Total synthesis of microcarpalide

Article abstract of DOI:10.1021/jo050193e

An efficient, convergent approach for the total synthesis of microcarpalide (1) is described. The synthetic strategy features the Sharpless asymmetric dihydroxylation, regioselective epoxide opening with various nucleophiles such as a lithium acetylide and cuprates derived from the vinyl stannane and the vinyl iodide for the construction of a C7-C8 trans-double bond and Yamaguchi macrolactonization as the key steps.

Full text of DOI:10.1021/jo050193e

Total Synthesis of Microcarpalide†
SCHEME 1. Retrosynthetic Analysis for
Microcarpalide (1)
Pradeep Kumar* and S. Vasudeva Naidu
Division of Organic Chemistry: Technology, National
Chemical Laboratory, Pune 411008, India
tripathi@dalton.ncl.res.in
Received January 31, 2005
ing enantioselective synthesis of naturally occurring
lactones3 and amino alcohols,4 we became interested in
developing a general route capable of providing not only
the target molecule 1 but also its congeners with desired
stereo- and enantioselectivities for studies on the rela-
tionship between structure and pharmacological activity.
Herein we report our successful endeavors toward the
total synthesis of 1 utilizing the Sharpless asymmetric
dihydroxylation as the source of chirality from the
commercially available starting materials 1,4-butane diol
and propargyl alcohol.
An efficient, convergent approach for the total synthesis of
microcarpalide (1) is described. The synthetic strategy
features the Sharpless asymmetric dihydroxylation, regio-
selective epoxide opening with various nucleophiles such as
a lithium acetylide and cuprates derived from the vinyl
stannane and the vinyl iodide for the construction of a C7-
C8 trans-double bond and Yamaguchi macrolactonization as
the key steps.
The retrosynthetic analysis is based on a convergent
approach as outlined in Scheme 1. We envisioned that
the ring closing could be effected via Yamaguchi macro-
lactonisation of 24, which in turn would be obtained by
Yamaguchi coupling of epoxide 19 with acetylene 10. The
acetylene 10 would be obtained through a Corey-Fuchs
protocol from the aldehyde 8, which in turn could be
obtained from the diol 5. In this strategy, the stereogenic
centers of both fragments were obtained through Sharp-
less asymmetric dihydroxylation of olefins 4 and 16,
which in turn could be obtained from the commercially
available starting materials 1,4-butane diol 2 and prop-
argyl alcohol 13.
Microcarpalide, a new alkyl-substituted nonenolide,
was isolated by Hemscheidt and co-workers in 2001 from
fermentation broths of an unidentified endophytic fungus
growing on the bark of Ficus microcarpa L.1 This
compound acts as a strong microfilament disrupting
agent and displayed a weak cytotoxicity to mammalian
cells, thus making it an attractive tool for studying cell
motility and metastasis and a potential lead structure
to develop new anticancer drugs.
So far five total syntheses of microcarpalide have been
reported in the literature.2 Most of the approaches
described are based on ring-closing metathesis for the
key macrocyclization to construct the olefin with selec-
tivities between 2:1 to 10:1 in favor of the desired (E)-
isomer. Moreover the stereogenic centers were mainly
derived from chiral pool starting materials such as
tartaric acid,2a,c (R)-glycidol,2a D-mannose,2b malic acid,2d
etc. As a part of our research program aimed at develop-
Synthesis of Fragment 10 (Scheme 2). The synthe-
sis of acetylene component 10 started from commercially
(3) (a) Pais, G. C. G.; Fernandes, R. A.; Kumar, P. Tetrahedron 1999,
55, 13445. (b) Fernandes, R. A.; Kumar, P. Tetrahedron: Asymmetry
1999, 10, 4349. (c) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem.
2002, 2921. (d) Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44,
6149. (e) Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2004,
45, 849. (f) Naidu. S. V.; Gupta, P.; Kumar, P. Tetrahedron Lett. 2005,
46, 2129.
(4) (a) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000, 3447.
