Total synthesis of (+)-xestoquinone using an asymmetric palladium-catalyzed polyene cyclization

Article abstract of DOI:10.1021/ja960807k

The first total asymmetric synthesis of (+)-xestoquinone (I) has been accomplished in 68% ee by a palladium(0)-catalyzed polyene cyclization of naphthyl triflate 44 using (S)-(+)-BINAP as the chiral ligand. Attempts at an asymmetric polyene cyclization using the corresponding naphthyl bromide 41 gave poor enantioselectivities even in the presence of silver salts, thus exemplifying the effect of the coordination state of palladium on the enantioselectivity. A new method for the preparation of 6,7-dihydroisobenzofurans is also described using a [1,2]-Wittig rearrangement on a seven-membered cyclic ether precursor.

Full text of DOI:10.1021/ja960807k

10766
J. Am. Chem. Soc. 1996, 118, 10766-10773
Total Synthesis of (+)-Xestoquinone Using an Asymmetric
Palladium-Catalyzed Polyene Cyclization
Shawn P. Maddaford, Neil G. Andersen, Walter A. Cristofoli, and Brian A. Keay*
Contribution from the Department of Chemistry, UniVersity of Calgary,
Calgary, Alberta, Canada T2N 1N4
ReceiVed March 12, 1996X
Abstract: The first total asymmetric synthesis of (+)-xestoquinone (1) has been accomplished in 68% ee by a
palladium(0)-catalyzed polyene cyclization of naphthyl triflate 44 using (S)-(+)-BINAP as the chiral ligand. Attempts
at an asymmetric polyene cyclization using the corresponding naphthyl bromide 41 gave poor enantioselectivities
even in the presence of silver salts, thus exemplifying the effect of the coordination state of palladium on the
enantioselectivity. A new method for the preparation of 6,7-dihydroisobenzofurans is also described using a [1,2]-
Wittig rearrangement on a seven-membered cyclic ether precursor.
(+)-Xestoquinone (1) and (+)-halenaquinone (2) are penta-
an enantioselective synthesis of a natural product. We report
herein a full account on our enantioselective total synthesis of
(+)-xestoquinone (68% ee). The first section describes our
initial strategy using a Heck reaction to attempt to create ring
C and the quaternary carbon center (Path A, Scheme 1).
Although this approach was unsuccessful, it led us to design a
route using an asymmetric palladium-catalyzed polyene cy-
clization which forms both rings C and D while simultaneously
introducing the asymmetric center in a single step (path B,
Scheme 1).
cyclic polyketides isolated from the Pacific sponges Xestospon-
gia sapra and Xestospongia exigua, respectively.1,2 Both 1 and
2 exhibit important biological activities. These compounds,
especially 2, are potent irreversible inhibitors of both the
oncogenic protein tyrosine kinase pp60V-src encoded by the Rous
sarcoma virus3 and the human epidermal growth factor kinase
(EGF). In addition to its antiproliferative activity, xestoquinone
is a potent cardiotonic agent resulting from its unique positive
inotropic effect on cardiac muscle.1,4 More recently, xesto-
quinone has been used as a specific biochemical probe for the
elucidation of structure and function of muscle contractile
machinery.5
Heck Reaction Approach
In our first approach toward 1, we envisaged performing a
Heck reaction on 3 to form ring C and the quaternary carbon
center of xestoquinone (1; path A, Scheme 1). Disconnection
of 3 led to the previously reported naphthalene 5 (R ) R1 )
H)10 and furan 6. We felt that 6 could be prepared from furan
8 via introduction of a suitable group at C-4 of 8 using our
previously reported methodology for the preparation of such
compounds11 followed by an intramolecular closure.
A diastereoselective synthesis of (+)-xestoquinone was
reported by Harada et al.6 starting from the optically pure
Wieland-Miescher ketone, and a formal total racemic synthesis,
via a furan ring transfer reaction, has been reported by
Kanematsu et al.7 An examination of the structures of 1 and 2
suggested that the chiral quaternary center could readily be
introduced by an asymmetric Heck or polyene cyclization.8 The
intramolecular Heck reaction is a powerful method for construc-
tion of complex polycyclic systems as demonstrated by its
application to the asymmetric synthesis of important natural
products,9 including (+)-halenaquinone.6d The power of the
asymmetric palladium-catalyzed polyene cyclization for the
construction of polycyclic ring structures has been demonstrated
only once, by Overman;8b however, it has not been applied to
We first investigated the feasibility of using an intramolecular
Barbier12 cyclization of 14 to form dihydroisobenzofuran 18
(8) For examples, see: (a) Cristofoli, W. A.; Keay, B. A. Synlett 1994,
8, 625. (b) Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc.
1993, 115, 2042. (c) Takacs, J. M.; Chandramouli, S. V. J. Org. Chem.
1993, 58, 7315. (d) Meyer, F. E.; Henniges, H.; de Meijere, A. Tetrahedron
Lett. 1992, 33, 8039. (e) Meyer, F. E.; Brandenburg, J.; Parson, P. J.; de
Meijere, A. J. Chem. Soc., Chem. Commun. 1992, 390. (f) Negishi, E.-i.
Pure Appl. Chem. 1992, 64, 323. (g) Meyer, F. E.; Parsons, P. J.; de Meijere,
A. J. Org. Chem. 1991, 56, 6487. (h) Oppolzer, W.; DeVita, R. J. J. Org.
Chem. 1991, 56, 6256. (i) Grigg, R.; Dorrity, M. J.; Malone, J. F.;
Visuvanathar, S.; Sukirthalingam, S. Tetrahedron Lett. 1990, 31, 1343. (j)
Zhang, Y.; Wu, G.-z.; Agnel, G.; Negishi, E.-i. J. Am. Chem. Soc. 1990,
112, 8590. (k) Abelman, M. M.; Overman, L. E. J. Am. Chem. Soc. 1988,
110, 2328.
* Corresponding author. Phone: 1-403-220-5354. Fax: 1-403-284-1372.
E-mail: keay@acs.ucalgary.ca.
X Abstract published in AdVance ACS Abstracts, October 15, 1996.
(1) Nakamura, H.; Kobayashi, J.; Kobayashi, M.; Ohizumi, Y.; Hirata,
Y. Chem. Lett. 1985, 713.
(2) Roll, D. M.; Scheuer, P. J.; Matsumoto, G. K.; Clardy, J. J. Am.
Chem. Soc. 1983, 105, 6177.
(3) Lee, R. H.; Slate, P. L.; Moretti, R.; Alvi, K. A.; Crews, P. Biochem.
Biophys. Res. Commun. 1992, 184, 765.
(4) Kobayashi, M.; Nakamura, H.; Kobayasi, J.; Ohizumi, J. J. Phar-
macol. Exp. Ther. 1991, 257, 90.
(5) Sakamoto, H.; Furukawa, K.; Matsunaga, K.; Nakamura, H.; Ohizumi,
Y. Biochemistry 1995, 34, 12570.
(9) For examples, see: (a) de Meijere, A.; Meyer, F. E. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2379. (b) Cabri, W.; Candiani, I. Acc. Chem. Res.
1995, 28, 2. (c) Kondo, K.; Sodeoka, M.; Shibasaki, M. Tetrahedron:
Asymmetry 1995, 6, 2453. (d) Kondo, K.; Sodeoka, M.; Shibasaki, M. J.
Org. Chem. 1995, 60, 4322 and references therein.
(6) (a) Harada, N.; Sugioka, T.; Uda, H.; Kuriki, T. J. Org. Chem. 1990,
55, 3158. (b) For a synthesis of halenaquinone, see: Harada, N.; Sugioka,
T.; Ando, Y.; Uda, H.; Kuriki, T. J. Am. Chem. Soc. 1988, 110, 8483. (c)
For approaches toward the pentacyclic ring skeleton of xestoquinone, see:
Burns, P. A.; Taylor, N. J.; Rodrigo, R. Can. J. Chem. 1994, 72, 42. (d)
For a recent asymmetric synthesis of halenaquinone, see: Kajima, A.;
Takemoto, T.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1996, 61, 4876.
(7) Kanematsu, K.; Soejima, S.; Wang, G. Tetrahedron Lett. 1991, 32,
4761.
(10) Smith, J. G.; Dibble, P. W.; Sandborn, R. P. J. Org. Chem. 1986,
51, 3762.
(11) (a) Cristofoli, W. A.; Keay, B. A. Tetrahedron Lett. 1991, 32, 5881.
(b) Keay, B. A.; Bontront, J.-L. J. Can. J. Chem. 1991, 69, 1326. (c) Bures,
E. J.; Keay, B. A. Tetrahedron Lett. 1988, 29, 1247. (d) Bures, E. J.; Keay,
B. A. Tetrahedron Lett. 1987, 28, 5965. (e) Spinazze, P.; Keay, B. A.
Tetrahedron Lett. 1989, 30, 1765.
(12) (a) Blomberg, C.; Hartog, F. A. Synthesis 1977, 18. (b) Pearce, P.
J.; Richards, D. H.; Scilly, N. F. J. Chem. Soc., Perkin Trans. 1 1972, 1655.
S0002-7863(96)00807-4 CCC: $12.00 © 1996 American Chemical Society

Total Synthesis of (+)-Xestoquinone
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10767
Scheme 1
workup provided 9 in 96% yield. Swern oxidation15 of 9 yielded
aldehyde 12, which, when treated with carbon tetrabromide and
PPh3 in a mixture of acetone/acetonitrile,16 provided a mixture
of geometrical isomers 14 and a small amount of diene 20 (5%).
