Enantioselective synthesis of anti-β-substituted γ,δ- unsaturated amino acids: A highly selective asymmetric thio-Claisen rearrangement

Article abstract of DOI:10.1021/ol801657q

(Chemical Equation Presented) A novel synthesis of optically active anti-β-substituted γ,δ-unsaturated amino acids via a thio-Claisen rearrangement has been achieved. A 2,5-diphenylpyrrolidine was used as a (C₂-symmetric chiral auxiliary to control the stereochemistry, giving good yields and excellent diastereoselectivities and enantioselectivities.

Full text of DOI:10.1021/ol801657q

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4105-4108
Enantioselective Synthesis of
anti-ꢀ-Substituted γ,δ-Unsaturated
Amino Acids: A Highly Selective
Asymmetric Thio-Claisen Rearrangement
Zhihua Liu, Hongchang Qu, Xuyuan Gu, Byoung J. Min, Joel Nyberg, and Victor
J. Hruby*
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721
hruby@u.arizona.edu
Received July 21, 2008
ABSTRACT
A novel synthesis of optically active anti-ꢀ-substituted γ,δ-unsaturated amino acids via a thio-Claisen rearrangement has been achieved. A
2,5-diphenylpyrrolidine was used as a C2-symmetric chiral auxiliary to control the stereochemistry, giving good yields and excellent
diastereoselectivities and enantioselectivities.
Synthesizing optically active nonproteinogenic amino acids
has played a crucial role in the development of peptides and
peptidomimetics as therapeutic agents.1 ꢀ-Substituted γ,δ-
unsaturated amino acids have turned out to be especially
important building blocks for these studies due to the
diversified reactivities of the terminal double bond and their
ability to introduce biologically active functionalities.2
Constructing this type of structural skeleton has been under
investigation for many years, and one of the most powerful
synthetic methods toward these goals is the Claisen rear-
rangement.3 Kazmaier et al. have reported stereoselective
syntheses of syn-ꢀ-substituted γ,δ-unsaturated amino acids
via a chelate Claisen rearrangement.4 However, progress on
making anti-ꢀ-substituted γ,δ-unsaturated amino acids was
(1) For reviews, see: (a) Sawyer, T. K. Peptidomimetic and Nonpeptide
Drug Discovery: Impact of Structure-Based Drug Design In Structure Based
Drug Design: Disease, Targets, Techniques and DeVelopment; Veerapan-
dian, P., Ed.; Marcel Dekker: New York, 1997; pp 559-634. (b) Patch,
J. A.; Kirshenbaum, K.; Seurynck, S. L.; Zuckermann, R. N.; Barron, A. E.
In Pseudopeptides in Drug DeVelopment; Nielsen, P. E., Ed.; Wiley-VCH:
Weinheim, Germany, 2004. (c) Hruby, V. J.; Li, G.; Haskell-Luevano, C.;
Shenderovich, M. D. Biopolymers 1997, 43, 219. (d) Hruby, V. J.; Slate,
C. Amino Acid Mimetics and Designing of Peptidomimetics for Opioid
and Melanocortin Receptors: General Perspectives In AdVances in Amino
Acid Mimetics and Peptidomimetics; Abell, A., Ed.; JAI Press Inc.:
Greenwich, 1999; pp 191-220. (e) Hruby, V. J.; Han, G.; Gitu, P. M.
Synthesis of Side-Chain Conformationally Restricted R-Amino Acids In
Methods of Organic Chemistry (Houben-Weyl); Goodman, M., Felix, A.,
Moroder, L., Toniolo, C., Eds.; Thieme Verlag: Stuttgart, 2002; pp 5-
51.
(2) (a) Ruties, T. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem.
Soc., Perkin Trans. 1 2000, 24, 4197. (b) Morimoto, Y.; Takaishi, M.;
Kinoshita, T.; Sakaguchi, K.; Shibata, K. Chem. Commun. 2001, 18, 1820.
(c) Gu, X.; Ying, J.; Min, B.; Cain, J.; Davis, P.; Willey, P.; Edita, N.;
Yamamura, H.; Porreca, F.; Hruby, V. J. Biopolymers 2005, 80, 151. (d)
Gu, X.; Cowell, S.; Ying, J.; Tang, X.; Hruby, V. J. Tetrahedron Lett. 2003,
44, 5863.
(3) (a) Ku¨bel, B.; Ho¨fle, G.; Steglich, W. Angew. Chem., Int. Ed. Engl.
1975, 14, 58. (b) Bartlett, P. A.; Barstow, J. F. J. Org. Chem. 1982, 47,
3933.
10.1021/ol801657q CCC: $40.75
Published on Web 08/15/2008
2008 American Chemical Society

