First enantioselective synthesis and absolute stereochemistry assignment of new monocyclic sesquiterpenes from Artemisia chamaemelifolia

Article abstract of DOI:10.1021/jo034424y

We herein report the first enantioselective synthesis of two new monocyclic sesquiterpenes from Artemisia chamaemelifolia starting from an enantiopure building block. The key feature of the present approach is to allow complete control of all the stereoge

Full text of DOI:10.1021/jo034424y

oxidation, most likely via an intermediate hydroperox-
ide.2 Our approach is outlined in Scheme 3.
F ir st En a n tioselective Syn th esis a n d
Absolu te Ster eoch em istr y Assign m en t of
New Mon ocyclic Sesqu iter p en es fr om
Ar tem isia ch a m a em elifolia
We recently reported the straightforward synthesis of
the required enantiopure building blocks, (1R,5S)-8,8-
dimethyl-2-methylene-6-oxabicyclo[3.2.1]octan-7-one, (+)-4
(karahana lactone), or its enantiomer.4 Starting from (+)-
4, allylic hydroxylation with SeO2/t-BuOOH (70 wt % in
water) in dichloromethane afforded, after stirring for 3
days under reflux, the alcohol (+)-5 as a single stereoi-
somer in 85% isolated yield.5
J ean-Pierre Uttaro, Ge´rard Audran, Elie Palombo, and
Honore´ Monti*
Laboratoire de Re´activite´ Organique Se´lective UMR 6516
Faculte´ des Sciences de St-J e´roˆme, Avenue Escadrille
Normandie-Niemen, 13397 Marseille Cedex 20, France
honore.monti@univ.u-3mrs.fr
Received April 2, 2003
The stereochemistry of the hydroxyl function was
inverted at this stage by a two-step procedure. Dess-
Martin periodinane6 oxidation of (+)-5 and subsequent
NaBH4-CeCl3 Luche reduction7 of the intermediate
ketone afforded the single stereomer epi-5 in 83% yield
over two steps. Each product was found to be pure enough
for the next step, but our attempts to stringently purify
them resulted in partial degradation. Thus, only a small
sample was purified by silica gel column chromatography
for the purpose of characterization. The stereochemistry
at the 3-position of epi-5 was unambiguously assigned,
based on NOESY analysis (Figure 2). A strong correlation
between the signal at δ ) 1.0 (Me) and δ ) 1.71 (4-H)
means that these chemical shifts could be assigned to
10â-Meax and 4â-Hax. Moreover, a NOE effect for 5â-Heq
(δ ) 4.34), 4â-Hax, for 4R-Heq (δ ) 2.50), 5â-Heq, 3-H (δ )
4.37) and the absence of NOE for 4â-Hax, 3-H established
the 3R-Hax position.
The protection of the hydroxyl group of epi-5 was
conducted on the crude alcohol, and TBS (tert-butyldim-
ethylsilane) derivative (+)-6 was obtained in 78% yield
using the usual method (TBSCl, imidazole, DMF).8
Reduction of (+)-6 with diisobutylaluminum hydride
(DIBAL) in toluene at -78 °C afforded a mixture of
diastereomeric lactols 7 in 89% yield. Application of the
mild and efficient barium hydroxide-promoted Horner-
Wadsworth-Emmons (HWE) reaction9 to the mixture 7,
using the barium derivative of diethyl-2-oxopropylphos-
phonate in THF at room temperature, gave 92% as an
easily separable 1:3 mixture of the expected derivative
(+)-8 and diastereomeric bicyclic compounds 9 resulting
from the intramolecular domino10 oxa-conjugate addition
of the hydroxyl group to the intermediate enone system
generated by the HWE reaction. Acetylation of (+)-8
using the usual procedure (Ac2O, pyridine) and irrevers-
ible retro-Michael acetylation of 9 by heating under reflux
with acetic anhydride and pyridinium p-toluenesulfonate
(PPTS) furnished crystalline (+)-10 (mp 40 °C) as a single
E stereomer (3J trans ) 15.8 Hz) in 91% and 89% yield,
Abstr a ct: We herein report the first enantioselective
synthesis of two new monocyclic sesquiterpenes from Arte-
misia chamaemelifolia starting from an enantiopure build-
ing block. The key feature of the present approach is to allow
complete control of all the stereogenic centers present in the
natural products and to elucidate their absolute stereochem-
istry, which to date is unknown.
Oxygenated monocyclic terpenoids are not very com-
mon metabolites in nature because biosynthetic processes
are usually based on polycyclization. However, during the
past few years, identification of several natural oxygen-
ated monocyclic sesquiterpenes suggests that they may
be more prevalent than it was presumed within the plant
kingdom.1 In 1996, Marco et al.2 isolated three new mono-
cyclic sesquiterpenes 1-3 from the aerial parts of Arte-
misia chamaemelifolia ssp. Chamaemelifolia (Figure 1).
