Total synthesis of (-)-heliannuol E

Full text of DOI:10.1021/jo0011437

J . Org. Chem. 2001, 66, 309-314
309
Sch em e 1
Tota l Syn th esis of (-)-Helia n n u ol E
Kenji Sato, Tomoyuki Yoshimura, Mitsuru Shindo, and
Kozo Shishido*
Institute for Medicinal Resources, University of Tokushima,
1-78 Sho-machi, Tokushima 770-8505, J apan
Shishido@ph2.tokushima-u.ac.jp
Received J uly 27, 2000
Heliannuol E (1)1 is a novel heliannane-type sesquit-
erpenoid, which was isolated from the extracts of He-
lianthus annuus L. cv. SH-222 by Mac´ıas and co-workers
in 1999. The gross structure and relative stereochemistry
were assigned on the basis of extensive spectral studies,
including 1H-1H COSY, 1H-13C HETCOR, and NOE
experiments. However, the absolute stereochemistry of
the two stereogenic centers at C2 and C4 has never been
established. On the basis of the bioassay results, it would
appear that heliannuol E is intricately involved in the
allelopathic action2 of cultivated sunflowers. Its irregular
terpenoid structure and significant biological activity
thus prompted our interest in a total synthesis of this
compound. Our strategy is illustrated in Scheme 1. We
thought that heliannuol E might be derived from a
selective dehydration of the triol 2, which could be
constructed by a 6-exo cyclization3 of the configurationally
defined epoxy hydroquinone 3. The epoxide 3 in turn
would be prepared through a chemoenzymatic desym-
metrization4 of σ-symmetrical 3-aryl-1,5-pentanediol 4 or
the corresponding diacetate.
Sch em e 2a
a
Reagents and conditions: (a) propargyl alcohol, (Ph3P)2PdCl2,
3-Arylpropargyl alcohol 6, prepared by Sonogashira
coupling5 of the iodide 56 with propargyl alcohol (Scheme
2), was reduced with LiAlH4 to give the cinnamyl alcohol
7. Reductive Claisen rearrangement7 of the vinyl ether
8 using iBu3Al provided the alkenyl alcohol 9, which was
subjected to sequential hydroboration-oxidation and
acetylation to furnish the diol 10 and the diacetate 11 in
good overall yield. Next we tried to determine the
optimum conditions for the desymmetrization of the
required substrates 10 and 11 by a chemoenzymatic
reaction. After several attempts to find the most suitable
Cul, Et2NH, benzene, rt (room temperature); (b) LiAlH4, THF, rt;
(c) CH2dCHOEt, Hg(OAc)2, reflux; (d) iBu3Al, CH2Cl2, rt; (e)
BH3‚SMe2, THF, 0 °C, and then NaOH, H2O2, rt; (f) Ac2O, pyridine,
rt.
enzyme, lipase AK,8 originating from Pseudomonas fluo-
rescens mediated transesterification of 10 using vinyl
acetate as an acetyl donor in Et2O at room temperature,
was found to produce the monoacetate (+)-12 in 34% yield
with 78% ee (Sheme 3), which was determined by HPLC
on a Chiralcel OD column. Hoping to improve the ee and
chemical yield, we then examined the asymmetric hy-
drolysis of the diacetate 11. Upon treatment with lipase
AK in phosphate buffer for 3.5 days, 11 gave the
enantiomeric monoacetate (-)-12 with 89% ee in 75%
yield. To establish the absolute configuration of (-)-12,
it was converted into the diastereomeric amides 14 via
condensation of the carboxylic acid 13 with (R)- and (S)-
phenylglycine methyl ester (PGME) by a conventional
five-step sequence as shown in Scheme 4. The positive
and negative values are oriented systematically on the
right and left side of PGME plane, respectively, and the
(1) Mac´ıas, F. A.; Varela, R. M.; Torres, A.; Molinillo, J . M. G.
Tetrahedron Lett. 1999, 40, 4725-4728.
(2) A definition of allelopathy: The inhibition of growth in one
species of plants by chemicals produced by another species. (a) Rice,
E. L. Allelopathy, 2nd ed.; Academic Press: New York, 1984. (b)
Mac´ıas, F. A.; Varela, R. M.; Torres, A.; Molinillo, J . M. G.; Fronczek,
F. R. Tetrahedron Lett. 1993, 34, 1999-2002. (c) Mac´ıas, F. A.;
Molinillo, J . M. G.; Varela, R. M.; Torres, A.; Fronczek, F. R. J . Org.
Chem. 1994, 59, 8261-8266.
(3) For the 7-exo cyclization of a phenolic epoxide leading to the total
synthesis of (()-heliannuol D, see: Vyvyan, J . R.; Looper, R. E.
Tetrahedron Lett. 2000, 41, 1151-1154. For the competitive 7-exo and
8-endo cyclization leading to the total syntheses of (-)-heliannuol D
and (+)-heliannuol A, see: Takabatake, K.; Nishi, I.; Shindo, M.;
Shishido, K. J . Chem. Soc., Perkin Trans. 1 2000, 1807-1808.
(4) Faber, K. In Biotransformations in Organic Chemistry; Springer-
Verlag: Berlin, Heidelberg, 1997.
(5) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467-4470. (b) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1980, 672-630.
(6) Hubig, S. M.; J ung, W.; Kochi, J . K. J . Org. Chem. 1994, 59,
6233-6244.
9
absolute configuration was determined to be S.
Chain elongation of the monoacetate (S)-12 by sequen-
tial oxidation, Wittig olefination, and reductive deacetyl-
ation gave the alcohol 16 (Scheme 5), which was protec-
ted as the tert-butyldiphenylsilyl (TBDPS) ether and
(7) (a) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1981, 20, 3985-3988. (b) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H.
Bull. Soc. Chem. J pn. 1984, 57, 446-451. (c) Mori, I.; Takai, K.;
Oshima, K.; Nozaki, H. Tetrahedron 1984, 40, 4013-4018.
(8) (a) Shishido, K.; Haruna, S.; Yamamura, C.; Iitsuka, H.; Nemoto,
H.; Shinohara, Y.; Shibuya, M. Bioorg. Med. Chem. Lett. 1997, 7, 2617-
2622. (b) Bando, T.; Shishido, K. Heterocycles 1997, 46, 111-114.
(9) Yabuuchi, T.; Kusumi, T. J . Org. Chem. 2000, 65, 397-404.
10.1021/jo0011437 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/09/2000

310 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
Sch em e 3
Sch em e 5a
Sch em e 4a
a
Reagents and conditions: (a) Dess-Martin oxdn, CH2Cl2, rt;
(b) Ph3P+iPrI-, tBuOK, THF, rt; (c) LiAlH4, THF, rt; (d) TBDPSCl,
imidazole, 4-DMAP, CH2Cl2, rt; (e) CAN, MeCN, H2O, 0 °C; (f)
Na2S2O4, THF, H2O, 0 °C; (g) TBSCl, imidazole, CH2Cl2, rt; (h)
mCPBA, phosphate buffer, 0 °C; (i) K2CO3, MeOH, rt; (j) MOMCl,
iPr2NEt, rt.
a
Reagents and conditions: (a) TBDPSCl, imidazole, 4-DMAP,
CH2Cl2, rt; (b) LiAlH4, THF, rt; (c) Dess-Martin periodinate,
CH2Cl2, rt; (d) PDC, DMF, rt; (e) (R)- or (S)-phenylglycine methyl
ester, PyBOP, HOBT, ET3N, CH2Cl2, 0 °C.
oxidized with CAN to provide the quinone 18. Reduction
of the quinone with Na2S2O4 followed by protection of the
phenolic hydroxyl groups as di-tert-butyldimethylsilyl
(TBS) ether produced 20 in good overall yield. Attempted
diastereoselective dihydroxylation employing AD-mix-R10
for the construction of the other stereogenic center
present in 1 yielded the diol as a 1:1 mixture. Discour-
aged by this result, we next turned our attention to the
direct epoxidation of 20. Treatment with mCPBA in CH2-
Cl2 and phosphate buffer provided an inseparable mix-
ture of the epoxides (S)-21/(R)-21 in a 1:1 ratio in 92%
yield. The crucial cyclization leading to the compound
with a basic carbon skeleton of 1 was realized by treating
the mixture with basic conditions (K2CO3 in MeOH) to
give an inseparable mixture of (2S,4R)-22/(2R,4R)-22 in
85% yield. Since the introduction of a vinyl functionality
at the benzylic position by sequential desilylation and
dehydration of 22 proved to be troublesome, the two
hydroxyl groups were protected as MOM ethers. Fortu-
nately, the di-MOM ethers could be separated by a
preparative HPLC to give (2S,4R)-23 and (2R,4R)-23 in
30% and 28% yield, respectively. At this stage, the
stereochemistry of (2R,4R)-23 was determined by NOE
experiments as shown in Figure 1.
