Enantio- and diastereocontrolled total synthesis of (+)-boronolide

Article abstract of DOI:10.1021/jo0603781

An efficient stereoselective total synthesis of (+)-boronolide from valeraldehyde is described. The key steps include a Sharpless asymmetric hydroxylation, a chelation-controlled vinyl Grignard reaction followed by a Sharpless asymmetric epoxidation, hydr

Full text of DOI:10.1021/jo0603781

Enantio- and Diastereocontrolled Total Synthesis of (+)-Boronolide†
Pradeep Kumar* and S. Vasudeva Naidu
DiVision of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
pk.tripathi@ncl.res.in
ReceiVed February 23, 2006
An efficient stereoselective total synthesis of (+)-boronolide from valeraldehyde is described. The key
steps include a Sharpless asymmetric hydroxylation, a chelation-controlled vinyl Grignard reaction followed
by a Sharpless asymmetric epoxidation, hydrolytic kinetic resolution, and a ring-closing metathesis.
Introduction
Many natural products with different biological activities,
such as insect growth inhibition, antitumor, antibacterial,
antifungal, or immunosuppressive properties, possess an R,â-
unsaturated δ-lactone moiety as an important structural feature.
1
R,â-Unsaturated δ-lactone functionality is presumed to be
responsible for biological activities as a result of its ability to
act as a Michael acceptor, enabling these molecules to bind to
a target enzyme. The pyrone units are widely distributed in all
parts of plants (Lamiaceae, Piperaceae, Lauraceae, and Annon-
aaceae families) including leaves, stems, flowers, and fruits.
R-Pyrones possessing polyhydroxy or polyacetoxy side chains
have attracted much attention from synthetic and medicinal
chemists as a result of their broad range of biological activities.
Examples of such compounds include (+)-boronolide 1 and its
deacetylated 1a and dideacetylated derivative 1b (Figure 1).
Boronolide 1 is an R,â-unsaturated C-12 lactone isolated from
FIGURE 1. Structure of (+)-boronolide (1).
3
leaves of Tetradenia barberae, which have been used as a local
4
folk medicine in Madagascar and South Africa. Deacetylated
1
a and dideacetylated boronolide 1b have been obtained from
5
Tetradenia riparia, a Central African species typically em-
ployed by the Zulu as an emetic, which is an infusion of the
leaf that has also been reported to be effective against malaria.
The relative stereochemistry of 1 was determined by X-ray
6
analysis. The R configuration at the C-6 position was proposed
2
the leaves and branches of Tetradenia fruticosa and from the
(
3) Davies-Coleman, M. T.; Rivett, D. E. A. Phytochemistry 1987, 26,
*
Corresponding Author: Telephone: +91-20-25902050. Fax: +91-20-
3
047-3050.
2
5902629.
†
(4) Watt, J. M.; Brandwijik, M. G. B. The Medicinal and Poisonous
Dedicated to Professor S. Chandrasekaran on the occasion of his 60th
birthday and in recognition of his seminal contributions to so many aspects of
organic chemistry.
Plants of Southern and Eastern Africa; Livingston: Edinburg, 1962; p 516.
(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, 1215-1218. (b) Van Puyvelde, L.; De Kimpe, N.; Dube, S.; Chagnon-
Dube, M.; Boily, Y.; Borremans, F.; Schamp, N.; Anteunis, M. J. O.
Phytochemistry 1981, 20, 2753-2755.
(
1) (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985,
4, 94-110.
2) (a) Davies-Coleman, M. T.; Rivett, D. E. A. Fortschr. Chem. Org.
2
(
Naturst. 1989, 55, 1-35. (b) Ohloff, G. Fortschr. Chem. Org. Naturst. 1978,
3
3
5, 431-527. (c) Aditychaudhury, N.; Das, A. K. J. Sci. Ind. Res. 1979,
8, 265-277. (d) Siegel, S. M. Phytochemistry 1976, 15, 566-567.
(6) Kjaer, A.; Norrestan, R.; Polonsky, J. Acta Chem. Scand., Ser. B
1985, 39, 745-750.
1
0.1021/jo0603781 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/18/2006
J. Org. Chem. 2006, 71, 3935-3941
3935

Kumar and Naidu
by application of Hudson’s lactone rule to the molecular rotation.
Later, the stereochemistry at the C-6 position was confirmed
by chemical degradation. The first synthesis of 1 was reported
from an acrolein derivative7 in racemic form. Most of the
enantioselective syntheses known for boronolide derive the
asymmetry from chiral pool starting materials such as glu-
SCHEME 1. Retrosynthetic Analysis for (+)-Boronolide
a
cose,7b mannitol, tartaric acid, D-glucono-δ-lactone and
7e,i
7d,j
7j
7
f
L-erythrulose, and so on. However, synthetic approaches
involving an achiral substrate as starting material are rather
scarce.7
c,h,k-l
As a part of our research program aimed at
developing an enantioselective synthesis of naturally occurring
lactones8 and amino alcohols,9 we now report a detailed
description of our study toward the enantio- and diastereocon-
trolled synthesis of (+)-boronolide. The key steps include a
Sharpless asymmetric dihydroxylation, a chelation-controlled
Grignard reaction, a hydrolytic kinetic resolution (HKR), a
Sharpless asymmetric epoxidation, and a ring-closing metathesis.
96% yield with 97% ee.7k,l,11 Treatment of diol 4a with 2,2-
dimethoxypropane in the presence of p-TSA gave the acetonide
ester (2R,3S)-4b, which on reduction with DIBAL-H furnished
the alcohol (2S,3S)-5b in 91% yield. The resulting alcohol 5b
was subjected to oxidation under Swern conditions12 to give
the aldehyde 6b in excellent yield. To establish the third
stereogenic center with the required stereochemistry, it was
thought worthwhile to examine stereoselective vinylation. Thus,
treatment of aldehyde 6b with vinylmagnesium bromide in THF
Results and Discussion
Our synthetic strategy for the synthesis of boronolide 1 is
outlined in Scheme 1. We envisioned that the lactone ring could
be constructed by the ring-closing metathesis of an acrylate ester,
which in turn would be obtained from an epoxide. The
enantiopure epoxide could be prepared either by the Sharpless
asymmetric epoxidation of an allylic alcohol or by the HKR of
a racemic epoxide. The chelation-controlled vinylation of an
aldehyde would install the third stereogenic center, while the
initial two stereocenters could easily be established by the
Sharpless asymmetric dihydroxylation of an olefin.
The synthesis of boronolide started from commercially
available valeraldehyde 2, as illustrated in Scheme 2. Thus,
valeraldehyde 2 was subjected to Horner-Emmons olefination
with triethyl phosphonoacetate to furnish the (E)-R,â-unsaturated
ester 3 in 89% yield. The ester 3 was treated with osmium
tetroxide and potassium ferricyanide as co-oxidant in the
presence of the (DHQ)2PHAL ligand under asymmetric dihy-
droxylation (AD) conditions10 to give the diol (2R,3S)-4a in
13
in the presence of MgBr ‚Et O at -78 °C furnished the allylic
2
2
alcohol 7b in 92% yield with moderate diastereomeric selectivity
(dr ) 3:1; syn/anti) as an inseparable mixture of diastereomers.
