Total synthesis of the hydroxyketone kurasoin A using asymmetric phase-transfer alkylation

Article abstract of DOI:10.1021/jo061395t

The total synthesis of the farnesyltransferase inhibitor kurasoin A has been achieved using a novel asymmetric phase-transfer-catalyzed glycolate alkylation reaction. 2,5-Dimethoxyacetophenone 7 with cinchonidinium catalyst 9 (10 mol %) and hydroxide base

Full text of DOI:10.1021/jo061395t

Total Synthesis of the Hydroxyketone Kurasoin A
Using Asymmetric Phase-Transfer Alkylation
Merritt B. Andrus,* Erik J. Hicken, Jeffrey C. Stephens, and
D. Karl Bedke
FIGURE 1. Hydroxyketone farnesyltransferase inhibitors kurasoin A
and B.
Department of Chemistry and Biochemistry, Brigham Young
UniVersity, C100 BNSN, ProVo, Utah 84602-5700
thesis of kurasoin A together with important findings concerning
the transformation of nonracemic ester products of this type
into ketone products without isomerization and epimerization.
The modular approach is accommodated through precursor
3 with suitable protecting groups for the phenolic and hydroxyl
functionality (Scheme 1). The protecting groups P and P′ must
be easily removed without epimerization of the R-hydroxyl,
prevent tautomerization to the hydroxyketone isomer, and allow
for benzyl addition to a suitable acyl derivative 4. The
4-hydroxyphenyllactate intermediate 4 is assembled using a
phase-transfer alkylation with the protected benzyl halide 5 and
the glycolate enolate 6. This flexible route can be easily
modified, using alternative reagents for acyl addition and enolate
alkylation, to directly access analogues of kurasoin A and B.
Asymmetric, catalytic enolate alkylation with sp3-electrophiles
is a challenging transformation that has been met with only
limited success with specific substrates. Koga pioneered the use
of chiral polyamines for alkylation of cyclic silylenol ethers,6
and List has recently demonstrated that iodoaldehydes undergo
intramolecular proline-catalyzed alkylations.7 More recently,
Jacobsen has employed chromium-salen catalysts for the
alkylation of cyclic tin enolates.8
mbandrus@chem.byu.edu
ReceiVed July 5, 2006
The total synthesis of the farnesyltransferase inhibitor
kurasoin A has been achieved using a novel asymmetric
phase-transfer-catalyzed glycolate alkylation reaction. 2,5-
Dimethoxyacetophenone 7 with cinchonidinium catalyst 9
(10 mol %) and hydroxide base with pivaloyl benzyl bromide
8 provided S-alkylation product 10 in high yield (80-99%)
and excellent enantioselectivity. Baeyer-Villiger oxidation,
Weinreb amide formation, and benzyl Grignard addition to
the TES-ether 17 gave the protected target. Lithium hydrox-
ide and peroxide generated kurasoin A ([R]D +8.4°) without
isomerization.
We previously reported the development of asymmetric PTC
glycolate alkylation of aryl ketone 7 with various electrophiles
using the cinchonidine-derived catalyst 9 of Park and Jew, which
was originally reported for glycine alkylation.5 The benzhydryl
group (DPM, diphenylmethyl) and the 2,5-dimethoxyphenyl
ketone 7 were essential for both reactivity and the selectivity
of the novel glycolate alkylation (Scheme 2). Alkylations of
this type were previously limited to the benzophenone imine-
protected glycine substrate of O’Donnell, where extended
π-delocalization allows for enolate formation and catalyst
interaction.9 In this case for glycolate alkylation, it was found
that liquid-solid PTC conditions with cesium hydroxide hydrate
Kurasoin A 1 and B 2 were isolated by Omura during a search
for protein farnesyltransferase (PFTase) inhibitors from the soil
fungus, Paecilomyces sp. (Figure 1).1 These simple compounds
hold potential for new lead development in that the aromatic
substituents can be easily modified in a modular fashion around
a central R-hydroxy ketone core.2 A combination of NMR
spectroscopy and synthesis was used to establish the absolute
stereochemistry. A seven-step asymmetric route from 4-hy-
droxyphenyl-2-ethanol (5% overall yield) to kurasoin A 1 was
used to establish the stereochemistry with a Sharpless asym-
metric epoxidation that gave a key intermediate in low yield,
25%.3 A racemic route to 1, using benzyl Grignard addition to
a Weinreb amide, was also reported.4 We recently developed
an efficient asymmetric, phase-transfer catalytic (PTC) glycolate
alkylation process for the synthesis of R-hydroxy ester products,
including a route to the diabetes drug (-)-ragaglitazar.5 We now
report the application of this new process for an efficient syn-
(5) (a) Andrus, M. B.; Hicken, E. J.; Stephens, J. S. Org. Lett. 2004, 6,
2289. (b) Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. J.
