Total Synthesis and Determination of the Absolute Configuration of Frondosin B

Article abstract of DOI:10.1021/ja0021060

Two concise syntheses of (+/-)-frondosin B (1), an interleukin-8 receptor antagonist, have been achieved from commercially available 5-methoxysalicylaldehyde. The seven-membered ring in ketone 33, the common intermediate for both syntheses, was built by a

Full text of DOI:10.1021/ja0021060

1878
J. Am. Chem. Soc. 2001, 123, 1878-1889
Total Synthesis and Determination of the Absolute Configuration of
Frondosin B
Masayuki Inoue,†,§ Matthew W. Carson,† Alison J. Frontier,‡, and
Samuel J. Danishefsky*,†,‡
Contribution from the Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer
Research, 1275 York AVenue, New York, NY 10021 and the Department of Chemistry,
Columbia UniVersity, HaVemeyer Hall, New York, NY 10027
ReceiVed June 12, 2000. ReVised Manuscript ReceiVed September 18, 2000
Abstract: Two concise syntheses of (()-frondosin B (1), an interleukin-8 receptor antagonist, have been achieved
from commercially available 5-methoxysalicylaldehyde. The seven-membered ring in ketone 33, the common
intermediate for both syntheses, was built by a classical Friedel-Crafts reaction. The key step of the first
route was facile cationic cyclization of the vinylogous benzofuran to the trisubstituted olefin (30 f 16 + 38)
to construct a six-membered carbocycle. Although this route demonstrated the efficacy of the stepwise approach
to the frondosin ring-system, it also resulted in olefinic isomers that were easily isomerized in acidic conditions.
In the second route, we utilized a Diels-Alder reaction between sterically demanding diene 42 and nitroethylene
to fix the double bond in its required position in the resultant dimethylcyclohexane ring. A third total synthesis
was devised for the purpose of determining the absolute configuration of frondosin B. It reached diene 42, this
time in the enantiomerically defined form. From this point, naturally configured frondosin B was obtained in
the enantiomerically enriched form. These studies establish the absolute configuration of the secondary methyl
center in frondosin B to be R.
Introduction
the marine sponge Euryspongia sp.3b,5 It is worth noting that
the frondosins, which were isolated at the NCI, exhibit opposite
optical rotations with different absolute values in comparison
to the previously isolated frondosins. Thus, the frondosins,
except for frondosin B, are apparently fashioned by nature in
both enantiomeric forms. It was anticipated that further biologi-
cal studies of frondosins could spur fruitful investigations into
IL-8 activity and present new possibilities for the development
of novel antiinflammatory agents. These considerations, as well
as the novel structure of the frondosins, prompted us to
undertake a program directed toward their total synthesis.
In the opening phase of inquiry we focused on frondosin B
(1)3a, which contains an intriguing benzofuran ring system fused
to a nor sesquiterpenoid (14-carbon) framework. In this paper,
we report an account of a highly efficient total synthesis of this
compound by three different routes.6 The third reaches the
naturally occurring enantiomer in 84% ee and establishes it to
be of the R configuration. We first focused on frondosin B
racemate as our goal. A number of “retrosynthetic disconnec-
tions” were employed in pursuing the racemate synthesis.
Initially, we planned to couple two fragments by forming a bond
between C6 and C7 then closing the seven-membered ring via
a C10-C11 bond formation (Scheme 1). The union of the left
and right domains can be envisioned as arising from the 1,4-
addition of a suitably functionalized benzofuran 3 to the
exocyclic enone, 2.7 We also took note of the possibility that
Interleukin-8 (IL-8), a chemoattractant for neutrophils, is
produced by macrophages and endothelial cells.1 IL-8 has been
implicated in a wide range of acute and chronic inflammatory
disorders, including psoriasis and rheumatoid arthritis.2 Fur-
thermore, various animal models of inflammation have estab-
lished IL-8 as a principal chemotactic factor directing neutrophil
recruitment to the inflammatory focus. Therefore, an IL-8
receptor antagonist represents a promising target for the
development of novel pharmacological agents against autoim-
mune hyperactivity.
Frondosins A-D were recently isolated from the sponge
Dysidea frondosa. Each of them inhibited the binding of IL-8
to its receptor in the low micromolar range.3a The structures of
these compounds, which bear a casual relationship to one
another, were determined mainly by NMR spectroscopy. Their
unifying architectural theme is the presence of bicyclo[5.4.0]-
undecane ring systems in the context of permuted linkages to
various hydroquinone-based moieties.4
A National Cancer Institute (NCI) team also obtained
frondosins A and D from the HIV-inhibitory organic extract of
† Sloan-Kettering Institute for Cancer Research.
‡ Columbia University.
§ Department of Chemistry, Graduate School of Science, Tohoku
University, Sendai 980-8578, Japan.
Department of Chemistry, Stanford University, Stanford, CA 94305.
(1) For a recent review of IL-8, see: Hock R. C.; Schrausta¨tter I. U.;
Cochrane C. G. J. Lab. Clin. Med. 1996, 128, 134.
(2) (a) Scitz, M.; Dewald, B.; Gerber, N.; Baggiolini, M. J. Clin. InVest.
1991, 87, 463. (b) Miller, E.; Cohen, A.; Nagos, S.; Griffith, D.; Maunder,
T.; Martin, T.; Weiner-Kronish, J.; Sticherling, M.; Christophers, E.;
Matthay, M. Am. ReV. Respir. Dis. 1992, 146, 427.
(3) (a) Patil, A. D.; Freyer, A. J.; Killmer, L.; Offen, P.; Carte, B.;
Jurewicz, A. J.; Johnson, R. K. Tetrahedron, 1997, 53, 5047. (b) Hallock,
Y. F.; Cardellina, J. H., II.; Boyd, M. R. Nat. Prod. Lett. 1998, 11, 153-
160.
(4) For a recent review of marine sesquiterpene/quinone, see: Capon,
R. J. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier Science: New York, 1995; Vol. 15, p 289.
(5) Boyd, M. R. In AIDS Etiology, Diagnosis, Treatment and PreVention;
DeVita, V. T., Jr., Hellman, S.; Rosenberg, S., Eds.; Lippincott: Philadelphia,
1988; p 305.
(6) For a preliminary account of this work, see: Inoue, M.; Frontier, A.
J.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 2000, 39, 761.
10.1021/ja0021060 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/10/2001

Absolute Configuration of Frondosin B
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1879
Scheme 2.a Claisen Rearrangement Strategy
Figure 1.
Scheme 1. Nucleophilic Coupling Strategy
a Reagents and conditions: (a) NaBH4, CeCl3‚7H2O, MeOH, 0 °C,
>90%; (b) Br2, CS2, reflux, 24 h, >90%; (c) 8, TsCl, pyridine, then 6,
78%; (d) Tebbe reagent, benzene, 0 °C to room temperature; (e) 80
°C, PhMe, 30 min, 82% (2 steps); (f) MeMgBr, 0 °C, 78%; (g)
NaCNBH3, ZnI2, 86%; (h) BH3‚Me2S, H2O2, NaOH; (i) Jones reagent,
37% (2 steps); (j) Tf2O, 2,6-di-tert-butylpyridine, CH2Cl2, reflux, 81%
(13:14 ) 2:3).
sequential 1,2-addition and oxy-Cope rearrangements could
provide an alternative to the 1,4-addition pathway.
Following preparation of the benzofuran derivative 3,8 the
first difficulty we encountered, even after screening numerous
reaction conditions, was that neither 1,4- or 1,2- addition could
be accomplished. Presumably, these difficulties reflect the steric
demand of the gem-dimethyl group. Apparently, the trajectory
for nucleophilic attack at the exocyclic methylene group incurs
serious hindrance from the proximal quarternary center.
