Sulfur-Directed Asymmetric 1,3-Dipolar Cycloadditions of Azomethine Ylides with Enantiopure Sulfinimines

Full text of DOI:10.1021/jo970005n

2316
J . Org. Chem. 1997, 62, 2316-2317
Sch em e 1
Su lfu r -Dir ected Asym m etr ic 1,3-Dip ola r
Cycloa d d ition s of Azom eth in e Ylid es w ith
En a n tiop u r e Su lfin im in es†,‡
Alma Viso,*,§ Roberto Ferna´ndez de la Pradilla,*,
Carlos Guerrero-Strachan, Marta Alonso,
Mart´ın Mart´ınez-Ripoll,| and Isabelle Andre´|
Departamento de Quı´mica Orga´nica I,
Facultad de Quı´mica, Universidad Complutense,
E-28040 Madrid, Spain, and Instituto de Qu´ımica
Orga´nica, CSIC, J uan de la Cierva, 3,
E-28006 Madrid, Spain, and Departamento de
Cristalografı´a, Instituto de Quı´mica-Fı´sica Rocasolano,
CSIC, Serrano 119, E-28006 Madrid, Spain
Received February 21, 1997
1,3-Dipolar cycloadditions are fundamental processes
in organic chemistry.1 In particular, the reaction of
azomethine ylides with alkenes is a powerful method for
the synthesis of pyrrolidines since up to four stereo-
centers are set in a single operation.2 This has fueled
intensive efforts toward the development of efficient
chiral auxiliaries to render the process enantioselective.3
In contrast, reports on cycloadditions between azo-
methine ylides and imines are scarce,4 despite the well-
established synthetic potential of the resulting imidazo-
lidines.5 Furthermore, it should be noted that the
asymmetric version of this process remains elusive. In
this paper, we report the first examples of a highly
diastereoselective 1,3-dipolar cycloaddition of azomethine
ylides with chiral sulfinimines to produce enantiopure
N-sulfinyl imidazolidines and the straightforward trans-
formation of one of these cycloadducts into an example
of a novel class of nonsymmetrical vicinal diamines.
Enantiopure sulfinimines, readily available in both
enantiomeric forms,6 are versatile intermediates for
enantioselective syntheses of a variety of targets.7 These
substrates display excellent facial selectivity upon reac-
tion with a number of nucleophiles, and furthermore,
removal or even recycling of the sulfinyl auxiliary is
readily carried out under mild reaction conditions.8
These desirable features, along with our interest in the
development of sulfur-directed methodology,9 attracted
our attention to these intermediates as potential precur-
sors to chiral imidazolidines by 1,3-dipolar cycloadditions
with azomethine ylides.
We selected sulfinimine 16a and N-benzylidene R-amino
acid ester-derived ylide 310 for our initial studies. Stan-
dard conditions (LiBr, Et3N, MeCN; AgOAc, DBU, Tol)
failed to promote the desired cycloaddition. Dipole
generation with LDA10 was then examined, and to our
delight, the reaction between sulfinimine 1 and phenyl-
alanine-derived dipole 3 led to a fair yield of a 95:5
mixture of cycloadducts 6 and 711 (Scheme 1), along with
15-20% of unreacted starting material. From this
mixture of 6 and 7, pure 6 (45-50%) was obtained by
recrystallization (hexane:ether). The reaction between
1 and dipole 4 produced imidazolidines 8 and 9 in almost
identical yield and selectivity to the case above. Simi-
larly, the more reactive substrate 212 afforded excellent
yields of adducts 10 and 12 as practically single isomers
upon reaction with dipoles 3 and 5, respectively.
* To whom correspondence should be addressed. Phone: 34-(1)-562-
2900 ext 210. Fax: 34-(1)-564-4853. E-mail: RIF@CC.CSIC.ES.
† Taken in part from the M.S. Theses of C.G.-S. and M.A.
‡ Dedicated to the late Dr. Mar´ıa Victoria Mart´ın (I. Q. O., CSIC).
§ Universidad Complutense.
The general structure of these adducts was readily
derived from their spectral features, and the relative
stereochemistry of the three ring chiral centers was
deduced from differential NOE experiments. However,
Instituto de Qu´ımica Orga´nica.
| Instituto de Qu´ımica-F´ısica Rocasolano.
(1) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984.
(2) For a review, see: Tsuge, O.; Kanemasa, S. Adv. Heterocycl.
Chem. 1989, 45, 231-349.
(3) For leading references, see: (a) Galley, G.; Liebscher, J .; Pa¨tzel,
M. J . Org. Chem. 1995, 60, 5005-5010. (b) Waldmann, H.; Bla¨ser, E.;
J ansen, M.; Letschert, H.-P. Chem. Eur. J . 1995, 1, 150-154. (c) Grigg,
R. Tetrahedron: Asymmetry 1995, 6, 2475-2486.
(7) For leading references, see: (a) Davis, F. A.; Szewczyk, J . M.;
Reddy, R. E. J . Org. Chem. 1996, 61, 2222-2225. (b) Davis, F. A.;
Portonovo, P. S.; Reddy, R. E.; Chiu, Y. Ibid. 1996, 61, 440-441. (c)
Hose, D. R. J .; Mahon, M. F.; Molloy, K. C.; Raynham, T.; Wills, M. J .
