γ-Chiral β-ketosulfones in asymmetric synthesis: A unified synthetic strategy for enantiopure γ-amino and γ-hydroxy vinyl sulfones

Article abstract of DOI:10.1016/S0957-4166(98)00235-3

Enantiopure γ-hydroxy and γ-amino vinyl sulfones have been prepared in a short synthetic sequence from the chiral pool derived γ-acetoxy/amino β- ketosulfones.

Full text of DOI:10.1016/S0957-4166(98)00235-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2311–2316
γ-Chiral β-ketosulfones in asymmetric synthesis: a unified
synthetic strategy for enantiopure γ-amino and γ-hydroxy vinyl
sulfones
∗
Saumitra Sengupta, Debarati Sen Sarma and Somnath Mondal
Department of Chemistry, Jadavpur University, Calcutta 700 032, India
Received 20 April 1998; accepted 11 June 1998
Abstract
Enantiopure γ-hydroxy and γ-amino vinyl sulfones have been prepared in a short synthetic sequence from the
chiral pool derived γ-acetoxy/amino β-ketosulfones. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
1
In recent years, γ-chiral vinyl sulfones have evolved as useful chiral probes. γ-Hydroxy vinyl sulfones
1
c
1d
have been extensively studied in this regard and through the pioneering works of Isobe and Fuchs and
2,3
of late, by Carretero and others, these synthons have shown impressive degrees of diastereoselection
1,2-asymmetric induction) in conjugate additions of organometallic and other heteroatomic nucleophiles
(
to their enesulfone moiety. Such diastereoselective features have also found elegant use in several natural
product syntheses. γ-Amino vinyl sulfones, the rational congeners, are equally interesting chiral probes
4
and by analogy with vinylogous amino acid esters, promise rich dividends in asymmetric synthesis.
5
However, while γ-amino vinyl sulfones are altogether unknown, synthetic studies with γ-hydroxy
vinyl sulfones are restricted only to the racemic series due to the lack of a convenient and general
synthetic repertoire for their enantiopure synthesis. Only recently, have a few enantiopure syntheses of
γ-hydroxy vinyl sulfones appeared in the literature viz. lipase mediated resolution of racemic γ-hydroxy
6
a
6b
vinyl sulfones, regioselective dehydration of homochiral β,γ-dihydroxy sulfones and Peterson-
3
a
olefination of enantiopure α-alkoxy aldehydes which however suffer from lengthy sequences and/or
are specific for a few substrate types. In order to enhance the overall appeal of γ-chiral vinyl sulfones
in EPC synthesis, new synthetic methodologies need to be developed which would not only broaden
the repertoire for enantiopure γ-hydroxy vinyl sulfones but would also provide access to a wide variety
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00235-3

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S. Sengupta et al. / Tetrahedron: Asymmetry 9 (1998) 2311–2316
of enantiopure γ-amino vinyl sulfones. In a program directed towards synthetic utilities of enantiopure
7
γ-chiral-β-ketosulfones, we had the opportunity to address these propositions and present herein an
unified chiral-pool strategy that leads to the enantiopure synthesis of both γ-hydroxy and γ-amino vinyl
sulfones.
