Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 1: Synthetic Strategy and Preparation of a Common Precursor

Article abstract of DOI:10.1021/op034130e

The synthetic strategy for producing multigram quantities of (+)-discodermolide (1) using a hybridized Novartis-Smith-Paterson synthetic route via common precursor 3 is described. In the first part of this five-part series, we present a multikilogram preparation of α-methyl aldehyde 10 from Roche ester, its syn-aldol reaction with Evans boron enolate, removal of the chiral auxiliary, and the preparation of Weinreb amide 3 (Smith common precursor). The common precursor was produced without any chromatography.

Full text of DOI:10.1021/op034130e

Organic Process Research & Development 2004, 8, 92−100
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product
(
+)-Discodermolide. Part 1: Synthetic Strategy and Preparation of a Common
Precursor
Stuart J. Mickel,* Gottfried H. Sedelmeier, Daniel Niederer, Robert Daeffler, Adnan Osmani, Klaus Schreiner,
Manuela Seeger-Weibel, Brigitte B e´ rod, Karl Schaer, and Remo Gamboni
Chemical and Analytical DeVelopment, NoVartis Pharma AG, CH 4002 Basel, Switzerland
Stephen Chen, Weichun Chen, Christopher T. Jagoe, Frederick R. Kinder, Jr., Mauricio Loo, Kapa Prasad, Oljan Repi cˇ ,
Wen-Chung Shieh, Run-Ming Wang, Liladhar Waykole, David D. Xu, and Song Xue
NoVartis Institutes for Biomedical Research, One Health Plaza, East HanoVer, New Jersey 07936, U.S.A.
3
Abstract:
mouse models (including PTX-resistant tumors). Discoder-
molide is currently undergoing phase I clinical trials.
The synthetic strategy for producing multigram quantities of
(+)-discodermolide (1) using a hybridized Novartis-Smith-
Paterson synthetic route via common precursor 3 is described.
In the first part of this five-part series, we present a multiki-
logram preparation of r-methyl aldehyde 10 from Roche ester,
its syn-aldol reaction with Evans boron enolate, removal of the
chiral auxiliary, and the preparation of Weinreb amide 3 (Smith
common precursor). The common precursor was produced
without any chromatography.
Structurally, discodermolide consists of a linear polypro-
pionate chain containing 13 stereocentres, six of which are
hydroxyl-bearing, with one of these esterified as a δ-lactone
(C5) with another as a carbamate (C19). It also features seven
methyl-bearing stereocentres and three Z-configured alkenes,
one of these being part of the terminal diene unit. Also
present in the structure is a common stereo triad (methyl,
hydroxyl, and methyl) that is repeated three times. The
Schreiber group has synthesized both antipodes, thus estab-
Introduction
A small, but structurally diverse collection of naturally
occurring non-taxane microtubule-stabilizing agents (MTS)
has been discovered over the past decade. These include the
epothilones (EPO), eleutherobin, laulimalide, and discoder-
molide. (+)-Discodermolide (1) is a novel polyketide natural
product first isolated from extracts of the marine sponge
Discodermia dissoluta by researchers at Harbor Branch
4
lishing the absolute configuration of 1. Since the publications
1
5-8
Oceanographic Institution (HBOI). Discodermolide stabi-
of Schreiber’s synthesis, several total syntheses
and
lizes microtubules faster and more potently than any of the
other known MTS agents and is a potent inhibitor of tumor
cell growth in vitro, including paclitaxel (PTX)- and EPO-
resistant cells. Discodermolide also demonstrates significant
human tumor growth inhibition in hollow fiber and xenograft
(
3) Kinder, F. R., Jr.; Bair, K. W.; Chen, W.; Florence, G.; Francavilla, C.;
Geng, P.; Gunasekera, S.; Guo, Q.; Lassota, P. T.; Longley, R. E.; Palermo,
M. G.; Paterson, I.; Pomponi, S.; Ramsey, T. M.; Rogers, L.; Sabio, M.;
Sereinig, N.; Sorensen, E.; Wang, R. M.; Wright, A. Synthesis and Antitumor
Activity of Analogues of the Novel Microtubule Stabilizing Agent Disco-
dermolide. In Abstracts of Papers; 224th American Chemical Society
National Meeting, Boston, MA, August 18-22, 2002; American Chemical
Society: Washington, DC, 2002; MEDI-236.
2
*
Author for correspondence. E-mail: stuart_john.mickel@pharma.novartis.
com.
(4) (a) Nerenberg, J. B.; Hung, D. T.; Sommers, P. K.; Schreiber, S. L. J. Am.
Chem. Soc. 1993, 115, 12621. (b) Hung, D. T.; Nerenber, J. B.; Schreiber,
S. L. J. Am. Chem. Soc. 1996, 118, 11054.
(5) (a) Smith, A. B.; Qui, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc.
1995, 117, 12011. (b) Smith, A. B.; Kaufmann, M. D.; Beauchamp, T. J.;
LaMarche, M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823; Additions and
corrections Org. Lett. 2000, 2, 1983. (c) Smith, A. B.; Beauchamp, T. J.;
LaMarche, M. J.; Kaufmann, M. D.; Qui, Y.; Arimoto, H.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 2000, 112, 8654.
(
1) (a) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K. J.
Org. Chem. 1990, 55, 4912, Correction J. Org. Chem. 1991, 56, 1346. (b)
Gunasekera, S. P.; Pomponi, S. A.; Longley, R. E.; U. S. Patent 5,840,750,
November 24, 1998. (c) Gunasekera, S. P.; Paul, G. K.; Longley, R. E.;
Isbrucker, R. A.; Pomponi, S. A. J. Nat. Prod. 2002, 65, 1643.