Even after protection of the hydroxy group of 7b with
different protecting groups such as TBS, MOM, Ac, and PMB,
we were unable to separate the diastereomers by flash chro-
matography. To determine the stereochemistry of the newly
generated third stereocenter, compound 7b was subjected to acid
treatment, followed by 1,3-dihydroxy protection as the ben-
zylidene derivative. The required major isomer 8 could easily
be separated by silica gel column chromatography (Scheme 3).
The newly generated stereocenter in 7b was assigned syn
configuration, which was based on the NOE studies, as strong
NOE correlations were observed between the 1,3-diaxial protons
of the cyclic derivative 8. (See the Supporting Information).
Subsequently, several attempts were made to achieve better
selectivity with the use of additives such as ZnCl2 or TiCl4 and
employing the addition of vinyllithium as an alkylating reagent
with different solvent systems (CH2Cl2 or diethyl ether).
However, the required syn selectivity could not be improved.
To explore the possibility of achieving a better syn selectivity
in the vinylation reaction, it was thought worthwhile to change
the protecting group. We assumed that the chelation between
MOM and aldehyde would be more effective as compared to
other protecting groups. Thus, the diol 4a was treated with
MOMCl in the presence of diisopropylethylamine to afford
(
7) (a) Jefford, C. W.; Moullin, M.-C. HelV. Chem. Acta 1991, 74, 336-
3
42. (b) Nagano, H.; Yasui, H. Chem. Lett. 1992, 1045-1048. (c) Honda,
T.; Horiuchi, S.; Mizutani, H.; Kanai, K. J. Org. Chem. 1996, 61, 4944-
4
1
2
948. (d) Ghosh, A. K.; Bilcer, G. Tetrahedron Lett. 2000, 41, 1003-
006. (e) Chandrasekhar, M.; Raina, S.; Singh, V. K. Tetrahedron Lett.
000, 41, 4969-4972. (f) Carda, M.; Rodriguez, S.; Segovia, B.; Marco, J.
A. J. Org. Chem. 2002, 67, 6560-6563. (g) Murga, J.; Falomir, E.; Carda,
M.; Marco, J. A. Tetrahedron: Asymmetry 2002, 13, 2317-2327. (h) Trost,
B. M.; Yeh, V. S. C. Org. Lett. 2002, 4, 3513-3516. (i) Chandrasekhar,
M.; Chandra, K. L.; Singh, V. K. J. Org. Chem. 2003, 68, 4039-4045. (j)
Hu, S. G.; Hu, T. S.; Wu, Y. L. Org. Biomol. Chem. 2004, 2, 2305-2310.
(
2
k) Naidu, S. V.; Gupta, P.; Kumar, P. Tetrahedron Lett. 2005, 46, 2129-
131. (l) Boruwa, J.; Barua, N. C. Tetrahedron 2006, 62, 1193-1198.
(8) (a) Pais, G. C. G.; Fernandes, R. A.; Kumar, P. Tetrahedron 1999,
5
5, 13445-13450. (b) Fernandes, R. A.; Kumar, P. Tetrahedron: Asym-
metry 1999, 10, 4349-4356. (c) Fernandes, R. A.; Kumar, P. Eur. J. Org.
Chem. 2002, 2921-2923. (d) Kandula, S. V.; Kumar, P. Tetrahedron Lett.
2
003, 44, 6149-6151. (e) Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron
Lett. 2004, 45, 849-851. (f) Kumar, P.; Naidu, S. V.; Gupta, P. J. Org.
Chem. 2005, 70, 2843-2846. (g) Kumar, P.; Naidu, S. V. J. Org. Chem.
(10) (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 448-451. (b) Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B.
Chem. ReV. 1994, 94, 2483-2547.
2
005, 70, 4207-4210.
(9) (a) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000, 3447-
3
2
2
2
2
449. (b) Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetrahedron Lett.
002, 43, 4425-4426. (c) Fernandes, R. A.; Kumar, P. Tetrahedron Lett.
000, 41, 10309-10312. (d) Naidu, S. V.; Kumar, P. Tetrahedron Lett.
003, 44, 1035-1037. (e) Kandula, S. V.; Kumar, P. Tetrahedron Lett.
003, 44, 1957-1958. (f) Gupta, P.; Fernandes, R. A.; Kumar, P.
(11) For the measurement of enantiomeric excess, the diol 4a was
converted into its dibenzoate 4d. The enantiomeric purity of the dibenzoate
4d was estimated to be >96% by chiral HPLC analysis (Chiral Cel OD,
petroleum ether/i-PrOH (98:2) 1 mL/min, 240 mm.
(12) For reviews of the Swern oxidation, see: (a) Tidwell, T. T. Synthesis
1990, 857-870. (b) Tidwell, T. T. Org. React. 1990, 39, 297-572.
(13) Keck, G. E.; Andrus, M. B.; Romer, D. R. J. Org. Chem. 1991, 56,
417-420.
Tetrahedron Lett. 2003, 44, 4231-4232. (g) Kondekar, N. B.; Kandula, S.
V.; Kumar, P. Tetrahedron Lett. 2004, 45, 5477-5479. (h) Pandey, S. K.;
Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2004, 45, 5877-5879.
3936 J. Org. Chem., Vol. 71, No. 10, 2006

Total Synthesis of (+)-Boronolide
SCHEME 2 a
a
Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et, LiBr, Et3N, THF, rt, overnight, 89%; (b) (DHQ)2PHAL, K2CO3, K3Fe(CN)6, MeSO2NH2, t-BuOH/
H2O (1:1), 0.1 M OsO4 (0.4 mol %), 0 °C, 24 h, 96%; (c) p-TSA, 2,2-DMP, CH2Cl2, 95%; (d) MOM chloride, DIPEA, CH2Cl2, 0 °C to room temperature,
overnight, 91%; (e) BzCl, pyridine, 0 °C to room temperature, overnight, 90%; (f) DIBAL-H, CH2Cl2, 0 °C to room temperature, 2 h (91% for 5b, 89% for
5
7
c); (g) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C to -60 °C, 95%. (h) CH2dCHMgBr, MgBr2‚Et2O, THF or CH2Cl2, -78 °C, 6 h, (92% for 7b, 90% for
c).
