Synthesis of eupomatilone-6 and assignment of its absolute configuration

Article abstract of DOI:10.1021/jo0516234

The Zn-mediated Barbier reaction of the biarylaldehyde 8 with crotyl bromide followed by hydroboration and oxidation provided the γ-butyrolactones 4 and 5. The stereoselective installation of methyl group at C-3 by using LiHMDS and MeI completed the synth

Full text of DOI:10.1021/jo0516234

Earlier we reported the synthesis of a putative struc-
ture of eupomatilone-6 (1).2b The discrepancy in the
spectral data of natural and synthetic eupomatilone-6
warranted revision of its relative stereochemistry as
either 3R,4â,5â-configuration (2) or 3â,4R,5â-configura-
tion (3). While the present work was in progress, Cole-
man and Gurrala2d reported the synthesis of racemic
eupomatilone-6 and confirmed its relative stereochem-
istry as shown in structure 2. Herein we disclosed a new
synthetic strategy to prepare racemic eupomatilone-6 and
then extended the protocol to synthesize optically active
(+)-eupomatilone-6.
Synthesis of Eupomatilone-6 and
Assignment of Its Absolute Configuration
Mukund K. Gurjar,* Bhargava Karumudi, and
C. V. Ramana
National Chemical Laboratory, Dr. Homi Bhabha Road,
Pune - 411 008, India
mk.gurjar@ncl.res.in
Received August 3, 2005
A retrosynthetic strategy for 2 and 3 is depicted in
Figure 1. The stereoselective methylation at C-3 of the
4,5-disubstituted γ-butyrolactones 4 and 5 was envisaged
to furnish 3,4,5-trans-cis and trans-trans-diastereomeric
products (2 and 3).3,4 The proposal to obtain both cis- and
trans-4,5-disubstituted-γ-butyrolactones (4 and 5), re-
spectively, from the syn- and anti-homoallylic alcohols 6
and 7 was envisioned as a straightforward proposition.5
The proposed investigation on crotylation of the biaryl
aldehyde 82b under Barbier6-type reaction conditions
would give rise to both the requisite syn- and anti-
products 6 and 7 (Scheme 1).
Treatment of 8 with crotyl bromide in the presence of
zinc and ammonium chloride gave an inseparable 1:1
mixture of syn- and anti-homoallylic alcohols 6 and 7.
However, subsequent hydroboration-oxidation of 6/7 by
using BH3‚SMe2 and H2O2 followed by treatment with
2,2-dimethoxypropane and PPTS gave the acetonide
derivatives 11 and 12, which were separated by silica
gel chromatography. The 1H NMR spectral analyses,
particularly the characteristic chemical shifts and cou-
pling constants of benzylic proton at C-5, were useful in
assigning the relative stereochemistries as depicted in
structures 11 and 12. For example, 11 revealed signals
of benzylic proton of the equilibrating atropisomers as
singlets at 4.77 and 4.87 ppm, whereas it appeared as
The Zn-mediated Barbier reaction of the biarylaldehyde 8
with crotyl bromide followed by hydroboration and oxidation
provided the γ-butyrolactones 4 and 5. The stereoselective
installation of methyl group at C-3 by using LiHMDS and
MeI completed the synthesis of racemic eupomatilone-6 (2)
and its diastereomer 3. The spectroscopic data of 2 was in
full agreement with reported spectra of natural product, thus
confirming the revised relative configuration of eupomatil-
one-6. Similarly, an optically active (3R,4R,5S)-isomer of
eupomatilone-6 (23) was prepared in which the aldol reaction
with thiazolidinethione as a chiral auxiliary was employed
as a key step. On the basis of the spectroscopic data and
optical rotation values of 23, the absolute configuration of
eupomatilone-6 was proposed.
(3) (a) Posner, G. H.; Loomis, G. L. J. Chem. Soc., Chem. Commun.
1972, 892. (b) Larson, E. R.; Raphael, R. A. J. Chem. Soc., Perkin
Trans. 1 1982, 521. (c) Kamlage, S.; Sefkow, M.; Pool-Zobel, B. L.; Peter,
M. G. Chem. Commun. 2001, 331.
(4) For synthesis of 3,4,5-trisubstituted γ-butyrolactones, see: (a)
Alker, D.; Jones, D. N.; Taylor, G. M.; Wood, W. W. Tetrahedron Lett.
