Highly diastereoselective addition of lithio vinyl sulfoxides to N-sulfinimines: An entry to enantiopure s-sulfinyl-2-5-cis-dihydropyrroles

Article abstract of DOI:10.1021/ol801878f

(Chemical Equation Presented The addition of enantiopure α-metalated vinyl and dienyl sulfoxides to enantiomerically pure N-sulfinimines takes place with high diastereoselectivity primarily directed by the N-sulfinimine sulfur. The resulting allylic amine

Full text of DOI:10.1021/ol801878f

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4775-4778
Highly Diastereoselective Addition of
Lithio Vinyl Sulfoxides to
N-Sulfinimines: An Entry to Enantiopure
3-Sulfinyl-2,5-cis-dihydropyrroles
Alma Viso,* Roberto Ferna´ndez de la Pradilla,* Mercedes Uren˜a, and
Ignacio Colomer
Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la CierVa 3,
28006 Madrid, Spain
iqoV379@iqog.csic.es (A.V.); igofp19@iqog.csic.es (R.F.P.)
Received August 12, 2008
ABSTRACT
The addition of enantiopure r-metalated vinyl and dienyl sulfoxides to enantiomerically pure N-sulfinimines takes place with high
diastereoselectivity primarily directed by the N-sulfinimine sulfur. The resulting allylic amines have been further transformed into highly
functionalized 3-sulfinyl and 3-sulfonyl 2,5-cis-dihydropyrroles by reaction with electrophiles.
Pyrroles and pyrrolidines constitute an important class of
heterocyclic compounds, and numerous methods have been
developed for their preparation. However, few syntheses
offer high efficiency and generality when applied to the
assembly of polysubstituted and enantiopure heterocycles.
Strategies that provide direct access to these five-
membered rings are of great interest nowadays.1 Some of
these routes rely on the cyclization of enantiopure γ,δ-
unsaturated amines,2 with the straightforward synthesis
of these precursors being a current challenge.3
Alternatively, N-sulfinimines have been applied to the
synthesis of ꢀ-amino-R-methylene carbonyl adducts through
the aza-Morita-Baylis-Hillman reaction (Aza-MBH).4 Al-
though nonracemic N-sulfinimines have proven to be efficient
chiral auxiliaries for this reaction, the loss of selectivity for
(2) (a) Donohoe, T. J.; Churchill, G. H.; Wheelhouse, K. M. P.; Glossop,
P. A. Angew. Chem., Int. Ed. 2006, 45, 8025–8028. (b) Komeyama, K.;
Morimoto, T.; Takaki, K. Angew. Chem., Int. Ed. 2006, 45, 2938–2941.
(c) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem.
Soc. 2007, 129, 2452–2453. (d) Sherman, E. S.; Fuller, P. H.; Kasi, D.;
Chemler, S. R. J. Org. Chem. 2007, 72, 3896–3905.
(3) For recent examples of stereoselective preparation of γ,δ-unsaturated
amines: (a) Tiecco, M.; Testaferri, L.; Bagnoli, L.; Scarponi, C.; Temperini,
A.; Marini, F.; Santi, C. Tetrahedron: Asymmetry 2007, 18, 2758–2767.
(b) Lee, C. L. K.; Loh, T. P. Org. Lett. 2005, 7, 2965–2967. (c) Kumar
Pandey, S.; Kumar, P. Synlett 2007, 2894–2896.
(1) For recent reports on the syntheses of enantiopure pyrrolidines, see:
(a) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem.
Soc. 2008, 130, 4196–4201. (b) Schomaker, J. M.; Bhattacharjee, S.; Yan,
J.; Borhan, B. J. Am. Chem. Soc. 2007, 129, 1996–2003. (c) Jiang, C.;
Frontier, A. J. Org. Lett. 2007, 9, 4939–4942. For recent synthesis using
the sulfinyl group as chiral auxiliary: (d) Davis, F. A.; Zhang, J.; Qiu, H.;
Wu, Y. Org. Lett. 2008, 10, 1433–1436. (e) Unthank, M. G.; Tavassoli,
B.; Aggarwal, V. K. Org. Lett. 2008, 10, 1501–1504. (f) Dong, C.; Mo, F.;
Wang, J. J. Org. Chem. 2008, 73, 1971–1974. (g) Garc´ıa Ruano, J. L.;
Tito, A.; Peromingo, M. T. J. Org. Chem. 2002, 67, 981–987.