SCHEME 3 a
with magnesium, as illustrated in Figure 2. After protection of
the hydroxyl group in compound 7c with TBSCl, the required
syn diastereomer (3R,4R,5S)-10 could easily be separated by
flash chromatography. To generate the final stereogenic center
with an appropriate functionality, a Sharpless asymmetric
epoxidation was employed in the next step (Scheme 4). Thus,
treatment of allylic alcohol 7c with titanium tetraisopropoxide
and tert-butyl hydroperoxide in the presence of (+)-DIPT for
a
Reagents and conditions: (a) (i) HCl, MeOH, rt, 12 h; (ii) PhCH(OMe)2,
14
4
days under Sharpless asymmetric epoxidation conditions
p-TSA, CH2Cl2, rt, overnight.
provided the epoxide 9 albeit in low yield and poor diastereo-
selectivity. The extra chelation of titanium-tetraisopropoxide
with MOM might be the possible cause for retarding the rate
of the epoxidation reaction. As a next alternative, it was thought
worthwhile to prepare first the diol 11 by the Sharpless
asymmetric dihydroxylation of olefin 10, which could further
be converted easily into the required epoxide 12a by standard
transformations. Accordingly, the olefin 10 was treated with
osmium tetroxide and potassium ferricyanide as co-oxidant in
the presence of the (DHQ)2AQN ligand under AD conditions10
to give the diol 11 in 91% yield with moderate diastereomeric
selectivity (dr ) 5:1; anti/syn) as an inseparable mixture of
diastereomers. In another attempt to improve the selectivity and
to examine the stereochemical outcome of the epoxidation reac-
tion, we carried out an epoxidation of olefin 10 using m-CPBA
in various solvent systems in the presence of Na HPO . The
FIGURE 2. Chelation-controlled transition models.
compound (2R,3S)-4c in excellent yield (Scheme 2). A subse-
quent reduction of the ester with DIBAL-H, followed by Swern
oxidation, gave the aldehyde 6c, which was used immediately
in the next reaction without any further purification. Thus, when
2
4
addition of phosphate could be effective in avoiding the un-
favorable acid-catalyzed ring opening of epoxide once formed.15
Thus, compound 10 was treated with m-CPBA/Na HPO in
6
c was subjected to chelation-controlled vinylation in CH2Cl2
2
4
13
at -78 °C with MgBr2‚Et2O, it furnished the allylic alcohol
7
1
CH Cl to afford the epoxide in 92% yield (dr ) 4:1; anti/syn)
2
2
c in 90% yield with an excellent diastereoselectivity (dr )
as a nonseparable mixture of diastereomers. Even with the use
of different solvent systems, we could not improve the selectiv-
1
13
9:1; syn/anti), as determined by H and C NMR spectral
analysis. The formation of the major syn diastereomer can be
explained by the chelated five-membered transition state, as
depicted in Figure 2. The improvement in the syn selectivity in
the case of 7c (19:1) as compared to 7b (3:1) could probably
be attributed to the extra chelation by the MOM protecting group
(14) (a) Katasuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5
974-5976. (b) Baker, S. R.; Boot, J. R.; Molgan, S. E.; Osborne, D. T.;
Ross, W. J.; Shrubsall, P. R. Tetrahedron Lett. 1983, 24, 4469-4472.
15) Azuma, H.; Tamagaki, S.; Ogino, K. J. Org. Chem. 2000, 65, 3538-
3541.
(
J. Org. Chem, Vol. 71, No. 10, 2006 3937

Kumar and Naidu
SCHEME 4 a
a
Reagents and conditions: (a) Ti(O-i-Pr)4, (+)DIPT, t-BuOOH, dry CH2Cl2, -20 °C, 4 days, 15%; (b) TBSTf, 2,6-lutidine, CH2Cl2, 0 °C, 30 min, 98%;
c) (DHQ)2AQN (1 mol %), 0.1 M OsO4 (0.4 mol %), K2CO3, K3Fe(CN)6, t-BuOH/H2O (1:1), 0 °C, 24 h, 91%; (d) m-CPBA, Na2HPO4, CH2Cl2, overnight,
(
9
1%; (e) (R,R)-salen-Co-(OAc) (0.5 mol %), dist. H2O, 42 h, (94% for 12a, 90% for 12b, according to the ratio of the starting material).
SCHEME 5 a
a
Reagents and conditions: (a) Ti(O-i-Pr)4, (+)DIPT, t-BuOOH, dry CH2Cl2, -20 °C, 48 h, 78% (yield based on 75% of syn compound); (b) TBSCl,
imidazole, cat. DMAP, CH2Cl2, 0 °C to room temperature, 98%; (c) CH2dCHMgBr, CuI, THF, -30 °C, 90%; (d) acryloyl chloride, Et3N, cat. DMAP,
CH2Cl2, 0 °C to room temperature, 88%; (e) 2 mol % (PCy3)2Ru(Cl)2dCHsPh, CH2Cl2, reflux, 16 h, 90%.
ity. To get the diastereomerically pure epoxide, we next
attempted the HKR method developed by Jacobsen. The HKR
method uses readily accessible cobalt-based chiral salen com-
plexes as the catalyst and water as the only reagent to afford
the chiral epoxide and diol of high ee in excellent yields. These
advantages have made it a very attractive asymmetric synthetic
tool. While the HKR was successfully employed for the reso-
complex (0.5 mol %) and water (0.4 equiv) to yield the epoxide
(2R,3R,3R,5S)-12a in 94% yield (as calculated from 80%
epoxide) and diol (2S,3R,3R,5S)-12b in 90% yield (as calculated
from 20% other epoxide). The diol 12b can be converted into
the required epoxide by the conventional method.
It is interesting to note that while asymmetric epoxidation of
7c gave a rather low yield of the product, the treatment of allylic
alcohol 7b with titanium tetra-isopropoxide and tert-butyl
hydroperoxide in the presence of (+)-DIPT under the Sharpless
1
6
lution of simple epoxides of small molecular weight, mono-
17
functional unbranched alkyl-substituted epoxides, and bisep-
1
8
14
oxides, its application to the multifunctional epoxides has not
been fully explored. Therefore, we decided to use this method
for the resolution of epoxide 12, which would further extend
the scope of this protocol for the multifunctionalized large
molecules having an olefin with a pre-existing adjacent chiral
center. Thus, epoxide 12 was resolved with R,R-salen-Co(OAc)
asymmetric epoxidation conditions furnished the desired
epoxide (2R,3R,3R,5S)-13 in good yield and high diastereomeric
1
13
excess (de ) >95%), as judged by H and C NMR spectral
analysis (Scheme 5). As expected, the Sharpless kinetic resolu-
tion in the epoxidation reaction has a pronounced effect in
enhancing the diastereomeric purity of the desired product. After
the protection of the hydroxyl group as the tert-butyldimeth-
ylsilyl ether, epoxide 13a was treated with vinylmagnesium
bromide in the presence of a catalytic amount of CuI in THF at
(
16) (a) Schaus, S. E.; Branalt, J.; Jacobson, E. N. J. Org. Chem. 1998,
6
3, 6776-6777. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobson, E. N. J. Am.
Chem. Soc. 2002, 124, 1307-1315.
(
17) Stavle, P. S.; Lamoreaux, M. J.; Berry, J, F.; Gandour, R. D.
(18) (a) Chow, S.; Kitching, W. Chem. Commun. 2001, 1040-1041. (b)
Chow, S.; Kitching, W. Tetrahedron: Asymmetry 2002, 13, 779-793.
