Highly diastereoselective addition of ketone enolates to N-sulfinyl imines: Asymmetric synthesis of syn- and anti-1,3-amino alcohol derivatives

Article abstract of DOI:10.1055/s-2004-820050

Lithium enolates derived from ketones may be added to N-sulfinyl imines with high diastereoselectivity. Diastereoselective reduction gave either the syn- or anti-1,3-amino alcohol derivative.

Full text of DOI:10.1055/s-2004-820050

LETTER
967
Highly Diastereoselective Addition of Ketone Enolates to N-Sulfinyl Imines:
Asymmetric Synthesis of syn- and anti-1,3-Amino Alcohol Derivatives
H
ighly Diastereose
n
lective
A
ddi
d
tion of
K
eton
r
e
Enola
e
tes to
N
-Su
w
lfinyl Imines Kennedy,a Adam Nelson,*b Alexis Perryb
a
GlaxoSmithKline, Old Powder Mills, Nr Leigh, Tonbridge, Kent, TN11 9AN, UK
b
School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
Fax +44(113)3436565; E-mail: adamn@chem.leeds.ac.uk
Received 12 February 2004
R
S
Abstract: Lithium enolates derived from ketones may be added to
N-sulfinyl imines with high diastereoselectivity. Diastereoselective
reduction gave either the syn- or anti-1,3-amino alcohol derivative.
O
NH
OH
3a
R1
R2
R
Key words: asymmetric synthesis, chiral auxiliaries, amino alco-
hols, stereoselective synthesis
R
S
1,3syn
or
1. LDA
reduce
S
O
2. R2CHO
O
N
N
OH
R
S
R1
R1
R2
O
NH
OH
1 (R=tBu)
N-Sulfinyl chiral auxiliaries have been widely exploited
in the asymmetric synthesis of amines.1 In particular, the
additions of organolithium and Grignard reagents to N-
sulfinyl imines are often highly diastereoselective and
may be used to prepare a-branched primary amines.2
3b
2
R1
R2
1,3anti
R
S
O
NH
OH
Previously, a convenient asymmetric synthesis of 1,3-
amino alcohols has also been developed (Scheme 1). Ad-
ditions of azaenolates, derived from imines 1 (R = t-Bu),
to aldehydes often yield b-hydroxy imines 2 with high
diastereoselectivity; the imines 2 may be reduced in either
sense to give 1,3syn- or 1,3anti-amino alcohol derivatives
(3a or 3b).3
3c
R1
R2
R
1,3syn
or
reduce
S
O
NH
O
R
S
O
R1
R2
O
NH
OH
R2
3d
5
R
S
R1
R2
1,3anti
In this paper, we describe an alternative approach in
which a ketone enolate is added to an N-sulfinyl imine 4
(→ 5);4 diastereoselective reduction yields the corre-
sponding 1,3-amino alcohol derivatives (e.g. 3c or 3d).
This approach is more direct than the addition of ester or
Weinreb amide enolates5 to N-sulfinyl imine (e.g. → 6),
followed by reaction with an organometallic reagent, R2M
(→ 5) and reduction (→ 3c,d).6
R2M
N
O
R1
O
R
S
4
OMe
O
N
NH
O
OMe
R1
N
6
The N-sulfinyl imines 7a–e were prepared by treatment of
a mixture of an aldehyde R1CHO and p-toluenesulfina-
mide with 1.5 equivalents of titanium(IV) ethoxide
(Scheme 2).7 The imines 7 were reacted at –78 °C with 1.6
equivalents of lithium enolate, generated by treatment of
a ketone (8, 10 or 12) with lithium hexamethyldisilazide
(LiHMDS) (Scheme 3 and Table 1). After quenching with
methanolic ammonium chloride solution, work-up and
purification, the b-amino ketone derivatives 9 and 11 were
obtained as single diastereoisomers. Unfortunately, the
reaction of the lithium enolate derived from cyclohex-
anone was less selective, and a mixture of all four possible
diastereoisomers (13) was obtained (entry 8).
