Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 4: Preparation of Fragment C7-24

Article abstract of DOI:10.1021/op034133r

Coupling of C_9-14 (4) and C_15-21 (5a) fragments to produce the cis-trisubstituted olefin was achieved using Suzuki-type coupling conditions employed by Marshall (5a/tert-BuLi/B-OMe-9-BBN added to 4/Cs ₂CO₃/Pd(dppf)₂). The terminal (Z)-diene moiety was attached to aldehyde 10 by using a sequential Nozaki-Hiyama allylation and Peterson olefination sequence; careful monitoring of the disappearance of both diastereomeric β-hydroxysilanes was found to be essential for achieving a high yield. In the oxidation of alcohols 12 and 16 to 13 and 7, respectively, using iodobenzene diacetate and TEMPO, addition of a trace of water was found to be crucial for complete conversion. The C_8-9 (Z)-olefin functionality was introduced on to aldehyde 13 using a Still-Gennari HWE reaction. Subsequent carbamate installation at C-19 followed by a reduction/oxidation sequence gave the title fragment C_7-24 (7) ready to be coupled with the C_1-6 fragment, which is described in Part 2 of this series.

Full text of DOI:10.1021/op034133r

Organic Process Research & Development 2004, 8, 113−121
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product
(+)-Discodermolide. Part 4: Preparation of Fragment C
7-24
Stuart J. Mickel,* Gottfried H. Sedelmeier, Daniel Niederer, Friedrich Schuerch, Manuela Seger, Klaus Schreiner,
Robert Daeffler, Adnan Osmani, Dominique Bixel, Olivier Loiseleur, Jacques Cercus, Hans Stettler, Karl Schaer, and
Remo Gamboni
Chemical and Analytical DeVelopment, NoVartis Pharma AG, CH 4002 Basel, Switzerland
Andrew Bach, Guang-Pei Chen, Weichun Chen, Peng Geng, George T. Lee, Eric Loeser, Joseph McKenna,
Frederick R. Kinder, Jr., Kurt Konigsberger, Kapa Prasad, Timothy M. Ramsey, Noela Reel, Oljan Repicˇ, Larry Rogers,
Wen-Chung Shieh, Run-Ming Wang, Liladhar Waykole, and Song Xue
NoVartis Institutes for Biomedical Research, One Health Plaza, East HanoVer, New Jersey 07936, U.S.A.
Gordon Florence and Ian Paterson
UniVersity of Cambridge, Chemical Laboratories Lensfield Road, Cambridge CB2 1EW, UK
Abstract:
elaboration to afford an advanced intermediate C7-24 (7) that
is needed for the final stage of the discodermolide synthesis.
This required the construction of the synthetically challenging
Z-trisubstituted double bond via sp3-sp2 cross coupling of
an alkyl iodide and a vinyl iodide and subsequent elaboration
of the product to the target aldehyde 7. In the course of this
synthetic sequence we smoothly make the transition from
the Smith strategy1 to the attractive end game approach of
Paterson2 (Scheme 1).
Coupling of C9-14 (4) and C15-21 (5a) fragments to produce the
cis-trisubstituted olefin was achieved using Suzuki-type coupling
conditions employed by Marshall (5a/tert-BuLi/B-OMe-9-BBN
added to 4/Cs2CO3/Pd(dppf)2). The terminal (Z)-diene moiety
was attached to aldehyde 10 by using a sequential Nozaki-
Hiyama allylation and Peterson olefination sequence; careful
monitoring of the disappearance of both diastereomeric â-hy-
droxysilanes was found to be essential for achieving a high yield.
In the oxidation of alcohols 12 and 16 to 13 and 7, respectively,
using iodobenzene diacetate and TEMPO, addition of a trace
of water was found to be crucial for complete conversion. The
Results and Discussion
Coupling of Fragments C9-14 and C15-21. The coupling
of C9-14 (4) and C15-21 (5a) fragments to produce the (Z)-
trisubstituted olefin 8 is shown in Scheme 2. We initially
examined a variation of the Negishi coupling3 as practiced
by Smith.1 This process produced several side products, as
indicated by the NMR spectrum of the crude reaction mixture
after workup, which were not separable from the desired
product. Marshall described4 an alternative Suzuki-type5
cross-coupling step in his approach to discodermolide. Em-
ploying this protocol for our coupling reaction, [5a/tert-BuLi/
9-methoxy-9-borabicyclo[3.3.1]nonane added to 4/Cs2CO3/
Pd(dppf)Cl2, resulted in a much cleaner reaction mixture.
The only byproduct generated was des-iodo compound 5b.
Some trans isomer of 8, carried over from the trans impurity
in 4, was also observed. Pure 8 was easily obtained from
the crude product in good yield (73%) by crystallization from
acetonitrile. The structure and absolute configuration of 8
C
8-9 (Z)-olefin functionality was introduced on to aldehyde 13
using a Still-Gennari HWE reaction. Subsequent carbamate
installation at C-19 followed by a reduction/oxidation sequence
gave the title fragment C7-24 (7) ready to be coupled with the
C1-6 fragment, which is described in Part 2 of this series.
Introduction
In the preceding contributions of this five-part series, the
large-scale preparations of the C1-6, C9-14, and C15-21
fragments that are required for the total synthesis of (+)-
discodermolide (1) are discussed.
(1) Smith, A. B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu,
Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122,
8654.
(2) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem, Int.
Ed. 2000, 39, 377.
(3) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102,
3298.
In this contribution we present the results of coupling the
key C9-14 (4) and C15-21 (5) fragments and further chain
* Corresponding author. E-mail: stuart_john.mickel@pharma.novartis.
com.
(4) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
(5) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
10.1021/op034133r CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/04/2003
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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Scheme 1. Synthetic strategy leading to the advanced fragment C7-24 (7) and (+)-discodermolide (1)
Scheme 2. Coupling of C9-14 and C15-21 fragmentsa
a Reagents: a) t-BuLi. 9-MeOBBN, THF, -78 °C; b) Cs2CO3, DMF, Pd(dppf)2Cl2, 20 °C; c) DDQ.
was confirmed by single-crystal X-ray analysis of 8b (Figure
1), obtained by removal of the p-methoxybenzyl protecting
group of 8 with DDQ.
With the first fragment union successfully completed,
the transition from the Smith approach to the Paterson route
was now required to arrive at the final C7-24 coupling part-
ner. This necessitates the elaboration of both termini to
introduce the (Z)-enal and the terminal (Z)-diene unit and
introduction of the pendant carbamate moiety as detailed in
Scheme 3.
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not be determined by TLC analysis since TLC could not
separate these two compounds. This was overcome by de-
veloping an HPLC method to monitor the Peterson elimina-
tion reaction. Aided by HPLC, we observed that diastereo-
mers 11a and 11b underwent syn-elimination at different
rates. As a result, it was important to ensure that both â-hy-
droxysilanes were consumed before work up and isolation.
This made the conversion of aldehyde 10 to diene 11 re-
producible and afforded the latter as an oil in 81% yield after
chromatography.
Conversion of C9 Alcohol to (Z)-Enal. Oxidative re-
moval of the two p-methoxybenzyl protecting groups of diene
11 with DDQ/H2O gave diol 12 as a foam in high yield
(88%) after chromatography. Oxidation of diol 12 with
iodobenzene diacetate and TEMPO produced aldehyde 13
as a red oil in 91% yield. Attempts to directly oxidize 11 to
13 were unsuccessful.8 Aldehyde 13 thus generated was used
without purification, since the iodobenzene generated from
the reduction was judged not to interfere in the next step. It
should be noted that traces of water have a dramatic effect
on this reaction. This oxidation when performed on a 300-
mg to 1-g scale with 2,2,6,6,-tetramethyl-1-piperidinyloxy
(TEMPO, 0.1 equiv) and iodobenzene diacetate (DAIB, 1.2
equiv) gave a good yield of 13. However, this reaction was
not reproducible on scale-up, and the yield dropped to 10%.
