A short stereoselective synthesis of (+)-boronolide

Article abstract of DOI:10.1016/j.tetlet.2006.08.062

A short and stereoselective synthesis of (+)-boronolide via oxidative functionalization of an olefin using a pendant sulfinyl group is described. Diastereoselective allylation was performed using Keck's protocol and the lactone moiety was prepared by ring

Full text of DOI:10.1016/j.tetlet.2006.08.062

Tetrahedron Letters 47 (2006) 7611–7614
A short stereoselective synthesis of (+)-boronolideI
Sadagopan Raghavan* and V. Krishnaiah
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 13 July 2006; revised 17 August 2006; accepted 18 August 2006
Abstract—A short and stereoselective synthesis of (+)-boronolide via oxidative functionalization of an olefin using a pendant
sulfinyl group is described. Diastereoselective allylation was performed using Keck’s protocol and the lactone moiety was prepared
by ring closing metathesis.
Ó 2006 Published by Elsevier Ltd.
(+)-Boronolide 1 was isolated from the bark and
branches of Tetradenia fruiticosa1 and from the leaves
of Tetradenia barbera.2 The partially deacetylated 2
and the totally deacetylated derivative 3 were isolated
from Tetradenia riparia.3 The extracts from the roots
and the leaves of these trees have been used as folk med-
icine in Madagascar and in southern Africa as an emetic
and in the treatment of malaria.4 Boronolide has an a,b-
unsaturated d-lactone moiety and a polyhydroxylated
side chain. This structural feature is characteristic of
the natural products possessing a wide range of biolog-
ical activity,5 making them attractive targets for total
syntheses. The relative stereochemistry of boronolide
was established by X-ray studies,6 and the absolute ste-
reochemistry was confirmed by chemical degradation.2
Sharpless dihydroxylation9 to construct the contiguous
oxygenated stereocentres. Our synthetic plan relied on
the oxidative functionalization of an olefin via the
participation of an intramolecular sulfinyl moiety.10
The synthesis commenced with the condensation of
(S)-methyl p-tolyl sulfoxide 4,11 and trans-ethyl hept-2-
enoate 5 following Solladie’s protocol12 to yield b-keto
25
sulfoxide 6 (60%, ½aꢀD ꢁ158 (c 1, CHCl3)). Diastereose-
lective reduction13 using DIBAL-H/ZnCl2 afforded allyl
25
alcohol 7 (>95% de, 84%, ½aꢀD ꢁ126 (c 1, CHCl3)).14 The
treatment of 7 with freshly recrystallized N-bromo-
succinimide (NBS) afforded regioisomeric bromodiols
8 and 9, resulting from 5-exo- and 6-endo-nucleophilic
attack, respectively, as an inseparable mixture in a 7:3
ratio (75%). In efforts to secure a single regioisomer,
the t-butyldimethylsilyl ether 10, obtained from 7
OP OP1
25
(94%, ½aꢀD ꢁ62 (c 1, CHCl3)), was reacted with NBS.
However, in this instance too, the reaction failed to
proceed regioselectively and an inseparable mixture of
bromohydrins 11 and 12 (72%, 3:1 ratio, respectively)
were isolated (Scheme 1).15
O
OP
O
1, P = P1 = C(O)CH3
2, P = H, P1 = C(O)CH3
3, P = P1 = H
The inseparable mixture of 11 and 12 was converted to
25
an epoxide 13 (89%, ½aꢀD +119 (c 1, CHCl3)), by treat-
ment with the anhydrous potassium carbonate, proving
beyond doubt that they were regioisomers. Also depro-
tection of the silyl group in 11 and 12 afforded a product
Earlier reported syntheses of boronolide have relied on
chiral pool starting materials,7 aldol reaction8 and
1
mixture whose H NMR spectra matched that of the
mixture of 8 and 9, thus proving that the facial selectiv-
ity of addition across the double bond was the same for
both allyl alcohol 7 and silyl ether 10. Having been
unable to secure a single isomer in the NBS reaction,
Keywords: (+)-Boronolide; Sulfinyl group; Oxidative functionaliza-
tion; Ring closing metathesis.