(b) Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2002,
43, 4425. (c) Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2000, 41,
10309. (d) Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44, 1035.
(e) Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44, 1957. (f)
Gupta, P.; Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44,
4231. (g) Kondekar, N. B.; Kandula, S. V.; Kumar, P. Tetrahedron Lett.
2004, 45, 5477. (h) Pandey, S. K.; Kandula, S. V.; Kumar, P.
Tetrahedron Lett. 2004, 45, 5877. (i) Gupta, P.; Naidu, S. V.; Kumar,
P. Tetrahedron Lett. 2004, 45, 9641. (j) Kumar, P.; Bodas, M. S. J.
Org. Chem. 2005, 70, 360.
* To whom correspondence should be addressed. Tel: +91-20-
25893300, ext 2050. Fax; +91-20-25893614.
† Dedicated to Professor Dr. Richard R. Schmidt on the occasion of
his 70th birthday.
(1) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemsheidt,
T. Org. Lett. 2001, 3, 3479.
(2) (a) Murga, J.; Falmoir, E.; Garcia-Fortanet, J.; Carda, M.; Marco,
J. A. Org. Lett. 2002, 4, 3447. (b) Gurjar, M. K.; Nagaprasad, R.;
Ramana, C. V. Tetrahedron Lett. 2003, 44, 2873. (c) Davoli, P.; Spaggiri,
A.; Castagnetti, L.; Prati, F. Org. Biomol. Chem. 2004, 2, 38. (d)
Banwell, M. G.; Loong, D. T. J. Heterocycles 2004, 62, 713. (e) Ishigami,
K.; Kitahara, T. Heterocycles 2004, 63, 785.
10.1021/jo050193e CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/12/2005
J. Org. Chem. 2005, 70, 4207-4210
4207

SCHEME 2a
SCHEME 3a
a Reagents and conditions: (a) Li, liq NH3, Fe(NO3)3, n-C6H13Br,
THF, -78 °C, 95%; (b) LiAlH4, THF, reflux, 96%; (c) N-chlorosuc-
cinimide, PPh3, CH2Cl2, 0 °C to rt, 3 h, 89%; (d) (DHQ)2PHAL,
K2CO3, K3Fe(CN)6, MeSO2NH2, OsO4 (0.1 M in toluene), t-BuOH/
H2O (1:1), 0 °C, 24 h, 91%; (e) NaOH, THF, 2 h, 0 °C to rt, 90%;
(f) MOMCl, i-Pr2EtN, CH2Cl2, 0 °C to rt, 6 h, 98%.
ing benzene.10 Tributyltin was then replaced with iodide
by using I2 in CH2Cl2 to afford the corresponding iodo
compound 12 in excellent yield.
a Reagents and conditions: (a) p-CH3OC6H4CH2Br, NaH, dry
DMF, cat. TBAI, 0 °C to rt, 1 h, 90%; (b) (i) (COCl)2, DMSO, Et3N,
CH2Cl2, -78 to -60 °C; (ii) Ph3PdCHCO2Et, benzene, reflux, 6 h,
89%; (c) (DHQD)2PHAL, K2CO3, K3Fe(CN)6, MeSO2NH2, OsO4 (0.1
M in toluene), t-BuOH/H2O (1:1), 0 °C, 24 h, 96%; (d) p-TSA, 2,2-
DMP, CH2Cl2, 95%; (e) DIBAL-H, CH2Cl2, 0 °C to rt, 2 h, 96%; (f)
(COCl)2, DMSO, Et3N, CH2Cl2, -78 to -60 °C, 94%; (g) CBr4,
PPh3, CH2Cl2, -78 °C, 2 h, 98%; (h) n-BuLi, THF, -78 °C, 1 h,
92%; (i) (n-Bu)3SnH, AIBN, C6H6, reflux, 4 h, 99%; (j) I2, CH2Cl2,
30 min, 96%.
