Arnaud Voituriez

Alejandro Pérez-Luna

Franck Ferreira

Candice Botuha

Fabrice Chemla
email: fabrice.chemla@upmc.fr

Stereo-and Enantioselective Synthesis of Acetylenic 2-Amino-1,3-Diol Stereotriads

The high-yielding and highly efficient stereoselective synthesis of enantiopure anti,anti and syn,anti acetylenic 2amino-1,3-diol stereotriads from α-alkoxy-tert-butanesulfinylimines bearing a stereocenter α to the imino group is reported. The stereoselectivity of the reaction of these tBS-imines with allenylzinc (±)-1 was found to be controlled only by the configuration of the tert-butanesulfinyl group. An excellent kinetic resolution of the racemic allenylzinc species was observed, allowing a high stereocontrol whatever the configuration or the protecting group of the αalkoxy group.

2-Amino-1,3-diol subunits constitute an important stereotriad pattern found in many natural molecules of biological interest, such as indolizidine and pyrrolizidine alkaloids. A straightforward synthetic approach to these alkaloids could involve the construction of the bicyclic skeleton from properly functionalized enantiopure acetylenic 2-amino-1,3-diols presenting an anti,anti or a syn,anti relationship (Figure 1). In this context we have recently shown 1 that allenylzinc species are highly valuable reagents to prepare acetylenic anti or syn β-aminoalcohols 2 (from the corresponding acetylenic aziridines 3,4,5 ) and anti or syn acetylenic aminoethers. 2,6 The reaction of reagent (±)-1 derived from 3methoxymethyl-1-trimethylsilyl-1-propyne with enantiopure tBS-imines gives the corresponding enantiopure acetylenic anti aminoethers 2 (Scheme 1). 2b,7 The key to these results is the highly efficient kinetic resolution of the racemic allenylzinc reagent brought about by the excellent stereocontrol of the tert-butanesulfinyl moiety for the addition onto the imine. The synthetic potential of this approach has been exploited recently for the enantiocontrolled synthesis of (-)-α-conhydrine 8 and for the formal total synthesis of the two quinolizidinyl alkaloids (-)-epiquinamide and (-)-homopumiliotoxine 223G. 9 In order to obtain acetylenic 2-amino-1,3-diols and thus access to the corresponding (O,N,O) stereotriads, we envisioned to apply this method to α-alkoxy tBS-imines 3 (Scheme 1). However, this approach raises to several important difficulties which have to be examined. The presence of the oxygen functionality in the imine electrophile could modify the intrinsic stereoinduction previously observed from the tertbutanesulfinyl group in such reactions. Another issue to be considered is the influence of the new stereocenter α to the imine on the stereofacial selectivity compared to the sulfinyl chiral auxiliary. A Cram-chelate versus a Felkin-Anh model could presumably be involved. Finally the introduction of this oxygen functionnality α to the imine group could possibly modify the kinetic resolution efficiency of the starting allenylzinc (±)-1. Prompted by a recent report 10 on the addition of enolates on α,β-dialkoxy tBS-imines for the assembly of the polyhydroxylated aminoacid constituents of microsclerodermins, we disclose hereafter our results concerning the reaction of allenylzinc reagent (±)-1 with stereochemically pure chiral α-alkoxy tBS-imines.