q IICT Communication No. 060708.
attempts were made to separate 8 and 9 by derivatizing
25
them suitably. The acetonides 14 (61%, ½aꢀD +156 (c 1,
25
*
Corresponding author. Tel.: +91 40 27160123; fax: +91 40
CHCl3)) and 15 (28%, ½aꢀD +167 (c 1, CHCl3)) proved
27160512; e-mail: sraghavan@iict.res.in
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.08.062

7612
S. Raghavan, V. Krishnaiah / Tetrahedron Letters 47 (2006) 7611–7614
O
S
O
O
O
Me
LDA, THF
-40 to 0 oC
DIBAL-H/ZnCl2,THF
-78 oC
S
+
EtO
p-Tol
Me
5
6
4
O
O
S
O
S
OP Br
OP
OP OH
NBS, Toluene
H2O, rt
S
+
p-Tol
p-Tol
p-Tol
OH
8, P = H
11, P = TBS
Br
7, P = H
TBS-Cl, Imidazole
CH2Cl2, rt
9, P = H
10, P = TBS
12, P = TBS
O
OTBS
K2CO3, MeOH
rt
S
p
-Tol
O
13
Scheme 1.
separable.14 Nucleophilic displacement of the bromide
in 14 and 15, by an oxygen nucleophile would afford a
product with three contiguous chiral centres as present
in the target. The attempted displacement of the bro-
mide in 14 with anhydrous potassium acetate in DMF,
yielded none of the expected acetate 16, but the elimi-
nated product 17 (79%, Scheme 2).
jected to a reaction with a suitable oxygen nucleophile.
Attempted reaction of the mixture of bromohydrins
with sodium nitrite however afforded a mixture of prod-
ucts. Having secured the triacetate, it remained to unra-
vel the aldehyde moiety by a Pummerer reaction and
subject it to diastereoselective allylation followed by
acrylate ester formation to set the stage for ring closing
metathesis. Activation of the sulfinyl group in 21 with
TFAA17 in the presence of 2,6-lutidine followed by
hydrolysis of intermediate 22 with aqueous saturated
sodium bicarbonate furnished aldehyde 23 (65%), which
proved unstable to column chromatography and hence
used in the next step without further purification. The
aldehyde was a key intermediate in the synthetic route
of Carda et al.7d The reagent controlled asymmetric
allylation using Keck et al. protocol18 furnished a
complex mixture of products. Among various methods,
allylation using allyltributyltin/BF3ÆEt2O19 proved
With sodium nitrite16 as the reagent, 14 reacted cleanly
25
to afford alcohol 18 (68%, ½aꢀD +149 (c 1, CHCl3)). In
a similar fashion acetonide 15 afforded alcohol 19
25
(86%, ½aꢀD +147 (c 1, CHCl3)). Deprotection of the
acetonides followed by acetylation of the resulting triol
25
20 (87%, ½aꢀD +198 (c 1, CHCl3))14 furnished triacetate
25
21 (96% ½aꢀD +86 (c 1, CHCl3)).14 Thus bromo-
diols 8 and 9 converged to give the same triacetate 21.
Two steps (acetonide formation and deprotection) could
be saved if the mixture of 8 and 9 could be directly sub-
Cat. CSA
O
S
O
S
O
S
O
S
OMe
OMe
OH Br
OH
OH OH
O
O
O
O
+
+
p-Tol
p-Tol
p-Tol
p-Tol
Acetone
rt
Br
Br
15
Br
14
8
9
O
S
O
S
O
S
OP OP
OP
O
O
O
Cat. CSA, MeOH
rt
NaNO2, DMF
90 oC
O
p-Tol
p
p-Tol
-Tol
OH
PO
20, P = H
21, P = C(O)CH3
19
Ac2O, Et3N,
DMAP, CH2Cl2
rt
16, P = C(O)CH3
18, P = H
O
O
S
O
p-Tol
17
Scheme 2.