11
Synthesis of Fragment 19 (Scheme 3). The synthe-
sis of epoxy component 19 commenced from propargyl
alcohol 13. Thus, alkylation of 13 with n-hexyl bromide
in THF gave the propargylic alcohol 14 in 95% yield,
which was further converted into (E)-allylic alcohol 15
in 96% yield by LiAlH4 reduction12 and then to the
chloride 16 in 89% yield. The allylic chloride 16 was
treated with osmium tetroxide in the presence of
(DHQ)2PHAL ligand under AD conditions to afford the
diol 17 in 91% yield and 95% ee.13 To minimize the
epoxide formation, the reaction was carried out under
“buffered” conditions14 (with 3 equiv of NaHCO3). Treat-
ment of diol 17 with 2 equiv of NaOH in THF at 0 °C
afforded the epoxide 18 in good yield. The protection of
the free hydroxy group of 18 with MOMCl in CH2Cl2 in
the presence of diisopropylethylamine gave the epoxy
compound 19 in excellent yield.
Coupling of Epoxide 19 with Different Nucleo-
philes (Scheme 4). Having completed the synthesis of
both fragments 10 and 19, we needed to couple two
fragments by regioselective epoxide opening and carry
out subsequent macrolactonization. To this end, we
studied the opening of epoxide with different nucleophiles
such as 10, 11, and 12. Thus, vinyl stannane 11 was
treated with n-BuLi in THF at -78 °C for 1 h and further
treated with CuCN followed by addition of epoxide 19 to
form the coupling product 20 in 51% yield.15 In the same
way compound 12 was transformed into the correspond-
ing cuprate by sequential treatment with n-BuLi and
CuCN followed by addition of epoxide to give compound
20 in 78% yield. In both these reactions 2-3 equiv of
cuprate was utilized. Though the compound 20 was
obtained with requisite trans-geometry of the double
available 1,4-butane diol. Thus selective mono hydroxyl
protection of 2 with p-methoxybenzyl bromide in the
presence of NaH gave 3 in 90% yield. Compound 3 was
oxidized to the corresponding aldehyde under Swern
conditions5 and subsequently treated with (ethoxycarbo-
nylmethylene)triphenylphosphorane in benzene under
reflux conditions to furnish the trans-olefin 46 in 89%
yield. The olefin 4 was treated with osmium tetroxide
and potassium ferricyanide as co-oxidant in the presence
of (DHQD)2PHAL ligand under AD conditions7 to give
the diol 5 in 96% yield with 97% ee.8 Treatment of diol 5
with 2,2-dimethoxypropane in the presence of catalytic
amount of p-TSA gave compound 6, which on subsequent
reduction using DIBAL-H provided the alcohol 7 in
excellent yield. Subsequent homologation to the acetylene
10 was carried out by Corey-Fuchs protocol9 in a three-
step sequence involving Swern oxidation, dibromometh-
ylenation of the aldehyde, and dehalogenation. Thus
compound 7 was oxidized to the aldehyde 8 using
standard Swern conditions followed by dibromomethyl-
enation with CBr4 and PPh3 in CH2Cl2 at -78 °C to
furnish the dibromo olefin 9 in essentially quantitative
yield. Treatment of 9 with an excess of n-BuLi in THF
at -78 °C provided the acetylene 10 in 92% yield, which
was readily converted into (E)-vinyl stannane 11 by
reaction with tri-n-butyltin hydride and AIBN in reflux-
(5) For reviews on the Swern oxidation, see: (a) Tidwell, T. T.
Synthesis 1990, 857. (b) Tidwell, T. T. Org. React. 1990, 39, 297.
(6) Chandrasekhar, S.; Mohapatra, S. Tetrahedron Lett. 1998, 39,
6415.
(7) (a) Becker, H.; Sharpless, K. B. Angew Chem., Int. Ed. Engl.
1996, 35, 448. (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K.
B. Chem. Rev. 1994, 94, 2483. (c) Torri, S.; Liu, P.; Bhuvaneswari, N.;
Amatore, C.; Jutand, A. J. Org. Chem. 1996, 61, 3055.