Chem. Soc., Perkin Trans. 1 1996, 691-703. (d) Garc´ıa Ruano, J . L.;
Ferna´ndez, I.; del Prado Catalina, M.; Alcudia Cruz, A. Tetrahedron:
Asymmetry 1996, 7, 3407-3414. (e) Fujisawa, T.; Kooriyama, Y.;
Shimizu, M. Tetrahedron Lett. 1996, 37, 3881-3884. (f) Balasubra-
manian, T.; Hassner, A. Ibid. 1996, 37, 5755-5758.
(8) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M. J . Org. Chem. 1995,
60, 7037-7039.
(9) (a) Marino, J . P.; Viso, A.; Ferna´ndez de la Pradilla, R.;
Ferna´ndez, P. J . Org. Chem. 1991, 56, 1349-1351. (b) Arjona, O.;
Ferna´ndez de la Pradilla, R.; Mallo, A.; Plumet, J .; Viso, A. Tetrahedron
Lett. 1990, 31, 1475-1478. (c) Ferna´ndez de la Pradilla, R.; Castro,
S.; Manzano, P.; Priego, J .; Viso, A. J . Org. Chem. 1996, 61, 3586-
3587.
(10) Kanemasa, S.; Hayashi, T.; Tanaka, J .; Yamamoto, H.; Sakurai,
T. J . Org. Chem. 1991, 56, 4473-4481 and previous papers from this
group.
(11) All new products were fully characterized by standard tech-
niques.
(12) Sulfinimine 2 was prepared in one step from p-nitrobenzalde-
hyde by the procedure of Davis (ref 6a).
(4) (a) Lown, J . W. In ref 1, Vol. 1, pp 653-732. (b) Bende, Z.; Bitter,
I.; Toke, L.; Weber, L.;. Toth, G.; J anke, F. Liebigs. Ann. Chem. 1982,
2146-2152. (c) Grigg, R.; Donegan, G.; Gunaratne, H. Q. N.; Kennedy,
D. A.; Malone, J . F.; Sridharan, V.; Thianpatanagul, S. Tetrahedron
1989, 45, 1723-1746. (d) Amornraksa, K.; Barr, D.; Donegan, G.; Grigg,
R.; Ratananukul, P.; Sridharan, V. Ibid. 1989, 45, 4649-4668. (e)
Lerestif, J . M.; Bazureau, J . P.; Hamelin, J . Tetrahedron Lett. 1993,
29, 4639-4642. (f) Padwa, A.; Dean, D. C.; Osterhout, H.; Precedo, L.;
Semones, M. A. J . Org. Chem. 1994, 59, 5347-5357. (g) Nagao, Y.;
Kim, K.; Komaki, Y.; Sano, S.; Kihara, M.; Shiro, M. Heterocycles 1994,
38, 587-593.
(5) For leading references, see: (a) Alexakis, A.; Lensen, N.; Tran-
chier, J .-P.; Mangeney, P.; Feneu-Dupont, J .; Declercq, J .-P. Synthesis
1995, 1038-1050. (b) Alexakis, A.; Tranchier, J .-P.; Lensen, N.;
Mangeney, P. J . Am. Chem. Soc. 1995, 117, 10767-10768.
(6) For leading references, see: (a) Davis, F. A.; Reddy, R. E.;
Szewczyk, J . M.; Portonovo, P. S. Tetrahedron Lett. 1993, 34, 6229-
6232. (b) Yang, T.-K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.; J iang, Y.-
Z.; Mi, A.-Q.; J ong, T.-T. J . Org. Chem. 1994, 59, 914-921 and
references cited therein.
S0022-3263(97)00005-4 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 8, 1997 2317
F igu r e 2.
Sch em e 3
Scheme 3 depicts our initial studies on the reactivity of
these sulfinyl imidazolidines. Treatment of 6 with TFA/
MeOH14 resulted in desulfinylation and fragmentation
to produce phenylalanine methyl ester. To avoid this
undesired process, reduction of the ester to the primary
alcohol was attempted. Treatment of 6 with an excess
of LAH resulted in concurrent deoxygenation and ester
reduction, affording sulfenamide 15 in fair yield.15 Cleav-
age of the sulfur-nitrogen bond and aminal methanolysis
took place smoothly to produce diamine 16 in good yield.16
The stereochemical outcome of this cyclization may be
understood in terms of predominant endo approach of the
ylide (relative to the Ar group) to the less hindered â face
of sulfinimines 1 and 2 (Figure 2) to provide adducts 6,
8, 10, and 12, respectively. Our process displays a
remarkable facial selectivity of opposite sense to that
found for most other additions to sulfinimines;6,7 this and
the high stereoselectivity found strongly support a 1,3-
dipolar cycloaddition pathway.
