Approach toward the total synthesis of orevactaene. 2. Convergent and stereoselective synthesis of the C18-C31 domain of orevactaene. Evidence for the relative configuration of the side chain.

Article abstract of DOI:10.1021/jo0201777

The synthesis of the C18-C31 subunit of orevactaene (1) in an enantioselective and convergent manner is reported. Four chiral centers in the structure (i.e., carbons 23, 25, 32, and 33) have unknown configuration; thus, a modular approach has been devised to link the two stereocenter-containing ends of the structure together via a trisubstituted olefin template to ultimately produce all possible diastereomers of the target. Keys to the success of this approach include (i) an efficient synthesis of four diastereomeric hydrophobic tails (C22-C29) of the molecule with two stereogenic centers at C23 and C25; (ii) the synthesis of three stereodefined trisubstituted olefins 37, 38, and 43 using palladium(0)-catalyzed hydrometalation and metallometalation; and (iii) the convergent assembly of the aforementioned sections by a 'one-pot' lithium/halogen exchange, boron/lithium exchange, borate ester saponification, and Suzuki cross-coupling followed by oxidative deprotection. The sequence provided the desired aldehydes 49 and 50 as single isomers in good yields. Compiled spectroscopic data from the literature and present work provides evidence that the relative configuration of the methyl groups in the side chain of orevactaene may be 1,3-syn, which will be confirmed when the total synthesis has been completed. These results have paved the way for a parallel synthesis approach to prepare all 16 possible stereoisomers of orevactaene so that the relative and absolute stereochemistry of this compound can be determined.

Full text of DOI:10.1021/jo0201777

Ap p r oa ch tow a r d th e Tota l Syn th esis of Or eva cta en e. 2.
Con ver gen t a n d Ster eoselective Syn th esis of th e C18-C31 Dom a in
of Or eva cta en e. Evid en ce for th e Rela tive Con figu r a tion of th e
Sid e Ch a in
Michael G. Organ,* Yaroslav V. Bilokin, and Svetoslav Bratovanov
Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3
organ@yorku.ca
Received March 13, 2002
The synthesis of the C18-C31 subunit of orevactaene (1) in an enantioselective and convergent
manner is reported. Four chiral centers in the structure (i.e., carbons 23, 25, 32, and 33) have
unknown configuration; thus, a modular approach has been devised to link the two stereocenter-
containing ends of the structure together via a trisubstituted olefin template to ultimately produce
all possible diastereomers of the target. Keys to the success of this approach include (i) an efficient
synthesis of four diastereomeric hydrophobic tails (C22-C29) of the molecule with two stereogenic
centers at C23 and C25; (ii) the synthesis of three stereodefined trisubstituted olefins 37, 38, and
43 using palladium(0)-catalyzed hydrometalation and metallometalation; and (iii) the convergent
assembly of the aforementioned sections by a ‘one-pot’ lithium/halogen exchange, boron/lithium
exchange, borate ester saponification, and Suzuki cross-coupling followed by oxidative deprotection.
The sequence provided the desired aldehydes 49 and 50 as single isomers in good yields. Compiled
spectroscopic data from the literature and present work provides evidence that the relative
configuration of the methyl groups in the side chain of orevactaene may be 1,3-syn, which will be
confirmed when the total synthesis has been completed. These results have paved the way for a
parallel synthesis approach to prepare all 16 possible stereoisomers of orevactaene so that the
relative and absolute stereochemistry of this compound can be determined.
In tr od u ction
be varied readily and coupled together easily to a central
template by one common series of transformations.3 By
using such a strategy, the complexity of generating the
chiral centers in 1 can be reduced by preparing them as
discrete units, where the control over stereocenter prepa-
ration can be maximized, and then coupling them to the
rest of the structure by templates that have been
designed for stereo- and regioselective bond construction
with any reacting partner.
Orevactaene (1), recently isolated from Epicoccum
nigrum WC47880, is a novel polyene representing a new
structural class of natural products.1 It has been shown
to be an effective binding inhibitor of the HIV-1 REV
protein to REV response element (RRE). The potential
importance of the biological implication, novelty, and
complexity of its structure make it an attractive target
for total synthesis.
A key segment of orevactaene (1) is the stereodefined
contiguous trisubstituted olefin section 2 (Figure 1)
comprising the terminal chiral R,γ-dimethyl-substituted
hexenyl chain (C22-C29) with unknown configuration
at C23 and C25. A versatile method for making all four
possible diastereomers of (Z)-4,6-dimethyl-2-[(E)-2-meth-
yl-3-oxo-1-propenyl]-2-octenoate (2), representing the
C18-C31 domain of orevactaene, has been developed,
and this is the focus of this report.
There are three distinct components of 1: (i) a sugar
moiety fused with a pyrone substructure; (ii) a polyene
segment; and (iii) a hydrophobic tail. Further adding to
the intrigue of preparing 1 is the fact that four of the
seven chiral centers in the structure (i.e., carbons 23, 25,
32, and 33) have yet to be confirmed relatively, which
means that the absolute configuration also remains
unknown. Thus, the synthetic route must be amenable
to preparing all 16 diastereomers of 1 in order to confirm
all questions surrounding its stereochemistry. We have
had experience with the parallel synthesis of biologically
active compounds,2,3 and the modular/template approach3
has proven to be an effective synthetic strategy for the
simultaneous preparation of many diverse compounds.
Here the target is divided into small fragments that can
(2) (a) Organ, M. G.; Dixon, C. E. Biotechnol. Bioeng. (Combinatorial
Chemistry) 2000, 71, 71-77. (b) Organ, M. G.; Arvanitis, E. A.; Dixon,
C. E.; Lavorato, D. J . J . Comb. Chem. 2001, 3, 473-476. (c) Organ, M.
G.; Mayhew, D.; Cooper, J . T.; Dixon, C. E.; Lavorato, D. J .; Kaldor, S.
W.; Siegel, M. G. J . Comb. Chem. 2001, 31, 64-67. (d) Organ, M. G.;
Kaldor, S. W.; Dixon, C. E.; Parks, D. J .; Singh, U.; Lavorato, D. J .;
Isbester, P. K.; Siegel, M. G. Tetrahedron Lett. 2000, 41, 8407-8411.
(e) Organ, M. G.; Arvanitis, E. A.; Dixon, C. E.; Cooper, J . T. J . Am.
Chem. Soc. 2002, 124, 1288-1294.
(1) Shu, Y.-Z.; Ye, Q.; Li, H.; Kadow, K. F.; Hussain, R. A.; Huang,
S.; Gustavson, D. R.; Lowe, S. E.; Chang, L.-P.; Pirnik, D. M.;
Kodukula, K. Bioorg. Med. Chem. Lett. 1997, 7, 2295-2298.
(3) Organ, M. G.; Cooper, J . T.; Rogers, L. R.; Soleymanzadeh, F.;
Paul, T. J . Org. Chem. 2000, 65, 7959-7970.
