Second-generation synthesis of syn- and anti-cycloheptadienylsulfone polyketide stereodiads

Article abstract of DOI:10.1021/jo702353e

(Chemical Equation Presented) Stereodiad sulfones 18a and 18b are key intermediates for polyketide synthesis. This note describes the synthesis of 18a and 18b from enantiopure epoxide 2. The two sequences have been optimized for large-scale synthesis to g

Full text of DOI:10.1021/jo702353e

SCHEME 1. First-Generation syn-Selective
Methylation-Sulfenylation
Second-Generation Synthesis of syn- and
anti-Cycloheptadienylsulfone Polyketide
Stereodiads
Mohammad N. Noshi, Ahmad El-Awa, and Philip L. Fuchs*
Department of Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907
pfuchs@purdue.edu
ReceiVed NoVember 29, 2007
SCHEME 2. MeMgBr versus MeLi Addition to 3
Stereodiad sulfones 18a and 18b are key intermediates for
polyketide synthesis. This note describes the synthesis of 18a
and 18b from enantiopure epoxide 2. The two sequences
have been optimized for large-scale synthesis to give 80-
85% overall yields in one operation (one operation implies
that no crystallization or distillation is required throughout
the synthesis) while avoiding chromatography.
SCHEME 3. First- versus Second-Generation Syntheses of
anti-Diad 10a
1. Diastereoselective Methylation/Epoxide Opening-
Sulfenylation: 1.1. syn-Methylation-Sulfenylation. The anti-
and syn-stereodiads 18a and 18b are pivotal intermediates of
polypropionate segments for many synthetic targets in our
laboratory. The first-generation synthesis of 18b subjected
achiral dienylsulfone 11 to Jacobsen asymmetric epoxidation
(now 1% catalyst loading)2 to give epoxide 2 in good yield and
very high enantiomeric excess (99%), both antipodes of 2 being
equally accessible. Base-promoted isomerization of epoxide 2
afforded dienyl alcohol 3 or its TMS ether 4, both in 90% yield.
MeLi addition to vinylsulfones 3 or 4 resulted in anticipated
OH-directed syn-selective methylation with the former and
unusual TMSO-directed syn-selective methylation3 with the
latter. The resulting allyl sulfonyl anion was quenched with
PhSSPh to give vinylsulfones 5a and 6 in 77-85% yield
(Scheme 1).
In the second-generation strategy, base-promoted isomeriza-
tion of epoxide 2 to dienyl alcohol 3 was found to be quantitative
employing 3-5 mol % of K2CO3/MeOH. As shown above, the
lithiated oxido anion of 3 was known to direct methyllithium
with superior stereocontrol than did substrate 4, simultaneously
avoiding deprotection of the TMS ether,4 but only afforded 5a
in 64% yield and dr > 10:1 (Scheme 2).2 Fortunately, favorable
results with MeMgBr on other substrates5 prompted its applica-
tion to 3 resulting in a 90-95% yield of 5a and dr > 14:1. It
is worth mentioning that 5a is initially received as an inseparable
3:1 diastereomeric mixture along with allylsulfone 10b and
epimers of 5a and 10b at the methyl position as judged by H
NMR. Thus, the 14:1 ratio was determined after transforming
5a to dienylsulfone 18b.
1
1.2. anti-Methylation-Sulfenylation. The first-generation
reaction of 7 with MeLi followed by PhSSPh resulted in a
mixture of 8a and diastereomer 8b in ratios ranging from 6 to
10:1 (Scheme 3). Since AlMe3 typically methylates cross-
conjugated vinyl epoxides in an anti fashion,6 reaction of
epoxide 2 with AlMe3 was investigated in the second-generation
strategy, giving the anti-1,2-addition product 9 with 25:1
selectivity with respect to alternative syn-1,2- and 1,4-addition
products (Scheme 3). Conversion of 9 to allylsulfone 10a
required O,C-dimetalation followed by PhSSPh quenching
(sulfenylation). It was expected that the initial mixture of
vinylsulfones obtained would need to be subsequently equili-
brated to allylsulfone 10a employing DBU. However, this
reaction interestingly produced the “already equilibrated” al-
lylsulfone 10a. Crude 10a contains residual PhSH/PhSSPh
impurities that complicate large-scale reactions. A continuous
(1) (a) Meyers, D. J.; Fuchs, P. L. J. Org. Chem. 2002, 67, 200. (b)
Park, T.; Torres, E.; Fuchs, P. L. Synthesis 2004, 11, 1895.
