First total synthesis of (+)-varitriol

Article abstract of DOI:10.1021/jo8013534

(Chemical Equation Presented) A highly stereoselective total synthesis of (+)-varitriol, an antitumor natural product, has been achieved for the first time from commercially available methyl α,D-mannopyranoside and 2,6-dihydroxybenzoic acid.

Full text of DOI:10.1021/jo8013534

First Total Synthesis of (+)-Varitriol†
Vikas Kumar and Arun K. Shaw*
DiVision of Medicinal and Process Chemistry, Central Drug Research Institute (CDRI),
Lucknow 226 001, India
akshaw55@yahoo.com
ReceiVed June 26, 2008
A highly stereoselective total synthesis of (+)-varitriol, an antitumor natural product, has been achieved
for the first time from commercially available methyl R,D-mannopyranoside and 2,6-dihydroxybenzoic
acid.
Introduction
has attracted an immense synthetic interest directed toward the
varitriols and their analogues.
Marine-derived biologically active natural products continue
to be a source of potential therapeutic compounds as well as
motivation to develop new synthetic strategies for their con-
struction.1 Recently, Barrero and co-workers reported the
isolation and structure elucidation of (+)-varitriol (1) from
marine strain (named M75-2) of the fungus Emericella Varie-
color, isolated from a sponge collected in Venezuelan waters
of the Caribbean Sea.2a This naturally occurring substance was
found to exhibit potent cytotoxicities toward a variety of cancer
cell lines. Strikingly, (+)-varitriol demonstrated a more than
100-fold increased potency (over the mean toxicity) toward the
RXF 393 (renal cancer, GI50 ) 1.63 × 10-7 M), T-47D (breast
cancer, GI50 ) 2.10 × 10-7 M), and SNB-75 (CNS cancer,
GI50 ) 2.44 × 10-7 M) cell lines and lower potency against
the DU-145 (prostate cancer, GI50 ) 1.10 × 10-6 M), HL-60
(TB) (leukemia, GI50 ) 2.52 × 10-5 M), CCRFCEM (leukemia,
Recently, Clemens et al.3a and subsequently the Taylor
group3b have achieved the total synthesis of unnatural (-)-
varitriol. In their studies, both groups utilized D-(-)-ribose to
construct the furanoside portion of (-)-varitriol and argued that
the synthesis of the natural isomer might be possible from
expensive L-(+)-ribose. Furthermore, synthetic analogues of
(+)-varitriol and their cytotoxicity have also been reported.4
Thus, the impressive biological activity, novel structural features,
and lack of literature report toward the total synthesis of (+)-
varitriol encouraged us to undertake the total synthesis of this
interesting natural product. Herein, we report the first total
synthesis of natural (+)-varitriol.
The retrosynthetic strategy for (+)-varitriol (1) is delineated
in Scheme 1. We envisaged that 1 could be elaborated from
the aromatic and carbohydrate portions 15a and 5a, respectively,
by utilizing the cross metathesis strategy. The fragment 5a,
which contains all of the four required stereocenters of the
natural product, could in turn be prepared from the key
intermediate 5 by replacing iodide at C6 with hydride and
inversion of configuration at C4 followed by Wittig olefination
at C2′. Aromatic part 15a could be obtained from triflate 1511,12
by Stille coupling.
GI50 ) 2.60 × 10-5 M), OVCAR-5 (ovarian cancer, GI50
)
6.82 × 10-5 M), SNB-19 (CNS cancer, GI50 ) 9.13 × 10-5
M), and COLO 205 (colon cancer, GI50 ) 9.59 × 10-5 M) cell
lines tested within the 60 cell line panel of the National Cancer
Institute (NCI).2 This array of interesting biological properties
† CDRI Communication no. 7535.
(1) Bugni, T. S.; Richards, B.; Bhoite, L.; Cimbora, D.; Harper, M. K.;
Ireland, C. M. J. Nat. Prod. 2008, 71, 1095–1098, and references therein.
(2) (a) Malmstrom, J.; Christophersen, C.; Barrero, A. F.; Oltra, J. E.; Justicia,
J.; Rosales, A. J. Nat. Prod. 2002, 65, 364–367. (b) Mayer, A. M. S.; Gustafson,
K. R. Eur. J. Cancer 2004, 40, 2676–2704.
(3) (a) Clemens, R. T.; Jennings, M. P. Chem. Commun. 2006, 2720–2721.
(b) McAllister, G. D.; Robinson, J. E.; Taylor, R. J. K. Tetrahedron 2007, 63,
12123–12130.
Results and Discussion
The synthesis of stereochemically pure tetrasubstituted
tetrahydrofuran (THF) subunit 5 was initiated from the
(4) Nagarapu, L.; Paparaju, V.; Satyender, A. Bioorg. Med. Chem. Lett. 2008,
18, 2351–2354.
7526 J. Org. Chem. 2008, 73, 7526–7531
10.1021/jo8013534 CCC: $40.75 2008 American Chemical Society
Published on Web 08/30/2008

First Total Synthesis of (+)-Varitriol
SCHEME 1. Retrosynthetic Strategy
SCHEME 2. Synthesis of Furanoside 12
commercially available methyl R,D-mannopyranoside 2 as
shown in Scheme 2. The terminal allylic alcohol 4 was
obtained in 60% yield by reductive zinc dust opening5 of
methyl 6-deoxy-6-iodo-2,3-di-O-benzyl-R,D-mannopyrano-
side 36a,b followed by sodium borohydride reduction. The
iodocyclization of the chromatographically pure terminal
allylic alcohol 4 involving the participation of secondary
benzyl-protected oxygen in cyclization followed by deben-
zylation furnished 4,5-cis tetrasubstituted THF 5 with very
high diastereoselectivity (>99:1).6a,c-e Here, the selectivity
may be attributed to the formation of iodine-π complex at
the re face of the double bond in the most favorable acyclic
conformation7 of allylic alcohol 4a while the si face approach
of the I2 across the double bond is completely blocked by
the benzyloxy group (Figure 1).
LiAlH4 reduction of 5 followed by selective silyl protection
of the primary alcohol furnished R-C-furanoside 6. At this stage,
among the four stereocenters in 6 three of them have the required
stereochemistry as present in the (+)-varitriol while C4 has the
opposite one. Thus, the inversion of C4-OH group in R-C-
furanoside 6 was achieved to provide the isomeric compound
7 by first exposing 6 to Dess-Martin periodinane and subse-
quent reduction of the resulting crude ketone with different
hydride reagents.8 Here, it is worth to mention that the
L-selectride which showed overall best result in terms of
selectivity (>99:1) as well as yield (90%) (Table 1, entry 4,
see Supporting Information) compared to other hydride reagents
screened for this reaction, is the reagent of choice.
