SN2 vs. E2 on quaternary centres: An application to the synthesis of enantiopure β2,2-amino acids

Article abstract of DOI:10.1039/b400282b

S_N2 and E2 competing reactions in cyclic sulfamidates can be modulated by the change of an amide group to an ester group attached to the quaternary carbon activated for the nucleophilic attack, allowing an easy approach to enantiopure α,α-disub

Full text of DOI:10.1039/b400282b

SN2 vs. E2 on quaternary centres: an application to the synthesis of
enantiopure b2,2-amino acids†
Alberto Avenoza,* Jesús H. Busto, Francisco Corzana, Gonzalo Jiménez-Osés and Jesús M.
Peregrina*
Departamento de Química, Universidad de La Rioja, Grupo de Síntesis Química de La Rioja, U.A.-C.S.I.C,
E-26006 Logroño, Spain. E-mail: alberto.avenoza@dq.unirioja.es; Fax: +34 941 299655; Tel: +34 941
299655
Received (in Cambridge, UK) 9th January 2004, Accepted 25th February 2004
First published as an Advance Article on the web 16th March 2004
SN2 and E2 competing reactions in cyclic sulfamidates can be
modulated by the change of an amide group to an ester group
attached to the quaternary carbon activated for the nucleophilic
attack, allowing an easy approach to enantiopure a,a-dis-
ubstituted b-amino acids.
nucleophilic attack—and, to the best of our knowledge, it is the first
time that such compounds have been opened by nucleophiles via
SN2 reaction on the quaternary carbon.
Firstly we synthesised sulfamidates (R)-4 and (R)-5 from chiral
diols (R)-2 and (R)-3 in good yield using Burgess’ reagent (Scheme
1). Single crystals of (R)-4 and (R)-5 were obtained in order to
confirm their structures by X-ray diffraction.‡,9 Diols (R)-2 and
(R)-3 were easily obtained from the Sharpless AD reaction on
olefin 1 using AD-mix a.10 Sulfamidate (R)-5 was also prepared
from sulfamidate (R)-4 by the action of TfOH in MeOH. Ring
opening of these sulfamidates was examined using nitrogen, sulfur,
oxygen, fluorine and carbon nucleophiles (Scheme 1, Table 1).
In our procedure, sulfamidate (R)-4 (1.0 equiv.) and the
nucleophile (1.3 equiv.) were heated in DMF at 25–50 °C for 1–12
h. The corresponding sulfamic acid intermediates were hydrolyzed
in an acid medium to give the desired SN2 products (Scheme 1). As
the basicity of the nucleophile was increased, for example in the
case of oxygen or fluorine nucleophiles, the SN2 reaction in
sulfamidate (R)-4 was accompanied by the elimination product 17.
This problem was solved by changing the amide group to an ester
group in the cyclic sulfamidate, therefore on using sulfamidate (R)-
5 instead of (R)-4 in the SN2 reactions, the E2 reaction was
b-Amino acids have recently attracted a great deal of attention due
to their applications in medicinal chemistry and molecular
recognition.1 In addition, peptides containing these amino acids
show an extraordinary proteolytic stability.2 In this area a-
substituted b-amino acids are particularly attractive compounds
since the presence of an alkyl substituent at the a-position favors
folded conformations in the b-peptides.3
On the other hand, five-membered cyclic sulfamidates have been
extensively used as reactive intermediates in organic synthesis,4
since the majority of ring-opening reactions of cyclic sulfamidates
with nucleophiles proceed by the SN2 pathway with total inversion
at the stereogenic centre.4 The development of both the catalytic
asymmetric dihydroxylation (AD) reaction5 to synthesize chiral
1,2-diols and the efficient method involving the Burgess-type
reagent6 for preparing five-membered cyclic sulfamidates from
chiral 1,2-diols has contributed to the expansion of the chemistry of
such systems.7
In an effort to combine the two aforementioned processes, and in
connection with our research into the asymmetric synthesis of
conformationally restricted amino acids, we focused our attention
on two five-membered cyclic a-methylisoserine-derived sulfami-
dates (R)-4 and (R)-5. It was believed that these two compounds
would be excellent chiral building blocks for the synthesis of a-
methylated b-amino acids by nucleophilic ring-opening reactions
(Scheme 1). We report here an easy synthetic approach to a varied
collection of b2,2-amino acids that are not accessible by previously
reported methodologies.8
Although the synthesis and reactivity of several sulfamidates
have been well documented, in all cases these compounds are
monosubstituted or a,b-disubstituted. In contrast, little is known
about five-membered cyclic sulfamidates that are gem-disub-
stituted at the 5-position—the quaternary carbon activated for
Scheme 1 (a) Ref. 10: AD-mix a, MeSO2NH2, tBuOH/H2O (1 : 1), 0 °C, 12
h, 81%, ee = 93%; (b) i) LiOH·H2O (5 equiv.), H2O/MeOH (1 : 3), rt, 2 h;
ii) AcCl, MeOH, reflux, 12 h, 85%; (c) Burgess’ reagent, THF, rt, 24 h,
96%; (d) TfOH, MeOH, 60 °C, 3 h, 97%; (e) i) Nuc (1.3 equiv.), DMF,
25–50 °C, 1 to 12 h, ii) 20% H2SO4 (aq.)/CH2Cl2 (1 : 1), rt, 12 h; (f) i) H2,
Pd–C, MeOH, rt, 12 h, ii) 6 M HCl (aq.), 100 °C, 12 h, iii) propylene oxide,
EtOH, reflux, 2 h; (g) The same conditions described in steps ii) and iii) of
(f); (h) i) LiOH·H2O (10 equiv.), H2O/MeOH (2 : 3), reflux, 48 h, ii) Dowex
H+.
