γ-Amino vinyl sulfoxides in asymmetric synthesis. Synthesis of optically pure α-substituted β-amino nitriles

Article abstract of DOI:10.1016/j.tet.2008.10.037

The synthesis of optically pure (E)- and (Z)-γ-amino vinyl sulfoxides derived from commercially available protected α-amino esters is reported. Hydrocyanation of the double bond with Et₂AlCN is completely stereoselective and provides enantiomer

Full text of DOI:10.1016/j.tet.2008.10.037

Tetrahedron 65 (2009) 357–363
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
g
-Amino vinyl sulfoxides in asymmetric synthesis. Synthesis of optically
pure
a-substituted
b-amino nitriles
,
a
a
Ricardo Alfaro a, Francisco Yuste a , Benjamın Ortiz , Ruben Sanchez-Obregon ,
*
´
´
´
´
b,
*
´
´
Jose L. Garcıa Ruano
a
´
´
´
´
´
Instituto de Quımica, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Cd. Universitaria, Coyoacan 04510, Mexico D.F., Mexico
Departamento de Qu´ımica Organica (C-1), Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
b
´
´
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of optically pure (E)- and (Z)-g-amino vinyl sulfoxides derived from commercially available
Received 16 September 2008
Received in revised form 13 October 2008
Accepted 15 October 2008
Available online 18 October 2008
protected
stereoselective and provides enantiomerically pure
of the configuration at the -carbon being exerted by the sulfinyl group.
Ó 2008 Elsevier Ltd. All rights reserved.
a
-amino esters is reported. Hydrocyanation of the double bond with Et2AlCN is completely
a
-substituted -amino nitriles with complete control
b
a
1. Introduction
2. Results and discussion
g
-Chiral vinyl sulfones are known to be useful chiral probes.1 In
Given that vinyl sulfoxides can be prepared by sequential re-
particular,
g
-oxygenated vinyl sulfones are versatile intermediates
duction and dehydration of
be easily obtained from esters, we envisioned the generation of (E)-
-amino -unsaturated sulfoxides via the synthetic sequence
b-keto sulfoxides, which in its turn can
in asymmetric synthesis mainly because they undergo highly
stereoselective conjugate addition of a large variety of nucleo-
g
a,b
philes.2
g
-Chiral vinyl sulfoxides are also interesting chiral
depicted in Scheme 1. As starting materials we have used the com-
mercially available enantiopure amino esters 1. The reaction thereof
with (R)-(þ)-methyl p-tolyl sulfoxide and LDA at ꢀ78 ꢁC, afford the
intermediates in which the sulfoxide moiety can transfer chiral
information in subsequent asymmetric transformations. In this
connection, several recent reports describe the preparation of op-
g
-amino-b
-keto sulfoxides 2.6 The reduction of 2 with NaBH4
tically pure
g
-oxygenated
a,
b
-unsaturated sulfoxides3 and the use
produced mixtures of the b-hydroxy sulfoxide diastereoisomers 3
thereof as intermediates for stereocontrolled carbon–carbon bond
formation reactions in the synthesis of optically active natural
products and bioactive molecules.4 In contrast, much less attention
O
O
O
S
OH
R2
O
S
has been devoted to
To the best of our knowledge, there is only one report concerning
the synthesis of chiral
-amino vinyl sulfones,5 which, however,
does not mention the potential synthetic utility of these species.
-Amino vinyl sulfoxides, which are potentially very interesting
g-nitrogenated vinyl sulfones and sulfoxides.
R1
R1
(i)
(ii)
R1
OMe
R2
R2
g
Tol
Tol
BocHN
BocHN
BocHN
anti syn
66 34
67 33
60 40
68 32
1a (R1=Me, R2=H)
1b (R1=Bn, R2=H)
1c (R1=i-Bu, R2=H)
1d (R1=i-Pr, R2=H)
g
2a (79%)
2b (65%)
2c (89%)
2d (60%)
3a (95%)
3b (98%)
3c (73%)
3d (90%)
chiral synthons, do not as yet appear to have been described in the
literature. In this article, we describe the synthesis of several
examples of both double bond isomers of such compounds. The
reactivity and synthetic utility of these compounds is illustrated by
their reaction with Et2AlCN, which has led to the generation of
MeSO2O
O
S
O
S
R1
BocHN
R1
(iv)
(iii)
enantiomerically pure
nitriles.
a
-methylsulfinyl substituted
b-amino
R2
R2
Tol
Tol
BocHN
4a
5a (77%)
5b (77%)
5c (61%)
5d (47%)
4b
4c
4d
* Corresponding authors. Tel.: þ52 55 5622 4406; fax: þ52 55 5616 2217 (F.Y.);
tel.: þ34 91 497 4701; fax: þ34 91 497 3966 (J.L.G.R.).
E-mail addresses: yustef@servidor.unam.mx (F. Yuste), joseluis.garcia.ruano@
Scheme 1. Reagents and conditions: (i) (þ)-(R)-p-TolSOMe, LDA, THF, ꢀ78 ꢁC. (ii)
NaBH4, MeOH, ꢀ78 ꢁC. (iii) MeSO2Cl, Et3N, CH2Cl2, 25 ꢁC. (iv) t-BuOK, DMSO, 25 ꢁC.
´
uam.es (J.L. Garcıa Ruano).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.037

358
R. Alfaro et al. / Tetrahedron 65 (2009) 357–363
O
S
R1
BocHN
O
O
R1
R1
R1
R2
O
(i)
H
(ii)
OMe
S
Tol
R2
R2
+
R2
Tol
BocHN
BocHN
BocHN
1a (R1=Me, R2=H)
1b (R1=Bn, R2=H)
1c (R1=i-Bu, R2=H)
1d (R1=i-Pr, R2=H)
5a (25%)
5b (27%)
5c (17%)
5d (27%)
5e (15%)
5f (9%)
6a (93%)
6b (95%)
6c (98%)
6d (95%)
ent-6a (92%)
ent-6b
7a (46%)
7b (36%)
7c (51%)
7d (55%)
7e (45%)
7f (41%)
ent-1a (R1=H, R2=Me)
ent-1b (R1=H, R2=Bn)
Scheme 2. Reagents and conditions: (i) DIBAH, CH2Cl2, ꢀ78 ꢁC. (ii) (þ)-(S)-p-TolSOCH2PO(OMe)2, n-BuLi, THF, ꢀ78 ꢁC/ 25 ꢁC.
(anti/synꢂ68:32) in high yields. Treatment of the so produced
mixtures of 3 with Et3N (2 equiv) and MsCl (2 equiv) in CH2Cl2 at
room temperature gave the mesylates 4, which, without further
purification, were subjected to the next reaction. The reaction of 4
with t-BuOK (1 equiv) in DMSO at room temperature gave the
(E)-vinyl sulfoxides 5 exclusively in high yields. Since the stereo-
chemistry of the double bond is not dependent on the configuration
of the hydroxyl group of the precursor, neither the stereoselective
reduction of the keto sulfoxides nor the isolation and separation of
the epimeric mesylates derived there from is necessary.
The reaction of the (E)-alkenyl sulfoxides 5a–d with Et2AlCN in
THF at room temperature afforded the -amino nitriles 8a–d as the
b
only diastereoisomers (Scheme 4). Hydrocyanation of the (Z) olefins
7a–d under identical conditions gave the epimeric nitriles 9a–d ex-
clusively, with quite different NMR spectra. Both the reactivity of the
(E) olefins and the hydrocyanation yields of them are slightly higher
than that observed for the (Z) isomers. The (E) isomers required
2.5–3 h for completion whereas 5–6 h was necessary for the
transformation of the (Z) isomers (Scheme 4). Similar trends were
observed in our previously reported vinyl sulfoxide hydrocyanation
reactions,10b which suggested a similar mechanism, based on the
assumption that the sulfinyl group is the stereochemical controlling
group. To confirm this assumption, we also studied the reaction of 7e
and 7f, the epimers of 7a and 7b at the amine carbon, with Et2AlCN.
These reactions were also completely stereoselective, only one
compound (9e or 9f) being obtained in each case (Scheme 4).
The (Z)-vinyl sulfoxides 7 were prepared by a Horner–Wittig
reaction of the N-Boc protected a-amino aldehydes 6, which were
obtained by DIBAH reduction (ꢀ78 ꢁC in CH2Cl27) of the commer-
cially available amino esters 1 (Scheme 2). Given the rather low
configurational stability of 6, these intermediates were prepared
and used immediately as crude products. Thus, reaction of 6 with
the lithio derivative of (þ)-(S)-dimethylphosphorylmethyl p-tolyl
sulfoxide8 directly afforded mixtures of the (E) and (Z) double bond
isomers 5 and 7, usually in good combined yields. Chromatographic
separation of these mixtures provided moderate yields of the de-
sired, major (Z)-7 isomers.
