Total synthesis of (+)-boronolide, (+)-deacetylboronolide, and (+)-dideacetylboronolide

Article abstract of DOI:10.1021/jo0269058

Total synthesis of (+)-boronolide, (+)-deacetylboronolide, and (+)-dideacetylboronolide has been achieved from a single intermediate 26, which was synthesized in 11 steps from a D-mannitol-derived intermediate 8 in an overall yield of 10%. The key steps in the synthesis are inversion of a chiral center by taking an advantage of the inherent mechanism involved in the ring closing to an epoxide via intramolecular S_N2 reaction and lactonization of a diol using Fetizons reagent. The strategy is amenable to preparation of analogues of (+)-boronolide in sufficient amount for further screening of biological activity.

Full text of DOI:10.1021/jo0269058

Total Synthesis of (+)-Boronolide, (+)-Deacetylboronolide, and
(+)-Dideacetylboronolide†
M. Chandrasekhar, Kusum L. Chandra, and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
vinodks@iitk.ac.in
Received December 24, 2002
Total synthesis of (+)-boronolide, (+)-deacetylboronolide, and (+)-dideacetylboronolide has been
achieved from a single intermediate 26, which was synthesized in 11 steps from a D-mannitol-
derived intermediate 8 in an overall yield of 10%. The key steps in the synthesis are inversion of
a chiral center by taking an advantage of the inherent mechanism involved in the ring closing to
an epoxide via intramolecular SN2 reaction and lactonization of a diol using Fetizons reagent. The
strategy is amenable to preparation of analogues of (+)-boronolide in sufficient amount for further
screening of biological activity.
Introduction
6-Substituted 5,6-dihydro-2H-pyran-2-ones (R,â-unsat-
urated δ-lactones) 1 are important structural subunits
in many biologically important natural products.1 These
units are important for a wide variety of biological
activities, such as insect growth inhibition and insect
antifeedal, antifungal, and antitumor properties. The
pyrone units are widely distributed in all parts of plants
(Lamiaceae, Piperaceae, Lauraceae, and Annonaceae
families) including leaves, stems, flowers, and fruits.
Various kinds of substitutions have been found at the
C-6 position of the ring such as polyacetoxy alkane,
polyhydroxy alkane, a combination of both, or even a
simple alkane. Biological activity of these types of
molecules, their structural complexities, and the chal-
lenge to synthesize them optically pure form made them
an attractive target for many total syntheses. (+)-
Boronolide 2, (+)-deacetylboronolide 3, and (+)-dide-
acetylboronolide 4 are such natural products, which have
attracted attention from several synthetic organic chem-
ists (Figure 1). These are R,â-unsaturated δ-lactones with
a highly oxygenated side chain at the C-6 position. The
(+)-boronolide 2 was isolated from the bark and branches
of Tetradenia fruticosa2 and from the leaves of Tetradenia
barbera,3 which have been used as local folk medicine in
Madagascar and southern Africa.4 (+)-Deacetylboronolide
3 and (+)-dideacetylboronolide 4 were obtained from
FIGURE 1.
Tetradenia riparia,5 a central African species widely used
as a tribal medicine. Medicinal properties of boronolides
have been exploited for a long time in crude form. Zulu
used roots of these plants as an emetic, and an infusion
of leaves has been reported to be effective against
malaria.4,5
Relative stereochemistry of 2 has been determined by
X-ray analysis,6 and the R-configuration at the C-6
position has been proposed by application of Hudson’s
lactone rule to the molecular rotation. Later, the stere-
ochemistry at the C-6 position was confirmed by chemical
degradation,3 thus confirming the structure and absolute
stereochemistry of boronolide as 2. Although several
syntheses of 2 have been reported7,8 in the literature,
there is no report on total syntheses of other boronolides
such as 3 and 4. In this paper, we delineate our efforts
on total synthesis of all the three naturally occurring (+)-
boronolides from D-mannitol.
(5) (a) Van Puyvelde, L.; Dube, S.; Uwimana, E.; Uwera, C.; Domisse,
R. A.; Esmans, E. L.; Van Schoor, O. Vlietinck, A. Phytochemistry 1979,
18, 1215. (b) Van Puyvelde, L.; De Kimpe, N.; Dube, S.; Chagnon-Dube,
M.; Boily, Y.; Borremans, F.; Schamp, N.; Anteunis, M. J. O. Phy-
tochemistry 1981, 20, 2753.
(6) Kjaer, A.; Norrestam, R.; Polonsky, J. Acta Chem. Scand. Ser.
B 1985, 39, 745.
(7) For a racemic synthesis, see: Jefford, C. W.; Moullin, M.-C. Helv.
Chim. Acta 1991, 74, 336.
(8) For asymmetric synthesis of (+)-boronolide, see: (a) Nagano, H.;
Yasui, H. Chem. Lett. 1992, 1045. (b) Honda, T.; Horiuchi, S.; Mizutani,
H.; Kanai, K. J. Org. Chem. 1996, 61, 4944. (c) Ghosh, A. K.; Bilcer,
G. Tetrahedron Lett. 2000, 41, 1003. (d) For formal synthesis, see:
Chandrasekhar, M.; Raina, S.; Singh, V. K. Tetrahedron Lett. 2000,
41, 4969. (e) Carda, M.; Rodriguez, S.; Segovia, B.; Marco, J. A. J. Org.
Chem. 2002, 67, 6560. (f) Trost, B. M.; Yeh, V. S. C. Org. Lett. 2002,
4, 3513.
* To whom correspondence should be addressed. Fax: 91-512-259-
7436.
† Dedicated to Professor G. Mehta on the occasion of his 60th
birthday.
(1) (a) Davies-Coleman, M. T.; Rivett, D. E. A. Fortschr. Chem. Org.
Naturst. 1989, 55, 1. (b) Ohloff, G. Fortschr. Chem. Org. Naturst. 1978,
35, 431. (c) Adityachaudhury, N.; Das, A. K. J. Sci. Ind. Res. (India)
1979, 38, 265. (d) Siegel, S. M. Phytochemistry 1976, 15, 566.
(2) Franca, N. C.; Polonsky, J. C. R. Hebd. Seances, Acad. Sci., Ser.
C. 1971, 273, 439.
(3) Davies-Coleman, M. T.; Rivett, D. E. A. Phytochemistry 1987,
26, 3047.
(4) Watt, J. M.; Brandwijk, M. G. B. The Medicinal and Poisonous
Plants of Southern and Eastern Africa; Livingston: Edinburgh, 1962;
p 516.
10.1021/jo0269058 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/17/2003
J. Org. Chem. 2003, 68, 4039-4045
4039

Chandrasekhar et al.
SCHEME 1a
a Reaction conditions: (a) PhCOCl, Py, DMAP (cat.), DCM, -80
to -20 °C, 4 h; (b) (i) MsCl, Et3N,DCM, -80 to -20 °C, 10 h, (ii)
K2CO3, MeOH, rt, 2.5 h; (c) Pr2CuCNLi, THF, -80 °C, 8 h; (d)
NaH, BnBr, THF, rt, 12 h; (e) CuCl2‚2H2O, MeCN, 0 °C, 45 min;
(f) (i) TsCl, Py, DCM, 0 °C, 24 h, (ii) K2CO3, MeOH, 0 °C, 1 h.