These authors established both the structure and relative
stereochemistry of 1-3 by spectroscopy, but since then,
only one racemic synthesis of 2 and 3 has been published3
and the absolute configurations still remain unknown.
Starting from an enantiopure building block for the
introduction and determination of the absolute stereo-
chemistry, we have carried out the first enantioselective
synthesis of (+)-1 to confirm the structural assignment
and to determine the absolute stereochemistry of the
four chiral centers present in the natural product. Our
methodology is depicted in Schemes 1 and 2. After
achieving the efficient synthesis of derivative (+)-1, we
then sought to use it as a valuable starting block for the
expeditious two-step synthesis of (-)-2. We had in mind
that the three remaining chiral centers share the same
absolute stereochemistry because it was suggested that
compound (+)-1 is formed from (-)-2 by enzymatic
(1) (a) Barrero, A. F.; Alvarez-Manzaneda R., E. J .; Alvarez-
Manzaneda R., R. Tetrahedron Lett. 1989, 30, 3351. (b) Barrero, A.
F.; Manzaneda R., E. A.; Manzaneda R., R. A.; Arseniyadis, S.; Guittet,
E. Tetrahedron 1990, 46, 8161. (c) Barrero, A. F.; Haidour, A.; Mun˜oz-
Dorado, M.; Akssira, M.; Sedqui, A.; Mansour, I. Phytochemistry 1998,
48, 1237. (d) Akihisa, T.; Arai, K.; Kimura, Y.; Koike, K.; Kokke, W.
C. M. C.; Nikaido, T. T. J . Nat. Prod. 1999, 62, 265. (e) Barrero, A. F.,
Alvarez-Manzaneda, E. J .; Herrador, M. M.; Alvarez-Manzaneda, R.;
Quilez, J .; Chahboun, R.; Linarez, P.; Rivas, A. Tetrahedron Lett. 1999,
40, 8273. (f) Akihisa, T.; Akai, K.; Kimura, Y.; Koike, K.; Kokke, W. C.
M. C.; Shibata, T.; Nikaido, T. Lipids 1999, 34, 1151. (g) Caglioti, L.;
Naef, H.; Arigoni, D.; J eger, O. Helv. Chim. Acta 1959, 42, 2557. (h)
Marco, J . A.; Sanz, J . F.; Yuste, A.; Carda, M.; J akupovic, J . Phy-
tochemistry 1991, 30, 3661.
(4) Galano, J . M.; Audran, G.; Monti, H. Tetrahedron 2000, 56, 7477.
(5) The data match spectral data for the enantiomer of (+)-5:
Audran, G.; Uttaro, J .-P.; Monti, H. Synlett 2002, 1261.
(6) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(7) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454.
(8) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(2) Marco, J . A.; Sanz-Cervera, J . F.; Morante, M. D.; Garcia-Lliso,
V.; Valles-Xirau, J .; J akupovic, J . Phytochemistry 1996, 41, 837.
(3) Barrero, A. F.; Alvarez-Manzaneda, E. J .; Chahboun, R.; Rivas,
A. R.; Palomino, P. L.; Tetrahedron 2000, 56, 6099.
(9) Paterson, I.; Yeung, K.-S.; Smaill, J . B. Synlett 1993, 774.
(10) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York,
1992. Reviews: Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Bunce, R.
A. Tetrahedron 1995, 51, 13103. (c) Rodriguez, J . Synlett 1999, 505.
10.1021/jo034424y CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/23/2003
J . Org. Chem. 2003, 68, 5407-5410
5407

F IGUR E 1. Natural monocyclic sesquiterpenes 1-3: (+)-1 and (-)-2 are represented with the absolute stereochemistry as
determined in this work.
SCHEME 1a
a
Reagents and conditions: (a) cat. SeO2, cat. salicylic acid, t-BuOOH 70% in water, CH2Cl2, reflux, 85%; (b) (i) Dess-Martin reagent,
CH2Cl2, (ii) NaBH4, CeCl3‚7H2O, MeOH, -18 °C, 83% (two steps), (iii) TBSCl, imidazole, DMF, rt, 78%; (c) DIBAL, toluene, -78 °C, 89%;
(d) (EtO)2P(O)CH2COMe, Ba(OH)2, THF, rt, 92%; (e) Ac2O, cat. DMAP, Pyr, rt, 91%; (f) Ac2O, PPTS, toluene, reflux, 89%; (g) HSnBu3,
cat. Pd(PPh3)4, ZnCl2, THF, rt,83%; (h) CH2dCHMgBr, THF, -20 °C, 90%.
SCHEME 2a
a
Reagents and conditions: (a) separated by flash chromatography; (b) TBAF, THF, rt, 95%; (c) LiAlH4, ether, rt, 99%.
SCHEME 3a
F IGURE 2. Selected NOESY interactions for epi-5.
respectively.11 The chemoselective 1,4-conjugate reduc-
tion of the R,â-enone system of (+)-10 using Bu3SnH/cat.