10.1021/jo0201777 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/20/2002
5176
J . Org. Chem. 2002, 67, 5176-5183

Toward the Total Synthesis of Orevactaene
F IGURE 1. Retrosynthetic analysis of orevactaene (1).
Resu lts a n d Discu ssion
tion9,10 and metallometalation,11-13 respectively. Propar-
gyl alcohol was elaborated to the requisite cross-coupling
partner 5 by stannylcupration8,11,13 followed electrophilic
capture at the cuprate site. While stannanes are suitable
partners for palladium-catalyzed cross-coupling reac-
tions,14,15 the substrates could also be transformed to
other reactive species, like iodides or boronic acids.15,16
According to our retrosynthetic analysis (Figure 1),
chiral alcohols 8 are focal intermediates to establish the
two asymmetric centers at C23 and C25 positions in
orevactaene (1). The γ-chiral center (C25) in the hydro-
phobic tail was set by starting the synthesis with (R)- or
(S)-2-methyl-1-butanol. To install the second chiral center
at C23, we employed a modification of the process first
suggested by Evans in the total synthesis of the polyether
antibiotic ionomycin.17 This approach utilized chiral
imide oxazolidinone substrates as chiral auxiliaries and
triflates as electrophiles. Using chiral primary â-branched
triflates as reactive alkylating agents,18 we have been
Syn th etic P la n . As the absolute stereochemistry of
two asymmetric centers in a subunit 2 was not assigned
in the original isolation work, our synthetic strategy grew
(Figure 1) from the desire to have a versatile approach
to make all four possible diastereomers of 2, along with
the defined stereochemistry of the contiguous trisubsti-
tuted olefin component. Stereodefined trisubstituted ole-
fins are challenging to prepare as single entities; thus,
preparing contiguous ones is an even greater task.
Strategies that bring the olefinic carbons together during
olefin formation often work with good selectivity for
disubstituted targets, but this is not the case for trisub-
stituted olefins.4-7 The route8 we have opted for to
prepare the stereodefined trisubstituted olefins 6 and 5
(Figure 1) is transition metal-catalyzed hydrometala-
(4) For Wittig approaches to stereodefined olefins, see: (a) Wittig,
G.; Rieber, M. Liebigs Ann. Chem. 1949, 562, 187-192. (b) Corey, E.
J .; Becker, K. B.; Varma, R. K. J . Am. Chem. Soc. 1972, 94, 8616-
8618. For reviews, see: (c) Nicolaou, K. C.; Harter, M. W.; Gunzner,
J . L.; Nadin, A. Liebigs Ann./ Recl. 1997, 1283-1301. (d) Vedejs, E.;
Peterson, M. J . Adv. Carbanion Chem. 1996, 2, 1-85. (e) Rein, T.;
Reiser, O. Acta Chem. Scand. 1996, 50, 369-379. (f) Vedejs, E.;
Peterson, M. J . Top. Stereochem. 1994, 21, 1-157. (g) Maryanoff, B.
E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.
(5) For Horner-Wadsworth-Emmons approaches to stereodefined
olefins, see: (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G.
Chem. Ber. 1959, 92, 2499-2505. (b) Wadsworth, W. S., J r.; Emmons,
W. D. J . Am. Chem. Soc. 1961, 83, 1733-1738. (c) Boutagy, J .; Thomas,
R. Chem. Rev. 1974, 74, 87-99. (d) Rathke, M. W.; Nowak, M. J . Org.
Chem. 1985, 50, 2624-2626. (e) Mori, Y.; Asai, M.; Kawade, J .-i.;
Furukawa, H. Tetrahedron 1995, 51, 5315-5330. (f) Scarlato, G. R.;
DeMattei, J . A.; Chong, L. S.; Ogawa, A. K.; Lin, M. R.; Armstrong, R.
W. J . Org. Chem. 1996, 61, 6139-6152.
(6) For Peterson olefination approaches to stereodefined olefins,
see: (a) Peterson, D. J . J . Org. Chem. 1968, 33, 780-784. (b) Carey,
F. A.; Court, A. C. J . Org. Chem. 1972, 37, 1926-1929. (c) Hurlick, P.
F.; Peterson, D.; Rona, R. J . J . Org. Chem. 1975, 40, 2263-2264. For
reviews, see: (d) Ager, D. J . Org. React. (N. Y.) 1990, 38, 1-223. (e)
Barrett, A. G. M.; Hill, J . M.; Wallace, E. M.; Flygare, J . A. Synlett
1991, 764-770.
(7) For J ulia olefination approaches to stereodefined olefins, see: (a)
J ulia, M.; Paris, J . M. Tetrahedron Lett. 1973, 4833-4836. (b)
Kocienski, P. J . Chem. Ind. (London) 1981, 548-551. (c) Baudin,
J . B.; Hareau, G.; J ulia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32,
1175-1178. (d) Bellingham, R.; J arowicki, K.; Kocienski, P.; Martin,
V. Synthesis 1996, 285-296. (e) Hayward, C. M.; Yohannes, D.;
Danishefsky, S. J . J . Am. Chem. Soc. 1993, 115, 9345-9346.
(8) Preliminary communication: Organ, M. G.; Bratovanov, S.
Tetrahedron Lett. 2000, 41, 6945-6949.
(9) Rossi, R.; Carpita, A.; Cossi, P. Tetrahedron 1992, 48, 8801-
8824.
(10) (a) Zhang, H. X.; Guibe, F.; Balavoine, G. J . Org. Chem. 1990,
55, 1857-1867. (b) Cochran, J . C.; Bronk, B. S.; Terrence, K. M.;
Phillips, H. K. Tetrahedron Lett. 1990, 31, 6621-6624. (c) Cochran, J .
C.; Terrence, K. M.; Phillips, H. K. Organometallics 1991, 10, 2411-
2418.
(11) For a leading list of references to this transformation, see:
Cuadrado, P.; Gonza´lez-Nogal, A. M.; Sa´nchez, A. J . Org. Chem. 2001,
66, 1961-1965.
(12) Casson, S.; Kocienski, P.; Reid, G.; Smith, N.; Street, J . M.;
Webster, M. Synthesis 1994, 1301-1309.
(13) (a) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Reuter, D.
C. Tetrahedron Lett. 1989, 30, 2065-2068. (b) Thibonnet, J .; Prie, G.;
Abarabri, M.; Duchene, A.; Parrain, J .-L. Tetrahedron Lett. 1999, 40,
3151-3154. (c) Thibonnet, J .; Abarbri, M.; Duchene, A.; Parrain, J .-L.
Synlett 1999, 141-143.
(14) (a) Crisp, G. T.; Scott, W. J .; Stille, J . K. J . Am. Chem. Soc.
1984, 106, 7500-7506. (b) Stille, J . K. Pure Appl. Chem. 1985, 57,
1171-1780. (c) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508-524. (d) Farina, V.; Krishnamurthy, V.; Scott, W. J . Org. React.
