Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 5: Linkage of Fragments C1-6 and C 7-24 and Finale

Article abstract of DOI:10.1021/op034134j

The finale of the large-scale preparation of 60 g of the highly complex marine natural product, (+)-discodermolide (1), using a hybridized Novartis-Smith-Paterson synthetic route is presented. This contribution, which is the concluding part of a five-part series, highlights a reagent-controlled stereoselective boron enolate aldol reaction between 2 and 3 forming the C7 hydroxyl-bearing stereocenter, selective reduction of 4a to generate the 1,3-anti-diol 5, and a global deprotection and concomitant lactonization leading to (+)-discodermolide (1). A novel procedure for converting the minor epimeric aldol adduct 4b into discodermolide using a five-step sequence is also described. This large-scale synthesis of discodermolide involved 39 steps (26 steps in the longest linear sequence) and several chromatographic purifications and delivered sufficient material for early-stage human clinical trials.

Full text of DOI:10.1021/op034134j

Organic Process Research & Development 2004, 8, 122−130
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product
(+)-Discodermolide. Part 5: Linkage of Fragments C1-6 and C7-24 and Finale
Stuart J. Mickel,* Daniel Niederer, Robert Daeffler, Adnan Osmani, Ernst Kuesters, Emil Schmid, Karl Schaer, and
Remo Gamboni
Chemical and Analytical DeVelopment, NoVartis Pharma AG, CH 4002 Basel, Switzerland
Weichun Chen, Eric Loeser, Frederick R. Kinder, Jr., Kurt Konigsberger, Kapa Prasad, Timothy M. Ramsey,
Oljan Repicˇ, and Run-Ming Wang
NoVartis Institutes for Biomedical Research, One Health Plaza, East HanoVer, New Jersey 07936, U.S.A.
Gordon Florence, Isabelle Lyothier, and Ian Paterson
UniVersity of Cambridge, Chemical Laboratories Lensfield Road, Cambridge CB2 1EW, UK
Abstract:
key step was in analogy with the corresponding methyl ester
of 2 that was used by Paterson and co-workers1 for the
controlled introduction of the C7 hydroxyl-bearing stereo-
center in their recent discodermolide total synthesis. This
complex aldol coupling requires the use of reagent-control
to reverse the intrinsic substrate selectivity, i.e. it is a
mismatched reaction. Initial screening of these conditions
[(+)-DIP-chloride, NEt3, ether] for the aldol reaction of
ketone 2 with aldehyde 3 were encouraging. However, on
large scale this reaction proved to be much more complex
than we expected, and the solution presented here is by no
means optimal but sufficient to achieve our objective. The
details of the steps leading to the production of (+)-disco-
dermolide are outlined in Scheme 1.
The finale of the large-scale preparation of 60 g of the highly
complex marine natural product, (+)-discodermolide (1), using
a hybridized Novartis-Smith-Paterson synthetic route is
presented. This contribution, which is the concluding part of a
five-part series, highlights a reagent-controlled stereoselective
boron enolate aldol reaction between 2 and 3 forming the C7
hydroxyl-bearing stereocenter, selective reduction of 4a to
generate the 1,3-anti-diol 5, and a global deprotection and
concomitant lactonization leading to (+)-discodermolide (1). A
novel procedure for converting the minor epimeric aldol adduct
4b into discodermolide using a five-step sequence is also
described. This large-scale synthesis of discodermolide involved
39 steps (26 steps in the longest linear sequence) and several
chromatographic purifications and delivered sufficient material
for early-stage human clinical trials.
Results and Discussion
Aldol Coupling. Reaction of 6.6 equiv of the correspond-
ing boron enolate of 2, prepared by treatment of 2 with
(+)-B-chlorodiisopinocampheylborane (DIP-Cl) and trieth-
ylamine in diethyl ether at 0 °C, followed by aldol addition,
at -78 °C, with cis-R,â-unsaturated aldehyde 3 led to alcohol
4a in 55-60% yield after chromatography on reverse-phase
silica gel, together with its epimer 4b in a ratio of ∼4:1.
The quality of commercial (+)-DIP-Cl was capricious.
We used commercially available solid (+)-DIP-Cl initially.
This reagent is difficult to obtain and to handle in large
quantity as it is hygroscopic and inherently unstable. On
storage it eliminates pinene, which reduces the quality of
the reagent. Obtaining a well-defined quality reagent on a
large scale from a commercial supplier was problematic.
Routine analytical methods are not really suitable for moni-
toring the quality of this boron reagent. On several occasions
we did not obtain the desired 4a but the trans-aldol 6 together
with its epimer 7 in a 3:1 ratio together with isomerized
aldehyde 8. Also obtained were significant amounts of allyl
alcohol 9 and its trans-isomer 10 resulting from the reduction
Introduction
After 36 chemical steps and a gallant effort by many
dedicated scientists, we now describe the finale that resulted
in the delivery of 60 g of (+)-discodermolide (1), attesting
to the power of contemporary organic synthesis in making
available sufficient quantities of a highly complex organic
molecule, sourced from nature in submilligram quantities,
for a thorough evaluation of its therapeutic potential.
Having described the synthesis of fragments C1-6 and
C7-24 in the preceding contributions in this series, the final
coupling of these two fragments was foreseen as proceeding
via a mismatched chiral boron enolate aldol reaction. This
(1) (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem.,
Int. Ed. 2000, 39, 377. (b) Cowden, C. J.; Paterson, I. Org. React. 1997,
51, 1.
* Author for correspondence. E-mail: stuart_john.mickel@pharma.novartis.
com.
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10.1021/op034134j CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/04/2003

Scheme 1. Linkage of fragments 2 and 3 and the end game
of the aldehyde 8 (see part 4 for NMR data). The mechanism
of this double bond isomerization is not clear. It occurs at
-78 °C even before the aldol reaction and may be the con-
sequence of an addition/elimination process of chloride or
triethylamine induced by boron coordination to the alde-
hyde oxygen atom, but this is speculative.
