Synthesis of anti-β-substituted γ,δ-unsaturated amino acids via Eschenmoser-Claisen rearrangement

Article abstract of DOI:10.1021/ol061414l

(Chemical Equation Presented) Anti-β-substituted γ,δ- unsaturated amino acids have been synthesized via a novel design of the Eschenmoser-Claisen rearrangement. The rearrangement gives good isolated yields and excellent diastereoselectivity due to (Z)-N,O-ketene acetal formation and the pseudochairlike conformations of the reaction intermediates. Upon reductive hydrolysis, important novel amino acids and amino alcohols were synthesized for the first time via this methodology.

Full text of DOI:10.1021/ol061414l

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4215-4218
Synthesis of Anti-
-Unsaturated Amino Acids via
Eschenmoser Claisen Rearrangement
â-Substituted
γ,δ
−
Hongchang Qu, Xuyuan Gu, Byoung J. Min, Zhihua Liu, and Victor J. Hruby*
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721
hruby@u.arizona.edu
Received June 9, 2006
ABSTRACT
Anti-â
-substituted
γ
,
δ
-unsaturated amino acids have been synthesized via a novel design of the Eschenmoser
−Claisen rearrangement. The
rearrangement gives good isolated yields and excellent diastereoselectivity due to (Z)-N,O-ketene acetal formation and the pseudochairlike
conformations of the reaction intermediates. Upon reductive hydrolysis, important novel amino acids and amino alcohols were synthesized
for the first time via this methodology.
In the course of synthesis and conformational studies of
biological active peptide ligands, a universal methodology
is needed for the synthesis of nonproteinogenic amino acids
with terminal unsaturation.1 The double bond has been a
useful building block in organic synthesis due to its potential
conversion to aldehydes, alcohols, halides, epoxides, amines,
or carboxylic acids.2 It also can be used in peptide macro-
cyclization via ring-closing metathesis.3 In addition, various
â-side chain groups can be introduced in the synthesis so
that the amino acid will provide biologically active func-
tionalities in conformational constrained peptides.4 The
Kazmaier-Claisen rearrangement has turned out to be very
useful in the synthesis of this kind of amino acids and their
applications in peptidomimetics.5 However, the Kazmaier
strategy does not work well for racemic anti-â-substituted
γ,δ-unsaturated amino acids. It is difficult to introduce an
anti-â-substituent using the Z-allyl alcohol as a starting
material, which is not always commercially available.
Furthermore, the cis-oriented side chain can destabilize the
chairlike transition state resulting in poor diastereoselectivi-
ties.6 The rearrangement product is a diastereomeric mixture
that is usually hard to purify. Previous studies also have
generated other ω-unsaturation by Ni(II) complex alkyl-
(1) (a) Grubbs, R. H.; Miller, S. J.; Blackwell, H. E. U.S. patent 5811515,
1998. (b) Bartlett, P. A.; Barstow, J. F. J. Org. Chem. 1982, 47, 3933. (c)
Gu, X.; Ying, J.; Min, B.; Cain, J. P.; Davis, P. et al. Biopolymers 2005,
80, 151.
(4) (a) Hruby, V. J.; Balse, P. M. Curr. Med. Chem. 2000, 7, 945. (b)
Hruby, V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich, M. Biopolymers
1997, 43, 219.
(2) Rutjes, T. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem. Soc.,
Perkin Trans. 1 2000, 24, 4197.
(3) (a) Fernandez, M. M.; Diez, A.; Rubiralta, M.; Montenegra,
E.; Casamitjana, N. J. Org. Chem. 2002, 67, 7587. (b) Hoffmann, T.;
Harald, L.; Waibel, R.; Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40,
3361.
(5) (a) Kazmaier, U. Angew. Chem., Int. Ed. 1994, 33, 998. (b) Kazmaier,
U.; Krebs, A. Angew. Chem., Int. Ed. 1995, 34, 2012. (c) Kazmaier,
U.; Mues, H.; Krebs, A. Chem. Eur. J. 2002, 8, 1850. (d) Kazmaier,
U.; Maier, S. J. Org. Chem. 1999, 64, 4574. (e) Qiu, W.; Gu, X.;
Soloshonok, V. A.; Carducci, M. D.; Hruby, V. J. Tetrahedron Lett. 2001,
42, 145.
10.1021/ol061414l CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/23/2006

