First asymmetric Hetero Diels-Alder reaction of 1-sulfinyl dienes with nitroso derivatives. A new entry to the synthesis of optically pure 1,4-imino-L-ribitol derivatives

Article abstract of DOI:10.1021/ol0063611

(Matrix Presented) Hetero Diels-Alder (HDA) cycloaddition of chiral 1-p-tolylsulfinyl-1,3-penladiene with benzyl nitrosoformate, under mild conditions, yields 2H-1,2-oxazine 3 with complete regioselectivity and π-facial diastereoselectivity. Sequential os

Full text of DOI:10.1021/ol0063611

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3165-3168
First Asymmetric Hetero Diels−Alder
Reaction of 1-Sulfinyl Dienes with
Nitroso Derivatives. A New Entry to the
Synthesis of Optically Pure
1,4-Imino-L-ribitol Derivatives
,‡
,‡
C. Arribas,† M. Carmen Carren˜o,* Jose´ L. Garc´ıa-Ruano,* Justo F. Rodr´ıguez,†
Mercedes Santos,† and M. Ascensio´n Sanz-Tejedor*
,†
Departamento de Qu´ımica Orga´nica (E.T.S.I.I.), UniVersidad de Valladolid,
Paseo del Cauce s/n, 47011, Valladolid, Spain, and Departamento de Qu´ımica
Orga´nica (C-I), UniVersidad Auto´noma de Madrid, Cantoblanco, 28049-Madrid, Spain
atejedor@dali.eis.uVa.es
Received July 21, 2000
ABSTRACT
Hetero Diels−Alder (HDA) cycloaddition of chiral 1-p-tolylsulfinyl-1,3-pentadiene with benzyl nitrosoformate, under mild conditions, yields
2H-1,2-oxazine 3 with complete regioselectivity and π-facial diastereoselectivity. Sequential osmylation and protection of the resulting glycol
gives the oxazine 5 which is directly transformed into enantiomerically pure 1,4,5-trideoxy-1,4-imino-L-ribitol 8 by reduction under Pd/C.
Optically pure 1-sulfinyl-1,3-butadienes have proved to be
efficient chiral dienes in asymmetric Diels-Alder reactions1
mainly due to their almost complete stereoselectivity control
and to the easy evolution of their adducts through a highly
stereocontrolled rearrangement.2 Despite this, their use in
asymmetric synthesis is strongly limited by their rather low
reactivity even with good dienophiles. Our group has recently
found that reactions of these dienes with heterodienophiles,
such as 4-methyl-1,2,4-triazoline-3,5-dione, evolve under
very mild conditions retaining the high stereoselectivity.3 This
result prompted us to investigate the usefulness of 1-sulfi-
nyldienes in other asymmetric HDA reactions.4 In this sense,
our interest in the synthesis of monosaccharides and related
compounds5 drew our attention toward reactions with nitroso
derivatives, because the adducts resulting from their reactions
with 1-sulfinyldienes could be properly transformed into
polyhydroxypyrrolidines according to the retrosynthetic
sequence shown in Scheme 1.
(3) Carren˜o, M. C.; Cid, B.; Garc´ıa Ruano, J. L.; Santos, M. Tetrahedron
Lett. 1998, 39, 1405.
† Universidad de Valladolid.
(4) For a recent review, see: Tietze L. F.; Kettschau. in Topics in Curent
Chemistry; Metz, P., Ed.; Springer-Verlag: Berlin 1997; Vol. 189; p 4.
(5) For recent references, see: (a) Arroyo, Y.; Lo´pez-Sastre, J. A.;
Rodr´ıguez, J. F.; Sanz-Tejedor, M. A. J. Chem. Soc., Perkin Trans. 1 1996,
2933. (b) Arroyo, Y.; Lo´pez-Sastre, J. A.; Rodr´ıguez, J. F.; Santos, M.;
Sanz-Tejedor, M. A. Tetrahedron: Asymmetry 1999, 10, 973. (c) Arroyo,
Y.; Rodr´ıguez, J. F.; Santos, M.; Sanz-Tejedor, M. A. Tetrahedron:
Asymmetry 2000, 11, 789.
