Regio- and stereoselective methods for the conversion of (2S,3R)-β-phenylglycidic acid esters to taxoids and other enantiopure (2R,3S)-phenylisoserine esters

Article abstract of DOI:10.1007/s11172-012-0302-4

A novel efficient method was proposed for the synthesis of enantiopure precursors of taxane-containing cytostatics, i.e., methyl esters of (2R,3S)- and (2S,3R)-N-benzoylphenylisoserine and similar taxoid esters. The method is based on the regio- and stereoselective hydrobromolysis of the corresponding trans-β-phenyl glycidate enatiomers, consecutive reactions of O-acylcarbamoylation of the obtained 3-bromohydrins, intramolecular cyclization to 4-phenyloxazolidin-2-one-5-carboxylic acid derivatives, and oxazolidinone ring opening.

Full text of DOI:10.1007/s11172-012-0302-4

Russian Chemical Bulletin, International Edition, Vol. 61, No. 11, pp. 2149—2162, November, 2012
2149
Regioꢀ and stereoselective methods for the conversion
of (2S,3R)ꢀꢀphenylglycidic acid esters to taxoids and other
enantiopure (2R,3S)ꢀphenylisoserine esters
A. A. Afon´kin,a,b L. M. Kostrikin,a A. E. Shumeiko,a A. F. Popov,a A. A. Matveev,a,b
†
V. N. Matvienko,b and A. F. Zabudkinb
aL. M. Litvinenko Institute of Physicoorganic Chemistry and Coal Chemistry, National Academy of Sciences of Ukraine,
70 ul. R. Lyuksemburg, 83114 Donetsk, Ukraine.
Еꢀmail: AAAfonkin@newmail.ru
bCo. Ltd "Sinbias Farma,"
181 ul. Krepil´shchikov, 83085 Donetsk, Ukraine
A novel efficient method was proposed for the synthesis of enantiopure precursors of
taxaneꢀcontaining cytostatics, i.e., methyl esters of (2R,3S)ꢀ and (2S,3R)ꢀNꢀbenzoylphenylꢀ
isoserine and similar taxoid esters. The method is based on the regioꢀ and stereoselective
hydrobromolysis of the corresponding transꢀꢀphenyl glycidate enatiomers, consecutive reacꢀ
tions of Оꢀacylcarbamoylation of the obtained 3ꢀbromohydrins, intramolecular cyclization to
4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀcarboxylic acid derivatives, and oxazolidinone ring opening.
Key words: taxane cytostatic agents, transꢀꢀphenylglycidic acid, phenylisoserine, 4ꢀphenylꢀ
oxazolidinꢀ2ꢀoneꢀ5ꢀcarboxylic acid esters, enantioselective synthesis.
In the modern anticancer chemotherapy, taxanes 1
and anthracycline derivatives are characterized by the most
versatility of application, unlike many other oncological
drugs acting according to the principle "one drug—one
type of cancer."1—3 The formation of cytotoxic activity of
taxanes is substantially affected by both the diterpene
baccatin core (the right part of the molecule) and the
Nꢀacylphenylisoserine moiety (the left part of the moleꢀ
cule 1b) in the rigid (2R,3S)ꢀconfiguration.4
thesis methods3,6—25 of phenylisoserine (PIS) and any isoꢀ
mers of its esters and amides, including the target isomer with
the synꢀconfiguration, are known to date. These methods
differ in the choice of a chirality source (substrate, reactant,
or catalyst) and the type of chemical transformations.
However, difficulties of baccatin III acylation with
phenylisoserine and high pharmacopeia requirements26
imposed on optical purity of the final products 1 substanꢀ
tially restrict the choice of the method for construction of
the (2R,3S)ꢀNꢀacylphenylisoserine unit. It is known that
the spatial structure of the baccatin core resembles in shape
a basket with the С(13)ꢀhydroxy group on the bottom
forming a strong hydrogen bond with the С(4)ꢀacetyl
group.27 As a result, Oꢀacylation at the C(13)OH fragꢀ
ment is difficult and is often accompanied by epimerizaꢀ
tion at the С(2´) atom of the side chain due to the possible
transformation of the acylating agent into a ketene derivaꢀ
tive. The content of an epimer admixture is the highest in
the case of acylation by the N,Oꢀdiprotected PIS itself.28
That is why, only the methods, where less prone to epimerꢀ
ization crypto forms of PIS (transꢀcinnamic,29 ꢀphenylꢀ
glycidic,9 oxazolinic,30 and oxazolidinic31 acids and ꢀlacꢀ
tams32) are used for acylation and the target fragment of
Nꢀacylphenylisoserine is formed by the subsequent transꢀ
formations of the residue of the introduced acid or directly
at the moment of ester bond formation (as for ꢀlactam),
have practical value as appropriate semisynthetic methods
towards taxane 1. Each of these methods has drawꢀ
1a: R1 = Ph, R2 = Ac (Paclitaxel (Taxol™));
1b: R1 = ButO, R2 = H (Docetaxel (Taxotere™))
A biogenetic precursor of taxanes, 10ꢀdeacetylbaccaꢀ
tin III (the right part of the structure of 1b), has recently
become accessible,5 since it was found in considerable
amounts in needles of the European yewꢀtree. Therefore, the
development of synthesis of the (2R,3S)ꢀNꢀacylphenylꢀ
isoserine moiety of taxanes became urgent. Numerous synꢀ
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2132—2145, November, 2012.
1066ꢀ5285/12/6111ꢀ2149 © 2012 Springer Science+Business Media, Inc.

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Afon´kin et al.
backs.9,28,33,34 In spite of the evidently optimum ꢀlactam
method, the potential of the method through transformaꢀ
tions of phenylglycidic esters is far from exhaustion beꢀ
cause of easy accessibility of all isomers of ꢀphenylglycidic
acid and its stability and ability to react quantitatively
with the baccatin III derivatives.
This work is aimed at developing a novel practical
method for the synthesis of taxanes 1 and other taxoids
from enantiopure ꢀphenylglycidic acid and the correꢀ
sponding 10ꢀdeacetylbaccatin III derivative.
glycidates. Our attempts to open the oxirane ring of
ꢀphenylglycidate with methyl trichloroacetimidate (see
Scheme 1, route С), which readily enters the intramolecuꢀ
lar reaction with oxiranes of different structure38 and then
easily forms the amino group under mild conditions,39
were also unsuccessful. Only the interaction of azide9,40
and halide anions8,20a with esters (including baccatin esꢀ
ters) of ꢀphenylglycidic acid provides high yields of the
products of oxirane ring opening. The stereoselectivity of
azidolysis of baccatin esters of (2R,3R)ꢀphenylglycidic
acid is satisfactory only in the presence of fairly toxic crown
ethers9b as catalysts. In the case of halide ions, stereoꢀ and
regioselectivities20а,41 of the process depend substantially
on the conditions. In addition, oxirane ring opening by
halide anions as a way to synꢀamino alcohols requires the
inversion of the formed chiral center С—Hal and, hence,
is applicable to the transꢀisomer of enantiopure ꢀphenylꢀ
glycidic acid ester only.
Based on the above presented results and taking into
account restrictions known for the chemistry of taxanes,3,5
we accomplished the method of synthesis of taxoids
(Scheme 2), including the reaction of (2S,3R)ꢀꢀphenylꢀ
glycidic acid 2a and diprotected 10ꢀdeacylbaccatin 3 to
give ester 4, the regioꢀ and stereoselective transformation
of the latter into the corresponding enantiomer of bromoꢀ
hydrin 5, and the reaction of 5 with acyl isocyanate folꢀ
lowed by the intramolecular stereospecific transformation
of intermediate 6 into oxazolidinone detivative 7, whose
conversion potentially leads to taxanes of the type 1.
Reaction of transꢀꢀphenylglycidic acid with diprotected
baccatin III. 7,10ꢀBisꢀО,O´ꢀ(2,2,2ꢀtrichloroethoxycarbonꢀ
yl)ꢀ10ꢀOꢀdeacetylbaccatin (3) was synthesized by the reꢀ
action of 10ꢀdeacetylbaccatin III with 2,2,2ꢀtrichloroethyl
The strategy based on the transformations of baccatin
esters of (2R,3R)ꢀphenylglycidic acid (Scheme 1) seems
to be most promising.
In this case, the oneꢀstep stereoselective opening of
the oxirane ring by an Nꢀnucleophile provides the target
synꢀconfiguration of the amino and hydroxy substituents
of the side chain. However, the range of nucleophiles suitꢀ
able for this purpose is small. The ammonolysis of ꢀpheꢀ
nyl glycidate under standard conditions (see Scheme 1,
route A) results in the cleavage of the ester bond to form
PIS amide and is accompanied, in any case, by inapproꢀ
priate levels of regioꢀ and stereoselectivity.8 Aminolysis is
resultant only for the reaction of sterically nonꢀhindered
ꢀphenylglycidic acid esters with anilines, which react,
most likely, not via the classical SN2 mechanism.35 Thereꢀ
fore, unlike the reaction of aliphatic amines, this reaction
is efficiently catalyzed by transition metal salts.7 Unlike
the known examples of satisfactory intermolecular benzꢀ
amidolysis of alicyclic epoxides,36a trifluoroacetamidolyꢀ
sis of terminal epoxides,36b and successful intramolecular
acylamidolysis of oxiranes of different structure,37 acylꢀ
amidolysis by primary amides (see Scheme 1, route B,
R = Ph, CF3, ButO) is inapplicable in the case of phenylꢀ
Scheme 1
R = H, Ac

