Total synthesis of 12,13-desoxyepothilone B (Epothilone D)

Article abstract of DOI:10.1016/j.bioorg.2004.11.002

A highly convergent total synthesis of 12,13-desoxyepothilone B (4, Epothilone D) is described involving the coupling of vinyl iodide (5) and olefin (6). Key steps in the synthesis are the introduction of chirality at C15 via highly enantioselective lipas

Full text of DOI:10.1016/j.bioorg.2004.11.002

Bioorganic Chemistry 33 (2005) 116–133
www.elsevier.com/locate/bioorg
Total synthesis of 12,13-desoxyepothilone B
(Epothilone D)
Robert L. Broadrupa,b,*, Hema M. Sundara,b,
Charles S. Swindella,b
a
Protarga, Inc., 2200 Renaissance Blvd., Suite 450, King of Prussia, PA 19406, USA
b
Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA 19010, USA
Received 20 September 2004
Available online 15 December 2004
Abstract
A highly convergent total synthesis of 12,13-desoxyepothilone B (4, Epothilone D) is
described involving the coupling of vinyl iodide (5) and olefin (6). Key steps in the synthesis
are the introduction of chirality at C15 via highly enantioselective lipase-mediated enzymatic
resolution, diastereoselective alkylation at C8, highly diastereoselective Evans aldol reaction to
establish C6–C7, and Mukaiyama aldol reaction to introduce chiral center C3. Palladium cat-
alyzed Suzuki coupling of (5) and (6) provided the methyl ester (27), which was converted to
12,13-desoxyepothilone B (4).
ꢀ 2004 Elsevier Inc. All rights reserved.
Keywords: Epothilone D; 12,13-desoxyepothilone B; Lipase resolution; Diastereoselective alkylation; aldol
reaction; Suzuki coupling
1. Introduction
Epothilones are macrolide natural products exhibiting potent antitumor activity
against a wide spectrum of human tumor cell lines including multi-drug resistant cell
*
Corresponding author. Fax: +1 801 757 9514.
E-mail address: organicrob@comcast.net (R.L. Broadrup).
0045-2068/$ - see front matter ꢀ 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2004.11.002

R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
117
Fig. 1. Structures of Epothilones A and B, Epothilones C and D, vinyl iodide 5, and olefin 6.
lines (Fig. 1) [1]. Hofle et al. [2] isolated epothilones from the myxobacterium Soran-
gium cellulosum. Bollag et al. [3] established that epothilones are microtubule stabi-
lizing agents, similar to the anticancer drug taxol. Since these findings numerous
syntheses have been reported on epothilones [4]. Danishefsky and co-workers [5]
demonstrated that 12,13-desoxyepothilone B (4, Epothilone D) has a more promis-
ing in vivo profile than Epothilone B. Epothilone D is currently undergoing clinical
trials [6] and is isolated only as a very minor constituent from bacterial fermentation
compared to the two major constituents, Epothilones A and B. In this paper, we de-
scribe an efficient synthesis of Epothilone D.
2. Results and discussion
Our approach to the synthesis of 12,13-desoxyepothilone B (Epothilone D) in-
volves palladium catalyzed Suzuki coupling of vinyl iodide (5) and olefin (6) followed
by macrolactonization. Synthesis of vinyl iodide (5) commenced from the known thi-
azole aldehyde (7) [7], utilizing a lipase-mediated enzymatic resolution (Scheme 1).
Aldehyde (7) was treated with propargyl bromide in the presence of activated zinc
dust in THF at room temperature to afford the racemic homopropargyl alcohol
(8). Enzymatic resolution of the racemic alcohol with Pseudomonas AK lipase at
˚
40 ꢁC for 18 h in the presence of vinyl acetate/3 A molecular sieves [8] provided
the S-homopropargyl alcohol (10) in >99% e.e. and in 80% yield along with the
R-acetate (9).
The absolute configuration at C15 in (10) was confirmed by its conversion to the
known S-homoallylic alcohol (11) via Lindlar reduction. Independently, Zhu and

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R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
Scheme 1. Synthesis of vinyl iodide (5). Reagents and conditions. (a) Propargyl bromide, activated Zn
˚
dust, THF, room temperature, 18 h, 80%; (b) Pseudomonas AK lipase, vinyl acetate, 3 A molecular sieves,
anhydrous hexanes, 40 ꢁC, 18 h, 80% yield, >99% e.e.; (c) H2/Lindlar catalyst, THF, room temperature,
1 h, 94%; and (d) TBDMS-OTf, 2,6-lutidine, CH2Cl2, 0 ꢁC.
Panek [9] reported the synthesis of (10) by a modified procedure. Silylation of (11)
using TBDMS-OTf and 2,6-lutidine provided (12), which was converted to the vinyl
iodide following the sequence of reactions reported in the literature [4d].
Synthesis of olefin (6) started from 5-benzyloxypentanoic acid (13), which was
prepared from the commercially available d-valerolactone as described in the litera-
ture [10]. Myersꢀs pseudoephedrine chiral auxiliary approach [11] was utilized to
introduce the chiral center at C8 (Scheme 2). Treatment of 5-benzyloxypentanoic
acid (13) with 1S,2S-pseudoephedrine in the presence of pivaloyl chloride and
Scheme 2. Synthesis of Weinreb amide (20). Reagents and conditions. (a) 1S,2S-pseudoephedrine, pivaloyl
chloride, Et3N, THF/CH3CN, 0 ꢁC to room temperature, 87%; (b) LDA, LiCl, CH3I, THF, À78 ꢁC to 0 ꢁC,
94%, >99% d.e.; (c) BH3 Æ NH3 complex, LDA, THF, 0 ꢁC to room temperature, 75%; (d) (COCl)2, DMSO,
Et3N, CH2Cl2, À78 ꢁC to À30 ꢁC, 84%; (e) Bu2B-OTf, Et3N, CH2Cl2, (S)-4-benzyl-3-propionyloxazolid-
inone, À78 ꢁC to 0 ꢁC, 95%, 96:4 mixture of diastereomers; (f) CH3ONHCH3 Æ HCl, Me3Al, THF, À5 ꢁC to
room temperature, 80%; and (g) TBDMS-OTf, 2,6-lutidine, CH2Cl2, 0 ꢁC, 30 min, 96%.