(8) For the measurement of enantiomeric excess, the diol 5 was
converted into its dibenzoate. The enantiomeric purity of the dibenzoate
was estimated to be 97% by chiral HPLC analysis using Lichocart 250-4
(4 mm i.d. × 25 cm) HPLC Cartridge (R.R.-Whelk-01), 1% iPrOH in
hexane, 1 mL/min.
(10) (a) Izzo, I.; Caro, S. D.; De Riccardis, F.; Spinella, A. Tetrahedron
Lett. 2000, 41, 3975. (b) Otaka, K.; Mori, K. Eur. J. Org. Chem. 1999,
1795. (c) Deng, Y.; Salomon, R. G. J. Org. Chem. 2000, 65, 6660.
(11) (a) Drouet, K. E.; Theodorakis, E. A. Chem. Eur. J. 2000, 6,
1987. (b) Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1998, 120,
3935. (c) Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738.
(12) Van Aar, M. P. M.; Thijs, L.; Zwaneburg, B. Tetrahedron 1995,
51, 11233.
(13) Zhang, Z.-B.; Wang, Z.-M.; Wang, Y.-X.; Liu, H.-Q.; Lei, G.-X.;
Shi, M. J. Chem. Soc., Perkin Trans. 2000, 1, 53.
(14) For “buffered” AD reaction of allylic chlorides, see: Vanhessche,
K. P. M.; Wang, Z.-M.; Sharpless, K. B. Tetrahedron Lett. 1994, 35,
3469.
(9) (a) Critcher, D. J.; Connolly, S.; Wills, M. J. Org. Chem. 1997,
62, 6638. (b) Horita, K.; Oikawa, Y.; Nagato, S.; Yonemitsu, O.
Tetrahedron Lett. 1998, 29, 5143. (c) Mukai, C.; Kim, J. S.; Sonobe,
H.; Hanaoka, M. J. Org. Chem. 1999, 64, 6822. (d) Gon’zalez, I. S.;
Forsyth, C. J. Org. Lett. 1999, 1, 319.
(15) (a) Corey, E. J.; Pan, B.-H.; Hua, D. H.; Deardorff, D. R. J. Am.
Chem. Soc. 1982, 104, 6816. (b) Corey, E. J.; Hua, D. H.; Pan, B.-H.;
Seitz, S. P. J. Am. Chem. Soc. 1982, 104, 6818. (c) Corey, E. J.; Niimura,
K.; Konishi, Y.; Hashimoto, S.; Hamada, Y. Tetrahedron Lett. 1986,
27, 2199.
4208 J. Org. Chem., Vol. 70, No. 10, 2005

SCHEME 4a
aldehyde using Swern conditions and further oxidation
using NaClO2 in DMSO under buffer conditions18 af-
forded the acid 24. The TBS group in 24 was removed
with TBAF to give the seco acid 25 for lactonization.
Macrolactonization of 25 under Yamaguchi conditions19
provided the macrocyclic lactone 26 in quantitative yield,
which on subsequent cleavage of the protective groups2a
afforded the target molecule 1 in 88% yield. The physical
and spectroscopic data of 1 were identical with those
reported.1,2a
In conclusion, a convergent and efficient total synthesis
of microcarpalide 1, with high enantioselectivities has
been developed in which all the stereocenters were
established by Sharpless asymmetric dihydroxylation.
Notable features of this approach include Corey-Fuchs
protocol to synthesize the acetylene fragment, various
nucleophiles used in the regioselective epoxide opening
to establish the C7-C8 trans-olefin geometry exclusively
and Yamaguchi protocol in the macrocyclization step. The
synthetic strategy described for 1 might be easily ame-
nable for the preparation of either enantiomer and its
double-bond isomer simply by partial hydrogenation
using Lindlar’s catalyst. Further application of this
methodology to the syntheses of other biologically active
compounds for the studies of structure activity relation-
ship is currently underway in our laboratory.
a Reagents and conditions: (a) For 11: n-BuLi/11, -78 °C for 1
h, -50 °C for 1.5 h, then CuCN, -78 °C, 1.5 h, then epoxide 19,
51%; for 12: n-BuLi/12, -78 °C, CuCN, THF, 5 h, 78%; (b) n-BuLi,
THF, -78 to -20 °C, 30 min, then BF3‚Et2O, -78 °C, 10 min, then
19, 30 min, 89%; (c) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 30 min,
98%; (d) Na/liq NH3, THF, -40 °C, 89%.