CN
O
S
O
S
CN
(R)
R1
R1
(S)
(ii)
(S)
(i)
(S)
Bn
SO2Tol
(S)
H
(8b)
H
Tol
Tol
BocHN
BocHN
H
BocHN
With the (E)- and (Z)-g-amino vinyl sulfoxides in hand,
5a (R1=Me)
5b (R1=Bn)
5c (R1=i-Bu)
5d (R1=i-Pr)
8a (66%)
8b (64%)
8c (69%)
8d (43%)
exploration of the reactivity of these entities was undertaken.
Hydrocyanation of double bonds is a highly interesting trans-
formation, which permits the formal direct conversion of alkenes
into carboxylic acid derivatives.9 We have recently reported the
highly stereoselective hydrocyanation of vinyl sulfoxides using
Et2AlCN.10 In those reactions, the sulfinyl group functioned to
control the intramolecular hydrocyanation stereoselectivity by
virtue of its prior association with the reagent (Et2AlCN) in a chair-
like transition state (Scheme 3).10b The application of this reaction
10b (80%)
R1
CN
O
CN
R1
S
(i)
(ii)
(S)
(S)
Bn
SO2Tol
H
S
(R)
(R)
Tol
O
(9b)
BocHN
H
H
Tol
BocHN
BocHN
7a (R1=Me)
7b (R1=Bn)
7c (R1=i-Bu)
7d (R1=i-Pr)
9a (30%)
to compounds 5 and 7 was expected to provide b-amino nitriles
9b (50%)
9c (45%)
9d (20%)
11b (78%)
containing two chiral centers, the synthetic usefulness of which as
chiral synthons is obvious. The stereochemical outcome of the
hydrocyanation of these vinyl sulfoxides is not necessarily pre-
dictable, however, because of the presence of an additional chiral
center, i.e., the Boc-amine bearing carbon atom.
CN
O
CN
H
(i)
(ii)
(R)
(R)
H
S
H
SO2Tol
R1
S
O
(R)
(R)
Tol
(9f)
BocHN
R1
Bn
Tol
BocHN
BocHN
7e (R1=Me)
7f (R1=Bn)
9e (60%)
9f (40%)
H
Et
NC
R2
11f (78%)
NC
R1
R1
O
O
(R)
Al
Tol
Tol
Scheme 4. Reagents and conditions: (i) Et2AlCN, THF, 0 ꢁC/ 25 ꢁC. (ii) MCPBA, CH2Cl2,
S
S
25 ꢁC.
Et
H
R2
R1
O
Et2AlCN
Tol
The absolute configuration of the b
-cyano sulfoxide 8a11 was
unequivocally assigned as (1S,2S,RS) by an X-ray diffraction study
(Fig. 1). The configuration of this nitrile at C-2 is S, predicted by the
mechanism depicted in Scheme 3.
The configuration of nitriles 9b and 9f at C-2 was determined by
chemical correlation with 8b. The MCPBA oxidation to the sulfones
10b, 11b, and 11f gave the results indicated in Scheme 4. The
S
H
R2
R1
O
S
NC
Al
Et
Et
Tol
R2
Scheme 3.

R. Alfaro et al. / Tetrahedron 65 (2009) 357–363
359
3.2.1. (3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-1-(p-tolylsulfinyl)-
2-butanone 2a6
Obtained from 4.06 g (20 mmol) of 1a. The crystalline crude
product was purified by crystallization from CH2Cl2–hexane to give
4.31 g of 2a. The mother liquors were purified by column chroma-
tography eluting with hexane–EtOAc 35:65 to produce, additionally,
0.82 g of 2a (79% yield). White crystals, mp 103–104 ꢁC; [
(c 1, CHCl3), de>97%; IR (CHCl3) nmax: 3437, 2984, 2931, 1706, 1496,
1370, and 1054 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
1.24 (d, 3H, J 7.2),
a
]
D þ183.9
d
1.43 (s, 9H), 2.42 (s, 3H), 3.78 and 4.13 (AB system, 2H, J 13.8), 4.20 (m,
1H), 5.25 (m, 1H, interchangeable with D2O), 7.34–7.57 (AA0BB0
system, 4H); 13C NMR (CDCl3, 75 MHz):
d 16.1, 21.4, 28.3, 56.0, 65.5,
Figure 1. X-ray structure of compound 8a.
80.3,124.1,130.1,140.2,142.4,155.0, 201.5; EIMS m/z 326 (2%, Mþþ1),
144 (100), 140 (74), 88 (36), 57 (98), 44 (84).
configuration of 10b is known (2S,3S) because it is derived from 8b.
Compound 11f is the enantiomer of 10b and therefore it must be
assigned as (2R,3R). Finally, 11b is a diastereoisomer of 11f and
therefore must be assigned as (2S,3R) since the starting amino
esters have the opposite configuration. This shows that the con-
figuration at C-2 induced in the hydrocyanation is the same starting
from compounds with different configurations at the nitrogen
bearing carbon (7a,b vs 7e,f), which means that it is the sulfur,
which completely controls the stereoselectivity of the reaction,
regardless the configuration at the second chiral center. The
mechanism indicated in Scheme 3 also explains the observation
that the configuration of the center created in the hydrocyanation
changes with the stereochemistry of the double bond. It confirms
that 11f is an enantiomer of 10b (starting products differ in ste-
reochemistry of the double bond and in the configuration at
nitrogenated carbon) and diastereoisomer of 11b (starting products
differ only in the stereochemistry of the double bond).
3.2.2. (3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-4-phenyl-1-
(p-tolylsulfinyl)-2-butanone 2b
Obtained from 12.0 g (43 mmol) of 1b. The crystalline crude
product was purified by crystallization from CH2Cl2–hexane to give
5.57 g of 2b. The mother liquors were purified by column chroma-
tography eluting with hexane–EtOAc 40:60 to produce, additionally,
5.63 g of 2b (65% yield). White crystals, mp 134–135 ꢁC; [
(c 1, CHCl3), de>97%; IR (KBr) nmax: 3384, 2972, 1720, 1691, 1602,
1513,1165, and 1043 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
1.38 (s, 9H),
a]
D þ140.3
d
2.41 (s, 3H), 2.87 (dd, 1H, J 8.1 and 14.1), 3.07 (dd, 1H, J 5.7 and 14.1),
3.71 and 4.05 (AB system, 2H, J 14.1), 4.31 (dd,1H, J 7.2 and 13.5), 5.18
(br d, 1H, interchangeable with D2O), 7.05–7.16 (m, 2H), 7.20–7.34
(m, 5H), 7.45–755 (m, 2H); 13C NMR (CDCl3, 75 MHz):
d 21.4, 28.2,
36.3, 61.4, 66.0, 80.2, 124.1, 126.9, 128.6, 129.3, 130.0, 136.2, 139.9,
142.2,155.2, 200.8; EIMS m/z 402 (2%, Mþþ1), 220 (72),164 (80),139
(43),120 (100), 91 (22), 57 (60). HMRS (EI): m/z calcd for C22H28NO4S
[Mþ1]: 402.1739; found: 402.1749.
In summary, we have reported the synthesis of the (E)-5 and (Z)-7
g
-amino vinyl sulfoxides of high optical purity from the readily avail-
able N-Boc protected amino esters 1. Reaction of these compounds
with Et2AlCN affords the -amino nitriles 8 and 9 with complete
3.2.3. (3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-5-methyl-1-
(p-tolylsulfinyl)-2-hexanone 2c12
b
control of the configuration being exerted by the sulfinyl group.
Obtained from 9.35 g (38 mmol) of 1c. The crystalline crude
product was purified by crystallization from CH2Cl2–hexane to give
8.45 g of 2c. The mother liquors were purified by column
chromatography eluting with hexane–EtOAc 40:60 to produce,
3. Experimental
additionally, 4.01 g of 2c (89% yield). White crystals, mp 112 ꢁC; [
a]
D
3.1. General methods
þ140.0 (c 1, CHCl3), de>97%; IR (CHCl3) nmax: 3439, 2962, 2933,
1707, 1598, 1495, 1369, and 1163 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
Melting points were determined in a Culatti melting point ap-
paratus in open capillary tubes and are uncorrected. All moisture
sensitive reactions were performed in flame-dried glassware
equipped with rubber septa under a positive pressure of argon and
monitored by TLC. Solvents were dried according to literature
procedures. Flash chromatography was performed using silica gel
60 (230–400 mesh ASTM). Optical rotations were measured on
a Perkin–Elmer 343 polarimeter at 20 ꢁC (concentration in g/
100 mL). The IR spectra were recorded on a Nicolet-5SX spectro-
photometer. The 1H and 13C NMR spectra were obtained either on
a Varian Unity 200 or Jeol Eclipse 300 NMR spectrometers at room
temperature on deuterochloroform using TMS as internal standard.
