Synthesis of (2R,3S)-isobutyl phenylisoserinate, the Taxol() side chain, from ethyl benzoylacetate

Article abstract of DOI:10.1016/S0957-4166(00)00172-5

Reduction of ethyl 2-chloro-3-phenyl-3-oxopropionate with borohydride affords predominately the syn-chlorohydrin. Resolution of this ester with the lipase MAP-10 gives (2S,3R)-2-chloro-3-hydroxypropionic acid which after esterification with MeOH/HCl is co

Full text of DOI:10.1016/S0957-4166(00)00172-5

Tetrahedron: Asymmetry 11 (2000) 2117±2123
Synthesis of (2R,3S)-isobutyl phenylisoserinate, the Taxol1
side chain, from ethyl benzoylacetate
Peter G. M. Wuts,* Rui Lin Gu and Jill M. Northuis
Chemical Process Research and Development, Pharmacia and Upjohn Inc., Kalamazoo, Michigan 49001, USA
Received 3 March 2000; accepted 2 May 2000
Abstract
Reduction of ethyl 2-chloro-3-phenyl-3-oxopropionate with borohydride a€ords predominately the syn-
chlorohydrin. Resolution of this ester with the lipase MAP-10 gives (2S,3R)-2-chloro-3-hydroxypropionic
acid which after esteri®cation with MeOH/HCl is converted to the cis-epoxide with potassium carbonate and
DMF. Aminolysis of the epoxide with aqueous ammonia results in ring opening and amide formation. The
amide is converted to an ester upon treatment with isobutyl alcohol and HCl(g) at 100ꢀC. Neutralization
then a€ords the Taxol1 side chain as the free amine. # 2000 Published by Elsevier Science Ltd.
1. Introduction
The importance of Taxol1,1 a complex diterpene, in the armamentarium against the scourge of
cancer is now well established.2 Initially, its only source was from the bark of the paci®c yew tree,
Taxus brevifolia, which cannot be considered a renewable resource because of its slow growth
and, therefore, the supply of Taxol1 was quite limited during the early clinical trials. On the other
hand, the supply of the key terpenoid fragment 10-desacetylbaccatin III (10-DAB) is readily
obtained from a rapidly renewed resource, the yew bush: Taxus baccata. Since the initial work by
the French group of Potier,3 a number of methods have been developed to convert 10-DAB to
Taxol1, all of which rely on coupling of a protected phenylisoserinate to a 7-protected baccatin
derivative.4,5 Because the side chain is not readily available from natural sources, its sole supply
must rely on chemical synthesis. As a result, several synthetic approaches have been developed
with varying degrees of eciency and simplicity.6 We wish to describe here an enzyme based
synthesis which we feel is straight forward, uses readily available materials and could easily be
scaled up to make multikilo quantities of material.
* Corresponding author. E-mail: peter.g.wuts@am.pnu.com
0957-4166/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00172-5

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2. Results and discussion
Lipase mediated syntheses are now well known and o€er rapid access to non-racemic chiral
substrates. We felt that the readily available racemic chlorohydrin 2 would serve as a suitable
substrate for a lipase and thus give us rapid access to the diastereomerically and enantiomerically
pure epoxide 6 (Scheme 1). Thus chloride 1,7 obtained by simple chlorination of ethyl benzoyl-
acetate, is reduced with NaBH4 to a€ord a 4:1 mixture of the syn- and anti-chlorohydrins whereas
reduction with Zn(BH4)2 a€ords a 9:1 mixture of the syn- and anti-chlorohydrins. The use of
NaBH4 also resulted in considerable over-reduction, but using NaBH3OAc minimized this while
still giving a 4:1 ratio of products. The two isomers were not readily separable and thus no
attempt was made to separate them. Enzymatic hydrolysis of this mixture using a number of
lipases (Table 1) showed that the best selectivity was obtained using the Amano MAP-10 lipase
which unexpectedly gave excellent syn/anti-selectivity as well as excellent enantioselectivity. The acid
was produced with 90% ee. The diastereoselectivity of MAP-10 was unique among the enzymes
tested. Generally, with the MAP-10 enzyme a 35% chemical yield of pure syn-chlorohydrin 4
could be obtained after isolation by a simple acid/base extraction protocol. The (2S,3R)-acid
is then converted to the methyl ester 5 with methanol and HCl(g). Ring closure to the cis-epoxide is
cleanly accomplished with K2CO3 in DMF.
Scheme 1.
The most common procedure for opening such an epoxide is with azide ion. Although this
reaction works well6o it is not suited to scale-up because the intermediate azido derivative has 1/3
the explosive potential of an equivalent weight of TNT. This was determined using di€erential
scanning calorimetry on the methyl ester 10.8 The other method often used to open epoxides is to

