Enantioselective formal synthesis of (-)-ovalicin using quinic acid as a chiral template

Article abstract of DOI:10.1016/S0957-4166(98)00284-5

The key intermediate 18 for the synthesis of (-)-ovalicin was synthesized using (-)-quinic acid as the chiral source, through a series of stereocontrolled and efficient chemical reactions, thus establishing a new, formal synthesis of the natural target. The featuring spirocyclic epoxide function has been installed by internal Williamson ether synthesis using the functionalities originally present at C-1 of (-)-quinic acid after the appropriate adjustments required to introduce the necessary functionality at C-2.

Full text of DOI:10.1016/S0957-4166(98)00284-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2857–2864
Enantioselective formal synthesis of (−)-ovalicin using quinic
acid as a chiral template †
Achille Barco,a Simonetta Benetti,a Carmela De Risi,b Paolo Marchetti,b Gian P. Pollini b,∗ and
Vinicio Zanirato b
aDipartimento di Chimica, Università di Ferrara, via L. Borsari 46, 44100 Ferrara, Italy
bDipartimento di Scienze Farmaceutiche, Università di Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy
Received 24 June 1998; accepted 17 July 1998
Abstract
The key intermediate 18 for the synthesis of (−)-ovalicin was synthesized using (−)-quinic acid as the chiral
source, through a series of stereocontrolled and efficient chemical reactions, thus establishing a new, formal synthe-
sis of the natural target. The featuring spirocyclic epoxide function has been installed by internal Williamson ether
synthesis using the functionalities originally present at C-1 of (−)-quinic acid after the appropriate adjustments
required to introduce the necessary functionality at C-2. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Angiogenesis, the formation and growth of new blood capillaries from pre-existing vessels, takes place
normally during wound healing. But abnormal angiogenesis is an important contributor to certain dis-
eases and accumulating evidence indicates that progressive tumor growth is dependent on angiogenesis.
Anti-angiogenesis treatments are designed to prevent the growth of tumor blood vessels and researchers
have been looking for inhibitors of angiogenesis because they can inhibit the growth of cancers. Even
though no definitive conclusions can be drawn, antiangiogenic therapy combined with conventional
anticancer therapies may represent a useful tool in the future care of patients with cancer.1
Recently, it has been reported that fumagillin 1, an antitumor, antibacteriophage and antiamoeba
metabolite isolated from Aspergillus fumagatus, exhibits a potent antiangiogenic activity. Although the
effectiveness of fumagillin as an inhibitor of tumor growth is limited because of its high toxicity, its
semi-synthetic analog AGM-1470 2 has just entered clinical trials for the treatment of human cancer.2
∗
†
Corresponding author. E-mail: pol@dns.unife.it
Keywords: natural products; antitumor compounds; stereospecific hydroxylation; oxiranes.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00284-5

2858
A. Barco et al. / Tetrahedron: Asymmetry 9 (1998) 2857–2864
On the other hand, the related sesquiterpene (−)-ovalicin 3, first isolated by cultures of Pseudorotium
ovalis Stolk,3 was found to be non-toxic, non-inflammatory and, above all, more potent than the structural
analog of fumagillin. As a result of these positive observations, Corey et al.4 modified the original total
synthesis of racemic ovalicin reported by himself and Dittami5 to obtain the natural enantiomer by a
catalytic asymmetric process, while Barton et al.6 described the total synthesis of (−)-ovalicin using the
naturally occurring cyclitol L-quebrachitol as the chiral synthon.
Our continuous interest in applications of (−)-quinic acid as the chiral template for asymmetric
synthesis,7,8 led us to recognize an opportunity to extend these studies in devising a new synthetic
entry to (−)-ovalicin. We envisaged the structure and the absolute stereochemistry9 of (−)-quinic acid
amenable for an efficient elaboration to the advanced chiral intermediate 18 from which (−)-ovalicin
has been obtained by application of the sequence reported by Barton et al.,6 thus establishing a new,
formal synthesis of the natural target. We were particularly intrigued by the possibility of installing the
spirocyclic epoxide function by internal Williamson ether synthesis using the functionalities originally
present at C-1 of (−)-quinic acid after the appropriate adjustments required to introduce the oxygenated
functionality at C-2.