This reagent problem was solved by utilizing a 70%
solution of (+)-DIP-Cl in hexane, which is, according to the
manufacturer, indefinitely stable at room temperature. A
solution is also more amenable to scale-up, eliminating the
problems associated with handling the solid reagent. When
carried out on a 250-mg scale, the reagent immediately
brought about the formation of the correct product 4a and
its epimer 4b (4:1) in around 45% yield after chromatography
on reverse-phase silica gel. Also isolated from this chroma-
tography were small quantities of acid 11. This most probably
arises from peroxide oxidation of 3. However, on scale-up
(50 g of 3) the yield of the desired product 4a was reduced
to 23%. What actually happened was the reduction of 3 to
9, and unfortunately 9 was not recoverable from the complex
reaction mixture. We surmised that the probable cause was
incomplete enolization. Extending the time for enolate for-
mation to 24 h at 0 °C on a small scale provided a yield of
50% yield of 4a together with significant amounts of the
Claisen condensation product (4R,6R)-5-(tert-butyl-dimeth-
ylsilanyloxy)-4,6-dimethylcyclohexane-1,3-dione (12).
On large scale, we were still unable to reproduce the result
of the small-scale experiment although the reduction was
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no longer a problem. After investigating the fate of the
desired aldol intermediate throughout the entire process, we
determined the reason for the low yield was due to the
apparent instability of the aldol adduct (or its boron complex)
to the workup conditions. Prior to the peroxide treatment,
quenching of the reaction mixture with water followed by
phase separation and evaporation of the ether led to a
reduction in yield of around 15%. A further reduction of
15-20% of the yield occurred after the peroxide workup.
The reason for this instability is still unclear as we could
not isolate any byproducts containing any of the structural
features of the reactants. Some loss of product also occurred
when the reaction mixture was purified on normal-phase
silica gel.
All these problems were overcome by simply omitting
these workup steps. After washing with water, the mixture
was directly applied to a reverse-phase silica gel column,
and elution with acetonitrile/tert-butyl methyl ether/water
removed all the “reactive components”. The product 4a was
obtained by further elution with acetonitrile/tert-butyl methyl
ether (1:1) followed by evaporation of the product-containing
fractions, extraction of the residue with tert-butyl methyl
ether, and re-evaporation, in 50-55% yield in a reproducible
manner. The epimer 4b is easily isolated by further elution
from the column and may be recycled to (+)-1 as described
below. We also examined other bases for enolate formation,
e.g., diisopropylamine, 2,6-lutidine, as well as increasing2a
or decreasing the excesses of 2. No positive effects were
noted, and we settled on the conditions described above.
Evans-Saksena reduction2 of 4a with tetramethylammo-
nium triacetoxyborohydride delivered the 1,3-anti-diol 5 in
high stereoselectivity and reasonable yield after chromatog-
raphy. Contrary to the corresponding methyl ester used by
Paterson1a where the product from the reduction was, on
some occasions, formed as a mixture of anti-diol and the
corresponding lactone in a ratio of 85:15, no lactone 13
derived from anti-diol 5 was observed.
Figure 1. Single-crystal X-ray structure of (+)-discoder-
molide.
of the reaction mixture, play no further part in the reaction,
and decrease the overall yield of 1. If this occurs they may
be readily isolated from the reaction mixture and recycled.
Neutralization of the reaction mixture followed by extractive
workup afforded crude 1. Chromatography on reverse-phase
silica gel with an acetonitrile/water mixture delivered (+)-1
in 70% yield. The compound thus isolated was shown by
HPLC to be a mixture of lactone and hydroxy acid 14
(92:8). This equilibrium was readjusted completely to the
lactone side by lowering the pH with hydrochloric acid.
Thus, on crystallization from acetonitrile/water (85:15)
at pH 4 the lactone was the only product isolated as sandy
crystals in 95% yield. The polymorphic form (monohydrate)
that was obtained by the above recrystallization method was
highly reproducible. Discodermolide 1 is known to exist in
several other polymorphic forms depending on the method
of isolation. All spectroscopic data, the single-crystal X-ray
structure, and optical rotation are in full agreement with the
data reported in the literature3 (Figure 1).
Recycling of Byproducts from the Desilylation Step.
In the desilylation step there are several intermediates formed
which eventually convert to the final product. After the
isolation of 1 in pure form from the reverse-phase column,
the combined remaining fractions indicated the following %
area composition by HPLC: 5.56% discodermolide, 5.68%
3-tert-butyldimethylsilyl discodermolide, 9.83% of a bis-
silylated discodermolide, and 78.92% of 3,11,17-tris-tert-
butyldimethylsilyl discodermolide 13. Treatment of this mix-
ture with 37% hydrochloric acid in acetonitrile/water (9/1)
Final Step and Isolation. With the diol 5 in hand, the
stage was set for the cleavage of silyl groups4 and lacton-
ization leading to 1. This cleavage reaction required carefully
controlled reaction conditions. Hydrochloric acid must be
added to 5 in portions during a period of around 10 h. Careful
washing of the reactor walls with portions of methanol was
necessary to keep 13 and other partially desilylated inter-
mediates in solution, otherwise these intermediates oil out
(2) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988,
110, 3560.
(3) Smith, A. B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu,
Y. P.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000,
122, 8654 and references therein.
(4) Gunasekera, S. P.; Mickel, S. J.; Daeffler, R.; Niederer, D.; Wright, A. E.;
Linley, P.; Pitts, T. J. Nat. Prod. Submitted November 2003.
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at 0 °C, workup, and crystallization from acetonitrile/water
gave discodermolide of around 90-95% purity (by HPLC).
Analysis of the mother liquors from this crystallization re-
vealed the presence of other side products. Extensive chro-
matography on silica gel with dichloromethane/methanol
mixtures enabled their isolation in pure state and character-
ization with the following proposed structures 16-18. Their
detailed isolation and spectral characteristics will be de-
scribed elsewhere.4 These compounds are also formed in
small amounts by treatment of discodermolide itself with
HCl/H2O.
2. Stereocontrolled 1,3-syn-reduction of 4b was accomplished
by utilizing modified Narasaka-Prasad conditions.5 Treat-
ment of 4b with dicyclohexylchloroborane-triethylamine
complex generated the corresponding boron aldolate that was
then reduced in situ with LiBH3OMe, which, after an
oxidative workup, afforded the expected 1,3-syn-diol 20 with
>97% diastereoselectivity.5 1,3-Syn-diol 20 was then con-
verted to 7-epi-TBS-discodermolide 21 in 98% yield by
treatment with acetic acid in MeCN and water.
With 21 in hand stereochemical correction of C7 was now
required. This would involve oxidation of the C7-OH to
the corresponding ketone followed by substrate controlled
reduction to the known keto-lactone 22.
A range of oxidants was investigated. Dess-Martin
periodinane gave the best result (80% yield), while a Swern
oxidation was not as clean, and the recovery was very poor.