Although 14 was a mixture of inseparable geometrical isomers,
we attempted a Barbier cyclization under a variety of reaction
conditions (using Li, Mg, and Zn).12,17 Complex mixtures were
always obtained, and the desired product 18 was never detected
in the reaction mixture. A final attempt using CrCl2 (generated
in situ)18 also provided a complex mixture even though allylic
chromium species have been reported to react with aldehydes.19
Since Barbier type closures did not provide any of the desired
product 18, we investigated using transition metals to form the
six-membered ring. Tabuchi and co-workers20 have reported
that allylic acetates react with aldehydes in the presence of
Pd(0) and SmI2. Acetate 10 was prepared as previously
described11a,13 and the hydroxymethyl group oxidized to provide
aldehyde 13 (Scheme 2). Treatment of 13 with 10 mol % Pd2-
(dba)3 and SmI2 in the presence of PPh3 in THF at 0 °C provided
only unreacted starting material; changing the reaction condi-
tions and amounts of reagents used did not provide any of the
expected product 18. Since the aldehyde was not reduced in
the presence of the SmI2, it must be sterically hindered by the
two large groups at the adjacent positions; thus, we attempted
a method which did not require an initial reaction with the
aldehyde. Although Semmelhack and co-workers21 have re-
ported that allylic halides and sulfonate esters react with
aldehydes in the presence of Ni(0), we found that acetate 13
did not react under similar conditions.
Scheme 2a
Although the above methods and others22 did not provide
the required precursor 18, we ultimately found that dihy-
droisobenzofurans could be easily prepared via a [1,2]-Wittig
rearrangement of a cyclic ether precursor. Yadav and Ravis-
hankar23 have used this intramolecular rearrangement to con-
struct the carbon framework of taxol by contracting a nine-
membered cyclic ether to an eight-membered carbocycle. The
use of this strategy for the preparation of 18 required a synthesis
of ether 15 (Scheme 2). This was accomplished by treatment
of 11, prepared by our modified in situ Suzuki reaction,11a,13
with DEAD and PPh3 (86%).24
Normally, the precursor for a [1,2]-Wittig rearrangement has
one of the two methylene groups (adjacent to the ether oxygen)
in an allylic or benzylic position. Treatment of the ether with
n-butyllithium results in the removal of a proton from the allylic
methylene resulting in a regiospecific rearrangement.25 Since
both methylene groups in 15 are adjacent to double bonds, two
products, 17 and 18, were possible from this rearrangement
(Scheme 2). Treatment of 15 with 2.5 equiv of n-butyllithium
in ether afforded only compound 17 in 92% yield. Since 17
a Reagents: (a) 2.2 equiv of n-BuLi, DME, 0 °C, 1 h; then add
(MeO)3B, 0 °C, 1 h; then add Pd(PPh3)4, 10% Na2CO3, 80 °C, 4 h,
and (i) (Z)-1-(TBSoxy)-3-iodo-2-butene (96%) or (ii) (Z)-1-acetoxy-
3-iodo-2-butene (88%) or (iii) (Z)-3-iodo-2-buten-1-ol (86%); (b)
acetone/acetonitrile, 0 °C (50-60%); (c) THF, 20 °C (86%); (d) THF,
0 °C (84%); (e) ether, -78 °C, 5 min; then 0 °C 1 h (92%, 17).
(Scheme 2). Bromide 14 was prepared in four steps starting
from 2-(tert-butyldimethylsilyl)-3-(hydroxymethyl)furan (8).11d
The four-carbon substituent was introduced using our modified
in situ variant of the Suzuki reaction.11a,13 Treatment of 8 with
2.2 equiv of n-butyllithium in DME resulted in a regiospecific
lithiation at C-4,11c which was quenched with trimethyl borate.
After the mixture was stirred for 1 h at 0 °C, Pd(PPh3)4 (10
mol %), 10% aqueous Na2CO3, and (Z)-3-iodo-1-((tert-
butyldimethylsilyl)oxy)-2-butene14 (1.5 equiv) were added fol-
lowed by heating the reaction to 80 °C for 4h. A standard
(15) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(16) Mattes, H.; Benezra, C. Tetrahedron Lett. 1987, 28, 1697.
(17) Gaudemar, M. Bull. Soc. Chem. Fr. 1962, 974.
(18) Hiyama, T.; Okude, Y.; Kimura, K.; Nozaki, H. Bull. Chem. Soc.
Jpn. 1982, 55, 561.
(19) Mulzer, J.; Kattner, L.; Strecker, A. R.; Schroder, C.; Buschmann,
J.; Lehmann, C.; Luger, P. J. Am. Chem. Soc. 1991, 113, 4218.
(20) (a) Tabuchi, T.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986,
27, 1195. (b) Tabuchi, T.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett.
1987, 28, 215.
(21) Semmelhack, M. F.; Brickner, S. J. J. Am. Chem. Soc. 1981, 103,
3945. The Ni(0) catalyst was prepared according to the procedure reported
by Schwartz; see: Schwartz, J.; Carr, D. B.; Hansen, R. T.; Dayrit, F. M.
J. Org. Chem. 1980, 45, 3053.
(22) Cristofoli, W. A. Ph.D. Dissertation, Department of Chemistry,
University of Calgary, Calgary, Alberta, Canada, 1995.
(23) Yadav, J. S.; Ravishankar, R. Tetrahedron Lett. 1991, 32, 2629.
(24) (a) Carlock, J. T.; Mack, M. P. Tetrahedron Lett. 1978, 5153. (b)
Mitsunobu, O.; Kimura, J.; Iiizumi, K.; Yanagida, N. Bull. Chem. Soc. Jpn.
1976, 49, 510.
(13) Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1994, 59, 6501.
(14) (Z)-1-((tert-butyldimethylsilyl)oxy)-3-iodo-2-butene was prepared
by the silylation of (Z)-3-iodo-2-buten-1-ol; see: (a) Corey, E. J.; Ven-
kateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190. (Z)-3-Iodo-2-buten-1-ol
was prepared by a LiEt3BH reduction of methyl (Z)-3-iodo-2-butenoate.
The latter was prepared according to the procedure of Normant: (b) Marek,
I.; Alexakis, A.; Normant, J.-F. Tetrahedron Lett. 1991, 32, 5329.

10768 J. Am. Chem. Soc., Vol. 118, No. 44, 1996
Maddaford et al.
Scheme 3a
TMEDA (THF, -78 °C, 1 h) lithiated exclusively at C-3. The
addition of 2-bromobenzaldehyde provided alcohol 23 in 73%
yield. Compound 23 was used as a model system to study the
Heck cyclization. Treatment of 23 with Pd(PPh3)4 in the
presence of Ag2CO3 provided a 61% yield of 25 in which 23
had undergone an oxidative debromination;27,28 the expected 26
1
(with a double bond) was not detected by either H NMR or
GC-MS analysis. To avoid this oxidative debromination
problem, we attempted to oxidize the alcohol in 23 prior to
performing the Heck reaction.29 Surprisingly, every oxidation
method tried to date (e.g., Swern oxidation, MnO2, PDC, PCC,
DDQ, Fe´tizon’s reagent, etc.) provided either unreacted starting
material or decomposed material. In our hands, ketone 24 could
not be prepared via the oxidation of alcohol 23. Finally, we
tried to close ring C by a free radical cyclization,30 but treatment
of 23 with n-Bu3SnH and AIBN in refluxing benzene did not
provide any of furan 26 (without a double bond).
With the failure of the Heck reaction, we turned our attention
toward designing an alternative route which would allow us to
prepare xestoquinone asymmetrically. The next section de-
scribes (1) how we overcame the problems associated with the
Heck reaction approach and (2) the asymmetric synthesis of
xestoquinone (1).
a Reagents: (a) imidazole, DMF (68%); (b) TMEDA, THF, -78
°C, 1 h; then 2-bromobenzaldehyde (73%); (c) Pd(PPh3)4, Ag2CO3,
toluene, 110 °C; (d) AIBN, benzene, reflux.
was the wrong isomer required for the synthesis of xestoquinone
(1), we investigated whether the bulky silane was responsible
for sterically blocking attack of the n-butyllithium at the furylic
position. The silyl group in 15 was removed (n-Bu4NF, THF)
to provide 16 and subjected to the same reaction conditions.
Furan 19 was isolated, indicating that the methylene protons
on the carbon adjacent to the double bond in the seven-
membered ring must be more acidic than those at the furylic
position. Changing the type of base, solvent, and/or temperature
did not result in the formation of the desired dihydroisobenzo-
furan.
Compound 17 could be isolated if appropriate precautions
were taken to prevent dehydration to form isobenzofuran 21.
Purification of 17 using silica gel resulted in the formation of
a small amount of 21 (∼14%); however, the addition of 10%
(w/w) potassium carbonate to the silica gel prior to the
preparation of the column suppressed the dehydration, and 17
could be isolated in 92% yield. Surprisingly, isobenzofuran 21
was relatively stable at room temperature for approximately 2
h which allowed us to obtain a 1H NMR spectrum. This unusual
stability at room temperature is in contrast to the literature which
states that isobenzofurans are difficult to isolate at room
temperature unless electron-withdrawing groups or bulky aro-
matic rings are present in the C-1 or C-3 position.26 Presumably
the presence of the bulky silane at C-1 reduces the tendency of
21 to polymerize at higher temperatures. We are currently
investigating the use of systems like 21 as intermediates in
natural product syntheses. Although the [1,2]-Wittig reaction
provided the wrong isomer, we decided to use 17 as a model to
determine if an aromatic ring could be attached to the furan
ring and if the Heck cyclization would work.