The cleavage of benzyl ether in 7 with H2 in the presence of
Pd(OH)2 and acetonation9 of the resulting syn diol with 2,2-
dimethoxypropane (DMP) and catalytic amount of camphor-
(6) (a) Kumar, V.; Gauniyal, H. M.; Shaw, A. K. Tetrahedron: Asymmetry
2007, 18, 2069–2078. (b) Sletten, E. M.; Liotta, L. J. J. Org. Chem. 2006, 71,
1335–1343. (c) Bew, S. P.; Knight, D. W.; Middleton, R. J. Tetrahedron Lett.
2000, 41, 4453–4456. (d) Chamberlin, A. R.; Mulholland, R. L., Jr.; Kahn, S. D.;
Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 672–677. (e) Reitz et. al. reported
haloetherification of D-arabinose-derived 1,2,3,4,-tetrabenzyloxy hex-5-ene with
NBS or Br2 to obtain a mixture of 2,3-cis/trans tetrasubstituted THF (cis:trans
ratio 87:13 with NBS and 90:10 with Br2); see:(f) Reitz, A. B.; Nortey, S. O.;
Maryanoff, B. E.; Liotta, D.; Monahan, R., III. J. Org. Chem. 1987, 52, 4191–
4202.
(7) For conformations of acyclic molecules, see:Hoffmann, R. W. Angew.
Chem. Int. Ed. 2000, 39, 2054–2070, and references therein.
(8) See Supporting Information.
(9) Acetonide protection on compound 8 was necessary because conversion
of compound 6 to compound 7 was diastereoselective. The diastereomeric mixture
of 7 obtained from NaBH4 or CBS reduction of intermediate ketone derived
from 6 could not be separated by column chromatography due to their close Rf
values (NMR of column purified sample showed mixture of two diastereoiso-
mers). Though, L-selectride reduction of the ketone was highly diastereoselective
as it was evident from NMR spectra of 7 showing only one isomer (see supporting
information), even then we preferred to perform acetonization of the resulting
diol obtained after debenzylation of 7 in order to purify the desired cis-diol
completely.
(5) (a) Kleban, M.; Kautz, U.; Greul, J.; Hilgers, P.; Kugler, R.; Dong, H.-
Q.; Ja¨ger, V. Synthesis 2000, 1027–1033. (b) Bernet, B.; Vasella, A. HelV. Chim.
Acta 1979, 62, 1990–2016.
J. Org. Chem. Vol. 73, No. 19, 2008 7527

Kumar and Shaw
SCHEME 3. Synthesis of Styrene 19
FIGURE 1. Proposed mechanism6 for the formation of THF 5.
FIGURE 2. NOESY correlations for compound 8.
sulfonic acid (CSA) in acetone delivered the acetonide 8 in 86%
yield as a single diastereoisomer. The stereochemistry of
compound 8 was confirmed on the basis of its NOESY
spectrum. The significant NOESY correlations are shown in
Figure 2. The H-6 showed the NOESY correlation with H-4
which is syn to H-3. The H-3 showed the NOESY correlation
with H-2′. The proton of the ꢀ methyl of acetonide ring showed
NOESY correlation with H-2 and H-5, while the R methyl
proton showed NOESY with H-3, H-4, and H-2′. All these
correlations confirmed the stereochemistry of 8.
SCHEME 4. Synthesis of (+)-1
The cleavage of silyl ether in 8 with TBAF in THF furnished
alcohol 8a. The oxidation of 8a with IBX in acetonitrile10 and
Wittig olefination of the resulting labile aldehyde to obtain the
desired vinylic furanoside was very sluggish, perhaps owing to
the highly volatile nature of aldehyde3a and vinylic furanoside.
To overcome this problem, we decided to replace acetonide
protection with an appropriate protecting group. Accordingly,
the acidic hydrolysis of 8 with 80% AcOH and protection of
the resulting syn diol 9 as their PMB ethers afforded 10 in 54%
yield. Now preparation of desired vinyl furanoside 12 became
possible from 10. Thus, the silyl ether deprotection of 10 to
obtain the primary alcohol 11, and its oxidation with IBX in
acetonitrile10 followed by Wittig olefination of the aldehyde
intermediate in succession afforded olefin 12 in 77% from
11(Scheme 2).
20 should then furnish the target molecule 1. Thus, the cross
metathesis15 of 12 and 19 in presence of Grubbs’ second-
generation catalyst (5 mol %) generated the fully protected
varitriol 20. Attempted deprotection of PMB ethers of 20 by
adopting standard procedures (DDQ, 10% TFA/DCM, 5% TFA/
DCM, 2% TFA/DCM) ended with complex mixture of products.
Fortunately, prolonged exposure of 20 to 1 M HCl in THF at
room temperature (∼ 35 °C) for 3 days afforded the natural
product (+)-varitriol 1 in 46% yield (Scheme 4).16
Conclusion
With the furanoside part in hand, our next attempt was
focused toward the construction of aromatic portion 19. Its
synthesis was started from commercially available phenolic acid
13 involving a series of reactions as depicted in Scheme 3. Stille
coupling of tributylvinyl tin (TBVT) with triflate 1511,12 in the
presence of tetrakis(triphenylphosphine)palladium(0) and lithium
chloride in a sealed tube13 at 80 °C afforded compound 16. The
compound 16 on LiAlH4 reduction14 gave diol 17. Its methy-
lation followed by silyl protection furnished 19 (Scheme 3).
Having synthesized the two building blocks 12 and 19, the
next step was to link them together to obtain the fully protected
natural product 20. The removal of all the protecting groups in
In summary, a highly convergent first total synthesis of
antitumor natural product (+)-varitriol has been disclosed.
Herein we have successfully constructed the carbohydrate
subunit from inexpensive methyl R,D-mannopyranoside in place
of highly expensive L-(+)-ribose. Other key features of the
synthetic venture include a highly diastereoselective (>99%)
iodocyclization reaction of 4 to deliver the key intermediate 5,
stereoselective L-selectride reduction of the ketone obtained
from 6, stille coupling of 15 with TBVT and an efficient cross
metathesis. Further application of this strategy toward the
synthesis of novel isomers of varitriol to evaluate their cyto-
toxicity is currently under progress and will be presented in
due course.
(10) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–3003.
(11) Hadfield, A.; Schweitzer, H.; Trova, M. P.; Green, K. Synth. Commun.
1994, 24, 1025–1028.