(6) For reviews, see: (a) Elbein, A. D. Am. ReV. Biochem. 1987, 56,
497. (b) Legler, G. AdV. Carbohydr. Chem. Biochem. 1990, 48, 319. (c)
Elbein, A. D. FASEB J. 1991, 5, 3055. (d) Winchester, B.; Fleet, G. W. J.
Glycobiology 1992, 2, 199.
‡ Universidad Auto´noma de Madrid.
(1) Recent reviews: (a) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Gianneto, P. Tetrahedron: Asymmetry 1997, 8, 1339. (b) Garc´ıa Ruano, J.
L.; Cid, B. In Topics in Current Chemistry; Page, P. C. B., Ed.; Springer-
Verlag: Berlin 1999; Vol. 204; pp 1-126.
(2) (a) Arce, E.; Carren˜o, M. C.; Cid, M. B.; Garc´ıa Ruano, J. L. J. Org.
Chem. 1994, 59, 3421. (b) Carren˜o, M. C.; Cid, M. B.; Garc´ıa Ruano, J. L.
Tetrahedron: Asymmetry 1996, 7, 2151. (c) Carren˜o, M. C.; Cid, M. B.;
Garc´ıa Ruano, J. L.; Santos, M. Tetrahedron Asymmetry 1997, 8, 2093. (d)
Carren˜o, M. C.; Cid, M. B.; Colobert, F.; Garc´ıa Ruano, J. L.; Solladie´, G.
Tetrahedron: Asymmetry 1995, 6, 1439.
10.1021/ol0063611 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/15/2000

metric Diels-Alder reactions with nitrosodienophiles22 have
also been used. These cycloadditions have been extensively
studied by Streith et al. in both racemic23 and optically active
series. Concerning these asymmetric cycloadditions, the best
results have been obtained with chiral nitroso dienophiles,9,24
whereas chiral dienes have been scarcely used since moder-
ated asymmetric inductions are usually observed.25 Thus,
starting from a chiral N-dienyl lactam, Streith has synthesized
a 3,4-dihydroxypyrrolidine.25a
Scheme 1
Glycosidase inhibitors have a large number of interesting
potential applications including treatment of AIDS and
diabetes as well as tumor metastasis inhibitors.6 The interest
of the polyhydroxypyrrolidines derives from the fact that they
have been found to be potent inhibitors for many glycosi-
dases.7 Therefore, 5-methyl polyhydroxypyrrolidines with
structures similar to that depicted in Scheme 1 have been
recently proved to be efficient inhibitors of R-L-fucosidase.8,9
The search for new methods for synthesizing these com-
pounds with modified structure and configuration is of
potential relevance.
The synthesis of polyhydroxylated pyrrolidines has been
performed from naturally occurring chiral compounds (L-
arabinopyranoside,10 D-xilose,11 D-gulono lactone,12 D-glu-
cose,13 D-galactofuranose,14 and L-lixopyranoside15) as well
as enantiomer resolution16 and asymmetric synthesis. Out-
standing examples of the latter methodology mainly involve
the use of enantiomerically pure chiral precursors controlling
the formation of a new stereogenic center (from L-proline,17
(R) and (S)-glutamic acid,18 (+) and (-)-serine,19 and (R)-
or (S)-phenylglycinol20), but enzymatic catalysis21 and asym-
With these precedents, our group has investigated the
reaction of [(S)R]-(1E,3E)-1-p-tolylsulfinyl-1,3-pentadiene
126 with benzyl nitrosoformate 2. The highly reactive
dienophile 2 was prepared in situ, in the presence of chiral
diene 1, by oxidation of the N-benzyloxycarbonyl hydrox-
amic acid with tetrabutylammonium periodate in CH2Cl2
solution.27 Fortunately the reaction took place under very
1
mild conditions (CH2Cl2, -78 to 0 °C). After 2 h, the H
NMR spectrum of the crude reaction revealed the existence
of a 2:1 mixture of the 2H-1,2-oxazine 3 and the unreacted
diene 1. The addition of new portions of Bu4NIO4 and
hydroxamic acid until complete disappearance of diene
allowed to obtain compound 3 in 54% yield.28
No other diastereoisomers could be detected from the
crude reaction by NMR, thus suggesting that both regio-
selectivity and stereoselectivity of the reaction are very high
(Scheme 2).