Pd(PPh3)4 in the presence of anhydrous ZnCl2 as the
reducing system12 yielded 83% of (+)-11. Subsequent
exposure of (+)-11 to vinylmagnesium bromide furnished
a
Reagents and conditions: (a) MsCl, CH2Cl2-Pyr (1:1), rt, (b)
the two desired diastereomeric alcohols 12 and 13 in a
5 equiv of LiAlH(O-t-Bu)3, Et2O, rt, 70% (two steps).
2:1 ratio and 90% combined yield.
parable in magnitude and the same in sign, indicating
the synthesis of the natural enantiomer.2 The remaining
task for the complete identification was the determina-
tion of the absolute stereochemistry of the quaternary
stereogenic center at the side chain of (+)-1. This ster-
eochemistry was unequivocally determined to be the R
configuration via reduction of (+)-1 to the corresponding
crystalline triol (-)-15 and subsequent X-ray crystal-
lographic analysis. Therefore, the absolute stereochem-
istry of the natural product was established as (+)-1,
depicted in Scheme 2 and Figure 1.
Gratifyingly, (+)-12 and (+)-13 differ significantly in
polarity and therefore proved to be chromatographically
separable at this stage (Scheme 2). Removal of the TBS
protecting group of (+)-12, the first eluted derivative, and
(+)-13 furnished the corresponding dihydroxy acetate
(+)-1 and (+)-14, respectively. The spectroscopic data (IR,
1H and 13C NMR) of synthetic (+)-1 matched that
reported for natural 1 and the specific rotation was com-
(11) Harrison, I. T.; Grayshan, R.; Williams, T.; Semenovski, A.;
Fried, J . H. Tetrahedron Lett. 1972, 13, 5151.
(12) (a) Four, P.; Guibe, F. Tetrahedron Lett. 1982, 23, 1825. (b) Xian,
Y. T.; Four, P.; Guibe, F.; Balavoine, G. Nouv. J . Chim. 1984, 8, 611.
With (+)-1 in hand, our attention was then focused on
the synthesis of the target molecule (-)-2 from (+)-1
5408 J . Org. Chem., Vol. 68, No. 13, 2003

for characterization. Mp ) 127 °C. [R]25D ) +94.7 (c 1.0, CHCl3).
IR (KBr): ν 3082, 1763, 1674, 1629, 891 cm-1 1H NMR (200
using, as the key step, the reductive transposition of an
allylic derivative (Scheme 3).
.
MHz, CDCl3): δ 6.28 (s, 1H), 5.53 (s, 1H), 4.51 (s, 1H), 3.15 (s,
1H), 2.83 and 2.66 (AB, J ) 19.7, 2.4, 1.8 Hz, 2H), 1.30 (s, 3H),
1.10 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 193.6 (C), 174.8 (C),
138.5 (C), 126.1 (CH2), 83.3 (CH), 56.3 (CH), 41.6 (C), 41.2 (CH2),
24.8 (CH3), 19.3 (CH3). Anal. Calcd for C10H12O3: C, 66.65; H,
6.71. Found: C, 66.87; H, 6.68.
Of the several methods available to reach our goal,13
the two-step procedure involving transformation of (+)-1
into 16 and hydrogenolysis of the crude allylic mesylate
with LiAlH(O-t-Bu)3 was found to be the most effective,
giving the desired target (-)-2 and its exocyclic double
bond regioisomer in a 92:8 ratio and 70% yield (two
steps). This byproduct posed minimal problem as it was
easily removed by careful flash chromatography to afford
pure (-)-2 whose optical rotation and spectroscopic prop-
erties are identical to those reported for the natural pro-
duct.2 This is in agreement with our working assumption
and therefore, the absolute stereochemistry of the natural
product was established as (-)-2, depicted in Scheme 3
and Figure 1.
To a stirred solution of the above ketone (950 mg, 5.27 mmol)
in MeOH (80 mL) was added CeCl3‚7H2O (2.55 g, 6.85 mmol)
under an argon atmosphere. After being stirred for 1 h at rt,
the solution was cooled to -18 °C and NaBH4 (220 mg, 5.80
mmol) was added. The solution was stirred for 15 min and
concentrated under reduced pressure. Water (200 mL) and CH2-
Cl2 (100 mL) were added to the residue. After extraction with
CH2Cl2, the combined extracts were dried with MgSO4 and
concentrated in vacuo to afford 813 mg of crude alcohol (85%
yield; 83% for the two steps). A part of the residue was
chromatographed on silica gel, recrystallized (Et2O-hexane),
and characterized. Mp ) 78 °C. [R]25 ) +162.0 (c 1.0, CHCl3).
In summary, an asymmetric synthesis of two new
monocyclic sesquiterpenes isolated from A. chamaemeli-
folia has been achieved for the first time, and the absolute
configurations have been fully determined. The merits
of this approach are high-yielding reaction steps, secured
absolute stereochemistry, and applicability of this meth-
odology to the synthesis of the enantiomers, starting from
(-)-4. We trust that this work will be useful for the
characterization of these molecules, in the event of their
isolation in other natural sources, and to deduce the
absolute configurations, simply by the measurement of
the specific rotation. This will enrich the natural products
databases.