P. G. M. Wuts et al. / Tetrahedron: Asymmetry 11 (2000) 2117±2123
2119
Table 1
Lipase screening results
form amines directly with anhydrous ammonia in EtOH at elevated temperatures and pressures
as done by Jacobson in his synthesis of the Taxol1 side chain.6n
We have found an experimentally much simpler method utilizing aqueous ammonia. Thus,
simply stirring the epoxide with concentrated aqueous ammonia results in clean opening of the
epoxide and converts the ester to the amide to a€ord amide 7 without the need to use pressure
rated equipment. It is at this point that the enantiopurity of the resulting amide is upgraded. The
racemic amide 7 is insoluble in MeOH and can thus be removed by simple ®ltration. This was
determined during an attempt to crystallize the amide from methanol. The racemic nature of the
solids was con®rmed by formation of the Mosher ester of the derived benzamide.
Finally, conversion of the amide to an acid or ester must be addressed. Normal methods for
hydrolysis of such amides tend to be problematic and in the case of amino acids the isolation is
not always straightforward. We found that conversion of the amide to the isobutyl ester was
conveniently achieved by heating an isobutyl alcohol slurry of the amide to 100ꢀC after saturating
with HCl gas.9 After neutralization and isolation a 70% overall yield of amine 9 from epoxide 6 is
obtained. At this point the material can be benzoylated to give the paclitaxel side chain, derivatized
with (BOC)2O to give the Taxotere1 side chain or alternately derivatized as part of an analog
program.
In conclusion, we have described a simple and safe synthesis of the phenylisoserine subunit of
paclitaxel that should be amenable to scale-up and uses only readily available low cost reagents.
We have shown that a lipase may be used for a very ecient resolution of a 2-chloro-3-hydroxy-
3-phenyl propionate, a process that has the potential to be extended to a number of other related

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P. G. M. Wuts et al. / Tetrahedron: Asymmetry 11 (2000) 2117±2123
substrates. In our synthesis, the free amine is isolated which gives this approach considerable
¯exibility with regard to analog development.
3. Experimental
3.1. Ethyl 2-chloro-3-hydroxy-3-phenylpropionate 2 from NaBH3OAc
A solution of 1 (100 g, 0.44 mol) and glacial acetic acid (25 mL, 0.44 mol) in ethanol (1 L) was
cooled to ^5ꢀC and stirred for 10 min. Sodium borohydride pellets (12.54 g, 0.33 mol, diam. 11
mm) were added in portions (4.2 gÂ3) with vigorous stirring. The reaction temperature was
maintained at ^5 to 0ꢀC. After the addition, the reaction mixture was stirred continuously at 0ꢀC
for 5 h and was then poured slowly into ice-water with stirring. The mixture was extracted with
ethyl acetate (1 L). The organic phase was washed three times with water (100 mL) and brine (100
mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure to give
crude 2 as an oil (105 g, 100%). The chlorohydrin 2 is a 1:4 mixture of the anti- and syn-isomers
1
as determined by NMR. MS m/z (CI+NH3) 246 (M++17), 228 (M+), 210, 194. anti-2: H NMR
(500 MHz, CDCl3) 7.60±7.50 (m, 5H), 5.33 (d, J=6.5 Hz, 1H), 4.64 (d, J=6.5 Hz, 1H), 4.33 (q,
J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H). 13C NMR (300 MHz, CDCl3) 167.9, 138.2, 128.7, 128.5,
1
126.7, 74.6, 62.9, 62.2, 13.7. syn-2: H NMR (500 MHz, CDCl3) 7.60±7.50 (m, 5H), 5.24 (d,
J=7.7 Hz, 1H), 4.58 (d, J=7.7 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H). 13C
NMR (300 MHz, CDCl3) 168.9, 138.8, 126.7, 126.5, 126.9, 75.2, 62.3, 59.2, 13.8.
3.2. Ethyl 2-chloro-3-hydroxy-3-phenylpropionate 2 from Zn(BH4)2
A solution of 1 (6.8 g, 30 mmol) in dichloromethane (68 mL) was cooled to ^5ꢀC and a 0.4 M
solution of zinc borohydride (38 mL, 15 mmol) in ethyl ether was added dropwise over 30 min.
After the addition, the reaction mixture was stirred at 0ꢀC for 30 min and then poured into a cold
solution (0ꢀC) of acetic acid (5 mL) in water (15 mL). The resulting mixture was extracted with
dichloromethane (30 mLÂ2). The combined organic phases were washed with water (30 mL) and
dried over magnesium sulfate, ®ltered and concentrated under reduced pressure. The residue was
chromatographed on silica gel using ethyl acetate in hexane (5±25%) to give 2 (4.9 g, 72%) as a
91:9 mixture of syn- and anti-isomers as determined by NMR.
3.3. (2S,3R)-2-Chloro-3-hydroxy-3-phenylpropionic acid 4
(þ)-Ethyl-2-chloro-3-hydroxy-3-phenyl propionate (5.5 g, 24 mmol, syn/anti=14:3) was incubated
with lipase MAP-10 (1 g) in 0.2 M pH 7.0 phosphate bu€er (100 mL). The reaction mixture was
stirred vigorously at 25ꢀC for 6 days. The conversion was checked by HPLC (nucleosil C-18
column, CH3CN:H2O, 30:70, ¯ow 2 mL/min, 207 nm) which showed 2 (60±65%, retention time
10.9 min) and 3 (40±35%, retention time 1.0 min). The resulting reaction mixture was acidi®ed
with 5% HCl (15 mL) to pH<2 and extracted with ethyl acetate (50 mLÂ3). The combined
organic solution was extracted with 10% aqueous potassium carbonate (25 mL) and then washed
with water (25 mLÂ2). The organic phase was dried (MgSO4) and concentrated under reduced
pressure to give 3 (3.3 g, 60%). The combined aqueous solution was washed with ethyl ether (30
mL) and acidi®ed with 10% HCl (50 mL) to pH<2. The acidic solution was extracted with ethyl