(12) Furstner, A.; Konetzki, I. Tetrahedron 1996, 52, 15071–15078.
(13) Han, Q.; Wiemer, D. F. J. Am. Chem. Soc. 1992, 114, 7692–7697.
(14) Bajwa, N.; Jennings, M. P. J. Org. Chem. 2006, 71, 3646–3649.
(15) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370, and references therein.
(16) See Supporting Information for detailed comparative 1H and 13C NMR
of synthetic (+)-varitriol and natural (+)-varitriol.
7528 J. Org. Chem. Vol. 73, No. 19, 2008

First Total Synthesis of (+)-Varitriol
was removed under reduced pressure. The residue was purified by
column chromatography to furnish 6 (3.17 g, 85% from 5) as a
colorless oil. Eluent for column chromatography: EtOAc/hexane (3/
47, v/v); [R]28D ) +40.0 (c 1.0 CHCl3); Rf 0.49 (1/4 EtOAc/hexane);
1H NMR (300 MHz, CDCl3 + CCl4) δ 7.76-7.65 (m, 4H, ArH),
7.47-7.31 (m, 11H, ArH), 4.67 (d, J ) 11.9 Hz, 1H, CH2Ph), 4.57
(d, J ) 11.9 Hz, 1H, CH2Ph), 4.19-4.16 (m, 1H, H-5), 4.08 (d, J )
1.2 Hz, 1H, H-3), 3.99 (d, J ) 2.0 Hz, 1H, H-4), 3.94 (br s, 1H, H-2),
3.84 (dd, J ) 2.6, 11.1 Hz, 1H, H-2′a), 3.63 (dd, J ) 1.8, 11.2 Hz,
1H, H-2′b), 1.39 (d, J ) 6.3 Hz, 3H, H-6), 1.08 (s, 9H, SiC(CH3)3);
13C NMR (75 MHz, CDCl3 + CCl4) δ 138.5 (ArqC), 136.4 (ArC),
136.3 (ArC), 133.1 (ArqC), 132.7 (ArqC), 130.6 (ArC), 130.5 (ArC),
129.1 (ArC), 128.6 (ArC), 128.5 (ArC), 128.4 (ArC), 128.2 (ArC),
87.7 (CH), 84.7 (CH), 78.6 (CH), 76.1 (CH), 72.4 (CH2), 65.4 (CH2),
27.5 (3 × CH3), 19.8 (qC), 14.1 (CH3); IR (neat, cm-1) 3439, 3065,
2932, 1650, 1515, 1460, 1102; mass (ESI-MS) m/z 476, found 499
[M + Na]+; EI-HRMS: calcd for C29H35O4Si [M - H]+ 475.2305,
measured 475.2300.
Compound 7. Dess-Martin periodinane (134 mg, 0.32 mmol) was
added to a solution of 6 (100 mg, 0.21 mmol) in dry dichloromethane
(10 mL) at 0 °C. After stirring for 2 h, saturated solution of NaHCO3
(15 mL) and 10% aqueous Na2S2O3 (20 mL) were added successively
and stirring was continued for another 1 h. The mixture was extracted
with DCM (3 × 5 mL), washed with brine and dried (Na2SO4). The
combined organic layer was concentrated under reduced pressure to
give clear oil (101 mg).
To the above crude oil (101 mg) dissolved in dry THF at -78 °C
(3 mL) was added L-selectride in THF (1.0 M sol, 0.32 mL, 0.32
mmol) and the reaction mixture was stirred at the same temperature
for 3 h. An aqueous solution of NH4Cl (5 mL) was added and the
resulting mixture was extracted with ethyl acetate (3 × 5 mL). The
combined organic phase was dried over Na2SO4 and concentrated under
reduced pressure which on column chromatography gave 7 (90 mg,
90% from 6) as a colorless oil. Eluent for column chromatography:
EtOAc/hexane (3/47, v/v); Rf 0.48 (1/4 EtOAc/hexane); 1H NMR (300
MHz, CDCl3 + CCl4) δ 7.67-7.61 (m, 4H, ArH), 7.41-7.25 (m,
11H, ArH), 4.65 (d, J ) 11.6 Hz, 1H, CH2Ph), 4.54 (d, J ) 11.6 Hz,
1H, CH2Ph), 4.02 (dd, J ) 3.1, 5.9 Hz, 1H, H-3), 3.97 (dd, J ) 3.5,
7.7 Hz, 1H, H-4), 3.77-3.71 (m, 1H, H-5), 3.64-3.59 (m, 3H, H-2,
H-2′), 1.28 (d, J ) 6.2 Hz, 3H, H-6), 1.06 (s, 9H, SiC(CH3)3); 13C
NMR (75 MHz, CDCl3 + CCl4) δ 137.7 (ArqC), 135.9 (ArC), 135.8
(ArC), 133.5 (ArqC), 133.3 (ArqC), 130.0 (ArC), 128.8 (ArC), 128.2
(ArC), 128.0 (ArC), 82.9 (CH), 79.6 (CH), 79.0 (CH), 76.4 (CH), 72.5
(CH2), 64.3 (CH2), 27.2 (3 × CH3), 19.5 (qC), 18.6 (CH3); IR (neat,
cm-1) 3439, 2929, 1629, 1108; mass (ESI-MS) m/z 476, found 494
[M + NH4]+; EI-HRMS: calcd for C25H27O4Si [M - C4H9]+
419.1679, measured 419.1678.
Experimental Section
Compound 4. To a stirred suspension of zinc dust (3.39 g, 51.84
mmol) and NH4Cl (2.77 g, 51.79 mmol) in methanol (90 mL) was
added cyanocobalamine (25 mg, 0.015 mmol). Compound 3 (2.50 g,
5.17 mmol) in methanol was added to the suspension after 10 min.
