Ring-opening of N-alkoxycarbonyl γ-lactams with lithium methylphenylsulphone: Application to the synthesis of cis 2,5-disubstituted pyrrolidines

Article abstract of DOI:10.1016/S0040-4039(02)02839-3

The ring-opening of N-alkoxycarbonyl γ-lactams with lithium methylphenyl sulphone was studied and applied to the synthesis of enantiopure cis 2,5-disubstituted pyrrolidines

Full text of DOI:10.1016/S0040-4039(02)02839-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1141–1143
Ring-opening of N-alkoxycarbonyl g-lactams with lithium
methylphenylsulphone: application to the synthesis of cis
2,5-disubstituted pyrrolidines
Antonio J. Mota and Nicole Langlois*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 12 November 2002; revised 15 December 2002; accepted 16 December 2002
Abstract—The ring-opening of N-alkoxycarbonyl g-lactams with lithium methylphenyl sulphone was studied and applied to the
synthesis of enantiopure cis 2,5-disubstituted pyrrolidines © 2003 Elsevier Science Ltd. All rights reserved.
The presence of N-protecting alkoxycarbonyl (or
sulphonyl) groups is well known to enhance consider-
ably the electrophilic character of lactam carbonyl
groups, due to their electron withdrawing aptitude.
Thus, numerous illustrations of heteronucleophilic
attacks at C-2 by hydrolysis or alcoholysis1 and by
aminolysis2 are reported in the literature. With respect
to carbon nucleophilic additions, Grignard reagents
opened such pyrrolidin-2-ones leading, in good yield, to
an equilibrium of the corresponding acyclic ketones and
cyclic quaternary a-hydroxy carbamates as outlined in
Scheme 1.3
tamic acid, and the use of the resulting b-ketosulphones
as intermediates in the synthesis of cis 2,5-disubstituted
pyrrolidines.
The study started with the opening of (S)-tert-butyl
N-benzyloxycarbonyl pyroglutamate 1 with deproto-
nated methylphenylsulphone and the main results are
summarized in Table 1.
Nucleophilic
addition
of
lithium
anion
of
methylphenylsulphone (1.28 equiv.) at −72°C afforded
the b-ketosulphone 2 in 63% yield, along with some
benzenesulphonylacetic acid benzyl ester 3 (13%), due
to the attack on the N-benzyloxycarbonyl group
(Scheme 2, Table 1, entry 1). The ketone 2 was charac-
terized particularly by its NMR spectra (l H2-6: 4.11
ppm, l C-5 (CO): 197.02 ppm). Small amounts (ca. 5%)
of the cyclized a-hydroxycarbamate isomer 4 was also
observed. By using almost 2 equiv. of the sulphone
carbanion, the opening of 1 at the same temperature
occurred in 74% yield and 3 was isolated in 21% yield
(entry 2).10 The absence of racemization was indicated
by NMR. The enantiomeric excess of 2 was shown to
be >95% by 1H NMR spectra in the presence of
[Eu(hfc)3] as chiral shift reagent, compared with those
of the racemate, and 99% ee was specified by chiral
Aryllithium were shown to be also effective in the ring
opening of N-Boc lactams,3b,4 but alkyllithium reagents
gave generally low yields. Among stabilized carbanions,
lithium enolates were reported to react regioselectively
in high yield at the g-lactam carbonyl of N-benzyloxy-
carbonyl pyroglutamates,5 and methyl p-tolylsulphinyl
carbanion similarly opened N-Boc analog.6 However,
only few examples accounted for the reactivity of
methylphenylsulphone anions in nucleophilic addition
to activated b-,7 g-,8 and d-lactam carbonyls.9 There-
fore, we report here the reaction of deprotonated
methylphenylsulphones with several functionalized N-
alkoxycarbonylpyrrolidin-2-ones derived from pyroglu-
Scheme 1.
* Corresponding author. Fax: +33-1-69077247; e-mail: nicole.langlois@icsn.cnrs-gif.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02839-3

