Process development of the Sharpless catalytic asymmetric dihydroxylation reaction to prepare methyl (2R,3S)-2,3-dihydroxy-3-phenylpropionate

Article abstract of DOI:10.1021/op000035j

A typical Sharpless catalytic asymmetric dihydroxylation (ADH) process to make methyl (2R,3S)-2,3-dihydroxy-3 phenylpropionate has been successfully developed. The ADH reaction was exothermic and complete in 2-3 h without affecting the optical purity and

Full text of DOI:10.1021/op000035j

Organic Process Research & Development 2000, 4, 575−576
Process Development of the Sharpless Catalytic Asymmetric Dihydroxylation
Reaction To Prepare Methyl (2R,3S)-2,3-Dihydroxy-3-phenylpropionate
Xinbo Lu,* Zhunle Xu, and Guojun Yang
Chemistry Department, Zhong Shan UniVersity, Guang Zhou, 32 Xingang Xi Road, P. R. China, and S&P Chiral-Tech
Research Center, Zhong Guan Cun Chuang Ye Building 1008, Shang-Di, Beijing, P. R. China
Abstract:
of the reactions were carried out at room temperature (25
°C), with no particular report about the exothermic effect.
The standard ADH temperature was at 0 °C;4 however, one
literature paper reported that the temperature actually had
no remarkable effect on ee % in a range from -100 to 78
°C in some specific ADH reactions.5
A typical Sharpless catalytic asymmetric dihydroxylation (ADH)
process to make methyl (2R,3S)-2,3-dihydroxy-3 phenylpropi-
onate has been successfully developed. The ADH reaction was
exothermic and complete in 2-3 h without affecting the optical
purity and yield. The major impurity of methyl (2R)-hydroxy-
3-keto-phenylpropionate, which may seriously damage the
quality of diol, has been identified and removed properly in
the process.
Here we report our solutions for successful, efficient,
industrial process development of the diol intermediate for
the taxol side chain synthesis. Commercial methyl cinnamate
was subjected to the N-methylmorpholine N-oxide (NMO)-
based ADH process at room temperature. The ligand, 1,4-
bis (9-O-dihydroquinine) phthalazine [(DHQ)2PHAL] used
in only 0.5 mol % NMO, was used as the cooxidant instead
of K3[Fe(CN)6]-K2CO3, which was found impractical on a
large scale.6 The reaction was run in t-BuOH/water. We
found that the reaction was complete in 2-3 h rather than
20 h with an obvious exothermic phenomenon not reported
in the original.7 Without control of the temperature, the
exothermic process would drive the temperature as high as
35-40 °C. Control of the reaction temperature at 25 °C
would drag the reaction time to about 20 h. In terms of the
enantioselectivity, the 2-3 h reaction at 35-40 °C would
not compromise the optical purity and yield in comparison
with the 20 h reaction at 25 °C; in both cases, the ee %
remained the same in the range of 87-90%. There had
always been a problem of impurity removal following the
literature work-up process, and the result of this process7
was inconsistent in impurity level. Later on, we identified
two impurities, one of which was the over-oxidized product
as the â-keto material, and the other, NMO. It was assumed
that the â-keto material resulted from over-oxidation of the
transitional diol intermediate complex, which could be
characterized from the HPLC monitoring (see Figure 1). The
unnecessary, over-long, agitation time of the oxidation
tremendously increased the impurity level. The addition of
Na2SO3 actually played an important role in removing this
complex by reduction of the osmium(VIII) to osmium(VI)
which was more highly soluble in the aqueous phase. We
found that the 2-3 h agitation of aqueous Na2SO3 reported
in the original literature7 was not long enough to remove
the transitional intermediate complex (by HPLC).
The Sharpless catalytic asymmetric dihydroxylation (ADH)
of olefins with osmium tetroxide in the presence of cinchona
alkaloid derivatives has been widely used in chiral drug
intermediate and natural product syntheses.1 The ADH
reaction is one of the most reliable and practical methods in
Taxol side chain synthesis.2a-d However, there were limita-
tions to performing the ADH reaction on a large scale. In
recent years, many reports3 appeared, exploring the possibil-
ity of repetitive use of osmium tetroxide to reduce the cost
and toxicity. There were also reports about the development
of polymer-bound cinchona alkaloid derivatives in hetero-
geneous ADHs, which were, as reported, still suffering from
many drawbacks such as low reactivity, poor enantioselec-
tivity, long reaction times, and poor yield.3 Our earlier
experiments on the ADH of the trans-methyl cinnamate-
vicinal diol process ran into many important issues, one of
which was about the previously unnoted exothermic effect
and its impact; the other major issue was about the impurity
profile and osmium removal.
As reported in the enantioselective synthesis of the Taxol
C-13 side chain through asymmetric dihydroxylation, most
(1) (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35,
448-451.(b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483-2547.
(2) (a) Wang, Z.-M.; Kolb, H. C.; Sharpless. K. B. J. Org. Chem. 1994, 59,
5104-5105. (b) Lohray, B. B.; Bhushan, D. Ind. J. Chem. 1995, 34B, 471-
473. (c). Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem. 1990, 55,