S. Raghavan, V. Krishnaiah / Tetrahedron Letters 47 (2006) 7611–7614
7613
O
S
OAc OAc
OAc OAc
OAc OAc
TFAA,
Aq. NaHCO3
0 oC
O
S
p-Tol
p-Tol
CF3(O)CO
CH2Cl2
0 oC
OAc
OAc
OAc
21
22
23
OAc OAc
OAc OAc
SnBu3
BF3.Et2O, CH2Cl2
-78 oC
OAc
O
OP OAc
24, P = H
25, P = C(O)CH=CH2
NMes
Cl
MesN
O
O
Ru
Cl
1
Cl
Ph
Et3N, DMAP
PCy
3
CH2Cl2, 0 oC
CH2Cl2, 40 oC
Scheme 3.
satisfactory20 and the desired product 24 and its epimer
(not depicted) was obtained as an inseparable mixture of
diastereomers (76%, 9:1 by NMR). The mixture of
alcohols was subjected to a treatment with acryloyl chlo-
ride in the presence of triethyl amine to afford 25 and its
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.
6. Kjaer, A.; Norrestam, R.; Polonsky, J. C. Acta Chem.
Scand. Ser. B 1985, 39, 745.
7. (a) Nagano, H.; Yasui, H. Chem. Lett. 1992, 1045; (b)
Chandrasekhar, M.; Raina, S.; Singh, V. K. Tetrahedron
Lett. 2000, 41, 4969; (c) Ghosh, A. K.; Bilcer, G.
Tetrahedron Lett. 2000, 41, 1003; (d) Carda, M.; Rodri-
guez, S.; Segovia, B.; Marco, J. A. J. Org. Chem. 2002, 67,
6560; (e) Chandrasekhar, M.; Chandra, K. L.; Singh, V.
K. J. Org. Chem. 2003, 68, 4039; (f) Hu, S. G.; Hu, T. S.;
Wu, Y. L. Org. Biomol. Chem. 2004, 2, 2305; (g) Boruwa,
J.; Barua, N. C. Tetrahedron 2006, 62, 1193.
epimer that could be separated by column chromatogra-
25
phy (79%, ½aꢀD +2 (c 0.5, CHCl3)). Compound 25 on
ring closing metathesis reaction using Grubbs’ second
generation catalyst afforded boronolide 1 (70%, Scheme
3). The spectroscopic data of 1 (1H NMR, 13C NMR,
IR) were in agreement with literature data.2
In summary, a short and stereoselective synthesis of (+)-
boronolide has been achieved utilizing our oxidative
functionalization strategy.
8. (a) Murga, J.; Falomir, E.; Carda, M.; Marco, J. A.
Tetrahedron: Asymmetry 2002, 13, 2317; (b) Trost, B. M.;
Yeh, V. S. C. Org. Lett. 2002, 4, 3513.
9. (a) Honda, T.; Horiuchi, S.; Mizutani, H.; Kanai, K. J.
Org. Chem. 1996, 61, 4944; (b) Kumar, P.; Naidu, S. V. J.
Org. Chem. 2006, 71, 3935.
Acknowledgements
10. Raghavan, S.; Rasheed, M. A.; Joseph, S. C.; Rajender
Chem. Commun. 1999, 1845.
11. Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew.
Chem., Int. Ed. 2005, 44, 7221.
12. Solladie, G.; Frechou, C.; Hutt, J.; Demailly, G. Bull. Soc.
Chim. Fr. 1987, 827.
13. (a) Solladie, G.; Demailly, G.; Greck, C. Tetrahedron Lett.
1985, 26, 435; (b) Solladie, G.; Frechou, C.; Demailly, G.;
Greck, C. J. Org. Chem. 1986, 51, 1912; (c) Carreno, M.
C.; Garcia Ruano, J. L.; Martin, A. M.; Pedregal, C.;
Rodriguez, J. H.; Rubio, A.; Sanchez, J.; Solladie, G. J.
Org. Chem. 1990, 55, 2120.
S.R. is thankful to Dr. J. S. Yadav, Director, IICT, for
constant support and encouragement. V.K. is thankful
to the CSIR, New Delhi, for a fellowship. Financial
assistance from DST (New Delhi) is gratefully acknowl-
edged. We thank Dr. A. C. Kunwar for the NMR spec-
tra and Dr. M. Vairamani for the mass spectra.