FIGURE 2. Retrosynthetic analysis of 2.
Results and Discussion
Retrosynthetic analysis of (+)-boronolide 2 is shown
in Figure 2. Inspection of the target 2 reveals that
lactonic moiety can be obtained from an epoxide 5 and a
functionalized three-carbon unit. The subtarget 5 can be
obtained from 6 by simple functional group transforma-
tions. Structural mapping of the new target 6 was done
with an epoxide 7 that can be directly correlated to 8,9
which can be obtained on a multigram scale in two simple
steps from D-mannitol 9. Since three of the four chiral
centers of boronolide 2 can directly be mapped onto
D-mannitol and its C2 symmetry makes it possible to
invert one of the chiral centers selectively, it was chosen
as an ideal starting material.10
1,2:3,4-Di-O-isopropylidene-D-mannitol 8 was prepared
according to the literature procedure.9 Inversion in the
stereochemistry of the secondary hydroxyl group in 8 was
planned via intramolecular SN2 displacement by the
adjacent primary hydroxyl group. To achieve this, the
primary hydroxyl group of the 8 was selectively protected
as a benzoate ester 10. It was essential to do the above
protection reaction at very low temperature in order to
avoid a problem of dibenzoylation and benzoyl migration.
Initial activation of the secondary hyroxyl group as
tosylate led to a partial migration. So it was activated
as a mesylate at -80 °C. Treatment of the crude mesy-
lated product with K2CO3 in methanol led to deprotection
of the benzoate ester to hydroxyl group with concomitant
ring closure via intramolecular SN2 displacement of
mesylate to provide the epoxide 7 with inverted stereo-
chemistry in 90% yield. After successful inversion of
configuration, the stage was set for introduction of the
three-carbon aliphatic side chain (Scheme 1). Treatment
of the epoxide 7 with n-propylmagnesium bromide or
n-propyllithium gave products due to both internal and
terminal attack along with some unidentified products.
Lowering of the reaction temperature did not have any
FIGURE 3.
effect on the outcome of the result. However, the ring
opening of the epoxide 7 with propylmagnesium bromide
in the presence of a stoichiometric amount of CuBr‚DMS
complex gave the desired product 11 in 85% yield. The
yield of the 11 could further be improved (95%) on the
use of higher order cuprate preapared in situ from
n-propyllithium and CuCN. The hydroxyl group in 11
was converted to the benzyl ether 6 under standard
conditions in quantitative yield. Selective hydrolysis of
the terminal acetonide in 6 was achieved by treating it
with CuCl2‚2H2O11 in MeCN at 0 °C for 40 min. Thus,
the desired product 12 was obtained in 85% yield.
Conversion of the diol 12 to the epoxide 5 was done via
usual selective tosylation of the primary alcohol, followed
by its treatment with K2CO3 in methanol at 0 °C.
The 5 had basic stereochemical framework of the target
2 and only construction of R,â-unsaturated-δ-lactone ring
was required. Initially we thought of constructing R,â-
unsaturated-δ-lactone by using the Ghosez lactonization
method.12 Thus, the epoxide 5 was treated with an anion
generated from 13 and n-BuLi. It was quite discouraging
to note that the reaction did not give any ring-opened
product. Use of similar stable sulfone reagents such as
sulfone acetal 1412 and sulfone silyl ether 1513 were also
unsuccessful. The presence of additives such as HMPA
or BF3‚OEt2 failed to activate the epoxide. The epoxide
ring opening was also unsuccessful with other nucleo-
philes derived from propiolic acid 1614 and propiolalde-
hyde diethylacetal 1715 (Figure 3).
(11) Saravanan. P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K.
Tetrahedron Lett. 1998, 39, 3091.
(9) Wiggins, L. J. Chem. Soc. 1946, 13.
(12) Carretero, J. C.; Ghosez, L. Tetrahedron Lett. 1988, 29, 2059.
(13) (a) Cossy, J.; Pete, J. P. Bull. Soc. Chim. Fr. 1988, 6, 989. (b)
Sasaki, M.; Tsukano, C.; Tachibana, K. Org. Lett. 2002, 4, 1747.
(14) Carlson, R. M.; Oyler, A. R.; Peterson, J. R. J. Org. Chem. 1975,
40, 1610.
(10) For D-mannitol in organic synthesis, see: (a) Raina, S.; Singh,
V. K. Tetrahedron 1996, 52, 4479. (b) Saravanan, P.; Raina, S.;
Sambamurthy, T.; Singh. V. K. J. Org. Chem. 1997, 62, 2669. (c)
Chandra, K. L.; Chandrasekhar, M.; Singh, V. K. J. Org. Chem. 2002,
67, 4630.
(15) Brown, R. C. D.; Kocienski, P. J. Synlett 1994, 415.
4040 J. Org. Chem., Vol. 68, No. 10, 2003

Total Synthesis of (+)-Boronolide
SCHEME 2a
SCHEME 3a
a Reaction conditions: (a) 15, n-BuLi, CuI, THF, -80 to -20
°C, 12 h; (b) TBAF, THF, rt, 8 h; (c) Ag2CO3-Celite, PhH, 85 °C,
24 h; (d) RuCl2(PPh3)3, PhH, rt, 15 h.
13. Cuprate was made by treating the sulfone silyl ether
anion with copper(I) salt (CuCN and CuBr‚DMS) in THF
at -80 °C, and then it was treated with a solution of
epoxide 5. Unfortunately, the ring-opening reaction did
not proceed. However, by changing the copper salt to CuI
gave the ring-opened product 23 in 95% yield. Deprotec-
tion of TBDMS group using TBAF in THF gave a diol 24
quantitatively. Conversion of the diol 24 into a lactone
was expected to be smooth. However, it turned out to be
quite problematic (Scheme 3). Refluxing the diol 24 in
benzene with excess Ag2CO3 - celite did not yield any
product and prolonged heating led to decomposition of
the starting material. The attempted oxidation of the diol
a Reaction conditions: (a) allylMgBr, CuCN, THF, -80 to -40
°C, 12 h; (b) (i) BH3‚DMS, PhCH3, 0 °C to rt, 12 h, (ii) EtOH, 3 M
NaOH, 30% H2O2, 2 h; (c) Ag2CO3-Celite, PhH, 85 °C, 12 h; (d)
CuCl2‚2H2O, MeCN, rt, 24 h; (e) (i) H2, Pd-C, EtOH, rt, 12 h, (ii)
Ac2O, Py, rt, 76% (for two steps).