(N. Y.) 1997, 50, 1-652. (e) Bellina, F.; Carpita, A.; Desantis, M.; Rossi,
R. Tetrahedron 1994, 50, 12029-12046.
(15) (a) Tsuji, T. Palladium Reagents and Catalysts: Innovations
in Organic Synthesis; J ohn Wiley & Sons: Chichester, UK, 1995. (b)
Marumoto, S.; Kogen, H.; Naruto, S. J . Org. Chem. 1998, 63, 2068-
2069. (c) Marumoto, S.; Kogen, H.; Naruto, S. Tetrahedron 1999, 55,
7145-7156.
(16) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(17) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J . M.; Zahler, R.
J . Am. Chem. Soc. 1990, 112, 5290-5313.
J . Org. Chem, Vol. 67, No. 15, 2002 5177

Organ et al.
SCHEME 1a
SCHEME 2a
a
Reagents and conditions: (a) TBDMSCl, imidazole, DMF, 0 °C
to room temperature; (b) DIBALH, THF, PhMe, -78 °C to room
temperature, then MeOH, -78 °C; (c) TsCl, pyridine, 0 °C to room
temperature; (d) CuI/MeLi (Me2CuLi), Et2O, -78 °C to room tem-
perature; (e) TBAF, THF, rt; (f) Tf2O, pyridine, CH2Cl2, -78 °C.
able to install the adjacent R-chiral center (C23) and to
make all four diastereomeric alcohols 8. Finally, com-
pounds 6, required to cross-coupling with 5, were ob-
tained from chiral alcohols 8 via the corresponding alkyne
esters 7.
a
Reagents and conditions: (a) (i) LiBH4, Me3SiCl, THF, 0 °C
to room temperature; (ii) MeOH, then 2.5 M NaOH, 0 °C; (b)
(EtO)2CO, K2CO3, 130-135 °C; (c) (i) n-BuLi, THF, -78 °C; (ii)
EtCOCl, THF, -78 °C to room temperature; (d) LDA, (S)-17, THF,
-78 °C to room temperature; (e) LDA, (R)-15, THF, -78 °C to
room temperature; (f) LiBH4, MeOH, Et2O, rt.
Syn th esis of F ou r P ossible Ster eoisom er s of 2,4-
Dim eth yl-1-h exa n ols (C22-C29 su bu n it). The devel-
opment of an efficient, enantioselective synthesis of the
acyclic 1,3-dimethyl segment poses a significant challenge
in natural product chemistry.19 For reliable enantio-
selective carbon-carbon bond formation, the asymmetric
alkylation of the R-carbon of carboxylic acid derivatives
is a reaction of fundamental importance in modern
synthetic organic chemistry.20 With a few exceptions, this
type of transformation is accomplished using chiral
auxiliary-based methodology. Foremost among these are
the oxazolidinone auxiliaries introduced by Evans and
co-workers.21 (R)/(S)-2-Methylbutyl trifluoromethane-
sulfonates 15 and 17 were prepared from corresponding
chiral 2-methyl-1-butanols 14 and 16 (Scheme 1). While
S-(-)-2-methyl-1-butanol (16) is commercially available,
albeit expensively, its R-(+) antipode 14 is not. Therefore,
it is not surprising that a number of research groups have
attempted to devise a practical synthesis of R-(+)-2-
methyl-1-butanol (14).22 Enatiomerically pure alcohol 14
was prepared starting from commercially available (S)-
methyl 3-hydroxy-2-methylpropionate (9) as shown in
Scheme 1. Alcohols 14 and 16 were then converted to
triflates 15 and 17.18
Although both (4S)- and (4R)-propionyloxazolidinones
21 and 26 are commercially available, they can be
synthesized in large scale much more economically using
both (S)- and (R)-phenylalanine. As shown in Scheme 2,
the reduction of amino acid 18 to amino alcohol 19 using
LiBH4/TMSCl proceeded smoothly and in high yield.23 In
turn, the oxazolidinone 2024 was prepared by heating 19
with diethyl carbonate followed by the low-temperature
N-alkylation of the lithiate of 4-benzyloxazolidinone 20
with propionyl chloride to give 21.25
Two general procedures for the diastereoselective alkyl-
ation of oxazolidinone amides have been tested. In the
first, the alkylation was conducted using excess of alkyl
triflate, and in the second, excess of enolate was used.
In a typical protocol employing excess alkylating agent,
the enolate suspension was treated with an alkylating
agent (2-4 equiv) at -78 °C and then warmed to room
(18) For relevant examples and a list of leading references, see:
Decicco, C. P.; Grover, P. J . Org. Chem. 1996, 61, 3534-3541.
(19) (a) For a review on synthetic strategies, see: Hoffmann, R. W.
Chem. Rev. 1989, 89, 1841-1860. (b) For
a general review on
conformational design of open-chain compounds, see: Hoffmann, R.
W. Angew. Chem., Int. Ed. 2000, 39, 2054-2070.
(22) (a) Logothetis, T. A.; Vleggaar, R. In Proc. ECSOC-3, Proc.
ECSOC-4, 1999, 2000; Pombo-Villar, E., Ed.; Molecular Diversity
Preservation International: Basel, 2000; pp 1064-1070. (b) Bell,
L.; Brookings, D. C.; Dawson, G. J .; Whitby, R. J .; J ones, R. V. H.;
Standen, M. C. H. Tetrahedron 1998, 54, 14617-14634. (c) Geresh,
S.; Valiyaveettil, T. J .; Lavie, Y.; Shani, A. Tetrahedron: Asymmetry
1998, 9, 89-96. (d) Mori, K.; Wu, J . Liebigs Ann. Chem. 1991, 213-
217. (e) Brown, H. C.; Naik, R. G.; Bakshi, R. K.; Pyun, C.; Singaram,
B. J . Org. Chem. 1985, 50, 5586-5592. (f) Brown, H. C.; Imai, T.; Desai,
M. C.; Singaram, B. J . Am. Chem. Soc. 1985, 107, 4980-4983.
(23) Giannis, A.; Sandhoff, K. Angew. Chem., Int. Ed. Engl. 1989,
28, 218-219.
(20) (a) Blaser, H. U. Chem. Rev. 1992, 92, 935-952. (b) Caine, D.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 3, pp 1-63. (c) Crosby, J .
Tetrahedron 1991, 47, 4789-4846. (d) Lutomski, K. A.; Meyers, A. I.
In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press: New
York, 1984; Vol. 3, pp 213-274. (e) Evans, D. A. In Asymmetric
Synthesis; Morrison, J . D., Ed.; Academic Press: New York, 1984; Vol.
3, pp 1-110.
(21) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc.
1982, 104, 1737-1739. (b) For a review on using chiral oxazolidinones
in asymmetric synthesis, see: Ager, D. J .; Prakash, I.; Schaad, D. R.
Aldrichimica Acta 1997, 30, 3-12.
(24) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 77-82.
(25) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 83-91.