(
2) (a) Jordan, M. A. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 1. (b)
Altmann, K. H. Curr. Opin. Chem. Biol. 2001, 5, 424. (c) He, L. F.; Orr,
G. A.; Horwitz, S. B. Drug DiscoVery Today 2001, 6, 1153. (d) He, L.;
Chia-Ping, H. Y.; Horwitz, S. B. Mol. Cancer Ther. 2001, 1, 3. (e)
Kowalsky, R. J.; Giannakakou, P.; Gunasekera, S. P.; Longley, R. E.; Day,
B. W.; Hamel, E. Mol. Pharmacol. 1997, 52, 613. (f) Kalesse, M.
ChemBiochem. 2000, 1, 171. (g) Longley, R. E.; Caddigan, D.; Harmody,
D.; Gunasekra, M.; Gunasekra, S. P. Transplantation 1991, 52, 650. (h)
Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekra, M.; Gunasekra, S.
P. Transplantation 1991, 52, 656. (i) Martello, L. A.; LaMarche, M. J.; He,
L.; Beauchamp, T. J.; Smith, A. B.; Horwitz, S. B. Chem. Biol. 2001, 8,
(6) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997,
62, 6098.
(7) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
(8) (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem.,
Int. Ed. 2000, 39, 377. (b) Paterson, I.; Florence, G. J. Tetrahedron Lett.
2000, 41, 6935. (c) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.;
Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535. (d) Paterson, I.; Delgado,
O.; Florence, G. L.; Lyothier, I.; Scott, J. P.; Sereinig, N. Org. Lett. 2003,
5, 35.
8
43.
9
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10.1021/op034130e CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/04/2003

Scheme 1. High-pressure phosphonium salt formation
9
Scheme 2. Last steps of Paterson’s route
preparations of various discodermolide fragments have
appeared in the literature. A useful review of the available
1
0
synthetic approaches has recently been published.
The compound supply for development cannot be met
through the isolation and purification of discodermolide from
Discodermia sp. (which must be harvested using manned
submersibles). Attempts to reproducibly isolate a discoder-
molide-producing microorganism for fermentation have not
been successful to date. Therefore, all discodermolide used
for late preclinical research and development activities as
well as for the ongoing clinical trial has been supplied by
total synthesis.
The synthetic route used for the preparation of multigram
amounts of discodermolide was envisaged as a hybrid
synthesis which advantageously incorporated the best features
of the published syntheses by Smith and Paterson (vide infra).
Selection of these two syntheses was made after a detailed
analysis of every publication on discodermolide and related
syntheses.
Smith’s publication of the one-gram synthesis of disco-
dermolide predisposed our selection, and we started practic-
ing this route because the starting material [(S)-Roche ester
2
] for this approach was readily available. It was clear from
the beginning of this venture that there was a need for
changing some chemistry in the late steps; for example, the
high-pressure reaction (12.8 kbar) used for introducing the
(9) For examples, see: (a) Francavilla, C.; Chen, W.; Kinder, F. R., Jr. Org.
Lett. 2003, 5, 1233-1236. (b) Arefolov, A.; Panek, J. S. Org. Lett. 2002,
4
, 2397. (c) Shahid, K. A.; Mursheda, J.; Okazaki, M.; Shuto, Y.; Goto, F.;
C
8-9 cis-double bond (Scheme 1) was not practicable on large
Kiyooka, S. Tetrahedron Lett. 2002, 43, 6377. (d) Shahid, K. A.; Li, Y. N.;
Okazaki, M.; Shuto, Y.; Goto, F.; Kiyooka, S. Tetrahedron Lett. 2002, 43,
scale (added in revision: Professor Smith has recognized
this limitation of his synthesis and has recently described a
solution to this problem. Smith, A. B.; Freeze, B. Scott;
Brouard, I.; Hirose, T. Org. Lett. 2003, 5, 4405-4408). On
the other hand, Paterson’s reagent-controlled, chiral boron
enolate methodology (Scheme 2) fit into our strategy. The
Paterson aldehyde 7 could be obtained via an advanced
6373. (e) Miyazawa, M.; Oonuma, S.; Maruyama, K.; Miyashita, M. Chem.
Lett. 1997, 1191. (f) Miyazawa, M.; Oonuma, S.; Maruyama, K.; Miyashita,
M. Chem. Lett. 1997, 1193. (g) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3,
3
995. (h) Golec, J. M. C.; Jones, S. Tetrahedron Lett. 1993, 34, 8159. (i)
Evans, P. L.; Golec, J. M. C.; Gillespie, R. J. Tetrahedron Lett. 1993, 34,
163. (j) Golec, J. M. C.; Gillespie, R. J. Tetrahedron Lett. 1993, 34, 8167.
8
(
(
k) Marshall, J. A.; Lu, Z. H.; Johns, B. A. J. Org. Chem. 1998, 63, 817.
l) Yang, G.; Myles, D. C. Tetrahedron Lett. 1994, 35, 1313. (m) Yang,
G.; Myles, D. C. Tetrahedron Lett. 1994, 35, 2503. (n) Paterson, I.;
Schlapbach, A. Synlett 1995, 498.
5
c
intermediate that was described by Smith. Thus, it seemed
logical to us that a combination of these two approaches
(10) Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 12, 2193.
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93

Scheme 3. Novartis synthetic route to (+)-discodermolide
could offer a viable opportunity to scale up the synthesis of
aluminium hydride was efficient; however, the workup
proved problematic. Large quantities of aluminum salts were
formed, which did not allow for efficient filtration (it required
>24 h). Switching the reducing agent to lithium borohydride
solved this problem and furnished alcohol 9 in >98% yield
after acetic acid quench and extractive isolation. Conversion
of 9 to 10 called for a Swern oxidation. This was not an
option for us on large scale, since the formation of methyl
sulfide (stench) as a byproduct was not environmentally
friendly. This reagent was replaced by a simple, two-phase,
TEMPO/bleach oxidation in dichloromethane, which af-
forded aldehyde 10 in quantitative yield. However, 10 was
not stable for extended storage. Racemization of the stereo-
genic centre was observed within 2 days of storage, even at
0 °C. To overcome this hurdle, crude 10 was subjected to
Evans’ syn-aldol reaction without further purification.
Evans’ syn-Aldol Reaction. Enolization of 3-propionyl-
(R)-4-benzyloxazolidinone (10a) with dibutylboron triflate
in the presence of triethylamine at 0 °C, followed by
treatment of the resulting enolate with crude 10 at -78 °C,
furnished alcohol 11 in 46-55% yield on a 20-25-kg scale.
