Asymmetric synthesis of new chiral β-amino acid derivatives by mannich-type reactions of chiral N -sulfinyl imidates with N -tosyl aldimines

Article abstract of DOI:10.1021/ol100073y

Figure presented New chiral β-(sulfonylamino)sulfinylimidates are synthesized in high overall yield and excellent diastereomeric excess via highly anti-selective Mannich-type reactions of chiral N-tert-butanesulfinyl imidates with N-tosyl aldimines. Depro

Full text of DOI:10.1021/ol100073y

ORGANIC
LETTERS
2010
Vol. 12, No. 9
1904-1907
Asymmetric Synthesis of New Chiral
ꢀ-Amino Acid Derivatives by Mannich-type
Reactions of Chiral N-Sulfinyl Imidates
with N-Tosyl Aldimines
Filip Colpaert, Sven Mangelinckx,† and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
UniVersity, Coupure Links 653, B-9000 Ghent, Belgium
norbert.dekimpe@UGent.be
Received January 12, 2010
ABSTRACT
New chiral ꢀ-(sulfonylamino)sulfinylimidates are synthesized in high overall yield and excellent diastereomeric excess via highly anti-selective
Mannich-type reactions of chiral N-tert-butanesulfinyl imidates with N-tosyl aldimines. Deprotection of the ꢀ-(sulfonylamino)sulfinylimidates
gave access to enantiopure imidate hydrochlorides in high yields, as useful intermediates for an easy transformation to new chiral ꢀ-sulfonylamino
amides upon simple heating in chloroform. Hydrolysis of the imidate hydrochlorides afforded the corresponding chiral ꢀ-sulfonylamino esters
with >98% ee as new chiral ꢀ-amino acid derivatives.
The enantioselective synthesis of ꢀ-amino acid derivatives,
as biologically active compounds, constituents of biologically
active natural products, chiral building blocks and monomers
for the preparation of ꢀ-peptides,1 continues to be of
significant interest.2 The asymmetric Mannich-type reaction
of enolates with activated imines is one of the most important
and versatile methods for the synthesis of optically pure
ꢀ-amino acid derivatives which is under continuous develop-
ment.3 Recently, the Kobayashi group developed a DBU-
catalyzed direct Mannich-type addition reaction of R-methyl-
substituted sulfonylimidates with activated aldimines leading
to racemic ꢀ-aryl-R-methyl-substituted ꢀ-amino acid deriva-
tives with high anti-diastereoselectivity.4 Subsequently, the
same group also developed direct additions of sulfonylimi-
dates to imines with controllable diastereoselectivities cata-
lyzed by alkaline earth metal alkoxides and a preliminary
asymmetric addition reaction leading to a ꢀ-aryl-R-methyl-
substituted ꢀ-aminosulfonylimidate in moderate ee.5 Re-
(3) (a) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797. (b)
Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes,
F. P. J. T. Chem. Soc. ReV. 2008, 37, 29. (c) Cordova, A. Acc. Chem. Res.
2004, 37, 102. (d) Arend, M.; Westermann, B.; Risch, N. Angew. Chem.,
Int. Ed. 1998, 37, 1045. (e) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999,
99, 1069. (f) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541.
(g) Kleinman, E. F. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 893. (h) Ueno,
M.; Kobayashi, S. In EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd
ed.; Juaristi, E., Soloshonok, V. A., Eds.; Wiley: New York, 2005; pp
139-157.
* To whom correspondence should be addressed. Tel: +32 (0)9 264 59
51. Fax: +32 (0)9 264 62 43.
† Postdoctoral Fellow of the Research Foundation - Flanders (FWO).
(1) (a) Fu¨lo¨p, F.; Martinek, T. A.; Toth, G. K. Chem. Soc. ReV. 2006,
35, 323. (b) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366.
(2) (a) Cole, D. C. Tetrahedron 1994, 50, 9517. (b) Liu, M.; Sibi, M. P.
Tetrahedron 2002, 58, 7991. (c) Cardillo, G.; Tomasini, C. Chem. Soc.
ReV. 1996, 25, 117. (d) EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd
ed.; Juaristi, E., Soloshonok, V. A., Eds.; Wiley: New York, 2005. (e) Abele,
S.; Seebach, D. Eur. J. Org. Chem. 2000, 1.
(4) (a) Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc.
2008, 130, 1804. (b) Matsubara, R.; Kobayashi, S. Synthesis 2008, 3009.