D
IR (KBr): ν 3451, 3083, 1762, 894 cm-1
;
1H NMR (500 MHz,
CDCl3): δ 5.28 (d, J ) 2.2 Hz, 1H), 5.00 (d, J ) 2.2 Hz, 1H),
4.37 (br t, J ) 8.0 Hz, 1H), 4.34 (d, J ) 4.3 Hz, 1H), 2.85 (s, 1H),
2.50 (ddd, J ) 13.4, 7.8, 4.3 Hz, 1H), 1.71 (dd, J ) 13.9, 9.7 Hz,
1H), 1.16 (s, 3H), 1.01 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
176.4 (C), 142.8 (C), 111.1 (CH2), 85.6 (CH), 65.9 (CH), 58.5 (CH),
42.9 (C), 34.8 (CH2), 24.8 (CH3), 20.2 (CH3). Anal. Calcd for
C
10H14O3: C, 65.92; H, 7.74. Found: C, 65.64; H, 7.72.
The above crude alcohol (725 mg, 3.98 mmol) was dissolved
in DMF (20 mL), imidazole (813 mg, 11.94 mmol) and tert-
butyldimethylsilyl chloride (1.20 g, 7.96 mmol) were added, and
the mixture was stirred for 12 h at rt. The solution was
concentrated in vacuo, and the residue was purified by column
chromatography to give 920 mg (78%) of compound (+)-6 as a
solid. Recrystallization from Et2O-hexane afforded pure (+)-6
as white crystals. Mp ) 72 °C. [R]25 ) +127.8 (c 1.0, CHCl3).
D
Exp er im en ta l Section
IR (KBr): ν 3086, 1761, 1642, 892 cm-1
.
1H NMR (300 MHz,
CDCl3): δ 5.24 (dd, J ) 2.1, 1.5 Hz, 1H), 4.94 (br s, 1H), 4.36-
4.30 (m, 2H), 2.84 (s, 1H), 2.38 (ddd, J ) 13.7, 7.8, 4.4 Hz, 1H),
1.71 (dd, J ) 13.8, 9.2 Hz, 1H), 1.16 (s, 3H), 1.01 (s, 3H), 0.89
(s, 9H), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
176.4 (C), 142.7 (C), 111.4 (CH2), 85.6 (CH), 66.7 (CH), 58.3 (CH),
42.9 (C), 35.7 (CH2), 25.7 (CH3), 24.8 (CH3), 20.3 (CH3), 18.1 (C),
-4.9 (CH3), -5.1 (CH3). Anal. Calcd for C16H28O3Si: C, 64.82;
H, 9.52. Found: C, 65.09; H, 9.48.
(1R ,3R ,5S )-3-H y d r o x y -8,8-d im e t h y l-2-m e t h y le n e -6-
oxa bicyclo[3.2.1]octa n -7-on e (+)-5. To a stirred solution of
(+)-4 (1.20 g, 7.22 mmol) in dry CH2Cl2 (80 mL) were added
selenium dioxide (321 mg, 2.89 mmol), tert-butyl hydroperoxide
(70 wt % in water, 2.60 g, 28.88 mmol), and a catalytic amount
of salicylic acid under an argon atmosphere. The reaction
mixture was heated to reflux for 3 days and cooled to rt, and
Na2SO3 (7.50 g, 60 mmol) and 1 mL of water were added. The
mixture was stirred for a further 30 min, filtered through a pad
of MgSO4, and concentrated to give a residue solid. After
purification by crystallization from Et2O-hexane, 1.13 g of pure
alcohol (+)-5 was obtained as white crystals (86%). Mp ) 157
°C. [R]25D ) +145.0 (c 1.0, CHCl3). IR (KBr): ν 3440, 3091, 1759,
(1′S,3′S,5′S)-(3E)-4-(5′-ter t-Bu tyld im eth ylsilyloxy-3′-h y-
d r oxy-2′,2′-d im eth yl-6′-m eth ylen ecycloh ex-1′-yl)bu t-3-en -
2-on e (+)-8 a n d (1S,3S,5S)-(3-ter t-Bu tyld im eth ylsilyloxy-
8,8-d im e t h y l-2-m e t h y le n e -6-o x a b ic y c lo [3.2.1]o c t -7-y l
Aceton e 9. A mixture of diethyl 2-oxopropylphosphonate (1.0
g, 5.18 mmol) and Ba(OH)2‚8H2O (653 mg, 2.07 mmol, heated
at 140 °C for 2 h under a flux of argon before use) in THF (6
mL) was stirred at rt for 30 min under an argon atmosphere. A
solution of 7 (772 mg, 2.59 mmol) in wet THF (6 mL, 40:1 THF/
H2O) was then added at this temperature. After being stirred
for 24 h, the reaction mixture was diluted with CH2Cl2 and
washed with aqueous NaHCO3 and brine. The organic extract
was dried (MgSO4), filtered, and concentrated. Purification by
column chromatography gave (+)-8 as a solid (204 mg) and a
partially separable mixture of diastereomers 9 (598 mg). (+)-8.