(21) (a) Ziegler, T.; Straub, A,; Effenberger, F. Angew. Chem. 1988, 100,
737. (b) Liu, K. K.-C.; Kagimoto, T.; Pederson, L. R.; Zhong, Z.; Ichikawa,
Y.; Porco, J. A.; Wong, Ch.-H. J. Am. Chem. Soc. 1991, 113, 6678. (c)
Liu, K. K.-C.; Kagimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong,
Ch.-H. J. Org. Chem. 1991, 56, 6280. (d) Wang, Y. F.; Dumas, D. P.;
Wong, Ch.-H. Tetrahedron Lett. 1993, 34, 403.
(7) (a) Iminosugars as Glycosidase Inhibitors-Nojirimycin and Beyond;
Stu¨zt, A. E., Ed., Wiley-VCH: Weinheim, 1999. (b) Bols, M. Acc. Chem.
Res. 1998, 31, 1.
(8) (a) Liu, K. K.-C.; Kagimoto, T.; Pederson, L. R.; Zhong, Z.; Ichikawa,
Y.; Porco, J. A.; Wong, Ch.-H. J. Am. Chem. Soc. 1991, 113, 6187. (b)
Wong, Ch-H.; Dumas, D. P.; Ichikawa, Y.; Koseki, K.; Danishefsky, S. J.;
Weston, B. W.; Lowe, J. B. J. Am. Chem. Soc. 1992, 114, 7321. (c) Quiao,
L.; Murray, B. W.; Shimazaki, M.; Schultz, J.; Wong, Ch-H. J. Am. Chem
Soc. 1996, 118, 7653.
(9) (a) Defoin, A.; Sifferlen, T.; Streith, J.; Dosbaaˆ, I.; Foglietti, M. J.
Tetrahedron: Asymmetry 1997, 8, 363. (b) Sifferlen, T.; Defoin, A.; Streith,
J.; Le Noue¨n, D.; Tarnus, C.; Dosbaaˆ, I.; Foglietti, M. J. Tetrahedron 2000,
56, 971.
(10) Reist, E. J.; Gueffroy, D. E.; Blackford, R. W.; Goodman, L. J.
Am. Chem Soc. 1966, 31, 4025.
(11) Fleet, G. W. J.; Smith, P. W. Tetrahedron 1986, 42, 5685.
(12) (a) Fleet, G. W. J.; Son, J. Ch. Tetrahedron 1988, 44, 2637. (b)
Horenstein, B. A.; Zabinski, R. F.; Schramm, V. L. Tetrahedron Lett. 1993,
34, 7213. (c) Furneaux, R. H.; Limberg, G.; Tyler, P. C. Tetrahedron 1997,
53, 2915.
(13) (a) Han, S.-Y.; Lidlell, P. A.; Joullie, M. M. Synth. Commun. 1988,
18, 275. (b) Fleet, G. W. J.; Witty, D. R. Tetrahedron: Asymmetry 1990,
1 119. (c) Kayakiri, H.; Nakamura, K.; Takae, S.; Setoy, H.; Uchida, I.;
Terano, H.; Hashimoto, M.; Tada, T.; Koda, S. Chem. Pharm. Bull. 1991,
39, 2807.
(14) Buchanan, J. G.; Lumbard, K. W.; Sturgeon, R. J.; Thomson, D.
K.; Wightman, R. H. J. Chem. Soc., Perkin Trans. 1 1990, 699.
(15) Takano, S.; Moriya, M.; Ogasawara, K. Tetrahedron: Asymmetry
1992, 3, 681.
(16) Witte, J. F.; McClard, R. W. Tetrahedron Lett. 1991, 32, 3927.
(17) (a) Guillerm, G.; Varkados, M.; Auvin, S.; Le Goffic, F. Tetrahedron
Lett. 1987, 28, 535. (b) Goli, D. M.; Cheesman, B. V.; Hassan, M. E.;
Lodaya, R.; Slama, J. T. Carbohydr. Res. 1994, 219. (c) Blanco, M. J.;
Sardina, F. J. J. Org. Chem. 1998, 63, 3411.
(22) For reviews, see: (a) Streith, J.; Defoin, A. Synthesis 1994, 1107.
(b) Streith, J.; Defoin, A. Synlett 1996, 189.
(23) (a) Behr, J.-B.; Defoin, A.; Streith, J. Heterocycles 1994, 37, 747.
