Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 3: Synthesis of Fragment C15-21

Article abstract of DOI:10.1021/op034132z

Smith's procedure of preparing fragment C_15-21 (5) from common precursor 3 was optimized. The ease of plant operations made this six-step route successful for the production of several kilograms of this fragment with high purity.

Full text of DOI:10.1021/op034132z

Organic Process Research & Development 2004, 8, 107−112
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product
(+)-Discodermolide. Part 3: Synthesis of Fragment C
15-21
Stuart J. Mickel,* Gottfried H. Sedelmeier, Daniel Niederer, Friedrich Schuerch, Guido Koch, E. Kuesters,
Robert Daeffler, Adnan Osmani, Manuela Seeger-Weibel, E. Schmid, Alfred Hirni, Karl Schaer, and Remo Gamboni
Chemical and Analytical DeVelopment, NoVartis Pharma AG, CH 4002 Basel, Switzerland
Andrew Bach, Stephen Chen, Weichun Chen, Peng Geng, Christopher T. Jagoe, Frederick R. Kinder, Jr., George T. Lee,
Joseph McKenna, Timothy M. Ramsey, Oljan Repicˇ, Larry Rogers, Wen-Chung Shieh, Run-Ming Wang, and
Liladhar Waykole
NoVartis Institutes for Biomedical Research, One Health Plaza, East HanoVer, New Jersey 07936, U.S.A.
Scheme 1. Synthetic strategy leading to fragment C15-21
(5) and (+)-discodermolide
Abstract:
Smith’s procedure of preparing fragment C15-21 (5) from
common precursor 3 was optimized. The ease of plant opera-
tions made this six-step route successful for the production of
several kilograms of this fragment with high purity.
Introduction
In the previous two parts of this series, large-scale
preparations of two key fragments required for the total
synthesis of (+)-discodermolide (1) are discussed.
In this contribution, the third part of the series, we present
the route and results leading to the synthesis of fragment
C
15-21. The strategy for the synthesis of this fragment (alkyl
iodide 5) from the common precursor 3 and its conversion
to 1 is outlined in Scheme 1.
Results and Discussion
(PMP) acetal 8 in 61% yield. This is one of several crystalline
intermediates in the synthesis that can be purified easily by
recrystallization of the crude material. Acetal 8 was produced
presumably by an oxidative cyclization pathway via cations
3a and 3b as shown in Scheme 3. Anhydrous conditions are
highly critical to obtain high yields of this reaction. If water
is not excluded completely, some further oxidized p-meth-
oxybenzyl cation 8a can be captured by water, leading to
benzoate 13 as a major byproduct (Scheme 4). Controlled
reduction of the Weinreb amide 8 with LiAlH4 provided
another crystalline compound, aldehyde 9, in high yield
(91%). Intermediate 9 was isolated with high purity by
crystallization and filtration.
The published route1 for the synthesis of fragment C15-21
(5) from the common precursor 3 was very attractive from
the scale-up point of view, since all intermediates en route
were reported as crystalline solids. We decided to further
develop this six-step sequence for our multigram synthesis
of (+)-discodermolide (Scheme 2).
Synthesis of PMP-Protected Aldehyde 9. Treatment of
the Smith common precursor 31 (described in Part 1) with a
solution of DDQ2 in toluene in the presence of 4-Å powdered
molecular sieves furnished crystalline p-methoxybenzylidene
* Corresponding author. E-mail: stuart_john.mickel@pharma.novartis.com.
(1) (a) 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. (b) Smith, A. B.; Kaufman, M. D.; Beauchamp, T. J.; LaMarche,
M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823.
Evans Aldol Reaction. To extend the carbon chain, the
Evans aldol condensation protocol was employed. Coupling
of aldehyde 9 with oxazolidinone 9a at -78 to -10 °C
(2) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 889.
10.1021/op034132z 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 2. Synthesis of fragment C15-21 from the common
precursor
Figure 1. NOE of 15.
Scheme 4. Formation of benzoate byproduct
Scheme 5. Formation of byproduct 14
quench, significant amounts of byproducts (14, major, and
15, minor) formed. Removal of byproduct 14 from the
desired product 10 by crystallization was difficult, since it
cocrystallized with the product. As a result, it was important
to keep the reaction mixture below 0 °C to suppress the
formation of these byproducts.
Scheme 3. Oxidative cyclization
Formation of these byproducts suggested instability of the
p-methoxybenzyl protecting group. Formation of 14 was
attributed to the presence of excess di-n-butylboron triflate
and enolate 9b, which could open the acetal ring mediated
by the boron (Lewis acid) (Scheme 5). The structure of
byproduct 14 was supported by NMR spectroscopy. The
structure of 15 was also supported by NMR experiments
(NOE indicated by arrows) as shown in Figure 1.