5178 J . Org. Chem., Vol. 67, No. 15, 2002

Toward the Total Synthesis of Orevactaene
SCHEME 3a
SCHEME 4a
a
Reagents and conditions: (a) LDA, (S)-17, THF, -78 °C to
room temperature; (b) LDA, (R)-15, THF, -78 °C to room tem-
perature; (c) LiBH4, MeOH, Et2O, rt.
temperature and held at that temperature for 16 h to
give 60% yield (based on enolate). Reactions employing
excess enolate were conducted similarly using 1.2 equiv
of enolate. In this case, yields exceeded 70% (based on
alkyl triflate). Ultimately, the alkylation of both enan-
tiomers of oxazolidinone amides 21 and 26 with chiral
triflates 15 and 17 was accomplished using the method
employing excess enolate (Schemes 2 and 3). The corre-
sponding 2,4-dimethyl-substituted oxazolidinones 22, 23,
27, and 28, accompanied by their C2 diastereomers, were
obtained in a ca. 20:1 ratio. The diastereomers were
readily separable by column chromatography to provide
the oxazolidinones in good yields and diastereomeric
purity.26 Reduction of oxazolidinones 22, 23, 27, and 28
with lithium borohydride in a mixture of methanol and
ether27 afforded the desired four optically pure alcohols
24, 25, 29, and 30,28 accompanied by about 60-65% of
recovered oxazolidinones.
a
Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2,
-78 °C to 0 °C; (b) CBr4, PPh3, CH2Cl2, 0 °C to room temperature;
(c) (i) n-BuLi, THF, -78 °C to 0 °C; (ii) ClCO2Et, -78 °C to room
temperature; (d) n-Bu3SnH, Pd(PPh3)4, THF, rt; (e) I2, CH2Cl2, rt.
under standard Swern conditions29 gave the correspond-
ing aldehyde that was used immediately in the next step.
Elaboration of the aldehyde to dibromoalkene 31 using
a variation of Corey-Fuchs reaction30 proceeded smoothly
(Scheme 4).
Treatment of 31 with n-butyllithium, followed by ethyl
chloroformate, gave the desired alkyne ester 33. Such
electron-deficient alkynes are known to undergo regio-
selective palladium-catalyzed hydrostannylation to place
the metal where necessary for the critical cross-coupling
step.9 Palladium(0)-catalyzed hydrostannylation with
tributylstannane provided (E)-35 in a regio- and stereo-
selective manner. The same sequence of reactions was
repeated to provide vinyl iodide 38 with the anti ar-
rangement of two methyl groups. Noteworthy, and fur-
ther confirming the steric considerations for stannanes,15
compounds with similar structure were found to be
completely unreactive when cross-coupling reactions were
attempted with vinyl8 and (hetero)aryl iodides.9 Thus,
while the tin moieties were critical for obtaining the
correct regio- and stereochemistry of the two trisubsti-
tuted olefin partners, the tin moieties could not be used
to assemble them together.
Syn th esis of Tw o Ster eod efin ed Ch ir a l Vin yl
Iod id es 37 a n d 38 (C21-C30 su bu n it) a s P r ecu r sor s
for Cr oss-Cou p lin g E xp er im en t s. Oxidation of 29
(26) The possibility of using racemic 2-methylbutyl trifluoromethane-
sulfonate as an alkylating agent was examined with the idea that the
two isomers 22 and 23 would be readily separable by flash chroma-
tography. The diastereomers produced (below), which were epimeric
at C4, proved to be inseparable in large scale using flash chromatog-
raphy.
(28) 2,4-Dimethyl-1-hexanols are volatile and must be recovered
with care.
(29) (a) Mancuso, A. J .; Brownfain, D. S.; Swern, D. J . Org. Chem.
1979, 44, 4148-4150. (b) For a review, see: Mancuso, A. J .; Swern,
D. Synthesis 1981, 165-185.
(30) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-
3772.
(27) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307-312.
J . Org. Chem, Vol. 67, No. 15, 2002 5179

Organ et al.
SCHEME 5a
SCHEME 6a
a
Reagents and conditions: (a) (i) NaH, THF, rt; (ii) NaI,
4-methoxybenzyl chloride, reflux; (b) n-Bu3SnCu(n-Bu)CNLi2,
THF, -78 °C; (c) MeI, HMPA, THF, -78 °C to room temperature;
(d) I2, THF, rt.
F in a l Assem bly of th e C18-C31 F r a gm en t of
Or eva cta en e Usin g Cr oss-Cou p lin g (Su zu k i r ea c-
tion ) a s a Key Rea ction . It is known that mixed alkyl-
tributylstannylcuprate intermediates react syn-stereo-
specifically with monosubstituted alkynes to place the
stannyl group at C1 and the copper atom at C2. The
vinylcuprate intermediate reacts regiospecifically with
some electrophiles to give a range of stereodefined
stannylalkenes,11 which could be converted to corre-
sponding boronic acids15,16 through intermediate iodo-
derivatives. Thus, vinyl iodide 43 was successfully as-
sembled through the synthetic steps depicted in Scheme
5.8 Addition of the (tributylstannyl)butylcuprate reagent
(n-Bu3SnCu(n-Bu)CNLi2)31 to alkyne 40 followed by trap-
ping of the intermediate alkenylcuprate 41 in situ with
MeI afforded vinylstannane 42, which was converted in
the same operation to vinyl iodide 43 (Scheme 5). The
iodide was activated later by lithium/halogen exchange.32
The choice of protecting group for alcohol 39 proved to
be more important than initially anticipated. Silyl pro-
tecting groups were found to be less stable to some
transformations than p-methoxybenzyl (PMB).8 Further,
PMB offers the advantage of providing directly the
desired aldehyde in 2 (e.g., Figure 1) during DDQ
oxidative deprotection.33
With compounds 43 and 37/38 efficiently prepared and
in hand, our attention shifted to the critical cross coupling
that would join these two units together. Boronic acids
are known to be less sterically demanding than the
corresponding stannane. Thus, our attempts of coupling
43 and 37/38 were focused on using a boron derivative.
Compound 43 does not contain any organolithium-
sensitive groups, so we chose to install the metal on it.
Treatment of 43 with n-butyllithium provided intermedi-
ate 44 that was quenched with triisopropylborate giving
rise to borate ester 45 (Scheme 6), which was hydrolyzed
to the corresponding acid 46, and compounds 37 or
38 were added directly to the pot followed by the
palladium(0) catalyst. The ‘one-pot’ lithium/halogen ex-
change, boron/lithium exchange, saponification, and cross-
a
Reagents and conditions: (a) n-BuLi, THF, -78 °C; (b)
(i-PrO)3B, -78 °C to room temperature; (c) NaOH, H2O, rt; (d) 37
or 38, Pd(PPh3)4, THF, 60 °C; (e) DDQ, 20:1 CH2Cl2/H2O, 0 °C to
room temperature.
coupling sequence provided the desired products 47 and
48 as single isomers in good yields. The DDQ oxidative
deprotection of the PMB group provided directly alde-
hydes 49 and 50 in excellent yields. The aldehydes
represent the C18-C31 domain of orevactaene and are
necessary to connect to the pyrone-polyene segment.