Org. Chem. 2005, 70, 9470. For auxiliary-based approaches to glycolate
alkylation, see: (c) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org.
Lett. 2000, 2, 2165. (d) Schmidt, B.; Wildermann, H. J. Chem. Soc., Perkin
Trans. 1 2002, 1050. (e) Chappell, M. D.; Stachel, S. J.; Lee, C. B.;
Danishefsky, S. J. Org. Lett. 2000, 2, 1633. (f) Burke, S. D.; Quinn, K. J.;
Chen, V. J. J. Org. Chem. 1998, 63, 8626.
(6) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K. J. Am.
Chem. Soc. 1994, 116, 8829.
(1) Uchida, R.; Shiomi, K.; Inokoshi, J.; Masuma, R.; Kawakubo, T.;
Tanaka, H.; Iwai, Y.; Omura, S. J. Antibiot. 1996, 49, 932.
(2) (a) Kohl, N. E.; Wilson, F. R.; Mosser, S. D.; Giuliani, E.; DeSolms,
S. J. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 9141. (b) Kohl, N. E.; Omer,
C. A.; Conner, M. W.; Anthony, N. J.; Davide, J. P. Nat. Med. 1995, 1,
792.
(3) (a) Sunazuka, T.; Hirose, T.; Zhi-Ming, T.; Uchida, R.; Shiomi, K.;
Harigaya, Y.; Omura, S. J. Antibiot. 1997, 50, 453. (b) Hirose, T.; Sunazuka,
T.; Zhi-Ming, T.; Handa, M.; Uchida, R.; Shiomi, K.; Harigaya, Y.; Omura,
S. Heterocycles 2000, 53, 777.
(7) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450.
(8) Doyle, A.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 62.
(9) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc.
1989, 111, 2353. (b) O’Donnell, M. J.; Delgado, F.; Hostettler, C.;
Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775. (c) Corey, E. J.; Xu, F.;
Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. (d) Lygo, B.; Wainwright,
P. G. Tetrahedron Lett. 1997, 38, 8595. (e) Ooi, T.; Kameda, K.; Maruoka,
K. J. Am. Chem. Soc. 1999, 121, 6519. (f) Jew, S.; Yoo, M.; Jeong, B.;
Park, I. Y.; Park, H. Org. Lett. 2002, 4, 4245. (g) Park, H.; Jeong, B.; Yoo,
M.; Lee, J.; Park, M.; Lee, Y.; Kim, M.; Jew, S. Angew. Chem., Int. Ed.
2002, 41, 3036.
(4) Uchida, R.; Shiomi, K.; Sunazuka, T.; Inokoshi, J.; Nishizawa, A.;
Hirose, T.; Tanaka, H.; Iwai, Y.; Omura, S. J. Antibiot. 1996, 49, 886.
10.1021/jo061395t CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/28/2006
J. Org. Chem. 2006, 71, 8651-8654
8651

SCHEME 1. Retrosynthetic Analysis of 1 Includes Acyl
Addition and Glycolate Alkylation
SCHEME 3. Weinreb Amide Formation and Benzyl
Grignard Addition with Methyl 4-Hydroxyphenyllactate 12
SCHEME 2. PTC Alkylation with Cinchonidinium Catalyst
9 and Baeyer-Villiger Oxidation Leading to Ester 11
SCHEME 4. Attempted Weinreb Amide Formation Using
TBS and PMB Ethers 14
At this point, the S-ester 11 was prepared for benzyl addition
to a suitable acyl derivative, and a quick end of the synthesis
was anticipated. Treatment with sodium methoxide in methanol-
THF cleanly provided the methyl ester diol 12 without racem-
ization (Scheme 3). This key hydroxyphenyllactate is the
intermediate employed previously by Omura, reported to give
kurasoin A following Weinreb amide formation and benzyl
Grignard addition.4 While a 67% yield was reported with use
of 6 equiv of N,O-dimethylhydroxyamine hydrochloride and
trimethylaluminum, in our hands, 12 was found to give amide
13 in 30% yield. It was found that, by increasing the amounts
of the reagents to 7 equiv (64 h), 13 was finally obtained in
76% yield. Again following the previous report,4 the benzyl
Grignard addition step was also addressed. With 5 equiv of
benzyl Grignard (2 M, THF) at 0 °C, the final target kurasoin
A was obtained with a disappointing 15% yield, not 65% as
reported. Concentration and equivalents, solvents, and temper-
ature variations did not lead to noticeable improvements for
this step. Benzyllithium formed from toluene and n-butyllithium
with added TMEDA (tetramethylethylenediamine) and other
variations was also ineffective. If recovered starting material is
taken into account, this final reaction can be seen to proceed
using excess reagents at best with only a 30% yield, based on
recovered starting material (borsm).