(2) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J.
Am. Chem. Soc. 1991, 113, 7063.
(3) Torres, E. Ph.D. Thesis, Purdue University, May 2004.
(4) See discussion in the Supporting Information.
(5) El-Awa, A. Ph.D. Thesis, Purdue University, 2007.
(6) Abe, N.; Hanawa, H.; Maruoka, K.; Sasaki, M.; Miyashita, M.
Tetrahedron Lett. 1999, 40, 5369.
10.1021/jo702353e CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/19/2008
3274
J. Org. Chem. 2008, 73, 3274-3277

SCHEME 4. In situ Equilibration in the anti Series
SCHEME 5. Optimized Vinylsulfone to Vinyl Sulfide
Rearrangement
SCHEME 6. First-Generation Elimination of
Benzenesulfinic Acid
extraction employing CH3CN/hexane was effective in com-
pletely removing these impurities on 30 g scale (Table 1 in
Supporting Information).7
2. Vinyl Sulfone to Vinyl Sulfide Rearrangement. It is well-
documented that vinylsulfones rearrange to allylsulfones under
basic conditions.8 While this equilibration occurs in the same
step of sulfinylation for the anti series, it requires an additional
step in the case of the syn series. In the anti series, treating
epoxide 9 with base quantitatively forms dianion 9a. Subsequent
sulfenylation of 9a affords vinylsulfone monoanion 9b presum-
ably as a diastereomeric mixture. Under the strongly basic
conditions, 9b is deprotonated to yield dianion 9c which
undergoes regio- and stereoselective quenching to 10a upon
workup (Scheme 4).
In contrast, in the syn series, the weakly basic9 benzenethiolate
anion requires ∼3 days for complete equilibration. Hence, 5a
was isolated and subsequently treated with catalytic DBU10 (0.05
equiv at ambient temperature for 1 day, or 0.01 equiv at 90 °C
for 6 h), which effected almost quantitative conversion of 5a
to 10b (Scheme 5). Crude 5a contains a significant amount of
PhSH. Attempting DBU equilibration of the crude mixture is
difficult because the catalytic DBU is deactivated by the PhSH
impurity. However, utilizing CH3CN/hexane extraction on crude
5a rendered it sufficiently pure to undergo the DBU equilibration
without chromatographic purification.
effectively preventing 1,2-elimination of the benzenesulfinate
group.13 However, in certain cases, base-promoted elimination
of sulfones is possible.14 Under E1 elimination conditions,
tertiary, allylic, and R-heteroatom-substituted sulfones can act
as nucleofuges followed by proton abstraction or nucleophilic
trapping.15 Finally, allylsulfones are viable substrates for oxida-
tive addition by metals to form π-allyl complexes,16 which can
be either attacked by a nucleophile or transformed to a diene in
the presence of a base.17
Compounds 10a and 10b are allylic sulfones bearing a
vinylogous γ-heteroatom and the first-generation reaction
with excess TMSOTf and Et3N produces dienyl sulfides 12a
and 12b in high yield after desilylation.4 However, the ex-
pense of TMSOTf prompted a search for more economical
elimination conditions. Moreover, the original conditions af-
forded silyloxy dienyl sulfides 11a and 11b requiring an
additional deprotection step. Desilylation could be performed
employing HOAc/THF/H2O or NaOH/MeOH/H2O. While NaOH/
MeOH/H2O requires 10 min for completion and does not
produce any side products, HOAc/THF/H2O requires 4 h and
gives a significant amount of cyclized products 13a and 13b
(Scheme 6). In the second-generation strategy, aluminum-
based Lewis acids were used. Initially, treating 10a or 10b with
AlCl3/Et3N in CH2Cl2 for 12-18 h afforded 12a or 12b in 70-
78% yield.18 Technical difficulties associated with AlCl3
3. Benzenesulfinic Acid Elimination. The secondary phenyl
sulfone moiety is a poor nucleofuge.11 Upon treatment with a
strong base, the proton R to the sulfone is abstracted,12
(7) Table 1 in the Supporting Information describes detailed optimization
for dianion formation-sulfenylation reaction of 9 to 10a.
