Asymmetric synthesis of 3-substituted unsaturated prolines from chiral sulfoximine substituted allyl titanium(IV) complexes

Article abstract of DOI:10.1016/j.tetlet.2004.09.062

An asymmetric synthesis of the 3-substituted Δ^3,4- unsaturated prolines 7a-e and 3-substituted 4-methylene prolines 14a-c starting from the corresponding. γ,δ-unsaturated α-amino acids 4a-e and 11a-c, respectively, is described. Amino acid deri

Full text of DOI:10.1016/j.tetlet.2004.09.062

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8343–8346
Asymmetric synthesis of 3-substituted unsaturated prolines from
chiral sulfoximine substituted allyl titanium(IV) complexes
Shashi Kant Tiwari, Andreas Schneider, Stefan Koep and Hans-Joachim Gais*
Rheinisch-Westfa¨lische Technische Hochschule (RWTH) Aachen, Institut fu¨r Organische Chemie,
Professor-Pirlet-Strasse 1, 52056 Aachen, Germany
Received 3 September 2004; accepted 8 September 2004
Available online 28 September 2004
Abstract—An asymmetric synthesis of the 3-substituted D3,4-unsaturated prolines 7a–e and 3-substituted 4-methylene prolines 14a–c
starting from the corresponding c,d-unsaturated a-amino acids 4a–e and 11a–c, respectively, is described. Amino acid derivatives
4a–e and 11a–d were obtained through aminoalkylation of the corresponding sulfoximine substituted allyl titanium(IV) complexes
2a–e and 10a–d, respectively, with the N-tert-butylsulfonyl imino ester 3. Activation of sulfoximines 4a–e and 11a–c through methyl-
ation of the sulfoximine group followed by a KF mediated isomerization of the vinyl aminosulfoxonium salts 5a–e and 12a–c,
respectively, to the corresponding allyl aminosulfoxonium salt 6a–e and 13a–c, respectively, and a subsequent intramolecular nucle-
ophilic substitution of the allylic aminosulfoxonium group afforded the enantio- and diastereomerically pure proline derivatives in
medium to high yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Cyclic a-amino acids and especially proline derivatives
have gained much attention in recent years.1 Incorpora-
tion of proline derivatives into peptides has been shown
to provide interesting mimetics that can serve as new
drugs and probes for receptor studies. In addition, pro-
line derivatives are of interest as small molecule drugs.
For example, 3-substituted prolines are being currently
considered as conformationally restricted arginine, nor-
leucine, phenylalanine, tyrosine, aspartic acid, and
glutamic acid analogues.2 This has led to intensive stud-
ies of proline derivatives in regard to biological activity
and synthetic methodology.2–6 Particularly interesting
are prolines that carry substituents at both the 3- and
4-position. This substitution pattern offers not only
new possibilities for the attainment of conformationally
restricted peptide mimetics but can also be found as core
structure in the kainoid amino acids,7 which show neu-
roexcitatory properties. Because of their function as
conformationally restricted L-glutamic acid analogues
the kanoids and their derivatives are interesting probes
for the asymmetric synthesis of 3-substituted D3,4
-
unsaturated5 and 3-substituted 4-methylene prolines,6
which should make excellent starting materials for the
synthesis of 3-monosubstituted and 3,4-disubstituted
prolines.3,4 We have recently described an asymmetric
synthesis of unsaturated bicyclic prolines9 and amino
acids10 based on sulfoximine substituted cyclic and acy-
clic allyl titanium(IV) complexes.11 We now describe a
flexible asymmetric synthesis of substituted endocyclic
and exocyclic unsaturated prolines based on sulfoximine
substituted acyclic allyl titanium(IV) complexes.
Treatment of the sulfoximine substituted allyl tita-
nium(IV) complexes 2a–e,11 which were prepared from
the corresponding enantiomerically pure allyl sulfox-
imines 1a–e through titanation following lithiation, with
the imino ester 312 afforded the corresponding amino
acid derivatives 4a–e with high regio- and diastereoselec-
tivities as described previously (Scheme 1).13 Gratify-
ingly, the new tert-butyl substituted titanium complex
2d, which was obtained in a similar way from the allylic
sulfoximine 1d,14 also reacted with 3 with high regio-
and diastereoselectivities (P98% de) and furnished the
tert-butyl substituted amino acid derivative 4d in 84%
yield. The synthesis of the D3,4-unsaturated prolines
7a–e started with the activation of the corresponding
sulfoximines 4a–e through methylation at the N-atom
upon treatment with Me3OBF4 (1.1equiv) in CH2Cl2
for the study of neurological disorder as for example
8
´
Alzheimeras disease. Despite the considerable interest
in proline derivatives, there is still a lack of methods
Keywords: Asymmetric synthesis; Unsaturated prolines.
*
Corresponding author. Tel.: +49 2418094686; fax: +49
2418092665; e-mail: gais@rwth-aachen.de
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.062