† Electronic supplementary information (ESI) available: experimental
details, spectroscopic characterization of all compounds, crystal structure
data and tables of electronic energies, enthalpies, entropies, Gibbs free
energies and coordinates for the conformations of structures. See http://
www.rsc.org/suppdata/cc/b4/b400282b/
Table 1 Synthesis of b2,2-amino acids (b-aa) from sulfamidates (Sul)
Entry
Sul
R2
Nuc (T, °C)
SN2 (%)a
Cond
R3
b-aa (%)b
1
2
3
4
5
(R)-4
(R)-4
(R)-5
(R)-5
(R)-5
N3
NaN3 (50)
(S)-6 (86)
(S)-7 (93)
(S)-8 (99)
(S)-9 (97)
(R)-10 (96)
f
NH2
SMe
OH
F
(S)-11 (70)
(S)-12 (81)
(S)-13 (85)
(S)-14 (83)
(R)-15 (98)
SMe
PNB-Oc
F
NaSMe (25)
PNB-OHc/ CsF (50)
NBu4F (25)
g
g
g
h
CN
NaCN (25)
CN
a Yield of SN2 product after column chromatography. b Overall yield corresponding to the transformations of SN2 product into b-aa. c PNB-OH = p-
nitrobenzoic acid.
980
C h e m . C o m m u n . , 2 0 0 4 , 9 8 0 – 9 8 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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suppressed (Table 1, entries 3–5). This functional groups exchange
has already been studied in order to modulate the regioselectivity in
the SN2 reaction on cyclic sulfates.11 Interestingly, an elimination
reaction on substrates (R)-4 or (R)-5 can be directed by the action
of DBU in THF at reflux, cleanly giving products 17 and 18,
respectively (Table 2). Some derivatives of these a-methylene-b-
alanines have been used as starting materials in the asymmetric
synthesis of b-amino acids,12 and as monomers in the production of
polymers with a high isotacticity.13
The approaches shown in Scheme 1 can be used to synthesize
b
2,2-amino acids with a variety of substituents in addition to the
methyl group. In this way we obtained, in enantiomerically pure
form, the following b2,2-amino acids: (S)-11, (S)-12, (S)-13, (S)-14
and (R)-15 (Table 1). The synthesis of b-amino-a-methylalanine14
(S)-11 was achieved from the SN2 product (S)-6 by hydrogenation
of the azide group and subsequent acid hydrolysis. The hydrolysis
of (S)-7 gave the new b2,2-amino acid S,a-dimethylisocysteine (S)-
12. In the same way, the known a-methylisoserine15 (S)-13 and a-
fluoro-a-methyl-b-alanine16 (S)-14 were obtained from (S)-8 and
(S)-9, respectively. Moreover, the new b2,2-amino acid 2-(amino-
methyl)-2-cyanopropanoic acid (R)-15 was obtained from (R)-10
by basic hydrolysis. Among these compounds it is worth high-
lighting b2,2-amino acid (S)-14; considering the significant effects
of the C–F bond on the activity of an HIV protease inhibitor,17 the
availability of a-fluorinated derivatives will serve to aid studies in
this field. The absolute configuration and the enantiomeric purity of
known b2,2-amino acids were established by comparison of the
optical rotations with literature values.14,15 The enantiomeric purity
of the rest of the amino acids was determined by GC–MS analysis
using a- or g-DEX™ chiral capillary columns.
A theoretical study was carried out in order to shed light on the
different reactivities of sulfamidates (R)-4 and (R)-5 with the
fluoride anion in the SN2 and E2 reactions. All ground state and
transition state (TS) geometries were located using hybrid density
functional theory (B3LYP)18 and the 6-31+G(d) basis implemented
in Gaussian 98.19 All the TS geometries were fully optimized and
characterized by frequency analysis. The energetic results of the
different TS with the fluoride anion and some relevant features of
the TS are shown in Fig. 1.
Fig. 1 TS calculated with (R)-4 and (R)-5 and fluoride anion.
We thank the MCYT (PPQ2001-1305) and the Universidad de
La Rioja (API-03/04, grant G. J.-O.).