Accordingly, we modified the coupling strategy to rely on
an intramolecular delivery modality. It was hoped that Claisen
rearrangement of compound 10 could serve to create the elusive
C6-C7 linkage (Scheme 2). To test this strategy, alcohol 6 was
prepared by 1,2-reduction of ketone 29 and compound 8 was
synthesized by installation of bromine at C10 via the known
carboxylic acid 7.10 The synthesis proceeded with the joining
of the two domains by standard esterification of 8 with 6. The
resultant ester 9 was smoothly transformed to diene 10 using
the Tebbe reagent.11 Gratifyingly, subsequent heating gave,
cleanly, the Claisen rearrangement product 11 in good yield.12
The ketone in 11 was converted to the required C19 methyl
function in two steps. Thus, addition of methylmagnesium
bromide, followed by reduction of the resultant carbinol with
sodium cyanoborohydride in the presence of anhydrous zinc
iodide as the Lewis acid,13 provided compound 12 in good yield.
Having successfully constructed the desired functionality, we
undertook a series of initiatives aimed at achieving ring closure.
A Heck reaction14 was attempted first as we began to evaluate
the applicability of palladium chemistry in this series. Experi-
ments were conducted on bromides 11 and 12. No cyclization
was observed under the various conditions we employed. We
then focused our attention on Stille-type reactions. Installation
of a ketone at C11 was achieved by hydroboration of 12 and
(11) Tebbe, F. N.; Marshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611.
(12) Kinney, W. A.; Coghlan, M. J.; Paquette, L. A. J. Am. Chem. Soc.
1985, 107, 7352.
(7) (a) White, J. D.; Skeean, G. L.; Trammell, G. L. J. Org. Chem. 1985,
50, 1939. (b) Adams, J.; Lepine-Frennette, C.; Spero, D. M. J. Org. Chem.
1991, 56, 4494.
(8) For an account of the many adversities arising from earlier efforts,
see: Frontier A. J.; Ph.D. Thesis, Columbia University, 1999.
(9) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226. (b) Luche, J.-L.;
Rodriquez-Hahn, L.; Crabbe´, P. J. Chem. Soc., Chem. Commun. 1978, 601.
(10) Tanaka, S. J. Am. Chem. Soc. 1951, 73, 872.
(13) Lau, C. K.; Dufresne, C.; Be´langer, P. C.; J. Org. Chem. 1986, 51,
3038.
(14) For excellent reviews, see: (a) Heck, R. F. Palladium Reagents in
Organic Syntheses; Academic Press: New York, 1985; p 179. (b) Meijere,
A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379.

1880 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Inoue et al.
Scheme 3a
Scheme 4
When the coupling of 18 and 19 was conducted under
ligandless conditions, as recommended for sterically demanding
substrates,19 the adduct was isolated in modest yield.20 In this
reaction, substantial amounts of 3-methoxybenzofuran were
obtained. Installation of a carboxylic acid at C9 was achieved
by a two-step procedure. Vilsmeier formylation21 successfully
introduced the aldehyde. Following oxidation,22 compound 21
was in hand. Our plan included activation of the tetrasubstituted
alkene in order to effect halolactonization. Unfortunately, the
lactonization could not be achieved. We took this disappointing
result to reflect the difficulties of attack by a viable iodonium
equivalent at C5, even in the presence of a proximal, and
presumably participating, carboxylate function. This negative
outcome provided further testimony to the high risks in
attempting to conduct chemistry proximal to the gem-dimethyl
quarternary center.
Even as these unsuccessful efforts were in progress, efforts
directed toward an alternative construction of the seven-
membered ring were initiated (Scheme 4). The methyl ester
vinyl triflate 24 and allyl-substituted vinyl triflate 25 were
synthesized as shown. However, merger of 24 or 25 with
activated benzofuran (19, 26, or 27) using palladium(0) as a
catalyst23 was low-yielding and unreliable. The coupling yields
deteriorated still further when the reaction was conducted on
scales larger than a few milligrams. Because we were unable
to solve this material availability problem, progress was severely
hindered, and this initiative was also abandoned.
a Reagents and conditions: (a) Me2CuLi, -78 °C to 0 °C, then
Comins Reagent, 55%; (b) Cu, quinoline, 220 °C, 70%; (c) n-BuLi,
-20 °C, 2 h, then Me3SnCl, 0 °C to room temperature, 70%; (d) 2.5
mol % Pd2(dba)3, 6 equivs LiCl, N-methylpyrrolidine, 50 °C, 23-34%;
(e) POCl3, DMF, (CH2Cl)2, reflux, 5h, 36% (65% BORSM); (f) AgNO3,
aq NaOH, 75%.
subsequent Jones oxidation. Enol triflation of the ketone with
Tf2O in the presence of base gave an ∼2:3 mixture of 13 and
14 (Scheme 2). Separation of these components proved to be
very difficult. Because a variety of conditions failed to improve
the selectivity of this triflation, we resorted to using the
unseparated mixture for the projected C10-C11 ring-closure.
Unfortunately, attempted palladium-catalyzed Stille reactions
of this material under various conditions were unsuccessful.15
In several instances, spectroscopic examination of the recovered
material suggested that the tetrasubstituted triflate had survived
intact.
These disappointing results underscored the need for a fresh
approach. The previous Claisen bond reorganization pathway,
which was actually quite promising in the rearrangement step,
had to be abandoned because of our inability to achieve
intramolecular merger between carbons 10 and 11. Our next
plan was to alter the sequence of events by first forming the
C10-C11 linkage through intermolecular means (Scheme 3).
A subsequent Claisen rearrangement of compound 23 was
planned with a view to building the seven-membered ring
through construction of a C6-C7 bond.16 The appropriately
functionalized components were assembled. Thus, the known
1717 was treated with lithium dimethyl cuprate. The resultant
enolate was trapped with Comins reagent18 to provide the triflate
18. Decarboxylation of 8, followed by lithiation and stannyla-
tion, led to the required stannane 19.
The series of negative results described above, augmented
by many others,8 underscored several important points: First,
bond formation in spatial proximity to the dimethyl group was
(19) Farina, V.; Roth, G. P. Tetrahedron Lett. 1991, 32, 6299.
(20) We also attempted Stille reactions on the C9 functionalized
benzofuran. However, none of the desired adduct iii was isolated.
(15) For successful applications of related Stille-type reactions, see: (a)
Kelly T. R.; Li Q.; Bhushan V. Tetrahedron Lett. 1990, 31, 161. (b) Grigg,
R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859. (c) Mori,
M.; Kaneta N.; Shibasaki, M. J. Org. Chem. 1991, 56, 3486. (d) Huang, A.
X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999.
(16) (a) Marvell, E. N.; Titterington, D. Tetrahedron Lett. 1980, 21, 2123.
(b) Ovaska, T. V.; Roark, J. L.; Shoemaker, C. M.; Bordner, J. Tetrahedron
Lett. 1998, 39, 5705.
(21) For a recent review of the Vilsmeier reaction, see: Jones G. Org.
React. 1997, 49, 1.
(22) Sharmma, M.; Rodrigues, H. R. Tetrahedron 1968, 24, 6583.
(23) For a review of coupling between sp2 carbon centers, see: Knight
D. W. In ComprehensiVe Organic Synthesis; Trost B. M., Fleming I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 3, p 481.
(17) Jung, M. E.; McCombs, C. A.; Takeda, Y.; Pan, Y.-G. J. Am. Chem.
Soc. 1981, 103, 6677.
(18) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.

