Efficient asymmetric synthesis of the C'9-C21 portion of the aplysiatoxin and oscillatoxin marine natural products

Full text of DOI:10.1021/jo981370x

J . Org. Chem. 1998, 63, 9113-9116
9113
As indicated in Scheme 1, (S)-methyl 3-hydroxy-2-
methylpropanoate was O-protected with the para-meth-
oxybenzyl (PMB) group6 and then reduced to the alde-
hyde 10,7 which was allowed to react with the Evans
enolate 118 to yield the aldol 12. It is important to note
that the phenylpropanolamine-derived oxazolidinone in
11 was best suited for this asymmetric aldol reaction,
compared to other oxazolidinone chiral auxiliaries, be-
cause the aldol product 12 could be isolated as a single
stereoisomer from the crude product mixture by crystal-
lization. In earlier studies,5b using acetal derivatives of
12, we demonstrated that the aldol product 12 did indeed
possess the desired 11S,12R (aplysiatoxin-oscillatoxin
numbering system) configuration at the newly introduced
stereogenic carbon centers.
Protection of the 11-hydroxyl group of 12 as the
triethylsilyl (TES) ether 13 and subsequent reductive
removal of the oxazolidinone9 yielded the alcohol 14,
which was smoothly converted to the iodide 15 using
Corey’s conditions.10 The C13 iodide in 15 was cleanly
displaced by the lithioenamine 16, derived from the
N-cyclohexylimine deriative of 3-(trimethylsilylethoxy-
methoxy)-acetophenone,11 yielding (after aqueous hy-
drolysis of the imine group) the ketone 17. Corey’s
asymmetric oxazaborolidine-catalyzed reduction12 of the
15-keto group of 17 produced the alcohol 19 as a single
stereoisomer, which we demonstrated earlier,5b using CD
spectroscopy, to be the desired 15S epimer. O-Methyla-
tion of the 15-hydroxyl group of 19 yielded the tripro-
tected product 20, and oxidative cleavage of the PMB
Efficien t Asym m etr ic Syn th esis of th e
C9-C21 P or tion of th e Ap lysia toxin a n d
Oscilla toxin Ma r in e Na tu r a l P r od u cts
Robert D. Walkup,*,1 J effrey D. Kahl, and
Robert R. Kane
Department of Chemistry and Biochemistry, Texas Tech
University, Lubbock, Texas 79409-1061
Received J uly 14, 1998
Metabolites of tropical marine bluegreen algae of the
class oscillatoriaeceae, the toxic aplysiatoxin, oscillatoxin
A, and their brominated variants (1-6) are significant
tumor promotors,2,3 whereas the nontoxic oscillatoxin D
(7) and 30-methyloscillatoxin D (8) possess antileukemic
activity.4,5 Because of their biological activities and
because they cannot be produced by fermentation of the
algae that produce them, these natural products have
been the goal of a number of synthetic studies.3,5 As part
of our synthetic efforts aimed at producing oscillatoxin
D,5a-c we have perfected a short (10 steps from com-
mercially available starting materials) and efficient (26%
overall yield) preparation of a selectively protected C9-
C21 portion of the aplysiatoxins and oscillatoxins, com-
pound 9, which can serve as an advanced intermediate
for the total synthesis of any one of the natural products
1-8. In this note, we describe the full details of our
synthesis of 9, using a route which is an improvement
over a similar route described in a preliminary report.5b
(1) Current address for all correspondence concerning this re-
search: Shallowater MedChem, 7117 Hwy 84, Shallowater, TX 79363.
(2) (a) Moore, R. E. Pure Appl. Chem. 1982, 54, 1919; (b) Moore, R.
E.; Blackman, A. J .; Cheuk, C. E.; Mynderse, J . S.; Matsumoto, G. K.;
Clardy, J . Woodard, R. W.; Craig, J . C. J . Org. Chem. 1984, 49, 2484.
(c) Fujiki, H.; Sugimura, T.; Moore, R. E. Environ. Health Perspect.
1983, 50, 85. (d) Fujiki, H.; Tanaka, Y.; Miyake, R.; Kikkawa, U.;
Nishizuka, Y.; Sugimura, T. Biochem. Biophys. Res. Commun. 1984,
120, 339. (e) Arcoleo, J . P.; Weinstein, I. B. Carcinogenesis 1985, 6,
213.
(3) (a) Park, P.-U.; Broka, C. A.; J ohnson, B. F.; Kishi, Y. J . Am.