(8) (a) O’Connor, D. E.; Lyness, W. I. J. Am. Chem. Soc. 1964, 86,
3840. (b) Inomata, K.; Hirata, T.; Suhara, H.; Kinoshita, H.; Kotake, H.;
Senda, H. Chem. Lett. 1988, 2009. (c) Ozawa, M.; Iwata, N.; Kinoshita,
H.; Inomata, K. Chem. Lett. 1990, 1689. (d) Short, K. M.; Ziegler, C. B.,
Jr. Tetrahedron Lett. 1995, 36, 355. (e) Nakamura, T.; Guha, S. K.; Ohta,
Y.; Abe, D.; Ukaji, Y.; Inomata, K. Bull. Chem. Soc. Jpn. 2002, 75, 2031.
(9) The pKa of benzene thiol is ca. 10 in DMSO and 6.5 in H2O; see:
Bordwell, F. G.; Hughes, D. L. J. Org. Chem. 1982, 47, 3224.
(10) The pKa of DBU is ca. 12 in DMSO; see: Blanchette, M. A.; Choy,
W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T.
Tetrahedron Lett. 1984, 25, 2183; Evans, D. A. Evans pKa table http://
daecr1.harvard.edu/ (April 2007); DBU or the 13000 times stronger P2-Et
phosphazene base are highly effective at promoting prototropic equilibration
of simple 5-7 ring vinylsulfones (Jin, Z.; Kim, S. H.; Fuchs, P. L.
Tetrahedron Lett. 1996, 37, 5247).
(13) An exception is the case of tert-sulfones, especially in presence
of a γ,δ-unsaturation. See: (a) Hamann, P. R.; Fuchs, P. L. J. Org.
Chem. 1983, 48, 914. (b) Fuchs, P. L.; Braish, T. F. Chem. ReV. 1986, 86,
903.
(14) Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107.
(15) (a) Trost, B. M.; Ghadiri, M. R. J. Am. Chem. Soc. 1984, 106, 7260.
(b) Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V. Tetrahedron
1989, 45, 4293. (c) Brown, S. D.; Hansson, T.; Ley, S. V. Synlett 1990,
48. (d) Brown, S. D.; Carreau, P.; Ley, S. V. Synlett 1990, 749. (e) Trost,
B. M.; Ghadiri, M. R. Bull. Soc. Chim. Fr. 1993, 130, 433. (f) Ghosh, A.
K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374 and ref 15.
(16) (a) Trost, B. M.; Schmuff, N. R.; Miller, M. J. J. Am. Chem. Soc.
1980, 102, 5979. (b) Trost, B. A.; Merlic, C. A. J. Org. Chem. 1990, 55,
1127 and ref 15.
(17) Such elimination reactions are precedented. See for example:
Suzuki, S.; Fujita, Y.; Nishida, T. Tetrahedron Lett. 1983, 24, 5737 and
ref 17.
(18) See Supporting Information (Table 2, optimization of AlCl3/Et3N
elimination of benzenesulfinic acid).
(11) Coulter, A. K.; Miller, R. E. J. Org. Chem. 1971, 36, 1898.
(12) The pKa of the proton on the R carbon to a sulfone is ca. 29 in
DMSO; see: Evans, D. A. Evans pKa table http://daecr1.harvard.edu/ (April
2007).
J. Org. Chem, Vol. 73, No. 8, 2008 3275

SCHEME 7. Second-Generation Desulfonylation of Silyl Ethers 14 and 16a
a Conditions: (a) TBSOTf (1.1 equiv), 2,6-lutidine (1.5 equiv), CH2Cl2; (b) i-Pr2NEt (3 equiv), AlMe3 (2.2 equiv), -78 to 25 °C, 45 min; (c) HMDS (0.5
equiv), I2 (0.01 equiv), CH2Cl2, 25 °C, 10 min; (d) 10% NaOH/MeOH.
SCHEME 8. Oxidation/TBS Protection of 12a and 12ba
of THF under Ar, and the resultant light yellow solution was cooled
to -70 °C. MeMgBr (6.4 mL, 8.9 mmol, 1.4 M in tol/THF ) 3:1)
was added at once, and the dry ice bath was immediately removed.