ation.7 However, attempts to prepare the anti product
have failed due to epimerization. On the other hand, the
Eschenmoser-Claisen rearrangement has been developed
as a useful methodology for synthesis of γ,δ-unsat-
urated carboxylic amide derivatives.8 We envisioned that
if an N,O-ketene acetal intermediate could be generated
in its cis configuration, a chairlike transition state con-
formation would provide an anti-â-substituted product
after rearrangement (Figure 1). During this study, we
Scheme 1. Meerwein Salt Formation and
Eschenmoser-Claisen Rearrangement
Figure 1. Syn- and anti-â-substituted γ,δ-unsaturated amino acids.
The Eschenmoser-Claisen rearrangement results are sum-
marized in Table 1. Various amounts of MeOTf were
investigated and 2.2 equiv was found to be the best.
Mechanistically, two equivs of methyl triflate was consumed
in intermediate 5 (Scheme 1). In practice, a minimum of
2.2 equiv of the alcohol was needed to get good yields.
Larger amounts of alcohol usually gave higher yields.
Stoichiometric amounts of 2,6-di-tert-butyl-pyridine were
used to scavenge triflic acid formed during the Meerwein
salt formation.11
The diastereomeric ratios were determined via proton
NMR spectra of the crude samples. We were delighted to
see that the reaction generated good to excellent diastereo-
selectivities. N,N-Diisopropylamine (Scheme 1, 4b) provided
a little better result in entry 5 (Table 1). These good
diastereoselectivities can be explained via unique (Z)-N,O-
ketene acetal formation and an excellent chairlike transition
state in the rearrangement.12 Unlike the Kazmaier-Claisen
intermediate where the enolate oxygen stays preferentially
cis to the glycyl nitrogen due to chelation control, the
Eschenmoser-Claisen intermediate could adopt two possible
configurations (Figure 2) due to the lack of the enolate
found that the Eschenmoser-Claisen rearrangement was
a straightforward methodology for the synthesis of the de-
sired amino acids. This methodology also can be used
for the synthesis of amino alcohols which are com-
mon structural components in bioactive nature products
and important synthetic building blocks in organic synthe-
sis.9
Glycine amide derivatives 4 were synthesized using the
secondary amine pyrrolidine 3a and N,N-diisopropyl-
amine 3b (Scheme 1), as we expected that a 2,5-diphenyl-
pyrrolidine C2-symmetric auxiliary and other enantiopure
secondary amines would provide an excellent enantioselec-
tive rearrangement later on.10 Various commercially avail-
able allyl alcohols were used successfully for the rearrange-
ment as shown in Table 1. After Meerwein salt formation
and lithium allyl oxide 6 addition, rearrangement provided
products with different â-substituents upon warmup. It should
be indicated that the â,â-dimethyl-γ,δ-unsaturated amino acid
derivative 8a-2 could not be synthesized by direct alkylation
using 3-bromo-3-methyl-1-butene because an SN2′ addition
would happen instead.
Table 1. Results of Eschenmoser-Claisen Rearrangement
a Isolated yields. Compounds a are from pyrrolidinylamide, and compounds b are from diisopropylamide. b Crotyl alcohol is a trans/cis mixture (19:1)
from Sigma-Aldrich.
4216
Org. Lett., Vol. 8, No. 19, 2006

