Imino ene reactions of enantiopure N-sulfinylimino esters: Asymmetric synthesis of 1-oxo-1 λ4-isothiazolidine-3-carboxylates

Article abstract of DOI:10.3987/com-02-s(m)16

The imino ene reaction of (R)-(-)-N-(tert-butanesulfinyl)iminoacetate (2), allyl benzene and SnCl₄ results in a novel rearrangement affording 1-oxide isothiazolidine-3-carboxylate (4) as the major product. The structure of 4 was established by

Full text of DOI:10.3987/com-02-s(m)16

HETEROCYCLES, Vol. 58, 2002, pp. 251-258, Received, 4th March, 2002
IMINO ENE REACTIONS OF ENANTIOPURE N-SULFINYLIMINO
4
l
ESTERS:
ASYMMETRIC
SYNTHESIS
OF
1-OXO-1
-
ISOTHIAZOLIDINE-3-CARBOXYLATES‡
Franklin A. Davis,* Junya Qu, Vaidyanathan Srirajan, Reni Joseph, and Donald
D. Titus
Department of Chemistry, Temple University, Philadelphia, PA 19122, U.S.A.
fdavis@temple.edu
Abstract – The imino ene reaction of (R)-(-)-N-(tert-butanesulfinyl)iminoacetate
(2), allyl benzene and SnCl4 results in a novel rearrangement affording 1-oxide
isothiazolidine-3-carboxylate (4) as the major product. The structure of 4 was
established by X-Ray crystallography and conversion into a-amino acids that
were prepared independently using the sulfinimine-mediated asymmetric Strecker
synthesis.
Glyoxylate imines provide access to nonproteinogenic a-amino acid derivatives through cycloaddition
reactions,1,2 radical addition,3 nucleophilic addition,4-7 or ene reactions.8 The imino ene reaction is
particularly attractive because it provides access to g ,d-unsaturated a-amino acids that are valuable building
blocks for organic syntheses.9 The diastereoselective imino ene reaction has been extensively explored by
Weinreb10 and others11 and an enantioselective catalytic version employing an N-tosyl glyoxylate imino ester
has been reported by Lectka.12 Recently we described the synthesis of enantiopure N-sulfinyl imino esters
((S)-(+)- 1) and ((R)-(-)-2) from the condensation of the corresponding chiral sulfinamides (RS(O)NH2)
Scheme 1
1) SnCl 4/DCM
O
S
H
O
S
2)
Ph
Ph
p-Tolyl
N
CO2Et
Tolyl-p
0
oC (66%)
3 (6 2% e e)
(S)-(+)-1
1) SnCl4/DCM
2)
Ph
O
S
H
3
4
CO2Et
CO2Et
NH
Ph
5
N
CO2Et
+
Ph
NH
2
0 oC (43%)
S
S
1
O
O
(R)-(-)-2
(1R,3S,5R)-(+)-4
(+)-5
________________________
‡ Dedicated to Professor Albert I. Meyers on the occasion of his 70th birthday and in recognition of his
pioneering contributions to the art of asymmetric synthesis.

with ethyl glyoxylate.13 The Lewis acid catalyzed addition of organometallic reagents to ethyl (R)-(-)-N-
(tert-butanesulfinyl)iminoacetate (2) resulted in a highly efficient asymmetric synthesis of α-amino acids.
In this paper we describe preliminary studies of the Lewis acid catalyzed imino ene reaction of 1 and 2 and
the discovery of a novel ring-forming reaction.
Reaction of iminoacetate ((S)-(+)-1) with 2.0 equiv of SnCl or Et AlCl at room temperature followed by
4
2
addition of 2 equivalents of allylbenzene afforded 65-67% yield of E-(+)-3-(p-toluenesulfinyl)-1-phenyl-1-
propene (3) based on the J1,2 coupling constant of 15.0 Hz (Scheme 1). A chiral shift reagent experiment
with Eu(hfc) indicates that the ee was 62%. Since attack of the alkene is apparently favored at the sulfinyl
3
group in 1, we next explored the ene reaction with (R)-(-)-2, which has the bulky tert-butyl sulfinyl group.
.