10.1021/ol100073y  2010 American Chemical Society
Published on Web 04/02/2010

cently, our group demonstrated that an efficient and stere-
oselective R-alkylation of N-sulfinyl imidates can be achieved
leading to chiral R-substituted N-sulfinyl imidates as useful
intermediates in the synthesis of enantiopure amides and
esters.6 Therefore, we envisioned that the addition reaction
of chiral N-tert-butanesulfinyl imidates across aromatic
N-tosyl aldimines could be a valuable alternative approach
toward the synthesis of ꢀ-aryl-R-methyl-substituted ꢀ-amino
acid derivatives, and the results are described herein. The
interest of this study not only arises from the fact that a new
and complementary entry toward chiral ꢀ-aryl-R-methyl-
substituted ꢀ-tosylamino acid derivatives, a synthetically
interesting class of compounds,7 will become accessible, but
also previously unreported optically pure ꢀ-sulfonylamino
imidates, which could serve as valuable chiral building blocks
for biologically active compounds,8 will be synthesized.
Whereas enolate additions across sulfinylimines has proven
to be a powerful method for the asymmetric synthesis of
various ꢀ-amino acids,2d,9 metalloenamines derived from
N-sulfinyl ketimines have been exploited to a limited extent
in Mannich-type additions across imines.10 Trans-2-ami-
nocyclopentane carboxylic acid has been prepared via an
intramolecular self-condensation of the bis-sulfinyl imine
derived from hexanedial.11 Deprotonation of the N-sulfinyl
ketimine derived from ketones and diastereoselective Man-
nich-type reaction with N-sulfonyl aldimines afforded ꢀ-ami-
no imines that were transformed into enantiomeric ꢀ-ami-
noketones and 1,3-diamines.12 The electron-withdrawing
character of the sulfinyl moiety strongly attenuates the
nucleophilicity of the metalloenamine, and therefore, the
more nucleophilic metalloenamines derived from N-tert-
butanesulfinyl amidines,13 and N-tert-butanesulfinyl imidates6
have been exploited advantageously in R-alkylation reactions
and is herein used for asymmetric Mannich-type reactions
to ꢀ-amino acid derivatives.
The addition reaction of N-sulfinyl imidate 1 with N-tosyl
aldimines 2 was optimized by systematically changing the
reaction conditions in the addition reaction of imidate 1 with
aldimine 2a (X ) Cl) for the synthesis of ꢀ-(sulfonylami-
no)sulfinylimidates 3a (Table 1 and Supporting Information
Table S1). The synthesis of N-sulfinyl imidate 1 was
performed by condensation of (RS)-tert-butanesulfinamide
and 1,1,1-trimethoxypropane with a catalytic amount of
p-TsOH without solvent.6,13 An initial attempt using similar
reaction conditions as applied in the synthesis of ꢀ-amino-
sulfonylimidates,4b namely reaction of imidate 1 with aldi-
mine 2a in the presence of a catalytic amount of DBU in
DMF, did not result in the formation of addition products,
even after prolonged stirring at room temperature (see
Supporting Information Table S1). Subsequently the use of
LDA to deprotonate imidate 1 gave no reaction with aldimine
2a at -78 °C, while increasing the temperature to 0 °C for
3 h led to a mixture of unidentified compounds. The use of
2.0 equivalents LiHMDS to deprotonate N-sulfinyl imidate
1 at -78 °C resulted, after addition of aldimine 2a and
reaction at -78 °C for 1 h in full conversion to ꢀ-(sulfo-
nylamino)sulfinylimidates 3a with high relative stereocontrol
(anti/syn ) 93/7) and moderate absolute stereocontrol in the
formation of the anti-adducts (see Supporting Information
1
Table S1). By H NMR analysis of the crude reaction
mixture, only three diastereomers could be detected, namely
(RS,S,R)-anti-3a/(RS,R,S)-anti-3a/(RS,S,S)-syn-3a in a 67/26/7
ratio. Better results were obtained when less equivalents of
LiHMDS (1.2 equiv) were used leading to complete relative
anti-diastereoselectivity and acceptable absolute stereocontrol
((RS,S,R)-anti-3a/ (RS,R,S)-anti-3a ) 75/25) leading to opti-
cally pure ꢀ-(sulfonylamino)sulfinylimidates (RS,S,R)-anti-
3a and (RS,R,S)-anti-3a in 59% and 21% yield, respectively,
after flash chromatography (entry 1). Analogously, several
other new chiral imidates 3 were prepared with excellent
anti-diastereoselectivity (anti/syn ) 93/7 to >99/1) and good
yields (84-87%) using the latter optimized reaction condi-
tions (entry 2 and 3). When the addition reaction was
performed with aldimine 2b (X ) H) derived from benzal-
dehyde, ꢀ-(sulfonylamino)sulfinylimidate (RS,S,S)-syn-3b
could also be isolated by flash chromatography in 5% yield.