SCHEME 5a
Experimental Section
2,3-Dihydroxy-6-(4-methoxybenzyloxy)-hexanoic Acid
Ethyl Ester (5). To a mixture of K3Fe(CN)6 (18.45 g, 56.0 mmol),
K2CO3 (7.74 g, 56.0 mmol) and (DHQD)2PHAL (145 mg, 1 mol
%), in t-BuOH-H2O (1:1, 100 mL) cooled at 0 °C was added OsO4
(0.79 mL, 0.1 M solution in toluene, 0.4 mol %) followed by
methanesulfonamide (1.78 g, 18.71 mmol). After being stirred
for 5 min at 0 °C, the olefin 4 (5.20 g, 18.68 mmol) was added in
one portion. The reaction mixture was stirred at 0 °C for 24 h
and then quenched with solid sodium sulfite (25 g). The stirring
was continued for an additional 45 min, and then the solution
was extracted with EtOAc (3 × 50 mL). The combined organic
extracts were washed with 10% KOH and brine, dried (Na2SO4),
and concentrated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc (3:2) as eluent gave the
a Reagents and conditions: (a) (i) (COCl)2, DMSO, Et3N, CH2-
Cl2, -78 to -60 °C, 95%; (ii) NaClO2, DMSO, H2O, NaH2PO4, rt,
1.5 h, 86%; (b) TBAF, THF, rt, overnight; (c) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF, then DMAP, benzene, 86% from 24; (d)
BF3‚Et2O, (CH2SH)2, CH2Cl2, 1 h, 88%.
bond, the drawback of this reaction was in employing 2-3
equiv of substrates 11 or 12 with respect to the epoxide.
The epoxide opening reaction did not work with the use
of 1-1.5 equiv of cuprates even in the presence of BF3‚
Et2O. Initially we tried Yamaguchi coupling of the
epoxide 19 with acetylide generated directly from the
debromination of dibromoalkene 9 in the presence of BF3‚
Et2O and n-BuLi; however, the reaction was not very
clean, affording only a mixture of compounds that could
not be separated. This may be attributed to the use of
excess of n-BuLi in the debromination reaction. To
circumvent these problems, the acetylide 10 (1.5 equiv)
was finally coupled with epoxide 19 (1 equiv) via Yamagu-
chi method16 in the presence of BF3‚Et2O at -78 °C to
afford 21 in 89% yield. The free hydroxy group of 21 was
protected with TBSCl to furnish compound 22. Reduction
diol 5 (5.63 g, 96%) as a colorless syrupy liquid. [R]25 +6.7 (c
D
1.6, CHCl3). IR (neat): νmax 3440, 2938, 2864, 1736, 1612, 1513,
1
1248, 1130, 1032 cm-1. H NMR (500 MHz, CDCl3): δ 7.26 (d,
2H, J ) 10.1 Hz); 6.88 (d, 2H, J ) 10.1 Hz), 4.44 (s, 2H), 4.26
(q, 2H, J ) 5.0 Hz), 4.06 (m, 1H), 3.91(d, 1H, J ) 5.3 Hz), 3.80
(s, 3H), 3.49 (t, 2H, J ) 6.1 Hz), 2.82 (br s, 2H), 1.73 (m, 4H),
1.30 (t, 3H, J ) 6.1 Hz). 13C NMR (125 MHz, CDCl3): δ 173.2,
158.8, 130.1, 128.9, 113.4, 73.4, 72.1, 69.5, 61.2, 54.8, 42.5, 30.0,
25.6, 13.7. Anal. Calcd for C16H24O6 (312.36): C, 61.52; H, 7.74.
