Synthesis of substituted cyclohexenyl-based β-amino acids by ring-closing metathesis

Article abstract of DOI:10.1021/ol0266121

(equation presented) A versatile ring-closing metathesis (RCM) approach has been developed for the preparation of cis and trans cyclohexenyl-based β-amino acids that are either unsubstituted (3) or substituted (10 and 12) at the α-position.

Full text of DOI:10.1021/ol0266121

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3663-3666
Synthesis of Substituted
Cyclohexenyl-Based â-Amino Acids by
Ring-Closing Metathesis
Andrew D. Abell* and James Gardiner
Department of Chemistry, UniVersity of Canterbury, Christchurch, New Zealand
a.abell@chem.canterbury.ac.nz
Received July 26, 2002
ABSTRACT
A versatile ring-closing metathesis (RCM) approach has been developed for the preparation of cis and trans cyclohexenyl-based â-amino
acids that are either unsubstituted (3) or substituted (10 and 12) at the r-position.
The assembly of simple monomeric units into larger more
complex structures that display well-defined secondary and
tertiary structures is an important means for the identification
and study of molecular function. One approach to this
endeavor has been to link simple monomeric units that
contain a fixed or defined conformation.1 These simple
conformationally constrained monomers impart important
physical and chemical properties onto the structures derived
from them. For example, proline and hydroxyprolines are
responsible for the structure and hence function of collagen,
one of nature’s most important structural proteins.2 Another
and nonnatural example is provided by cyclic â-amino acids,
oligomers of which have recently been shown to adopt
helices.1,3 These structures show discrete and predictable
folding patterns that resemble those derived from nature’s
R-amino acids. A host of cyclic R-amino acids are known;
however, there remains a clear need to develop a range of
cyclic â-amino acids if one is to control the structure and
hence function of â-peptides derived from them in a
predictable fashion.4 New and versatile methods for the
preparation of cyclic â-amino acids,5,6,7 particularly those
bearing substituents, are needed to achieve this goal.
In this paper we present a versatile ring-closing metathesis
(RCM) approach8 to cyclic â-amino acids that allows the
preparation of examples that are either unsubstituted (3) or
substituted at the R-position (10 and 12). This second class
represents a new and important addition to this family of
compounds. The constituent olefin of these units is able to
be hydrogenated to give the corresponding saturated ana-
logue, simple examples of which have already found wide
use in the production of â-peptides or, alternatively, been
functionalized7 to give new and important derivatives.
Our goal was to develop a method whereby both the R-free
and R-substituted derivatives were accessible from a common
precursor. The basic synthetic strategy involves the stereo-
(4) Fu¨lo¨p, F. Chem. ReV. 2001, 101, 2181.
(5) Appella, D. H.; LePlae, P. R.; Raguse, T. L.; Gellman, S. H. J. Org.
Chem. 2000, 65, 4766. Appella, D. H.; Christianson, L. A.; Karle, I. L.;
Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 6206.
(6) Schultz, A. G. Acc. Chem. Res. 1990, 23, 207. Xu, D.; Prasad, K.;
Repi, O.; Blacklock, T. J. Tetrahedron: Asymmetry 1997, 8, 1445. Enders,
D.; Wiedemann, J. Leibigs. Ann./Recl. 1997, 699. Kobayashi, S.; Kamiyama,
K.; Ohno, M., J. Org. Chem. 1990, 55, 1169. Nohira, H.; Ehara, K.;
Miyashita, A. Bull. Chem. Soc. Jpn. 1970, 43, 2230.
(1) For a recent review in this area, see: Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. ReV. 2001, 101, 3219.
(2) Jenkins, C. L.; Raines, R. T. Nat. Prod. Rep. 2002, 19 (1), 49.
(3) Barchi, J. J.; Huang, X.; Appella, D. H.; Christianson, L. A.; Durell,
S. R.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122, 2711. Appella, D. H.;
Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem.
Soc. 1999, 121, 6206 and references therein. Abele, S.; Guichard, G.;
Seebach, D. HelV. Chim. Acta 1998, 81, 2141 and references therein.
Seebach, D.; Overhand, M.; Ku¨hnle, F. N. M.; Martinoni, B.; Oberer, L.;
Hommel, U.; Widmer, H. HelV. Chim. Acta 1996, 79, 913.
(7) Wipf, P.; Wang, X. Org. Lett. 2002, 4, 1197. Wipf, P.; Wang, X.
Tetrahedron Lett. 2000, 8747.
(8) For a review on the application of ring-closing metathesis to nitrogen-
containing heterocycles, alkaloids, and peptidomimetics, see: Phillips, A.
J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75.
10.1021/ol0266121 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/12/2002

