Improved large-scale synthesis of phenylisoserine and the taxol C-13 side chain

Article abstract of DOI:10.1016/S0040-4039(02)02434-6

Dihydrodihydroxycinnamic acids and their esters react with acetonitrile or benzonitrile in the presence of sulfuric acid to afford the corresponding syn-β-amino-α-hydroxypropionic acid derivatives. High yields and diastereoselectivity of this transformation allows preparation of various phenylisoserine derivatives on a practical scale.

Full text of DOI:10.1016/S0040-4039(02)02434-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 407–409
Improved large-scale synthesis of phenylisoserine and the taxol
C-13 side chain
Michael V. Voronkov,* Alexander V. Gontcharov and Zhi-Min Wang
Lexicon Pharmaceuticals, 279 Princeton-Hightstown Road, East Windsor, NJ 08520, USA
Received 25 September 2002; revised 25 October 2002; accepted 28 October 2002
Abstract—Dihydrodihydroxycinnamic acids and their esters react with acetonitrile or benzonitrile in the presence of sulfuric acid
to afford the corresponding syn-b-amino-a-hydroxypropionic acid derivatives. High yields and diastereoselectivity of this
transformation allows preparation of various phenylisoserine derivatives on a practical scale. © 2002 Elsevier Science Ltd. All
rights reserved.
The efficiency and high enantioselectivity of the Sharp-
less Asymmetric Dihydroxylation (AD) provides an
excellent entry to various chiral building blocks.1
Among those are syn-diols derived from cinnamate
esters,2 important intermediates en route to phenyliso-
serine and its analogs, notably, N-benzoylphenylisoser-
ine, a C-13 side chain of taxol. Several approaches to
the conversion of cinnamate diols to the corresponding
syn-b-amino-a-hydroxy derivatives have been reported,
all of them having a common strategy: the b-hydroxyl
group is appropriately activated, then displaced with a
halide which is finally substituted with azide or benzo-
ylisothiocyanate.3a,b Thus, the syn-geometry of the
resulting aminoalcohol is achieved through a double
inversion at the b-carbon. We now report a simple
one-step protocol for the preparation of various
phenylisoserine derivatives from 2,3-dihydroxycinnamic
acids or its esters which is based on the Ritter reaction.4
for converting cis-indanediol to cis-aminoindanol based
on Ritter reaction5 (Scheme 1). Vicinal diols react with
nitriles in the presence of an acid through oxazoline
intermediates;6 in the indane case cis-aminoalcohol is
the only possible isomer that can form due to a rigid
cis-geometry of the two fused five-membered cycles.
Acyclic diols, as in our case of dihydroxydihydrocinna-
mates, would not be expected to have such stringent
stereocontrol.
In fact, when acetonitrile solutions of dihydroxy dihy-
drocinnamate esters (easily prepared by AD from com-
mercially available cinnamates3a) or the corresponding
acids were treated with concentrated sulfuric acid at
−10°C, mixtures of diastereomeric aminoalcohols were
isolated after aqueous HCl hydrolysis of the initially
formed oxazolines7 (Scheme 2). However, the levels of
diastereoselectivity were surprisingly high: 20:1 to 11:1
(Table 1) in favor of the syn isomer. The major syn
isomer was separated from the mixture by crystalliza-
tion from isopropanol in 78–86% yield. The geometry
of the product was confirmed by comparing the NMR
data of aminoacid 3a with those of the authentic sam-
ples of the corresponding syn- and anti-b-amino-a-
hydroxyacid derivatives.6 The geometry of other
products was assigned by correlation of their spectro-
scopic data with that of 3a.
The Ritter reaction is a powerful yet rather underuti-
lized synthetic tool, which allows one to convert alco-
hols to amines or their derivatives by treating the
alcohol with a nitrile in the presence of a strong acid.
Reportedly, the reaction proceeds though a carboca-
tionic intermediate thus often scrambling the stereo-
chemistry of the starting alcohol and limiting the
synthetic value of the reaction.
However, certain factors can sometimes lead to high
stereoselectivity levels in this transformation. For exam-
ple, Buckland et al. developed a stereoselective process
* Corresponding author. Tel.: +1-609-448-8200; fax: +1-609-448-8299;
e-mail: mvoronkov@lexpharma.com
Scheme 1.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02434-6

