Chemoenzymatic synthesis of functionalized cyclohexylglycines and α-methylcyclohexylglycines via Kazmaier-Claisen rearrangement

Article abstract of DOI:10.1016/S0960-894X(01)00013-0

The synthesis of homochiral functionalized cyclohexylglycines and α-methylcyclohexylglycines via chelated Kazmaier-Claisen rearrangement is described. These were shown to be potent scaffolds for the development of MMP inhibitors.

Full text of DOI:10.1016/S0960-894X(01)00013-0

Bioorganic & Medicinal Chemistry Letters 11 (2001) 627±629
Chemoenzymatic Synthesis of Functionalized Cyclohexylglycines
and ꢀ-Methylcyclohexylglycines via Kazmaier±Claisen
Rearrangement
Tomas Hudlicky,a Ko® Oppong,a Caiming Duan,a Charles Stanton,a
Matthew J. Laufersweilerb and Michael G. Natchusb,*
aDepartment of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
bProcter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, OH 45040, USA
Received 26 October 2000; accepted 15 December 2000
AbstractÐThe synthesis of homochiral functionalized cyclohexylglycines and a-methylcyclohexylglycines via chelated Kazmaier±
Claisen rearrangement is described. These were shown to be potent sca€olds for the development of MMP inhibitors. # 2001
Elsevier Science Ltd. All rights reserved.
There continues to be a high demand for ecient
methods for the preparation of unnatural amino acids
as new natural and medicinal targets emerge. Some
unnatural amino acids have been demonstrated to be
useful sca€olds for the preparation of potent inhibitors
of the matrix metalloproteinases (MMPs).1À4 Many of
these inhibitors have been evaluated for ecacy against
a wide array of disease processes where tissue remodel-
ing plays a key role,5 including osteoarthritis,6 rheuma-
tiod arthritis,7À9 tumor metastasis,10,11 multiple
sclerosis,12 congestive heart failure13 and others (Fig. 1).
We sought to prepare a series of chiral, substituted
cyclohexylglycine and a-methylcyclohexylglycine deri-
vatives of type 1 and 2 to be used as intermediates in the
synthesis of MMP inhibitors. Structural and stereo-
chemical features of these targets are reminiscent of
amino acid 3, which was recently prepared by the
Hudlicky group as an intermediate in an anticipated
synthesis of morphine.14 Structures of this type can be
synthesized in a stereoselective fashion by means of a
chelated Kazmaier±Claisen rearrangement from diene-
diol 4 after appropriately functionalizing the 5-hydroxyl
group. Compound 4 has been exploited in the asym-
metric synthesis of many natural products15 and is
readily available by biooxidation of bromobenzene with
toluene dioxygenase expressed in one of several suitable
hosts.16,17 In this case, 4 was seen as a convenient
potential synthon for the preparation of cyclohexyl-
glycines of type 1 and 2, which have been previously
synthesized
asymmetrically
from
4-hydroxy-
phenylglycine, but with no control of cis versus trans
stereochemistry.18 In this manuscript we report pre-
liminary details for the preparation of both 1 and 2, and
the initial results of their screening.
Our approach to the 4-substituted cyclohexyl glycines
was adapted from the synthesis of amino acid 3.14 The
synthesis of glycine derivative 1 began with potassium
azodicarboxylate mediated reduction of 4 followed by
the protection of the 5-hydroxyl group with thexyl-
dimethylsilyl chloride and attachment of the N-Boc
Figure 1. Cyclohexylglycine and a-methylcyclohexylglycine targets.
*Corresponding author. Tel.: +1-513-622-3646; e-mail: natchus.mg@
pg.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00013-0