The success of this reaction was largely dependent on the
quality of dibutylboron triflate. Aged reagent did not perform
1
1
. The resulting hybridized synthetic approach for producing
is outlined in Scheme 3.
Our work progressed in three stages: proof of synthesis,
preparation of a 6-g batch, and production of 60 g of (+)-
discodermolide. The present five-part publication describes
our experience with large-scale preparation of 1. In Part 1,
we discuss some of the problems we encountered, and the
solutions we found in scaling up the preparation of 3. In
Part 2, we describe the conversion of this common inter-
mediate into fragments C1-6 (6) and C9-14 (4). Part 3
describes the preparation of the C15-21 fragment (5). Part 4
.
relates to the preparation of fragment C7-C24 (7) Part 5
illustrates the linkage of fragments C1-6 and C7-24 and the
final steps leading to the production of 60 g of 1.
Results and Discussion
5c
Smith’s approach to 3 from Roche ester 2 is outlined in
Scheme 4. This pathway was optimized by us into a more
efficient route for the large-scale production of 3.
Chiral Aldehyde. The formation of the 4-methoxybenzyl
ether 8 from Roche ester 2 proceeded in > 98% yield,
employing Smith’s protocol. Reduction of 8 with lithium
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Scheme 4. Smith’s synthesis of the common precursor
could be recovered by crystallization from the reaction mix-
ture after workup. The purity of 3 obtained by this protocol
was 85%. The remaining 15% was a series of minor by-
products: one being generated in this reaction (compound
13), and the rest were impurities carried through the synthesis
from preceding steps.
We studied this reaction by calorimetry and found that
the addition of triisobutylaluminum to a suspension of N,O-
dimethylhydroxylamine hydrochloride in THF was highly
exothermic. It was noted that the resulting complex of
triisobutylaluminum/N,O-dimethylhydroxylamine/THF was
thermally unstable. According to DSC, this complex started
to give off heat at 30 °C and reached the maximum at 140
Figure 1. Single-crystal X-ray structure of 11.
well and resulted in low yield (<35%). This may be
overcome by distillation of the reagent; however, a distillation
is not practical for large-scale operation. On a 20-50-g scale
in the lab, we routinely achieved yields of >75% for this
aldol reaction, but we were unable to replicate it in the pilot
plant. The reasons for this are still unclear. More work is
required to achieve a completely robust and reproducible
process. The acceptable quality of dibutylboron triflate
especially needs to be better defined. A recent publication
°C, resulting in the release of a total of -406 kJ/kg of energy.
The instability is presumably due to an aluminum-catalyzed
polymerization reaction of tetrahydrofuran. Thus, in case of
a cooling failure in the plant, the chance of a thermal runaway
could be very high. The high risk in process safety made
this process unfeasible for scale-up. To make this chemistry
more amenable to the pilot plant, we investigated the
following variations: inverse addition, alternative solvents,
extending the addition times, and lowering the temperature.
In all cases, we observed the formation of significant amount
of byproduct 13, attributed to the opening of the oxazolidi-
none ring. We were unable to define conditions which could
minimize this competitive ring-opening reaction.
1
1
may be able to assist in solving this quality definition.
The aldol reaction was completely stereoselective, and
none of the undesired diastereoisomer was ever detected by
us. The reaction can also be run at room temperature without
detriment to the selectivity. In contrast to the published
procedure, which purified 11 by chromatography, we were
able to crystallize the aldol product 11 with 80% recovery.
This was accomplished by dissolving the crude aldol adduct
in a mixture of n-butanol and diisopropyl ether, followed
by careful addition of heptane over an extended period of
time to afford crystalline 11 of high purity; the structure was
confirmed by single-crystal X-ray analysis (Figure 1).
Transamidation. The Smith approach employed tri-
methylaluminum-promoted transamidation of 11 into Wein-
reb amide 3, which was a nice one-step conversion. However,
trimethylaluminum was not an ideal choice of reagent for a
large-scale plant operation due to its pyrophoric properties.
We decided to replace it with triisobutylaluminum, which
was safer and which had been utilized on an industrial scale
in Ziegler-Natta processes. We found that the N,O-dimeth-
ylhydroxylamine/triisobutylaluminum complex (3.5 equiv)
had reacted efficiently with 11 (1 equiv) at room temperature
and produced the desired 3 in 75-80% yield, depending on
the purity of 11. Two-thirds of 4-benzyloxazolidinone 12
In view of these results, we decided to abandon the
transamidation protocol and to investigate two other methods.
Amide Formation Employing Chloroformate. Forma-
tion of an amide bond from a carboxylic acid via a
mixed anhydride was investigated as the first alternative
(Scheme 5).
(11) Medina, J. R.; Cruz, G.; Cabrera, C. R.; Soderquist, J. A. J. Org. Chem.
2003, 68, 4631.
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95

Scheme 5. Synthetic route to 3 using isobutyl chloroformate
Scheme 6. Alternative route to 3 using CDMT
Without further purification, we proceeded to cleave the
oxazolidinone by treating it sequentially with hydrogen
peroxide and lithium hydroxide in a mixture of water and
methanol. After workup, the resulting acid was isolated as a
crystalline salt of (R)-2-phenylethylamine (14) in 84% yield
from 11. Crystallisation of the salt at this stage is the first
purification carried out thus far in the synthesis and also
serves to protect the rather unstable acid from decomposition.
Chiral auxiliary 12 was easily recovered by crystallization
without degradation of either chemical or enantiomeric purity
dimethoxy-1,3,5-triazine (CDMT) as the coupling reagent
was investigated (Scheme 6). CDMT had been used to
activate a carboxylic acid by forming an activated triazine
ester, which was subsequently coupled with an amine in the
1
2
same pot to generate an amide. Treating 11 with hydrogen
peroxide and lithium hydroxide furnished acid 18 as an oil
in 71% yield. After activation of 18 with CDMT in the
presence of N-methylmorpholine, we found the resulting
triazine ester 19 to be quite stable, and its formation could
be monitored by HPLC. As soon as the formation of 19 had
been completed, the amine (MeNHOMe) was added to afford
3 in good yield. A large batch of 3 (1.34 kg) was produced
in 85% yield and with high purity (95.8% HPLC) without
chromatography. The major triazine byproduct 20 generated
during this reaction was easily removed from the product
during aqueous acid and base workup. Another minor
byproduct, 21, was identified.
