Stereo- And enantioselective synthesis of acetylenic 2-amino-1,3-diol stereotriads

Article abstract of DOI:10.1021/ol802912f

The high-yielding and highly efficient stereoselective synthesis of enantiopure anti,anti and syn,anti acetylenic 2-amino-1,3-diol stereotriads from α-alkoxy-tert-butanesulfinylimines bearing a stereocenter α to the imino group is reported. The stereosele

Full text of DOI:10.1021/ol802912f

ORGANIC
LETTERS
2009
Vol. 11, No. 4
931-934
Stereo- and Enantioselective Synthesis
of Acetylenic 2-Amino-1,3-diol
Stereotriads
Arnaud Voituriez, Alejandro Pe´rez-Luna, Franck Ferreira, Candice Botuha, and
Fabrice Chemla*
UPMC UniV Paris 06, UMR7611, Laboratoire de Chimie Organique,
Institut de Chimie Mole´culaire (FR2769), case 183, 4 place Jussieu,
F-75252 Paris Cedex 05, France
fabrice.chemla@upmc.fr
Received December 18, 2008
ABSTRACT
The high-yielding and highly efficient stereoselective synthesis of enantiopure anti,anti and syn,anti acetylenic 2-amino-1,3-diol stereotriads
from r-alkoxy-tert-butanesulfinylimines bearing a stereocenter r to the imino group is reported. The stereoselectivity of the reaction of these
tert-butanesulfinyl (tBS)-imines with allenylzinc (()-1 was found to be controlled only by the configuration of the tBS group. An excellent
kinetic resolution of the racemic allenylzinc species was observed, allowing a high stereocontrol no matter what the configuration or the
protecting group of the r-alkoxy 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.1 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
Figure 1. Acetylenic 2-amino-1,3-diol stereotriads.
1). In this context, we have recently shown2 that allenylzinc
species are highly valuable reagents to prepare acetylenic
anti- or syn-ꢀ-amino alcohols3 (from the corresponding
acetylenic aziridines4-6 ) and anti- or syn-acetylenic ami-
noethers.2,7
The reaction of reagent (()-1 derived from 3-meth-
oxymethyl-1-trimethylsilyl-1-propyne with enantiopure
tBS-imines gives the corresponding enantiopure acetylenic
(1) (a) Michael, J. P. Nat. Prod. Rep 2008, 25, 139. (b) Ayad, T.;
Genisson, Y.; Baltas, M. Curr. Org. Chem. 2004, 8, 1211.
(2) Botuha, C.; Chemla, F.; Ferreira, F.; Pe´rez-Luna, A.; Roy, B. New
J. Chem. 2007, 31, 1552.
(3) (a) Palais, L.; Chemla, F.; Ferreira, F. Synlett 2006, 1039. (b) Chemla,
F.; Ferreira, F.; Gaucher, X.; Palais, L. Synthesis 2007, 1235.
(4) (a) Bernard, N.; Chemla, F.; Normant, J. Tetrahedron Lett. 1999,
40, 75. (b) Chemla, F.; Bernard, N.; Ferreira, F.; Normant, J.-F. Eur. J.
Org. Chem. 2001, 3295. (c) Chemla, F.; Hebbe, V.; Normant, J.-F.
Tetrahedron Lett. 1999, 40, 8093. (d) Chemla, F.; Ferreira, F.; Hebbe, V.;
Stercklen, E. Eur. J. Org. Chem. 2002, 1385. (e) Ferreira, F.; Bejjani, J.;
Denichoux, A.; Chemla, F. Synlett 2004, 2051.
(5) (a) Chemla, F.; Ferreira, F. Synlett 2004, 983. (b) Chemla, F.;
Ferreira, F. J. Org. Chem. 2004, 69, 8244.
10.1021/ol802912f CCC: $40.75
Published on Web 01/14/2009
2009 American Chemical Society