Chem. Soc. 1987, 109, 6205. (b) Ireland, R. E.; Thaisrivongs, S.;
Dussault, P. H. J . Am. Chem. Soc. 1988, 110, 5768. (c) Toshima, H.;
Yoshida, S.-i.; Suzuki, T.; Nishiyama, S.; Yamamura, S. Tetrahedron
Lett. 1989, 30, 6721. (d) Toshima, H.; Suzuki, T.; Nishiyama, S.;
Yamamura, S. Tetrahedron Lett. 1989, 30, 6725.
(4) Entzeroth, M.; Blackman, A. J .; Mynderse, J . S.; Moore, R. E. J .
Org. Chem. 1985, 50, 1255.
(5) (a) Walkup, R. D.; Cunningham, R. T. Tetrahedron Lett. 1987,
28, 4019. (b) Walkup, R. D.; Kane, R. R.; Boatman, P. D., J r.;
Cunningham, R. T. Tetrahedron Lett. 1990, 31, 7587. (c) Walkup, R.
D.; Boatman, P. D., J r.; Kane, R. R.; Cunningham, R. T. Tetrahedron
Lett. 1991, 32, 3937. (d) Toshima, H.; Goto, T.; Ichihara, A. Tetrahedron
Lett. 1994, 35, 4361. (e) Toshima, H.; Goto, T.; Ichihara, A. Tetrahedron
Lett. 1995, 65, 3373.
(6) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 4139.
(7) Corey, E. J .; Nicolaou, K. C.; Toru, J . J . J . Am. Chem. Soc. 1975,
97, 2287.
(8) Evans, D. A. Aldrichimica Acta 1982, 15, 23. The procedure for
producing the diethylboron triflate precursor to the boron enolate 11
in situ, which produced optimum yields and stereoselectivity of the
aldol product 12, came from Oppolzer, W.; Blagg, J .; Rodriguez, I.;
Walther, E. J . Am. Chem. Soc. 1990, 112, 2767.
(9) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Towell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307.
(10) Corey, E. J .; Pyne, S. G.; Su, W. Tetrahedron Lett. 1983, 24,
4883.
(11) Whitesell, J . W.; Whitesell, M. A. Synthesis 1983, 517.
(12) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V.
K. J . Am. Chem. Soc. 1987, 109, 7925.
10.1021/jo981370x CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/06/1998

9114 J . Org. Chem., Vol. 63, No. 24, 1998
Notes
solutions in a 10-cm cell. Elemental analyses were conducted
by Desert Analytics, Tucson, Arizona. High-resolution mass
spectrometric analyses were conducted by the Midwest Center
for Mass Spectrometry, Department of Chemistry, University
of Nebraska-Lincoln. All solvents were predistilled using
methods described by Perrin and Armarego14 and stored over
oven-dried 4A molecular sieves.
Sch em e 1
(S)-3-(4′-Meth oxyph en yl)m eth oxy-2-m eth ylpr opan al (10).
To a stirring mixture of 17.03 g (123.29 mmol) of 4-methoxy-
benzyl alcohol in 150 mL of ether at room temperature under
nitrogen was added 0.46 g of a 60% dispersion of sodium hydride
in mineral oil (∼11.63 mmol of NaH). The resulting suspension
was allowed to stir until the solid had dissolved and gas
evolution had ceased (approximately 1 h). Then, the mixture
was cooled to 0 °C, and 12.36 mL (123.30 mmol) of trichloroac-
etonitrile was added over 15 min. The mixture was stirred at 0
°C for another 5 min and at room temperature for 20 min. It
was then transferred to a separatory funnel, washed with
saturated sodium bicarbonate and brine, dried (MgSO4), and
concentrated to yield the crude 4-methoxybenzyl trichloroace-
timidate as a yellow oil. That oil was stirred in 150 mL of
dichloromethane with 9.07 mL (82.20 mmol) of (S)-methyl
3-hydroxy-2-methylpropanoate and 0.90 g (3.59 mmol) of pyri-
dinium p-toluenesulfonate at room temperature for 22 h (a white
solid forms during the reaction). The reaction mixture was then
washed with saturated sodium bicarbonate and brine, dried
(MgSO4), and concentrated under vacuum. The resulting semi-
solid mixture was triturated with 1:1 hexanes/dichloromethane,
and the triturant solution was concentrated to an oil, which was
distilled under 0.07 mmHg vacuum, with collection of pure (S)-
m eth yl 3-(4′-m eth oxyph en yl)m eth oxy-2-m eth ylpr opan oate
as the fraction distilling at 98-110 °C in a yield of 13.10 g
(67%): 1H NMR δ 7.24 (d, J ) 8.7, 2H), 6.87 (d, J ) 8.7, 2H),
4.45 (s, 3H), 3.80 (s, 3H), 3.69 (s, 3H), 3.63 (d of d, J ) 9.2, 7.4,
1H), 3.45 (d of d, J ) 9.2, 5.9, 1H), 2.77 (m, 1H), 1.17 (d, J )
7.1, 3H); 13C NMR δ 159.2, 129.4, 129.2, 113.8, 72.8, 71.7, 71.5,
55.3, 51.7, 40.2, 14.0; [R]25D +9.67° (c 8.38, CHCl3). Anal. Calcd
for C13H18O4: C, 65.52; H, 7.61. Found: C, 65.34; H, 7.45.