Asymmetric Palladium-Catalyzed Polyene Cyclization
Approach
In our second approach toward xestoquinone (1), we envis-
aged performing an asymmetric palladium-catalyzed polyene
cyclization8 of dienyl bromide 4 (Scheme 1), which would create
the C and D rings and also allow for the introduction of the
stereogenic center in the later stages of the synthesis. Discon-
nection of 4 gave naphthalene 5 (R ) Cl, R1 ) H or OMe) and
furan 7, which could be prepared using our previously reported
method for synthesis of 2,3,4-trisubstituted furan rings.11,13 We
initially chose to use naphthalene 5 (R ) Cl, R1 ) H) in our
synthetic approach since it was readily available from 3-bromo-
2-naphthaldehyde,10 and we felt that after the palladium-
catalyzed cyclization, ring A of the pentacyclic intermediate
could be oxidized to a quinone using literature methods.31
Furan 8 was regioselectively lithiated11c with 2.2 equiv of
13,32
n-BuLi in DME at -78 °C and trapped with B(O-i-Pr)3
(Scheme 4). In situ treatment of the borate with water or 2 M
33
Na2CO3 followed by a Pd(0) cross-coupling with 2-bromo-
propene afforded 3-isopropenylfuran 27 in 95% yield. Subse-
(27) A search of the literature revealed that Tamaru et al. have reported
that alcohols can be oxidized to ketones or acids in the presence of
Pd(OAc)2 and bromobenzene. Thus, the conversion of 23 into 25 must be
an intramolecular variant of this type of oxidation. (a) Tamaru, Y.; Yamada,
Y.; Inoue, K.; Yamamoto, Y.; Yoshida, Z.-I. J. Org. Chem. 1983, 48, 1286.
(b) Tamaru, Y.; Inoue, K.; Yamada, Y.; Yoshida, Z.-I. Tetrahedron Lett.
1981, 22, 1801. (c) Tamaru, Y.; Yamamoto, Y.; Yamada, Y.; Yoshida,
Z.-I. Tetrahedron Lett. 1979, 20, 1401.
(28) We have recently reported a new one-pot desilylation-oxidation
procedure using catalytic amounts of PdCl2 in the presence of bromo-
mesitylene; see: Wilson, N. S.; Keay, B. A. J. Org. Chem. 1996, 61, 2918.
(29) We felt the presence of ketone would also make the Heck reaction
more facile, since it has been reported that Heck reactions proceed in higher
yield and at lower temperatures when the aromatic ring containing the halide
is substituted with electron-withdrawing groups; see: Heck, R. F. Org.
React. 1982, 27, 345.
The hydroxy group in 17 was protected under standard
conditions to yield silyl ether 22 (68%; Scheme 3), which upon
treatment with 2.5 equiv of n-butyllithium in the presence of
(25) The mechanism of a [1,2]-Wittig rearrangement is believed to be
radical in nature, in which the two radicals arise from the carbon-oxygen
homolysis of an R-anionic intermediate followed by the recombination of
the radical and radical-anion fragments; see: (a) Marshall, J. A. In The
Wittig Rearrangement; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
New York, 1991; Vol. 3, p 975. (b) Scho¨llkopf, U. Angew. Chem., Int. Ed.
Engl. 1970, 9, 763.
(26) (a) Pollart, D. J.; Rickborn, B. J. Org. Chem. 1986, 51, 3155. (b)
Hayakawa, K.; Yamaguchi, Y.; Kamenatsu, K. Tetrahedron Lett. 1985, 26,
2689.
(30) Neumann, W. P. Synthesis 1987, 665.
(31) (a) Haines, A. H. Methods for the Oxidation of Organic Compounds-
Alkanes, Alkenes, Alkynes and Arenes; Academic Press, Inc.: Orlando, FL,
1985; pp 182, 358. (b) Hudlicky, M. Oxidations in Organic Chemistry;
American Chemical Society: Washington, DC, 1990; p 94. (c) Periasamy,
M.; Bhatt, M. V. Tetrahedron Lett. 1978, 4561. (d) Adam, W.; Ganeshpure,
P. A. Synthesis 1993, 280. (e) Jpn. Kokai Tokkyo Koho JP 58,153,762,
1982 Chem. Abstr. 1984, 100, 459. (f) Bockmair, G.; Fritz, H. P.
Electrochim. Acta 1976, 21, 1099. (g) Parker, V. D.; Dirlam, J. P.; Eberson,
L. Acta. Chem. Scand. 1971, 25, 341.

Total Synthesis of (+)-Xestoquinone
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10769
Scheme 4a
a Reagents: (a) n-BuLi (2.2 equiv), DME; then B(O-i-Pr)3, -78 °C to room temperature, 1 h; then 2 M Na2CO3, 3 mol % Pd(PPh3)4,
2-bromopropene, 13 h, reflux (95%); (b) CH2Cl2, room temperature (85%); (c) THF, 1 h, reflux (95%); (d) Na2HPO4, MeOH, 10 °C, 6 h (90%);
(e) hexanes, reflux (32, 77%), 1 drop of DMF (36 and 38, 99%); (f) -95 °C; then add B(OMe)3; then add H2O2, NaOH; then 10% HCl (87%); (g)
NEt3 (79%); (h) MeOH:H2O (9:1), reflux (95%); (i) i. 29 with 1.5 equiv of n-BuLi, 1.2 equiv of HMPA, THF, -78 °C, 1 h; then 32, -78 °C, 1
h (79%); ii. 29 + s-BuLi, -78 °C, THF, 20 min; then add 36 (42% from 34, three steps) or 38 (70% from 37); (j) THF, 0 °C (95%); (k) DMF,
room temperature, used immediately; (l) i. 39 or 40 with 10 mol % Pd(PPh3)4, NEt3, toluene, reflux, 12 h, (74-79%); ii. 41 with 10 mol % Pd(PPh3)4,
or Pd2(dba)3, Et3N, NMP, reflux (82%); iii. 44 with Pd2(dba)3 (2.5 mol %), S-(+)-BINAP (10 mol %), PMP (8 equiv), 22 h (82% from 43) (68%
ee with 44); (m) 1 atm, 4 h (99%); (n) CH3CN/H2O, 0 °C, 5 min.
quent PDC oxidation of 27 provided aldehyde 28, which was
converted into dienylfuran 29 by a standard Wittig reaction.
Since a ketone was necessary between the naphthalene and
furan rings in 4 (Scheme 1), we investigated the direct
condensation of the anion of 29 with 3-bromo-2-naphthoyl
chloride (32). Acid chlorides34a and nitriles34b have been
reported to react well with furyl anions for the preparation of
ketones in one step. 3-Bromo-2-naphthoyl chloride (32) was
prepared in two steps from the readily available 3-bromo-2-
naphthaldehyde10 (30; Scheme 4). Naphthaldehyde 30 was
oxidized to the corresponding acid 31 by a NaClO2/H2O2
oxidation in 90% yield, which, when treated with oxalyl chloride
in hexane, provided the required acid chloride 32 in 77% yield.
Acid chloride 32 was distilled and used immediately in the
coupling reaction with the anion of furan 29. Treatment of 29
with 1.5 equiv of n-BuLi in the presence of 1.2 equiv of HMPA
(THF, -78 °C) followed by the addition of acid chloride 32
provided ketone 39 in 79% yield. With ketone 39 in hand, we
investigated the palladium-catalyzed polyene cyclization reac-
tion.
Treatment of 39 with 10 mol % Pd(PPh3)4 in toluene (NEt3,
12 h, reflux) provided a 1:2 mixture of 46 and 48 in 74% yield.
The formation of the highly strained 46 was initially surprising
since AM1 level semiempirical calculations indicated that 48
was 25.1 kcal/mol more stable than 46. Since the final step
involved in the formation of furans 46 and 48 is a syn
elimination of H-Pd-Br, which has been reported to be a fast
process,35 we conclude that the 1:2 ratio of 46:48 is a kinetic
ratio. Adjusting the reaction conditions (type of catalyst,
solvent, time, and temperature) did not noticeably change the
ratio. Furans 46 and 48 were separated by column chroma-
tography, and 48 was used to attempt a synthesis of (()-
xestoquinone (1). The double bond in 48 was reduced by
catalytic hydrogenation to provide 51 in 65% yield. A variety
of methods31 were used to oxidize the A ring of 51 into a
quinone (CrO3-AcOH, ceric ammonium sulfate/H2SO4, Mn2-
SO4, and electrochemistry); however, complex mixtures were
obtained, and the quinone ring was never detected by 1H NMR
analysis. Furan rings are easily oxidized under similar condi-
tions,36 and presumably this was the reason for the complex
mixtures.
(32) Trapping of the lithio anion at low temperatures with the more
sterically hindered triisopropyl borate minimizes the possibility of double
addition to the borate. Di- or triaryl species do not undergo Suzuki cross
coupling with aryl halides; see: Thompson, W. J.; Guadino, J. J. Org. Chem.
1984, 49, 5237 and references therein.
(33) It has been shown that the transmetalation of boron with the Pd(II)
species in Suzuki cross couplings is enhanced by the addition of bases like
Na2CO3 or methoxide; see: (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth.