Scheme 1 Altenative strategies for the asymmetric synthesis of 1,3-
amino alcohols using N-sulfinyl imines
Ar
Ar
S
Ti(OEt)4
N
O
S
R1CHO
H2N
O
R1
Ar = p-MeC6H4-
7a; R1=2-furyl, 98%
7b; R1=Ph, 97%
7c; R1=O2NC6H4-, 91%
7d; R1=MeOC6H4-, 94%
7e; R1=cHex, 87%
Scheme 2 Preparation of the N-sulfinyl imines 7
The yield of the addition reaction 7 + 8 → 9 was depen-
dent on the substituents R1 and R2. Excellent yields of the
b-sulfinamino ketones 9a and 9c were obtained when 1.6
SYNLETT 2004, No. 6, pp 0967–0970
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-820050; Art ID: D03904ST
© Georg Thieme Verlag Stuttgart · New York
0
6.
0
5.
2
0
0
4

968
A. Kennedy et al.
LETTER
Table 1 Asymmetric Addition of Ketone Enolates to N-Sulfinyl Iminesa
Entry
Imine
Ketone
R1
R2
Method
Product
9a
Deb
Yield (%)c
1a
1b
2
7a
8a
2-Furyl
2-Furyl
A
Bd
C
>95:5
>95:5
>95:5
>95:5
–
87
9a
69
7b
7c
7d
7e
7a
7a
7a
8a
8a
8a
8a
8b
10
12
Ph
2-Furyl
2-Furyl
2-Furyl
2-Furyl
Ph
9b
9c
59 (30e)
3
p-O2NC6H4-
p-MeOC6H4-
Cyclohexyl
2-Furyl
–
A
A
A
C
83
4
–
–
5
–
–
–
6
9d
11
>95:5
>95:5
25:20:10:1
81 (31e)
97
7
–
A
A
8
–
–
13
82f
a Methods: A: 1. 1.6 equiv lithium enolate, –78 °C, THF; 2. NH4Cl, MeOH, –78 °C; B: 1. 1.6 equiv lithium enolate, –50 °C, THF; 2. HOAc,
–50 °C; C: 1. 3.0 equiv lithium enolate, –78 °C, THF; 2. NH4Cl, MeOH.
b Detemined by 1H NMR (500 MHz) spectroscopy of the crude reaction mixture.
c Yield of single diastereoisomer.
d Final concentration: 0.25 M in 7a (442 mmol scale).
e By method A.
f Yield of mixture of inseparable isomers.
equivalents of the lithium enolate derived from 2-acetyl The preparation of the b-amino ketone 9a on a large (442
furan (8a; R2 = 2-furyl) were added to the imines 7a and mmol) scale (entry 1b, Table 1) required considerable op-
7c (R1 = 2-furyl and p-O2NC6H4-; R2 = 2-furyl; entries 1 timisation since the product was susceptible to b-elimina-
and 3, Table 1). However, low yields of the b-sulfinamino tion under the concentrated reaction conditions (final
ketones 9b and 9d were obtained under these conditions; concentration: 0.25 M in the sulfinamide 7a). The elimi-
these reactions could be optimised by reacting 3 equiva- nation of the product could be suppressed by quenching
lents of lithium enolate with the required imine (entries 2 the reaction with acetic acid (in place of methanolic am-
and 6, Table 1). Attempted addition of the lithium enolate monium chloride solution) after 30 minutes below –40 °C.
derived from 8a to the imines 7d and 7e (R1 = p- Lower yields of the b-sulfinamino ketone 9a were ob-
MeOC6H4- and cyclohexyl) was, however, unsuccessful.
tained when LDA, rather than LiHMDS, was used as the
base.