Phenylglycidic route to taxanes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2151
Scheme 2
1а: R1 = Ph, R2 = Ac; 1b: R1 = ButO, R2 = H; 6,7: R3 = Ph, CCl3
Troc = Cl3CCH2OCO
chloroformate in pyridine.42 The desired enantiomer of
(2S,3R)ꢀꢀphenylglycidic acid was obtained (Scheme 3)
as isobutyl ester 2b by the chemoenzymatic transesterifiꢀ
cation of racemic methyl transꢀꢀphenyl glycidate,9a
which was synthesized by the epoxidation of methyl transꢀ
cinnamate.43
Scheme 3
(2S,3R)ꢀꢀPhenylglycidate 2b was hydrolyzed by the
treatment with 0.1 М NaOH in THF. Acidic form 2а
obtained after neutralization was extracted with toluene
and used as a toluene solution for the acylation of baccatin
derivative 3. Esterification* of 3 with 2.0 equiv. of acid 2а
in the presence of 2.1 equiv. of DCC and 0.5 equiv. of
DMAP** in toluene at ambient temperature gives the
13ꢀОꢀacylation product 4 in 97% yield. If the process is
* An attempt to synthesize the 13ꢀepiꢀОꢀphenylglycidyl derivaꢀ
tive of diprotected baccatin by the Mitsunobu acylation44 was
unsuccessful. Esterification with acid 2а in the presence of actiꢀ
vators of different structure, viz., DCC/1ꢀhydroxybenztriazole,
propanephosphonic cycloanhydride, BOP/diisopropylethylꢀ
amine, and others with a low epimerization level in peptide and
ester formation processes,45 did not either yield the target
product 4.
carried out thoroughly, an admixture of С(2´)ꢀepimer of
the side chain does not exceed 10%.
Synthesis of bromohydrins of esters of phenylpropionic acid
Optimization of the reaction conditions of the subseꢀ
quent transformations of ester 4 (see Scheme 2) was perꢀ
** Comparable results were obtained using 2ꢀmethylpyridine
Nꢀoxide instead of DMAP.

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Afon´kin et al.
Scheme 4
R = diꢀTrocꢀdeacylbaccatin
Reagents and conditions: i. TiBr4, CH2Cl2—HMPA (10 : 1), –75—+5 C; ii. MgBr2•2Et2O, –75—+5 C.
formed on similar model reactions involving simpler anaꢀ
logs 2b,c. It was found that the regioselective interaction
of the bromide anion with esters of the type 2b,c occurs
successfully only in the presence of Lewis acids and the
required level of stereoselectivity is provided by low temꢀ
peratures of the process. We found that the use of TiBr4 in
a dichloromethane—HMPA (10 : 1 vol/vol) mixture or
magnesium dibromide etherate MgBr2•2Et2O in diethyl
ether gives predominantly compounds 8 or 9 (Scheme 4) in
high yields (98 and 96%, respectively) of two possible regiꢀ
omers. Their structures are indicated by the characteristic
signals from the С(2)Н and С(3)Н protons (H 4.5—4.7
and H 5.3—5.4, respectively), while in the case of 2ꢀbromo
regioisomers, these protons should give doublet signals in
a stronger field: H 4.3—4.4 and H 5.0—5.1 (see Refs 46,
9a, 9b, and 20a). The 1H NMR spectral data for the unpuriꢀ
fied reaction products show that the content of 2ꢀbromoꢀ
3ꢀhydroxy isomers PhCH(OH)CH(Br)COOR does not
exceed 1%.
transꢀphenyl glycidate with magnesium dibromide etherꢀ
ate.20a We found that products 8 and 9, as expected, were
rightꢀ and leftꢀrotating enantiomers, respectively, and their
[]D values corresponded to the literature data.9a,9b,20a
When using TiBr4 and MgBr2•2Et2O, the indicated
yields of products 8 and 9 are attained with reaction duraꢀ
tions of 3.5 and 6.5 h, respectively (see Scheme 4). In all
cases, freshly prepared47a magnesium dibromide etherate
is 20—30% more active than the commercially available
reagent. The both brominating agents are also efficient for
baccatin ester 4. However, the rates of reactions (see
Scheme 4) with this substrate are significantly lower for
both reagents: under comparable concentration and temꢀ
perature conditions, the 95% conversion is attained within
30 h for TiBr4 and within 120 h for MgBr2•2Et2O. As in
the case of simpler esters 2b,c, oxirane ring opening in the
side chain of compound 4 yields 3ꢀbromoꢀ2ꢀhydroxy deꢀ
rivative 5 with the signals characteristic of this regioisomer
at H 4.5 and 5.3.9b
The reactions in the temperature range from
Reactions of 3ꢀbromoꢀ2ꢀhydroxyꢀ3ꢀphenylpropionic
acid esters with acyl iso(thio)cyanates. To convert the
bromoalkyl moiety of compounds 8, 9, and 5 to the target
amino function, we used the method based on the inꢀ
tramolecular SN2 substitution for halogen by the Nꢀacyl
carbamate anion formed by the acylation of the vicinal
OH group with acyl isocyanate followed by the NHꢀdeproꢀ
tonation with a strong base48,49 (alternative but less effiꢀ
cient method for the solution of this problems were deꢀ
scribed50—54). Both stages of this route were studied for
model bromohydrins 8 and 9.
–
–
75— 55 С (onset of the process) to –10—+5 С (comꢀ
pletion of the process) involving both MgBr2•2Et2O and
TiBr4 (with a HMPA additive)9b afford predominantly
antiꢀstereoisomers of bromohydrins 8 and 9 with the conꢀ
tent of synꢀisomers not higher than 2% (see Scheme 4).
An insignificant content of the synꢀisomers is indicatꢀ
ed by the absence of satellite signals in the characꢀ
teristic4b,9a,9b,20a 1H NMR spectral ranges of the isolated
products and by the results of direct determination of an
enantiomeric excess in the case of bromolysis of active

Phenylglycidic route to taxanes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2153
The reaction (Scheme 5) of compounds 8 and 9 with
benzoyl isocyanate 10а in THF occurs readily at low temꢀ
perature and in 3 h completes by the formation of Оꢀ(Nꢀ
benzoyl carbamate) derivatives 11a and 12a, respectively,
in 94% yield.
the structure of acyl iso(thio)cyanate 10 (Table 1). Reacꢀ
tants 10b and 10e interact with bromohydrins with the
same high rate as 10а but give lower or comparable chroꢀ
matographic purity of the products formed.
Unlike primary alcohols, bromohydrins 8 and 9 react
with ethoxycarbonyl isothiocyanate 10c and trichloroꢀ
acetyl isothiocyanate 10d very slowly (see Table 1). Satisꢀ
factory yields were not attained by either replacement of
THF by more polar MeCN, or the use of basic catalysts,
or increasing temperature to 50 С.
Scheme 5
In the reactions with acyl isocyanates 10а,b, baccatin
derivative of bromohydrin 5 is 8—10 times less active
than esters 8 and 9. So, the 90% conversion of bromohyꢀ
drin 5 in the reaction with reactant 10а was achieved within
28 h in THF and within 3 h in acetonitrile.
Cyclization of Оꢀacyl carbamate derivatives of bromoꢀ
hydrins. Conversion (Scheme 6) of benzoyl carbamate deꢀ
rivatives 11 and 12 to oxazolidinones 13 and 14 is achieved
by the treatment with sodium hydride in THF at low temꢀ
peratures. The structures of the isolated products of inꢀ
tramolecular cyclization are determined by both the eleꢀ
mental analysis results (the absence of halogen) and the
characteristic changes in the spectra. The 1H NMR specꢀ
trum contains no signals from the NHꢀimide fragment,
while the doublet signals from the С(2)Н and С(3)Н protons
undergo a slight downfield shift to H 4.9 and 5.6, respecꢀ
tively. In the IR spectra, the bands of stretching vibrations
of the NH group disappear and the bands of three С=О
groups (1801, 1761, and 1688 cm–1) become more inꢀ
tense. The values of specific rotation decrease for comꢀ
pounds 13 and 14 to []D20 +1.5 and –13.7, respectively,
whereas the signs of optical rotation remain still opposite.
R = diꢀTrocꢀdeacetylbaccatin
R´ = Ph, Y = O (a); R´ = CCl , Y = O (b)
Scheme 6
3
R´ = EtO, Y = S (c); R´ = CCl , Y = S (d)
3
As initial bromohydrins 8 and 9, products of their
Оꢀcarbamoylation 11a and 12a differ in signs of specific
rotation []D +14.2 and –23.1, respectively.
One of the key stages of the synthesis shown in Scheme 2
is oxazolidinone ring opening in compound 7 to form the
target amino alcohol derivative and, hence, the correꢀ
sponding functionalization of this fragment is important.
Therefore, the Оꢀcarbamoylation of bromohydrins with
the labile55 Nꢀacyl group 10b,e and isothiocyanate derivaꢀ
tives 10c—d with the readily modified C=S function was
studied.56 It was found that the result of interaction (see
Scheme 5) of compounds 8 and 9 depends substantially on