R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
119
triethylamine afforded the pseudoephedrine amide (14) in 87% yield. Alkylation of
(14) with methyl iodide in the presence of LDA and LiCl at À78 ꢁC furnished (15)
in 94% yield with >99% d.e. Alcohol (16) was obtained in 75% yield by the reduction
of the amide (15) with borane-ammonia complex and LDA at 0 ꢁC. After completion
of our synthesis, Altmann et al. [12] reported the synthesis of alcohol (16) utilizing
(S)-4-benzyloxazolidinone as a chiral auxiliary.
The aldol condensation approach has been used by several groups to establish the
C6–C7 bond, although only a few have described high diastereoselectivity for this
process [13]. Our strategy involved the application of Evansꢀ aldol methodology to
introduce C6–C7 with high diastereoselectivity in a highly convergent route. Thus,
Swern oxidation of (16) afforded the aldehyde (17), which was subsequently used
in an Evans aldol reaction [14] with (S)-4-benzyl-3-propionyloxazolidinone in the
presence of dibutylboron trifluoromethanesulfonate to generate C6–C7 carbon–car-
bon bond. The aldol product was isolated in 95% yield as an inseparable mixture of
diastereomers by TLC [96:4, in favor of the desired isomer (18)]. Separation of the
diastereomers was achieved by converting (18) to the corresponding Weinreb amide
via transamidation (AlMe3, MeO(Me)NH Æ HCl) [15]. The major diastereomer (19)
was isolated in 80% yield after purification by flash chromatography on silica gel
(Scheme 2).
Introduction of the chiral center at C3 was achieved by Lewis acid-mediated
Mukaiyama aldol reaction of the aldehyde (23), which was prepared from (19)
through a six-step sequence (Scheme 3). Silylation of (19) provided (20), followed
Scheme 3. Synthesis of primary alcohol (25). Reagents and conditions. (a) DIBAL-H, THF, À78 ꢁC to
À50 ꢁC, 91%; (b) Prenylmagnesium chloride, THF, room temperature, 1 h, 94%; (c) TPAP, NMO,
CH3CN:CH2Cl2 (4:1), room temperature, 2 h, 76%; (d) OsO4, NMO, THF:t-butanol:H2O (4:2:1), room
temperature, 16 h; (e) NaIO4, THF:H2O (1:1), room temperature, 6 h, 92% for 2 steps; (f) 1-t-
butyldimethylsilyloxy-1-methoxyethene, BF3 Æ Et2O, CH2Cl2, À78 ꢁC, 5 h, 97%; (g) TBDMS-OTf, 2,6-
lutidine, CH2Cl2, 0 ꢁC, 30 min, 97%; and (h) H2, Pd(OH)2 on carbon, room temperature, atm. pressure,
CH3OH, 7 h, 68%.

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Scheme 4. Synthesis of olefin (6) and epothilone D (4). Reagents and conditions. (a) 2-NO2-PhSeCN,
Bu3P, pyridine, THF, room temperature, 16 h, 96%; (b) MCPBA, CH2Cl2, À15 ꢁC (30 min), then
(iPr)2NH, room temperature, 30 min, 67%; and (c) 9-BBN, THF, room temperature, 6 h, then vinyl iodide
(5), PdCl2(dppf), Cs2CO3, Ph3As, DMF, H2O, room temperature, 15 h, 84%.
by reduction with DIBAL-H in THF provided aldehyde (21). Reaction of (21) with
prenyl magnesium chloride followed by oxidation with catalytic tetra-n-propylam-
monium perruthenate (TPAP) in the presence of N-methyl morpholine oxide [16]
afforded ketone (22) in 76% yield. Transformation to aldehyde (23) was achieved
by sequential OsO4 dihydroxylation and oxidative cleavage with NaIO4.
Condensation of the aldehyde (23) with 1-tert-butyldimethylsilyloxy-1-methoxy-
ethene in the presence of boron trifluoride etherate [17] followed by silylation of
the resulting aldol product with TBDMS-OTf and 2,6-lutidine provided the silyl
ether (24) as an inseparable 2.6:1 mixture of diastereomers at C3 (diastereomeric ra-
tio was determined by 1H NMR based on the chemical shift of the methine proton at
C3). Debenzylation of (24) afforded a mixture of primary alcohols (25) and (26),
which were easily separated by flash chromatography to furnish the desired diaste-
reomer in 68% yield (Scheme 3). Alcohol (25) was transformed into olefin (6) via sel-
enoxide elimination [18].
Hydroboration of (6) with 9-BBN and subsequent coupling of the resulting trial-
kylborane adduct with vinyl iodide (5) [19] catalyzed by PdCl2(dppf) provided the
methyl ester (27) in 84% yield. Finally, the methyl ester (27) was converted to
12,13-desoxyepothilone B (4) by a four-step sequence via Yamaguchiꢀs macrolacton-
ization as reported in the literature [4d–4f] (Scheme 4).
3. Materials and methods
3.1. General methods
All glassware was dried in the oven prior to use. All reactions were carried out
under an argon atmosphere. Precoated soft layer silica gel GF uniplates (Analtech)

R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
121
were used for TLC, and the plates were visualized with UV light or potassium per-
manganate and ammonium molybdate sprays. Silica gel, Merck, (230–400 mesh,
1
60 A, VWR Scientific) was used for flash chromatography. H (300 MHz) and 13C
˚
NMR (75 MHz) spectra were recorded in CDCl3 using a Bruker FT-NMR spec-
trometer. Chemical shifts and coupling constants are reported in ppm and Hz,
respectively.
3.2. 4-[(1E,3S)-3-Hydroxy-2-methylhex-1-en-5-ynyl]-2-methylthiazole (10)
Activated zinc dust (4.69 g, 72 mmol) was added to a solution of the aldehyde
(4.0 g, 24 mmol) in dry tetrahydrofuran (50 mL) at room temperature. Propargyl
bromide (7.1 mL, 80 wt % solution in toluene) was then added dropwise over a
period of 10 min, and the resulting suspension was stirred at room temperature
for 15 h. The reaction was quenched by the addition of 10% aq. NH4Cl solution
(25 mL) and stirred for 1 h. The reaction mixture was then filtered through a celite
pad, which was rinsed with dichloromethane (50 mL). The combined filtrate was
concentrated at reduced pressure. The resulting crude product was purified by flash
chromatography, eluting with 1:1 ethyl acetate: hexane, to furnish 3.97 g of racemic
homopropargyl alcohol 8 (80%).
To a dilute solution of the racemic homopropargyl alcohol 8 (1.42 g, 6.85 mmol)
in dry hexanes (213 mL) at room temperature was added lipase powder (Pseudomo-
˚
nas species, Amano AK, 2.84 g), followed by powdered dry molecular sieves (3 A,
1.18 g) and vinyl acetate (3.2 mL). The resulting suspension was stirred at 40 ꢁC un-
der argon overnight. The reaction mixture was diluted with dichloromethane
(100 mL) and filtered through Whatman No. 3 filter paper to remove the molecular
sieves and lipase. The filtrate was concentrated under reduced pressure to give a yel-
low oil which was purified immediately by flash chromatography, eluting with 3:7
ethyl acetate: hexane followed by 1:1 ethyl acetate: hexane, to furnish the R-acetate
9 followed by the 570 mg of S-alcohol 10 (80%, yield, >99% e.e.).
[a]D: À2.8ꢁ (c = 1.41, chloroform); (literature [9b]: À2.6, c = 0.58,
dichloromethane).
IR (of racemate 8) (Film, cmÀ1): 3281, 2916, 2112, 1508, 1430, 1193, 1154, 1034,
972, 875, 793.
1H NMR: d 2.07(s, 3 H), 2.21(t, J = 3 Hz, 1 H), 2.48–2.64 (m, 2 H), 2.71 (s, 3 H),
4.33–4.39 (m, 1 H), 6.61 (s, 1 H), 6.97 (s, 1 H).
13C NMR: d 164.99, 152.60, 140.32, 119.85, 116.08, 81.0, 75.50, 70.86, 26.18,
19.28, 14.35.
HRMS (of racemate 8) (FAB) m/z calculated for C11H13NOS (M + H)+ 208.0796.
Found 208.0802.
3.3. 4-[(1E,3S)-3-Hydroxy-2-methylhex-1,5-dienyl]-2-methylthiazole (11)
To a solution of the S-homopropargyl alcohol 10 (2.56 g, 12.3 mmol) in dry tet-
rahydrofuran (100 mL) was added Lindlar catalyst (20 wt % Pd on C, 200 mg, pur-
chased from Aldrich) and the reaction mixture was stirred under a hydrogen