Commun. 1981, 11, 513. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457 and references therein. However, as 1 equiv of methoxide is
liberated in the in situ method, the addition of external base makes no
improvement in the yield; see ref 11a.
Since the A ring of 51 could not be oxidized without
destroying the molecule, we decided to develop a synthesis of
3-bromo-5,8-dimethoxy-2-naphthoyl chloride (38). If 38 could
(35) Heck, R. F. Vinyl Substitutions with Organopalladium Intermediates.
In ComprehensiVe Organic Chemistry; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 4, p 833.
(36) (a) Dean, F. M. AdV. Heterocycl. Chem. 1982, 30, 167. (b) Dean,
F. M. AdV. Heterocycl. Chem. 1982, 31, 237.
(34) (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Petrini, P.
J. Org. Chem. 1988, 53, 1748. (b) Siemanowski, W.; Witzel, H. Liebigs.
Ann. Chim. 1984, 1731.

10770 J. Am. Chem. Soc., Vol. 118, No. 44, 1996
Maddaford et al.
be successfully coupled with furan 29 and subsequently ring
closed, then the oxidation of the para-oriented methoxy groups
into a quinone would not be a problem since Harada oxidized
a similar intermediate into xestoquinone.6
Naphthalene 33 was prepared as previously described37 and
hydrolyzed with K2CO3 in refluxing methanol/water solution
to give acid 37. Treatment of 37 with oxalyl chloride in
methylene chloride at room temperature in the presence of a
catalytic amount of DMF provided acid chloride 38. Depro-
tonation of 29 with 1.3 equiv of s-BuLi38 and reaction with 38
gave the polyene precursor 40 in 70% yield from 37.
The polyene cyclization of 40 was first investigated with an
achiral Pd(0) catalyst. Treatment of 40 with Pd(PPh3)4 and
triethylamine (TEA) in refluxing toluene gave a 1:2 mixture of
products consistent with structures 47 and 49 (Scheme 4),
consonant with our previous findings.8a It was hoped that
conditions could be found that would preclude the formation
of the 6,5-ring system. Changing the solvent from toluene to
NMP resulted in a 1:2.5 mixture of 45 and 49. Similar results
were obtained in NMP using Pd2(dba)3 without added phos-
phine. In light of the strong preference for exo selectivity,39
the formation of even small amounts of the seven-membered
ring product 45 derived from an endo mode of cyclization is
unusual. Recently, Rigby et al. have shown that the Jeffery
conditions (10 mol % Pd(OAc)2, n-Bu4NCl (2 equiv), KOAc,
DMF, 100 °C) give exclusively endo cyclization, whereas
standard Heck conditions afforded mostly exo addition.39 This
unusual regioselectivity was attributed to a reduced coordination
sphere around the palladium capable of accommodating the
more substituted alkene site during the migratory insertion. This
may suggest a similar effect when NMP was used, where a
smaller solvent-coordinated palladium may be formed upon
displacement of phosphine ligands.
The formation of the highly strained five-membered ring,
likely formed under kinetic control,8a could be precluded if the
polyene cyclization was performed after removal of the silyl
group from 40 (Scheme 4). Thus, the polyene cyclization of
41, prepared by treatment of 40 with TBAF, afforded only
pentacycle (()-50 in 87% yield in which a 6-exo ring closure
in the first step was followed by a rare 6-endo ring closure in
the subsequent step.
With the successful preparation of (()-50, we attempted to
perform the cyclization in the presence of a chiral influence.
Asymmetric polyene cyclizations of 41 were examined using a
variety of chiral palladium catalysts; however, the enantio-
selectivities were poor at best ((i) Pd2(dba)3((R)-BINAP)2/Et3N
(5% ee); (ii) Pd2(dba)3((R)-BINAP)2/PMP (13% ee); (iii) Pd2-
(dba)3((2R,3R)-chiraphos)2/PMP (7% ee)) and could not be
improved by the addition of silver salts like Ag3PO4 or AgOTf.40
In hopes of improving the enantioselectivity, we investigated
the polyene cyclization of the corresponding triflate 44.41
Naphthyl bromide 33 was the starting point in the synthesis of
44. Halogen metal exchange of 33, trapping with B(OMe)3,
and subsequent oxidation/in situ hydrolysis afforded naphthol
acid 34. Compound 34 was treated with TfOSi(tert-Bu)Me2
(2.2 equiv) to give 35 which was subsequently converted to
acid chloride 36 (oxalyl chloride, DMF). Reaction of the anion
of 29 with 36 at -78 °C provided 42 in good yield (42% from
34, three steps). Both silyl groups in 42 were removed with
TBAF to give naphthol 43 which was converted to the triflate
44 by treatment with NaH and PhNTf2 in DMF.
Initially, the asymmetric polyene cyclization was performed
with Pd2(dba)3((R)-(-)-BINAP)4, which provided 50 in 68%
ee (78% yield). To determine if 50 had the correct absolute
stereochemistry needed for (+)-xestoquinone (1), it was con-
verted into xestoquinone by a catalytic hydrogenation to provide
52 followed by a ceric ammonium nitrate (CAN) oxidation
(Scheme 4).6,7 Comparison of the CD spectrum (run in CH3-
CN) of our synthetic sample with a CD spectrum of (+)-1
supplied to us by Professor Harada6 indicated synthetic 1 (and
thus 52 and 50) had the wrong absolute stereochemistry.
Repeating the polyene cyclization on 44 using Pd2(dba)3((S)-
(+)-BINAP)4 gave the pentacyclic product (+)-50 with high
yield and enantioselectivity (82% from 43, 68% ee).42 Finally,
(+)-xestoquinone (1) was prepared by a catalytic hydrogenation
of (+)-50 over 5% Pd/C (100%) followed by a CAN oxidation6
1
of (+)-52. The H NMR and CD spectra of synthetic (+)-
xestoquinone (1) prepared using Pd2(dba)3((S)-(+)-BINAP)4 was
identical with those provided by Prof. Harada.6
Thus, we have developed the first asymmetric synthesis of
(+)-xestoquinone which represents the first application of an
asymmetric palladium-catalyzed polyene cyclization directed
toward the synthesis of a natural product. We are currently
investigating the use of the polyene cyclization toward other
natural products and developing conditions to improve the
enantioselectivity of the reaction.
Experimental Section
Methods and Materials. Compound 8,11b (Z)-3-iodo-2-buten-1-
ol,14 3-bromo-2-naphthaldedhyde (30),10 ethyl 3-bromo-5,8-dimethoxy-
2-naphthoate (33),36 and the CAN oxidation of 526 were prepared or
carried out according to literature procedures. All NMR spectra were
run in CDCl3 unless otherwise stated. All melting points are uncor-
rected. Elemental analyses and HRMS spectra were obtained by Dorthy
Fox at The University of Calgary.
2-((1,1-Dimethylethyl)dimethylsilyl)-4-(propen-2-yl)-3-
(hydroxymethyl)furan (27). Furan 8 (0.71 g, 3.35 mmol) in DME
(13 mL) at -78 °C under N2 was treated with n-butyllithium (2.5 M
in hexane, 2.29 mL, 7.37 mmol). The solution was warmed to 0 °C
and stirred for 1 h. B(OMe)3 (0.96 mL, 6.70 mmol) was added and
the mixture stirred for 1 h. Into a second flask were placed Pd(PPh3)4
(0.12 g, 0.10 mmol), 2-bromopropene (0.45 mL, 5.03 mmol), and DME
(6 mL). The contents of the first flask were transferred by syringe
into the second flask followed by the addition of water (3 mL). The
flask was immersed into a preheated oil bath at 70 °C. After 1 h ether
was added, the organic layer separated and dried (Na2SO4), and the
solvent removed. The crude product was purified by flash chroma-
tography on silica gel using hexane:ethyl acetate (8:1) to provide 27
as a colorless white solid (0.50 g, 59%) which was recrystallized from
1
ethyl acetate: mp 46-47 °C; IR (neat) 3297, 1471, 1251 cm-1; H
NMR (200 MHz) δ 7.60 (s, 1H), 5.41 (br s, 1H), 5.07 (br s, 1H), 4.63
(s, 2H), 2.07 (dd, 3H, J ) 1.4, 0.7 Hz), 1.50 (br s, 1H, OH), 0.93 (s,
9H), 0.33 (s, 6H); 13C NMR (50 MHz) δ 157.9, 144.7, 135.2, 133.1,
126.7, 112.9, 55.6, 26.3, 23.5, 17.1, -5.5; MS (EI, m/z) 252 (5, M+),
237 (18, M+ - 15), 195 (100, M+ - 57). Anal. Calcd for C14H24O2-
Si: C, 66.61; H, 9.58. Found: C, 66.55; H, 9.85.
(37) Andersen, N. G.; Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1996,
61, 2885.
(38) Previously, the anion of 29 was generated by treatment with 1.5
equiv of n-BuLi in the presence of HMPA; see ref 8a.
(39) Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995,
117, 7834.
(40) For a discussion of the role of silver salts, see: (a) Sato, Y.; Sodeoka,
M.; Shibasaki, M. Chem. Lett. 1990, 1953. (b) Sato, Y.; Watanabe, S.;
Shibasaki, M. Tetrahedron Lett. 1992, 33, 2589. (c) Sato, Y.; Nukui, S.;
Sodeoka, M.; Shibasaki, M. Tetrahedron 1994, 50, 371.
