3-Hydroxypyrrolidines from epoxysulfonamides and dimethylsulfoxonium methylide

Article abstract of DOI:10.1039/b606583j

N-Tosyl-protected 3-hydroxypyrrolidines are prepared by reaction of dimethylsulfoxonium methylide with readily available epoxysulfonamides. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606583j

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COMMUNICATION
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3-Hydroxypyrrolidines from epoxysulfonamides and
dimethylsulfoxonium methylide{
David M. Hodgson,* Matthew J. Fleming, Zhaoqing Xu, Changxue Lin and Steven J. Stanway{
Received (in Cambridge, UK) 10th May 2006, Accepted 26th May 2006
First published as an Advance Article on the web 22nd June 2006
DOI: 10.1039/b606583j
epoxysulfonamides 1 (PG = RSO2), since the latter are commonly
accessed by base-induced aza-Payne rearrangement of N-tosyl
2-aziridinemethanols;11 another synthetically useful route to
epoxysulfonamides 1 (PG = RSO2) proceeds by epoxidation of
allylic sulfonamides.12
N-Tosyl-protected 3-hydroxypyrrolidines are prepared by
reaction of dimethylsulfoxonium methylide with readily avail-
able epoxysulfonamides.
The 3-hydroxypyrrolidine motif 5 is found in a range of naturally
occurring bioactive alkaloids,1 pharmaceuticals2 and drug inter-
mediates,3 and a number of synthetic approaches to 3-hydro-
xypyrrolidines have been developed.3,4 In connection with our
interest in the reactions of sulfur ylides with three-membered
heterocycles,5 and stimulated by a report in 2004 by Borhan and
co-workers concerning the synthesis of 3-hydroxytetrahydrofurans
from epoxy alcohols using dimethylsulfoxonium methylide 2,6 we
considered whether 3-hydroxypyrrolidines 5 could be obtained
from aminoepoxides 1 using ylide 27 (Scheme 1).
Direct application of Borhan’s conditions [Me3S(O)I (10 equiv.),
NaH (10 equiv.), DMSO, 85 uC, 24 h]6 to 2-aziridinemethanol 613
gave the desired 3-hydroxypyrrolidine 8a (44%), likely by way of
(deprotonated) epoxysulfonamide 7a from in situ aza-Payne
rearrangement (Scheme 2). However, the potential restriction to
using 2-aziridinemethanols as starting materials, together with the
requirement for a large excess of the ylide 214 and prolonged
reaction time, led us to focus on optimising conditions for
3-hydroxypyrrolidine synthesis from epoxysulfonamides.15,16
Scheme 2 3-Hydroxypyrrolidine 8a from aziridinemethanol 6.
Epoxysulfonamide 7a{ (0.1 M in DMSO) was completely
consumed within 70 min following reaction with ylide 2 [3 equiv.,
generated from Me3S(O)I and NaH] at 80 uC, however
3-hydroxypyrrolidine 8a was obtained in only 30% yield, with
no other products being isolated. Generating ylide 2 from
Me3S(O)I (3 equiv.) and n-BuLi (3 equiv.) in THF proved more
encouraging, giving 3-hydroxypyrrolidine 7a in 60% yield after 16 h
at rt (Table 1, entry 1); reduced reaction times at rt gave lower
yields of 8a, with starting epoxide 7a being recovered. Lowering
the concentration of epoxide 7a to 0.02 M slightly reduced the
efficiency of the reaction (entry 2). A modest improvement in the
yield of 7a to 65% was obtained by refluxing the reaction mixture
for 70 min (entry 3).17 The yield of 8a fell when lowering the
amount of ylide 2 (to 2 equiv.) either directly (51%, entry 4), or by
deprotonating epoxide 7a with NaH (1 equiv.) first (52%). Using
NaHMDS as the base also had a detrimental effect on the yield of
8a. However, switching solvent to DMPU gave a significant
increase in yield of 8a (87%, entry 5) and, more usefully, this
improvement was also observed when using DMPU as an additive
(up to 20 equiv.) in THF (entries 6–9). Under the latter conditions,
2 h at reflux was optimal (70 min or 3 h gave slightly reduced
yields of 8a).
Scheme 1 3-Hydroxypyrrolidines 5 from aminoepoxides 1.