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R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
atmosphere at room temperature for about 1 h. The reaction mixture was filtered
through a pad of celite, which was rinsed with dichloromethane (50 mL). The com-
bined filtrate was concentrated under reduced pressure. The crude reaction mixture
was purified by flash chromatography, eluting with 3:7 ethyl acetate: hexane, to af-
ford 2.4 g of homoallylic alcohol 11 as a yellow oil (94%).
[a]D: À19.5ꢁ (c = 1.43, chloroform); (literature [4d]: À15.9, c = 4.9, chloroform).
1H NMR: d 2.05 (s, 3 H), 2.32–2.69 (m, 2 H), 2.71 (s, 3 H), 4.19–4.28 (m, 1 H),
5.11–5.19 (m, 2 H), 5.74–5.89 (m, 1 H), 6.56 (s, 1H), 6.95 (s, 1 H).
3.4. (1S, 2S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-
N-methyl-5-benzyloxypentamide (14)
To a solution of 5-benzyloxypentanoic acid (8.6 g, 41.35 mmol) in dry acetonitrile
(170 mL) at 0 ꢁC was added triethylamine (5.76 mL, 41.35 mmol) followed by piva-
loyl chloride (5.1 mL, 41.35 mmol). Dry tetrahydrofuran (35 mL) was added to en-
able stirring of the thick white suspension. After being stirred at 0 ꢁC for 30 min, a
solution of 1S,2S-pseudoephedrine (7.5 g, 45.5 mmol) and triethylamine (6.34 mL,
45.5 mmol) in dry tetrahydrofuran (120 mL) was added rapidly via cannula. The
reaction mixture was stirred between 0 and 5 ꢁC for about 1 h, warmed to room
temperature over a period of 2 h, and then quenched by the addition of water
(50 mL). After removal of solvents under reduced pressure, the aqueous phase
was extracted with dichloromethane (3 · 150 mL). The combined organic phase
was washed with 1 N aq. HCl (150 mL), saturated aq. NaHCO3 (150 mL), brine,
dried (Na2SO4), and concentrated under reduced pressure. The crude reaction mix-
ture was purified by flash chromatography, eluting with a gradient of 3:7 ethyl ace-
tate: hexane to 8:2 ethyl acetate: hexane, to furnish 12.74 g of 14 as a thick viscous
liquid (87%).
[a]D: 78.98 (c = 2.15, chloroform).
IR (Film, cmÀ1): 3392, 2936, 2863, 1622, 1455, 1405, 1104, 1051, 737, 700.
1H NMR (mixture of rotamers): d 0.97 and 1.1 (d, J = 7 Hz, 3 H, NACHACH3,
rotamers) 1.63–1.76 (m, 4 H), 2.23–2.48 (m, 2 H), 2.78 and 2.91 (s, 3 H, NAMe rota-
mers), 3.47–3.53 (m, 2 H), 4.40–4.48 (m, 1 H) 4.5 (s, 2 H), 4.53–4.59 (m, 1 H), 7.26–
7.35 (m, 10 H).
13C NMR (mixture of rotamers): 174.4 and 173.7 (C@O), 142.05, 141.68, 138.14,
138.10, 128.06, 127.93, 127.91, 127.85, 127.53, 127.25, 127.19, 127.11, 127.05, 126.51,
126.16, 75.49, 74.72, 72.42, 69.73, 69.64, 57.86, 56.72, 33.39, 32.79, 31.64, 28.95,
28.80, 26.56, 21.67, 21.36, 15.06, 13.94.
MS: C22H29NO3, 356.3 (MH+).
3.5. (1S,2S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N,2-dimethyl-5-
benzyloxypentamide (15)
To a suspension of anhydrous LiCl (9 g, 211.2 mmol) in tetrahydrofuran (45 mL)
was added diisopropylamine (11.1 mL, 79.2 mmol), and the resulting suspension was
cooled to À78 ꢁC in a dry ice-acetone bath. A solution of n-BuLi (1.6 M in hexanes,