P. G. M. Wuts et al. / Tetrahedron: Asymmetry 11 (2000) 2117±2123
2121
acetate (50 mLÂ2). The organic phase was dried (MgSO4) and concentrated under reduced
pressure to give 4 (1.9 g, 39.5%). The overall reaction time can be reduced by using a higher
25
D
1
loading of the enzyme. Compound 3: the ratio of syn:anti was 2:1 from H NMR; ‰ꢀŠ +6.35 (c
3.23, CHCl3). Compound 4: an analytical sample was prepared by recrystallization by dissolving
the acid in 5 mL/g hot chloroform, adding 1.5 mL/g heptane then cooling to 0ꢀC for 1 h. Filtration
and drying gives colorless crystals: mp 98±100ꢀC; ‰ꢀŠD25=+1.95 (c 1.48, MeOH) and ^3.9 (c 1.5,
CHCl3); 1H NMR (300 MHz, CDCl3) 7.42±7.39 (m, 5H), 5.28 (d, J=8.4 Hz, 1H), 4.58 (d, J=8.4
Hz, 1H). Anal. calcd for C9H9O3Cl: C 53.87, H 4.52, Cl 17.71. Found: C 53.50, H 4.68, Cl 17.45.
MS m/z 200 (M+), 165, 147, 129, 119, 107, 91, 79, 65, 51; HRMS calcd for C9H9O3Cl 200.0240,
obsd 200.0240.
3.4. Methyl (2S,3R)-2-chloro-3-hydroxy-3-phenylpropionate 5
A solution of (2S,3R)-2-chloro-3-hydroxy-3-phenyl propionic acid 4 (2 g, 10 mmol) in methanol
(20 mL, saturated with HCl) was stirred at 25ꢀC for 1 h. The reaction mixture was poured into
saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (20 mLÂ3). The
combined organic phases were washed with water (20 mL) and dried over magnesium sulfate.
Filtration and solvent removal under reduced pressure gave the methyl ester 5 (2.05 g, 95%):
25
1
‰ꢀŠD =^5.0 (c 1.5, CHCl3); H NMR (300 MHz, CDCl3) 7.41±7.35 (m, 5H), 5.19 (d, J=6.2 Hz,
1H), 4.51 (d, J=6.2 Hz, 1H), 3.70 (s, 3H); 13C NMR (300 MHz, CDCl3) 168.4, 138.1, 128.7,
128.5, 126.5, 74.4, 62.8, 53.0.
3.5. Methyl (2R,3R)-2,3-epoxy-3-phenylpropionate 6
To a solution of (2S,3R)-methyl-2-chloro-3-hydroxy phenylpropionate 5 (31.6 g, 0.15 mol) in
DMF (730 mL) was added water (13.5 mL) followed by potassium carbonate (62 g, 0.45 mol) at
25ꢀC with stirring. The mixture was allowed to stir at 25ꢀC for 72 h and then poured into a
mixture of ethyl acetate (3 l) and water (500 mL). The organic layer was separated and the aqueous
layer was back washed with ethyl acetate (400 mLÂ2). The combined organic layers were washed
with water (400 mLÂ3). The water layers were extracted with ethyl acetate (100 mL). The combined
organic solution was dried over anhydrous magnesium sulfate, ®ltered and concentrated under
reduced pressure to about 800 mL. The organic solution was again washed with water (250
mLÂ4), dried over magnesium sulfate, ®ltered and the solvent removed under reduced pressure to
give the epoxide 6 as a colorless oil (26 g, 99%): ‰ꢀŠ2D5=+15.0 (c 1.52, chloroform); 1H NMR (300
MHz, CDCl3): 7.45±7.33 (m, 5H), 4.30 (d, J=4.6 Hz, 1H), 3.88 (d, J=4.6 Hz, 1H), 3.58 (s, 3H).
13C NMR (300 MHz, CDCl3): 167.0, 132.7, 128.5, 128.0, 126.5, 57.5, 55.8, 52.0. MS m/z 178
(M+), 161, 131, 107, 105, 91, 79, 77, 51.
3.6. (2R,3S)-3-Amino-2-hydroxy-3-phenylpropionamide 7
Epoxy ester (+)-6 (21.2 g, 0.12 mol) was added to a cold (0ꢀC) solution of ammonium
hydroxide (220 mL, 30%) with stirring (the addition took about 30 min). The reaction mixture
was then stirred at 25ꢀC for 4 days. The resulting mixture was evaporated to dryness under
vacuum (ꢁ27 in) in a 30±35ꢀC water bath to give amide (+)-7 (20.9 g, 97.5%). An analytical
sample was prepared by recrystallization: The crude product (2 g) was dissolved in re¯uxing
methanol (30 mL). After 15 min of re¯uxing, the suspension was ®ltered at the boiling temperature