Ar
The configurations of the b-amino ketone derivatives
9a–d were assigned by analogy with that of 11 which was
determined by X-ray crystallography (Figure 1). The
sense of induction observed in the synthesis of 11 is con-
sistent with attack of the Z-configured8 lithium enolate on
the N-sulfinyl imine via a fused transition state 14 in
which the S-(p-tolyl) substituent occupies an ‘outside’ po-
sition. The transition state 15, which would lead to the b-
amino ketone derivatives 9a–d, is similar to a model
which has been proposed to explain the diastereoselective
attack of ester enolates on N-sulfinyl imines (Figure 2).5b
O
S
1. LiHMDS
O
NH
O
R2
2. 7
R1
R2
8a; R2=2-furyl
8b; R2=Ph
9a; R1=2-furyl, R2=2-furyl
9b; R1=Ph, R2=2-furyl
9c; R1=p-O2NC6H4-, R2=2-furyl
9d; R1=2-furyl, R2=Ph
Ar
S
O
O
O
NH
O
1. LiHMDS
2. 7a
Ph
Ph
Me
10
11
Ar
S
O
O
NH
O
1. LiHMDS
2. 7a
O
12
13
Scheme 3 Asymmetric addition of ketone enolates to N-sulfinyl
imines
Figure 1 X-ray crystal structure of the b-sulfinamino ketone 11
Synlett 2004, No. 6, 967–970 © Thieme Stuttgart · New York

LETTER
Highly Diastereoselective Addition of Ketone Enolates to N-Sulfinyl Imines
969
Ar
S
R2
O
R1
O
Ph
Li
O
O
NH
OH
Li
O
N
O
H
O
N
O
H
S
Me
Ar
S
S
Ar
Ar
1,3syn-16
O
O
NH
O
reduce
14 → 11
15 → 9a–d
Ar
S
O
(see Table 2)
Figure 2 Proposed transition states for the addition reaction
O
NH
OH
O
O
9a
A range of reaction conditions was screened for the reduc-
tion of the ketone 9a (Scheme 4 and Table 2); the diaste-
reoselectivity of each process was determined by
analytical HPLC and/or by 1H NMR (500 MHz) spectros-
copy. The reduction of 9a with NaBH4 was unselective
(entries 1 and 2) and, in THF, competing b-elimination
and subsequent reduction (→ 17) was observed. We have,
however, been able to identify conditions under which the
ketone 9a may be selectively converted into either of the
diastereoisomeric 1,3-amino alcohols 1,3syn- or 1,3anti-16.
The reductions with Superhydride (entry 3), K-selectride
(entry 4) and DIBALH (entries 5a,b) were selective in
favour of the alcohol 1,3syn-16. In contrast, the use of
LiAlH4 (entry 6) gave a 71:29 mixture in favour of 1,3anti-
16.
1,3anti-16
OH
O
O
17
Scheme 4 Diastereoselective reduction of the b-sulfinamino ketone
9a
identified for the stereoselective reduction of 9a to give
the 1,3syn- or the 1,3anti- 1,3-amino alcohol derivatives 16.
Diastereoselective Addition of Ketone Enolates to N-Sulfinyl
Imines
Table 2 Diastereoselective Reduction of the b-Sulfinamido Ketone
9a
Synthesis of 9a: A solution of acetyl furan (151 mg, 1.37 mmol) in
THF (3 mL) was added dropwise to a stirred solution of LiHMDS
(1.37 mL of a 1 M solution in THF, 1.37 mmol) in THF (5 mL) at
–78 °C. After 0.5 h, a solution of the imine 7a (200 mg, 0.859
mmol) in THF (5 mL) was added dropwise and the resulting reac-
tion mixture stirred at –78 °C for 1 h. The reaction was quenched at
–78 °C by addition of a sat. methanolic NH4Cl solution (4 mL),
warmed to r.t. and poured onto H2O (10 mL) and EtOAc (10 mL).