After the completion of reaction (TLC control, 30 min), the reaction
mixture was passed through a Celite bed. The resulting filtrate was
evaporated to dryness under reduced pressure to give a residue that
was dissolved in ethyl acetate (100 mL). It was washed with a mixture
of brine and water (1:1 v/v, 20 mL each). The organic layer was
separated, dried (Na2SO4), and concentrated under reduced pressure
to give clear oil (1.70 g). The oil without further purification was taken
in methanol (25 mL) and reduced with NaBH4 (294 mg, 7.77 mmol)
at 0 °C. After completion of reaction (TLC control, 2 h), 10 mL of
acetone was added to neutralize excess NaBH4. The solvent was then
concentrated to dryness to give the residue that was dissolved in ethyl
acetate (15 mL) and was washed with water and brine. The organic
layer was dried over Na2SO4 and evaporated under reduced pressure
to obtain clear oil which on column purification yielded 4 (1.02 g,
60% from 3) as a colorless oil. Eluent for column chromatography:
EtOAc/hexane (9/41, v/v); [R]28 ) +23.3 (c 0.56 CHCl3); Rf 0.42
D
(2/3 EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 7.37-7.28 (m,
10H, ArH), 5.99 (ddd, J ) 4.9, 10.6, 17.2 Hz, 1H, H-5), 5.40 (dt, J )
1.6, 17.3 Hz, 1H, H-6a), 5.24 (dt, J ) 1.5, 10.6 Hz, 1H, H-6b),
4.72-4.57 (m, 4H, 2 × CH2Ph), 4.37 (brs, 1H, H-4), 3.87 (dd, J )
3.2, 12.1 Hz, 1H, H-1a), 3.75 (dd, J ) 2.6, 14.5 Hz, 1H, H-1b),
3.69-3.67 (m, 2H, H-2, H-3,), 2.71 (brs, 0.7H, OH); 13C NMR (50
MHz, CDCl3 + CCl4) δ 139.1 (dCH), 138.3 (ArqC), 138.2 (ArqC),
129.2 (ArC), 129.1 (ArC), 128.7 (ArC), 128.6 (ArC), 128.5 (ArC),
116.2 (dCH2), 80.4 (CH), 80.0 (CH), 75.1 (CH2), 72.9 (CH2), 72.0
(CH), 60.9 (CH2); IR (neat, cm-1) 3467, 3393, 3093, 2934, 1652, 1515,
1457, 1219, 1097; mass (ESI-MS) m/z 328, found 351 [M + Na]+,
311 [M - OH]+; Elemental analysis for C20H24O4: calcd C, 72.16; H,
7.42; found C, 72.16; H, 7.82.
Compound 5. To chilled solution of diol 4 (1.52 g, 4.63 mmol) in
DCM (25 mL) was added iodine (1.77 g, 6.97 mmol) in four portions
during 1 h. After stirring for an additional 1 h, 10% aqueous Na2S2O3
(30 mL) was added to the reaction mixture and extracted with DCM
(4 × 20 mL). The combined organic layer was dried over Na2SO4
and concentrated under reduced pressure to obtain a residue that was
subjected to column chromatography to afford compound 5 (1.32 g,
78%) as a white solid (mp 94-96 °C). Eluent for column chroma-
tography: EtOAc/hexane (1/4, v/v); [R]28D ) +62.8 (c 0.50 CHCl3);
Rf 0.55 (1/1, EtOAc/hexane); 1HNMR (300 MHz, CDCl3 + CCl4) δ
7.38-7.27 (m, 5H, ArH), 4.65 (d, J ) 11.9 Hz, 1H, CH2Ph), 4.54 (d,
J ) 11.9 Hz, 1H, CH2Ph) 4.30-4.25 (m, 1H, H-5), 4.20 (brs, 1H,
H-4), 4.14 (d, J ) 1.9 Hz, 1H, H-2), 3.97 (d, J ) 1.3 Hz, 1H, H-3),
3.83 (dd, J ) 2.5, 11.7 Hz, 1H, H-2′a), 3.62 (dd, J ) 1.9, 11.7 Hz,
1H, H-2′b), 3.36-3.24 (m, 2H, H-6); 13C NMR (75 MHz, CDCl3 +
CCl4) δ 138.0 (ArqC), 129.2 (ArC), 128.6 (ArC), 128.3 (ArC), 87.1
(CH), 85.7 (CH), 83.4 (CH), 74.7 (CH), 72.6 (CH2), 63.2 (CH2), 0.6
(CH2I); IR (KBr, cm-1) 3516, 3377, 2919, 1649, 1516, 1461, 1085,
1025; mass (ESI-MS) m/z 364, found 387 [M + Na]+, EI-HRMS:
calcd for C13H18O4I [M + H]+ 365.0250, measured 365.0251.
Compound 6. To a stirred solution of 5 (2.86 g, 7.86 mmol) in
dry THF (50 mL) at -78 °C was added LiAlH4 (358 mg, 9.43 mmol).
The reaction mixture was then warmed to room temperature, and
stirring was continued for 3 h. Ethyl acetate (∼30 mL) was added to
quench the excess reducing agent. To this mixture, water was added
and extracted with ethyl acetate (3 × 20 mL). The combined organic
layer was dried (Na2SO4) and concentrated under reduced pressure to
give clear oil (1.90 g).
Compound 8. A catalytic amount of Pd(OH)2 (∼20 mg) was added
to a solution of 7 (100 mg, 0.21 mmol) in methanol (10 mL). A vacuum
was created in a round bottomed flask containing the above reaction
mixture with the help of pump and the mixture was stirred under H2
in a balloon at 1 atm. After the completion of the reaction (TLC, 12 h)
catalyst was removed by filtration, washed with methanol twice and
the combined filtrate was concentrated to afford a compound (82 mg)
as colorless oil which was immediately used for the next step.
To above colorless oil (82 mg, 0.21 mmol) in acetone (3 mL) was
added 2,2-dimethoxypropane (0.03 mL, 0.25 mmol) followed by
camphorsulfonic acid (24 mg, 0.11 mmol). After 6 h of stirring, the
reaction mixture was concentrated under reduced pressure to a colorless
oil which on column chromatographic purification gave the pure
compound 8 (77 mg, 86% from 7) as a colorless oil. Eluent for column
chromatography: EtOAc/hexane (1/49, v/v); [R]28 ) +8.72 (c 1
D
CHCl3); Rf 0.56 (1/9, EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ
7.64-7.59 (m, 4H, ArH), 7.34-7.27 (m, 6H, ArH), 4.64 (dd, J )
3.6, 6.6 Hz, 1H, H-3), 4.17 (t, J ) 6.5 Hz, 1H, H-4), 3.96-3.89 (m,
2H, H-2, H-5), 3.70 (d, J ) 4.0, Hz, 2H, H-2′), 1.45 (s, 3H, -C(CH3)2),
1.27 (s, 3H, -C(CH3)2), 1.22 (d, J ) 6.3 Hz, 3H, H-6), 0.98 (s, 9H,
SiC(CH3)3); 13C NMR (50 MHz, CDCl3) δ 136.5 (ArC), 136.4 (ArC),
134.2 (ArqC), 134.0 (ArqC), 130.5 (ArC), 130.4 (ArC), 128.5 (ArC),
To the precooled (0 °C) solution of the above crude oil in pyridine
(4 mL) was added TBDPSCl (2.25 mL, 8.65 mmol). The temperature
of the reaction mixture was raised to room temperature. After 12 h, a
saturated aqueous solution of NH4Cl (15 mL) was added and the
resulting solution was extracted with dichloromethane (4 × 20 mL).