To a stirring solution of 3.00 g (12.58 mmol) of the ester in
125 mL of dry dichloromethane, at -78 °C under nitrogen was
added diisobutylaluminum hydride (10.49 mL of a 1.5 M solution
in toluene, 15.7 mmol) dropwise over 2 h. The solution was
stirred for an additional hour at -78 °C and 3 mL of anhydrous
methanol was added dropwise. The mixture was warmed to
room temperature, diluted with 100 mL of ether, mixed carefully
with 2 mL of water, and then stirred for 15 min. The milky
suspension was then filtered through a 3-cm pad of Celite, and
the filtrate was concentrated under vacuum to yield 2.69 g
(>100%) of a clear liquid. NMR analysis of this crude product
indicated that it was ∼95% pure aldehyde 10. Due to concerns
about the tendency of this aldehyde to undergo self-condensation
reactions and to epimerize during purification procedures, the
crude material was carried on to the next step without further
purification: 1H NMR δ 9.71 (d, J ) 1.5, 1H), 7.24 (d, J ) 8.6,
2H), 6.88 (d, J ) 8.6, 2H), 4.45 (s, 2H), 3.80 (s, 3H), 3.63 (m,
2H), 2.65 (m, 1H), 1.08 (d, J ) 6.1, 3H); 13C NMR δ 204.0, 159.2,
ether group in 20, under conditions which did not affect
the benzylic ether group at C15, produced the C9-C21
building block, 9, for the aplysiatoxin and oscillatoxin
natural products.
In summary, a concise synthesis of an advanced
intermediate for the preparation of an entire class of
natural products, using methodology amenable for large
scale preparation, is reported. The choice of protecting
groups is worth noting; we have found, for instance, that
the TES ether group at C11 can be cleanly removed
without affecting the SEM ether group at C20.13 Syn-
thetic studies using the intermediate 9 will be the
objective of future research.
130.0, 129.2, 113.8, 73.0, 69.7, 55.2, 46.8, 10.7; [R]25 +29.4° (c
D
9.06, CH2Cl2).
(2′R,3′S,4′S,4R,5S)-3-(3′-Hyd r oxy-5′-[4′′-m eth oxyp h en yl]-
m eth oxy-2′,4′-d im eth ylp en ta n oyl)-5-p h en yl-4-m eth yl-2-ox-
a zolid in on e (12). To a 100-mL round-bottomed flask contain-
ing 4.7 mL of a 1.0 M solution of triethylborane in hexanes (3.9
mmol) at 0 °C under nitrogen was added dropwise 0.41 mL (3.9
mmol) of trifluoromethanesulfonic acid. The solution was
warmed using a 40 °C oil bath, with stirring, for 30 min (gas
evolution ceased at that time). The solution was then cooled to
0 °C, and 0.91 g (3.9 mmol) of (4R,5S)-4-methyl-5-phenyl-3-
propionyloxazolidin-2-one in 45 mL dichloromethane was added,
followed by 0.81 mL (4.1 mmol) of ethyldiisopropylamine. After
30 min, the reaction mixture was cooled to -78 °C, and 0.8 g
(3.9 mmol) of the freshly prepared aldehyde 10 was slowly added.