2. Results and discussion
8
Our synthetic strategy was designed according to the Julia-protocol in which enantiopure γ-acetoxy
and γ-amino-β-ketosulfones upon reduction followed by dehydration, were envisaged to produce the
respective γ-chiral vinyl sulfones in a short synthetic sequence. In the event, we started from the γ-
acetoxy and γ-amino-β-ketosulfones 1 and 2 which were readily prepared in high yields starting from
the chiral pool derived enantiopure α-acetoxy and α-amino diazoketones, respectively, via sequential
7
a
treatment with 47% HBr and NaSO Tol, according to our recently published procedure. Alternatively,
2
the γ-amino-β-ketosulfones 2 could also be prepared through low temperature condensation of N–CO Et
2
9
protected amino acid esters with α,α-dilithio methyl tolyl sulfone. Borohydride reduction of 1 and
2
was found to be anti-selective, as expected for chelation controlled reductions and produced the
respective β-hydroxy sulfones 3 and 4 as diastereomeric mixtures (anti:syn≥75:35) which, without
further purification, were subjected to dehydration with excess MsCl in pyridine to give the γ-acetoxy
and γ-amino vinyl sulfones 5 and 6 in good overall yields (Scheme 1, Table 1). For reasons not clear to
us, dehydrations in the γ-acetoxy series were found to be much slower (ca. 36 h) and required a larger
excess of MsCl than that needed in the γ-amino series. Moreover, in both cases, the putitive mesylate
intermediate could not be isolated or observed in TLC-monitoring of these reactions. The γ-acetoxy vinyl
sulfones 5a–c were subsequently hydrolyzed with LiOH in THF–H O at room temperature (preferred
2
over KOH in MeOH) to give the corresponding γ-hydroxy vinyl sulfones 7a–c in high yields (Table 1).
Scheme 1. (i) NaBH
4
, THF–MeOH, 0°C; (ii) MsCl, Py, RT; (iii) LiOH·2H
2 2
O, THF–H O, RT

S. Sengupta et al. / Tetrahedron: Asymmetry 9 (1998) 2311–2316
2313
Table 1
Synthesis of enantiopure γ-hydroxy and γ-amino vinyl sulfones (Scheme 1)
Similarly, the N–CO Et–(S)-proline derived β-ketosulfone 87 upon borohydride reduction (to 9)
a
2
followed by dehydration with MsCl in pyridine smoothly gave rise to the prolyl vinyl sulfone 10 in
72% overall yield (Scheme 2).
Scheme 2. Reaction conditions (i) and (ii) are the same as in Scheme 1
Interestingly, the γ-amino-β-hydroxy sulfones 4 could also be converted to the corresponding vinyl
sulfones via treatment with SOCl /Et N in CH Cl . As shown for 4a,b, dehydration by this latter
2
3
2
2
method produced the γ-amino vinyl sulfones 6a,b in 50–55% yields (Scheme 3), presumably, via
initial in situ formation of the cyclic sulfamidites 1110 followed by Et N induced β-elimination. These
3
seminal examples of dehydrations of 1,2-amino alcohols via cyclic sulfamidites bear close analogy
6
b,11
to the SOCl /Et N induced dehydrations of 1,2-diols via cyclic sulfite formations
and promise
2
3
much broader synthetic ramifications. Indirect support for this hypothesis also comes from the fact that
dehydrations of γ-acetoxy-β-hydroxy sulfones 3 could not be achieved with SOCl /Et N since these
2
3
substrates cannot form any cyclic sulfite intermediates. This also rules out the formation of any β-chloro
sulfone intermediate during dehydrations of 4a,b with thionyl chloride.
2 3 2 2
Scheme 3. (i) SOCl , Et N (5 equiv.), CH Cl , RT
In summary, we have developed a facile new chiral-pool synthesis of enantiopure γ-hydroxy and
γ-amino vinyl sulfones. The methodology is comparable, if not superior, to the existing repertoire
and is attractive on several counts: it involves a short synthetic sequence, is operationally simple and
produces uniformly good overall yields. Moreover, the unified strategy described here which caters to
the enantiopure synthesis of both the γ-hydroxy and γ-amino congeners is expected to greatly enhance
their prospects in EPC synthesis.

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S. Sengupta et al. / Tetrahedron: Asymmetry 9 (1998) 2311–2316
3. Experimental
1
All melting points are uncorrected. IR spectra were taken on a Perkin–Elmer R-297 spectrometer. H
NMR spectra were recorded in CDCl on JEOL FX-100 (100 MHz), Bruker DPX-200 (200 MHz) and
3
DPX-300 (300 MHz) instruments. Optical rotations were measured in CHCl at 25°C on a JASCO DIP-
3
3
60 polarimeter. The γ-acetoxy and γ-amino-β-ketosulfones 1a–c and 2a–d were prepared according to
7
a,9
reported procedures.