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Afon´kin et al.
Table 1. Conditionsa and the results of the actions of bromohydrins 8, 9, and 5 with acyl iso(thio)cyanates 10
Bromoꢀ Acyl iso(thio)ꢀ Product
Solvent
T/C
t/h
Converꢀ
sion (%)
Chromatographic Yieldc (%)
purityb (%)
hydrin
cyanate 10
8
8
8
8
8
8
8
8
8
8
9
9
5
5
5
5
5
5
10а
10b
10c
10c
10c
10c
10d
10e
10e
10e
10а
10b
10а
10а
10а
10а
10b
10a
11a
11b
11c
11c
11c
THF
THF
THF
MeCN
MeCN
–4—+25
25
3
2.5
3
98
98
40d
40
73d
50
4d
22d
92
99
96
93
58
90
90
91
95
96
78
88
—
—
94
90
—
—
—
—
—
—
—
92
92
88
—
—
—
—
74
83
25
25
25
25
25
25
25
25
4
23
118
23
3.5
0.5
2
2.5
2
5
28
24
3
4.5
5.5
11c MeCN—CH2Cl2 (1 : 1)
—
11d
11e
11e
11e
12a
12b
6a
6a
6a
6a
6b
THF
Et2O
CH2Cl2
CH2Cl2
THF
THF
THF
THF
CH2Cl2
MeCN
MeCN
MeCN
—
82
80
82
84
78
72
73
85
82
87
–4—+25
–4—+25
0—25
0—25
0—25
0—25
0—25
0—25
6a
a In the most cases, the bromohydrin : reactant 10 ratio is 1 : 1.25.
b Chromatographic purity of the product at the maximum conversion.
c Yield of the isolated product.
d The use of additional amounts of reactant 10 does not result in a substantial increase in the conversion of bromohydrin.
The best yields of products 13 and 14 (88 and 86%,
respectively) are attained by the following prerequisites:
the temperature of the process from –15 to 25 С, using
not more than a threefold excess of the deprotonating
agent, portionwise addition of the deprotonating agent to
the reaction mixture, and, principally, the use of a solvent
with a residual water content at most 0.03%. Otherwise,
products of ester group hydrolysis are predominantly
formed instead of the target oxazolidinones, since baccaꢀ
tin derivatives 6 are especially susceptible to hydrolysis.
In the case of trichloroacetyl carbamate derivative 15,
intramolecular cyclization is complicated by the lability
of the Nꢀacyl group in addition to the factors listed above
(Scheme 7). Both in the course of the reaction and during
the isolation of product 16, the trichloroacetamide group
is readily hydrolyzed even at pH 7 to form deacylated
oxazolidinone 17. In our opinion, the route with prelimiꢀ
nary deacylation of the initial substrate followed by the
cyclization of the formed carbamate to oxazolidinone is
less probable.
If the conditions are fulfilled thoroughly, the reaction
can be stopped at the stage of formation of compound 16
as the major product (see Scheme 7). However, the further
manipulations spontaneously transform compound 16 into
final product 17 (HPLC data). The preparative yield of
compound 17 is 71%.
Attempts of cyclization of Оꢀ(Nꢀchlorosulfonylcarbꢀ
amate) derivatives of bromohydrin of the type 11e by the
action of sodium hydride in THF were unsuccessful: an
inseparable multicomponent mixture was obtained.
Intramolecular cyclization (Scheme 8) of baccatin acyl
carbamate derivatives 6 under the action of deprotonating
Scheme7

Phenylglycidic route to taxanes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2155
Scheme 8
R is diꢀTrocꢀdeacetylbaccatin.
R´ = Ph (a), CCl3 (b)
agents has additional singularities along with high sensiꢀ
tivity to the water content in the reaction medium.
sence of the signal from the NH proton (H 8.6) can unꢀ
ambiguously be established against the background of nuꢀ
merous signals from the aliphatic protons, and the ratio of
integral intensities of signals from the aromatic and aliꢀ
phatic protons corresponds to the expected structure of
compound 7a.
Acylation of diprotected baccatin III 3 with transꢀꢀ
phenylglycidic acid 2a affords some amount of an admixꢀ
ture fairly similar in structure to that of expected product 4
(see Scheme 2), which appears as a characteristic shoulꢀ
der on the chromatographic peaks of this product. Acꢀ
cording to patented information and our experience in
taxane chemistry, the observed admixture (inseparable by
purification) was interpreted as С(2´)ꢀepimer synꢀ4 (see
Scheme 8). At the next synthesis stages, this epimer unꢀ
dergoes the same transformations as major epimer antiꢀ4
and the corresponding admixtures follow the major prodꢀ
ucts up to the cyclization stage. However, at this stage the
back intramolecular attack is hindered for intermediate
synꢀ6. Indeed, neither an increase in the sodium hydride
concentration to 5—8 equiv., nor the use of catalytic and
stoichiometric amounts of 18ꢀcrownꢀ6, nor the transition
to another deprotonating agent (BuLi), nor the variation
of the structure of acyl fragment R´, nor an increase in the
temperature reaction time result in the expected cyclizaꢀ
tion of admixture synꢀ6. When 97% conversion the comꢀ
pletion of transformation of isomer antiꢀ6 to compound 7
is achieved (2 h, 3 equiv. NaH in THF, low temperature),
the further increase in the reaction time results only in
hydrolysis of all baccatin esters to the initial substrate 3.
Such a pronounced difference in chemical behavior of
antiꢀ6 and synꢀ6 indicates stereospecificity of the intramoꢀ
lecular cyclization of the studied Оꢀcarbamate derivatives
of bromohydrins. The transformation of the imide fragꢀ
ment of the side chain, which is present in structure 6a
(R´ = Ph), is indicated by characteristic changes in the
1H NMR spectrum of the cyclization product: the abꢀ
The structure of compound 7a synthesized by us was
proved by the independent synthesis. Baccatin (4S,5R)ꢀ
3ꢀbenzoylꢀ4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀcarboxylates were
described in the patent.57 They are obtained in the 31%
yield by the DCC/DMAPꢀactivated acylation of the corꢀ
responding baccatin derivative with the indicated acid,
which was synthesized by the cyclization of the phenylꢀ
isoserine derivative. The corresponding acid synthesized
by us using acidic hydrolysis of ester 13 was introduced
into the esterification reaction with 7,10ꢀO,O´ꢀbis(2,2,2ꢀ
trichloroethoxycarbonyl)ꢀ10ꢀdeacetylbaccatin 3 under the
earlier described conditions.57 Contrary to expectation,
acylation proceeds very slowly and the esterification prodꢀ
uct is formed only in insignificant amounts (up to 4—5%).
Nevertheless, its retention time under various HPLC analꢀ
ysis conditions (isocratic and gradient reverseꢀ and directꢀ
phase variants) is identical to the retention time of comꢀ
pound 7a obtained by us.
Oxazolidinone cycle cleavage to amino alcohol fragment.
The key stage of the method described in Scheme 2 is the
conversion of the oxazolidinone fragment of compound 7a
to the target amino alcohol fragment of phenylisoserine.
This process requires endocyclic heterocycle opening
(Scheme 9, route А), which for oxazolidinones of different
structure can be attained by acidic58 or alkaline (more freqꢀ
uently) hydrolysis.58,59 In addition, for esters of phenyloxꢀ
azolidinone acids 13, 14, and 7a, exocyclic hydrolysis with