To summarize, readily available sulfinimines react
with lithiated R-imino esters with remarkable selectivity
to generate enantiopure N-sulfinyl imidazolidines. In
this cycloaddition, the chirality of sulfur is transferred
to three asymmetric centers in a single synthetic opera-
tion with almost complete stereocontrol. We are cur-
rently examining the scope and limitations of this
methodology as well as further applications of these
cycloadducts in synthesis.
F igu r e 1. Final X-ray model for 6 showing its absolute
chirality. Numbers only refer to C atoms.
Sch em e 2
a definitive proof of the relative configuration of the ring
centers and the chiral sulfur was required to establish
unequivocally the predominant facial sense of the pro-
cess. This was solved by an X-ray analysis of 6, and the
results obtained are shown in Figure 1.13
To secure that 6 and 7 were facial isomers, a sample
of pure 6 was oxidized to tosyl imidazolidine 14 (Scheme
2). Under identical conditions, an enriched sample of 7
led to enantiomerically enriched ent-14 of identical
spectral features to those of 14 and optical rotation of
opposite sign.
These cycloadducts are nicely functionalized for sub-
sequent manipulations. Indeed, both nitrogen atoms are
already differentiated, and in principle, both aryl rings
could be varied readily. Furthermore, the ester group
should be an additional handle for synthetic applications.
Ack n ow led gm en t. This research was supported by
DGICYT (PB93-0154 and PB94-0104). We thank Pro-
fessors B. Rodr´ıguez and S. Valverde for encouragement
and support.
(13) Crystal data for 6: C31H30N2O3S, Mr ) 510.63, monoclinic, P21,
Z ) 4, a ) 11.896(1) Å, b ) 22.893(2) Å, c ) 11.621(1) Å, â ) 116.57-
(1)°, F(000) ) 1080, Dx ) 1.198 g cm-3, µ ) 1.277 mm-1, prismatic
colorless crystal of 0.4 × 0.3 × 0.2 mm, graphite-monochromated Cu
KR radiation (λ ) 1.5418 Å, 293 K, ω/2θ scans, no intensity decay,
absorption corrected using azimuthal scans (minimum and maximum
transmision factors 0.82 and 1.00), 9402 reflections measured up to
2θ ) 130°, 0 < h < +12, -26 < k < +26, -12 < l < +12, 7872 observed
with criterion I > 2σ(I). Structure solved by direct methods (SIR92:
Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.; Giacovazzo,
G.; Guagliardi, A.; Polidori, G. SIR92, Program for Crystal Stucture
Solution, University of Bari, Italy, 1992), weighted full-matrix least-
squares refinement against F2 using all reflections (SHELX93: Sheld-
rick, G. M. J . Appl. Crystallogr. Manuscript in preparation), H-atoms
found in difference map and refined in riding mode, 676 parameters,
extinction coefficient 0.001(1), goodness of fit for all reflections 1.048,
maximum shift/error 0.001, absolute structure coefficient 0.02(2)
(Flack, H. D. Acta Crystallogr. A 1983, 39, 876-881), R ) 0.056 and
Rw ) 0.136 for the observed reflections, R ) 0.069 and Rw ) 0.151 for
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for all new compounds (8
pages).
J O970005N
(14) Mikolajczyk, M.; Drabowicz, J .; Bujnicki, B. J . Chem. Soc.,
Chem. Commun. 1976, 568-569.
(15) We found this reduction to be very sluggish presumably due to
the carboxylate being very hindered. Short reaction times resulted in
recovery of starting material. Intermediate reaction times (5 h) afforded
mixtures of 15 and the expected sulfinamide, whose treatment with
TFA/MeOH also led to diamine 16. We are examining other procedures
to carry out the selective reduction of the ester.
(16) Vicinal diamines are important chiral auxiliaries. For a review,
see: Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33,
497-526. For a leading reference see: Trost, B. M.; Breit, B.; Peukert,
S.; Zambrano, J .; Ziller, J . W. Angew. Chem., Int. Ed. Engl. 1995, 34,
2386-2388. For leading references on synthesis of vicinal diamines,
see: (a) Richardson, P. F.; Nelson, L. T. J .; Sharpless, K. B. Tetrahedron
Lett. 1995, 36, 9241-9244. (b) Shimizu, M.; Kamei, M.; Fujisawa, T.
Tetrahedron Lett. 1995, 36, 8607-8610. (c) Park, Y. S.; Boys, M. L.;
Beak, P. J . Am. Chem. Soc. 1996, 118, 3757-3758.
all reflections, residual electron density between -0.20 and 0.16 e Å-3
.
The author has deposited atomic coordinates for this structure with
the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ. UK.