The reaction mixture was maintained at -78 °C for 3 h and then
warmed to room temperature. Four hours later the reaction was
Exp er im en ta l Section
Gen er a l. Thin-layer chromatography (TLC) was performed
using silica gel UV254 coated onto aluminum plates. Chroma-
tography was performed using 230-240 mesh silica gel and
predistilled solvents. NMR spectra were obtained from solutions
in CDCl3. Proton chemical shifts are reported in δ units relative
to the signal for trace chloroform in the solvent (δ 7.24), and
13C chemical shifts were also reported relative to deuteriochlo-
roform (δ 77.00). Optical rotations were measured using dilute
(13) Walkup, R. D.; Kahl, J . D., manuscript submitted for publica-
tion.
(14) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed., Pergamon Press: New York, 1988.

Notes
J . Org. Chem., Vol. 63, No. 24, 1998 9115
quenched by the addition of 25 mL of pH 7 buffer, and the
aqueous layer was extracted with dichloromethane (2 × 25 mL).
The combined organic extracts were concentrated, and the
resulting yellow oil was dissolved in 35 mL of methanol, cooled
in an ice-water bath, and mixed with 12 mL of 30% aqueous
H2O2. This solution was warmed to room temperature over the
course of 1 h, 60 mL of water was added, the methanol was
removed under vacuum, and the aqueous suspension was
extracted with dichloromethane. The combined organic extracts
were washed with brine, dried over MgSO4, and concentrated
to afford a clear oil which slowly crystallized. The white solid
was recrystallized from diethyl ether to yield 1.2 g (70%) of the
pure product 12. The mother liquor from the crystallization was
concentrated and chromatographed (7:3 hexanes/ethyl acetate)
to yield an additional 0.2 g (9%) of the pure product: 1H NMR
δ 7.40 (m, 5H), 7.28 (d, J ) 8.7, 2H), 6.87 (d, J ) 8.7, 2H), 5.62
(d, J ) 7.1, 1H), 4.74 (p, J ) 6.7, 1H), 4.45 (s, 2H), 3.90 (m, 2H),
3.80 (br, 1H), 3.79 (s, 3H), 3.57 (m, 2H), 1.97 (m, 1H), 1.22 (d, J
) 6.8, 3H), 0.96 (d, J ) 7.0, 3H), 0.90 (d, J ) 6.6, 3H); 13C NMR
δ 175.93, 159.27, 152.82, 133.24, 129.82, 129.40, 128.71, 125.62,
113.81, 78.95, 75.58, 74.75, 73.19, 55.26, 55.21, 40.85, 35.90,
in a yield of 0.95 g (∼100%), which was pure according to 1H
NMR analysis. In some cases, the crude material was passed
through a 2-cm pad of silica gel with 9:1 hexanes/ethyl acetate
to yield a purer product. The iodide thus obtained was used in
the next step without further purification: 1H NMR δ 7.23 (d, J
) 8.7, 2H), 6.85 (d, J ) 8.7, 2H), 4.39 (d of d, J ) 9.0, 4.6, 2H),
3.79 (s, 3H), 3.63 (d of d, J ) 6.2, 3.2, 1H), 3.58-3.40 (m, 2H),
3.27-3.10 (m, 3H), 1.87 (m, 2H), 0.99-0.87 (m, 18H), 0.57 (q, J
) 8.0, 6H); 13C NMR δ 159.1, 130.6, 129.2, 113.7, 77.4, 72.7, 72.3,
55.2, 39.6, 38.1, 26.1, 25.8, 25.6, 18.4, 15.2, 14.9, 14.6, -3.7, -4.1;
[R]25 +11.9° (c 4.33, CHCl3); HRMS m/z 323.2043, C18H31O3Si
D
(M - C3H6I) calcd 323.2042; low resolution FAB-MS (NBA-Na+
matrix) m/z 515.2 (M+ + Na).