Mass spectra were measured on a Jeol JMS-SX 102A or JMS-AX
505HA mass spectrometers at 70 eV and 190 ꢁC.
d
0.89 (d, 3H, J 6.6), d 0.90 (d, 3H, J 6.6), 1.20–1.35 (m, 1H), 1.43 (s,
9H), 1.60–1.75 (m, 2H), 2.42 (s, 3H), 3.75 and 4.19 (AB system, 2H, J
13.8), 4.10–4.26 (m, 1H), 5.15 (br d, 1H, interchangeable with D2O),
7.33 and 7.58 (AA0BB0 system, 4H); 13C NMR (CDCl3, 75 MHz):
d 21.4,
23.1, 24.7, 28.3, 39.0, 58.7, 66.1, 80.2, 124.3, 130.1, 140.4, 142.3 155.6,
201.9; EIMS m/z 368 (3%, Mþþ1), 312 (10), 186 (65), 140 (38), 130
(98), 86 (100), 57 (63).
3.2.4. (3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-4-methyl-1-
(p-tolylsulfinyl)-2-pentanone 2d
Obtained from 13.04 g (56.45 mmol) of 1d. The crystalline crude
product was purified by crystallization from CH2Cl2–hexane to give
6.58 g of 2d. The mother liquors were purified by column chroma-
tography eluting with hexane–EtOAc 35:65 to produce, additionally,
3.2. Preparation of
b
-keto sulfoxides 2
4.72 g of 2d (57% yield). White crystals, mp 113–114 ꢁC; [
1, CHCl3), de>97%; IR (KBr) nmax: 3272, 2975, 1702, 1594, 1521, 1363,
1275,1163, and 1037 cmꢀ1;1HNMR (CDCl3, 300 MHz):
0.74 (d, 3H, J
a
]D þ226 (c
To a solution of (R)-(þ)-methyl p-tolyl sulfoxide (2 equiv) in THF
(2 mL/mmol) was added dropwise to a solution of LDA (2 equiv) in
THF (2.5 mL/mmol) at ꢀ78 ꢁC. The mixture was stirred at ꢀ78 ꢁC for
2 h. Then, a solution of 1 (1 equiv) in THF (4 mL/mmol) was added
and the resulting mixturewas stirredat ꢀ25 ꢁC for 12 h. The reaction
mixture was decomposed with saturated ammonium chloride so-
lution (2 mL/mmol) and extracted with CH2Cl2 (4ꢃ5 mL/mmol). The
organic phase was washed with brine, dried, and evaporated.
d
6.8), 0.95 (d, 3H, J 6.8),1.44 (s, 9H), 2.18 (m,1H), 2.42 (s, 3H), 3.74 and
4.18 (AB system, 2H, J 14.4), 4.16 (m, 1H), 5.36 (br d, 1H, in-
terchangeable with D2O), 7.33 and 7.59 (AA0BB0 system, 4H); 13C
NMR (CDCl3, 75 MHz):
d 16.8, 19.7, 21.4, 28.2, 29.2, 64.9, 66.7, 80.0,
124.2,130.0,140.2,142.3 155.8, 201.4; EIMS m/z 354 (1%, Mþþ1),172
(75),116 (84), 72 (100), 57 (63). HMRS (EI): m/z calcd for C18H28NO4S
[Mþ1]: 354.1739; found: 354.1726.

360
R. Alfaro et al. / Tetrahedron 65 (2009) 357–363
3.3. Preparation of
b
-hydroxy sulfoxides 3
with D2O), 5.00 (br, 1H, interchangeable with D2O), 7.30 and 7.51
(AA0BB0 system, 4H); 13C NMR (CDCl3, 50 MHz):
19.3, 19.7, 21.4,
d
NaBH4 reduction. To a solution of NaBH4 (1 equiv) in MeOH
28.3, 30.2, 59.6, 60.3, 65.6, 79.1, 124.0, 130.0, 139.0, 141.6, 156.4;
EIMS m/z 355 (3%, Mþ), 282 (14), 183 (46), 160 (69), 139 (75), 116
(82), 72 (100), 57 (83).
(5 mL/mmol) at ꢀ78 ꢁC was added dropwise a solution of
b-keto
sulfoxide 2 (1 equiv) in MeOH (5 mL/mmol) at ꢀ78 ꢁC. The reaction
mixture was stirred for 1 h to completion and the excess of NaBH4
was decomposed by addition of saturated ammonium chloride
solution (5 mL/mmol). The solvents were removed under vacuum
and the residue was treated with a 5% HCl solution (10 mL/mmol)
and extracted with Et2O (3ꢃ10 mL/mmol). The organic phase was
washed with brine, dried, and evaporated.
3.4. Preparation of mesylates 4
To a solution of b-hydroxy sulfoxide 3 (1 equiv) in dry CH2Cl2
(10 mL/mmol) at 0 ꢁC was added dropwise triethylamine (2 equiv).
The mixture was kept for 30 min and then was added dropwise
methanesulfonyl chloride (2 equiv). The reaction mixture was
stirred for 1 h and then was decomposed by the addition of satu-
rated ammonium chloride solution (5 mL/mmol). The organic
phase was separated, washed with brine, dried, and evaporated.
3.3.1. (2S,3S,RS) and (2R,3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-
1-(p-tolylsulfinyl)-2-butanol 3a
Obtained from 1.0 g (3.07 mmol) of 2a. The crude product was
purified by column chromatography eluting with hexane–EtOAc
65:35 to give 0.95 g (95% yield) of 3a as white crystals, mp 99–
101 ꢁC (CH2Cl2–hexane). IR (KBr) nmax: 3362, 2977, 1692, 1510, 1170,
and 1048 cmꢀ1; 1H NMR (CDCl3, 200 MHz) data of the major isomer
3.5. Preparation of (E)-vinyl sulfoxides 5
To a solution of mesylate 4 (1 equiv) in DMSO (10 mL/mmol)
was added dropwise a solution of potassium tert-BuOK (1 equiv) in
DMSO (10 mL/mmol) at 25 ꢁC and the resulting mixture was stirred
for 30 min. Then, the reaction was decomposed with saturated
ammonium chloride solution and extracted with toluene. The or-
ganic phase was separated, washed with brine, dried, and
evaporated.
(2S,3S,RS): d 1.14 (d, 3H, J 6.8), 1.40 (s, 9H), 2.42 (s, 3H), 2.63 (dd,1H, J
1.8 and 13.6), 3.07 (dd, 1H, J 10.0 and 13.6), 3.62 (br s, 1H), 4.07 (ddd,
1H, J 1.8, 4.4, and 10.2), 4.68 (br d, 1H, interchangeable with D2O),
7.35 and 7.51 (AA0BB0 system, 4H); 13C NMR (CDCl3, 50 MHz):
d 15.8,
21.4, 28.4, 50.4, 58.5, 69.6, 79.7,124.1, 130.0, 139.5, 141.7,155.4; EIMS
m/z 327 (3%, Mþ), 265 (15), 263 (17),183 (53),139 (100),132 (75), 88
(34), 57 (94).
3.5.1. (E,3S,RS)-tert-Butyl-1-(p-tolylsulfinyl)but-1-en-3-
ylcarbamate 5a
3.3.2. (2S,3S,RS) and (2R,3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-
4-phenyl-1-(p-tolylsulfinyl)-2-butanol 3b
Obtained from 0.28 g (0.85 mmol) of 3a. The crude product was
purified by column chromatography eluting with hexane–EtOAc
60:40 to give 0.20 g (77% yield) of 5a as white crystals, mp 106–
Obtained from 5.04 g (12.5 mmol) of 2b. The crude product was
purified by column chromatography eluting with hexane–EtOAc
65:35 to give 4.96 g (98% yield) of 3b as white crystals, mp 115–
117 ꢁC (CH2Cl2–hexane). IR (KBr) nmax: 3355, 2978, 1696, 1520, 1170,
1040, and 1021 cmꢀ1; 1H NMR (CDCl3, 300 MHz) data of the major
107 ꢁC (CH2Cl2–hexane). [
a]
þ117 (c 1, CHCl3); IR (KBr) nmax
:
D
3389, 2979, 1706, 1520, 1247, 1166, and 1033 cmꢀ1
;
1H NMR
(CDCl3, 200 MHz): 1.28 (d, 3H, J 6.6), 1.39 (s, 9H), 2.40 (s, 3H),
d
isomer (2S,3S,RS):
d
1.35 (s, 9H), 2.41 (s, 3H), 2.59 (dd, 1H, J 1.6 and
4.50 (b, 2H), 6.30 (dd, 1H, J 1.2 and 15.0), 6.54 (dd, 1H, J 4.6 and
13.5), 2.81–3.07 (m, 2H), 3.16 (dd,1H, J 10.2 and 13.5), 3.58–3.62 (m,
1H), 4.11–4.17 (m, 1H), 4.51 (br d, 1H, interchangeable with D2O),
7.14–7.55 (m, 9H); EIMS m/z 403 (4%, Mþ), 312 (15), 208 (76), 164
(49), 139 (46), 120 (100), 72 (37), 57 (68).