Evid en ce for th e Rela tive Con figu r a tion of th e
Sid e Ch a in of Or eva ct a en e Ba sed on 13C NMR
Sh ifts. Orevactaene (1) incorporates a terminal chiral
R,γ-dimethyl-substituted heptenyl chain (C21-C29) in
which the relative configuration of the two stereocenters
(C23 and C25) is unknown. On the basis of computa-
tional34 and experimental35 data, it has been demon-
strated that a series of compounds containing an R,γ-
dimethylated heptenyl segment could serve as a valuable
tool in relative structure elucidation of syn and anti
arrangements of 1,3-skipped dimethyl groups. We were
interested in analyzing the relation between relative
configuration and 13C NMR chemical shifts in unsatur-
ated, 1,3-dimethylated hydrocarbon sequences, thus gain-
ing some possible insight on the relative configuration
of the side chain in 1. We chose a set of compounds
(Tables 1 and 2) with known 1,3-syn or -anti arrange-
ments of terminal alkenyl chains to compare their
(31) For the preparation of SnBu3Cu(Bu)CNLi2 see: Organocopper
Reagents: A Practical Approach; Taylor, R. J . K., Ed.; Oxford Univer-
sity Press: Oxford, U.K., 1994; Chapter 12, p 279.
(32) Luithle, J . E. A.; Pietruszka, J . Eur. J . Org. Chem. 2000, 2557-
2562.
(33) Nakajima, N.; Uoto, K.; Yonemitsu, O. Heterocycles 1990, 31,
5-8.
(34) Stahl, M.; Schopfer, U.; Frenking, G.; Hoffmann, R. W. J . Org.
Chem. 1996, 61, 8083-8088.
(35) Clark, A. J .; Ellard, J . M. Tetrahedron Lett. 1998, 39, 6033-
6036.
5180 J . Org. Chem., Vol. 67, No. 15, 2002

Toward the Total Synthesis of Orevactaene
TABLE 1. Selected Exp er im en ta l 13C NMR Sh ifts of
TABLE 2. Selected Exp er im en ta l 13C NMR Sh ifts of
Som e Sid e Ch a in s Ha vin g C23/C25 An ti Ar r a n gem en ta
Som e Sid e Ch a in s Ha vin g C23/C25 Syn Ar r a n gem en ta
a
The atom numbering of orevactaene (1) is used for all
compounds. Data from ref 35. c This work. Data from ref 41.
e Syn relative configuration of the two methyl groups in the side
chain of L-755,807 (57) was deduced by comparing the calculated
and observed NMR spectra of model compounds.34,35 The absolute
stereochemistry of the epoxy-γ-lactam part is also unknown.
b
d
TABLE 3. Selected Exp er im en ta l 13C NMR Sh ifts of
Or eva cta en e (1)a
a
The atom numbering of orevactaene (1) is used for all
compounds. Data from ref 35. c This work. Data from ref 40.
b
d
measured 13C NMR chemical shifts. It was reported34,35
that for such compounds the most significant differences
in chemical shifts might be expected for carbons analo-
gous to C26, C28, and C29 on orevactaene. For simplicity,
the numbering system of orevactaene has been adopted
for this exercise. The most remarkable experimental
feature found in compounds with 1,3-syn or 1,3-anti
methyl arrangements is the shift difference between the
methyl signals.35 The shift difference is larger for syn
compounds, a fact well reproduced by computational
methods.34
For compounds possessing a C23/C25 anti arrange-
ment (Table 1), chemical shift intervals from 28.9 to 29.5
ppm appear for C26, from 19.4 to 19.5 ppm for C28, and
from 20.2 to 20.8 ppm for C29. The chemical shift
differences between C28 and C29 (on the same com-
pound) range from 0.8 to 1.3 ppm. Different data and
trends were observed for compounds with a C23/C25 syn
arrangement (Table 2): chemical shift intervals from 30.0
to 30.4 ppm appear for C26, from 18.9 to 19.2 ppm for
C28, and from 21.0 to 21.6 ppm for C29. The shift data
for the syn compounds are close in agreement with that
of orevactaene (Table 3). The chemical shift differences
between C28 and C29 now fall between 2.1 and 2.5 ppm.
a
Data from ref 1.
These spectroscopic data suggest that the relative con-
figuration of the methyl groups in the side chain of
orevactaene is syn. Thus, the protected alcohol 47 and
aldehyde 49 seem to be the most likely candidates to
represent the relative configuration of the side chain of
orevactaene, although the synthesis will need to be
completed in order to confirm this tentative assignment.
Con clu sion s
In our effort directed toward the total synthesis of
orevactaene, a recently isolated but yet to be synthesized
natural product, we have successfully completed the
synthesis of the C18-C31 subunit in an enantioselective
J . Org. Chem, Vol. 67, No. 15, 2002 5181

Organ et al.
solution of LiBH4 (140 mg, 6.43 mmol) in 15 mL of THF/Et2O
(2:3). The reaction was stirred at 0 °C for 45 min and then
allowed to warm to room temperature. After 1 h, NaOH (0.9
g, 22.5 mmol) in 10 mL of water was added, and stirring was
continued until both phases were clear. The mixture was
poured into a separatory funnel and washed successively with
water and brine. The organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (silica gel, 2:3 Et2O/pentane) yielded 29
(668 mg, 92%) as a clear, colorless liquid, and 624 mg of (4R)-
4-benzyl-2-oxazolidinone (63%) was recovered. 29: Rf 0.28 (1:5
EtOAc/hexanes); [R]D -3.8 (c 1.65, CHCl3) [lit.38 [R]D -3.9 (c
and convergent manner. Our convergent approach to this
fragment was based on (i) a general strategy allowing
us to synthesize four diastereomeric hydrophobic tails
(C22-C29) of the molecule with two stereogenic centers
at C23 and C25; (ii) the synthesis of two stereodefined
trisubstituted olefins using palladium(0)-catalyzed hy-
drometalation and metallometalation as key reactions;
and (iii) the final convergent assembly of these olefin
templates to form the contiguous trisubstituted olefins
of orevactaene using Pd coupling. The direct, convergent
coupling of the two olefinic domains illustrated here
allowed for the facile preparation of two of the diaster-
eomers of compound 2. Additionally, compiled spectro-
scopic data from the literature and the present study
provide evidence that the relative configuration of the
methyl groups in the side chain of orevactaene is syn,
which will be confirmed once the total synthesis has been
completed.
1
1.63, CHCl3)]; H NMR (CDCl3, 400 MHz) δ 0.87 (t, J ) 7.3
Hz, 3H), 0.88 (d, J ) 6.2 Hz, 3H), 0.93 (d, J ) 6.7 Hz, 3H),
0.86-0.97 (m, 1H), 1.10 (m, 1H), 1.21-1.49 (m, 3H), 1.71 (sx,
J ) 6.5 Hz, 1H), 3.39 (dd, J ) 6.8, 10.3 Hz, 1H), 3.53 (dd, J )
5.0, 10.3 Hz, 1H); 13C NMR (CDCl3, 100.6 MHz, APT pulse
sequence: evens up (+), odds down (-)) δ 11.1 (-), 17.3 (-),
19.8 (-), 29.0 (+), 31.6 (-), 33.2 (-), 40.6 (+), 68.4 (+).