As the original report by Piancatelli9 mentioned that the
reaction “...can be performed in an open flask without any
particular precautions, e.g., inert atmosphere or dry sol-
vent...”, we felt that these factors may be crucial for the
progress of the reaction. This conclusion led to the addition
of water (0.1 equiv) and resulted in a dramatic acceleration
of the oxidation reaction.
Figure 1. Single-crystal X-ray structure of fragment 8b.
Installation of the Terminal Diene. The elaboration of
intermediate 8 to the advanced C7-24 fragment (7) is
described in Scheme 3. Cleavage of the p-methoxyphenyl
(PMP) acetal with DIBAL6 afforded alcohol 9 in high yield
(92%). Oxidation of 9 under Parikh-Doering conditions with
SO3/pyridine in DMSO gave aldehyde 10 in 93% yield. A
cautious workup of the reaction mixture was critical for a
high yield. If the reaction mixture was not rendered slightly
basic, significant amounts (up to 20%) of the, â-unsaturated
aldehyde 17 could be generated via elimination of p-meth-
oxybenzyl alcohol.
Introduction of the cis-double bond C8-9 was accom-
plished utilizing the Still-Gennari variation of the Horner-
Wadsworth-Emmons reaction.10 Thus, generation of the
anion of bis-2,2,2-trifluoroethylphosphonoacetic acid methyl
ester with potassium hexamethyldisilazide in the presence
of 18-crown-6 and reaction with crude aldehyde 13 gave cis-
olefin 14 in 76% yield from 12. About 2.5% of the trans-
olefin 18 was formed under these conditions. The trans-
isomer was separated by chromatography on silica gel, since
we felt that purification at this stage was appropriate.
Compound 18 was used to make the corresponding trans-
isomers 19-21 for reference.
With the aldehyde 10 in hand, we departed from Smith’s
approach and turned our attention to the installation of the
terminal diene. Numerous strategies have been employed for
the introduction of this motif within the context of disco-
dermolide syntheses. We chose to adopt the highly attractive
Paterson two-step, one-pot protocol.7 This was achieved by
first employing Nozaki-Hiyama allylation conditions, whereby
aldehyde 10 and allyl bromide 10b were added to a
suspension of CrCl2 in dry THF to yield a â-hydroxysilane
intermediate, which on treatment with KH underwent a
Peterson syn-elimination to afford the required (Z)-diene.
Reproducibility of this protocol was initially problematic after
we had replaced KH with KOH as the base for reasons of
safety and ease of operation. We observed that diene 11 was
consistently contaminated with significant amounts of an
impurity as shown by NMR. Further investigation suggested
that a mixture of diastereomeric â-hydroxysilanes 11a and
11b was generated under our modified conditions (Scheme
4). Whether conversion of 11a to 11 was completed could
Formation of carbamate 15 proceeded in quantitative yield
by reaction of 14 with trichloroacetyl isocyanate followed
(8) (a) Nakajima, N.; Uoto, K.; Yonemitsu, O. Heterocycles 1990, 31, 5. (b)
McDonald, C. E.; Nice, L. E.; Kennedy, K. E. Tetrahedron Lett. 1994, 35,
57. (c) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org. Chem. 2002,
67, 5176.
(6) (a) Takano, S.; Akiyama, M.; Sano, S.; Ogasawara, K. Chem. Lett. 1983,
1593. (b) Evans, D. A.; Ng, H. P. Tetrahedron Lett. 1993, 34, 2229.
(7) Paterson, I.; Schlapbach, A. Synlett 1995, 498.
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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Scheme 3. Synthesis of fragment C7-24 (7)
Scheme 4. Installation of the terminal diene unit
by methanolysis as described by Paterson2 in his modification
of the Kocovsky procedure.11 Reduction of the ester group
15 with DIBAL in dichloromethane at -78 °C yielded a
mixture of alcohol 16 and aldehyde 7 (10-20%, depending
on the reaction time). Attempts to reduce ester 15 exclusively
to aldehyde 7 were unsuccessful, since the latter was easily
reduced to alcohol 16. This mixture was used in the next
step without further purification. Oxidation of 16 with iodo-
benzene diacetate and TEMPO in the presence of traces of
water afforded 7 as a white foam in 80% yield (two steps
from 15) after chromatography. Three byproducts (22, 23,
and 24) were also isolated during the purification. Their
origin could be attributed to byproducts present in the
previous steps.
Having successfully assembled the pivotal fragment C7-24
,
(9) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J.
Org. Chem. 1997, 62, 6974.
(10) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(11) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
we were ready to address the most challenging phase of the
entire campaign, the finale based on the C6-C7 coupling.
The following contribution describes the chemistry involved
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and the problems encountered in the large-scale synthesis
of (+)-discodermolide.
0.88 (m, 15H), 0.85 (d, J ) 6.3 Hz, 3H), 0.62 (d, J ) 6.5
Hz, 3H), 0.05 (s, 3H), 0.00 (s, 3H).
(B) Negishi Procedure. A solution of 5 (13.7 g, 25 mmol)
in 400 mL of diethyl ether was treated with 26 mL of a 1.0
M solution of zinc chloride (1.0 M in diethyl ether), and the
resulting thin suspension was cooled to an internal temper-
ature of -75 °C. A solution of tert-butyllithium (40 mL,
1.7 M solution in pentane, 65 mmol) was added dropwise
over 60 min. The solution was stirred for 30 min at -75 °C
and slowly warmed to 20 °C within 60 min. The resulting
white suspension was stirred for 60 min at 20 °C and treated
with a solution of 4 (10.4 g, 20 mmol) in diethyl ether (140
mL). Tetrakis(triphenylphosphine)palladium(0) (1.0 g) was
added, and the suspension was stirred for 3 h at 20 °C. The
reaction mixture was treated with water (250 mL) and stirred
for 30 min at 20 °C. The mixture was then filtered through
Cellflock, and the solids were rinsed with 300 mL of tert-
butyl methyl ether. The organic phase was separated and
washed with brine (200 mL). The solvent was removed in
vacuo at 30 °C to give 21.5 g of an oil. This oil was purified
by silica gel chromatography eluting with hexane/ethyl
acetate mixtures (1.5 L, 98/2 then 2 L, 94/6). The appropriate
fractions were combined and evaporated to dryness to give
12.5 g, 76.8%, of 8 as a pink oil. This oil was dissolved in
acetonitrile (200 mL) containing 10% hexane. The mixture
was concentrated at 30 °C in vacuo (ca. 60 mL distilled)
and cooled to 20 °C to induce crystallization. The suspension
was stirred for 60 min at 25 °C and cooled to 0 °C, stirred
for 60 min, and filtered. The solid was rinsed with 35 mL
of cold acetonitrile, dried in vacuo at 20 °C to give 8 (10.0
g, 62% based on 4): mp 79-80.5 °C; NMR identical to
that above.