Noteworthy, the addition reaction of imidate 1 with aldimine
2c (X ) OMe) led to a reversed absolute anti-stereocontrol
with ꢀ-(sulfonylamino)sulfinylimidate (RS,R,S)-anti-3c as
major product. The use of KHMDS as a base led to a
significant decrease in relative stereocontrol (anti/syn ) 75/
25) with an improved absolute stereocontrol of the R-methyl-
substituted center (entry 4). The use of NaHMDS led also
to a decrease in relative stereocontrol (anti/syn ) 73/27)
without an improved absolute stereocontrol (entry 5). The
addition of ZnCl2 or HMPA, or the use of toluene instead
of THF, did not improve the diastereoselectivity of the
reaction (see Supporting Information Table S1). In a last
(5) Van Nguyen, H.; Matsubara, R.; Kobayashi, S. Angew. Chem., Int.
Ed. 2009, 48, 5927.
(6) Colpaert, F.; Mangelinckx, S.; Verniest, G.; De Kimpe, N. J. Org.
Chem. 2009, 74, 3792.
(7) For enantioselective synthesis of ꢀ-aryl-R-methyl-substituted ꢀ-to-
sylamino acid derivatives, see: (a) Davis, F. A.; Qui, H.; Song, M.;
Gaddiraju, N. V. J. Org. Chem. 2009, 74, 2798. (b) Davis, F. A.; Song, M.
Org. Lett. 2007, 9, 2413. (c) Raheem, I. T.; Jacobsen, E. N. AdV. Synth. &
Cat. 2005, 347, 1701. (d) Ma, Z. H.; Zhao, Y. H.; Jiang, N.; Jin, X. L.;
Wang, J. B. Tetrahedron Lett. 2002, 43, 3209. (e) Roos, G. H. P.;
Balasubramaniam, S. Synth. Commun. 1999, 29, 755. (f) Kashima, C.;
Fukasaka, K.; Takahashi, K. J. Heterocycl. Chem. 1997, 34, 1559. (g) Davis,
F. A.; Reddy, G. V.; Liang, C.-H. Tetrahedron Lett. 1997, 38, 5139. (h)
Abrahams, I.; Motevalli, M.; Robinson, A. J.; Wyatt, P. B. Tetrahedron
1994, 50, 12755.
(8) For synthetic applications of achiral ꢀ-sulfonylamino imidates, see:
(a) Weinstein, D. S. Chem. Abstr. 2007, 146, 251831 (US 0049628). (b)
Litzinger, E. A.; Marta´sek, P.; Roman, L. J.; Silverman, R. B. Bioorg. Med.
Chem. 2006, 14, 3185. (c) Davies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly,
R. J.; Leech, M. A.; Price Mortimer, A. J.; Roberts, P. M.; Smith, A. D.
Org. Biomol. Chem. 2004, 2, 2630. (d) Bailly, C.; Houssin, R.; Bernier,
J.-L.; Henichart, J.-P. Tetrahedron 1988, 44, 5833. (e) Buschauer, A.;
Wegner, K.; Schunack, W. Arch. Pharm. 1983, 316, 515. (f) Dziuron, P.;
Schunack, W. Arch. Pharm. 1974, 307, 470.
(9) Ferreira, F.; Botuha, C.; Chemla, F.; Pe´rez-Luna, A. Chem. Soc. ReV.
2009, 38, 1162
.
(10) For reports on additions of metalloenamines from N-sulfinyl
ketimines across aldehydes, see :(a) Kochi, T.; Tang, T. P.; Ellman, J. A.
J. Am. Chem. Soc. 2002, 124, 6518. (b) Kochi, T.; Tang, T. P.; Ellman,
J. A. J. Am. Chem. Soc. 2003, 125, 11276. (c) Denolf, B.; Mangelinckx,
S.; To¨rnroos, K. W.; De Kimpe, N. Org. Lett. 2007, 9, 187. (d) Patterson,
A. W.; Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2008, 73, 4362.
(11) Schenkel, L. B.; Ellman, J. A. Org. Lett. 2004, 6, 3621.
(12) (a) Zhao, C.-H.; Liu, L.; Wang, D.; Chen, Y.-J. Eur. J. Org. Chem.
2006, 2977. (b) Lanter, J. C.; Chen, H. F.; Zhang, X. Q.; Sui, Z. H. Org.
Lett. 2005, 7, 5905.
(13) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652.