The layers were separated and the aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organic extracts were dried
(MgSO4) and evaporated under reduced pressure to give a crude
product which was purified by flash chromatography, eluting with
3:7 EtOAc–petrol ether, to give the ketosulfinamide 9a (256 mg,
Entry
Conditions
De 1,3syn:1,3anti
40:60a,b
48:52c,d
92:8c
1
NaBH4, THF, 25 °C
NaBH4, EtOH, 25 °C
Li BHEt3, THF, –78 °C
K BHsBu3, THF, –78 °C
i-Bu2AlH, THF, –78 °C
i-Bu2AlH, THF, 25 °C
LiAlH4, THF, –78 °C
Li AlH(Ot-Bu)3
2
3
4
79:21c
5a
5b
6
86:14c,e
72:28c,f
29:71c
20
87%) as a colourless oil; RF 0.7 (EtOAc); [a]D +103.7 (c 1.1 in
CHCl3). IR (thin film): nmax = 3148, 2922, 1671, 1467 and 1089
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.57 (2 H, d, J = 8.2 Hz, 2¢-
and 6¢-H), 7.55 (1 H, dd, J = 1.4 and 0.8 Hz, 3-furyl 5-H), 7.35 (1
H, dd, J = 1.9 and 0.9 Hz, 1-furyl 5-H), 7.27 (2 H, d, J = 8.2 Hz, 3¢-
and 5¢-H), 7.15 (1 H, dd, J = 3.5 and 0.8 Hz, 3-furyl 3-H), 6.51 (1
H, dd, J = 3.5 and 1.4 Hz, 3-furyl 4-H), 6.36 (1 H, dd, J = 3.2 and
0.9 Hz, 1-furyl 3-H), 6.32 (1 H, dd, J = 3.2 and 1.9 Hz, 1-furyl 4-H),
5.07 (2-H, m, NH and 1-H), 3.49 (1 H, dd, J = 17.1 and 5.9 Hz, 2-
H), 3.37 (1 H, dd, J = 17.1 and 5.2 Hz, 2-H) and 2.39 (3 H, s, Me).
13C NMR (75 MHz, CDCl3): d = 186.6, 153.7, 152.6, 147.1, 142.7,
142.2, 141.8, 130.0, 126.0, 118.2, 112.8, 110.9, 108.3, 49.1, 43.5
and 21.8. MS (ES): m/z (%) = 344 (85%) [MH+] and 190 (100) [M
– C7H7SON]. Found: MNa+, 366.0760. C18H17NO4S requires MNa,
366.0776.
7
48:52c
a Determined by 1H NMR (500 MHz) spectroscopy of the crude
reaction mixture.
b Flash column chromatography gave 1,3syn-16 (12%), 1,3anti-16
(24%), 17 (51%) and p-toluenesulfinamide (63%).
c Determined by analytical HPLC.
d A >98% yield of a 48:52 mixture of diastereoisomers was obtained;
flash column chromatography gave 1,3syn-16 (44%) and 1,3anti-16
(46%).
e Flash column chromatography gave 1,3syn-16 (68%).
f Flash column chromatography gave 1,3syn-16 (58%).
20
Compound 9b: Rf = 0.1 (3:7 EtOAc–petrol ether); [a]D +84.5 (c
In conclusion, we have developed an approach to the syn-
thesis of 1,3-amino alcohols with relies on the diastereo-
selective addition of a ketone enolate to a N-sulfinyl
1.51 in CHCl3). IR (thin film): nmax = 3209, 2922, 1671, 1467, 1089
and 1062 cm–1. 1H NMR (500 MHz, CDCl3): d = 7.58 (2 H, d, J =
8.1 Hz, 2¢- and 6¢-H), 7.52 (1 H, dd, J = 1.4 and 0.8 Hz, furyl 5-H),
imine. The methods have been optimised to avoid com- 7.46 (2 H, d, J = 7.4 Hz, Ph 2- and Ph 6-H), 7.37 (2 H, t, J = 7.4 Hz,
Ph 3-H and 5-H), 7.30 (1 H, t, J = 7.4 Hz, Ph 4-H), 7.27 (2 H, d, J =
peting b-elimination, and have been exploited on a large
8.1 Hz, 3¢- and 5¢-H), 7.11 (1 H, dd, J = 3.4 and 0.8 Hz, furyl 3-H),
scale. Complementary reaction conditions have been
6.48 (1 H, dd, J = 3.4 and 1.4 Hz, furyl 4-H), 5.13 (1 H, d, J = 4.8
Hz, NH), 5.03 (1 H, app. q, J = 5.2 Hz, 1-H) 3.39 (1 H, dd, J = 16.7
Synlett 2004, No. 6, 967–970 © Thieme Stuttgart · New York

970
A. Kennedy et al.
LETTER
and 5.2 Hz, 2-HA), 3.33 (1 H, dd, J = 16.7 and 7.5 Hz, 2-HB) and
2.39 (3 H, s, Me). 13C NMR (75 MHz, CDCl3): d = 187.1, 152.7,
147.2, 142.7, 141.8, 141.0, 130.0, 129.2, 128.4, 127.9, 125.8, 118.2,
112.9, 55.0, 46.2 and 21.8. MS (ES): m/z (%) = 707 (100) [M2H+]
and 354 (42) [MH+]. Found: MNa+, 376.0966. C20H19NO3S requires
MNa, 376. 0983.