References and notes
1. Franca, N. C.; Polonsky, J. C. R. Hebd. Seances, Acad.
Sci., Ser. C. 1971, 273, 439.
2. Davies-Coleman, M. T.; Rivett, D. E. A. Phytochemistry
1987, 26, 3047.
3. (a) Van Puyvelde, L.; Dube, S.; Uwimana, E.; Uwera, C.;
Domisse, R. A.; Esmans, E. L.; Van Schoor, O.; Vlietnick,
A. Phytochemistry 1979, 18, 1215; (b) Van Puyvelde, L.;
De Kimpe, N.; Dube, S.; Chagnon-Dube, M.; Boily, Y.;
Borremans, F.; Schamp, N.; Antenuis, M. J. O. Phyto-
chemistry 1981, 20, 2753.
4. Watt, J. M.; Brandwijk, M. G. B. The Medicinal and
Poisonous Plants of Southern and Eastern Africa; Living-
stone: Edingburgh, 1962; p 516.
14. Selected data. Compound 7: 1H NMR (300 MHz, CDCl3)
d 7.53 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 5.78–
5.67 (m, 1H), 5.43 (dd, J = 15.8, 6.8 Hz, 1H), 4.62–4.52
(m, 1H), 4.02 (br s, 1H), 3.03 (dd, J = 12.8, 8.3 Hz, 1H),
2.72 (dd, J = 12.8, 3.7 Hz, 1H), 2.42 (s, 3H), 2.01 (q,
J = 6.7 Hz, 2H), 1.38–1.24 (m, 4H), 0.88 (t, J = 6.8 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 13.7, 21.2, 21.9, 30.8,
31.6, 63.3, 68.9, 123.9, 129.81, 129.88, 133.3, 140.2, 141.6.
Compound 8: 1H NMR (400 MHz, CDCl3) d 7.53 (d,
J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 4.74 (dd,
J = 9.8, 1.6 Hz, 1H), 4.11–4.03 (m, 2H), 3.38 (d, J =
9.0 Hz, 1H, –OH), 3.29 (dd, J = 13.9, 9.8 Hz, 1H), 2.69
(dd, J = 13.9, 2.4 Hz, 1H), 2.43 (s, 3H), 2.19–2.05 (m,
1H), 1.81–1.67 (m, 1H), 1.61–1.49 (m, 1H), 1.44–1.21 (m,
3H), 0.89 (t, J = 7.3 Hz, 3H). Compound 9: 1H NMR
5. (a) Davies-Coleman, M. T.; Rivett, D. E. A. Fortschr.
Chem. Org. Naturst. 1989, 55, 1; (b) Ohloff, G. Fortschr.

7614
S. Raghavan, V. Krishnaiah / Tetrahedron Letters 47 (2006) 7611–7614
(400 MHz, CDCl3) d 7.54 (d, J = 8.2 Hz, 2H), 7.33 (d,
13C NMR (75 MHz, CDCl3) d 13.9, 21.3, 22.6, 27.8, 33.4,
61.0, 68.5, 72.8, 75.0, 124.8, 130.1, 139.6, 141.7. Com-
pound 21: 1H NMR (400 MHz, CDCl3) d 7.49 (d,
J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 5.51–5.45 (m,
1H), 5.11 (t, J = 5.7 Hz, 1H), 5.03–4.97 (m, 1H), 2.92 (dd,
J = 13.1, 3.2 Hz, 1H), 2.83 (dd, J = 13.1, 9.0 Hz, 1H), 2.43
(s, 3H), 2.1 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 1.54–1.45 (m,
2H), 1.34–1.17 (m, 4H), 0.88 (t, J = 6.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3) d 13.7, 20.5, 20.6, 20.8, 21.3, 22.2,
26.9, 30.2, 59.2, 66.4, 71.1, 73.5, 124.0, 130.1, 140.3, 141.9,
169.5, 169.3, 170.2.
