Welwistatin support studies: Expansion and limitation of aryllead(IV) coupling reactions

Article abstract of DOI:10.1021/jo071156l

(Chemical Equation Presented) Recent support studies on the total synthesis of the welwistatin system are described. The target step involves lead-mediated arylation of sterically demanding aryl groups and carbon acid coupling partners in order to establi

Full text of DOI:10.1021/jo071156l

Welwistatin Support Studies: Expansion and Limitation
of Aryllead(IV) Coupling Reactions
Jibo Xia, Lauren E. Brown, and Joseph P. Konopelski*
Department of Chemistry and Biochemistry, UniVersity of California, Santa Cruz, California 95064
joek@chemistry.ucsc.edu
ReceiVed May 31, 2007
Recent support studies on the total synthesis of the welwistatin system are described. The target step
involves lead-mediated arylation of sterically demanding aryl groups and carbon acid coupling partners
in order to establish the highly congested tetracyclic core structure. Type 7 â-ketoesters and â-ketonitriles
were successfully arylated with a variety of ortho- and meta-substituted aryllead compounds generated
by a halogen-boron-lead exchange sequence. The enolates of compounds 15, 19, and 25, each bearing
all-carbon quaternary centers adjacent to the arylation site, failed to couple.
Introduction
Guided by biological activity data, Moore and co-workers
described the isolation and structure elucidation of the welwit-
indolinones, a class of structurally distinct blue-green algae-
derived alkaloids.1 Representative members of this class of
compounds include welwitindolinone C isothiocyanate (wel-
wistatin, 1), the N-methyl analogue 2, and welwitindolinone A
isonitrile (3). While the original interest in 1 and 2 was focused
on the ability of these alkaloids to reverse P-glycoprotein-
mediated multiple drug resistance (MDR), additional studies
provided strong evidence for innate cytotoxicity at the nanogram
level.2
Synthetic efforts have increased substantially in the new
millennium, with contributions from groups headed by Zard,5
Jung,6 Avendan˜o,7 Rawal,8 Simpkins,9 Funk,10 and Shea.11
Notable among these achievements is the advanced intermediate
Interest in the total synthesis of welwitindolinones began
slowly, with only our initial studies3 and the substantive efforts
of Wood and co-workers4 published in the 20th century.
(5) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. Angew. Chem.,
Int. Ed. 2000, 39, 731-733.
(6) Jung, M. E.; Slowinski, F. Tetrahedron Lett. 2001, 42, 6835-6838.
(7) (a) Lo´pez-Alvarado, P.; Garc´ıa-Granda, S.; AÄ lvarez-Ru´a, C.; Aven-
dan˜o, C. Eur. J. Org. Chem. 2002, 1702-1707. (b) For a review of synthetic
studies on 2, see Avendan˜o, C.; Mene´ndez, J. C. Curr. Org. Syn. 2004, 1,
65-82.
(8) MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421-
3424.
(9) Baudoux, J.; Blake, A. J.; Simpkins, N. S. Org. Lett. 2005, 7, 4087-
4089.
(10) Greshock, T. J.; Funk, R. L. Org. Lett. 2006, 8, 2643-2645.
(11) Lauchii, R.; Shea, K. J. Org. Lett. 2006, 8, 5287-5289.
(1) (a) Stratman, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.;
Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem.
Soc. 1994, 116, 9935-9942. (b) Jiminez, J. I.; Huber, U.; Moore, R. E.;
Patterson, G. M. L. J. Nat. Prod. 1999, 62, 569-572.
(2) (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.;
Moore, R. E. Mol. Pharm. 1995, 47, 241-247. (b) Zhang, X.; Smith, C.
D. Mol. Pharm. 1996, 49, 288-294.
(3) Konopelski, J. P.; Deng, H.; Schiemann, K.; Keane, J. M.; Olmstead,
M. M. Synlett. 1998, 1105-1107.
(4) Wood, J. L.; Holubec, A. A.; Stoltz, B. M.; Weiss, M. M.; Dixon, J.
A.; Doan, B. D.; Shamji, M. F.; Chen, J. M.; Heffron, T. P. J. Am. Chem.
Soc. 1999, 121, 6326-6327.
10.1021/jo071156l CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/09/2007
J. Org. Chem. 2007, 72, 6885-6890
6885

Xia et al.
SCHEME 1. Coupling Partners
produced by Greshock and Funk, which possesses both fully
substituted centers at C11 and C12. In addition, the total
synthesis of (+)-3 by Baran12 and (()-3 by Wood13 have been
communicated recently.