15.0), 7.30 and 7.50 (AA0BB0 system, 4H); 13C NMR (CDCl3,
50 MHz):
d 20.4, 21.4, 28.3, 47.1, 79.8, 125.0, 130.1, 134.3, 140.0,
140.5, 141.7, 154.7; EIMS m/z 310 (1%, Mþþ1), 292 (11), 236 (100),
192 (30), 57 (35). HMRS (EI): m/z calcd for C16H24NO3S [Mþ1]:
310.1477; found: 310.1470.
3.3.3. (2S,3S,RS) and (2R,3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-
5-methyl-1-(p-tolylsulfinyl)-2-hexanol 3c
3.5.2. (E,3S,RS)-tert-Butyl-4-phenyl-1-(p-tolylsulfinyl)but-1-en-3-
ylcarbamate 5b
Obtained from 0.104 g (0.25 mmol) of 3b. The crude product was
purified by column chromatography eluting with hexane–EtOAc
65:35 to give 0.076 g (77% yield) of 5b as white crystals, mp 103–
Obtained from 0.8 g (2.17 mmol) of 2c. The crude product was
purified by column chromatography eluting with hexane–EtOAc
65:35 to give 0.58 g (73% yield) of 3c as white crystals, mp 79–80 ꢁC
(CH2Cl2–hexane). IR (KBr) nmax: 3361, 2955, 1690, 1525, 1174, and
1039 cmꢀ1
;
1H NMR (CDCl3, 200 MHz) data of the major isomer
105 ꢁC (CH2Cl2–hexane). [
a
]
þ116.6 (c 1, CHCl3); IR (KBr) nmax
:
D
(2S,3S,RS):
d
0.87 (d, 3H, J 6.4), 0.91 (d, 3H, J 6.4), 1.20–1.35 (m, 2H),
3371, 2976, 1690, 1514, 1251, 1172, and 1045 cmꢀ1; 1H NMR (CDCl3,
200 MHz): 1.36 (s, 9H), 2.40 (s, 3H), 2.90 (dd, 2H, J 2.8 and 6.2),
4.56 (br, 2H), 6.21 (dd, 1H, J 1.4 and 15.0), 6.53 (dd, 1H, J 9.6 and
15.0), 7.11–7.45 (m, 9H); 13C NMR (CDCl3, 50 MHz):
21.4, 28.2,
1.40 (s, 9H), 1.45–1.70 (m, 1H), 2.43 (s, 3H), 2.67 (dd, 1H, J 1.8 and
13.6), 3.03 (dd, 1H, J 10.2 and 13.4), 3.60 (m, 1H), 4.04 (m, 1H), 4.44
(br d, 1H, interchangeable with D2O), 7.34 and 7.52 (AA0BB0 system,
d
d
4H); 13C NMR (CDCl3, 50 MHz):
d
21.4, 23.6, 24.6, 28.3, 39.2, 53.2,
40.9, 52.4, 80.0, 125.1, 126.9, 128.6, 129.5, 130.0, 135.4, 136.2, 137.3,
140.3, 141.8, 154.8; EIMS m/z 368 (15%, Mþꢀ17), 312 (54), 190 (61),
146 (52), 91 (33), 57 (100).
59.0, 70.1, 79.8, 124.0, 130.1, 139.7, 141.6, 156.3; EIMS m/z 369 (1%,
Mþ), 296 (8), 278 (9), 186 (27), 183 (30), 174 (42), 139 (66), 130 (70),
86 (100), 57 (89).
3.5.3. (E,3S,RS)-tert-Butyl-5-methyl-1-(p-tolylsulfinyl)hex-1-en-3-
ylcarbamate 5c
Obtained from 0.5 g (1.35 mmol) of 3c. The crude product was
purified by column chromatography eluting with hexane–EtOAc
65:35 to give 0.29 g (61% yield) of 5c as white crystals, mp 87–88 ꢁC
3.3.4. (2S,3S,RS) and (2R,3S,RS)-N-(tert-Butoxycarbonyl)-3-amino-
4-methyl-1-(p-tolylsulfinyl)-2-pentanol 3d
Obtained from 0.32 g (0.92 mmol) of 2d. The crude product was
purified by column chromatography eluting with hexane–EtOAc
65:35 to give 0.29 g (90% yield) of 3d as white crystals, mp 173–
175 ꢁC (CH2Cl2–hexane). IR (KBr) nmax: 3317, 2956, 1681, 1532, 1170,
and 1030 cmꢀ1; 1H NMR (CDCl3, 300 MHz) data of the major isomer
(CH2Cl2–hexane). [
2959, 1688, 1510, 1174, and 1046 cmꢀ1; 1H NMR (CDCl3, 200 MHz):
0.93 (d, 6H, J 6.8), 1.23–1.45 (m, 2H), 1.38 (s, 9H), 1.60–1.77 (m, 1H),
a
]D þ115.7 (c 1, CHCl3); IR (KBr) nmax: 3386, 3018,
d
(2S,3S,RS):
d
0.88 (d, 3H, J 6.4), 0.91 (d, 3H, J 6.5), 1.40 (s, 9H), 1.84 (m,
2.40 (s, 3H), 4.42 (br, 2H), 6.31 (d, 1H, J 15.0), 6.50 (dd, 1H, J 4.8 and
1H), 2.42 (s, 3H), 2.66 (dd, 1H, J 1.8 and 13.8), 3.02 (t, 1H, J 9.6), 3.12
(dd, 1H, J 10.5 and 13.8), 4.38 (m, 1H), 4.85 (d, 1H, interchangeable
15.0), 7.29 and 7.50 (AA0BB0 system, 4H); 13C NMR (CDCl3, 75 MHz):
d
21.4, 22.2, 22.6, 24.7, 28.2, 43.8, 49.8, 79.7, 125.1, 130.1, 134.5, 139.6,

R. Alfaro et al. / Tetrahedron 65 (2009) 357–363
361
140.5, 141.7, 155.0; EIMS m/z 334 (7%, Mþꢀ17), 278 (100), 234 (30),
THF (5 mL/mmol) was added. After 5 min, the reaction mixture was
warmed to 25 ꢁC and stirred for 3 h. The reaction mixture was
decomposed with saturated ammonium chloride solution and
extracted with CH2Cl2 (50 mL/mmol). The organic phase was
washed with brine, dried, and evaporated.
190 (19), 57 (51).
3.5.4. (E,3S,RS)-tert-Butyl-4-methyl-1-(p-tolylsulfinyl)pent-1-en-3-
ylcarbamate 5d
Obtained from 0.5 g (1.40 mmol) of 3d. The crude product was
purified by column chromatography eluting with hexane–EtOAc
3.7.1. (Z,3S,RS)-tert-Butyl-1-(p-tolylsulfinyl)but-1-en-3-
ylcarbamate 7a
65:35 to give 0.22 g (47% yield) of 5d as an oil. [
CHCl3); IR (KBr) nmax: 3302, 2967, 1705, 1520, 1170, and 1043 cmꢀ1
1H NMR (CDCl3, 200 MHz):
0.92 (d, 3H, J 7.0), 0.95 (d, 3H, J 6.8),
a]
þ85.0 (c 1,
D
;
Obtained from 0.45 g (2.60 mmol) of 6a. The crude product was
purified by chromatography eluting with hexane–EtOAc 65:35 to
give 0.20 g (25%) of 5a and 0.37 g (46%) of 7a. Isomer 7a, white
d
1.38 (s, 9H), 1.80–1.97 (m, 1H), 2.40 (s, 3H), 4.18 (m, 1H), 4.58 (br d,
1H, interchangeable with D2O), 6.31 (dd, 1H, J 1.2 and 15.0), 6.51
(dd, 1H, J 5.2 and 15.0), 7.29 and 7.50 (AA0BB0 system, 4H); 13C NMR
crystals (CH2Cl2–hexane), mp 123–124 ꢁC. [
a
]
D ꢀ180.3 (c 1, CHCl3);
IR (KBr) nmax: 3266, 2976, 1705, 1534, 1251, 1166, and 1012 cmꢀ1; 1H
NMR (CDCl3, 300 MHz): 1.37 (d, 3H, J 6.9), 1.45 (s, 9H), 2.39 (s, 3H),
(CDCl3, 50 MHz):
d
18.0, 18.8, 21.3, 28.2, 32.3, 56.7, 79.7, 125.1, 130.1,
d
135.6, 137.8, 140.6, 141.8, 155.3; EIMS m/z 338 (5%, Mþþ1), 320 (15),
282 (32), 264 (100), 220 (30),190 (44), 57 (77). HMRS (EI): m/z calcd
for C18H28NO3S [Mþ1]: 338.1790; found: 338.1785.