628
T. Hudlicky et al. / Bioorg. Med. Chem. Lett. 11 (2001) 627±629
glycine side chain via DCC coupling to provide 5 in
60% yield over three steps (Scheme 1). Exposure of 5 to
2 equiv of LDA in the presence of ZnCl2 with slow
warming from À78 ꢀC to room temperature over a 36 h
period provided, via the chelated Kazmaier±Claisen
rearrangement, amino acid 6 in reasonable diaster-
eomeric excess (4:1, in favor of the syn isomer) and
excellent chemical yield (75%). The crude acids were
converted immediately to their methyl esters, which
were easily separated by ¯ash chromatography. It is
interesting to note here that the faster-eluting major (R)-
isomer can be equilibrated to the (S)-isomer, which is
the intermediate required for the targeted synthesis of
morphine and is a precursor to amino acid 3.
install the sulfonamide20 to furnish 10. The Claisen
rearrangement of 10 to 12 worked smoothly under the
conditions employed for the preparation of the glycine
derivative, albeit in a lower yield, presumably because
of the lowered chelating potential of the sulfonamide as
compared to carbamate 5. The synthesis of 12 also did
not proceed with the same preference for the R isomer,
probably because of the increased size of the sulfona-
mide functionality and reduced preference for the chair
transition state. Nevertheless, acids 12 (3:1 mixture of
isomers at the a-center) were converted to methyl esters
13, the precursors for MMP inhibitors (Scheme 2).
Because the Claisen rearrangement also worked well
with the alanine ester (11), we prepared 14 (49% yield
over three steps, 3:1 ratio) and attempted to introduce
the sulfonamide group at this stage. However, as all
attempts to transform the methyl ester of 14 to 13 pro-
duced only trace amounts of product, we settled for the
longer but higher yielding route. The sulfonation was
attempted wth the esters of 14 as well as with its fully
hydrogenated derivative, but the hindered nitrogen
proved very unreactive.
The reasons for the non-stereospeci®c rearrangement
stem from competition between the mixed transition
states (chair and boat) operating in the Claisen rear-
rangement of moderately to heavily substituted systems
such as 5, as rationalized in an earlier report15 and as
explained by Kazmaier.19 It is highly probable that only
the chelated (Z)-enolate is generated prior to the rear-
rangement and that both transition states operate with
preference for the chair transition state.15 Ester 7 was
eventually converted to a series of MMP inhibitors of
the general structure 8, as outlined in Scheme 1.
Scheme 1. Reagents and conditions: (a) potassium azodicarboxylate,
HOAc, MeOH; (b) thexyldimethylsilyl chloride, imidazole, DMF; (c)
DCC, DMAP, N-Boc-glycine, CH2Cl2; (d) ZnCl2, LDA, THF,
À78 ꢀC; (e) CH2N2, Et2O; (f) H2 (40 psi), PtO2, Et3N, MeOH; (g)
tBu4NF, THF.
Scheme 2. Reagents and conditions: (a) alanine N-sulfonamide, DCC;
(b) N-Boc alanine, DCC; (c) TFA, CH2Cl2; (d) 4-methoxy-1,10-biphenyl-
sulfonyl chloride, Et3N, THF; (e) ZnCl2, LDA, THF, À78 ꢀC; (f)
CH2N2, Et2O; (g) H2 (40 psi), PtO2, Et3N, MeOH; (h) tBu4NF, THF.
This protocol was also applied to the synthesis of the a-
methyl derivative 2. Approaches to compounds of this
type are dicult via enolate alkylation or aldol-type
condensation. As the Claisen route seems especially
suited for preparation of this type of hindered amino
acid, we adapted the glycinate route to this target as
well. Starting with mono-TBS protected diol 9, we were
unable to introduce the a-methyl moiety already equip-
ped with the biphenylsulfonyl group via DCC coupling
(Scheme 2). We therefore prepared ester 11 and, fol-
lowing the removal of the Boc group, were able to
The Kazmaier±Claisen route appears to be the most
e€ective means of preparation for these compounds.
Improvement of stereocontrol remains a priority both in
the MMP inhibition area and in the morphine total
synthesis e€ort. Although it is possible to isomerize the
(R)-isomer of glycinate 7 to the corresponding (S)-isomer,

T. Hudlicky et al. / Bioorg. Med. Chem. Lett. 11 (2001) 627±629
629
it will be instructive to study the potentials for stereo-
Acknowledgements
control in the rearrangement of the glycinates in more
detail. The substrates used by us di€er in complexity
from the ones previously reported by Kazmaier,21 Bar-
tlett,22 and Steglich.23 The stereospeci®city of the trans-
fer of sp3 stereochemistry from C-6 of the diol to C-2
depends on the steric bulk of groups at the adjacent
positions. As long as both these positions are sub-
stituted, the only possibility for optimizing the opera-
tion of either the chair or boat transition state is to
adjust the kind and the size of the chelating agent. Such
a strategy has been successfully employed in the area of
aldol condensation and the control of syn and anti
ratios from stereospeci®cally generated enolate species.
We expect that the bulk of the chelating Lewis acid
(with attendant solvent participation) can override the
size of either the halogen or phenyl groups at C-1, the
ether at C-5, or the amide or carbamate moieties on the
nitrogen atom. Further studies will investigate the use of
lanthanide or transition-metal-based Lewis acids in this
rearrangement. We will report the results in this area as
well as progress toward morphine from acid 3 in due
course.
The authors wish to thank Procter and Gamble Phar-
maceuticals for support of this project, as well as the
National Science Foundation (CHE-9615112 and CHE-
9910412, the Environmental Protection Agency
(R826113), and TDC Research, Inc.
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Four of the esters prepared in this study have been
saponi®ed and tested for inhibition activity against
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