2. Results and discussion
The starting point of the synthetic approach was the readily available bromobenzoate 5,10,11 easily
obtained in a high-yield two-step sequence involving the regiospecific N-bromosuccinimide promoted
opening of the lactone ring of the benzylidene quinide 412 derived from (−)-quinic acid following the
protocol developed by Hanessian.13 The bromine atom was subsequently successfully removed by a
free-radical mediated hydride reduction using n-tributyltin hydride in the presence of AIBN to produce
the intermediate 6. Opening of the lactone ring and concomitant saponification of the benzoate ester
occurred cleanly by treatment of 6 with methanolic potassium carbonate affording the triol ester 7. At
this point, having as the goal the interception of the advanced intermediate 18 already transformed
by Barton et al.6 into (−)-ovalicin, we tried the selective protection of the vicinal diol moiety of 7
using triethylsilyl chloride (TESCl) in order to minimize unnecessary manipulations. Unfortunately, this
operation proceeded with poor selectivity producing a mixture of mono- and bis-protected derivatives,
the latter being prevalent, forcing us to choose a more hindered silylating agent. Thus, we selected
tert-butyldimethylsilyl chloride (TBDMSCl) for the selective protection of the C-3 hydroxy group
of 7. This was accomplished performing the reaction in N,N-dimethylformamide at 0°C for 30 min
then at room temperature overnight giving rise to the formation of an unseparable mixture of mono-
protected derivatives 8 and 9 (combined yield 72%). Gratifyingly, the oxidation of the mixture of 8
and 9 with pyridinium chlorochromate in the presence of 3 Å molecular sieves followed by phosphorus
oxychloride/pyridine dehydration produced the α,β-unsaturated ketone 10 as the only isolated product
(overall yield of 60%) after flash chromatography of the crude mixture. It is likely that the regioisomer 8
could undergo a more complicated transformation during these operations with formation of aromatized
products. The reduction of the carbonyl group of 10 with sodium borohydride proceeded smoothly

A. Barco et al. / Tetrahedron: Asymmetry 9 (1998) 2857–2864
2859
at 0°C to produce a 1:4 mixture of the diastereomers 11 and 12, which were separated by silica gel
chromatography as reported by Giese and Almstead14 for the racemic compound. The alkylation of the
predominant α-alcohol 12 with methyl iodide in the presence of silver oxide led to the formation of
the corresponding methyl ether 13. The overall sequence from (−)-quinic acid to 13 is summarized in
Scheme 1.
Scheme 1.
Having in hand 13, the stage was set to perform the cis-dihydroxylation of the double bond, requiring,
as anticipated, a modification of the TBDMS protecting group into TES in order to intercept the advanced
intermediate 18 already transformed by Barton et al.6 into (−)-ovalicin.
The deprotection–reprotection manipulation was accomplished by standard procedure in
excellent overall yield to furnish the cycloalkene 15, which was submitted to osmylation to give
diastereoselectively 16 as the sole product, the osmium reagent undergoing a more favored addition
from the less hindered convex face. The stereochemistry of the newly introduced hydroxyl groups was
inferred by 1H NMR spectroscopic analysis (J2,3=9.6 Hz).
To introduce the spirocyclic epoxide function, the crude diol 16 was sequentially transformed by
treatment with lithium aluminum hydride into the triol 17, then mono-tosylated at the primary hydroxyl
function and submitted to basic treatment in order to perform the crucial intramolecular Williamson ether
synthesis to give 18 in good overall yield. The complete sequence is summarized in Scheme 2.
In summary, using one of the two original chiral centers of (−)-quinic acid,9 the other one being
removed in the initial debromination step, the required configuration at the different chiral centers of
the natural target (−)-ovalicin has been correctly established. The synthesis of (−)-ovalicin from 18 has
been reported,6 so the present synthesis of this compound represents an alternative formal synthesis of
(−)-ovalicin, stressing once more the versatility15 of (−)-quinic acid as a chiral template for the synthesis
of natural compounds.