The α-alkoxy tBS-imines necessary for our study were prepared by the reaction of the corresponding α-alkoxy aldehydes with enantiopure tert-butanesulfinamide 11 under standard conditions. 12,13 Scheme 1. Synthesis of acetylenic aminoethers and approach to acetylenic stereotriads Following our previously reported kinetic resolution conditions ((±)-1, 4 equiv., -80 °C), 4 the reaction of racemic allenylzinc (±)-1 with enantiopure tBS-imines (S,R S )-3a and (S,R S )-3b proceeded in high yield and with high stereocontrol, as only one diastereomer 4a (from 3a) and 4b (from 3b) was obtained after hydrolysis. The relative and absolute configurations of the newly created stereocenters were determined unambiguously by various selective transformations into known compounds or oxazolidinones (see below). From all the correlation experiments we could determine that allenylzinc (±)-1 reacts with imines (S,R S )-3a,b from their Re face to give with a high stereoselectivity the corresponding protected acetylenic 2-amino-1,3-diols presenting an anti,anti relationship. The reactivity of the tBS-imines (S,S S )-3c,d was then examined. A difference in the diastereoselectivity of the reaction could be expected, as these imines are diastereomeric to the imines 3a,b previously used and a matched / mismatched effect might thus be expected. However, to our delight, here again, under kinetic resolution conditions, an excellent stereoselectivity in the reaction with (±)-1 (4 equiv.) was oberved as only one diastereomer 4c (resp. 4d) was obtained from imine 3c (resp. 3d, Scheme 3), both presenting a syn,anti relationship. Allenylzinc (±)-1 reacts therefore with imines (S,S S )-3c,d from their Si face to give with high stereoselectivity the corresponding protected acetylenic 2amino-1,3-diols presenting a syn,anti relationship. The results reported above indicate that a high stereoinduction can be expected from the reaction of αalkoxy tBS imines with allenylzinc (±)-1. To generalize this statement, we then tried the reaction of the two diastereomeric imines (R,S S )-3e and (S,S S )-3f derived from (+)-and (-)-mandelic acid respectively. The reaction occurred smoothly under the same conditions as reported above and here again we obtained only one diastereomer 4e and 4f respectively (scheme 4). From structural determinations (analoguous to those reported in the Figure 2)14 it could be unequivocally concluded that the reaction of (±)-1 with imines (R,S S )-3e and (S,S S )-3f occurred from the Si face to give stereoselectively the corresponding anti,anti or syn,anti acetylenic stereotriad.

• H MOMO ZnBr TMS (±)-1 R TMS HN OMOM N S tBu O Et 2 O + R N S tBu O R 1 R 2 O (±)-1 HN S tBu O R 1 R 2 O TMS OMOM Cram-chelate
The addition of organometallic reagents onto tBS-imines has been largely studied 16 and various models have been proposed to rationalize the stereoselectivity of such processes. More specifically, the influence of an oxygen or heteroatom functionality in the imine electrophile is a matter of interest since these groups can change the stereoinduction from the tertbutanesulfinyl group, as reported for example by Ellman who observed a reversal of the stereofacial selectivity from simple tBS-imines 17 to αalkoxy tBS-imines. 18 The origins for the inversion of the facial selectivity compared to simple alkyl tBS-imines remain under discussion and models involving E/Z isomerization of imines as well as chelate versus open transition states have been proposed to account for the atypical stereochemical behaviour. Moreover, it should be noted that this inversion in stereoselectivity does not seem general: it has been observed for tBS-imines derived from aldehydes bearing an α-alkoxy 10,18 or an α-chloro group, 19 independently of the organometallic species used (alkyl organometallics or enolates). By contrast it has not been observed in the case of tBS-imines derived from aldehydes bearing an α-amino group, 20 nor in the case of tBS-imines derived from ketones bearing an α-alkoxy group. 18b The reduction of tBS-imines derived from ketones bearing an α-chloro group proceeds with face selectivities depending on the nature of the reducing agent. 21 In our case no inversion of the stereochemical induction from the tBS group was noted, as the facial selectivity was the same in all cases we studied: imines (S,R S )-3a and (S,R S )-3b presenting a (R) configuration at the sulfur center reacted with (±)-1 on their Re face, whereas products arising from the addition of imines (S,S S )-3c, (S,S S )-3d, (R,S S )-3e and (S,S S )-3f presenting a (S) configuration at the sulfur center were obtained through reaction on the Si face.

Another point of interest concerns the relative influence on the stereofacial selectivity of the stereocenter α to the imine compared to the sulfinyl chiral auxiliary. A Cramchelate versus a Felkin-Anh model could presumably be involved, and the two possibilities have also been reported by Ellman. 12 Former reports dealing with organometallic species addition on α-alkoxy- 10,12 or α-amino-tBS-imines 20 bearing a stereocenter α to the imino group showed that generally the stereoselectivity is mainly defined by the sulfinyl moiety and not by the α stereocenter, although some cases a drop in selectivity was observed. 12 In our case the stereoselectivity is always excellent, and independent of the α stereocenter configuration, whatever the protecting group (TBS or Bn) on the oxygen atom. Though the stereoselectivity we obtained in the case of imines (S,R S )-3a, (S,R S )-3b and (R,S S )-3e is consistent with a Felkin-type control, in the case of imines (S,S S )-3c, (S,S S )-3d and (S,S S )-3f, anti-Felkin products are observed.