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Afon´kin et al.
Scheme 9
R = Bui (13), Me (14); diꢀTrocꢀdeacetylbaccatin (7a)
Nꢀdeacylation of the cycle (Scheme 9, route В) is possible
and also potentially leads to PIS ester. A very undesirable
hydrolysis of the ester bond (Scheme 9, route С), which is
weaker than the imide bond, is also possible.
However, as it was revealed, in the case of esters 13
and 7a, oxazolidinone cycle opening is always preceded
(Scheme 11) by transesterification with the formation of
intermediate 4S,5Rꢀ14, and the product of its further transꢀ
formations is methyl ester 2R,3Sꢀ18. The physicochemiꢀ
cal characteristics of enantiomers 18 completely correꢀ
spond to the literature data.6,9а,20а,20b,61
Among many acidic and basic hydrolytic agents sucꢀ
cessfully used59,60 for oxazolidinones of different strucꢀ
ture, we failed to find a universal agent providing selective
endocyclic hydrolysis (see Scheme 9, route А) that does
not involve the ester group. In the case of compound 14,
alkali carbonates in an anhydrous* МеОН—THF mediꢀ
um resulting in Nꢀbenzoylphenylisoserine methyl ester
2R,3Sꢀ18 is efficient. With an increase in the reaction
time, the latter undergoes a more complete transformaꢀ
tion and forms (Scheme 10) methyl ester of PIS 19.
Cesium carbonate is most active in the series of studied
carbonates. In the presence of 0.2 equiv. Cs2CO3, the conꢀ
version of compound 14 to Nꢀbenzoylphenylisoserine meꢀ
thyl ester 2S,3Rꢀ18 in an anhydrous МеОН—THF (2 : 1)
mixture achieves 99% within 1.5 h. The rate and selectiviꢀ
ty of the process can be controlled by the fraction of THF
in the reaction mixture.
Conversion of compound 13 was ceased at the stage of
formation of transesterificated intermediate 4S,5Rꢀ14, usꢀ
ing less reactive lithium carbonate as a reagent. Most likeꢀ
ly, the methoxide ion generated by the carborate anion
acts as a reacting species (see Schemes 10 and 11) in all
cases. In fact, on going from methanol to isopropyl alcoꢀ
hol, the carbonateꢀpromoted hydrolysis of substrate 13
affords isopropyl (4S,5R)ꢀ3ꢀbenzoylꢀ4ꢀphenyloxazolidinꢀ
2ꢀoneꢀ5ꢀcarboxylate. At the same time, under similar conꢀ
ditions, 2,2,2ꢀtrifluoroethanol and isobutyl alcohol are not
involved in either transesterification or oxazolidinone cyꢀ
cle opening with the formation of the PIS derivative, and
tertꢀbutyl alcohol causes racemization of enantiomer 13
in the presence of potassium tertꢀbutoxide, which generalꢀ
ly indicates significance of the basicity (nucleophilicity)
and steric factor when choosing the alkoxide reagent. We
found that, in the series of methoxides, the nature of the
counterion exerts a substantial effect on the selectivity of
hydrolysis. The treatment of compound 13 with magneꢀ
sium methoxide62 (Scheme 12) resulted in the inversion of
the order of bond cleavage: in a МеОН—THF mixture in
the presence of 20 equiv. Mg(OMe)2, the imide bond of
* It is known57 that in aqueous media alkali carbonates efficientꢀ
ly hydrolyze esters of the types 13 and 14 to form free acids. We
found that the acidic hydrolysis of these esters in the presence of
hydrochloric acid in a THF—water (1 : 1) mixture is characterꢀ
ized by almost the same efficiency. For example, for the hydrꢀ
olysis of compound 13 the 90% yield of (4S,5R)ꢀ3ꢀbenzoylꢀ4ꢀ
phenyloxazolinꢀ2ꢀoneꢀ5ꢀcarboxylic acid is achieved after reꢀ
flux for 1 h.

Phenylglycidic route to taxanes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2157
Scheme 10
Reagents and conditions: i. M2CO3 (M = Li, K, Cs), MeOH—THF.
Scheme 11
R = Bui (13), diꢀTrocꢀdeacetylbaccatin (7a)
Reagents and conditions: i. Li2CO3, MeOH—THF; ii. Cs2CO3, MeOH—THF; iii. HCl, THF—H2O.
the heterocycle undergoes cleavage first to form the target
product 20, which further either undergoes Nꢀdebenzoyꢀ
lation or transesterification with the formation of byꢀprodꢀ
ucts 21 and 2R,3Sꢀ18, respectively. Finally, these prodꢀ
ucts are transformed into PIS methyl ester 2R,3Sꢀ19. Acꢀ
cording to the chromatographic composition of the reacꢀ
tion mixture, none of the variants of exocyclic hydrolysis
with the formation of products 4S,5Rꢀ14 and 17 occurs.
Under the indicated conditions, the maximum yield of
product 20 is 51% at the 80% conversion of the starting
substrate 13, which is achieved in 45—50 min at 20 С.
The fraction of product 2R,3Sꢀ19 reaches 75% with an
increase in the duration time to 22 h.
crypro form) of PIS. We found that substrate 7a, being
treated with 0.2 equiv. cesium carbonate in anhydrous
methanol for 30 min at lowered temperature, undergoes
(see Scheme 11) transesterification to the methyl derivaꢀ
tive of oxazolidinic acid with the recovery of the initial
baccatin alcohol 3, which further converts to 10ꢀdeacetylꢀ
baccatin III. The search for selective procedures aimed at
the required transforming baccatin ester 7a among nuꢀ
merous traditional method was unsuccessful. However,
we succeeded to find a practical method for selective hetꢀ
erocycle cleavage in compound 7a to give the correspondꢀ
ing PIS derivatives, which will be discussed elsewhere.
To conclude, the novel method for the synthesis of
practically significant compounds, viz., enantiopure (2R,3S)ꢀ
(–)ꢀNꢀbenzoylꢀ3ꢀphenylisoserine methyl ester (2R,3Sꢀ18)
and taxoids of the type 7, from ꢀ(2S,3R)ꢀphenylglycidic
acid has appropriate preparative yields and achieved levels
of regioꢀ and stereoselectivity at each individual stage.
Baccatin esters are more sensitive to bases, and their
stability under the "hydrolysis" conditions depends on the
structure of the acyl fragment62: under alkaline condiꢀ
tions, the ester bond of the Nꢀacyl form of PIS sometimes
is more stable than the N,Oꢀdiprotected forms (or the