These data agree with the literature data.38,39
(3S,5S)-1,1-Dibr om o-3,5-d im eth yl-1-h ep ten e (31). To a
stirring solution of oxalyl chloride (0.61 mL, 6.99 mmol) in CH2-
Cl2 (20 mL) at -78 °C was added slowly dimethyl sulfoxide
(0.89 mL, 12.54 mmol). After 15 min, 29 (657 mg, 5.045 mmol)
in CH2Cl2 (10 mL followed by 2 ¥ 1 mL rinses) was added via
cannula over 5 min. The reaction mixture was stirred for 30
min, and triethylamine (3.4 mL, 24.39 mmol) was added. The
thick slurry was stirred for 30 min, warmed to 0 °C, further
stirred for 45 min, and then quenched with saturated aqueous
NH4Cl (50 mL). The aqueous layer was extracted with 4:1
Et2O/pentane, and the combined organic extracts were dried
over anhydrous Na2SO4, filtered, and evaporated in vacuo
using an ice-cold distilling bath on the rotory evaporator to
give the crude aldehyde as a yellow oil: Rf 0.49 (1:9 EtOAc/
hexanes). The crude aldehyde was used in the next step
without further purification.
To a cold (0 °C) solution of Ph3P (4.782 g, 18.23 mmol) in 10
mL of CH2Cl2 was added slowly a solution of CBr4 (3.068 g,
9.25 mmol) in CH2Cl2 (10 mL). The mixture was stirred for
15 min followed by dropwise addition of the crude aldehyde
in CH2Cl2 (10 mL) over a 10 min period. The reaction mixture
was stirred at 0 °C for 15 min and at room temperature for
2.5 h. Following dilution with 50 mL of Et2O/pentane (4:1),
the slurry was filtered through a plug of florisil and washed
with a 4:1 Et2O/pentane solution (4 × 50 mL). Organic solvents
were evaporated and the residue was purified by flash chro-
matography (florisil, hexanes) to give dibromoalkene 31 (1.162
g, 81%, two steps from 29) as a colorless oil: Rf 0.66 (hexanes);
[R]D +15.8 (c 1.50, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.89
(t, J ) 7.3 Hz, 3H), 0.90 (d, J ) 6.1 Hz, 3H), 1.01 (d, J ) 6.7
Hz, 3H), 1.08-1.21 (m, 2H), 1.28-1.41 (m, 3H), 2.58 (m, 1H),
6.15 (d, J ) 9.3 Hz, 1H); 13C NMR (CDCl3, 100.6 MHz,
APT pulse sequence: evens up (+), odds down (-)) δ 11.2 (-),
19.2 (-), 19.8 (-), 29.9 (+), 32.3 (-), 36.2 (-), 43.4 (+), 87.0
(+), 144.6 (-): HRMS (CI) calcd for C9H16Br2 [M]+ 281.9619,
found 281.9648.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under a
positive atmosphere of dry nitrogen unless otherwise indicated.
Melting points were uncorrected. Solvents were distilled prior
to use: THF and Et2O were distilled from sodium benzophe-
none ketyl; CH2Cl2, pyridine, HMPA and Et3N were distilled
from CaH2. Anhydrous DMF, DMSO, and MeOH were stored
over 4 Å molecular sieves. Acetone was dried over drierite
(anhydrous CaSO4) for a few days and distilled under nitrogen
from 4 Å molecular sieves prior to use. p-Toluenesulfonyl
chloride was recrystallized from toluene/hexanes. Tetrakis-
(triphenylphosphine)palladium(0) was prepared by reduction
of PdCl2(PPh3)2 with hydrazine.36 Chemical shifts are listed
1
relative to residual CHCl3 (δ 7.28) for H NMR and relative to
the middle peak for the triplet of CDCl3 (δ 77.00) for 13C NMR.
Rep r esen ta tive P r oced u r e for P r ep a r a tion of 4-Ben -
zyl-3-(2,4-d im eth ylh exa n oyl)-1,3-oxa zolid in -2-on es 22, 23,
27, a n d 28. Syn th esis of (4R)-4-Ben zyl-3-[(2S,4S)-2,4-
d im eth ylh exa n oyl]-1,3-oxa zolid in -2-on e (27). To a cold
(-78 °C) solution of 26 (2.33 g, 10.0 mmol) in dry THF (50
mL) was added lithium diisopropylamide (5.8 mL, 11.6 mmol,
2 M solution in heptane/THF/ethyl benzene). After being
stirred for 1 h, the resulting solution was treated with 17 (1.85
g, 8.4 mmol) and allowed to stir at -78 °C for 4.5 h and then
at room temperature for 1.5 h. The reaction was quenched with
ice-cold water, and the aqueous layer was extracted with
EtOAc. The combined organic extracts were dried (anhydrous
Na2SO4), concentrated in vacuo, and chromatographed (silica
gel, 1:4 EtOAc/hexanes) to provide recovered starting material
26 (265 mg, 11.4%) and 1.78 g (70%) of pure 2737 as a yellow
oil: Rf 0.58 (1:1 EtOAc/hexanes); [R]D -28.9 (c 2.22, CHCl3);
1H NMR (CDCl3, 400 MHz) δ 0.91 (t, J ) 7.6 Hz, 3H), 0.93 (d,
J ) 6.1 Hz, 3H), 1.19 (d, J ) 6.8 Hz, 3H), 1.13-1.25 (m, 2H),
1.34-1.48 (m, 2H), 1.89 (m, 1H), 2.76 (dd, J ) 9.8, 13.3 Hz,
1H), 3.31 (dd, J ) 2.7, 13.3 Hz, 1H), 3.96 (qdd, J ) 6.8, 6.8,
6.8 Hz, 1H), 4.15-4.23 (m, 2H), 4.71 (m, 1H), 7.23-7.37 (m,
5H); 13C NMR (CDCl3, 100.6 MHz, APT pulse sequence: evens
up (+), odds down (-)) δ 11.3 (-), 18.0 (-), 19.5 (-), 29.2 (+),
32.4 (-), 35.3 (-), 38.1 (+), 41.0 (+), 55.4 (-), 65.9 (+), 127.3
(-), 129.0 (-), 129.5 (-), 135.4 (+), 153.1 (+), 177.7 (+).
Rep r esen ta tive P r oced u r e for P r ep a r a tion of 2,4-
Dim eth yl-1-h exa n ols 24, 25, 29, a n d 30. Syn th esis of
(2S,4S)-2,4-Dim eth yl-1-h exa n ol (29). To a cooled (0 °C)
solution of imide 27 (1.70 g, 5.593 mmol) in Et2O (120 mL)
was added 262 µL of methanol (6.43 mmol) followed by a
Eth yl (4S,6S)-4,6-Dim eth yl-2-octyn oa te (33). To a solu-
tion of 31 (1.042 g, 3.67 mmol) in THF (20 mL) at -78 °C was
added n-BuLi (6.88 mL, 11.01 mmol, 1.6 M solution in
hexanes) after which the mixture was stirred for 1 h and then
at 0 °C for 1 h. After the mixture was cooled to -78 °C, ethyl
chloroformate (0.88 mL, 995 mg, 9.17 mmol) was added
dropwise over 20 min. The reaction mixture was stirred for 1
h at -78 °C, 30 min at 0 °C, and 30 min at room temperature.