(4) Reviews: (a) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem.,
Int. Ed. 2007, 46, 4614–4628. (b) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem.
2007, 2905–2916. N-Sulfinimines in Aza-MBH: (c) Aggarwal, V. K.; Martin
Castro, A. M.; Mereu, A.; Adams, H. Tetrahedron Lett. 2002, 43, 1577–
1581. (d) Shi, M.; Xu, Y.-M. Tetrahedron: Asymmetry 2002, 13, 1195–
1200.
10.1021/ol801878f CCC: $40.75
Published on Web 09/27/2008
2008 American Chemical Society

trisubstituted double bonds and the long reaction times are
still drawbacks to be overcome. Besides, in contrast to
sulfonimines,5 Lewis acids are required for the less electro-
philic sulfinimines.
As an alternative to the diastereoselective version of the
Aza-MBH reaction and due to our experience in chiral sulfur
chemistry,6 we envisioned the reaction between metalated
vinyl sulfoxides B and enantiopure N-sulfinimines A7
(Scheme 1) as an efficient access to analogous chiral
sulfinamides C (X ) NSOp-Tol).8
We submitted a number of enantiomerically pure sulfin-
imines (R)-1 and (S)-1 to treatment with (RS,E)-lithio vinyl
sulfoxides [generated from (R)-2 and LDA]10 obtaining in
all cases good to excellent yields (69-98%) and moderate
to high diastereoselectivities of allylic sulfinamides 3 and 4
(Table 1). Moreover, undesired byproducts from self-addition
Table 1. Addition of Lithio Vinyl and Dienyl Sulfoxides to
N-Sulfinimines R-1 and S-1d
Scheme 1. Nucleophilic Addition of Lithio Vinyl Sulfoxides
Previous results revealed a poor stereocontrol for the
addition of lithio vinyl sulfoxides B to aldehydes to afford
equimolecular mixtures of allylic alcohols (C, X ) O).9
Moreover, our first attempt to achieve the analogous nitrogen
adducts using sulfonimines led to a 50:50 mixture of
sulfonamides (C, X ) NTs). However, the additional chiral
sulfur of sulfinimines could provide a double diastereose-
lection scenario based on two chiral sulfur atoms that could
render sulfinamides (C, X ) NSOpTol) with stereocontrol.
Thus, we now report the diastereoselective addition of vinyl
and dienyl sulfoxides to chiral sulfinimines to provide
2-sulfinyl allylic sulfinamides. In addition, we have examined
the reactivity of dienyl sulfinamides C (R′ ) CHdCH2)
finding an efficient entry to enantiopure 3-sulfinyl and
3-sulfonyl 2,5-cis-disubstituted dihydropyrroles.
product
dr
entry
1 (R)
2 (R′)
(yield %)a (3:3′ or 4:4′)b
1
2
3
4
5
6
7
R-1a (Ph)c
S-1a (Ph)c
R-1a (Ph)
S-1a (Ph)
R-1b (i-Pr) R-2b (CHdCH2)
S-1b (i-Pr) R-2b (CHdCH2)
R-1c (n-Bu) R-2b (CHdCH2)
R-2a (n-Bu)
R-2a (n-Bu)
R-2b (CHdCH2)
R-2b (CHdCH2)
3a(90)
4a(69)
3b(95)
4b(91)
3c(93)
4c(69)
3d(98)
91:9
82:18
99:1
87:13
99:1
75:25
99:1
a Combined yield. b Ratio determined by 1H NMR analysis. c 3.0 equiv
of LDA and 1 was employed. d Comparative matched vs mismatched pair.
of vinyl sulfoxides (R)-2 were not observed under these
conditions. These results highlight the crucial role of the
absolute configuration of the sulfinimine in the process since
both yields and selectivities increased when (R)-1 was
employed (entries 1, 3, 5, and 7, matched pair).