Absolute Configuration of Frondosin B
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1881
Scheme 5
hydrogenated using palladium on carbon. Subsequent saponi-
fication furnished carboxylic acid 34 in quantitative yield. In
the hydrogenation step, extended reaction times resulted in
formation of significant quantities of dihydrobenzofuran. For-
tunately, the critical Friedel-Crafts reaction could be ac-
complished. Thus, reaction of 34 with oxalyl chloride and
treatment of the resultant acid chloride with stannic chloride
gave ketone 33 in good yield.28
Nucleophilic attack of the cerium reagent,29 prepared from
4-methyl-3-pentenylmagnesium bromide, led to an addition
product. Dissolution of the resultant tertiary alcohol in chloro-
form afforded the diene 30 as a 5:1 mixture with its endo isomer
in 93% yield. The remarkable susceptibility of the tertiary
alcohol to dehydration presumably arises from participation of
the benzofuran in stabilizing an intermediate bearing cationoid
character. Fortunately, acid-induced cyclization of 30 proceeded
under mild conditions in reasonable yield. Various acid com-
binations (BF3‚OEt2, HCOOH, H3PO4,) resulted in the formation
of the six-membered ring in an approximately 2.5:1 mixture
favoring the desired compound 16 and olefinic isomer mixture
38. Mercury trifluoroacetate-mediated reaction,30 in which olefin
isomerization after cyclization was expected to be minimal, also
proceeded smoothly. Unfortunately, following reductive cleav-
age of the carbon-mercury bond, very similar isomeric ratios
were obtained. The results of these reactions suggested that the
product distribution might be reflecting the thermodynamic
stability order of rapidly equilibraiting isomers. However, there
remains the possibility that the nonvariant ratio could arise from
kinetic factors.
Although these isomers were inseparable by silica gel
chromatography, we attempted to complete the total synthesis,
hoping for a later-stage separation (Scheme 6). Deprotection
of the methyl ether was effected with boron tribromide to afford
(()-frondosin B (1) and its olefinic isomers 39 in 87% yield.
These isomers were separated with HPLC (silica gel, 5% ethyl
emerging as rather difficult and would be particularly risky with
advanced intermediates. Furthermore, attachment of tetrasub-
stituted olefin derivatives to the â-position of the furan
(corresponding to C10 of the target frondosin) by organometallic
methods, appears to be highly problematic.
1
acetate-hexane). The H, 13C NMR and IR spectra obtained
With these considerations in mind, we developed a totally
revised approach to the problem. The new perception involved
incorporation of the cyclohexene ring containing the gem-
dimethyl group onto a preexisting matrix wherein the seven-
membered ring was already in place (Scheme 5). More
specifically, in this stepwise approach, the seven-membered ring
diene 30 would be synthesized by addition of a homoprenyl
group to a ketone such as 33. This bond formation would set
the stage for subsequent acid-induced cyclization, exploiting the
activated benzofuran ring to promote and guide the sense of
electrophilic attack on the cycloheptenyl double bond (see 30
f 16).24 We hoped that the tetra-substituted olefin between C5
and C11 would be markedly more stable than trisubtituted
isomers and could accordingly be generated under equilibrating
conditions.25
from synthetic frondosin B were identical with those reported
from the naturally occurring material.31 Thus, the total synthesis
of racemic frondosin B has been achieved in 9 steps from
commercially available 2-hydroxy-5-methoxybenzaldehyde. Al-
though this synthesis is highly concise and ensures quick access
to reasonable amounts of material, the unsolved problem
associated with control over the regiochemistry of olefin
formation still remained irksome and prompted a fresh approach.
We noted that subjection of 1 and 39 separately to a variety
of acidic conditions led to formation of a 2.5:1 mixture of the
same products (Scheme 6). These data seemed to confirm that
the mixture of double-bond isomers (16 and 38 or 1 and 39).
Accordingly, to achieve control in our synthesis, it would be
necessary to construct the dimethylcyclohexene from 33 without
recourse to acidic catalysis in the formation of the fully mature
A ring or after its construction.
The synthesis started from the acetyl benzofuran 35, which
was prepared from 2-hydroxy-5-methoxy benzaldehyde by the
known protocol,26 shown in Scheme 6. Four-carbon extension
of 35 by Wittig methodology proceeded smoothly to give olefin
37 (Z:E ) 3:2) in 87% yield.27 The olefin in 37 was
(27) Danheiser, R. L.; Halgason, A. L. J. Am. Chem. Soc. 1994, 116,
9471.
(28) Friedel-Crafts cyclization to benzofuran is relatively rare. For an
example leading to a six-membered ring, see: Bhide, G. V.; Tikotkar, N.
L.; Tilak, B. D. Tetrahedron 1960, 10, 223-229.
(24) For a review of cationic cyclizations, see: (a) Bartlett P. A. In
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York,
1984; Vol 3, pp 341. (b) Sutherland, J. K. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol 3, p 341.
(25) It is known that a double bond can generally be fixed on the most
substituted position in a Decalin system using acidic conditions. For
example, see: Ayer, A. W.; Hellou, J.; Tischler, M.; Andersen, R. J.
Tetrahedron Lett, 1984, 25, 141.
(29) (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (b) Fujiwara, T.; Iwasaki,
T.; Takeda, T. Chem. Lett. 1993, 1321. (c) Guevel, A. C.; Hart, D. J. J.
Org. Chem. 1996, 61, 465.
(30) (a) Kurbanov, M.; Semenovsky, A. V.; Smit, W. A.; Shmelev, L.
V.; Kucherov, V. F. Tetrahedron Lett. 1972, 22, 2175. (b) Corey, E. J.;
Tius, M. A.; Das, J. J. Am. Chem. Soc. 1980, 102, 1742. (c) Sato, C.; Ikeda,
S.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1982, 23, 2099.
(31) We note that direct comparison of synthetic racemate and material
product was not possible because a specimen of natural frondosin furnished
to us reached our lab in a totally decomposed and unrecognizable state.
(26) Landelle, H.; Godard, A. M.; Laduree, D.; Chenu, E.; Robba, M.
Chem. Pharm. Bull. 1991, 39, 3057.

1882 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Scheme 6.a Cationic Cyclization Strategy
Inoue et al.
a Reagents and conditions: (a) chloroacetone, K2CO3, 2-butanone, 80 °C, 72%; (b) Br-Ph3P+(CH2)3CO2Et (36), NaN(SiMe3)2, THF, 0 °C to
room temperature, 87% (Z:E ) 3:2); (c) H2, Pd/C, EtOH, room temperature; (d) LiOH, THF-MeOH-H2O, 100% (2 steps); (e) (COCl)2, CH2Cl2,
reflux, then SnCl4, -78 °C to -10 °C, 67%; (f) 4-methyl-3-pentene magnesium bromide, CeCl3, THF, -78 °C; (g) CDCl3, 93% (2 steps, endo:exo
) 5:1); (h) BF3‚Et2O, MeCN, room temperature, 81%, (16:38 ) 2.5:1); (i) BBr3, CH2Cl2, -78 °C to room temperature, 98%, (1:39 ≈ 2.5:1); (j)
HPLC separation (silica gel, 5% ethyl acetate-hexane); (k) p-TsOH, PhH, 80 °C.
Given these constraints, which were by now well appreciated,
we modified the synthetic route to attain a completely regio-
controlled outcome. To install the double bond at the proper
C5-C11 position without the requirement for acidic conditions,
we came to favor a Diels-Alder-inspired logic to form the C1-
C2 and C3-C4 bonds.32 Accordingly, construction of the
corresponding diene (see structure 42) was initiated via the aldol
condensation of ketone 33 with acetone (Scheme 7). The zinc
enolate of the ketone, prepared by transmetalation of the lithium
enolate, reacted with acetone to furnish adduct 40 in 85% yield.33
Not surprisingly, this compound was prone to retro-aldolization,
especially in acidic media. Indeed, treatment of 40 with
p-toluenesulfonic acid produced ketone 33 in 77% yield along
with a trace amount of olefin 41. After several experiments,
dehydration of the tertiary alcohol was accomplished by
treatment of 40 with mesyl chloride and triethylamine. This
protocol gave rise to a mixture of olefinic isomers (∼1:1) in
88% yield. Treatment of this mixture of sodium methoxide in
methanol effected isomerization of the â-γ unsaturated olefin
tautomers to provide the desired compound 41 in 96% yield.34
Finally, diene 42 was prepared in 97% yield following exposure
of 41 to the Tebbe reagent11 buffered with pyridine.
reactive ethylene equivalent under acid-free conditions.36 It was
expected that the nitro group could be easily removed through
a free radical protocol. In addition, it was anticipated that the
nitro group might actually be useful for synthesizing structural
analogues for biological investigations.