1991, 32, 1667. (b) Satoh, M.; Washida, S.; Takeuchi, S.; Asaoka, M.
Heterocycles 2000, 52, 227. (c) Bercot, E. A.; Kindrachuk, D. E.; Rovis,
T. Org. Lett. 2005, 7, 107.
In 1991, Taylor et al. isolated a series of novel lignans
named as eupomatilones-1-7 from the shrubs Eupomatia
bennettii F. Muell. Their relative configurations were
elucidated by extensive NMR studies.1 Eupomatilones are
characterized by the biaryl system with a substituted
γ-lactone ring attached to one of the aryl rings. Some of
the eupomatilone molecules, including eupomatilone-6,
exist as a mixture of fluctional atropisomers. Eupoma-
tilones are the subject of intense synthetic activities.2
(5) For synthesis of 4,5-disubstituted γ-butyrolactones, see: (a)
Bystro¨m, S.; Ho¨gberg, H.-E.; Norin, T. Tetrahedron 1981, 37, 2249.
(b) Marino, J. P.; Fernandez de la Pradilla, R. Tetrahedron Lett. 1985,
26, 5381. (c) Nubbemeyer, U.; Ohrlein, R.; Gonda, J.; Ernst, B.; Bellus,
D. Angew. Chem., Int. Ed. Engl. 1991, 30, 1465. (d) Brown, H. C.;
Kulkarni, S. V.; Racherla, U. S. J. Org. Chem. 1994, 59, 365. (e) Doyle,
M. P.; Zhou, Q.-L.; Dyatkin, A. B.; Ruppar, D. A. Tetrahedron Lett.
1995, 36, 7579. (f) Fukuzawa, S.; Seki, K.; Tatsuzawa, M.; Mutoh, K.
J. Am. Chem. Soc. 1997, 119, 1482. (g) Benedetti, F.; Forzato, C.; Nitti,
P.; Pitacco, G.; Valentin, E.; Vicario, M. Tetrahedron: Asymmetry 2001,
12, 505. (h) Wu, Y.; Shen, X.; Tang, C.-J.; Chen, Z.-L.; Hu, Q.; Shi, W.
J. Org. Chem. 2002, 67, 3802. (i) Ozeki, M.; Hashimoto, D.; Nishide,
K.; Kajimoto, T.; Node, M. Tetrahedron: Asymmetry 2005, 16, 1663.
(6) (a) Pe´trier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910. (b)
Pe´trier, C.; Einhorn, C.; Luche, J.-L. Tetrahedron Lett. 1985, 26, 1449.
(c) For reviews, see: Li, C.-J.; Chan, T.-H. Organic Reactions in
Aqueous Media; Wiley & Sons: New York, 1997; Ch. 4. (d) Erdik, E.
Organozinc Reagents in Organic Synthesis; CRC Press: Boca Raton,
FL, 1996; Ch. 4.
* Corresponding author. Phone: +91-20-25882456. Fax: +91-20-
25893614.
(1) (a) Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991, 44, 1615.
(b) Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991, 44, 1705.
(2) For synthesis of eupomatilone-6 and its diastereomers, see: (a)
Hong, S.-P.; McIntosh, M. C. Org. Lett. 2002, 4, 19. (b) Gurjar, M. K.;
Cherian, J.; Ramana, C. V. Org. Lett. 2004, 6, 317. (c) Hutchison, J.
M.; Hong, S.-P.; McIntosh, M. C. J. Org. Chem. 2004, 69, 4185. (d)
Coleman, R. S.; Gurrala, S. R. Org. Lett. 2004, 6, 4025.
10.1021/jo0516234 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/12/2005
9658
J. Org. Chem. 2005, 70, 9658-9661

FIGURE 1. Representative natural eupomatilones and the alternative structures suggested for the eupomatilone-6 and the
retrosynthetic strategy.
1
SCHEME 1. Synthesis of 1,4-Diols 9 and 10
3 (Scheme 3). The H NMR spectrum of 3 was substan-
tially different from that of the natural eupomaltinone-
6.
After successfully establishing the relative stereochem-
istry of racemic eupomatilone-6, we felt the need to
design, on the basis of our new findings, the asymmetric
synthetic protocol that would establish the absolute
configuration of eupomatilone-6. It is pertinent to men-
tion that eupomatilone-6 inherently exists in nature, as
a mixture of atropisomers whose separation is still being
precluded.
