Enantioselective rearrangement of proline sulfonamides: An easy entry to enantiomerically pure α-aryl quaternary prolines

Article abstract of DOI:10.1002/chem.201000989

(Figure Presented) Enantiopure quaternary prolines have been prepared by stereoselective rearrangement of N-(arylsulfonyl)proline tert-butyl esters under basic conditions (see scheme), without any external source of stereochemical information. The sulfonamide aromatic ring must contain an electron-withdrawing group (EWG), which stabilizes an intermediate Meisenheimer complex. The overall process provides easy entry to a series of optically pure a-aromatic prolines.

Full text of DOI:10.1002/chem.201000989

COMMUNICATION
DOI: 10.1002/chem.201000989
Enantioselective Rearrangement of Proline Sulfonamides: An Easy Entry to
Enantiomerically Pure a-Aryl Quaternary Prolines
Francesca Foschi,[a] Dario Landini,[a] Vittoria Lupi,[a, b] Voichit¸a Mihali,[a]
Michele Penso,*[c] Tullio Pilati,[c] and Aaron Tagliabue*[a]
In the past few decades natural and non-natural pro-
lines—and among the latter, a-quaternary derivatives are of
great interest—have found wide application in the design of
new organocatalysts[1] and chiral auxiliaries[2] for asymmetric
synthesis. Furthermore, non-natural proline units have been
incorporated in new peptide chains, affording peptidomimet-
ics with different conformational flexibility and correlated
drastic changes of their secondary structures.[3] In the best
cases, these alterations enhance the resistance of the modi-
fied proteins to metabolic and chemical degradation and
hence their overall biological activity.
Recently, we reported a straightforward protocol for the
enantioselective synthesis of quaternary N-alkyl-a-4-nitro-
phenyl-a-amino tert-butyl esters, through N-alkylation of the
corresponding a-N-(4-nitrophenyl)sulfonamido esters, fol-
lowed by degradative rearrangement, with loss of SO2.[8]
The one-pot overall process is highly stereoselective, eeꢀs up
to 98%; in contrast, the reaction conducted with the pre-
formed N-alkyl-a-N-(4-nitrophenyl)sulfonamido ester gave
the corresponding quaternary amino ester with very low
eeꢀs, for example, 28% ee in the case of N-allyl phenylala-
nine derivative. In the present paper we describe the rear-
rangement under basic conditions of N-(arylsulfonyl)proline
tert-butyl esters 1, which showed a different behavior of that
found for N-alkylated open-chain sulfonamido esters. Pre-
liminary runs (Table 1), conducted on N-(4-nitrobenzenesul-
A number of strategies[4]—and, among them, those that
adopt the well-known Kawabataꢀs principles of “memory of
chirality” (MOC)[5] and of “chiral non-racemic enolate”[6]
emerge as the most appealing—have been proposed for the
stereoselective synthesis of quaternary a-amino acids. In
particular, the synthetic methods for quaternary prolines[7]
involve the enantioselective functionalization of l-proline
derivatives, for example, through self-reproduction of chiral-
ity, diastereoselective alkylation, or transfer of stereochemi-
cal information via cyclic ammonium ylides.
Table 1. Rearrangement of proline derivative 1a in the presence of sev-
eral bases.[a]
Entry
Base
t [h]
0.25
1.5
1
26
1
24
0.25
96
48
48
48
2a [%]
ee [%]
[a] F. Foschi, Prof. Dr. D. Landini, Dr. V. Lupi, V. Mihali,
Dr. A. Tagliabue
1
2
3
4
5
6
7
8
9
NaNH2
NaNH2
NaNH2
NaH
NaH/NH3
LiNH2
LDA
LDA
tBuOK
DBU
90
94
96
94
94
94
–
89[b]
68[c]
79
Department of Organic and Industrial Chemistry
Universitꢁ degli Studi, Via Venezian 21
20133 Milano (Italy)
Fax : (+39)0250314159
E-mail: aaron.tagliabue@unimi.it
[d]
97
–
[e]
[f]
[b] Dr. V. Lupi
–
–
40[c]
15
77
92
–
Present address: Nerviano Medical Sciences
Viale Pasteur 10, 20014 Nerviano (Italy)
[e]
10
11
–
–
[c] Dr. M. Penso, Dr. T. Pilati
[g]
MeONa
–
Institute of Molecular Science and Technoligies
CNR, Via Golgi 19, 20133 Milano (Italy)
Fax : (+39)0250314159
[a] Sulfonamide 1a (1 mmol), base (2.5 mmol), DMA (6 mL), 08C. [b] At
ꢀ208C. [c] In DMF as a solvent. [d] By using NaH and ammonia gas.
[e] Starting compund 1a was recovered unchanged. [f] Starting compound
1a decomposes. [g] The corresponding p-CH3O sulfonamide 1i was re-
covered in 72% yield.
E-mail: michele.penso@istm.cnr.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000989.
Chem. Eur. J. 2010, 16, 10667 – 10670
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10667