Lewis acids such as BF OEt , ZnCl , Ti(OEt) , and Yb(O SCF ) failed to give any reaction with
3
2
2
4
3
3
allylbenzene, and Me Al or Me AlCl resulted in decomposition. However, with 2.0 equiv of SnCl in
3
2
4
o
DCM at 0 C followed by addition of 1.0 equiv of allylbenzene unexpectedly resulted in a 43% isolated
yield, following preparative TLC, of 5- and 4-benzyl-1-oxide-isothiazolidine-3-carboxylates (4) and (5) as
1
a 1.5:1 mixture of products (Scheme 1). The structures of 4 and 5 are supported by the absences in the H
NMR of protons characteristic of olefinic and tert-butyl groups and the presence of benzyl protons at δ 2.9-
-1
-1
3.3 ppm. The IR spectrum exhibits absorptions at 3500-3300 cm (NH) and at 1082 cm (SO). To date
all attempts to improve the yield and/or ratio of 4 and 5 by varying reaction conditions have proved
unsuccessful.
The relative stereochemistry of the major isomer ((+ )-4) was
determined by X-Ray crystallography and is shown in Figure 1. To
establish the absolute stereochemistry of 4 the sulfoxide moiety was
removed, which afforded an α-amino acid whose structure would
be determined by independent asymmetric synthesis. Oxidation of
(+)-4 with m-CPBA gave the sulfonamide ((+)-6) in 92% yield
(Scheme 2). γ -Sultams such as 6 are analogs of pyroglutamic acid
and have been used in the development of peptide inhibitors and to
generate abzymes.14 Surprisingly, desulfurization of 6 with Raney Ni
Figure 1: ORTEP view of (+)-4.
resulted in two α-amino acids ((S)-(+)-7) and ((S)-(-)-8) that differed only in the number of N-ethyl groups
and were isolated by preparative TLC in 28 and 12% yield, respectively. Reductive amination caused by
acetaldehyde in the ethanol is the likely cause for the formation of these products.
The absolute configurations of amino acids (7) and (8) were established by independent synthesis using the
sulfinimine-mediated asymmetric Strecker synthesis (Scheme 3).15 4-Phenylbutyraldehyde was condensed
with commercially available (S)-(+)-p-toluenesulfinamide (9) and Ti(OEt)4 to give sulfinimine ((S)-(+)-10) in
83% yield.16 Next, the sulfinimine was treated with ethylaluminum cyanoisopropoxide [EtAl(O-i-Pr)CN],
generated in situ by addition of 1.0 equiv of i-PrOH to 1.5 equiv. of diethylaluminum cyanide (Et AlCN), to
2
give the amino nitrile (11) in 73% yield and 70% de. Since the sulfinyl group controls the stereoselectivity
Re face addition of CN affords (S ,S)-(+)-11 as the major diastereoisomer. 15 The diastereomeric amino
S

Scheme 2
CO 2Et
CO2Et
R-N-E t
m-CPBA
Raney-Ni
EtOH
(1R,3S,5R)-(+)-4
Ph
NH
S
(92%)
Ph
O2
(S)-(+)-7: R = H (28%)
(S)-(-)-8: R = Et (12%)
(3S,5R)-(+)-6
nitriles were separated by flash chromatography and treated with 4 N HCl-EtOH. This treatment not only
removes the sulfinyl group, but hydrolyzes the nitrile to give the a-amino acid ((S)-(+)-12) in 79% yield.
The hydrochloride salt of (+)-12 was reacted with acetaldehyde followed by reduction with sodium
triacetoxyborohydride to give (+)-7 and (-)-8 in 40 and 44% yield. This result establishes that the amino
esters have the S-configuration, and by extension isothiazolidine ((+)-4) has the (1R,3S,5R)- configuration.
Sch em e 3
CN
O
S
O
Et2AlCN
Ph
HN
p-To lyl
N
p-Tolyl
p-Tolyl
NH2
Ph
S
Ph
S
O
i-PrOH
5 equiv Ti(OEt)4
(83%)
O
(S)-(+)-9
(73%)
(SS,S)-11
(S)-(+)-10
70% de
1) Me CHO
2) NaBH(OAc)3
CO2Et
NH2
4 N HCl/EtO H
(79%)
(S)-(+)-7: R = H (40%)
(S)-(-)-8: R = Et(44%)
Ph
(S)-(+)12
We tentatively assign the structure of the other isomer to (+)-5 based on COSEY, NOESY, and HETCOR
experiments. The 13C NMR chemical shift of C-5, adjacent to the sulfinyl groups, appears in 4 and 5 at 66
and 59 ppm respectively, and that of C-4 at 34 and 45 ppm, respectively. Furthermore, an NOE was noted
between proton C-3 and the benzyl protons in 5, but was absent in 4.