F igu r e 1. NOE for (2R,4R)-23.
Sch em e 6a
a Reagentsandconditions: (a)nBu4NF,THF,rt; (b)o-NO2C6H4SeCN,
nBu3P, THF, rt; (c) H2O2, THF, rt; (d) 6N HCl, THF, rt.
heliannuol E (1) in 68% overall yield from (2S,4R)-23 for
1
the four steps. H and 13C NMR, IR, and mass spectral
data as well as optical rotation, [R]D -69.8 (c 0.1, CHCl3)
[for the natural 11, [R]D -68.6 (c 0.1, CHCl3)], were
indistinguishable from those of the natural product. In
conclusion, the first total synthesis of a novel heliannane
sesquiterpenoid (-)-heliannuol E has been accomplished
and the absolute configurations of the two stereogenic
centers were determined to be 2S and 4S, respectively.
The synthetic route developed here holds considerable
promise for the synthesis of related natural products.
The desired isomer (2S,4R)-23 was desilylated with
tetra-n-butylammonium fluoride to give the primary
alcohol 24 (Scheme 6), which was sequentially treated
under the conditions for dehydration developed by Grieco11
and with 6 N HCl to provide, via the selenide 25,
(10) Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483-2547.
(11) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485-1486.

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 311
with ether (200 mL) and poured into 1 M HCl (60 mL). The
separated organic layer was washed with brine, dried over Na2-
SO4, and concentrated in vacuo to give a crude mixture. Column
chromatography (silica gel, hex/AcOEt ) 95/5) gave 9 (1.04 g,
92%) as a pale yellow oil: IR (neat) 1046, 1210, 1397, 1465, 1504,
1636, 3387 cm-1; 1H NMR (400 MHz, CDCl3 + D2O) δ 1.74 (1H,
dddd, J ) 13.2, 9.1, 4.8, 4.8 Hz), 2.08 (1H, m), 2.20 (3H, s), 3.44
(1H, ddd, J ) 11.4, 5.0, 4.8 Hz), 3.58 (1H, ddd, J ) 11.4, 10.0,
5.0 Hz), 3.77 (3H, s), 3.80 (3H, s), 3.98 (1H, dt, J ) 8.2, 6.8 Hz),
5.09 (1H, d, J ) 10.5 Hz), 5.12 (1H, d, J ) 17.3 Hz), 6.05 (1H,
ddd, J ) 17.3, 10.5, 6.8 Hz), 6.62 (1H, s), 6.71 (1H, s); 13C NMR
(75 MHz, CDCl3) δ 16.3 (q), 37.5 (t), 37.8 (d), 56.0 (q), 56.6 (q),
60.7 (t), 110.6 (d), 114.1 (t), 114.5 (d), 125.3 (s), 129.5 (s), 141.4
(d), 150.5 (d), 152.2 (s); MS (EI) m/z 236 (M+), 191 (base peak);
HRMS calcd for C14H20O3 236.1368, found 236.1398.
3-(2,5-Dim eth oxy-4-m eth ylp h en yl)p en ta n e-1,5-d iol (10).
BH3•SMe2 (90%, 9.05 mL, 85.9 mmol) was added dropwise to a
stirred solution of 9 (26.0 g, 110 mmol) in dry THF (650 mL) at
0 °C. After 30 min, the solution was warmed to room tempera-
ture. After being stirred for 1.5 h, NaOH(aq) (3 N, 48.8 mL) was
added dropwise at 0 °C, followed by addition of 35% aqueous
H2O2 (14.2 mL). After being stirred for 1.5 h at room tempera-
ture, the mixture was diluted with ether, washed with water
and brine, dried over Na2SO4, and concentrated in vacuo.
Column chromatography (silica gel, hex/AcOEt ) 75/25) gave
10 (26.0 g, 93%) as colorless prisms: mp 67.7-68.6 °C (benzene/
hexane); IR (CHCl3) 1046, 1214, 1423, 1522, 3684 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.72-1.85 (4H, m and OH × 2 D2O
exchangeable), 1.93-2.04 (2H, m), 2.21 (3H, s), 3.36-3.43 (3H,
m), 3.52-3.57 (2H, dt, J ) 10.5, 4.9 Hz), 3.78 (3H, s), 3.80 (3H,
s), 6.63 (1H, s), 6.72 (1H, s); 13C NMR (75 MHz, CDCl3) δ 16.1
(q), 29.8 (d), 38.9 (t), 56.0 (q), 56.7 (q), 60.8 (t), 109.8 (d), 114.6
(d), 125.3 (s), 129.7 (s), 151.0 (s), 152.6 (s); MS (EI) m/z 254 (base
peak, M+); HRMS calcd for C14H22O4 254.1518, found 254.1526.
Anal. Calcd for C14H22O4: C, 66.12; H, 8.72. Found: C, 65.91;
H, 8.69.
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR were measured in CDCl3 solu-
tion and referenced to TMS (0.00 ppm) using Bruker AM400,
J EOL GSX400 (400 MHz), and J EOL AL300 (300 MHz) spec-
trophotometers, unless otherwise noted. 13C NMR were mea-
sured in CDCl3 solution and referenced to CDCl3 (77.0 ppm)
using Bruker AM400 (100 MHz), J EOL GSX400 (100 MHz), and
J EOL AL300 (75 MHz) spectrometers. IR spectra were recorded
on J ASCO FT/IR-410 spectrometer. Mass spectra were obtained
on a J EOL GX303. Column chromatography was performed on
silica gel, Fuji Silysia Chemical BW-127ZH (100-270 mesh).
Thin-layer chromatography was performed on precoated plates
(0.25 mm, silica gel Merck Kieselgel 60 F245). Melting points were
measured with a Bu¨chi 535 melting point apparatus and are
uncorrected. All reactions were performed in oven-dried glass-
ware under positive pressure of argon, unless otherwise noted.
Reaction mixtures were stirred magnetically. Solutions of alky-
llithium reagents were transferred by syringe or cannula and
were introduced into reaction vessels through rubber septa.
3-(2,5-Dim eth oxy-4-m eth ylp h en yl)-2-p r op yn -1-ol (6). To
a flask charged with bis(triphenylphosphine)palladium(II) chlo-
ride (1.45 g, 2.06 mmol) and copper iodide (2.62 g, 13.7 mmol)
was added a solution of 1-iodo-2,5-dimethoxy-4-methylbenzene6
(19.1 g, 68.7 mmol) in benzene (400 mL), and the mixture was
then cooled to 0 °C. To the resulting red solution were added
diethylamine (36.5 mL, 481 mmol) and propargyl alcohol (20.0
mL, 343 mmol). After being stirred for 20 h at 25 °C, the reaction
was quenched with 30 mL of saturated NH4Cl solution and
extracted with ether. The combined organic layer was washed
with brine, dried over Na2SO4. Removal of the solvent and
column chromatography (silica gel, hex/AcOEt ) 75/25) gave the
alcohol 6 (14.2 g, quantitative) as colorless crystals: mp 85-87
°C; IR (CHCl3) 1216, 2222, 3605 cm-1; 1H NMR (400 MHz, CDCl3
+ D2O) δ 2.22 (3H, s), 3.77 (3H, s), 3.84 (3H, s), 4.53 (2H, s),
6.69 (1H, s), 6.84 (1H, s); 13C NMR (75 MHz, CDCl3) δ 16.6 (q),
51.6 (q), 55.8 (q), 56.3 (q), 82.0 (s), 90.7 (s),108.7 (s) 113.9 (d),
114.9 (d), 129.0 (s), 151.3 (s), 154.0 (s); MS (EI) m/z 206 (base
peak, M+); HRMS calcd for C12H14O3 206.0943, found 206.0949.