Our most recent published work described the synthesis of
indole 4 and the corresponding N-methyloxindole 5, prepared
by the highly stereoselective formation of the C4-C11 bond
(welwistatin numbering) via an aryllead(IV) coupling reaction.14
Herein we disclose more recent efforts toward the welwistatin
system, including (1) expansion of the scope of lead-mediated
arylation to include a wider array of aryl substrates and (2)
investigation of the lead coupling reaction on substrates,
including enantiomerically pure substrates, already substituted
at C12, so as to accomplish the challenging task of establishing
welwistatin’s contiguous quaternary centers.15
Results and Discussion
The key limitation in incorporating a variety of aryl synthetic
handles via lead arylation is the occasional difficulty in obtaining
the lead reagents themselves. Lead reagents can generally be
made in one of two ways: direct plumbation (which is limited
to very simple systems) or, more commonly, metal-lead
exchange reactions.16 Standard protocol begins with an aryl
halide, which undergoes sequential halogen-tin and tin-lead
exchanges. While this sequence is generally quite reliable, we
found it to fail in a number of the aryl substrates we envisioned
to be potential oxindole precursors. Initially, it appeared that
sterics played a role in limiting this exchange, as there were
difficulties obtaining a number of o-alkylated lead reagents.
However, additional troubles in generating both the m-nitro-
and the m-bromoaryllead(IV) reagents forced us to consider the
importance of electronic interactions in the tin-lead exchange
as well. Hence, we turned to boron-lead exchange as a method
of generating our aryllead coupling partners.
In 1990, Morgan and Pinhey reported the generation of
aryllead triacetates from the reaction of arylboronic acids and
lead tetraacetate,17 and Moloney has employed this technology
extensively.18 Several boronic acids of interest (6a-c) are
commercially available; others, such as 6d, can be synthesized
easily from the corresponding aryl bromides via the methods
of Li et al.19 (Scheme 1, eq 1). The lead reagent is then generated
by treatment with lead(IV) acetate and a catalytic amount of
mercury trifluoroacetate, followed by addition of the carbon acid
coupling partner. The preparation of carbon acids 7a and 7b
has already been described;20 preparation of the -OTBDPS
compound 7c proceeds in a manner similar to that of 7b (eq 2),
namely, zinc enolate formation of 8,21 condensation with
acetone/dehydration (9), and enolate formation/dimethyl carbon-
(12) (a) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394-
15396. (b) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446,
404-408.
(13) Reisman, S. E., Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J.
L. J. Am. Chem. Soc. 2006, 1448-1449.
(14) Deng, H.; Konopelski, J. P. Org. Lett. 2001, 3, 3001-3004.
(15) Reviews: (a) Douglas, C. J.; Overman, L. E. Proc. Nat. Acad. Sci.
U.S.A. 2004, 101, 5363-5367. (b) Peterson, E. A.; Overman, L. E. Proc.
Nat. Acad. Sci. U.S.A. 2004, 101, 11943-11948.
(16) For a review, see: Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001,
57, 5683-5705.
(17) Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1990, 715-
720.
(18) Dyer, J.; King, A.; Keeling, S.; Moloney, M. G. J. Chem. Soc.,
Perkin Trans. 1 2000, 2793-2804.
(19) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, S.; Cai, D.; Larsen,
R. D.; Reider, P. J. Org. Chem. 2002, 67, 5394-5397.
(20) Deng, H. Ph.D. Dissertation, University of California, Santa Cruz,
CA, 2001.
6886 J. Org. Chem., Vol. 72, No. 18, 2007

Welwistatin Support Studies
SCHEME 2. Effect of Substitution
SCHEME 3. Synthesis of EP 15
SCHEME 4. Synthesis of EP 19
ate treatment to the desired material. Preparation of 7d arises
from Luche reduction of 9 to give 10 followed by Claisen
rearrangement with CH3C(OEt)3 to afford 11. Treatment with
BH3‚THF yielded diol 12, which is selectively protected on the
primary alcohol prior to Dess-Martin oxidation to yield 13 as
a single diastereomer. Carbomethoxy installation affords 7d as
a mixture of keto and enol forms of the desired structure (eq
3). Finally, 7e arises from 14 (the -OTBS analogue of 920) via
LDA/TosCN treatment (eq 4).22
Previous work in this laboratory has demonstrated that
substitution at varied positions around the ring can greatly affect
the yields of aryllead(IV) coupling reactions to cyclohex-
anones.23 As shown in Scheme 2, methyl substitution at C4 or
C5 of the methyl cyclohexan-2-one carboxylate template allows
arylation to proceed in 65% and 74% yield, respectively.
However, movement of the methyl group to the C6 position
cuts the yield dramatically to 23%. Since the synthesis of the
welwistatin structure would require the installation of the
quaternary C12 center adjacent to the fully substituted C11
center, we set out to explore the limitations of aryllead(IV)
reagents for the production of such highly congested centers.
In addition, we undertook preliminary studies on the formation
of enantiomerically pure (EP) cyclohexanone derivatives as
possible synthetic intermediates toward the production of
welwistatin in its natural form.
We first turned our focus toward the production of a simple
C12 gem-dimethyl substrate, and known compound 1524 was
chosen for synthesis by a nonenzymatic route (Scheme 3).
Known enantiopure compound 16 was prepared from quinic
acid (17) following literature procedures.25 Conjugate addition
of dimethyl cuprate, followed by trapping with TMSCl, afforded
the expected trimethylsilyl enol ether, which was oxidized to
known enone 18 with DDQ and hexamethyldisilazane. Finally,
following the literature procedure,24 a second cuprate addition
in the presence of methyl cyanoformate afforded desired
â-ketoester 15.