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Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012
Afon´kin et al.
Scheme 12
ate with ethyl chloroformate and trichloroacetyl chloride, reꢀ
spectively, using the published method.47b
Experimental
7,10ꢀO,O´ꢀBis(2,2,2ꢀtrichloroethoxycarbonyl)ꢀ10ꢀdeacetylꢀ
baccatin (3) was synthesized using the known procedure.42
A mixture of 2,2,2ꢀtrichloroethyl chloroformate (7 mL, 10.77 g,
50.8 mmol) and dichloromethane (21 mL) was added to a preꢀ
cooled to –20 С solution of 10ꢀdeacetylbaccatin III (10 g,
18.8 mmol) in anhydrous pyridine (100 mL) by portions mainꢀ
taining the reaction temperature below 0 С. The reaction mixꢀ
ture was kept at 0 С for 35 min and treated with water and
dichloromethane. The organic phase containing the target prodꢀ
uct of 90% purity was separated and multiply washed with waꢀ
ter. Compound 3 with 99.9% chromatographic purity was obꢀ
tained by preparative chromatography on Silicagel Si60 (eluent
dichloromethane—hexane, 98 : 2) followed by crystallization
from methanol in a yield of 15 g (91%). The physicochemical
characteristics of the synthesized product correspond to the litꢀ
erature data.42
1
Н NMR spectra (200 and 400 MHz) were measured on
Bruker AMꢀ200 and Bruker AMꢀ400 spectrometers using Me4Si
as an internal standard. IR spectra were recorded on a Shimadzu
FTIRꢀ8400S spectrometer in KBr pellets. The optical rotation
was determined as an arithmetical mean of five measurements
on an ATAGO APꢀ100 automated polarimeter. The comꢀ
pleteness of reactions and chromatographic purity of the obꢀ
tained products were monitored on an HPLC Shimadzu inꢀ
strument equipped with a UV detector (232 and 254 nm)
and columns Zorbax SBꢀC18 5.0 /150 mm/4.6 mm (mobile
phases: a gradient (water (рН 7.0; AcONH4/AcOH)—MeCN
mixture from 70 : 30 to 10 : 90) and an isocratic (water (рН 5.5;
AcONH4/AcOH)—MeCN (57 : 43) mixture) and HypersilꢀSiliꢀ
ca 5.0 /150 mm/4.6 mm (mobile phase: an isocratic nꢀhexꢀ
ane—ethyl acetate—acetonitrile (72 : 17 : 11) mixture). Melting
points were determined on a Boetius heating stage. Solvents
were purified and dried using standard methods.63 The residual
water content in dried solvents was monitored by the Fischer
nonꢀaqueous titration on a Metrohm 787 KF Titrino/703 Ti
Stand instrument.
Methyl transꢀꢀphenylglycidate (2), racemate. mꢀChloroꢀ
peroxybenzoic acid (70%, 124 g, 0.50 mol) was added to a soluꢀ
tion of freshly distilled methyl transꢀcinnamate (65 g, 0.40 mol)
in dichloromethane (500 mL). The reaction mixture was reꢀ
fluxed for 50 h to 85% conversion, the residue of mꢀchlorobenꢀ
zoic acid formed was filtered off through a layer of neutral Al2O3,
the solvent was removed on a rotary evaporator under reduced
pressure, and the viscous residue was distilled in vacuo. Product 2
with 96% chromatographic purity was obtained in a yield of 51 g
Trifluoroacetamide was synthesized by the reaction of triꢀ
fluoroacetic anhydride with an ammonia excess in anhydrous
methanol. NꢀTrimethylsilylbenzamide was obtained by the reꢀ
action of benzamide with trimethylsilyl chloride in benzene in
the presence of triethylamine.64 tertꢀButoxycarbonylacetimide
was synthesized by the reaction of tertꢀbutoxycarbonylacetamide
(Aldrich) with sodium hydride in anhydrous THF followed by
the reaction with acetyl chloride. Methyl trichloroacetimidate
was obtained by the dehydration of trichloroacetamide with Р2О5
to form trichloroacetonitrile65 followed by the reaction of the
latter with methanol in СН2Сl2 in the presence of DBN.66 The
physicochemical characteristics of the indicated target products
correspond to literature data.
10ꢀDeacetylbaccatin III (Shanghai Synnad Chemical Co.
Ltd) was used. Commerically available benzoyl isocyanate 10a,
trichloroacetyl isocyanate 10b, and chlorosulfonyl isocyanate
10e (Aldrich) were used without additional purification. Ethꢀ
oxycarbonyl isothiocyanate 10c and trichloroacetyl isothiocyanꢀ
ate 10d were synthesized by the reaction of potassium thiocyanꢀ
1
(71%), b.p. 114—116 С (0.30—0.35 Torr). Н NMR (CDCl3),
: 7.25—7.40 (m, 5 H, Ar); 4.08—4.12 (d, 1 H, CH); 3.70 (s, 3 H,
CH3); 3.52—3.55 (d, 1 H, CH).
Enantioselective transesterification of racemic ester 2 was carꢀ
ried out using the known method.9a A suspension containing 300 g
of lipase PSꢀC M. miehei (Amano International Enzyme Co.),
100 g (0.56 mol) of methyl racꢀtransꢀꢀphenyl glycidate 2, 400 mL
of isobutyl alcohol, and 400 mL of nꢀhexane was shaken for 55 h
at 30 С. The solid phase was filtered off, the solvent was evapoꢀ
rated, and the residue was fractionated twice in vacuo.
(+)ꢀIsobutyl (2S,3R)ꢀ3ꢀphenylglycidate (2b). The yield was
60 g (48%), b.p. 105—107 С (0.10 Torr) (cf. Ref. 9a: b.p.
117—119 С (0.1 Torr)). Chromatographic purity was 96%;
20
20
[]D +127 (с 1.5, CHCl3), cf. Ref. 9a: []D +129 (с 1.5,
CHCl3)). 1Н NMR (CDCl3), : 7.25—7.40 (m, 5 H, Ar):