d = 7.53 (2 H, d, J = 8.2 Hz, 2¢- and 6¢-H), 7.37 (1 H, br s, 1-furyl 5-
H), 7.29 (1 H, br s, 3-furyl 5-H), 7.23 (2 H, d, J = 8.2 Hz, 3¢- and 5¢-
H), 6.31 (1 H, dd, J = 3.0 and 1.8 Hz, 1-furyl 4-H), 6.27 (1 H, dd, J
= 3.0 and 1.9 Hz, 3-furyl 4-H), 6.24 (1 H, d, J = 3.0 Hz, 1-furyl 3-
H), 6.19 (1 H, d, J = 3.0 Hz, 1-furyl 3-H), 4.90 (1 H, d, J = 8.5 Hz,
NH), 4.84 (1 H, ddd, J = 9.6, 4.7 and 4.7 Hz, 3-H), 4.77 (1 H, td, J
= 8.5 and 4.7 Hz, 1-H), 3.81 (1 H, d, J = 4.7 Hz, OH), 2.41 (1 H,
ddd, J = 14.0, 9.6 and 4.7 Hz, 2-H), 2.38 (3 H, s, Me) and 2.21 (1 H,
ddd, J = 14.0, 8.5 and 4.7 Hz, 2-H). 13C NMR (75 MHz, CDCl3): d
= 156.4, 155.3, 142.7, 142.4, 142.2, 142.1, 130.1, 126.0, 110.7,
110.6, 107.1, 106.4, 64.4, 50.9, 40.3 and 21.8. MS (ES+): m/z (%)
= 346 (15) [MH+], 328 (30) [M – OH] and 234 (100) [M –
FuCHOHCH2]. C18H19NO4S requires MNa, 368.0932. Found:
MNa+, 368.0938. Also isolated was 1,3anti-16 (23 mg, 46%) as a co-
lourless oil, Rf 0.6 (7:3 EtOAc–petrol ether); [a]D20 +53.3 (c 0.3 in
CHCl3). IR (thin film): nmax = 3306, 2924, 1596, 1504, 1011 and 736
cm–1. 1H NMR (500 MHz, CDCl3): d = 7.55 (2 H, d, J = 8.1 Hz, 2¢-
and 6¢-H), 7.40 (1 H, br s, 1-furyl 5-H), 7.32 (1 H, br s, 3-furyl 5-H),
7.26 (2 H, d, J = 8.1 Hz, 3¢- and 5¢-H), 6.35 (1 H, dd, J = 3.2 and 1.7
Hz, 1-furyl 4-H), 6.33 (1 H, d, J = 3.2 Hz, 1-furyl 3-H), 6.28 (1 H,
dd, J = 3.0 and 1.7 Hz, 3-furyl 4-H), 6.21 (1 H, d, J = 3.0 Hz, 3-furyl
3-H), 4.90 (1 H, d, J = 6.0 Hz, NH), 4.82 (2 H, m, 1-H and 3-H),
3.44 (1 H, d, J = 3.8 Hz, OH), 2.40 (4 H, m, 2-H and Me), and 2.31
(1 H, ddd, J = 14.3, 9.3 and 8.3 Hz, 2-H). 13C NMR (75 MHz,
CDCl3): d = 156.4, 154.6, 142.8, 142.4, 142.2, 141.9, 130.0, 125.9,
110.7, 110.6, 107.8, 106.3, 66.4, 51.8, 41.0 and 21.8. MS (ES+):
m/z (%) = 346 (15) [MH+], 328 (30) [M – OH] and 234 (100) [M –
FuCHOHCH2]. C18H19NO4S requires MNa, 368.0932. Found:
MNa+, 368.0938.