Conformational rigidity has been shown to have a marked
effect on arylations of simple systems. For example, Pinhey
has shown that while the mono- and diarylation of 2,4-
pentandione proceeds sluggishly at 19% and 2.5% yields,
respectively, the same conditions employed on dimedone gave
diarylated product in 75-82% yields.26 Encouraged by these
results, we focused our attention on synthesizing two bicyclic
substrates for the coupling reaction studies.
The synthesis of the simpler bicyclic substrate 19 is shown
in Scheme 4. From compound 18, addition of vinyl Grignard
reagent in the presence of CuBr-Me2S affords the C12
quaternary center in a 14:1 diastereomeric ratio. Hydroboration
of 20 gives the desired alcohol with concomitant reduction of
the ketone to give 21. This diol can be selectively monofunc-
tionalized on the primary hydroxyl with ethyl chloroformate to
afford 22, and disubstituted product 23 can be recycled to 21
in good yield. Oxidation of 22, followed by lactone formation,27
gives bicyclic product 19, shown to exist entirely as the enol
1
form by H and 13C NMR.
In addition, we synthesized 25, a bicyclic analogue of 7b
containing the exocyclic double bond as a potential synthetic
handle for further transformations. Starting from (S)-carvone
(26), diastereoselective epoxidation gives 27, which is followed
by reduction with anhydrous hydrazine to afford known
compound 28 in 81% yield over the two steps (Scheme 5).28
Pivaloyl protection to 29 is followed by allylic oxidation with
(21) Okamura, W. H.; Elnagar, H. Y.; Ruther, M.; Dobreff, S. J. Org.
Chem. 1993, 58, 600-610.
(22) Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22, 5011-5014.
(23) Elliot, G. I.; Konopelski, J. P.; Olmstead, M. M. Org. Lett. 1999,
1, 1867-1870.
(24) Galano, J. M.; Audran, G.; Monti, H. Tetrahedron 2000, 56, 7477-
7481.
(26) Pinhey, J. T.; Rowe, B. A. Aust. J. Chem. 1979, 32, 1561-1566.
(27) Cho, Y. S.; Carcache, D. A.; Tian, Y.; Li, Y. M.; Danishefsky, S.
J. J. Am. Chem. Soc. 2004, 126, 14358-14359.
(25) (a) Trost, B. M.; Romero, A. G. J. Org. Chem. 1986, 51, 2332-
2342. (b) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738-3740.
(28) Dupuy, C.; Luche, J. L. Tetrahedron 1989, 45, 3437-3444.
J. Org. Chem, Vol. 72, No. 18, 2007 6887

Xia et al.
SCHEME 5. Synthesis of EP 25
SCHEME 6. Arylation of 15
that the silyl protection group at the C5 center of the 2-oxocy-
clohexanenitriles and methyl cyclohexan-2-one carboxylates is
critical to the stereochemistry of the newly formed chiral
center.29
Unfortunately, standard conditions for arylation employing
p-methoxyphenyllead triacetate30 with either 15 and pyridine
or the preformed sodium salt of 15 at both room temperature
and conventional heating to 60 °C proved fruitless and forced
us to explore a number of modified reaction conditions.
Unpublished work in our laboratory suggested that, although
monosubstitution at C6 afforded poor yields of coupled product,
use of microwave irradiation rather than conventional heating
could modestly increase the formation of desired material.
Inspired by the work of Moloney and co-workers, we also
decided to explore the use of different bases to act as lead
ligands in place of pyridine.31 The Oxford team demonstrated
that the use of DMAP, 1,10-phenanthroline, and in the most
successful case, a premade DABCO-lead reagent complex can
dramatically increase the rate of arylation. It seems reasonable
to suggest that bases such as 1,10-phenanthroline may be helpful
in driving the aryllead reaction to completion by binding to the
metal center in a bidentate fashion that can drive the aryl and
carbon acid groups from their initial apical positions to the
necessary cis-type apical/equatorial positions required for reduc-
tive elimination (coupling) of the organic fragments.32
Interestingly, while no reaction conditions were able to
transform 15 to the desired arylation product, a number of
reaction conditions gave small amounts of diarylated compound
36, as well as trace amounts of both diastereomers of the C3
monoarylated compound (Scheme 6). The most successful of
these reactions was in the presence of DMAP ((CH2Cl)2 as
solvent, microwave, 300 W), which afforded the diarylated
product in 25% yield. Small amounts of diarylated and
monoarylated compounds were also seen in reactions performed
at room temperature and at 65 °C, with the premade lead-
DABCO complex and with 1,10-phenanthroline, respectively.
The relatively large amount of diarylated compound compared
to monoarylated compound was not surprising, as the second
arylation proceeds much more rapidly due to enhanced proton
acidity.
TABLE 1. Arylation with Substituted Aryllead(IV) Reagents
entry
substrate
boronic acid
product (yield, %)
1
2
3
4
5
6
7
7a
7b
7c
7c
7c
7d
7e
6c
6b
6a
6c
6d
6c
6d
35a (70)
35b (77)
35c (72)
35d (67)
35e (67)
35f (52)
35g (78)
chromium(VI) oxide and 3,5-dimethylpyrazole, which proceeds
sluggishly to give 30 in 32% yield. The resultant enone is then
subjected to vinyl cuprate addition to afford 31 in good
diastereoselectivity and yield. Compound 31 is subjected to
hydroboration to give 32 and bis-carbonate formation to give
dicarbonate 33. Oxidation of the secondary alcohol with Dess-
Martin periodinone gives compound 34, which then undergoes
cyclization to 25 with concomitant elimination upon treatment
with potassium hydride.