The mechanism for formation of 4 and 5 is unknown. We speculate, however, that 4 could result from a
rearrangement of b,g -unsaturated a-amino acid (13), which may be formed in an imino ene reaction
(Scheme 4). Indeed this amino acid was detected in the 1H NMR of the crude reaction mixture (d 6.6, 6.4
ppm), but could not be isolated. Activation of the olefinic double bond in 13 by SnCl ,17 followed by attack
4
of the sulfinyl sulfur at C-3 of the alkene (i.e., 14) would furnish the product. The driving force for this
novel ring-forming reaction is the expulsion of a molecule of isobutylene. Other mechanistic schemes
cannot at this time be ruled out.

Scheme 4
CO2Et
NH
CO2 Et
NH
(+ )-4
Ph
S
Ph
O
S
O
H
13
14
ACKNOWLEDGMENT
We thank Professor David Dalton, Temple University, for stimulating discussions. This work was
supported by grants from the National Institutes of Health (GM57870) and the National Science Foundation.
EXPERIMENTAL
General procedure. Column chromatography was performed on silica gel, Merck grade 60 (230-400
mesh). Analytical and preparative thin-layer chromatography was performed on precoated silica gel plates
(250 and 1000 microns) purchased from Analtech Inc. TLC plates were visualized with UV in an iodine
chamber. THF was freshly distilled under argon from a purple solution of sodium and benzophenone.
Dichloromethane was distilled over calcium hydride under argon.
Ethyl (S)-(+)-N-(p-toluenesulfinyl)iminoacetate (1),13 ethyl (R)-(-)-N-(tert-butanesulfinyl)iminoacetate
(2),13 and (S)-(+)-p-toluenesulfinamide (9)16 were prepared as previously described.13 4-Phenyl-1-
butyraldehyde was prepared by Swern oxidation of 4-phenyl-1-butanol.18 Unless stated otherwise, all
reagents were purchased from commercial sources and used without additional purification.
(+)-(E-3-Phenylprop-2-ene)-p-toluenesulfoxide (3). In a 25-mL single-neck, round-bottom flask
equipped with a magnetic stir bar and argon-filled balloon was placed (S)-(+)-N-(p-
0
toluenesulfinyl)iminoacetate (1) (0.058 g, 0.24 mmol) in CH2Cl2 (5 mL) at 0 C. To the reaction mixture
was added SnCl4 (0.0572 mL, 0.49 mmol) and allylbenzene (0.072 mL, 0.54 mmol). The reaction,
monitored by TLC (EtOAc-pentane 1:1), was completed in 3 h and quenched with H2O (2 mL). The
solution was washed with CH2Cl2 (2 ¥ 5 mL), the combined organic phases were washed with brine (10
mL), dried (MgSO4), and concentrated. The crude sulfoxide was purified by preparative TLC (EtOAc-
pentane 1:1) to afford 0.041 g (66%) of a solid; mp 96∞C; [a]D20 +10.2o (c 0.20, CHCl3); IR (KBr) 1703,
1
1605, 1495, 1080 cm-1; H NMR (CDCl3) d 2.41 (s, 3H), 3.68 (d, J = 6.4 Hz, 2H), 6.00 (m, 1H), 6.45
13
( d, J = 15.0 Hz, 1H), 7.20~7.40 (m, 7H), 7.52 (d, J = 8.1 Hz, 2H). C NMR (CDCl3) d 22.1, 61.5,
116.9, 125.1, 127.2, 128.8, 129.3, 130.4, 136.8, 139.0, 140.4, 142.3. HRMS calcd for C16H16OS
(M+Na) 279.0810. Found (M+Na) 279.0820.