Alcohol 8b Crystal for X-ray. To a solution of olefin 8
(1.33 g, 1.6 mmol) in 16 mL of dichloromethane under a
nitrogen atmosphere at 0 °C was added water (75 mg, 4.1
mmol). To this solution was added solid DDQ (387 mg, 1.7
mmol). The red-brown suspension was stirred at 0 °C for 4
h. The mixture was dried over MgSO4, diluted with 20 mL
of dichloromethane, and filtered. The filtrate was passed
through a 1-in. thick pad of silica gel that was pre-wetted
with ethyl acetate/hexane (1:1). The pad was rinsed with 25
mL of ethyl acetate/hexane (1:1). The filtrate was evaporated
under vacuo to give an off-white solid (1.2 g). This solid
was partially dissolved in 50 mL of ethanol at 23 °C. To the
suspension was added solid sodium borohydride (250 mg,
6.7 mmol) at 23 °C. The resulting suspension was stirred
for 20 min at 23 °C. The mixture was cooled to 0 °C, and
quenched with saturated aqueous ammonium chloride (50
mL). The mixture was concentrated under vacuum to remove
the ethanol. The residue was partitioned between dichlo-
romethane (200 mL) and water (100 mL). The dichlo-
romethane layer was separated, washed with water (100 mL),
dried over MgSO4, filtered, and evaporated under vacuum
to give a crude white solid (1.1 g, 100%). A single crystal
of suitable size was grown for X-ray studies by dissolving
20 mg of this solid in 2-propanol and allowing the solvent
to evaporate slowly under ambient conditions.
Experimental Section
(4S,5S)-4-[(Z)-(1R,2R,3S,7S,8R,9S)-2,8-bis-(tert-butyl-
dimethylsilanyloxy)-10-(4-methoxybenzyloxy)-1,3,5,7,9-
pentamethyldec-5-enyl]-2-(4-methoxyphenyl)-5-methyl-
[1,3]dioxane (8). (A) Suzuki Procedure. A solution of tert-
butyllithium (2.4 kg, 15%, 5.63 mol) in diethyl ether was
diluted with 3 L of hexane and cooled to an internal
temperature of -80 °C. To this solution was added a pre-
cooled (-40 °C) solution of iodide 5a (1.58 kg, 2.91 mol)
in 16 L of tetrahydrofuran in 30 min, followed by the addition
of a pre-cooled (-40 °C) solution of 9-methoxy-BBN (530
g, 3.49 mol) in tetrahydrofuran (5 L) in 15 min. A suspension
formed after the addition. The cooling bath was removed,
and this borane intermediate was added to a mixture of vinyl
iodide 4 (1.1 kg, 2.12 mol) in DMF (19 L) containing
Pd(dppf)Cl2 (78 g, 0.10 mol) and cesium carbonate (2.4 kg,
7.37 mol, predissolved in 2 L of water) within 2.5 h. The
resulting mixture was allowed to warm to 25 °C and stirred
for an additional 20 h. The mixture was filtered through
Cellflock (filter aid). The solid was rinsed with heptane, and
the combined heptane filtrates were evaporated to a volume
of about 12 L. Ethanolamine (235 g, 3.85 mol) was added,
and the mixture was stirred for 15 min and filtered through
Cellflock. The solids were rinsed with heptane (3 × 3 L).
The combined heptane filtrates were evaporated to a volume
of about 3 L. This concentrate was chromatographed on silica
gel eluting with a mixture of heptane/tert-butyl methyl ether
to give, after evaporation of the solvent, 2.07 kg of a light-
orange oil. This oil was redissolved in a mixture of 8 L of
acetonitrile and 2 L of heptane and warmed to 30 °C. About
2.5 L of the solvent was removed by distillation at 30 °C
(mainly heptane), and the product began to crystallize. The
suspension was cooled to room temperature, and the thick
suspension was diluted with 3.5 L of acetonitrile. The
suspension was cooled to 0 °C, stirred for 30 min, and
filtered. The solid was rinsed with cold acetonitrile (1 L)
and dried in a vacuum to give olefin 8 (1.26 kg, 73% based
1
on 4): [R]D +27.7 (c ) 1, CHCl3); H NMR (CDCl3) δ
7.36 (m, 2H), 7.22 (m, 2H), 6.85 (m, 4H), 5.37 (s, 1H), 4.99
(d, J ) 9.97 Hz, 1H), 4.36 (ABq, J ) 11.8 Hz, 2H), 4.09
(dd, J ) 11.0 4.8 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.60
(dd, J ) 7.0 & 1.9 Hz, 1H), 3.50-3.40 (m, 3H), 3.37 (dd,
J ) 6.3 4.8 Hz, 1H), 3.18 (pseudo t, J ) 8.9 Hz, 1H), 2.50
(m, 1H), 2.31 (m, 1H), 2.11-1.82 (m, 4H), 1.65 (m, 1H),
1.54 (s, 3H), 1.04 (d, J ) 6.9 Hz, 3H), 0.93 (d, J ) 7.7 Hz,
3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.72 (d, J ) 6.2 Hz, 3H),
0.02 (s, 3H), 0.00 (s, 9H). Note: The mother liquors were
concentrated and chromatographed on silica gel to yield an
additional 60-80 g of 8. Further elution of the chromatog-
raphy column led to the isolation of 5b.
tert-Butyl-((R)-1-{(R)-1-[(4S,5S)-2-(4-methoxyphen-
yl)-5-methyl-[1,3]dioxan-4-yl]-ethyl}-2-methylpropoxy)-
dimethylsilane (5b): H NMR (d6-DMSO) δ 7.30 (m, 2H),
6.92 (m, 2H), 5.45 (s, 1H), 4.02 (dd, J ) 11.9 5.5 Hz, 1H),
3.78 (s, 3H), 3.60-3.45 (m, 3H), 2.0-1.80 (m, 3H), 1.00-
1
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(Z)-(2S,3S,4R,5R,6S,10S,11R,12S)-5,11-Bis-(tert-bu-
tyldimethylsilanyloxy)-3,13-bis-(4-methoxybenzyloxy)-
2,4,6,8,10,12-hexamethyltridec-8-en-1-ol (9). A solution of
olefin 8 (1.92 kg, 2.36 mol) in toluene (17 L) was cooled to
an internal temperature of -15 to -20 °C. A solution of
DIBAL in toluene (10.9 kg of a 1.0 M solution, 10.9 mol)
was added dropwise within 60 min. The reaction mixture
was warmed to 0-5 °C and stirred for 60 min. Ethyl acetate
(15 L) was then added within 45 min, maintaining the
temperature at 0 °C, followed by a solution of saturated
sodium potassium tartrate (60 L). The mixture was warmed
to 25 °C and stirred for an additional 60 min. The organic
layer was separated. The aqueous phase was re-extracted with
ethyl acetate (12 L). The combined organic phases were
washed with 10 L of water. The organic layer was dried
with MgSO4 and filtered, and the solvent was removed in
vacuo at 50 °C to give 1.91 kg of an oil. This oil was
chromatographed on silica gel eluting with heptane/ethyl
acetate, 3/1. The appropriate fractions were combined and
concentrated to give 9 as an oil (1.78 kg, 92%): 1H NMR
(CDCl3) δ 7.32 (m, 4H), 6.85 (m, 4H), 5.01 (d, J ) 10.5
Hz, 1H), 4.49 (ABq, J ) 9.2 Hz, 2H), 4.36 (ABq, J ) 11.7
Hz, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.73 (dd, J ) 11.3 &
2.9 Hz, 1H), 3.60-3.43 (m, 4H), 3.35 (m, 1H), 3.19 (pseudo
t, J ) 8.8 Hz, 1H), 2.80-2.67 (br s, exch D2O, 1H), 2.49
(m, 1H), 2.22 (pseudo t, J ) 12.0 Hz, 1H), 2.01-1.84 (m,
4H), 1.73 (m, 1H), 1.57 (s, 3H), 1.03 (m, 6H), 0.92 (m, 12H),
0.86 (m, 12H), 0.72 (d, J ) 6 Hz, 3H), 0.06 (s, 6H), 0.00 (s,
6H).