Compound 9c: mp 138.4–139.1 °C (CHCl3–Et2O); Rf = 0.2 (colour-
less needles from 3:7 EtOAc–petrol ether). C20H18N2SO5 requires:
C, 60.3; H, 4.55; N, 7.0; S, 8.1%. Found: C, 60.0; H, 4.70; N, 7.0;
20
S, 8.0; [a]D +84.3 (c 0.56 in CHCl3). IR (thin film): nmax = 3206,
1
2923, 1671, 1520, 1347 and 1088 cm–1. H NMR (300 MHz,
CDCl3): d = 8.23 (2 H, d, J = 8.7 Hz, Ar 2- and 6-H), 7.65 (2 H, d,
J = 8.7 Hz, Ar 3- and 5-H), 7.58 (2 H, d, J = 8.1 Hz, 2¢- and 6¢-H),
7.55 (1 H, dd, J = 1.6 and 0.8 Hz, furyl 5-H), 7.32 (2 H, d, J = 8.1
Hz, 3¢- and 5¢-H), 7.15 (1 H, dd, J = 3.4 and 0.8 Hz, furyl 3-H), 6.53
(1 H, dd, J = 3.4 and 1.6 Hz, furyl 4-H), 5.24 (1 H, d, J = 6.1 Hz,
NH), 5.08 (1 H, app. q, J = 6.1 Hz, 1-H), 3.42 (1 H, d, J = 6.0 Hz,
2-H2) and 2.39 (3 H, s, Me). 13C NMR (75 MHz, CDCl3): d = 186.4,
152.5, 148.8, 147.8, 147.4, 142.3, 141.8, 130.2, 128.7, 125.8, 142.4,
118.4, 113.1, 54.3, 45.6 and 21.8. MS (ES): m/z (%) = 797 (100)
[M2H+] and 399 (63) [MH+].
Compound 9d: mp 91.0–92.7 °C (colourless needles from EtOAc–
petrol ether). Rf = 0.2 (3:7 EtOAc–petrol ether). C20H19NSO3 re-
quires: C, 68.0; H, 5.40; N, 4.0; S, 9.1%. Found: C, 67.8; H, 5.55;
N, 3.9; S, 8.9; [a]D20 +87.5 (c 0.64 in CH2Cl2). IR (thin film): nmax
=
3189, 2920, 1683, 1448, 1090 and 1066 cm–1. 1H NMR (300 MHz,
CDCl3): d = 7.86 (2 H, d, J = 7.4 Hz, Ph 2- and Ph 6-H), 7.59 (2 H,
d, J = 8.1 Hz, 2¢- and 6¢-H), 7.56 (1 H, t, J = 7.4 Hz, Ph 4-H), 7.43
(2 H, t, J = 7.4 Hz, Ph 3- and Ph 5-H), 7.35 (1 H, dd, J = 1.8 and 0.8
Hz, furyl 5-H), 7.27 (2 H, d, J = 8.1 Hz, 3¢- and 5¢-H), 6.38 (1 H, dd,
J = 3.2 and 0.8 Hz, furyl 3-H), 6.33 (1 H, dd, J = 3.2 and 1.8 Hz,
furyl 4-H), 5.11 (2 H, m, NH and 1-H), 3.66 (1 H, dd, J = 17.1 and
5.5 Hz, 2-HA), 3.52 (1 H, dd, J = 17.1 and 5.0 Hz, 2-HB) and 2.39 (3
H, s, Me). 13C NMR (75 MHz, CDCl3): d = 198.6, 153.8, 142.6,
142.3, 141.8, 136.8, 133.9, 130.0, 129.1, 128.5, 126.0, 111.0, 108.4,
49.3, 43.7 and 21.8. MS (ES): m/z (%) = 707 (100) [M2H+] and 354
(35) [MH+].
Acknowledgement
We thank EPSRC and GlaxoSmithKline for funding.
References
(1) For a review, see: Ellman, J. A.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984.
Compound 11: mp 120.8–121.5 °C (colourless plates from MeOH–
H2O); Rf = 0.3 (3:7 EtOAc–petrol ether); C21H21NSO3 requires: C,
68.6; H, 5.75; N, 3.8; S, 8.7%. Found: C, 68.5; H, 5.70; N, 3.7; S,
(2) (a) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121,
268. (b) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999,
55, 8883. (c) Plobeck, N.; Powell, D. Tetrahedron:
Asymmetry 2002, 13, 303. (d) Han, Z.; Krishnamurthy, D.;
Pflum, D.; Grover, D.; Wald, S. A.; Senanayake, C. H. Org.