3-(2,5-Dim eth oxy-4-m eth ylp h en yl)-2E-p r op en ol (7). To a
suspension of lithium aluminum hydride (22.5 g, 0.593 mol) in
THF (2.0 L) at 0 °C was added a solution of 6 (122.3 g, 0.593
mol) in THF (400 mL) dropwise. After the reaction mixture was
stirred for 2 h at room temperature, water was added. The
resulting mixture was filtered through a short pad of Celite and
washed with ether, and the filtrate was dried over Na2SO4.
Removal of the solvent and column chromatography (silica gel,
hex/AcOEt ) 75/25) gave 7 (120.1 g, 98%) as a pale yellow oil:
3-(2,5-Dim eth oxy-4-m eth ylp h en yl)p en ta m eth ylen e Di-
a ceta te (11). A solution of 10 (21.5 g, 84.6 mmol) in pyridine
(10 mL) and acetic anhydride (10 mL) was stirred for 2 h at room
temperature and then concentrated in vacuo. To the residue was
added water (50 mL), followed by extraction with CH2Cl2 (100
mL). The organic phase was washed with 5% aqueous HCl (2 ×
50 mL), saturated NaHCO3(aq), and brine and dried over
anhydrous Na2SO4. Removal of the solvent and column chro-
matography (silica gel, hex/AcOEt ) 95/5) provided 11 (27.2 g,
95%) as a colorless oil: IR (neat) 1045, 1241, 1467, 1506, 1737,
1
2954 cm-1; H NMR (300 MHz, CDCl3) δ 1.98 (4H, dt, J ) 7.2,
6.9 Hz), 1.99 (6H, s), 2.19 (3H, s), 3.19 (1H, quint, J ) 7.2 Hz),
3.73 (3H, s), 3.77 (3H, s), 3.93 (4H, t, J ) 6.9 Hz), 6.58 (1H, s),
6.65 (1H, s); 13C NMR (75 MHz, CDCl3) δ 16.1 (q), 20.9 (q), 32.7
(d), 34.1 (t), 56.0 (q), 56.1 (q), 66.4 (t), 110.5 (d), 114.2 (d), 125.3
(s), 128.5 (s), 151.3 (s), 151.8 (s), 171.0 (s); MS (EI) m/z 338 (M+,
base peak); HRMS calcd for C18H26O6 338.1729, found 338.1713.
(3R)-5-Hyd r oxy-3-(2,5-d im eth oxy-4-m eth ylp h en yl)p en -
tyl Aceta te ((R)-12). To a solution of 10 (30 mg, 0.10 mmol) in
dry ether (0.6 mL) were added lipase AK (15 mg) and vinyl
acetate (0.02 mL), and the mixture was stirred at room tem-
perature for 14 h. After filtration and removal of the solvent,
the resulting oil was chromatographed (silica gel, hex/AcOEt )
75/25) to afford the enantiomerically enriched monoacetate ((R)-
12) (12 mg, 34%). [R]D ) +14.0 (c 0.33, CHCl3) (78% ee: Daicel,
IR (CHCl3) 973, 1045, 1218, 3607 cm-1 1H NMR (400 MHz,
;
CDCl3 + D2O) δ 2.20 (3H, s), 3.80 (3H, s), 3.81 (3H, s), 4.32 (2H,
d, J ) 6.2 Hz), 6.34 (1H, dt, J ) 16.0, 6.2 Hz), 6.70 (1H, s), 6.90
(1H, d, J ) 16.0 Hz), 6.91 (1H, s); 13C NMR (75 MHz, CDCl3) δ
16.3 (q), 55.8 (q), 56.2 (q), 64.0 (t), 108.6 (d), 114.4 (d), 123.3 (s),
126.1 (d), 127.2 (s), 128.1 (d), 150.6 (s), 151.8 (s); MS (EI) m/z
208 (base peak, M+); HRMS calcd for C12H16O3 208.1099, found
208.1086.
1-(2,5-Dim et h oxy-4-m et h ylp h en yl)-3-(et h en yloxy)-1E-
p r op en e (8). A mixture of 7 (19.1 g, 91.7 mol), mercury(II)
acetate (8.80 g, 27.5 mmol), and freshly distilled ethyl vinyl ether
(1.2 L) was refluxed for 24 h under argon atmosphere. The
mixture was poured into 5% KOH solution (300 mL), extracted
with hexane, and dried over anhydrous potassium carbonate.
Removal of the solvent and column chromatography (silica gel,
hex/AcOEt ) 95/5) gave 8 (18.9 g, 88%) as a pale yellow oil: IR
i
Chiral Cel OD (0.46 × 25 cm), 5% PrOH/hex (v/v); flow rate,
0.5 mL/min; retention time, 25.72 min for (R), 27.95 min for (S);
eluent detection monitored by UV absorbance at 220 nm); IR
(neat) 1046, 1240, 1467, 1508, 1735, 2954, 3685 cm-1; 1H NMR
(400 MHz, CDCl3 + D2O) δ 1.66 (1H, m), 1.92-2.08 (3H, m),
1.99 (3H, s), 2.20 (3H, s), 3.34 (2H, ddd, J ) 12.4, 7.2, 6.8 Hz),
3.49 (1H, m), 3.78 (6H, s), 3.95 (2H, m), 6.60 (1H, s), 6.70 (1H,
s); 13C NMR (75 MHz, CDCl3) δ 16.0 (q), 20.8 (q), 30.8 (d), 34.2
(t), 39.2 (t), 56.0 (q), 56.4 (q), 60.6 (t), 63.1 (q), 109.7 (d), 114.5
(d), 125.3 (s), 129.0 (s), 151.1 (s), 152.4 (s), 171.0 (s); MS (FAB)
m/z: 296 (M+, base peak); HRMS calcd for C16H24O5 296.1624,
found 296.1613.
1
(neat) 1046, 1211, 1509, 1615, 1634 cm-1; H NMR (400 MHz,
CDCl3) δ 2.22 (3H, s), 3.79 (3H, s), 3.80 (3H, s), 4.05 (1H, dd, J
) 6.8, 0.9 Hz), 4.28 (1H, dd, J ) 14.1, 0.9 Hz), 4.40 (2H, d, J )
5.9 Hz), 6.28 (1H, dt, J ) 16.4, 5.9 Hz), 6.52 (1H, dd, J ) 14.1,
6.8 Hz), 6.69 (1H, s), 6.91 (1H, s), 6.95 (1H, d, J ) 16.4 Hz); 13
C
NMR (75 MHz, CDCl3) δ 16.3 (q), 55.8 (q), 56.2 (q), 69.4 (t), 87.1
(t), 108.6 (d), 114.5 (d), 123.0 (s), 123.7 (d), 127.6 (s), 128.2 (d),
150.8 (s), 151.4 (d), 151.8 (s); MS (EI) m/z: 234 (M+), 83 (base
peak); HRMS calcd for C14H18O3 234.1256, found 234.1261.
