was then fitted with a reflux condenser and the stirring reaction
mixture was heated at 70 ЊC under nitrogen for 4 hours, after
which time the reaction mixture was allowed to cool to room
temperature and concentrated. The residue was then purified by
column chromatography (3% MeOH in DCM) to give 1.34 g
(71%) of ketene thioacetal 22 as a colourless, viscous oil; [α]D22
Ϫ29 (c = 4.6 in CHCl3); Rf 0.40 (9 : 1 DCM : MeOH); Found: C,
51.5; H, 6.2; N, 3.4; C18H25NO6S2 requires C, 52.0; H, 6.1; N,
3.4; νmax (thin film/cmϪ1) 1695 (C᎐O), 1044 (S–O); δ (400 MHz,
ϩ176 (c = 0.5 in DMSO); Found: C, 67.7; H, 6.3; N,
8.0; C20H22N2O4 requires C, 67.8; H, 6.3; N, 7.9; Rf 0.57 (4 : 1
DCM : MeOH); νmax (cmϪ1) 1698 (C᎐O), 1586, 1412, 1358,
᎐
1099; δH (300 MHz, DMSO-d6) 3.01–3.12 (1H, m, CHCO2H),
3.28–3.68 (5H, m, CHNBn and 2×CbzNCH2), 3.88 (2H, d,
J 5.7, NCH2Ph), 5.04–5.08 (2H, m, NCO2CH2Ph), 7.30–7.40
(10H, m, Ar); δC (75 MHz, DMSO-d6) 44.2 (d), 45.0 (d), 46.9
(t), 47.4 (t), 49.0 (t), 49.4 (t), 50.2 (t), 50.3 (t), 56.5 (d), 57.4 (d),
65.9 (t), 127.4 (d), 127.4 (d), 127.5 (d), 127.6 (d), 127.8 (d), 128.4
(d), 128.4 (d), 128.5 (d), 128.5 (d), 137.0 (q), 137.9 (q), 138.1 (q),
153.9 (q), 172.9 (q), 173.1 (q); m/z (CIϩ) 355 (MHϩ, 60), 91
(100); Found: Mϩ, 354.1585. C20H22N2O4 requires 354.1580.
᎐
H
CDCl3, ca. 1 : 1 mixture of rotamers) 2.16–2.34 (1.5H, m),
2.61–2.78 (1H, m), 2.86–3.14 (2.5H, m), 3.34–3.50 (8H, m,
2×OCH3 and NCH2CH(OMe)2), 3.51–3.63 (1H, m, CHSO),
4.04 (0.5H, dd, J 15.6, 5.4, NCH CH᎐C), 4.29–4.44 (1.5H, m,
᎐
2
(؉)-cis-(4R,3R)-4-Aminopyrrolidine-3-carboxylic acid 19.
Carbamate 24 (177 mg, 0.5 mmol) and palladium hydroxide on
carbon (90 mg, 25 mol%, 0.125 mmol) were placed in a 250 mL
three-neck round bottomed flask under nitrogen with a mag-
netic stirrer bar. Ethanol (90 mL) was added and the flask was
flushed three times with hydrogen gas. The suspension was
stirred vigorously and heated at 40 ЊC for two hours, or until the
reaction had gone to completion according to TLC observ-
ations. The reaction was allowed to cool to room temperature,
filtered through a short Celite pad and washed with methanol.
The reaction mixture was concentrated in vacuo to give a pale
pink oil which was triturated with ethanol until fine crystals
were formed. The crystals were triturated with methanol and
ethanol and dried in vacuo to give 55 mg (85%) of amino acid 25
as white crystals; mp 166–167 ЊC (1 : 1 MeOH : EtOH); [α]D22
ϩ25.9 (c = 0.9 in MeOH); Found: C, 45.9; H, 7.7; N, 21.1;
C5H10N2O2 requires C, 46.1; H, 7.7; N, 21.5; Rf 0.18 (3 : 1 : 1
n-BuOH:AcOH:H2O); νmax (cmϪ1) 2438, 1549, 1398, 1281;
δH (400 MHz, CD3OD) 3.02–3.09 (1H, m), 3.12 (1H, dd, J 12.1,
4.0), 3.29–3.38 (2H, m), 3.50 (1H, dd, J 11.7, 8.4), 3.79 (1H, dd,
J 10.3, 5.9); δC (100 MHz, CD3OD) 46.5, 51.3, 52.5, 53.3, 177.0;
m/z (electrospray) 131 (MHϩ, 91), 115 (22), 101 (46).