fonyl)-proline tert-butyl ester (1a), evidenced that the best
yields and eeꢀs of the quaternary proline ester 2a could be
reached by using the strong, non-hindered base NaNH2 at
08C (entry 1), in DMA as the solvent. Longer reaction
times were necessary by operating at ꢀ208C (entry 2). The
use of DMF instead of DMA as a solvent (entry 3), or NaH
as a base (entry 4) resulted in poor yields of 2a. Starting
compound 1a was quantitatively recovered with LiNH2
(entry 6), while very poor or no results were obtained with
the more sterically demanding tBuOK, DBU and LDA (en-
tries 7–10). Furthermore, the use of sodium methoxide
(entry 11) promoted the NO2!MeO nucleophilic aromatic
gas confirmed this hypothesis: the target product 2a was iso-
lated in very good yield and ee (entry 5).
With the aim of extending the rearrangement to the syn-
thesis of different quaternary a-aryl proline derivatives 2,
the best reaction conditions found for 1a were then applied
to a series of substituted arylsulfonamido proline esters 1b–j
(Table 2).
The presence on the aromatic ring of an electron-with-
drawing group (EWG), which must be able to stabilize an
intermediate Meisenheimer complex, is essential for the re-
action progress. For that reason, compounds 1a–e, bearing
ortho- and para-nitro or para-cyano groups, gave good re-
sults, whereas compounds containing in the arylsulfonyl
moiety meta-nitro (entry 10) or electron-donating groups,
such as methyl or methoxy (entries 12 and 13), were unreac-
tive. The presence of substituents in the ortho- or meta-posi-
tion on the aromatic ring (entries 2, 4 and 8), increasing the
steric hindrance, was detrimental to the overall process, de-
creasing the reaction yields. The N-(2,4-dinitrobenzenesulfo-
nyl)proline tert-butyl ester 1g, in contrast, reacted rapidly,
but gave only a series of byproducts (entry 11). The pyrroli-
dine carboxamide 1j (entry 14) was unreactive, due to the
low ability of the carbonyl EWG. Finally, rearrangement of
methyl ester 3 (Scheme 1) using sodium amide gave the ex-
pected proline 4, even if with low yield, whereas with
sodium hydride 2-(4-nitrophenyl)-1-pyrroline (6) was only
formed, possibly through formation of an unstable bicycle
aziridinone 5, and elimination of carbon oxide from this in-
termediate. This hypothesis was corroborated by direct con-
version of the isolated methyl ester 4 into pyrroline 6
(Scheme 1).
substitution on the starting sulfonamide and N-(4-meth
ACHTUNGTNERoNUNG xy-
ACHTUNGTRENNUNG
product. The compound 1i, in turn, was stable under these
reaction conditions and the related quaternary derivative 2i
was not formed, even in traces (see Table 2, entry 13).
Table 2. Reactivity of different proline sulfonamido esters 1a–j.[a]
Sulfonamide
Y
Product
Yield [%] ee [%]
Entry
X
Z
t [h]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a NO2
1b NO2
1b NO2
1c NO2
1c NO2
1d CN
1d CN
H
CF3
CF3
H
H
H
H
H
H
NO2
H
H
H
H
H
H
H
OMe
OMe 24
H
H
NO2
NO2 48
H
NO2
H
H
0.25 2a 90
0.33 2b 64
94
94
–
91
93
96
96
94
–
–
–
–
–
[b,c]
48
0.5
2b
2c 50
2c 64[b]
–
0.33 2d 61
48
2d 44[b]
1e
1e
1 f
H
H
H
0.33 2e 54
[b,c]
[c]
2e
2 f
2g
2h
2i
–
–
–
–
–
–
48
0.5
24
24
24
[d]
1g NO2
1h Me
1i MeO
1j CON
[c]
[c]
[c,e]
A
H
2j
–
[a] Sulfonamide 1 (1 mmol), NaNH2 (2.5 mmol), DMA (6 mL), 08C.
[b] Reaction by using NaH (2 mmol). [c] Starting sulfonamide was recov-
ered unchanged. [d] The substrate rapidly decomposed. [e] Pyrrolidine
amide.
Scheme 1. Rearrangement of sulfonamido methyl ester 3.
The elevated reaction rates, together with the high yields
and eeꢀs, highlight the paramount efficiency of NaNH2: in
fact, the reaction was 102 times faster than with NaH, even
if the formation of the anion took about 5 min with both
bases. By using sodium amide, the ammonia produced in the
process, in all probability, solvates the sodium ion associated
to the carbanion derived from 1a, forming a loose ion-pair
that is much more reactive than the unsolvated tight ion-
pair generated by deprotonation with sodium hydride. A
run conducted by generating the anion with NaH and then
saturating the reaction mixture with anhydrous ammonia
Similarly to open-chain derivatives, the formation of a
spiro-Meisenheimer complex (Scheme 2) is supposed to be
the key step of the degradative rearrangement. Deprotona-
tion of the less crowded conformer of the substrate 1a, in
which the arylsulfonyl group is far from the tert-butyl ester,
gives the non-racemic enolate A.[9] This intermediate,
through a Re-face attack, evolves into a chiral spiro-Meisen-
heimer complex B that, in turn, undergoes the stereoselec-
ꢀ
tive S Ca migration of the aryl group, with an overall con-
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Chem. Eur. J. 2010, 16, 10667 – 10670