3-(2,5-Dim et h oxy-4-m et h ylp h en yl)-4-p en t en -1-ol (9). A
solution of triisobutylaluminum (0.96 M in hexane, 10 mL, 9.6
mmol) was added to a solution of 8 (4.8 mmol, 1.12 g) in CH2Cl2
at 25 °C and then stirred for 2.5 h. The mixture was diluted
(3S)-5-H yd r oxy-3-(2,5-d im et h oxy-4-m et h ylp h en yl)p en -
tyl Aceta te ((S)-12). Lipase AK (8.2 g) was added to 11 (33.2
g, 98.1 mmol) dispersed in 0.1 M phosphate buffer (pH 7, 1.66
L), and the reaction mixture was stirred for 3.5 days at room

312 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
temperature while pH was kept constantly by addition of 1 N
NaOH by means of a pH-check sheet. The mixture was filtered
through a short pad of Celite and then extracted with AcOEt.
The combined organic layer was washed with brine and dried
over anhydrous Na2SO4. Removal of the solvent and column
chromatography (silica gel, hex/AcOEt ) 85/15) gave (S)-12 (21.8
g, 75%) as a colorless oil: [R]D ) -15.8 (c 0.33, CHCl3) (89% ee);
(2S ,3′S )-N -(5′-(t er t -B u t y ld ip h e n y ls ilo x y )-3′-(2′′,5′′-
d im et h oxy-4′′-m et h ylp h en yl)p en t ylca r b on yl)p h en -ylgly-
cin e Meth yl Ester (S-14) a n d (2R,3′S)-N-(5′-(ter t-Bu tyld i-
p h e n y ls ilo x y )-3′-(2′′,5′′-d im e t h o x y -4′′-m e t h y lp h e n y l)-
pen tylcar bon yl)ph en ylglycin e Meth yl Ester ((R)-14). Accord-
ing to the general procedure, the crude carboxylic acid (15 mg,
ca. 0.030 mmol) was converted into the amide (9.0 mg, 70% from
the alcohol), a colorless oil, after purification by column chro-
matography (silica gel, hex/AcOEt ) 4/1): for (S)-14, 1H NMR
(400 MHz, CDCl3) δ 0.997 (9Η, s), 1.913 (2Η, dd, J ) 6.8, 4.0
Hz), 2.208 (3H, s), 2.630 (2H, m), 3.520 (1H, m), 3.537 (2H, m),
3.591 (3H, s), 3.675 (3H, s), 3.675 (3H, s), 5.446 (1H, d, J ) 6.8
Hz), 6.536 (1H, s), 6.629 (1H, s), 6.994-7.626 (15H, m); for (R)-
14, 1H NMR (400 MHz, CDCl3) δ: 1.013 (9Η, s), 1.918 (2Η, dd,
J ) 6.8, 4.0 Hz), 2.199 (3H, s), 2.631 (2H, m), 3.520 (1H, m),
3.545 (2H, m), 3.591 (3H, s), 3.675 (3H, s), 3.675 (3H, s), 5.435
(1H, d, J ) 6.8 Hz), 6.577 (1H, s), 6.589 (1H, s), 7.098-7.610
(15H, m).
IR (neat) 1046, 1240, 1467, 1508, 1735, 2954, 3685 cm-1 1H
;
NMR (400 MHz, CDCl3 + D2O) δ 1.66 (1H, m), 1.92-2.08 (3H,
m), 1.99 (3H, s), 2.20 (3H, s), 3.34 (2H, ddd, J ) 12.4, 7.2, 6.8
Hz), 3.49 (1H, m), 3.78 (6H, s), 3.94 (1H, ddd, J ) 11.8, 7.2, 5.8
Hz), 3.94 (1H, ddd, J ) 11.8, 6.8, 6.4 Hz), 6.60 (1H, s), 6.70 (1H,
s); 13C NMR (75 MHz, CDCl3) δ 16.0 (q), 20.8 (q), 30.8 (d), 34.2
(t), 39.2 (t), 56.0 (q), 56.4 (q), 60.6 (t), 63.1 (q), 109.7 (d), 114.5
(d), 125.3 (s), 129.0 (s), 151.1 (s), 152.4 (s), 171.0 (s); MS (EI)
m/z 296 (M+, base peak); HRMS calcd for C16H24O5 296.1624,
found 296.1639.
(3S)-5-(ter t-Bu tyld ip h en ylsiloxy)-3-(2,5-d im eth oxy-4-m e-
th ylp h en yl)p en ta n oic a cid (13). Imidazole (14 mg, 0.202
mmol), tert-butyldiphenylchlorosilane (14 mg, 0.202 mmol), and
4-(dimethylamino)pyridine (0.3 mg, 2.5 µmol) were added to a
solution of the alcohol (S)-12 (50 mg, 0.169 mmol) in dry CH2-
Cl2 (1 mL). After being stirred at room temperature for 1 h, the
mixture was quenched with saturated NaHCO3(aq) and ex-
tracted with CH2Cl2. The organic layer was washed with brine,
dried over MgSO4, and concentrated to give a residue, which
was purified by column chromatography (silica gel, hex/AcOEt
) 97/3) to give acetoxy silyl ether (90 mg, 100%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 1.02 (9H, s), 1.89-2.12 (4H,
m), 1.98 (3H, s), 2.20 (3H, s), 3.47 (1H, m), 3.60 (2H, t, J ) 9.3
Hz), 3.68 (3H, s), 3.72 (3H, s), 3.93 (2H, t, J ) 9.6 Hz), 6.58 (1H,
s), 6.63 (1H, s), 7.31-7.41 (4H, m), 7.55-7.64 (6H, m). To a
suspension of lithium aluminum hydride (21 mg, 0.169 mol) in
THF (0.60 mL) at 0 °C was added a solution of the acetoxy silyl
ether (90 mg, 0.169 mol) in THF (0.60 mL). After the reaction
mixture was stirred for 3 h at room temperature, water was
added. The crude product was filtered through a short pad of
Celite with ether, and the filtrate was concentrated. Column
chromatography (silica gel, hex/AcOEt ) 97/3) provided an
alcohol (89 mg, quantitative) as a light yellow oil: 1H NMR (300
MHz, CDCl3 + D2O) δ 1.02 (9H, s), 1.92-2.16 (4H, m), 2.21 (3H,
s), 3.30 (1H, m), 3.34-3.48 (2H, m), 3.60 (2H, t, J ) 6.5 Hz),
3.72 (6H, s), 6.58 (1H, s), 6.68 (1H, s), 7.30-7.40 (4H, m), 7.53-
7.64 (6H, m). To a solution of the alcohol (87 mg, 0.177 mmol)
in CH2Cl2 (1.0 mL) was added, via cannula, a suspension of
Dess-Martin periodinate (115 mg, 0.268 mmol) in CH2Cl2 (0.8
mL) at room temperature. The reaction mixture was stirred for
2 h and then diluted successively with saturated NaHCO3
solution, saturated Na2S2O3(aq), and CH2Cl2 and stirred for 30
min. The mixture was extracted with CH2Cl2. The combined
organic solution was washed with saturated NaHCO3(aq) and
brine, dried over MgSO4, filtered, and concentrated. Column
chromatography (silica gel, hex/AcOEt ) 97/3) provided an
aldehyde (70 mg, 82%) as a clear oil: 1H NMR (400 MHz, CDCl3)
δ 1.03 (9H, s), 1.86-2.04 (2H, m), 2.20 (3H, s), 2.67 (2H, dd, J )
10.9, 2.5 Hz), 3.59 (2H, t, J ) 6.4 Hz), 3.71 (6H, s), 3.80 (1H, m),
6.61 (1H, s), 6.65 (1H, s), 7.31-7.41 (4H, m), 7.55-7.64 (6H, m),
9.62 (1H, d, J ) 2.5 Hz). To a solution of pyridinium dichromate
(83 mg, 0.22 mmol) in DMF (0.7 mL) was added a solution of
the aldehyde (35 mg, 73.0µmol) in DMF (0.3 mL). After being
stirred for 14 h at room temperature, the reaction mixture was
poured into water. The mixture was extracted with ether. The
combined organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated. The crude carboxylic acid 13
(30 mg) was used to the next reaction without further purifica-
tion.