As is shown in Table 1, the boron-lead exchange/coupling
sequence affords desired material in good yield using both
â-ketoester and â-ketonitrile substrates. In particular, the boron-
lead exchange reaction was successful in generating the m-
nitroaryllead coupling partner, and the subsequent lead arylation
could be performed in yields ranging from 52 to 70% (entries
1, 4, and 6). Moreover, the m-bromoaryllead reagent could also
be successfully generated and coupled to â-ketoester 7b in 77%
yield (entry 2). Earlier work from our laboratory demonstrated
Likewise, no arylation conditions were successful on bicyclic
carbon acids 19 and 25. In addition, attempts to arylate with
palladium or copper catalysis, or bismuth reagents,33 also proved
unsuccessful. Thus, our original observation would seem to hold
(29) Konopelski, J. P.; Lin, J.; Wenzel, P. J.; Deng, H.; Elliott, G. I.;
Gerstenberger, B. S. Org. Lett. 2002, 4, 4121-4124.
(30) Kozyrod, R. P.; Pinhey, J. T. Org. Synth. 1984, 62, 24-30.
(31) Buston, J. E. H.; Moloney, M. G.; Parry, A. V. L.; Wood, P.
Tetrahedron Lett. 2002, 43, 3407-3409.
(32) Morgan, J.; Buys, I.; Hambley, T. W.; Pinhey, J. T. J. Chem. Soc.,
Perkin Trans. 1 1993, 1677-1681.
(33) Ooi, T.; Goto, R.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
10494-10495.
6888 J. Org. Chem., Vol. 72, No. 18, 2007

Welwistatin Support Studies
7.43 (m, 6H), 4.22 (m, 1H), 3.67 (dt, J ) 7.5, 1.0 Hz, 2H) 2.97
(dd, J ) 13.2, 4.5 Hz, 1H), 2.89 (dt, J ) 13.2, 6.0 Hz, 1H), 2.13
(ddd, J ) 13.2, 4.5, 2.7 Hz, 1H), 2.03 (m, 2H), 1.90 (m, 1H), 1.72
(m, 1H), 1.49 (m, 2H), 1.13 (s, 9H), 0.97 (m, 3H), 0.93 (s, 3H),
0.90 (s, 9H), 0.05 (s, 3H), 0.49 (s, 3H); 13C NMR δ 212.8, 135.9,
135.8, 134.0, 133.9, 129.9, 127.8, 67.2, 60.1, 52.0, 42.2, 39.2, 36.4,
35.6, 33.4, 27.2, 26.2, 25.7, 24.9, 19.4, -5.1; IR (neat) 3071, 2956,
truessubstitution at the adjacent center to that undergoing the
coupling reaction severely compromises the aryllead(IV) reac-
tion, to the point where the transformation is not synthetically
useful.
In conclusion, lead-mediated arylations that were previously
seen as challenging due to varied substitution on the aryl
coupling partner can be achieved via an efficient boron-lead
exchange protocol. In addition, our studies have shown that
while lead-mediated arylation seemed a plausible strategy for
the establishment of diastereoselectivity at C11 of 1, it does
not prove successful in more sterically hindered systems.
1713, 1471, 1427, 1363, 1255, 1112, 1087, 997, 836, 702 cm-1
HRMS for C33H53O3Si2 calcd 553.3527, found 553.3617.
;
Methyl 3-[3-((tert-Butyldimethylsilyloxy)-1,1-dimethylpropyl]-
5-(tert-butyldiphenylsilyloxy)-2-oxocyclohexanecarboxylate (7d).
At 0 °C, n-BuLi (2.5 M, 0.18 mL, 0.45 mmol) was added slowly
to diisopropylamine (0.061 mL, 0. 46 mmol) in THF (6 mL). The
reaction was kept at 0 °C for 30 min and then cooled to -78 °C
under argon. A solution of compound 13 (200 mg, 0.36 mmol) in
THF (2 mL) was added dropwise, and the mixture was stirred for
1 h while the temperature was held at -78 °C. Methyl cyanoformate
(0.45 mmol, 0.35 mL) in THF (2 mL) was added to the reaction
mixture. The reaction mixture was allowed to stir for 20 min at
-78 °C and then 1 h at -20 °C. The reaction was quenched with
ammonium chloride and extracted with ethyl acetate (3 × 10 mL).