anti amino ethers 2 (Scheme 1).3b,8 The key to these results
is the highly efficient kinetic resolution of the racemic
The R-alkoxy tBS-imines necessary for our study were
prepared by the reaction of the corresponding R-alkoxy
aldehydes with enantiopure tert-butanesulfinamide12 under
standard conditions.13,14
Following our previously reported kinetic resolution
conditions ((()-1, 4 equiv, -80 °C),4 the reaction of racemic
allenylzinc (()-1 with enantiopure tBS-imines (S,RS)-3a and
(S,RS)-3b proceeded in high yield and with high stereocontrol,
as only one diastereomer 4a (from 3a) and 4b (from 3b)
was obtained after hydrolysis.
Scheme 1
.
Synthesis of Acetylenic Amino Ethers and Approach
to Acetylenic Stereotriads
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 experi-
ments we could determine that allenylzinc (()-1 reacts with
imines (S,RS)-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
(Scheme 2).
Scheme 2. Reactions with Imines (S,RS)-3a,b
allenylzinc reagent brought about by the excellent stereo-
control of the tert-butanesulfinyl (tBS) moiety for the addition
onto the imine. The synthetic potential of this approach has
been exploited recently for the enantiocontrolled synthesis
of (-)-R-conhydrine9 and for the formal total synthesis of
the two quinolizidinyl alkaloids (-)-epiquinamide and (-)-
homopumiliotoxine 223G.10 In order to obtain acetylenic
2-amino-1,3-diols and thus access to the corresponding
(O,N,O) stereotriads, we envisioned applying this method
to R-alkoxy tBS-imines 3 (Scheme 1). However, this
approach raises several important difficulties which have to
be examined. The presence of the oxygen functionality in
the imine electrophile could modify the intrinsic stereoin-
duction previously observed from the tert-butanesulfinyl
group in such reactions. Another issue to be considered is
the influence of the new stereocenter R 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 R to the imine group could possibly
modify the kinetic resolution efficiency of the starting
allenylzinc (()-1. Prompted by a recent report11 on the
addition of enolates on R,ꢀ-dialkoxy tBS-imines for the
assembly of the polyhydroxylated amino acid constituents
of microsclerodermins, we disclose hereafter our results
concerning the reaction of allenylzinc reagent (()-1 with
stereochemically pure chiral R-alkoxy tBS-imines.
The reactivities of the tBS-imines (S,SS)-3c,d were 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 observed as only one diastereomer 4c (respectively 4d)
was obtained from imine 3c (respectively 3d, Scheme 3),
Scheme 3. Reactions with Imines (S,SS)-3c,d
(6) Ferreira, F.; Audouin, M.; Chemla, F. Chem.sEur. J. 2005, 11, 5269
(7) Roy, B; Pe´rez-Luna, A.; Ferreira, F.; Botuha, C.; Chemla, F.
Tetrahedron Lett. 2008, 49, 1534
(8) Chemla, F.; Ferreira, F. Synlett 2006, 2613
.
.
both presenting a syn,anti relationship. Allenylzinc (()-1
reacts therefore with imines (S,SS)-3c,d from their Si face to
give with high stereoselectivity the corresponding protected
acetylenic 2-amino-1,3-diols presenting a syn,anti relation-
ship.
.
(9) Voituriez, A.; Ferreira, F.; Chemla, F. J. Org. Chem. 2007, 72, 5358.
(10) Voituriez, A.; Ferreira, F.; Pérez-Luna, A.; Chemla, F. Org. Lett.
2007, 9, 4705.
(11) Hjelmgaard, T.; Faure, S.; Lemoine, P.; Viossat, B.; Aitken, D. J.
Org. Lett. 2008, 10, 841.
932
Org. Lett., Vol. 11, No. 4, 2009