(see Experimental Section).
After liberation of the acid, by treatment of the salt 14
with hydrochloric acid and extractive isolation, formation
of a mixed anhydride with isobutyl chloroformate followed
by reaction with N,O-dimethylhydroxylamine afforded Wein-
reb amide 3 in 75-80% yield. The choice of chloroformate
was an important factor for the success of this process. The
use of ethyl chloroformate resulted in the formation of several
byproducts (15, 16, and 17). Replacing ethyl chloroformate
with isobutyl chloroformate minimized the byproducts.
To ensure total conversion of 19 to 3, the reaction vessel
Amide Formation Employing CDMT. An alternative
strategy of amide bond formation utilizing 2-chloro-4,6-
(
12) (a) Kaminski, Z. J. Synthesis 1987, 10, 917-920. (b) Kaminski, Z. J.; Paneth,
P.; Rudzinski, J. J. Org. Chem. 1998, 63, 4248.
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must be kept closed so that no volatile N,O-dimethylhy-
droxylamine escapes from the reaction medium.
With the common precursor in hand, we were ready to
proceed to the next stage of discodermolide synthesis, which
is described in the following contributions.
toluenesulphonate (3.79 kg, 15 mol) was added in one portion
and the reaction mixture stirred for 3 h at 0 to 5 °C. After
this time a suspension formed, and the temperature of the
mixture was raised to 24 °C and stirred for a further 18 h.
The suspension was filtered and the solid rinsed with heptane
(
3 × 20 kg). The combined filtrate was concentrated under
Conclusions
vacuum at 25 °C to a volume of about 71 L. Heptane (379
kg) was added to the oily residue, followed by Cellflock (17.9
kg). The suspension was stirred for 30 min at room
temperature and filtered. The solid was rinsed with heptane
In summary, Smith’s procedure for the preparation of
common precursor 3 from Roche ester 2 was modified to
facilitate large-scale production in the pilot plant. Evan’s syn-
aldol reaction product was crystallized, and the structure was
confirmed by X-ray. Kilogram quantities of Weinreb amide
(
3 × 35 kg), and the combined filtrate was evaporated under
vacuum at 30 °C to give 8 (69.6 kg) as an oil (GC, 96.5
25
area %, corrected to 67.16 kg, 100% yield): [R]
D
-12.0
) δ 7.28 (m, 2H), 6.84
m, 2H), 4.45 (s, 2H), 3.81 (s, 3H), 3.70 (s, 3H), 3.65 (dd,
3
were prepared using two peptide synthesis protocols, which
1
(
(
2 2 3
c ) 1, CH Cl ); H NMR (CDCl
eliminated the use of trialkylaluminum. Intermediate 3 was
thus prepared in six steps without chromatography.
J ) 12.0, 6.0 Hz, 1H), 3.45 (dd, J ) 12.0, 6.0 Hz, 1H),
.75(m, 1H), 1.15 (d, J ) 10.0 Hz, 3H).
R)-3-(4-Methoxybenzyloxy)-2-methylpropan-1-ol (9).
A) Reduction with Lithium Aluminium Hydride. Lithium
aluminium hydride (32.1 kg of a 10% solution) was diluted
with anhydrous THF (179.2 kg) and cooled to 0 °C. A
solution of ester (8) (18.6 kg, 100%, 77.73 mol) in THF (54.1
L) was added over 60 min. The reaction was exothermic,
and gas evolution was observed. After the addition was
complete, the reaction mixture was stirred for another 2 h at
2
Experimental Section
(
For this five-part series the following general experimental
details apply: Reagents and solvents were obtained from
commercial sources and used as received. Proton and carbon-
(
13 NMR data were recorded on a Brucker SP 400 instrument
at 400.1 and 100.2 MHz, respectively. Melting points were
determined on an Electrothermal 8101 apparatus and are
uncorrected. IR spectra were recorded with a NICOLET
Magna 550 instrument. Optical rotations were measured with
a JASCO-P 1030 polarimeter.
0
°C. After this time, a solution of potassium sodium tartrate
(14.8 kg, 54.45 mol) in water (23 L) was added slowly.
(
S)-3-(4-Methoxybenzyloxy)-2-methylpropionic Acid
Methyl Ester (8). To a stirred suspension of sodium hydride
1.31 kg of a 60% suspension in mineral oil, 32.75 mol) in
During the initial phase of the addition, this quench was very
exothermic, and vigorous gas evolution was observed.
Finally, the gray suspension was stirred overnight at room
temperature. The suspension was filtered (filtration was
extremely slow) and the solid rinsed with THF (2 × 18 kg).
The combined filtrate was evaporated to dryness under
vacuum at 25 °C to give alcohol 9 (16.49 kg, 100%) as an
(
6
4
7.5 kg of tert-butyl methyl ether was added a solution of
-methoxybenzyl alcohol (45 kg, 325.69 mol) in tert-butyl
methyl ether (15 kg) over a period of 30 min, maintaining
the temperature at 20-22 °C. The addition equipment was
washed with 10 kg of tert-butyl methyl ether, and the
resulting reaction mixture was stirred for a further 90 min
at 20-22 °C. The mixture was cooled to 0-4 °C, and
trichloroacetonitrile (50.3 kg, 348.36 mol) was added over
oil, which was used without further purification: [R]
D
+14.6
) δ 7.23 (m, 2H), 6.86 (m,
H), 4.43 (ABq, J ) 12 Hz, 2H), 3.79 (s, 3H), 3.64-3.49
m, 3H), 3.37 (dd, J ) 9.57, 8.17 Hz, 1H), 2.60 (br m, 1H),
.05 (m, 1H), 0.85 (d, J ) 6.9 Hz, 3H).