Because of the failure of the original strategy for
constructing R,â-unsaturated-δ-lactone, a different ap-
proach was adopted. The epoxide 5 was treated with
allylmagnesium bromide in the presence of stoichiometric
amount of CuCN at -80 °C with a gradual warming to
-40 °C.16 It was heartening to note that the allylated
product 18 was obtained in a quantitative yield. This was
subjected to hydroboration under standard conditions,
followed by oxidative workup to provide a diol 19 in 77%
yield.17 Oxidation of the diol 19 with Fetizons reagent18
went smoothly without any problem. The diol 19, when
treated with large excess of Ag2CO3-Celite in benzene
under reflux condition, gave a desired lactone 20 in good
yield. Cleavage of the acetonide in the 20 with CuCl2‚
2H2O gave a diol 21, which was converted into 22 by
hydrogenolysis of the benzyl ether followed by acetylation
of the hydroxyl groups. Although the conversion of 22 to
boronolide 2 was reported in the literature, we still
wished to reach the target. When 22 was subjected to
dehydrogenation with benzeneseleninic anhydride under
the reported conditions,6-8 only 25% of the desired
product 2 was obtained along with unreacted starting
material (Scheme 2). Repetition of this process improved
the conversion to 50%. This could be due to impurities
in technical grade of benzeneseleninic anhydride which
was only 70% pure.
19
24 with RuCl2(PPh3)3 gave a complex mixture of prod-
ucts.
Failure to reach the target by the above two approaches
prompted us to complete the total synthesis from the
lactone 20 by usual phenylselenation and elimination
reactions.20 To accomplish this, the benzyl group in the
20 was removed by hydrogenation to give a hydroxy
lactone 25 in quantitative yield. Then, the hydroxy
lactone 25 was subjected to R-phenylselenation, by treat-
ment with 2.5 equiv of LDA in a mixture of THF and
HMPA and quenching the enolate by addition of a freshly
prepared phenylselenyl bromide. The selenated product
was subjected to oxidative syn-elimination with H2O2 and
pyridine to give the desired R,â-unsaturated-δ-lactone 26.
Deprotection of acetonide in the 26 with Amberlite H+
resin at 70 °C gave (+)-deacetylboronolide 3. Acetylation
of 26 under standard conditions gave 27 and removal of
acetonide with CuCl2‚2H2O gave the (+)-dideacetylbo-
ronolide 4. Acetylation of 4 under standard conditions
gave the (+)-boronolide 2. Thus, the total synthesis of
all the naturally occurring boronolides was accomplished
(Scheme 4).
Failure to reach the target 2 from the triacetate 22 in
an effective manner led us to think about usage of
sulfonyl anion once again. Since higher order cuprates
worked effectively in the ring opening of the epoxides 5
and 7, we thought of using cuprate made from sulfonyl
anion in this case also. We chose 15 as an ideal sulfone
reagent as the silyl protecting group does not interfere
with the protecting groups already present in the epoxide
5 and it is also more stable than the sulfone ortho ester
In conclusion, we have completed the total synthesis
boronolides from a single chiral intermediate obtained
from D-mannitol. The synthesis is more flexible and can
easily be adopted for preparation of its various analogues.
Experimental Section
1H NMR spectra were recorded on 400 MHz NMR spectro-
photometer using TMS as internal standard. Chemical shifts
(16) (a) Krause, N. Angew. Chem., Int. Ed. 1999, 38, 79. (b) Krause,
N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186. (c) Lipshutz,
B. H. Synthesis 1987, 325. (d) Lipshutz, B. Synlett 1990, 119.
(17) Lane, C. F. J. Org. Chem. 1974, 39, 1437.
(18) Fetizon, M.; Golfier, M. C. R. Hebd. Seances, Acad. Sci., Ser.
C. 1968, 267, 900.
(19) Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H.; Tetrahedron
Lett. 1981, 22, 1605.
(20) For selenium chemistry, see: Nicolaou, K. C.; Petasis, N. A.
Selenium in Natural Products Synthesis; Cis, Inc.: Philadelphia, 1984.
J. Org. Chem, Vol. 68, No. 10, 2003 4041

Chandrasekhar et al.
SCHEME 4a
g (83%) of pure monobenzoate 10 as a colorless liquid: Rf 0.59
(20% EtOAc in petroleum ether); [R]25D +16.85 (c 3.22, CHCl3);
IR (thin film) 3451, 3055, 1720, 1451 cm-1 ; 1H NMR (400 MHz,
CDCl3) δ 1.36 (s, 3H), 1.38 (s, 3H), 1.40 (s, 3H), 1.47 (s, 3H),
3.76 (bs, 1H, -OH), 3.83 (t, J ) 7.8 Hz, 1H), 3.95 (t, J ) 7.6
Hz, 1H), 4.03 (m, 2H), 4.10 (m, 1H), 4.22 (dd, J ) 8.5, 6.1 Hz,
1H), 4.39 (dd, J ) 11.6, 6 Hz, 1H), 4.66 (dd, J ) 11.6, 2.6 Hz,
1H), 7.44 (m, 2H), 7.56 (m, 1H), 8.08 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 25.1, 26.4, 26.8, 26.82, 66.4, 67.9, 71, 76.4, 80.3,
81, 109.8, 110.3, 128.3 (2C), 130.2, 132.9, 166.6; MS (FAB) 367
(M+ + 1). Anal. Calcd for C19H27O7: C, 62.29; H, 7.38. Found:
C, 62.16; H, 7.26.
1,2:3,4-Di-O-isopropylidene-5-oxiranyl-D-mannitiol 7.
To a cooled (-80 °C) solution of the benzoate 10 (6.9 g, 18.9
mmol) and triethylamine (4.2 mL, 29.9 mmol) in dry DCM (60
mL) was added methanesulfonyl chloride (1.76 mL, 22.6 mmol)
dropwise. The reaction mixture was stirred for 15 min at the
same temperature and kept in a freezer (-20 °C) overnight.
The reaction mixture was diluted with more DCM and washed
with water and brine. The DCM layer was dried over anhy-
drous Na2SO4 and concentrated on rotary evaporator. The
crude yellow solid was dissolved in MeOH, 6.5 g (47.25 mmol,
2.5 equiv based on theoretical yield) of finely powdered K2-
CO3 was added, and the mixture was stirred vigorously at rt
for 2 h. MeOH was evaporated on rotary evaporator. The
residue was taken in water and extracted with diethyl ether,
and the combined organic layers were washed with brine and
dried over anhydrous Na2SO4 before concentration. The crude
product was chromatographed over silica gel to give the
epoxide 7 as a colorless liquid (3.8 g, 82%): Rf 0.54 (10% EtOAc
in petroleum ether); [R]25D -16.50 (c 1.15, CHCl3); IR (thin film)
a Reaction conditions: (a) H2, Pd-C, EtOH, rt, 12 h; (b) (i) LDA,
PhSeBr, THF, HMPA, -80 °C, (ii) 30% H2O2, Py, rt, 6 h; (c)
Amberlite IR 120 H+, 70 °C, H2O, 7 h; (d) Ac2O, Py, DCM, rt, 12
h; (e) CuCl2‚2H2O, MeCN, rt, 12 h; (f) Ac2O, Py, rt, 12 h.
are reported in ppm, and coupling constants are reported in
Hz. Routine monitoring of reactions was performed using silica
gel-G obtained from Acme. Column chromatographic separa-
tions were done by using silica gel (Acme’s 60-120 mesh).