4.61 (br, 1H, interchangeable with D2O), 5.07 (dd, 1H, J 6.9 and 9.3),
5.92 (t, 1H, J 9.3), 6.14 (dd, 1H, J 0.9 and 9.6), 7.28 and 7.68 (AA0BB0
system, 4H); 13C NMR (CDCl3, 75 MHz):
d
21.3 (2C), 28.4, 45.1, 79.9,
124.6, 129.8, 136.6, 141.0 (2C), 141.7, 154.6.
3.6. Preparation of N-Boc protected amino aldehydes 6
3.7.2. (Z,3S,RS)-tert-Butyl-4-phenyl-1-(p-tolylsulfinyl)but-1-en-3-
ylcarbamate 7b
Obtained from 0.62 g (2.49 mmol) of 6b. The crude product was
purified by chromatography eluting with hexane–EtOAc 70:30 to
give 0.258 g (27%) of 5b and 0.345 g (36%) of 7b. Isomer 7b: white
To a cooled (ꢀ78 ꢁC) solution of the amino ester 1 (1 equiv) in
CH2Cl2 (2 mL/mmol) under argon atmosphere a solution of DIBAH
in hexanes (2.1 equiv) was added dropwise over 20 min. The re-
action mixture was stirred at ꢀ78 ꢁC for 1.5 h and then quenched
with water. It was then allowed to come to 25 ꢁC and the resulting
white precipitate was removed by filtration over Celite. The organic
phase was separated, washed with brine, dried, and concentrated
under reduced pressure yielded the aldehydes 6, which were used
immediately as crude products.
semisolid; [
a]
D ꢀ164.0 (c 1, CHCl3); IR (film) nmax: 3353, 2977, 1697,
1530, 1252, 1166, and 1014 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d
1.42
(s, 9H), 2.39 (s, 3H), 3.01 (m, 2H), 4.65 (br, 1H, interchangeable with
D2O), 5.25 (m, 1H), 5.96 (t, 1H, J 9.6), 6.17 (d, 1H, J 9.6), 7.22–7.38 (m,
7H), 7.63 (br d, 2H); 13C NMR (CDCl3, 75 MHz):
d 21.4, 28.3, 41.1,
49.9, 80.0, 124.5, 127.1, 128.7, 129.5, 129.9, 135.9, 137.5, 139.4, 140.8,
141.1, 154.7.
3.6.1. (S)-N-(tert-Butoxycarbonyl)-2-aminopropanal 6a
White crystals (93% yield), mp 76–77 ꢁC; [
a]
D ꢀ30.1 (c 1, MeOH)
[lit13
[a
]
D ꢀ25.0 (c 1, MeOH)]; 1H NMR (CDCl3, 300 MHz):
d
1.33 (d,
3.7.3. (Z,3S,RS)-tert-Butyl-5-methyl-1-(p-tolylsulfinyl)hex-1-en-3-
ylcarbamate 7c
3H, J 7.2), 1.45 (s, 9H), 4.23 (q, 1H, J 6.9), 5.10 (br s, 1H, in-
terchangeable with D2O), 9.56 (s, 1H).
Obtained from 0.20 g (0.93 mmol) of 6c. The crude product was
purified by chromatography eluting with hexane–EtOAc 65:35 to
3.6.2. (S)-N-(tert-Butoxycarbonyl)-2-amino-3-phenylpropanal 6b
give 0.056 g (17%) of 5c and 0.166 g (51%) of 7c. Isomer 7c: oil; [
ꢀ183.2 (c 1, CHCl3); IR (film) nmax: 3286, 2959, 1705, 1522, 1170, and
1037 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
0.99 (d, 3H, J 6.6), 1.03 (d,
3H, J 6.6), 1.46 (s, 9H), 1.40–1.58 (m, 2H), 1.65–1.80 (m, 1H), 2.40 (s,
3H), 4.55 (br, 1H, interchangeable with D2O), 5.02 (m, 1H), 5.83 (t,
1H, J 9.6), 6.17 (d, 1H, J 9.6), 7.29 and 7.71 (AA0BB0 system, 4H); 13C
a]
D
White crystals (95% yield), mp 104–105 ꢁC; [
a
]
ꢀ37.9 (c 1,
D
MeOH) [lit13
d
[
a
]
D
ꢀ35.7 (c 1, MeOH)]; 1H NMR (CDCl3, 200 MHz):
d
1.43 (s, 9H), 3.11 (d, 2H, J 6.6), 4.42 (m, 1H), 5.02 (br s, 1H, in-
terchangeable with D2O), 7.14–7.36 (m, 9H), 9.63 (s, 1H).
3.6.3. (S)-N-(tert-Butoxycarbonyl)-2-amino-4-methylpentanal 6c
NMR (CDCl3, 75 MHz): d 21.4, 22.5, 22.6, 24.6, 28.4, 44.1, 47.7, 80.0,
124.6, 129.8, 137.3 (2C), 140.4, 140.9, 154.7.
Oil (98% yield); [
a
]
D
ꢀ45.5 (c 1, MeOH) [lit13
[
a]
ꢀ30.0 (c 1,
D
MeOH)]; 1H NMR (CDCl3, 200 MHz):
d 0.96 (d, 6H, J 6.6),1.45 (s, 9H),
1.30–1.80 (m, 3H), 4.25 (m, 1H), 4.90 (br, 1H, interchangeable with
D2O), 9.60 (s, 1H).
3.7.4. (Z,3S,RS)-tert-Butyl-4-methyl-1-(p-tolylsulfinyl)pent-1-en-3-
ylcarbamate 7d
Obtained from 1.0 g (4.97 mmol) of 6d. The crude product was
purified by chromatography eluting with hexane–EtOAc 70:30 to
give 0.452 g (27%) of 5d and 0.922 g (55%) of 7d. Isomer 7d: white
3.6.4. (S)-N-(tert-Butoxycarbonyl)-2-amino-3-methylbutanal 6d
Oil (95% yield); [
a]
ꢀ11.5 (c 1, MeOH) [lit13
[
a
]
ꢀ11.0 (c 1,
D
D
MeOH)]; 1H NMR (CDCl3, 200 MHz):
d
0.95 (d, 3H, J 6.8), 1.03 (d, 3H,
crystals (CH2Cl2–hexane), mp 83–84 ꢁC; [
a
]
D ꢀ208.5 (c 1, CHCl3); IR
(film) nmax: 3258, 2970, 1702, 1533, 1174, and 1011 cmꢀ1 1H NMR
(CDCl3, 300 MHz): 1.03 (d, 3H, J 6.9), 1.06 (d, 3H, J 6.9), 1.47 (s, 9H),
J 6.8), 1.45 (s, 9H), 2.27 (m, 1H), 4.25 (m, 1H), 5.08 (br, 1H, in-
terchangeable with D2O), 9.65 (s, 1H).
;
d
1.82 (m, 1H), 2.39 (s, 3H), 4.64 (br, 1H, interchangeable with D2O),
3.6.5. (R)-N-(tert-Butoxycarbonyl)-2-aminopropanal ent-6a
4.75 (m, 1H), 5.87 (t, 1H, J 9.6), 6.23 (d, 1H, J 9.9), 7.28 and 7.69
White crystals (92% yield), mp 76–77 ꢁC; [
a
]
D þ30.3 (c 1, MeOH)
(AA0BB0 system, 4H); 13C NMR (CDCl3, 75 MHz):
d 18.6, 18.9, 21.4,
[lit14
[
a]
D þ28.53 (c 2.45, MeOH)]; 1H NMR (CDCl3, 200 MHz):
d
1.33
28.4, 32.6, 54.7, 79.8, 124.6, 129.8, 138.5 (2C), 141.0, 141.1, 155.0.
(d, 3H, J 7.2), 1.45 (s, 9H), 4.23 (q, 1H, J 6.9), 5.10 (br s, 1H, in-
terchangeable with D2O), 9.56 (s, 1H).