To improve the efficiency of amide formation, silyl and
benzyl ether protected substrates were explored. Protection of
the phenol hydroxyl at this point would also lower the number
of equivalents of reagent needed for amide formation. Protection
of 12 as either the TBS (tert-butyldimethylsilyl) or PMB (p-
methoxybenzyl) ether under standard conditions gave bis-silyl
and bis-PMB ethers 14 in high yields (Scheme 4). Surprisingly,
there are only a few examples of R-hydroxy-protected esters
that are known to successfully undergo Weinreb amide forma-
tion.11 Much to our disappointment, 14 with P as TBS or PMB
both failed to generate the corresponding amide, further il-
lustrating a limitation to this important transformation.
as base in a 1:1 mixture of methylene chloride and hexanes
gave optimal results.5b Using 7, pivaloyl benzyl bromide 8 (5
equiv), and cinchonidinium 9 (10 mol %, 24 h), S-ketone 10
was obtained in 95% isolated yield as previously reported. Chiral
HPLC analysis indicated that the alkylation again occurred with
83% ee on gram scale. Use of other protected benzyl bromides,
Bn (benzyl), TIPS (triisopropylsilyl), or Bz (benzoyl) in place
of the pivaloyl group gave lower yield (60-70%) and selectivi-
ties (74-65% ee). In addition, the Piv-protected substrate 8 is
crystalline (58-60 °C, mp) and is easily made from 4-hydroxy-
benzyl alcohol. The excess material following PTC alkylation
can also be conveniently recovered during the isolation.
At this point, the labile DPM group was removed by treating
10 with titanium tetrachloride at -78 °C to give the free
hydroxyl product in 92% yield (Scheme 2). The pivaloate ester
remained in place under these conditions. The Baeyer-Villiger
conditions of Shibasaki-Noyori using bis-trimethylsilylperoxide
(2 equiv), tin tetrachloride, and racemic cyclohexane-bistolu-
enesulfonamide with added 4 Å molecular sieves10 generated
the desired aryl ester 11 in 83% isolated yield. Use of MCPBA
(m-chloroperbenzoic acid) and other peracids failed to produce
the desired ester. Recrystallization of the product 11 (94-96
°C, mp) from diethyl ether generated the ester in highly
enantioenriched form (96% ee). Total isolated yield in this case,
including both the Baeyer-Villiger oxidation and the recrys-
tallization steps, was 75%. These peroxide conditions do not
promote alkene epoxidation and expand the scope of the PTC
alkylation reaction to allyl electrophiles, where the alkene
functionality is maintained.5b
(11) (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.;
Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 10879. (b) Hulme, A. N.;
Montgomery, C. H. Tetrahedron Lett. 2003, 44, 7649. (c) Okitsu, O.; Suzuki,
R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809. (d) Dineen, T. A.; Roush,
W. R. Org. Lett. 2005, 7, 1355.
(10) (a) Sawanda, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000,
122, 10521. (b) Go¨ttlich, R.; Yamakoshi, K.; Sasai, H.; Shibasaki, M. Synlett
1997, 971.
8652 J. Org. Chem., Vol. 71, No. 22, 2006

TABLE 1. Deprotection Conditions to Kurasoin A 1
SCHEME 5. Thioester Formation and Attempted
Palladium-Catalyzed Benzylzinc Coupling
entry
conditions
combined yield, % ratio 1:19
1
2
3
4
3 M HCl, dioxane, 80 °C
3 N NaOH, then 1 M HCl
TBAF, THF then 1 N NaOH
TBAF, THF then LiOH/H2O2
decomp.