The combined organic phase was dried over Na2SO4 and the solvent
J. Org. Chem. Vol. 73, No. 19, 2008 7529

Kumar and Shaw
128.4 (ArC), 114.8 (qC), 86.9 (CH), 84.9 (CH), 83.0 (CH), 81.3 (CH),
65.1 (CH2), 28.3 (CH3), 27.6 (3 × CH3), 26.4 (CH3), 20.1 (qC), 19.9
(CH3); IR (neat, cm-1) 2931, 1628, 1430, 1216, 1110; mass (ESI-
MS) m/z 426, found 444 [M + NH4]+; EI-HRMS: calcd for
C24H31O4Si [M - CH3]+ 411.1992, measured 411.1991.
the reaction mixture was allowed to stir at room temperature for 1 h.
A saturated solution of NH4Cl was added to it and resulting solution
was extracted with ethyl acetate (3 × 15 mL). The combined organic
layer was dried (Na2SO4) and concentrated in vacuo to a residue which
was purified by column chromatography to give pure compound 11
as a white solid material (470 mg, 95%), mp 84-86 °C. Eluent for
column chromatography: EtOAc/hexane (2/3, v/v); [R]28D) -5.0 (c
0.32 CHCl3); Rf 0.32 (1:1 EtOAc/hexane); 1H NMR (300 MHz, CDCl3
+ CCl4) δ 7.22 (dd, J ) 3.3, 8.6 Hz, 4H, ArH), 6.83 (d, J ) 8.6 Hz,
4H, ArH), 4.55-4.41 (m, 4H, 2 × OCH2Ar), 4.04 (t, J ) 6.2 Hz, 1H,
H-5), 3.99 (dd, J ) 3.5, 7.0 Hz, 1H, H-2), 3.83 (t, J ) 5.3 Hz, 1H,
H-3), 3.78 (s, 6H, 2 × OCH3), 3.68 (dd, J ) 3.3, 11.9 Hz, 1H, H-2′a),
3.47 (dd, J ) 3.4, 11.9 Hz, 1H, H-2′b), 3.37 (t, J ) 5.8 Hz, 1H, H-4),
1.89 (brs, 1H, OH), 1.19 (d, J ) 6.3 Hz, 3H, H-6); 13C NMR (75
MHz, CDCl3 + CCl4) δ 160.0 (ArqC), 159.9 (ArqC), 130.7 (2 ×
ArqC), 130.1 (ArC), 130.0 (ArC), 114.4 (ArC), 114.3 (ArC), 83.2
(CH), 83.0 (CH), 77.9 (CH), 77.3 (CH), 72.4 (CH2), 72.3 (CH2), 63.2
(CH2), 55.7 (2 × CH3), 19.8 (CH3); IR (KBr, cm-1) 3460, 3109, 1597,
1216, 1036; mass (ESI-MS) m/z 388, found 406 [M + NH4]+; DART-
HRMS: calcd for C22H32NO6 [M + NH4]+ 406.2230, measured
406.2215.
Compound 8a. To a stirred solution of 8 (238 mg, 0.56 mmol) in
THF (5 mL) was added TBAF (0.75 mL, 1.0 M solution in THF) at
0 °C and left for stirring at room temperature. After 2 h, aqueous
saturated solution of NH4Cl (20 mL) was added and the resulting
mixture was extracted with EtOAc (3 × 15 mL). The combined organic
layer was dried (Na2SO4) and concentrated under reduced pressure.
The residue obtained on column purification afforded 8a (82 mg, 78%)
as a colorless oil. Eluent for column chromatography: EtOAc/hexane
(3/7, v/v); [R]28D ) +10.0 (c 0.1 CHCl3); Rf 0.42 (1:1, EtOAc/hexane);
1H NMR (300 MHz, CDCl3 + CCl4) δ 4.62 (dd, J ) 4.5, 6.9 Hz, 1H,
H-3), 4.23 (dd, J ) 5.2, 6.9 Hz, 1H, H-4), 4.03-3.96 (m, 2H, H-2,
H-5), 3.83 (dd, J ) 3.2, 11.9 Hz, 1H, H-2′a), 3.68 (dd, J ) 4.2, 11.8
Hz, 1H, H-2′b), 1.54 (s, 3H, -C(CH3)2), 1.34 (s, 3H, -C(CH3)2), 1.31
(d, J ) 6.4 Hz, 3H, H-6); 13C NMR (75 MHz, CDCl3 + CCl4) δ
115.3 (qC), 86.8 (CH), 84.8 (CH), 82.2 (CH), 81.2 (CH), 63.3 (CH2),
28.1 (CH3), 26.2 (CH3), 19.5 (CH3); IR (neat, cm-1) 3447, 3018, 2929,
1215, 1078; mass (ESI-MS) m/z 188, found 144 [M - C3H8]+; DART-
HRMS: calcd for C9H17O4 [M + H]+ 189.1127, measured 189.1134.
Compound 9. Compound 8 (1.45 g, 3.40 mmol) was taken in 80%
acetic acid (20 mL) and stirred for 2 h at 80 °C. After completion of
reaction (TLC), the acidic solution was concentrated under reduced
pressure to give a crude product which was purified by column
chromatography to yield compound 9 (1.24 g, 94%) as a colorless
oil. Eluent for column chromatography: EtOAc/hexane (1/3, v/v);
[R]28D ) +10.4 (c 0.48, CHCl3); Rf 0.5 (2:3 EtOAc/hexane); 1H NMR
(300 MHz, CDCl3 + CCl4) δ 7.61-7.56 (m, 4H, ArH), 7.32-7.25
(m, 6H, ArH), 4.07 (t, J ) 5.3 Hz, 1H, H-3), 3.76-3.72 (m, 2H, H-2,
H-5), 3.66 (t, J ) 3.1, 3.9 Hz, 2H, H-2′), 3.61 (t, J ) 6.0 Hz, 1H,
H-4), 2.81 (brs, 2H, 2 × OH), 1.21 (d, J ) 6.2 Hz, 3H, H-6), 0.98 (s,
9H, SiC(CH3)3); 13C NMR (75 MHz, CDCl3 + CCl4) δ 136.1 (ArC),
136.0 (ArC), 133.6 (ArqC), 133.5 (ArqC), 130.2 (ArC), 130.1 (ArC)
128.2 (ArC), 128.1 (ArC), 84.5 (CH), 79.3 (CH), 77.2 (CH), 72.8 (CH),
Compound 12. To a solution of 11 (110 mg, 0.28 mmol) in
acetonitrile (6 mL) was added IBX (238 mg, 0.85 mmol) and the
reaction mixture was allowed to stir under reflux for 1 h. The resulting
mixture was diluted with anhydrous ether, cooled to 0 °C and filtered
through a Celite bed. The filtrate obtained was concentrated under
reduced pressure to give crude labile aldehyde 11a (106 mg) which
was immediately used for next step without further purification.