Pyridine/SO3 complex in DMSO with an excess of Et3N gave
no reaction. Oxidation with TPAP, NMO, and 4-Å molecular
sieves seemed at first very clean; however, only 50% of the
desired product was isolated. The stereocontrolled reduction
of 22 was then investigated. Gratifyingly, reduction with
K-Selectride in toluene proceeded cleanly in favor of the
desired (7S)-configuration in 13 (85%, 97:3 dr).7 On scaling
up, the recovery of 13 decreased to around 60-70% yield.
Two factors were attributed to the significant loss in yield:
(1) the sensitivity of the substrate to the oxidative workup
employed and (2) chromatography on “normal phase” silica
gel. Finally, global deprotection as described earlier led to
(+)-1. This efficient five-step sequence recycles the C7
epimer 4b to the target drug substance with complete
stereocontrol; as a result, the byproduct proves to be highly
valuable rather than an inconvenience.
Conclusions
Over 60 g of (+)-discodermolide (Figure 2) was prepared
in 39 steps and required 17 chromatographic purifications.
The entire process took some 20 months to complete, an
average of one step per fortnight. Surprisingly, the majority
of the steps were transferred to larger scale without any great
problems. We identified around seven problematic steps, of
which three occur early in the route. Clearly, improving the
yields of these problematic areas would be highly beneficial,
especially at the beginning of the synthesis, to reduce the
quantities of early intermediates. An improved route to the
common intermediate would be an advantageous, one
avoiding the difficult boron aldol (part 1), as reagent quality
was suboptimal. The end game is far from ideal; after such
a synthetic sequence the final few steps leading to the final
drug substance need to be kept “simple”. The arduous
chromatography of the final aldol coupling product (part 5)
is clearly not practical to move into production; fortunately,
the predicted low dosage levels should keep the yearly
manufacturing requirements to a minimum.
We also noticed the presence of a trace of trans-diene 19
under these desilylation conditions. As the Nozaki-Hiyama-
Peterson sequence6 of generating the cis-diene is clean, the
formation of trans-diene was attributed to subsequent acid-
catalyzed isomerization.
Conversion of the Epimeric Aldol Adduct 4b to
Discodermolide. The undesired aldol epimer 4b was con-
verted to 1 following the five-step process shown in Scheme
One major problem associated with a synthesis of this
length is the proper laboratory examination of the later
reactions in a sequence. Initially, there are no answers to
(5) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am.
Chem. Soc. 2001, 123, 9535.
(7) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott, J. P.; Sereinig,
(6) Paterson, I.; Schlapbach, A. Synlett 1995, 498.
N. Org. Lett. 2003, 5, 35.
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Figure 2. (+)-Discodermolide.
Scheme 2. Epimer 4b to 1
these supply problems; one just has to run the small-scale
reaction and hope that on transfer to larger scale the reaction
proceeds as expected. We certainly stumbled over this exact
point during the final aldol coupling, and as a result the
project very nearly ended in failure, or at least the required
amount of discodermolide would not have been able to be
delivered. On a positive note, this project was a first for
Novartis, and its progress was avidly followed by the entire
department who were all interested in the “disco”. The
success of this project and its chemistry paves the way for
other, perhaps even more complex, natural products to be
prepared for early-phase clinical evaluations and sends a
positive message to the both the isolation and synthetic aca-
demic community and possibly other pharmaceutical com-
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panies that: “your work need not just be of academic
interest” and it may be worth taking a few risks.
(pseudo t, J ) 10.9 Hz, 1H), 5,72 (d, J ) 11.7 Hz, 1H),
5.33 (pseudo t, J ) 10.3 Hz, 1H), 5.22 (dd, J ) 16.8 2.0
Hz, 1H), 5.14 (d, J ) 10.6 Hz, 1H), 4.33-4.20 (br s, 2H),
3.68-3.55 (m, 2H), 3.38 (dd, J ) 7.4 2.8 Hz, 1H), 3.33
(dd, J ) 7.6 3.5 Hz, 1H), 2.80 (m, 1H), 2.33 (m, 1H), 2.11
(pseudo t, J ) 12.5 Hz, 1H), 1.89-1.65 (m, 3H), 1.56 (s,
3H), 1.00 (d, J ) 7.3 Hz, 3H), 0.96 (d, J ) 6.3 Hz, 3H),
0.93 (d, J ) 7.1 Hz, 3H), 0.91-0.88 (m, 21H), 0.69 (d, J )
6.7 Hz, 3H), 0.07 (s, 6H), 0.06 (s, 6H). (M+ + Na) ) 703,
(M+ - H) ) 679.
A total of over 43 chemists participated in the concept of
the synthesis, experimental design, and execution. Several
early steps were carried out in our pilot plant. The hybridized
Novartis-Smith-Paterson synthetic route that resulted from
this exercise, and the preparation of 60 g of a structurally
complex molecule containing 13 stereogenic centers is a
crowning achievement to all those who participated in this
endeavor. The option of optimizing the present synthesis
further or replacing with a better one is a topic of our ongoing
studies, and we are confident of climbing this mountain as
the situation demands.
(b) With (+)-Dip-Cl 70% in Hexane (Aldol Reaction Final
Conditions). A solution of (+)-DIP-Cl in hexane (263 g, 70%
in hexane, 0.574 mol) was diluted with diethyl ether (453
g) and the resulting solution cooled to 0-3 °C. Triethylamine
(71.4 g, 0.71 mol) was added within 5 min. The addition
funnel was washed with diethyl ether (14.2 mL) and the
suspension stirred at 0 °C for 5 min. A solution of 2 (234 g,
0.706 mol) in diethyl ether (305 mL) was added within 22
min, and the addition funnel was washed with diethyl ether
(122 mL). The resulting suspension was stirred at 0 °C for
at least 10 h and cooled to an internal temperature of -78
°C. A solution of 3 (71 g, 0.107 mol) in diethyl ether (305
mL) was added within 30 min. The addition funnel was
washed with diethyl ether (122 mL) and the reaction mixture
stirred at -78 °C for 1 h. After this time the reaction mixture
was warmed to -65 °C over 15 min and stirred for 3 h.
Warming was then continued until -55 °C was reached
within 15 min and the mixture stirred at -55 °C for 3.75 h.
After further warming to -45 °C over 15 min and stirring
for 105 min, the reaction mixture was warmed to -30 °C
within 15 min and stirred for 55 min. Water (1530 g) was
added followed by tert-butyl methyl ether (305 mL). The
mixture was stirred for 5 min and the organic layer separated.
