Novel anti-β-functionalized γ,δ-unsaturated amino acids via a thio-Claisen rearrangement

Article abstract of DOI:10.1016/j.tetlet.2010.04.102

A significantly improved thio-Claisen rearrangement method was developed for preparing anti-β-functionalized γ,δ-unsaturated amino acids, which are extremely useful nonproteinogenic amino acids used in chemistry and biology research. The mild reaction condition successfully introduced base labile functional groups into the amino acids with excellent anti/syn selectivities.

Full text of DOI:10.1016/j.tetlet.2010.04.102

Tetrahedron Letters 51 (2010) 3518–3520
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel anti-b-functionalized c,d-unsaturated amino acids via a
thio–Claisen rearrangement
*
Zhihua Liu, Hongchang Qu, Xuyuan Gu, Kwang-Soo Lee, Bryan Grossman, Vlad K. Kumirov, Victor J. Hruby
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A significantly improved thio–Claisen rearrangement method was developed for preparing anti-b-func-
tionalized ,d-unsaturated amino acids, which are extremely useful nonproteinogenic amino acids used
in chemistry and biology research. The mild reaction condition successfully introduced base labile func-
tional groups into the amino acids with excellent anti/syn selectivities.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 31 March 2010
Revised 22 April 2010
Accepted 23 April 2010
Available online 28 April 2010
c
Nonproteinogenic amino acids are among the most useful small
molecules in modern biology, chemistry, and drug discovery.1–3
Design and synthesis of unnatural amino acids with novel func-
tional groups for different chemical and pharmacological applica-
tions are in great demand, especially since peptides have
emerged as a reliable resource for new drug development.4–7 b-
ily introduced into the b-position with excellent anti/syn selectiv-
ities for the first time. Upon removing the auxiliaries from the
thioamides, novel, biologically interesting amino acids were
prepared.
Since a mild and efficient condition to form the Claisen rear-
rangement precursor is the critical step to expand functional group
compatibility, we hypothesized that using the thioamide as a
nucleophile to react with the electrophilic allylic bromide would
be a viable solution.19 This is because the resulting thioiminium
Functionalized c,d-unsaturated amino acids have drawn significant
research interest8,9 for two main reasons: first, the b-functionaliza-
tion allows the introduction of pharmaceutically interesting side
chain groups and second, the orthogonal reactivity of the terminal
double bond during peptide synthesis provides access to further
chemical modification. These amino acids have also been observed
to occur naturally and have enzyme inhibition activities.10,11
Several synthetic methodologies have been developed for the
construction of these molecules,12–18 among which the Claisen
rearrangement is the most often used. Chelation–Claisen rear-
rangement has proven to be effective in producing syn-b-function-
Table 1
Allylation condition screening for thio–Claisen rearrangement
S
Br
S
+
NHCbz
Catalyst
N
NHCbz
N
alized c
,d-unsaturated amino acids,14,15 but the corresponding anti
Conditions
amino acids were not readily available with high enantiopurities
until we introduced the Eschenmoser–Claisen rearrangement and
the thio–Claisen rearrangement methods.16–18 Despite these suc-
cesses, the amino acids produced were generally limited to those
having only hydrocarbon groups in the b-position. This can be
attributed to the harsh reaction conditions that were employed
in the above-mentioned syntheses: usually requiring strong base
treatment to form the enolate dianion (or equivalent) for the alkyl-
ation. Since nature uses much more than just hydrophobic amino
acids, such as glutamic acid and glutamine, therefore, it is of great
importance to develop a general and mild method to provide more
versatile amino acid derivatives. We report here a greatly im-
proved thio–Claisen rearrangement reaction, which features a
FeBr3-catalyzed allylation. Base labile functional groups were read-
2
S
S
TEA, THF,
-78 ºC ~ r.t.
N
N
+
NHCbz
NHCbz
3e ( ) anti
3e ( ), syn
Entry
Catalyst
Conditions
Solvent
Yielda
1
2
3
4
5
6
7
8
No catalyst
No Catalyst
No catalyst
No catalyst
20 mol % ZnBr2
20 mol % ZnBr2
20 mol % FeBr3
20 mol % FeBr3
Rt, 24 h
Rt, 24 h
Rt, 24 h
45 °C, 24 h
45 °C, 12 h
45 °C, 24 h
45 °C, 24 h
45 °C, 48 h
CH2Cl2
THF
0
0
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
32
41
64
74
76
* Corresponding author. Tel.: +1 520 621 6332; fax: +1 520 621 8407.
E-mail address: hruby@u.arizona.edu (V.J. Hruby).
a
Isolated yield of total isomers.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.102