NCH CH᎐C and CH(OMe) ), 4.48 (0.5H, t, J 4.9, CH(OMe) ),
᎐
2
2
2
4.61 (0.5H, dd, J 15.6, 5.4, NCH CH᎐C), 5.07–5.21 (2H, m,
᎐
2
OCH Ph), 6.56–6.65 (1H, m, CH᎐C), 7.31–7.40 (5H, m, Ph);
᎐
2
δC (100 MHz, CDCl3) 14.8 (t), 15.0 (t), 46.5 (t), 47.0 (t), 49.0 (t),
49.2 (t), 50.4 (t), 54.8 (CH3), 55.0 (CH3), 55.2 (t), 56.1 (t), 67.7
(t), 68.0 (t), 103.7 (d), 103.9 (d), 128.0 (d), 128.3 (d), 128.6 (d),
128.7 (d), 133.2 (d), 136.0 (q), 136.2 (q), 148.0 (q), 155.6 (q);
m/z (EIϩ) 430 (70), 415 (Mϩ, 10), 398 (60), 384 (30), 91 (100);
Found: Mϩ, 415.1125. C18H25NO6S2 requires 415.1123.
(؉)-[1ЈR,3ЈR]-1-Benzyl-1Ј,3Јdioxospiro[1Ј,3Ј-dithiane-2Ј,3-
pyrrolo[3,4-c]isoxazole]-5-carboxylic acid benzyl ester 23. To a
stirring solution of acetal 22 (985 mg, 2.37 mmol) in distilled
acetone (250 mL) was added toluene-p-sulfonic acid mono-
hydrate (451 mg, 2.37 mmol) under nitrogen. The reaction mix-
ture was heated at 60 ЊC under a condenser for 3 hours, until no
starting material was visible by TLC. The stirring reaction mix-
ture was then cooled to room temperature, after which sodium
hydrogencarbonate (1.19 g, 14.2 mmol) was added, followed by
N-benzylhydroxylamine hydrochloride (416 mg, 2.61 mmol).
The reaction mixture was stirred under nitrogen for a further 16
hours at room temperature, after which time the reaction mix-
ture was filtered through a short pad of Celite, washed with
DCM and concentrated. The residue was purified by column
chromatography (2% MeOH in DCM) to give 820 mg (73%) of
isoxazolidine 23 as a white foam; [α]2D2 ϩ2 (c = 1.1 in CHCl3); Rf
0.5 (9 : 1 DCM : MeOH); Found: C, 57.7; H, 6.0; N, 5.8;
C23H26N2O5S2 requires C, 58.2; H, 5.5; N, 5.9; νmax (thin film/
cmϪ1) 1698 (C᎐O), 1414, 1346, 1049 (S–O); δ (300 MHz,
Although the HBr salt of the racemate has been described,56
this is the first report of the free base.
Acknowledgements
We would like to thank Celltech R ϩ D Ltd and the EPSRC for
a CASE studentship to S. J. R.
᎐
H
CDCl3, 1 : 1 mixture of rotamers) 1.17–1.29 (0.5H, m,
SCCHCH2N), 2.07–2.16 (1H, m, SCH2CH2), 2.60–2.85 (2H,
m), 2.94–3.05 (2H, m), 3.20–3.42 (1H, m), 3.43–3.69 (1.5H, m,
SCCHCH2N and BnNCH ), 3.98–4.16 (4H, m, NCH2Ph and
CH2NCbz), 4.23–4.40 (2H, m, CH2NCbz), 5.09–5.21 (2H, m,
NCO2CH2Ph), 7.28–7.39 (10H, m, Ar); δC (100 MHz, CDCl3)
13.7 (t), 15.2 (d), 16.8 (d), 43.8 (t), 45.5 (t), 45.9 (t), 47.3 (t), 49.0
(t), 49.3 (t), 52.8 (d), 53.2 (d), 53.8 (t), 63.0 (t), 67.0 (t), 67.3 (t),
69.5 (d), 70.0 (d), 70.9 (d), 73.0 (t), 104.1 (q), 127.9 (d), 128.2
(d), 128.6 (d), 128.6 (d), 136.0 (q), 136.5 (q), 154.4 (q); m/z (CIϩ)
473 (Mϩ-1, 40), 427 (40), 383 (60), 337 (92), 311 (72), 293 (82),
286 (40), 245 (95), 196 (90), 91 (100); Found: MHϩ, 475.1363.
C23H27N2O5S2 requires 475.1361.
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acid-1-benzyl ester 24. A solution of (ϩ)-isoxazolidine 23 (292
mg, 0.616 mmol) in glacial acetic acid (12 ml) was transferred to
a miniclave fitted with a magnetic stirrer bar. Palladium (10%
on carbon, 65 mg, 0.0616 mmol, 10 mol%) was added to the
reaction mixture and the vessel was sealed. After flushing three
times with hydrogen the reaction mixture was placed under 7
atmospheres of hydrogen pressure and vigorously stirred at
room temperature for 24 hours, after which time the reaction
mixture was filtered through a Celite pad and washed thor-
oughly with methanol. The solvent was removed in vacuo to
give a yellow oil which was purified by column chromatography
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690