1957-1959. (d) Koshinen, A. M. P.; Karvinen, E. K.; Siirila, J. P. J. Chem.
Soc. 1994, 21-22. (e) Desai, S. B.; Argade, N. P.; Ganesh, K. N. J. Org.
Chem. 1996, 61, 6370-6372. (f) Zhou, W.-S.; Yang, Z.-C. Tetrahedron
Lett. 1993, 34, 7075-7076. (g) Rao, A. V.; Reddy, T. K. L.; Rao, A. S.
Tetrahedron Lett. 1994, 35, 5043-5046.
(4) Kolb, H. C.; VanNnieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
2483-2547.
(5) Fuji, K.; Tanaka, K.; Miyamoto, H. Tetrahedron Lett. 1992, 33, 4021-
4024.
(3) (a) Song, C. E.; Yang, J.; Ha, H. J.; Lee, S.-g. Tetrahedron: Asymmetry
1996, 7, 645-648. (b) Lohray, B. B.; Nandanan, E.; Bhushan, V.
Tetrahedron: Asymmetry 1996, 7, 2805-2808.
(6) Lohray, B. B.; Bhushan, D. Ind. J. Chem. 1995, 34B, 471-473.
(7) Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem. 1994, 59, 5104-
5105.
10.1021/op000035j CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 09/16/2000
Vol. 4, No. 6, 2000 / Organic Process Research & Development
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process were off-white, poor looking solids. This process
proved very successful in the pilot production of 50-kg scale,
during which the exothermic effect was controllable and no
thermal runaway was observed (in any case, the reaction
temperature should be closely controlled under 40 °C). The
newly developed process was very reliable and consistent
in the pilot production and manufacturing.
Experimental Section
Preparation of methyl (2R,3S)-2,3-dihydroxy-3-phenyl-
propionate. In a 1000 L reactor were charged 50 kg (308.3
mol, 1×) of methyl cinnamate and 155 L (3.1×) of t-BuOH,
then 1.2 kg (1.54mol, 0.024×) of (DHQ)2PHAL, 235 g
(0.638 mol, 4.7×) of K2OsO4, and 93 L (1.86×) of NMO
(50%). The reaction mixture was agitated at room temper-
ature (23 °C); after 2 h, the exothermic effect drove the
temperature maximum up to 40 °C (the temperature should
be controlled under 40 °C). In-process HPLC monitoring
after 2 h of reaction showed the reaction complete. After
the temperature came back to rt, 46.3 kg (367 mol, 0.926×)
of sodium sulfite dissolved in 155 L water were charged in,
and the temperature was kept at 45 °C for 30 min. At the
end of agitation, the reaction was monitored by HPLC, and
when the Os-cinnamate complex peak was <2%, the
agitation was stopped, and the mixture was allowed to stand
for 15 min.. After the phase cut, the t-BuOH phase was
concentrated into half the volume (about 360 L) by vacuum
distillation and extracted three times with the ethyl acetate.
The combined organic phase 770 L was washed with 10%
NaC1 90 L twice. The aqueous phase was extracted with
ethyl acetate twice. The combined organic phase was
concentrated to make sure all of the ethyl acetate was stripped
out of the system by adding toluene during the distillation
(determined by GLC). The total volume of the organic phase
was kept at about 185 L (3.7×) at the end of the distillation,
and then 10 L of heptane was added. The temperature was
lowered to about 5-10 °C, and the crystals were formed
and agitated for another hour and then filtered, and vacuum-
dried at 40 °C; the crystals weighed about 41.9 kg. (Yield:
70%, ee > 98%. Chemical purity: 99.9%, mp 85-86 °C.)
The ee % was determined by GLC on â-cyclodextrin, J&W
Figure 1. â-Keto impurity profile by HPLC after 2-h reaction
time.
Table 1. Variation of T °C/time Impact of Na2SO3
ADH rxn
Na2SO3 workup
ee
entry °C time
°C
time
crude final yield %
1
2
3
4
25
25
35
35
21
21
3
25
23
25
45
3
18
18
0.5
87
88
87
87
99.8
99.7
99.8
99.8
59
65
73
76
3
The â-keto material was identified has the following
structure:
From the in-process data of HPLC, the start material was
identified at 2.849 min and started shrinking very fast once
the reactants mixed, and meanwhile the product diol of 1.985
min peak grew until all the start material disappeared. A
companion half-height peak at 2.150 min behind the product
was also present with the diol. We assumed that to be the
transitional complex of the osmium(VIII) with the resulting
diol. Efficient removal of this 2.150-minute peak by proper
treatment with aqueous Na2SO3 was very helpful in the diol
quality control, and there was a direct relationship between
the impurity level and the 2.150-minute peak existence. With
all of the 2.150-minute peak removed, the diol would be
very good in quality; otherwise, the diol with a lot of the
â-keto impurity. On the basis of the observation, we designed
a new work-up process by stretching the agitation time of
Na2SO3 from 2 h to 18 h for which the 2.150-min. peak
would eventually disappear, shown by HPLC. Later on, we
changed the agitation of 18 h at 25 °C to a 35 min at 45 °C,
monitoring by HPLC. With this change we found that the
diol quality and yield were tremendously improved see Table
1).
1
CDX-B column, 165 °C; [R]D + 3.4° (c 1.19, EtOH); H
NMR (CDCl3 400 MHz) δH 2.89 (br, 1H), 3.21 (s,3H), 4.36
(d, J ) 2.8 Hz, 1H), 5.01 (d, J ) 2.8 Hz,1H), 7.36 (m,5H);
13C NMR (CDCl3, 400 MHz) δC 173.1, 139.9, 128.4, 128.1,
126.2, 74.7, 74.4, 52.8.
Received for review March 28, 2000.
OP000035J
Entries 3 and 4 products obtained are snow-white needle-
like crystals, while those of entries 1 and 2 from the old
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Vol. 4, No. 6, 2000 / Organic Process Research & Development