Scheme 2. Reductive Hydrolysis, Amino Acid, and Amino
Alcohol Generation
Figure 2. (Z)- and (E)-N,O-ketene acetal reaction intermediates.
oxygen. Presumably, the thermodynamically more stable
intermediate 9 is the predominant configuration.13 It should
be noted that we tried to quench intermediate 9 using several
saturated alcohols. However, this N,O-ketene acetal inter-
mediate was unstable and hydrolyzed easily even in neutral
aqueous solution.
The hydrolysis of these rearranged amides was tricky
because of the presence of a terminal double bond and
the N-Cbz protecting group. There are many amide bond
hydrolysis methods reported.14 However, basic condi-
tions cleaved the Cbz group and caused epimerization. Strong
acidic conditions also removed the Cbz group and led
to partial hydrolysis of the terminal double bond. A re-
duction-hydrolysis approach was convenient in this case,
and among many reducing agents, lithium trimethoxyalu-
minum hydride15 and sodium aluminum hydride16 worked
well.
dized simultaneously to the carboxylic acid. Several amino
alcohols were obtained from further reduction of the amino
aldehydes that were isolated at low temperature by extraction
(Scheme 2). Little epimerization was observed during the
workup process. The diastereomerically pure amino alcohols
were obtained after flash column chromatography purifica-
tion.
Epimerization was observed during workup because
amino aldehydes are notorious for racemerization under
either basic or acidic conditions.17 The presence of a
â-substituent and a γ-double bond makes the R-proton
even more labile. The side reaction was initiated upon
aldehyde generation during the hydrolysis of the re-
duced complex. To minimize epimerization, we devel-
oped in situ modified Lindgren oxidation18 at low temper-
ature (Scheme 2). In this way, the aldehyde was oxi-
(6) Kazmaier, U. J. Org. Chem. 1996, 61, 3694.
Figure 3. 1H NMR spectra of 12-5 from different oxidation
approaches. Left: in situ oxidation. Right: oxidation after workup.
(7) (a) Gu, X.; Scott, C.; Ying, J.; Tang, X.; Hruby, V. J. Tetrahedron
Lett. 2003, 44, 5863. (b) Gu, X.; Ndungu, J. M.; Qiu, W.; Ying, J.; Carducci,
M. D.; Wooden, H.; Hruby, V. J. Tetrahedron 2004, 60, 8233.
(8) (a) Coates, B.; Montgomery, D.; Sterenson, P. J. Tetrahedron Lett.
1991, 32, 4199. (b) Coats, B.; Montgomery, D.; Sterenson, P. J. Tetrahedron
Lett. 1994, 50, 4025.
The lack of epimerization using the modified reduc-
tive hydrolysis and aldehyde oxidation was demon-
(9) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(10) (a) He, S.; Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 2000,
122, 190. (b) Qian, X.; Moris-Varas, F.; Fitzgerald, M. C.; Wong, C. Bioorg.
Med. Chem. 1996, 4, 2055.
(11) Resendes, R.; Nelson, J. M.; Fischer, A.; Jakle, F.; Bartole, A.;
Lough, A. J.; Manners, I. J. Am. Chem. Soc. 2001, 123, 2116.
(12) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, NY, 1991; Vol. 5, p 827 and
references therein.
(13) (a) Welch, J. T.; Eswarakrishman, S. J. Org. Chem. 1985, 50, 5909.
(b) Bartlett, P.; Hahne, W. F. J. Org. Chem. 1979, 44, 882. (c) Ziegler, F.
E. Acc. Chem. Res. 1977, 10, 227.
(14) (a) Groves, J. T.; Dias, R. M. J. Am. Chem. Soc. 1979, 101, 1033.
(b) Hub, D. H.; Jeong, J. S.; Lee, H. B.; Ryu, H.; Kim, Y. G. Tetrahedron
2002, 58, 9925. (c) Gassmart, P. C.; Hodgson, P. K. G.; Balchunis, R. J. J.
Am. Chem. Soc. 1976, 98, 1275. (d) Moghaddam, F. M.; Ghaffarzadeh, M.
Synth. Commun. 2001, 31, 317.
(15) Brown, H. C.; Weissman, P. M. J. Am. Chem. Soc. 1965, 87, 5614.
(16) Zakharkin, L. I.; Maslin, D. N.; Gavriljinko, V. V. Tetrahedron 1969,
25, 5555.
(17) (a) Ito, J. J.; Golebiowshi, A. Chem. ReV. 1989, 89, 149. (b) Rittle,
K. E.; Homnick, C. F.; Ponticelle, G. S.; Evans, B. E. J. Org. Chem. 1982,
47, 3016.
Figure 4. Rotational interexchange study of 12-5 by NOE.
(18) Kraus, G. A.; Bruce Roth, B. J. Org. Chem. 1980, 45, 4825.
Org. Lett., Vol. 8, No. 19, 2006
4217

change peak at 4.78 ppm. The size of the exchange
peak increased as the NOE mixing time was increased.
The relative stereochemistry of 12-3 was confirmed by
comparing its 13C NMR chemical shift to the minor product
synthesized from an ester enolate Claisen rearrangement.1
A single-crystal X-ray structure of compound 8b-5 also was
obtained (Figure 5). An anti relationship of the R-amino
group and the â-phenyl group was unambiguously shown
in this structure.
In summary, we have developed a convenient method-
ology for the synthesis of anti-â-substituted γ,δ-unsat-
urated amino acids for the first time using a Meer-
wein Eschenmoser-Claisen rearrangement. This [3,3]-sig-
matropic rearrangement gives excellent diastereoselectivities.
Both the amino acid and the amino alcohol can be easily
purified and are ready for scale-up. The enantiomerically pure
synthesis of these novel compounds using enantiopure C2-
symmetric 2,5-diphenylpyrrolidine is currently under inves-
tigation.
Figure 5. X-ray structure of product 8b-5 with an anti-â-
Acknowledgment. This work was supported by U.S.
Public Health Service grants DK 17420 and the National
Institute of Drug Abuse, DA 06284 and DA 13449. We also
thank Prof. Richard Glass (the University of Arizona) for
useful discussions regarding the rearrangement reaction
mechanisms.
substituent.
strated using an 1H NMR spectra comparison between
the epimerized and the diastereomerically pure product 12-5
(Figure 3). The downfield minor diastereomeric peaks
from in situ oxidation are almost undetectable, indi-
cating minimum epimerization. The broad peak at 4.63
ppm was likely from a rotamer of the product. This was
proven by NOE experiments (Figure 4).19 Irradiation of
the peak at 4.63 ppm resulted in the inversion of its ex-
Supporting Information Available: Experimental
procedures 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.
(19) Hatano, T.; Hemingwei, R. W. J. Chem. Soc., Perkin Trans. 2 1997,
1035.
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