(S)-3-(2,5-Dim eth oxy-4-m eth ylp h en yl)-6-m eth yl-5-h ep te-
n yl Aceta te (15). To a solution of alcohol (S)-12 (15.0 g, 50.9
mmol) in CH2Cl2 (200 mL) was added, via cannula, a suspension
of Dess-Martin periodinate (25.9 g, 61.1 mmol) in CH2Cl2 (200
mL) at room temperature. The reaction mixture was stirred for
2.5 h and then diluted with saturated NaHCO3(aq) (50 mL),
saturated Na2S2O3(aq) (50 mL), and CH2Cl2 (100 mL) and stirred
for 30 min. The mixture was extracted with CH2Cl2, and the
organic phase was washed with saturated NaHCO3(aq) and
brine, dried over MgSO4, filtered, and concentrated. Column
chromatography (silica gel, hex/AcOEt ) 95/5) provided an
aldehyde (13.8 g, 94%) as a colorless oil: [R]D ) -17.3 (c 1.20,
1
CHCl3); IR (neat) 1044, 1211, 1466, 1506, 1735, 2953 cm-1; H
NMR (400 MHz, CDCl3) δ 1.92-2.11 (2H, m), 2.00 (3H, s), 2.19
(3H, s), 2.73 (2H, m), 3.59-3.69 (1H, m), 3.76 (3H, s), 3.77 (3H,
s), 6.61 (1H, s), 6.67 (1H, s), 9.64 (1H, t, J ) 2.1 Hz); 13C NMR
(75 MHz, CDCl3) δ 16.0 (q), 20.8 (q), 31.3 (d), 33.3 (t), 49.1 (t),
55.8 (q), 56.0 (q), 62.6 (t), 110.9 (d), 114.2 (d), 125.8 (s), 127.7
(s), 150.9 (s), 151.7 (s), 171.0 (s), 202.1 (d); MS (EI) m/z: 294
(M+, base peak); HRMS calcd for C16H22O5 294.1467, found
294.1463. To isopropyltriphenylphosphonium iodide (92.3 g,
0.214 mol) suspended in dry THF (200 mL) at room temperature
under nitrogen was added t-BuOK (23.8 g, 0.214 mol) in THF
(100 mL). After the mixture was stirred for 30 min, the aldehyde
(18.2 g, 61.2 mmol) in THF (60 mL) was added. After 3.5 h, water
was added and the resulting mixture was poured into ether-
brine. The mixture was extracted with ether. The combined
organic solution was washed with brine, dried over MgSO4.
Removal of the solvent and column chromatography (silica gel,
hex/AcOEt ) 95/5) afforded the olefin 15 which was used to the
next reaction without further purification: [R]D ) -3.11 (c 0.96,
CHCl3); IR (neat) 1047, 1505, 2932 cm-1; 1H NMR (400 MHz +
D2O, CDCl3) δ 1.55 (3H, s), 1.65 (3H, s), 1.83-2.05 (2H, m), 1.98
(3H, s), 2.19 (3H, s), 2.28 (2H, dd, J ) 7.0, 7.0 Hz), 3.13 (1H, m),
3.74 (3H, s), 3.78 (3H, s), 5.07 (1H, tm, J ) 7.0 Hz), 6.61 (1H, s),
6.66 (1H, s); 13C NMR (75 MHz, CDCl3) δ 16.1 (q), 17.8 (q), 20.9
(q), 25.7 (q), 33.1 (t), 34.0 (t), 35.6 (d), 56.1 (q), 56.2 (q), 63.4 (t),
110.5 (d), 114.3 (d), 122.7 (d), 124.7 (s), 130.5 (s), 132.4 (s), 151.2
(s), 151.8 (s), 171.0 (s); MS (EI) m/z 320 (M+), 179 (base peak);
HRMS calcd for C19H28O4 320.1988, found 320.2001.
(S)-3-(2,5-Dim eth oxy-4-m eth ylph en yl)-6-m eth yl-5-h epten -
1-ol (16). To a suspension of lithium aluminum hydride (1.16
g, 30.6 mmol) in THF (300 mL) at 0 °C was added dropwise a
solution of crude acetate 15 (27.1 g, 61.2 mmol) in THF (240
mL). After the mixture was stirred for 1.5 h at room tempera-
ture, water was added. The crude product was filtered through
a short pad of Celite with ether, and the filtrate was concen-
trated. Column chromatography (silica gel, hex/AcOEt ) 95/5)
provided alcohol 16 (15.7 g, 92% from the aldehyde) as a light
yellow oil: [R]D ) -2.71 (c 1.0, CHCl3); IR (neat) 1047, 1240,
1465, 1504, 2932, 3389 cm-1; 1H NMR (400 MHz + D2O, CDCl3)
δ 1.52-1.60 (1H, m), 1.60 (3H, s), 1.65 (3H, s), 2.04 (1H, dddd,
J ) 13.1, 7.2, 6.9, 6.8 Hz), 2.20 (3H, s), 2.33 (2H, ddd, J ) 13.4,
7.6, 6.8 Hz), 3.23 (1H, ddd, J ) 11.2, 7.2, 5.8 Hz), 3.31 (1H, ddd,
J ) 11.2, 7.6, 5.5 Hz), 3.49 (1H, m), 3.78 (3H, s), 3.81 (3H, s),
5.08 (1H, t, J ) 7.2 Hz), 6.63 (1H, s), 6.70 (1H, s); 13C NMR (75
MHz, CDCl3) δ 15.9 (q), 17.7 (q), 25.5 (q), 34.00 (d), 34.04 (t),
38.3 (t), 55.8 (q), 56.4 (q), 60.7 (t), 109.8 (d), 114.4 (d), 122.9 (d),
124.5 (s), 130.8 (s), 132.0 (s), 150.9 (s), 152.1 (s); MS (EI) m/z
Gen er a l P r oced u r e for th e Con d en sa tion of P h en ylg-
lycin e Meth yl Ester (P GME) w ith Ca r boxylic Acid . To a
stirred solution of a mixture of the carboxylic acid (1 equiv) and
PGME (1.2 equiv) in DMF was successively added (benzotriazol-
1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Py-
BOP, 1.2 equiv), 1-hydroxybenzotriazole (HOBT, 1.2 equiv), and
triethylamine (1.2 equiv) at 0 °C. After the reaction was
completed, the mixture was diluted with AcOEt, washed with
5% HCl(aq) and saturated NaHCO3(aq), and dried over Na2SO4.
Removal of the solvent and column chromatography (silica gel,
hex/AcOEt ) 80/20) afforded the amide.

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 313
278 (M+), 179 (base peak); HRMS calcd for C17H26O3 278.1882,
found 278.1896.
δ 0.126 (3H, s), 0.136 (3H, s), 0.144 (3H, s), 0.151 (3H, s), 0.94
(9H, s), 1.00 (9H, s), 1.01 (9H, s), 1.49 (3H, s), 1.61 (3H, s), 1.85-
1.96 (2H, ddd, J ) 10.8, 7.2, 6.8 Hz), 2.11 (3H, s), 2.16 (2H, m),
3.01-3.15 (1H, m), 3.55-3.65 (2H, m), 4.99 (1H, dd, J ) 7.0,
(S)-7-(ter t-Bu tyld ip h en ylsiloxy)-5-(2,5-d im eth oxy-4-m e-
th ylp h en yl)-2-m eth yl- 2-h ep ten e (17). Imidazole (110 mg,
1.61 mmol), tert-butyldiphenylchlorosilane (192 mg, 0.70 mmol),
and 4-(dimethylamino)pyridine (0.3 mg, 2.5 µmol) were added
to a solution of the alcohol 16 (157 mg, 0.56 mmol) in dry CH2-
Cl2 (3 mL). After being stirred at room temperature for 1 h, the
mixture was quenched with H2O and extracted with CH2Cl2. The
organic layer was washed with brine, dried over MgSO4, and
concentrated to give a residue which was purified by column
chromatography (silica gel, hex/AcOEt ) 98/2) to give silyl ether
17 (285 mg, 98%) as a colorless oil; [R]D ) -2.58 (c 1.2, CHCl3);
IR (neat) 1048, 1210, 1465, 1503, 2930 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.02 (9H, s), 1.52 (3H, s), 1.63 (3H, s), 1.82-1.96 (2H,
m), 2.20 (3H, s), 2.23 (2H, m), 3.21 (1H, m), 3.54 (2H, dd, J )
10.8, 5.5 Hz), 3.68 (3H, s), 3.72 (3H, s), 5.07 (1H, t, J ) 7.2 Hz),
6.59 (1H, s), 6.63 (1H, s), 7.28-7.43 (6H, s), 7.56-7.70 (4H, m);
13C NMR (75 MHz, CDCl3) δ 16.1 (q), 17.8 (q), 18.4 (s), 25.8 (q),
26.8 (q), 34.0 (t), 35.3 (d), 37.2 (t), 56.09 (q), 56.14 (q), 59.7 (t),
110.9 (d), 114.2 (d), 123.2 (d), 124.2 (s), 127.46 (d), 127.49 (d),
127.56 (d), 129.3 (d), 129.4 (d), 129.5 (d), 131.5 (s), 132.0 (s), 134.2
(s), 135.5 (d), 151.3 (s), 151.6 (s); MS (EI) m/z 516 (M+), 447 (base
peak); HRMS calcd for C33H44O3Si 516.3060, found 516.3070.