Intermediate 10 was unstable at ambient temperature and
underwent epimerization at the C16 position. This can be
completely suppressed by storing it at temperatures below
-10 °C. Thus, rapid workup and isolation were essential to
achieve a higher yield. Epimerization was most likely caused
mediated by di-n-butylboron triflate afforded the desired
C15-21 backbone. The success of the aldol reaction was
dependent largely on the quality of the di-n-butylboron
triflate, as previously discussed (see Part 1 in this series).
Gratifyingly, intermediate 10 was also a crystalline solid and
could be readily isolated from the reaction mixture after
workup, crystallization, and filtration in 85% yield. The
diastereomeric excess of this compound was so high that
none of the undesired diastereoisomer was detected. How-
ever, when the same reaction was carried out either at room
temperature or allowed to warm to room temperature before
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Scheme 6. Reduction via a thio ester
Silyl ether 16 was also reduced under the same conditions
to furnish diol 18 as an analytical reference. Interestingly,
the partially reduced, mono-oxazolidinone 19 was also
isolated.
by retro-aldol/aldol reactions initiated by the unprotected
hydroxy group. This was supported by the fact that silyl ether
11, formed by silylation of 10 with TBDMSOTf/lutidine in
quantitative yield, was found to be stable at ambient tem-
perature. Both hydroxyl groups of byproduct 14 were also
silylated to furnish bis-silyl ether 16 as a stable reference
sample.
Conversion to the Iodo Intermediate 5. Reductive
removal of the oxazolidinone chiral auxiliary from 11 leading
to an alcohol was required. Treatment of 11 with a solution
of lithium borohydride in THF/EtOH3 gave an average yield
of 60% of the desired alcohol 12 after chromatography on
silica gel. We were unable to reproduce the high yields
(>80%) reported in the literature,1 despite examining various
other reducing agents, solvents, etc. For example, reduction
of 11 with sodium borohydride4 was very slow and resulted
in a very messy reaction. Another alternative approach, where
11 was converted into a thio ester 175 followed by reduction,6
did not improve the yield (Scheme 6). Attempts to reduce
11 to the corresponding aldehyde with the Schwartz reagent,
according to a recently described procedure,7 were also
unsuccessful.
Finally, conversion of alcohol 12 into the desired alkyl
iodide 5 was accomplished by employing Ph3P/I2/imidazole.
The desired product was isolated as an oil in 90% yield
without chromatography. Iodide 5 is light sensitive and forms
a low-melting crystalline solid.
In conclusion, fragment C15-21 (5) was produced in six
steps from the common precursor 3 with an overall yield of
24%. Although the yield was about half of what was reported
by Smith (56%),1a the ease of plant operations made this
route successful for the production of several kilograms of
this fragment with high purity.
Experimental Section
(R)-N-Methoxy-2-[(4S,5S)-2-(4-methoxyphenyl)-5-meth-
yl-1-[1,3]dioxin-4-yl]-N-methyl- propionamide (8). To a
solution of common precursor 3 (18.1 kg, 77% purity, 42.83
mol) in toluene (260 kg) was added powdered 4-Å molecular
sieves (18.1 kg). The suspension was cooled to 0 °C, and a
solution of DDQ (15.0 kg, 66.1 mol) in toluene (90.4 kg)
was added over 60 min. The addition equipment was washed
with toluene (17 kg). The suspension was stirred overnight
at 0 °C. Cellflock (filter aid) (18.1 kg) was added and the
suspension filtered. The solid was washed with toluene (1
× 175 kg, followed by 2 × 36.4 kg). The combined filtrates
were washed with 2 M aqueous sodium hydroxide solution
(92.1 kg). The organic phase was then washed with four
times with water (128 kg) containing 15% aqueous NaCl
(26.8 kg) and concentrated under vacuum at 45 °C to about
one-third of the original volume. The residue was filtered,
and the solid was rinsed with toluene (2 × 9.1 kg). The
combined filtrate was concentrated under vacuum at 45 °C
to give an oil. The oily residue was dissolved in diisopropyl
ether (15.8 kg), and the resulting solution was stirred for 60
min at room temperature after which time crystallization
began. The suspension was cooled to 0 °C, and stirred for
an additional 2.5 h. The product was isolated by filtration,
washed with 10 kg of a 2/1 diisopropyl ether/heptane mixture
We found the lower yield was caused by several compet-
ing reactions that led to four byproducts 20-23; 20 was the
major byproduct. It is obvious that 20, 22, and 23 were
generated by uncontrolled reductions of the carbonyl groups
internal and external to the oxazolidinone ring. The exact
pathway for the formation of 21 was unclear.