To a suspension of methyltriphenylphosphonium bromide (740 mg,
2.07 mmol) in dry THF (6 mL) was added KHMDS (3.1 mL, 0.5 M
in toluene) at -78 °C under argon atmosphere and the resulting mixture
was stirred at -78 °C for 20 min. To this mixture at -78 °C was then
added the solution of crude aldehyde 11a (106 mg) in dry THF (2
mL) and the reaction mixture was allowed to stir at room temperature.
After 1 h the reaction mixture was filtered through a Celite bed. The
filtrate obtained was concentrated and dissolved in anhydrous ether to
precipitate Ph3PO. The organic layer was separated and concentrated
to obtain a residue which on column chromatography yielded 12 (84
mg, 77% from 11) as a colorless oil. Eluent for column chromatog-
raphy: EtOAc/hexane (7/43, v/v); [R]28D ) -20.8 (c 0.24 CHCl3); Rf
64.7 (CH2), 27.4 (3 × CH3), 19.7 (qC), 19.2 (CH3); IR (neat, cm-1
)
3430, 3020, 1517, 1216, 1105; mass (ESI-MS) m/z 386, found 404
[M + NH4]+; DART-HRMS: calcd for C22H34NO4Si [M + NH4]+
404.2257, measured 404.2259.
1
0.5 (1:4 EtOAc/hexane); H NMR (300 MHz, CDCl3 + CCl4) δ
Compound 10. To a solution of compound 9 (372 mg, 0.96 mmol)
in DMF (5 mL) was added NaH (96 mg, 60% suspension in mineral
oil) at 0 °C followed by addition of p-methoxybenzyl chloride (0.39
mL, 2.88 mmol) and TBAI (107 mg, 0.29 mmol) in succession. After
2 h, methanol was added to quench the excess reagent. The residue
obtained after evaporation of the solvent was dissolved in ether and
washed with water. The organic layer was separated and dried
(Na2SO4) and concentrated under reduced pressure. The resulting crude
product was purified by column chromatography to give compound
10 (325 mg, 54%) as a colorless oil. Eluent for column chromatog-
raphy: EtOAc/hexane (3/22, v/v); [R]28D ) -21.7 (c 0.85 CHCl3); Rf
7.25-7.19 (m, 4H, ArH), 6.83 (d, J ) 8.4 Hz, 4H, ArH), 5.76 (ddd,
J ) 6.3, 10.4, 16.9 Hz, 1H, H-2′), 5.32 (d, J ) 17.1 Hz, 1H, H-2″a),
5.14 (d, J ) 10.4 Hz, 1H, H-2”b), 4.55-4.34 (m, 5H, 2 × OCH2Ar,
H-2), 4.05 (quintet, J ) 6.2 Hz, 1H, H-5), 3.79 (s, 6H, 2 × OCH3),
3.61 (t, J ) 5.2 Hz, 1H, H-3), 3.40 (t, J ) 5.8 Hz, 1H, H-4), 1.22 (d,
J ) 6.3 Hz, 3H, H-6);13C NMR (75 MHz, CDCl3 + CCl4); δ 159.9
(2 × ArqC), 137.9 (dCH), 130.7 (ArqC), 130.6 (ArqC), 130.1 (ArC),
130.0 (ArC), 117.2 (dCH2), 114.4 (ArC), 83.3 (CH), 82.6 (CH), 81.2
(CH), 77.8 (CH), 72.4 (CH2), 72.2 (CH2), 55.7 (2 × CH3), 20.1 (CH3);
IR (Neat, cm-1): 3018, 2927, 1613, 1513, 1216, 1125, 1036; mass
(ESI-MS) m/z 384, found 402 [M + NH4]+; DART-HRMS: calcd for
C23H32NO5 [M + NH4]+ 402.2281, measured 402.2280.
1
0.46 (1:4 EtOAc/hexane); H NMR (300 MHz, CDCl3 + CCl4) δ
7.69-7.63 (m, 4H, ArH), 7.44-7.35 (m, 6H, ArH), 7.28-7.22 (m,
4H, ArH), 6.85-6.81 (m, 4H, ArH), 4.62-4.41 (m, 4H, 2 × OCH2Ar),
4.09-3.99 (m, 3H, H-2, H-3, H-5), 3.81 (s, 6H, 2 × OMe), 3.65 (d,
J ) 3.6 Hz, 2H, H-2′), 3.45 (dd, J ) 5.3, 7.2 Hz, 1H, H-4), 1.26 (d,
J ) 6.2 Hz, 3H, H-6), 1.05 (s, 9H, SiC(CH3)3); 13C NMR (75 MHz,
CDCl3 + CCl4) δ 159.7 (ArqC), 159.6 (ArqC), 136.1 (ArC), 136.0
(ArC), 133.8 (ArqC), 133.6 (ArqC), 130.7 (ArqC), 130.6 (ArqC), 130.1
(ArC), 130.0 (ArC), 129.8 (ArC), 129.7 (ArC), 128.1 (ArC), 128.0
(ArC), 114.2 (ArC), 114.1 (ArC), 83.5 (CH), 83.2 (CH), 77.3 (CH),
76.7 (CH), 72.1 (CH2), 71.8 (CH2), 64.7 (CH2), 55.4 (2 × CH3), 27.3
(3 × CH3), 19.7 (qC), 19.4 (CH3); IR (neat, cm-1) 3013, 2931, 1614,
1513, 1246, 1218, 1109, 1036; mass (ESI-MS) m/z 626, found 644
[M + NH4]+, 505 [M - PMB]+; DART-HRMS: calcd for
C38H50NO6Si [M + NH4]+ 644.3407, measured 644.3388.
Compound 16. A steel seal tube was charged with Pd(PPh3)4 (171
mg, 0.15 mmol), LiCl (488 mg, 11.51 mmol), tributylvinyltin (0.5 mL),
triflate 15 (500 mg, 1.53 mmol) and THF (50 mL). The reaction
mixture in the seal tube was flushed with nitrogen before the tube
was sealed. The seal tube containing the reaction mixture was heated
at 80 °C for 30 h. After being cooled to room temperature the reaction
mixture was diluted with ether (50 mL) and washed with water twice.