The aqueous layer was re-extracted with tert-butyl methyl
ether (1220 mL), and the organic layers were combined (1525
mL total volume). This product solution was chromato-
graphed on reverse-phase silica gel (20 kg, LiChroprep
PR-18) eluting with 584 kg of a mixture of acetonitrile/tert-
butyl methyl ether/water (75/12.5/12.5) followed by 152 kg
of an acetonitrile/tert-butyl methyl ether mixture (51.5/48.5).
The product-containing fractions were combined, and the
solvent was removed by distillation until a volume of around
35 L was obtained. tert-Butyl methyl ether (23 L) was added,
the mixture was stirred for 10 min, and the organic phase
was separated. The lower phase was re-extracted with tert-
butyl methyl ether (5 L), and the organic extracts were
combined. The solvent was removed in vacuo at a temper-
ature of 30 °C. tert-Butyl methyl ether (1 L) was added, the
mixture was stirred for 10 min, and the organic phase was
separated. The lower phase was re-extracted with tert-butyl
methyl ether (1 L), and the organic extracts were combined.
The solvent was removed in vacuo at a temperature of 30
°C to give 66.9 g, 62.8%, of the desired 4a as a nonhygro-
Experimental Section
Coupling of 2 with 3. (a) With Solid (+)-DIP-Cl. A
solution of (+)-DIP-Cl (0.99 g, of 95% purity, 0.94 g, 2.93
mmol) in diethyl ether (10 mL) was cooled to 0-3 °C, and
triethylamine (0.3 g, 2.93 mmol) was added. The resulting
suspension was stirred for 5 min at 0 °C, and a solution of
2 (0.96 g, 2.89 mmol) in diethyl ether (2 mL) was added
within 10 min. The enolate was allowed to form over 2 h at
0 °C, cooled to -78 °C, and 3 (1.28 g, 1.93 mmol) in diethyl
ether (2 mL) was added within 20 min. The mixture was
warmed slowly to -7 °C and stirred overnight. The reaction
was quenched with methanol (20 mL) and the solvent
evaporated to give an oil. This was redissolved in methylene
chloride, and 50 mL of pH 7 phosphate buffer was added.
The two-phase system was treated with hydrogen peroxide
solution (0.41 g of a 30% solution) and stirred for 10 min.
The organic layer was separated and washed with 20 mL of
a 50% solution of sodium thiosulfate followed by 50 mL of
water. The organic solution was dried over sodium sulphate
and filtered, and the solvent was removed to give 2.17 g of
an oil. This oil was purified by filtration over 40 g of reverse-
phase silica gel initially eluting with acetonitrile, then
acetonitrile/tert-butyl methyl ether (85/15), and finally with
acetonitrile/ tert-butyl methyl ether (80/20) to give 0.44 g
(23% yield) of 6. Also isolated was an inseparable mixture
of 3, 8, 9, and 10.
Carbamic acid (6Z,11E)-(1S,2R,3R,4S,8S,9S,10S,13S,-
16R,17S,18R)-3,9,17-tris-(tert-butyldimethylsilanyloxy)-
13-hydroxy-18-(methoxymethylcarbamoyl)-2,4,6,8,10,16-
hexamethyl-1-((Z)-(S)-1-methylpenta-2,4-dienyl)-15-oxo-
1
nonadeca-6,11-dienyl ester (6): H NMR (CDCl3) δ 6.57
(dt, J ) 16.7 10.3 Hz, 1H), 6.01 (pseudo t, J ) 10.6 Hz,
1H), 5.63 (dd, J ) 15.7 7.7 Hz, 1H), 5.50-5.25 (m, 2H),
5.20 (d, J ) 17.5 Hz, 1H), 5.10 (d, J ) 10.6 Hz, 1H), 4.90
(d, J ) 11.0 Hz, 1H), 4.82-4.42 (m, 4H), 4.27 (dd, J ) 7.7
3.5 Hz, 1H), 3.68 (s, 3H), 3.37 (m, 1H), 3.26 (m, 1H), 3.13-
2.88 (m, 5H), 2.81-2.25 (m, 6H), 2.09-1.47 (m, 10H), 1.10
(d, J ) 6.8 Hz, 3H), 1.04 (d, J ) 7.2 Hz, 3H), 0.99-0.80
(m, 39H), 0.68 (d, J ) 6.5 Hz, 3H), 0.13 to -0.03 (m, 18H).
Further elution provided small quantities of (2Z,7Z,-
15Z)-(4S,5S,6S,10S,11R,12R,13S,14S)-5,11-bis-(tert-butyl-
dimethylsilanyloxy)-13-carbamoyloxy-4,6,8,10,12,14-hex-
amethyloctadeca-2,7,15,17-tetraenoic acid (11). 1H NMR
(CDCl3) δ 12.5-12.0 (br s, exch D2O, 1H), 6.61 (dtd, J )
16.6, 10.5 1.0 Hz, 1H), 6.44 (dd, J ) 11.9 9.9 Hz, 1H), 6.12
1
scopic foam. H NMR (CDCl3) δ 6.53 (dt, J ) 16.8 10.1
Hz, 1H), 5.96 (pseudo t, J ) 10.7 Hz, 1H), 5.43 (pseudo t,
J ) 10.7 Hz, 1H), 5.35-5.24 (m, 2H), 5.15 (d, J ) 16.8
Hz, 1H), 5.06 (d, J ) 10.1 Hz, 1H), 4.98 (d, J ) 10.1 Hz,
1H), 4.72 (td, J ) 8.0 2.1 Hz, 1H), 4.65 (pseudo t, J ) 6.06
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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127

Hz, 1H), 4.55-4.41 (br s, 2H), 4.25 (dd, J ) 7.8 4.3 Hz,
1H), 3.66 (s, 3H), 3.35 (pseudo t, J ) 3.35 Hz, 1H), 3.23
(pseudo t, J ) 10.8 Hz, 1H), 3.03 (s, 3H), 2.93 (m, 2H),
2.76-2.62 (m, 3H), 2.40 (m, 1H), 1.94-1.75 (m, 2H), 1.65-
1.48 (m, 5H), 1.21 (d, J ) 6.8 Hz, 3H), 1.15 (d, J ) 7.3 Hz,
3H), 1.07 (d, J ) 6.5 Hz, 3H), 1.04 (d, J ) 6.7 Hz, 3H),
0.90-0.77 (m, 30H), 0.65 (d, J ) 6.8 Hz, 3H), 0.06 to -0.05
(m, 18H).