12-hexamethyltrideca-2,8-dienal (17): 1H NMR (CDCl3)
δ 9.37 (s, 1H), 7.22 (m, 2H), 6.84 (m, 2H), 6.36 (d, J ) 9.5
Hz, 1H), 5.00 (d, J ) 10.3 Hz), 4.36 (ABq, J ) 12.7 Hz,
2H), 3.78 (s, 3H), 3.45 (m, 2H), 3.35 (dd, J ) 4.83, 4.2 Hz,
1H), 3.19 (pseudo t, J ) 7.8 Hz, 1H), 2.87 (m, 1H), 2.46
(m, 1H), 1.94 (m, 1H), 1.74 (s, 3H), 1.54 (s, 3H), 1.05 (d, J
) 6.6 Hz, 3H), 0.91 (m, 12H), 0.86 (m, 12H), 0.72 (d, J )
6.6 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.00 (s, 6H).
â-Hydroxysilanes 11a and 11b. A dried 5-L, four-
necked, round-bottomed flask equipped with paddle stirrer,
rubber septum, thermometer, and a glass stopper was filled
with argon and placed in a dry bag under nitrogen purge.
Chromium(II) chloride (23.1 g, 0.19 mol) was transferred
to the flask in the dry bag under nitrogen purge. The flask
was sealed and placed on a mechanical stirrer. Anhydrous,
degassed THF (1.0 L, inhibited with 250 ppm of 2,6-di-tert-
butyl-4-methylphenol) was added via cannula, and the green
suspension was cooled to 0 °C under argon purge. A solution
of aldehyde 10 (34.0 g, 0.04 mol) in anhydrous, degassed
THF (2.2 L) was further degassed with argon for 30 min
and transferred via cannula to the reaction flask. Allyl
bromide 10b (40.4 g, 0.21 mol) was added via syringe. With
cooling bath in place and positive argon pressure applied,
the reaction mixture was allowed to warm to 25 °C and
stirred for an additional 16 h. Analytical samples for 11a
and 11b were obtained by flash chromatography on SiO2
(hexanes/ethyl acetate, 95/5, for 11a and hexanes/ethyl
acetate, 90/10, for 11b).
â-Hydroxysilane 11a: colorless oil; Rf 0.35 (toluene); [R]-
25
(Z)-(2R,3R,4R,5R,6S,10S,11R,12S)-5,11-Bis-(tert-bu-
tyldimethylsilanyloxy)-3,13-bis-(4-methoxybenzyloxy)-
2,4,6,8,10,12-hexamethyltridec-8-enal (10). A solution of
alcohol 9 (1.64 kg, 2.01 mol) in 10.5 L of dichloromethane
containing 5.8 L of dimethyl sulfoxide was treated with 660
g, (6.52 mol) of triethylamine. The mixture was cooled to
-5 °C, and a solution of sulfur trioxide/pyridine complex
(768 g, 4.83 mol) in 9 L of dimethyl sulfoxide was added
dropwise within 30 min. The mixture was stirred for 60 min
at 0 °C, and heptane (30 L) was added followed by water
(20 L). The organic phase was separated and washed
sequentially with water (10 L), saturated sodium bicarbonate
(10 L), and finally water (4 × 10 L). The organic phase was
dried with MgSO4 and filtered, and the solvent was removed
to give an oil. This oil was purified by chromatography on
silica gel to give 10 as an oil (1.53 kg, 93%): 1H NMR
(CDCl3) δ 9.79 (d, J ) 2.4 Hz, 1H), 7.21 (m, 4H), 6.84 (m,
4H), 5.01 (d, J ) 10.2 Hz, 1H), 4.45 (ABq, J ) 11.2 Hz,
2H), 4.35 (ABq, J ) 11.9 Hz, 2H), 3.76 (s, 6H), 3.57-3.52
(m, 2H), 3.45 (dd, J ) 9.2, 4.4 Hz, 1H), 3.36 (dd, J ) 6.5,
4.8 Hz, 1H), 3.19 (pseudo t, J ) 9.2 Hz, 1H), 2.73 (m, 1H),
2.49 (m, 1H), 2.23 (pseudo t, J ) 12.3 Hz, 1H), 1.93 (m,
3H), 1.64 (m, 1H), 1.56 (s, 3H), 1.10 (d, J ) 7.1 Hz, 3H),
1.01 (d, J ) 6.8 Hz, 3H), 0.94-0.89 (m, 12H), 0.88-0.83
(m, 12H), 0.71 (d, J ) 6.5 Hz, 3H), 0.05 (s, 3H), 0.04 (s,
3H), 0.00 (s, 6H). The following compound (17) was also
isolated from the chromatography.
D -3.3 (c ) 0.5, CHCl3); IR (KBr) 3496, 2957, 2930, 2856,
1613, 1514, 1463, 1360, 1302, 1172 cm-1; 1H NMR (CDCl3)
δ 7.28-7.21 (m, 4H), 6.90-6.82 (m, 4H), 5.98 (ddd, J )
17.4, 10.4, 10.4 Hz, 1H), 5.03 (d, J ) 10.2 Hz, 1H), 4.95
(dd, J ) 10.2, 2.1 Hz, 1H), 4.83 (dd, J ) 17.3, 2.1 Hz, 1H),
4.52 (ABq, JAB ) 10.8 Hz, ∆δAB ) 29.3 Hz, 2H), 4.38 (ABq,
JAB ) 11.6 Hz, ∆δAB ) 19.4 Hz, 2H), 3.86 (b, 1H), 3.80 (s,
3H), 3.79 (s, 3H), 3.76-3.71 (m, 1H), 3.52 (dd, J ) 6.6,
2.0, 1H), 3.48 (dd, J ) 9.2, 4.9 Hz, 1H), 3.39 (dd, J ) 6.3,
4.7 Hz, 1H), 3.34 (dd, J ) 6.4, 3.5 Hz, 1H), 3.21(dd, J )
8.7, 8.7 Hz, 1H), 2.57-2.44(m, 1H), 2.32 (dd, J ) 12.4,
12.4, 1H), 2.01-1.79 (m, 4H), 1.73 (bd, J ) 10.7, 1H), 1.68
(bd, J ) 11.3, 1H), 1.59 (s, 3H), 0.97 (d, J ) 7.0, 3H), 0.93
(d, J ) 7.5, 3H), 0.92 (s, 9H), 0.89 (d, J ) 7.5, 3H), 0.88 (s,
9H), 0.77 (d, J ) 6.9, 3H), 0.74 (d, J ) 6.7, 3H), 0.068 (s,
3H), 0.062 (s, 3H), 0.037 (s, 9H), 0.029 (s, 3H), 0.023 (s,
3H); 13C NMR (CDCl3) δ 159.8, 159.4, 136.3, 132.0, 131.9,
131.4, 130.5, 129.9, 129.4, 114.3, 114.1, 113.8, 87.4, 78.8,
77.9, 75.3, 75.0, 73.1, 72.9, 55.7, 42.0, 41.3, 39.9, 39.2, 37.8,
36.1, 35.3, 32.0, 26.7, 26.5, 23.6, 23.0, 18.9, 18.8, 17.5, 16.2,
14.9, 14.5, 13.0, 12.2, -1.8, -2.8, -2.9, -3.4, -3.5. Anal.