For the chemistry shown in Scheme 1 to succeed, regioselective
ring-opening of the epoxide by the ylide 2 should be followed by
5-exo-tet cyclisation in preference to oxetane8 formation. It was
anticipated that a suitably acidifying N-protecting group (e.g.
PG = RSO2) would assist pyrrolidine formation, because the
amino functionality would then likely be deprotonated under the
reaction conditions9 (as shown in intermediates 3 and 4). Potential
complications10 due to aziridine formation from intermediate 3
by aza-Payne rearrangement should be avoided by using
Department of Chemistry, University of Oxford, Chemistry Research
Laboratory, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: david.hodgson@chem.ox.ac.uk
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data for all new epoxysulfonamides and
A series of epoxysulfonamides 7, prepared in two steps from the
corresponding allylic alcohols by Sharpless aziridination13 followed
by aza-Payne rearrangement11 [KH (4 equiv.), THF, 278 uC to
0 uC, 2 h],{ were then subjected to the optimised conditions
1
3-hydroxypyrrolidines, and H and 13C NMR spectra for 3-hydroxypyr-
rolidines. See DOI: 10.1039/b606583j
{ GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow,
Essex, CM19 5AW, UK
3226 | Chem. Commun., 2006, 3226–3228
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Table 1 Optimisation of 3-hydroxypyrrolidine 8a synthesis from
epoxysulfonamide 7a
Table 2 3-Hydroxypyrrolidines 8 from epoxysulfonamides 7
Entry
1
Epoxide 7
Pyrrolidine 8
Yield (%)
86
Entrya DMPU (equiv.) Temperature/uC Time/h Yield (%)
1
—
—
—
—
Neat
5
10
15
20
rt
rt
16
16
1.2
1.2
2
2
2
2
2
60
50
65
51
87
69
75
83
86
2b
3
Reflux
Reflux
80 uC
Reflux
Reflux
Reflux
Reflux
4c
5
6
7
8
9
2
3
4
5
83
74
76
72
a
0.1 M in epoxide 7a with n-BuLi (3.3 equiv.) and Me3S(O)I
(3 equiv.) used unless indicated otherwise. 0.02 M in epoxide 7a.
n-BuLi (2.3 equiv.) and Me3S(O)I (2 equiv.) used.
b
c
developed above (Table 1, entry 9) to give the corresponding
3-hydroxypyrrolidines 8 in 72–88% yield (Table 2).§
Either trans- or cis-2-substituted-3-hydroxypyrrolidines 8 could
be prepared in good yield, starting from the corresponding anti- or
syn-epoxysulfonamides 7 (entries 1–4). The simple 3-hydroxypyr-
rolidine 8c (entry 5), 2-aryl-3-hydroxypyrrolidines 8d and 8e
(entries 6 and 7), tertiary alcohol-containing pyrrolidine 8f (entry 8)
and 2,2-disubstituted-3-hydroxypyrrolidine 8g (entry 9) were all
accessible using this methodology. The relative stereochemistries of
3-hydroxypyrrolidines 8 were generally determined by NOE
experiments. In the case of 2-aryl-3-hydroxypyrrolidine 8e, the
structure was supported by X-ray crystallographic analysis
(Fig. 1).18
6
7
88
82
8
9
80
72
Fig. 1 X-Ray structure of 3-hydroxypyrrolidine 8e with thermal
ellipsoids at the 40% probability level.
Both spiro- and cis-fused hydroxypyrrolidines 10a and cis-10b
could be made using this chemistry (Table 3, entries 1 and 2).
Interestingly, the more strained trans-fused [4.3.0] system trans-10b
was also successfully generated (entry 3). Epoxysulfonamides 9a
and syn-9b were prepared by epoxidation (the latter in a
highly diastereoselective manner)12 of the corresponding allylic
sulfonamides.{
In summary, we have established a process of useful generality
for the conversion of epoxysulfonamides to stereodefined 3-hydro-
xypyrrolidines. The method uses readily available reagents and
occurs under experimentally straightforward conditions.
Additional studies in the area of epoxysulfonamides and sulfonium
ylides are currently underway.