(3) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J.
M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307.
(4) Prashad, M.; Har, D.; Kim, Hong-Yong; Repicˇ, O. Tetrahedron Lett. 1998,
39, 7067.
(5) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.;
Tedrow, J. S. J. Org. Chem. 1999, 64, 6411.
(6) Liu, H. J.; Bukownik, R.; Pednekar, P. R. Synth. Commun. 1981, 11, 599.
(7) White, J. M.; Ashok, R T.; Georg, G. I. J. Am. Chem. Soc. 2000, 122,
11995.
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and dried at 30 °C to give 8 (6.9 kg, 50%) as a white
crystalline solid: 1H NMR (CDCl3) δ 7.40 (m, 2H), 6.86
(m, 2H), 5.46 (s, 1H), 4.40 (dd, J ) 11.6, 4.0 Hz, 1H), 3.90-
3.76 (m, 4H), 3.51 (pseudo t, J ) 10.9 Hz, 1H), 3.22-3.11
(m, 4H), 1.95 (m, 1H), 1.26 (d, J ) 6.9 Hz, 3H), 0.75 (d, J
) 6.9 Hz, 3H). The following compound (13) was also
isolated by chromatography from the mother liquors.
4-Methoxybenzoic acid (2S,3S,4R)-3-hydroxy-4-(meth-
oxymethylcarbamoyl)-2-methyl-pentyl ester (13): 1H NMR
(CDCl3) δ 7.92 (m, 2H), 6.84 (m, 2H), 4.48 (A part of ABq,
J ) 11.7, 3.7 Hz, 1H), 4.30 (B part of ABq, J ) 11.7, 6.7
Hz, 1H), 4.10 (br s, exch D2O, 1H), 3.79 (s, 3H), 3.76-
3.70 (m, 1H), 3.20-2.98 (m, 4H), 1.99 (m, 1H), 1.12 (d, J
) 6.7 Hz, 3H), 0.94 (d, J ) 7.5 Hz, 3H).
min at 0 °C, and a 50% aqueous solution of sodium
thiosulphate (10 kg) was added slowly (very exothermic for
the addition of the first 2-3 kg). The mixture was stirred
for 30 min at 5 °C, and the organic phase was separated,
washed with water (13 L), dried over MgSO4, and filtered.
The solvent was concentrated under vacuum at 30 °C to give
the crude product as an oil. This oil was dissolved in
2-propanol (2.6 L), and heptane (6.5 L) was added dropwise.
The solution was seeded and stirred at room temperature for
60 min. More heptane (5.2 L) was added to the suspension
and stirred for 20 h at 20 °C. The solid was collected by
filtration, rinsed, and dried at 20 °C to afford 10 (2.066 kg,
85%) as a white crystalline solid: [R]25 -16.3 (c ) 1,
D
CHCl3); 1H NMR (CD3OD) δ 7.41-7.23 (m, 7H), 6.90 (m,
2H), 5.51 (s, 1H), 4.69 (m, 1H), 4.27-4.07 (m, 4H), 4.01
(dd, J ) 6.9, 4.9 Hz, 1H), 3.81 (s, 3H), 3.67 (dd, J ) 10.0,
1.7 Hz, 1H), 3.57 (pseudo t, J ) 11.0 Hz, 1H), 3.16 (A part
of ABq, J ) 13.5, 3.5 Hz, 1H), 2.95 (B part of ABq, J )
13.5, 7.9 Hz, 1H), 2.13-1.94 (m, 2H), 1.27 (d, J ) 6.93
Hz, 3H), 1.09 (d, J ) 7.3 Hz, 3H), 0.82 (d, J ) 6.6 Hz,
3H).
2-[(4R,5S,6S)-2-(4-Methoxyphenyl)-5-methyl-[1,3]dioxin-
4-yl]-propionaldehyde (9). A solution of amide 8 (1.953
kg, 6.04 mol) in anhydrous THF (16 L) was cooled to -75
°C. A solution of lithium aluminum hydride (1.2 kg of a 10
wt/wt % solution in THF, 3.16 mol) was added dropwise
over 30 min. The reaction mixture was warmed to -20 °C,
and ethyl acetate (0.58 kg, 6.6 mol) was added dropwise
over 15 min. The mixture was treated with 50% (w/v)
aqueous solution of sodium potassium tartrate (16 L) and
stirred for 60 min. The organic layer was separated, and the
aqueous phase was re-extracted with THF (7 L). The organic
layers were concentrated under vacuum, and toluene (10 L)
was added to the residue. The toluene solution was extracted
with 20% aqueous solution of citric acid (2 × 3 L), followed
by washing with water (3 × 3 L). The organic phase was
concentrated under vacuum at 40 °C, and heptane (6 L) was
added to the residue. Crystallization began immediately. The
suspension was cooled to 4 °C and stirred for 3.5 h. The
solid was collected by filtration, rinsed with heptane (2 ×
Chromatography of mother liquors on silica gel allowed
the isolation of byproducts 14 and 15.