Z. Liu et al. / Tetrahedron Letters 51 (2010) 3518–3520
3519
ion formed should increase the acidity of the
cantly, making it more acidic than the NH proton. Therefore, only
one equivalent of a weak base should be sufficient to deprotonate
a
-proton signifi-
amide 1 by using Lawesson’s reagent.20 2 was allylated using the
optimized conditions illustrated in entry 7 (Table 1). All reactions
proceeded smoothly giving the desired thio–Claisen rearrange-
ment products (3a–h). The results are summarized in Table 2.
The good to excellent anti/syn ratios were as expected, when con-
sidering the formation of the favored Z-thioenol ether after depro-
tonation21 and the chair-like six-membered ring transition
state18,22 (A in Fig. 1) of the Claisen rearrangement. Most notice-
ably, ester groups were successfully introduced into the b-position
for the first time. Thus, this mild reaction condition has expanded
the variety of functional groups which can be introduced at the b-
position. Moreover, compound 3g and 3h were obtained as diaste-
reopure products. We attribute these excellent results to a possible
bicyclic transition state model: the ester carbonyl group would
the
a-proton and trigger the rearrangement as compared to the
multi equivalents of strong base used previously. Fortunately, by
monitoring the reaction of just mixing the thioamide 3 and crotyl
bromide in dry MeCN at ambient temperatures, the reaction pro-
ceeded based on the consumption of the thioamide. Upon adding
TEA as the base to deprotonate the resulting thioiminium cation
and initiate the rearrangement, we successfully isolated the thio–
Claisen rearrangement product 3e (Table 1). Despite the low yield
of this reaction, we were encouraged by this result and optimized
the reaction conditions by varying the temperatures and solvents
(Table 1, entries 1–4). We found that heating and the use of a polar
aprotic solvent accelerated the allylation process. We also envi-
sioned that facilitating C–Br bond breaking should improve the
allylation yield and hence the rearrangement yield. Indeed, both
ZnBr2 and FeBr3 gave significantly improved yields via a Friedel–
Crafts alkylation type reaction (Table 1, entries 5–8), with FeBr3
providing somewhat better results.
Cbz
NHCbz
H
N
S
S
O
R3
N
N
O
Several more examples were studied with pyrrolidine as the
auxiliary, and the benzyloxycarbonyl group was selected as
the N -protecting group. The thioamide 2 was prepared from the
A
A'
a
Figure 1. Proposed transition state models for thio–Claisen rearrangement.
Table 2
Results of thio–Claisen rearrangement
1)
R2
Br
R3
R1
+
S
O
Lawesson
reagent
NHCbz
NHCbz
20-40 mol% FeBr3
N
N
1
2
R2
S
R
S
R
R3
2 R3
3 R2
2) TEA, THF,
-78 oC ~ 45 oC
N
N
S
+
R1
NHCbz
R1
NHCbz
R1
NHCbz
N
3 ( ), syn
3 ( ), anti
3e. R1, R2 = H; R3 = Me
3f. R1, R2 = H; R3 = Ph
3g. R1, R2 = H; R3 = COOMe
3a. R1, R2, R3 = H
3b. R1 = Me; R2, R3 = H
3c. R1 = H; R2, R3 = Me
3d. R1 = COOEt; R2, R3 = H
3h. R1, R2 = H; R3 = COOEt
Pdt
3a
Allylation reagent
Anti/syn
n/a
Yieldsa
68
Br
Br
3b
n/a
69
3c
n/a
n/a
42
72
Br
Br
3d
COOEt
3e
3f
10:1b
8:1b
74
51
82
72
Br
Br
Br
Br
Ph
3g
3h
>49:1b
>49:1b
COOMe
COOEt
a
Isolated yield of total isomers.
Determined by 1H NMR.
b

3520
Z. Liu et al. / Tetrahedron Letters 51 (2010) 3518–3520
Table 3
Acknowledgments
Results of amino acid generation
This work was supported by US Public Health Service Grants DK
1) m-CPBA,CH2Cl2,
S
17420 and the National Institute of Drug Abuse DA 06284, DA
13449. We also thank Professor Richard Glass (the University of
Arizona) for useful discussions.
R
3 R2
O
R3 R
-78 oC ~ rt
2
N
HO
R1
NHCbz
3 ( ), Anti
2) I2, THF/H2O, 4d
3) Zn dust, AcOH, 70 oC
R1
NHCbz
4 ( ), Anti
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.102.
Entry
R1, R2, R3
Anti/syn
Yieldsa
4d
4e
4g
4h
COOEt, H, H
H, H, Me
H, H, COOMe
H, H, COOEt
n/a
78
76
82
83
10:1b
>49:1b
>49:1b
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a
Isolated yield of total isomers.
Determined by 1H NMR.
b
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conditions not only offered good to excellent anti/syn selectivities
in high yield but also make it possible to greatly expand the func-
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of the enantioselective synthesis of these novel amino acids, the
scope of this synthetic methodology, and the applications of these
synthesized novel amino acids to drug design is in progress.
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