3.1. General procedure for the preparation of γ-acetoxy and γ-amino vinyl sulfones 5, 6 and 10
NaBH (1.0 mmol) was added to a solution of the β-ketosulfones 1, 2 or 8 (0.5 mmol) in MeOH:THF
4
(
1:3) (5 ml) at 0°C. After 30 min at 25°C, the reaction was quenched with a few drops of HOAc and
extracted with CH Cl . The organic layer was washed with water, dried and the solvent removed under
2
2
reduced pressure to give the corresponding β-hydroxy sulfones 3, 4 or 9. The latter was dissolved in
pyridine (8 ml) and was treated with MsCl (3.0–5.0 mmol for 3a–c, 1.5–2.0 mmol for 4a–d and 9) and
a catalytic amount of DMAP at 0°C. Stirring was continued at 25°C till completion of reaction (36 h
for 3a–c, 4 h for 4a–d and 9) after which it was diluted with CH Cl (15 ml), washed successively with
2
2
dil. HCl and water and dried. Removal of solvent at reduced pressure followed by chromatography over
silica gel (30–40% EtOAc in pet. ether) gave the respective vinyl sulfones 5a–c, 6a–d and 10 (Table 1).
3
.1.1. (S)-(E)-3-Acetoxy-4-phenyl-1-(p-tolylsulfonyl)but-1-ene (5a)
−1
Mp 63–65°C (pet. ether–EtOAc); [α] −1.7 (c 1.7); IR (Nujol): 1730, 1640, 1450, 1370, 1280 cm ;
D
1
H NMR: 2.0 (s, 3H), 2.40 (s, 3H), 2.97 (m, 2H), 5.66 (m, 1H), 6.40 (dd, 1H, J=1.7, 16 Hz), 6.90 (dd,
1
H, J=4, 16 Hz), 7.26 (m, 7H), 7.72 (d, 2H, J=8 Hz); found: C, 66.16; H, 6.06; C H O S requires C,
19 20 4
66.28 and H, 5.80%.
3
.1.2. (S)-(E)-3-Acetoxy-5-methyl-1-(p-tolylsulfonyl)hex-1-ene (5b)
−1 1
Oil; [α] −26.6 (c 3.0); IR (Nujol): 1730, 1625, 1590, 1450, 1365 cm ; H NMR: 0.91 (d, 3H, J=5
D
Hz), 0.92 (d, 3H, J=5 Hz), 1.60 (m, 3H), 2.06 (s, 3H), 2.44 (s, 3H), 5.52 (m, 1H), 6.44 (dd, 1H, J=1.6,
15 Hz), 6.92 (dd, 1H, J=4, 15 Hz), 7.36 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz); found: C, 60.24; H, 6.63;
C H O S requires C, 61.9 and H, 7.09%.
16
22
4
3
.1.3. (S)-(E)-3-Acetoxy-4-methyl-1-(p-tolylsulfonyl)pent-1-ene (5c)
−1 1
Oil; [α] −14.6 (c 2.7); IR (neat): 1735, 1630, 1590, 1450, 1370 cm ; H NMR: 0.94 (d, 3H, J=6
D
Hz), 0.98 (d, 3H, J=6 Hz), 1.85 (m, 1H), 2.06 (s, 3H), 2.47 (s, 3H), 5.29 (m, 1H), 6.36 (dd, 1H, J=1.8, 15
Hz), 6.86 (dd, 1H, J=3.9, 15 Hz), 7.33 (d, 2H, J=8 Hz), 7.73 (d, 2H, J=8 Hz); found: C, 60.70; H, 6.75;
C H O S requires C, 60.81 and H, 6.76%.