Calcd for C53H94O7Si3: C, 68.63; H, 10.21; Si, 9.08.
Found: C, 68.74; H, 10.02; Si, 9.03.
â-Hydroxysilane 11b: colorless oil; Rf 0.07 (toluene);
[R]25 +3.2 (c ) 0.8, CHCl3); IR (KBr) 2957, 2931, 2856,
D
1
1613, 1513, 1463, 1376, 1312, 1249, 1080, 1039 cm-1; H
NMR (CDCl3) δ 7.25 (d, J ) 5.65, 2 H), 7.24 (d, J ) 5.8
Hz, 2H), 6.90-6.82 (m, 4H), 5.82 (ddd, J ) 17.1, 10.4, 10.4
Hz, 1H), 5.04 (d, J ) 10.2 Hz, 1H), 5.00 (dd, J ) 10.4, 2.0
(2E,8Z)-(4R,5R,6S,10S,11R,12S))-5,11-Bis-(tert-butyl-
dimethylsilanyloxy)-13-(4-methoxybenzyloxy)-2,4,6,8,10,-
118
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Hz, 1H), 4.91 (dd, J ) 17.1, 1.8 Hz, 1H), 4.54 (ABq, JAB
)
gel eluting with toluene/ethyl acetate mixtures (initially 97.5/
2.5, finally 90/10). The fractions containing product were
combined and concentrated to afford diol 12 as a foam (792
g, 88%): 1H NMR (CDCl3) δ 6.62 (dtd, J ) 16.8, 11.7,
1.09 Hz, 1H), 6.13 (pseudo t, J ) 10.9 Hz, 1H), 5.32 (pseudo
t, J ) 10.4 Hz, 1H), 5.22 (d, J ) 16.7 Hz, 1H), 5.14 (d, J
) 10.1 Hz, 1H), 4.99 (d, J ) 10.4 Hz, 1H), 3.66 (dd, J )
10.9, 4.5 Hz, 1H), 3.61 (dd, J ) 5.8, 3.3 Hz, 1H), 3.39 (dd,
J ) 6.9, 3.8 Hz, 1H), 3.33 (dd, J ) 8.1, 3.0 Hz, 1H), 2.80
(m, 1H), 2.57 (m, 1H), 2.17 (pseudo t, J ) 11.7 Hz, 1H),
1.95-1.75 (m, 7H, becomes 5H on D2O), 1.62 (s, 3H), 1.00-
0.88 (m, 30H), 0.75 (d, J ) 6.6 Hz, 3H), 0.09 (s, 6H), 0.08
(s, 6H).
(5Z,13Z)-(2R,3R,4S,8S,9R,10R,11S,12S)-3,9-Bis-(tert-
butyldimethylsilanyloxy)-11-hydroxy-2,4,6,8,10,12-
hexamethylhexadeca-5,13,15-trienal (13). To a solution of
alcohol 12 (782 g, 1.31 mol) in dichloromethane (4 L) was
added water (2.4 g). A mixture of iodobenzene diacetate (620
g, 1.92 mol) and TEMPO (40.1 g) was added in five portions
over a period of 30 min with vigorous stirring. The orange
reaction mixture was stirred for an additional 60 min at 25
°C and a 25% solution of sodium thiosulphate was added.
The mixture was stirred for 15 min, and the organic phase
was separated. The aqueous phase was re-extracted with
dichloromethane (5 L), and the combined organic phases
were treated with solid sodium bicarbonate (400 g). The
suspension was filtered. The filtrate was washed with water
(2 L) and evaporated in vacuo at 20 °C to give aldehyde 13
as a red oil (1.10 kg): 1H NMR (CDCl3) δ 9.63 (s, 1H),
6.64 (dt, J ) 16.8, 11.7 Hz, 1H), 6.15 (pseudo t, J ) 10.9
Hz, 1H), 5.35 (pseudo t, J ) 10.2 Hz, 1H), 5.25 (d, J )
16.7 Hz, 1H), 5.17 (d, J ) 9.8 Hz, 1H), 4.83 (d, J ) 10.5
Hz, 1H), 3.76 (dd, J ) 8, 3.6 Hz, 1H), 3.62 (dd, J ) 5.8,
3.3 Hz, 1H), 3.36 (dd, J ) 7.6, 3.3 Hz, 1H), 2.83 (m, 1H),
2.54 (m, 1H), 2.19 (pseudo t, J ) 12.4 Hz, 1H), 1.96-1.72
(m, 4H), 1.60 (s, 3H), 1.08 (d, J ) 7.1 Hz, 3H), 1.01-0.86
(m, 27H), 0.74 (d, J ) 6.5 Hz, 3H), 0.10 (s, 9H), 0.07 (s,
3H). This oil was used without further purification.
10.8 Hz, ∆δAB ) 25.9 Hz, 2H), 4.38 (ABq, JAB ) 11.6 Hz,
∆δAB ) 17.9 Hz, 2H), 4.16-4.10 (m, 1H), 3.79 (s, 3H),
3.78 (s, 3H), 3.52 (dd, J ) 5.6, 3.4 Hz, 1H), 3.48 (dd, J )
9.2, 4.9 Hz, 1H), 3.43 (dd, J ) 5.6, 5.6 Hz, 1H), 3.40 (dd,
J ) 6.1, 4.7 Hz, 1H), 3.21 (dd, J ) 8.8, 8.8 Hz, 1H), 2.62
(b, 1H), 2.56-2.46 (m, 1H), 2.28 (dd, J ) 12.4, 12.4 Hz,
1H), 2.01-1.88 (m, 3H), 1.88-1.74 (m, 2H), 1.71 (bd, J )
12.1 Hz, 1H), 1.60 (s, 3H), 1.01 (d, J ) 7.0 Hz, 3H), 0.99
(d, J ) 7.0 Hz, 3H), 0.95 (d, J ) 6.6 Hz, 3H), 0.94 (s, 9H),
0.89 (s, 9H), 0.88 (d, J ) 7.3 Hz, 3H), 0.76 (d, J ) 6.7 Hz,
3H), 0.071 (s, 3H), 0.068 (s, 3H), 0.03 (s, 3H), 0.025 (s,
3H), 0.021 (s, 9H); 13C NMR (CDCl3) δ 159.1, 159.0, 138.0,
131.54, 131.49, 131.0, 130.9, 129.0, 114.0, 113.77, 113.68,
85.0, 78.4, 77.6, 75.2, 72.7, 72.5, 69.7, 55.3, 42.1, 40.2, 39.3,
38.8, 36.8, 35.7, 35.1, 26.3, 26.1, 23.1, 22.7, 18.5, 18.4, 17.1,
14.1, 13.4, 11.7, 10.8, -1.9, -3.2, -3.8, -3.9. Anal. Calcd
for C53H94O7Si3: C, 68.45; H, 9.84; Si, 9.13. Found: C,
68.57; H, 10.20; Si, 9.06.