The titanium enolate of N-propionylthiazolidinethione
15 was reacted with the biarylaldehyde 8 to give 16,
whose free hydroxyl group was protected as TBS-ether
17.8 The reductive removal of the thiazolidinethione
auxiliary from 17 with NaBH4 in THF-EtOH gave 18.9
The Dess-Martin periodinane oxidation and consequent
Wittig reaction with PPh3dCH2 gave the olefin derivative
19, from which the TBS group was departed in the
presence of 1 M solution n-Bu4NF in THF to afford 20.
Compound 20 was subjected to successive hydroboration
and oxidation to give the lactone derivative 22. The chiral
HPLC analysis (Chiracel-OD column) of 22 and 4 estab-
lished the enantiomeric excess of 97%. The alkylation of
22 was executed by using essentially the same reaction
(LiHMDS-MeI) as reported above to give (3R,4R,5S)-
eupomatilone-6 (23), whose spectroscopic data was in full
agreement with reported spectra (Scheme 4). The optical
rotation observed {[R]25D 24.7 (c 0.5, CHCl3)} for synthetic
doublets at 4.33 and 4.36 ppm with J ) 9.4 Hz in the
case of compound 12.
The diol 9, obtained by hydrolysis of 11, was converted
into the lactone derivative 4 by oxidation with NCS and
TEMPO (Scheme 2).2d,7 After screening several reagents,
we observed that the diastereoselectivity of methylation
at C-3 was highest with LiHMDS-MeI. The dialkylated
product 13 was also isolated as a minor product. The
spectral data of 2 was in complete agreement with the
data published for the naturally occurring eupomatilone-
6.1,2d Similarly, compound 12 was transformed by adopt-
ing the same strategy into diastereomeric eupomatilone
(8) (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. (b)
Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894. (c) Vela´zquez, F.; Olivo, H. F. Curr. Org. Chem.
2002, 6, 303.
(9) (a) Wu, Y.; Shen, X.; Tang, C.-J.; Chen, Z.-L.; Hu, Q.; Shi, W. J.
Org. Chem. 2002, 67, 3802. (b) Reynolds, A. J.; Scott, A. J.; Turner, C.
I.; Sherburn, M. S. J. Am. Chem. Soc. 2003, 125, 12108.
(7) (a) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org.
Chem. 1996, 61, 7452. (b) Kamal, A.; Sandbhor, M.; Shaik, A. A.
Tetrahedron: Asymmetry 2003, 14, 1575.
J. Org. Chem, Vol. 70, No. 23, 2005 9659

SCHEME 2. Synthesis of (()-Eupomatilone-6 (2)
lished the relative stereochemistry of the natural eupoma-
tilone-6. Further studies on optically active (3R,4R,5S)-
isomer (23) proposed the absolute configuration of
naturally occurring eupomatilone-6 as (3S,4S,5R).
Experimental Section
Synthesis of syn-Lactone 4. A biphasic mixture of diol 9 (2
g, 5.1 mmol), TEMPO (80 mg, 0.51 mmol), n-Bu4NI (190 mg,
0.51 mmol) and N-chlorosuccinimide (2.05 g, 15.4 mmol), aque-
ous NaHCO3 (0.5M, 10 mL), and aqueous K2CO3 (0.05M, 10 mL)
and CH2Cl2 (20 mL) was vigorously stirred for 3 h at room
temperature. The organic layer was separated, and the aqueous
phase was extracted with CH2Cl2. The organic layer was washed
with brine, dried, and evaporated. The residue was purified by
silica gel column chromatography by eluting with light petroleum/
ethyl acetate (4:1) to give 4 (1.6 g, 81%). IR (CHCl3): 3020, 1776,
1599, 1483, 1324, 1215, 1080, 1042, 929, 757, 669 cm-1. 1H NMR
(500 MHz, CDCl3): δ 0.68 (d, J ) 7.3 Hz, 3H), 0.70 (d, J ) 7.3
Hz, 3H), 2.20-2.30 (m, 4H), 2.69 (dd, J ) 7.8, 6.3 Hz, 1H), 2.72
(dd, J ) 7.8, 6.3 Hz, 1H), 3.65 (s, 3H), 3.66 (s, 3H), 3.91 (s, 12H),
5.42 (d, J ) 5.6 Hz, 1H), 5.51 (d, J ) 5.6 Hz, 1H), 6.02-6.03 (m,
2H), 6.04-6.05 (m, 2H), 6.58 (dd, J ) 7.9, 1.6 Hz, 1H), 6.62 (d,
J ) 1.6 Hz, 1H), 6.70 (dd, J ) 7.9, 1.6 Hz, 1H), 6.73 (d, J ) 1.6
Hz, 1H), 6.81 (s, 1H), 6.82 (s, 1H), 6.85 (d, J ) 7.9 Hz, 1H), 6.88
(d, J ) 7.9 Hz, 1H). 13C NMR (75 MHz): 15.2 (q), 15.3 (q), 33.6
(d), 33.8 (d), 37.7 (t), 56.0 (q), 60.6 (q), 60.9 (q), 81.9 (d), 101.0
(t), 104.8 (d), 108.0 (d), 108.2 (d), 109.5 (d), 110.5 (d), 122.3 (d),
123.3 (d), 126.3 (s), 126.4 (s), 128.9 (s), 130.0 (s), 141.6 (s), 146.8
(s), 146.9 (s), 147.5 (s), 151.4 (s), 152.7 (s), 176.1 (s) ppm. Maldi
top Calcd for C21H22O7: 386.14, obsd: 387.16 (M+ + 1), 409.13
(M+ + Na). Anal. Calcd for C21H22O7: C, 65.28; H, 5.74%.