Compound 14: 1H NMR (C6D6) δ 7.50 (m, 2H), 7.20-
7.00 (m, 8H), 6.88 (m, 2H), 6.71 (m, 2H), 5.01-4.87 (m,
2H), 4.32 (m, 2H), 3.89 (m, 1H), 3.75-3.40 (m, 10H), 3.32
(m, 1H), 3.28 (s, 3H), 3.17 (t, J ) 6.5 Hz, exch D2O, primary
OH, 1H), 2.88 (A part of ABq, J ) 13.5, 3.5 Hz, 1H), 2.64
(B part of ABq, J ) 13.5, 7.9 Hz, 1H), 2.32-2.16 (m, 2H),
1.45-1.35 (m, 7H, becomes 6H on D2O exch), 1.04 (d, J )
6.7 Hz, 3H), 0.98 (d, J ) 7.2 Hz, 3H). After derivitization
with trichloroacetyl isocyanate, the following spectrum was
obtained: 1H NMR (C6D6) δ 7.45 (m, 2H), 7.20-6.95 (m,
8H), 6.82 (m, 2H), 6.76 (m, 2H), 5.23 (dd, J ) 9.0, 4.0 Hz,
1H, CHOH), 4.85 (d, J ) 11.0 Hz, 1H, OCHPhOMe), 4.75
(qd, J ) 11.0, 4.0 Hz, OCCH(CH3)OCHPhOMe), 4.50 (dd,
J ) 10.2, 5.0 Hz, 1H), 4.40 (m, 1H), 4.30 (m, 1H), 3.43 (m,
1H), 3.72 (pseudo t, J ) 10 Hz, 1H), 3.60-3.45 (m, 4H),
3.30-3.18 (m, 5H), 2.83-2.67 (m, 3H), 2.35 (B part of ABq,
J ) 13.5, 8.4 Hz, 1H), 1.86 (m, 1H), 1.30-1.20 (m, 6H),
0.98 (d, J ) 6.7 Hz, 3H), 0.89 (d, J ) 7.0 Hz, 3H).
(R)-4-Benzyl-3-{(R)-2-[4S,5R]-6-((S)-2-hydroxy-1-
methylethyl)-2-(4-methoxyphenyl)-5-methyl[1,3]dioxin-4-
500 mL), and dried to give aldehyde 9 (1.455 kg, 91%) as
1
a white crystalline solid: [R]25 +10.3 (c ) 1, CHCl3). H
D
NMR (CDCl3) δ 9.74 (d, J ) 0.61 Hz, 1H), 7.32 (m, 2H),
6.84 (m, 2H), 5.47 (s, 1H), 4.13 (dd, J ) 11.3, 4.7 Hz, 1H),
4.05 (dd, J ) 9.7, 2.8 Hz, 1H), 3.77 (s, 3H), 3.56 (pseudo t,
J ) 11.7 Hz, 1H), 2.56 (qd, J ) 7.21, 2.8 Hz, 1H), 2.09 (m,
1H), 1.22 (d, J ) 7.2 Hz, 3H), 0.79 (d, J ) 6.6 Hz, 3H).
(R)-4-Benzyl-3-{(2R,3S,4S)-3-hydroxy-4-[(4S,5S)-2-(4-
methoxyphenyl)-5-methyl-[1,3]dioxin-4-yl]-2-methylpen-
tanoyl}-oxazolidin-2-one (10). A solution of (R)-4-benzyl-
3-propionyloxazolidin-2-one 9a (1.81 kg, 7.76 mol) in
dichloromethane (6.5 L) was cooled to -2 to 0 °C. A 26 wt
% solution of di-n-butylboron triflate (2.44 kg, 8.54 mol)
was added within 20 min. Triethylamine (995 g, 9.85 mol)
was added within 20 min, and the mixture was stirred for
60 min at 0 °C. The resulting enolate solution was cooled
to -78 °C, and a solution of aldehyde 9 (1.3 kg, 4.92 mol)
was added dropwise within 15 min. The mixture was stirred
for an additional 1 h at this temperature. The reaction mixture
was warmed stepwise to 0 °C by holding at -50 °C for 1 h
and at -22 °C for 16 h. Upon reaching 0 °C, aqueous
phosphate buffer solution (6.5 L, pH 7.0) was added,
followed by dropwise addition of aqueous hydrogen peroxide
(1.52 kg, 35% solution) over 45 min, maintaining the
temperature at 0 °C. The reaction mixture was stirred for 60
1
yl]-propionyl}-oxazolidin-2-one (15): H NMR (C6D6) δ
7.52 (m, 2H), 7.05 (m, 3H), 6.83 (m, 4H, 5.50 (s, 1H), 4.56
(m, 1H), 4.31 (dd, J ) 10.0, 2.1 Hz, 1H), 4.20 (m, 1H),
3.70-3.58 (m, 3H), 3.44 (dd, J ) 10.5, 4.3 Hz, 1H), 3.31
(s, 3H), 3.15 (pseudo t, J ) 9.5 Hz, 1H), 2.94 (dd, J ) 12.5,
4.1 Hz, 1H), 2.25 (dd, J ) 12.2, 8.2 Hz, 1H), 2.06-1.90
(m, 2H), 1.56 (d, J ) 6.8 Hz, 3H), 1.13 (d, J ) 6.9 Hz, 3H),
0.66 (d, J ) 7.4 Hz, 3H).