3.7.5. (Z,3R,RS)-tert-Butyl-1-(p-tolylsulfinyl)but-1-en-3-
ylcarbamate 7e
3.7. Preparation of (Z)-vinyl sulfoxides 7
Obtained from 0.47 g (2.71 mmol) of ent-6a. The crude product
was purified by chromatography eluting with hexane–EtOAc 65:35
to give 0.057 g (15%) of 5e and 0.378 g (45%) of 7e. Isomer 7e: white
To
a
solution of (þ)-(S)-dimethylphosphorylmethyl p-tolyl
sulfoxide8 (1.1 equiv) in THF (10 mL/mmol) was added dropwise
a solution of n-BuLi in hexanes (1.2 equiv) at ꢀ78 ꢁC. The mixture
was stirred at ꢀ78 ꢁC for 30 min. Then, a solution of 6 (1 equiv) in
crystals (CH2Cl2–hexane), mp 79–80 ꢁC; [
NMR (CDCl3, 300 MHz):
a]
D ꢀ262.2 (c 1, CHCl3); 1H
d
1.29 (d, 3H, J 6.9), 1.47 (s, 9H), 2.40 (s, 3H),
4.77 (br, 1H, interchangeable with D2O), 4.87 (m, 1H), 5.99 (m, 1H),

362
R. Alfaro et al. / Tetrahedron 65 (2009) 357–363
6.18 (dd, 1H, J 0.9 and 9.6), 7.31 and 7.53 (AA0BB0 system, 4H); 13C
NMR (CDCl3, 75 MHz): 21.3, 21.4, 28.4, 45.8, 80.2, 124.3, 130.1,
142.1, 155.9; EIMS m/z 379 (10%, Mþþ1), 323 (40), 305 (20), 279
d
(40), 183 (100), 140 (55), 91 (30), 86 (50), 57 (95).
136.9, 140.9, 141.4, 141.5, 154.8.
3.8.4. (2S,3S,RS)-(tert-Butyl)-2-cyano-4-methyl-1-(p-
tolylsulfinyl)pentan-3-ylcarbamate 8d
Obtained from 0.595 g (1.7 mmol) of 5d. The crystalline crude
product was purified by crystallization from CH2Cl2–hexane to give
0.247 g (40% yield) of 8d as white crystals, mp 107–108 ꢁC. [
3.7.6. (Z,3R,RS)-tert-Butyl-4-phenyl-1-(p-tolylsulfinyl)but-1-en-3-
ylcarbamate 7f
Obtained from 0.45 g (1.80 mmol) of ent-6b (Aldrich). The crude
product was purified by chromatography eluting with hexane–
EtOAc 70:30 to give 0.062 g (9%) of 5f and 0.285 g (41%) of 7f.
a]
D
þ71.0 (c 1, CHCl3); IR (film) nmax: 3282, 2972, 2243, 1705, 1525, 1168,
and 1042 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
1.05 (d, 3H, J 6.6), 1.07
Isomer 7f: white crystals (CH2Cl2–hexane), mp 146 ꢁC; [
a]
D ꢀ222.6
d
(c 1, CHCl3); 1H NMR (CDCl3, 300 MHz):
d
1.48 (s, 9H), 2.37 (s, 3H),
(d, 3H, J 6.6), 1.46 (s, 9H), 1.85 (m, 1H), 2.42 (s, 3H), 2.96 (dd, 1H, J 4.5
and 13.5), 3.12 (dd, 1H, J 9.0 and 13.5), 3.51 (ddd, 1H, J 2.7, 4.8, and
9.0), 3.82 (dt, 1H, J 2.4 and 10.2), 4.68 (br d, 1H, interchangeable
with D2O), 7.34 and 7.57 (AA0BB0 system, 4H); 13C NMR (CDCl3,
2.85 (dd, 1H, J 8.1 and 13.2), 3.10 (dd, 1H, J 6.0 and 13.5), 4.81 (br, 1H,
interchangeable with D2O), 5.05 (m, 1H), 6.05 (t, 1H, J 9.3), 6.18 (dd,
1H, J 0.9 and 9.6), 7.05–7.35 (m, 9H); 13C NMR (CDCl3, 75 MHz):
d
21.3, 28.4, 41.6, 51.2, 80.3, 124.2, 127.0, 128.8, 129.6, 130.0, 136.6,
75 MHz): d 19.3, 19.8, 21.4, 28.2, 29.8, 32.0, 56.3, 57.4, 80.4, 117.9,
138.0, 138.9, 140.7, 141.2, 154.7.
123.9, 130.1, 139.2, 142.1, 156.1; EIMS m/z 365 (2%, Mþþ1), 309 (15),
169 (75), 139 (50), 81 (45), 57 (100). HMRS (EI): m/z calcd for
C19H29N2O3S [Mþ1]: 365.1899; found: 365.1897.
3.8. Preparation of b-cyano sulfoxides 8
To a solution of vinyl sulfoxide (1 equiv) in THF (10 mL/mmol)
was added dropwise a solution 1 M of Et2AlCN in toluene (3 equiv)
at 0 ꢁC. The mixture was stirred at 25 ꢁC for 2.5–3 h. The reaction
mixture was decomposed with 30 mL of saturated Rochelle’s salt
and extracted with AcOEt (2ꢃ40 mL). The organic phase was
washed with brine, dried, and evaporated.
3.9. Preparation of b-cyano sulfoxides 9
The procedure described for the preparation of b-cyano sulf-
oxides 8 was followed (reaction time 5–6 h).
3.9.1. (2R,3S,RS)-(tert-Butyl)-2-cyano-1-(p-tolylsulfinyl)butan-3-
ylcarbamate 9a
3.8.1. (2S,3S,RS)-(tert-Butyl)-2-cyano-1-(p-tolylsulfinyl)butan-3-
ylcarbamate 8a
Obtained from 0.20 g (0.64 mmol) of 7a. The crude product was
purified by column chromatography eluting with hexane–EtOAc
Obtained from 0.211 g (0.68 mmol) of 5a. The crystalline crude
product was purified by crystallization from CH2Cl2–hexane to
give 0.154 g (66% yield) of 8a as white crystals, mp 102 ꢁC. IR (KBr)
65:35, to give 0.065 g (30% yield) of 9a as an oil. [
CHCl3); IR (film) nmax: 3304, 2979, 2243, 1706, 1523, 1250, and
1046 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
1.33 (d, 3H, J 6.8), 1.42 (s,
a
]
þ127.0 (c 1,
D
d
nmax: 3238, 2978, 2241, 1702, 1530, 1250, and 1032 cmꢀ1
;
1H NMR
9H), 2.43 (s, 3H), 2.90 (m, 2H), 3.48 (dd, 1H, J 6.9 and 14.1), 3.93 (m,
(CDCl3, 300 MHz):
d
1.39 (d, 3H, J 6.8), 1.46 (s, 9H), 2.42 (s, 3H),
1H), 4.80 (br d,1H, interchangeable with D2O), 7.36 and 7.57 (AA0BB0
2.95 (dd, 1H, J 4.8 and 13.2), 3.15 (dd, 1H, J 8.8 and 13.2), 3.28 (m,
system, 4H); 13C NMR (CDCl3, 75 MHz):
d 17.5, 21.4, 28.2, 33.9, 47.5,
1H), 4.32 (m, 1H), 4.71 (br d, 1H, interchangeable with D2O), 7.34
57.4, 80.4, 118.1, 124.0, 130.3, 139.8, 142.5, 154.7.
and 7.58 (AA0BB0 system, 4H); 13C NMR (CDCl3, 75 MHz):
d 19.8,
21.4, 28.3, 33.5, 46.1, 56.8, 80.5, 117.8, 124.0, 130.2, 139.0, 142.1,
155.5; EIMS m/z 337 (1%, Mþþ1), 263 (12), 141 (100), 140 (36), 57
(65). HMRS (EI): m/z calcd for C17H25N2O3S [Mþ1]: 337.1586;
found: 337.1579.