1-[(5Z,13Z)-(2S,3R,4S,8S,9R,10R,11S,12S)-11-(4-Meth-
oxybenzoxy)-3,9-bis-(tert-butyldimethylsilanyloxy)-2,4,6,8,-
10,12-hexamethylhexadeca-5,13,15-trienyloxymethyl]-4-
methoxybenzene (11). A suspension of chromium(II) chloride
(980 g, 7.97 mol) in tetrahydrofuran (90 L) was cooled to 0
°C and treated with a solution of aldehyde 10 (1.52 kg, 1.87
mol) in tetrahydrofuran (20 L). To the suspension was added
a solution of 1-bromoallyltrimethylsilane (2.0 kg, 10.4 mol)
in tetrahydrofuran (10 L). The mixture was stirred for 15
min at 0 °C and warmed to 15 °C, stirred for 60 min, and
recooled to 0 °C. Methanol (7.5 L) was added followed by
15 L of a 6 M solution of potassium hydroxide. The mixture
was warmed to 25 °C and stirred for 16 h. The organic phase
was separated and the aqueous phase re-extracted with 30 L
of tetrahydrofuran. The combined organic layers were
washed with brine (10 L) and concentrated to give 1.71 kg
of an oil. The oil was purified by chromatography on silica
gel eluting with heptane/isopropyl alcohol mixtures to give
cis-diene 11 as an oil (1.27 kg, 81%): 1H NMR (CDCl3) δ
7.24 (m, 4H), 6.84 (m, 4H), 6.57 (dt, J ) 16.5, 10.5 Hz,
1H), 5.99 (pseudo t, J ) 10.6 Hz, 1H), 5.55 (pseudo t, J )
10.4 Hz, 1H), 5.18 (d, J ) 16 Hz, 1H), 5.09 (d, J ) 9.0 Hz,
1H), 4.94 (d, J ) 10 Hz, 1H), 4.50 (ABq, J ) 9.6 Hz, 2H),
4.35 (ABq, J ) 11.2 Hz, 2H), 3.77 (s, 3H), 3.76 (2, 3H),
3.42 (m, 2H), 3.34 (m, 1H), 3.26-3.14 (m, 2H) 2.98 (m,
1H), 2.43 (m, 1H), 2.06-1.89 (m, 2H), 1.85-1.69 (m, 2H),
1.51 (s, 3H), 1.09 (d, J ) 6.9 Hz, 3H), 0.98 (d, J ) 6.9 Hz,
3H), 0.93 (m, 9H), 0.90 (d, J ) 6.4 Hz, 3H), 0.86 (m, 9H),
0.84 (d, J ) 6.9 Hz, 3H), 0.69 (d, J ) 6.9 Hz, 3H), 0.08 (s,
6H), 0.00 (s, 6H).
(2Z,7Z,15Z)-(4S,5S,6S,10S,11R,12R,13S,14S)-5,11-Bis-
(tert-butyldimethylsilanyloxy)-13-hydroxy-4,6,8,10,12,14-
hexamethyloctadeca-2,7,15,17-tetraenoic Acid Methyl Es-
ter (14). A solution of 18-crown-6 (315 g), and bis-2,2,2-
trifluoroethylphosphonoacetic acid methyl ester (570 g, 1.8
mol) in 10.3 L of toluene was cooled to 0 °C and treated
with a solution of potassium hexamethyldisilazide in toluene
(3 kg, 0.5 M solution, 1.72 mol). The red solution was stirred
for 45 min at 0 °C and cooled to -20 °C. A solution of
crude aldehyde 13 (1.05 kg, 1.76 mol) in toluene (3 L) was
added within 15 min. The reaction mixture was stirred for
10 min, warmed to 0 °C, and stirred for an additional 90
min. The reaction was quenched with saturated aqueous
ammonium chloride solution (10 L). The organic phase was
separated, washed with brine (10 L), dried over MgSO4,
filtered, and concentrated to produce a yellow oil. Chroma-
tography over silica gel eluting with hexane/ethyl acetate,
15/1, afforded ester 14 (622 g, 76% from 12): [R]20D +53.7
(5Z,13Z)-(2S,3R,4S,8S,9R,10R,11S,12S)-3,9-Bis-(tert-
butyldimethylsilanyloxy)-2,4,6,8,10,12-hexamethylhexadeca-
5,13,15-triene-1, 11-diol (12). To a solution of diene 11 (1.28
kg, 1.51 mol) in 20 L of dichloromethane was added solid
DDQ (983 g, 4.33 mol). The red-brown suspension was
stirred for 75 min at 25 °C and filtered through Cellflock.
The solid was rinsed with 20 L of dichloromethane in two
portions, and the solvent was concentrated to give 1.41 kg
of a red oil. This was purified by chromatography over silica
1
(c ) 1, CHCl3); H NMR (CDCl3) δ 6.64 (dtd, J ) 16.9,
10.6, 1.0 Hz, 1H), 6.36 (dd, J ) 11.9, 9.7 Hz, 1H), 6.12
Vol. 8, No. 1, 2004 / Organic Process Research & Development
•
119

(pseudo t, J ) 11.1 Hz, 1H), 5.70 (d, J ) 11.4 Hz, 1H),
5.33 (pseudo t, J ) 10.6 Hz, 1H), 5.23 (dd, J ) 16.8, 2.0
Hz, 1H), 5.14 (d, J ) 9.8 Hz, 1H), 4.90 (d, J ) 10.6 Hz,
1H), 3.71-3.61 (m, 4H), 3.57 (dd, J ) 5.7, 3.5 Hz, 1H),
3.38-3.29 (m, 2H), 2.80 (m, 1H), 2.31 (m, 1H), 2.09 (pseudo
t, J ) 12.4 Hz, 1H), 1.89-1.73 (m, 2H), 1.64 (d, J ) 11.6,
1H), 1.55 (s, 3H), 1.00 (d, J ) 6.9 Hz, 3H), 0.96 (d, J ) 6.4
Hz, 3H), 0.93 (d, J ) 6.7 Hz, 3H), 0.91-0.89 (m, 18H),
0.81 (d, J ) 6.9 Hz, 3H), 0.69 (d, J ) 6.6 Hz, 3H), 0.07 (s,
3H), 0.05 (s, 9H). Further elution of the chromatography
column led to the isolation of 18.
(CDCl3) δ 6.93 (dd, J ) 15.9, 7.2 Hz, 1H), 6.59 (dt, J )
16.9, 10.6 Hz, 1H), 5.99 (pseudo t, J ) 11.1 Hz, 1H), 5.63
(dd, J ) 15.5, 2.4 Hz, 1H), 5.33 (pseudo t, J ) 10.2 Hz,
1H), 5.23-5.06 (m, 2H), 4.85 (d, J ) 4.8 Hz, 1H), 4.69
(pseudo t, J ) 6.3 Hz, 1H), 4.51 (s, 2H, NH2), 3.74-3.53
(m, 5H), 3.51-3.26 (m, 2H), 2.77 (m, 1H), 2.55-2.33 (m,
2H), 2.10 (pseudo t, J ) 12.5 Hz, 1H), 1.90-1.07 (m, 4H),
1.54 (s, 3H), 0.99 (d, J ) 7 Hz, 3H), 0.95-0.78 (m, 27H),
0.68 (d, J ) 6.7 Hz, 3H), 0.04 (s, 3H), 0.00 (s, 9H).
Carbamic Acid (6Z,11Z)-(1S,2R,3R,4S,8S,9S,10S)-3,9-
Bis-(tert-butyl-dimethylsilanyloxy)-13-hydroxy-2,4,6,8,10-
pentamethyl-1-((Z)-(S)-1-methylpenta-2,4-dienyl)-trideca-
6,11-dienyl Ester (16). A solution of carbamate 15 (789 g,
1.14 mol) in dichloromethane (15 L) was cooled to -78 °C.