Petroleum ether used was of boiling range 60-80 °C. Reactions
that needed anhydrous conditions were run under the atmo-
sphere of nitrogen or argon using flame-dried glasswares. The
organic extracts were dried over anhydrous sodium sulfate.
Evaporation of solvents was performed at reduced pressure.
Tetrahydrofuran (THF) was distilled from sodium benzophe-
none ketyl under nitrogen. Benzene, toluene, and CH2Cl2 were
distilled from CaH2.
1
3054, 1454, 1423 cm-1; H NMR (400 MHz, CDCl3) δ 1.34 (s,
3H), 1.38 (s, 3H), 1.40 (s, 3H), 1.41 (s, 3H), 2.80 (d, J ) 3.2
Hz, 2H), 3.10 (m, 1H), 3.83 (dd, J ) 7.4, 4.8 Hz, 1H), 3.89 (t,
J ) 7.8 Hz, 1H), 3.99 (dd, J ) 8.5, 4.1 Hz, 1H), 4.07 (m, 1H),
4.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 25.2, 26.6, 26.8,
27, 44.8, 52.1, 67.8, 77, 78.5, 80.3, 109.7, 110.2; MS (FAB) 245
(M+ + 1). Anal. Calcd for C12H20O5: C, 59.02; H, 8.20. Found:
C, 58.92; H, 8.01.
5-Hydroxy 1,2:3,4-Di-O-isopropylidenenonane 11. To a
suspension of CuCN (2.20 g, 24.59 mmol) in THF (50 mL) at
-80 °C was added n-PrLi (15.7 mL, 49.1 mmol, 3.14 M) slowly
under N2 atmosphere. After the mixture was stirred for 30
min at the same temperature, the epoxide 7 (3 g, 12.3 mmol)
in anhydrous THF (25 mL) was added dropwise. The reaction
was allowed to proceed at the same temperature for 8 h and
quenched by the addition of saturated NH4Cl solution. The
organic layer was separated, and the aqueous layer was
extracted with ether. The combined organic layers were dried
over Na2SO4, concentrated, and chromatographed over silica
gel to give the product 11 as a colorless viscous liquid (3.47 g,
1,2:3,4-Di-O-isopropylidene-D-mannitol 8. Compound 8
was prepared according to the literature procedure9 with minor
modifications. A solution of 1,2:3,4:5,6-tri-O-isopropylidene-
D-mannitol (35.6 g) in 70% aqueous ethanol (810 mL) was
treated with concentrated HCl (2.5 mL) at 45 °C for 1 h. The
reaction was quenched by an addition of large excess of solid
K2CO3. The ethanol layer was separated, and aqueous layer
was extracted with EtOAc once. The combined organic layers
were concentrated on rotary evaporator and residue was taken
in cold water. The unreacted starting material (13.2 g)
separated out as a solid and it was filtered. Aqueous layer was
extracted with EtOAc to give the diol 8 in essentially pure
form: yield 8.5 g (42% based on SM recovery) as a low melting
solid; Rf 0.29 (40% EtOAc in petroleum ether); [R]25D +5.15 (c
98%): Rf 0.42 (10% EtOAc in petroleum ether); [R]25 +1.11
D
(c 1.35, CHCl3); IR (thin film) 3487, 3054, 1456 cm-1; 1H NMR
(400 MHz, CDCl3) 0.92 (t, J ) 6.8 Hz, 3H), 1.35 (s, 3H), 1.38
(s, 3H), 1.41 (s, 3H), 1.42 (s, 3H), 1.34-1.57 (m, 6H), 2.12 (d,
J ) 9.3 Hz, -OH), 3.66 (m, 1H), 3.91 (m, 2H), 3.96 (m, 1H),
4.05 (m, 1H), 4.14 (m, 1H); 13C NMR (100 MHz, CDCl3) 14.0,
22.7, 25.30, 26.6, 27.1, 27.2, 28.1, 34.5, 67.8, 70.3, 77.3, 77.6,
82.9, 109.3, 109.8; MS (FAB) 289 (M+ + 1). Anal. Calcd for
C15H28O5: C, 62.47; H, 9.79. Found: C, 62.50; H, 9.69.
1.8, CHCl3); IR (thin film) 3451, 3054, 1423 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 1.377 (s, 6H), 1.38 (s, 3H), 1.47 (s, 3H),
2.53 (bs, 1H, -OH), 3.77 (m, 5H), 3.91 (t, J ) 7.3 Hz, 1H),
4.05 (m, 1H), 4.22 (dd, J ) 8.4, 6.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 25.0, 26.3, 26.78, 26.8, 63.8, 68, 72.2, 76.5, 80.7
(2 C), 109.6, 110.8; MS (FAB) 263 (M+ + 1). Anal. Calcd for
C12H22O6: C, 54.96; H, 8.40. Found: C, 54.64; H, 8.30.
5-Benzyloxy-1,2:3,4-di-O-isopropylidenenonane 6. To a
suspension of sodium hydride (50% suspension in mineral oil,
1.4 g, 2.5 equiv) in THF (30 mL) was slowly added a solution
of the alcohol 11 (3.3 g, 11.4 mmol) in THF (20 mL). After 10
min, benzyl bromide (1.8 mL, 14.8 mmol) was added, and the
reaction was allowed to proceed at rt for 12 h. THF was
removed in vacuo, and the reaction was quenched by careful
addition of water. The aqueous phase was extracted with ether.
The combined organic layers were dried over Na2SO4, concen-
trated, and chromatographed over silica gel to give the product
6 as yellow oil (4.11 g, 95%): Rf 0.83 (10% EtOAc in petroleum
6-O-Benzoyl-1,2:3,4-di-O-isopropylidene-D-mannitol 10.
To a solution of the diol 8 (6 g, 22.9 mmol) and DMAP (0.1
equiv) in dry DCM (60 mL) was added dry pyridine (3.7 mL,
45.8 mmol) at -80 °C under N2 atmosphere. This was followed
by a dropwise addition of benzoyl chloride (2.8 mL, 24.05
mmol) with vigorous stirring. The reaction was allowed to
proceed for 4 h with gradual warming to -20 °C. The reaction
mixture was diluted with DCM and washed with saturated
NaHCO3 solution, water, and brine. The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. The
crude product was chromatographed over silica gel to give 6.9
4042 J. Org. Chem., Vol. 68, No. 10, 2003

Total Synthesis of (+)-Boronolide
ether); [R]25D +16.93 (c 0.95, CHCl3); IR (thin film) 3053, 1454,
as colorless oil: Rf 0.45 (10% EtOAc in petroleum ether); [R]25
D
1
1423 cm-1; H NMR (400 MHz, CDCl3) δ 0.9 (t, J ) 6.8 Hz,
+2.70 (c 1.41, CHCl3); IR (thin film) 3442, 3067, 3030, 1454
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.89 (t, J ) 5.8 Hz, 3H),
3H), 1.34 (s, 3H), 1.36 (m, 3H), 1.38 (s, 6H), 1.44 (s, 3H), 1.67
(m, 3H), 3.53 (m, 1H), 3.90 (m, 1H), 4.01 (m, 2H), 4.09 (m,
2H), 4.63 (ABq, J ) 11.5 Hz, 2H), 7.31 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 14.0, 22.8, 25.2, 26.5, 27.0, 27.3, 28.0, 30.9,
67.5, 72.5, 77.2, 77.4, 78.2, 82.0, 109.4, 109.6, 127.5, 127.7,
128.2, 138.7; MS (FAB) 379 (M+ + 1). Anal. Calcd for
C22H34O5: C, 69.84; H, 8.99. Found: C, 69.73; H, 8.68.