Tetrahedron: Asymmetry 1998, 9, 1843-1846.
3938 J. Org. Chem., Vol. 71, No. 10, 2006

Total Synthesis of (+)-Boronolide
SCHEME 6 a
5.76 (dt, J ) 15.7, 1.3 Hz, 1H), 4.18 (q, J ) 7.1 Hz, 2H), 2.17 (q,
J ) 8 Hz, 2H), 1.37-1.40 (m, 4H), 1.27 (t, J ) 7.6 Hz, 3H), 0.91
13
(
t, J ) 7.1 Hz, 3H). C NMR: 165.9, 148.5, 132.0, 59.4, 31.4,
2
1.7, 13.7.
2R,3S)-2,3-Dihydroxyheptanoic Acid Ethyl Ester (4a). [R]25
8.8 (c 0.9, CHCl ). IR (neat): νmax 3400, 3133, 3018, 2926, 2854,
(
D
-
3
-
1
1
1
732, 1460, 1401, 1215, 760, 667 cm . H NMR (200 MHz,
): δ 0.88 (t, J ) 7.3 Hz, 3H), 1.24-1.37 (m, 6H), 1.59 (t,
J ) 13.6 Hz, 3H), 3.20 (br s, 2H), 3.85 (dt, J ) 6.8, 2.4 Hz, 1H),
.06 (d, J ) 2.4 Hz, 1H), 4.25 (q, J ) 7.2 Hz, 2H). 13C NMR (50
MHz, CDCl ): δ 13.7, 13.81, 22.3, 27.6, 32.9, 61.5, 72.4, 73.2,
73.5.
(2R,3S)-5-Butyl-2,2-dimethyl-[1,3]dioxolane-4-carboxylic Acid
Ethyl Ester (4b). To a solution of the diol 4a (2.45 g, 12.90 mmol)
and p-TSA (100 mg) in CH Cl (75 mL) was added 2,2-dimeth-
oxypropane (2.02 g, 19.35 mmol), and the mixture was stirred
overnight. Solid NaHCO (1 g) was added, and the stirring con-
CDCl
3
4
3
1
a
Reagents and conditions: (a) CH2dCHMgBr, CuI, THF, -30 °C, 86%;
b) acryloyl chloride, Et3N, cat. DMAP, CH2Cl2, 0 °C to room temperature,
1%; (c) 2 mol % (PCy3)2Ru(Cl)2dCHsPh, CH2Cl2, reflux, 8 h, 89%; (d)
(
9
2
2
BF3‚SMe2, -30 °C, then aq HF, CH3CN, rt, then Ac2O, Et3N, cat DMAP,
CH2Cl2, rt, (50% overall).
3
tinued for 30 min. The reaction was filtered through a pad of neutral
alumina and concentrated. Silica gel column chromatography of
-
20 °C to furnish the homoallylic alcohol 14 in excellent yield.
Treatment of 14 with acryloyl chloride and Et3N in the presence
7l
the crude product using petroleum ether/EtOAc (9:1) gave 4b (2.52
of a catalytic amount of DMAP in CH2Cl2 provided the acrylate
g, 95%) as a colorless liquid. [R]25 -13.2 (c 3.22, CHCl ). IR
D
3
15 in 88% yield. Olefin metathesis of 15 with the commercially
(neat): ν 3400, 3133, 3018, 2926, 2854, 1732, 1460, 1401, 1215,
max
19
-1
1
available first-generation Grubbs catalyst (2 mol %) in the
presence of Ti(OPr-i)4 (0.3 equiv) in refluxing CH2Cl2 afforded
the R,â-unsaturated δ-lactone 16 in 90% yield. Finally, all
protecting groups in compound 16 were deprotected, and
the resulting triol was acetylated with acetic anhydride to give
760, 667 cm . H NMR (200 MHz, CDCl
3
): δ 4.20 (q, J ) 8.0
Hz, 2H), 4.09 (m, 2H), 1.62 (t, J ) 8.2 Hz, 3H), 1.44 (s, 3H), 1.42
1
3
(
s, 3H), 1.27-1.35 (m, 6H), 0.89 (t, J ) 7.0 Hz, 3H). C NMR
(50 MHz, CDCl ): δ 170.7, 110.5, 79.1, 60.9, 33.0, 27.0, 25.5,
2.3, 13.9, 13.6.
2R,3S)-2,3-Bismethoxymethoxyheptanoic Acid Ethyl Ester
4c). To a solution of the diol 4a (2.10 g, 11.04 mmol) and
diisopropylethylamine (4.99 g, 38.64 mmol) in dry CH Cl (50 mL)
7
h
3
2
(
(+)-boronolide 1.
(
In the same manner, the ring opening of epoxide 12a was
2
2
carried out with vinylmagnesium bromide in the presence of a
catalytic amount of CuI in THF at -20 °C to furnish the
homoallylic alcohol 17 in excellent yield (Scheme 6). The
reaction of 17 with acryloyl chloride and Et3N in the presence
of a catalytic amount of DMAP in CH2Cl2 provided the acrylate
was added MOMCl (2.13 g, 26.49 mmol) under argon over 5 min
at 0 °C, and the mixture was allowed to warm to room temperature
overnight. After cooling to 0 °C, the reaction mixture was quenched
with water and extracted with CH
organic extracts were washed with water (3 × 50 mL) and brine,
dried (Na SO ), and concentrated. Silica gel column chromatog-
raphy of the crude product using petroleum ether/EtOAc (8:2) gave
c (2.80 g, 91%) as a colorless liquid. [R]25
+59.2 (c 2.21, CHCl ).
IR (CHCl ): νmax 3016, 2955, 2824, 2402, 1726, 1466, 1382, 1215,
Cl
2 2
(3 × 50 mL). The combined
ester 18 in 91% yield. Olefin metathesis of 18 with commercially
2
4
available first-generation Grubbs catalyst19 (2 mol %) in the
4
D
3
presence of Ti(i-PrO)4 (0.3 equiv) in refluxing CH2Cl2 afforded
the R,â-unsaturated lactone 19 in 89% yield. Finally, all
protecting groups in 19 were deprotected, and the resulting triol
was acetylated with acetic anhydride to give (+)-boronolide 1.
The physical and spectroscopic data were identical with those
3
-
1 1
1
4
3
3
102, 1036 cm . H NMR (200 MHz, CDCl ): δ 4.70 (s, 2H),
.62 (s, 2H), 4.19 (m, 3H), 3.91 (m, 1H), 3.37 (s, 3H), 3.31 (s,
H), 1.64 (t, J ) 8.2 Hz, 3H), 1.22-1.30 (m, 6H), 0.88 (t, J ) 7.1
13
3
Hz, 3H). C NMR (50 MHz, CDCl ): δ 13.6, 13.8, 22.3, 27.2,
30.2, 55.4, 55.8, 60.5, 76.9, 77.3, 78.1, 96.3, 170.4. Anal. Calcd
7
h
reported.