The scope of the reaction was examined by varying the
nature of R in sulfinimines (Table 1, (R)-1a-c, (S)-1a,b).
In addition, alkyl and alkenyl substitution at vinyl sulfoxide
(R)-2a,b gave outstanding yields and selectivities (91:9-99:
1) for the matched pair.
The synthesis of sulfinamide 3b has been carried out on a
3 g scale uneventfully using 3.5 g of N-sulfinimine (R)-1a.
It should be mentioned that the excess of imine is recovered
without racemization after purification of the crude by flash
chromatography.
The stereochemical outcome for the addition can be
understood in terms of a rigid transition state depicted in
Scheme 2, where the lithium coordinates the two oxygen
atoms of sulfoxide (R)-2 and sulfinimine 1.11 The nucleo-
philic addition would take place mostly anti to the p-tolyl
(5) Tosyl imines in Aza-MBH: (a) Lee, H. S.; Kim, J. M.; Kim, J. N.
Tetrahedron Lett. 2007, 48, 4119–4122. (b) Qi, M. J.; Shi, M. Tetrahedron
2007, 63, 10415–10424. (c) Shi, Y. L.; Shi, M. Tetrahedron 2006, 62, 461–
475. (d) Balan, D.; Adolfsson, H. J. Org. Chem. 2002, 67, 2329–2334.
(6) (a) Ferna´ndez de la Pradilla, R.; Alhambra, C.; Castellanos, A.;
Ferna´ndez, J.; Manzano, P.; Montero, C.; Uren˜a, M.; Viso, A. J. Org. Chem.
2005, 70, 10693–10700. (b) Ferna´ndez de la Pradilla, R.; Castellanos, A.;
Ferna´ndez, J.; Lorenzo, M.; Manzano, P.; Me´ndez, P.; Priego, J.; Viso, A.
J. Org. Chem. 2006, 71, 1569–1575. (c) Viso, A.; Ferna´ndez de la Pradilla,
R.; Garc´ıa, A.; Flores, A.; Tortosa, M.; Lo´pez-Rodr´ıguez, M. L. J. Org.
Chem. 2006, 71, 1442–1448. (d) Viso, A.; Ferna´ndez de la Pradilla, R.;
Garc´ıa, A.; Guerrero-Strachan, C.; Alonso, M.; Tortosa, M.; Flores, A.;
Mart´ınez-Ripoll, M.; Fonseca, I.; Andre´, I.; Rodr´ıguez, A. Chem.-Eur. J.
2003, 9, 2867–2876. (e) Ferna´ndez de la Pradilla, R.; Tortosa, M.; Lwoff,
´
N.; del Aguila, M. A.; Viso, A. J. Org. Chem. 2008, 73, 6716–6727.
(7) For some recent applications of N-sulfinimines: (a) Davis, F. A. J.
Org. Chem. 2006, 71, 8993–9003. (b) Maji, M. S.; Fro¨hlich, R.; Studer, A.
Org. Lett. 2008, 10, 1847–1850. (c) Almansa, R.; Guijarro, D.; Yus, M.
Tetrahedron: Asymmetry 2008, 19, 603–606. (d) Lin, G.-Q.; Xu, M.-H.;
Zhong, Y.-W.; Sun, X.-W. Acc. Chem. Res. 2008, 41, 831–840. (e) Morton,
D.; Stockman, R. A. Tetrahedron 2006, 62, 8869–8905. (f) Beenen, M. A.;
An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910–6911.