905 cm-1 1H NMR (200 MHz, CDCl3): δ 5.18 (s, 1H), 5.07 (s,
.
1H), 4.42 (d, J ) 6.1 Hz, 1H), 4.35 (br d, J ) 3.7 Hz, 1H), 2.76
(s, 1H), 2.23 (dd, J ) 15.7, 3.8 Hz, 1H), 2.08 (ddd, J ) 15.7, 6.1,
1.5 Hz, 1H), 1.21 (s, 3H), 0.94 (s, 3H). 13C NMR (50 MHz,
CDCl3): δ 176.6 (C), 143.9 (C), 117.0 (CH2), 84.4 (CH), 67.9 (CH),
56.6 (CH), 42.8 (C), 32.6 (CH2), 25.3 (CH3), 20.1 (CH3). Anal.
Calcd for C10H14O3: C, 65.92; H, 7.74. Found: C, 65.72; H, 7.71.
(1S,3S,5S)-3-(ter t-Bu tyld im eth ylsilyloxy)-8,8-d im eth yl-
2-m eth ylen e-6-oxabicyclo[3.2.1]octan -7-on e (+)-6. To a stirred
solution of alcohol (+)-5 (1.00 g, 5.49 mmol) in dry CH2Cl2 (40
mL) at 0 °C was added Dess-Martin periodinane (3.48 g, 8.24
mmol) under an argon atmosphere. After being stirred for 1 h
at rt, the mixture was poured into a solution of Na2SO3 (4.84 g,
38.43 mmol) and extracted with CH2Cl2. The organic layers were
combined, washed with a saturated solution of NaHCO3 and
brine, dried, filtered, and concentered to afford 970 mg (98%
crude) of ketone. A small sample of the oily residue was
chromatographed on silica gel and recrystallized (Et2O-hexane)
Mp ) 87 °C. [R]25 ) +58.4 (c 1.0, CHCl3). IR (KBr): ν 3423,
D
3083, 3021, 1735, 1663, 910 cm-1. H NMR (300 MHz, CDCl3):
1
δ 6.90 (dd, J ) 15.8, 10.2 Hz, 1H), 6.05 (d, J ) 15.9 Hz, 1H),
4.94 (s, 1H), 4.59 (s, 1H), 4.33 (br s, 1H), 3.81 (br dd, J ) 10.0,
3.6 Hz, 1H), 2.98 (d, J ) 10.0 Hz, 1H), 2.25 (s, 3H), 1.90 (dt, J
) 13.1, 4.4 Hz, 1H), 1.66 (ddd, J ) 13.0,10.2, 3.1 Hz, 1H), 0.94
(s, 3H), 0.85 (s, 9H), 0.80 (s, 3H), -0.02 (s, 3H), -0.03 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 198.3 (C), 149.1 (C), 145.7 (CH),
133.4 (CH), 110.8 (CH2), 73.2 (CH), 72.6 (CH), 51.2 (CH), 40.2
(C), 39.5 (CH2), 27.2 (CH3), 26.3 (CH3), 25.7 (CH3), 18.1 (C), 14.7
(CH3), -4.8 (CH3), -5.2 (CH3). Anal. Calcd for C19H34O3Si: C,
(13) (a) Tsuji, J . Palladium Reagents and Catalysts; J ohn Wiley &
Sons Ltd.: Chichester, 1999; pp 366-379. (b) Hegedus, L. S. In
Organometallics in Synthesis. A Manual; Schlosser, M., Ed.; J ohn
Wiley & Sons Ltd.: Chichester, 2002; pp 1191-1195. (c) Larock, R.
C.; J ohn Wiley & Sons: New York, 1999; pp 229-231.
67.40; H, 10.12. Found: C, 67.74; H, 10.09. Major 9. [R]25
)
D
+44.6 (c 1.0, CHCl3). IR (film): ν 3068, 1722, 1654, 925 cm-1
.
1H NMR (200 MHz, CDCl3): δ 5.16 (br t, J ) 2.0 Hz, 1H), 4.75
J . Org. Chem, Vol. 68, No. 13, 2003 5409

(br t, J ) 2.1 Hz, 1H), 4.58 (td, J ) 6.7, 3.8 Hz, 1H), 4.38 (tt, J
) 8.6, 2.5 Hz, 1H), 3.75 (d, J ) 4.1 Hz, 1H), 2.70 and 2.48 (ABX,
J ) 16.7, 6.9, 6.6 Hz, 2H), 2.39 (d, J ) 3.7 Hz, 1H), 2.15 (m
partially overlapped, 1H), 2.14 (s, 3H), 1.52 (dd, J ) 13.4, 9.1
Hz,1H), 1.14 (s, 3H), 0.95 (s, 3H), 0.91 (s, 9H), 0.09 (s, 3H), 0.07
(s, 3H). 13C NMR (50 MHz, CDCl3): δ 206.7 (C), 148.1 (C), 111.6
(CH2), 83.0 (CH), 74.7 (CH), 68.1 (CH), 57.4 (CH), 45.1 (CH2),
42.7 (C), 38.7 (CH2), 30.8 (CH3), 25.9 (CH3), 25.2 (CH3), 22.2
(CH3), 18.2 (C), -4.6 (CH3), -4.9 (CH3). Anal. Calcd for C19H34O3-
Si: C, 67.40; H, 10.12. Found: C, 67.13; H, 10.08.