R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
123
45.8 mL, 73.22 mmol) was added dropwise via cannula. The resulting yellow suspen-
sion was stirred at 0 ꢁC for 10 min and then cooled to À78 ꢁC. An ice-cold solution
of amide 14 (12.5 g, 35.2 mmol) in dry tetrahydrofuran (45 mL followed by 20 mL
rinse) was added via cannula over a period of 10 min. The reaction mixture was stir-
red at À78 ꢁC for 1 h, then stirred at 0 ꢁC for 15 min, and finally stirred at room tem-
perature for 5 min before being recooled to 0 ꢁC. Methyl iodide was added, and the
reaction mixture was stirred at 0 ꢁC for 45 min. The reaction was quenched by the
addition of saturated aq. NH4Cl solution (5 mL). The reaction mixture was parti-
tioned between saturated aq. NH4Cl solution (300 mL) and ethyl acetate
(200 mL). The aqueous layer was separated and extracted with ethyl acetate
(2 · 100 mL). The combined organic layers were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The crude product was purified by flash
chromatography, eluting with 3:7 ethyl acetate:hexane followed by 1:1 ethyl acetate:
hexane to furnish 12.25 g of 15 as a thick viscous liquid (94%).
[a]D: 92.22 (c = 2.4, chloroform).
IR (Film, cmÀ1): 3391, 2936, 2864, 1615, 1455, 1409, 1103, 1050, 738, 700.
1H NMR (mixture of rotamers): d 0.96 and 1.01 (d, J = 7 Hz, 3 H, NACHACH3,
rotamers), 1.16 (d, J = 7 Hz, 3 H), 1.39–1.79 (m, 4 H), 2.59–2.68 (m, 1 H), 2.73 and
2.91 (s, 3 H, NAMe rotamers), 3.39–3.51 (m, 2 H), 4.29–4.45 (m, 1 H), 4.45 and 4.48
(s, 2 H, C6H5CH2, rotamers), 4.54–4.61 (m, 1 H), 4.8–5.29 (brs, 1 H, OH), 7.24–7.37
(m, 10 H).
13C NMR (mixture of rotamers): 177.88 and 177.14 (C@O), 142.18, 141.79,
138.07, 128.06, 127.93, 127.91, 127.75, 127.53, 127.33, 127.24, 127.17, 127.14,
127.08, 126.94, 126.49, 125.97, 125.88, 75.54, 74.72, 72.48, 72.41, 69.88, 69.73,
58.20, 57.53, 35.67, 34.88, 32.75, 30.66, 30.28, 30.11, 27.09, 26.94, 26.85, 17.22,
17.05, 15.29, 13.95.
MS: C23H31NO3, 370.3 (MH+).
3.6. 2-Methyl-5-benzyloxypentanol (16)
To a solution of lithium diisopropylamide in tetrahydrofuran (140 mL) [prepared
from diisopropylamine (19.1 mL, 136.5 mmol) and n-BuLi (1.6 M solution in hex-
anes, 79.2 mL, 126.75 mmol)] at 0 ꢁC was added BH3ÆNH3 complex (4.5 g,
130 mmol) in one portion. The resulting suspension was stirred at 0 ꢁC for 15 min,
warmed to room temperature, and stirred for 15 min. The reaction mixture was then
recooled to 0 ꢁC, and amide 15 (12 g, 32.5 mmol) in tetrahydrofuran (85 mL fol-
lowed by 20 mL rinse) was added via cannula. The reaction mixture was warmed
to room temperature, stirred for 16 h, cooled to 0 ꢁC and quenched by the addition
of 3 N aq. HCl (330 mL) and then stirred at 0 ꢁC for 30 min. The reaction mixture
was extracted with diethyl ether (3 · 160 mL), and the combined organic extracts
were washed with 3 N aq. HCl (60 mL), 2 N aq. NaOH (60 mL), followed by brine,
dried (Na2SO4), and concentrated under reduced pressure. The residue was stirred
with 1 N aq. NaOH (65 mL) for 1 h and extracted with diethyl ether (3 · 150 mL).
The combined organic phase was washed with water, brine, and dried (Na2SO4).
After evaporation of the solvent, the crude alcohol was purified by flash chromatog-

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R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
raphy, eluting with 2:8 ethyl acetate: hexane, to afford 5.1 g of the alcohol 16 as a
colorless liquid (75%).
IR (Film, cmÀ1): 3391, 2936, 2870, 1496, 1455, 1361, 1205, 1099, 1029, 737, 698.
1H NMR: d 0.93 (d, J = 6.7 Hz, 3 H), 1.1–1.3 (m, 1 H), 1.45–1.78 (m, 4 H), 3.41–
3.51 (m, 4 H), 4.51 (s, 2 H), 7.26–7.35 (m, 5 H).
13C NMR: d 138.09, 128.01 (2 C), 127.33 (2 C), 127.20, 72.54, 70.39, 67.21, 35.16,
29.25, 26.74, 16.3.
MS: C13H20O2, 209.2 (MH+).
3.7. 2-Methyl-5-benzyloxypentanal (17)
To a cold (À78 ꢁC) solution of oxalyl chloride (2.44 mL, 28 mmol) in dry dichlo-
romethane (60 mL) was added dry dimethylsulfoxide (3.98 mL, 56 mmol). After
5 min, a solution of the alcohol 16 (4.2 g, 20 mmol) in dichloromethane (10 mL)
was added via cannula, and the resulting white suspension was stirred at À78 ꢁC
for 30 min. Triethylamine (12.28 mL, 88 mmol) was then added, followed by
20 mL of dichloromethane to enable stirring of the thick suspension. After stirring
at À30 ꢁC for 40 min, the reaction mixture was diluted with pentane (300 mL).
The organic phase was washed with 1 M aq. NaHSO3 solution (2 · 100 mL) fol-
lowed by water (2 · 100 mL). The combined organic layer was dried (Na2SO4),
and the solvent was removed at reduced pressure (bath temperature 30–35 ꢁC). Puri-
fication by flash chromatography, eluting with 2:8 ethyl acetate:hexane, afforded
3.44 g of the pure aldehyde 17 (84%).
1H NMR: d 1.10 (d, J = 6.7 Hz, 3 H), 1.41–1.52 (m, 1 H), 1.61–1.71 (m, 2 H),
1.73–1.88 (m, 1 H), 2.04–2.39 (m, 1 H), 3.48 (t, J = 6 Hz, 2 H), 4.52 (s, 2 H),
7.26–7.38 (m, 5 H), 9.61 (d, J = 4 Hz, 1 H, CHO).
13C NMR: d 204.83, 138.09, 128.27 (2 C), 127.50 (2 C), 127.46, 72.82, 69.82, 45.93,
27.04 (2 C), 13.24.
3.8. 3-(2R,3S,4S)-(2,4-Dimethyl-3-hydroxy-7-benzyloxyheptanoyl)-(4S)-4-
benzyl-2-oxazolidinone (18)
To a solution of (S)-4-benzyl-3-propionyloxazolidinone (7.78 g, 33.4 mmol) in
dichloromethane (48 mL) at À78 ꢁC was added di-n-butylboron triflate (1.0 M solu-
tion in dichloromethane, 36.74 mL, 36.74 mmol) over a period of 50 min. The solution
turned orange during the addition. After completion of the addition, triethylamine
(5.6 mL, 40.08 mmol) was added over a period of 10 min. The resulting pale yellow
reaction mixture was stirred at 0 ꢁC for 45 min, recooled to À78 ꢁC, and then aldehyde
17 (3.44 g, 16.7 mmol) was added in one portion (neat, followed by 2 mL rinse with
dichloromethane). The reaction mixture was stirred at À78 ꢁC for 30 min and then
at 0 ꢁC for 2 h. The reaction was quenched by the addition of aq. phosphate buffer
(pH 7, 72 mL) followed by slow addition of 30% aq. H2O2 (7.2 mL), and the reaction
mixture was stirred at 5 ꢁC for 30 min. The aqueous phase was separated and ex-
tracted with dichloromethane (2 · 100 mL). The combined organic phase was washed
once with water (100 mL), brine, dried (Na2SO4), and concentrated under reduced