(41) Higher asymmetric induction can be achieved when triflates are used
as the leaving group in the Heck reaction. This has been ascribed to an
increase in the liability of the Pd-OTf bond in the oxidative addition
complex and allows bidentate coordination of the chiral ligand; see ref 9b.
3-Formyl-2-((1,1-dimethylethyl)dimethylsilyl)-4-(propen-2-yl)-
furan (28). To a flask containing CH2Cl2 (25 mL) at -78 °C was
(42) Enantiomeric excess was determined by HPLC: Chiralcel OJ, 85:
15 hexanes:ethanol, λ ) 350 nm. The absolute stereochemistry of (+)-50
was extrapolated by comparing the CD spectrum of synthetic (+)-
xestoquinone with a copy of the original CD spectrum sent to us by Prof.
N. Harada.6a

Total Synthesis of (+)-Xestoquinone
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10771
added oxalyl chloride (1.1 equiv). DMSO (2.2 equiv) was added slowly
and the mixture stirred for 2 min. Furan 27 (0.30 g, 1.19 mmol) in
CH2Cl2 (10 mL) was added dropwise over 5 min. After 15 min Et3N
(5 equiv) was added and the mixture warmed to room temperature.
Water (50 mL) was added and the aqueous layer extracted with CH2-
Cl2 (5 × 25 mL). The organic layer was washed with 5% HCl (15
mL), 5% Na2CO3 (15 mL), and water (15 mL) and dried (Na2SO4) and
the solvent removed to provide 28 as a colorless liquid (0.23 g, 77%):
mL). The solution was placed under N2 and cooled to -95 °C (hexanes/
liquid N2) and n-BuLi (80 µL of 2.5 M in hexanes, 0.20 mmol, 1.05
equiv) added. The solution was stirred for 3 min followed by the
addition of B(OMe)3 (3 equiv, 0.57 mmol, 65 µL), subsequently warmed
to room temperature over a period of 2 h, and stirred for an additional
15 h. The resulting solution, containing a white precipitate, was cooled
to 0 °C, 2 N aqueous NaOH (4 equiv, 0.76 mmol, 0.25 mL) and 30%
H2O2 (4 equiv, 87 µL) were added, and the mixture was stirred overnight
at room temperature. The solid was dissolved in water and the solution
extracted with CH2Cl2 until the organic phase was colorless. The
aqueous phase was acidified (10% HCl), resulting in a bright yellow
precipitate which was extracted with CH2Cl2. The organic extracts were
dried (Na2SO4), filtered, and evaporated to provide 34 as a yellow solid
(41.2 mg, 87%) which was recrystallized from CH2Cl2: mp 266-268
°C; IR (KBr) 3275, 1668, 1463, 1289, 1194 cm-1; 1H NMR (200 MHz,
DMSO-d6) δ 8.68 (s, 1H), 7.40 (s, 1H), 6.87 (d, 1H, J ) 8.4 Hz), 6.65
(d, 1H, J ) 8.4 Hz), 3.90 (s, 3H), 3.88 (s, 3H); 13C NMR (50 MHz,
DMSO-d6) δ 171.3, 156.5, 149.6, 147.1, 130.0, 126.3, 119.1, 114.5,
107.0, 105.5, 101.3, 55.7, 55.5; MS (EI, m/z) 248 (52.4, M+), 231 (16.1),
230 (100), 216 (12.4), 215 (97.1), 187 (33.6), 115 (17.3). HRMS: calcd
for C13H12O5, 248.0685; found, 248.0679.
(1,1-Dimethylethyl)dimethylsilyl 5,8-Dimethoxy-3-((1,1-dimeth-
ylethyl)dimethylsiloxy)-2-naphthoate (35). The acid 34 (70 mg, 0.28
mmol) was partially dissolved in dry CH2Cl2 (3 mL). Triethylamine
(236 µL, 1.69 mmol, 3 equiv) was added followed by TfOSi(tert-Bu)-
Me2 (136 µL, 0.59 mmol, 2.1 equiv). The resulting solution was stirred
at room temperature for 21 h. The solution was filtered through silica
gel using hexanes:ethyl acetate (8:1) containing a few drops of TEA.
The solvent was evaporated to give an oil (106 mg, 79%). The crude
product 35 was used in the acid chloride reaction without further
purification. An analytical sample was purified by radial chromatog-
raphy (15:1 hexanes:ethyl acetate): 1H NMR (200 Hz) δ 8.65 (s, 1H),
7.58 (s, 1H), 6.72 (d, 1H, J ) 8.1 Hz), 6.56 (d, 1H, J ) 8.1 Hz), 3.95
(s, 3H), 3.94 (s, 3H), 1.06 (s, 9H), 1.05 (s, 9H), 0.42 (s, 6H), 0.28 (s,
6H); 13C NMR (50 Mz) δ 165.9, 152.6, 150.3, 148.4, 129.3, 126.9,
125.2, 121.0, 111.4, 105.8, 101.7, 56.0, 55.9, 26.1, 26.0, 18.7, 18.1,
-4.1, -4.4.
1
bp 56-70 °C/0.06 Torr; IR (neat) 1690, 1471, 1253 cm-1; H NMR
(200 MHz) δ 10.10 (s, 1H), 7.57 (s, 1H), 5.25 (br s, 1H), 5.13 (br s,
1H), 2.06 (d, 3H, J ) 0.8 Hz), 0.95 (s, 9H), 0.37 (s, 6H); 13C NMR
(50 MHz) δ 186.6, 171.9, 144.6, 135.9, 134.7, 127.1, 115.8, 26.3, 23.3,
17.4, -5.5; MS (EI, m/z) 250 (1, M+), 235 (8, M+ - 15), 193 (100,
M+ - 57). Anal. Calcd for C14H22O2Si: C, 67.15; H, 8.86. Found:
C, 66.83; H, 8.93.
3-Ethenyl-2-((1,1-dimethylethyl)dimethylsilyl)-4-(propen-2-yl)-
furan (29). Methyltriphenylphosphonium bromide was purified by
washing numerous times with hot toluene followed by drying under
high vacuum for 8 h. In a nitrogen-purged 3-necked flask, the purified
phosphonium salt (0.28 g, 0.77 mmol) was suspended in THF (10 mL)
and cooled to 0 °C. n-Butyllithium (2.5 M in hexane, 0.14 mL, 0.33
mmol) was added slowly via a syringe and the reaction mixture warmed
to room temperature and allowed to stir for 20 min. A solution of
aldehyde 28 (77.6 mg, 0.31 mmol) was dissolved in THF (5 mL) in an
addition funnel and added to the orange-yellow solution of the ylide.
After refluxing the mixture for 3 h, it was cooled to room temperature,
poured into ether (20 mL), and allowed to stir overnight. The solvent
was evaporated in Vacuo to leave a yellow solid which was purified
by flash chromatography on silica gel using hexane:ethyl acetate (100:
1) to yield 29 as a colorless liquid (66.6 mg, 87%): bp 38-50 °C/0.06
Torr; IR (neat) 1633, 1251 cm-1; 1H NMR (200 MHz) δ 7.48 (s, 1H),
6.67 (dd, 1H, J ) 17.9, 11.2 Hz), 5.46 (dd, 1H, J ) 17.9, 2.1 Hz),
5.25 (dd, 1H, J ) 11.2, 2.1 Hz), 5.15 (br s, 1H), 5.02 (br s, 1H), 2.02
(dd, 3H, J ) 1.4, 1.0 Hz), 0.93 (s, 9H), 0.27 (s, 6H); 13C NMR (50
MHz) δ 156.4, 143.7, 136.5, 135.0, 129.1, 126.7, 117.3, 114.0, 26.5,
23.2, 17.7, -5.2; MS (EI, m/z) 248 (40, M+), 191 (100, M+ - 57).
Anal. Calcd for C15H24OSi: C, 72.52; H, 9.74. Found: C, 72.46; H,
9.86.
5,8-Dimethoxy-3-((1,1-dimethylethyl)dimethylsiloxy)-2-naph-
thoyl Chloride (36). The silyl ester 35 (0.106 g, 0.223 mmol) was
dissolved in dry CH2Cl2 (2.5 mL). Oxalyl chloride (2.5 equiv, 0.56
mmol, 48 µL) and DMF (1 µL) were added resulting in a vigorous
release of CO gas. The yellow solution was stirred for 19 h at room
temperature and the solvent evaporated to give a yellow solid which
was used in the next reaction without further purification. The reaction
3-Bromo-2-naphthoic Acid (31). Naphthaldehyde 3010 (10.55 g,
2.34 mmol) was dissolved in methanol (8.8 mL). NaH2PO4 (0.16 g)
in water (2 mL), two portions of NaClO2 (0.69 g, 6 mL), and 30%
H2O2 (0.6 mL) were added 3h apart while keeping the temperature at
10 °C. After 6.5 h, Na2SO3 (0.4 g) was added followed by the addition
of 10% aqueous HCl. The reaction mixture was stored in the
refrigerator overnight, and the next morning the solid white fluffy
precipitate was filtered to provide acid 31 (0.54 g, 92%) which was
recrystallized from CHCl3: mp 222-223 °C (lit.43 mp 220 °C); IR
1
appeared quantitative by H NMR analysis: 1H NMR (200 MHz) δ
8.99 (s, 1H), 7.56 (s, 1H), 6.80 (d, 1H, J ) 8.4 Hz), 6.60 (d, 1H, J )
8.4 Hz), 3.98 (s, 3H), 3.95 (s, 3H), 1.06 (s, 9H), 0.32 (s, 6H).
3-Bromo-5,8-dimethoxy-2-naphthoic Acid (37). The ester 3336
(176 mg, 0.53 mmol) was dissolved in 9:1 methanol:H2O (10 mL).
