduction of the corresponding ketone 18, which in turn would be made following oxidation of the sulfone-stabilised carbanion derived from 19.The pyrrolidine ring in 19 would be prepared from vinylic sulfone 20 via the 5-endo-trig cyclisation.Compound 20 would be assembled according to the methodology described above, from methylsulfonylbenzene, N-SES protected aziridine 21 and phenylacetalaldehyde. Aziridine 21 would be accessed from L-serine 22.

Scheme 5
Aziridine 21 was prepared in seven steps and 12% overall yield from 22 by adaptation of work described by Rapoport 16 as shown in Scheme 6. N-Tosyl protection of L-serine 22 was followed by the Grignard addition of n-octyl magnesium iodide to give ketone 24.The ketone was reduced in a two-step sequence via dithiane 25 to give the N-tosyl amino alcohol 26.Formation of aziridine 27 was achieved using the modified Wessig 12 conditions, and subsequent replacement of the N-tosyl group in 27 with the SES protecting group via the unprotected aziridine 28 provided the desired aziridine 21.At the outset, we had envisaged that the SES group would be introduced at the start of the synthetic sequence thus avoiding a protectiondeprotection-reprotection strategy.Unfortunately the instability of the SES group to excess organometallic reagent (4 equivalents were used in the reaction), presumably due to deprotonation α to the sulfonyl group prevented the use of this approach.Ring-opening of aziridine 21 using the lithio-anion of methylsulfonylbenzene provided the expected product 29.In the subsequent carbon-carbon bond forming step, using similar conditions to those described in Scheme 3, the major product was not the desired vinylic sulfone 20 but the allylic sulfone 30, as a mixture of diastereoisomers.We reasoned that the acidity of the α-protons in phenylacetalaldehyde was responsible for the formation of 30 as the major product.This result is also consistent with the greater thermodynamic stability of allylic sulfones over vinylic sulfones.In spite of this observation, our earlier experience, shown in Scheme 4, had suggested that 30 would also be a substrate for the 5-endo-trig reaction.Indeed, stirring allylic sulfone 30 with 15 equivalents of TBAF in THF at reflux for 38 hours provided the desired pyrrolidine 19 as a single diastereoisomer in 78% yield after chromatography.This observation actually made the synthesis of 19 more convergent as we were able to access 30 in two steps from the sodium salt of benzenesulfinic acid as shown in Scheme 7. The completion of the total synthesis of (+)-preussin was achieved as depicted in Scheme 8. Thus, the N-methyl derivative 33 was prepared by reductive amination of 19 using aqueous formaldehyde and sodium cyanoborohydride.With compound 33 in hand, the acidity of the sulfone α-protons, which had been pivotal during the whole synthetic route, was exploited again in an oxidative desulfonylation reaction according to the procedure described by Hwu. 17 This provided ketone 34 in good yield based on recovered starting material.The final step in the sequence was the stereoselective reduction of the ketone from the less hindered α-face using lithium aluminium hydride to provide 1 in 86% yield.The spectroscopic characteristics of the synthetic material were identical to those reported for the natural product.In summary, we have improved the synthesis of highly decorated pyrrolidine ring systems via our 5-endo-trig reaction by utilizing an N-SES protecting group strategy.The methodology was further extended following the observation that vinylic sulfones, the precursors for the 5endo-trig cyclisation, may be generated in situ from readily accessible allylic sulfones.These improvements to our methodology were applied to the total synthesis of (+)-preussin, which has been prepared in 12 steps and 5% overall yield from L-serine and (E)-3-phenyl-1-(phenylsulfonyl)-2-propene.

Experimental Section
General Procedures.Melting points were determined using Stuart Scientific SMP1 melting point apparatus and are uncorrected.Optical rotations were measured using an Optical Activity Ltd AA-1000 polarimeter and are given in deg.g -1 .cm 2 units.Infrared spectra were recorded on a Mattson 5000 FTIR spectrometer.Proton magnetic resonance ( 1 H nmr) spectra and carbon magnetic resonance ( 13 C nmr) spectra were recorded in CDCl 3 (unless otherwise stated) on a Bruker DRX-300 spectrometer or Bruker DRX-400.Chemical shifts are in parts per million (ppm) and are referenced relative to the residual solvent ( 1 H nmr: 7.27 ppm for CDCl 3 , 3.35 for CD 3 OD; 13 C nmr: 77.0 ppm for CDCl 3 , 49.5 ppm for CD 3 OD).Mass spectra (CI or FAB ionisation) were recorded using VG-7070B, VG707E, VG Autospec Q or Jeol SX-102 instruments.Elemental analyses were performed at the microanalytical laboratory of North London University.Analytical thin layer chromatography (TLC) was performed on Merck Kieselgel 60 F 254 pre-coated glass-backed plates.Visualisation was effected with ultraviolet light, iodine, acidic ammonium molybdate (IV) or potassium permanganate.Flash chromatography was performed using BDH (40-63 µm) silica gel.Standard solvents were distilled under nitrogen prior to use; Et 2 O and THF from sodium-benzophenone ketyl, CH 2 Cl 2 from P 2 O 5 or CaH, toluene from sodium.DMF was dried over 4Å molecular sieves.Petrol refers to the fraction bp 40-60 °C, which was distilled before use.All other solvents were reagent grade.