(R)-4-Benzyl-3-{(2R,3S,4R)-3-(tert-butyl-dimethylsila-
nyloxy)-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-[1,3]-
dioxin-4-yl]-2-methylpentanoyl}-oxazolidin-2-one (11).
Compound 10 (2.05 kg, 4.12 mol) was dissolved in dichlo-
romethane (15 L) and treated with 2,6-lutidine (850 g, 7.93
mol). The solution was cooled to -10 °C, and tert-
butyldimethylsilyl triflate (1.8 kg, 6.81 mol) was added
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dropwise over 15 min. The reaction mixture was stirred at
-10 °C for a further 30 min and warmed to 0 °C. The
mixture was diluted with tert-butyl methyl ether (24 L) and
washed with 10% aqueous solution of sodium hydrogen
sulphate (15 L). The organic phase was separated and washed
with brine, dried over MgSO4, filtered, and concentrated
under vacuum to give silyl ether 11 as an oil (2.881 kg,
114%), which was used without further purification: 1H
NMR (CDCl3) δ 7.38 (m, 2H), 7.25 (m, 3H), 7.15 (m, 2H),
6.81 (m, 2H), 5.45 (s, 1H), 4.27 (m, 1H), 4.10 (dd, J ) 6.8,
4.5 Hz, 1H), 4.05-3.90 (m, 2H), 3.80-3.70 (m, 4H), 3.48
(pseudo t, J ) 10.6 Hz, 1H), 3.08 (A part of ABq, J ) 13.5,
3.5 Hz, 1H), 2.58 (B part of ABq, J ) 13.5, 7.9 Hz, 1H),
2.10-1.90 (m, 2H), 1.18 (d, J ) 6.8 Hz, 3H), 1.05 (d, J )
7.4 Hz, 3H), 0.9 (s, 9H), 0.71 (d, J ) 6.7 Hz, 3H), 0.02 (s,
6H).
Compound 16. Compound 14 (0.46 g, 0.63 mmol) was
silylated in the same fashion as 11 to produce 0.95 g of 16:
1H NMR (CDCl3) δ 7.40-7.20 (m, 10H), 7.15 (m, 2H), 6.86
(m, 2H), 4.80-4.65 (m, 2H), 4.45 (m, 2H), 4.18-3.90 (m,
4H), 3.80 (s, 3H), 3.66 (m, 1H), 3.63-3.52 (m, 3H), 3.30
(m, 1H), 2.95 (m, 2H), 3.16 (A part of ABq, J ) 13.5, 3.5
Hz, 1H), 2.63 (B part of ABq, J ) 13.5, 7.9 Hz, 1H), 2.10
(m, 1H), 1.61 (m, 1H), 1.05 (m, 6H), 1.00-0.78 (m, 22H),
0.08-0.00 (m, 12H).
(2R,3S,4R)-3-(tert-Butyldimethylsilanyloxy)-4-[(4S,5S)-
2-(4-methoxyphenyl)-5-methyl-[1,3]dioxan-4-yl]-2-meth-
ylpentanoic acid ((R)-1-benzyl-2-hydroxyethyl)-amide
1
(20): H NMR (CDCl3) δ 7.47 (m, 2H), 7.22 (m, 3H), 7.01
(m, 2H), 6.95 (m, 2H), 5.54-5.49 (m, 2H), 4.12 (m, 2H),
3.96 (m, 1H), 3.86 (m, 2H), 3.79 (s, 3H), 3.51 (pseudo t, J
) 11.5 Hz, 1H), 3.44 (dd, J ) 10.9, 3.6, 1H), 3.16 (dd, J )
11.5, 6.7 Hz, 1H), 2.71-2.57 (br s, 1H), 2.55-2.45 (m, 2H),
2.23 (dd, J ) 13.9, 7.3 Hz, 1H), 2.11-1.96 (m, 2H), 1.02-
0.97 (m, 6H), 0.92 (s, 9H), 0.73 (d, J ) 6.7 Hz, 3H), 0.08
(s, 3H), 0.04 (s, 3H).