(1R, 3S, 5R)-(+)-5-Benzyl-1-oxo-1 4 -isothiazolidine-3-carboxylic acid ethyl ester (4) and
l
(+)-4-benzyl-1-oxo-1 4 -isothiazolidine-3-carboxylic acid ethyl ester (5). In a 50-mL,
l
single-neck, round-bottom flask equipped with a magnetic stir bar and argon filled balloon was placed (-)-2
(0.069 g, 0.34 mmol) in CH2Cl2 (3 mL). The solution was cooled to 0 0C, SnCl4 (0.067 mL, 0.57 mmol)

and allylbenzene (0.090 mL, 0.68 mmol) were added. The reaction mixture was warmed to rt, monitored
by TLC for completion (2.5 h), and quenched by addition of sat. NH4Cl solution (2 mL). The solution
was washed with CH2Cl2 (2 ¥ 10 mL), brine (10 mL), dried (Na2SO4), and concentrated. Purification by
preparative TLC (EtOAc-pentane 1:1) gave 0.024 g (26%) (+)-4 as a white solid and 0.016 g (17%) (+)-5
as a colorless liquid. (+)-4: mp 97 ∞C; [a]20 +5.3o (c 1.0, CHCl3); IR (KBr) 3292, 2932, 1721, 1179,
D
1082 cm-1; 1H NMR (CDCl3) d 1.25 (t, J= 7.0 Hz, 3H), 2.51 (m, 1H), 2.60 (m, 1H); 2.91 (m, 1H), 3.18
(m, 2H), 4.19 (m, 2H), 4.54 (m, 1H), 4.92 (s, 1H), 7.31 (m, 5H); 13C NMR (CDCl3) d 14.8, 31.8, 34.0,
61.9, 62.6, 66.5, 127.5, 129.5, 129.6, 139.0, 172.7. HRMS calcd for C13H17NO3S (M+H) 268.1007.
Found (M+H) 268.1003.
1
(+)-5: [a]20D +2.6o (c 1.0, CHCl3); IR (NaCl) 3235, 2980, 1736 cm-1; H NMR (CDCl3) d 1.27 (t, J 7.0
Hz, 3H), 2.83 (m, 1H), 3.03 (m, 2H); 3.12 (m, 1H), 3.31 (m, 1H), 4.21 (q, J 6.6 Hz, 2H), 4.54 (m,
1H), 4.89 (s, 1H), 7.31 (m, 5H); 13C NMR (CDCl3) d 14.8, 41.2, 45.0, 59.4, 62.7, 67.7, 127.3, 129.4,
129.8, 139.6, 172.2. HRMS calcd for C13H17NO3S (M+H) 268.1007. Found (M+H) 268.0999.
(3S, 5R)-(+)-5-Benzyl-1, 1-dioxo-1 6 -isothiazolidine-3-carboxylic acid ethyl ester (6). In
l
a 50-mL, single-neck, round-bottom flask equipped with a magnetic stir bar and argon filled balloon was
placed (+)-4 (0.039 g, 0.15 mmol) in CH2Cl2 (5 mL). m-Chloroperbenzoic acid (70%) (0.12 g, 0.49
mmol) was added, and the solution was stirred at rt for 4.5 h. The reaction mixture was washed with
sodium thiosulfate solution (5 mL), sat. sodium bicarbonate (5 mL), dried (MgSO4), and concentrated.
Filtration through a short column of silica gel afforded 0.038 g (92%) (+)-6; mp 93∞C; [a]20D +4.3o (c 1.5,
CHCl3); IR (KBr) 3279, 2984, 1734 cm-1; 1H NMR (CDCl3) d 1.27 (t, J = 7.3 Hz, 3H), 2.53 (m, 2H),
2.87 (dd, J = 9.2, 14.0 Hz, 1H); 3.21 (m, 1H), 3.35 (dd, J = 5.5, 14.0 Hz, 1H), 4.10 (m, 1H), 4.27 (m,
13
2H), 5.06 (d, J = 3.3 Hz, 1H), 7.31 (m, 5H); C NMR (CDCl3) d 14.8, 31.8, 34.0, 61.9, 62.6, 66.5,
127.5, 129.5, 129.6, 139.0, 172.7. HRMS calcd for C13H17NO4S (M+H) 284.0943. Found (M+H)
284.0948.