15
20
4
3
.1.4. (S)-(E)-3-(Ethoxycarbonyl amino)-4-phenyl-1-(p-tolylsulfonyl)but-1-ene (6a)
−1 1
Mp 105–106°C (pet. ether–EtOAc); [α] −4.0 (c 1.5); IR (Nujol): 3340, 1680, 1280, 1140 cm ; H
D
NMR: 1.17 (t, 3H, J=7 Hz), 2.44 (s, 3H), 2.93 (m, 2H), 4.07 (q, 2H, J=7 Hz), 4.48–4.96 (br m, 2H), 6.33
(dd, 1H, J=1.8, 16 Hz), 6.94 (dd, 1H, J=4, 16 Hz), 7.08–7.30 (m, 7H), 7.73 (d, 2H, J=8 Hz); found: C,
6
4.19; H, 6.09; N, 3.70; C H NO S requires C, 64.34; H, 6.17 and N, 3.75%.
20
23
4

S. Sengupta et al. / Tetrahedron: Asymmetry 9 (1998) 2311–2316
2315
1
3
.1.5. (S)-(E)-3-(Ethoxycarbonyl amino)-5-methyl-1-(p-tolylsulfonyl)hex-1-ene (6b)
−1
Mp 73–74°C (pet. ether–EtOAc); [α] −22.6 (c 1); IR (Nujol): 3200, 1685, 1260, 1150 cm ; H
D
NMR: 0.94 (d, 6H, J=5 Hz); 1.19 (t, 3H, J=7 Hz), 1.3–1.96 (m, 3H), 2.44 (s, 3H), 4.07 (q, 2H, J=7 Hz),
4
7
4
.24–5.00 (br m, 2H), 6.40 (dd, 1H, J=1.8, 16 Hz), 6.86 (dd, 1H, J=4, 16 Hz), 7.32 (d, 2H, J=8 Hz),
.76 (d, 2H, J=8 Hz); found: C, 60.15; H, 7.30; N, 4.12; C H NO S requires C, 60.18; H, 7.37 and N,
17
25
4
.13%.
3
.1.6. (S)-(E)-3-(Ethoxycarbonyl amino)-4-methyl-1-(p-tolylsulfonyl)pent-1-ene (6c)
−1 1
Oil; [α] −10.4 (c 0.5); IR (neat): 3350, 1680, 1250, 1140 cm ; H NMR: 0.88 (d, 3H, J=5 Hz), 0.94
D
(d, 3H, J=5 Hz), 1.18 (t, 3H, J=6 Hz), 1.52–2.16 (m, 1H), 2.44 (s, 3H), 4.09 (q, 2H, J=6 Hz), 4.24–4.48
m, 1H), 4.68 (br d, 1H), 6.44 (dd, 1H, J=1.8, 16 Hz), 6.92 (dd, 1H, J=4, 16 Hz), 7.36 (d, 2H, J=8 Hz),
(
7.78 (d, 2H, J=8 Hz); found: C, 59.01; H, 7.03; N, 4.21; C H NO S requires C, 59.08; H, 7.08 and N,
16 23 4
4.31%.
3
.1.7. (S)-(E)-3-(Ethoxycarbonyl amino)-1-(p-tolylsulfonyl)but-l-ene (6d)
−1 1
Oil: [α] −21.4 (c 2.5); IR (neat): 3345, 1730, 1230, 1140 cm ; H NMR: 1.14 (d, 3H, J=7 Hz), 1.24
D
(t, 3H, J=7 Hz), 2.41 (s, 3H), 4.07 (q, 2H, J=7 Hz), 4.32–4.80 (br m, 2H), 6.38 (dd, 1H, J=1.8, 16 Hz),
6.88 (dd, 1H, J=4, 15 Hz), 7.32 (d, 2H, J=8 Hz), 7.76 (d, 2H, J=8 Hz); found: C, 56.43; H, 6.29; N, 6.60;
C H NO S requires C, 56.56; H, 6.39 and N, 4.71%.