(4S,5R,6S)-7-(4′-Meth oxyp h en ylm eth oxy)-4,6-d im eth yl-
5-(t r iet h ylsilyloxy)-1-(3′′-(2′′′-t r im et h ylsilylet h oxym et h -
oxy)p h en yl)-1-h ep ta n on e (17). To a stirring solution of 0.641
g (4.71 mmol) of 3-hydroxyacetophenone and 1.22 mL (7.0 mmol)
of diisopropylethylamine in 10 mL of dichloromethane at 0 °C
under nitrogen was added 1.0 mL (5.65 mmol) of 2-trimethyl-
silylethoxymethyl chloride dropwise over 5 min. The solution
was then diluted with 25 mL of ether; washed successively with
water, saturated sodium bicarbonate, and brine; dried (MgSO4);
and concentrated. Chromatography (9:1 hexanes/ethyl acetate)
yielded 0.985 g (79%) of 3-(2′-tr im eth ylsilyleth oxym eth oxy)
a cetop h en on e: 1H NMR δ 7.59 (m, 2H), 7.38 (t, J ) 7.8, 1H),
7.24 (m, 1H), 5.26 (s, 2H), 3.76 (d of d, J ) 8.3, 8.3, 2H), 2.59 (s,
3H), 0.96 (d of d, J ) 8.3, 8.3, 2H), -0.01 (s, 9H); 13C NMR δ
197.76, 157.57, 138.48, 129.56, 121.72, 121.02, 115.64, 92.84,
66.39, 26.70, 17.98, -1.46. Anal. Calcd for C14H22O3Si: C,
63.12; H, 8.33. Found: C, 63.09; H, 8.43.
14.31, 13.55, 9.51; [R]25 +23.7° (c 9.87, CH2Cl2). Anal. Calcd
D
for C25H31NO6: C, 68.00; H, 7.08. Found: C, 69.13; H, 7.20.
(2′R,3′S,4′S,4R,5S)-3-(5′-[4′′-Meth oxyph en yl]m eth oxy-2′,4′-
d im eth yl-3′-tr ieth ylsilyloxyp en ta n oyl)-5-p h en yl-4-m eth yl-
2-oxa zolid in on e (13). To 0.44 g (1.0 mmol) of the aldol product
12 in 20 mL of dichloromethane stirring at 0 °C under nitrogen
was added 0.21 mL (1.4 mmol) of diisopropylethylamine and 0.24
mL (1.2 mmol) of triethylsilyl triflate. The reaction mixture was
allowed to stir at 0 °C for 30 min, and then 10 mL of saturated
sodium bicarbonate solution was added. The aqueous layer was
extracted with diethyl ether, and the combined organic layers
were washed with brine, dried over MgSO4, and concentrated.
Chromatography (8:2 hexanes/ethyl acetate) yielded 0.54 g (98%)
of the product 13 as a thick colorless oil: 1H NMR δ 7.42-7.16
(m, 7H), 6.80 (d, J ) 8.8), 4.96 (d, J ) 7.1, 2H), 4.50 (p, J ) 6.8,
1H), 4.35 (d of d, J ) 15.0, 11.4, 2H), 4.02-3.85 (m, 2H), 3.63 (s,
3H), 3.58 (d of d, J ) 9.1, 5.9, 1H), 3.45 (d of d, J ) 14.9, 7.0,
1H), 1.94 (m, 1H), 1.67 (br s, 1H), 1.21 (d, J ) 6.3, 3H), 0.99 (d,
J ) 6.2, 3H), 0.94 (s, 9H), 0.80 (d, J ) 6.5, 3H), 0.61 (q, J ) 8.0,
6H); 13C NMR δ 175.8, 159.0, 152.4, 133.3, 130.8, 129.3, 128.5,
125.6, 113.6, 78.5, 72.7, 71.7, 65.8, 55.1, 54.9, 41.9, 38.4, 15.5,
15.2, 14.7, 14.2, 7.1, 5.4; [R]25D -6.9° (c 1.52, CHCl3). Anal. Calcd
for C31H45O6NSi: C, 67.46; H, 8.24. Found: C, 66.35; H, 7.22.
(2R,3S,4S)-2,4-Dim eth yl-5-[4′-m eth oxyp h en yl]m eth oxy-
3-tr ieth ylsilyloxyp en ta n ol (14). The silyl ether 13 (1.46 g,
2.69 mmol) and 0.17 mL (2.9 mmol) of absolute ethanol were
stirred at 0 °C under nitrogen, and then 2.96 mL of a 1.1 M
solution of LiBH4 in THF (3.5 mmol) was added. The reaction
mixture was allowed to stir at 0 °C until the starting material
was consumed, according to TLC analysis (generally after 2 h).
The reaction was then quenched with 1 M NaOH (15 mL), and
the aqueous layer was extracted with diethyl ether (3 × 15 mL).