8344
S. K. Tiwari et al. / Tetrahedron Letters 45 (2004) 8343–8346
NMe
Ph
O
NMe
Ph
R
S
O
1) 1.1 n-BuLi, THF
2) 2.1 ClTi(OiPr)3
2
R
S
Ti(OiPr)2
2a−e
1a−e
Bus
N
CO2Et
3
Bus
Bus
NMe
Ph
NMe2
O
NH
O
NH
1.1 Me3OBF4
S
S
EtO2C
Ph
EtO2C
CH2Cl2, RT, 2 h
R
R
BF4
4a−e
5a−e
5−10 KF, H2O
CH2Cl2, RT
Bus = SO2tBu
O
NMe2
Ph
R
Bus
S
NH
O
EtO
S
CO2Et
N
Ph
NMe2
BF4
O
R
Bus
7a−e
8
6a−e
a: R = Me, b: R = iPr, c: R = cC6H11, d: R = tBu, e: R = Ph
Scheme 1. Synthesis of D3,4-unsaturated prolines 7a–e.
Table 1. Synthesis of D3,4-unsaturated prolines 7a–e
the corresponding allyl aminosulfoxonium salts 6a–
e.9,16 Because of the high nucleofugacity of the allylic
aminosulfoxonium group9,16 salts 6a–e undergo a facile
cyclization with formation of the corresponding prolines
7a–e. After having accomplished a synthesis of prolines
7a–e, a perhaps facile synthesis of the 3-substituted 4-
methylene prolines 14 was envisioned starting from the
methyl substituted amino acid derivatives 11 (Scheme 2).
Entry Compd
R
t (h) Yield (%) 7 Yield (%) 8
1
2
3
4
5
a
b
c
d
e
Me
i-Pr
3
51
89
86
92
66
83
96
90
96
84
1
c-C6H11
t-Bu
Ph
2
1
0.75
at room temperature for 2h. The thus obtained amino-
sulfoxonium salts 5a–e (P95% yield) were then sub-
jected to a treatment with aqueous KF (5–10equiv) in
CH2Cl2 at room temperature, which afforded the corre-
sponding prolines 7a–e with P98% ee in medium to high
yields (Table 1). The conversion of 4a–e into 7a–e,
respectively, can be carried out with the same results
without isolation of any intermediate. It is noteworthy
that the yields of 7 were especially good with amino acid
derivatives 4 carrying a sterically demanding substituent
at the b-position (entries 2–4). The moderate yield of the
methyl substituted proline derivative 7a (entry 1) seems
to be due to a competing reaction of the aminosulfoxo-
nium salt 5a with KF at the sulfonamide group with
formation of 3 and the corresponding allyl aminosul-
foxonium salt. In addition to the proline derivatives
7a–e sulfinamide 8 with P98% ee was isolated in high
yields. Conversion of sulfinamide 8 to (S)-N,S-di-
methyl-S-phenylsulfoximine15 of P98% ee, the starting
material for the synthesis of 1a–e, has already been
described.16
It was speculated that the methyl substituted vinyl
aminosulfoxonium salts 12 would experience a regio-
selective FÀ-catalyzed isomerization to the allyl
aminosulfoxonium salts 13, leaving the stereogenic cen-
ter at the b-position intact. Prerequisite to a successful
realization of such a synthesis of 14 would be a highly
stereoselective reaction of the methyl substituted tita-
nium complexes 10 with 3. Aside from the present objec-
tive it was of interest to see whether the methyl group of
complexes 11 would have any influence on the stereose-
lectivity of the reaction with 3. Lithiation of the enantio-
merically pure allylic sulfoximines 9a, 9b,16 9c, and 9d,17
which were obtained from (S)-N,S-dimethyl-S-phenyl-
sulfoximine15 and the corresponding ketones by the
one-pot
addition–elimination–isomerization
route
including a chromatographic separation of the E/Z-iso-
mers,18 with n-BuLi (1.1equiv) at À78°C in THF fol-
lowed by a titanation with ClTi(i-OPr)3 (2.1equiv)
gave the corresponding allyl titanium(IV) complexes
10a–d. Gratifyingly, reaction of complexes 10a–d with
39 (1.1equiv) in THF at À78°C for 12h also proceeded
with high regio- and diastereoselectivities and afforded
the corresponding amino acid derivatives E-11a–d and
Z-11a–c in good yields (Table 2).
It is assumed that the vinyl aminosulfoxonium salts 5a–e
suffer a FÀ-catalyzed isomerization with formation of