Lett. 2002, 4, 4025.
20
8.8; [a]D +160 (c 0.76 in CH2Cl2). IR (thin film): nmax = 3194,
1
2976, 1679, 1448, 1090 and 1066 cm–1. H NMR (300 MHz,
CDCl3): d = 7.83 (2 H, d, J = 7.3 Hz, Ph 2- and Ph 6-H), 7.54 (2 H,
d, J = 8.1 Hz, 2¢- and 6¢-H), 7.54 (1 H, t, J = 7.3 Hz, Ph 4-H), 7.41
(2 H, t, J = 7.4 Hz, Ph 3- and Ph 5-H), 7.34 (1 H, dd, J = 1.7 and 0.8
Hz, furyl 5-H), 7.23 (2 H, d, J = 8.1 Hz, 3¢- and 5¢-H), 6.33 (1 H, dd,
J = 3.1 and 0.8 Hz, furyl 3-H), 6.29 (1 H, dd, J = 3.1 and 1.7 Hz,
furyl 4-H), 4.89 (1 H, dd, J = 6.9 and 6.9 Hz, 1-H), 4.77 (1 H, d, J =
6.9 Hz, NH), 3.98 (1 H, app. qn, J = 6.9 Hz, 2-H), 2.38 (3 H, s, Me)
and 1.22 (3 H, d, J = 6.9 Hz, 2-Me). 13C NMR (75 MHz, CDCl3): d
= 201.6, 153.2, 142.1, 141.7, 141.4, 135.7, 133.3, 129.5, 128.6,
128.3, 125.6, 110.5, 108.5, 53.1, 44.6, 21.4 and 13.7. MS(ES+):
m/z (%) = 735 (100) [M2H+] and 368 (73) [MH+].
Synthesis of 1,3Syn- and 1,3anti-16: Sodium borohydride (11 mg,
0.292 mmol) was added to a stirred solution of 9a (50 mg, 0.146
mmol) in EtOH (8 mL). After 1.5 h, the reaction was quenched with
H2O (10 mL), the layers were separated and the aqueous portion
was extracted with EtOAc (3 × 10 mL). The combined organic ex-
tracts were dried (MgSO4) and the solvent was evaporated under re-
duced pressure to give a crude product. Purification by flash
chromatography, eluting with 3:7 EtOAc–petrol ether, gave 1,3syn-
16 (22 mg, 44%) as a colourless oil, Rf = 0.7 (7:3 EtOAc–petrol
ether); [a]D20 +75.6 (c 0.27 in CHCl3). IR (thin film): nmax = 3306,
2924, 1596, 1504, 1012 and 737 cm–1. 1H NMR (500 MHz, CDCl3):
(3) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 6518.
(4) See also: Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
(5) (a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819.
(b) Koriyama, Y.; Nozawa, A.; Hayakawa, R.; Shimizu, M.
Tetrahedron 2002, 58, 9621. (c) Huang, L.; Brinen, L. S.;
Ellman, J. A. Bioorg. Med. Chem. 2003, 11, 21. (d) Davis,
F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5,
925. (e) Jacobsen, M. F.; Skrydstrup, T. J. Org. Chem. 2003,
68, 7112.
(6) Tandem ester enolate addition–Claisen ester condensation
reactions, which also yield b-sulfinamino ketones, have been
reported: (a) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 17.
(b) Davis, F. A.; Yang, B.; Deng, J. J. Org. Chem. 2003, 68,
5147.
(7) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J.
A. J. Org. Chem. 1999, 64, 1278.
(8) (a) Kleschick, W. A.; Buse, C. T.; Heathcock, C. H. J. Am.
Chem. Soc. 1977, 99, 247. (b) Lampe, J.; Heathcock, C. H.
J. Org. Chem. 1983, 48, 4330.
Synlett 2004, No. 6, 967–970 © Thieme Stuttgart · New York