(b) Behr, J.-B.; Defoin, A.; Mahmood, N.; Streith, J. HelV. Chim. Acta 1995,
78, 1166.
(24) Defoin, A.; Sifferlen, T.; Streith, J. Synlett 1997, 1294.
(25) (a) Defoin, A.; Pires, J.; Streith, J. Synlett 1991, 417. (b) Behr, J.-
B.; Defoin, A.; Pires, J.; Streith, J.; Macko, L.; Zehnder, M. Tetrahedron
1996, 52, 3283. (c) Hussain, A.; Wyatt, P. B. Tetrahedron 1993, 49, 2123.
(26) Solladie´, G.; Ruiz, P.; Colobert, F.; Carren˜o, M. C.; Garc´ıa-Ruano,
J. L. Synthesis 1991, 1011.
(27) (a) Kirby, G. W.; Sweeny, J. G. J. Chem. Soc., Chem. Commun.
1973, 704. (b) Keck, G. E.; Fleming, St. A. Tetrahedron Lett. 1978, 4763.
(28) To a solution of diene 1 (2.7 g, 13.00 mmol) and Bu4NIO4 (2.9 g,
6.00 mmol) in CH2Cl2 (20 mL, with ca. 50 beads of 4 Å molecular sieves)
at -78 °C was added within 1 h, portionwise, hydroxamic acid (3.3 g,
19.00 mmol) in CH2Cl2 (10 mL). The mixture was warmed to 0 °C and
stirred for 2 h. Then the mixture was cooled at -78 °C, and new portions
of Bu4NIO4 (6.00 mmol) and hydroxamic acid (19.00 mmol) were added.
After stirring for 2 h at 0 °C, the mixture was poured into CH2Cl2 (20 mL),
washed with Na2SO3 (10%, 2 × 10 mL) and saturated NaHCO3 (2 × 10
mL), and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were dried over Na2SO4 and evaporated. The residue was purified by flash
chromatography (Et2O:hexane, 3:1), to give [3S,6R,(S)R]-N-benzyloxycar-
bonyl-3,6-dihydro-3-methyl-6-(p-tolylsulfinyl)-2H-1,2-oxazine 3 as a white
solid 2.6 g, 7.01 mmol, 54%); mp ) 195 °C; [R]20 ) +26.1° (c 0.97,
D
1
CHCl3); H NMR (CDCl3) δ 0.89 (d, 3H, J ) 6.9, CH3-C3), 2.40 (s, 3H,
CH3-C6H4), 4.41 (cddd, 1H, J ) 1.3, 2.7, 4.4, 6.9, H-C3), 5.17, 5.23 (system
AB, 2H, J ) 12.2, PhCH2-), 5.61 (ddd, 1H, J ) 1.6, 1.3, 2.7, H-C6), 5.85
(ddd, 1H, J ) 1.3, 1.3, 10.4, H-C5), 5.94 (ddd, 1H, J ) 1.6, 4.4, 10.4,
H-C4), 7.26-7.34 (m, 7H, C6H5- and -C6H4-), 7.60 (system AA′BB′, 2H,
-C6H4-); 13C NMR (CDCl3) δ 17.9 (CH3-C3), 21.3 (CH3-C6H4), 51.1 (C3),
68.0 (PhCH2-), 89.6 (C6), 117.1 (C4), 125.9, 128.1, 128.4, 128.6, 129.3
(HC-arom), 133.7 (C5), 134.8, 135.5, 142.4 (C-arom), 155.1 (CdO).
(29) This interaction, which is similar to the allylic strain, must also be
responsible for the preferred axial orientation of the phenyl group (bulkier
than the methyl one) in N-alkoxycarbonyl derivatives of 3-phenyl 1,4-
thiazanes (Garc´ıa Ruano, J. L.; Martinez, M. C.; Rodriguez, J. H.;
Olefirowicz, E. M.; Eliel, E. L. J. Org. Chem. 1992, 57, 4215).
(18) Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1990, 38, 2712.
(19) Huang, Y.; Dalton J. J. Org. Chem. 1997, 62, 372.
(20) (a) Meyers, A.; Andres, C. J.; Resek, J. E.; McLaughlin, M. A.;
Wooddall, C.-C.; Lee, H. J. Org. Chem. 1996, 61, 2586. (b) Dudot, B.;
Micouin, L.; Baussamne, I.; Royer, J. Synthesis 1999, 688.