6.8 Hz, 3H), 0.06 to -0.07 (m, 18H). [R]D +37.8, (c ) 1 in
CHCl3).
(+)-Discodermolide (1). (Note: discodermolide is a
cytotoxic agent, and appropriate measures must be taken to
ensure safe handling and nonexposure of personnel.) To a
solution of 5 (77.5 g, 77.7 mmol) in methanol (22 kg) was
added every 15 min a 1.02-kg portion of 3 M hydrochloric
acid. This was repeated 16 times. Finally four portions of
2.03 kg of 3 M hydrochloric acid were added every 15 min.
The reactor walls were washed with 2.4 kg of methanol and
the reaction mixture stirred for 3 h at room temperature. A
further portion of hydrochloric acid (8.13 kg, 3 M) was
added, and stirring continued for a further 2 h. A solution
of saturated sodium bicarbonate (144 kg) was added slowly
(gas evolution) followed by 5.54 kg of a pH 7 phosphate
buffer solution. The methanol was removed by distillation
in vacuo at 30 °C until 33 L had been collected. (pH control
is necessary; the pH may rise above 7; if that is the case, it
may be adjusted by the addition of small portions of 3 M
hydrochloric acid until a value of 6.5 is obtained.) Ethyl
acetate (16.0 kg) and tert-butyl methyl ether (20.7 kg) were
added, and the mixture was extracted. The organic phase
was separated and the aqueous phase re-extracted with the
ethyl acetate (16.0 kg) and tert-butyl methyl ether (20.7 kg)
mixture. The organic phase was separated and combined with
the first extract. The combined extracts were dried over
magnesium sulphate and filtered, and the solid was washed
with tert-butyl methyl ether (13.2 kg). The solvent was
removed in vacuo at 30 °C to give 38 g, 82.4%, of crude 1.
This material was redissolved in 2-propanol (8.81 kg), and
water (78.4 kg) was added. This solution was passed through
a filter onto a column containing 15 kg of ODS-RP-18
reverse-phase silica gel and eluted with acetonitrile/water (25/
75). The product-containing fractions were combined and
evaporated to around 66% of the original volume. The
remaining aqueous phase was extracted twice with ethyl
acetate (2 × 30 kg). The ethyl acetate was removed in vacuo
to give 28.0 g, 60.6% of (+)-1 as a foam, which was
crystallized as described below. The filter was washed with
2-propanol and the solvent removed to give an oil. This oil
mostly contained the fully protected discodermolide 13 which
was hydrolyzed according to ref 4.
1
Further elution provided the 7-epi isomer 4b. H NMR
(CDCl3) δ 6.55 (dt, J ) 16.6 10.1 Hz, 1H), 5.98 (pseudo t,
J ) 10.5 Hz, 1H), 5.50-5.24 (m, 4H), 5.17 (d, J ) 16.2
Hz, 1H), 5.07 (d, J ) 9.1 Hz, 1H), 4.89 (d, J ) 8.8 Hz,
1H), 4.82-4.57 (m, 4H), 4.25 (dd, J ) 8.8 3.4 Hz, 1H),
3.70 (s, 3H), 3.35 (m, 1H), 3.24 (dd, J ) 7.8 2.7 Hz, 1H),
3.16 (s, 3H), 3.05-2.85 (m, 2H), 2.70 (m, 1H), 2.42-2.25
(m, 2H), 2.05 (pseudo t, J ) 11.8 Hz, 1H), 1.94-1.73 (m,
3H), 1.58 (s, 3H), 1.08 (d, J ) 6.8 Hz, 3H), 1.03 (d, J ) 7.3
Hz, 3H), 0.94 (d, J ) 6.7 Hz, 3H), 0.90-0.80 (m, 39H),
0.65 (d, J ) 6.8 Hz, 3H), 0.10 to -0.05 (m, 18H).
Carbamic Acid (6Z,11Z)-(1S,2R,3R,4S,8S,9S,10S,-
13S,15S,16S,17S,18R)-3,9,17-Tris-(tert-butyldimethyl-si-
lanyloxy)-13,15-dihydroxy-18-(methoxymethylcarbamoyl)-
2,4,6,8,10,16-hexamethyl-1-((Z)-(S)-1-methyl-penta-2,4-
dienyl)-nonadeca-6,11-dienyl Ester (5). A solution of
tetramethylammonium triacetoxy borohydride (385 g, 1.46
mol) in 410 g of tetrahydrofuran was treated with glacial
acetic acid (972 g). The mixture was stirred for 20-30 min
at room temperature and cooled to -25 °C. A solution of
4a (103 g, 0.103 mol) in tetrahydrofuran (343 g) was added
within 30 min. The addition funnel was rinsed with 104 mL
of tetrahydrofuran and the reaction mixture stirred for 30
min at -25 °C. The mixture was warmed within 30 min to
0 °C and stirred at that temperature for 18 h. The reaction
was quenched with a sodium-potassium tartrate solution
(462 mL of a 50% solution), allowing the temperature to
rise to 20 °C. Water (4.6 L) was added followed by tert-
butyl methyl ether (1.03 kg). The two-phase mixture was
vigorously stirred during the addition of sodium hydroxide
solution until a pH of 6.5-7.5 was reached (around 2.6 kg
of a 30% solution required). The organic phase was separated
and the aqueous phase re-extracted with tert-butyl methyl
ether (1.03 kg). The organic phase was separated and
combined with the first extract. The combined organic phases
were washed sequentially with brine (1.66 kg) and saturated
sodium bicarbonate solution (1.47 kg). The organic phases
were dried with sodium sulfate and filtered, and the solvent
was removed to give the crude product as an oil (101.3 g).