A solution of DIBAL (5.6 L, 1.0 M solution in dichlo-
romethane) was added dropwise over 60 min. The mixture
was stirred for an additional 60 min at -78 °C and quenched
with 12 L of a saturated aqueous solution of sodium
potassium tartrate. Water (10 L) was added followed by tert-
butyl methyl ether (10 L). The mixture was stirred vigorously
for 15 min. The organic layer was separated and washed
with water (2 × 7 L). The solvent was concentrated in vacuo
(2E,7Z,15Z)-(4S,5S,6S,10S,11R,12R,13S,14S)-5,11-Bis-
(tert-butyldimethylsilanyloxy)-13-hydroxy-4,6,8,10,12,14-
hexamethyloctadeca-2,7,15,17-tetraenoic acid methyl ester
1
(18): H NMR (CDCl3) δ 6.94 (dd, J ) 15.3, 7.4 Hz, 1H),
6.59 (dtd, J ) 16.8, 10.65, 1.1 Hz, 1H), 6.10 (pseudo t, J )
11.9 Hz, 1H), 5.64 (dd, J ) 15.9, 1.7 Hz, 1H), 5.30 (pseudo
t, J ) 10.8 Hz, 1H), 5.20 (dd, J ) 16.5, 2.3 Hz, 1H), 5.12
(d, J ) 10.2 Hz, 1H), 4.88 (d, J ) 10.3 Hz, 1H), 3.74-3.53
(m, 5H), 3.51-3.26 (m, 2H), 2.77 (m, 1H), 2.55-2.33 (m,
2H), 2.10 (pseudo t, J ) 12.5 Hz, 1H), 1.90-1.77 (m, 4H),
1.54 (s, 3H), 0.99 (d, J ) 7 Hz, 3H), 0.95-0.78 (m, 27H),
0.68 (d, J ) 6.7 Hz, 3H), 0.04 (s, 3H), 0.00 (s, 9H).
(2Z,7Z,15Z)-(4S,5S,6S,10S,11R,12R,13S,14S)-5,11-Bis-
(tert-butyldimethylsilanyloxy)-13-carbamoyloxy-4,6,8,10,-
12,14-hexamethyloctadeca-2,7,15,17-tetraenoic Acid Meth-
yl Ester (15). To a solution of ester 14 (739 g, 1.14 mol) in
dichloromethane (5 L) was added dropwise trichloroacetyl
isocyanate (332 g, 1.76 mol) over a period of 30 min. The
reaction mixture was stirred for 90 min, and methanol (3 L)
was added. The mixture was concentrated in vacuo at 20 °C
until no more solvent distilled. Methanol (7.5 L) was added
to the residue followed by solid sodium carbonate (365 g).
The suspension was stirred at 25 °C for 2 h, and water (10
L) and tert-butyl methyl ether (10 L) were added. The
organic phase was separated, and the aqueous phase was re-
extracted with tert-butyl methyl ether (7.5 L). The combined
organic layers were dried over MgSO4, filtered, and con-
centrated to give carbamate 15 (789 g, 100%) as a foam:
[R]20D +76.3 (c ) 1, CHCl3); 1H NMR (CDCl3) δ 6.58 (dtd,
J ) 17, 10.6, 1.0 Hz, 1H), 6.36 (dd, J ) 11.6, 9.79 Hz, 1H),
6.01 (pseudo t, J ) 11.4 Hz, 1H), 5.69 (dd, J ) 11.6, 0.8
Hz, 1H), 5.37 (pseudo t, J ) 10.8 Hz, 1H), 5.20 (dd, J )
17, 1.8 Hz, 1H), 5.12 (d, J ) 10.1 Hz, 1H), 4.87 (d, J )
10.3 Hz, 1H), 4.71 (pseudo t, J ) 5.9 Hz, 1H), 4.51 (s, 2H,
NH2), 3.71-3.61 (m, 4H), 3.39 (pseudo t, J ) 4.5 Hz, 1H),
3.33 (dd, J ) 7.2, 2.8 Hz, 1H), 2.97 (m, 1H), 2.27 (m, 1H),
1.99 (pseudo t, J ) 12.8 Hz, 1H), 1.91-1.74 (m, 2H), 1.54
(s, 3H), 1.00 (d, J ) 7.2 Hz, 3H), 0.98 (d, J ) 7.0 Hz, 3H),
0.91 (m, 21H), 0.86 (d, J ) 7.0 Hz, 3H), 0.67 (d, J ) 6.9
Hz, 3H), 0.07 (s, 3H), 0.06 (s, 6H), 0.05 (s, 3H). This was
used without further purification.
at 20 °C to give crude alcohol 16 (810 g): [R]20 +76.3 (c
D
) 1, CHCl3); 1H NMR (CDCl3) δ 6.56 (dtd, J ) 16.8, 10.6,
1.1 Hz, 1H), 5.99 (pseudo t, J ) 11.0 Hz, 1H), 5.59-5.67
(m, 2H), 5.32 (pseudo t, J ) 10.6 Hz, 1H), 5.18 (dd, J )
16.8, 2 Hz, 1H), 5.09 (d, J ) 10.3 Hz, 1H), 4.92 (d, J )
10.3 Hz, 1H), 4.67 (pseudo t, J ) 6.1 Hz, 1H), 4.57-4.65
(s, 2H, NH2), 4.04 (dd, J ) 10.8, 3 Hz, 2H), 3.35 (dd, J )
5.7, 3.6 Hz, 1H), 3.21 (dd, J ) 7.2, 3.4 Hz, 1H), 2.94 (m,
1H), 2.60 (m, 1H), 2.33 (m, 1H), 1.83 (m, 1H), 1.63-1.53
(m, 6H), 0.95 (d, J ) 6.6 Hz, 3H), 0.92-0.86 (m, 24H),
0.84 (d, J ) 6.6 Hz, 3H), 0.66 (d, J ) 6.8 Hz, 3H), 0.05 (s,
3H), 0.04 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H). This was used
without further purification.
Carbamic Acid (6Z,11E)-(1S,2R,3R,4S,8S,9S,10S)-3,9-
Bis-(tert-butyl-dimethylsilanyloxy)-13-hydroxy-2,4,6,8,10-
pentamethyl-1-((Z)-(S)-1-methylpenta-2,4-dienyl)-trideca-
6,11-dienyl Ester (20). Employing the same procedure for
converting 15 to 16, the trans-allyl alcohol 20 can be
obtained from the corresponding trans-ester 19 in a similar
1
manner: H NMR (CDCl3) δ 6.57 (dt, J ) 16.9, 0.5 Hz,
1H), 6.00 (pseudo t, J ) 10.8 Hz, 1H), 5.65 (d, J ) 7.4 Hz,
1H), 5.61 (d, J ) 7.9 Hz, 1H), 5.52 (m, 1H), 5.34 (pseudo
t, J ) 10.5 Hz, 1H), 5.19 (d, J ) 10.5 Hz, 1H), 5.10 (d, J
) 10.1 Hz, 1H), 4.91 (d, J ) 10.16 Hz, 1H), 4.69 (pseudo
t, J ) 6.1 Hz, 1H), 4.55-4.45 (s, 2H, NH2), 4.05 (m, 1H),
3.31 (m, 2H), 3.24 (m, 1H), 2.90 (m, 1H), 2.55-2.33 (m,
2H), 2.10 (pseudo t, J ) 12.5 Hz, 1H), 1.90-1.77 (m, 4H),
1.54 (s, 3H), 0.99 (d, J ) 7 Hz, 3H), 0.95-0.78 (m, 27H),
0.68 (d, J ) 6.7 Hz, 3H), 0.04 (s, 3H), 0.00 (s, 9H).