63
51
65
75:25
92:8
100:0
SCHEME 6. Amide Formation and Benzyl Grignard
Addition with TES (triethylsilyl) Ether 17
with removal of both the Piv ester and TES ether in 63% yield
(entry 2). In this case, 25% of the material was found to be the
racemic, isomerized hydroxy ketone 19, presumed to arise by
enolization and tautomerization of 1.15 To minimize the amount
of this unwanted isomerization product, TBAF (tetrabutylam-
monium fluoride) was used followed by treatment with NaOH
and acidification (entry 3). Under these conditions, kurasoin A
1 was obtained in 51% with only 8% formation of 19. Finally,
it was found that use of TBAF followed by addition of lithium
hydroxide and hydrogen peroxide generated kurasoin A 1 in
65% yield ([R]D +8.4°, mp 120-122 °C, nat. material [R]D
+7 °, mp 121-123°)1 identical in all respects to natural material.
In summary, a novel, seven-step phase-transfer catalysis-based
approach to the simple farnesyltransferase inhibitor kurasoin A
has been developed using efficient glycolate alkylation and
Grignard addition in 24% overall yield. The modular approach
also allows for the ready incorporation of diverse substituents
on both sides of the core hydroxy ketone functionality. New
insights into Weinreb amide formation and reactivity were also
obtained together with new deprotection conditions for this
sensitive substrate.
An alternative approach to benzyl ketone installation under
palladium catalysis following the conditions of Fukuyama was
also explored (Scheme 5).12 Thioesters have recently been shown
to undergo coupling reactions with alkyl zinc reagents, including
benzyl zinc bromide under palladium catalyst conditions. The
needed dodecylthio ester 15 was produced from 11, and various
protecting groups were then explored for the R-hydroxyl 16,
including acetate and TBS. Using standard conditions with 10
mol % of PdCl2(PPh3)2 in toluene with benzyl zinc bromide,
attempted couplings with 16 (P ) Ac and H) gave only complex
mixtures, and TBS-16 showed only unreacted starting material
under these mild coupling conditions.
Undaunted, we returned to the aryl ester 11 in an effort to
establish a direct, efficient route through acyl activation and
benzyl addition. Gratifyingly, direct addition to the aryl ester
using N,O-dimethylhydroxyamine hydrochloride and trimethyl-
aluminum was found to give the corresponding hydroxy amide
in 92% isolated yield (Scheme 6). Aryl esters had not been
known previously to undergo this type of transformation. Due
to the lack of reactivity found previously with the TBS group,
the smaller, more labile TES (triethylsilyl) group was installed
to give 17 in high yield. It was unclear how these conditions
would affect the pivaloate ester and if removal of this group
could occur without racemization. Danishefsky reported an
R-TES ether Weinreb amide that was shown to react with a
Grignard reagent to give a ketone product.13 Following this lead,
it was found that benzyl Grignard addition proved efficient at
0 °C, giving the desired benzyl ketone 18 in high isolated yield,
81%.