1.34 (m, 3H), 1.40 (s, 3H), 1.42 (s, 3H), 1.45-1.73 (m, 5H), 2.12
(m, 1H), 2.27 (m, 1H), 3.12 (bs, 1H, -OH), 3.58 (m, 2H), 3.80
(t, J ) 6.8 Hz, 1H), 3.96 (dd, J ) 8.0, 3.2 Hz, 1H), 4.63 (ABq,
J ) 11.4 Hz, 2H), 5.01 (dd, J ) 17.6, 10.2 Hz, 2H), 5.82 (m,
1H), 7.32 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 13.9, 22.7,
26.8, 27.0, 28.4, 29.5, 29.9, 32.5, 71.5, 72.9, 78.0, 79.0, 79.8,
108.3, 114.6, 127.9, 128.1, 128.4, 137.6, 138.5; MS (FAB) 363
(M+ + 1). Anal. Calcd for C22H34O4: C, 72.93; H: 9.39. Found:
C, 72.89; H, 9.28.
1-[5-(1-Benzyloxypentyl)-2,2-dimethyl[1,3]dioxolan-4-
yl]ethane-1,2-diol 12. To a solution of the benzyl ether 6 (3.5
g, 9.26 mmol) in MeCN (20 mL) was added CuCl2‚2H2O (1.57
g, 9.26 mmol) at 0 °C. After 40 min, the reaction was quenched
by addition of saturated NaHCO3 at the same temperature.
The reaction mixture was filtered through Celite and washed
with EtOAc, the organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic layers
were dried over anhydrous Na2SO4, concentrated, and chro-
matographed over silica gel to give 1.0 g of unreacted starting
material and 2.01 g (yield after SM recovery 85%) of the diol
12 as a white solid: mp 47 °C; Rf 0.17 (20% EtOAc in
petroleum ether); [R]25D -12.52 (c 0.70, CHCl3); IR (CCl4 soln)
1-[5-(1-Benzyloxypentyl)-2,2-dimethyl[1,3]dioxolan-4-
yl]pentane-1,5-diol 19. To a cooled solution of the alcohol
18 (343 mg, 0.948 mmol) in dry hexane (1 mL) was added BH3‚
DMS (100 µL, 0.948 mmol, 1 equiv) at 0 °C under N2
atmosphere. The reaction was allowed to proceed for 12 h with
gradual warming to rt. Excess borane was destroyed by
addition of EtOH (1 mL). To this was added 3 M NaOH (350
µL) in one portion followed by dropwise addition of 30% H2O2
(350 µL), and the mixture was stirred for another 2 h at rt.
Solvent was evaporated in vacuo, and the residue was taken
in water and extracted with EtOAc. The combined organic
layers were dried over Na2SO4, concentrated, and chromato-
graphed over silica gel to give the diol 19 (277 mg, 77%) as
1
3578, 3405, 1456 cm-1; H NMR (400 MHz, CDCl3) δ 0.89 (t,
J ) 6.8 Hz, 3H), 1.31 (m, 3H), 1.36 (s, 3H), 1.39 (s, 3H), 1.51
(m, 1H), 1.60 (m, 1H), 1.70 (m, 1H), 2.2 (bs, 1H, -OH), 3.60-
3.79 (m, 5H), 3.91 (t, J ) 8.0 Hz, 1H), 4.00 (dd, J ) 8.3, 3.4
Hz, 1H), 4.65 (s, 1H), 4.66 (s, 1H), 7.35 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 14.0, 22.7, 26.89, 26.9, 28.6, 29.7, 64.0, 72.5,
73.6, 76.6, 78.1, 80.4, 108.9, 128.2, 128.3, 128.6, 137.1; MS
(FAB) 339 (M+ + 1). Anal. Calcd for C19H30O5: C, 67.45; H,
8.87. Found: C, 67.50; H, 8.8.
colorless oil: Rf 0.39 (40% EtOAc in petroleum ether); [R]25
D
+2.54 (c 0.59, CHCl3); IR (thin film) 3413, 3051, 2932, 1456
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.89 (t, J ) 6.8 Hz, 3H),
1.25-1.48 (m, 6H), 1.37 (s, 3H), 1.39 (s, 3H), 1.52-1.73 (m,
6H), 2.29 (bs, 1H, -OH), 3.43 (bs, 1H, -OH), 3.59 (m, 4H),
3.79 (t, J ) 7.6 Hz, 1H), 3.97 (dd, J ) 8.0, 3.2 Hz, 1H), 4.63
(ABq, J ) 11.5 Hz, 2H), 7.32 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 14.0, 21.4, 22.7, 26.9, 27.1, 28.5, 29.9, 32.5, 32.9, 62.4,
72.2, 73.0, 78.1, 79.1, 80.0, 108.4, 128.0, 128.2, 128.5, 137.6;
MS (FAB) 381 (M+ + 1). Anal. Calcd for C22H36O5: C, 69.47;
H, 9.47. Found: C, 69.50; H, 9.30.