3.9.2. (2R,3S,RS)-(tert-Butyl)-2-cyano-4-phenyl-1-(p-
tolylsulfinyl)butan-3-ylcarbamate 9b
Obtained from 0.10 g (0.25 mmol) of 7b. The crude product was
purified by column chromatography eluting with hexane–EtOAc
70:30 to give 0.053 g (50% yield) of 9b as white crystals (CH2Cl2–
3.8.2. (2S,3S,RS)-(tert-Butyl)-2-cyano-4-phenyl-1-(p-
tolylsulfinyl)butan-3-ylcarbamate 8b
hexane), mp 115–116 ꢁC. [
a
]D þ158.7 (c 1, CHCl3); IR (KBr) nmax: 3379,
2981, 2245, 1701, 1511, 1246, 1169, and 1049 cmꢀ1; 1H NMR (CDCl3,
300 MHz): 1.32 (s, 9H), 2.42 (s, 3H), 2.86–2.98 (m, 3H), 3.13 (dd,1H,
J 4.2 and 14.7), 3.35 (dd,1H, J 7.5 and 14.7), 4.14 (m,1H), 4.50 (brd,1H,
interchangeable with D2O), 7.17–7.36 (m, 7H), 7.50–7.54 (m, 2H); 13
NMR (CDCl3, 75 MHz): 21.4, 28.1, 32.3, 38.0, 52.2, 57.3, 80.5, 118.4,
Obtained from 2.69 g (5.6 mmol) of 5b. The crystalline crude
product was purified by crystallization from CH2Cl2–hexane to give
0.713 g (35% yield) of 8b as white crystals, mp 123–125 ꢁC. IR (film)
d
C
nmax: 3272, 2977, 2243, 1706, 1526, 1499, 1251, 1167, and 1043 cmꢀ1
;
d
1H NMR (CDCl3, 200 MHz):
3H), 3.07–3.27 (m, 2H), 4.42 (m, 1H), 4.78 (br d, 1H, interchangeable
with D2O), 7.20–7.50 (m, 9H); 13C NMR (CDCl3, 50 MHz):
21.4, 28.1,
d
1.38 (s, 9H), 2.41 (s, 3H), 2.86–3.00 (m,
124.0, 127.3, 128.9, 129.3, 130.3, 135.3, 139.8, 142.4, 154.9.
d
3.9.3. (2R,3S,RS)-(tert-Butyl)-2-cyano-5-methyl-1-(p-
31.3, 40.0, 51.6, 56.7, 80.5, 117.8, 123.9, 127.3, 128.9, 129.0, 130.1,
135.7, 142.1, 143.4, 155.7; EIMS m/z 412 (Mþ not observed), 217 (65),
140 (25), 91 (97), 57 (100).
tolylsulfinyl)hexan-3-ylcarbamate 9c
Obtained from 0.05 g (0.14 mmol) of 7c. The crude product was
purified by column chromatography eluting with hexane–AcOEt
75:25 to give 0.024 g (45% yield) of 9c as an oil. [
CHCl3); IR (film) nmax: 3293, 2967, 2930, 2243, 1706, 1525, 1247, and
1168 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
0.89 (d, 3H, J 6.3), 0.95 (d,
a
]
þ83.8 (c 1,
D
3.8.3. (2S,3S,RS)-(tert-Butyl)-2-cyano-5-methyl-1-(p-
tolylsulfinyl)hexan-3-ylcarbamate 8c
d
Obtained from 0.151 g (0.43 mmol) of 5c. The crystalline crude
product was purified by crystallization from CH2Cl2–hexane to give
3H, J 6.6), 1.41 (s, 9H), 1.40–1.52 (m, 2H), 1.70 (m, 1H), 2.43 (s, 3H),
2.91 (d, 2H, J 7.5), 3.33 (dd, 1H, J 7.5 and 14.1), 3.80–3.94 (m, 1H),
4.57 (br d, 1H, interchangeable with D2O), 7.36 and 7.57 (AA0BB0
0.091 g (56% yield) of 8c as white crystals, mp 110–112 ꢁC. [
a]
D
þ48.6 (c 1, CHCl3); IR (film) nmax: 3348, 2960, 2927, 2225,1707,1514,
1250 and 1167 cmꢀ1 1H NMR (CDCl3, 300 MHz):
0.96 (d, 3H, J
system, 4H); 13C NMR (CDCl3, 75 MHz):
d 21.1, 21.5, 23.5, 24.7, 28.2,
;
d
33.7, 40.7, 49.9, 57.3, 80.4, 118.4, 124.0, 130.3, 139.8, 142.5, 155.1.
6.4), 0.97 (d, 3H, J 6.4), 1.44 (s, 9H), 1.25–1.80 (m, 3H), 2.42 (s, 3H),
2.96 (dd, 1H, J 4.4 and 13.0), 3.17 (dd, 1H, J 9.0 and 13.0), 3.28 (m,
1H), 4.25 (m, 1H), 4.68 (br d, 1H, interchangeable with D2O), 7.34
3.9.4. (2R,3S,RS)-(tert-Butyl)-2-cyano-4-methyl-1-(p-
tolylsulfinyl)pentan-3-ylcarbamate 9d
Obtained from 0.16 g (0.47 mmol) of 7d. The crude product was
purified by column chromatography eluting with hexane–EtOAc
and 7.59 (AA0BB0 system, 4H); 13C NMR (CDCl3, 75 MHz):
d
21.4, 21.7,
22.7, 24.9, 28.2, 32.6, 42.6, 48.5, 57.0, 80.4, 117.9, 123.9, 130.1, 139.0,

R. Alfaro et al. / Tetrahedron 65 (2009) 357–363
363
70:30 to give 0.034 g (20% yield) of 9d as an oil. [
CHCl3); IR (film) nmax: 3308, 2970, 2243, 1708, 1526, 1247, and
1169 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
0.93 (d, 3H, J 6.9), 0.98 (d,
a
]
þ181.6 (c 1,
52.3, 54.8, 80.6, 117.7, 127.3, 128.4, 128.9, 129.2, 130.2, 135.1, 135.3,
145.8, 154.9; EIMS m/z 429 (3%, Mþþ1), 373 (20), 237 (25), 155 (50),
81 (75), 57 (100).
D
d
3H, J 6.6), 1.38 (s, 9H), 1.80 (m, 1H), 2.43 (s, 3H), 2.96 (m, 2H), 3.20
(m, 1H), 3.84 (dt, 1H, J 3.6 and 10.2), 4.58 (br d, 1H, interchangeable
with D2O), 7.34 and 7.54 (AA0BB0 system, 4H); 13C NMR (CDCl3,
3.10.3. (2R,3R)-(tert-Butyl)-2-cyano-4-phenyl-1-(p-
tolylsulfonyl)butan-3-ylcarbamate 11f
75 MHz):
123.9, 130.3, 139.8, 142.4, 155.8.
d
15.2, 20.0, 21.4, 28.1, 29.9, 31.0, 55.6, 57.9, 80.3, 118.4,
From 0.021 g (0.05 mmol) of 9f, 0.017 g (78% yield) of 11f was
obtained. Mp 156 ꢁC (CH2Cl2–hexane); [
a]
D þ23.8 (c 1, CHCl3). The
spectroscopic data were identical to those of 10b.
3.9.5. (2R,3R,RS)-(tert-Butyl)-2-cyano-1-(p-tolylsulfinyl)butan-3-
ylcarbamate 9e
Acknowledgements
Obtained from 0.05 g (0.16 mmol) of 7e. The crude product was
purified by column chromatography eluting with hexane–EtOAc
We thank M. I. Cha´vez, E. Garcı´a-Rı´os, S. Herna´ndez, E. Huerta, R.
65:35 to give 0.032 g (60% yield) of 9e as an oil. [
CHCl3); IR (film) nmax: 3259, 2979, 2243, 1706, 1525, 1250, and
1167 cmꢀ1 1H NMR (CDCl3, 300 MHz):
1.35 (d, 3H, J 6.9), 1.38 (s,
a
]
þ161.8 (c 1,
D
´
´
Patin˜o, M. A. Pen˜a, J. Perez, B. Quiroz, H. Rıos, L. Velasco, and M. N.
Zavala for their technical assistance and to Consejo Nacional de
;
d
´
´
Ciencia y Tecnologıa (CONACYT-Mexico) for a predoctoral fellow-
ship to R.A. We also thank Dr. J. M. Muchowski for their critical
reviewing of the manuscript.
9H), 2.43 (s, 3H), 2.90–3.10 (m, 2H), 3.30 (m, 1H), 3.96 (m, 1H), 4.78
(br d, 1H, interchangeable with D2O), 7.35 and 7.54 (AA0BB0 system,
4H); 13C NMR (CDCl3, 75 MHz):
d 19.8, 21.4, 28.1, 34.7, 47.8, 57.4,
80.4, 117.9, 123.9, 130.3, 139.4, 142.3, 155.1.
References and notes
3.9.6. (2R,3R,RS)-(tert-Butyl)-2-cyano-4-phenyl-1-(p-
tolylsulfinyl)butan-3-ylcarbamate 9f
1. (a) Suizer-Mosse, S.; Alexakis, A. Chem. Commun. 2007, 3123; (b) Tsogoeva, S. B.
Eur. J. Org. Chem. 2007, 1701; (c) Meadows, D. C.; Gervay-Hague, J. Med. Res. Rev.
2006, 26, 793; (d) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon:
Oxford, 1993; (e) Fuchs, P. L.; Braish, T. F. Chem. Rev. 1986, 86, 903.