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P. G. M. Wuts et al. / Tetrahedron: Asymmetry 11 (2000) 2117±2123
and a white powder (300 mg)10 collected which did not dissolve in methanol. This material
proved to be the racemic amide based on derivatization as Mosher's ester. The ®ltrate was kept in
the freezer at ^20ꢀC overnight to give the ®rst crop of crystals (730 mg). The mother liquor was
evaporated under reduced pressure to a volume of about 10 mL. After standing at ^20ꢀC, a second
crop of crystals (500 mg) was obtained: mp 175±178ꢀC (lit.9 mp 172±173ꢀC); ‰ꢀŠD25=+60 (c 0.66,
1
MeOH); IR (mineral oil) 3425, 3416, 3139, 1640, 1451, 1316, 996, 971, 647 cm^1. H NMR (300
MHz, DMSO-d6: D2O, 3:1): 7.13±7.36 (m, 5H), 4.10 (d, J=3.2 Hz, 1H), 3.88 (d, J=3.2 Hz, 1H).
13C NMR (300 MHz, DMSO-d6: D2O, 3:1): 174.8, 144.1, 127.7, 127.0, 126.3, 75.5, 57.2. MS m/z
181 (M++1), 164, 106, 105; HRMS m/z calcd for C9H12N2O2+H1 181.0977, obsd 181.0975.
3.7. Isobutyl (2R,3S)-3-amino-2-hydroxy-3-phenylpropionate 9
To a suspension of (2R,3S)-2-hydroxy-3-amine-3-phenylpropionamide (180 mg, 1 mmol) in
isobutyl alcohol (2.5 mL) was bubbled anhydrous hydrogen chloride gas until saturated allowing
the temperature to rise. The reaction mixture was then heated to 100ꢀC overnight. The resulting
solution was evaporated to dryness under reduced pressure at 50ꢀC. The residue was dissolved in
water (5 mL), and neutralized with saturated potassium carbonate solution to pH>9. The aqueous
phase was extracted with ethyl acetate (15 mLÂ3). The combined organic solution was dried over
magnesium sulfate, ®ltered and the solvent removed under reduced pressure. The residue was
puri®ed by ¯ash chromatography (1±5% methanol in dichloromethane) to give the isobutyl ester
9 (165 mg, 70% overall from epoxide 6) as a colorless oil: 1H NMR (300 MHz, CDCl3) 7.44±7.28
(m, 5H), 4.34 (d, J=3.3 Hz, 1H), 4.30 (d, J=3.3 Hz, 1H), 4.00 (d, J=6.7 Hz, 2H), 1.95 (m, 1H),
0.95 (d, J=6.7 Hz, 6H). 13C NMR (300 MHz, CDCl3) 173.5, 142.3, 128.5, 127.5, 126.7, 75.0,
71.8, 58.0, 27.6, 18.9. MS m/z 238 (M++1), 165, 136, 118, 107, 106, 104, 91, 79, 77, 57. HRMS m/z
calcd for C13H19N1O3+H1 238.1443, obsd 238.1441.
Acknowledgements
We express our appreciation to Eric Seest from our structural analytical laboratory for deter-
mination of enantiopurity.
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1
same as the methanol crystallized sample. A sample was benzoylated and derivatized as the Mosher ester, which
by NMR proved to be a 1:1 diastereomeric mixture. Thus, the methanol insoluble material is racemic.