(5R,6S)-3-[(R)-1-Benzyl-2-(tert-Butyldimethylsilanyloxy)-
ethyl]-6-{(R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-
[1,3]dioxan-4-yl]ethyl}-5-methyl-[1,3]oxazinane-2,4-di-
1
one (21): H NMR (CDCl3) δ 7.40 (m, 2H), 7.34-7.22 (m,
5H), 6.90 (m, 2H), 5.44 (s, 1H), 4.64 (m, 2H), 4.14 (m, 2H),
4.03 (pseudo t, J ) 8.6 Hz, 1H), 3.95 (dd, J ) 8.43, 3.7 Hz,
1H), 3.84 (s, 3H), 3.55 (m, 1H), 3.45 (dd, J ) 10.4, 2.5 Hz,
1H), 3.34 (m, 1H), 2.82 (dd, J ) 13.6, 11.1 Hz, 1H), 2.66
(qd, J ) 7.4, 3.3 Hz, 1H), 2.18 (m, 2H), 1.27 (d, J ) 7.2
Hz, 3H), 1.24 (d, J ) 6.5 Hz, 3H), 0.95 (s, 9H), 0.81 (d, J
) 6.5 Hz, 3H), 0.33 (m, 6H).
(R)-2-({(2S,3R,4R)-3-(tert-Butyldimethylsilanyloxy)-4-
[(4S,5S)-2-(4-methoxyphenyl)-5-methyl[1,3]dioxan-4-yl]-
2-methylpentyl}-methylamino)-3-phenylpropan-1-ol
1
(2S,3R,4R)-3-(tert-butyldimethylsilanyloxy)-4-[(4S,5S)-
2-(4-methoxyphenyl)-5-methyl-[1,3]dioxin-4-yl]-2-meth-
ylpentan-1-ol (12). Silyl ether 11 (5.0 kg, 8.17 mol) was
dissolved in THF (50.0 kg), and the solution was cooled to
-35 °C. Ethanol (0.957 kg) was added, followed by dropwise
addition of a 10 wt % solution of lithium borohydride in
THF (4.52 kg, 20.75 mol) over a period of 35 min. The
mixture was warmed to 23 °C within 60 min and stirred for
2 h. A 1.0 M aqueous solution of sodium hydroxide (44.4
kg) was added slowly, and the mixture was stirred for 2 h at
20 °C. tert-Butyl methyl ether (31.6 kg) was added. The
organic layer was separated, washed with brine (50 kg), dried
over Na2SO4, and concentrated under vacuum at 25 °C to
give the crude product as an oil (4.72 kg, 131%). The crude
material was dissolved in a mixture of cyclohexane (32.8
kg) and methanol (7.46 kg). Water (2.36 kg) was added, and
the two-phase mixture was stirred for 10 min. The organic
phase was separated and concentrated under vacuum to give
an oil (3.39 kg). This material was divided into three portions,
and each (1.13 kg) was chromatographed over 25 kg of silica
gel eluting with hexane/ethyl acetate mixtures (starting with
15% of ethyl acetate, followed by 20, 30, and finally 75%
of ethyl acetate). The fractions containing the desired product
from all three chromatographies were combined and con-
(22): H NMR (CDCl3) δ 7.41 (m, 2H), 7.23 (m, 3H), 7.08
(m, 2H), 6.90 (m, 2H), 5.44 (s, 1H), 4.13 (d, J ) 11.4, 4.7
Hz, 1H), 3.82 (s, 3H), 3.69 (d, J ) 7.1 Hz, 1H), 3.61 (d, J
) 9.4 Hz, 1H), 3.54 (pseudo t, J ) 11.4 Hz, 1H), 3.40-
3.30 (m, 2H), 2.98-2.87 (m, 2H), 2.43 (dd, J ) 12.6, 8.3
Hz, 1H), 2.35-2.24 (m, 6H, becomes 5H on D2O exch),
2.15-2.01 (m, 2H), 1.92 (m, 1H), 1.05 (d, J ) 7.4 Hz, 3H),
0.95 (s, 9H), 0.90 (d, J ) 6.8 Hz, 3H), 0.77 (d, J ) 6.8 Hz,
3H), 0.07 (m, 6H).