Diels-Alder reaction of 42 with excess nitroethylene in the
presence of di-tert-butyl pyridine at 80 °C afforded adduct 43
in 79% yield. The nitro group was removed by radical reduction
to afford O-methyl frondosin B 16 in 58% yield.37 Finally,
synthesis of geometrically pure frondosin B (1) was achieved
by deprotection of the methyl group, this time with sodium
ethanethiolate (94%).38 In this alternative route, the total
synthesis of (()-frondosin B was realized in 12 steps. The
method clearly has potential for the synthesis of numerous
structural variants.
Having completed the synthesis of racemic frondosin B, we
embarked on an enantio-defined preparation of the natural
product. The goal was not only to gain access to the naturally
occurring enantiomer but also included determination of the
absolute configuration of frondosin B. We would start with a
chiral precursor of known absolute configuration and use it to
(35) Side-reactions could involve acid-catalyzed 1,5-proton shift cy-
cloadditions or ene-reactions with maleic anyhydride.
As was noted in preliminary reconnaissance experiments,
compound 42 is sensitive to acid. In addition, it is relatively
unreactive. However, reaction of 42 with maleic anhydride at
110 °C for 2 days did give a Diels-Alder adduct, albeit in only
27% yield.35 Considering the acid-sensitivity of 42 as well as
the expected tendency toward olefin migration of the product,
a Lewis acid-promoted Diels-Alder reaction would be prob-
lematic. Accordingly, we elected to use nitroethylene as a
(32) For a related Diels-Alder reaction producing a Decalin system,
see: Omodani T.; Shishido, K. Chem. Commun. 1994, 2781.
(33) (a) Hagiwara, H.; Uda, H.; Kodama, T. J. Chem. Soc., Perkin Trans.
1 1980, 963. (b) Witschel, M. C.; Bestmann, H. J. Synthesis 1997, 107.
(34) Guerriero, A.; Cuomo, V.; Vanzanella, F.; Pietra, F. HelV. Chim.
Acta. 1990, 73, 2090.
(36) (a) Ranganatham, D.; Rao, C. B.; Ranganatham, S.; Mehrotra, A.
K.; Iyengar, R. J. Org. Chem. 1980, 45, 1185. (b) Corey, E. J.; Myers, A.
G. J. Am. Chem. Soc. 1985, 107, 5574.
(37) Ono, N.; Kaji, A. Synthesis 1986, 693.
(38) Feutrill, G. I.; Mirrington, R. N. Aust. J. Chem. 1972, 25, 1719.

Absolute Configuration of Frondosin B
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1883
Scheme 7.a Diels-Alder Strategy
droxy-5-(E)-heptanoate (46)41 with tert-butyl hydroperoxide
using catalytic TiCl4 and (+)-diisopropyl-L-tartrate gave (-)-
methyl 5-(S), 6-(S)-epoxy-7-hydroxyheptanoate (47)40a in 63%
yield, although only in 84% enantiomeric excess (ee). Low-
temperature ring opening of epoxy alcohol 47 with excess
AlMe3 provided (+)-methyl 6-(R), 7-dihydroxy-5-(R)-methyl
heptanoate (48) in 60% yield with >95% diasteromeric excess
(de).42 Periodate-induced cleavage of 48 yielded crude 5-(R)-
methyl-6-oxohexanoate, which was converted smoothly to
alkyne 44 by treatment with potassium dimethyl(methyl)-
phosphonate (Gilbert reagent).43 Potassium dimethyl(methyl)-
phosphonate seemed to be a suitable reagent for the preparation
of R-chiral aldehydes, as was shown in our recent synthesis of
(-)-halichlorine.44 The preparation of 2-iodo-4-methoxyphenol
(45) was straightforward (Scheme 10). 45 was generated via
directed ortho-lithiation45 of the diethyl carbamate of 4-methoxy-
1-phenol (49) followed by removal of the carbamoyl group.
With alkyne 44 and iodophenol 45 in hand, we directed our
efforts toward the synthesis of the benzofuran framework. There
have been a number of reports on the palladium-catalyzed
heteroannulation of acetylenic compounds. Recently, Botta and
Corelli46 have expanded on existing protocols and have shown
that either chiral propargylamines or alcohols undergo heteroan-
nulations with 2-iodophenol, in the presence of catalytic PdCl2-
(PPh3)2 and CuI, as well as tetramethylguanidine (TMG) at 40
°C, to give homochiral 2-benzofuranyl carbamines or carbinols,
respectively, in good yields (60-80%). Unfortunately, in our
case, under these conditions described, the reaction of 2-iodo-
4-methoxyphenol (45) with (-)-methyl 5-(R)-methyl-6-hep-
tynoate (44) gave 2-substituted benzofuran (-)-50 in low yields
(20-40%), along with apparent decomposition products (Table
1, entry 1). In hopes of circumventing the problem of decom-
position, the reaction was conducted at room temperature and
using the slightly stronger amine base piperidine.47 As shown
in Table 1 (entry 2), by carrying out the reaction at room
temperature, the internal alkyne (-)-51 was generated as the
principal product (57%) and benzofuran (-)-50 was produced
in only 20% yield. When the reaction was run under conditions
reported by Kundu48 (catalytic PdCl2(PPh3)2 and CuI; 2 equivs
triethylamine, 25 °C, then 50 °C), alkynyl phenol (-)-51 was
produced in good yield (74%) along with only a trace amount
of the desired product, (-)-50 (Table 1, entry 3). With these
results in mind, we focused our efforts on optimizing the
Sonogashira coupling reaction between iodophenol 45 and
alkyne (-)-44 to provide alkynyl phenol (-)-51. To this end,
(-)-51 was isolated in excellent yield (93%) when the reaction
was conducted under Kundu conditions at room temperature
only (Table 1, entry 4). Finally, it was found that the cyclization
a Reagents and conditions: (a) LiN(SiMe3)2, ZnCl2, acetone, THF,
-78 °C to -40 °C, 81% (96% BORSM); (b) MsCl, Et3N, CH2Cl2, 0
°C, 88%; (c) NaOMe, MeOH, 0 °C, 96%; (d) Tebbe reagent, pyridine,
THF, -40 °C, 97%; (e) excess nitroethylene, di-tert-butyl pyridine,
80 °C, 79% (5:1 mixture of diastereomers); (f) tri-n-butyltin hydride,
AIBN, PhMe, 110 °C, 58%; (g) NaSEt, DMF, reflux, 94%.
reach either frondosin B or the enantiomer of frondosin B. In
either case, we would have answered our question. Because the
Diels-Alder route (Scheme 7) had provided racemic frondosin
B in a regio-controlled fashion, benzofuran 34, an intermediate
in the synthesis of the racemate, appeared to be a reasonable
target (Scheme 8). The annulation between alkyne 44 and
4-methoxy-2-iodophenol (45) to afford an enantio-enriched
2-substituted benzofuran system would then serve as one of the
key steps in synthesis.
With this program in mind, a method for enantioselectively
installing the secondary methyl group was required. Prior work39
had shown that treatment of 2,3-epoxy alcohols with AlMe3
results in the regioselective ring opening of epoxides to give
3-methyl-1,2-diols. Thus, we felt that the Sharpless asymmetric
epoxidation 40 of a prochiral alcohol followed by C-methylation
of the epoxy alcohol via AlMe3 would serve as a highly regio-
and stereoselective method for introducing the secondary methyl
group and could ultimately lead to enantio-enriched alkyne 44.
As shown in Scheme 9, the synthesis of (+) frondosin B (1)
commenced with the epoxidation of the known methyl 7-hy-
(41) Prepared according to the general method reported by Patterson, J.
W. Synthesis 1985, 337.
(42) It should be noted that when epoxy alcohol 47 was treated with
AlMe3 at temperatures greater than ca. -50 °C, an apparent intramolecular
ring opening of the epoxide by the attack of the carbonyl oxygen competed
with intermolecular methylation.