not satisfying because of the relative unavailability of
Z-allylic alcohol sources and the competing rearrangement
boatlike transition state when a Z-allylic alcohol is applied.5
The ester-enolate Claisen rearrangement has been reported
for the synthesis of these molecules; however, limited chiral
starting materials and epimerization during the synthesis are
problems that remain to be solved.6 Most recently, our group
has achieved a synthesis of such amino acids via the
Eschenmoser-Claisen rearrangement with excellent diaste-
reoselectivity and good enantioselectivity.7 Here we report
on another novel, complementary synthesis via a thio-Claisen
rearrangement. This method is straightforward and highly
selective using a bulky C2 symmetric chiral auxiliary, and
the chiral auxiliary can be recycled after producing the final
amino acids.
the sulfur position. Thio-Claisen rearrangement occurred
when the reaction mixture was warmed up slowly to room
temperature or higher (when necessary) to afford thioamides
5 and 6 (Scheme 1).
Our first attempts at this reaction with 2.2 equiv of LDA
gave unsatisfactory results. The yields were extremely low
with large amounts of starting materials recovered. After
examining the structure more carefully, we realized that this
might be caused by a two-step deprotonation. The proton
on the R amino group is the most acidic one, which would
be removed first to give A. However, this makes the
deprotonation of the R proton much harder.10 The resulting
thioenolate dianion B is a new system that has never been
examined before to our knowledge. We postulated that B
might be capable of pulling the proton on the diisopropy-
lamine back, making the dianion formation a reversible
process (Scheme 2).11 If so, an excess amount of LDA
The C2 symmetric chiral auxiliary (2R,5R)-2,5-diphe-
nylpyrrolidine (1) was prepared in optically pure form8 and
coupled to NR-Cbz glycine to generate amide 2 using DIC/
HOAt as the coupling reagent. This coupling reaction gave
excellent yields despite the steric hindrance of the phenyl
rings (Scheme 1). A thionation reaction with Lawesson’s
Scheme 2. Equilibrium of Thio-Enolate Dianion Deprotonation
Scheme 1
.
Generation of Thio-Enolate Dianion and Asymmetric
Thio-Claisen Rearrangement
possibly can push the equilibrium toward the dianion, or
using a stronger base to make it an irreversible process might
solve the problem. To test this hypothesis, we increased the
amount of LDA to 3.2 equiv, and a significant improvement
in the reaction was observed: the yields were much better
and no starting material was observed after work up. A 2.2-
equiv portion of nBuLi also gave acceptable results, but extra
nBuLi is not desired because of the nucleophilicity of the
n-butyl anion. HMPA was also added before adding the
allylic bromide, and this was found to increase the product
yield and reduce the formation of C-alkylation side products.
The results of the rearrangement studied on six commercially
available allylic bromides are summarized in Table 1.
reagent converted the amide to the thioamide 3 in quantitative
yield.9 The thio-enolate was made by treatment of 3 with
freshly prepared LDA in THF at -78 °C, and then the allylic
bromide was added to the reaction to alkylate the enolate at
(4) (a) Kazmaier, U. Angew. Chem., Int. Ed. Engl. 1994, 33, 998. (b)
Kazmaier, U. Synlett. 1995, 11, 1138. (c) Kazmaier, U.; Maier, S. Chem.
Commun. 1995, 19, 1991. (d) Mues, H.; Kazmaier, U. Synthesis 2001, 3,
487. (e) Qiu, W.; Gu, X.; Soloshonok, V. A.; Carducci, M. D.; Hruby,
V. J. Tetrahedron Lett. 2001, 42, 145. (f) Kazmaier, U.; Mues, H.; Krebs,
A. Chem. Eur. J. 2002, 8, 1850.
Despite higher temperatures being required in some cases,
the diastereoselectivities generally were excellent, and only
anti products were obtained as expected. In many cases, only
optically pure compounds were obtained. The absolute
configuration of the product 5d was determined by X-ray
(5) Kazmaier, U. J. Org. Chem. 1996, 61, 3694.
(6) (a) Sakaguchi, K.; Suzuki, H.; Ohfune, Y. Chirality 2001, 13, 357.
(b) Sakaguchi, K.; Yamamoto, M.; Kawamoto, T.; Ymada, T.; Shinada,
T.; Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 2004, 45, 5869.
(7) (a) Qu, H.; Gu, X.; Min, B. J.; Liu, Z.; Hruby, V. J. Org. Lett. 2006,
8, 4215. (b) Qu, H.; Gu, X.; Liu, Z.; Min, B. J.; Hruby, V. J. Org. Lett.
2007, 9, 3997.
(10) Ishida, T.; Shinada, T.; Ohfune, Y. Tetrahedron Lett. 2005, 46,
311.
(8) Chong, J. M.; Clarke, I. S.; Koch, I.; Olbach, P. C.; Taylor, N. J.
Tetrahedron: Asymmetry 1995, 6, 409.
(11) (a) Laube, T.; Dunitz, T. D.; Seebach, D. HelV. Chim. Acta 1985,
68, 1373. (b) Aebi, J. D.; Seebach, D. HelV. Chim. Acta 1985, 68, 1507.
(9) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 22, 5061.
4106
Org. Lett., Vol. 10, No. 18, 2008