This was purified by chromatography on silica gel eluting
with heptane/ethyl acetate mixtures to produce 76 g, 73.3%
(+)-Discodermolide Monohydrate (1). The material (65
g) obtained from several chromatographies, as described
earlier, was redissolved in 8.73 kg of a mixture of acetoni-
trile/water (85/15) at pH 4. The solution was concentrated
in vacuo to a volume of 3.3 L. Water (1.27 kg) was added
and the resulting thin suspension concentrated in vacuo to a
volume of 1.4 L. The resulting suspension was cooled to 0
°C and stirred for 2 h. The product was collected by filtration,
thoroughly washed with water, and dried in a vacuum at 35
°C for 16 h to give 61.7 g (95% yield) of (+)-discodermolide
1
of 5 as a nonhygroscopic foam. H NMR (CDCl3) δ 6.52
(dt, J ) 16.5 10.3 Hz, 1H), 5.95 (pseudo t, J ) 11.1 Hz,
1H), 5.55-5.24 (m, 2H), 5.15 (d, J ) 16.9 Hz, 1H), 5.05
(d, J ) 10.7 Hz, 1H), 4.91 (d, J ) 9.8 Hz, 1H), 4.64 (pseudo
t, J ) 6.2 Hz, 1H), 4.61-4.49 (m, 3H), 4.10 (d, J ) 8.9 Hz,
1H), 3.91-3.82 (br s, 2H), 3.66 (s, 3H), 3.33 (m, 1H), 3.19
(pseudo t, J ) 6.2 Hz, 1H), 3.13 (s, 3H), 3.07-3.00 (m,
1H), 2.91 (m, 1H), 2.59 (m, 1H), 2.34 (m, 1H), 2.03 (m,
1H), 1.89-1.45 (m, 7H), 0.95-0.75 (m, 45H), 0.63 (d, J )
1
monohydrate. H NMR (CD3CN) δ 6.58 (dtd, J ) 16.73,
10.5 0.89 Hz, 1H), 5.99 (pseudo t, J ) 11.1 Hz, 1H), 5.46
(pseudo t, J ) 10.5 Hz, 1H), 5.38-5.25 (m, 2H), 5.17 (dd,
J ) 17.1 2.0 Hz, 1H), 5.10-4.92 (br m, 3H), 4.88 (d, J )
10.1 Hz, 1H), 4.63 (dd, J ) 7.99 3.85 Hz, 1H), 4.48-4.30
(m, 2H), 3.54 (pseudo q, J ) 5.18 Hz, 1H), 3.25 (d, J )
128
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4.88 Hz, 1H), 3.10-2.94 (m, 3H), 2.74 (d, J ) 5.33 Hz,
1H), 2.62 (d, J ) 5.33 Hz, 1H), 3.57 (d, J ) 6.8 Hz, 1H),
2.55-2.44 (m, 2H), 2.18 (m, 1H), 1.80-1.46 (m, 8H), 1.38
(ddd, J ) 14.5, 10.7 2.2 Hz, 1H), 1.10 (d, J ) 7.3 Hz, 3H),
0.92 (d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 7.0 Hz, 3H), 0.86 (d,
J ) 6.8 Hz, 3H), 0.80 (d, J ) 5.8 Hz, 3H), 0.71 (d, J ) 7.0
Hz, 3H). 13C NMR (CD3CN) δ 173.4, 157, 132.9, 132.5,
132.4, 131.9, 129.8, 127.2, 116.9, 78.5, 77.9, 76.1, 74.7, 71.9,
62.0, 42.7, 40.9, 37.2, 35.7, 35.3, 35.0, 33.3, 32.9, 22.0, 18.4,
16.9, 16.3, 14.5, 14.3, 11.8, 7.9. [R]D ) +20.1 (c ) 1 in
MeOH).
Also isolated from the column was the trans-diene 19.
1H NMR (d6-DMSO) δ 6.58 (dtd, J ) 16.73, 10.5 0.89
Hz, 1H), 5.99 (pseudo t, J ) 11.1 Hz, 1H), 5.46 (pseudo t,
J ) 10.5 Hz, 1H), 5.38-5.25 (m, 2H), 5.17 (dd, J ) 17.1
2.0 Hz, 1H), 5.10-4.92 (br m, 3H), 4.88 (d, J ) 10.1 Hz,
1H), 4.63 (dd, J ) 7.99 3.85 Hz, 1H), 4.48-4.30 (m, 2H),
3.54 (pseudo q, J ) 5.18 Hz, 1H), 3.25 (d, J ) 4.88 Hz,
1H), 3.10-2.94 (m, 3H), 2.74 (d, J ) 5.33 Hz, 1H), 2.62
(d, J ) 5.33 Hz, 1H), 3.57 (d, J ) 6.8 Hz, 1H), 2.55-2.44
(m, 2H), 2.18 (m, 1H), 1.80-1.46 (m, 8H), 1.38 (ddd, J )
14.5, 10.7 2.2 Hz, 1H), 1.10 (d, J ) 7.3 Hz, 3H), 0.92 (d, J
) 6.8 Hz, 3H), 0.90 (d, J ) 7.0 Hz, 3H), 0.86 (d, J ) 6.8
Hz, 3H), 0.80 (d, J ) 5.8 Hz, 3H), 0.71 (d, J ) 7.0 Hz,
3H).
Conversion of 4b to 1. (2R,3S,4S,5S,7R,8Z,10S,11S,-
12S,13Z,16S,17R,18S,19S,20S,21Z)-3,11,17-Tris-(tert-bu-
tyldimethylsilyloxy)-5,7-dihydroxy-19-carbamoyloxy-N,2,4,-
10,12,14,16,18,20-nonamethyl-N-methoxy-tetracosa-
8,13,21,23-tetranamide (20). Aldol adduct 4b (1 g, 1.004
mmol) was dissolved in THF (20 mL) and cooled to
-78 °C. cHex2BCl/Et3N mixture, freshly prepared from
cHex2BCl (2.07 mL, 10 mmol) and Et3N (1.32 mL, 18 mmol)
in THF (5 mL) at 0°C, (2 M solution, 3.01 mL, 6.02 mmol,
6 equiv) was added, and the reaction mixture was stirred at
-78 °C for 40 min. A freshly prepared [by adding at 0 °C
MeOH (0.9 mL, 22 mmol) to a suspension of LiBH4 (440
mg, 20 mmol) in THF (20 mL) and stirring at room
temperature for 1.5 h] 1 M solution of LiBH3OMe (15.06
mL, 15.06 mmol, 15 equiv) was added slowly, and the
mixture was stirred at -78 °C for 1 h. It was allowed to
warm very slowly (up to -10 °C over 2 h) and was then
stirred at 0 °C for 3 h. A pH 7 buffer (10 mL) was added
very slowly, followed by MeOH (5 mL) and 30% aqueous
H2O2 (2 mL), dropwise, and the reaction mixture was stirred
at room temperature for 40 min. After dilution with water
(200 mL), the aqueous layer was extracted with dichlo-
romethane (4 × 50 mL) and ethyl acetate (2 × 50 mL). The
combined organic extracts were dried (Na2SO4) and con-
centrated under vacuum. The cyclohexanol was removed by
Kugelrohr distillation (50 °C, 0.5 mmHg). Purification by
flash chromatography on silica gel (petroleum ether/ethyl
acetate, 4:1) then afforded the desired syn-diol 19 (1.01 g,
quantitative yield).