(8) Precedents of diastereoselective reactions of imines and R-sulfinyl
carbanions: (a) Garc´ıa Ruano, J. L.; Alcudia, A.; del Prado, M.; Barros,
D.; Maestro, M. C.; Ferna´ndez, I. J. Org. Chem. 2000, 65, 2856–2862. (b)
García Ruano, J. L.; Alema´n, J.; del Prado, M.; Ferna´ndez, I. J. Org. Chem.
2004, 69, 4454–4463. (c) Midura, W. H. Tetrahedron Lett. 2007, 48, 3907–
3910.
(10) Vinyl and dienyl sulfoxides 2 are available in one step by the
procedure of Craig: Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron
1993, 49, 11263-11304.
(9) Marino, J. P.; Anna, L. J.; Ferna´ndez de la Pradilla, R.; Mart´ınez,
M. V.; Montero, C.; Viso, A. J. Org. Chem. 2000, 65, 6462–6473.
4776
Org. Lett., Vol. 10, No. 21, 2008

E isomer at the double bond after the addition process, in
contrast to other base-catalyzed procedures,5c 13 allowed us
,
Scheme 2. Stereochemical Outcome of the Addition of Lithio
Vinyl Sulfoxides (R)-2 to N-Sulfinimines (R)-1 and (S)-1
to address the synthesis of nitrogen heterocycles. For this
purpose, we examined the protection of amines 5 and 6 with
different groups, and Ts (7, 8) and Boc (9) moieties were
uneventfully installed using standard protocols (Scheme 3).
With these products in hand, we studied their behavior
under two conditions for intramolecular cyclization (Scheme
4). We first treated sulfinamide 3b with m-CPBA14 in toluene
resulting in a fast oxidation of both sulfinyl groups followed
by slow epoxidation at the distal double bond and producing
a mixture of diastereomeric epoxides that was not isolated.15
Cyclization in situ of these epoxides with a catalytic amount
of CSA afforded a 75:25 mixture of sulfonyl dihydropyrroles
10 and 11 in good yield, where 2,5-cis stereochemistry
resulted predominant. Pursuing to preserve the sulfoxide
moiety, after considerable experimentation, we tried the
halocyclization by using tetrabutylammonium tribromide
(TBATB) as a halogen source. The reaction of TBATB with
sulfinamide 3b in the presence of K2CO3 produced only a
small amount of a complex mixture of pyrrolines. Besides,
no reaction was observed when carbamate 9b was tested.
In contrast, we could obtain 3-sulfinyl dihydropyrroles
through the use of the more acidic sulfonamido group, 7b.
Moreover, we were delighted to detect the formation of a
major product 12b initially assigned as a 2,5-cis isomer by
1D-NOE experiments. To generalize the reaction, dienyl
sulfonamides 7c and 7d (R ) n-Bu, i-Pr) were submitted to
halocyclization with TBATB rendering sulfinyl pyrroles 12c
and 12d in moderate yields and good diastereoselectivities.
Additional efforts to obtain similar structures from dias-
tereomer 8b or from the related dienyl sulfone (prepared by
oxidation of 7b) failed in giving the expected dihydropyr-
roles. This suggests that both the oxidation state and the
relative stereochemisty of the substrate are crucial for a
successful cyclization.
group of the sulfinimine arranged in an s-cis conformation,
onto the re face of (R)-1 for the matched pair or the si face
of (S)-1 for the mismatched pair. Interestingly, in terms of
facial discrimination, sulfinimines behave as in the addition
of R-sulfinyl carbanions8a and R-imino enolates6d but op-
posite to Baylis-Hillman nucleophiles4c,d and other
enolates.7a
Subsequent cleavage of the sulfinamides by acidic treat-
ment12 provided very good yields of allylic amines 5 and 6
(Scheme 3). Removal of the sulfinamide stereogenic center
Scheme 3
.
Selective Cleavage of Sulfinamides and Protection of
the Allylic Amines
To confirm the stereochemical pathway for both cycliza-
tions, pyrroline 12b was oxidized to obtain 3-sulfonyl
dihydropyrrole 14 in good yield. On the other hand, treatment
of hydroxymethyl dihydropyrrole 10 with CBr4/PPh3 led also
to compound 14, thus correlating the stereochemistries of
the major products 10 and 12.