Org. Lett., Vol. 12, No. 9, 2010
1905

Table 1. Optimization of the Addition Reaction of N-Sulfinyl Imidate 1 across Aldimines 2
(RS,S,R)-3/
(RS,R,S)-3/
(RS,S,S)-3a
entry
1
X
1 (equiv)
reaction conditions
anti/syna
>99/1
yield (%)
Cl
1.2
1) 1.2 equiv LiHMDS, THF, -78 °C, 45 min
2) -78 °C, 1 h
1) 1.2 equiv LiHMDS, THF, -78 °C, 45 min
2) -78 °C, 1 h
75/25/0
67/26/7
(RS,S,R)-3a (59),
(RS,R,S)-3a (21)
(RS,S,R)-3b (58),
(RS,R,S)-3b (24),
(RS,S,S)-3b (5)
(RS,S,R)-3c (34),
(RS,R,S)-3c (50)
-
2
H
1.2
93/7
3
4
5
6
OMe
Cl
1.2
1.2
1.2
1.2
1) 1.2 equiv LiHMDS, THF, -78 °C, 45 min
2) -78 °C, 1 h
1) 1.2 equiv KHMDS, THF, -78 °C, 45 min
2) -78 °C, 1 h
1) 1.2 equiv NaHMDS, THF, -78 °C, 45 min
2) -78 °C, 1 h
1) 1.2 equiv LiHMDS, THF, -78 °C, 45 min
+1.2 equiv MgBr2, 15 min
2) -78 °C, 1 h
38/60/2
63/12/25
51/22/27
87/4/9
98/2
75/25
73/27
91/9
Cl
-
-
Cl
7
8
9
a
Cl
1.2
1.2
1.2
1) 1.2 equiv LiHMDS, THF, -97 °C, 45 min
+1.2 equiv MgBr2, 15 min
2) -97 °C, 1 h
1) 1.2 equiv LiHMDS, THF, -97 °C, 45 min
+1.2 equiv MgBr2, 15 min
2) -97 °C, 1 h
1) 1.2 equiv LiHMDS, THF, -78 °C, 45 min
+1.2 equiv MgBr2, 15 min
2) -78 °C, 1 h
91/0/9
89/6/5
93/1/6
91/9
95/5
94/6
(RS,S,R)-3a (76),
(RS,S,S)-3a (6)
H
(RS,S,R)-3b (77),
(RS,R,S)-3b (3),
(RS,S,S)-3b (4)
(RS,S,R)-3c (73),
(RS,S,S)-3c (5)
OMe
1
Determined via H NMR analysis of the crude reaction mixture.
attempt involving addition of MgBr2 as Lewis acid, the
relative anti-stereoselectivity was maintained. Importantly,
the absolute stereocontrol was increased leading to a mixture
of diastereomers in a 87/4/9 ratio (entry 6). Even better results
were achieved upon performing the reaction at -97 °C
leading to high yields of (RS,S,R)-anti-3a-b (76-77%) after
flash chromatography (entry 7-8). Noteworthy, the addition
reaction of imidate 1 with aldimine 2c (X ) OMe) at -97
°C led only to a 31% conversion, while performing the
reaction at -78 °C led to full conversion and a yield of 73%
for (RS,S,R)-anti-3c as major product (entry 9).
In a next step, all the chiral ꢀ-(sulfonylamino)sulfinylimi-
dates 3 were N-deprotected by simple treatment with a
saturated solution of anhydrous HCl in dioxane (Scheme 1).
Initially, upon treating the chiral ꢀ-(sulfonylamino)sulfi-
nylimidates 3 with 20 equivalents HCl in dioxane at room
temperature for 1 h, a mixture of imidate hydrochlorides 4
and amides 5 was formed.6 However full conversion of
imidates 3 to imidate hydrochlorides 4 (63-92% yield) was
obtained after addition of 2 equivalents HCl (saturated
solution of HCl in dioxane) in ethanol at 0 °C for 0.5 h.
Furthermore, these imidate hydrochlorides 4 proved to be
excellent intermediates for an easy transformation to new
chiral ꢀ-sulfonylamino amides 5 upon simple heating at
reflux temperature in chloroform for 16 h (Scheme 1).
Purification involving recrystallization from diethyl ether
afforded the chiral amides 5 in generally high yields
(57-91%) and enantiomeric excess (>98% ee). The enan-
tiomeric excess of amides 5 was determined by chiral HPLC
(see Supporting Information).
Finally, hydrolysis of the imidate hydrochlorides 4 allowed
access to the corresponding new chiral ꢀ-sulfonylamino
esters 6. After carefull optimization, it was found that stirring
imidate hydrochlorides 4 in water at 55 °C for 7 h afforded
the new chiral esters 6 in good to excellent yields (63-94%)
and excellent enantiomeric excess (>98% ee) (Scheme 1).