(43) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997.
(44) Trauner, D.; Schwartz, J. B.; Danishefsky, S. J. Angew. Chem., Int.
Ed. Engl. 1999, 38, 3542.
(45) (a) Snieckus, V. J. Org. Chem. 1983, 48, 1983. (b) Snieckus, V.
Chem. ReV. 1990, 90, 879.
(46) (a) Messina, F.; Botta, M.; Corelli, F.; Mugnaini, C. Tetrahedron
Lett. 1999, 40, 7289. (b) Botta, M.; Summa, V.; Corelli, F.; Di Pietro, G.;
Lombardi, P. Tetrahedron: Asymmetry 1996.
(47) (a) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli
F. J. Org. Chem. 1996, 61, 9280. (b) Arcadi, A.; Marinelli F. Synthesis
1986, 749.
(48) Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem.
Soc. Chem. Commun. 1992, 41.
(39) (a) Rousch, W. R.; Adam, M. A.; Peseckis, S. M. Tetrahedron Lett.
1983, 24, 1377. (b) Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K.;
Nozaki, H. Tetrahedron Lett. 1982, 23, 3597. (c) Miyashita, M.; Hoshino,
M.; Yoshikoshi, A. J. Org. Chem. 1991, 56, 6484.
(40) (a) Rossiter, B. E.; Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc.
1981, 103, 464. (b) Hill, J. G.; Sharpless, K. B.; Exon, C. M.; Regenye R.;
Organic Syntheses; Wiley: New York, 1990; Coll. Vol. VII, p 461. (c)
Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922. (d) Hill, J.
G.; Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1983, 48, 3607. (e)
Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5976. (f) Hanson,
R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.

1884 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Inoue et al.
Scheme 8
Scheme 9a
(CSP) HPLC analysis of the material revealed that (-)-33 had
been prepared in 84% ee.
Because we were concerned with the possibility of racem-
ization at the C8 chiral center, we were forced to proceed
cautiously in our approach to the condensation of the enolate
of ketone (-)-33 with acetone. As shown in Scheme 12, a
control experiment revealed that the lithium enolate of (-)-33
could be formed almost quantitatively without racemization at
C8. This was evidenced by the fact that the reaction of (-)-33
with 1 equiv of LiHMDS, followed by MeOD quench, gave
recovered (-)-33 exclusively with 95% incorporation of deu-
terium at C5. Aldol condensation between the zinc enolate of
(-)-33, prepared from the lithium enolate, and acetone gave
alcohol 40 in 55% yield along with ketone 33 in 45% yield.
However, recovered ketone (-)-33, most likely regenerated via
a retro-aldol reaction, had a 24% ee (Scheme 12). Future studies
would show that the C8 center in 41 was most likely racemized
as well (vide infra). The racemization at the C8 center is
probably due to the excess base remaining after the formation
of the enolate of (-)-33. Deprotonation at C8 of the zinc chelate
of 40 may serve as the racemization step. Unfortunately, the
aldol product 40 was generated in low yields when only 1 equiv
of LiHMDS was used. Gratifyingly, though, the problems of
racemization and the retro aldol reaction were circumvented by
generating the silyl enol ether of (-)-33 in situ.49 As depicted
in Scheme 12, (+)-52 was then smoothly transformed to tertiary
alcohol 40 without epimerization at C8 (60% de) in 70% yield
by the Mukaiyama reaction.50
a Reagents and conditions: (a) TBHP-PhMe, Ti(i-PrO)4, (+)-L-
DIPT, CH2Cl2, -15 °C, 63%; (b) AlMe3, CH2Cl2-hexane, -78 °C, 3
days, 60%; (c) NaIO4, THF:H2O; (d) N2CHPO(MeO)2, t-BuOK, THF,
-78 °C to -50 °C, 71% (2 steps).
Scheme 10a
a Reagents and conditions: (a) sec-BuLi, THF-c-C6H6, -78 °C,
1.5 h then I2-THF, -78 °C; (b) 2 N NaOH, MeOH, reflux, 4 days,
50% (2 steps).
Unfortunately, the dehydration of 40 resulted in another
setback. As in the synthesis of the racemate (Scheme 7),
conversion of 40 to its mesyl ether, followed by elimination,
provided ∼1:1 mixture of olefinic isomers (Scheme 13).
However, treatment of the olefinic isomers with sodium
methoxide in methanol delivered olefin 41 exclusively as its
racemate. In a parallel experiment with MeOD as the solvent,
1H NMR analysis revealed that 40 was partially deuterated
of (-)-51 proceeded smoothly to give (-)-50 in 62% yield under
Kundu conditions at 50 °C (Scheme 11).
At this point, the asymmetric synthesis nominally intersected
with the racemic synthesis of frondosin B when 2-substituted
benzofuran (-)-50 was converted to carboxylic acid (-)-34 by
saponification. Under identical conditions previously described
(Scheme 6), ketone (-)-33 was furnished in good yield via the
intramolecular Friedal-Crafts acylation of the acyl chloride that
was derived from carboxylic acid (-)-34. Chiral stationary phase
(49) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
(50) (a) Mukaiyam, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503. (b) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977, 16, 817.
(c) Mukaiyama, T. Org. React. 1982, 28, 203.(d) Banno, K.; Mukaiyama,
T. Chem. Lett. 1976, 238-240.

Absolute Configuration of Frondosin B
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1885
Table 1. Palladium (II)-Catalyzed Reactions between 4-Methoxy-2-iodophenol (45) and Methyl (-)-5(R)-6-heptynoate (44)
products, % yield
entry
mol % CuI
equiv base
temp °C
time h
(-)-50
(-)-51
1
2
3
4
2.7
5.0
13.4
13.4
3 .0 TMG
1.0 piperidine
2.0 NEt3
40
25
25-50
25
4
48
48
24
20-40
0
57
74
93
20
5
2.0 NEt3
3
Scheme 11a
reaction of nitroethylene and 42 was the most effective way
that we found to introduce the dimethylcyclohexane A ring with
regiochemical definition. Subsequently, a route to the natural
antipode of frondosin B was developed. An unexpectedly
difficult obstacle in this synthesis was that of maintaining the
enantioenrichment of the secondary methyl center of compound
33. Eventually, this problem was solved and frondosin B was
obtained in 84% ee. The route, which was followed, establishes
the absolute configuration of frondosin B as R. It is appropriate
to note that in various anti-HIV evaluations, the racemic, fully
synthetic frondosin B did not meaningfully suppress viral
growth. Thus, the future of frondosin B in AIDS therapy, at
least, does not appear to be promising. Further biological studies
on frondosin B are currently underway.
Experimental Section
a Reagents and conditions: (a) PdCl2(PPh3)2, CuI, NEt3, 50 °C, 62%
(b) LiOH, THF-MeOH-H2O, 25 °C, 99%; (c) (COCl)2, CH2Cl2, 25-
40 °C then SnCl4, -78 °C to -10 °C, 62%.