B) Reduction with Lithium Borohydride. To a solution
1
3 3
(c ) 1, CHCl ); H NMR (CDCl
2
(
2
100 min. The reaction mixture was stirred for 90 min,
warmed to room temperature, and concentrated under
vacuum to a final volume of about 100 L. At room
temperature, the concentrate was treated sequentially with
heptane (143 kg) and methanol (1.05 kg) containing 25 g of
an antistatic agent. To the resulting suspension was added
Cellflock filter aid (5 kg); the mixture was stirred for 30
min at room temperature and filtered. The solid was rinsed
with heptane (2 × 25 kg), and the combined filtrate was
concentrated under vacuum to a final volume of about 85 L
at a maximum temperature of 30 °C to produce 97.2 kg of
the intermediate trichloroimidate as an oil.
(
of lithium borohydride (172 kg of a 10% w/w solution in
THF) was added dropwise a solution of ester 8 (65 kg, 272.81
mol, as obtained) in THF (133 kg) and ethanol (42.4 kg)
over 3 h, maintaining the temperature at 20 °C. After the
addition was complete, the mixture was stirred at 20 °C for
a further 2 h. After this time the reaction mixture was diluted
with tert-butyl methyl ether (79.5 kg) and acetic acid (398
kg of a 2 M solution) was added within 5 h. Vigorous gas
evolution was noted, and the reaction was exothermic. When
the addition was completed, the two-phase mixture was
stirred for 15 min at room temperature and the organic layer
separated. The organic layer was washed with aqueous
sodium hydroxide solution (212 kg, 2 M). The organic layer
was separated and washed with brine (192 kg), dried over
A solution of (S)-3-hydroxy-2-methyl propionic acid
methyl ester (33.3 kg, 281.89 mol) in a mixture of 118 kg
of dichloromethane and 132 kg of cyclohexane was cooled
to 0 °C, and the trichloroimidate (89.9 kg, corresponding to
79.7 kg of trichloroimidate with 100% purity, 282.06 mol),
prepared as described above, was added over 45 min,
maintaining the temperature between 0 and 5 °C. The
addition funnel was rinsed with a mixture of dichloromethane
2 4
Na SO (11 kg), and filtered. The solid was rinsed with tert-
butyl methyl ether (2 × 20 kg), and the combined filtrate
was evaporated under vacuum at 25 °C to yield product 9
(50 kg, 100%).
(59 kg) and cyclohexane (68.8 kg). Solid pyridine p-
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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97

(
S)-3-(4-Methoxybenzyloxy)-2-methylpropionalde-
Example of Crystallization of 11. The crude aldol
product (53.8 kg) containing ∼44 area % by HPLC of 11
was dissolved in butanol (26.1 kg), and diisopropyl ether
(39.0 kg) and heptane (76.4 kg) were added. The solu-
tion was seeded with pure 11 (10 g) and stirred for 22 h
at 22 °C. The thin suspension was cooled in a linear man-
ner to 8-12 °C over 2 h and stirred for 6.5 h. The suspen-
sion was warmed to 20 °C over 30 min and stirred for
16 h. The suspension was cooled to 8-12 °C over 1 h in a
linear fashion, and heptane (75.6 kg) was added over 6 h.
After the addition was completed, stirring was continued for
a further 1 h and the suspension warmed to 20 °C. Finally
the suspension was stirred for 20 h at 20 °C, filtered, and
rinsed three times with a mixture of heptane (34 kg) and
butanol (4.3 kg). The solid was dried under vacuum at
30 °C for 24 h to yield 11 (19.0 kg, 80%): mp 69-70 °C;
hyde (10). A solution of alcohol (9) (29 kg, 137.85 mol)
in dichloromethane (470 kg) was cooled to 0 °C.
TEMPO (210 g, 1.34 mol) was added followed by a 2.75 M
aqueous solution of potassium bromide (34.9 kg) and a 1.6
M aqueous solution of potassium hydrogen carbonate (152
kg). To the rapidly stirred two-phase mixture was added a
solution of bleach (126 kg of a 11% solution, 185.5 mol)
over 90 min. The resulting mixture was stirred for a further
4
0 min at 0 to 5 °C. A 1.0 M aqueous solution of sodium
thiosulphate (79.9 kg) was added. The mixture was then
warmed to room temperature within 15 min, and the layers
were separated. The organic layer was washed with water
(
2 × 184 kg). Sodium sulphate (7.5 kg) was added, and the
suspension was stirred for 10 min at room temperature and
filtered. The solid was rinsed with dichloromethane (2 × 22
kg), and the combined filtrate was concentrated under
vacuum at 20-25 °C to afford aldehyde 10 (28.6 kg) as an
2
5
1
[R]
D
2 2 3
-35.6 (c ) 1, CH Cl ); H NMR (CDCl ) δ 7.35-
7.10 (m, 7H), 6.80 (m, 2H), 4.61 (m, 1H), 4.38 (s, 2H),
4.12 (m, 2H), 3.88 (m, 1H), 3.80 (m, 1H), 3.74 (s, 3H),
3.50-3.40 (m, 2H), 3.27 (dd, J ) 13, 3.0 Hz, 1H), 2.70
(dd, J ) 13.6, 9.7 Hz, 1H), 1.91 (m, 1H), 1.52 (br s, exch
2
5
oil, which was used immediately in the next step: [R]
D
1
+
1
(
30.7 (c ) 1, CH
.5 Hz, 1H), 7.19 (m, 2H), 6.83 (m, 2H), 4.40 (s, 2H), 3.75
s, 3H), 3.62-3.53 (m, 2H), 2.60 (m, 1H), 1.10 (d, J ) 7.3
Hz, 3H).
2 2 3
Cl ); H NMR (CDCl ) δ 9.64 (d, J )
D
2
O, 1H), 1.19 (d, J ) 6.7 Hz, 3H), 0.88 (d, J ) 6.93 Hz,
3H).