R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
125
pressure. The crude reaction mixture was purified by flash chromatography, eluting
with 2:8 ethyl acetate:hexane followed by 3:7 ethyl acetate: hexane, to afford 14 g of
the aldol product 18 as a 96:4 mixture of diastereomers (95%).
1H NMR (major diastereomer): d 0.89 (d, J = 6.8 Hz, 3 H), 1.23 (d, J = 7 Hz, 3
H), 1.49–1.86 (m, 5 H), 2.77 (dd, J = 13.4, 9.5 Hz, 1 H), 2.99 (brs, 1 H), 3.25 (dd,
J = 13.3, 3.2 Hz, 1 H), 3.43–3.54 (m, 2 H), 3.62 (dd, J = 9, 2 Hz, 1 H), 3.95 (dd,
J = 9, 3.2 Hz, 1 H), 4.15–4.27 (m, 2 H), 4.5 (s, 2 H), 4.64–4.74 (m, 1 H), 7.21–7.53
(m, 10 H).
13C NMR (major diastereomer): d 177.83, 152.82, 138.55, 135.00, 129.37 (2 C),
128.90 (2 C), 128.28 (2 C), 127.59 (2 C), 127.42, 127.36, 75.03, 72.81, 70.78, 66.08,
55.10, 39.46, 37.69, 35.46, 29.11, 26. 80, 15.36, 9.63.
3.9. (2R,3S,4S)-N-Methoxy-N-2,4-trimethyl-3-hydroxy-7-benzyloxyheptanamide
(19)
To a suspension of N,O-dimethylhydroxylamine hydrochloride (9.15 g, 93.8 mmol)
in dry tetrahydrofuran (55 mL) at À5 ꢁC was added trimethylaluminum (2.0 M solu-
tion in hexanes, 48 mL, 96 mmol) via cannula (with gas evolution during initial addi-
tion), and the resulting clear solution was stirred at room temperature for 45 min. It
was recooled to À5 ꢁC, and a solution of the aldol product 18 (13.73 g, 31.24 mmol)
in tetrahydrofuran (55 mL) was added via cannula. The reaction mixture turned clou-
dy but became clear after 15–20 min. The reaction mixture was gradually warmed to
room temperature over 16 h, cannulated into saturated aq. Rochelle salt solution
(150 mL), and stirred for 1 h. The organic layer was separated, and the aqueous phase
was extracted with dichloromethane (3 · 100 mL). The combined organic phases were
washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The
crude reaction mixture was purified by flash chromatography, eluting with 1:1 t-butyl
methyl ether:hexane to afford 8.00 g of the pure diastereomer 19 as a viscous oil (80%).
[a]D: À11.97 (c = 1.57, chloroform).
IR (Film, cmÀ1): 3460, 2937, 2872, 1651, 1456, 1386, 1101, 993, 739, 699.
1H NMR: d 0.86 (d, J = 6.8 Hz, 3 H), 1.14 (d, J = 6.3 Hz, 3 H), 1.19–1.28 (m, 1
H), 1.49–1.64 (m, 2 H), 1.72–1.87 (m, 2 H), 3.08–3.10 (m, 1 H), 3.19 (s, 3 H), 3.43–
3.53 (m, 3 H), 3.69 (s, 3 H), 3.99 (s, 1 H), 4.50 (s, 2 H), 7.24–7.34 (m, 5 H).
13C NMR: d 178.44, 138.56, 128.17 (2 C), 127.49 (2 C), 127.28, 75.21, 72.22, 70.85,
61.37, 35.45, 35.06, 31.80, 28.79, 26.84, 15.32, 9.61.
MS: C18H29NO4, 324.2 (MH+).
3.10. (2R,3S,4S)-N-Methoxy-N,2,4-trimethyl-3-(t-butyldimethylsilyoxy)-
7-benzyloxyheptanamide (20)
To a solution of Weinreb amide 19 (8.00 g, 25 mmol) in dichloromethane (60 mL)
at 0 ꢁC was added 2,6-lutidine (10.2 mL, 87.5 mmol) followed by t-butyldimethylsilyl
triflate (12 mL, 52.25 mmol), and the reaction mixture was stirred at 0 ꢁC for 30 min.
The reaction was quenched by the addition of saturated aq. NaHCO3 solution
(100 mL). The organic layer was separated, and the aqueous layer was extracted with

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R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
dichloromethane (2 · 100 mL). The combined organic layers were washed with
water, brine, dried (Na2SO4), and concentrated under reduced pressure. The crude
reaction mixture was purified by flash chromatography, eluting with 2:8 ethyl ace-
tate:hexane. The product obtained after the evaporation of solvent was taken up
in dichloromethane (45 mL) and hexane (150 mL), concentrated under reduced pres-
sure, and dried at high vacuum for 16 h to afford 10.5 g of the silyl ether 20 as a col-
orless liquid (96%).
IR (Film, cmÀ1): 2935, 2857, 1652, 1463, 1385, 1257, 1053, 997, 837, 775, 698.
1H NMR: d À0.06 (s, 3 H), À0.58 (s, 3 H), 0.85 (s, 9 H), 0.88 (d, J = 6.8 Hz, 3 H),
1.07 (d, J = 6.9 Hz, 3 H), 0.91–1.08 (m, 1 H), 1.35–1.67 (m, 4 H), 3.06 (s, 3 H), 3.02–
3.06 (m, 1 H), 3.37 (5, J = 6.5 Hz, 2 H), 3.57 (s, 3 H), 3.81 (dd, J = 8.2, 2 Hz, 1 H),
4.42 (s, 2 H), 7.19–7.28 (m, 5 H).
13C NMR: 176.81, 138.35, 127.92 (2 C), 127.19 (2 C), 127.05, 76.33, 72.45, 70.47,
60.97, 38.43, 37.76, 31.90, 27.77, 27.59, 25.79 (3 C), 18.02, 16.00, 15.26, À4.21,
À4.28.
MS: C24H43NO4Si, 438.4 (MH+).
3.11. (2R,3S,4S)]-2,4-Dimethyl-3-(t-butyldimethylsilyoxy)-7- benzyloxyheptanal
(21)
To a cold solution (À78 ꢁC) of the silylated Weinreb amide 20 (10.4 g, 24 mmol) in
tetrahydrofuran (90 mL) was added di-iso-butylaluminumhydride (1.0 M solution in
toluene, 50 mL, 50 mmol) over a period of 30 min. The reaction mixture was stirred for
30 min at À78 ꢁC after the completion of addition and then warmed to À50 ꢁC over a
period of 30 min. Excess di-iso-butylaluminumhydride was quenched by the addition
of methanol (1.5 mL, 37 mmol) at À78 ꢁC, and the reaction mixture was then stirred
for 30 min. The reaction mixture was cannulated into a saturated aq. Rochelle salt
solution (250 mL). Dichloromethane (100 mL) was added and the mixture was stirred
at room temperature for 30 min. The organic phase was separated, and the aqueous
phase was extracted with dichloromethane (2 · 100 mL). The combined organic phase
was washed with brine, dried (Na2SO4), and concentrated under reduced pressure
(bath temperature 30–35 ꢁC). The crude aldehyde was purified on a short silica gel
column, eluting with 2:8 ethyl acetate:hexane, to provide 8.1 g of aldehyde 21 (91%).
1H NMR: d 0.0 (s, 3 H), 0.06 (s, 3 H), 0.87 (s, 9 H), 0.92 (d, J = 7 Hz, 3 H), 1.1 (d,
J = 7 Hz, 3 H), 1.09–1.16 (m, 1 H), 1.46–1.78 (m, 4 H), 2.36–2.52 (m, 1 H), 3.45 (t,
J = 6.5 Hz, 2 H), 4.00 (dd, J = 5.5, 3.6 Hz, 1 H), 4.5 (s, 2 H), 7.26 - 7.38 (m, 5 H),
9.72 (d, J = 1 Hz, 1 H).
13C NMR: 205.06, 138.47, 128.26 (2 C), 127.55 (2 C), 127.42, 74.80, 72.87, 70.46,
49.80, 37.94, 29.02, 27.66, 25.85 (3 C), 18.16, 15.79, 8.59, À4.25 (2 C).
3.12. (5R,6S,7S-)-3,3,5,7-Tetramethyl-6-(t-butyl)dimethylsilyloxy-
10-benzyloxy-dec-1-ene-4-one (22)
To a cold solution (0 ꢁC) of aldehyde 21 (8 g, 21.34 mmol) in THF (40 mL) was
added dropwise a solution (0.78 M, 45 mL, 35 mmol) of prenylmagnesium chloride