Preparation of Olefin 37. To a stirred solution of phosphonium
salt 36 (16.5 g, 36.1 mmol) in THF (35 mL) was added NaHMDS (1.0
M solution in THF, 32 mL, 32 mmol) at 0 °C. After 30 min at 0 °C,
methyl ketone 35 (3.7723 g, 21.2 mmol) in THF (20 + 10 mL) was
added to the ylide via cannula, and the resultant solution was stirred at
0 °C for 30 min and at room temperature for 1.5 h. The reaction mixture
was quenched with saturated aqueous NH4Cl and diluted with EtOAc
(400 mL). The organic layer was washed with H2O and brine, dried
(Na2SO4), and concentrated. Flash column chromatography (10-20%
EtOAc-hexane) gave olefin 37 as a 3:2 mixture of Z:E isomers (5.25
(50%-d1) at C8. Given this outcome, the dehydration of 40 was
repeated and the mixture of olefinic isomers was carefully
separated via column chromatography to give the desired 41 in
35% yield (84% ee) along with its geometric isomer (40%). A
separate study showed that PdCl2(MeCN)2 in refluxing benzene
effected isomerization of the olefinic mixture to 41 in 93% yield
without further racemization.51
As shown in Scheme 14, the completion to the synthesis of
(+)-frondosin B (1) was accomplished in a fashion analogous
to that employed for (() frondosin B. Analyses indicated that
(+)-frondosin B (1) had been generated in approximately 84%
ee with an optical rotation of +15.2°. The literature reports that
pure (+)-frondosin B has an optical rotation of +18.5°.3 Because
the signs of optical rotations compare closely for synthetic
frondosin B and natural frondosin B, we conclude that (+)-
frondosin exists as the R-enantiomer.
g, 86%): IR (film) 2980, 1731, 1474, 1208, 1029 cm-1 1H NMR
;
(CDCl3, 500 MHz) δ 7.33 (d, J ) 8.9 Hz, 3/5 H), 7.28 (d, J ) 8.9 Hz,
2/5 H), 6.99 (d, J ) 2.6 Hz, 3/5 H), 6.96 (d, J ) 2.6 Hz, 2/5 H), 6.86
(dd, J ) 8.9 Hz, 2.6 Hz, 3/5 H), 6.82 (dd, J ) 8.9 Hz, 2.6 Hz, 2/5 H),
6.57 (s, 3/5 H), 6.49 (s, 2/5 H), 6.29 (td, J ) 7.3 Hz, 1.2 Hz, 2/5 H),
5.57 (td, J ) 7.3 Hz, 1.2 Hz, 3/5 H), 4.13 (q, J ) 7.1 Hz, 2H), 3.83 (s,
9/5 H), 3.82 (s, 6/5 H), 2.86 (q, J ) 7.2 Hz, 6/5 H), 2.57 (q, J ) 7.3
Hz, 4/5 H), 2.48 (t, J ) 7.6 Hz, 2H), 2.08 (d, J ) 1.1 Hz, 9/5 H), 2.03
(d, J ) 1.1 Hz, 6/5 H), 1.25 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 173.2, 173.0, 158.4, 157.4, 155.9, 155.8, 149.5, 149.4,
129.7, 129.6, 128.9, 126.5, 125.8, 125.3, 112.9, 112.5, 111.4, 111.1,
104.8, 103.3, 103.1, 101.7, 60.4, 60.3, 55.9, 34.5, 33.9, 25.0, 23.7, 21.8,
14.2, 13.3; HRMS (FAB) [M]+ calcd for C17H20O4, 288.1362; found,
288.1355.
Summary
In summary, several interrelated routes to racemic frondosin
B have been developed. The intermolecular Diels-Alder
Carboxylic Acid 34. A solution of olefin 37 (2.07 g, 7.19 mmol)
and Pd/C (400 mg) in EtOAc (50 mL) was stirred at room temperature
under hydrogen for 2h. The mixture was filtered through Celite and
concentrated to give the crude ester, which was used in the next reaction
(51) For another example of this type of Pd(II)-catalyzed isomerization,
see: Whang, K.; Cooke, R. J.; Okay, G.; Cha, J. K. J. Am. Chem. Soc.
1990, 112, 8985.

1886 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Inoue et al.
Scheme 12a
a Reagents and conditions: (a) 1.1 equiv LiHMDS, THF, -40 °C, 0.5 h; MeOD, -40 °C; (b) 1.5 equivs LiHMDS, THF, -40 °C, 0.5 h; 1.5
equivs ZnCl2, Et2O, -40 °C, 10 min; 2.0 equivs Me2CO, -40 °C, 0.5 h; (c) 3.0 equivs LiHMDS, 3.0 equivs TMSCl, THF, -40 °C, 1 h; (d) 1.1
equivs TiCl4, 2.0 equivs Me2CO, 0 °C, 1 h.
Scheme 13a
a Reagents and conditions: (a) MsCl, NEt3, CH2Cl2, 0 °C; (b) MeONa, MeOD(H), 0 °C; (c) PdCl2(MeCN)2, PhH, reflux, 93%.
without further purification: IR (film) 2967, 1732, 1476, 1205, 1179
raphy (5-10% MeOH-CHCl3) gave carboxylic acid 34 (1.88 g,
100%): IR (film) 3300-2500, 2935, 1707, 1476, 1205 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 7.29 (d, J ) 8.9 Hz, 1H), 6.96 (d, J ) 2.6 Hz,
1H), 6.80 (dd, J ) 8.9 Hz, 2.6 Hz, 1H), 6.32 (s, 1H), 3.82 (s, 3H),
2.90-2.96 (m, 1H), 2.35 (t, J ) 7.1 Hz, 2H), 1.76-1.85 (m, 1H), 1.60-
1.70 (m, 3H), 1.32 (d, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
δ 179.6, 163.9, 155.7, 149.5, 129.3, 111.5, 111.1, 103.2, 101.1, 55.9,
34.7, 33.9, 33.5, 22.3, 18.9; HRMS (FAB) [M]+ calcd for C15H18O4,
262.1205; found, 262.1203.
(-)-(R)-Carboxylic Acid 34. A mixture of benzofuran (-)-50 (432
mg, 1.56 mmol) and LiOH‚H2O (197 mg, 4.69 mmol) in THF-
MeOH-H2O (4:1:1; 16.5 mL) was stirred at room temperature for 2 h
before acidification with 5 mL of 1 N HCl. After typical workup as
1
cm-1; H NMR (CDCl3, 500 MHz) δ 7.28 (d, J ) 8.9 Hz, 1H), 6.95
(d, J ) 2.6 Hz, 1H), 6.79 (dd, J ) 8.9 Hz, 2.6 Hz, 1H), 6.32 (s, 1H),
4.10 (q, J ) 7.2 Hz, 2H), 3.81 (s, 3H), 2.89-2.94 (m, 1H), 2.29 (t, J
) 7.2 Hz, 2H), 1.75-1.80 (m, 1H), 1.58-1.67 (m, 3H), 1.31 (d, J )
7.0 Hz, 3H), 1.23 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ
173.5, 164.0, 155.6, 149.4, 129.3, 111.4, 111.1, 103.1, 101.1, 60.3,
55.9, 34.7, 34.2, 33.4, 22.5, 18.9, 14.2.
A solution of the above ester in THF-MeOH-H2O (4:1:1, 60 mL)
was treated with LiOH‚H2O (930 mg, 22.2 mmol), and the mixture
was stirred at room temperature for 2 h. The solution was acidified
with 1N HCl (45 mL) and extracted with CHCl3 (100 mL × 2, 50 mL
× 2). Drying (Na2SO4), concentration, and flash column chromatog-

Absolute Configuration of Frondosin B
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1887
Scheme 14a
SO4), concentration, and flash column chromatography (10-30%
EtOAc-hexane) gave tertiary alcohol 40 as a 1:2.5 mixture of isomers
(504 mg, 85%), along with recovered starting material 33 (54.4 mg,
11%): IR (film) 3446, 2968, 1618, 1473, 1177 cm-1; 1H NMR (CDCl3,
500 MHz) δ 7.61 (d, J ) 2.6 Hz, 2/7 H), 7.56 (d, J ) 2.6 Hz, 5/7 H),
7.32 (d, J ) 8.8 Hz, 2/7 H), 7.30 (d, J ) 8.8 Hz, 5/7 H), 6.89 (dd, J
) 8.8 Hz, 2.6 Hz, 1H), 5.85 (br s, 5/7 H), 4.80 (br s, 2/7 H), 3.87 (s,
6/7 H), 3.86 (s, 15/7 H), 3.30 (m, 2/7 H), 3.23 (m, 5/7 H), 2.77 (dd, J
) 11.2 Hz, 4.8 Hz, 5/7H), 2.71 (dd, J ) 11.3 Hz, 3.8 Hz, 2/7H), 2.24-
2.30 (m, 2/7 H), 2.10-2.19 (m, 2/7 H), 1.75-1.80 (m, 4/7 H), 1.56-
1.61 (m, 10/7 H), 1.50 (d, J ) 7.0 Hz, 6/7 H), 1.39 (d, J ) 7.0 Hz,
15/7 H), 1.25 (s, 27/7 H), 1.07 (s, 15/7 H); 13C NMR (CDCl3, 125
MHz) δ 204.5, 202.4, 169.8, 169.3, 157.1, 148.7, 148.4, 133.3, 127.0,
126.9, 118.2, 117.8, 114.04, 114.00, 111.2, 111.1, 104.4, 104.1, 73.7,
73.0, 63.5, 63.3, 60.3, 55.96, 55.92, 37.0, 33.3, 32.1, 32.0, 28.9, 28.8,
25.5, 25.1, 24.3, 22.4, 20.2, 17.9; HRMS (FAB) [M + H]+ calcd for
C18H23O4, 303.1596; found, 303.1589.