In conclusion, a practical and stereoselective total synthesis
of (+)-boronolide 1 has been achieved in 13 steps from
commercially available valeraldehyde 2 in an overall yield of
for C13
9.12.
26 6
H O (278.34): C, 56.10; H, 9.42. Found: C, 56.44; H,
(2S,3S)-(5-Butyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (5b).
To a solution of 4b (2.40 g, 10.42 mmol) in dry CH Cl (80 mL)
2
2
1
8% using Sharpless asymmetric dihydroxylation, chelation-
at 0 °C was added dropwise DIBAL-H (25.8 mL, 25.8 mmol, 1 M
in toluene) through a syringe. The reaction mixture was allowed
to warm to room temperature over 2 h, recooled to 0 °C, and treated
with saturated sodium/potassium tartrate. The solid material was
filtered through a pad of Celite and concentrated. Silica gel column
chromatography of the crude product using petroleum ether/EtOAc
controlled addition of vinyl Grignard, epoxidation, Jacobson’s
HKR, and ring-closing metathesis as the key steps. The HKR
on the multifunctional terminal olefin having chiral centers
was successfully utilized for the synthesis of boronolide. We
believe our new approach is, thus, the most efficient route to
2
5
(+)-boronolide reported so far and would permit maximum
(7:3) as eluent gave 5b (1.79 g, 91%) as a colorless oil. [R]
D
variability in product structure with regard to stereochemical
diversity, which is particularly important for making various
synthetic analogues required for the screening for biological
activity.
-21.5 (c 1.08, CHCl ). IR (neat): νmax 3440, 2926, 1460, 1361,
3
1 1
-
1216, 764, 667 cm . H NMR (200 MHz, CDCl
3
): δ 3.75 (m,
H), 3.58 (dd, J ) 11.3, 3.9 Hz, 2H), 2.17 (s, 1H), 1.44-1.62 (m,
H), 1.42 (s, 3H), 1.41 (s, 3H), 1.37-1.42 (m, 4H), 0.91 (t, J )
.7 Hz, 3H). 13C NMR (50 MHz, CDCl
): δ 13.7, 22.5, 26.8, 27.1,
7.9, 32.6, 62.0, 77.00, 81.6, 108.3. Anal. Calcd for C10
2
2
6
2
3
20 3
H O
Experimental Section
(
188.26): C, 63.80; H, 10.71. Found: C, 64.09; H, 10.58.
-(5-Butyl-2,2-dimethyl-[1,3]-dioxolan-4-yl)-prop-2-en-1-ol (7b).
To a solution of oxalyl chloride (1.405 g, 0.966 mL, 11.074 mmol)
in dry CH Cl (100 mL) at -78 °C was added dropwise dry DMSO
1
Hept-2-enoic Acid Ethyl Ester (3). IR (neat): νmax 2924, 2856,
724, 1655, 1466, 1366, 1310, 1178, 1128, 1045, 980, 721 cm-1
1
.
1
H NMR (200 MHz, CDCl
3
): δ 6.95 (dt, J ) 15.7, 7.1 Hz, 1H),
2
2
(
1.730 g, 1.57 mL, 22.15 mmol) in CH
2
Cl
2
2
(20 mL). After 30 min,
Cl (20 mL) was added
alcohol 5b (1.39 g, 7.382 mmol) in CH
over 10 min giving a copious white precipitate. After stirring for 1
h at -78 °C, the reaction mixture was brought to -60 °C, and
2
(
19) For reviews on ring-closing metathesis, see: (a) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413-4450. (b) Prunet, J. Angew. Chem.,
Int. Ed. 2003, 42, 2826-2830.
J. Org. Chem, Vol. 71, No. 10, 2006 3939

Kumar and Naidu
3
Et N (2.988 g, 2.169 mL, 29.53 mmol) was added slowly and stirred
stirred for 1 h and then overnight at room temperature. The solution
for 30 min, allowing the reaction mixture to warm to room
temperature. The reaction mixture was poured into water (150 mL),
and the organic layer was separated. The aqueous layer was
was treated with saturated aqueous NaHCO
extracted with CH Cl . The organic layer was washed with brine,
dried (Na SO ), and concentrated. Silica gel column chromatog-
3 2 2 3
and Na S O and
2
2
2
4
extracted with CH
layers were washed with water (3 × 50 mL) and brine (50 mL),
dried (Na SO ), and passed through a short pad of silica gel. The
2
Cl
2
(2 × 50 mL), and the combined organic
raphy using petroleum ether/EtOAc (9:1) as eluent gave the epox-
ide 12 (0.89 g, 91%) as an inseparable mixture of diastereomers
(anti/syn ) 4:1) as a colorless syrupy liquid.
2
4
filtrate was concentrated to give the aldehyde 6b (1.31 g) as a pale
yellow oil, which was used as such for the next step without
purification.
Hydrolytic Kinetic Resolution of Epoxide 12. A solution of
epoxide 12 (0.574 g, 1.46 mmol) and (R,R)-salen-Co(III)-OAc (4
mg, 0.007 mmol) in THF (10 µL) was stirred at 0 °C for 5 min,
and then distilled water (10 µL, 0.584 mmol) was added. After
stirring for 42 h, it was concentrated and purified by silica gel
column chromatography using petroleum ether/EtOAc (8:2) to
afford 12a (431 mg, 94%) as a colorless syrupy liquid and as a
The crude aldehyde 6b dissolved in CH
added via cannula to a stirred suspension of MgBr
mL round-bottom flask at 0 °C. After stirring for 10 min, the flask
was cooled to -78 °C and treated with vinylmagnesium bromide
14.94 mL, 14.94 mmol; purchased from Aldrich as 1.0 M solu-
2
Cl
2
under argon was
‚Et O in a 250-
2
2
1
13
(
single isomer (determined by H and C NMR analysis). Continued
chromatography with petroleum ether/EtOAc (3:2) provided the diol
12b (103 mg, 90%) as a brown colored liquid and as a single
diastereomer.