2860
A. Barco et al. / Tetrahedron: Asymmetry 9 (1998) 2857–2864
Scheme 2.
3. Experimental section
3.1. General remarks
Melting points were determined on a Büchi–Tottoli apparatus and are uncorrected. Optical rotations
were measured with a Perkin–Elmer 241 polarimeter. Infrared (IR) spectra were taken on a Perkin–Elmer
FT-IR Paragon 500 spectrometer. Nuclear magnetic resonance (1H NMR) spectra were recorded on a
Bruker AC-200 spectrometer for solutions in CDCl3 unless otherwise noted and chemical shifts are given
in parts per million downfield from tetramethylsilane as the internal standard. Coupling constants (J) are
given in hertz. Organic solutions were dried over anhydrous magnesium sulfate and evaporated with a
rotary evaporator. Light petroleum refers to the fractions boiling in the range 40–60°C and ether to diethyl
ether. Flash chromatography was carried out with Merck silica gel (230–400 mesh). All reactions were
carried out under an Ar atmosphere. Elemental analyses were effected by the microanalytical laboratory
of the Dipartimento di Chimica, University of Ferrara.
3.2. (1S,3R,4R)-4-Benzoyloxy-1-hydroxycyclohexane-1,3-carbolactone 6
A solution of 5 (16 g, 46.92 mmol) in anhydrous benzene (150 ml) containing n-Bu3SnH (18.65 ml,
70.38 mmol) and a catalytic amount of AIBN was heated at reflux for 4 h. After cooling, most of the
solvent was removed under reduced pressure and the solid residue was taken up in light petroleum (250
ml). The resulting suspension was stirred overnight, then filtered to give 6 (12 g, 97%) as a white solid,
which could be used in the next step without further purification. An analytical sample was obtained by
crystallization (EtOAc) or flash chromatography (eluent: EtOAc:light petroleum, 1:3), m.p.: 143–145°C,
[α]D −29 (c 0.77, MeOH). IR (KBr): 3448, 1786, 1720 cm−1; 1H NMR (DMSOd6): δ 1.8–2.3 (m, 6H),
25
2.83 (s, 1H), 4.97 (m, 1H), 5.34 (m, 1H), 7.4–7.7 (m, 3H), 8.04 (d, 2H, J=7). Anal. calcd for C14H14O5:
C, 64.10; H, 5.38. Found: C, 64.03; H, 5.45.
3.3. (1S,3R,4R)-1-Methoxycarbonyl-cyclohexane-1,3,4-triol 7
A solution of 6 (3.37 g, 12.86 mmol) in MeOH (45 ml) was treated with K2CO3 (0.23 g) and stirred
at room temperature for 1 h. The cooled (0°C) reaction mixture was neutralized with AcOH and the
solvent evaporated. The residue was purified by flash chromatography (eluent: EtOAc:MeOH, 9.5:0.5)
25
to afford 7 (2.17 g, 89%) as a white solid, m.p.: 101–103°C, [α]D −17.6 (c 0.74, MeOH). IR (KBr):
1
3351, 1730 cm−1; H NMR (DMSOd6): δ 1.4–1.7 (m, 5H), 1.85 (m, 1H), 3.13 (m, 1H), 3.38 (m, 1H),

A. Barco et al. / Tetrahedron: Asymmetry 9 (1998) 2857–2864
2861
3.61 (s, 3H), 4.56 (d, 1H, J=4.2, D2O exchangeable), 4.58 (d, 1H, J=3.74, D2O exchangeable), 5.25 (s,
1H, D2O exchangeable). Anal. calcd for C8H14O5: C, 50.50; H, 7.42. Found: C, 50.48; H, 7.44.