14
19
4
3
.1.8. (S)-(E)-2-[(N-Ethoxycarbonyl) pyrrolidin-2-yl]-1-(p-tolylsulfonyl)ethylene (10)
−1 1
Mp 70–72°C; [α] −37.0 (c 1.0): IR (KBr): 1700, 1260, 1140 cm ; H NMR: 1.22 (t, 3H, J=7 Hz),
D
1.68–2.24 (m, 4H), 2.40 (s, 3H), 4.01 (q, 2H, J=7 Hz), 4.28–4.76 (br m, 1H), 6.28 (dd, 1H, J=1.6, 16 Hz),
.82 (dd, 1H, J=4, 16 Hz), 7.30 (d, 2H, J=8 Hz), 7.74 (d, 2H, J=8 Hz); found: C, 59.41; H, 6.43; N, 4.32;
6
C H NO S requires C, 59.44; H, 6.50 and N, 4.33%.
16
21
4
3.2. General procedure for the hydrolysis of γ-acetoxy vinyl sulfones 5a–c
LiOH·H O (1.5 mmol) was added to a solution of 5a–c (1 mmol) in THF:H O (3:1) (15 ml) and
2
2
was stirred at RT for 36 h. The reaction mixture was then neutralized with dil. HCl and the solvent
removed under reduced pressure. The residue was partitioned between brine and CH Cl , the organic
2
2
layer separated, dried and removed in vacuo. The crude γ-hydroxy vinyl sulfones 7a–c thus obtained were
further purified by chromatography over silica gel (30% EtOAc in pet. ether) or through recrystallization
(Table 1).
3.2.1. (S)-(E)-4-Phenyl-1-(p-tolylsulfonyl)but-1-ene-3-ol (7a)
Mp 174–176°C (pet. ether–EtOAc); [α] +13.3 (c 0.9); IR (KBr): 3460, 1620, 1490, 1450, 1390, 1280
D
−1 1
cm ; H NMR: 1.82 (d, 1H, J=4 Hz), 2.44 (s, 3H), 2.92 (m, 2H), 4.60 (m, 1H), 6.60 (dd, 1H, J=1.8, 15
Hz), 7.04 (dd, 1H, J=4, 15 Hz), 7.28 (m, 7H), 7.78 (d, 2H, J=8 Hz); found: C, 67.23, H, 6.11; C H O S
17
18
3
requires C, 67.55 and H, 5.96%.
3.2.2. (S)-(E)-5-Methyl-1-(p-tolylsulfonyl)hex-1-ene-3-ol (7b)
Mp 102–103°C (pet. ether–EtOAc); [α] +30.5 (c 0.7); IR (Nujol): 3490, 1615, 1590, 1450, 1365,
270 cm ; H NMR: 0.92 (d, 6H, J=7 Hz), 1.40 (m, 2H), 1.80 (br m, 2H), 2.44 (s, 3H), 4.40 (m, 1H),
.56 (dd, 1H, J=1.2, 15 Hz), 6.96 (dd, 1H, J=4, 15 Hz), 7.32 (d, 2H, J=8 Hz), 7.76 (d, 2H, J=8 Hz); found:
D
−1 1
1
6
C, 62.39; H, 7. 38; C H O S requires C, 62.68 and H, 7.46%.
14
20
3

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S. Sengupta et al. / Tetrahedron: Asymmetry 9 (1998) 2311–2316
3.2.3. (S)-(E)-4-Methyl-1-(p-tolylsulfonyl)pent-1-ene-3-ol (7c)
Mp 50–52°C (pet. ether–EtOAc); [α] +36.8 (c 1.3); IR (KBr): 3510, 1620, 1590, 1450, 1400, 1300
D
−1 1
cm ; H NMR: 0.91 (d, 3H, J=7 Hz), 0.94 (d, 3H, J=7 Hz), 1.85 (m, 2H), 2.44 (s, 3H), 4.19 (m, 1H),
.59 (dd, 1H, J=1.8, 15 Hz), 6.97 (dd, 1H, J=4, 15 Hz), 7.33 (d, 2H, J=8 Hz), 7.76 (d, 2H, J=8 Hz); found:
C, 61.13; H, 7.23; C H O S requires C, 61.41 and H, 7.08%.