5.29 (m, 3H), 5.21 (dd, J ) 16.8, 1.5 Hz, 1H), 5.12 (d, J )
10.1 Hz,1H), 4.99 (d, J ) 10.1 Hz,1H), 4.73 (dd, J ) 6.1,
6.1,), 4.58 (br s, 2H), 4.57-4.50 (m, 1H), 4.15 (dd, J ) 9.7,
2.6 Hz, 1H), 4.00 (br s, 1H), 3.74 (s, 3H), 3.52 (s, 1H), 3.41
(dd, J ) 4.8, 4.3 Hz, 1H), 3.32 (dd, J ) 6.9, 3.6 Hz, 1H),
3.30-3.05 (m, 5H), 2.99 (m, 1H), 2.69-2.59 (m, 1H), 2.49-
2.39 (m, 1H), 2.11 (dd, J ) 12.5, 12.4 Hz, 1H), 1.96-1.82
(m, 2H), 1.80-1.50 (m, 4H), 1.59 (s, 3H), 1.16 (3H, d, J )
6.9 Hz, Me2); 0.99 (3H, d, J ) 6.8 Hz, Me20), 0.96-0.89
(m, 36H), 0.85 (d, J ) 7.0 Hz, 3H), 0.11-0.04 (m, 18H);
13C NMR (CDCl3): δC 177.8, 157.0, 133.7, 133.6, 132.5,
132.3, 132.1, 130.9, 129.7, 117.8, 80.7, 78.6, 77.1, 74.2, 73.9,
68.2, 61.7, 46.5, 41.8, 38.4, 38.1, 37.4, 36.5, 36.2, 34.8, 34.5,
32.4, 26.2 (2 signals), 26.0, 22.8, 18.5, 18.4, 18.3, 18.1, 17.8,
17.4, 16.5, 13.5, 12.4, 10.2, -3.3, -3.4 (2C), -3.9, -4.2,
-4.4; HRMS (ES+) calcd for C53H104N2O9Si3Na [M + Na]+
1019.6947, found 1019.6993.
3,11,17-Tris-(tert-butyldimethylsilyl)-7-epi-discoder-
molide (21). Diol 19 (1 g, 1.004 mmol) was dissolved in
acetonitrile (10 mL), water (10 mL), and acetic acid (10 mL).
The reaction mixture was stirred at 50 °C for 5 h and then
at room temperature for 20 h, before being quenched with
saturated aqueous sodium bicarbonate (50 mL). The aqueous
layer was extracted with ethyl acetate (5 × 50 mL). The
combined extracts were dried (sodium sulfate) and concen-
trated under reduced pressure. Purification by flash chro-
matograph on silica gel (hexane/ethyl acetate, 6:1) afforded
the title compound 20 (920 mg, 98%).
Rf 0.45 (35% EtOAc/Hexane); [R]D +20.0 (c ) 0.33,
CHCl3); IR (thin film) 3460, 2958, 2930, 2857, 1726, 1600,
1462, 1385 cm-1; 1H NMR (CDCl3) δH 6.60 (ddd, J ) 16.8,
10.7, 10.6 Hz, 1H), 6.03 (dd, J ) 11.0, 11.0 Hz, 1H), 5.59
(dd, J ) 10.7, 10.6 Hz, 1H), 5.42-5.28 (m, 2H), 5.22 (d, J
) 16.7 Hz, 1H), 5.13 (d, J ) 10.2 Hz, 1H), 5.04 (d, J ) 9.7
Hz, 1H), 4.72 (dd, J ) 6.0, 5.8 Hz, 1H), 4.71-4.63 (m, 1H),
4.56 (br s, 2H), 4.32 (dd, J ) 9.2, 8.5 Hz, 1H), 3.65 (br s,
1H), 3.41 (dd, J ) 4.3, 4.1 Hz, 1H), 3.29 (dd, J ) 5.9, 3.8
Hz, 1H), 3.02-2.98 (m, 1H), 2.78-2.69 (m, 1H), 2.65-
2.57 (m, 1H), 2.47-2.38 (m, 1H), 2.14 (dd, J ) 12.5, 12.5
Hz, 1H), 2.05-1.95 (m, 1H), 1.95-1.84 (m, 4H), 1.77-
1.66 (m, 1H), 1.62 (s, 3H), 1.26 (d, J ) 7.1 Hz, 3H), 0.99
(d, J ) 6.1 Hz, 3H), 0.98 (d, J ) 6.1 Hz, 3H), 0.96-0.83
(m, 36H), 0.71 (d, J ) 6.6 Hz, 3H), 0.10-0.04 (m, 18H);
13C NMR (CDCl3) δC 173.6, 156.9, 135.7, 133.8, 132.5,
132.1, 131.4, 131.0, 129.8, 117.9, 80.8, 79.2, 78.6, 76.1, 74.3,
64.9, 43.8, 40.7, 38.1, 36.7, 36.6, 36.4, 34.8, 34.5, 33.9, 26.3,
26.2, 25.7, 22.7, 19.4, 18.5, 18.4, 17.9, 17.4 (2C), 16.2, 14.0,
13.3, 10.2, -3.3, -3.5 (2C), -3.7, -4.5, -4.8; m/z (ES+)
958 (100, [M + Na]+); HRMS (ES+) calcd for C51H97O8-
NSi3Na [M + Na]+ 958.6420, found 958.6449.
3,11,17-Tris-(tert-butyldimethylsilyl)-7-oxo-discoder-
molide (22). Compound 21 (125 mg, 0.133 mmol) was
dissolved in dichloromethane (5 mL), and Dess-Martin
periodinane (113 mg, 0.266 mmol, 2 equiv) was added. The
reaction mixture was stirred at room temperature for 4 h.
Purification by flash chromatography on silica gel (petroleum
ether/ethyl acetate, 4:1) afforded the title compound (100
mg, 80%) as a white solid.