3166
Org. Lett., Vol. 2, No. 20, 2000

Scheme 2
Scheme 4
Structurally significant 1H NMR parameters of compound
3 are depicted in Scheme 3. Vicinal coupling constants J3,4
formed into its acetonide 532 by treatment with DMP in
PTSA (rt, 12 h, 89%).
The absolute configuration of compound 5 was unequivo-
cally assigned as S3,S4,S5,R6 by X-ray analysis33 (Figure 1).
On the basis of this assignment the absolute configuration
of diol 4 and cycloadduct 3 can be established.
Scheme 3
The stereochemical course of the HDA reaction can be
explained by considering that the heterodienophile ap-
proaches to the less hindered face of dienesthe one that
(32) [3S,4S,5S,6R]-N-Bencyloxycarbonyl-3,4,5,6-tetrahydro-4,5-dihidroxy-
3-methyl-6-(p-tolylsulfonyl)-1,2-oxazine 4: syrup, [R]20D ) -16.8° (c 0.57,
1
CHCl3); H NMR (CDCl3) δ 1.31 (d, 3H, J ) 7.3, CH3-C3), 2.43 (s, 3H,
CH3-C6H4), 2.85 and 3.78 (2s, each 1H, OH-C4, OH-C5) (exchangeable
with D2O), 3.97 (dd, 1H, J ) 2.7, 2.7, H-C4), 4.46-4.50 (m, 2H, H-C5
and H-C3); 5.01-5.11 (m, 3H, PhCH2- and H-C6), 7.26-7.34 (m, 7H,
C6H5- and -C6H4-), 7.8 (system AA′BB′, 2H, -C6H4-); 13C NMR (CDCl3)
δ 13.9 (CH3-C3), 21.8 (CH3-C6H4-), 56.3 (C3), 62.8 y 69.4 (C4, C5), 67.9
(PhCH2-), 89.1 (C6), 128.0, 128.2, 128.4, 129.1 y 129.7 (HC-arom), 132.8,
135.4, 145.9 (C-arom), 156.1 (CdO). EM (m/q) (id, ie): 422 (100%, M +
1), 378 (84, C19H21NO5S+), 222 (37, C6H8NO6S+), 157 (19, C6H7NO4+).
[3S,4S,5S,6R]-N-Benzyloxycarbonyl-3,4,5,6-tetrahydro-3-methyl-4, 5-(di-
(4.4 Hz) and J5,6 (1.3 Hz) are consistent with the relative
pseudoequatorial and pseudoaxial arrangements for H-3 and
H-6, thus suggesting that the conformation B is the favored
one. This conformational preference can be explained by
assuming the conjugation of the nitrogen with the alkoxy
carbonyl group. This fact determines that the interactions of
their oxygens with the almost eclipsed equatorial substituents
at C-329 shift the conformational equilibrium toward B,
displaying the methyl group in axial orientation, thus forcing
the p-tolylsulfinyl group to adopt an equatorial arrangement.
This would explain the low tendency of compound 3 to give
the sulfoxide-sulfenate rearrangement (it requires the axial
arrangement of the sulfinyl group) in contrast with other
adducts derived from 1-sulfinyldienes.2,3
methylmetilendioxy)-6-(p-tolylsulfonyl)-1,2-oxazine 5: white solid; Tf ) 143
1
°C; [R]20 ) +13.3° (c 0.62, CHCl3); H NMR (CDCl3) δ 1.35 and 1.36
D
(2s, each 3H, C(CH3)2), 1.35 (d, 1H, J ) 7.2, CH3-C3), 2.43 (s, 3H, CH3-
C6H4), 4.16 (dd, 1H, J ) 1.1, 5.0, H-C4), 4.61 (cd, 1H, J ) 1.1, 7.2, H-C3),
4.74-4.81 (m, 2H, H-C5, H-C6), 4.90, 5.00 (system AB, 2H, J ) 12.0,
PhCH2-), 7.19-7.34 (m, 7H, -C6H5 and -C6H4-), 7.83 (system AA′BB′,
2H, -C6H4-); 13C NMR (CDCl3) δ 15.6 (CH3-C3), 21.8 (CH3-C6H4), 26.0
and 27.8 (C(CH3)2), 52.0 (C3), 66.7 and 74.9 (C4, C5), 68.1 (PhCH2-),
90.7 (C6), 110.9 (C(CH3)2), 128.3, 128.4, 128.5, 129.3, 129.7 (HC-arom),
133.4, 135.3, 145.5 (C-arom), 155.4 (CdO). EM (m/q) (id, ie): 462 (100%,
M + 1), 418 (64, C20H20NO7S+), 290 (21; C15H17NO5+), 200 (20, C9H14-
NO4+), 171 (56, C8H13NO3+), 156 (69, C7H8SO2+). HMRS calcd for C23H28-
NO7S 462.158649, found 462.157129.