Experimental Section
(S)-4-(3-(Methoxy(methyl)amino)-3-oxo-2-(triethylsilyloxy)-
propyl)phenyl pivalate (17). To a flame dried 10 mL round-bottom
flask were added N,O-dimethylhydroxylamine hydrochloride (0.073
g, 0.750 mmol) and CH2Cl2 (1.3 mL). Then AlMe3 (0.370 mL, 2.0
M in hexane) was added dropwise, and the solution was stirred at
ambient temperature for 30 min. Then (S)-2,5-dimethoxyphenyl
2-hydroxy-3-(4-phenylpivalate)propanoate 11 (0.050 g, 0.124 mmol)
was added to a CH2Cl2 solution (1.0 mL + 0.3 mL rinse), and the
mixture was stirred for 5 h at ambient temperature. The reaction
was then quenched by the addition of a 0.5 M HCl solution (2
mL) and diluted with CH2Cl2 and H2O. The layers were mixed
and separated, and the aqueous layer was extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were washed with a
saturated aqueous NaCl solution, dried over Na2SO4, filtered, and
concentrated. The residual oil was purified via radial chromatog-
raphy (1 mm plate, 60% EtOAc/hexane) to afford 0.036 g (92%)
of alcohol, (S)-4-(2-hydroxy-3-(methoxy(methyl)amino)-3-oxopro-
pyl)phenyl pivalate, as a yellow oil: TLC Rf ) 0.34 (80% EtOAc/
hexane); [R]23D -38.0° (c 1.5, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 7.24-7.22 (m, 2H), 6.99-6.98 (m, 2H), 4.61 (bm, 1H), 3.71 (s,
3H), 3.32 (bm, 1H), 3.24 (s, 3H), 3.05, (dd, J ) 3.5, 13.5 Hz, 1H),
2.86 (dd, J ) 7.5, 14.0 Hz, 1H), 1.35 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 177.3, 174.2, 150.1, 134.8, 130.5, 121.5, 69.8, 61.6,
Even with the success of the benzyl Grignard addition, it
remained unclear how the TES and Piv groups would be
removed without racemizing the hydroxyl stereocenter. Indeed,
intermediate 18 was found to be highly sensitive to the known
deprotection conditions for these groups (Table 1).14 Treatment
of 18 with HCl (3 M) in dioxane at 80 °C (entry 1) gave only
decomposition. NaOH (3 N), followed by acidification with
dilute HCl (1 M), proved to be superior, generating product 1
(12) Fukuyama, T.; Tokuyama, H. Aldrichimica Acta 2004, 37, 87.
(13) Rivkin, A.; Biswas, K.; Chou, T.-C.; Danishefsky, S. J. Org. Lett.
2002, 4, 4081.
(15) (a) Creary, X.; Geiger, C. C. J. Am. Chem. Soc. 1982, 104, 4151.
(b) Hartman, M.; Christian, R.; Zbiral, E. Liebigs Ann. Chem. 1990, 83. (c)
Ivonin, S. P.; Lapandin, A. V. Synth. Commun. 2004, 34, 3727.
(14) Bengtsson, S.; Hogberg, T. J. Org. Chem. 1993, 58, 3538.
J. Org. Chem, Vol. 71, No. 22, 2006 8653

40.6, 39.2, 32.6, 27.3. To a 25 mL round-bottom flask containing
(S)-4-(2-hydroxy-3-(methoxy(methyl)amino)-3-oxopropyl)phenyl piv-
alate (0.032 g, 0.104 mmol) was added DMF (1.0 mL) followed
by imidazole (0.028 g, 0.416 mmol). Then chlorotriethylsilane
(0.035 mL, 0.208 mmol) was added, and the reaction was stirred
at ambient temperature for 5 h at which time H2O (10 mL) was
added and the mixture extracted with EtOAc (3 × 10 mL). The
combined organic layers were then dried over Na2SO4, filtered, and
concentrated. The product was isolated via radial chromatography
(1 mm plate, 20% EtOAc/hexane) to provide 0.040 g (91%) of the
title compound 17 as a colorless oil: TLC Rf ) 0.52 (40% EtOAc/
hex); [R]23D +3.1° (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
7.24-7.21 (m, 2H), 6.97-6.94 (m, 2H), 4.69 (bm, 1H), 3.52 (s,
3H), 3.17 (s, 3H), 3.05 (dd, J ) 5.4, 13.2 Hz, 1H), 2.87 (dd, J )
7.8, 13.2 Hz, 1H), 1.35 (s, 9H), 0.89-0.84 (m, 9H), 0.55-0.46
(m, 6H); 13C NMR (CDCl3, 75 MHz) δ 177.4, 150.1, 135.4, 130.8,
121.5, 70.9, 41.0, 39.3, 32.7, 27.4, 6.8, 4.8; HRMS (FAB+) found
446.2344 [M + Na]+, calcd 446.2333 for C22H37O5NSiNa.