4-(1-Benzyloxypentyl)-2,2-dimethyl-5-oxiranyl[1,3]di-
oxolane 5. To the diol 12 (1.5 g, 4.44 mmol) in a mixture of
dry DCM (4 mL) and dry pyridine (4 mL) was added tosyl
chloride (889 mg, 4.6 mmol) in portions at 0 °C. The reaction
was allowed to proceed at 0 °C for 24 h. The reaction mixture
was poured into a mixture of ice-cold ether and 6 N HCl (10
mL). The ether layer was separated, and the aqueous layer
was extracted with ether. The combined organic layers were
washed with water and brine. Finally, it was dried over
anhydrous Na2SO4 and concentrated in vacuo. The crude
tosylate was taken in MeOH (20 mL), and finely powdered K2-
CO3 (0.62 g) was added at 0 °C. The reaction was allowed to
proceed at 0 °C for 1 h. MeOH was removed on rotary
evaporator. The residue was taken in water and extracted with
ether. The combined organic layers were dried over Na2SO4
and concentrated on rotary evaporator, and the crude product
was chromatographed over silica gel to give 1.0 g (72% for two
steps) of the epoxide 5 as a colorless oil: Rf 0.45 (10% EtOAc
in petroleum ether); [R]25D - 8.60 (c 1.29, CHCl3); IR (thin film)
6-[5-(1-Benzyloxypentyl)-2,2-dimethyl[1,3]dioxolan-4-
yl]tetrahydropyran-2-one 20. To a solution of the diol 19
(270 mg,0.71 mmol) in dry benzene (10 mL) was added freshly
prepared Ag2CO3-Celite (6.07 g, 15 equiv), and the mixture
was refluxed under N2 atmosphere for 12 h. The reaction
mixture was filtered, concentrated, and chromatographed over
silica gel to give 192 mg (72%) of the lactone 20 as a colorless
oil: Rf 0.42 (20% EtOAc in petroleum ether); [R]25 +11.61 (c
D
1
1.55, CHCl3); IR (thin film) 2931, 1741, 1455, 1372 cm-1; H
NMR (400 MHz, CDCl3) δ 0.89 (t, J ) 6.85 Hz, 3H), 1.26-
1.64 (m, 5H), 1.39 (s, 3H), 1.44 (s, 3H), 1.64-2.01 (m, 4H), 2.40
(m, 1H), 2.52 (m, 2H), 3.58 (m, 1H), 4.02 (m, 2H), 4.26 (ddd,
J ) 10.2, 6.6, 3.4 Hz, 1H), 4.51 (d, J ) 11.7 Hz, 1H), 4.69 (d,
J ) 11.7 Hz, 1H), 7.30 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
14.1, 18.1, 22.9, 24.5, 27.0, 27.2, 28.2, 29.9, 30.9, 72.8, 78.1,
80.7, 81.3, 109.6, 127.5, 128.1, 128.3, 138.6, 170.3; MS (FAB)
377 (M+ + 1). Anal. Calcd for C22H32O5: C, 70.21; H, 8.51.
Found: C, 70.10; H, 8.42.
1
3060, 3029, 1456 cm-1; H NMR (400 MHz, CDCl3) δ 0.89 (t,
J ) 6.8 Hz, 3H), 1.32 (m, 3H), 1.42 (s, 3H), 1.43 (s, 3H), 1.62
(m, 3H), 2.66 (dd, J ) 4.9, 2.4 Hz, 1H), 2.79 (dd, J ) 4.9, 4.1
Hz, 1H), 3.03 (m, 1H), 3.49 (m, 1H), 3.75 (dd, J ) 7.6, 5.6 Hz,
1H), 4.08 (dd, J ) 7.8, 4.4 Hz, 1H), 4.63 (s, 2H), 7.31 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 14.0, 22.7, 26.7, 26.9, 28.0, 30.5,
45.0, 52.1, 72.9, 77.0, 78.3, 81.0, 109.5, 127.6, 127.9, 128.3,
138.5; MS (FAB) 321 (M+ + 1). Anal. Calcd for C19H28O4: C,
71.25; H, 8.75. Found: C, 71.12; H, 8.60.
6-(3-Benzyloxy-1,2-dihydroxyheptyl)tetrahydropyran-
2-one 21. A solution of the lactone 20 (150 mg, 0.4 mmol) in
MeCN (2 mL) was treated with CuCl2‚2H2O (204 mg, 1.20
mmol). The reaction mixture was stirred at rt for 36 h and
then quenched by addition of saturated NaHCO3 solution and
extracted with EtOAc. The combined organic layers were dried
over Na2SO4, concentrated, and chromatographed over silica
gel to give 21 107 mg (85%) as a white solid: Rf 0.42 (50%
1-[5-(1-Benzyloxypentyl)-2,2-dimethyl[1,3]dioxolan-4-
yl]pent-4-en-1-ol 18. To a suspension of CuCN (196 mg, 2.18
mmol) in dry ether (4 mL) at -80 °C was slowly added
allylmagnesium bromide (4.4 mmol, 1.11 M in ether) under
N2 atmosphere. After the mixture was stirred for 30 min at
the same temperature, the epoxide 5 (350 mg, 1.09 mmol) in
2 mL of ether was added dropwise. The reaction was allowed
to proceed at the same temperature for 8 h with gradual
warming to -20 °C. The reaction was quenched by addition
of saturated NH4Cl, the organic layer was separated, and the
aqueous layer extracted with ether. The combined organic
layers were dried over Na2SO4, concentrated, and chromato-
graphed over silica gel to give 378 mg (96%) of the alcohol 18
EtOAc in petroleum ether); [R]25 +19.8 (c 0.61, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 0.84 (t, J ) 6.8 Hz, 3H), 1.17-1.34
(m, 5H), 1.51-1.84 (m, 4H), 2.06 (m, 1H), 2.39 (m, 1H), 2.51
(m, 1H), 3.16 (bs, 1H, -OH), 3.50 (m, 2H), 3.79 (bs, 1H), 4.25
(ddd, J ) 10.7, 8.1, 3.4 Hz, 1H), 4.35 (d, J ) 11.2 Hz, 1H),
4.62 (d, J ) 11.2 Hz, 1H), 7.24 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 18.0, 22.9, 24.2, 27.4, 29.4, 29.7, 68.9, 71.5, 74.2,
79.2, 81.7, 128.0, 128.1, 128.7, 137.5, 171.3. Anal. Calcd for
C19H28O5: C, 67.86; H, 8.33. Found: C, 67.46; H, 8.21.
J. Org. Chem, Vol. 68, No. 10, 2003 4043

Chandrasekhar et al.
Acetic Acid 2,3-Diacetoxy-1-(6-oxotetrahydropyran-2-
yl)heptyl Ester 22. A solution of the 21 (75 mg, 0.223 mmol)
in dry EtOH (2 mL) was treated with a catalytic amount of
Pd-C. The suspension was evacuated and purged with H2 gas;
this process was repeated two times, and the reaction was
allowed to proceed under H2 balloon for 24 h at rt. The reaction
mixture was filtered through Celite, washed with some EtOH,
and concentrated in vacuo. The crude product in pyridine (2
mL) was treated with DMAP (10 mg) and Ac2O (100 µL, 10
equiv based on theoretical yield) under N2 atmosphere. The
reaction mixture was stirred at rt for 16 h. The reaction
mixture was poured into ice-cold 6 N HCl and extracted with
EtOAc. The combined organic layers were washed with
saturated aqueous NaHCO3 solution, water, and brine. Finally,
the combined organic layers were dried over Na2SO4, concen-
trated, and chromatographed over silica gel to give the lactone
22 (63 mg, 76% for two steps) as a colorless oil: Rf 0.57 (50%
EtOAc in petroleum ether); [R ]25D -20.0 (c 0.13, EtOH) [lit.7,8
purged with hydrogen gas; this process was repeated three
times, and finally reaction was allowed to proceed for 12 h
under hydrogen balloon. The reaction mixture was filtered
through a Celite pad and washed with EtOAc. On concentra-
tion, hydroxy lactone 25 was obtained in quantitative yield,
which was used as such in the next step: Rf 0.26 (25% EtOAc
in petroleum ether); [R]25D -12.6 (c 1.98, CHCl3); 1H NMR (400
MHz, CDCl3) δ 0.91 (t, J ) 7.1 Hz, 3H), 1.25-1.50 (m, 4H),
1.40 (s, 3H), 1.44(s, 3H), 1.54 (m, 2H), 1.72 (m, 1H), 1.86 (m,
1H), 1.97 (m, 1H), 2.13 (m, 1H), 2.47 (m, 1H), 2.58 (m, 1H),
3.67 (m, 1H), 3.96 (dd, J ) 7.4, 2.4 Hz, 1H), 4.05 (t, J ) 7.3
Hz, 1H), 4.31 (ddd, J ) 13.7, 7.6, 3.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 13.8, 17.9, 22.5, 24.8, 26.9, 27.0, 27.8, 29.6,
34.4, 70.2, 77.6, 81.2, 82.1, 109.6, 170.2. Anal. Calcd for
C15H26O5: C, 62.91; H, 9.15. Found: C, 62.86; H, 9.10.