(CH3), 25.7 (CH3), 21.1 (CH3), 20.0 (CH2), 18.2 (C and CH3), -4.8
(CH3), -5.2 (CH3). Anal. Calcd for C23H42O4Si: C, 67.27; H,
10.31. Found: C, 67.49; H, 10.29.
(1S,3R,5S,3′R)-3-(3′-Hyd r oxy-3′-m eth ylp en t-4′-en yl)-5-h y-
d r oxy-2,2-d im eth yl-4-m eth ylen ecycloh exyl Aceta te (+)-1
a n d (1S,3R,5S,3′S)-3-(3′-Hyd r oxy-3′-m eth ylp en t-4′-en yl)-5-
h yd r oxy-2,2-d im eth yl-4-m eth ylen ecycloh exyl Aceta te (+)-
14. To a solution of (+)-12 (250 mg, 0.61 mmol) in THF (12 mL)
was added dropwise tetra-n-butylammonium fluoride (1.0 M in
THF, 1.8 mL, 1.83 mmol). The reaction mixture was stirred at
rt for 12 h and then concentrated. The residual oil was chro-
matographed on silica gel to afford 172 mg (95%) of (+)-1. The
(1S,3S,5S)-5-ter t-Bu tyld im eth ylsilyloxy-2,2-d im eth yl-4-
m eth ylen e-3-[(1′E)-3′-oxobu t-1′-en yl]cycloh exyl Acetate (+)-
10. The alcohol (+)-8 (175 mg, 0.52 mmol) was dissolved in
pyridine-dichloromethane (1:1, 6 mL), Ac2O (212 mg, 2.08
mmol) and a catalytic amount of 4-(dimethylamino)pyridine
(DMAP) were added under an argon atmosphere, and the
mixture was stirred for 3 h at rt. The solution was poured into
water and extracted with ether. The combined organic extracts
were washed with water, dried, filtered, and concentrated.
Column chromatography gave 179 mg (91%) of (+)-10 as
corlorless crystals. A solution of 9 (550 mg, 1.62 mmol) and Ac2O
(497 mg, 4.87 mmol) in toluene (10 mL) was treated with PPTS
(123 mg, 0.49 mmol) and heated at 110 °C for 7 h. After being
cooled to 25 °C, the reaction mixture was diluted with Et2O,
washed with aqueous NaHCO3 and brine, and dried (MgSO4).
After concentration, column chromatography gave (+)-10 (550
mg, 89% yield) as colorless crystals. Mp ) 40 °C. [R]25D ) +61.9
same conditions starting from (+)-13 yielded (+)-14. (+)-1. [R]25
D
) +19.8 (c 1.0, CHCl3) [lit.2 [R]25 ) +14.0 (c 0.84, CHCl3)]. IR
D
1
(film): ν 3440, 3061, 1722, 1653, 916 cm-1. H NMR (200 MHz,
CDCl3): δ 5.90 (dd, J ) 17.4, 10.7 Hz, 1H), 5.18 (dd, J ) 17.3,
1.2 Hz, 1H), 5.10 (s, 1H), 5.05 (dd, J ) 10.7, 1.2 Hz, 1H), 4.96
(dd, J ) 7.5, 4.5 Hz, 1H), 4.77 (s, 1H), 4.37 (br t, J ) 5.4 Hz,
1H), 2.13 (br d, J ) 10.2 Hz, 1H), 2.04 (s, 3H), 1.91 (ddd, J )
13.5, 7.8, 4.4 Hz, 1H), 1.82 (ddd, J ) 13.5, 7.6, 4.4 Hz, 1H), 1.70-
1.50 (m, 3H), 1.31-1.26 (m, 1H), 1.27 (s, 3H), 0.97 (s, 3H), 0.80
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 170.6 (C), 148.6 (C), 145.1
(CH), 111.6 (CH2), 109.9 (CH2), 76.7 (CH), 73.3 (C), 69.8 (CH),
49.4 (CH), 40.9 (CH2), 39.2 (C), 36.1 (CH2), 27.6 (CH3), 26.2
(CH3), 21.2 (CH3), 20.0 (CH2), 17.7 (CH3). Anal. Calcd for
C17H28O4: C, 68.89; H, 9.52. Found: C, 68.57; H, 9.47. (+)-14.