2. (a) Mauleon, P.; Alonso, I.; Rodrı´guez Rivero, M.; Carretero, J. C. J. Org. Chem.
2007, 72, 9924; (b) Llamas, T.; Go´mez Arraya´s, R.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2007, 46, 3329; (c) Mauleon, P.; Carretero, J. C. Chem. Commun. 2005,
4961; (d) Mauleon, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195; (e) Garrido, J. L.;
Obtained from 0.05 g (0.12 mmol) of 7f. The crude product was
purified by column chromatography eluting with hexane–EtOAc
65:35 to give 0.021 g (40% yield) of 9b as white crystals (CH2Cl2–
hexane), mp 112 ꢁC. [
a]
þ142.0 (c 1, CHCl3); IR (KBr) nmax: 3386,
D
2979, 2249, 1702, 1495, 1369, 1256, 1117, and 1048 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz): 1.34 (s, 9H), 2.41 (s, 3H), 2.82–3.06 (m, 2H), 3.16
d
´
Alonso, I.; Carretero, J. C. J. Org. Chem. 1998, 63, 9406; (f) Carretero, J. C.; Gomez
(m, 1H), 4.01 (m, 1H), 4.72 (br d, 1H, interchangeable with D2O),
Arraya´s, R. J. Org. Chem. 1998, 63, 2993; (g) Adrio, J.; Carretero, J. C. Tetrahedron
1998, 54, 1601; (h) Alonso, I.; Carretero, J. C.; Garrido, J. L.; Magro, V.; Pedregal,
C. J. Org. Chem. 1997, 62, 5682; (i) Jackson, R. F. W.; Standen, S. P.; Clegg, W. J.
J. Chem. Soc., Perkin Trans. 1 1995, 149 and references cited therein.
7.13–7.35 (m, 7H), 7.41–7.46 (m, 2H); 13C NMR (CDCl3, 75 MHz):
d
21.4, 28.1, 31.9, 40.5, 53.4, 57.1, 80.6, 117.9, 123.9, 127.3, 129.0 (2C),
130.3, 135.6, 139.3, 142.2, 155.3.
´ ˜
3. (a) Guerrero de la Rosa, V.; Ordonez, M.; Llera, J. M. Tetrahedron: Asymmetry
2001, 12, 1089; (b) Guerrero de la Rosa, V.; Ordo´ n˜ez, M.; Llera, J. M. Tetrahedron:
Asymmetry 2000, 11, 2991; (c) Ferna´ndez de la Pradilla, R.; Buergo, M. V.;
Manzano, P.; Montero, C.; Priego, J.; Viso, A.; Cano, F. H.; Martı´nez-Alca´zar, M. P.
J. Org. Chem. 2003, 68, 4797; (d) Marino, J. P.; Anna, L. J.; Ferna´ndez de la Pra-
3.10. Preparation of
b-cyano sulfones
To a solution of -cyano sulfoxide 8b, 9b or 9f (1 equiv) in dry
b
´
dilla, R.; Martınez, M. V.; Montero, C.; Viso, A. J. Org. Chem. 2000, 65, 6462; (e)
CH2Cl2 (10 mL/mmol) was added MCPBA (1.5 equiv) at 25 ꢁC and
the mixture was stirred for 1 h. The reaction was decomposed with
NaHSO3 solution and then washed with saturated sodium bi-
carbonate solution. The organic phase was separated, washed with
brine, dried, and evaporated.
Westwell, A. D.; Thornton-Pett, M.; Rayner, C. M. J. Chem. Soc., Perkin Trans. 1
1995, 847.
4. For reviews on synthetic applications of sulfoxides, see: (a) Garcı´a Ruano, J. L.;
Alema´n, J.; Cid, M. B.; Fernandez-Iban˜ez, M. A.; Maestro, M. C.; Martı´n, M. R.;
´
Martın-Castro, A. M. In Organosulfur Chemistry in Asymmetric Synthesis; Toru, T.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2008; Chapter 3, pp 55–161; (b) Pel-
lissier, H. Tetrahedron 2006, 62, 5559; (c) Hanquet, G.; Colobert, F.; Lanners, S.;
Solladie´, G. ARKIVOC 2003, vii, 328; (d) Garcı´a Ruano, J. L.; Cid de la Plata, B. Top.
Curr. Chem. 1999, 204, 1; (e) Carren˜o, M. C. Chem. Rev. 1995, 95, 1717 and ref-
erences cited therein.
3.10.1. (2S,3S)-(tert-Butyl)-2-cyano-4-phenyl-1-(p-
tolylsulfonyl)butan-3-ylcarbamate 10b
From 0.042 g (0.10 mmol) of 8b, 0.035 g (80% yield) of 10b was
obtained. Mp 143 ꢁC (CH2Cl2–hexane); [
5. Sengupta, S.; Sen Sarma, D.; Mondal, S. Tetrahedron: Asymmetry 1998, 9, 2311.
´
´
6. Yuste, F.; Ortiz, B.; Carrasco, A.; Peralta, M.; Quintero, L.; Sanchez-Obregon, R.;
Walls, F.; Garcı´a Ruano, J. L. Tetrahedron: Asymmetry 2000, 11, 3079.
7. Fujii, T.; Ohba, M.; Kawamura, H.; Nakashio, Y.; Honda, K.; Matsubara, S. Chem.
Pharm. Bull. 1994, 42, 1045.
a
]
ꢀ21.0 (c 1, CHCl3); IR
D
(film) nmax: 3364, 2975, 2933, 2247,1705,1600,1519,1293,1167, and
1145 cmꢀ1 1H NMR (CDCl3, 300 MHz):
;
d
1.37 (s, 9H), 2.45 (s, 3H),
8. Mikolajczyk, M.; Midura, W.; Grzejszczak, S.; Zatorski, A.; Chefczynska, A. J. Org.
Chem. 1978, 43, 473.
9. Effenberger, F.; Ziegler, T. In Methods of Organic Chemistry (Houben-Weyl);
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme:
Stuttgart, 1995; Vol. E21b.
2.84 (dd, 1H, J 8.4 and 15.8), 2.97 (dd, 1H, J 7.5 and 14.1), 3.09 (m,
1H), 3.40 (m, 2H), 4.70 (m, 1H), 4.74 (br d, 1H, interchangeable with
D2O), 7.16–7.34 (m, 7H), 7.66–7.79 (m, 2H); 13C NMR (CDCl3,
75 MHz):
d 21.7, 28.1, 31.7, 40.0, 53.2, 55.3, 80.7, 117.2, 127.3, 128.2,
10. (a) Garcı´a Ruano, J. L.; Cifuentes, M.; Martin Castro, A.; Rodrı´guez, J. H.
128.9, 129.0, 130.2, 134.9, 135.6, 145.6, 155.3; EIMS m/z 429 (3%,
´
´
Org. Lett. 2002, 4, 55; (b) Garcıa Ruano, J. L.; Cifuentes Garcıa, M.; Nieves,
M.; Laso, A.; Castro, M.; Rodrı´guez Ramos, J. H. Angew. Chem., Int. Ed. 2001,
40, 2507.
Mþþ1), 373 (20), 237 (25), 155 (50), 81 (75), 57 (100).
11. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 703226 (8a). Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
12. Ortiz, B.; Herna´ndez, A.; Quintero, L.; Sa´nchez-Obrego´n, R.; Yuste, F.; Garcı´a
3.10.2. (2R,3S)-(tert-Butyl)-2-cyano-4-phenyl-1-(p-
tolylsulfonyl)butan-3-ylcarbamate 11b
From 0.021 g (0.05 mmol) of 9b, 0.017 g (78% yield) of 11b was
obtained. Mp 130–1 ꢁC (CH2Cl2–hexane); [
NMR (CDCl3, 300 MHz): d 1.34 (s, 9H), 2.47 (s, 3H), 2.85 (dd, 1H, J 9.3
a
]
D ꢀ5.5 (c 1, CHCl3); 1H
´
´
Ruano, J. L. Rev. Soc. Quım. Mex. 2001, 45, 163; Chem. Abstr. 2002, 137, 311168.
13. Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. J. Org. Chem. 1999,
64, 8962.
and 13.8), 3.09 (dd, 1H, J 4.2 and 13.8), 3.30–3.40 (m, 3H), 4.11 (m,
1H), 4.60 (br d, 1H, interchangeable with D2O), 7.16–7.42 (m, 7H),
14. Chakravarty, P. K.; Greenlee, W. J.; Parsons, W. H.; Patchett, A. A.; Combs, P.;
Roth, A.; Busch, R. D.; Mellin, T. N. J. Med. Chem. 1989, 32, 1886.
7.79–7.83 (m, 2H); 13C NMR (CDCl3, 75 MHz):
d 21.7, 28.2, 31.8, 37.5,