3.4. (1S,3R,4R)-1-Methoxycarbonyl-3-(1,1-dimethylethyl)dimethylsilyloxy-cyclohexane-1,4-diol 8 and
(1S,3R,4R)-1-methoxycarbonyl-4-(1,1-dimethylethyl)dimethylsilyloxy-cyclohexane-1,3-diol 9
To an ice-cooled solution of 7 (2.83 g, 14.9 mmol) and imidazole (2.23 g, 32.78 mmol) in dry DMF
(13 ml) was added TBDMSCl (2.69 g, 17.88 mmol). After being stirred for 30 min at 0°C, the reaction
mixture was allowed to stand at room temperature overnight. The solvent was evaporated and the crude
product was subjected to flash chromatography (eluent: EtOAc:light petroleum, 1:3) affording the solid
mixture of 8 and 9 (3.28 g, 72%). IR (film): 3466, 1740 cm−1; 1H NMR: δ 0.10 and 0.11 (2s, 6H), 0.89
and 0.90 (2s, 9H), 1.6–2.1 (m, 6H), 2.42 (d, 1H, J=1.7, D2O exchangeable), 2.46 (d, 1H, J=1.85, D2O
exchangeable), 3.02 (s, 1H), 3.45 (m, 1H), 3.7–3.9 (overlapping s, 3H and m, 1H).
3.5. (6R)-3-Methoxycarbonyl-6-(1,1-dimethylethyl)dimethylsilyloxy-cyclohex-2-en-1-one 10
To a solution of 8 and 9 (0.74 g, 2.43 mmol) in dry CH2Cl2 (5 ml), 3 Å powder molecular sieves
(1.4 g), pyridine (0.78 ml, 9.72 mmol) and PCC (2.09 g, 9.72 mmol) were added and the mixture was
stirred for 2 h at room temperature. Ether and Celite (0.5 g) were added and the resulting suspension was
filtered through a pad of Celite. The solids were washed with ether (5×20 ml) and the filtrate evaporated
to an oil which was dissolved in pyridine (3.6 ml) and treated with POCl3 (0.59 ml, 6.45 mmol) at 0°C.
The mixture was kept at room temperature for 4 h, treated with ice-cold saturated aqueous NH4Cl (20
ml), extracted with CH2Cl2 (5×10 ml), dried and evaporated. The crude product was purified by flash
chromatography (eluent: EtOAc:light petroleum, 1:9) to furnish 10 (0.37 g, 60%) as a yellowish oil which
25
crystallized on standing in the freezer, m.p.: 26–28°C, [α]D +70.3 (c 0.35, CHCl3). IR (KBr): 1723,
1703 cm−1; 1H NMR: δ 0.08 (s, 3H), 0.15 (s, 3H), 0.9 (s, 9H), 2.0–2.3 (m, 2H), 2.5–2.7 (m, 1H), 2.7–2.9
(dt, 1H, J=4.7), 3.83 (s, 3H), 4.18 (dd, 1H, J=10.7, 5), 6.73 (d, 1H, J=2). Anal. calcd for C14H24SiO4: C,
59.12; H, 8.51. Found: C, 59.08; H, 8.53.
3.6. (1R,6R)-3-Methoxycarbonyl-6-(1,1-dimethylethyl)dimethylsilyloxy-cyclohex-2-en-1-ol 11 and
(1S,6R)-3-methoxycarbonyl-6-(1,1-dimethylethyl)dimethylsilyloxy-cyclohex-2-en-1-ol 12
To a stirred solution of 10 (1.14 g, 4.01 mmol) in MeOH (20 ml) at 0°C was added sodium borohydride
(0.15 g, 4.01 mmol) in one portion. After 5 min, the mixture was neutralized with AcOH, the solvent
removed under reduced pressure and the residue extracted with ether (3×10 ml). The combined extracts
were dried and evaporated. Purification of the residue by flash chromatography (eluent: ether:light
25
petroleum, 1:4) furnished 11 (0.18 g) and 12 (0.8 g) as colorless oils (86% overall yield). 11: [α]D
−19.6 (c 5.56, CHCl3). IR (neat): 3550, 1720 cm−1; 1H NMR: δ 0.11 (s, 6H), 0.90 (s, 9H), 1.5–2.0 (m,
2H), 2.17 (d, 1H, J=3.79), 2.2–2.6 (m, 2H), 3.6–3.7 (m, 1H), 3.74 (s, 3H), 4.14 (m, 1H), 6.76 (bs, 1H).