selective allylation of 3-Cbz-aminohex-5-enoate 1, obtained
from Cbz-protected allyl-glycine,9 to give a diene that is then
cyclized by RCM to give the corresponding unsubstituted
aminocyclohexanecarboxylic acid (Scheme 1). In addition,
Scheme 2a
Scheme 1a
a Conditions: (i) LiCl, 2 equiv of LDA, THF, -78 °C, MeI or
EtI; (ii) LiCl, 2 equiv of LDA, THF, allyl bromide; (iii) 7, benzene
reflux.
2 into a known, but important, aminocyclohexane carboxylic
acid (4). To this end, treatment of 2 with Grubbs ruthenium
catalyst 711 gave the cyclic â-amino acid 3 as a single
diastereoisomer in excellent yield.12 The relative stereochem-
istry of this compound was confirmed after hydrogenation
in the presence of 10% Pd-on-C, followed by reprotection
with benzyl chloroformate to give the literature compound
4;13 this result confirmed the assigned relative configuration
of diene 2. Compound 3 was also hydrolyzed to give 5, a
suitable intermediate for incorporation into peptides. This
point was demonstrated by coupling 5 with phenylalanine
methyl ester, under standard conditions, to give epimers 6,
which were partially separable by silica-based chromatog-
raphy.
a Conditions: (i) LiCl, 2 equiv of LDA, -78 °C, THF, allyl
bromide; (ii) 7, benzene reflux; (iii) H2, Pd/C, MeOH, then DIEA,
CbzCl, DMAP, CH2Cl2; (iv) NaOH, MeOH; (v) EDCI, HOBt,
DIEA, L-PheOMe‚HCl, CH2Cl2.
the R-substituted cyclohexenyl â-amino acids were prepared
by an alkylation-allylation sequence, the order of which
dictates the stereochemistry of the ring substituents (Scheme
2).
With the basic methodology for the synthesis of cyclic
â-amino acids in place, our attention was turned to the
synthesis of R-substituted cyclic â-amino acids where a
second substituent is introduced stereoselectively at the
R-position (see Scheme 2). Derivative 1 was again utilized
as the key starting material. Alkylation of 1 with either
methyl or ethyl iodide, in the presence of LDA (2 equiv)
and LiCl, gave the R-methyl and R-ethyl substituted esters
8a and 8b, respectively. A second alkylation with allyl
bromide gave the diallylated compounds 9a and 9b with the
While a number of methods have been developed for the
stereoselective preparation of â-amino acids, access to
R-substituted â-amino acids of the type required here remains
a challenge. However, the key starting diene 2 was obtained
in 59% by allylation of 1 with allyl bromide in the presence
of LDA (2 equiv) and LiCl. It is well documented9,10 that
these conditions proceed via a doubly lithiated intermediate
to give the relative stereochemistry shown in 2 (see Scheme
2).
We next demonstrated the basic methodology for the
preparation of cyclic â-amino acids with the conversion of
(11) Grubbs, R. H.; Miller, S. J.; Blackwell, H. E. J. Am. Chem. Soc.
1996, 118, 9606.
(9) Podlech, J.; Seebach, D. Leibigs Ann. 1995, 1217 and references
therein.
(10) Seebach, D.; Esterman, H. Tetrahedron Lett. 1987, 28, 3103.
Seebach, D.; Esterman, H. HelV. Chim. Acta 1988, 71, 1824. Seebach, D.;
Wasmuth, D. Angew. Chem. 1981, 20, 971.
(12) Comparable results were obtained using Grubbs second generation
catalyst, tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)-4,5-di-
hydroimidazole-2-ylidene benzylidene]ruthenium(IV) dichloride.
(13) Appella, D. H.; LePlae, P. R.; Raguse, T. L.; Gellman, S. H. J.
Org. Chem. 2000, 65, 4766.
3664
Org. Lett., Vol. 4, No. 21, 2002