1142
A. J. Mota, N. Langlois / Tetrahedron Letters 44 (2003) 1141–1143
Table 1. Ring-opening of N-alkoxycarbonylpyrrolidin-2-ones by methylphenylsulphone carbanion (in THF at −72°C)
Entry
N-Alkoxycarbonylpyrrolidin-2-ones
R1
Nucleophile (equiv.)
b-Ketosulphone (%)
PhSO2CH2CO2Bn (%)
1
2
3
4
5
6
7
8
1
1
5
6
Bn
Bn
Bn
Bn
t-Bu
t-Bu
t-Bu
t-Bu
PhSO2CH2Li (1.28)
PhSO2CH2Li (1.94)
PhSO2CH2Li (1.6)
PhSO2CH2Li (1.9)
PhSO2CH2Li (2.0)
PhSO2CH2Li (1.85)
PhSO2CHLi2 (1.05)
PhSO2CH2Li (2.0)
2 (63)
2 (74)
7 (58)
8 (62)
12 (95)
13 (84)
13 (55)
14 (90)
13
21
25
18
9
Not observed
Not observed
Not observed
Not observed
10
10
11
Scheme 2.
HPLC.11a The pyrrolidin-2-ones 5 and 6 derived from
(S)-pyroglutaminol gave similar results, affording 7 and
8, respectively (entries 3 and 4). Attempts to increase
the regioselectivity of the reaction gave only poor
results and led us to employ more sterically hindered
N-Boc protecting group. Accordingly, the compounds
9–1112 were opened to give the corresponding b-keto-
sulphones 12–14. In all cases, an excess (ca. 2 equiv.) of
monolithium alkylsulphone was needed to obtain high
yields (95, 84, and 90%, respectively), owing to the
acidity of the resulting b-ketosulphones (Table 1,
entries 5, 6, and 8), whereas a more complex mixture
was formed in the reaction of 10 with dilithium
reagent13 providing 13 in lower yield (55%, entry 7).
Hydrogenation of pyrroline intermediates are known to
afford cis 2,5-dialkylpyrrolidines and cis 5-alkyl proli-
nates.14 Thus, in order to develop a stereoselective and
efficient route to cis 2,5-disubstituted pyrrolidines,15 the
ketone 2 was desulphonylated with 4–5% Na–Hg amal-
gam leading to 15 in 58% yield and 98.5% ee, as
demonstrated by chiral HPLC.11b Similarly, desulpho-
nylation of 7 and 8 in the same conditions, afforded the
methylketones 16 and 17 (63 and 65%, respectively).
The methylketone 15 was subjected to a cyclization–
reduction domino sequence under N-deprotection con-
ditions (H2, 1 atm, Pearlman’s catalyst, rt) giving rise to
18 (91%) with complete cis diastereoselectivity (Scheme
3). The reduction of 18 with LiAlH4 led to the known
Scheme 3.