Found: C, 65.21; H, 5.53%.
SCHEME 3. Synthesis of 3
Synthesis of Eupomatilone-6 (2) and Its 3-Methylated
Derivative 13. To a solution of 4 (0.50 g, 1.3 mmol) in
anhydrous THF (5 mL) at -78 °C was added LiHMDS (1 M
solution in THF, 1.55 mL). After 1 h, MeI (0.09 mL, 1.45 mmol)
was added and stirring was continued for an additional 1 h at
-78 °C. The reaction mixture was quenched with saturated
ammonium chloride, extracted with ethyl acetate, dried over
sodium sulfate, and concentrated. The crude residue was purified
by silica gel chromatography by eluting with light petroleum/
ethyl acetate (9:1) to give 13 (0.05 g, 9%) and 2 (0.33 g, 63%).
Spectral data of eupomatilone-6 (2). IR (CHCl3): 3429, 2932,
1773, 1596, 1457, 1406, 1326, 1226, 1197, 1127, 1040, 937, 754,
product was in agreement with reported value {[R]25
D
-25.6 (c 0.5)}1b but with opposite sign. The minor
quantity of dialkylated product (24) was also isolated and
characterized.
In summary, we have devised a four-step synthesis of
eupomatilone-6 (2) and its diastereomer 3 that estab-
667 cm-1 1H NMR (500 MHz, CDCl3): δ 0.70 (d, J ) 7.1 Hz,
.
SCHEME 4. Synthesis of (+)-Eupomatilone-6 (23)
9660 J. Org. Chem., Vol. 70, No. 23, 2005

3H), 0.73 (d, J ) 7.1 Hz, 3H), 1.19 (d, J ) 7.4 Hz, 3H), 1.20 (d,
J ) 7.4 Hz, 3H), 1.93-2.04 (m, 2H), 2.37 (sextet, J ) 7.2 Hz,
2H), 3.63 (s, 3H), 3.64 (s, 3H), 3.89 (s, 6H), 3.90 (s, 6H), 5.53 (d,
J ) 6.9 Hz, 1H), 5.64 (d, J ) 6.9 Hz, 1H), 6.01-6.03 (m, 4H),
6.59 (dd, J ) 7.9, 1.6 Hz, 1H), 6.64 (d, J ) 1.5 Hz, 1H), 6.66 (2s,
2H), 6.70 (dd, J ) 7.9, 1.6 Hz, 1H), 6.72 (d, J ) 1.5 Hz, 1H),
6.86 (d, J ) 7.9 Hz, 1H), 6.88 (d, J ) 7.9 Hz, 1H). 13C NMR (125
MHz): 14.8 (q), 14.9 (q), 15.3 (q), 15.5 (q), 41.2 (d), 41.5 (d), 42.5
(d), 42.6 (d), 56.1 (q), 60.8 (q), 61.0 (q), 61.1 (q), 79.8 (d), 79.8
(d), 101.1 (t), 101.2 (t), 104.6 (d), 104.7 (d), 108.1 (d), 108.3 (d),
109.9 (d), 110.9 (d), 122.6 (d), 123.7 (d), 127.0 (s), 127.1 (s), 128.9
(s), 129.0 (s), 130.3 (s), 141.7 (s), 146.8 (s), 146.9 (s), 147.6 (s),
147.6 (s), 151.5 (s), 152.8 (s), 179.7 (s) ppm. Maldi top Calcd for
C22H24O7: 400.15, obsd: 400.57 (M+), 401.57 (M+ + 1), 423.57
(M+ + Na). Anal. Calcd for C22H24O7: C, 65.99; H, 6.04%.