relative stereochemistry shown. RCM of each of these
diallylated compound (9a and 9b) gave 10a and 10b,
respectively,12 each as a single diastereoisomer as shown;
the indicated stereochemistry is based upon the results of
the previous sequence (see Scheme 1) and literature prece-
dence.9,10
Synthesis of the alternative cis isomer 12 was achieved
by reversing the order of the alkylation steps, i.e., alkylation
of 1 with allyl bromide followed by alkylation with methyl
iodide. This resulted in 11, an epimer of 9a, that gave rise
to 12 upon RCM (see Scheme 2). Therefore, it is possible
to prepare either the cis or trans R-substituted cyclic â-amino
acids using this methodology. It is interesting to note that
while cis isomers of type 12 have not been used to prepare
â-peptides, they are of interest as inhibitors of matrix
metalloproteases.14
Compound 16a was next converted into (+)-1 (such that the
sequence outlined in Scheme 1 could be repeated with
optically active material) by ester hydrolysis and re-esteri-
fication with diazomethane. This material gave an optical
rotation18 in close agreement with literature.20 We also
prepared the methyl ester (+)-1 from 13 by alkylation with
methyl bromoacetate, rather than tert-butyl bromoacetate, to
give 14b. Hydrolysis of the chiral auxiliary gave (-)-15b,
which was then subjected to the Curtius rearrangement
conditions to give (+)-1 directly (Scheme 3).
Scheme 3a
In the final sequence, we demonstrate that it is possible
to prepare a single enantiomer of the cyclic â-amino acids
using Evans chiral auxiliary chemistry15,16 to prepare (+)-1,
which was then subjected to our R-allylation, RCM strategy.
The anion of the N-acyl oxazolidinone 1317 was alkylated
with tert-butyl bromoacetate to give the alkylated imide 14a18
in 83%. The absolute configuration of 14a was confirmed
as shown by X-ray crystallography.19 Cleavage of the chiral
auxiliary was then carried out using lithium hydroperoxide15
to give the differentially protected diacid 15a18 in 95%. A
Curtius rearrangement procedure was then adopted for the
conversion of 15a to give the optically active18 Cbz-protected
â-allyl glycine tert butyl ester 16a. This was achieved by
refluxing the acid 15a in the presence of diphenylphosphoryl
azide and triethylamine15 to give an intermediate isocyanate,
which was subsequently trapped with benzyl alcohol. This
procedure was also carried out using tert-butyl alcohol as
the trapping agent to give the known Boc-protected derivative
17, the optical rotation18 of which agreed with literature.16
(14) Duan, J.; Ott, G.; Chen, L.; Lu, Z.; Maduskuie, T. P., Jr.; Voss, M.
E.; Xue, C.-B. PCT Int. Appl. WO 0170673 A2 20010927, 2001.
(15) Evans, D. A.; Wu, L. D.; Wiener, J. J.; Johnson, J. S.; Ripin, D. H.
B.; Tedrow J. S. J. Org. Chem. 1999, 64, 6411.
(16) Sibi, M. P.; Deshpande, P. K. J. Chem. Soc., Perkin Trans. 1 2000,
1461.
(17) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F., Jr.
Tetrahedron 1998, 44, 5525.
(18) Optical rotations [R]D for: (+)-1, +4.2° (c 2, CHCl3) (lit.20 +4.7°
(c 2, CHCl3)); (+)-2, +8.2° (c 1, DCM); (-)-3, -31.2° (c 1.0 CHCl3)
(lit.21 -33.5°); (-)-4, -18.4° (c 0.9, CHCl3) (lit.13 -18° (c 0.9, CHCl3));
(+)-14a, +51.2° (c 1, DCM); (+)-15a, +3.4° (c 1.4 DCM) (lit.16 +3.4° (c
1.4, DCM)); (-)-15b, -2.4° (c 0.5, DCM); (+) 16a, +1.8° (c 1, DCM);
(-)-17, -9.8° (1.1 MeOH) (lit.16 -10.09° (c 1.1 MeOH)).
(19) Crystallographic data for 14a: C21H27NO5, M ) 373.44, crystal
dimensions 0.55 × 0.38 × 0.33 mm3, orthorhombic, a ) 5.773 (6) Å, b )
10.373 (13) Å, c ) 33.36 (4) Å, R ) 90 (2)°, â ) 90 (2)°, γ ) 90 (2)°, V
a Conditions: (i) NaHMDS, tert-butylbromoacetate or methyl
bromoacetate, THF, -78 °C; (ii) LiOH-H2O2, THF-H2O, 0 °C;
(iii) DPPA, Et3N, toluene reflux, BnOH; (iv) TFA/CH2Cl2, Me2S,
CH2N2; (v) LiCl, 2 equiv LDA, allyl bromide, THF, from -78 °C
to room temperature; (vi) 7, CH2Cl2; (vii) H2, Pd/C, MeOH then
DIEA, CbzCl, DMAP, CH2Cl2; DPPA, Et3N, toluene reflux,
t-BuOH.
) 1998 (4) Å3, space group P2(1)2(1)2(1), Z ) 4, F(000) ) 800, Dcalcd
)
1.242 mg/m3, absorption coefficient 0.088 mm-1, θ range for data collection
) 2.31-26.41, index ranges -5 e h e 2, -12 e k e 12, -41 e l e 41,
data/restraints/parameters ) 3563/0/244, GOF on F2 was 0.905, final R
indices [I > 2σ(I)] R1 ) 0.0322, wR2 ) 0.0656, R indices (all data) R1 )
0.0454, wR2 ) 0.0685, largest difference peak and hole were 0.125 and
-0.185 eÅ-3, respectively. A unique data set was measured at 168(2) K.
Of the 8924 reflections obtained, 3563 were unique (Rint ) 0.0221) and
used in the full-matrix least-squares refinement. The structure was solved
by direct methods. Hydrogen atoms were fixed in idealized positions. All
non-hydrogen atoms were refined with anisotropic atomic displacement
parameters. Neutral scattering factors and anomalous dispersion corrections
for non-hydrogen atoms were taken from Ibers and Hamilton (Ibers, J. A.,
Hamilton, W. C., Eds.; International Tables for Crystallography; Kynoch
Press: Birmingham, UK, 1992; Vol. C).
The final stage of the synthesis of the optically active
cyclic â-amino acid (Scheme 3) was carried out as described
for the racemic series (see Scheme 1). In particular, (+)-1
(20) For an alternative synthesis, see: Shono, T.; Kise, N.; Sanda, F.;
Ohi, S.; Tsubata, K. Tetrahedron Lett. 1988, 29, 231.
Org. Lett., Vol. 4, No. 21, 2002
3665