Solid K2CO3 monohydrate (290 mg, 3.3 equiv) was added and the
solution refluxed for 4 h under N2. The solution was cooled and the
methanol evaporated to give a solid. Dilute HCl (10%, 10 mL) was
added to the solid resulting in a bright yellow precipitate. Ethyl acetate
(10 mL) was added and the mixture transferred to a separatory funnel.
The layers were separated, the aqueous phase was extracted with ethyl
acetate (2 × 10 mL), and the combined organic layers were dried (Na2-
SO4), filtered, and evaporated to give a yellow solid (158 mg, 95%):
mp 242-243 °C; IR (KBr) 2943 (br), 1699 cm-1; 1H NMR (200 MHz)
δ 8.92 (s, 1H), 8.54 (s, 1H), 6.86 (d, 1H, J ) 8.4 Hz), 6.76 (d, 1H, J
) 8.4 Hz), 3.98 (s, 3H), 3.96 (s, 3H); 13C NMR (acetone-d6) δ 167.7,
151.0, 149.3, 130.8, 128.5, 127.6, 124.4, 118.5, 108.5, 56.8, 56.7; MS
(EI, m/z) 312, 310 (85.2, M+), 297, 295 (100, M+ - 15), 269 (13.4),
267 (13.5), 217 (40.1). HRMS: calcd for C12H8O4Br, 309.9841; found,
309.9870.
5-((3-Bromonaphth-2-yl)carbonyl)-3-ethenyl-2-((1,1-dimethyleth-
yl)dimethylsilyl)-4-(propen-2-yl)furan (39). To a mixture of divin-
ylfuran 29 (0.22 g, 0.89 mmol) and HMPA (0.18 mL, 1.06 mmol) in
THF (5 mL) at -78 °C was added n-butyllithium (2.5 M solution in
hexane, 0.43 mL, 1.33 mmol), and the solution was stirred for 1 h. In
a second flask, acid chloride 32 (0.35 g, 1.30 mmol) was dissolved in
THF (4 mL) and cooled to -78 °C. The contents of the first flask
were transferred via a cannula to the second flask and the mixture stirred
1
(Nujol) 3200-2920 (br s), 1701, 1460 cm-1; H NMR (200 MHz) δ
8.58 (s, 1H), 8.22 (s, 1H), 7.95 (dd, 1H, J ) 8.0, 1.1 Hz), 7.72 (d, 1H,
J ) 7.8, 1.0 Hz), 7.61 (m, 2H); 13C NMR (50 Mz) ((CD3)2CO) δ 167.4,
136.1, 133.8, 132.8, 132.3, 131.4, 130.8, 129.8, 128.2, 127.8, 117.4;
MS (EI, m/z) 252, 250 (100, M+), 235, 233 (50, M+ - 17). Anal.
Calcd for C11H7O2Br: C, 52.62; H, 2.81. Found: C, 52.12; H, 2.65.
HRMS: calcd for C11H7O281Br, 251.9610; found, 251.9597.
3-Bromo-2-naphthoyl Chloride (32). Acid 31 (0.91 g, 3.62 mmol)
and dry hexane (25 mL) were added to a nitrogen-purged single-necked
round bottom flask. The reaction flask was cooled to 0 °C, and oxalyl
chloride (1.15 mL, 13.2 mmol) was added. The reaction mixture was
stirred at 0 °C for 5 min. A condenser was attached, and the reaction
flask was immersed in a preheated oil bath at 65 °C and allowed to
reflux gently overnight. After 12 h the flask was cooled to room
temperature, the solvent removed in Vacuo, and the flask back-purged
with nitrogen. The crude material was distilled and used immediately
in the next reaction. Acid chloride 32 was obtained as a colorless liquid
1
(0.75 g, 72%): bp 100 °C/0.06 Torr; IR (neat) 1776, 1433 cm-1; H
NMR (200 MHz) δ 8.64 (s, 1H), 8.11 (s, 1H), 7.93 (dd, 1H, J ) 6.6,
1.0 Hz), 7.71-7.52 (m, 3H); 13C NMR (50 MHz) δ 165.5, 135.9, 135.8,
133.6, 131.5, 130.7, 130.4, 129.3, 127.7, 126.7, 115.8.
2-Hydroxy-5,8-dimethoxy-2-naphthoic Acid (34). Bromonaph-
thalene 3336 (63.2 mg, 0.191 mmol) was dissolved in dry THF (1.6
(43) Young, S. D.; Wiggins, J. M.; Huff, J. R. J. Org. Chem. 1988, 53,
1114.

10772 J. Am. Chem. Soc., Vol. 118, No. 44, 1996
Maddaford et al.
for 1 h. Saturated aqueous NH4Cl was added at -78 °C, and after the
mixture stirred for 10 min the dry ice bath was removed and the reaction
mixture was allowed to come to room temperature. The aqueous layer
was extracted with ether (5 × 5 mL), the combined extracts were dried
(Na2SO4) and filtered, and the solvent was removed in Vacuo. The
crude product was purified on a Chromatotron using hexane:ethyl
acetate (100:1) to provide 39 as a white powder (0.34 g, 79%) which
was recrystallized from CHCl3: mp 94.5-96 °C; IR (KBr) 1657, 1554,
crude acid chloride 36 (0.22 mmol) in THF (6 mL) at -78 °C. The
resulting solution was stirred for 50 min and the reaction quenched
with saturated NH4Cl (9 mL). The mixture was warmed to room
temperature and partitioned with ethyl acetate (2 × 25 mL). The
combined layers were dried (Na2SO4), filtered, and evaporated. The
product was purified by radial chromatography on silica gel (20:1
hexanes:ethyl acetate) to provide 42 as a yellow oil (70 mg, 42% from
34, three steps): IR (film) 1632, 1463, 1263 cm-1; 1H NMR (200 MHz)
δ 8.24 (s, 1H), 7.50 (s, 1H), 6.72 (d, 1H, J ) 8.3 Hz), 6.59 (dd, 1H,
J ) 11.5, 17.8 Hz), 6.56 (d, 1H, J ) 8.3 Hz), 5.61 (dd, 1H, J ) 1.7,
17.8), 5.22 (dd, 1H, J ) 1.7, 11.5 Hz), 5.13 (m, 1H), 4.96 (m, 1H),
3.96 (s, 3H), 3.91 (s, 3H), 2.05 (br s, 3H), 0.85 (s, 9H), 0.84 (s, 9H),
0.20 (s, 6H), 0.18 (s, 6H); 13C NMR (50 MHz) δ 184.9, 160.9, 151.5,
150.6, 148.6, 137.3, 135.3, 134.5, 133.3, 128.6, 127.6, 124.3, 121.4,
117.6, 117.3, 109.5, 105.2, 101.6, 56.1, 55.8, 26.6, 25.8, 23.1, 18.3,
17.7; MS (EI, m/z) 592 (1, M+), 535 (100). HRMS: calcd for C30H39O5-
Si2 (M+ - C4H9), 535.2336; found, 535.2317.
5-((3-Hydroxy-5,8-dimethoxynaphth-2-yl)carbonyl)-3-ethenyl-4-
(propen-2-yl)furan (43). Disilane 42 (53.9 mg, 0.091 mmol) was
dissolved in dry THF (5 mL) and cooled to 0 °C under N2.
Tetrabutylammonium fluoride (186 µL of a 1 M solution in THF, 0.186
mmol, 2.05 equiv) was added resulting in a red solution. After 5 min,
the reaction was quenched with saturated NH4Cl (6 mL) and the mixture
extracted with CH2Cl2 (3 × 6 mL). The fractions were combined, dried
(Na2SO4), filtered, and evaporated to give a red oil which was purified
by radial chromatography (4:1 hexanes:ethyl acetate) to provide 43 as
a red oil (33.1 mg, 0.091 mmol, 99%): IR (film) 1642 cm-1; 1H NMR
(200 MHz) δ 10.34 (s, 1H, OH), 9.10 (s, 1H), 7.81 (s, 1H), 7.66 (s,
1H), 6.75 (d, 1H, J ) 8.3 Hz), 6.51 (d, 1H, J ) 8.3 Hz), 6.49 (ddd,
1H, J ) 0.7, 11.2, 17.8 Hz), 5.68 (dd, 1H, J ) 1.3, 17.8 Hz), 5.34-
5.28 (7 line m, 2H), 5.02 (dd, 1H, J ) 0.89, 1.7 Hz), 3.95 (s, 3H), 3.94
(s, 3H), 2.08 (t, 3H, J ) 1.3 Hz); 13C NMR (50 Mz) δ 219.2, 216.3,
158.2, 151.0, 148.4, 142.6, 136.7, 129.7, 126.5, 125.5, 117.9, 116.7,
111.0, 110.0, 107.4, 107.3, 100.9, 56.1, 55.8, 23.1; MS (EI, m/z) 364
(2, M+). HRMS: calcd for C22H20O5, 364.1311; found, 364.1288.
5-((5,8-Dimethoxy-3-((trifluoromethyl)sulfonyl)naphth-2-yl)car-
bonyl)-3-ethenyl-4-(propen-2-yl)furan (44). A solution of naphthol
43 (14.4 mg, 0.039 mmol) in dry DMF (2 mL) was cannulated into an
ice-cooled flask containing solid sodium hydride (3.8 mg, 4 equiv).