As the reaction warmed to 25 °C, its color changed to deep orange.24
After vigorous stirring for 1 h at 25 °C, PhSSPh (1.3 g, 5.9 mmol)
was added via a solids addition arm,25 and the reaction was stirred
for an additional hour26 and then quenched by addition of 5% HCl
(10 mL). The crude reaction mixture was transferred to a separatory
funnel; 40 mL of water was added, and the mixture was extracted
with ether (2 × 30 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and purified by flash column
chromatography (hex/EtOAc ) 2:1 to hex/EtOAc ) 1:1) to give
1.49 g (95%) of 5a (as an inseparable 3:1 mixture of epimers)27 as
a light yellow oil. This procedure was repeated successfully on 10
g of 3, quantitatively affording 5a. Continuous extraction employing
CH3CN/hexane (see preparation of 10a) is necessary before the
next transformation.
a Conditions: (a) 30% H2O2 (2 equiv), Na2WO4 (0.02 equiv), Ph-
P(O)(OH)2 (0.02 equiv), Oct3MeNHSO4 (0.02 equiv), toluene, 0 to 25 °C,
3 h; (b) TBSOTf (1.1 equiv), Et3N (2 equiv), CH2Cl2, 0 to 25 °C, 2 h
(yields are quantitative for Noyori’s oxidation and -OTBS protection).
(especially on large scale)19 led to further optimization employ-
ing AlMe3/i-Pr2NEt in CH2Cl2 for 45 min, giving 12a or 12b
in >90% yield. TMS or TBS protection of 10a afforded the
desired dienyl sulfides 12a and 15 in 96 and 100% overall yields
(from 10a), respectively (Scheme 7).20
DBU (24 µL, 0.16 mmol)28 was added to a solution of 5a (1.18
g, 3.2 mmol) in toluene (13 mL) and stirred at 110 °C.29 The
reaction color changed from light yellow to dark brown a few
minutes after addition of the DBU. After 4 h, the reaction mixture
was cooled to 25 °C and concentrated by rotary evaporation
followed by vacuum drying to give 1.18 g (100%) of 10b as a
4. Dienyl Sulfide to Dienyl Sulfone Oxidation/TBS Protec-
tion. The final hurdle in the second-generation syntheses of 18a
and 18b is the oxidation of dienyl sulfides to 17a and 17b. The
difficulty arises because many oxidants cannot selectively
oxidize a sulfoxide to a sulfone in the presence of an olefin
bearing a free alcohol.21 The first-generation reaction relied on
stoichiometric MCPBA as an oxidant, which indeed provided
unwanted epoxidation. On the basis of successful results from
the optimized synthesis of 1, Noyori’s catalyst system was
initially investigated in the second-generation strategy.22 This
protocol was well-suited to this transformation and afforded 17a
and 17b in 90-100% yield from 12a and 12b, respectively.
Subsequent TBS protection of 17a and 17b quantitatively
delivered 18a and 18b (Scheme 8).10
1
dark brown oil. H NMR analysis of the crude mixture showed
two components in ca. 2:1 ratio.30 For analytical purposes, an
enriched sample of each component was obtained by flash column
chromatography (hex/EtOAc ) 2:1 f hex/EtOAc ) 3:2) and are
named here as 10b-A and 10b-B.31 This procedure was repeated
successfully on 10 g of 5a, quantitatively affording 10b.
Vinyl sulfide 10b (10 g, 26.7 mmol) was dissolved in CH2Cl2
(90 mL) and treated with HMDS (3.34 mL, 16.0 mmol) and l2 (68
mg, 0.27 mmol). The reaction was stirred at 25 °C for 10 minutes
then i-Pr2NEt (13.9 mL, 80.1 mmol) was added. The mixture was
(23) See Supporting Information for detailed experimental and charac-
terization data.
(24) If crude 3 is used for the reaction, its THF solution is colored orange
and no color change is observed upon MeMgBr addition.
(25) PhSSPh can also be added via cannula as a THF solution with similar
reaction outcome.
(26) Stirring for longer than 1 h after PhSSPh should be avoided as the
desired product starts to decompose.
(27) Other minor isomers co-elute with 5a, which include 10b and
epimers of 5a and 10b at the Me position. Because of that, the reported
14:1 diastereoselectivity of the reaction is determined after conversion to
dienylsulfone 18b.
Experimental Section23
Preparation of syn-Cycloheptadienylsulfone 18b. Chromato-
graphically purified dienyl alcohol 3 (1.04 g, 4.2 mmol) was
azeotropically dried with toluene (2 × 30 mL) followed by addition
(19) See detailed discussion in Supporting Information.
(20) See Supporting Information (Table 3, optimization of AlMe3/iPr2-
NEt elimination of benzenesulfinic acid).
(21) See for example: (a) Schultz, S. H.; Freyermuth, H. B.; Buc, S. R.