Enantioselective Rearrangements
COMMUNICATION
Figure 1. ORTEPIII projection of derivative 8 with the crystallographic
numbering scheme. Ellipsoids at 50% probability level. Only one of the
groups (atoms with the suffix A) used to model the disorder is plotted.
For clarity H atoms were omitted.
graphic data).[13] Several derivatives of compounds 2b–e
were prepared, but none of these compounds could be ob-
tained in a crystalline form suitable for X-ray crystal struc-
ture determination. However, the comparison of both chiral
HPLC retention times (the major enantiomer eluted
second) and sign of optical rotations (minus, in all cases) of
2a–e,[14] even if empirical correlations, indicate that com-
pounds 1b–e presumably rearrange following the same
stereoACTHNUGRTNEUNGchemical course observed for 1a.
Scheme 2. Mechanism of the Rearrangement.
In summary, a series of EWG bearing N-(arylsulfonyl)-
proline tert-butyl esters 1 have been stereoselectively trans-
formed under mild reaction conditions, with good yields and
excellent eeꢀs, into the quaternary a-aryl-a-proline deriva-
tives 2. These new hindered quaternary prolines are not
easily accessible through other synthetic protocols. The
enantioselectivity is promoted by the rigidity of the proline
ring and the geometric distribution of the functional groups
around the enolate anion, which allows the stabilization of a
favored conformer.
figuration retention. Compounds 1b–e—due to the rigidity
of the proline ring and the presence of aryl groups that gen-
erate similar or increased steric hindrance—are expected to
rearrange through the same stereochemical pathway. The
high ee values found for the products 2a–e prove the elevat-
ed difference of stability of the two possible conformers of
the starting sulfonamide 1 (Scheme 2), thus supporting our
hypothesis.
To confirm the rearrangement stereochemistry, 2a was
transformed into the carboxylic acid hydrochloride (R)-7
(Scheme 3, path i). The comparison of its optical rotatory
value with that of the literature enantiomer (S)-7[10] (the
only quaternary proline derivative of this type known) was
not decisive for determining the geometry of compound
(R)-7.[11] Compound 2a was then converted into the corre-
sponding acyl derivative 8 (path ii) that, after crystallization,
was subjected to X-ray analysis (Figure 1). The absolute
configuration was determined by anomalous dispersion scat-
tering and the refined Flack parameter[12] for the actual con-
figuration was 0.012(14) (see details in deposited crystallo-
Experimental Section
Synthesis of (R)-tert-butyl 2-(4-nitrophenyl)pyrrolidine-2-carboxylate
(2a): General procedure for the rearrangement of N-(arylsulfonyl)proline
esters 1: In a flame-dried, round bottomed flask cooled at 08C, contain-
ing a mixture of 95% sodium amide (103 mg, 2.5 mmol) and anhydrous
N,N-dimethylacetamide (DMA, 1.5 mL), a solution of sulfonamido ester
1a (356 mg, 1 mmol) in DMA (4.5 mL) was rapidly added by syringe,
under nitrogen atmosphere. The heterogeneous mixture was stirred until
the reaction was complete (15 min, TLC analysis: AcOEt/hexane - 1:4),
then was quenched with saturated NH4Cl solution (2 mL). After extrac-
tion with AcOEt (3ꢃ5 mL), the organic phase was washed with water
(3ꢃ2 mL) and brine (3 mL), dried over MgSO4, and evaporated under
reduced pressure; the crude was purified by flash column chromatogra-
phy (FCC: AcOEt/hexane 1:4) on silica gel. Product 2a (263 mg, 90%)
was isolated as a clear wax; [a]2D0 =ꢀ36.6 (c=0.8 in CHCl3), ee 94%
(CHIRALCEL OJ-H, hexane/iPrOH (95:5), flow rate 1 mLminꢀ1, P
26 bar, t1 =10.321, t2 =12.062); 1H NMR (300 MHz, [D6]acetone): d=
8.39–8.35 (m, 2H), 7.82–7.79 (m, 2H), 3.62–3.44 (m, 2H), 3.04–2.95 (m,
1H), 2.61–2.50 (m, 1H), 2.39–2.23 (m, 1H), 2.17–2.04 (m, 1H), 1.43 ppm
(s, 9H). 13C NMR (75 MHz, [D6]acetone): d=168.1 (CO), 148.3, 141.6
(2CAr), 127.6, 123.7 (4CArH), 85.2, 74.2 (2 C), 44.7 (CH2N), 33.3, 21.8 (2
CH2), 26.2 ppm (3CH3 tBu); IR (Nujol): n˜ =3276, 1720, 1519, 1461, 960,
863 cmꢀ1; elemental analysis calcd (%) for C15H20N2O4: C 61.63, H 6.90,
N 9.58; found: C 61.66, H 6.87, N 9.63.
Scheme 3. Preparation of compound (R)-7 and 8. Reagents and condi-
tions: i) TFA, CHCl3, 708C. ii) (4-Bromophenyl)acetyl chloride, pyridine,
58C.
Chem. Eur. J. 2010, 16, 10667 – 10670
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10669