The resulting dark red solution was stirred at 0 °C for 15 min under
N2 followed by the addition of N-phenyltriflimide (PhNTf2) (56 mg, 4
equiv) which rapidly decolorized the solution. The resultant colorless
solution was stirred for 3.5 h, diluted with CH2Cl2 (20 mL), and
extracted with saturated NaCl (3 × 5 mL). The organic layer was
dried (Na2SO4), filtered, and evaporated. Excess DMF and PhNTf2
were removed by heating under vacuum (0.1 Torr, 40 °C) to give the
crude triflate 44. The crude triflate was used in the polyene cyclization
without further purification.
1
1255, 754 cm-1; H NMR (200 MHz) δ 8.09 (s, 1H), 7.91 (s, 1H),
7.91-7.70 (m, 2H), 7.61-7.45 (m, 2H), 6.61 (dd, 1H, J ) 17.8, 11.5
Hz), 5.64 (dd, 1H, J ) 17.8, 1.6 Hz), 5.24 (dd, 1H, J ) 11.5, 1.6 Hz),
5.18 (br s, 1H), 5.07 (br s, 1H), 2.05 (t, 3H, J ) 1.3 Hz), 0.85 (s, 9H),
0.24 (s, 6H); 13C NMR (50 MHz) δ 183.6, 161.8, 150.4, 137.9, 136.7,
135.4, 135.2, 134.5, 131.4, 131.2, 129.2, 128.3, 127.9, 127.1, 127.0,
126.9, 117.9, 117.4, 116.8, 26.3, 22.6, 17.4, -5.6; MS (EI, m/z) 482,
480 (82, M+), 425, 423 (54, M+ - 57), 401 (12, M+ - Br). Anal.
Calcd for C26H29O2BrSi: C, 64.85; H, 6.07. Found: C, 65.04; H, 6.16.
5-((3-Bromo-5,8-dimethoxynaphth-2-yl)carbonyl)-3-ethenyl-2-
((1,1-dimethylethyl)dimethylsilyl)-4-(propen-2-yl)furan (40). The
bromo acid 37 was distilled at high vacuum (bp 130-180 °C/0.1 Torr)
and dissolved in dry CH2Cl2 (3 mL). Oxalyl chloride (30.2 µL, 0.35
mmol, 1.2 equiv) was added followed by the addition of DMF (1 µL)
resulting in the evolution of gas. The solution was stirred for 6 h at
room temperature and the solvent removed in Vacuo to provide acid
chloride 38 as a yellow solid. This material was used without further
purification.
Furan 29 was dissolved in dry THF (2 mL) and cooled to -78 °C
under N2. s-BuLi (0.23 mL of 1.28 M in cyclohexane, 0.289 mmol)
was added to the furan solution and the resulting yellowish solution
stirred for 15 min. The furyl-anion solution (-78 °C) was cannulated
into a solution of acid chloride 38 in THF (-78 °C) and stirred for 50
min. The cold solution was quenched with saturated NH4Cl (10 mL)
and then warmed to room temperature. The solution was extracted
with ethyl acetate, dried (Na2SO4), filtered, and evaporated. 1H NMR
of the crude revealed a 71% yield (based on starting furan). The oil
was purified by radial chromatography (4:1 hexanes:ethyl acetate) to
give a yellowish oil (109 mg, 70%): IR (film) 1768, 1657, 1583, 1461,
1108 cm-1; 1H NMR (200 MHz) δ 8.48 (s, 1H), 8.29 (s, 1H), 6.77 (d,
1H, J ) 8.4 Hz), 6.70 (d, 1H, J ) 8.4 Hz), 6.61 (dd, 1H, J ) 11.5,
17.8 Hz), 5.64 (dd, 1H, J ) 1.7, 17.9 Hz), 5.26 (dd, 1H, J ) 1.7, 11.5
Hz), 5.14 (t, 1H, J ) 1.6 Hz), 5.05 (dd, 1H, J ) 1.0, 1.8 Hz), 3.95 (s,
3H), 3.90 (s, 3H), 2.03 (t, 1H, J ) 1.0 Hz), 0.87 (s, 9H), 0.24 (s, 6H);
13C NMR (50 MHz) δ 184.0, 162.0, 150.2, 148.6, 137.8, 137.1, 135.8,
127.8, 127.4, 126.3, 124.5, 124.3, 118.1, 117.0, 67.0, 105.9, 104.4,
56.1, 55.9, 26.6, 23.0, 17.8; MS (EI, m/z) 542, 540 (39, M+), 485, 483
(23, M+ - 57). HRMS: calcd for C28H33O4BrSi, 542.1320; found,
542.1299.
5-((3-Bromo-5,8-dimethoxynaphth-2-yl)carbonyl)-3-ethenyl-4-
(propen-2-yl)furan (41). Silane 40 (109 mg, 0.20 mmol) was dissolved
in THF (3 mL) and cooled to 0 °C under N2. Tetra-n-butylammonium
fluoride (0.22 mL, 1 M in THF, 1.1 equiv) was added dropwise and
the solution stirred for 15 min. The reaction was quenched with
saturated NH4Cl (0.5 mL), the mixture was passed through a short silica
gel column (ethyl acetate eluent), and the solvent was evaporated. The
solid was purified by radial chromatography (4:1 hexanes:ethyl acetate)
to give a bright yellow solid (82 mg, 0.19 mmol, 95%) which was
recrystallized from ethyl acetate: mp 107-112 °C; IR (film) 1653,
12b-Methyl-4-((1,1-dimethylethyl)dimethylsilyl)-1H-benzo[6,7]-
phenanthro[10,1-bc]furan-6(12bH)-one (48) and 3-((1,1-Dimethyl-
ethyl)dimethylsilyl)-11b-methyl-2-methylidene-1H-naphth[2′,3′:4,5]-
indeno[7,1-bc]furan-5(11bH)-one (46). A flask containing a mixture
of compound 39 (0.22 g, 0.46 mmol), toluene (4 mL), Pd(PPh3)4 (52
mg, 0.045 mmol), and triethylamine (2 mL) was immersed into a
preheated oil bath (100 °C). After 12 h, the reaction was complete by
GC-MS, and the mixture was filtered through Celite and the solvent
removed in Vacuo. The crude mixture was purified by flash chroma-
tography on silica gel using hexane:ethyl acetate (30:1) to provide a
2:1 mixture of 48:46.
1
1461, 1267, 1107 cm-1; H NMR (200 MHz) δ 8.45 (s, 1H), 8.25 (s,
1H), 7.65 (d, 1H, J ) 0.4 Hz), 6.80 (d, 1H, J ) 8.4 Hz), 6.74 (d, 1H,
J ) 8.4 Hz), 6.38 (dd, 1H, J ) 5.9, 17 Hz), 5.61 (dd, 1H, J ) 1.3, 17
Hz), 5.25 (dd, 1H, J ) 1.3, 11.2 Hz), 5.10 (t, 1H, J ) 1.6 Hz), 4.97
(dd, 1H, J ) 1, 1.7 Hz), 3.97 (s, 3H), 3.93 (s, 3H), 1.95 (t, 3H, J ) 1.0
Hz); 13C NMR (50 MHz) δ 184.0, 150.1, 148.6, 147.8, 143.1, 137.5,
136.3, 135.9, 127.9, 126.6, 126.5, 125.4, 124.4, 124.0, 118.6, 117.4,
116.6, 106.1, 104.6, 56.1, 56.0, 23.00; MS (EI, m/z) 428, 426 (65, M+).
HRMS: calcd for C22O4H19Br, 428.0451; found, 428.0478.
5-((3-((1,1-Dimethylethyl)dimethylsilyl)-5,8-dimethoxynaphth-2-
yl)carbonyl)-3-ethenyl-2-((1,1-dimethylethyl)dimethylsiloxy)-4-(pro-
pen-2-yl)furan (42). Furan 29 (59 mg, 0.25 mmol, 1.1 equiv) was
dissolved in dry THF and cooled to -78 °C under N2. s-BuLi (0.23
mL of a 1.22 M solution in cyclohexane, 0.29 mmol, 1.3 equiv) was
added. After 20 min the mixture was cannulated into a solution of the
Compound 48: bp 136-140 °C/0.07 Torr; IR (neat) 1672, 1624,
1
1462 cm-1; H NMR (200 MHz) δ 8.95 (s, 1H), 8.04 (br d, 1H, J )
7.8 Hz), 7.90 (s, 1H), 7.87 (br d, 1H, J ) 7.2 Hz), 7.62-7.48 (m, 2H),
6.71 (dd, 1H, J ) 9.7, 2.7 Hz), 6.11 (ddd, 1H, J ) 9.7, 6.3, 2.7 Hz),
3.80 (dd, 1H, J ) 16.7, 6.3 Hz), 2.67 (dt, 1H, J ) 16.7, 2.7 Hz), 1.52
(s, 3H), 0.98 (s, 9H), 0.40 (s, 6H); 13C NMR (50 MHz) δ 172.5, 160.8,
147.3, 145.7, 144.0, 134.6, 131.9, 130.9, 129.5, 128.3, 127.9, 127.2,
126.3, 123.8, 123.6, 123.6, 119.3, 39.7, 35.2, 32.3, 26.3, 17.3, -5.9,
-6.0; MS (EI, m/z) 400 (20, M+), 385 (2, M+ - 15), 343 (100, M+
-
57). Anal. Calcd for C26H28O2Si: C, 77.95; H, 7.04. Found: C, 77.58;
H, 6.87. HRMS: calcd for C26H28O2Si, 400.1859; found, 400.1851.