(33) Crystal structure analysis of 5 (C23H27NO7S): orthorhombic, space
group P212121; a ) 8.776 (15), b ) 15.118 (3), c ) 17.358 (3) Å; V )
2303.1 (7) Å3; Z ) 4; Fcalcd ) 1.366 mg/m3. Crystals were obtained by
slow difussion of hexane into concentrated solution of 5 in Et2O at rt. Crystal
Cis-dihydroxylation of adduct 3, performed with catalytic
amounts of OsO4 in the presence of the N-methylmorpholine
N-oxide, afforded diol 4 (42%) as the only diastereoisomer,
along with a small amount of R,â-unsaturated lactame.30 As
can be seen, the sulfinyl group has been oxidized to sulfone
in this process (Scheme 4). The optical purity of diol 4 is
size: 0.26 × 0.2 × 0.2 mm3. Theta range: 1.79 to 23.32°. µ(Mo KR mm-1
)
) 0.19. T ) 573 K. Reflections collected: 12752. Independent reflections:
3332 (Rint ) 0.0505). Refinement method full-matrix least squares on F2.
Data/restraints/parameters ) 3332/0/293. Goodness-of-fit on F2 ) 0.902.
Final R indices [ I>2σ(I)]: R1 ) 0.0312, wR2 ) 0.0610. R indices (all
data) R1 ) 0.0462, wR2 ) 0.0656. Absolute structure parameter ) 0.09-
(7). Largest diff. peak and hole: 0.106 and 0.135 e Å-3
.
1
almost complete (>98% ee), as established by H NMR
(34) ([2R,3S,4S]-N-Benzyloxycarbonyl-1,4,5-tridesoxy-1,4-imine-2,3-O-
isopropylidene-L-ribitol) 8: syrup; [R]20 ) +36.6° (c 0.03, CHCl3); 1H
studies of its (R)- and (S)-di-MPTA esters,31 which revealed
that both HDA cycloaddition and dihydroxylation have
occurred with total π-facial selectivity. Diol 4 was trans-
D
NMR (CDCl3, rt) δ 1.10 and 1.16 (2d, each 3H, J ) 6.9, CH3-C2 I and II),
1.30 (s, 6H, C(CH3)2), 1.43 (s, 6H, C(CH3)2), 3.45 (dd, 2H, J ) 5.2, 12.9,
H.-C5), 3.84 and 3.91 (2d, each 1H, J ) 12.9, H′-C5 I and II), 4.19 and
4.24 (2c, each 1H, J ) 6.9, H.-C2 I and II), 4.38 (d, 2H, J ) 5.8, H.-C3),
4.75 (dd, 2H, J ) 5.2, 5.8, H.-C4), 5.10, 5.18 (sist. AB, 4H, J ) 12.3,
PhCH2-), 7.30-7.37 (m, 10H, -C6H5); 13C NMR(CDCl3) δ 16.3 and 17.0
(CH3-C2 I and II), 24.8 and 26.8 (C(CH3)2), 50.7 and 50.9 (C5 I and II),
58.9 and 59.2 (C2 I and II), 66.8 (PhCH2-), 85.1 and 85.8 (C4, C3), 111.7
(C(CH3)2), 127.7, 127.9, 128.4 (HC-arom), 138.8 (C-arom), 155.4 and 157.5
(CdO). EM (m/q) (id, ie): 291 (12.76%, M+), 276 (16.07, M - CH3), 91
(100, C7H7+). HRMS (EI) calcd for C16H21NO4 291.147058, found
291.146580. Restricted rotation around the N-CO2Bn bond determines that
(30) A small amount (18%) of N-benzyloxycarbonyl 5-methylpyrrolin-
2(5H)-one was also isolated. Its formation from 3 can be rationalized
according to a similar evolution to that described for Firl and Kresce for
other oxazine derivatives bearing electron-withdrawing groups at C-6, which
are transformed into pyrrolinone derivatives by treating with base (Firl, J.;
Kresce, G. Chem. Ber. 1966, 99, 3695. Defoin, A.; Geffroy, G.; Le Nouen,
D.; Spileers, D.; Streth, J. HelV. Chim. Acta 1988, 71, 1642).