Found: C, 61.78; H, 7.82.
Tributyl-(2-{5-[3-(4-methoxybenzyloxy)-propyl]-2,2-di-
methyl-[1,3]dioxolan-4-yl}-vinyl)-stannane (11). To a stirred
solution of 10 (0.500 g, 1.64 mmol) in benzene (25 mL) were
added n-Bu3SnH (0.65 mL, 2.45 mmol) and AIBN (catalytic) at
room temperature under N2. The reaction mixture was gently
refluxed with stirring for 4 h. The solvent was removed and the
residue was purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1) as eluent to give 11 (968 mg, 99%)
17
of the alkyne under Birch conditions using Na/liq NH3
proceeded smoothly with the required E-geometry of the
C7dC8 double bond and concomitant removal of the PMB
group affording 23 in good yield. Thus the E-selective
construction of C7dC8 double bond in the synthesis of
target molecule 1 is a significant improvement over all
reported syntheses.
as a yellowish oil. [R]25 +8.4 (c 0.9, CHCl3). IR (CHCl3): νmax
D
3004, 2957, 2928, 2853, 1612, 1513, 1464, 1378, 1247, 1173, 1036
1
cm-1. H NMR (300 MHz, CDCl3): δ 7.25 (d, J ) 8.8 Hz, 2H),
Synthesis of Microcarpalide 1 (Scheme 5). Oxida-
tion of primary alcohol in 23 to the corresponding
6.89 (d, J ) 8.8 Hz, 2H), 6.36 (d, J ) 19.0 Hz, 1H), 5.95 (dd, J
(18) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
(19) Inanaga, J.; Hirata, K.; Sacki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(16) Yamaguchi, M.; Hirano, I. Tetrahedron Lett. 1983, 24, 391.
(17) Schon, I. Chem. Rev. 1984, 84, 287.
J. Org. Chem, Vol. 70, No. 10, 2005 4209

) 19.0, 5.1 Hz, 1H), 4.44 (s, 2H), 3.98 (t, J ) 7.3 Hz, 1H), 3.81
(s, 3H), 3.73-3.79 (m, 1H), 3.48 (t, J ) 5.9 Hz, 2H), 1.61-1.69
(m, 4H), 1.42-1.48 (m, 8H), 1.41 (s, 3H), 1.38 (s, 3H), 1.26-
1.31 (m, 10H), 0.88-0.93 (m, 9H). 13C NMR (75 MHz, CDCl3):
δ 159.0, 144.8, 134.1, 130.6, 129.1, 113.6, 108.3, 85.3, 80.2, 80.4,
72.4, 69.7, 55.1, 29.1, 29.0, 28.5, 27.3, 27.1, 26.9, 26.1, 13.6, 11.1,
10.6, 10.1, 9.4, 8.8. Anal. Calcd for C30H52O4Sn (595.43): C,
60.51; H, 8.80; Sn, 19.94. Found: C, 60.73; H, 8.64; Sn, 20.12.