12: [α]D +42.54 (c 0.55, CHCl3). IR (neat): 3546, 1720 cm−1; 1H NMR: δ 0.12 (s, 6H), 0.90 (s, 9H),
25
1.5–1.8 (m, 1H), 1.8–2.1 (m, 1H), 2.1–2.5 (m, 2H), 2.56 (d, 1H, J=7.5), 3.75 (s, 3H), 4.00 (m, 1H), 4.15
(m, 1H), 6.78 (d, 1H, J=3). Anal. calcd for C14H26SiO4: C, 58.71; H, 9.16. Found: C, 58.74; H, 9.13.

2862
A. Barco et al. / Tetrahedron: Asymmetry 9 (1998) 2857–2864
3.7. (3S,4R)-1-Methoxycarbonyl-3-methyloxy-4-(1,1-dimethylethyl)dimethylsilyloxy-cyclohex-1-ene 13
A solution of 12 (0.97 g, 3.39 mmol) in CH2Cl2 (12 ml) was treated with CH3I (2.11 ml, 33.9 mmol)
and Ag2O (1.3 g, 5.59 mmol) and heated at reflux in the dark for 24 h. Additional CH3I (4.22 ml) and
Ag2O (1.3 g) were added and reflux was continued for 24 h. The cooled reaction mixture was filtered
through Celite and the solvent evaporated. Purification of the residue by flash chromatography (eluent:
25
ether:light petroleum, 1:9) afforded 13 (0.9 g, 88%) as a yellow oil, [α]D +77.8 (c 0.27, CHCl3). IR
1
(neat): 1721, 1650 cm−1; H NMR: δ 0.09 (s, 6H), 0.89 (s, 9H), 1.5–1.7 (m, 1H), 1.8–2.05 (m, 1H),
2.1–2.3 (m, 1H), 2.4–2.6 (m, 1H), 3.49 (s, 3H), 3.73 (overlapping s, 3H and m, 1H), 4.04 (m, 1H), 6.82
(bs, 1H). Anal. calcd for C15H28SiO4: C, 59.96; H, 9.40. Found: C, 60.01; H, 9.35.
3.8. (3S,4R)-4-Hydroxy-1-methoxycarbonyl-3-methyloxy-cyclohex-1-ene 14
To a solution of 13 (0.52 g, 1.73 mmol) in THF (10 ml) was added n-Bu4NF·3H2O (1.64 g, 5.19
mmol) and the mixture stirred at room temperature for 3 h. The solvent was evaporated and the residue
extracted with CH2Cl2 (3×10 ml). Evaporation of the dried organic extracts gave a brown oil, which
was subjected to flash chromatography (eluent: ether:light petroleum, 4:1) to yield 14 (0.3 g, 94%) as a
colorless oil, [α]D25 +120 (c 1.07, CHCl3). IR (neat): 3478, 1715, 1652 cm−1; 1H NMR: δ 1.64 (m, 1H),
1.95 (m, 1H), 2.1–2.3 (m, 1H), 2.3–2.6 (m, 2H), 3.44 (s, 3H), 3.68 (s, 3H), 3.77 (m, 1H), 4.0 (m, 1H),
6.76 (bs, 1H). Anal. calcd for C9H14O4: C, 58.04; H, 7.58. Found: C, 58.00; H, 7.63.
3.9. (3S,4R)-1-Methoxycarbonyl-3-methyloxy-4-triethylsilyloxy-cyclohex-1-ene 15
To a solution of 14 (0.3 g, 1.61 mmol) in pyridine (28 ml) was added TESCl (0.54 ml, 3.22 mmol).