Finally, it should be noted that we have always used racemic allenylzinc (±)-1. The excellent selectivities we obtained in all cases can only be explained by a very efficient kinetic resolution: only one enantiomer of the racemic mixture in 1 is allowed to react with the enantiopure sulfinimines. We propose the Felkin-type transition state TS1 depicted in Scheme 5 to explain the stereoselectivities observed in the reactions with (S,R S )-3a and (S,R S )-3b. In this transition state the tBS-imine is adopting its ground-state conformation where the S-O bond and the lone pair on the nitrogen atom are antiperiplanar. 5,22 The reaction of imine (R,S S )-3e to afford 4e presumably follows a transition state enantiomeric to TS1. On the other hand, the anti-Felkin-type transition state TS2 is proposed for the reactions of imines (S,S S )-3c, (S,S S )-3d and (S,S S )-3f.

19 (a) Denolf, B.; Mangelinckx, S.; Tornoos, K. W.; De Kimpe, N. Org. Lett. 2006, 8, 3129; (d) In each case only the matched reacting enantiomer of (±)-1 is represented. In conclusion, we have disclosed a high-yielding and highly efficient stereoselective synthesis of enantiopure anti,anti and syn,anti acetylenic 2-amino-1,3-diol stereotriads from α-alkoxy-tBS-imines bearing a stereocenter α to the imino group. The stereoselectivity was found to be controlled only by the configuration of the tert-butanesulfinyl group and an excellent kinetic resolution of racemic allenylzinc (±)-1 was observed, whatever the configuration or the protecting group of the α-alkoxy substituent. These acetylenic stereotriads should be highly versatile stereodefined building blocks for the total synthesis of indolizidine or quinolizidine alkaloids. Further studies in this area from our lab will be reported in due course.

Figure 1 .

 1 Figure 1. Acetylenic 2-amino-1,3-diol stereotriads

Scheme 2 .

 2 Scheme 2. Reactions with imines (S,R S )-3a,b

Scheme 3 .Figure 2 .

 32 Scheme 3. Reactions with imines (S,S S )-3c, d

Scheme 4 .

 4 Scheme 4. Reaction with imines (R,S S )-3e and (S,S S )-3f

Scheme 5 .

 5 Scheme 5. Plausible transition states TS1 and TS2.

  Hodgson, D. M.; Kloesges, J.;Evans, B. Org. Lett., 2008, 10, 2781.

20

(a) Prakash, G. K. S.; Mandal, M. J.

Am. Chem. Soc. 2002, 124, 6538; (b)

Liu, J.; Li, Y.; Hu, J. J. Org. Chem. 2007, 72, 3119. 21 (a) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org. Chem. 2007, 72, 3211; (b) B. Denolf, B.; Leemans, E.; De Kimpe, N. J. Org. Chem. 2008, 73, 5662. 22 (a) Bharatam, P. V.; Uppal, P.; Amita; Kaur, D. J. Chem. Soc., Perkin Trans. 2, 2000, 43; (b) Bharatam, P. V.; Amita; Kaur, D. J. Phys. Org. Chem., 2002, 15, 197.

see Supporting Information.

Poisson, J. F.; Normant, J.-F. Org. Lett. 2001, 3, 1889.

For a general review on chiral sulfinimines, see: (a) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869; (b) Ferreira, F.; Botuha, C.; Chemla, F.;

Acknowledgment Thanks are due to Patrick Herson for single crystal X-ray analysis and to the CNRS for a postdoctoral fellowship grant (to AV).

Supporting Information Available Preparation and characterization data for imines 3e and 3f, acetylenic aminoethers 4a-f and chemical correlations into known compounds 5a-c and 2-oxazolidin-3-ones 6a-e, including 1 H and 13 C data. This material is available free of charge via the Internet from http://pubs.acs.org