The combined organic extracts were washed with 10 mL brine,
dried over MgSO4, and concentrated. Chromatography (8:2
hexanes/ethyl acetate) yielded 0.73 g (72%) of the alcohol 14 as
a clear oil: 1H NMR δ 7.23 (d, J ) 8.8, 2H), 6.85 (d, J ) 8.8,
2H), 4.40 (s, 2H), 3.78 (s, 3H), 3.70 (d of d, J ) 6.2, 3.2, 1H),
3.58-3.42 (m, 3H), 3.26 (d of d, J ) 9.0, 6.9, 1H), 1.90 (m, 3H),
0.95 (t, J ) 7.4, 9H), 0.95 (d, J ) 6.9, 3H), 0.83 (d, J ) 6.9, 3H),
0.57 (q, J ) 8.0, 6H); 13C NMR δ 159.1, 130.6, 129.2, 113.7, 75.3,
A mixture of 2.0 g (7.51 mmol) of this acetophenone and 3.43
mL (30 mmol) of cyclohexylamine, 5 g of activated 4A molecular
sieves, and 15 mL of benzene were refluxed under a benzene-
filled Dean-Stark trap for 12 h, cooled, filtered, and concen-
trated to yield 2.36 g (91%) of a yellow oil that, according to NMR
analysis, was >95% pure N-1-(3′-[2′′-tr im eth ylsilyleth oxym eth -
oxy]p h en yl)eth ylid in ecycloh exyla m in e. In practice, this
imine was used in the next step without further purification.
However, distillation provided a purer product with minimal loss
of material: bp 185° (2 mmHg); 1H NMR δ 7.41 (m, 1H), 7.37 (d
of d of d, J ) 7.7, 1.6, 1.1, 1H), 7.26 (d of d, J ) 7.7, 8.1, 1H),
7.04 (d of d of d, J ) 8.1, 2.5, 1.1, 1H), 5.24 (s, 2H), 3.76, (d of d,
J ) 9.6, 7.1, 2H), 3.47 (m, 1H), 2.22 (s, 3H), 1.83, (m, 2H), 1.70
(m, 3H), 1.60 (m, 2H), 1.36 (m, 3H), 0.96 (d of d, J ) 9.6, 7.1,
2H), 0.00 (s, 9H); 13C NMR δ 162.10, 157.33, 143.50, 129.09,
120.14, 116.71, 114.77, 92.0, 66.15, 59.85, 33.51, 25.78, 24.85,
18.01, 15.36, -1.42. Anal. Calcd for C20H33NO2Si: C, 69.11;
H, 9.57. Found: C, 69.48; H, 9.66.
To 5 mL of a 1.0 M solution of LDA in hexane (4.9 mmol) and
0.1 mL (4.9 mmol) of hexamethylphosphoric triamide stirring
at 0 °C under nitrogen was added 0.15 g (4.9 mmol) of the imine
in 2.5 mL of THF. The resulting bright yellow solution was
stirred at 0 °C for 10 min, then cooled to -78 °C, and stirred for
an additional 30 min. The neat iodide 15 (0.12 g, 2.4 mmol)
was then added dropwise. The mixture was allowed to warm
to room temperature over the course of 3 h, and then maintained
at room temperature for an additional 7 h. Then, pH 4 buffer
(15 mL) was added, and the mixture was stirred for 2 h. The
aqueous phase was then extracted with ether, and the combined
organic phases were washed with brine, dried (MgSO4), and
concentrated. Chromatography (20:1 hexanes/ethyl acetate)
yielded 1.38 g (91%) of the ketone 17 as a slightly yellow oil:
1H NMR δ 7.55 (m, 2H), 7.34 (t, J ) 7.8, 1H), 7.23 (m, 3H), 6.83
(d, J ) 8.8, 2H), 5.24 (s, 2H), 4.39 (d of d, J ) 10.0, 7.7, 2H),
3.77 (s, 3H), 3.73 (d of d, J ) 12.2, 5.6, 2H), 3.50 (m, 1H), 3.25
(d of d, J ) 6.0, 4.9, 1H), 3.01-2.82 (m. 2H), 1.91 (m, 1H), 1.79
(m, 1H), 1.62 (m, 3H), 0.96-0.86 (m, 18), 0.56 (q, J ) 5.3, 6H),
-0.3 (s, 9H); 13C NMR δ 200.0, 159.0, 157.6, 138.5, 130.9, 129.5,
129.1, 121.4, 120.8, 115.5, 113.7, 92.9, 77.9, 72.7, 66.4, 55.2, 37.8,
36.9, 35.8, 29.7, 29.2, 18.0, 15.0, 13.7, 7.1, 5.5, -1.4; [R]25D -11.2°
(c 1.91, CHCl3). Anal. Calcd for C35H58O6Si2: C, 66.61; H, 9.28.