(S)-2-(1-(2-(ter t-Bu tyld ip h en ylsiloxy)eth yl)-4-m eth yl-3-
p en ten yl)-5-m eth yl- p-ben zoqu in on e (18). To a solution of
17 (820 mg, 1.59 mmol) in acetonitrile (16 mL) was added
aqueous cerium ammonium nitrate (2.0 g, 3.65 mmol) portion-
wise over 5 min at 0 °C. After being stirred for 15 min at 0 °C,
the reaction mixture was extracted with ether (2 × 10 mL). The
organic layer was washed with brine, dried over MgSO4, and
concentrated. The residue was purified by column chromatog-
raphy (silica gel, hex/AcOEt ) 95/5) to give 18 (741 mg, 87%) as
a brown oil; [R]D ) +0.72 (c 0.83, CHCl3); IR (neat) 1110, 1247,
6.6 Hz), 6.50 (2H, s), 7.24-7.44 (6H, m), 7.58-7.62 (4H, m); 13
C
NMR (75 MHz, CDCl3) δ -4.4 (q), -4.1 (q), 16.5 (q), 17.9 (q),
18.2 (q), 19.1 (s), 25.8 (q), 26.8 (q), 33.6 (d), 33.7 (t), 38.4 (t),
62.2 (t), 116.8 (d), 119.0 (d), 121.2 (s), 123.0 (d), 127.5 (d), 127.7
(d), 128.3 (s), 129.8 (d), 129.9 (d), 132.6 (s), 132.9 (s), 133.0 (d),
135.5 (s), 135.7 (d), 147.8 (s), 148.5 (d); MS (EI) m/z 716 (M+),
73 (base peak); HRMS calcd for C43H68O3Si3 716.4476, found
716.4491.
(3S,5S)- a n d (3R,5S)-7-(ter t-Bu tyld ip h en ylsiloxy)-3-(2,5-
d i-ter t-bu tyld im eth ylsiloxy-4-m eth yl p h en yl)-2-m eth yl-2,3-
ep oxyh ep ta n e (21). To a solution of 20 (45 mg, 58.2 µmol) in
ether (0.8 mL) and 0.1 M phosphate buffer (0.8 mL) was added
m-chloroperbenzoic acid (mCPBA, 14 mg, 83.6 µmol) at 0 °C.
After being stirred for 25 min at 0 °C, the reaction mixture was
extracted with ether (2 × 5 mL). The organic layer was washed
with saturated NaHCO3 solution and brine, dried over MgSO4,
and concentrated. Column chromatography (silica gel, hex/
AcOEt ) 4/1) provided a diastereomeric mixture of 21 (40 mg,
92%) as a yellow oil: IR (neat) 1114, 1144, 1188, 2950, 3055
cm-1 1H NMR (400 MHz, CDCl3) δ 0.12 (6/2H, s), 0.13 (6/2H,
;
s), 0.15 (6/2H, s), 0.17 (6/2H, s), 0.99 (9/2H, s), 1.01 (9/2H, s),
1.05 (18/2H, s), 1.07 (18/2H, s), 1.18 (3H, s), 1.20 (3/2H, s), 1.23
(3/2H, s), 1.57-2.01 (4H, m), 2.15 (3H, s), 2.64 (1/2H, dd, J )
6.7, 6.6 Hz), 2.86 (1/2H, dd, J ) 7.2, 6.8 Hz), 3.35-3.40 (1H, m),
3.49-3.58 (1H, ddd, J ) 10.5, 7.2, 5.5 Hz), 3.58-3.64 (1H, m),
6.47 (1/2H, s), 6.49 (1/2H, s), 6.67 ((1/2H, s), 6.70(1/2H, s), 7.30-
7.41 (6H, m), 7.59-7.68 (4H, m); 13C NMR (75 MHz, CDCl3) δ
-4.4 (q), -4.3 (q), -4.1 (q), -4.0 (q), 16.5 (q), 16.6(q), 17.9 (q),
18.2 (q), 19.1 (s), 19.2 (s),25.8 (q), 26.8 (q), 26.9 (q), 33.6 (d), 33.7
(t), 38.4 (t), 62.2 (t), 62.4 (t), 116.8 (d), 119.0 (d), 121.2 (s), 123.0
(d), 127.5 (d), 127.7 (d), 128.3 (s), 129.8 (d), 129.9 (d), 132.6 (s),
132.9 (s), 133.0 (d), 135.5 (s), 135.7 (d), 147.7 (s), 147.8 (s), 148.5
(s).
1
1655, 2853, 3071 cm-1; H NMR (400 MHz, CDCl3) δ 1.01 (9H,
s), 1.56 (3H, s), 1.64 (3H, s), 1.72-1.96 (2H, m), 2.02 (3H, s),
2.16 (2H, dd, J ) 7.2, 6.8 Hz), 3.02 (1H, m), 3.54 (2H, dd, J )
8.0, 8.0 Hz), 4.69 (1H, t, J ) 7.2 Hz), 6.40 (1H, s), 6.52 (1H, s),
7.34-7.47 (6H, m), 7.61-7.70 (4H, m); 13C NMR (75 MHz,
CDCl3) δ 15.3 (q), 17.8 (q), 19.0 (q), 25.7 (q), 26.8 (q), 32.7 (t),
35.2 (d), 35.7 (t), 61.8 (t), 121.2 (d), 127.6 (d), 129.5 (d), 132.1
(d), 133.57 (s), 133.60 (s), 133.7 (s), 133.8 (d), 135.4 (d), 144.8
(s), 151.8 (s), 187.2 (s), 188.1 (s); MS (EI) m/z 486 (M+), 351 (base
peak); HRMS calcd for C31H38O3Si 486.259, found 486.2593.