6-[5-(1-Hydroxypentyl)-2,2-dimethyl[1,3]dioxolan-4-
yl]-5,6-dihydropyran-2-one 26. A mixture of diisopropy-
lamine (245 µL, 2.44 mmol) and HMPA (1 mL) in anhydrous
THF (2 mL) was cooled to -80 °C under N2 atmosphere.
n-BuLi (1.7 mL, 2.39 mmol, 1.4 M in hexanes) was added
dropwise, and the mixture was stirred for 10 min at the same
temperature. A solution of hydroxy lactone 25 in anhydrous
THF (1 mL) was added dropwise over a period of 15 min and
stirred for 45 min at the same temperature. The enolate was
quenched by addition of a freshly prepared solution of phe-
nylselenyl bromide in THF [prepared by addition of bromine
(150 µL, 2.37 mmol) to diphenyldiselenide (915 mg, 2.43 mmol)
in THF (1 mL) at 0 °C]. After being stirred for 1 h at -80 °C,
the reaction was quenched by addition of saturated NH4Cl at
the same temperature. The organic layer was separated, and
the aqueous layer was extracted with ether. The combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. The crude product was chromatographed over silica gel
and subjected to oxidative elimination. To the product in DCM
(1 mL) were added pyridine (725 µL, 8.82 mmol) and 30% H2O2
(300 µL, 2.64 mmol) at 0 °C. The reaction mixture was stirred
for 6 h with gradual warming to rt. The reaction mixture was
diluted with more DCM and washed with water and brine.
Finally, the organic layer was dried over Na2SO4, concentrated,
and chromatographed over silica gel to give 26 as a colorless
oil: yield 140 mg (50%); Rf 0.30 (30% EtOAc in petroleum
ether). This compound was characterized after conversion of
the hydroxy group to acetate.
[R ]25 -19.3 (c 0.36, EtOH)]; 1H NMR (400 MHz,CDCl3)8
δ
D
0.87 (t, J ) 6.6 Hz, 3H), 1.27-1.97 (m, 10H), 2.07 (s, 3H), 2.10
(s, 3H), 2.13 (s, 3H), 2.4-2.6 (m, 2H), 4.42 (ddd, J ) 10.7, 5.8,
3.4 Hz, 1H), 5.02 (q, J ) 6.4 Hz, 1H), 5.20 (dd, J ) 5.8, 4.4 Hz,
1H), 5.35 (dd, J ) 5.8, 4.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)7
δ 13.8, 18.1, 20.6, 20.7, 20.9, 22.3, 23.4, 26.9, 29.5, 30.2, 70.6,
71.3, 71.7, 77.8, 169.7, 169.8, 170.0, 170.4. Anal. Calcd for
C18H28O8: C, 58.05; H, 7.58. Found: C, 58.00; H, 7.56.
Benzeneseleninic Anhydride Dehydrogenation of 22.
The lactone 22 (20 mg, 0.054 mmol) in anhydrous chloroben-
zene (3 mL) was treated with benzeneseleninic anhydride (31
mg, 0.086 mmol) under N2 atmosphere. The reaction mixture
was refluxed for 72 h. The cholorobenzene was removed in
vacuo, and the residue was chromatographed over silica gel
to give a 1:3 mixture of 2 and 22 (ratio determined by NMR).
3-Benzenesulfonyl-1-[5-(1-benzyloxypentyl)-2,2-dimeth-
yl[1,3]dioxolan-4-yl]-5-(tert-butyldimethylsilanyloxy)-
pentan-1-ol 23. To the sulfone silyl ether 15 (926 mg, 2.95
mmol) in anhydrous THF (9 mL) was added n-BuLi (2 mL 1.46
M in hexanes) dropwise at 0 °C under N2 atmosphere. The
yellow reaction mixture was stirred at the same temperature
for 30 min. A suspension of CuI (280 mg, 1.47 mmol) in dry
THF (5 mL) was prepared separately. The suspension was
cooled to -80 °C. The sulfone silyl ether anion formed
previously was added and stirred at the same temperature for
1 h. The epoxide 5 (235 mg. 0.74 mmol) in THF (1.5 mL) was
added to the cuprate and stirred for 12 h with gradual
warming to -20 °C. The reaction was quenched by addition
of saturated aqueous NH4Cl solution. The organic layer was
separated, and the aqueous layer was extracted with ether.
The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The crude product was chromato-
graphed over silica gel to give 23 in 95% yield: Rf 0.24 (10%
Acetic Acid 1-[2,2-Dimethyl-5-(6-oxo-3,6-dihydro-2H-
pyran-2-yl)[1,3]dioxolan-4-yl]pentyl Ester 27. A solution
of hydroxy lactone 26 (140 mg) in dry pyridine (500 µL)was
treated with few crystals of DMAP and cooled to 0 °C. This
was treated with Ac2O (50 µL) and stirred overnight at rt. The
reaction mixture was concentrated under vacuum, and the
residue was chromatographed over silica gel to give 27 as a
colorless liquid yield 93%: Rf 0.41 (25% EtOAc in petroloeum
EtOAc in petroleum ether); [R]25 + 10.6 (c 0.96, CHCl3); IR
ether); [R]25 +40.65 (c 1.39, CHCl3); 1H NMR (400 MHz,
D
D
(thin film) 3054, 2931, 1449 cm-1; 1H NMR (400 MHz, CDCl3)
δ 0.00 (m, 6H), 0.85 (m, 9H), 0.89 (t, J ) 6.8 Hz, 3H), 1.26-
1.38 (m, 9H), 1.63-1.94 (m, 5 H), 2.10-2.39 (m, 1H), 3.48-
3.74 (m, 6H), 3.94 (dt, J ) 7.3, 3.2 Hz, 1H), 4.62 (m, 2H), 7.34
(m, 5H), 7.55 (m, 2H), 7.65 (m, 1H), 7.90 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ -5.4, 14.0, 18.1, 22.7, 25.8, 25.86, 26.9,
27.1, 28.4, 30.2, 30.9, 32.3, 32.5, 32.9, 58.2, 58.4, 59.9, 60.5,
69.8, 70.9, 73.1, 78.1, 78.3, 79.1, 79.3, 80.8, 81.0, 108.8, 127.8,
127.9, 128.0, 128.2, 128.4, 128.44, 128.9, 128.98, 129.06,
129.12, 133.6, 137.7; MS (FAB) 635 (M+ + 1). Anal. Calcd for
C34H54O7SSi: C, 64.32; H, 8.57. Found: C, 64.29; H, 8.52.