J. Org. Chem. 1963, 28, 1140. (b) Charette, A. B.; Berthelette, C.; St-
Martin, D. Tetrahedron Lett. 2001, 42, 5149. (c) Sivaramakrishnan, A.;
Nadolski, G. T.; McAlexander, I. A.; Davidson, B. S. Tetrahedron Lett.
2002, 43, 213.
(22) (a) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.; Ryoji, N. Tetrahedron
2001, 57, 2469. (b) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003,
1977.
(28) Runs of this reaction with as low as 1 mol% of DBU were equally
successful.
(29) Running the reaction for 24 h at 100 °C resulted in intramolecular
addition of the alcohol group to the vinylsulfone.
(30) That both components were converted to 10b indicates that they
are epimeric at the vinylsulfone position.
(31) 10b-A is the component with higher Rf, and 10b-B is the one with
lower Rf.
3276 J. Org. Chem., Vol. 73, No. 8, 2008

then cooled to -78 °C for 10 minutes and 25% AIMe3 in hexanes
(23.5 mL, 58.7 mmol) was added dropwise at -78 °C then the dry
ice bath was immediately removed. The reaction was stirred at 25
°C for 45 minutes and the reaction was checked for completion by
TLC (50% ethyl acetate/hexanes). The reaction was then carefully
poured into a beaker containing 10% NaOH (50 mL/ice). The
reaction flask was washed with CH2Cl2 (2 × 10 mL) and the
washings were added to the beaker then the mixture was stirred at
25 °C for 30 minutes. MeOH (50 mL) was added to give a
homogenous phase, and the reaction was stirred for 30 min. Brine
(100 mL) was added, the aqueous phase was discarded, and the
organic phase was washed with brine (100 mL) containing 5% HCl
(60 mL, 82.2 mmol) to remove i-Pr2NEt. The mixture was then
carefully neutralized with 5% HCl using phenolphthalein as
indicator. The organic phase was separated, dried over Na2SO4,
and then concentrated via rotary evaporation to give a crude yellow
oil.32 After celite-pad filtration, the crude oil was submitted to
Noyori oxidation as described below to give sulfone 17b as a yellow
(50 mL), dried over Na2SO4, then concentrated via rotary evapora-
tion to afford a crude yellowish oil (dr 25:1). Purification by flash
column chromatography (20% ethyl acetate/hexanes) afforded 9
as a colorless oil (4.9 g, 93%). Crystallization from ether gave 9
as white prisms (3.2 g, 60%). Mp 74.8-75.4 °C. TLC (50% ethyl
acetate/hexanes) Rf 0.26.
A solution of alcohol 9 (30 g, 120 mmol) in THF (300 mL) was
cooled to -78 °C for 30 min, then 2 M NaHMDS in THF (180
mL, 360 mmol) was added dropwise over 10 min to give a clear
yellow solution that eventually turned into a deep red clear solution.
The dry ice bath was removed, and the mixture was stirred at 25 °C
for 4 h to give a bright orange suspension. Reaction is checked for
complete dianion formation using TLC (50% ethyl acetate/hexane).
Dianion 9a quantitatively quenches on TLC to produce allyl sulfone
20 and does not return any vinyl sulfone 9 (see Supporting
Information). A solution of PhSSPh (26.4 g, 120 mmol) in THF
(120 mL) was added via cannula at 25 °C to the reaction mixture
where the orange suspension dissolves and re-forms immediately.
After stirring for 1 h, reaction was quenched with 5% HCl (300
mL) and diluted with ether (300 mL). Five percent HCl (300 mL)
was added, and the mixture was stirred for 1 h. After discarding
the aqueous phase, a solution of K2CO3 (168 g, 1.2 mol) in DI-
H2O (600 mL) was added and the mixture was stirred at 25 °C for
another 1 h. Organic phase was separated, washed with brine, and
dried over Na2SO4 for 2 h. Concentration of the organic phase via
rotary evaporation afforded 10a as a brown oil.
Continuous Extraction Purification of 10a. The brown oil from
above was dissolved in CH3CN (300 mL) and was transferred to a
6840 continuous extraction apparatus (ACE Glass Catalog 2005 p.
150) that was fitted with an overhead condenser and a side arm
500 mL round-bottom flask. Hexane (400 mL) was added to give
a biphasic system where the lower layer was the CH3CN layer
(clear, brown) and the upper was the hexane layer (clear, colorless).