The combined organic layers were successively washed with
saturated sodium bicarbonate and brine, dried over Na2SO4, filtered,
and concentrated to give a crude product. The residue was purified
by silica gel chromatography to furnish the pure product as a
colorless oil (197 mg, 90%) and a mixture of diastereomers in keto
and enol forms (approximately 3:2 mixture by NMR): 1H NMR δ
7.72 (m), 7.41 (m), 4.25 (m), 4.15 (m), 3.77 (s), 3.74 (s), 3.28 (m),
3.05 (m), 3.01 (m), 2.91 (m), 2.16 (m). 1.9 (m), 1.53 (m), 1.29
(m), 1.10 (s), 1.00 (s), 0.93 (s), 0.08 (m); 13C NMR δ 212.7, 207.8,
207.0, 170.1, 135.9, 134.0, 133.9, 130.1, 129.9, 127.9, 127.8, 127.7,
127.6, 67.3, 66.5, 60.2, 60.0, 54.2, 52.1, 51.9, 42.3, 39.2, 38.6, 36.6,
36.4, 35.5, 33.4, 27.2, 27.1, 26.2, 25.6, 24.9, 24.8, 19.5, 18.5, 14.4,
-5.1; IR (neat) 3459, 2931, 17423, 1715, 1428, 1254, 1241, 1111,
1053, 822, 702 cm-1; HRMS for C35H54O5Si2Na calcd 633.3402,
found 633.3431.
Experimental Section
Ethyl 3-[5-(tert-Butyldiphenylsilyloxy)cyclohex-1-enyl]-3-me-
thylbutyrate (11). A catalytic amount of propionic acid (1 drop)
was added to a mixture of compound 10 (450 mg, 1.14 mmol) and
triethyl orthoacetate (5 mL), and the resulting solution was heated
at 138 °C for 8 h under conditions for the distillative removal of
ethanol. When the reaction was complete (GC, TLC), unreacted
orthoacetate was distilled under reduced pressure. The residue was
chromatographed on silica gel with hexane/ethyl acetate (100:1)
which afforded the product as a colorless oil (451 mg, 85%): Rf
0.75 (EtOAc-hexane 1/8); 1H NMR δ 7.72 (m, 4H), 7.40 (m, 6H),
5.37 (m, 1H), 4.02 (dq, J ) 7.1, 1.7 Hz, 2H), 3.94 (m, 1H), 2.21
(m, 2H), 1.88 (m, 2H), 1.76 (m, 2H), 1.56 (m, 2H), 1.16 (t, J )
7.1 Hz, 3H), 1.11 (s, 9H), 1.08 (m, 6H); 13C NMR δ 172.0, 140.6,
135.9, 134.9, 134.8, 129.6, 127.6, 118.7, 45.5, 38.0, 34.3, 31.2,
27.2, 26.9, 24.3, 19.3, 14.4; IR (neat) 3050, 2932, 1732, 1462, 1427,
1367, 1242, 1110, 822, 702 cm-1; HRMS for C29H41O3Si calcd
465.2819, found 465.2807.
4-(tert-Butyldiphenylsilyloxy)-2-(3-hydroxy-1,1-dimethylpro-
pyl)cyclohexanol (12). To a stirred solution of compound 11 (330
mg, 0.71 mmol) in dry THF (5 mL) at 0 °C was added a 1 M
solution of BH3 in THF (1.42 mL, 1.42 mmol). The mixture was
stirred at 0 °C for 6 h and then at rt for 12 h. A solution of NaOH
(1.88 mL, 3 M) was slowly added at 0 °C followed by a solution
of H2O2 (1.88 mL, 30%). The mixture was stirred for another 6 h
and then extracted with ethyl acetate (3 × 20 mL). The combined
organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure and purified by column
chromatography with hexane/EtOAc (2:1) to afford as a colorless
oil (197 mg, 63%): Rf 0.32 (EtOAc-hexane 1/2); 1H NMR δ 7.69
(m, 4H), 7.40 (m, 6H) 4.06 (m, 1H), 3.79 (m, 2H), 3.53 (dt, J )
10.5, 3.7 Hz, 1H), 3.19 (Br, 2H), 2.17 (m, 2H), 1.98 (dq, J ) 10.5,
3.7 Hz, 1H), 1.75 (m, 2H), 1.68 (m, 1H), 1.49 (td, J ) 14.2, 5.6
Hz, 1H), 1.33 (m, 1H), 1.12 (s, 9H), 0.97 (m, 1H), 0.91 (s, 3H),
0.85 (s, 3H); 13C NMR δ 136.9, 134.7, 134.5, 129.7, 127.7, 73.0,
67.7, 59.5, 45.3, 43.4, 34.8, 33.4, 32.1, 28.1, 27.2, 25.0, 19.5; IR
(neat) 3335, 3071, 2933, 1427, 1389, 1265, 1110, 1045, 822, 739
702 cm-1; HRMS for C27H41O3Si calcd 441.2819, found 441.2806.