(R)-2-({(2S,3R,4R)-3-(tert-Butyldimethylsilanyloxy)-4-
[(4S,5S)-2-(4-methoxyphenyl)-5-methyl[1,3]dioxan-4-yl]-
1
2-methylpentylamino}-3-phenylpropan-1-ol (23): H NMR
(CDCl3) δ 7.44 (m, 2H), 7.33 (m, 2H), 7.27 (m, 1H), 7.22
(m, 2H), 6.89 (m, 2H), 5.44 (s, 1H), 4.10 (dd, J ) 10.9, 4.1
Hz, 1H), 3.83-3.31 (m, 6H, becomes 5H on D2O exch),
3.53 (d, J ) 8.2 Hz, 1H), 3.50-3.44 (m, 2H), 3.33 (dd, J )
14.5, 7.6 Hz, 1H), 3.13 (m, 1H), 2.72 (td, J ) 10.6, 4.0 Hz,
1H), 2.55 (td, J ) 11.2, 2.3 Hz, 1H), 2.52-2.44 (m, 2H),
2.15-2.00 (br m, 2H, becomes 1H on D2O exch), 1.80 (m,
1H), 0.96 (d, J ) 6.8 Hz, 3H), 0.89 (s, 9H), 0.72 (d, J ) 6.7
Hz, 3H), 0.63 (d, J ) 6.5 Hz, 3H), 0.00 (s, 3H), -0.04 (s,
3H).
(2R,3S,4R)-3-(tert-Butyldimethylsilanyloxy)-4-[(4S,5S)-
2-(4-methoxyphenyl)-5-methyl-[1,3]dioxin-4-yl]-2-meth-
ylpentanethioic acid S-decyl ester (17). A solution of
1-decanethiol (89.7 mg, 0.48 mmol) in THF (3 mL) was
cooled to -78 °C and treated with n-butyllithium (0.739 mL,
1.18 mmol). The solution was stirred for 5 min, and a
solution of 11 (0.3 g, 0.47 mmol) in THF (5 mL) was added
dropwise. The mixture was stirred at -78 °C for 10 min,
warmed to 0 °C, and stirred for 30 min. The reaction was
quenched by the addition of saturated aqueous ammonium
chloride solution (20 mL) and diluted with tert-butyl methyl
centrated under vacuum to give alcohol 12 (1.989 kg, 56%)
1
as an oil: [R]25 +38.6 (c ) 1, CHCl3); H NMR (CDCl3)
D
δ 7.34 (m, 2H), 6.83 (m, 2H), 5.36 (s, 1H), 4.06 (dd, J )
8.1, 4.7 Hz, 1H), 3.81 (dd, J ) 7.0, 2.4 Hz, 1H), 3.76 (s,
3H), 3.36-3.38 (m, 3H), 2.10-1.85 (m, 2H), 1.70 (br t, exch
D2O, 1H), 0.99 (d, J ) 7.0 Hz, 3H), 0.85 (s, 9H), 0.81 (d,
J ) 6.7 Hz, 3H), 0.71 (d, J ) 7.1 Hz, 3H), 0.00 (s, 3H),
-0.03 (s, 3H). The following byproducts (20-23) were also
isolated by chromatography on further elution.
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111

ether (10 mL). The organic layer was separated, washed with
water, dried over Na2SO4, and concentrated under vacuum
at 30 °C to give an oil (0.35 g). Chromatography on silica
gel gave thio ester 17 (0.188 g, 66%) as a waxy solid: 1H
NMR (CDCl3) δ 7.41 (m, 2H), 6.86 (m, 2H), 5.43 (s, 1H),
4.19 (dd, J ) 6.8, 3.6 Hz, 1H), 4.09 (dd, J ) 11.3, 4.54 Hz,
1H), 3.79 (s, 3H), 3.61 (dd, J ) 10.5, 1.9 Hz, 1H), 3.49
(pseudo t, J ) 11.0 Hz, 1H), 2.98 (qd, J ) 6.8, 3.3 Hz, 1H),
2.79 (td, J ) 7.8, 2.3 Hz, 2H), 2.02-1.90 (m, 2H), 1.51 (m,
1H), 1.36-1.20 (m, 16H), 1.12 (d, J ) 7.1 Hz, 3H), 1.01
(d, J ) 7.1 Hz, 3H), 0.89-0.87 (m, 12H), 0.71 (d, J ) 6.7
Hz, 3H), 0.00 (s, 3H), -0.04 (s, 3H).
was dissolved in a mixture of toluene (30 kg) and acetonitrile
(4.77 kg). Imidazole (1.37 kg, 20.13 mol) and triphenylphos-
phine (2.70 kg, 10.3 mol) were added, and the solution was
cooled to 10-15 °C. A solution of iodine (2.59 kg, 10.2
mol) in toluene (24.5 kg) containing acetonitrile (3.89 kg)
was added dropwise over 25 min. The mixture was warmed
to room temperature within 30 min and stirred for 3 h. A
5% aqueous solution of sodium thiosulphate (58 kg) was
added, and the reaction mixture was stirred for 10 min. The
organic phase was separated and washed sequentially with
5% aqueous sodium thiosulphate (58 kg) and brine (66 kg).