J = 8.2 Hz, 2H), 4.82 (dd, J = 8.2, 4.0 Hz, 1H), 4.54–4.45
(m, 1H), 3.91–3.80 (m, 1H), 3.60 (d, J = 9.0 Hz, 1H,
–OH), 3.22 (dd, J = 13.9, 2.4 Hz, 1H), 2.91 (dd, J = 13.9,
3.3 Hz, 1H), 2.47 (s, 3H), 2.19–2.05 (m, 1H), 1.81–1.67 (m,
1H), 1.61–1.49 (m, 1H), 1.44–1.21 (m, 3H), 0.91 (t,
J = 7.3 Hz, 3H). Compound 14: 1H NMR (300 MHz,
CDCl3) d 7.54 (d, J = 7.5 Hz, 2H), 7.30 (d, J = 7.5 Hz,
2H), 4.50–4.44 (m, 1H), 3.91–3.79 (m, 2H), 3.34 (dd,
J = 12.8, 2.2 Hz, 1H), 2.79 (dd, J = 12.8, 10.5 Hz, 1H),
2.42 (s, 3H), 1.78–1.64 (m, 1H), 1.62–1.50 (m, 1H), 1.49–
1.22 (m, 4H), 1.44 (s, 6H), 0.93 (t, J = 6.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3) d 13.6, 21.1, 21.6, 26.9, 27.2, 28.5,
34.5, 55.9, 63.6, 75.1, 82.7, 110.1, 123.6, 129.7, 141.2.
Compound 15: 1H NMR (500 MHz, CDCl3) d 7.53 (d,
J = 7.6 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 4.45 (td,
15. The intramolecular functionalization was attempted on
alcohol 26 an isomer of 7, elaborated from (R)-methyl p-
tolyl sulfoxide. Disappointingly, a regioisomeric mixture
of products 27 and 28 (70%, 3:1 ratio, respectively) was
obtained upon reaction with NBS.
O
O
O
S
O
Me
LDA, THF
-40 to 0 oC
DIBAL-H, THF
S
+
EtO
-78 oC
p
-Tol
Me
5
Ent-6
Ent-4
O
O
S
O
S
OH Br
OH
OH OH
NBS, Toluene
H2O, rt
S
+
-Tol
p
p
-Tol
p
-Tol
OH
27
Br
28
26
J = 10.5, 1.9 Hz, 1H), 3.89 (td, J = 10.5, 2.8 Hz, 1H),
3.38–3.29 (m, 2H), 2.61 (dd, J = 13.4, 10.5 Hz, 1H), 2.42
(s, 3H), 1.59 (s, 3H), 1.48–1.40 (m, 2H), 1.44 (s, 3H), 1.37–
1.25 (m, 4H), 0.91 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 13.9, 19.3, 21.3, 22.3, 26.7, 29.3, 32.9, 51.9, 62.9,
69.0, 73.8, 99.9, 123.9, 129.9, 141.4, 141.6. Compound 20:
1H NMR (200 MHz, CDCl3) d 7.54 (d, J = 7.8 Hz, 2H),
7.36 (d, J = 7.8 Hz, 2H), 4.77 (d, J = 3.1 Hz, 1H, –OH),
4.31 (dd, J = 10.1, 2.3 Hz, 1H), 3.81–3.68 (m, 1H), 3.34
(dd, J = 14.0, 10.1 Hz, 1H), 3.25–3.01 (m, 3H, CH–OH, 2
–OH), 2.72 (dd, J = 14.0, 2.3 Hz, 1H), 2.44 (s, 3H), 1.62–
1.44 (m, 2H), 1.40–1.18 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H).
The sulfones obtained by treatment of 27 and 28 with m-
CPBA were found to be identical to the sulfones obtained
from 8 and 9.
16. Raduchel, B. Synthesis 1980, 292.
17. Felman, K. S. Tetrahedron 2006, 62, 5003.
18. (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem.
Soc. 1993, 115, 8467; (b) Keck, G. E.; Geraci, L. S.
Tetrahedron Lett. 1993, 34, 7827.
19. Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265.
20. The conditions reported by Carda et al. using allyl
bromide and indium powder was also found to proceed
cleanly to afford the product as reported.