408
M. V. Voronko6 et al. / Tetrahedron Letters 44 (2003) 407–409
Scheme 2.
Table 1. Reaction of dihydroxycinnamic acids and esters with nitriles in the presence of sulfuric acid
Entry
R
R1
Product
Diastereomer ratios
Yield (%)
1
2
3
4
5
6
7
8
9
Me
H
Me
H
Me
H
Me
H
H
H
Me
Me
F
F
H
H
Me
Me
3a
3a
3b
3b
3c
3c
4a
4a
4b
4b
18:1
13:1
15:1
14:1
11:1
11:1
20:1
20:1
20:1
20:1
86
61
82
77
81
78
52
59
54
64
Me
H
10
N-Benzoylphenylisoserines 4a and 4b were prepared in
a similar fashion from either 1a and 2a or 1b and 2b
and benzonitrile. The oxazoline intermediates were
treated by dilute acid at room temperature to effect
opening of the oxazoline and ester hydrolysis and to
keep the amide bond intact.9 The pure hydroxyamido
acids crystallized from the reaction mixture and were
purified by crystallization (Table 1, entries 7–10).3a In
this case acids 2a,b rather that esters 1a,b proved to be
beneficial due to simplified work-up.
References
1. Kolb, H. C.; Vamnieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
2. (a) Cho, G. Y.; Park, J. N.; Ko, S. Y. Tetrahedron Lett.
2000, 41, 1789; (b) Rho, H. S.; Ko, B. S. Synth. Commun.
1999, 29, 2875; (c) Kang, S. K.; Park, D. C.; Rho, H. S.;
Yoon, S. H.; Shin, J. S. J. Chem. Soc., Perkin Trans. 1
1994, 24, 3531; (d) Kolb, H. C.; Sharpless, K. B. Tetra-
hedron 1992, 48, 10515; (e) Hoffman, R. V.; Kim, H. O. J.
Org. Chem. 1991, 56, 6759.
To explain such a high level of stereocontrol in the
reaction we have to assume that the benzylic carboca-
tion generated from the alcohol in the presence of the
acid is stabilized by the neighboring hydroxyl group,
i.e. the cis-epoxide-like intermediate locks the stereo-
chemistry at the benzylic position and then reacts with
the nucleophilic nitrogen of the nitrile.
3. (a) Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org.
Chem. 1994, 59, 5104; (b) Cho, G. Y.; Ko, S. Y. J. Org.
Chem. 1999, 64, 8745.
4. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213.
5. Buckland, B. C.; Connors, N. C.; Chartrain, M. M.;
Gailliot, F. P.; Greasham, R. L.; Jackey, B.; Heimbuch,
B.; Lee, C.; Olewinski, R. C., Jr.; Roberts, F. E.; Reider,
P. J.; Verhoeven, T. R.; Senanayake, C. H. US Pat.
5,858,737, January 12, 1999.
In conclusion, an efficient one-step protocol for prepa-
ration of both phenylisoserine derivatives and the cor-
responding taxol C-13 side chain has been
demonstrated on a 0.2 mol scale. This method compli-
ments the AD reaction and allows preparation of vari-
ous phenylisoserine derivatives in enantio- and
diastereoselective fashion.
6. Voronkov, M. V.; Gontcharov, A. V.; Wang, Z.-M.; Kolb,
H. C. ARKIVOC 2001, 9, 160.
7. In a typical procedure, methyl (2R,3S)-2,3-dihydroxy-3-
phenylpropionate 1a (39.2 g, 0.20 mol) was mixed with 100
mL of actonitrile and the mixture was cooled to −10°C in
an ice/NH4Cl bath. Concentrated sulfuric acid (20 mL)

M. V. Voronko6 et al. / Tetrahedron Letters 44 (2003) 407–409
409
was added dropwise and the resulting solution was allowed
to warm to room temperature over a period of 2 h. The
stirring was continued until no starting material was
detected by GC analysis. At that point, the reaction mixture
was treated with aqueous KOH to bring pH to 2. The
intermediate oxazoline was extracted with ethyl acetate
(3×70 mL), the solvent was evaporated and the oily residue
was heated at reflux with 250 mL of 2 M hydrochloric acid
for 2 h. Water was removed in vacuum yielding crude HCl
salt of 3a. Recrystallization from isopropanol afforded pure
3a·HCl (36.9 g, 86%) as colorless crystals: mp (decomp.)
218–219°C (lit.8 mp 222–224°C). Hydroxyaminoacids 3b
and 3c were prepared according to the similar procedure.
8. Ogima, I.; Habus, I.; Zhao, M.; Georg, G. I.; Jayasinghe,
L. R. J. Org. Chem. 1991, 56, 1681.
9. Literature suggests that acidic hydrolysis of the oxazoline
leads to the equilibrium mixture of N- and O-benzoyl
derivatives. In our case, only the former derivative had
crystallized out of the acidic aqueous solution, while the
latter remained dissolved. See: Bunnage, M. E.; Davies, S.
G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1993, 1375
and references cited therein.