(31) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Yamaguchi, S. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1983; Vol. 1, p 125.
1
the H NMR signals corresponding to Me-C2, H-C5, and H-C2 appear as
a serie of two sets of same intensity signals when the spectrum is registered
at temperature below 50 °C.
Org. Lett., Vol. 2, No. 20, 2000
3167

of the sulfonyl moiety with formation of an unstable
aminoaldehyde, cyclization to the corresponding pyrroline
derivative, and final reduction of the CdN have taken place
in only one synthetic step (Scheme 5).
Scheme 5
Figure 1. Structure of 5 in the crystal.
supports the lone electron pair at sulfurswith the sulfinyl
group in a s-trans arrangement with respect to C(1)dC(2).
The same approach has also been suggested to explain the
results obtained in other 1-sulfinyl diene reactions with
dienophiles such as N-methylmaleimide and maleic anhy-
dride,2 or heterodienophiles as 4-methyl-1,2,4-triazoline-3,5-
dione.3 In these cases, electrostatic repulsion between the
carbonyl and sulfinyl oxygens in the transition structure was
invoked to justify the higher reactivity of the s-trans
conformation of the sulfinyl oxygen. However, the fact that
such a conformation was also required to explain the results
of the nitroso derivatives suggests it could be highly preferred
(or the most reactive one) for 1-sulfinyl dienes, regardless
of the possible interactions present in the transition structure
with other groups present at dienophiles and heterodieno-
philes. The reasons for this preference are not easily
understandable.
Concerning the stereochemical course observed for the cis-
hydroxylation step, the attack of the reagent from the opposite
face of the double bond to that containing the methyl and
SOTol groups (see Scheme 4) must be clearly favored from
a steric point of view.
The transformation of the 1,2-oxazine 5 into pyrrolidine
7 was performed with H2 in the presence of Pd/C as the
catalyst (rt, 1 h). Hydrogenolysis of the benzyl residue
followed by decarboxylation of the resulting carbamic acid
afforded 1,2-oxazine 6, which can be isolated in 72% yield.
Subsequent reaction of this compound with the reducing
agent afforded directly pyrrolidine 7. This can be explained
by assuming that hydrogenolysis of the N-O bond, removal
As dihydroxypyrrolidine 7 is difficult to purify (isolated
yield 23%), it was characterized as its N-benzyloxycarbonyl
derivative 8.34 Finally we have found reaction conditions that
allow a one-pot transformation of 5 into 8. Hydrogenolysis
of 5 for 8 h at rt, followed by treatment with benzyl
chloroformate in aqueous NaHCO3 (0 °C, 1 h), afforded
dihydroxypyrrolidine 8 in 96% yield.
In summary, we have reported the first asymmetric HDA
reaction of 1-sulfinyldienes with acylnitroso derivatives.
Diene 1 evolves with benzyl nitrosoformate under very mild
conditions (contrasting with the low reactivity exhibited with
homodienophiles) with complete regioselectivity and ste-
reoselectivity to afford enantiomerically pure 2H-1,2-oxazine
3. Dihydroxylation followed by hydrogenolysis of the
N-benzyloxycarbonyl 6-sulfonyl-1,2-oxazine ring provides
an easy new access to optically pure dihydroxypyrrolidines.
In this paper we have applied this sequence to prepare
compound 8. The use of different 1-sulfinyldienes, as well
as the application of other dihydroxylation procedures, to
obtain a variety of dihydroxypyrrolidines, are currently in
progress.
Acknowledgment. We thank the DGICYT (Grants PB98-
0078) and JCYL (VA07/00B) for financial support. We thank
Dr. Daniel Miguel for structural elucidation.
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Org. Lett., Vol. 2, No. 20, 2000