Synthesis of (-)-bestatin and the Taxotere side-chain via nitroaldol reaction of (1R)-8-phenylmenthyl glyoxylate

Article abstract of DOI:10.1016/j.tetlet.2003.09.154

The nitroaldol reaction of (1R)-8-phenylmenthyl glyoxylate 6 with 1-nitro-2-phenylethane or with phenylnitromethane led stereoselectively to adducts 4 and 12, which where then transformed into (-)-bestatin hydrochloride and the Taxotere side-chain in over

Full text of DOI:10.1016/j.tetlet.2003.09.154

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8685–8687
Synthesis of (−)-bestatin and the Taxotere® side-chain via
nitroaldol reaction of (1R)-8-phenylmenthyl glyoxylate
Iwona Kudyba,a Jerzy Raczkoa,b and Janusz Jurczaka,c,
*
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
bZD CHEMIPAN, Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
cDepartment of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Received 8 July 2003; revised 9 September 2003; accepted 18 September 2003
Abstract—The nitroaldol reaction of (1R)-8-phenylmenthyl glyoxylate 6 with 1-nitro-2-phenylethane or with phenylnitromethane
led stereoselectively to adducts 4 and 12, which where then transformed into (−)-bestatin hydrochloride and the Taxotere®
side-chain in overall yields of 31 and 52%.
© 2003 Published by Elsevier Ltd.
In recent years, stereoselective synthesis of b-amino
a-hydroxy acids has attracted much attention due to
their presence in various medicinally important
molecules.1 Additionally, a number of their amide
derivatives, isolated recently from bacterial cultures,
displayed significant activity against aminopeptidases.2
For this reason, several stereoselective synthetic meth-
ods for formation of b-amino a-hydroxy acids were
recently presented, including aminohydroxylation,3
reduction of a-ketoacid derivatives,4 nucleophilic addi-
tion to chiral aldehydes,5 amides6 or imines,7 cycloaddi-
tion reactions,8 chiral epoxides9 and b-lactam
ring-opening procedures,10 halocyclocarbamation of
allylamines11 and chiral a-amino or a-amino acid trans-
formations.12 Very recently, we have investigated
nitroaldol reaction of chiral derivatives of glyoxylic
acid bearing various auxiliaries, such as (1R)-8-phenyl-
menthol, (2R)-bornane-10,2-sultam, (4R)-methyl-(5S)-
phenyloxazolidinone and 7,7-dimethylnorbornane-
(1S,2R)-oxazolidinone with simple nitroalkanes.13 In
most cases the reaction proceeded with high stereoselec-
tivity. The configuration of the major diastereoisomers
formed in these reactions was established as (2S,3R)-
like in most of the biologically important b-amino
a-hydroxy carboxylic acid derivatives. Thus, the readily
available nitroalcohols formed by this facile procedure
appeared to be very convenient precursors for b-amino
a-hydroxy acids. To illustrate this, we decided to syn-
thesize (−)-bestatin 1,14 the potent inhibitor of leucine
aminopeptidase and aminopeptidase B.2b The retrosyn-
thetic analysis shown in Scheme 1 makes it clear that a
chiral glyoxylate could serve as a starting material. On
the basis of our model studies on diastereoselective
nitroaldol additions, we chose (1R)-8-phenylmenthol as
a convenient and efficient chiral auxiliary.
The reaction of (1R)-8-phenylmenthyl glyoxylate 615
with 1-nitro-2-phenylethane 5, catalyzed by activated
aluminum oxide and carried out at −20°C, afforded a
mixture (71:19:6:5) of diastereoisomeric nitroalcohols 4
in 89% yield (Scheme 2).
The major diastereoisomer 4, which was isolated in
63% yield by column chromatography, was catalytically
hydrogenated, followed by protection of the amino
Keywords: nitroalcohols; nitroaldol reactions; asymmetric induction;
chiral auxiliary.
* Corresponding author. Tel.: +48-22-8230944; fax: +48-22-8230944;
e-mail: jjurczak@chem.uw.edu.pl
Scheme 1.
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.154

8686
I. Kudyba et al. / Tetrahedron Letters 44 (2003) 8685–8687
cohol 12, isolated by column chromatography in 81%
yield, was catalytically reduced and then protected with
di-tert-butyl dicarbonate to give the appropriate N-Boc
derivative in 93% overall yield. Subsequent acetylation
(95% yield) and hydrolysis of the ester functionality
(89% yield) furnished the amino acid 13, which was
esterified with diazomethane to afford the methyl ester
14 in 90% yield. Finally, the acetyl group was removed
to give the ester 15 in 90% yield. Both compounds 14
and 15 had optical rotations and spectral properties
identical to those reported in the literature.16
Scheme 2. Reagents and conditions: (a) activated Al2O3, dry
THF, rt, 7 h; (b) column chromatography; (c) H2, catalytic
Raney-Ni, MeOH, rt, 16 h; (d) (Boc)2O, satd aq. NaHCO3,
AcOEt, rt, 2 h; (e) DMP, catalytic TsOH, toluene, 50°C, 5 h;
(f) MeONa, MeOH, rt, 24 h; (g) N-ethylmorpholine, isobutyl
In conclusion, we have demonstrated that enantiomeri-
cally pure b-amino a-hydroxy acids can be readily
synthesized by transformation of nitroalcohols
obtained from (1R)-8-phenylmenthyl glyoxylate 6 via
nitroaldol reactions. (−)-Bestatin and the Taxotere®
side-chain were successfully synthesized in overall yields
of 31 and 52%, respectively.
chloroformate,
L-LeuOMe, THF (dry), −5°C“rt, 1 h; (h)
catalytic TsOH, MeOH, rt, 24 h; (i) 1N HCl, rt, 16 h.
group using di-tert-butyl dicarbonate to afford product
7 in 95% overall yield. Compound 7 was then reacted
with 2,2-dimethoxypropane (DMP) to give, after
hydrolysis of the ester functionality, the acid 8 in 78%
yield. The protected b-amino a-hydroxy acid 8 was
Acknowledgements
This work was supported by the State Committee for
Scientific Research (Project PBZ 605/T09/1999).
coupled with the methyl ester of
L-leucine using the
mixed anhydride method, to afford dipeptide 9 (95%
yield) which was finally deprotected in a two-step reac-
tion sequence with 70% overall yield. (−)-Bestatin
hydrochloride 10, obtained in the eight-step sequence
(31% overall yield), was shown to be identical in optical
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