M. Penso, A. Tagliabue et al.
Synthesis of pyrroline 6 by reaction of methyl ester 4 with NaH: A solu-
tion of sulfonamido ester (50 mg, 0.2 mmol) in anhydrous DMA
[4] For recent reviews, see: a) C. Cativiela, M. D. Dꢇaz-de-Villegas, Tet-
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4
(0.9 mL) was added to a suspension of 60% sodium hydride (20 mg,
0.5 mmol) in anhydrous DMA (0.3 mL) at 08C, under nitrogen atmos-
phere. The resulting solution was stirred at 08C until the reaction was
complete (30 min, TLC), then was quenched and purified as given in the
general procedure for the rearrangement of esters 1. Pyrroline 6 (34 mg,
89%). FCC: AcOEt/hexane (1:4); yellow solid, m.p. 85–868C (decomp);
1H NMR (300 MHz, CDCl3): d=8.28–8.23 (m, 2H), 8.02–7.97 (m, 2H),
4.16–4.10 (m, 2H), 3.01–2.94 (m, 2H), 2.15–2.05 ppm (m, 2H). 13C NMR
(75 MHz, CDCl3) d=171.7 (C=N), 148.9, 140.2 (2CAr), 128.5, 123.7
(4CArH), 62.0, 35.1, 22.7 ppm (3CH2); IR (Nujol): n˜ =1617, 1595, 1513,
1334, 856, 726 cmꢀ1; MS (ESI): m/z (%) calcd for C10H10N2O2 [M+H]+:
191.1 (100), 192.1 (11.0), found 191.2 (100), 192.2 (11); elemental analysis
calcd (%) for C10H10N2O2: C 63.15, H 5.30, N 14.73; found: C 63.12, H
5.35, N 14.70.
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Acknowledgements
This research was carried out within the framework of the National Proj-
ect “Nuovi sistemi catalitici stereoselettivi e sintesi stereoselettive di mo-
lecole funzionali”, and it is supported by MIUR (Rome) and CNR
(Italy).
Keywords: enantioselectivity · prolines · rearrangement ·
sulfonamides
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even if they showed opposite sign. We suppose that the reason of
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[13] CCDC-765702 contains supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
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request/cif.
[14] See the Supporting information for [a]Dꢀs and HPLC chromato-
grams.
Di Ste
G
Received: April 16, 2010
G. Lucente, Bioorg. Med. Chem. 2003, 11, 1677–1683.
Published online: July 30, 2010
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Chem. Eur. J. 2010, 16, 10667 – 10670