The reaction mixture was stirred for 30 min at room temperature. Evaporation of the solvent followed by
flash chromatography of the residue (eluent: EtOAc:light petroleum, 1:9) afforded 15 (0.4 g, 83%) as a
yellow oil, [α]D +102.5 (c 0.89, CHCl3). IR (neat): 1720, 1654 cm−1; 1H NMR: δ 0.62 (q, 6H, J=8),
25
0.97 (t, 9H, J=8), 1.55–1.75 (m, 1H), 1.8–2.05 (m, 1H), 2.1–2.35 (m, 1H), 2.4–2.6 (m, 1H), 3.51 (s, 3H),
3.73 (overlapping s, 3H and m, 1H), 3.99 (m, 1H), 6.86 (m, 1H). Anal. calcd for C15H28SiO4: C, 59.96;
H, 9.40. Found: C, 60.01; H, 9.35.
3.10. (1R,2S,3S,4R)-1-Methoxycarbonyl-3-methyloxy-4-triethylsilyloxy-cyclohexane-1,2-diol 16
A solution of 15 (0.52 g, 1.73 mmol), NMO (0.28 g, 2.07 mmol), pyridine (0.84 ml, 10.38 mmol),
water (0.17 ml, 9.51 mmol) and OsO4 (0.027 g, 0.106 mmol) was refluxed in the dark for 30 min. After
cooling, the reaction mixture was filtered through a pad of Celite and florisil and washed with EtOAc
(20 ml). The eluant was concentrated in vacuo and the crude product purified by flash chromatography
25
(eluent: ether:light petroleum, 1:1) to afford 16 (0.53g, 91%) as a yellowish oil, [α]D −65.91 (c 0.22,
CHCl3). IR (neat): 3480, 1739 cm−1; 1H NMR: δ 0.61 (q, 6H, J=8), 0.98 (t, 9H, J=8), 1.5–1.9 (m, 3H),
2.24 (td, 1H, J=4.8), 2.55 (bs, 1H), 3.18 (dd, 1H, J=2.5, 9.6), 3.42 (overlapping s, 3H and m, 1H), 3.81 (s,
3H), 4.19 (d, 1H, J=9.6), 4.27 (m, 1H). Anal. calcd for C15H30SiO6: C, 53.86; H, 9.05. Found: C, 53.88;
H, 9.03.

A. Barco et al. / Tetrahedron: Asymmetry 9 (1998) 2857–2864
2863
3.11. (1S,2S,3S,4R)-1-Hydroxymethyl-3-methyloxy-4-triethylsilyloxy-cyclohexane-1,2-diol 17
A solution of 16 (0.5 g, 1.49 mmol) in THF (5 ml) was added slowly to a slurry of lithium aluminum
hydride (0.11 g, 2.98 mmol) in THF at 0°C and the reaction mixture stirred at the same temperature
for 2 h. Excess hydride was quenched by careful addition of water, then Celite (0.5 g) was added and
the slurry vigorously stirred for 30 min. The solids were filtered through Celite and washed with EtOAc
(40 ml). The filtrate was stripped of solvent in vacuo and the residue purified by flash chromatography
25
(eluent: EtOAc:light petroleum, 3:1) yielding 17 (0.27 g, 60%) as a clear viscous oil, [α]D −63.3 (c
0.94, CHCl3). IR (neat): 3401 cm−1; 1H NMR: δ 0.59 (q, 6H, J=8), 0.96 (t, 9H, J=8), 1.4–2.0 (m, 4H),
2.6–3.1 (br, 3H), 3.23 (dd, 1H, J=2.5, 9.6), 3.43 (overlapping s, 3H and m, 1H), 3.77 (d, 1H, J=11), 3.91
(d, 1H, J=9.5), 4.25 (m, 1H). Anal. calcd for C14H30SiO5: C, 54.87; H, 9.87. Found: C, 54.89; H, 9.85.
