Heterocyclisation via 1,3-Cyclic Sulfates.
Asymmetric Synthesis of (+)-Sedridine

Benjamin J. Littler,a Timothy Gallagher,a Ian K. Boddyb and Peter D. Riordanb

aSchool of Chemistry, University of Bristol, Bristol, BS8 1TS, UK
bAgrEvo UK Ltd, Chesterford Park, Saffron Walden, CB10 1XL, UK

Abstract. 1,3-Cyclic sulfates (1b-d) participate in heterocyclisation reactions to give pyrrolidines (2b) and piperidines (2c/d). Cyclic sulfate activation, when coupled to the enantio- and diastereoselective generation of 1,3-diols, provides a synthesis of (+)-sedridine (9).

The use of cyclic sulfates to activate diols towards nucleophilic attack provides an efficient and versatile process offering potential in heterocyclic synthesis.1 While 1,2-cyclic sulfates (2,2-dioxide-1,3,2-dioxathiolanes), like epoxides, undergo cyclisation reactions with heteroatom nucleophiles,2 the 1,3-homologues have yet to be fully evaluated within this context.3 In this communication we describe the synthesis and cyclisation of 1,3-cyclic sulfates (2,2-dioxide-1,3,2-dioxathianes) as a route to representative 2-(2-hydroxyethyl)pyrrolidines and piperidines. In addition, we illustrate a more general feature of this chemistry by a synthesis of (+)-sedridine.

A series of 1,3-cyclic sulfates (1a-c), carrying a sulfonamide moiety as the latent nucleophile, were prepared in 77-88% yield from the corresponding 1,3-diol using the two-step protocol developed by Sharpless4 (Scheme 1). In order to proceed efficiently, the cyclisation step required sulfonamide activation. This was achieved using NaH (in THF at r.t.) and the heterocyclic products (2) were then isolated following an anhydrous acidic work-up (to cleave the intermediate sulfate ester). The results are shown in Table 1.

The 3-(2-aminoethyl) derivative (1a) did not give an identifiable heterocyclic product (azetidine or piperidine) under these conditions. The homologue (1b) did, however, undergo regioselective cyclisation and the 2-substituted pyrrolidine (2b) was isolated in 65% yield. Cyclisation of the 3-(4-aminobutyl) variant (1c) was very efficient and provided piperidine (2c) in almost quantitative yield. The N-Cbz substrate (1d) has been evaluated as an alternative N-nucleophile but piperidine formation (to give (2d)) was lower yielding and significantly slower when compared to the cyclisation of the sulfonamide analogue (1c).5

A very important feature associated with the use of 1,2-diol activation via cyclic sulfates is the ability to couple a potent level of electrophilic reactivity with highly efficient asymmetric dihydroxylation6 (to prepare the precursor 1,2-diol). While this has proved to be a powerful combination, a related and equally potent synergy is available with 1,3-cyclic sulfates. This is based on asymmetric reduction of a beta-dicarbonyl to establish the absolute stereochemistry of the requisite 1,3-diol precursor. Exemplification of this strategy is presented in Scheme 2 by a stereocontrolled synthesis of (+)-sedridine (9), a piperidine alkaloid originally isolated from Sedum acre.7

Regiospecific alkylation8 of methyl acetoacetate with the N-protected 3-bromopropylamine (3) gave (4) in 49% yield. Efficient asymmetric reduction of beta-ketoester (4) was achieved using the method reported by King9 to give the (3R)-hydroxyester (5) in 92% yield and in >95%e.e.10 Oxidative cleavage of the p-methoxybenzyl (PMB) moiety from (5) followed by conversion of the methyl ester to the corresponding beta-hydroxyketone (6) was achieved in 3 steps and in 63% overall yield. Syn-selective11 reduction of ketone (6) proceeded with complete control of stereochemistry and conversion of the resulting 1,3-diol (7) to 1,3-cyclic sulfate (8) was carried out in the usual way. Exposure of (8) to NaH followed by an acidic work-up and subsequent reductive cleavage of the sulfonamide residue gave (+)-sedridine (9)12 in 77% overall yield from (8).

In summary, 1,3-cyclic sulfates provide viable substrates for N-heterocyclisation reactions leading to 5- and 6-membered rings. A more important general feature of this methodology is an ability to harness this electrophilic reactivity to the efficient methods now available for the enantio- and diastereoselective synthesis of 1,3-diols. As a consequence, it is clear that 1,3-cyclic sulfates, like their 1,2-diol counterparts, also offer significant potential in asymmetric synthesis.