The inner glass tube was filled completely with hexanes and inserted
into the extractor. The side arm flask containing hexanes was placed
in an oil bath and was heated at 80 °C. The extraction was continued
for 10 h during which time the hexane layer turns yellow and the
color is gradually transferred to the side arm flask. After cooling
the system to 25 °C, the CH3CN phase was separated and
concentrated via rotary evaporation to give highly pure (as checked
by 1H NMR) vinyl sulfide 10a as a brown oil. Crystallization from
boiling ether afforded 10a as tan crystals (72%). Repeating the
above procedure employing alcohol 9 (1.0 g, 4 mmol) followed by
purification via flash column chromatography (20% ethyl acetate/
hexanes) afforded 10a as a yellowish crystalline solid (1.28 g, 86%).
Mp range 114.4-117.8 °C; TLC (50% ethyl acetate/hexanes) Rf
0.5. Elimination of 10a to 12a, oxidation to 17a, and silylation to
18a was carried out as with 18b (see Supporting Information for
the detailed experimental procedure).
1
oil (6.8 g, 96%). The H NMR of the crude material was clean
enough for the next transformation.
EtOAc (270 mL) was added to crude33 12b (18.8 g, 0.081 mol)
and stirred under air to give a brown solution. Na2WO4 (2 mL, 4
mmol, 1 M in H2O), PhP(O)(OH)2 (2 mL, 4 mmol, 1 M in H2O),
MeOct3NHSO4 (4 mL, 4 mmol, 0.5 M in tol), and H2O2 (28 mL,
0.24 mol, 30% in H2O) were added to the above solution and
vigorously stirred at 25 °C. After 4 h, the reaction was judged
complete by TLC,34,35 and the mixture was transferred to a
separatory funnel, and brine (200 mL) was added. The aqueous
layer was extracted with ether (2 × 100 mL), and the combined
organic layers were washed with saturated Na2SO3 solution, dried
over Na2SO4, and concentrated via rotary evaporation to give 17b
as an orange oil. The crude oil was purified by flash column
chromatography (hex/EtOAc ) 1:1 f hex/EtOAc) 2:3) to give
14 g (65% overall yield) of 17b as a light yellow viscous oil.36
TLC (50% ethyl acetate/hexanes) Rf 0.39. Silylation of 17b as
previously described provides a quantitative yield of syn-stereodiad
18b.
Preparation of anti-Cycloheptadienylsulfone 18a. A solution
of 25% AlMe3 in hexanes (30 mL, 60 mmol) in dry CH2Cl2 (50
mL) was cooled to -20 °C for 30 min, then DI-H2O (216 µL, 12
mmol) was added dropwise and very carefully over 30 min. The
dry ice bath was removed, and the reaction was stirred for 1 h.
Solid epoxide 2 (5 g, 20 mmol) was added in portions, and the
reaction was stirred at 25 °C for 40 min. Reaction was checked for
completion using TLC (50% ethyl acetate/hexanes), then the
reaction mixture was cooled again to -40 °C for 30 min. Careful
dropwise addition of aq 10% NaOH (until CH4 gas evolution
stopped) was followed by adding aq 10% NaOH (50 mL), then the
mixture was allowed to stir at 25 °C for 30 min (alternatively,
pouring the cold reaction on 10% NaOH/ice is more convenient
and safer). The organic phase was separated, washed with brine
Acknowledgment. We are grateful to Dr. Douglas Lantrip
for his intellectual and technical support. We acknowledge
Arlene Rothwell and Karl Wood for providing the MS data.
M.N. deeply thanks Nelson Vinueza for technical support. We
thank Dr. Phillip Fanwick for providing the crystal structure
data.
(32) The celite-pad filtration step is performed to eliminate Cl- ions from
the product as they inhibit the catalyst used in the subsequent oxidation
step.
(33) 12b must be purified from any traces of halide ions as they inhibit
the Na2WO4 catalyst used in this reaction.
(34) The reaction time may vary due to the possible presence of trace
halide ions.
(35) The reaction starts as a dark brown solution and slowly changes to
a yellowish orange solution, which usually signifies complete conversion.
(36) Because of the high viscosity of 17b, it is more accurate to determine
the yield after conversion to TBS derivative 18b.
Supporting Information Available: Detailed discussion, de-
1
tailed experimental procedures, schemes, optimization tables, H
NMR, 13C NMR, X-ray, and MS data. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO702353E
J. Org. Chem, Vol. 73, No. 8, 2008 3277