2-[3-((tert-Butyldimethylsilyloxy)-1,1-dimethylpropyl]-4-(tert-
butyldiphenylsilyloxy)cyclohexanone (13). Triethylamine (0.07
mL, 0.54 mmol) and TBSCl (41.27 mg, 0.27 mmol) were added to
the mixture of compound 12 (120 mg, 0.27 mmol) and DMAP (34
mg, 0.27 mmol) dissolved in CH2Cl2 (5 mL). The mixture was
stirred for 2 h and was washed with brine (10 mL), dried over
Na2SO4, and concentrated to give an oil which was passed through
a short pad of silica. Dess-Martin reagent (1.6 mL, 15% weight
in CH2Cl2) was added to a stirred solution of the above product
(360 mg, 0.65 mmol) in CH2C12 (5 mL). The solution was stirred
for another 2 h at rt. Saturated sodium bicarbonate solution (10
mL) containing 3 g of Na2S2O3 was poured into the reaction and
stirred for 10 min. The organic layer was separated and washed
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure and purified by column chromatography with
hexane/EtOAc (20:1) to afford the product as a colorless oil (119
mg, 80%): Rf 0.65 (EtOAc-hexane 1/8); 1H NMR δ 7.69 (m, 4H)
(4S,6R)-4-Pivaloxy-6-isopropenyl-3-methyl-2-cyclohexenone
(30). 3,5-Dimethylpyrazole (30.5 g, 31.8 mmol) was added a slurry
of CrO3 (31.8 g, 318 mmol, dried over P2O5 for 24 h) in CH2Cl2
at -20 °C as quickly as possible. The mixture was stirred for 20
min before a solution of compound 29 (10 g, 42.4 mmol) in CH2-
Cl2 (50 mL) was added dropwise. The reaction mixture was slowly
warmed from -20 to 0 °C over 15 h. Ether (1000 mL) was added,
and the solids were filtered off. The filtrate was washed with
saturated NaHCO3, 1 M HCl, saturated NaHCO3, and brine, dried
over Na2SO4, filtered, and concentrated to give a crude product.
The residue was purified by silica gel chromatography with hexane/
ether (100:5 to 100:20) to furnish the pure product as a colorless
oil (3.39 g, 32%): [R]D -29.2 (c 2.70, MeOH); Rf 0.5 (EtOAc-
hexane 4/1); 1H NMR δ 5.92 (m, 1H), 5.46 (m, 1H), 4.92 (m, 1H),
4.73 (m, 1H), 3.16 (dd, J ) 8.5, 4.9 Hz, 1H), 2.36 (ddd, J ) 13.7,
8.5, 4.2 Hz, 1H), 2.07 (ddd, J ) 13.7, 6.0, 4.9 Hz, 1H), 1.90 (s,
3H), 1.74 (s, 3H), 1.20 (s, 9H); 13C NMR δ 198.4, 177.9, 156.6,
142.0, 128.9, 114.0, 68.6, 50.6, 39.1, 32.7, 27.2, 21.1, 20.8; IR
(neat) 2974, 1730, 1680, 1480, 1397, 1277, 1147, 1034, 978, 905
cm-1; HRMS for C15H23O3 calcd 251.1642, found 251.1667.
(2R,4S,5R)-4-Pivaloxy-2-isopropenyl-5-methyl-5-vinylcyclo-
hexanone (31). A solution of compound 30 (200 mg, 0.8 mmol)
in THF (10 mL) was added dropwise to a solution of vinylmag-
nesium bromide (2.4 mmol, 2.4 mL of 1 M in THF) and CuBr‚
Me2S (18 mg, 0.083 mmol) in THF (10 mL) at -40 °C. The mixture
was stirred for 30 min at -40 °C then was poured onto saturated
NH4Cl solution. The whole mixture was extracted with ether three
times. The combined organic layer was washed with saturated
NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated
to give a crude product. The residue was purified by silica gel
chromatography with hexane/EtOAc (100:5 to 100:20) to furnish
the pure product as a white solid (222 mg, 87%): Rf 0.7 (EtOAc-
1
hexane 1/4); mp 40-42 °C; [R]D 79.8 (c 4.00, MeOH); H NMR
J. Org. Chem, Vol. 72, No. 18, 2007 6889

Xia et al.
δ 5.70 (dd, J ) 17.6, 11.0 Hz, 1H), 5.12 (m, 2H), 5.01 (m, 1H),
4.93 (m, 1H), 4.72 (m, 1H), 3.12 (dd, J ) 12.3, 6.1 Hz, 1H), 2.54
(dd, J ) 14.5 Hz, 2H), 2.21 (ddd, J ) 14.5, 12.3, 2.5 Hz, 1H),
1.99 (ddd, J ) 14.5, 6.1, 4.1 Hz, 1H), 1.67 (s, 3H) 1.27 (s, 9H)
1.06 (s, 3H); 13C NMR δ 208.5, 177.6, 142.4, 142.2, 115.7, 114.1,
73.5, 52.7, 47.1, 45.5, 39.3, 31.7, 27.4, 24.5, 20.5; IR (neat) 2973,
(4S,5S)-5-Pivaloxy-8-hydroxy-7-isopropylidene-4-methyloc-
tahydroisochromenone (25). A solution of compound 34 (698.3
mg, 1.52 mmol) in THF (5 mL) was slowly added to a suspension
of KH (67 mg, 1.7 mol, 223.3 mg of 30% KH in mineral oil, washed
three times with hexane) in THF (5 mL) and stirred at rt for 5 h.