was allylated with allyl bromide, via the doubly lithiated
intermediate, to give the diallylated derivative (+)-2,18 as a
single distereoisomer by NMR, which underwent RCM in
excellent yield12 to give (-)-3, the optical rotation18 of which
agreed with the literature.21 The absolute configuration was
further confirmed as shown by conversion of (-)-3 to (-)-
4,18 a literature compound.13
In summary, we have demonstrated a new and simple
procedure for the synthesis of cyclohexenyl â-amino acids
based on RCM chemistry. This methodology was used to
prepare the unsubstituted trans cyclic â-amino acids 3 and
4 from the simple diene 2 precursor. An R-substituent, as in
10 and 12, can also be introduced by employing an allylation/
alkylation sequence, the order of which defines the absolute
configuration of the product. Finally, we have shown that
optically active 3 and 4 can be prepared using optically active
(+)-1.
Acknowledgment. We acknowledge financial support
from the Royal Society of New Zealand Marsden Fund. We
also thank Professor Ward Robinson (University of Canter-
bury) for help with the X-ray crystallography.
Supporting Information Available: General procedures
for the alkylation and RCM experimental procedures and
spectroscopic data for 2, 3, 10, and 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) Kobayashi, S.; Kamiyama, K.; Iimori, T.; Ohno, M. Tetrahedron
Lett. 1984, 25, 2557.
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