S. K. Tiwari et al. / Tetrahedron Letters 45 (2004) 8343–8346
NMe
8345
Me
O
R
NMe
S
1) 1.1 n-BuLi, THF
2) 2.1 ClTi(OiPr)3
Me
O
Ph
R
S
2
Ph
Ti(OiPr)2
10a−d
9a−d
3
Bus
Bus
NMe
Ph
NMe2
O
O
S
NH Me
NH Me
1.1 Me3OBF4
S
Ph
EtO2C
EtO2C
CH2Cl2, RT, 2 h
R
R
11a−c
BF4
12a−c
11a−d
5−10 KF, H2O
CH2Cl2, RT
Bus = SO2tBu
R
Bus
NMe2
Ph
O
NH
S
8
CO2Et
EtO2C
N
R
Bus
BF4
13a−c
14a−c
a: R = Me, b: R = iPr, c: R = cC6H11, d: R = Ph
Scheme 2. Synthesis of 4-methylene prolines 14a–c.
Table 2. Synthesis of a-amino acid derivatives 11a–d
Table 3. Synthesis of 4-methylene prolines 14a–c
Entry Compd
R
Yield (%) E-11 Yield (%) Z-11
Entry
Compd
R
Yield (%) 14
Yield (%) 8
1
2
3
4
a
b
c
Me
i-Pr
33
64
38
10
16
—
1
2
3
4
a
a
b
c
Me (E-11)
Me (Z-11)
i-Pr
63
54
77
72
98
52
94
84
c-C6H11 45
Ph 58
d
c-C6H11
respectively, can be carried out with the same results
without isolation of any intermediate. In addition to
the proline derivatives 14a–c sulfinamide 8 with P98%
ee was isolated in high yields.
The E- and Z-isomers were each formed with P98% de.
Because of the further synthetic studies the E- and Z-iso-
mers of 11a–d were separated by preparative HPLC.
Thus both the methyl substituted complexes 10 and
the unsubstituted complexes 2 exhibit in the reaction
with 3 similar high syn diastereoselectivities. However,
the methyl group of 10 causes the reaction to be of
low E/Z-selectivity in regard to the double bond. Such
a difference in E/Z-selectivity between 10 and 2 was
not observed in their reactions with aldehydes.19 Inter-
estingly, the reaction of the phenyl substituted complex
10d with 3 was highly E-selective.
Finally, deprotection of the proline derivatives 7b and
14b upon treatment with CF3SO3H in CH2Cl2 (0.05–
0.1M)20 afforded the proline esters 15 and 16, respec-
tively, in good yields (Scheme 3).21
iPr
iPr
1) 3.1 CF3SO3H
CH2Cl2, 0 ˚C, 2 h
Methylation of sulfoximines 11a–c through treatment
with Me3OBF4 (1.1equiv) in CH2Cl2 afforded the corre-
sponding aminosulfoxonium salts 12a–c in high yields
(P95%). Isomerization of 12a–c and cyclization of
13a–c both proceeded readily upon treatment of the for-
mer salts with aqueous KF (5–10equiv) in CH2Cl2 and
furnished the corresponding cis-configured 3-substituted
4-methylene prolines 14a–c with P98% ee and P98% de
in medium to good yields (Table 3). Both isomers Z-11a
and E-11a afforded the proline derivative 14a. Thus a
separation of the E- and Z-isomers is not required for
the synthesis of 14a and presumably also not for that
of 14b and 14c. The conversion of 11a–c into 14a–c,
CO2Et
CO2Et
N
N
H
2) sat. NaHCO3, H2O
80%
Bus
7b
15
iPr
iPr
1) 3.3 CF3SO3H
CH2Cl2, 0 ˚C, 2 h
CO2Et
CO2Et
N
N
H
2) H2O, NaOH, pH 6.8
76%
Bus
14b
16
Scheme 3. Deprotection of the unsaturated prolines 7b and 14b.

8346
S. K. Tiwari et al. / Tetrahedron Letters 45 (2004) 8343–8346
44, 6779–6780; (f) Flo¨gel, O.; Amombo, M. G. O.; Reißig,
Conclusion: We have developed a new asymmetric syn-
thesis of 3-substituted D3,4-unsaturated prolines and
cis-configured 3-substituted 4-methylene prolines both
carrying various substituents at the 3-position including
sterically demanding ones. This method should give
access to proline derivatives that were previously not
or only difficultly accessible.
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Financial support of this work by the Grunenthal
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GmbH, Aachen, the Deutsche Forschungsgemeinschaft
(Collaborative Research Center ÔAsymmetric Synthesis
with Chemical and Biological MethodsÕ SFB 380 and
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eren for the HPLC separations.
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