Found: C, 65.85; H, 5.91%.
Methylation of anti-Lactone 5. Compound 5 (0.5 g, 1.29
mmol) was subjected to essentially the same reaction conditions
to produce 14 (0.068 g, 12%) and 3 (0.37 g, 71%). Spectral data
of compound 3. IR (CHCl3): 3429, 2932, 1772, 1596, 1457, 1406,
1326, 1226, 1197, 1127, 1040, 937, 754 cm-1. 1H NMR (200 MHz,
CDCl3): δ 0.87 (d, J ) 6.0 Hz, 3H), 0.89 (d, J ) 6.0 Hz, 3H),
1.23 (s, 3H), 1.26 (s, 3H), 1.92-2.24 (m, 4H), 3.62 (s, 3H), 3.63
(s, 3H), 3.91 (s, 12H), 4.78 (d, J ) 9.4 Hz, 1H), 4.80 (d, J ) 9.4
Hz, 1H), 6.01-6.03 (m, 4H), 6.61-6.73 (m, 6H), 6.83-6.87 (m,
2H). 13C NMR (50 MHz): 12.9 (q), 14.3 (q), 43.3 (d), 47.6 (d),
56.1 (q), 60.8 (q), 60.9 (q), 61.0 (q), 82.5 (d), 82.6 (d), 101.1 (2t),
105.1 (d), 105.1 (d), 107.8 (d), 108.1 (d), 110.5 (d), 111.4 (d), 123.3
(d), 124.3 (d), 128.8 (s), 128.9 (s), 129.9 (s), 130.6 (s), 130.8 (s),
142.6 (s), 146.8 (s), 146.9 (s), 147.3 (s), 147.5 (s), 151.2 (s), 151.2
(s), 153.3 (s), 178.4 (s), 178.5 (s) ppm. Maldi top Calcd for
C22H24O7: 400.15, obsd: 400.57 (M+), 401.57 (M+ + 1), 423.57
(M+ + Na). Anal. Calcd for C22H24O7: C, 65.99; H, 6.04%.
Found: C, 66.15; H, 6.07%.
on silica gel by using light petroleum/ethyl acetate (4:1) as an
eluent to give 18 (2.91 g, 82%). [R]25 -8.5 (c 1.05, CHCl3). IR
D
(CHCl3): 3389, 2930, 1598, 1481, 1402, 1384, 1322, 1232, 1125,
1040, 939, 872, 838, 757 cm-1 1H NMR (200 MHz, CDCl3): δ
.
-0.15 (s, 3H), -0.15 (s, 3H), 0.01 (s, 6H), 0.75 (d, J ) 6.9 Hz,
3H), 0.78 (d, J ) 6.9 Hz, 3H), 0.92 (s, 18H), 1.53-1.68 (br m,
2H), 3.33 (s, 2H), 3.36 (s, 2H), 3.62 (s, 3H), 3.63 (s, 3H), 3.89 (s,
6H), 3.90 (s, 6H), 4.80 (d, J ) 2.7 Hz, 1H), 4.89 (d, J ) 2.7 Hz,
1H), 6.01-6.04 (m, 4H), 6.60 (dd, J ) 7.8, 1.7 Hz, 1H), 6.63-
6.67 (m, 3H), 6.85 (d, J ) 7.8 Hz, 1H), 6.87 (d, J ) 8.1 Hz, 1H),
6.93 (s, 2H). 13C NMR (50 MHz): -5.2 (q), -4.5 (q), 9.6 (q), 18.0
(s), 25.8 (q), 42.4 (d), 42.6 (d), 55.6 (q), 60.7 (q), 60.8 (q), 60.9 (q),
65.8 (t), 70.7 (d), 100.9 (t), 106.3 (d), 107.8 (d), 107.9 (d), 109.9
(d), 111.4 (d), 122.5 (d), 124.0 (d), 126.0 (s), 129.6 (s), 129.7 (s),
137.7 (s), 137.8 (s), 140.6 (s), 146.4 (s), 146.5 (s), 147.3 (s), 147.4
(s), 150.9 (s), 152.0 (s) ppm. Maldi top Calcd for C26H38O7Si:
490.24, obsd: 513.57 (M+ + Na). Anal. Calcd for C26H38O7Si:
C, 63.64; H, 7.81%. Found: C, 63.81; H, 7.76%.