Tertiary Alcohol 40 from (+)-(R)-Silyl Enol Ether 52. A solution
of 60.1 mg (0.190 mmol) of (+)-(R)-silyl enol ether 52 in 0.80 mL of
CH2Cl2 was added dropwise to a solution (0 °C) of 23.0 µL (0.227
mmol) of titanium (IV) chloride and 15.0 µL (0.204 mmol) of acetone
in 0.8 mL of CH2Cl2. The resulting orange-red solution was stirred at
0 °C for 1 h, cooled to -40 °C, and quenched with 1 mL of water.
The mixture was warmed, the layers were separated, and the aqueous
layer was extracted with EtOAc. The combined organic layers were
dried (Na2SO4) and concentrated via rotary evaporation. Column
chromatography (10-20% EtOAc-hexanes) of the crude residue
afforded 39.6 mg (69%) of the titled compound as well as 5.7 mg (12%)
of (-)-(R)-ketone 33. CSP HPLC analysis showed that the recovered
ketone 33 had an ee of 84% (er, 92:8).
a Reagents and conditions: (a) Tebbe reagent, THF, -40 °C, 98%;
(b) nitroethylene 2,6-di-tert-butylpyridine, PhH, 80 °C, 36 h, 65%; (c)
Bu3SnH, AIBN, PhMe, 110 °C, 4 h, 40%; (d) EtSNa, DMF, 140 °C,
4 h, 78%.
Olefin 41. A solution of tertiary alcohol 40 (55.5 mg, 0.183 mmol)
and Et3N (260 µL, 1.86 mmol) was cooled to 0 °C and treated with
methanesulfonyl chloride (71 µL, 0.92 mmol). After being stirred at 0
°C for 1h, the mixture was diluted with EtOAc (20 mL) and washed
with H2O and brine. Drying (Na2SO4), concentration, and flash column
chromatography (10% EtOAc-hexane) gave a 1:1 mixture of olefinic
isomers (45.8 mg, 88%), which was used in the next reaction without
further purification. A solution of the above olefinic mixture (45.8 mg,
0.161 mmol) in MeOH (2 mL) was cooled to 0 °C and treated with
NaOMe (25 wt % in MeOH, 100 µL, 0.460 mmol). After being stirred
at 0 °C for 4 h, the solution was acidified with Dowex 50-X8 and
filtered. Concentration and flash column chromatography (10% EtOAc-
hexane) gave olefin 41 (43.9 mg, 96%): IR (film) 2934, 1650, 1626,
1557, 1473 cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.76 (d, J ) 2.7 Hz,
1H), 7.31 (d, J ) 8.9 Hz, 1H), 6.87 (dd, J ) 8.9 Hz, 2.7 Hz, 1H), 3.87
(s, 3H), 3.25-3.31 (m, 1H), 2.61 (ddd, J ) 14.7 Hz, 5.4 Hz, 5.4 Hz,
1H), 2.37 (ddd, J ) 14.7 Hz, 9.5 Hz, 6.1 Hz, 1H), 2.20-2.26 (m, 1H),
2.03 (s, 3H), 1.89 (s, 3H), 1.62-1.71 (m, 1H), 1.45 (d, J ) 7.0 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 193.3, 168.5, 157.0, 148.6, 141.0,
135.3, 127.4, 117.7, 113.7, 111.2, 104.1, 55.9, 33.0, 32.9, 26.3, 22.2,
21.6, 17.9; HRMS (FAB) [M + H]+ calcd for C18H21O3, 285.1491;
found, 285.1487.
described above and concentration of the organic layers, the crude oil
was purified by column chromatography (5% CHCl3-MeOH) to afford
423 mg (100%) of the enantio-enriched carboxylic acid 34: [R]27
-20.6 (c 0.795, CHCl3).
)
D
Ketone 33. A solution of carboxylic acid 34 (280 mg, 1.07 mmol)
in CH2Cl2 (6 mL) was treated with (COCl)2 (2.0 M in CH2Cl2, 0.80
mL, 1.60 mmol), and the mixture was stirred at room temperature for
30 min and at 40 °C for 30 min. The solution was cooled to -78 °C
and was treated with SnCl4 (321 µL, 2.74 mmol). The mixture was
stirred at -78 °C for 30 min and warmed to -10 °C, and the stirring
was continued for 30 min. The reaction was then quenched with 1N
HCl (3 mL). The solution was diluted with EtOAc (50 mL) and washed
with 1N HCl, saturated aqueous NaHCO3, and brine. Drying (Na2SO4),
concentration, and flash column chromatography (20% EtOAc-hexane)
gave ketone 33 (175 mg, 67%): IR (film) 2935, 1647, 1559, 1473,
1
1273 cm-1; H NMR (CDCl3, 500 MHz) δ 7.74 (d, J ) 2.7 Hz, 1H),
7.27 (d, J ) 8.9 Hz, 1H), 6.86 (dd, J ) 8.9 Hz, 2.7 Hz, 1H), 3.85 (s,
3H), 3.30-3.34 (m, 1H), 2.79 (t, J ) 6.9 Hz, 2H), 2.16-2.22 (m, 1H),
1.99-2.03 (m, 1H), 1.86-1.90 (m, 1H), 1.75-1.80 (m, 1H), 1.45 (d,
J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 198.2, 169.3, 156.9,
148.4, 127.5, 117.1, 113.8, 110.8, 104.8, 55.9, 44.9, 35.7, 33.4, 20.2,
19.8; HRMS (FAB) [M + H]+ calcd for C15H17O3, 245.1178; found,
245.1172.
(-)-(R)-Olefin 41. A solution of 128 mg (0.423 mmol) of tertiary
alcohol 40, prepared from (+)-52, and 0.165 mL (2.13 mmol) of
methanesulfonyl chloride in 4.2 mL of CH2Cl2 was cooled to 0 °C and
0.590 mL (4.23 mmol) of triethylamine was added dropwise. The
resulting yellow mixture was stirred at 0 °C for 3 h. The mixture was
then diluted with 80 mL of EtOAc and washed with 15-mL portions
of water; 1 N HCl; saturated, aqueous sodium bicarbonate; and brine.
The organic layer was dried (Na2SO4) and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (5%
EtOAc-hexanes) to give 42.0 mg (35%) of the desired (-)-(R)-olefin
41 and 47.7 mg (40%) of its olefinic isomer. In a separate experiment,
the olefinic mixture (7.4 mg, 0.026), generated from dehydration of
(-)-40 as described above, was refluxed for 3 h in 0.45 mL of benzene
in the presence of 7.0 mg (0.027 mmol) of bis(acetonitrile) palladium
(II) chloride. The benzene was removed under vacuum and the crude
residue was purified via column chromatography (5-10% EtOAc-
(-)-(R)-Ketone 33. The titled ketone was prepared from (-)-34 in
a similar manner as racemate ketone 33: [R]27 ) +16.0 (c 0.0860,
D
CHCl3). The enantiomeric purity was determined by CSP HPLC (1%
i-PrOH-hexane at 2.0 mL/min; tR (major enantiomer) ) 7.4 min, tR
(minor enantiomer) ) 8.8 min). The enantiomeric purity of the material
was determined to be 84% [i.e., enantiomeric ratio (er) ) 92:8].