The reaction mixture was quenched with a solution of satu-
rated NaHCO3 (20 mL) at 0 °C and was diluted with Et2O (35
(38) Stoermer, D.; Caron, S.; Heathcock, C. H. J . Org. Chem. 1996,
61, 9115-9125.
(36) (a) Coulson, D. R. Inorg. Synth. 1990, 28, 107-109. (b) Tellier,
F.; Sauvetre, R.; Normant, J . F. J . Organomet. Chem. 1985, 292, 19-
28.
(37) The compound that was epimeric at C-2 (i.e., (2R,4S)-2,4-
dimethylhexanoyloxazolidinone) was isolated (3.5% yield) and char-
acterized. For details, see: Supporting Information.
(39) Nakamura, S.; Inagaki, J .; Kitaguchi, J .; Tatani, K.; Hashimoto,
S. Chem. Pharm. Bull. 1999, 47, 1330-1333.
(40) Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217-3220.
(41) Lam, Y. K. T.; Hensens, O. D.; Ransom, R.; Giazobbe, R. A.;
Polishook, J .; Zink, D. Tetrahedron 1996, 52, 1481-1486.
5182 J . Org. Chem., Vol. 67, No. 15, 2002

Toward the Total Synthesis of Orevactaene
mL). Following the separation of the two layers, the aqueous
phase was additionally extracted with Et2O. The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
evaporated in vacuo. The residue was purified by flash
chromatography (silica gel, 1:9 Et2O/hexanes) to afford alkyne
33 (706 mg, 98%) as a pale yellow oil: Rf 0.46 (1:9 Et2O/
hexanes); [R]D +27.9 (c 1.78, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 0.89 (d, J ) 6.7 Hz, 3H), 0.90 (t, J ) 7.3 Hz, 3H), 1.14-
1.36 (m, 3H), 1.24 (d, J ) 6.8 Hz, 3H), 1.33 (t, J ) 7.1 Hz,
3H), 1.59 (m, 2H), 2.67 (m, 1H), 4.23 (q, J ) 7.1 Hz, 2H); 13C
NMR (CDCl3, 100.6 MHz, APT pulse sequence: evens up (+),
odds down (-)) δ 11.1 (-), 14.0 (-), 18.6 (-), 20.5 (-), 23.8
(-), 29.8 (+), 32.3 (-), 43.1 (+), 61.7 (+), 73.3 (+), 93.2 (+),
154.0 (+); HRMS (CI) calcd for C12H21O2 [MH]+ 197.1542,
found 197.1547.
were separated, and the aqueous layer was extracted with
Et2O. The combined organic layers were dried over anhydrous
Na2SO4, filtered, and evaporated in vacuo. The residue was
chromatographed on silica gel (1:9 Et2O/hexanes) to yield 43
(1.733 g, 88%, ‘one-pot’ from 40) as a light brown oil: Rf 0.32
(1:9 Et2O/hexanes); 1H NMR (CDCl3, 400 MHz) δ 1.88 (s, 3H),
3.83 (s, 3H), 4.00 (s, 2H), 4.44 (s, 2H), 6.30 (s, 1H), 6.91 (d, J
) 8.3 Hz, 2H), 7.27 (d, J ) 8.3 Hz, 2H); 13C NMR (CDCl3, 100.6
MHz, APT pulse sequence: evens up (+), odds down (-)) δ
21.6 (-), 55.3 (-), 71.7 (+), 73.7 (+), 78.6 (-), 113.9 (-), 129.4
(-), 130.0 (+), 145.0 (+), 159.3 (+).
Eth yl (Z,4S,6S)-2-{(E)-3-[(4-Meth oxyben zyl)oxy]-2-m eth -
yl-1-p r op en yl}-4,6-d im eth yl-2-octen oa te (47). To a cold
(-78 °C) solution of 43 (434 mg, 1.36 mmol) in 20 mL of dry
THF was added n-BuLi (1.2 mL, 1.92 mmol, 1.6 M solution in
hexanes). After stirring for 1 h, (i-PrO)3B (0.45 mL, 366 mg,
1.94 mmol) was added. The mixture was warmed slowly to
room temperature over 1 h, and NaOH (384 mg, 9.56 mmol)
in 1.5 mL of degassed water was added dropwise. After 20 min,
37 (329 mg, 1.015 mmol) in 5 mL of THF and Pd(PPh3)4 (161
mg, 0.139 mmol) were added. The reaction mixture was heated
at 60-65 °C for 2 h, cooled to 0 °C, and quenched with water
(30 mL). The layers were separated, and the aqueous layer
was extracted with Et2O. The combined organic layers were
dried over anhydrous Na2SO4, filtered, and evaporated in
vacuo. The residue was purified by flash chromatography
(silica gel, 1:5 Et2O/hexanes) to yield 47 (303 mg, 77%) as a
yellow oil: Rf 0.28 (1:5 Et2O/hexanes); [R]D +30.7 (c 2.19,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.85 (d, J ) 5.6 Hz, 3H),
0.87 (t, J ) 7.1 Hz, 3H), 1.04 (d, J ) 6.4 Hz, 3H), 1.13 (m,
2H), 1.30 (m, 3H), 1.33 (t, J ) 7.0 Hz, 3H), 1.74 (s, 3H), 3.06
(m, 1H), 3.82 (s, 3H), 3.96 (s, 2H), 4.25 (q, J ) 7.0 Hz, 2H),
4.44 (s, 2H), 5.62 (d, J ) 10.3 Hz, 1H), 6.11 (s, 1H), 6.90 (d, J
) 8.5 Hz, 2H), 7.29 (d, J ) 8.5 Hz, 2H); 13C NMR (CDCl3, 100.6
MHz, APT pulse sequence: evens up (+), odds down (-)) δ
11.3 (-), 14.2 (-), 15.1 (-), 19.0 (-), 21.4 (-), 30.1 (+), 31.5
(-), 32.5 (-), 44.6 (+), 55.2 (-), 60.5 (+), 71.3 (+), 75.7 (+),
113.7 (-), 124.9 (-), 128.8 (+), 129.4 (-), 130.5 (+), 134.7 (+),
148.8 (-), 159.1 (+), 168.2 (+); HRMS (CI) calcd for C24H37O4
[MH]+ 389.2692, found 389.2681.