R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
127
[prepared from prenyl chloride (5.65 mL, 50 mmol) and Mg turnings (3.65 g,
150 mmol mmol) in tetrahydrofuran (64 mL)], and the reaction mixture was stirred
at room temperature for 1 h and quenched by the addition of saturated aq. NH4Cl
solution (40 mL). The residue obtained after evaporation of the solvent under re-
duced pressure was extracted with dichloromethane (2 · 100 mL). The combined or-
ganic phase was washed with brine, dried (Na2SO4), and concentrated under reduced
pressure. Purification by flash chromatography, eluting with 2:98 ethyl acetate:hex-
ane followed by 5:95 ethyl acetate:hexane, afforded 9.00 g of the alcohol as a mixture
of diastereomers (94%).
To a solution of the diastereomeric mixture of alcohols (9.00 g, 20 mmol) in
˚
dichloromethane:acetonitrile (4:1, 45 mL) were added powdered 4 A molecular
sieves (10 g) and anhydrous N-methylmorpholine-N-oxide (4.7 g, 40 mmol), fol-
lowed by tetra-n-propylammonium perruthenate (705 mg, 2 mmol). The resulting
dark colored suspension was stirred at room temperature for 2 h, followed by solvent
removal under reduced pressure. The residue was purified by flash chromatography,
using a column with a small quantity of celite on top, eluting with 2:98 t-butyl methyl
ether:hexane followed by 5:95 ethyl acetate:hexane, to afford 6.8 g of ketone 22
(76%) as a pale yellow liquid.
IR (Film, cmÀ1): 2932, 2857, 1703, 1634, 1463, 1362, 1256, 1114, 987, 877, 837,
775, 735, 697.
1H NMR: d 0.0 (s, 6 H), 0.84 (s, 9 H), 0.85 (d, J = 5.6 Hz, 3 H), 0.97 (d, J = 7 Hz,
3 H), 1.01–1.11 (m, 1 H), 1.14 (s, 3 H), 1.17 (s, 3 H), 1.2–1.43 (m, 3 H), 1.58–1.68 (m,
1 H), 3.08 (quintet, J = 7 Hz, 1 H), 3.38 (t, J = 6.4 Hz, 2 H), 3.75 (dd, J = 8, 2 Hz, 1
H), 4.44 (s, 2 H), 5.07 (dd, 2 H), 5.87 (dd, J = 17, 11 Hz, 1 H), 7.19–7.29 (m, 5 H).
13C NMR: d 216.15, 142.31, 138.56, 128.21 (2 C), 127.44 (2 C), 127.35, 114.21,
76.99, 72.75, 70.76, 51.35, 44.36, 38.63, 27.95, 27.26, 26.13 (3 C), 23.95, 23.72,
18.39, 17.26, 16.67, À3.79, À3.82.
3.13. (5R,6S,7S-)-2,2,4,6-tetramethyl-5-(t-butyl)dimethylsilyloxy-9-
benzyloxynonanal (23)
To a solution of ketone 22 (6.8 g, 15.22 mmol) in a mixture of tetrahydrofuran
(24 mL) and t-butanol (12 mL) was added water (6 mL), followed by N-meth-
ylmorpholine-N-oxide (2.2 g, 18.78 mmol) and osmium tetroxide (2.5 wt % solu-
tion in t-butanol, 8 mL, 0.787 mmol). The resulting yellow solution was stirred
at room temperature for 16 h. The reaction was quenched by the addition of
Na2SO3 (8.35 g) followed by water (150 mL), and the resulting dark reaction mix-
ture was stirred at room temperature for 45 min. The organic layer was separated,
and the aqueous phase was extracted with ethyl acetate (2 · 100 mL). The com-
bined organic phase was washed once with water followed by brine, dried
(Na2SO4), and concentrated under reduced pressure. The residue was purified
by flash chromatography, eluting with 2:8 ethyl acetate:hexane followed by 1:1
ethyl acetate:hexane. The diol was isolated as a thick viscous liquid slightly con-
taminated with t-butanol and was used for the next reaction without further
purification.