(2R,3S,4S)-3-Hydroxy-5-(4-methoxybenzyloxy)-2,4-di-
(
R)-4-Benzyl-3-[(2R,3S,4S)-3-hydroxy-5-(4-methoxy-
benzyloxy)-2,4-dimethyl-pentanoyl]-oxazolidin-2-one (11).
A solution of (R)-4-benzyl-3-propionyloxazolidin-2-one (30.0
kg, 128.61 mol) in dichloromethane (233 kg) was cooled to
methylpentanoic Acid Methoxymethylamide (3). (A) Tri-
isobutylaluminum-Promoted Amide Formation. A suspension
of N,O-dimethylhydroxylamine hydrochloride (13 g, 133.35
mmol) in THF (97 mL) was cooled to 0 °C and treated with
triisobutylaluminum (133.35 mL, 1.0 M in hexane). The
suspension slowly turned into a solution as the mixture was
warmed to room temperature over 15 min. The solution of
the aluminum complex was stirred for 60 min at room
temperature and a solution of 11 (16.84 g, 38.14 mmol) in
THF (30 mL) was added over 45-60 min. The reaction
mixture was stirred for 3 h at room temperature, cooled to
0 °C, and quenched carefully with a 2.0 M aqueous
hydrochloric acid (194 mL). The mixture was warmed to
room temperature and stirred for 30 min. The phases were
separated, and the organic layer was washed with a saturated
solution of sodium bicarbonate (194 mL), followed by brine
0
°C and treated with dibutylboron triflate (193 kg, 1.0 M
in dichloromethane). The solution was stirred for 10 min at
-5 °C, and triethylamine (22.1 kg, 218 mol) was added
0
dropwise. The addition funnel was rinsed with dichlo-
romethane (67 kg), and the reaction mixture was stirred for
45 min at 0-5 °C. The resulting enolate solution was cooled
to -80 to -75 °C. A solution of 10 (24.3 kg, 116.68 mol)
in dichloromethane (72.5 kg) was added over 60 min. The
addition funnel was rinsed with dichloromethane (15 kg),
and the reaction mixture was stirred for 60 min at -75 °C.
The reaction mixture was warmed to -45 °C over 30 min
and stirred for 60 min. Finally the reaction was warmed to
0
°C within 30 min and stirred for a further 60 min. Water
(100 kg) was added, and the two-phase system was stirred
2 4
(194 mL). The organic layer was dried over Na SO , filtered,
for 10 min. The organic phase was separated, treated with a
pH 7 phosphate buffer solution (242 kg), and cooled to 0 to
and concentrated under vacuum to give crude product 3 (25.4
g) as an oil. This oil was dissolved in a mixture of tert-
butyl methyl ether (21.2 mL) and heptane (6.8 mL) and
seeded with (R)-4-benzyloxazolidin-2-one (12). The suspen-
sion was stirred for 60 min at room temperature. Heptane
(6.8 mL) was added dropwise, and the mixture was cooled
to 0 °C and stirred for an additional 60 min. The mixture
was treated with heptane (3.4 mL) and stirred for 2 h at 0
°C. The solid was isolated by filtration to recover 12 (5.22
g, 77%). The filtrate was evaporated to dryness to give 3
(17.6 g, contaminated with 12) as an oil, which was utilized
without further purification. Chromatography on silica gel
5
3
°C. Hydrogen peroxide (28.8 kg of 35% w/w solution,
17.6 mol) was added slowly, and the mixture was stirred
for 60 min at 0-5 °C. Excess peroxide was destroyed by
the addition of a 2.0 M aqueous solution of sodium sulphite
(
213 kg) over 30 min (exothermic). The mixture was warmed
to room temperature, and the organic phase was separated,
washed with water (2 × 350 kg), and treated with Na SO
20 kg). The suspension was filtered and the solid rinsed
2
4
(
with dichloromethane (2 × 30 kg). The filtrate was evapo-
rated under vacuum at 35 °C to a final volume of 65 L. To
remove butanol formed by the oxidation process, toluene
eluting with heptane/ethyl acetate, 2/1, afforded a pure
1
(409 kg) was added to the residue and evaporated at 45 °C
sample: H NMR (CDCl
3
) δ 7.25 (m, 2H), 6.85 (m, 2H),
under vacuum. This procedure was repeated once more and
delivered aldol product 11 (68.4 kg, 62% by HPLC, corrected
yield 82%) as an oil.
4.43 (s, 2H), 3.75 (s, 3H), 3.70-3.50 (m, 7H), 3.18 (s, 3H),
3.05 (br s exch D O, 1H), 1.89 (m, 1H), 1.15 (d, J ) 7.0
Hz, 3H), 0.0.97 (d, J ) 6.8 Hz, 3H).
2
98
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Also isolated was 1.5 g of byproduct 13: 1H NMR
CDCl ) δ 7.30-7.10 (m, 7H), 6.82 (m, 2H), 5.21 (br s, exch
O, 1H), 4.40 (m, 3H), 4.05 (m, 3H), 3.75 (s, 3H), 3.60-
be present. The chemical purity was determined by HPLC
(as previously) to be >99.8% (m/m).
(2R,3S,4S)-3-Hydroxy-5-(4-methoxybenzyloxy)-2,4-di-
methylpentanoic Acid (18). A solution of 11 (2980 g, 6.75
mol) in THF (14.5 L) was cooled to 0 °C, and then H O
2
(3.6 L) was added, while maintaining the temperature at 0
(
D
3
2
3.40 (m, 5H), 3.05 (s, 3H), 2.87-2.70 (m, 3H), 2.35 (m,
1H), 1.85 (m, 1H), 1.05 (d, J ) 7.0 Hz, 3H), 0.76 (d, J )
7.1 Hz, 3H).
(2R,3S,4S)-3-Hydroxy-5-(4-methoxybenzyloxy)-2,4-di-
°C. The solution was cooled to -5 °C, and a 30% aqueous
methylpentanoic Acid (R)-1-Phenylethylamine Salt (14).