(S)-4-(3-Oxo-4-phenyl-2-(triethylsilyloxy)butyl)phenyl piv-
alate (18). To a 25 mL round-bottom flask containing (S)-4-(3-
(methoxy(methyl)amino)-3-oxo-2-(triethylsilyloxy)propyl)phenyl piv-
alate (0.114 g, 0.269 mmol) was added THF (4.5 mL), and the
solution was cooled to 0 °C. Then benzylmagnesium chloride (0.540
mL, 2.0 M in THF) was added slowly over 5 min. The reaction
mixture was stirred at 0 °C for 2.5 h at which time H2O was added
(15 mL), and the mixture was then extracted with EtOAc (3 × 20
mL). The combined organic layers were dried over Na2SO4, filtered,
and concentrated. The crude product was purified via radial
chromatography (1 mm plate, 5% EtOAc/hexane) to afford 0.100
(+)-Kurasoin A (1). To a 25 mL round-bottom flask containing
(S)-4-(3-oxo-4-phenyl-2-(triethylsilyloxy)butyl)phenyl pivalate 18
(0.038 g, 0.084 mmol) was added THF (2.0 mL), and the solution
was cooled to 0 °C. Then tetrabutylammonium fluoride (0.090 mL,
1.0 M in THF) was added, and the reaction mixture was stirred at
0 °C for 15 min. Then H2O (1.0 mL) was added followed by H2O2
(0.038 mL, 30% aqueous). Then LiOH(H2O) (0.007 g, 0.167 mmol)
was added, and the reaction mixture was stirred for an additional
25 min at 0 °C. Then a saturated aqueous Na2S2O3 solution (2 mL)
was added followed by a saturated aqueous NH4Cl solution (20
mL). The mixture was then extracted with EtOAc (1 × 15 mL)
and CH2Cl2 (3 × 15 mL). Then combined organic layers were dried
over Na2SO4, filtered, and concentrated. The crude product was
then dissolved in a minimal amount of CH2Cl2 and purified via
column chromatography (40% EtOAc/hexane) to provide 0.014 g
(65%) of the title compound 1 as a white solid: TLC Rf ) 0.39
(50% EtOAc/hex); [R]23D +8.4° (c 0.5, CH3OH), lit.2 synthetic )
[R]22D +9° (c 1.0, CH3OH), natural ) [R]22D +7° (c 0.1, CH3OH);
1
mp ) 120-122 °C, lit.2 mp ) 121-123 °C; H NMR (CD3OD,
500 MHz) δ 7.28-7.01 (m, 7H), 6.70-6.68 (m, 2H), 4.33 (dd, J
) 5.0, 7.5 Hz, 1H), 3.78 (d, J ) 17.0 Hz, 1H), 3.72 (d, J ) 16.5
Hz, 1H), 2.95 (dd, J ) 5.0, 14.5 Hz, 1H), 2.75 (dd, J ) 7.5, 14.0
Hz, 1H); 13C NMR (CD3OD, 125 MHz) δ 212.4, 157.3, 135.6,
131.7, 131.0, 129.6, 129.5, 127.9, 116.3, 78.9, 46.7, 40.4. HRMS
(FAB+) found 279.0989 [M + Na]+, calcd 279.0992 for C16H16O3-
Na.
g (82%) of the desired product 18 as a colorless oil: TLC Rf )
Acknowledgment. We thank the American Chemical So-
ciety Petroleum Research Foundation for funding (41552-AC1).
1
0.75 (40% EtOAc/hex); [R]23 -46.0° (c 2.0, CHCl3); H NMR
D
(CDCl3, 500 MHz) δ 7.31-7.22 (m, 3H), 7.19-7.16 (m, 2H), 7.07
(d, J ) 7.0 Hz, 2H), 6.98-6.96 (m, 2H), 4.36 (dd, J ) 4.5, 7.5
Hz, 1H), 3.77 (d, J ) 16.5 Hz, 1H), 3.67 (d, J ) 17.0 Hz, 1H),
2.92 (dd, J ) 4.5, 13.5 Hz, 1H), 2.84 (dd, J ) 7.5, 13.5 Hz, 1H),
1.36 (s, 9H), 0.90-0.87 (m, 9H), 0.54-0.45 (m, 6H); 13C NMR
(CDCl3, 125 MHz) δ 210.7, 177.2, 150.2, 134.3, 134.0, 131.0,
130.0, 128.6, 127.0, 121.5, 79.6, 45.1, 41.2, 39.2, 27.3, 6.9, 4.8;
HRMS (FAB+) found 455.2608 [M + H]+, calcd 455.2612 for
C27H39O4Si.
Supporting Information Available: Experimental procedures
and characterization for all compounds, and NMR spectral data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO061395T
8654 J. Org. Chem., Vol. 71, No. 22, 2006