The reaction was quenched by ammonium chloride and extracted
with ethyl acetate (3 × 10 mL). The combined organic layers were
successively washed with saturated NaHCO3 and brine, dried over
Na2SO4, filtered, and concentrated to give a crude product. The
residue was purified by silica gel chromatography to furnish the
desired product (320.4 mg, 46%) as a mixture of keto and enol
forms (approximately 1:3 mixture by NMR): Rf 0.35 (EtOAc-
1729, 1717, 1480, 1281, 1149, 1033, 1000, 925, 911, 768 cm-1
HRMS for C17H26O3Na calcd 301.1774, found 301.1792.
;
(2R,4S,5S)-4-Pivaloxy-2-(2-hydroxy-1-methylethyl)-5-(2-hy-
droxyethyl)-5-methylcyclohexanol (32). To a stirred solution of
compound 31 (140 mg, 0.5 mmol) in dry THF (5 mL) at 0 °C was
added 1 M BH3 in THF (1.5 mL, 1.5 mmol). The mixture was
stirred at 0 °C for 6 h and then rt for 12 h. A solution of NaOH
(1.33 mL, 3 M) was slowly added at 0 °C followed by a H2O2
solution (1.33 mL, 30%). The mixture was stirred for another 6 h
and then extracted with ethyl acetate (3 × 20 mL). The combined
organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure and purified by column
chromatography with hexane/EtOAc (1:1) to furnish the desired
product as a 2:1 mixture of alcohol isomers (75.84 mg, 48%): Rf
1
hexane 1/4); H NMR δ 4.71 (m), 4.42 (m), 4.17 (m), 3.88 (m),
2.84 (m), 2.34 (m), 2.23 (s), 2.04 (m), 1.85 (s), 1.70 (m), 1.38 (s),
1.26 (s), 1.23 (s), 1.2 (m), -1.71 (s); 13C NMR δ 177.9, 171.1,
136.7, 129.7, 128.8, 127.2, 126.3, 97.3, 75.6, 65.9, 39.2, 35.5, 33.6,
33.5, 32.0, 30.0, 29.8, 29.2, 28.8, 27.5, 27.3, 27.1, 26.2, 23.6, 23.0,
22.9, 21.0, 20.8, 20.7, 14.4, 13.7, 13.6; IR (neat) 3441, 2973, 1730,
1633, 1594, 1480, 1417, 1294, 1156, 1080, 1030, 892, 673 cm-1
HRMS for C18H27O5 calcd 323.1853, found 323.1841.
;
1
0.36 (EtOAc-hexane 2/1); mp 82-83 °C; H NMR δ 4.68 (d, J
Gerneral Procedure for Organolead Coupling Reactions. To
the boronic acid derivative (10 mmol) in chloroform (100 mL) were
added successively lead(IV) tetraacetate (9.5 mmol) and mercury-
(II) trifluoroacetate (0.5 mmol) under argon. The reaction was
warmed to 60 °C for 2 h and then overnight at rt. The resulting
mixture was warmed to 60 °C again for another 2 h. The premixed
solution of â-ketoester (1.0 equiv) or â-ketonitrile (1.0 equiv) and
pyridine (4 equiv) in CHCl3 (20 mL), which had been stirred for
10 min, was added to the above mixture at 60 °C. The reaction
was stirred for another 12 h and filtered through a bed of Celite,
and 2 M H2SO4 was added to the filtrate. The aqueous layer was
extracted with CHCl3 (3 × 30 mL). The combined organic layers
were successively washed with 2 M H2SO4, H2O, saturated sodium
bicarbonate, and brine, dried over Na2SO4, filtered, and concentrated
to give a crude product. The residue could be purified by silica gel
chromatography to furnish the pure product.
) 14.5 Hz, 1H), 3.75 (m, J ) 8.5 Hz, 2H), 3.52 (m, 1H), 3.35 (d,
J ) 6.5 Hz, 2H), 2.16 (ddd, J ) 12.0, 4.5, 3.0 Hz, 1H), 1.97 (m,
2H), 1.53 (m, 3H), 1.38 (m, 2H), 1.19 (m, 9H), 0.91 (d, J ) 7.0
Hz, 3H), 0.83 (s, 3H); 13C NMR δ 117.8, 76.5, 76.3, 70.0, 63.6,
58.2, 40.7, 40.2, 40.0, 39.2, 38.3, 37.5, 37.2, 36.7, 35.5, 35.4, 27.4,
24.8, 21.0, 17.7, 16.2; IR (neat) 3306, 2962, 2931, 1724, 1705,
1480, 1462, 1286, 1160, 1032, 957, 737 cm-1; HRMS for C17H32O5-
Na calcd 339.2142, found 339.2119.
(2R,4S,5S)-4-Pivaloxy-2-(2-ethoxycarbonyloxy-1-methylethyl)-
5-(2-ethoxycarbonyloxyethyl)-5-methylcyclohexanol (33). Ethyl
chloroformate (0.22 mL, 2.2 mmol) was added to a stirred solution
of compound 32 (0.35 g, 1.1 mmol) and dry pyridine (5.5 mmol,
0.45 mL) in CH2Cl2 (10 mL) at rt under argon and stirred overnight.
The mixture was washed with saturated NaHCO3 and brine, dried
over Na2SO4, filtered, and concentrated to give a crude product.