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To a solution of the diol in tetrahydrofuran (75 mL), NaIO4 (5 g, 23.38 mmol)
was added in one portion followed by water (75 mL), and the resulting colorless slur-
ry was stirred at room temperature for 6 h. The reaction mixture was diluted with
dichloromethane (100 mL). The organic layer was separated, and the aqueous phase
was extracted with dichloromethane (2 · 100 mL). The combined organic layer was
washed with water, brine, dried (Na2SO4), and concentrated under reduced pressure.
The residue was purified by flash chromatography, eluting with 2:8 ethyl acetate:hex-
ane, to afford 6.29 g of the aldehyde 23 (92% for 2 steps).
1H NMR: d 0.05 (s, 3 H), 0.06 (s, 3 H), 0.89 (s, 9 H), 0.91 (d, J = 7 Hz, 3 H), 1.02
(d, J = 7.3 Hz, 3 H), 1.01–1.25 (m, 1 H), 1.32 (s, 3 H), 1.33 (s, 3 H), 1.25–1.53 (m, 2
H), 1.65–1.74 (m, 2 H), 3.05 (quintet, J = 7 Hz, 1 H), 3.45 (t, J = 7.6 Hz, 2 H), 3.86
(dd, J = 7.6, 2.6 Hz, 1 H), 4.49 (s, 2 H), 7.22–7.35 (m, 5 H), 9.59 (s, 1 H).
13C NMR: d 212.29, 200.54, 138.53, 128.19 (2 C), 127.46 (2 C), 127.34, 76.35,
72.76, 70.49, 60.97, 45.31, 38.96, 27.88 (2 C), 26.03 (3 C), 19.83, 19.72, 18.31,
16.61, 15.38, À3.97 (2 C).
3.14. Methyl(3R,6R,7S,8S)-3,7-di-(t-butyldimethylsilyloxy)-4,4,6,8-
tetramethyl-5-oxo-11-benzyloxyundecanoate and methyl (3S,6R,7S,8S)-3,7-di-
(t-butyldimethylsilyloxy)-4,4,6,8-tetramethyl-5-oxo- 11-benzyloxyundecanoate (24)
To a solution of aldehyde 23 (6.3 g, 14.1 mmol) in dry dichloromethane at À78 ꢁC
was added BF3 Æ Et2O (1.8 mL, 14.2 mmol), and the reaction mixture was stirred for
5 min. The silyl ketene acetal, 1-t-butyldimethylsilyloxy-1-methoxyethene (3.2 g,
16.9 mmol), was added, and the reaction mixture was stirred at À78 ꢁC for 5 h.
The reaction was quenched by the addition of aq. phosphate buffer (pH 7) and ex-
tracted with dichloromethane (3 · 100 mL). The combined organic phase was
washed once with water, brine, dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by flash chromatography, eluting with 95:5 ethyl
acetate:hexane followed by 2:8 ethyl acetate:hexane to afford 7.1 g of the aldol prod-
uct (97%) as a mixture of diastereomers (2.6:1) epimeric at C-3.
To a solution of the above aldol product (7.1 g, 13.62 mmol) in dichloromethane
(55 mL) at 0 ꢁC was added 2,6-lutidine (6 mL, 51.5 mmol) followed by t-butyldim-
ethylsilyl triflate (6.5 mL, 28.3 mmol), and the reaction mixture was stirred at 0 ꢁC
for 30 min. The reaction was quenched by the addition of saturated aq. NaHCO3
solution (50 mL), and the reaction mixture was then filtered through celite to clarify
the thick emulsion. The organic layer was separated, and the aqueous layer was ex-
tracted with dichloromethane (2 · 100 mL). The combined organic phase was
washed with water, brine, dried (Na2SO4), and concentrated under reduced pressure.
The residue was taken up in dichloromethane (15 mL) and hexane (50 mL), and con-
centrated under reduced pressure to remove 2,6-lutidine. This residue was purified by
flash chromatography, eluting with 5:95 ethyl acetate:hexane, and the resulting puri-
fied material was dried under high vacuum for 16 h to afford 8.4 g of silyl ether 24
(mixture of diastereomers epimeric at C-3, 2.6:1) as a colorless liquid (97%).
IR (Film, cmÀ1): 2931, 2857, 1744, 1695, 1472, 1361, 1256, 1097, 988, 837, 776,
734, 698.

R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
129
1H NMR (major diastereomer): d 0.01 (s, 3 H), 0.06 (s, 3 H), 0.07 (s, 3 H), 0.09 (s,
3 H), 0.87 (s, 9 H), 0.91 (s, 9H). 0.90 (d, J = 6.8 Hz, 3 H), 1.05 (d, J = 6.8 Hz, 3 H),
1.08 (s, 3 H), 1.23 (s, 3 H), 1.26–1.45 (m, 4 H), 1.58–1.78 ( m, 1 H), 2.22 (dd, J = 16,
7.1 Hz, 1 H), 2.36 (dd, J = 16, 3 Hz, 1 H), 3.09 (quintet, J = 7 Hz, 1 H), 3.42 ( t, 2
H), 3.61 (s, 3 H), 3.74 (dd, J = 7.5, 1.8 Hz, 1 H), 4.35 (dd, J = 7, 3 Hz, 1 H), 4.44
(s, 2 H), 7.22–7.5 (m, 5 H).
3.15. Methyl(3S,6R,7S,8S)-3,7-di-(t-butyldimethylsilyloxy)-4,4,6,8-
tetramethyl-5-oxo-11-hydroxyundecanoate (25)
To a solution of silyl ether 24 (3 g, 4.7 mmol) in methanol (15 mL) was added Pearl-
manꢀs catalyst (10% Pd(OH)2 on carbon, 500 mg, purchased from Aldrich), and the
reaction mixture was stirred at room temperature under a hydrogen atmosphere
maintained with a balloon for 7 h. The reaction mixture was filtered through celite,
and the celite pad was washed with ethyl acetate (3 · 60 mL). The combined ethyl ace-
tate filtrate was concentrated under reduced pressure. The crude reaction mixture was
purified by flash chromatography, eluting first with 5:95 ethyl acetate:hexane followed
by 1:9 ethyl acetate:hexane, to afford 1.75 g of the major diastereomer 25 (68%).
IR (Film, cmÀ1): 3445, 2955, 2858, 1745, 1695, 1473, 1373, 1257, 1090, 989, 837,
776, 670.
1H NMR: d À0.05 (s, 3 H), 0.00 (s, 6 H), 0.04 (s, 3 H), 0.81 (s, 9 H), 0.84 (s, 9 H),
0.87 (d, J = 6.8 Hz, 3 H), 0.99 (d, J = 6.9 Hz, 3 H), 1.03 (s, 3 H), 1.16 (s, 3 H), 1.19–
1.66 (m, 6 H), 2.22 (dd, J = 16, 7.1 Hz, 1 H), 2.36 (dd, J = 16, 3 Hz, 1 H), 3.09 (quin-
tet, J = 7 Hz, 1 H), 3.57 (t, J = 6.6 Hz, 2 H), 3.61 (s, 2 H), 3.73 (dd, J = 7.3, 2 Hz, 1
H), 4.34 (dd, J = 7, 3 Hz, 1 H).
13C NMR: d 218.53, 172.91, 77.95, 73.94, 63.61, 53.89, 52.03, 45.51, 40.51, 38.87,
31.35, 27.19, 26.58 (3 C), 26.34 (3 C), 24.08, 19.38, 18.86, 18.56, 18.04, 16.10, À3.29,
À3.39, À4.12, À4.24.
HRMS (FAB) m/z calculated for C28H58O6Si2 (M + H)+ 547.3850. Found
547.3849.
Elution of the column with 1:1 ethyl acetate:hexane afforded 670 mg of the minor
diastereomer 26 (26%).
1H NMR: d À0.04 (s, 3 H), À0.01 (s, 3 H), 0.00 (s, 6 H), 0.78 (s, 9 H), 0.83 (s, 9 H),
0.87 (d, J = 6.8 Hz, 3 H), 0.98 (d, J = 7 Hz, 3 H), 1.01–1.1 (m, 4 H), 1.14 (s, 3 H),
1.17–1.65 (m, 5 H), 2.24 (dd, J = 16, 6.7 Hz, 1 H), 2.33 (dd, J = 16, 3.8 Hz, 1 H),
3.07 (quintet, J = 7 Hz, 1 H), 3.55 (t, J = 6.6 Hz, 2 H), 3.61 (s, 2 H), 3.75 (dd,
J = 7.3 Hz, 1.8 Hz, 1 H), 4.48 (dd, J = 6.7 Hz, 3.8 Hz, 1 H).
3.16. Methyl (3S,6R,7S,8S)-3,7-bis [(t-butyl) dimethylsilyloxy]-4,4,6,8-tetramethyl-
5-oxoundec-11-enoate (6)
To a solution of alcohol 25 (4.2 g, 7.68 mmol) in dry tetrahydrofuran (12 mL) and
pyridine (4 mL) was added o-nitrophenyl selenocyanate (4.36 g, 19.2 mmol), fol-
lowed by tri-n-butylphosphine (4.8 mL, 19.3 mmol), and the resulting dark red sus-
pension was stirred under argon at room temperature in the dark for 16 h. Solvent