Compound 46: 69 mg, 39%; bp 130-138 °C/0.07 Torr; IR (neat)
1
1685, 1660, 1464, 1253 cm-1; H NMR (200 MHz) δ 8.90 (s, 1H),

Total Synthesis of (+)-Xestoquinone
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10773
7.99 (dd, 1H, J ) 7.9, 1.2 Hz), 7.85 (dd, 1H, J ) 8.0, 1.3 Hz), 7.79 (s,
1H), 7.62-7.45 (m, 2H), 5.48 (m, 1H), 5.36 (m, 1H), 3.51 and 3.38
(complex ABq, 1H each), 1.65 (s, 3H), 0.99 (s, 9H), 0.41 (s, 3H), 0.38
(s, 3H); 13C NMR (50 MHz) δ 172.8, 163.4, 162.5, 145.8, 145.4, 141.5,
139.7, 134.5, 134.3, 131.7, 130.8, 129.7, 128.4, 127.1, 126.4, 125.5,
110.5, 55.6, 41.5, 32.2, 26.4, 15.2, -6.0, -6.7); MS (EI, m/z) 400 (40,
M+), 343 (100, M+ - 57). Anal. Calcd for C26H28O2Si: C, 77.95; H,
7.04. Found: C, 77.72; H, 7.09.
0.35 (s, 3H); 13C NMR (50 MHz) δ 172.6, 162.0, 148.2, 146.8, 146.1,
134.6, 132.2, 131.6, 131.5, 129.6, 129.5, 128.2, 127.3, 126.2, 123.1,
36.3, 34.3, 31.9, 26.4, 19.4, 19.2, 17.7, -6.1, -6.2; MS (EI, m/z) 402
(20, M+), 387 (2, M+ - 15), 359 (2, M+ - 28), 345 (100, M+ - 57).
HRMS: calcd for C26H30O2Si, 402.2016; found, 402.2028. Anal. Calcd
for C26H30O2Si: C, 77.56; H, 7.51. Found: C, 77.04; H, 7.69.
(12bS)-2,3-Dihydro-8,11-dimethoxy-12b-methyl-1H-benzo[6,7]-
phenanthro[10,1-bc]furan-6(12bH)-one ((+)-52). The alkene (+)-
50 (5 mg) was dissolved in ethyl acetate (1.0 mL) and hydrogenated
(1 atm of H2) at room temperature over Pd/C (5%, 1 mg) for 6.5 h.
The solution was filtered through silica gel and the solvent evaporated.
The product was purified by radial chromatography on silica gel (4:1
hexanes:ethyl acetate) to give xestoquinol dimethyl ether (5 mg, 100%).
The 1H NMR spectrum of (+)-52 was identical with the literature
spectrum:6a 1H NMR (200 MHz) δ 9.28 (s, 1H), 8.27 (s, 1H), 7.48 (t,
1H, J ) 1.4 Hz), 6.82 (d, 1H, J ) 8.4 Hz), 6.70 (d, 1H, J ) 8.4 Hz),
3.98 (s, 6H), 2.88 (dd, 2H, J ) 16.7, 7.7 Hz), 2.70-2.58 (m, 2H),
1.83 (ddd, 2H, J ) 13.2, 13.2, 4.1 Hz), 1.53 (s, 3H).
(+)-Xestoquinone (1). The (+)-dimethoxynaphthalene 52 (3 mg,
0.009 mmol) was dissolved in acetonitrile (1 mL) and treated with a
solution of ceric ammonium nitrate (12 mg, 0.022 mmol, 3 equiv) in
H2O (0.5 mL). The solution was stirred for 10 min at 0 °C and
subsequently filtered through a silica plug using ethyl acetate (eluent).
The solvent was evaporated to provide (+)-xestoquinone (1): 1H NMR
(200 MHz) δ 9.08 (s, 1H), 8.25 (s, 1H), 7.55 (br t, 1H), 7.06 (s, 2H),
3.0-2.8 (m, 1H), 2.70-2.54 (m, 2H), 2.28-2.08 (m, 2H), 1.84-1.76
(m, 1H), 1.56 (s, 3H).
(12bS)-8,11-Dimethoxy-12b-methyl-1H-benzo[6,7]phenanthro-
[10,1-bc]furan-6(12bH)-one ((+)-50). The crude triflate 44 (∼0.039
mmol) was dissolved in dry toluene (2 mL). Pentamethylpiperidine
(29 µL, 4 equiv) and a toluene solution of Pd((S)-BINAP)2 (99 µL, 2.5
mol %; prepared by dissolving (S)-(+)-BINAP (13.9 mg) and Pd2(dba)3
(5.1 mg) in toluene (1 mL), 0.01 mmol/mL) were added. The solution
was heated at 110 °C for 10 h under N2. TLC (9:1 ether:CH2Cl2)
indicated the presence of unreacted triflate. An additional aliquot of
the catalyst solution (99 µL, 2.5 mol %) and PMP (29 µL) were added,
and the solution was heated for a further 12 h. The crude reaction
mixture was filtered through a pad of silica gel (2:1 hexanes:ethyl
acetate) and purified by radial chromatography (8:1 hexanes:ethyl
acetate) to afford a yellow solid (10.7 mg, 0.032 mmol, 82% from
naphthol 43). The enantiopurity was assessed by dissolving the sample
in CH2Cl2/hexanes/ethanol and separating the enantiomers by chiral
HPLC (85:15 hexanes:ethanol; Chiralcel OJ, λ ) 350 nm, flow rate )
1.3 mL/min). The relative peak areas (12 and 15.5 min) indicated an
ee of 68%. For comparison, racemic 50, prepared from dienyl bromide
41 and Pd(PPh3)4, was injected and gave two peaks of equal intensity
1
at 12 and 15.5 min: IR (film) 1727, 1672, 1622 cm-1; H NMR (200
MHz) δ 9.30 (s, 1H), 8.26 (s, 1H), 7.57 (s, 1H), 6.82 (d, 1H, J ) 8.4
Hz), 6.71 (d, 1H, J ) 8.4 Hz), 6.62 (dd, 1H, J ) 2.4, 9.7 Hz), 6.11
(ddd, 1H, J ) 2.4, 6.2, 9.7 Hz), 3.99 (s, 6H), 3.15 (dd, 1H, J ) 6.2, 17
Hz), 2.67 (br d, 1H, J ) 17 Hz); 13C NMR (50 MHz) δ 172.9, 151.2,
149.0, 146.0, 144.6, 144.4, 141.6, 131.6, 129.0, 127.8, 125.1, 124.5,
118.5, 117.8, 106.4, 103.8, 56.0, 35.7, 32.4, 29.9; MS (EI, m/z) 346
(21, M+). HRMS: calcd for C22H18O4, 346.1205; found, 346.1207.
2,3-Dihydro-12b-methyl-4-((1,1-dimethylethyl)dimethylsilyl)-1H-
benzo[6,7]phenanthro[10,1-bc]furan-6(12bH)-one (51). A mixture
of compound 48 (76 mg, 0.19 mmol), ethanol (1 mL), and 5% Pd/C
(15 mg, 20% by weight) was stirred vigorously under an atmosphere
of H2 (1 atm). After 12 h a second batch of 5% Pd/C (15 mg) was
added. After 24h the mixture was filtered through Celite and washed
with ethyl acetate (3 × 5 mL). The solvent was removed and the crude
product purified by flash chromatography with silica gel using hexane:
ethyl acetate (20:1) to provide 51 as a yellow viscous liquid (50 mg,
65%): bp 130-140 °C/0.07 Torr; IR (neat) 1666 cm-1; 1H NMR (200
MHz) δ 8.92 (s, 1H), 7.99 (d, 1H, J ) 7.7 Hz), 7.90 (s, 1H), 7.88 (d,
1H, J ) 8.1 Hz), 7.54 (m, 2H), 2.93 (ddd, 1H, J ) 9.4, 7.3, 2.3 Hz),
2.69 (m, 1H), 2.58 (dt, 1H, J ) 9.2, 3.4 Hz), 2.40-2.10 (m, 2H), 1.81
(dt, 1H, J ) 12.7, 4.6 Hz), 1.53 (s, 3H), 0.97 (s, 9H), 0.36 (s, 3H),
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) and the
University of Calgary for financial support. We also thank the
Alberta Heritage Foundation for Medical Research (AHFMR)
for funding (for S.P.M.). Finally, we thank Prof. Nobuyuki
Harada for generously supplying NMR and CD spectra of (+)-
xestoquinone (1).
Supporting Information Available: Experimental proce-
dures and characterization data for (Z)-3-iodo-1-((methylcar-
bonyl)oxy)-2-butene, (Z)-1-((tert-butyldimethylsilyl)oxy)-3-
iodo-2-butene, (Z)-3-iodo-2-buten-1-ol, and compounds 9-17,
19-23, 25, 49, 47, and 45; 1H and 13C NMR spectra for
compounds 36 (1H NMR only), 34, 35, 37, 40-43, and (+)-
50; and HPLC trace used to determine the ee of (+)- and (-)-
50 (30 pages). See any current masthead page for ordering and
Internet access instructions.
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