4-(2-Iodovinyl)-5-[3-(4-methoxybenzyloxy)-propyl]-2,2-
dimethyl-[1,3]dioxolane (12). To a cooled (0 °C), stirred
solution of 11 (250 mg, 0.42 mmol) in CH2Cl2 (15 mL) was added
iodine (213 mg, 0.84 mmol). After 10 min at 0 °C, the reaction
mixture was diluted with CH2Cl2 and washed with saturated
Na2S2O3 and 10% KF solutions, and brine. The organic layer
was dried (Na2SO4), filtered, and concentrated. Silica gel column
chromatography of the crude product using petroleum ether/
EtOAc (9.5:0.5) as eluent gave 12 (174 mg, 96%) as a yellowish
oil. [R]25D +7.6 (c 1.1, CHCl3). IR (CHCl3): νmax 2946, 2932, 2856,
with brine, dried (Na2SO4), and concentrated. Silica gel column
chromatography of the crude product using petroleum ether/
EtOAc (8:2) as eluent gave compound 21 (789 mg, 89%) as a
yellowish liquid. [R]25 +10.3 (c 1.24, CHCl3). IR (CHCl3): νmax
D
3414, 3019, 2933, 2860, 2400, 1612, 1513, 1465, 1372, 1216,
1097, 757 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.25 (d, J ) 8.7
Hz, 2H), 6.89 (d, J ) 8.2 Hz, 2H), 4.65 (s, 2H), 4.44 (s, 2H), 4.23
(d, J ) 7.8 Hz, 1H), 3.96 (dt, J ) 7.8, 4.6 Hz, 1H), 3.78 (s, 3H),
3.77 (dt, J ) 5.5, 1.9 Hz, 1H), 3.64 (dt, J ) 6.0, 1.9 Hz, 1H),
3.47-3.50 (m, 2H), 3.41 (s, 3H), 2.72 (br s, 1H), 2.44-2.49 (m,
1H), 2.39 (ddd, J ) 15.1, 7.8, 1.4 Hz, 1H), 1.63-1.80 (m, 6H),
1.44 (s, 3H), 1.39 (s, 3H), 1.26-1.31 (m, 8H), 0.89 (t, J ) 6.1 Hz,
3H). 13C NMR (125 MHz, CDCl3): δ 159.1, 131.5, 130.6, 129.11,
113.72, 113.54, 109.3, 96.8, 83.6, 81.4, 80.7, 78.8, 72.4, 71.6, 70.1,
69.6, 55.7, 55.1, 31.6, 30.7, 29.29, 28.97, 27.0, 26.2, 25.90, 25.24,
24.0, 22.5, 13.9. Anal. Calcd for C29H46O7 (506.67): C, 68.74; H,
9.15. Found: C, 68.81; H, 9.24.
Microcarpalide (1). A stirred solution of compound 26 (40
mg, 0.104 mmol) in CH2Cl2 (5 mL) was cooled to 0 °C and treated
with BF3‚Et2O (13 µL, 0.104 mmol), and ethanedithiol (38 µL,
0.45 mmol). The resulting mixture was stirred at 0 °C for 1 h
and then quenched with aqueous NaHCO3, and the aqueous
layer was extracted with diethyl ether (3 × 10 mL). The
combined organic extracts were washed with brine, dried (Na2-
SO4), and concentrated. Silica gel column chromatography of the
crude product using EtOAc as eluent gave microcarpalide 1 as
a yellow syrupy liquid (28 mg, 88%) and a 3.2:1 (as judged by
1612, 1513, 1465, 1372, 1174, 1092, 947 cm-1 1H NMR (200
.
MHz, CDCl3): δ 7.29 (d, J ) 8.6 Hz, 2H), 6.53 (d, J ) 8.7 Hz,
2H), 6.29 (m, 2H), 4.44 (s, 2H), 3.94-4.01 (m, 1H), 3.81 (s, 3H),
3.63-3.76 (m, 1H), 3.47 (t, J ) 5.8 Hz, 2H), 1.61-1.78 (m, 4H),
1.40 (s, 3H), 1.40 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 161.4,
147.6, 129.5, 128.6, 114.0, 101.7, 86.5, 81.6, 75.8, 74.3, 70.1, 56.2,
28.8, 26.2, 25.5. Anal. Calcd for C18H25IO4 (432.29): C, 50.01;
H, 5.83, I, 29.36. Found: C, 50.42; H, 5.75, I, 30.01.
2-(1-Methoxymethoxyheptyl)-oxirane (19). A solution of
hydroxy epoxide 18 (2.1 g, 13.27 mmol) and DIPEA (6.8 mL,
39.30 mmol) in dry CH2Cl2 (50 mL) was treated under argon
with MOM chloride (1.27 g, 1.2 mL, 15.77 mmol) at 0 °C and
the reaction mixture was stirred for 6 h at room temperature.