[R]25D ) +33.8 (c 1.0, CHCl3). IR (film): ν 3451, 3059, 1719, 1658,
910 cm-1. 1H NMR (200 MHz, CDCl3): δ 5.88 (dd, J ) 17.4, 10.8
Hz, 1H), 5.19 (dd, J ) 17.4, 1.3 Hz, 1H), 5.10 (s, 1H), 5.05 (dd,
J ) 10.8, 1.3 Hz, 1H), 4.95 (dd, J ) 7.4, 4.4 Hz, 1H), 4.75 (s,
1H), 4.35 (br t, J ) 5.6 Hz, 1H), 2.13 (br d, J ) 12.9 Hz, 1H),
2.03 (s, 3H), 1.90 (ddd, J ) 13.6, 6.8, 4.4 Hz, 1H), 1.82 (ddd, J
) 13.6, 7.5, 4.5 Hz, 1H), 1.70-1.40 (m, 3H), 1.37-1.22 (m, 1H),
1.27 (s, 3H), 0.97 (s, 3H), 0.80 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 170.6 (C), 148.6 (C), 144.9 (CH), 111.6 (CH2), 109.8
(CH2), 76.7 (CH), 73.4 (C), 69.8 (CH), 49.4 (CH), 40.7 (CH2), 39.2
(C), 36.2 (CH2), 28.2 (CH3), 26.3 (CH3), 21.2 (CH3), 20.0 (CH2),
17.8 (CH3). Anal. Calcd for C17H28O4: C, 68.89; H, 9.52. Found:
C, 67.18; H, 9.49.
(c 1.0, CHCl3). IR (KBr): ν 3080, 3015, 1739, 1660, 911 cm-1
.
1H NMR (300 MHz, CDCl3): δ 6.90 (dd, J ) 15.8, 10.1 Hz, 1H),
6.09 (d, J ) 15.7 Hz, 1H), 5.07 (dd, J ) 9.6, 4.0 Hz, 1H), 5.00 (s,
1H), 4.65 (s, 1H), 4.33 (br q, J ) 2.9 Hz, 1H), 3.06 (d, J ) 9.8
Hz, 1H), 2.26 (s, 3H), 2.03 (s, 3H), 1.96-1.89 (m, 1H), 1.76-
1.67 (m, 1H), 0.87 (br s, 15H), 0.04 (s, 3H), 0.01 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 197.9 (C), 170.1 (C), 148.5 (C), 145.0 (CH),
133.2 (CH), 111.0 (CH2), 75.6 (CH), 71.6 (CH), 52.0 (CH), 39.1
(C), 36.4 (CH2), 27.4 (CH3), 26.3 (CH3), 25.6 (CH3), 21.1 (CH3),
18.1 (C), 16.8 (CH3), -4.9 (CH3), -5.2 (CH3). Anal. Calcd for
C
21H36O4Si: C, 66.27; H, 9.53. Found: C, 65.99; H, 9.49.
(1S,3S,5S)-5-ter t-Bu tyld im eth ylsilyloxy-2,2-d im eth yl-3-
(3′-h yd r oxy-3′-m et h ylp en t -4′-en yl)-4-m et h ylen ecycloh ex-
yl Aceta tes 12 a n d 13. To a solution of (+)-11 (500 mg, 1.30
mmol) in THF (15 mL) at -20 °C under an argon atmosphere
was added dropwise vinylmagnesium bromide (1 M in THF, 2.0
mL, 2.0 mmol). The mixture was stirred at -20 °C for 15 min,
allowed to warm to 0 °C, and quenched with aqueous NH4Cl.
After being warmed to 25 °C, the reaction mixture was extracted
with Et2O. The organic layer was dried (MgSO4) and concen-
trated to afford 483 mg (90%) of diastereomers 12 and 13.
Purification by flash chromatography gave 267 mg of pure (+)-
12 (first eluted) and 138 mg of pure (+)-13. (+)-12. [R]25D ) +14.0
(c 1.0, CHCl3). IR (film): ν 3474, 3069, 1723, 1649, 888 cm-1. 1H
NMR (300 MHz, CDCl3): δ 5.90 (dd, J ) 17.4, 10.8 Hz, 1H),
5.19 (d, J ) 17.4 Hz, 1H), 5.06 (s, 1H), 5.04 (d, J ) 10.5 Hz,
1H), 4.98 (dd, J ) 8.2, 4.0 Hz, 1H), 4.68 (s, 1H), 4.30 (dd, 1H, J
) 6.2, 4.1 Hz), 2.12 (br d, J ) 11.9 Hz, 1H), 2.03 (s, 3H), 1.88
(ddd, J ) 13.2, 6.5, 4.1 Hz, 1H), 1.74-1.49 (m, 4H), 1.35-1.29
(m, 1H), 1.27 (s, 3H), 0.96 (s, 3H), 0.89 (s, 9H), 0.78 (s, 3H), 0.05
(s, 3H), 0.02 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 170.3 (C),
148.8 (C), 145.2 (CH), 111.5 (CH2), 109.2 (CH2), 76.9 (CH), 73.2
(C), 70.7 (CH), 49.2 (CH), 40.9 (CH2), 39.2 (C), 37.2 (CH2), 27.5
(CH3), 26.2 (CH3), 25.7 (CH3), 21.2 (CH3), 19.9 (CH2), 18.2 (C),
17.6 (CH3), -4.8 (CH3), -5.2 (CH3). Anal. Calcd for C23H42O4Si:
(1S,3R,3′R)-3-(3′-H yd r oxy-3′-m et h ylp en t -4′-en yl)-2,2,4-
tr im eth ylcycloh ex-4-en yl Aceta te (-)-2. To a solution of
crude 16 (135 mg) in dry ether (5 mL) was slowly added a freshly
prepared solution of LiAlH(O-t-Bu)3 (1.8 mmol, 1.35 mL, 1.33
M in ether) at 0 °C. The solution was allowed to warm to rt.