Rf 0.25 (20% AcOEt/PE); [R]D +30.4 (c ) 0.20, CHCl3);
IR (thin film) 3450, 2958, 2928, 1663, 1252, 1093, 1037,
834, 774 cm-1; 1H NMR (CDCl3) δH: 6.60 (ddd, J ) 16.8,
10.9, 10.4 Hz, 1H), 6.03 (dd, J ) 11.0, 11.0 Hz,1H), 5.44-
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129

Rf 0.21 (20% EtOAc/Hexane); [R]D+77.8 (c ) 1.3,
CHCl3); IR (thin film) 3372, 2958, 2931, 2857, 1732, 1606,
1472, 1385 cm-1; 1H NMR (CDCl3) δH 6.60 (ddd, J ) 16.6,
10.7, 10.6 Hz, 1H), 6.25 (dd, J ) 11.3, 9.8 Hz, 1H), 6.10
(d, J ) 11.5 Hz, 1H), 6.03 (dd, J ) 11.1, 11.0 Hz, 1H),
5.39 (dd, J ) 10.6, 10.5 Hz, 1H), 5.22 (d, J ) 16.2 Hz,
1H), 5.14 (d, J ) 10.2 Hz, 1H), 4.86 (d, J ) 10.2 Hz, 1H),
4.77 (ddd, J ) 9.7, 5.0, 5.0 Hz, 1H), 4.74 (dd, J ) 6.2, 6.0
Hz, 1H), 4.61 (br s, 2H), 3.66 (dd, J ) 2.8, 2.8 Hz, 1H),
3.63-3.54 (m, 1H), 3.45-3.35 (m, 2H), 2.99 (ddq, J ) 10.0,
6.6, 6.0 Hz, 1H), 2.86 (dd, J ) 16.1, 5.4 Hz, 1H), 2.70 (dd,
J ) 16.1, 5.0 Hz, 1H), 2.63 (qd, J ) 7.4, 3.6 Hz, 1H), 2.38-
2.27 (m, 1H), 2.20-2.08 (m, 1H), 2.08-2.00 (m, 1H), 1.90-
1.80 (m, 2H), 1.65-1.57 (m, 1H), 1.57 (s, 3H), 1.30-1.20
(m, 3H), 1.08-0.95 (3 × d, J ) 6.0, 6.6, 7.0 Hz, 9H), 0.95-
0.80 (m, 33H), 0.69 (d, J ) 6.8 Hz, 3H), 0.15-0.05 (m,
18H); 13C NMR (CDCl3) δC 196.8, 173.7, 157.0, 152.4,
133.7, 132.7, 132.1, 130.3, 129.8, 125.4, 117.9, 80.5, 78.7,
77.8, 77.2, 74.1, 46.8, 43.7, 38.1, 38.0, 37.7, 36.2, 34.9, 34.4,
33.5, 26.2, 26.1, 25.7, 22.7, 18.5, 18.4, 18.2, 18.0, 17.5 (2C),
16.0, 13.8, 13.7, 10.1, -3.3, -3.5 (2C), -3.9, -4.5, -4.8;
m/z (ES+) 956 (100, [M + Na]+); HRMS (ES+) calcd for
C51H95O8NSi3Na [M + Na]+ 956.6263, found 956.6279.
Ketolactone 22 (10 mg, 0.0107 mmol) was dissolved in
toluene (1 mL) and cooled to -78 °C. K-Selectride (1 M in
THF, 32 L, 0.032 mmol, 3 equiv) was added, and the reaction
mixture was stirred at -78 °C for 6 h. It was quenched with
1 drop of acetic acid and allowed to warm to room
temperature. The reaction mixture was directly purified by
flash chromatography on silica gel (20-50% ethyl acetate
in hexane) to yield compound 13 (8.5 mg, 85%) as a white
solid.
1253, 1037, 836 cm-1; 1H NMR (CDCl3) δH 6.60 (ddd, J )
17.1, 10.7, 10.2 Hz, 1H), 6.03 (dd, J ) 11.0, 10.7 Hz, 1H),
5.51 (dd, J ) 10.6, 10.2 Hz, 1H), 5.40-5.30 (m, 2H), 5.22
(d, J ) 16.6 Hz, 1H), 5.13 (d, J ) 10.3 Hz, 1H), 5.01 (d br,
J ) 9.8 Hz, 1H), 4.80-4.70 (m, 1H), 4.72 (dd, J ) 6.2, 5.6
Hz, 1H), 4.68-4.58 (m, 1H), 4.49 (s br, 2H), 3.70 (m, 1H),
3.50-3.45 (m, 1H), 3.27 (dd, J ) 5.0, 4.7 Hz, 1H), 3.05-
2.95 (m, 1H), 2.80-2.70 (m, 1H), 2.70-2.60 (m, 1H), 2.48-
2.39 (m, 1H), 2.09 (dd, J ) 12.6, 11.9 Hz, 1H), 1.98-1.75
(m, 5H), 1.68-1.50 (m, 5H), 1.26 (d, J ) 7.5 Hz, 3H), 1.03-
0.80 (m, 39H), 0.71 (d, J ) 6.5 Hz, 3H), 0.62 (t, J ) 7.9
Hz, 3H), 0.60 (t, J ) 7.9 Hz, 3H), 0.11 (s, 3H), 0.08 (s,
3H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3) δ C 173.9,
156.9, 134.8, 133.6, 132.1, 132.0, 131.4, 131.2, 129.8, 118.0,
80.6, 78.8, 77.2, 76.9, 74.5, 63.9, 44.1, 41.2, 37.9, 37.0, 36.3,
36.2, 35.1, 34.5, 34.4, 26.3, 26.2, 22.9, 19.1, 18.5 (2C), 17.5,
17.1, 16.3, 13.8, 13.7, 10.1, 6.8, 4.9, -3.1, -3.4, -3.5, -3.9;
m/z (CI+) 958.8 (100, [M + Na]+); HRMS (ES+) Calcd for
C51H98O8NSi3 [M + H]+ 936.6595, Found: 936.6592.
Acknowledgment
To list the names of all people who contributed to the
success of this project is a major undertaking, but we are
highly indebted to all of them. We are very grateful for the
support of all of our pilot-plant staff who, at one time or
another, participated in this project. The immense contribu-
tion from our analytical department deserves special mention.
We specially thank our management team for their support,
understanding, patience, and many useful and strategic
discussions in bringing a project of this magnitude to a
successful conclusion.
Received for review September 16, 2003.
OP034134J
Rf 0.39 (33% AcOEt in hexane); [R]D +42 (c ) 0.167,
CHCl3); IR (thin film) 3354, 2959, 2931, 2880, 1727, 1598,
130
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