Phenylglycidic route to taxanes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2159
4.08—4.12 (d, 1 H, CH, J = 4.5 Hz); 3.95—4.06 (m, 2 H, CH2
BuiO); 3.52—3.55 (d, 1 H, CH, J = 4.5 Hz); 1.90—2.10 (m, 1 H,
CH, BuiO); 0.95, 1.00 (both s, 6 H, 2 CH3 BuiO).
B. A solution of transꢀphenylglycidic acid ester (30 mmol) in
a mixture of CH2Cl2 (160 mL) and hexamethylphosphoramide
(16 mL) with the total content of residual water at most 0.15%
was cooled to –75 С (0 С in the case of substrate 4), and TiBr4
(33 mmol) was added by portions with stirring. The reaction
mixture was stirred, gradually increasing the temperature to
–8 С (5 С in the case of substrate 4). The reaction course was
monitored by the consumption of substrate 2а, 2b, and 4. After
the completion of the reaction, Н2О (140 mL) containing 5%
NaCl was added to the reaction mixture, which was stirred to
decoloration of the solution. The organic phase was separated,
washed with water, and dried over Na2SO4. The subsequent
distilling off the solvent gives bromohydrins 5, 8, or 9 with apꢀ
propriate chromatographic purity, and an HMPA admixture in
the product exerts no effect on the occurrence of the next stage.
Both methods of hydrobromolysis give identical results.
(–)ꢀMethyl (2R,3S)ꢀ3ꢀphenylglycidate (2c). The yield was
18 g (18%), b.p. 88—95 С (0.12 Torr) (cf. Ref. 9a: b.p. 85—95 С
(0.1—0.05 Torr)). Chromatographic purity was 95%; []D20 –160
(с 1.5, CHCl3) (cf. Ref. 9a: []D20 –163  (с 1.5, CHCl3). 1Н NMR
(CDCl3), : 7.25—7.40 (m, 5 H, Ar); 4.08—4.12 (d, 1 H, CH,
J = 6.0 Hz); 3.67 (s, 3 H, CH3); 3.52—3.55 (d, 1 H, CH, J = 5.5 Hz).
13ꢀОꢀ((2S,3R)ꢀ3ꢀPhenylglycidoyl)ꢀ7,10ꢀО,O´ꢀbis(2,2,2ꢀtriꢀ
chloroethoxycarbonyl)ꢀ10ꢀdeacetylbaccatin (4). Aqueous 1.0 М
NaOH (22 mL) was added dropwise with stirring to a solution of
compound 2b (2.43 g, 11 mmol) in THF (60 mL) cooled to 0 С.
The mixture was stirred for 40 min at ambient temperature, and
then Н2О (75 mL) and diethyl ether (80 mL) were added. The
aqueous phase was separated, and toluene (100 mL) was added.
The obtained mixture was cooled to 0—2 С and acidified with
1.0 М HCl to рН 3—4. The organic phase was separated, the
aqueous phase was repeatedly extracted with toluene (100 mL),
and combined organic extracts were dried over Na2SO4. A soluꢀ
tion of acid 2a in toluene was concentrated to a volume of 20 mL.
Anhydrous toluene (85 mL), substrate 3 (4.9 g, 5.56 mmol),
DCC (2.38 g, 11.5 mmol), and DMAP (0.34 g, 2.78 mmol) were
added to the residue with stirring, the mixture was stirred at
ambient temperature to the reaction completion (10 min).
Dichloromethane (200 mL) was added to the reaction mixture,
which was washed with a dilute aqueous solution of NaHCO3
and water, and the organic phase was dried over Na2SO4. An
amorphous residue (7.3 g) obtained after distilling off the solvent
on a rotary evaporator was dissolved in an acetone—dichloroꢀ
methane (1.5 : 98.5 vol/vol) mixture, and the nonꢀseparated part
was filtered off. Compound 4 was isolated by preparative chromꢀ
atography on Silicagel Si60 (column 3.5×60 cm, eluent
acetone—dichloromethane (1.5 : 98.5% vol/vol), detection at
 = 254 nm) in a yield of 5.54 g (97%), white solid, []D20 –45.8
Isobutyl (2S,3S)ꢀ(+)ꢀ3ꢀbromoꢀ2ꢀhydroxyꢀ3ꢀphenylpropiꢀ
onate (8). The yield of the unpurified product was 96—98%;
chromatographic purity was 96% (by method А) and 95% (by
20
method B); []D +97 (с 0.7, CHCl3). 1Н NMF (CDCl3),
: 7.25—7.40 (m, 5 H, Ar); 5.3 (d, 1 H, C(3)H, J = 6.0 Hz); 4.70
(dd, 1 H, 2 CH, J = 3.0 Hz, J = 5.8 Hz); 3.9—4.0 (m, 2 H, CH2
BuiO); 3.00 (br.s, 1 H, С(2)OH, in exchange); 1.90—2.10
(m, 1 H, CH of BuiO); 0.95, 1.00 (both s, 6 H, 2 CH3, BuiO).
Methyl (2R,3R)ꢀ(–)ꢀ3ꢀbromoꢀ2ꢀhydroxyꢀ3ꢀphenylpropionꢀ
ate (9). The yield of the unpurified product was 96—98%; chromꢀ
atographic purity was 97% (by method А) and 98% (by methꢀ
22
20
od B); []D –134 (с 1.2, CHCl3) (cf. Ref. 20a: []D –134
(с 1.1, CHCl3)), –138 (с 1.5, CHCl3)). 1Н NMR (CDCl3),
: 7.30—7.50 (m, 5 H, Ar); 5.30 (d, 1 H, C(3)H, J = 4.5 Hz);
4.70 (dd, 1 H, C(2)H, J = 4.8 Hz, J = 6.8 Hz); 3.70 (s, 3 H,
CH3); 3.00 (br.s, 1 H, С(2)OH, in exchange).
13ꢀОꢀ((2S,3S)ꢀ3ꢀBromoꢀ2ꢀhydroxyꢀ3ꢀphenylpropionyl)ꢀ
7,10ꢀO,O´ꢀbis(2,2,2ꢀtrichloroethoxycarbonyl)ꢀ10ꢀdeacetylbaccaꢀ
tin (5). The yield of the unpurified product was 96%; chromatoꢀ
graphic purity was 96% (by method А) and 92% (by method B).
1Н NMR (CDCl3), : 8.00—8.10 (m, 2 H, Ar); 7.30—7.50
(m, 8 H, Ar); 6.15—6.30 (m, 2 H); 5.50—5.70 (m, 2 H); 5.27
(d, 1 H, CHBr, J = 6.2 Hz); 4.90 (m, 2 H); 4.60—4.80 (m, 3 H);
4.50 (m, CHOH); 4.00—4.30 (m, 3 H); 3.00 (br.s, 1 H, CHOH);
2.60—2.70 (m, 1 H); 2.40 (s, 3 H); 2.00—2.30 (s, 3 H); 1.80—1.90
(m, 6 H); 1.60—1.75 (m, 4 Н, in exchange); 1.20, 1.30 (both s,
6 H, 2 CH3). The spectrum of compound 5 is consistent with
that described previously.9b Found (%): С, 46.67; H, 4.10;
Br, 7.15; Cl, 20.08. C43H43BrCl6O16. Calculated (%): С, 46.60;
H, 3.91; Br, 7.21; Cl, 19.19.
Reaction of acyl iso(thio)cyanates 10 with bromohydrins 8 and
9 (general procedure). A solution of benzoyl isocyanate (5.4 g,
37 mmol) in THF (15 mL) was added by portions with stirring to
a cooled to –4 С solution of isobutyl (2S,3S)ꢀ(+)ꢀ3ꢀbromoꢀ2ꢀ
hydroxyꢀ3ꢀphenylpropionate 8 (obtained by method B) (8.9 g,
29.6 mmol) in THF (50 mL) with a residual water content at
most 0.02%. The mixture was stirred for 3 h at –4—20 С to the
completion of the reaction. An excess of the reactant was deꢀ
composed by the addition of water (1 mL). The solvent was
removed under reduced pressure, a viscous residue was dissolved
in an acetone—toluene mixture, and the solvent was evaporated
to dryness. The product was isolated by preparative chromatogꢀ
raphy on Silicagel Si60 (column 3.5×60 cm, eluent dichloroꢀ
methane, detection at  = 254 nm).
1
(с 0.5, EtOH). Н NMR (CDCl3), : 8.00—8.10 (m, 2 H, Ar);
7.30—7.70 (m, 8 H, Ar); 6.25—6.30 (m, 2 H); 5.60—5.70
(m, 2 H); 4.9 (m, 2 H); 4.60—4.80 (m, 3 H); 4.20—4.30 (m, 2 H);
2.60—2.70 (m, 1 H); 2.3—2.4 (m, 2 H); 2.10, 2.20 (both s, 6 H,
2 CH3); 2.00—2.05 (m, 1 H); 1.85 (s, 3 H, CH3); 1.60—1.75 (br.s,
1 Н, in exchange); 1.20, 1.30 (both s, 6 H, 2 CH3). The 1H NMR
spectrum is consistent with that described earlier.9b Found (%):
С, 50.35; H, 4.02; Cl, 20.78. C43H42Cl6O16. Calculated (%):
С, 50.26; H, 4.12; Cl, 20.70.
Hydrobromolysis of transꢀphenylglycidates 2b, 2c, and 4 (genꢀ
eral procedure). A. A mixture of MgBr2•2Et2O2 (Aldrich)
(15 mmol) was added to diethyl ether (50 mL) with a residual
water content of 0.02% and cooled to –55 С (–18 С in the case
of substrate 4). A solution of transꢀphenylglycidic acid ester
(10 mmol) in diethyl ether (10 mL) was added by portions with
stirring. The reaction mixture was stirred maintaining the temꢀ
perature in the range from –18 to 3 С. The reaction course was
visually monitored by the formation of a milkꢀwhite finely disꢀ
persed suspension of the magnesium derivative of bromohydrin
5, 8, or 9 and using HPLC by the disappearance of the starting
substrate. After the completion of the reaction, water (70 mL)
containing 5% NaCl was added, and the mixture was stirred to
suspension dissolution. The organic phase was separated, and
the aqueous phase was repeatedly extracted with diethyl ether
(50 mL). Combined organics were dried over Na2SO4. The subꢀ
sequent evaporation of the solvent gives bromohydrins 5, 8, or 9
fairly pure for further work.
Isobutyl (2S,3S)ꢀ(+)ꢀ2ꢀ[Nꢀbenzoyl(carbamoyloxy)]ꢀ3ꢀbroꢀ
moꢀ3ꢀphenylpropionate (11a). The yield was 12.47 g (94%), m.p.