After 24 h, celite (2 g) and Na2SO4‚10H2O (2 g) were added, and
the solution was stirred for a further 60 min. The mixture was
filtered through a pad of celite and concentrated to afford a 92:8
ratio of (-)-2 and the exocyclic double-bond regioisomer in 70%
yield. Careful silica gel column chromatography gave pure (-)-
2. [R]25 ) -24 (c 1.0, CHCl3) [lit.2 [R]25 ) -27 (c 4.0, CHCl3)].
D
D
1
IR (film): ν 3474, 1724, 917 cm-1. H NMR (300 MHz, CDCl3):
δ 5.91 (dd, J ) 17.4, 10.7 Hz, 1H), 5.21 (dd, J ) 17.4, 1.0 Hz,
1H), 5.20 (m, 1H), 5.06 (dd, J ) 10.8, 1.0 Hz, 1H), 4.68 (t, J )
6.4 Hz, 1H), 2.26 (br d, J ) 15.6 Hz, 1H), 2.04-1.94 (m partially
overlapped, 1H), 2.02 (s, 3H), 1.70 (s, 3H), 1.28 (s, 3H), 1.78-
1.53 (m, 3H), 1.52-1.24 (m, 2H), 0.90 (s, 3H), 0.88 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 170.8 (C), 145.0 (CH), 136.7 (C), 117.5
(CH), 111.8 (CH2), 76.4 (CH), 73.5 (C), 49.4 (CH), 44.2 (CH2),
36.9 (C), 28.7 (CH2), 27.7 (CH3), 25.8 (CH3), 22.9 (CH2), 22.7
(CH3), 21.3 (CH3),18.6 (CH3). Anal. Calcd for C17H28O3: C, 72.82;
H, 10.06. Found: C, 73.14; H, 10.09.
C, 67.27; H, 10.31. Found: C, 67.61; H, 10.33. (+)-13. [R]25
)
D
+28.5 (c 1.0, CHCl3). IR (film): ν 3482, 3059, 1727, 1641, 879
cm-1 1H NMR (300 MHz, CDCl3): δ 5.87 (dd, J ) 17.4, 10.7
.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and complete 1H and 13C NMR spectral data for 7,
(+)-11, (-)-15, and 16. Spectra (1H NMR, 13C NMR) for
compounds (+)-1, (-)-2, (+)-5, (+)-epi-5, (+)-6, (+)-8, (+)-10,
(+)-12, (+)-13, (+)-14 and (-)-15. X-ray crystallographic data
and ORTEP view for (+)-15. This material is available free of
charge via the Internet at http://pubs.acs.org.
Hz, 1H), 5.18 (d, J ) 17.4 Hz, 1H), 5.05 (d, J ) 10.7 Hz, 1H),
5.04 (s, 1H), 4.96 (dd, J ) 7.6, 3.8 Hz, 1H), 4.66 (s, 1H), 4.29
(dd, J ) 6.6, 4.0 Hz, 1H), 2.11 (br d, J ) 10.7 Hz, 1H), 2.03 (s,
3H), 1.87 (ddd, J ) 13.2, 6.9, 3.9 Hz, 1H), 1.70 (ddd, J ) 12.1,
7.6, 3.9 Hz, 1H), 1.61-1.50 (m, 3H), 1.32-1.26 (m, 1H), 1.27 (s,
3H), 0.96 (s, 3H), 0.88 (s, 9H), 0.78 (s, 3H), 0.04 (s, 3H), 0.01 (s,
3H). 13C NMR (50 MHz, CDCl3): δ 170.2 (C), 148.9 (C), 145.0
(CH), 111.5 (CH2), 109.0 (CH2), 77.1 (CH), 73.3 (C), 70.4 (CH),
49.5 (CH), 40.9 (CH2), 39.1 (C), 37.3 (CH2), 28.2 (CH3), 26.4
J O034424Y
5410 J . Org. Chem., Vol. 68, No. 13, 2003