To a solution of crude 11 (25 kg, 56.6 mol) in methanol
solution of H
maintaining the temperature at 0 °C. A solution of lithium
hydroxide monohydrate (354.1 g, 8.44 mol) in H O (3.6 L)
2 2
O (2493 g, 22.0 mol) was added dropwise,
(167.2 kg) was added water (105.6 kg) and hydrogen
2
peroxide (24.6 kg of 35% w/w solution, 253.24 mol). A 2
M aqueous solution of lithium hydroxide (60.8 kg) was added
over 2 h (oxygen was evolved), and the mixture was stirred
for 2 h at room temperature. A 2.0 M aqueous solution of
sodium sulphite (52.0 kg) was added slowly (exothermic).
The mixture was stirred for 10 min at room temperature and
extracted with toluene (102.6 kg). The aqueous phase was
re-extracted with toluene (2 × 102.6 kg). The combined
toluene phases contained 12, which could be recovered
according to the procedure described below.
was added, while maintaining the temperature 0 °C. The
reaction was stirred for 30 min at 0 °C. The reaction was
quenched by adding a solution of Na
2 3
SO (2600 g, 20.63
mol) in H O (16 L), maintaining the temperature at 0 °C.
2
The mixture was concentrated under vacuum at 25 °C, and
the residual mixture was washed with tert-butyl methyl ether
(3 × 2 L). The aqueous layer was cooled to 3 °C and adjusted
to pH 2 with 12 M HCl (750 mL). The oily precipitate was
extracted with tert-butyl methyl ether (2 × 4 L). The
combined organic layers (containing product) were washed
Toluene (77 kg) was added to the aqueous phase, and
the two-phase mixture was treated with concentrated hy-
drochloric acid until the pH reached 2.0-2.5 (ca. 15.8 kg
of 37% HCl required). More toluene (70 kg) was added,
and the mixture was stirred for 15 min at room tempera-
ture. The organic phase was separated, and the aqueous phase
was extracted with toluene (140 kg). The combined tol-
uene extracts were washed with water (176 kg) and
concentrated under vacuum at 35 °C to a volume of about
with H
concentrated under vacuum at 25 °C. The residual oil was
cooled to 5 °C and dissolved in saturated NaHCO (10 L).
The resulting aqueous solution was washed with ethyl acetate
(2 × 8 L) and tert-butyl methyl ether (2 × 2 L). The pH of
the aqueous layer was adjusted to 2 with 12 M HCl (600
mL), while maintaining the temperature at 0 °C. The oily
precipitate was extracted into tert-butyl methyl ether (3 × 3
L). The combined extracts (containing product) were washed
2
O (2 × 2 L) and saturated NaCl (2 L) and
3
1
24 L, which was filtered, and the solid (inorganic salts)
with H
2
O (2 × 2 L) and brine (2 L), dried over MgSO
4
(500
was washed with toluene (2 × 40 kg). The combined fil-
trate containing acid 18 was transferred to a second re-
actor containing toluene (22 kg). The concentration of acid
g), and filtered. The filter cake was rinsed with tert-butyl
methyl ether (2 × 1 L). The combined filtrates were
concentrated to afford 18 (1342 g, 71%) as a viscous
1
8 was determined by titration of the toluene solution. The
toluene solution was treated with (R)-1-phenylethylamine
7.14 kg, 59 mol) and stirred for 1 h at room tempera-
colorless oil: IR (CHCl
cm ; H NMR 300 MHz (CDCl ) δ 7.23 (d, J ) 8.5 Hz,
2H), 6.88 (d, J ) 8.5 Hz, 2H), 4.45 (s, 2H), 3.92 (dd, J )
8.5, 3.3 Hz, 1H), 3.79 (s, 3H), 3.63 (dd, J ) 9.2, 4.1 Hz,
1H), 3.50 (apparent t, J ) 8.5 Hz, 1H), 2.64-2.61 (m, 1H),
2.05 (s, 1H), 1.21-1.14 (m, 1H), 1.17 (d, J ) 7.0 Hz, 3H),
0.89 (d, J ) 7.0 Hz, 3H); C NMR (75 MHz, CDCl
159.0, 129.5, 129.3, 113.0, 76.0, 74.0, 73.0, 55.0, 42.0, 35.0,
13.0, 9.0. Anal. Calcd for C15
Found: C, 63.43; H, 7.90.
(2R,3S,4S)-3-Hydroxy-5-(4-methoxybenzyloxy)-2,4-di-
methylpentanoic Acid Methoxymethyl Amide (3). (A)
Isobutyl Chloroformate Procedure. A suspension of salt 14
(34.0 kg, 84.26 mol) in water (63 L) and dichloromethane
(168 kg) was cooled to 0 °C. A 1.0 M aqueous solution of
hydrochloric acid (87.3 kg) was added over 15 min and
stirred for an additional 20 min at 0 °C. The phases were
separated, and the aqueous layer was extracted with dichlo-
romethane (112 kg). The combined organic phases were
3
) 3010.6, 1747.2, 1612.7, 1514.0
-
1 1
3
(
ture (crystallization began towards the end of the amine
addition). The suspension was cooled to 0 °C, stirred for
2
2
.5 h, filtered, and the solid was rinsed with toluene (3 ×
1
3
5 kg). The solid was dried under vacuum at 30 °C to give
3
) δ
1
salt 14 (19.13 kg, 84%): [R]
NMR (CDCl
becomes 2H on D
Hz, 1H), 3.78 (s, 3H), 3.65 (br m, 1H), 3.55 (Br m, 1H),
.42 (br m, 1H), 2.30 (br m, 1H), 1.80 (br m, 1H), 1.50 (d,
D
+16.9 (c ) 1, CH
2
Cl
2
); H
3
) δ 7.40-7.20 (m, 7H), 7.15-6.80 (br m, 6H
O exch), 4.40 (s, 2H), 4.18 (q, J ) 7.0
22 5
H O : C, 63.81; H, 7.86.
2
3
J ) 8.0 Hz, 3H), 0.95 (d, J ) 8.5 Hz, 3H), 0.80 (d, J ) 8.0
Hz, 3H).
Recovery of 12. The toluene extracts from several
reactions were combined to give a total volume of 2000 L.