Found: C, 67.42; H, 9.15.
72.7, 72.6, 66.2, 55.2, 38.9, 37.4, 15.1, 7.0, 5.3; [R]25 -3.4° (c
D
2.95, CHCl3). Anal. Calcd for C21H38O4Si: C, 65.91, H, 10.03.
Found: C, 66.04; H, 10.19.
(2R,3S,4S)-2,4-Dim eth yl-5-[4′′-m eth oxyp h en yl]m eth oxy-
3-tr ieth ylsilyloxy-1-iod op en ta n e (15). Triphenylphosphine
(0.76 g, 2.85 mmol), imidazole (0.2 g, 2.85 mmol), diisopropyl-
ethylamine (0.4 mL, 2.85 mmol), 10 mL of benzene, 10 mL of
diethyl ether, and 0.73 g (2.85 mmol) of iodine were stirred at
room temperature for 30 min. To the resulting bronze mixture
was added 0.73 g (2.0 mmol) of the alcohol 14 in 5 mL of ether.
After 30 min, the reaction was quenched by the addition of
saturated sodium bicarbonate. The aqueous layer was extracted
with diethyl ether, and the combined organic layers were washed
with brine, dried over MgSO4, and concentrated. The crude
material was triturated with hexane, and the combined hexane
triturants were concentrated to afford the iodide as a clear oil
(1S,4S,5R,6S)-7-(4′-Meth oxyp h en ylm eth xoxy)-4,6-d im e-
t h y l -5 -( t r i e t h y l s i l y l o x y ) -1 -( 3 ′′-( 2 ′′′-t r i m e t h y l s i -
lylet h oxym et h oxy)p h en yl)-1-h ep t a n ol (19). To a stirring
solution of 10 mL of THF, 0.29 mL (1.5 mmol) of a 1.0 M solution
of borane in THF, and 0.012 g (0.15 mmol) of the (R)-oxaboro-

9116 J . Org. Chem., Vol. 63, No. 24, 1998
Notes
lidine 18 (prepared from (R)-(+)-2-(diphenylhydroxymethyl)
pyrrolidine and methyl boronic acid)12 at 0 °C under nitrogen
was added 1.18 g (2.9 mmol) of the ketone 17 dropwise as a
solution in 0.5 mL of THF. The mixture was maintained at 0
°C for 1 h, at which time TLC analysis indicated that the reaction
was incomplete. Another 0.29 mL of 1.0 M borane solution (1.5
mmol) was added, and the reaction mixture was allowed to stir
at 0 °C for an additional 30 min. The reaction (now complete,
according to TLC analysis) was then quenched by the addition
of 3 mL of methanol, followed by 15 mL of saturated sodium
bicarbonate. The aqueous phase was extracted with diethyl
ether, and the combined organic phases were washed with brine,
dried (MgSO4), and concentrated. Chromatography (20:1 hex-
anes/ethyl acetate) afforded 0.17 g (95%) of the alcohol 19 as a
clear oil: 1H NMR δ 7.22 (m, 3H), 6.94 (m, 3H), 6.84 (d, J ) 8.8,
2H), 5.19 (s, 2H), 4.58 (d of d, J ) 7.3, 5.6, 1H), 4.37 (d of d, J )
10.0, 7.7, 2H), 3.76 (s, 3H), 3.73 (d of d, J ) 12.2, 5.6, 2H), 3.45
(m, 1H), 3.40 (m, 1H), 3.21 (d of d, J ) 6.5, 5.0, 1H), 2.02-1.48
(m, 5H), 1.23-1.17 (m, 3H), 0.96-0.79 (m, 17H), 0.49 (q, J )
5.0, 6H), -0.02 (s, 9H); 13C NMR δ 158.9, 157.6, 146.6, 130.8,
129.4, 129.2, 119.1, 114.9, 113.6, 92.9, 77.9, 74.9, 74.5, 72.6, 66.2,
55.2, 37.6, 37.3, 36.6, 35.9, 35.8, 30.7, 18.0, 15.2, 13.8, 7.1, 6.0,
5.4, 4.8, -0.93, -1.4; [R]25D -13.2° (c 2.74, CHCl3). Anal. Calcd
for C35H60O6Si2: C, 66.39; H, 9.57. Found: C, 67.03; H, 9.67.