Table 1. Results of Asymmetric Thio-Claisen Rearrangement
Figure 2
rangement.
. Proposed transition state model of thio-Claisen rear-
a Determined by chiral HPLC. b Isolated yield of total isomers.
at 5.61 ppm resulted in the inversion of its exchange peak
at 5.51 ppm, which indicates these two peaks arise from the
same proton. The relative intensity of the exchange peak
increased as the NOE mixing time was increased, which
demonstrated that the irradiation selectivity was good.
crystal structural analysis (Figure 1). It shows an R-
configuration at all of the four chiral centers. This result is
consistent with the model (Figure 2) suggested by He et al.12
when they studied the thio-Claisen reaction on tertiarythioa-
mide. Deprotonation of the thioamide 3 gives the Z-
Figure 3. Rotational interexchange study of 5c by NOE.
Figure 1. X-ray crystal structure of 5d.
thioenolate as the primary product.13 The two possible
chairlike transition states are shown as C and D in Figure 2,
and C is favored for the obvious steric reasons. A decrease
of the diastereoselectivity was observed during the study as
the size of R3 was increased (entries e and f). Presumably,
this was caused by the increasing steric repulsion between
the Cbz group and R3.
The step of removing the chiral auxiliary was tricky.
Regular acidic or basic hydrolysis is obviously not good
because such harsh conditions will cause epimerization at
the R carbon and may cleave the NR-Cbz protecting group.
Besides, it is impossible to reduce a thioamide like an amide
to an alcohol or aldehyde because thioamides are inert to
regular metal hydride reducing reagents.16 In our case,
R-amino thioamides are especially unreactive due to a
possible hydrogen bonding between the NH and the sulfur.17
It shows no reactivity when using the common BF4OEt2
method12,18 even when the reaction was performed in
dichloroethane at 80 °C. Fortunately, we were finally able
The diastereoselectivity was determined by chiral HPLC
after converting the thioamide to an amide.14 It should be
pointed out that although most products contain only one
1
diastereomer, the H NMR shows two sets of peaks, which
was confirmed to be caused by Cbz rotamers after we
performed an NOE study (Figure 3).15 Irradiation of the peak
(15) Hatano, T.; Hemingwei, R. W. J. Chem. Soc., Perkin Trans. 2 1997,
5, 1035.
(16) To the best of our knowledge, direct metal hydride reduction of
thioamides has not been reported to date.
(12) He, S.; Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122,
190.
(17) (a) Hollo´si, M.; Majer, Zs.; Zewdu, M.; Ruff, F.; Kajta´r, M.; Ko¨ve´r,
K. E. Tetrahedron 1988, 44, 195. (b) Hansen, P. E.; Duus, F.; Bolvig, S.;
Jagodzinski, T. S. J. Mol. Struct. 1996, 378, 45.
(13) Tamaru, Y.; Furukawa, Y.; Mizutani, M.; Kitao, O.; Yoshida, Z.
J. Org. Chem. 1983, 48, 3631.
(14) (a) Kochhar, K. S.; Cottrell, D. A.; Pinnick, H. W. Tetrahedron
Lett. 1983, 24, 1323. (b) See Supporting Information for details.
(18) (a) Branda¨nge, S.; Lindblom, L. Acta Chem. Scand. B 1979, 33,
187. (b) Heitz, M. P.; Overman, L. E. J. Org. Chem. 1989, 54, 2591
.
Org. Lett., Vol. 10, No. 18, 2008
4107