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Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012
Afon´kin et al.
20
1
123—124 С; []D +14.2 (с 0.5, EtOH). Н NMR (CDCl3),
: 8.20 (s, 1 H, NH); 7.20—7.80 (both m, 10 H, Ar); 5.75 (d, 1 H,
C(3)H, J = 5.0 Hz); 5.40 (d, 1 H, C(2)H, J = 5.5 Hz); 3.90—4.00
(m, 2 H, CH2, BuiO); 1.90—2.00 (m, 1 H, CH, BuiO); 0.90, 0.95
(both s, 6 H, 2 CH3, BuiO). IR, /cm–1: 3250, 2964 (m); 1772
(s); 1759 (s); 1749 (s); 1689 (m); 1524 (s); 1493 (m); 1217 (m);
1192 (s); 1059 (m); 698 (m). Found (%): С, 56.34; H, 4.85;
Br, 17.69; N, 3.33. C21H22BrNO5. Calculated (%): С, 56.26;
H, 4.95; Br, 17.82; N, 3.12.
to ambient one within 3—6 h and monitoring the reaction course
by HPLC. After the reaction completion, dichloromethane
(15 mL) was added to the reaction mixture. An excess of NaH
was decomposed with 5% HCl, maintaining pH not higher
than 7.5. The organic phase was separated, washed with a 5%
aqueous solution of NaCl, and dried over Na2SO4. The solꢀ
vent was evaporated. Products 13, 14, and 17 were crystallized
from EtOH, and product 7 was isolated by chromatography
on Silicagel Si60 (column 3.5×60 cm, eluent dichloromethꢀ
ane—acetone, 98 : 2).
Isobutyl (4S,5R)ꢀ3ꢀbenzoylꢀ4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀ
carboxylate (13). The yield was 88%, m.p. 143 С (EtOH),
[]D20 +1.5 (с 0.5, CH2Cl2). 1Н NMR (CDCl3), : 7.30—7.70
(m, 10 H, Ar); 5.60—5.70 (d, 1 H, C(3)H, J = 5.5 Hz), 4.85—4.95
(d, 1 H, C(2)H, J = 5.2 Hz); 4.05—4.15 (d, 2 H, CH2, BuiO);
1.95—2.10 (m, 1 H, CH, BuiO); 0.95, 1.05 (both s, 6 H, 2 CH3,
BuiO). IR, /cm–1: 2962 (m); 1801 (s); 1761 (s); 1688 (s); 1323
(s); 1308 (s); 1294 (s); 1221 (s); 1182 (s); 1111 (s); 696 (m).
Found (%): С, 68.64; H, 5.85; N, 3.73. C21H21NO5. Calculatꢀ
ed (%): С, 68.65; H, 5.76; N, 3.81.
Methyl (4R,5S)ꢀ3ꢀbenzoylꢀ4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀcarbꢀ
oxylate (14). The yield was 86%; []D20 –13.7 (с 0.5, CH2Cl2).
1Н NMR (CDCl3) : 7.35—7.70 (m, 10 H, Ar); 5.65—5.70
(d, 1 H, C(3)H, J = 5.2 Hz); 4.90 (d, 1 H, C(2)H, J = 5.0 Hz);
3.90 (s, 3 H, CH3). Found (%): С, 66.34; H, 4.52; N, 4.42.
C18H15NO5. Calculated (%): С, 66.46; H, 4.65; N, 4.31.
7,10ꢀO´,OꢀBis(2,2,2ꢀtrichloroethoxycarbonyl)ꢀ10ꢀdeacetylꢀ
baccatinꢀ13Oꢀyl (4S,5R)ꢀ3ꢀbenzoylꢀ4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀ
carboxylate (7). The conversion of the target substrate was 97%.
1Н NMR (CDCl3), : 8.00—8.10 (m, 2 H, Ar); 7.30—7.80
(m, 15 H, Ar); 6.15—6.35 (m, 2 H); 5.50—5.70 (m, 2 H); 5.30
(d, 1 H, CHPh, J = 6.0 Hz); 4.90 (m, 2 H); 4.60—4.90 (m, 3 H);
4.30—4.40 (m, C(O)CHCHPh); 4.10—4.30 (m, 3 H); 2.60—2.70
(m, 1 H); 2.40 (s, 3 H); 2.00—2.30 (m, 3 H); 1.80—1.90 (m, 6 H);
1.60—1.80 (m, 4 Н); 1.20, 1.30 (both s, 6 H, 2 CH3). Found (%):
С, 52.22; H, 3.96; Cl, 18.20; N, 1.14. C51H47Cl6NO18. Calcuꢀ
lated (%): С, 52.15; H, 4.03; Cl, 18.11; N, 1.19.
Isobutyl (2S,3S)ꢀ(+)ꢀ3ꢀbromoꢀ2ꢀ[Nꢀ(2,2,2ꢀtrichloroacetyl)ꢀ
carbamoyloxy]ꢀ3ꢀphenylpropionate (11b). []D +16 (с 0.5,
EtOH). Н NMR (CDCl3), : 8.30 (s, 1 H, NH); 7.20—7.60
20
1
(m, 5 H, Ar); 5.75 (d, 1 H, C(3)H, J = 5.1 Hz); 5.50 (d, 1 H,
C(2)H, J = 5.0 Hz); 3.90—4.00 (m, 2 H, CH2, BuiO); 1.90—2.00
(m, 1 H, CH, BuiO); 0.90, 0.95 (both s, 6 H, 2 CH3, BuiO).
Isobutyl (2S,3S)ꢀ(+)ꢀ3ꢀbromoꢀ2ꢀ[Nꢀ(chlorosulfonyl)carbꢀ
amoyloxy]ꢀ3ꢀphenylpropionate (11e). 1Н NMR (CDCl3), : 8.40
(s, 1 H, NH); 7.20—7.65 (m, 5 H, Ar); 5.75 (d, 1 H, C(3)H,
J = 5.2 Hz); 5.50 (d, 1 H, C(2)H, J = 5.1 Hz); 3.90—4.00
(m, 2 H, CH2, BuiO); 1.90—2.00 (m, 1 H, CH, BuiO); 0.90, 0.95
(both s, 6 H, 2 CH3, BuiO).
Methyl (2R,3R)ꢀ(–)ꢀ2ꢀbenzoylcarbamoyloxyꢀ3ꢀbromoꢀ3ꢀ
20
1
phenylpropionate (12a). []D –23.1 (с 0.5, EtOH). Н NMR
(CDCl3), : 8.20 (s, 1 H, NH); 7.20—7.80 (m, 10 H, Ar); 5.75
(d, 1 H, C(3)H, J = 4.8 Hz); 5.40 (d, 1 H, C(2)H, J = 5.0 Hz);
3.70 (s, 3 H, CH3). Found (%): С, 53.44; H, 4.00; Br, 19.39;
N, 3.36. C18H16BrNO5. Calculated (%): С, 53.22; H, 3.97;
Br, 19.67; N, 3.45.
13ꢀОꢀ[(2S,3S)ꢀ2ꢀ[NꢀBenzoyl(carbamoyloxy)ꢀ3ꢀbromoꢀ3ꢀ
phenylpropionyl]ꢀ7,10ꢀO,O´ꢀbis(2,2,2ꢀtrichloroethoxycarbonyl)ꢀ
10ꢀdeacetylbaccatin (6a). A solution of benzoyl isocyanate (0.24 g,
1.62 mmol) in acetonitrile (3 mL) was added by portions with
stirring at 20 С to a solution of compound 5 (1.45 g, 1.3 mmol)
in acetonitrile (15 mL) with the residual water content at most
0.01%. The mixture was stirred for 8 h at ambient temperature
until the 95—97% conversion of the starting bromohydrin was
achieved. A 3% aqueous solution of NH4Cl (30 mL) was added
to the reaction mixture, and organics were extracted with diethyl
ether (2×40 mL). The organic phase was washed with water
(50 mL) and dried over Na2SO4. The solvent was evaporated.
Compound 6a was isolated by preparative chromatography of
the amorphous residue on Silicagel Si60 (column 3.5×60 сm,
eluent acetone—dichloromethane (1.5 : 98.5 vol/vol), detection
at  = 254 nm) in a yield of 1.4 g (83% at the 92% conversion of
the substrate). 1Н NMR (CDCl3), : 8.6 (s, 1 H, NH); 8.00—8.10
(m, 2 H, Ar); 7.30—7.80 (m, 15 H, Ar); 6.20—6.35 (m, 2 H);
5.50—5.80 (m, 2 H); 5.30 (d, 1 H, CHBr, J = 6.0 Hz), 4.90 (m, 2 H);
4.60—4.80 (m, 3 H); 4.35 (m, C(2´)H); 4.10—4.30 (m, 3 H);
2.60—2.70 (m, 1 H); 2.40 (s, 3H); 2.00—2.30 (m, 3 H); 1.80—1.90
(m, 6 H); 1.60—1.80 (m, 4 Н); 1.20, 1.30 (both s, 6 H, 2 CH3).
Found (%): С, 48.72; H, 3.92; Br, 6.24; Cl, 17.05; N, 1.13.
C51H48BrCl6NO18. Calculated (%): С, 48.79; H, 3.85; Br, 6.36;
Cl, 16.94; N, 1.12.
Isobutyl (4S,5R)ꢀ4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀcarboxylate (17)
was synthesized similarly from compound 15. The yield was 71%;
20
1
[]D +1.1 (с 0.1, EtOH). Н NMR (CDCl3), : 7.35—7.45
(m, 5 H, Ar); 5.70—5.80 (br.s, 1 H, NH); 5.00 (d, 1 H, C(3)H,
J = 5.2 Hz); 4.80 (d, 2 H, C(2)H, J = 5.3 Hz); 4.00 (d, 2 H, CH2,
BuiO, J = 5.2); 1.95—2.05 (m, 1 H, CH, BuiO); 0.95, 1.05 (both s,
6 H, 2 CH3, BuiO). IR, /cm–1: 3240 (m); 3146 (m); 2980 (m);
1761 (s); 1753 (s); 1452 (m); 1385 (m); 1230 (m); 1205 (s); 1078
(s); 930 (m). Found (%): С, 63.84; H, 6.45; N, 5.23. C14H17NO4.
Calculated (%): С, 63.87; H, 6.51; N, 5.32.
Cleavage of 4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀcarboxylates under
the action of alkali carbonates (general procedure). Anhydrous
MeOH (4 mL) was added to a solution of 4ꢀphenyloxazolidinꢀ2ꢀ
oneꢀ5ꢀcarboxylate 13, 14, or 7a (0.25 mmol) in anhydrous THF
(2 mL), and then Li2CO3 or K2CO3 (0.25 mmol) or Cs2CO3
(0.05 mmol) was added with stirring. The mixture was stirred at
ambient temperature until the starting substrate disappeared,
monitoring the reaction course by HPLC. Unreacted carbonate
was filtered off (in the case of Cs2CO3, its residue was neutralꢀ
ized with dilute HCl), and the organic solvent was evaporated on
a rotary evaporator.
Intramolecular cyclization of compounds 6, 11, and 12 (genꢀ
eral procedure). Sodium hydride (1.5—3.0 equiv., 60% disperꢀ
sion in mineral oil) was added under an inert gas atmosphere in
portions for 1 h with stirring to a solution cooled to –15 С of
3ꢀbromoꢀ2ꢀacylcarbamoyloxyꢀ3ꢀphenylpropionic acid ester
(1 mmol) in THF (10 mL) with the residual water content at
most 0.03%. The mixture was kept for 2 h under the indicated
conditions, and 18ꢀcrownꢀ6 (0.05 equiv.) was added. Stirring
was continued, gradually raising the temperature of the mixture
(2S,3R)ꢀ(+)ꢀNꢀBenzoylꢀ3ꢀphenylisoserine methyl ester
(2S,3Rꢀ18) was synthesized from compound 14 in the presence
of 0.2 equiv. cesium carbonate (Aldrich). The reaction time was
1.5 h. The yield was 54%, m.p. 180—182 С (cf. Ref. 9a:

Phenylglycidic route to taxanes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2161
1
181—183 С). Н NMR (CDCl3), : 7.30—7.80 (m, 10 H, Ar);
3. Taxol: Science and Application, Ed. M. Suffness, CRS Press,
Boca Raton—London—New York—Washington (DC), 1995,
426 pp.
4. (a) M. Hepperle, G. Georg, Drugs Future, 1994, 19, 573;
(b) F. GuéritteꢀVoegelein, D. Guénard, F. Lavelle, M.ꢀT.
Le Goff, L. Mangatal, P. Potier, J. Med. Chem., 1991, 34,
992; (c) D. G. Kingston, G. Samaranayaka, C. A. Ivey, J. Nat.
Prod., 1990, 53, 1.
7.20 (d, 1 H, NH); 5.70 (dd, 1 H, J = 2.0 Hz, J = 8.5 Hz); 4.65
(d, 1 H, J = 2.0 Hz); 3.80 (s, 3 H, CH3); 2.90 (br.s, 1 H, ОН).
(2R,3S)ꢀ(–)ꢀNꢀBenzoylꢀ3ꢀphenylisoserine methyl ester
(2R,3Sꢀ18) was synthesized from isobutyl ester 13 similarly to comꢀ
pound 2S,3Rꢀ18. The yield was 51%, m.p. 180—182 С (cf. Ref. 9a:
181—183 С); []D20 –44 (с 0.9, EtOH) (cf. Ref. 9a: []D20 –49
1
(с 1.0, МеOH)). Н NMR (CDCl3), : 7.30—7.80 (m, 10 H,
Ar); 7.20 (br.s, 1 H, NH); 5.70 (dd, 1 H, J = 2.0 Hz, J = 8.5 Hz);
4.75 (d,1 H, J = 3.0 Hz); 3.80 (s, 3 H, CH3); 3.00 (br.s, 1 H).
Methyl (4S,5R)ꢀ3ꢀbenzoylꢀ4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀcarbꢀ
oxylate (4S,5Rꢀ14) was synthesized from isobutyl ester 13 in the
presence of lithium carbonate (1.0 equiv.). The reaction time
5. D. G. Kingston, J. Nat. Prod., 2000, 63, 726.
6. H. Hónig P. SeuferꢀWasserthal, H. Weber, Tetrahedron,
1990, 46, 3841.
7. (a) B. Bhatia, S. Jain, A. De, I. Bagchi, J. Iqbal, Tetrahedron
Lett., 37, 1996, 7311; (b) J. M. Chong, K. B. Sharpless,
J. Org. Chem., 1985, 50, 1560.
1
was 3 h. The yield was 95%. Н NMR (CDCl3), : 7.40—7.80
(m, 10 H, Ar); 5.60—5.70 (d, 1 H, C(3)H, J = 5.0 Hz); 4.85—4.95
(d, 1 H, C(2)H, J = 5.0 Hz); 3.90 (s, 3 H, CH3). Found (%):
С, 66.57; H, 4.50; N, 4.38. C18H15NO5. Calculated (%):
С, 66.46; H, 4.65; N, 4.31.
8. (a) K. Harada, Y. Nakajima, Bull. Chem. Soc. Jpn., 1974, 47,
2911; (b) E. Kaji, A. Igarashi, S. Zen, Bull. Chem. Soc. Jpn.,
1976, 49, 3181.
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58, 1287; (b) T. Yamaguchi, N. Harada, K. Ozaki, M. Haꢀ
yashi, H. Arakawa, T. Hashiyama, Tetrahedron, 1999, 55,
1005; (c) J. N. Denis, A. Correa, A. E. Greene, J. Org. Chem.,
1990, 55, 1957; (d) T. Yamaguchi, N. Harada, K. Ozaki,
M. Hayashi, T. Hashiyama, Tetrahedron Lett., 1998, 39,
5575; (e) US Pat. 5677470; http://patft.uspto.gov.
10. (a) R. N. Patel, A. Banerjee, J. M. Howell, C. G. McNamee,
D. Brozozowski, D. Mirfakhrae, V. Nanduri, J. K. Thotꢀ
tathil, L. J. Szarka, Tetrahedron: Asymmetry, 1993, 4, 2069;
(b) H. Hamamoto, V. A. Mamedov, M. Kitamoto, H. Haꢀ
yashi, S. Tsuboi, Tetrahedron: Asymmetry, 2000, 11, 4485.
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1991, 56, 6939; (b) A. M. Kanazawa, A. Correa, J. N. Denis,
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Goodwin, J. Chem. Soc., Perkin Trans.1, 1993, 1375.
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31, 6429.
17. (a) US Pat. 5175315, http://patfl.uspto.gov/netahtml/PTO/
srchnum.htm; (b) R. A. Holton, J. H. Lin, Bioorg. Med. Chem.
Lett., 1993, 3, 2475.
(2R,3S)ꢀ(–)ꢀ3ꢀPhenylisoserine methyl ester (2R,3Sꢀ19).
Methanolysis of isobutyl ester 13 under the action of magnesium
methoxide was carried out according to a described procedure.62а
Anhydrous MeOH (9 mL) was added to a solution of compound 13
(0.27 g, 0.73 mmol, 1 equiv.) in anhydrous THF (6 mL). Then
a freshly prepared methanolic solution of magnesium methoxide
was added at ambient temperature with stirring in such a way
that its content would be 20 equiv. The mixture was stirred,
monitoring the reaction course by HPLC. When the required
conversion of the substrate was achieved, the reaction mixture
was neutralized with an acetate buffer to рН 7. Brine (15 mL)
was added, and the product was extracted with dichloromethꢀ
ane (2×40 mL). The organic phase was separated and dried over
sodium sulfate. Exhaustive methanolysis (25 h) gives compound
2R,3Sꢀ19 in 75% yield (after a series of additional purifications).
1Н NMR (CDCl3), : 7.35—7.45 (m, 5 H, Ar); 5.55 (m, 1 H);
5.00 (d, 1 H, J = 3.0 Hz); 4.75 (d, 1 H, J = 3.0 Hz); 3.85 (s, 3 H,
CH3); 1.60—1.90 (m, 2 H). Found (%): С, 61.57; H, 6.64;
N, 7.08. C10H13NO3. Calculated (%): С, 61.53; H, 6.71; N, 7.17.
The treatment of compound 2R,2Sꢀ19 with benzoyl chloride
in the presence of Et3N gives (2R,3S)ꢀ(–)ꢀNꢀbenzoylꢀ3ꢀphenylꢀ
isoserine methyl ester (2R,3Sꢀ18), whose characteristics are idenꢀ
tical to those described above.
3ꢀBenzoylꢀ4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀcarboxylic acid. Conꢀ
centrated hydrochloric acid (1 mL) was added to a solution of
compound 13 (0.09 g, 0.25 mmol) in THF (3 mL), and the
mixture was refluxed for 1 h. 3ꢀNꢀBenzoylꢀ4ꢀphenyloxazolidinꢀ
2ꢀoneꢀ5ꢀcarboxylic acid that formed was isolated as described
above for the enantiomer of transꢀphenylglycidic acid (see synꢀ
thesis of compound 4).
18. (a) I. Ojima, I. Habus, M. Zhao, G. I. Georg, L. R. Jayasingꢀ
ha, J. Org. Chem., 1991, 56, 1681; (b) I. Ojima, I. Habus,
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Acylation of 7,10ꢀО,О´ꢀbis(2,2,2ꢀtrichloroethoxycarbonyl)ꢀ
10ꢀdeacetylbaccatin (3) with a toluene solution of (4S,5R)ꢀ3ꢀNꢀ
benzoylꢀ4ꢀphenyloxazolidinꢀ2ꢀoneꢀ5ꢀcarboxylic acid was carꢀ
ried out as described in the patent.57
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Received January 21, 2012;
in revised October 3, 2012