3.12. (3S,4S,5S,6R)-5-Methyloxy-6-triethylsilyloxy-1-oxaspiro[2.5]octan-4-ol 18
A cooled (0°C) solution of 17 (0.1 g, 0.32 mmol) in CH2Cl2 (1 ml) was treated with Et3N (0.11 ml,
0.76 mmol), p-toluenesulfonyl chloride (0.16 g, 0.84 mmol) and a catalytic amount of DMAP. After
being stirred at 0°C for 30 min, the reaction mixture was kept at room temperature for 24 h. Additional
triethylamine (0.05 ml, 0.35 mmol) was added and stirring was continued for 12 h. The mixture was
treated with water (5 ml), extracted with CH2Cl2 (5×5 ml), dried and evaporated. The crude orange
oil residue was dissolved in MeOH (1 ml) and stirred at room temperature for 5 h in the presence of
K2CO3 (0.05 g, 0.36 mmol). Most of the solvent was evaporated and the residue was extracted with
EtOAc (3×5 ml). The extracts were dried and concentrated to furnish a crude oil, which was purified
by flash chromatography (eluent: EtOAc:light petroleum, 1:6) yielding 18 (0.076 g, 81%) as a colorless
25
25
oil, [α]D −63 (c 2.39, CHCl3) {lit.6: [α]D −60 (c 1.28, CHCl3)}. IR (neat): 3430 cm−1; 1H NMR:
δ 0.60 (q, 6H, J=8), 0.96 (t, 9H, J=8), 1.26 (m, 1H), 1.71 (m, 2H), 2.26 (m, 2H), 2.61 (d, 1H, J=5), 3.09
(dd, 1H, J=2.5, 9), 3.10 (d, 1H, J=5), 3.43 (s, 3H), 4.08 (dd, 1H, J=5.4, 9), 4.32 (m, 1H). 13C NMR: 4.90,
6.84, 26.24, 28.94, 50.15, 57.76, 60.07, 66.71, 67.47, 85.24. Anal. calcd for C14H28SiO4: C, 59.12; H,
8.51. Found: C, 59.10; H, 8.53.
Acknowledgements
This work was financially supported by the Consiglio Nazionale delle Ricerche (CNR) and Ministero
dell’Università e della Ricerca Scientifica e Tecnologica (MURST 40 and 60%).
References
1. Powell, D.; Skotnicki, J.; Upeslacis, J., Annu. Rep. Med. Chem., 1997, 32, 161–170.
2. Folkman, J.; Ingber, D. E., Semin. in Cancer Biol., 1992, 3, 555–557.
3. Sigg, H. P.; Weber, H. P., Helv. Chim. Acta, 1968, 51, 1395–1408.
4. Corey, E. J.; Guzman-Perez, A.; Noe, M. C., J. Am. Chem. Soc., 1994, 116, 12109–12110.
5. Corey, E. J.; Dittami, J. P., J. Am. Chem. Soc., 1985, 107, 256–257.
6. Barton, D. H. R.; Bath, S.; Billington, D. C.; Gero, S. D.; Quiclet-Sire, B.; Samadi, M., J. Chem. Soc., Perkin Trans. 1,
1995, 1551–1558.
7. Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V., Tetrahedron Lett., 1997, 38, 681–684.
8. Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V., Tetrahedron, 1997, 53, 17177–17194.
9. Eliel, E. L.; Ramirez, M. B., Tetrahedron: Asymmetry, 1997, 8, 3551–3554.

2864
A. Barco et al. / Tetrahedron: Asymmetry 9 (1998) 2857–2864
10. Bartlett, P. A.; Maitra, U.; Chouinard, P. M., J. Am. Chem. Soc., 1986, 108, 8068–8071.
11. White, J. D.; Cammack, J. H.; Sakuma, K.; Rewcastle, G. W.; Widener, R. K., J. Org. Chem., 1995, 60, 3600–3611.
12. Lesuisse, D.; Berchtold, G. A., J. Org. Chem., 1985, 50, 888–890.
13. Hanessian, S.; Plessas, N. R., J. Org. Chem., 1969, 34, 1035–1044.
14. Giese, B.; Almstead, N. G., Tetrahedron Lett., 1994, 35, 1677–1680 and references cited therein.
15. Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.; Zanirato, V., Tetrahedron: Asymmetry, 1997, 8, 3515–3545.