6
13
18
3
Acknowledgements
Professor B. H. Lipshutz is warmly thanked for helpful discussions. Financial supports from CSIR
01/1371/EMR-II/95) and JU (senior research fellowships to D.S.S and S.M) are gratefully acknowl-
(
edged.
References
1. Reviews: (a) Simpkins, N. S. Sulfones in Organic Synthesis, Pergamon Press, Oxford, 1993; (b) Simpkins, N. S.
Tetrahedron 1990, 46, 6951; (c) Isobe, M. In Perspectives in the Organic Chemistry of Sulfur, Zwanenberg, D.; Klunder,
A. J. H., Eds., Elsevier, New York, 1987, Vol. 28, p. 209; (d) Fuchs, P. L.; Braish, T. F. Chem. Rev. 1986, 86, 903.
. (a) Carretero, J. C.; Arrayas, R. G.; de Gracia, I. S. Tetrahedron Lett. 1997, 38, 8537; (b) Alonso, I.; Carretero, J. C.;
Garrido, J. L.; Magro, V.; Pedregal, C. J. Org. Chem. 1997, 62, 5682; (c) Adrio, J.; Carretero, J. C.: Arrayas, R. G.
Synlett 1996, 640; (d) Carretero, J. C.; Arrayas, R. G. J. Org. Chem. 1995, 60, 6000; (e) Dominguez, E.; Carretero, J. C.
Tetrahedron 1994, 50, 7557 and previous references cited therein.
2
3. (a) Enders, D.; Jandeleit, B.; von Berg, S. Synlett 1997, 421; (b) Jackson, R. F. W.; Turner, D.; Block, M. H. ibid, 1997,
789; (c) Holzapfel, C. W.; van der Merwe, T. L. Tetrahedron Lett. 1996, 37, 2303; (d) Jackson, R. F. W.; Stander, S. P.;
Clegg, W. ibid, 1991, 32, 5393; (e) Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1990, 112, 9601.
4
. For some recent studies, see (a) Kauppinen, P. M.; Koskinen, A. M. P. Tetrahedron Lett. 1997, 38, 3103; (b) Reetz, M. T.;
Strack, T. J.; Mutulis, F.; Goddard, R. ibid, 1996, 37, 9293; (c) Schreiner, E. P.; Gstach, H. Synlett 1996, 1131; (d) Koskinen,
A. M. P. Pure Appl. Chem. 1995, 67, 1031; (e) Plummer, J. S.; Emery, L. A.; Stier, M. A.; Suto, M. J. Tetrahedron Lett.
1993, 34, 7529.
5
6
7
. There is a solitary report on an enantiopure γ-amino vinyl sulfonate that has been used in peptidomimetic studies: Gennari,
C.; Salom, B.; Potenza, D.; Williams, A. Angew. Chem. lnt. Ed. Engl. 1994, 33, 2067.
. (a) Carretero, J. C.; Dominguez, E. J. Org. Chem. 1992, 57, 3867; (b) Kang, S.-K.; Park, Y.-W.; Kim, S.-G.; Jeon, J.-H. J.
Chem. Soc., Perkin Trans. 1 1992, 405.
. (a) Sengupta, S.; Sen Sarrna, D.; Mondal, S. Synth. Commun. in press; (b) Sengupta, S.; Sen Sarrna, D.; Mondal, S.
Tetrahedron in press.
8
9
. Julia, M.; Launay, M.; Stanico, J. P.; Verpeaux, J. N. Tetrahedron Lett. 1982, 23, 2465.
. Lygo, B. Synlett. 1992, 723.
10. Lohray, B. B. Synthesis 1992, 1035.
11. (a) Clayden, J.; Nelson, A.; Warren, S. Tetrahedron Lett. 1997, 38, 3471; (b) Sharpless, K. B.; Bennani, Y. L. ibid, 1993,
34, 2083.