tion in THF); the solvent was removed in vacuo and diluted with
CH Cl three times over 30 min and allowed to warm to 0 °C. The
reaction mixture was diluted with saturated NH Cl and extracted
with CH Cl
(3 × 50 mL). The combined organic layers were
washed with brine, dried (Na SO ), and concentrated. Silica gel
2
2
4
Data of Compound 12a. [R]25 -7.1 (c 1.28, CHCl ). IR
2
2
D
3
2
4
(neat): νmax 2954, 2932, 2893, 2859, 1471, 1376, 1361, 1252, 1215,
1 1
-
column chromatography of the crude product using petroleum ether/
EtOAc (9:1) as eluent gave the allylic alcohol 7b as an inseparable
mixture of diastereomers (syn/anti ) 3:1; 1.39 g, 92%) as a pale
yellowish oil. IR (neat): νmax 3358-3250, 2924, 2855, 1466, 1372,
1102, 1042, 919, 839, 776, 759 cm . H NMR (200 MHz,
CDCl ): δ 4.80 (d, J ) 6.1 Hz, 1H), 4.74 (d, J ) 6.3 Hz, 2H),
3
4.65 (d, J ) 6.5 Hz, 1H), 3.81 (m, 1H), 3.62 (dd, J ) 6.2, 4.0 Hz,
1H), 3.57 (m, 1H), 3.39 (s, 3H), 3.37 (s, 3H), 3.27 (m, 1H), 2.67-
2.76 (m, 2H), 1.61-1.66 (m, 2H), 1.25-1.36 (m, 4H), 0.91 (s,
-
1 1
1
(
3
7
6
3
220, 761, 669 cm . H NMR (200 MHz, CDCl ): δ 5.81-5.91
12H), 0.08 (s, 3H), 0.06 (s, 3H). 13C NMR (50 MHz, CDCl ): δ
m, 1H), 5.34-5.39 (m, 1H), 5.26 (m, 1H), 4.28-4.30 (m, 1H),
3
.91-3.96 (m, 1H), 3.69 (dd, J ) 7.9, 3.9 Hz, 1H), 3.61 (dd, J )
.5, 4.5 Hz, 1H, minor diastereomer), 1.49-1.60 (m, 3H), 1.39 (s,
96.6, 96.3, 83.3, 79.9, 55.6, 55.2, 52.9, 44.2, 28.5, 25.7, 22.9, 17.9,
13.9, -4.86, -5.33. Anal. Calcd for C H O Si (392.60): C, 58.13;
19
40
6
13
H), 1.31-1.36 (m, 3H), 0.89 (t, J ) 7.1 Hz, 3H). C NMR (50
H, 10.27; Si, 7.15. Found: C, 58.51; H, 10.11; Si, 7.54.
Data of Compound 12b. [R]25 +19.6 (c 1.03, CHCl ). IR
MHz, CDCl
3.0, 77.37, 77.2, 72.7, 72.2, 33.7, 33.0, 28.0, 27.3, 26.9, 22.5, 13.7
mixture of diastereomers). Anal. Calcd for C12 (214.30): C,
7.26; H, 10.35. Found: C, 67.51; H, 10.11.
,5-Bismethoxymethoxynon-1-en-3-ol (7c). Compound 7c was
3
): δ 137.1, 136.3, 116.7, 116.3, 108.6, 108.3, 83.51,
D
3
8
(
6
(neat): νmax 3400, 2933, 2862, 1473, 1367, 1214, 1179, 1027, 929,
-
1 1
H O
22 3
874, 638, 758 cm . H NMR (200 MHz, CDCl ): δ 4.79 (d, J )
3
6.6 Hz, 1H), 4.74 (d, J ) 6.3 Hz, 1H), 4.71 (d, J ) 6.4 Hz, 2H),
3.91 (m, 2H), 3.86 (m, 2H), 3.63 (m, 2H), 3.44 (s, 3H), 3.42 (s,
4
prepared following the procedure as described for compound 7b
in 90% yield as an inseparable mixture of diastereomers (syn/anti
3H), 1.73 (br s, 1H), 1.59 (br s, 1H), 1.26-1.39 (m, 6H), 0.91 (t,
1
3
J ) 7.1 Hz, 3H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). C NMR
)
19:1) as a pale yellowish oil. [R]25
D
+26.43 (c 0.8, CHCl
3
). H
1
(50 MHz, CDCl
55.8, 30.8, 27.6, 25.7, 22.6, 22.5, 17.8, 13.8, -4.3, -5.0. Anal.
Calcd for C19 Si (410.62): C, 55.58; H, 10.31; Si, 6.84.
3
): δ 97.8, 96.7, 80.5, 77.0, 72.6, 70.6, 63.3, 56.1,
NMR (200 MHz, CDCl ): δ 5.87-6.04 (m, 1H), 5.36 (td, J )
3
2
1
1
2
3.8, 17.2 Hz, 2H), 4.79 (d, J ) 6.7 Hz, 1H), 4.70 (d, J ) 6.7 Hz,
42 7
H O
H), 4.68 (s, 2H), 4.32 (tt, J ) 5.5, 1.6 Hz, 1H), 3.64-3.73 (m,
H), 3.44 (s, 3H), 3.39 (s, 3H), 2.97 (br s, 1H), 1.58-1.68 (m,
Found: C, 55.69; H, 10.12; Si, 6.48.
(5-Butyl-2,2-dimethyl-[1,3]-dioxolan-4-yl)-oxiranylmethanol
(13). To a solution of titanium(IV) isopropoxide (729 mg, 2.56
mmol) and (-)-diisopropyl-D-tartrate (710 mg, 3.03 mmol) in
CH Cl (20 mL) at -20 °C was added olefin 7b (500 mg, 2.33
13
H), 1.26-1.35 (m, 4H), 0.88 (t, J ) 7 Hz, 3H). C NMR (50
MHz, CDCl
7
1
3
): δ 13.8, 22.6, 27.3, 27.7, 30.1, 30.4, 55.7, 56.0, 71.6,
1.9, 78.1, 78.3, 83.0, 83.2, 96.6, 96.9, 97.9, 98.3, 115.9, 116.5,
37.3, 137.7. Anal. Calcd for C13 (262.34): C, 59.52; H, 9.99.
2
2
H O
26 5
2 2
mmol) in CH Cl (4 mL) followed by tert-butyl hydroperoxide (420
Found: C, 59.86; H, 9.63.
1-(1,2-Bismethoxymethoxy-hexyl)-allyloxy]-tert-butyldi-
methylsilane (10). To a stirred solution of allylic alcohol 7c (1.20
g, 4.57 mmol) in CH Cl (50 mL) and 2,6-lutidine (2.94 g, 3.175
mL, 27.44 mmol) was added TBSTf (1.33 g, 5.031 mmol) at 0 °C,
and the mixture was stirred at the same temperature for 30 min.
The reaction mixture was quenched with water and extracted with
mg, 0.52 mL, 4.66 mmol). After 48 h at -20 °C, the reaction
mixture was diluted with ether and saturated sodium sulfate. The
mixture was stirred vigorously for 2 h at room temperature and
filtered. The filtrate was concentrated, and the residue was
chromatographed over silica gel to give epoxide 137k (314 mg, 78%;
[
2
2
2
5
yield based on 75% of syn compound) as a colorless oil. [R]
-3.7 (c 0.9, CHCl ). IR (neat): νmax 3453, 2956, 2931, 2893, 2859,
1379, 1254, 1192 cm . H NMR (200 MHz, CDCl
D
3
-
1 1
CH
with brine, dried (Na
chromatography of the crude product using petroleum ether/EtOAc
2
Cl
2
(3 × 30 mL). The combined organic layers were washed
3
): δ 4.02-
2
SO ), and concentrated. Silica gel column
4
4.09 (m, 1H), 3.83-3.90 (m, 1H), 3.68 (t, J ) 7.13 Hz, 1H), 3.22-
3.28 (m, 1H), 2.77-2.89 (m, 2H), 2.09 (s, 1H), 1.46-1.66 (m,
(
3:1) as eluent gave compound 10 (1.69 g, 98%) as a colorless oil.