The organic phase was separated, dried (Na2SO4) and concentrated
under reduced pressure to give colorless oil which on column
purification afforded 16 as colorless oil (295 mg, 94%) as a colorless
oil. Eluent for column chromatography: EtOAc/hexane (3/97, v/v);
1H NMR (300 MHz, CDCl3 + CCl4) δ 7.73 (dd, J ) 10.9, 17.4 Hz,
1H, H-5′), 7.45 (t, J ) 8.0 Hz, 1H, H-7), 7.25 (d, J ) 8.0 Hz, 1H,
H-8), 6.86 (d, J ) 8.2 Hz, 1H, H-6), 5.68 (dd, J ) 1.1, 17.4 Hz, 1H,
H-5′′a), 5.41 (dd, J ) 1.2, 10.9 Hz, 1H, H-5”b), 1.72 (s, 6H, 2 ×
CH3); 13C NMR (50 MHz, CDCl3 + CCl4) δ 160.2 (C ) O), 157.2
Compound 11. TBAF (2.4 mL, 1.0 M sol in THF) was added to
a solution of compound 10 (800 mg, 1.28 mmol) in THF at 0 °C and
7530 J. Org. Chem. Vol. 73, No. 19, 2008

First Total Synthesis of (+)-Varitriol
(ArqC), 142.9 (ArqC), 135.9 (dCH), 135.5 (ArC), 121.8 (ArC), 118.2
(CH2), 116.9 (ArC), 111.4 (qC), 105.5 (qC), 26.2 (2 × CH3); IR (neat,
cm-1) 2923, 2361, 1726, 1635, 1575, 1267,1209, 1044; mass (ESI-
MS) m/z 204, found 205 [M + H]+; EI-HRMS: calcd for C12H12O3
[M]+ 204.0787, measured 204.0775.
Compound 20. To a 50 mL two necked oven-dried round-bottom
flask fitted with a reflux condenser and septum was added Grubbs IInd
generation catalyst (15 mg, 0.018 mmol) under argon atmosphere. Dry
degassed CH2Cl2 (10 mL) was then added to the above solution through
a syringe and the solution was kept for stirring. Compounds 12 (60
mg, 0.16 mmol) and 19 (62 mg, 0.22 mmol) in DCM (2 mL each)
were added simultaneously through a syringe to the stirring solution.
The septum was replaced with a glass stopper while the stirring was
continued. The solution was refluxed for 12 h. The temperature of the
mixture was cooled slowly to room temperature. The organic solvent
was evaporated under reduced pressure to give a black residue which
was purified by column chromatography to give 20 as colorless oil
(51 mg, 51%). Eluent for column chromatography: EtOAc/hexane (7/
43, v/v); [R]28D ) -13.3 (c 0.85 CHCl3); Rf 0.51 (1:4, EtOAc/ Hexane);
1H NMR (300 MHz, CDCl3 + CCl4); δ 7.28-7.04 (m, 7H, 6 × ArH,
H-1′), 6.87-6.76 (m, 5H, ArH), 6.07 (dd, J ) 6.6, 15.8 Hz, 1H, H-2′),
4.79 (s, 2H, H-1”), 4.62-4.53 (m, 4H, 3 × CHAr, H-3′), 4.45 (d, J )
11.5 Hz, 1H, CHAr), 4.12 (t, J ) 6.2 Hz, 1H, H-6′), 3.85-3.81 (m,
9H, 3 × OCH3), 3.74 (t, J ) 5.3 Hz, 1H, H-4′), 3.49 (t, J ) 5.9 Hz,
1H, H-5′), 1.29 (d, J ) 6.2 Hz, 3H, H-7′), 0.89 (s, 9H, SiC(CH3)3),
0.06 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3 + CCl4); δ 159.9
(2 × ArqC), 158.1 (ArqC), 139.4 (ArqC), 131.6 (ArC), 130.8 (ArqC),
130.6 (ArqC), 130.2 (ArqC), 130.1 (ArC), 130.0 (ArC), 129.1 (ArC),
127.2 (ArqC), 119.6 (dCH), 114.4 (ArC), 110.3 (dCH), 83.5 (CH),
82.9 (CH), 81.5 (CH), 77.8 (CH), 72.4 (CH2), 72.2 (CH2), 56.6 (CH2),
56.1 (CH3), 55.7 (CH3), 55.6 (CH3), 26.7 (3 × CH3), 20.1 (CH3), 19.1
(qC), -4.5 (2 × CH3); IR (neat, cm-1) 3010, 2929, 1611, 1582, 1464,
1250, 1219, 1040; mass (ESI-MS) m/z 634, found 652 [M + NH4]+;
DART-HRMS: calcd for C37H50O7Si [M]+ 634.3326, measured
634.3287.
Compound (+)-1. A solution of compound 20 (50 mg, 0.079
mmol) in THF (5 mL) was stirred with 1 M HCl (10 mL) for 3 days
at room temperature. To this reaction mixture was added a saturated
solution of NaHCO3 and the resulting mixture was extracted with
CH2Cl2 (6 × 5 mL). The combined organic layer was separated, dried
over Na2SO4 and concentrated under reduced pressure to give oil which
was purified by column chromatography to give (+)-varitriol (1) (10
mg, 46%) as a colorless oil. Eluent for column chromatography:
acetone/DCM (3/7, v/v); [R]28D ) +19.4 (c 0.16 MeOH); Rf 0.3 (2:3,
acetone/DCM); 1H NMR (400 MHz, acetone-d6); δ 7.21 (t, J ) 8.0
Hz, 1H, H-4), 7.12 (d, J ) 13.6 Hz, 1H, H-1′), 7.11 (d, J ) 8.1 Hz,
1H, H-5), 6.88 (d, J ) 8.1 Hz, 1H, H-3), 6.19 (dd, J )6.6, 15.8 Hz,
1H, H-2′), 4.71 (s, 2H, OCH2-C-1), 4.30-4.27 (m, 2H, H-3′, OH),
3.90 (t, J ) 5.6 Hz, 1H, H-4′), 3.84-3.83 (m, 1H, H-6′), 3.81 (s, 3H,
OCH3), 3.68 (t, J ) 5.7 Hz, 1H, H-5′), 2.95 (brs, 2H, OH), 1.26 (d, J
) 6.3 Hz, 3H, H-7′); 13C NMR (100 MHz, acetone-d6) δ 158.9 (ArqC),
139.0 (ArqC), 132.5 (dCH), 129.4 (dCH), 129.3 (ArC), 127.9 (ArqC),
119.3 (ArC), 110.6 (ArC), 85.3 (CH), 80.0 (CH), 77.1 (CH), 76.5 (CH),
56.0 (OCH3), 55.5 (CH2), 19.5 (CH3); IR (neat, cm-1) 3380, 2925,
1592, 1218, 1088; EI-HRMS: calcd for C15H20O5 [M]+ 280.1311,
measured 280.1300.