(S)-2-(1-(2-(ter t-Bu tyld ip h en ylsiloxy)eth yl)-4-m eth yl-3-
p en ten yl)-5-m eth yl- h yd r oqu in on e (19). To a solution of 18
(741 mg, 1.52 mmol) in THF (15 mL) was added aqueous sodium
hydrosulfite (1.32 g, 7.62 mmol) portionwise over 10 min at 0
°C. After being stirred for 10 min at 0 °C, the reaction mixture
was extracted with ether (2 × 10 mL). The organic layer was
washed with brine, dried over MgSO4, and concentrated. The
residue was purified by column chromatography (silica gel, hex/
AcOEt ) 90/10) to give 19 (741 mg, 88%) as a light yellow oil:
[R]D ) -10.4 (c 1.35, CHCl3); IR (neat) 1111, 1144, 1186, 2853,
(2S,4R)- a n d (2R,4R)-4-(2-(ter t-Bu t yld ip h en ylsiloxy)-
eth yl)-3,4-d ih yd r o-6-h yd r oxy-2-(1-h yd r oxy-1-m eth yl)eth yl-
7-m eth yl-2H-1-ben zop yr a n (22). To a solution of 21 (45 mg,
0.056 mmol) in MeOH (0.2 mL) was added K2CO3 (54 mg, 0.89
mmol). The mixture was stirred at 50 °C for 12 h. The mixture
was extracted with CH2Cl2, dried over Na2SO4, and concentrated
in vacuo to give a crude mixture that was purified by column
chromatography (silica gel, hex/AcOEt ) 8/2), giving an insepa-
rable diastereomeric mixture of the benzopyran 22 (25 mg, 85%)
as a light yellow oil: IR (neat) 1110, 1210, 3585 cm-1; 1H NMR
(300 MHz + D2O, CDCl3) δ 1.09 (9H, s), 1.18 (3H, s), 1.23 (3H,
s), 1.26 (1H, m), 1.67-1.77 (2H, m), 1.85 (1H, ddd, J ) 10.2,
6.5, 6.3 Hz), 2.16 (3H, s), 3.00 (1H, m), 3.68 (1H, dd, J ) 6.9, 6.9
Hz), 3.79 (2H, t, J ) 6.0 Hz), 6.34 (1H, s), 6.60 (1H, s), 7.36-
7.46 (6H, m), 7.66-7.72 (4H, m); 13C NMR (75 MHz, CDCl3) δ
15.6 (q), 19.2 (s), 24.1 (q), 25.8 (q), 26.2 (t), 29.7 (d), 40.2 (t),
60.9 (t), 72 (s), 77.4 (d), 115.1 (d), 118.4 (d), 123.5 (s), 124 (s),
127.7 (d), 129.7 (d), 129.8 (d), 133.7 (s), 133.9 (s), 135.6 (s), 147.3
(s), 147.7 (s); MS(EI) m/z: 504 (M+), 41 (base peak); HRMS calcd
for C31H40O4Si 504.2696, found 504.2725.
3071 cm-1 1H NMR (400 MHz, CDCl3 + D2O) δ 1.08 (9H, s),
;
1.21-1.30 (1H, m), 1.60 (3H, s), 1.70 (3H, s), 1.85-1.96 (1H, m),
2.18 (3H, s), 2.29 (2H, dd, J ) 9.3, 6.8 Hz), 3.02 (1H, m), 3.51
(1H, ddd, J ) 11, 10.9, 3.5 Hz), 3.63 (1H, ddd, J ) 11, 5.4, 3.0
Hz), 5.10 (1H, t, J ) 7.2 Hz), 6.49 (1H, s), 6.73 (1H, s), 7.34-
7.47 (6H, m), 7.61-7.70 (4H, m); 13C NMR (75 MHz, CDCl3) δ
15.5 (q), 17.9 (q), 19.1 (s), 25.8 (q), 26.8 (q), 33.6 (d), 33.7 (t),
38.2 (t), 62.2 (t), 113.0 (d), 119.0 (d), 122.3 (s), 122.9 (s),127.7
(s), 129.3 (s), 129.8 (d), 129.9 (d) 133.0 (d), 135.57 (s), 135.61 (s),
135.7 (d), 147.8 (s), 148.5 (s); MS (EI) m/z 488 (M+), 353 (base
peak); HRMS calcd for C31H40O3Si 488.2745, found 488.2761.
(S)-5-(2,5-Bis(ter t-bu tyldim eth ylsiloxy)-4-m eth ylph en yl)-
7-ter t-bu tyld ip h en ylsiloxy-2-m eth yl-2-h ep ten e (20). Imi-
dazole (110 mg, 1.61 mmol), tert-butyldimethylchlorosilane (384
mg, 1.40 mmol), and 4-(dimethylamino)pyridine (0.3 mg, 2.5
µmol) were added to a solution of 19 (150 mg, 0.55 mmol) in dry
CH2Cl2 (3 mL). After being stirred at room temperature for 1 h,
the mixture was quenched with H2O and extracted with CH2-
Cl2. The organic layer was washed with brine, dried over MgSO4,
and concentrated to give a residue which was purified by column
chromatography (silica gel, hex/AcOEt ) 9/1) to give 20 (302
mg, 95%) as a yellow oil: [R]D ) -13.8 (c 1.0, CHCl3); IR (neat)
1120, 1146, 1192, 2968, 3049 cm-1; 1H NMR (400 MHz, CDCl3)
(2S,4R)-4-(2-(ter t-Bu tyldiph en ylsiloxy)eth yl)-3,4-dih ydr o-
6-(m eth oxym eth yl)-2-(1-(m eth oxym eth yl)-1-m eth yleth yl)-
7-m eth yl-2H-1-ben zop yr a n (23). Chloromethyl methyl ether
(0.4 mL) was added to a solution of 22 (18.1 mg, 35.9 µmol) in
dry diisopropylethylamine (0.7 mL). After being stirred at room
temperature for 17 h, the reaction mixture was diluted with CH2-
Cl2, washed with water and brine, dried over MgSO4, and
evaporated. Purification by column chromatography (15% EtOAc/
hex) provided 23 (31 mg, 65%) as a diastereomeric mixture. The
isomers were separated with preparative HPLC (Hibar RT 250-
25LiChrosorbSi 60 (7 µm), hex/AcOEt ) 95/5 (v/v), flow rate 10
mL/min), as a yellow oil. (2S,4R)-23 (retention time 39.50 min):
[R]D ) -13.0 (c 1.2, CHCl3); IR (neat) 1039, 1149, 1498, 2931
cm-1 1H NMR (300 MHz, CDCl3) δ 1.08 (9H, s), 1.25 (3H, s),
;
1.30 (3H, s), 1.63-1.93 (4H, m), 2.18(3H, s), 3.03 (1H, m), 3.33
(3H, s), 3.47 (3H, s), 3.74-3.80 (3H, m), 4.73 (1H, d, J ) 7.2
Hz), 4.78 (1H, d, J ) 7.2 Hz), 5.04 (1H, d, J ) 6.3 Hz), 5.07 (1H,
d, J ) 6.3 Hz), 6.64 (1H, s), 6.78 (1H, s), 7.38-7.43 (6H, m),
7.57-7.69(4H, m); 13C NMR (75 MHz, CDCl3) δ 16.0 (q), 19.2
(s), 21.7 (q), 23.5 (q), 25.7 (t), 26.9 (q), 30.2 (d), 40.3 (t), 55.2 (q),

314 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
56.0 (q), 61.3 (t), 76.8 (d), 77.2 (s), 91.2 (t), 95.5 (t), 115.8 (d),
118.6 (d), 123.9 (s), 127.2 (s), 127.7 (d), 129.6 (d), 133.9 (s), 135.6
(d), 148.9 (s), 149.2 (s); MS (EI) m/z 592 (M+), 57 (base peak);
HRMS calcd for C35H48O6Si 592.3220, found 592.3213. (2R,4R)-
23 (retention time 44.14 min): 1H NMR (300 MHz, CDCl3) δ
1.05 (9H, s), 1.27 (3H, s), 1.33 (3H, s), 1.60 (2H, m), 2.10-2.26
(2H, m), 2.17 (3H, s), 2.31 (1H, m), 3.08 (1H, m), 3.34 (3H, s),
3.48 (3H, s), 3.75 (1H, d, J ) 11.2 Hz), 3.82 (2H, t, J ) 6.5 Hz),
4.74 (1H, d, J ) 7.5 Hz), 4.82 (1H, d, J ) 7.5 Hz), 5.06 (1H, d,
J ) 6.5 Hz), 5.10 (1H, d, J ) 6.5 Hz), 6.67 (1H, s), 6.87 (1H, s),
7.35-7.48 (6H, m), 7.66-7.75 (4H, m); 13C NMR (75 MHz,
CDCl3) δ 15.9 (q), 19.2 (s), 21.6 (q), 23.5 (q), 26.8 (q), 28.7 (t),
31.8 (d), 37.7 (t), 55.2 (q), 56.0 (q), 61.7 (t), 91.3 (t), 95.7 (t), 113.5
(d), 118.8 (d), 124.1 (s), 127.6 (s), 129.6 (d), 133.8 (s), 135.6 (d),
149.3 (s), 150.0 (s); MS (EI) m/z 592 (M+), 69 (base peak); HRMS
calcd for C35H48O6Si 592.3220, found 592.3208.