A. J. Mota, N. Langlois / Tetrahedron Letters 44 (2003) 1141–1143
1143
(2S,5S)-2-hydroxymethyl-5-methylpyrrolidine
19,16a
the products were extracted with CH2Cl2 (3×25 mL). The
combined organic phases were dried over MgSO4 and
evaporated to dryness. The residue was purified by chro-
matography (eluent: heptane–Et2O–MeOH 50:50:1 v/v)
to give compound 3 (61 mg, 21%) and ketosulphone 2
(347 mg, 74%) as a colourless syrup: [h]2D3 −6 (c 1.40,
CHCl3); IR (film): 3366, 2979, 2935, 1722, 1523, 1449,
1369, 1323, 1227, 1154 cm−1; 1H NMR (300 MHz, CDCl3
(l ppm=7.27), J (Hz)): l 7.86 (d, 2H, J=8, SO2Ph), 7.66
(dd, 1H, SO2Ph), 7.55 (dd, 2H, JꢀJ%=7, SO2Ph), 7.34
(m, 5H, CH2Ph), 5.38 (bd, 1H, JNH,2=7.5, NH), 5.08
(2d, 2H, J=12, PhCH2), 4.19 (m, 1H, H-2), 4.11 (s, 2H,
SO2CH2), 2.78 (m, 2H, H2-4), 2.15 (m, 1H, Ha-3), 1.82
(m, 1H, Hb-3), 1.45 (s, 9H, t-Bu); 13C NMR (75.0 MHz,
CDCl3 (centred l ppm=77.0)): l 197.02 (CO), 170.76
(OCO), 156.00 (NCO2), 138.66 (qC, Ar), 136.18 (qC, Ar),
134.23, 129.29, 128.49, 128.18, 128.05 (CH, Ar), 82.60
(qC, t-Bu), 66.93, 66.84 (OCH2Ph, SO2CH2), 53.28
(NCH), 40.06 (COCH2), 27.88 (CH3, t-Bu), 26.46 (C-3);
MS (ESI) m/z: 514 (M+K)+, 498 [(M+Na)+, 100%], 467,
458, 442, 339.
characterized also as its benzylcarbamate 20,16b,17 and
these results ascertain the configurations of stereogenic
centres.
In conclusion, the opening of N-alkoxycarbonyl-pro-
tected g-lactams with lithiated methylphenylsulphone
led to functionalized acyclic b-ketosulphones and
allowed the preparation of cis 2,5-disubstituted pyrro-
lidines, particularly 5-alkyl prolinate, with high
diastereoselectivity. The extension of this methodology
to other more complex sulphones, as well as the cis
introduction by this way of other alkyl groups at C-5,
are currently under investigation.
Acknowledgements
We are grateful to Professor J.-Y. Lallemand for a
grant (A.J.M.).
11. (a) HPLC Daicel Chiralcel OD, hexane/ethanol 4/1; (b)
HPLC Daicel Chiralcel OD, hexane/2-propanol 9/1.
12. Ackermann, J.; Matthes, M.; Tamm, C. Helv. Chim. Acta
1990, 73, 122–132.
13. Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; John Wiley and Sons: New York, 1995; pp.
3568–3570 and references cited therein.
14. (a) Jegham, S.; Das, B. C. Tetrahedron Lett. 1989, 30,
2801–2804; (b) Van der Werf, A.; Kellogg, R. M. Tetra-
hedron Lett. 1991, 32, 3727–3730.
15. Pichon, M.; Figade`re, B. Tetrahedron: Asymmetry 1996,
7, 927–964.
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17. Data for 19 and 20. Compound 19: [h]2D4 +12.7 (c 0.70,
4. Momotake, A.; Togo, H.; Yokohama, M. J. Chem. Soc.,
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5. Ohta, T.; Kimura, T.; Sato, N.; Nozoe, S. Tetrahedron
EtOH), lit.:16a +8.8 (c 0.4, EtOH); IR (film): 3308 cm−1
;
1H NMR (300 MHz, CDCl3): l 4.69 (bs, 1H, NH), 3.56
(dd, 1H, Ja,b=10.3, Ja,2=3.8, CHaOH), 3.35 (dd, 1H,
Lett. 1988, 29, 4303–4304.
Jb,2=5.8, CHbOH), 3.30 (m, 1H, H-2), 3.22 (m, 1H,
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H-5), 1.82 (m, 2H, Ha-3, Ha-4), 1.57 (m, 1H, Hb-3), 1.29
(m, 1H, Hb-4), 1.13 (bd, 3H, J=6.2, CH3); 13C NMR
(75.0 MHz, CDCl3): l 65.16 (CH2O), 58.95 (C-2), 54.32
(C-5), 33.35 (C-4), 27.71 (C-3), and 21.81 (CH3).
7. Baldwin, J. E.; Adlington, R. M.; Russel, A. T.; Smith,
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Compound 20: [h]2D3 −7.5 (c 1.92, CHCl3); IR (film): 3428,
1
1694, 1681, 771, 698 cm−1; H NMR (300 MHz, CDCl3):
l 7.36 (m, 5H, H-Ar), 5.15 (2d, 2H, J=12.3, CH2Ph),
4.61 (bs, 1H, NH), 4.05 (m, 1H, H-5), 3.99 (m, 1H, H-2),
9. Langlois, N. Org. Lett. 2002, 185–187.
10. Preparation of 2: To a solution of methylphenylsulphone
(311 mg, 1.99 mmol) in dry THF (6.0 mL), stirred at
−72°C under argon, was added n-BuLi (1.6 M solution
in hexanes, 1.20 mL, 1.92 mmol). After stirring for 30
min at −72°C, a solution of lactam 1 (316 mg, 0.99 mmol)
in THF (4.0 mL) was added dropwise. The mixture was
stirred for 1.75 h at the same temperature and a saturated
aqueous solution of NH4Cl (5 mL) was then added. The
cooling bath was removed, water (10 mL) was added and
3.72 (bd, 1H, CHaOH), 3.60 (dd, 1H, Ja,b=11.2, Jb,2
=
7.2, CHbOH), 1.97 (m, 2H), 1.71 (m, 1H), 1.58 (m, 1H),
H2-3 and H2-4), 1.18 (bd, 3H, J=5.7, CH3); 13C NMR
(75.0 MHz, CDCl3): l 157.38 (NCO2), 136.45 (qC, Ar),
128.50, 128.04, 127.86 (CH, Ar), 68.20 (OCH2), 67.25
(OCH2), 61.99, 54.85 (C-2, C-5), 31.31, 26.75 (C-4, C-3),
+
’
21.43 (CH3); MS (EI) m/z: 249 (M ), 218, 174, 91
(100%).