to develop a one-pot alkylation-reduction-oxidation reac-
tion that could readily recycle the chiral auxiliary and turn
the amino thioamide into amino acids with a minimal loss
of optical activity. To our knowledge, this is the first example
of successfully reducing an R-amino tertiarythioamide to an
aldehyde. After screening several alkylation reagents and
conditions, we found that methyl triflate provided a high-
yield S-alkylation at ambient temperatures, and this allowed
the resulting thioiminium salt 9 to be reduced to an N,S-
acetal by Superhydride. This was followed by amino
aldehyde generation by quenching and an in situ modified
Lindgren oxidation at low temperature19 to provide the
desired products 10 with little or no epimerization (Scheme
3). The results of this reaction are summarized in Table 2.
Table 2. Results of Amino Acid Generation
compound 10
anti:syna
eeb (%)
yield (%)c (three steps)
a
b
c
d
e
f
NA
NA
NA
100:9
100:22
100:12
94
95
96
98
87
81
42
37
32
40
44
34
a Determined by 1H NMR. b Determined by chiral HPLC by comparison
with the racemic compounds prepared from previously reported Eschen-
moser-Claisen rearrangement.7a c Isolated yield of total isomers after three-
step reaction.
a complete loss of optical activity as this type of compound
was known not to be stable at room temperature.20
In summary, we have developed a novel method to
synthesize anti-ꢀ-substituted γ,δ-unsaturated amino acids.
The thio-Claisen rearrangement gives excellent diastereose-
lectivities, and optically active amino acids were obtained
after a low-racemization one-pot alkylation-reduction-
oxidation reaction to cleave the chiral auxiliary. This reaction
is ready to be scaled up, and the application of these amino
acids for preparing cyclic peptideomimetics will be reported
in the future.
Scheme 3
.
Alkylation-reduction-oxidation for Amino Acids
Generation and Chiral Auxiliary Recycle
Acknowledgment. This work was supported by U.S.
Public Health Service grants DK 17420 and the National
Institute of Drug Abuse DA 06284, DA 13449. We also
thank Prof. Richard Glass (the University of Arizona) for
useful discussions.
The anti/syn ratio and enantioselectivity were determined by
1H NMR and chiral HPLC by comparing them with authentic
samples, respectively. An increase of ee value with a decrease
of anti/syn ratio at the same time was observed in the last
three entries. This should be caused by losing chirality at
the R-carbon but not at the ꢀ-carbon during the synthesis.
The results are consistent with the results of compounds 5.
When the aldehyde was separated and purified, we observed
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization (1H NMR, 13C
NMR, HRMS, IR) of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL801657Q
(20) (a) Rittle, K.E.; Homnick, C. F.; Ponticelle, G. S.; Evans, B. E. J.
Org. Chem. 1982, 47, 3016. (b) Ito, J. J.; Golebiowshi, A. Chem. ReV. 1989,
89, 149.
(19) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825.
4108
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