(S)-(+)-4-Phenylbutylidene-p-toluenesulfinamide (10). In a 100-mL single-neck round-bottom
flask equipped with a magnetic stir bar and argon-filled balloon was placed (S)-(+)-p-toluenesulfinamide
(9) (1.10 g, 7.1 mmol) and 4-phenyl-1-butyraldehyde (0.80 g, 5.5 mmol) in CH2Cl2 (20 mL). Titanium
(IV) ethoxide (6.3 mL, 30.0 mmol) was added and the reaction mixture was stirred for 8 h at rt. At this
time the solution was cooled to 0 ∞C, H2O (40 mL) was added and the solution was filtered through Celite.
The Celite was washed with CH2Cl2 (40 mL), the phases were separated, and the organic phase was
washed with brine (30 mL), dried (MgSO4), and concentrated. Flash chromatography (EtOAc: hexane,
15:85) afforded 1.30 g (83%) of (+)-10 as a colorless oil; [a]20 +241o (c 1.3, CHCl3); IR (NaCl) 3026,
D
1
2924, 1620 cm-1; H NMR (CDCl3) d 1.91 (m, 2H), 2.40 (s, 3H), 2.50 (m, 2 H), 2.65 (t, J = 7.3 Hz,
2H), 7.13~7.40 (m, 7H), 7.56 (d, J = 8.1 Hz, 2H), 8.24 (t, J = 4.8 Hz, 1H); 13C NMR (CDCl3) d 21.8,
27.3, 35.5, 35.6, 124.9, 126.4, 128.8, 128.9, 130.2, 141.7, 142.1, 142.2, 167.1. HRMS calcd for
C17H19NOS (M+H) 286.579. Found (M+H) 286.571.
(2S)-(+)-[N-(S)-p-Toluenesulfinyl]-2-amino-5-phenylpentanenitrile (11). In a 100-mL
single-neck round-bottom flask equipped with a magnetic stir bar and argon-filled balloon was placed (+)-
10 (0.30 g, 1.1 mmol) in THF (10 mL) and cooled to –78 ∞C. In a separate 25-mL single-neck round-

bottom flask equipped with a magnetic stir bar and a argon-filled balloon was added a solution of
diethylaluminium cyanide (1.6 mL, 1.6 mol) in THF (10 mL) and the solution was cooled to -78∞C. To the
solution was added i-PrOH (0.081 mL, 1.1 mmol), the reaction mixture was brought to rt, stirred for 30
min, and cannulated to the solution of (+)-10 at –78 ∞C. After the reaction mixture was slowly brought to
rt, and stirred for 10 h, it was cooled to –78 ∞C and quenched with sat. NH4Cl solution (5 mL). The
suspension was filtered through Celite, extracted with EtOAc (3 ¥ 20 mL), washed with brine (20 mL),
dried (MgSO4), and concentrated. Flash chromatography (EtOAc:hexane: CHCl3, 20:50:30) afforded 0.24
g (73%) of (+)-11 as a white solid; mp 86∞C; [a]20 +52.5o (c 1.0, CHCl3); IR (KBr) 3222, 3024, 2956,
D
2241 cm-1; 1H NMR (CDCl3) d 1.80~1.88 (m, 4H), 2.43 (s, 3H), 2.65 (t, J = 7.3 Hz, 2H), 4.08 (dd, J =
13
7.0, 14.0 Hz, 1H), 4.41 ( d, J = 7.3 Hz, 1H), 7.15~7.40 (m, 7H), 7.59 (d, J = 8.1 Hz, 2H). C NMR
(CDCl3) d 22.1, 27.6, 35.4, 35.5, 42.3, 119.3, 126.6, 126.9, 129.1, 129.2, 130.7, 140.0, 141.4, 143.1;
HRMS calcd for C18H20N2OS (M+Na) 335.1194. Found (M+Na) 335.1198.