Acknowledgements. We thank EPSRC and AgrEvo UK Ltd. for a CASE award and acknowledge the use of the EPSRC's Chemical Database Service at Daresbury.13

References

  1. Lohray, B. B. Synthesis 1992, 1035.
  2. Kalanter, T. H.; Sharpless, K. B. Acta Chem. Scand. 1993, 47, 307; Beauchamp, T. J.; Powers, J. P.; Rychnovsky, S. D. J. Am. Chem. Soc. 1995, 117, 12873.
  3. For an example of a cyclisation reaction of a 1,3-cyclic sulfate leading to an oxetane, see Denmark, S. E. J. Org. Chem. 1981, 46, 3144. 4. Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538.
  4. Cyclisation of (1c) was complete within 1h, but under the same conditions (temperature and substrate concentration) cyclisation of (1d) occurred over 24h. In the absence of NaH, substrates (1b-d) still undergo cyclisation, to give (2b-d) respectively, but this latter process is much slower.
    The following basic experimental protocol was used for heterocyclisation reactions. A solution of cyclic sulfate (8) (273 mg, 0.72 mmol) in THF (25 cm3) at r.t. was treated with NaH (35mg, 60% dispersion in oil, 0.87 mmol). After 45 min the excess of NaH was destroyed by dropwise addition of ethanol, and concentrated hydrochloric acid (0.1 cm3) was added. At this point a colourless precipitate formed. After 20 min the mixture was diluted with H2O (10 cm3) and most of the THF was removed in vacuo. The product was extracted with CH2Cl2 (3 x 20 cm3) and the extracts were dried (MgSO4) and concentrated. Filtration through a pad of silica gel (eluting with EtOAc-hexane, 1:1) gave N-tosyl sedridine (214 mg, 99%) as a colourless oil which crystallised on standing.
  5. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
  6. Isolation of (+)-sedridine (9): (a) Beyerman, H. C.; Muller, Y. M. F. Rec. Trav. Chim. 1955, 74, 1568. (b) Schöpf, C.; Unger, R. Experimentia 1956, 12, 19. Assignment of absolute configuration of (+)-sedridine: (c) Butruille, D.; Fodor, G.; Saunderson Huber, C.; Letourneau, F. Tetrahedron 1971, 27, 2055 and references therein. Asymmetric syntheses of (+)-sedridine (other than methods involving resolution): (d) Murahashi, S.; Imada, Y.; Kohno, M.; Kawakami, T. Synlett, 1993, 395. (e) Louis, C.; Hootelé, C. Tetrahedron: Asymmetry 1995, 6, 2149.
  7. Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082.
  8. King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57, 6689.
  9. Attempts to achieve an asymmetric reduction of (4) using bakers' yeast failed under both aqueous and non-aqueous reaction conditions. The enantiomeric excess of (5) was determined by 1H NMR using the Mosher ester derivative, with (±)-(5) being used as a standard.
  10. Syn-Selective reduction: Chen, K.-M.; Gunderson, K.G.; Hardtmann, G. E.; Prasad, K.; Repic, O; Shapiro, M. J. Chemistry Lett. 1987, 1923. Reduction of (6) to give the anti-diol (10) (in 72%d.e.) was achieved using Me4NB(OAc)3H (Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560). Anti-diol (10) has been converted to (-)-allosedridine using the same procedures as illustrated in Scheme 2.

  11. Synthetic (+)-sedridine (9) was isolated, following sublimation, as a colourless solid m.p. 82-83°C {lit.7a,d 83-84°C}; [alpha]D22 + 25 (c 1.32, EtOH) {lit., [alpha]D20 + 28.6 (c 2.28, EtOH)7a; [alpha]D24 + 28.5 (c 2.32, EtOH)7d; [alpha]D22 + 26 (c 1.3, EtOH)7e}.
  12. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. J. Chem. Inf. Comput. Sci. 1996, 36, 746.

Scheme 1.

Reagents: i, SOCl2 then RuCl3 (cat.), NaIO4; ii, NaH, THF, r.t. then concentrated HCl

TABLE 1

1,3-Cyclic sulfate (1) Heterocyclic Product (2) (% yield)
(1a)complex mixture of products
(1b) (2b) 65 %
(1c)
(2c) 99 %
(1d) (2d) 61 %

Scheme 2.

Reagents: i, MeCOCH2CO2Me, NaH followed by n-BuLi, then (3); ii, [(R)-(BINAP)RuCl2]2.NEt3, H2 (200 psi), aq. HCl (cat.), MeOH; iii, CAN, MeCN/H2O; iv, LiCH2SO2Ph (5 eq.), THF; v, Bu3SnH, AIBN, PhMe; vi, Et2BOMe then NaBH4; vii, SOCl2 then RuCl3, NaIO4; viii, NaH, THF then H3O+; ix, Na, liq. NH3.

Heterocyclisation via 1,3-Cyclic Sulfates. Asymmetric Synthesis of (+)-Sedridine

Benjamin J. Littler,a Timothy Gallagher,a* Ian K. Boddyb and Peter D. Riordanb

a School of Chemistry, University of Bristol, Bristol BS8 1TS U.K.
b AgrEvo UK Ltd., Chesterford Park, Saffron Walden CB10 1XL U.K.

Heterocyclisation via 1,3-Cyclic Sulfates. Asymmetric Synthesis of (+)-Sedridine.
Benjamin J. Littler, Timothy Gallagher, Ian K. Boddy and Peter D. Riordan
1,3-cyclic sulfates, heterocyclisation, pyrrolidines, piperidines