Notes and references
‡ (a) Crystal data of (R)-4: C8H14N2O7S, Mw = 282.28, colorless prism, T
= 173 K, orthorhombic, space group P212121, Z = 4, a = 8.8646(3), b =
10.9014(4), c = 12.4336(5) Å, V = 1201.54(8) Å3, dcalc = 1.561 g cm23
,
F(000) = 592, l = 0.71073 Å (Mo-Ka), m = 0.299 mm21, Nonius kappa
CCD diffractometer, q range 3.7–27.9°, 2787 unique reflections, full-matrix
least-squares (SHELXL97),9 R1 = 0.0400, wR2 = 0.1029, goodness of fit
= 1.04, residual electron density between 0.26 and 20.29 e Å23; CCDC
228173. (b) Crystal data of (R)-5: C7H11NO7S, Mw = 253.24, colorless
prism, T = 173 K, orthorhombic, space group P212121, Z = 4, a =
8.2367(3), b = 8.9543(4), c = 14.8873(7) Å, V = 1098.0(8) Å3, dcalc
1.532 g cm23, F(000) = 528, l = 0.71073 Å (Mo-Ka), m = 0.316 mm21
Nonius kappa CCD diffractometer, q range 3.4–35.0°, 4609 unique
reflections, full-matrix least-squares (SHELXL97),9 R1 = 0.0591, wR2
0.1591, goodness of fit = 1.02, residual electron density between 0.41 and
20.51 e Å23. Hydrogen atoms were located from mixed methods (electron-
density maps and theoretical positions). CCDC 227600. See http://
www.rsc.org/suppdata/cc/b4/b400282b/ for crystallographic data in .cif or
other electronic format.
=
,
=
As far as substrate (R)-4 is concerned, the TS obtained for the E2
reaction (TS4_e) was slightly lower in energy (0.60 Kcal mol21
more stable) than that resulting from the nucleophilic attack of the
fluoride anion (TS4_s). This situation is in qualitative agreement
with the chemoselectivity experimentally observed. In contrast,
with (R)-5 the difference in energy between the TS (TS5_e and
TS5_s) is considerably higher, with the SN2 route now being
favored by ca. 2 Kcal mol21. This fact can be explained by
considering the electrophilic character of Ca. Thus, whereas the net
charge at Ca in (R)-5 is +0.54 electrons, this value is only +0.29 in
(R)-4.
1 D. Seebach and J. L. Matthews, Chem. Commun., 1997, 2015; R. P.
Cheng, S. H. Gellman and W. F. DeGrado, Chem. Rev., 2001, 101,
3219; M. Liu and M. P. Sibi, Tetrahedron, 2002, 58, 7991.
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5 I. Ojima, Catalytic Asymmetric Synthesis, 2nd Edn., Wiley-VCH: New
York, 2000, pp. 357–398.
Finally, in terms of geometry the hydrogen of the methyl group
in TS4_e (Fig. 1) is perfectly aligned anti with respect to the C–O
breaking bond. This feature is not possible with any of the
diastereotopic hydrogens of the ring, which explains the experi-
mental finding that only olefin 17 was formed as a product of the E2
reaction with sulfamidate (R)-4.
6 G. M. Atkins and E. M. Burgess, J. Am. Chem. Soc., 1972, 94, 6135.
7 K. C. Nicolaou, X. Huang, S. A. Snyder, P. B. Rao, M. Bella and M. V.
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structures, University of Göttingen, Germany, 1997.
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11 A. Avenoza, J. H. Busto, F. Corzana, J. I. García and J. M. Peregrina, J.
Org. Chem., 2003, 68, 4506.
Table 2 SN2 vs. E2 on cyclic sulfamidates (Sul)
12 D. Saylik, E. M. Campi, A. C. Donohue, W. R. Jackson and A. J.
Robinson, Tetrahedron: Asymmetry, 2001, 12, 657.
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3125.
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15 A. Avenoza, J. H. Busto, F. Corzana, G. Jiménez-Osés, M. París, J. M.
Peregrina, D. Sucunza and M. M. Zurbano, Tetrahedron: Asymmetry,
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7207.
Entry
R1
Sul
Conda
SN2 (%)
E2 (%)
1
2
3
4
N(OMe)Me
OMe
N(OMe)Me
OMe
(R)-4
(R)-5
(R)-4
(R)-5
A
A
B
B
(S)-16 (32)
(S)-9 (97)
—
17 (68)
—
17 (88)
18 (80)
—
a Conditions: A: i) NBu4F (1.2 equiv.), DMF, 50 °C, 12 h, ii) 20% H2SO4
(aq.)/CH2Cl2 (1 : 1), rt, 12 h. B: DBU (2.0 equiv.), THF, reflux, 12 h.
18 A. D. Becke, J. Chem. Phys., 1993, 98, 1372.
19 Gaussian 98, Revision A.11, Gaussian, Inc., Pittsburgh PA, 2001.
C h e m . C o m m u n . , 2 0 0 4 , 9 8 0 – 9 8 1
981