This was evaporated under vacuum at 35 °C to a final volume
of about 200 L, cooled to 20 °C, and seeded with commercial
1
2 (10 g). The resulting suspension was cooled to 0 °C,
stirred for 1 h, and filtered. The solid was rinsed with a
mixture (9/1) of heptane/ethyl acetate (60 kg) and dried under
vacuum at 40 °C to recover 12 (47.7 kg). Chiral HPLC,
2 4
washed with brine (50 kg) and dried over Na SO (11 kg).
The suspension was filtered, and the solid was rinsed with
dichloromethane (2 × 25 kg). The combined filtrate contain-
ing the acid 18 was concentrated under vacuum at 35 °C to
a volume of about 84 L, which was then cooled to 0 °C.
N-Methylpiperidine (8.76 kg, 88.48 mol) was charged,
(
Chiralcel-OD column, 250 mm × 4.6 mm, eluting with
n-hexane/ethanol, 75/25, flow rate 0.7 mL/min, at 15 °C and
15 nM detection) showed none (<0.1%) of the antipode to
2
Vol. 8, No. 1, 2004 / Organic Process Research & Development
•
99

followed by dropwise addition of isobutyl chloroformate
11.5 kg, 84.25 mol). The mixture was stirred at 0 °C for
suspension was cooled to 10 °C, and N,O-dimethylhydroxyl-
amine hydrochloride (449.8 g, 4.61 mol) was added. Next,
N-methylmorpholine (466.5 g, 4.61 mol) was added drop-
wise, while maintaining the temperature at 10 ° C. The
resulting heavy suspension was stirred for 24 h at 18 °C.
The suspension was filtered, and the filter cake was rinsed
with tert-butyl methyl ether (2 × 1 L). The combined filtrate
was concentrated under vacuum at 25 °C. The residual oil
was dissolved in tert-butyl methyl ether (6 L) and washed
(
another 20 min. To the resulting mixed anhydride solution
was added a 103-kg of a mixture of N,O-dimethylhydroxy-
lamine hydrochloride (10.4 kg, 106.72 mol) and N-meth-
ylpiperidine (11.1 kg, 112.1 mol) in dichloromethane (96.6
kg) within 20 min. The reaction mixture was stirred for
another 30 min at 0 °C and treated with N-methylpiperidine
(0.876 kg, 8.85 mol), followed by a second portion of
isobutyl chloroformate (1.16 kg, 8.5 mol). The reaction was
stirred for 15 min at 0 °C, and a second portion (10.3 kg) of
the mixture of N,O-dimethylhydroxylamine hydrochloride
and N-methylpiperidine in dichloromethane, from above, was
added over 15 min at 0 °C. The reaction was stirred for 30
min at 0 °C and warmed to 20°C, and 1.0 M hydrochloric
acid (147 kg) was added. The phases were separated, and
the aqueous phase was extracted with dichloromethane (140
kg). The combined dichloromethane phases were washed
with saturated aqueous solution of sodium bicarbonate (130
kg) and water (2 × 105 L). The organic phase was dried
with H
saturated NaHCO
2
O (2 × 2 L), 1 M HCl (3 × 2 L), H
(2 × 2 L), H O (2 × 2 L), and brine (1
(500 g),
2
O (2 × 2 L),
3
2
× 2 L). The organic layer was dried over MgSO
4
filtered, and rinsed with tert-butyl methyl ether (2 × 500
mL). The combined filtrate was concentrated under vacuum
at 20 °C to afford 3 (1309 g, 85%) as a colorless oil: [R]25
D
-10.8 (c ) 1.0, CHCl
1585, 1513, 1461, 1421, 1385, 1301, 1247 cm ; H NMR
(C ) δ 7.25 (d, J ) 8.6 Hz, 2H), 6.85 (d, J ) 8.6 Hz,
2H), 4.44 (AB , JAB ) 11.6 Hz, ∆δAB ) 17 Hz, 2H), 3.79
3
); IR (film) 3459, 2964, 2936, 1612,
-
1 1
6 6
D
q
(s, 3H), 3.7 (ddd, J ) 8.2, 3.2, 2.2 Hz, 1H), 3.66 (s, 3H),
3.62 (dd, J ) 9.0, 4.0 Hz, 1H), 3.53 (dd, J ) 9.1, 5.9 Hz,
1H), 3.17 (s, 3H), 3.07-3.01 (m, 1H), 1.91-1.84 (m, 1H),
over Na
C to give crude 3 (28.62 kg, HPLC purity 76.7%, corrected
yield 80%).
B) CDMT Procedure. A cold (3 °C) solution of acid 18
2 4
SO (11 kg) and concentrated under vacuum at 35
°
1.17 (d, J ) 7.0 Hz, 3H), 0.98 (d, J ) 7.0 Hz, 3H); 13
C
(
NMR (125 MHz, C
76.3, 73.2, 71.6, 61.2, 55.2, 39.0, 38.9, 37.8, 14.4, 12.9. Anal.
Calcd for C17 27NO5: C, 62.74; H, 8.37; N,4.31. Found: C,
6 6
D ) δ 174.9, 159.3, 130.7, 126.1, 113.7,
(1340 g, 4.75 mol) in THF (12 L) was charged with CDMT
(915 g, 5.22 mol). To the resulting solution, N-methylmor-
H
pholine (528.3 g, 5.22 mol) was added dropwise, while
maintaining the temperature at 0 °C. The reaction was stirred
for an additional 1 h at 3 °C. Next, N,O-dimethylhydroxy-
lamine hydrochloride (926.5 g, 9.5 mol) was added to the
cold suspension (3 °C), followed by dropwise addition of
N-methylmorpholine (961.1 g, 9.5 mol), while maintaining
the temperature at 0 °C. The nitrogen purge was discontin-
ued, and the reaction flask was sealed. The reaction was
allowed to warm to 23 °C and stirred for 18 h. The
62.58; H, 8.07; N, 4.22.
Acknowledgment
This five-part series is dedicated to the memory of Pro-
fessor Malcolm M. Campbell, University of Bath, England.
Received for review September 16, 2003.
OP034130E
100
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