(1S,4S,5R,6S)-7-(4′-Meth oxyp h en ylm eth oxy-1-m eth oxy)-
4,6-d im e t h yl-5-(t r ie t h ylsilyloxy)-1-(3′′-(2′′′-t r im e t h ylsi-
lyleth oxym eth oxy)p h en yl) h ep ta n e (20). To a hexane-
washed suspension of potassium hydride (from 0.1 g of a 35%
mineral oil dispersion, 0.7 mmol) in 5 mL THF stirring at 0 °C
under nitrogen, was added 0.24 g (0.35 mmol) of the alcohol 19
in 1 mL of THF. The suspension was allowed to warm to room
temperature over 1 h and then recooled to 0 °C. Then, methyl
iodide (0.1 mL, 0.7 mmol) was added, and the reaction was
maintained at 0 °C for 2 h, after which the reaction was
quenched by the careful addition of ice. The mixture was then
added to a separatory funnel containing ether and water. The
layers were separated, and the aqueous layer was extracted with
ether. The combined organic extracts were washed with brine,
dried (MgSO4), and concentrated. Chromatography (9:1 hex-
anes/ethyl acetate) afforded 0.24 g (97%) of the methyl ether 20
as a colorless oil: 1H NMR δ 7.23 (m, 3H), 6.89 (m, 5H), 5.20 (s,
2H), 4.36 (d of d, J ) 9.4, 7.7, 2H), 3.99 (t, J ) 4.4, 1H), 3.77 (s,
3H), 3.75 (d of d, J ) 11.2, 6.0, 1H), 3.46 (d of d, J ) 5.9, 2.6,
1H), 3.37 (d of d, J ) 4.7, 2.0, 1H), 3.21 (m, 1H), 3.19 (s, 3H),
1.83 (m, 2H), 1.58 (m, 2H), 1.24 (m, 2H) 0.96-0.83 (m, 14H),
0.78 (d, J ) 4.5, 3H), 0.47 (q, J ) 5.4, 6H), -0.02 (s, 9H); [R]25
D
-27.6° (c 2.17, CHCl3). Anal. Calcd for C30H62O6Si: C, 67.03;
H, 9.67. Found: C, 68.68; H, 10.15.
(2S,3R,4S,7S)-7-Meth oxy-2,4-dim eth yl-3-(tr ieth ylsilyloxy)-
7-(3′-(2′′-t r im e t h ylsilyle t h oxym e t h oxy)p h e n yl)-1-h e p -
ta n ol (9). To 0.9 g (1.4 mmol) of the ether 20 stirring in 10 mL
of dichloromethane and 4 mL of pH 7 buffer at room temperature
was added 0.44 g (1.69 mmol)of 2,3-dichloro-5,6-dicayanoben-
zoquinone. After 30 min, the dark green mixture was added to
a separatory funnel containing diethyl ether and saturated
sodium bicarbonate solution. The layers were separated, and
the aqueous layer was extracted with ether. The combined
organic layers were washed with brine, dried (MgSO4), and
concentrated. Chromatography (80:20 hexanes/ethyl acetate)
afforded 0.68 g (92%) of the alcohol 9 as a thick clear oil: 1H
NMR δ 7.23 (d of d, J ) 5.6, 5.1, 1H), 6.90 (m, 3H), 5.20 (s, 2H),
3.98 (t, J ) 5.6, 1H), 3.73 (d of d, J ) 8.3, 7.7, 2H), 3.56 (m, 2H),
3.44 (d of d, J ) 5.9, 4.0, 1H), 3.19 (s, 3H), 1.78 (m, 2H), 1.54
(m, 2H), 1.31 (m, 2H), 0.96-0.81 (m, 17H), 0.55 (q, J ) 8.2, 6H),
-0.02 (s, 9H); 13C NMR δ 157.7, 144.1, 129.3, 119.9, 115.1, 114.4,
92.9, 84.1, 81.4, 66.2, 56.7, 37.6, 36.4, 29.6, 18.0, 15.9, 14.7, 6.9,
5.2, -1.5; [R]25 -28.7° (c 1.63, CHCl3).
D
Ack n ow led gm en t. This research was made possible
by funding from the Robert A. Welch Foundation (grant
D-1147) and the National Cancer Institute (grant
CA49307).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 9, 10, 12-14, 17, and 19 and the 1H
NMR spectra of compounds 15 and 20 (16 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O981370X