Attempted Oxidation of 24 with RuCl2(PPh3)3. The
solution of 24 (177 mg, 0.466 mmol) in dry benzene (3 mL)
was treated with RuCl2(PPh3)3 (223 mg, 0.233 mmol) at 50 °C
for 15 h. The reaction mixture was filtered through Celite, and
the organic layer was concentrated in vacuo.
CDCl3) δ 0.90 (t, J ) 6.8 Hz, 3H), 1.26-1.38 (m, 4H), 1.40 (s,
3H), 1.45 (s, 3H), 1.69 (m, 2H), 2.12 (s, 3H), 2.53 (m, 2H), 3.98
(m, 1H), 4.17 (dd, J ) 6.6, 3.4 Hz, 1 H), 4.42 (q, J ) 7.1 Hz,
1H), 5.06 (ddd, J ) 12.2, 5.1, 3.4 Hz, 1H), 6.04 (td, J ) 10, 1.7
Hz, 1H), 6.91 (td, J ) 9.8, 4.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 21.0, 22.5, 25.9, 26.9, 27.6, 29.7, 30.8, 72.5, 77.3,
78.1, 79.9, 11.6, 121.5, 144.5, 162.7, 170.6. Anal. Calcd for
C17H26O6: C, 62.56; H, 8.03. Found: C, 62.47; H, 7.98.
Deacetylboronolide 3. To 26 (75 mg, 0.307 mmol) in
distilled water (1 mL) was added Amberlite H+ (100 mg), and
the reaction mixture was kept at 70 °C for 7 h. All the solids
were removed by filtration, and the aqueous layer was
concentrated in vacuo. The residue was crystallized from a 2:1
mixture of hexane and benzene to give 3 as a white solid: yield
60 mg (90%); mp 101 °C (lit.3 mp 99-100 °C); Rf 0.43 (100%
EtOAc); [R]25D + 54.0 (c 0.55, EtOH) [lit.3 [R]25D +56.0 (c 0.07,
EtOH)]: 1H NMR (400 MHz, CDCl3) 0.90 (t, J ) 6.8 Hz, 3H),
1.34 (m, 3H), 1.58 (m, 3H), 2.51 (m, 1H), 2.62 (m, 1H), 3.75
(m, 2H), 3.84 (d, J ) 7.6 Hz, 1H), 4.52 (ddd, J ) 11.6, 7.2, 4.4
Hz, 1H), 6.02 (dd, J ) 10.0, 2.4 Hz, 1H), 6.94 (ddd, J ) 9.6,
6-[5-(1-Hydroxypentyl)-2,2-dimethyl[1,3]dioxolan-4-yl]-
tetrahydropyran-2-one 25. The lactone 20 in dry ethanol
(2 mL) was treated with a catalytic amount of 10% Pd on
activated charcoal. The reaction vessel was evacuated and
4044 J. Org. Chem., Vol. 68, No. 10, 2003

Total Synthesis of (+)-Boronolide
6.0, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.9, 22.6, 25.8,
27.6, 35.6, 70.0, 74.5, 74.6, 76.7 (along with CDCl3 peaks),
121.1, 145.8, 163.7.
cooled to 0 °C, and Ac2O (250 µL) was added. The reaction
mixture was stirred at rt for 18 h. The reaction mixture was
poured into ice-cold dilute HCl and extracted with EtOAc. The
organic layer was dried over Na2SO4, concentrated, and
chromatographed over silica gel to give 50 mg (92%) of 2 as
white solid: mp 88 °C (lit.3 mp 89-90 °C); Rf 0.57 (50% EtOAc
in petroleum ether); [R]25 +25.44 (c 0.63, CHCl3) [lit.2 [R]25
Dideacetylboronolide 4. A solution of 27 (100 mg, 0.306
mmol) in distilled MeCN (1 mL) was treated with CuCl2‚2H2O
(156 mg, 0.917 mmol). The reaction mixture was stirred at rt
for 24 h and quenched by addition of saturated NaHCO3. The
solids were removed by filtration, and aqueous layer was
extracted with EtOAc. The combined organic layers were dried
over Na2SO4, concentrated, and chromatographed over silica
gel to give 45b as a viscous liquid: yield 80 mg (88%); Rf 0.19
(50% EtOAc in petroleum ether); [R]25D +35.0 (c 0.72, CHCl3);
1H NMR (400 MHz, CDCl3) δ 0.83 (t, J ) 6.8 Hz, 3H), 1.26
(m, 4H), 1.59 (m, 2H), 2.04 (s, 3H), 2.46 (m, 2H), 2.82 (bs, 2H),
3.74 (d, J ) 6.4, 1H), 3.84 (d, J ) 5.4 Hz, 1H), 4.43 (ddd, J )
10.7, 6.8, 4.9 Hz, 1H), 4.95 (q, J ) 6.6 Hz, 1H), 5.95 (d. J )
9.8 Hz, 1H), 6.88 (ddd, J ) 9.8, 5.6, 3.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 13.9, 21.1, 22.5, 25.6, 27.3, 30.4, 70.2, 72.0,
75.5, 77.3, 121.0, 145.7, 163.7, 171.7. Anal. Calcd for C14H22-
O6: C, 58.73; H, 7.74. Found: C, 58.84; H, 7.80.
D
D
1
+25 (EtOH); [R]25 +28 (c 0.08, EtOH)]; H NMR (400 MHz,
D
CDCl3) δ 0.83 (t, J ) 7.1 Hz, 3H), 1.23 (m, 4H), 1.52 (m, 2H),
2.02 (s, 3H), 2.05 (s, 3H), 2.09 (s, 3H), 2.16-2.30 (m, 1H), 2.43-
2.52 (m, 1H), 4.48 (m, 1H), 4.98 (q, J ) 6.1 Hz, 1H), 5.29 (m,
2H), 5.97 (dd, J ) 9.8, 1.9 Hz, 1H), 6.83 (ddd, J ) 2.4, 6.1, 9.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7, 20.5, 20.6, 20.8,
22.3, 25.1, 26.9, 30.2, 70.5, 70.6, 71.6, 75.1, 121.3, 144.1, 162.3,
169.5, 169.8, 170.3.
Acknowledgment. V.K.S. thanks DST for a Swar-
najayanti fellowship project. K.L.C. thanks CSIR for a
senior research fellowship.
Boronolide 2. To 4 (46 mg, 0.16 mmol) in pyridine (1 mL)
were added few crystals of DMAP. The reaction mixture was
JO0269058
J. Org. Chem, Vol. 68, No. 10, 2003 4045