It has also been found possible to extend the methodology to
a
2,3-disubstituted epoxide, when one of the substituents
We thank the EPSRC and GlaxoSmithKline for an Industrial
CASE award (M. J. F.). We also thank the Royal Society for an
International Incoming Fellowship (Z. X.) and a Sino-British
Fellowship Trust award (C. L.) and the EPSRC National Mass
Spectrometry Service Centre for mass spectra.
supports the ring-opening process. Thus, 2,3,4-trisubstituted
pyrrolidine 12 was formed in 77% yield from epoxysulfonamide
11{ (Scheme 3). The relative stereochemistry was assigned from
NOE experiments.
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1 (a) A.-F. M. Rizk, in Naturally occurring pyrrolizidine alkaloids, ed.
A.-F. M. Rizk, CRC Press, Boca Raton, 1991, pp. 1–89; (b) S. G.
Pyne and M. Tang, Curr. Org. Chem., 2005, 9, 1393–1418. Detoxin A1:
(c) W.-R. Li, S.-Y. Han and M. M. Joullie´, Heterocycles, 1993, 36,
359–388. Anisomycin: (d) E. M. Rosser, S. Morton, K. S. Ashton,
P. Cohen and A. N Hulme, Org. Biomol. Chem., 2004, 2, 142–149.
2 Barnidipine: (a) K. Tamazawa, H. Arima, T. Kojima, Y. Isomura,
M. Okada, S. Fujita, T. Furuya, T. Takenaka, O. Inagaki and M. Terai,
J. Med. Chem., 1986, 29, 2504–2511. DX-9065a: (b) T. Nagahara,
Y. Yokoyama, K. Inamura, S. Katakura, S. Komoriya, H. Yamaguchi,
T. Hara and M. Iwamoto, J. Med. Chem., 1994, 37, 1200–1207.
3 Z. Li, H.-J. Feiten, D. Chang, W. A. Duetz, J. B. van Beilen and
B. Witholt, J. Org. Chem., 2001, 66, 8424–8430.
Table 3 Spiro- and fused-hydroxypyrrolidines 10 from epoxysulfo-
namides 9
Entry
1
Epoxide 9
Pyrrolidine 10
Yield (%)
81
2
3
69
66
4 For a review, see: (a) D. M. Flanagan and M. M. Joullie´, Heterocycles,
1987, 26, 2247–2265. For more recent selected approaches, see: (b)
Y. Tamaru, S. Kawamura, T. Bando, K. Tanaka, M. Hojo and
Z. Yoshida, J. Org. Chem., 1988, 53, 5491–5509; (c) S. E. Denmark and
M. E. Schnute, J. Org. Chem., 1994, 59, 4576–4595.
5 D. M. Hodgson, M. J. Fleming and S. J. Stanway, Org. Lett., 2005, 7,
3295–3298.
6 J. M. Schomaker, V. R. Pulgam and B. Borhan, J. Am. Chem. Soc.,
2004, 126, 13600–13601.
7 (a) E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87,
1353–1364. For a recent review of sulfur ylide chemistry, see: (b)
V. Aggarwal and J. Richardson, in Science of synthesis, ed. A. Padwa
and D. Bellus, Thieme, Stuttgart, 2004, vol. 27, pp. 21–104.
8 (a) K. Okuma, Y. Tanaka, S. Kaji and H. Ohta, J. Org. Chem., 1983,
48, 5133–5134; (b) A. O. Fitton, J. Hill, D. E. Jane and R. Millar,
Synthesis, 1987, 1140–1142.
9 The pKa of the trimethylsulfoxonium ion in DMSO at 25 uC is 18.2
(C. R. Johnson, in Comprehensive Organic Chemistry, ed. D. N. Jones,
Pergamon Press, Oxford, 1979, vol. 3, pp. 247–260).
10 U. K. Nadir, R. L. Sharma and V. K. Koul, J. Chem. Soc., Perkin
Trans. 1, 1991, 2015–2019.
11 (a) T. Ibuka, K. Nakai, H. Habashita, Y. Hotta, A. Otaka,
H. Tamamura, N. Fujii, N. Mimura, Y. Miwa, T. Taga, Y. Chounan
and Y. Yamamoto, J. Org. Chem., 1995, 60, 2044–2058; (b) T. Ibuka,
Chem. Soc. Rev., 1998, 27, 145–154.