The residue was purified by silica gel chromatography with hexane/
EtOAc (100:20) to furnish the pure product as a colorless oil (440
mg, 87%) as a 2:1 mixture of alcohol isomers: Rf 0.7 (EtOAc-
hexane 1/1); 1H NMR δ 4.75 (m, 1H), 4.15 (m, 8H), 3.99 (dt, J )
10.8, 5.7 Hz, 1H), 2.26 (m, 1H), 1.86 (s, 2H), 1.66 (m, 5H), 1.27
(m, 6H), 1.19 (s, 9H), 1.05 (d, J ) 6.8 Hz, 3H), 0.85 (d, J ) 8.0
Hz, 3H); 13C NMR δ 177.5, 155.5, 155.3, 75.6, 75.5, 71.4, 70.9,
67.3, 65.0, 64.0, 63.9, 39.2, 38.6, 38.5, 38.1, 36.9, 36.8, 36.7, 35.2,
33.7, 33.6, 27.3, 25.1, 24.6, 23.9, 15.6, 14.4; IR (neat) 3534, 2977,
1744, 1480, 1468, 1403, 1255, 1157, 1010, 940, 792 cm-1; HRMS
for C23H41O9 calcd 461.2745, found 461.2702.
Methyl 1-[2-(2-Allyloxyethyl)phenyl]-5-(tert-butyldiphenylsi-
lyloxy)-3-isopropylidene-2-oxocyclohexanecarboxylate (35e). Fol-
lowing the general procedure used for organolead coupling
reactions, the desired compound was isolated from the reaction of
7c and 6d as a white solid (67%): Rf 0.55 (EtOAc-hexane 1/2);
1
mp 51-52 °C; H NMR δ 7.74 (m, 2H), 7.60 (m, 3H), 7.43 (m,
3H), 7.35 (m, 3H), 7.23 (m, 2H), 6.82 (m, 1H), 5.91 (ddd, J )
16.1, 10.9, 5.7 Hz, 1H), 5.23 (ddd, J ) 13.8, 10.9, 1.4 Hz, 2H),
4.02 (m, 1H), 3.94 (m, 2H), 3.79 (s, 3H), 3.56 (dd, J ) 13.9, 8.2
Hz, 2H), 3.12 (dd, J ) 13.9, 8.2 Hz, 2H), 2.51 (m, 4H), 2.13 (m,
3H), 1.67 (m, 3H), 1.07 (m, 9H); 13C NMR δ 198.6, 172.5, 149.1,
139.0, 137.0, 135.9, 135.8, 134.9, 134.3, 133.8, 131.0, 129.8, 129.2,
128.1, 127.8, 127.4, 126.2, 117.0, 71.9, 70.5, 66.5, 65.5, 53.0. 43.0,
37.6, 33.5, 27.1, 23.8, 23.2, 19.3; IR (neat) 3070, 2932, 2858, 1735,
1683, 1428, 1265, 1231, 1104, 1057, 822, 703 cm-1; HRMS for
C38H47O5Si calcd 611.3187, found 611.3121.
(2R,4S,5S)-4-Pivaloxy-2-(2-ethoxycarbonyloxy-1-methylethyl)-
5-(2-ethoxycarbonyloxyethyl)-5-methylcyclohexanone (34). Dess-
Martin reagent (2.5 mL, 15% by weight in CH2Cl2) was added to
a stirred solution of compound 33 (460.3 mg, 1 mmol) in CH2C12
(5 mL). The solution was stirred for 3 h at rt. Saturated aqueous
NaHCO3 (10 mL containing 3 g of Na2S2O3) was added and the
mixture stirred for 10 min. The organic layer was separated, washed
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure and purified by column chromatography with
hexane/EtOAc (2:1) to furnish the pure product as a colorless oil
(366 mg, 80%): Rf 0.5 (EtOAc-hexane 1/4); [R]D 43.8 (c 2.50,
Acknowledgment. We thank the NIH (CA98878) for
generous support of this work. Purchase of the 600 MHz NMR
used in these studies was supported by funds from the National
Institutes of Health (S10RR019918) and National Science
Foundation (CHE-0342912).
1
MeOH); H NMR δ 4.98 (m, 1H), 4.13 (m, 5H), 3.95 (m, 3H),
2.56 (m, 2H), 2.2 (m, 1H), 2.06 (m, 2H), 1.79 (m, 1H), 1.61 (m,
2H), 1.27 (m, 6H), 1.25 (s, 9H), 1.0 (s, 3H), 0.92 (d, J ) 23.5, 6.9
Hz, 3H); 13C NMR δ 209.6, 177.1, 155.3, 154.7, 74.2, 71.5, 70.5,
64.2, 64.0, 49.4, 39.2, 35.8, 33.6, 27.3, 25.9, 24.0, 15.4, 14.4; IR
(neat) 2976, 1746, 1714, 1463, 1397, 1369, 1257, 1151, 1010, 877,
792 cm-1; HRMS for C23H39O9 calcd 459.2588, found 459.2534.
Supporting Information Available: Remaining general pro-
cedures, complete spectroscopic data, and 1H and 13C NMR spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO071156L
6890 J. Org. Chem., Vol. 72, No. 18, 2007