3H), 1.42 (s, 3H), 1.39 (s, 3H), 1.26-1.36 (m, 3H), 0.91 (t, J )
25
1
13
[R]
D
+31.90 (c 0.9, CHCl
3
). H NMR (200 MHz, CDCl
3
): δ
7.1 Hz, 3H). C NMR (50 MHz, CDCl
3
): δ 108.9, 81.3, 79.5,
5
7
6
1
.88-6.04 (m, 1H), 5.16 (dd, J ) 27.3, 17.8 Hz, 2H), 4.91 (d, J )
.04 Hz, 1H), 4.71 (d, J ) 7.04 Hz, 2H), 4.63 (s, 2H), 4.37 (t, J )
.7 Hz, 1H), 3.56-3.64 (m, 1H), 3.40 (s, 3H), 3.38 (s, 3H), 1.51-
.74 (m, 2H), 1.26-1.33 (m, 4H), 0.89 (s, 12H), 0.06 (s, 3H), 0.03
71.5, 52.3, 44.6, 33.8, 28.2, 27.4, 27.0, 22.7, 13.9.
tert-Butyl-[(5-butyl-2,2-dimethyl-[1,3]-dioxolan-4-yl)-oxiranyl-
methoxy]dimethylsilane (13a). To a stirred solution of epoxy
alcohol 13 (0.40 g, 1.737 mmol) and imidazole (260 mg, 3.82
mmol) in CH Cl (50 mL) was added TBSCl (0.392 g, 2.61 mmol)
(
s, 3H). 13C NMR (50 MHz, CDCl
3
): δ 138.1, 115.4, 98.3, 96.9,
1.7, 77.6, 74.1, 55.8, 55.7, 30.9, 27.5, 25.7, 22.7, 17.9, 13.9, -4.8,
4.9. Anal. Calcd for C19 Si (376.60): C, 60.60; H, 10.71;
Si, 7.46. Found: C, 60.89; H, 10.42.
2,3-Bismethoxymethoxy-1-oxiranylheptyloxy)-tert-butyldi-
methylsilane (12). To a stirred solution of olefin 10 (0.940 g, 2.49
mmol) and Na HPO (709 mg, 4.99 mmol) in THF (30 mL) was
added m-CPBA (1.72 g, 4.99 mmol) at 0 °C. The mixture was
2
2
8
-
at 0 °C, and the reaction mixture was stirred at the same temperature
for 30 min. The reaction mixture was quenched with water and
extracted with CH Cl (3 × 30 mL). The combined organic layers
40 5
H O
2
2
(
2 4
were washed with brine, dried (Na SO ), and concentrated. Silica
gel column chromatography of the crude product using petroleum
2
4
ether/EtOAc (9:1) as eluent gave compound 13a (586 mg, 98%)
as a colorless oil. [R]25
-18.1 (c 0.8, CHCl
). H NMR (200 MHz,
1
D
3
3940 J. Org. Chem., Vol. 71, No. 10, 2006

Total Synthesis of (+)-Boronolide
CDCl
H), 2.72-2.88 (m, 2H), 1.48-1.66 (m, 2H), 1.43 (s, 3H), 1.39
s, 3H), 1.24-1.37 (m, 4H), 0.91 (s, 12H), 0.08 (s, 3H), 0.06 (s,
3
): δ 3.91-4.12 (m, 2H), 3.68 (t, J ) 7.2 Hz, 1H), 3.24 (m,
which was stirred at the room temperature for 30 min. The reaction
mixture was quenched with water and extracted with CH Cl . The
combined organic layers were washed with brine, dried (Na SO ),
and concentrated to give an oily material that was dissolved in
MeCN (5 mL) and treated with 45% aq HF (172 mg, 0.15 mL, 4.1
mmol) at room temperature. After stirring at room temperature
1
(
3
4
2
2
2
4
H). 13C NMR (50 MHz, CDCl
3.9, 33.7, 28.3, 27.4, 27.0, 24.5, 22.8, 16.2, 13.86, -4.8, -4.9.
Si (344.56): C, 62.74; H, 10.53; Si, 8.15.
Found: C, 62.46; H, 10.87; Si, 8.52.
-(tert-Butyldimethylsilanyloxy)-6,7-bismethoxymethoxy-un-
): δ 108.7, 81.4, 78.9, 72.3, 53.4,
3
36 4
Anal. Calcd for C18H O
overnight, the reaction mixture was quenched with NaHCO
The aqueous layer was extracted with CH Cl , and the organic layer
was washed with brine, dried (Na SO ), and concentrated. Silica
3
(1 g).
5
2
2
dec-1-en-4-ol (17). Compound 15 was prepared following the
procedure as described for compound 14 in 86% yield as a colorless
2
4
gel column chromatography of the crude product using EtOAc as
2
5
liquid. [R]
D
+26.3 (c 0.9, CHCl
3
). IR (neat): νmax 3029, 2956,
eluent gave deacetylated boronolide 1a (106 mg, 86%) as a white
-1
7h
25
2
931, 2859, 1644, 1464, 1255, 1102, 1036, 918, 873, 837, 776 cm .
H NMR (200 MHz, CDCl
solid: mp 101 °C (lit. 99-100 °C); [R]
D
+57.4 (c 0.71, EtOH)
1
7h
25
1
3
): δ 5.83-6.04 (m, 1H), 5.07-5.17
(lit. [R]
D
+56 (c 0.07, EtOH)). H NMR (200 MHz, CDCl ): δ
3
(
m, 2H), 4.78 (d, J ) 6.7 Hz, 1H), 4.73 (t, J ) 1.96 Hz, 3H),
6.95 (ddd, J ) 9.6, 6.1 Hz, 1H), 6.02 (dd, J ) 10.1, 2.6 Hz, 1H),
4.52 (ddd, J ) 11.5, 7.3, 4.1 Hz, 1H), 3.85 (d, J ) 7.1 Hz, 1H),
3.64 (br s, 2H), 3.01 (br s, 3H), 2.64 (ddd, J ) 18.7, 5.2, 4.2 Hz,
1H), 2.51 (ddd, J ) 18.8, 11.5, 2.5 Hz, 1H), 1.46-1.66 (m, 2H),
3
3
1
.80-3.88 (m, 2H), 3.75 (t, J ) 3.52 Hz, 1H), 3.64-3.68 (m, 1H),
.43 (s, 3H), 3.41 (s, 3H), 2.17-2.25 (m, 2H), 1.60-1.72 (m, 2H),
13
.21-1.36 (m, 4H), 0.89 (s, 12H), 0.12 (s, 3H), 0.10 (s, 3H).
C
13
NMR (50 MHz, CDCl
3.6, 70.1, 55.7, 37.2, 29.6, 28.6, 25.7, 22.7, 18.0, 13.9, -4.8, -4.9.
Anal. Calcd for C21 Si (420.66): C, 59.96; H, 10.54; Si, 6.68.