Synthesis of 19. A suspension of alcohol 18 (2.0 g, 4.1 mmol)
and Dess-Martin periodinane (2.08 g, 4.9 mmol) in CH2Cl2 (10
mL) was stirred at 0 °C for 1.5 h, filtered through Celite, and
concentrated to procure the aldehyde (1.8 g, 90%). To a suspen-
sion of methyltriphenylphosphonium iodide (7.4 g, 18.3 mmol)
in anhydrous THF (30 mL) at 0 °C was added n-BuLi (23 mL of
1.6 M in hexane). The mixture was stirred for 1 h at room
temperature and then transferred into the above prepared
aldehyde solution in THF (10 mL) maintained at 0 °C. The
reaction mixture was allowed to attain room temperature and
was further stirred for 12 h. The reaction was quenched with
saturated aqueous NH4Cl, extracted with ethyl acetate, dried
(Na2SO4), and concentrated. Purification of the residue on silica
gel by using light petroleum/ethyl acetate (19:1) furnished 19
(1.49 g, 75%). [R]25D -8.1 (c 1, CHCl3). IR (CHCl3): 3379, 2932,
2856, 1597, 1481, 1401, 1322, 1195, 1157, 1083, 1040, 938, 837,
1
Synthesis of 16 by Aldol Reaction between Biaryl
Aldehyde (8) and Thiazolidine Thione (15). To a solution
of N-propionylthiazolidinethione (15, 9.2 g, 34.7 mmol) in dry
CH2Cl2 (90 mL) at 0 °C were added TiCl4 (6.3 g, 33.4 mmol) and
TMEDA (8.9 g, 87 mmol) and stirred for 20 min. To this dark
red enolate solution was added biaryl aldehyde 8 (10.0 g, 31.6
mmol) in dry CH2Cl2 (30 mL) and stirring was continued for an
additional 2 h at 0 °C. The reaction was quenched with aqueous
NH4Cl (60 mL), and the layers were separated. The aqueous
layer was extracted with ethyl acetate. The combined organic
layer was dried over sodium sulfate, filtered, and concentrated.
Purification of the residue by column chromatography on silica
gel with light petroleum/ethyl acetate (4:1) as eluent gave 16
(12 g, 65%). [R]25D +133 (c 1.0, CHCl3). IR (CHCl3): 3400, 3019,
1672, 1597, 1456, 1341, 1215, 1041, 938, 759, 668 cm-1. 1H NMR
(200 MHz, CDCl3): δ 1.23 (d, J ) 7.0 Hz, 3H), 1.27 (d, J ) 7.0
Hz, 3H), 2.79 (d, J ) 11.4 Hz, 1H), 2.80 (d, J ) 11.4 Hz, 1H),
2.87-3.19 (m, 8H), 3.56 (s, 3H), 3.58 (s, 3H), 3.86 (s, 6H), 3.94
(s, 6H), 4.31-4.39 (m, 2H), 4.72-4.89 (m, 4H), 5.94 (d, J ) 1.3
Hz, 1H), 5.96 (d, J ) 1.3 Hz, 1H), 6.02 (d, J ) 1.5 Hz, 1H), 6.08
(d, J ) 1.5 Hz, 1H), 6.59-6.66 (m, 4H), 6.78 (d, J ) 7.7 Hz, 1H),
6.99 (d, J ) 7.8 Hz, 1H), 6.98 (s, 1H), 6.99 (s, 1H), 7.19-7.39
(m, 10H). 13C NMR (50 MHz): 11.3 (q), 11.5 (q), 32.4 (t), 32.5
(t), 36.2 (t), 44.4 (d), 55.8 (q), 60.5 (q), 60.7 (q), 60.8 (q), 68.7 (d),
68.8 (d), 71.5 (d), 71.7 (d), 100.7 (t), 101.0 (t), 105.2 (d), 105.3
(d), 107.4 (d), 108.2 (d), 110.0 (d), 111.6 (d), 122.4 (d), 124.1 (d),
127.0 (d), 127.2 (s), 128.7 (d), 128.8 (s), 129.1 (d), 134.7 (s), 134.8
(s), 136.1 (s), 141.3 (s), 141.3 (s), 146.4 (s), 146.5 (s), 147.0 (s),
147.3 (s), 151.0 (s), 151.1 (s), 152.5 (s), 152.5 (s), 178.2 (s), 178.3
(s), 200.2 (s), 200.5 (s) ppm. Anal. Calcd for C30H31NO7S2: C,
61.94; H, 5.37; N, 2.41; S, 11.02%. Found: C, 62.02; H, 5.54; N,
2.40; S, 11.29%.