(S)-(+)-2-Amino-5-phenylpentanoic acid ethyl ester (12). In a 100-mL, single-neck, round-
bottom flask equipped with a magnetic stir bar and a water condenser was placed (+)-11 (0.21 g, 0.7
mmol) in 4.0 N HCl- EtOH (20 mL). The solution was refluxed for 5 h, cooled to rt, concentrated, H2O
(10 mL) added, and neutralized with ammonium hydroxide. The reaction mixture was extracted with
EtOAc (3 ¥ 20 mL), washed with brine (20 mL), dried (MgSO4), and concentrated. Flash chromatography
20
(EtOAc: hexane, 70:30) afforded 0.12 g (79%) of (+)-12 as a colorless oil; [a]D +14.5o (c 2.0,
1
CHCl3); ); IR (NaCl) 3336, 3276, 2986, 1710, 1129 cm-1; H NMR (CDCl3) 1.26 (t, J = 6.9 Hz, 3H),
1.54~1.75 (m, 4H), 2.65 (m, 2H), 3.43 (dd, J = 5.1, 7.3 Hz, 1H), 4.16 ( q, J = 7.0 Hz, 2H),
13
7.17~7.40 (m, 5H). C NMR (CDCl3) d 14.9, 28.1, 35.2, 36.2, 55.1, 61.4, 126.5, 129.0, 129.1, 142.6,
176.7. HRMS calcd for C13H19NO2 (M+H) 222.1494. Found (M+H) 222.1494.
(S)-(+)-2-Ethylamino-5-phenylpentanoic acid ethyl ester (7) and (S)-(-)-2-diethylamino-
5-phenylpentanoic acid ethyl ester (8). In a 50-mL, single-neck, round-bottom flask equipped
with a magnetic stir bar and water condenser was placed (+)-6 (0.028 g, 0.1 mmol) in EtOH (5 mL). To
this solution was added Raney nickel (ca. 1.0 g) and the reaction mixture was heated and refluxed for 7 h.
At this time the solution was filtered, concentrated, and purified by preparative TLC (EtOAc: hexane, 1: 1)
to afford (+)-7 (0.007 g, 28%) and (-)-8 (0.004 g, 12%) as colorless oils.
(S)-(+)-7: [a]20D +6.8o (c 0.5, CHCl3); IR (NaCl) 3321, 2932, 1731 cm-1; 1H NMR (CDCl3) d 1.07 (t, J
= 7.0 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H), 1.67 (m, 4H), 2.48 (m, 1H), 2.62 (m, 3H), 3.24 (t, J = 6.2 Hz,
13
1H), 4.20 (q, J = 7.0 Hz, 2H), 7.13~7.30 (m, 5H); C NMR (CDCl3) d 15.0, 16.0, 28.1, 33.9, 36.3,
43.1, 61.1, 62.0, 126.4, 129.0, 129.1, 142.7, 176.3; HRMS calcd for C15H23NO2 (M+H) 250.1807.
Found (M+H) 250.1808.
1
(S)-(-)-8: [a]20 –2.7o (c 1.3, CHCl3); IR (NaCl) 2968, 1730 cm-1; H NMR (CDCl3) d 1.00 (t, J = 7.0
D
Hz,6H), 1.24 (t, J = 7.0 Hz, 3H), 1.63~2.73 (m, 4H), 2.45 (m, 2H), 2.61~2.73 (m, 4H), 3.35 (t, J =
6.9 Hz, 1H), 4.13 (m, 2H), 7.13~7.30 (m, 5H); 13C NMR (CDCl3) d 15.0, 16.0, 28.1, 33.9, 36.3, 43.1,

61.1, 62.0, 126.4, 129.0, 129.1, 142.7, 176.3. HRMS calcd for C17H27NO2 (M+H) 278.2120. Found
(M+H) 278.2119.
From amino acid ((S)-(+)-12). In a 50-mL single-neck, round-bottom flask equipped with a magnetic
stir bar and an argon-filled balloon was placed the HCl salt of (+)-12 (0.038 g, 0.17 mmol) in
dichloroethane (6 mL), followed by acetaldehyde (ca. 0.08 mL, 2.3 mmol). The solution was stirred for 15
min at rt and acetic acid (0.012 mL, 0.21 mmol) and sodium triacetoxyborohydride (0.053 g, 0.25 mmol)
were added. After 25 min the reaction mixture was quenched with sat. NH4Cl solution (3 mL), the solution
was extracted with DCM (2 ¥ 10 mL), and the combined organic phases were washed with brine (10 mL),
dried (MgSO4), and concentrated. Purification by preparative TLC (EtOAc:hexane, 1:1) afforded (+)-7
(0.017 g, 40%) and (-)-8 (0.021 g, 44%) as colorless oils. Their properties were identical to the materials
prepared from (+)-6.
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