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R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
was removed under reduced pressure, and the residue was purified by flash chroma-
tography, eluting with 5:95 ethyl acetate:hexane followed by 1:9 ethyl acetate:hex-
ane, to afford 5.4 g of the selenide as a yellow viscous liquid (96%).
To a solution of the selenide (5.4 g, 7.4 mmol) in dichloromethane (15 mL) at
À15 ꢁC was added m-chlorobenzoic acid (57–86%, 2.7 g) in one portion. The reac-
tion mixture became a red suspension, which was stirred at À15 ꢁC for 30 min. Diiso-
propylamine (2.2 mL, 15.7 mmol) was added, and the resulting dark red solution was
warmed to room temperature and stirred for 30 min. Water was added followed by
saturated aq. NaHCO3, and the reaction mixture was extracted with ethyl acetate
(3 · 100 mL). The combined organic phase was washed with saturated aq. NaHCO3,
followed by brine, dried (Na2SO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography, eluting with 2:98 ethyl acetate:hexane
followed by 5:95 ethyl acetate:hexane, to afford 2.6 g of olefin 6 as a yellow oil (67%).
IR (Film, cmÀ1): 2956, 2858, 1747, 1695, 1641, 1472, 1297, 1256, 1091, 989, 837,
776, 668.
1H NMR: d 0.01 (s, 3 H), 0.06 (s, 3 H), 0.07 (s, 3 H), 0.09 (s, 3 H), 0.87 (s, 9 H),
0.89 (d, J = 6 Hz, 3 H), 0.91 (s, 9 H), 1.05 (d, J = 7 Hz, 3 H), 1.08 (s, 3 H), 1.23 (s, 3
H), 1.35 - 1.45 (m, 1 H), 1.79–1.90 (m, 1 H), 2.27 (dd overlapped with a multiplet,
J = 16, 7 Hz, 2 H), 2.42 (dd, J = 16, 3 Hz, 1 H), 3.16 (quintet, J = 7 Hz, 1 H),
3.67 (s, 3 H), 3.82 (dd, J = 8, 1.8 Hz, 1 H), 4.41 (dd, J = 7, 3.2 Hz, 1 H), 4.97–
5.03 (m, 2 H), 5.66–5.79 (m, 1 H).
13C NMR: d 217.98, 172.37, 137.76, 115.68, 77.65, 73.66, 53.50, 51.59, 45.62,
40.19, 38.00, 35.16, 26.24 (6 C), 25.96 (3 C), 23.68, 19.11, 18.54, 18.18, 18.00,
15.72, À3.53, À3.66, À4.51, À4.63.
3.17. Methyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tri-(t-butyldimethylsilyloxy)-
4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-5-yl)-5-oxoheptadeca-12,16 dienoate
(27)
To a solution of olefin 6 (2.5 g, 4.73 mmol) in dry tetrahydrofuran under argon
was added a solution of 9-borabicyclo[3.3.1]nonane (0.4 M solution in tetrahydrofu-
ran, 24 mL, 9.6 mmol), and the reaction mixture was stirred at room temperature for
6 h. In a separate flask, cesium carbonate (3.1 g, 9.5 mmol) was added to a solution
of the vinyl iodide (5, 2.85 g, 6.15 mmol) in dry dimethylformamide under vigorous
stirring, followed by triphenylarsine (156 mg, 0.51 mmol), PdCl2(dppf) (416 mg,
0.51 mmol), and water. To this flask was added the borane solution via cannula.
The orange reaction mixture turned dark brown for a brief period and then to pale
yellow over several hours. The reaction mixture was stirred at room temperature for
14 h, poured into water, and the aqueous phase was extracted with diethyl ether. The
combined ether layer was washed with water followed by brine, dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by flash chromatog-
raphy, eluting with 5:95 ethyl acetate:hexane, to afford 4.25 g of the ester 27 as
yellow oil (84%).
IR (Film, cmÀ1): 2931, 2858, 1744, 1695, 1472, 1361, 1256, 1084, 989, 837, 776,
669.

R.L. Broadrup et al. / Bioorganic Chemistry 33 (2005) 116–133
131
1H NMR: d À0.05 (s, 6H), À0.04 (s, 3 H), À0.01 (s, 3H), 0.00 (s, 3H), 0.04 (s, 3 H),
0.84 (d, J = 6 Hz, 3 H), 0.84 (s, 9 H), 0.83 (s, 9 H), 0.81 (s, 9 H), 0.98 (d, J = 6.8 Hz, 3
H), 1.01 (s, 3 H), 1.04–1.39 (m, 6 H), 1.17 (s, 3 H), 1.57 (s, 3 H), 1.94 (singlet over-
lapped with a multiplet, 4 H), 2.21 (dd, J = 16, 7 Hz, overlapped with a multiplet, 3
H), 2.37 (dd, J = 16, 3 Hz, 1 H), 2.66 (s, 3 H), 3.08 (quintet, J = 7 Hz, 1 H), 3.62 (s, 3
H), 3.71 (dd, J = 7, 1.7 Hz, 1 H), 4.03 (t, J = 6.6 Hz, 1 H), 4.34 (dd, J = 7, 3 Hz, 1
H), 5.08 (t, J = 6 Hz, 1 H), 6.40 (s, 1 H), 6.86 (s, 1 H).
13C NMR: d 217.9, 173.5, 164.0, 153.5, 142.8, 136.8, 121.1, 118.6, 114.9, 78.6,
76.8, 73.5, 53.5, 51.2, 45.1, 40.1, 38.9, 35.5, 32.4, 30.9, 26.1 (3 C), 25.9 (3 C), 25.2
(3 C), 23.2, 19.1, 19.2, 18.2, 18.3, 18.0, 16.1, 14.5, À3.2, À4.1, À4.5.
HRMS (FAB) m/z calculated for C46H87NO6SSi3 (M + H)+ 866.5640. Found
866.5628.
Acknowledgment
R.L.B. and H.M.S. would like to thank Protarga, Inc. for generous financial
support.
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