The absolute configuration of the new stereogenic carbons
as well as the configurational stability of the sulfinyl group
under the reaction conditions were secured by X-ray crystal-
lography of 3-sulfinyl dihydropyrrole 13b (Figure 1).
In conclusion, we have developed a very useful synthetic
route for the preparation of functionalized 2-sulfinyl allylic
allowed us to identify compounds 5 and 6 as diastereomers
at the allylic carbon. In addition, the minor isomer from the
mismatched pair (4′) and the major isomer from the matched
pair (3) afforded allylic amine 5. Finally, the structural
assignment was secured by X-ray analysis of a derivative
of 3b (see below).
(13) (a) Back, T. G.; Rankic, D. A.; Sorbetti, J. M.; Wulff, J. E. Org.
Lett. 2005, 7, 2377–2379. (b) Sorbetti, J. M.; Clary, K. N.; Rankic, D. A.;
Wulff, J. E.; Parvez, M.; Back, T. G. J. Org. Chem. 2007, 72, 3326–3331.
(14) Previous epoxidation-cyclization procedures with analogous ni-
trogenated structures: (a) Wipf, P.; Stephenson, C. R. J.; Walczak, M. A. A.
Org. Lett. 2004, 6, 3009–3012. (b) Singh, S.; Han, H. Tetrahedron Lett.
2004, 45, 6349–6352.
At this point, we focused our attention on adducts with a
diene functionality in the structure. The isolation of a single
(15) In related epoxidation experiments with other reagents, we have
observed that isolated mixtures of epoxides cyclized to mixtures of cis-
and trans-hydroxymethyl pyrrolines in identical ratio to the oxiranes. Some
examples of epoxidation of dienyl sulfoxides: (a) Ferna´ndez de la Pradilla,
R.; Manzano, P.; Montero, C.; Priego, J.; Mart´ınez-Ripoll, M.; Mart´ınez-
Cruz, L. A. J. Org. Chem. 2003, 68, 7755–7767. (b) Ferna´ndez de la Pradilla,
R.; Castellanos, A. Tetrahedron Lett. 2007, 48, 6500–6504.
(11) (a) Bharatam, P. V.; Uppal, P.; Kaur, A.; Kaur, D. J. Chem. Soc.,
Perkin Trans. 2 2000, 43–50. (b) Bloch, R. Chem. ReV. 1998, 98, 1407–
1438.
(12) Viso, A.; Ferna´ndez de la Pradilla, R.; Lo´pez-Rodr´ıguez, M. L.;
Garc´ıa, A.; Flores, A.; Alonso, M. J. Org. Chem. 2004, 71, 1542–1547.
Org. Lett., Vol. 10, No. 21, 2008
4777

Scheme 4. Synthesis of Enantiopure 2,5-cis-Disubstituted Dihydropyrroles
sulfinamides from readily available chiral sulfinimines and
R-metalated vinyl and dienyl sulfoxides. The two chiral
sulfinyl groups in both starting materials contributed to the
formation of a new carbon-carbon bond in a highly
diastereoselective manner. Electrophilic cyclizations of dienyl
sulfonamides 7 provide a valuable application of the reaction
to the diastereoselective synthesis of 3-sulfonyl and 3-sulfinyl
cis-2,5-disubstituted dihydropyrroles 10 and 12. Further
explorations on these reactions are now underway in our
laboratory.
Acknowledgment. This research was supported by DGI
MEC (CTQ2006-04522/BQU) and CM (S-SAL-0249-2006).
We also thank CM for the additional support to MU, CSIC-
FSE for a fellowship to IC, and Ce´sar J. Pastor from X-Ray
Laboratory of UAM.
Supporting Information Available: Experimental pro-
cedures, compound characterization, NMR spectra, and X-ray
crystallography data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 1. X-ray structure of trans isomer 13b.
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Org. Lett., Vol. 10, No. 21, 2008