E t h yl (Z,4S,6S)-4,6-Dim et h yl-2-[(E)-2-m et h yl-3-oxo-1-
p r op en yl]-2-octen oa te (49). To a solution of 47 (259 mg, 0.67
mmol) in CH2Cl2 (16 mL) and water (0.8 mL) at 0 °C was added
DDQ (378 mg, 1.67 mmol). The mixture was stirred for 15 min
and then further stirred at room temperature for 1.5 h. Then
the reaction mixture was quenched at 0 °C by simultaneous
addition of water (40 mL) and Et2O (40 mL). The layers were
separated, and the aqueous layer was extracted with Et2O.
The combined organic layers were dried over anhydrous Na2-
SO4, filtered, and evaporated in vacuo. The residue was
purified by flash chromatography (silica gel, 1:5 Et2O/hexanes)
to give 49 (156 mg, 88%) as a yellow oil: Rf 0.30 (1:5 Et2O/
hexanes); [R]D +62.2 (c 2.42, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 0.85 (d, J ) 5.6 Hz, 3H), 0.86 (t, J ) 7.1 Hz, 3H), 1.07
(d, J ) 6.4 Hz, 3H), 1.16 (m, 2H), 1.24-1.41 (m, 3H), 1.35 (t,
J ) 7.3 Hz, 3H), 1.80 (s, 3H), 3.05 (m, 1H), 4.30 (q, J ) 7.3
Hz, 2H), 6.01 (d, J ) 10.5 Hz, 1H), 6.90 (s, 1H), 9.46 (s, 1H);
13C NMR (CDCl3, 100.6 MHz, APT pulse sequence: evens up
(+), odds down (-)) δ 10.2 (-), 11.2 (-), 14.1 (-), 18.9 (-),
21.0 (-), 30.0 (+), 32.3 (-), 32.6 (-), 44.3 (+), 61.1 (+), 129.1
(+), 137.6 (+), 147.0 (-), 154.3 (-), 166.9 (+), 195.1 (-); HRMS
(CI) calcd for C16H27O3 [MH]+ 267.1960, found 267.1952.
Eth yl (E,4S,6S)-4,6-Dim eth yl-2-(tr ibu tylstan n yl)-2-octen -
oa te (35). To a solution of alkyne 33 (577 mg, 2.94 mmol) and
Pd(PPh3)4 (104 mg, 0.09 mmol) in dry and degassed THF at
room temperature was added dropwise n-Bu3SnH (0.815 mL,
883 mg, 3.03 mmol) at room temperature over 1 h. The reaction
mixture was stirred for 2 h, after which the solvent was
removed in vacuo. The residue was filtered through a plug (10
cm) of silica gel using 1:4 benzene/hexanes (400 mL) as a wash.
The organic phase was evaporated in vacuo, and the residue
was purified by flash chromatography (silica gel, 1:4 benzene/
hexanes) to give 35 (1.346 g, 94%) as a colorless oil: Rf 0.34
(3:7 benzene/hexanes); [R]D +38.1 (c 2.23, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ 0.82-1.19 (m, 26H), 1.24-1.37 (m, 12H),
1.43-1.59 (m, 6H), 3.07 (m, 1H), 4.15 (q, J ) 7.0 Hz, 2H), 5.69
(d, J ) 9.7 Hz, 1H); 13C NMR (CDCl3, 100.6 MHz, APT pulse
sequence: evens up (+), odds down (-)) δ 10.3 (+), 11.4 (-),
13.7 (-), 14.4 (-), 19.0 (-), 21.4 (-), 27.3 (+), 28.9 (+), 30.2
(+), 32.5 (-), 33.9 (-), 44.4 (+), 59.9 (+), 133.8 (+), 158.7 (-),
171.4 (+); HRMS (CI) calcd for C24H49O2Sn [MH]+ 489.2759,
found 489.2698; HRMS (CI) calcd for C20H39O2Sn [M + H -
+
C4H10
]
431.1976, found 431.1939.
Eth yl (E,4S,6S)-2-Iod o-4,6-d im eth yl-2-octen oa te (37).
To a solution of 35 (1.148 g, 2.356 mmol) in CH2Cl2 (45 mL)
at room temperature was added iodine (608 mg, 2.395 mmol).
The mixture was stirred for 3.5 h and concentrated in vacuo.
The residue was dissolved in Et2O (100 mL) and stirred with
semisaturated KF solution (110 mL) at room temperature for
2 h. The phases were separated, and the organic phase was
additionally extracted with Et2O. The combined organic layers
were dried over anhydrous Na2SO4, filtered, and evaporated
in vacuo. The residue was purified by flash chromatography
(silica gel, 3:7 benzene/hexanes) to afford 37 (733 mg, 96%) as
a yellow oil: Rf 0.34 (3:7 benzene/hexanes); [R]D +45.5 (c 2.22,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.83 (d, J ) 5.9 Hz, 3H),
0.88 (t, J ) 7.0 Hz, 3H), 1.02-1.20 (m, 2H), 1.03 (d, J ) 6.7
Hz, 3H), 1.30 (m, 3H), 1.34 (t, J ) 7.1 Hz, 3H), 3.17 (m, 1H),
4.27 (q, J ) 7.1 Hz, 2H), 6.60 (d, J ) 10.5 Hz, 1H); 13C NMR
(CDCl3, 100.6 MHz, APT pulse sequence: evens up (+), odds
down (-)) δ 11.3 (-), 14.1 (-), 18.9 (-), 20.5 (-), 29.9 (+), 32.4
(-), 35.8 (-), 44.0 (+), 62.2 (+), 83.0 (+), 160.9 (-), 164.1 (+);
HRMS (CI) calcd for C12H22IO2 [MH]+ 325.0655, found 325.0632.
1-({[(E)-3-Iodo-2-m eth yl-2-pr open yl]oxy}m eth yl)-4-m eth -
oxyben zen e (43). To a suspension of CuCN (832 mg, 9.29
mmol, dried at ca. 200 °C for 1 h under the stream of dry N2)
in THF (50 mL) at -78 °C was added n-BuLi (11.7 mL, 18.58
mmol, 1.6 M solution in hexanes). Upon completing the
addition (10 min), the reaction mixture was stirred at room
temperature for 30 min and cooled to -78 °C, and n-Bu3SnH
(5.408 g, 5.0 mL, 18.58 mmol) was added over 10 min. The
mixture was kept at -78 °C for 1 h, and HMPA (4.31 mL, 4.44
g, 24.77 mmol) was added followed by 40 (1.091 g, 6.19 mmol).
The reaction mixture was stirred at -78 °C for 45 min, MeI
(3.85 mL, 8.79 g, 61.93 mmol) was added, and stirring was
continued for 1 h at room temperature. The reaction mixture
was cooled to 0 °C, and iodine (3.142 g, 12.38 mmol) was added.
The mixture was stirred at room temperature for 16 h,
quenched with saturated aqueous Na2S2O4 (60 mL). The layers
Ack n ow led gm en t. This work was supported by
funding from the Ontario Research and Development
Challenge Fund (ORDCF) and NSERC (Canada).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds prepared in this study. Experi-
mental details for preparation of compounds 10-15, 17, 19-
25, 28, 30, 32, 34, 36, 38, 40, 48, and 50. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0201777
J . Org. Chem, Vol. 67, No. 15, 2002 5183