775 cm-1. H NMR (200 MHz, CDCl3): δ -0.19 (s, 3H), -0.18
(s, 3H), -0.06 (s, 6H), 0.88-0.91 (m, 6H), 0.89 (s, 18H), 2.11-
2.25 (m, 2H), 3.63 (s, 6H), 3.89 (s, 6H), 3.90 (s, 6H), 4.52 (d, J )
3.6 Hz, 1H), 4.57 (d, J ) 3.6 Hz, 1H), 4.67 (ddd, J ) 17.2, 1.8,
1.3 Hz, 2H), 4.82 (br. ddd, J ) 10.2, 1.7, 0.9 Hz, 2H), 5.58 (ddd,
J ) 17.2, 10.2, 7.3 Hz, 1H), 5.60 (ddd, J ) 17.2, 10.2, 7.3 Hz,
1H), 6.01-6.04 (m, 4H), 6.60-6.69 (m, 4H), 6.84-6.95 (m, 4H).
13C NMR (50 MHz): -4.9 (q), -4.6 (q), 12.3 (q), 12.4 (q), 18.2
(s), 25.8 (q), 44.7 (d), 44.8 (d), 55.7 (q), 60.7 (q), 60.9 (q), 61.0 (q),
74.3 (d), 100.9 (t), 106.2 (d), 106.3 (d), 107.8 (d), 107.9 (d), 109.9
(d), 111.8 (d), 113.6 (t), 115.3 (d), 120.0 (s), 122.5 (d), 124.4 (d),
126.4 (s), 129.4 (d), 129.7 (s), 129.9 (s), 138.2 (s), 140.6 (s), 142.5
(d), 142.6 (d), 146.4 (s), 146.5 (s), 147.3 (s), 150.8 (s), 152.0 (s)
ppm. Anal. Calcd for C27H38O6 Si: C, 66.63; H, 7.87%. Found:
C, 66.87; H, 7.78%.
Synthesis of (+)-Eupomatilone-6 (23) and 3-Methyl
Derivative 24. To solution of 22 (0.10 g, 0.258 mmol) in
anhydrous THF (1 mL) at -78 °C, 1 M LiHMDS solution in THF
(0.3 mL) was added. After 1 h, MeI (0.02 mL, 0.32 mmol) was
added and stirring was continued for an additional 1 h. The
reaction mixture was quenched with saturated ammonium
chloride, extracted with ethyl acetate, dried over sodium sulfate,
and concentrated. The crude residue was purified by silica gel
chromatography by eluting with light petroleum/ethyl acetate
(9:1) to give 24 (0.015 g, 14%) and 23 (0.06 g, 58%).
23 [R]25 +24.7 (c 0.5, CHCl3) Lit.1b {[R]25 -25.6 (c 0.5)}.
D
D
24 [R]25 -40.8 (c 0.5, CHCl3).
D
Acknowledgment. K.B. thanks CSIR, New Delhi,
for the financial assistance in the form of a research
fellowship.
Synthesis of 18. Compound 17 (5 g, 7.2 mmol) and NaBH4
(540 mg, 14.3 mmol) in THF (25 mL) and EtOH (5 mL) were
stirred at room temperature for 5 h. Excess borohydride was
quenched at 0 °C with diluted HCl and concentrated. The residue
was partioned between water-ether, and the organic layer was
separated and washed with 1 M NaOH, H2O, and brine, dried
over sodium sulfate, and concentrated. The crude was purified
Supporting Information Available: Experimental pro-
cedures, analytical and/or spectral data for all new compounds
(5-7, 9-14, 17), NMR spectra of 2-5, 11-14, and HPLC
chromatograms for 2, 23, 4, 22. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO0516234
J. Org. Chem, Vol. 70, No. 23, 2005 9661