Compound 17. LiAlH4 (83 mg, 2.2 mmol) was added to a solution
of compound 16 (300 mg, 1.47 mmol) in THF (20 mL) at -78 °C.
The mixture was warmed to room temperature. After 2 h the reaction
mixture was diluted with ethyl acetate (30 mL) and washed with water.
The organic layer was separated, dried (Na2SO4) and concentrated
under reduced pressure to a residue that was purified by column
chromatography to give compound 17 (159 mg, 72%) as a colorless
oil. Eluent for column chromatography: EtOAc/hexane (1/4, v/v); Rf
1
0.48 (2:3 EtOAc/ Hexane); H NMR (300 MHz, CDCl3 + CCl4) δ
7.70 (brs, 0.7H, C1-OH), 7.11 (t, J ) 7.9 Hz, 1H, H-5), 6.93 (d, J )
7.6 Hz, 1H, H-6), 6.84 (dd, J ) 10.9, 17.2 Hz, 1H, H-3′), 6.75 (d, J
) 8.0 Hz, 1H, H-4), 5.52 (dd, J ) 1.3, 17.2 Hz, 1H, H-3”a), 5.29 (dd,
J ) 1.2, 10.8 Hz, 1H, H-3”b), 4.91 (s, 2H, H-2′), 2.02 (brs, 0.8 H,
C2′-OH); 13C NMR (50 MHz, CDCl3 + CCl4) δ 157.2 (ArqC), 138.4
(ArqC), 134.9 (dCH), 129.9 (ArC), 122.8 (ArqC), 119.5 (ArC), 118.4
(dCH2), 116.9 (ArC), 60.7 (CH2); IR (neat, cm-1) 3401, 3019, 2924,
1579, 1461, 1268, 1217; mass (ESI-MS) m/z 150, found 174 [M + H
+ Na]+, 133 [M - OH]+; EI-HRMS: calcd for C9H9O2 [M - H]+
149.0603, measured 149.0615.
Compound 18. vTo a stirred solution of 17 (100 mg, 0.67 mmol)
in dry acetone (5 mL) was added anhydrous K2CO3 (185 mg, 1.34
mmol), methyl iodide (0.08 mL, 1.34 mmol) and the resulting
mixture was allowed to reflux. After 6 h the reaction mixture was
brought to room temperature and concentrated under reduced
pressure to a residue that was dissolved in ethyl acetate (30 mL)
and washed with water. The organic layer was collected, dried and
concentrated under reduced pressure to an oil which was purified
by column chromatography to give 18 (96 mg, 88%) as a colorless
oil. Eluent for column chromatography: EtOAc/hexane (3/22, v/v);
Rf 0.49 (3:7 EtOAc/hexane); 1H NMR (300 MHz, CDCl3 + CCl4)
δ 7.24-7.18 (m, 1H, H-4), 7.07 (dd, J ) 10.1, 17.4 Hz, 2H, H-5,
H-6′), 6.79 (d, J ) 8.1 Hz, 1H, H-3), 5.63 (dd, J ) 1.3, 17.4 Hz,
1H, H-6”a), 5.35 (dd, J ) 1.2, 10.9 Hz, 1H, H-6”b), 4.75 (s, 2H,
H-1′), 3.87 (s, 3H, OCH3), 2.04 (brs, 0.8H, OH); 13C NMR (50
MHz, CDCl3 + CCl4) δ 157.9 (ArqC), 138.7 (ArqC), 134.4 (dCH),
128.8 (ArC), 126.0 (ArqC), 119.0 (ArC), 117.4 (dCH2), 109.6
(ArC), 56.7 (CH2), 55.5 (CH3); IR (neat, cm-1) 3430, 3019, 2928,
1576, 1261, 1215, 1075; mass (ESI-MS) m/z 164, found 147 [M
- OH]+; EI-HRMS: calcd for C10H11O2 [M - H]+ 163.0759,
measured 163.0764.
Compound 19. To a solution of 18 (35 mg, 0.21 mmol) in DCM
(10 mL) was added imidazole (44 mg, 0.64 mmol), TBSCl (36 mg,
0.23 mmol) and then the mixture was allowed to stir at room
temperature for 1 h. A saturated solution of NH4Cl (15 mL) was added
and the mixture was extracted with DCM (3 × 10 mL). The organic
layer was separated, dried (Na2SO4) and evaporated under vacuo to
give a residue that was purified by column chromatography to give
55 mg of compound 19 (93%) as a colorless oil. Eluent for column
chromatography: EtOAc/hexane (1/49, v/v); Rf 0.58 (1:9, EtOAc/
Hexane); 1H NMR (300 MHz, CDCl3 + CCl4) δ 7.37-7.25 (m, 3H,
H-3, H-4, H-6′), 6.92 (d, J ) 8.0 Hz, 1H, H-5), 5.82 (dd, J ) 1.5,
17.5 Hz, 1H, H-6”a), 5.46 (dd, J ) 1.4, 11.0 Hz, 1H, H-6”b), 4.96 (s,
2H, H-1′), 3.98 (s, 3H, OCH3), 1.04 (s, 9H, SiC(CH3)3), 0.20 (s, 6H,
Si(CH3)2); 13C NMR (50 MHz, CDCl3 + CCl4) δ 157.3 (ArqC), 139.8
(ArqC), 135.2 (dCH), 128.5 (ArC), 126.4 (ArqC), 118.5 (ArC), 115.9
(dCH2), 109.8 (ArC), 55.9 (CH2), 55.5 (CH3), 26.1 (3 × CH3), 18.5
(qC), -5.1 (2 × CH3); IR (neat, cm-1) 3010, 2932, 1577, 1468, 1256,
1217, 1068; mass (ESI-MS) m/z 278, found 279 [M + H]+; EI-HRMS:
calcd for C15H23O2Si [M - CH3]+ 263.1467; found 263.1468.
Acknowledgment. We are thankful to Sophisticated Analytical
Instrument Facility, CDRI for providing spectral data and Mr. A. K.
Pandey for technical assistance. V.K. thanks CSIR New Delhi for
financial support.
Supporting Information Available: General experimental
details, full characterization and copies of 1HNMR and 13CNMR
spectra of compounds 4-12, 16-20, and 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8013534
J. Org. Chem. Vol. 73, No. 19, 2008 7531