The enantiomeric excess of esters 6 was determined by chiral
HPLC analysis (see Supporting Information). The synthesis
of the racemic mixtures of esters 6a-c was already reported
in the literature via a Mannich-type transformation of
aldimines with an R,ꢀ-unsaturated ester and a hydrosilane
catalyzed by a cationic rhodium(I) complex.14 Comparison
of the 1H and 13C NMR spectral data confirmed the assigned
(14) Muraoka, T.; Kamiya, S.; Matsuda, I.; Itoh, K. Chem. Commun.
2002, 1284.
1906
Org. Lett., Vol. 12, No. 9, 2010

in Lit., [R]D (S,S)-trans-8b -232.9 (c 0.3, CHCl3) vs -228.5
(c 1.0, CHCl3, ee ) 97%) in Lit.)15 confirming the assigned
absolute stereochemistry of the N-tosylated 2-arylazetidines
8 and compounds anti-3-6. Also, the (R,R)-enantiomer of
alcohol (S,S)-syn-7b is a known compound in the literature,
and thus allowed a comparison of the optical rotations ([R]D
(S,S)-syn-7b -24.3 (c 0.4, MeOH) vs (R,R)-syn-7b +25.4
and +26.1 (c 1.0, MeOH) in Lit.)7c,g confirming the absolute
stereochemistry of γ-sulfonylamino alcohol syn-7b and
compounds (RS,S,S)-syn-3b, (S,S)-syn-4b and (S,S)-syn-6b.
The enantiomeric excess of the N-tosylated 2-arylazetidines
8 was determined by chiral HPLC analysis (see Supporting
Information).
Scheme 1. Synthesis of Chiral ꢀ-Sulfonylamino Imidate
Hydrochlorides 4, Amides 5, Esters 6, γ-Amino Alcohols 7, and
N-Tosylazetidines 8 from ꢀ-(Sulfonylamino)sulfinylimidates 3
In analogy with a report on the DBU-catalyzed addition
reactions of N-sulfonyl imidates,4a the relative anti-diaste-
reoselectivity of the addition reactions of N-sulfinyl imidate
1 with N-tosyl aldimines 2 can be explained with a model
in which the reaction proceeds via transition state A instead
of B (Figure 1). Upon deprotonation of imidate 1, the
Figure 1. Proposed transition state model.
E-enolate will be preferentially formed with the methyl group
and the NSOtBu group at opposite sides of the C-C double
bond, while the N-tosyl aldimines adopt an E-configuration.
Considering the steric repulsion between the sulfinyl group
of imidate 1 and the aryl group of aldimine 2 and that
between the methyl substituent and the tosyl group in
transition state B, led to the conclusion that transition state
A may be favored to give the anti-diastereomers as major
products.
In conclusion, it was demonstrated that new chiral ꢀ-(sul-
fonylamino)sulfinylimidates are formed as new chiral ꢀ-ami-
no ester equivalents in high overall yield and excellent
diastereomeric excess via high anti-selective addition reac-
tions of N-sulfinyl imidates across N-tosyl aldimines. The
ꢀ-(sulfonylamino)sulfinylimidates could be deprotected into
chiral imidate hydrochlorides in high yields and further
transformed into chiral ꢀ-sulfonylamino amides and esters
by heating in chloroform or hydrolysis, respectively.
relative anti-selectivity of the addition reactions of imidate
1 across aldimines 2 for the synthesis of ꢀ-(sulfonylamino)-
sulfinylimidates 3.
To determine the absolute stereochemistry of compounds
3-6, γ-sulfonylamino alcohols 7 and N-tosylazetidines 8 were
synthesized starting from esters 6 according to literature
procedures (Scheme 1). Reduction of esters 6 with LiAlH4
in THF for 2.5 h afforded γ-sulfonylamino alcohols 7 in good
yields (63-87%).7c In a next step these alcohols 7 were
cyclized under Mitsunobu conditions to the corresponding
N-tosylazetidines 8 in high yields (74-94%) with high
enantiomeric excess (>98% ee).15 N-Tosylazetidines 8b are
reported compounds in the literature and thus allowed a
comparison of the optical rotations ([R]D (R,R)-trans-8b
+235.6 (c 0.2, CHCl3) vs +238.5 (c 1.0, CHCl3, ee >99%)
Acknowledgment. We are indebted to the Research
Foundation - Flanders (FWO - Vlaanderen) and Ghent
University (BOF) for financial support.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Enders, D.; Gries, J. Synthesis 2005, 3508.
Org. Lett., Vol. 12, No. 9, 2010
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