The organic phase was dried over Na2SO4 and concentrated
under vacuum at 40 °C until a final volume of 10 L was
reached. Hexane (37.4 kg) was added, and the suspension
was stirred for 10 min. The solid was filtered and rinsed
with heptane (2 × 10 kg). The combined filtrates were cooled
to 2 °C and stirred for 8 h. The solid was filtered and rinsed
with heptane (4 kg). The combined filtrates were charged
with methanol (17.4 kg) and water (5.5 kg). The resulting
two-phase system was stirred for 10 min, and the organic
phase was separated. This procedure was repeated once more.
The combined organic layers were dried over Na2SO4 and
concentrated under vacuum at 30 °C to give iodo compound
5 (3.11 kg 90%) as a light-sensitive oil. If required, this
material may be purified by chromatography on silica gel
eluting with hexane/tert-butyl methyl ether: 1H NMR
(CDCl3) δ 7.36 (m, 2H), 6.83 (m, 2H), 5.37 (s, 1H), 4.05
(dd, J ) 11.0, 4.7 Hz, 1H), 3.81 (dd, J ) 7.2, 2.1 Hz, 1H),
3.75 (s, 3H), 3.48-3.40 (m, 2H), 3.10 (dd, J ) 7.2, 2.0 Hz,
1H), 2.10-1.95 (m, 2H), 1.80 (m, 1H), 0.97 (d, J ) 7.0 Hz,
3H), 0.93 (d, J ) 6.8 Hz, 3H), 0.85 (s, 9H), 0.68 (d, J ) 6.7
Hz, 3H), 0.02 (s, 3H), 0.00 (s, 3H).
Silyl ether 16 was reduced using the same procedure as
described for the conversion of 11 to 12. The following two
compounds (18 and 19) were isolated.
(2S,3R,4R,5S,6S)-3,7-Bis-(tert-butyldimethylsilanyloxy)-
5-[3-hydroxy-1-(4-methoxyphenyl)-2-methylpropoxy]-2,4,6-
1
trimethylheptan-1-ol (18): H NMR (CDCl3) δ 7.20 (m,
2H), 6.85 (m, 2H), 4.15 (d, J ) 10 Hz, 1H), 3.85 (br m,
1H), 3.75 (s, 3H), 3.70-3.50 (m, 4H), 3.37 (dd, J ) 11.0,
8.0 Hz, 1H), 3.20 (d, J ) 6.0 Hz, 1H), 3.05-2.90 (m, 3H),
2.25-2.05 (m, 2H), 1.60 (m, 2H), 0.96 (d, J ) 7.0 Hz, 3H),
0.90 (m, 12H), 0.80 (s, 9H), 0.60 (d, J ) 6.5 Hz, 3H), 0.52
(d, J ) 6.8 Hz, 3H), 0.02 to -0.04 (m, 12H).
(R)-4-Benzyl-3-{(2R,3S,4R,5S,6S)-3,7-bis-(tert-butyl-
dimethylsilanyloxy)-5-[3-hydroxy-1-(4-methoxyphenyl)-2-
methylpropoxy]-2,4,6-trimethylheptanoly}-oxazolidin-2-
1
one (19): H NMR (CDCl3) δ 7.20 (m, 7H), 6.82 (m, 2H),
6.02 (br m, exch D2O, 1H), 4.30 (d, J ) 10 Hz, 1H), 4.20
(m, 2H), 3.85 (s, 3H), 3.80-3.30 (m, 8H), 2.90 (A part of
ABq, J ) 13.5, 3.5 Hz, 1H), 2.60 (B part of ABq, J ) 13.5,
7.9 Hz, 1H), 2.40-2.20 (m, 2H), 1.60 (m, 4H), 1.00 (d, J )
7.2 Hz, 3H), 0.95-0.75 (m, 15H), 0.70 (s, 9H), 0.58 (d, J )
6.5 Hz, 3H), 0.02 to -0.05 (m, 12H).
tert-Butyl-((1S,2R)-3-iodo-1-{(R)-1-[(4S,5S)-2-(4-meth-
oxyphenyl)-5-methyl-[1,3]dioxin-4-yl]-ethyl}-2-methylpro-
poxy)-dimethylsilane (5). Alcohol 12 (2.75 kg, 6.27 mol)
Received for review September 16, 2003.
OP034132Z
112
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