(2S,4R)-3,4-Dih yd r o-4-(2-h yd r oxyeth yl)-6-(m eth oxym e-
th yl)-2-(1-(m eth oxym eth yl)-1-m eth yleth yl)-7-m eth yl-2H-1-
ben zop yr a n (24). To a stirred solution of (2S,4R)-23 (36 mg,
0.061 mmol) in THF (1 mL) was added 1 M tetrabutylammonium
fluoride in THF (0.1 mL) at 0 °C. After being stirred for 2.5 h at
room temperature, the reaction mixture was poured into water
and extracted with ether. The combined organic layer was dried
over MgSO4 and evaporated. Purification by column chroma-
tography (silica gel, hex/AcOEt ) 60/40) afforded 24 (20 mg, 93%)
as a colorless oil: [R]D ) -31.9 (c 0.69, CHCl3); IR (neat) 1075,
1150, 3433 cm-1; 1H NMR (300 MHz, CDCl3 + D2O) δ 1.30 (3H,
s), 1.37 (3H, s), 1.72-2.03 (4H, m), 2.18 (3H, s), 2.97 (1H, m),
3.38 (3H, s), 3.48 (3H, s), 3.78 (2H, dd, J ) 6.3, 6.3 Hz), 3.84
(1H, dd, J ) 11.7, 1.2 Hz), 4.78 (1H, d, J ) 7.2 Hz), 4.83 (1H, d,
J ) 7.2 Hz), 5.10 (2H, s), 6.65 (1H, s), 6.78 (1H, s); 13C NMR (75
MHz, CDCl3) δ 16.0 (q), 21.6 (q), 23.6 (q), 25.9 (q), 30.6 (d), 40.2
(t), 55.2 (q), 55.9 (q), 76.7 (d), 77.3 (s), 91.3 (t), 95.4 (t), 115.5 (s),
118.7 (s), 123.5 (s), 127.2 (s), 149.0 (s), 149.1 (s); MS (EI) m/z:
354 (M+), 45 (base peak); HRMS calcd for C19H30O6 354.2042,
found 354.2034.
(2S,4S)-3,4-Dih yd r o-4-(2-((2-n it r op h en yl)selen o)et h yl)-
6-(m eth oxym eth yl)-2-(1-(m eth oxym eth yl)-1-m eth yleth yl)-
7-m eth yl-2H-1-ben zop yr a n (25). A solution of alcohol 24 (20
mg, 0.056 mmol) in THF (0.5 mL) containing o-nitrophenyl
selenocyanate (16 mg, 0.115 mmol) under nitrogen was treated
with tributylphosphine (20 mg, 0.115 mmol) at room tempera-
ture. After the reaction was stirred for 3.5 h, the solvent was
removed in vacuo. Purification by column chromatography (silica
gel, hex/AcOEt ) 92/8) afforded the crude product which was
used to the next reaction without further purification.
(2S,4S)-3,4-Dih yd r o-4-et h en yl-6-(m et h oxym et h yl)-2-(1-
(m eth oxym eth yl)-1-m eth yleth yl)-7-m eth yl-2H-1-ben zop y-
r a n (26). A solution of 25 (40 mg, 0.056 mmol) in THF (1.0 mL)
was treated dropwise with 35% H2O2 (0.14 mL, 1.49 mmol) at
room temperature. After the reaction was stirred for 2.5 h, the
solvent was removed in vacuo. The residue was extracted with
ether, washed with brine, and evaporated. Purification by
column chromatography (silica gel, hex/EtOAc ) 95/5) afforded
26 (20 mg, 91%) as a colorless oil: [R]D ) -52.4 (c 0.45, CHCl3);
1
IR (neat) 1075, 1150, 3433 cm-1; H NMR (300 MHz, CDCl3
+
D2O) δ 1.29 (3H, s), 1.35 (3H, s), 1.88 (1H, ddd, J ) 13.0, 10.1,
5.4 Hz), 1.94 (1H, ddd, J ) 13.0, 2.8, 2.8 Hz), 2.19 (3H, s), 3.37
(3H, s), 3.48 (3H, s), 3.49 (1H, m), 3.7 (1H, dd, J ) 11.7, 1.8 Hz),
4.78 (1H, d, J ) 7.2 Hz), 4.83 (1H, d, J ) 7.2 Hz), 4.90 (1H, d,
J ) 17 Hz), 5.07 (1H, d, J ) 10.8 Hz), 5.10 (2H, s), 5.99 (1H,
ddd, J ) 17.0, 10.8, 6.3 Hz), 6.67 (1H, s), 6.72 (1H, s); 13C NMR
(75 MHz, CDCl3) δ 16.0 (q), 21.7 (q) 23.5 (q), 27.1 (t), 38.2 (d),
55.2 (q), 55.9 (q), 76.8 (d), 77.1 (s), 91.3 (d), 95.4 (t), 115.6 (t),
116.2 (d), 118.7 (s), 120.4 (s), 127.6 (s), 142.3 (d), 149.0 (s), 150.0
(s); MS (EI) m/z 336 (M+, base peak); HRMS calcd for C19H28O5
336.1937, found 336.1945.
Helia n n u ol E (1). To a solution of 26 (20 mg, 0.056 mmol)
in THF (1.0 mL) was added dropwise 6 N HCl (3.5 mL, 1.49
mmol) at room temperature. After the mixture was stirred for
24 h, H2O was added and the solution was extracted with ether,
washed with brine, and evaporated. Purification by column
chromatography (silica gel, hex/AcOEt ) 90/10) afforded 1 (10
mg, 89%) as a colorless oil: [R]27 ) -69.8 (c 0.11, CHCl3) [lit.1
D
[R]D ) -68.6 (c 0.1, CHCl3)]; IR (neat) 1196, 1636, 3374 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.25 (3H, s), 1.28 (3H, s), 1.85 (1H,
ddd, J ) 12.6, 2.9, 2.2 Hz), 1.89 (1H, ddd, J ) 12.6, 10.1, 5.4
Hz), 2.18 (3H, s), 3.46 (1H, m), 3.72 (1H, dd, J ) 10.1, 2.9 Hz),
4.90 (1H, d, J ) 17 Hz), 5.05 (1H, d, J ) 10.1 Hz), 5.96 (1H,
ddd, J ) 17.0, 10.1, 6.3 Hz), 6.48 (1H, s), 6.66 (1H, s); 13C NMR
(75 MHz, CDCl3) δ 15.7 (q), 24.2 (q) 25.0 (q), 27.5 (t), 37.9 (d),
71.9 (s), 77.5 (d), 115.8 (t), 115.9 (d), 118.5 (d), 120.7 (s), 124.5
(s), 142.1 (d), 147.4 (s), 148.3 (s); MS (EI) m/z 248 (M+, base
peak), 233 (M - Me)+ (17.8), 230 (M - H2O)+ (62.4), 215 (M -
H2O - Me)+ (49.3).
Ack n ow led gm en t. We are grateful to Professor
Francisco Mac´ıas, University of Ca´diz, for valuable
discussions and Dr. Yoshihiko Hirose, Amano Pharma-
ceutical Co., Ltd., for providing lipase AK. This work
was supported by Grants-in-Aid for Scientific Research
(No. 11557172) from the Ministry of Education, Science,
Sports, and Culture, Government of J apan.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 6-11, (R)-12, (R)-14 (1H NMR
only), (S)-14 (1H NMR only), 15-21, (2S,4R)-22, (2R,4R)-22
(1H NMR only), (2S,4R)-23, (2R,4R)-23, 24-26, and 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0011437