The relative and absolute configurations of the stereo-
centers in 4a-d were determined unambiguously after
selective transformations15 into the oxazolidinones 6a-c
(Figure 2) and 1H NMR coupling constant measurements.16
of 4e into a known compound.16 The compound 4f was also
transformed after desilylation into the corresponding acety-
lenic alcohol 5f, the configuration of which has been
determined by X-ray crystallographic analysis. It could be
unequivocally concluded that the reaction of (()-1 with
imines (R,SS)-3e and (S,SS)-3f occurred from the Si face to
give stereoselectively the corresponding anti,anti or syn,anti
acetylenic stereotriad.
The addition of organometallic reagents onto tBS-imines has
been largely studied,18 and various models have been proposed
to rationalize the stereoselectivity of such processes. More
specifically, the influence of an oxygen or heteroatom func-
tionality in the imine electrophile is a matter of interest since
these groups can change the stereoinduction from the tert-
butanesulfinyl group, as reported, for example, by Ellman, who
observed a reversal of the stereofacial selectivity from simple
tBS-imines19 to R-alkoxy tBS-imines.20 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 stereo-
chemical behavior. 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
R-alkoxy10,18 or an R-chloro group,21 independent of the
organometallic species used (alkyl organometallics or eno-
lates). By contrast, it has not been observed in the case of
tBS-imines derived from aldehydes bearing an R-amino
group22 nor in the case of tBS-imines derived from ketones
bearing an R-alkoxy group.18b The reduction of tBS-imines
derived from ketones bearing an R-chloro group proceeds
with face selectivities depending on the nature of the reducing
agent.23 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,RS)-3a and (S,RS)-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,SS)-3c, (S,SS)-
3d, (R,SS)-3e, and (S,SS)-3f presenting a (S) configuration at
the sulfur center were obtained through reaction on the Si
face.
Figure 2. Oxazolidinones 6a-c for stereochemical correlations.
The multistep transformation of compound 4a into a known
compound17 was also performed.
The results reported above indicate that a high stereoin-
duction can be expected from the reaction of R-alkoxy tBS
imines with allenylzinc (()-1. To generalize this statement,
we then tried the reaction of the two diastereomeric imines
(R,SS)-3e and (S,SS)-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 or 4f, respectively
(Scheme 4).
Scheme 4. Reaction with Imines (R,SS)-3e and (S,SS)-3f
Another point of interest concerns the relative influence on
the stereofacial selectivity of the stereocenter R to the imine
compared to the sulfinyl chiral auxiliary. A Cram chelate 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 R-
alkoxy-10,12 or R-amino-tBS-imines20 bearing a stereocenter
Structural determinations analoguous to those reported in
the Figure 2 were conducted,14 including the transformation
(12) (a) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317. (b) Weix,
D. J.; Ellman, J. A. Org. Synth. 2005, 82, 157.
(18) 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.; Pe´rez-Luna, A. Chem. Soc. ReV. 2009, DOI: 10.1039/
B809772K.
(13) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948.
(14) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278.
(15) See the Supporting Information.
(19) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883.
(20) (a) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051. (b) Tang, T. P.;
Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66, 8772.
(21) (a) Denolf, B.; Mangelinckx, S.; Tornoos, K. W.; De Kimpe, N.
Org. Lett. 2006, 8, 3129. (d) Hodgson, D. M.; Kloesges, J.; Evans, B. Org.
Lett. 2008, 10, 2781.
(16) It is known that vicinal coupling constants in 4,5-disubstituted
oxazolidinones are higher for the cis (6-8 Hz) than for the trans isomer
(4-6 Hz); see: (a) Reference 3a and: (b) Foglia, T. A.; Swern, D. J. Org.
Chem. 1969, 34, 1680. (c) Futagawa, S.; Inui, T.; Shiba, T. Bull. Chem.
Soc. Jpn. 1973, 46, 3308. (d) Bonini, B. F.; Comes-Franchini, M.; Fochi,
M.; Laboroi, F.; Mazzanti, G.; Ricci, A.; Varchi, G. J. Org. Chem. 1999,
64, 8008. (e) Poisson, J.-F.; Chemla, F.; Normant, J. F. Synlett 2001, 305.
(17) Poisson, J. F.; Normant, J.-F. Org. Lett. 2001, 3, 1889.
(22) (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.
Org. Lett., Vol. 11, No. 4, 2009
933

R to the imino group showed that generally the stereoselec-
tivity is mainly defined by the sulfinyl moiety and not by
the R stereocenter, although in some cases a drop in
selectivity was observed.12 In our case, the stereoselectivity
is always excellent, and independent of the R stereocenter
configuration, whatever the protecting group (TBS or Bn)
on the oxygen atom. Though the stereoselectivity we obtained
in the case of imines (S,RS)-3a, (S,RS)-3b, and (R,SS)-3e is
consistent with a Felkin-type control, in the case of imines
(S,SS)-3c, (S,SS)-3d, and (S,SS)-3f, anti-Felkin products are
observed.
(S,RS)-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.5,24 The reaction
of imine (R,SS)-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,SS)-3c, (S,SS)-3d, and (S,SS)-3f. 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 R-alkoxy-
tBS-imines bearing a stereocenter R 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,
no matter what the configuration or the protecting group of the
R-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 laboratory will be reported in due
course.
Finally, it should be noted that we have always used racemic
allenylzinc (()-1. The excellent selectivities we obtained in all
Scheme 5. Plausible Transition States TS1 and TS2
Acknowledgment. Thanks are due to Patrick Herson for
single-crystal X-ray analysis and to the CNRS for a post-
doctoral fellowship grant (to A.V.).
Supporting Information Available: Preparation and
characterization data for imines 3e and 3f and acetylenic
aminoethers 4a-f and chemical correlations into known
compounds 5a-c and 2-oxazolidin-3-ones 6a-e, including
1H and 13C data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL802912F
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,RS)-3a and
(23) (a) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org. Chem. 2007,
72, 3211. (b) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org. Chem. 2008,
73, 5662.
(24) (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.
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Org. Lett., Vol. 11, No. 4, 2009