Carbamic Acid (6Z,11Z)-(1S,2R,3R,4S,8S,9S,10S)-3,9-
Bis-(tert-butyl-dimethylsilanyloxy)-2,4,6,8,10-pentamethyl-
1-((Z)-(S)-1-methylpenta-2,4-dienyl)-13-oxo-trideca-6,11-
dienyl Ester (7). A solution of crude alcohol 16 (810 g, 1.22
mol) in dichloromethane (5 L) was charged with water (1.8
g). A mixture of iodobenzene diacetate (478 g, 1.5 mol) and
TEMPO (31 g) was added in five portions over a period of
(2E,7Z,15Z)-(4S,5S,6S,10S,11R,12R,13S,14S)-5,11-Bis-
(tert-butyldimethylsilanyloxy)-13-carbamoyloxy-4,6,8,10,-
12,14-hexamethyloctadeca-2,7,15,17-tetraenoic Acid Meth-
yl Ester (19). Employing the same procedure for converting
14 to 15, the trans-carbamate 19 can be obtained from the
1
corresponding trans-ester 18 in a similar manner: H NMR
120
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Vol. 8, No. 1, 2004 / Organic Process Research & Development

30 min with vigorous stirring. The orange reaction mixture
was stirred for 60 min at 25°C, and a 25% solution of sodium
thiosulphate was added. The mixture was stirred for 15 min,
and the organic phase was separated. The aqueous phase was
re-extracted with dichloromethane (5 L). The combined
organic phases were treated with solid sodium bicarbonate
(400 g). The suspension was filtered, and the filtrate was
washed with water (2 L) and concentrated in a vacuum at
20 °C to give 1.04 kg of a red oil. This was purified by
chromatography over silica gel eluting sequentially with
mixtures of hexane/ethyl acetate, 12/1, 10/1, 8/1, and finally
4/1. The product fractions were combined, and the solvent
(m, 24H), 0.63 (d, J ) 7.3 Hz, 3H), 0.04 (s, 3H), 0.03 (s,
6H), 0.00 (s, 3H); MS (Na+) 714.4.
1
Alcohol 23: H NMR (CDCl3) δ 9.75 (d, J ) 7.9 Hz,
1H), 6.86 (pseudo t, J ) 10.9 Hz, 1H), 6.54 (dt, J ) 16.6,
10.3 Hz, 1H), 5.98 (pseudo t, J ) 10.9 Hz, 1H), 5.84 (dd, J
) 10.3, 8.0 Hz, 1H), 5.28-5.09 (m, 2H), 4.86 (m, 1H),
3.39-3.04 (m, 3H), 2.98 (m, 1H), 2.20 (m, 1H), 1.94-1.62
(m, 7H), 1.04 (d, J ) 6.9 Hz, 3H), 0.965 (d, J ) 6.9 Hz,
3H), 0.90-0.79 (m, 24H), 0.62 (d, J ) 7.3 Hz, 3H), 0.04-
0.00 (m, 12H).
Carbamic Acid (6Z,11E)-(1S,2R,3R,4S,8S,9S,10S)-3,9-
Bis-(tert-butyldimethylsilanyloxy)-2,4,6,8,10-pentamethyl-
1-((Z)-(S)-1-methylpenta-2,4-dienyl)-13-oxo-trideca-6,11-
dienyl Ester (21). Employing the same procedure for
converting 16 to 7, trans-aldehyde 21 can be obtained from
was concentrated to give aldehyde 7 (647 g, 80%) as a white
1
foam: [R]20 +84.9 (c ) 1, CHCl3); H NMR (CDCl3) δ
D
9.78 (d, J ) 8.1 Hz, 1H), 6.67 (pseudo t, J ) 11.0 Hz, 1H),
6.54 (dtd, J ) 17.0, 10.4 Hz, 0.95H, 1H), 5.94 (pseudo t, J
) 10.7 Hz, 1H), 5.84 (dd, J ) 11.3 & 8.5 Hz, 1H), 5.32
(pseudo t, J ) 10.7 Hz, 1H), 5.16 (dd, J ) 17.0, 2.0 Hz,
1H), 5.08 (d, J ) 10.4 Hz, 1H), 4.87 (d, J ) 10.4 Hz, 1H),
4.67 (pseudo t, J ) 4.4 Hz, 1H), 4.56-4.41 (s, 2H, NH2),
3.42-3.27 (m, 2H), 2.92 (m, 1H), 2.24 (m, 1H), 1.79 (m,
2H), 1.53 (s, 3H), 1.04 (d, J ) 6.9 Hz, 3H), 0.96 (d, J ) 6.9
Hz, 3H), 0.90-0.78 (m, 24H), 0.63 (d, J ) 7.3 Hz, 3H),
0.04 (s, 3H), 0.03 (s, 6H), 0.00 (s, 3H). The following
byproducts (22 and 23) were also isolated by chromatogra-
phy.
1
the corresponding trans-alcohol 20 in a similar manner: H
NMR (CDCl3) δ 9.42 (d, J ) 7.6 Hz, 1H), 6.83 (dd, J )
16.3, 7.0 Hz, 1H), 6.57 (dt, J ) 16.7, 10.8 Hz, 1H), 6.01-
5.89 (m, 2H), 5.31 (pseudo t, J ) 10.8 Hz, 1H), 5.16 (d, J
) 16.7 Hz, 1H), 5.08 (d, J ) 10.1 Hz, 1H), 4.92 (d, J )
10.1 Hz, 1H), 4.66 (pseudo t, J ) 5.9 Hz, 1H), 4.55-4.38
(s, 2H, NH2), 3.42-3.29 (m, 2H), 2.93 (m, 1H), 2.61 (m,
1H), 2.35 (m, 1H), 1.81 (m, 2H), 1.57-1.49 (m, 5H), 1.03
(d, J ) 6.9 Hz, 3H), 0.94 (d, J ) 6.9 Hz, 3H), 0.89-0.78
(m, 24H), 0.64 (d, J ) 7.3 Hz, 3H), 0.04 (s, 3H), 0.00 (s,
9H).
1
Formyl carbamate 22: H NMR (d6-DMSO) δ 10.91
Acknowledgment
(d, J ) 9.2 Hz, 1H), 9.78 (d, J ) 8.1 Hz, 1H), 8.87 (d, J )
8.5 Hz, 1H), 6.67-6.56 (m, 2H), 6.05 (pseudo t, J ) 10.7
Hz, 1H), 5.83 (dd, J ) 11.3, 8.5 Hz, 1H), 5.39 (pseudo t, J
) 10.7 Hz, 1H), 5.25 (d, J ) 17 Hz, 1H), 5.17 (d, J ) 11.3
Hz, 1H), 5.00 (d, J ) 10.4 Hz, 1H), 4.82 (pseudo t, J ) 5.1
Hz, 1H), 3.55-3.20 (m, 4H [partially obscured by solvent]),
3.06 (m, 1H), 2.24 (m, 1H), 1.79 (m, 2H), 1.53 (s, 3H), 1.04
(d, J ) 6.9 Hz, 3H), 0.96 (d, J ) 6.9 Hz, 3H), 0.90-0.78
We thank Dr. Grety Rihs for performing the X-ray
analysis of compound 8b. We appreciate Mr. Karl Gunder-
son’s assistance in analyzing the NMR spectra of compounds
11a and 11b.
Received for review September 16, 2003.
OP034133R
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