Scheme 3 Preparation and determination of stereochemistry of trisub-
stituted hydroxypyrrolidine 12.
12 (a) A. H. Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev., 1993, 93,
1307–1370; (b) P. O’Brien, A. C. Childs, G. J. Ensor, C. L. Hill,
J. P. Kirby, M. J. Dearden, S. J. Oxenford and C. M. Rosser, Org. Lett.,
2003, 5, 4955–4957.
13 J. U. Jeong, B. Tao, I. Sagasser, H. Henniges and K. B. Sharpless, J. Am.
Chem. Soc., 1998, 120, 6844–6845.
Notes and references
§ Typical procedure for synthesis of 3-hydroxypyrrolidines from epoxysulfo-
namides: n-BuLi (1.6 M in hexanes 0.38 mL, 0.61 mmol) was added
dropwise to a stirred suspension of Me3S(O)I (123 mg, 0.56 mmol) in THF
(1.4 mL) at 278 uC and stirred at this temperature for 15 min, and then at
0 uC for 15 min. The mixture was re-cooled to 278 uC and a solution of
anti-7a (0.19 mmol) in THF (0.5 mL) was added dropwise, followed by
DMPU (0.45 mL, 3.74 mmol) and the reaction then warmed to rt over
5 min and heated to reflux. After 2 h, 5% aq. NH4Cl (10 mL) and EtOAc
(10 mL) were added and the layers separated. The aqueous layer was
extracted with EtOAc (3 6 20 mL) and the combined organic layers were
dried (MgSO4) and evaporated under reduced pressure. The residue was
purified by column chromatography (60% Et2O in petrol) to give the
corresponding trans-8a (45 mg, 86%) as a colourless oil; Rf 0.18 (70% Et2O
in petrol); IR (neat)/cm21 3510br, 2960s, 1599s, 1494s, 1336s, 1156s; 1H
NMR (400 MHz) d 7.74 (d, J = 8 Hz, 2H), 7.31 (d, J = 8 Hz, 2H), 4.05 (d,
J = 3 Hz, 1H), 3.49–3.44 (m, 2H), 3.24 (ddd, J = 10.5, 9.5, 7 Hz, 1H), 2.41
(s, 3H), 2.06–1.97 (m, 1H), 1.77–1.67 (m, 3H), 1.50–1.33 (m, 2H), 1.26 (br,
1H), 0.94 (t, J = 7 Hz, 3H); 13C NMR (100 MHz) d 143.4, 134.2, 129.5,
127.7, 74.8, 69.1, 46.2, 37.3, 32.4, 21.5, 19.5, 14.0; MS m/z (CI) 301 (M +
14 Use of 5 equivalents of ylide 2 gave 3-hydroxypyrrolidine 8a in 13%
yield.
15 M. J. Fleming, D. Phil. thesis, University of Oxford, 2005.
16 During the preparation of this manuscript, the in situ process was
reported: R. A. Jones, J. M. Schomaker and B. Borhan, Ylide-mediated
expansion of 2,3-aziridin-1-ols to substituted pyrrolidines: Application
to the syntheses of pyrrolizidine alkaloids, Abstracts of Papers, 231st
ACS National Meeting, Atlanta, March 26–30, 2006, CHED-568.
17 Using Me3S(O)Cl as a source of ylide 2 under these conditions gave an
identical yield of 8a.
18 Crystallographic data for 8e: C17H18BrNO3S, Mr = 396.30, crystal size
0.04 6 0.04 6 0.20 mm, colourless needles, crystal system triclinic, a =
˚
7.4856(4), b = 9.7383(5), c = 11.5200(6) A, a = 95.766(2), b = 96.244(2),
c = 92.306(3)u, V = 829.49(8) A , Z = 2, Dc = 1.587 mg m23, F000 = 404,
3
˚
T = 150 K, space group P1, Z = 2, m = 2.617 mm21, 10663 reflections
¯
were measured, R = 0.0423, wR = 0.0507. CCDC 602881. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/b606583j.
+
NH4 , 100), 284 (68), 130 (50), 48 (33), 86 (29), 72 (30); HRMS calcd for
+
C14H25N2O3S (M + NH4 ) 301.1586, found 301.1577.
3228 | Chem. Commun., 2006, 3226–3228
This journal is ß The Royal Society of Chemistry 2006