3
): δ 136.2, 116.2, 99.1, 96.4, 85.8, 79.3,
1.26-1.34 (m, 4H), 0.89 (t, J ) 7.1 Hz, 3H). C NMR (50 MHz,
CDCl
7
3
): δ 163.9, 145.9, 120.9, 77.1, 76.7, 74.3, 70.1, 33.4, 27.7,
H O
44 6
25.8, 22.6, 14.0.
Found: C, 60.11; H, 10.61; Si, 6.82.
Boronolide (1). Acetic anhydride (0.18 mL, 1.96 mmol) was
added dropwise to a stirred and cooled (0 °C) solution of 1a (48
Acrylic Acid 1-[1-(tert-Butyldimethylsilanyloxy)-2,3-bismeth-
oxymethoxy-heptyl]-but-3-enyl Ester (18). Compound 18 was
prepared following the procedure as described for compound 15
mg, 0.196 mmol), i-Pr EtN (0.5 mL, 2.94 mmol), and DMAP
2
(catalytic amount) in CH Cl (5 mL). The resulting mixture was
2
2
2
5
in 91% yield as a yellowish syrupy liquid. [R]
D
-42.14 (c 0.84,
allowed to stir for 6 h at room temperature. The resulting mixture
CHCl ). IR (neat): νmax 2931, 2858, 1726, 1638, 1254, 1256, 1192
3
was diluted with Et O (40 mL). The organic phase was washed
2
-
1 1
cm . H NMR (200 MHz, CDCl
3
): δ 6.45 (ddd, J ) 17.2, 1.6
with saturated NH Cl, water, and brine, dried (Na SO ), and
4
2
4
Hz, 1H), 6.09 (dd, J ) 17.2, 4.3 Hz, 1H), 5.83 (dd, J ) 10.2, 1.5
concentrated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc (7:3) as eluent gave com-
pound 1 (62 mg, 85%) as a clear oil that solidified on standing:
Hz, 1H), 5.75 (dd, J ) 11.7, 1.6 Hz, 1H), 5.18 (m, 1H), 5.01 (m,
1
8
2
3
1
5
H), 4.67 (m, 2H), 4.54 (m, 2H), 3.64-3.66 (m, 1H), 3.92 (dt, J )
.2, 1.6 Hz, 1H), 3.37-3.42 (m, 2H), 3.33 (s, 3H), 3.30 (s, 3H),
.24-2.48 (m, 2H), 1.27-1.34 (m, 6H), 0.81 (s, 12H), -0.04 (s,
7
25
7h
25
mp 88-90 °C (lit. 90 °C); [R] +26.4 (c 0.7, EtOH) (lit. [R]
D
D
1
+25 (c 0.2, EtOH)). H NMR (200 MHz, CDCl ): δ 6.89 (ddd, J
) 9.7, 6.2, 2.7 Hz, 1H), 6.01 (dd, J ) 9.8, 2.4 Hz, 1H), 5.33-5.38
3
H), -0.05 (s, 3H). 13C NMR (50 MHz, CDCl
): δ 165.7, 134.6,
3
31.7, 128.2, 117.1, 98.8, 96.9, 80.8, 79.4, 75.82, 74.4, 74.0, 56.1,
6.0, 32.8, 29.6, 29.4, 28.5, 22.7, 18.2, 14.1, -4.1, -4.7. Anal.
(m, 2H), 5.01 (q, J ) 6.1 Hz, 1H), 4.55 (dt, J ) 12.1, 4.5 Hz, 1H),
2.51 (dddd, J ) 18.1, 11.8, 2.6, 2.5 Hz, 1H), 2.31 (m, 1H), 2.11 (s,
3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.54 (m, 2H), 1.17-1.30 (m, 4H),
46 7
Calcd for C24H O Si (474.70): C, 60.72; H, 9.77; Si, 5.92.
0.89 (t, J ) 6.7 Hz, 3H). 13C NMR (50 MHz, CDCl ): δ 170.5,
Found: C, 61.09; H, 9.62; Si, 6.21.
-[1-(tert-Butyldimethylsilanyloxy)-2,3-bismethoxymethoxy-
3
6
169.8, 169.5, 162.5, 144.0, 121.2, 75.1, 71.6, 70.6, 70.5, 30.1, 27.1,
25.2, 22.3, 21.1, 20.6, 13.8.
heptyl]-5,6-dihydropyran-2-one (19). Compound 19 was prepared
following the procedure as described for compound 16 in 89% yield
2
5
as a colorless syrupy liquid. [R]
D
+51.4 (c 1.18, CHCl
3
). IR
Acknowledgment. S.V.N. thanks CSIR New Delhi for
financial assistance. P.K. is thankful to Department of Science
and Technology, New Delhi, for generous funding of the project
(
neat): νmax 2954, 2934, 2856, 1712, 1469, 1386, 1252, 1149, 1123,
-
1 1
1
5
1
3
3
102, 1018, 923, 838, 779 cm . H NMR (200 MHz, CDCl ): δ
.92 (ddd, J ) 8.2, 6.3, 2.0 Hz, 1H), 5.99 (dd, J ) 9.7, 2.3 Hz,
H), 4.58-4.82 (m, 4H), 4.21 (dd, J ) 8.2, 1.7 Hz, 1H), 3.62-
.70 (m, 1H), 3.46-3.49 (m, 2H), 3.39 (s, 6H), 2.77 (m, 1H), 2.17
(
Grant No. SR/S1/OC-40/2003). We are grateful to Dr. M. K.
Gurjar for his support and encouragement. This is NCL
communication No. 79.
(
ddd, J ) 19.9, 5.9, 3.9 Hz, 1H), 1.31-1.42 (m, 6H), 0.88 (s, 12H),
0
1
2
.16 (s, 3H), 0.11 (s, 3H). 13C NMR (50 MHz, CDCl
3
): δ 164.0,
Supporting Information Available: Experimental procedures
and spectroscopic data of compounds 3, 4a, 4d, 5c, 9, 11, 14-16;
45.6, 120.7, 98.9, 96.4, 79.2, 78.28, 78.21, 73.8, 56.1, 55.9, 29.6,
8.3, 25.9, 22.9, 22.7, 18.2, 14.0, -4.2, -4.3. Anal. Calcd for
22 42 7
C H O Si (446.65): C, 59.16; H, 9.48; Si, 6.29. Found: C, 59.45;
1
13
H and C NMR spectra of compounds 1a, 3, 4a-4d, 5b, 5c, 7b,
7
c, 8, 10, 12a, 12b, 13, 16-19, and (+)-boronolide 1, NOE of 8,
H, 9.34; Si, 6.19.
and HPLC of 4d. This material is available free of charge via the
Deacetylated Boronolide (1a). Lactone 19 (182 mg, 0.41 mmol)
was dissolved in dimethyl sulfide (3 mL) and cooled to -10 °C.
Internet at http://pubs.acs.org.
3
Then BF ‚Et
2
O (1.02 mL, 8.15 mmol) was added to the solution,
JO0603781
J. Org. Chem, Vol. 71, No. 10, 2006 3941