The reaction was quenched by addition of water and the aqueous
layer was extracted with CH2Cl2 (3 × 50 mL). The combined
organic layer was washed with brine, dried (Na2SO4), and
concentrated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc (9:1) as eluent gave 19
1H NMR spectra) mixture of conformers. [R]25 -23.4 (c 0.9,
D
MeOH); [lit.1,2a -22.0 (c 0.67, MeOH)]. IR (neat): 3370, 2922,
2863, 1711, 1430, 1226, 1153, 1067. 1H NMR (500 MHz, CD3-
CN): δ 5.69 (dd, J ) 15.5, 2.5 Hz, 1H), 5.50 (dddd, J ) 15.6,
9.9, 5.1, 2.1 Hz, 1H), 4.81 (ddd, J ) 11.1, 4.8, 3.3 Hz, 1H), 4.11
(br, 1H), 3.78 (br, 1H), 3.54 (br m, 1H), 3.08 (br d, 1H), 2.85 (br
m, 2H), 2.47-2.50 (m, 1H), 2.15-2.25 (m, 2H), 1.98-2.14 (m,
2H), 1.77-1.93 (m, 1H), 1.38-1.44 (m, 2H), 1.29-1.36 (m, 8H).
0.88 (t, J ) 6.8 Hz, 3H). 13C NMR (125 MHz, CD3CN, observed
as a mixture of two conformers): δ 176.3, 174.1, 134.5, 126.6,
79.7, 73.5, 72.8, 72.3, 36.7, 34.2, 32.5, 29.9, 26.4, 26.1, 23.3, 14.4.
(2.63 g, 98%) as a colorless oil. [R]25 +4.2 (c 1.1, CHCl3). IR
D
1
(neat): νmax 2943, 2859, 1615, 1518, 1244, 1132, 1030 cm-1. H
NMR (500 MHz, CDCl3): δ 4.71 (s, 2H), 3.75-3.80 (q, J ) 10.9
Hz, 1H), 3.64-3.71 (m, 2H), 3.57 (dd, J ) 10.9, 5.8 Hz, 1H), 3.42
(s, 3H), 1.53-1.63 (m, 2H), 1.29-1.36 (m, 8H), 0.89 (t, J ) 7.3
Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 13.9, 22.4, 25.2, 29.2,
30.7, 31.6, 45.9, 55.8, 72.7, 79.2, 96.8. Anal. Calcd for C11H22O3
(202.29): C, 65.31; H, 10.96. Found: C, 65.64; H, 11.01.
1-{5-[3-(4-Methoxybenzyloxy)-propyl]-2,2-dimethyl-[1,3]-
dioxolan-4-yl}-5-methoxymethoxy-undec-1-yn-4-ol (21). To
a solution of acetylene 10 (0.8 g, 2.63 mmol) in THF (20 mL)
was added n-BuLi (1.6 M solution in hexane) (1.8 mL, 2.88 mmol)
at -78 °C and the reaction mixture was stirred for 10 min. Then,
BF3‚Et2O (2.89 mmol, 0.36 mL) was added to the reaction
mixture and stirring was continued for 10 min at -78 °C. Finally
a solution of epoxide 19 (354 mg, 1.75 mmol) in THF (2 mL)
was added, and after stirring for 30 min at -78 °C, the reaction
was quenched by adding aqueous ammonium chloride. After the
two layers were separated, the aqueous layer was extracted with
EtOAc (3 × 20 mL) and the combined organic layer was washed
Acknowledgment. S.V.N. thanks CSIR New Delhi
for a research fellowship. Financial support from De-
partment of Science and Technology (DST), New Delhi
(Project Grant No. SR/S1/OC-40/2003) is gratefully
acknowledged. We are grateful to Dr. M. K. Gurjar for
his support and encouragement. This is NCL com-
munication No. 6677.
Supporting Information Available: The spectroscopic
data and full experimental procedure for compounds 3, 4, 6,
7, 9, 10, 14-18, 20, 22-24, 26, and 1H and 13C NMR spectra
of compounds 4, 5, 9-11, 17-19, 21, 22, 26, and microcar-
palide 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO050193E
4210 J. Org. Chem., Vol. 70, No. 10, 2005