Tertiary Alcohol 40. A solution of LiHMDS (1.0 M solution in
THF, 2.4 mL, 2.4 mmol) in THF (3 mL) was cooled to -78 °C, and
ketone 33 (479 mg, 1.96 mmol) in THF (2 + 1 + 1 mL) was added to
this solution. The mixture was stirred at -78 °C for 20 min and at
-40 °C for 20 min. To this solution was added ZnCl2 (1.0 M in Et2O,
2.4 mL, 2.4 mmol) at -40 °C, and the resultant mixture was stirred at
the same temperature for 10 min. This solution was treated with acetone
(350 µL, 4.77 mmol) and stirred at -40 °C for 20 min. The reaction
mixture was quenched with H2O; diluted with EtOAc (80 mL); and
washed with H2O, saturated aqueous NaHCO3, and brine. Drying (Na2-
hexane) to give 6.9 mg (93%) of (-)-(R)-olefin 41: [R]27 ) -24.2
D
(c 0.627, CHCl3).
Diene 42. A solution of olefin 41 (183 mg, 0.644 mmol) and pyridine

1888 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Inoue et al.
(130 µL, 1.60 mmol) in THF (8 mL) was cooled to -40 °C and treated
with Tebbe reagent (0.5 M in toluene, 3.2 mL, 1.6 mmol). After being
stirred at -40 °C for 1h, the reaction mixture was diluted with Et2O
(12 mL), and 15% aqueous NaOH. and solid Na2SO4 was added to
this mixture. The resulting mixture was stirred at room temperature
for 1.5 h and filtered through Celite. Concentration and flash column
chromatography (10% EtOAc-hexane) gave diene 42 (176 mg,
97%): IR (film) 2930, 1614, 1474, 1200 cm-1; 1H NMR (CDCl3, 500
MHz) δ 7.32 (d, J ) 8.9 Hz, 1H), 7.17 (d, J ) 2.6 Hz, 1H), 6.81 (dd,
J ) 8.9 Hz, 2.6 Hz, 1H), 5.55 (d, J ) 2.2 Hz, 1H), 5.11 (d, J ) 2.2
Hz, 1H), 3.85 (s, 3H), 3.05-3.11 (m, 1H), 2.55-2.60 (m, 1H), 2.42-
2.50 (m, 1H), 2.00-2.07 (m, 1H), 1.85-1.91 (m, 1H), 1.80 (s, 3H),
1.70 (s, 3H), 1.33 (d, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
δ 159.8, 155.9, 149.1, 140.6, 135.7, 128.4, 126.1, 116.2, 114.7, 111.2,
111.1, 103.0, 56.0, 33.8, 31.9, 29.3, 22.3, 19.9, 18.6; HRMS (FAB)
[M + H]+ calcd for C19H23O2, 283.1698; found, 283.1696.
1H), 3.13-3.22 (m, 1H), 2.52 (t, J ) 5.8 Hz, 2H), 2.05-2.17 (m, 2H),
1.63-1.70 (m, 3H), 1.52-1.57 (m, 3H), 1.34 (d, J ) 6.9 Hz, 3H),
1.08 (s, 3H), 1.07 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 160.2, 150.7,
149.1, 144.3, 129.6, 123.7, 116.5, 111.1, 110.8, 107.3, 39.5, 38.5, 35.7,
34.7, 30.5, 28.9, 27.9, 26.0, 20.0, 19.7; HRMS (FAB) [M]+ calcd for
C20H24O2, 296.1776; found, 296.1784.
(+)-(R)-Frondosin B (1). The titled compound was prepared from
(+)-O-methyl frondosin B 16 in a similar manner as racemate frondosin
B (1): [R]25D ) +15.2 (c 0.125, MeOH). The enantiomeric purity was
determined by CSP HPLC [5% i-PrOH-hexane at 2.0 mL/min; tR
(major enantiomer) ) 3.8 min, tR (minor enantiomer) ) 5.0 min]. The
enantiomeric purity of the material was determined to be 84% (i.e., er
) 92:8).
(-)-Methyl 5(S), 6(S)-epoxy-7-hydroxyheptanoate (47). Titanium
(IV) isopropoxide (0.380 mL, 1,27 mmol) was added dropwise to a
mixture of (+)-diisopropyl-L-tartrate and crushed molecular sieves in
225 mL of CH2Cl2 at 5 °C. The mixture was cooled to -20 °C and
tert-butyl hydroperoxide (3.4 M, 7.70 mL, 26.2 mmol) was added
dropwise. The resulting mixture was warmed to -15 °C and methyl
7-hydroxy-5-(E)-heptenoate (46) was added over a 5-min period. The
contents of the flask were stirred at -15 °C for 3 h before the slow
addition of cellulose phosphate (-40 °C), which removed the titanium
catalyst. The mixture was filtered, and the solid was washed with
copious amounts of EtOAc (∼400 mL). The solvent was removed via
rotary evaporator, and the crude residue was purified by flash
chromatography (20-40-50-60% EtOAc-hexane) to give 1.38 g
(+)-(R)-Diene 42. The titled diene was prepared in a similar manner
as racemate diene 42: [R]24 ) +22.0 (c 1.26, CHCl3).
D
Diels-Alder Adduct 43. A solution of diene 42 (313.9 mg, 1.11
mmol), nitroethylene (800 mg, 10.9 mmol) and 2,6-di-tert-butylpyridine
(110 mg, 0.574 mmol) in benzene (7 mL) was placed in a sealed tube
and heated at 80 °C for 36 h. After being cooled to room temperature,
the solution was concentrated. Flash column chromatography (5-10%
EtOAc-hexane) gave Diels-Alder Adduct 43 as a 5:1 mixture of
isomers (311.6 mg, 79%): IR (film) 2970, 1588, 1543, 1473, 1369,
1
1209 cm-1; H NMR (CDCl3, 500 MHz) δ 7.31 (d, J ) 8.9 Hz, 1/5
(63%) of the known epoxide:40a [R]27 ) -27.9 (c 0.654, CHCl3); IR
H), 7.30 (d, J ) 8.9 Hz, 4/5 H), 7.06 (d, J ) 2.5 Hz, 4/5 H), 7.05 (d,
J ) 2.5 Hz, 1/5 H), 6.82 (dd, J ) 8.9 Hz, 2.5 Hz, 1H), 4.67 (dd, J )
10.4 Hz, 3.2 Hz, 4/5 H), 4.63 (dd, J ) 12.4 Hz, 2.9 Hz, 1/5 H), 3.83
(s, 3H), 3.21 (m, 4/5 H), 3.18 (m, 1/5 H), 2.74-2.76 (m, 2H), 2.21-
2.37 (m, 3H), 2.04-2.14 (m, 2H), 1.79-1.83 (m, 1H), 1.38 (d, J )
7.0 Hz, 3H), 1.36 (s, 3/5 H), 1.34 (s, 12/5 H), 1.14 (s, 12/5 H), 1.11 (s,
3/5 H); 13C NMR (CDCl3, 125 MHz) of major isomer δ 160.7, 155.4,
149.0, 140.9, 128.6, 123.9, 115.5, 111.1, 111.0, 104.9, 92.6, 56.1, 39.7,
38.2, 33.4, 27.2, 26.1, 25.4, 23.9, 22.3, 20.1; HRMS (FAB) [M]+ calcd
for C21H25NO4, 355.1784; found, 355.1776. (+)-(R)-diene 42 was
converted to 43 in the same manner as described above.
D
(film) 3450 (br), 2952, 2871, 1736, 1438, 1255, 1202 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 3.89 (dd, J ) 13.7 Hz, 2.2 Hz, 1H), 3.67 (s, 3H),
1.57-1.66 (m, 2H), 3.63 (dd J ) 13.7 Hz, 4.2 Hz, 1H), 2.91-2.97
(m, 2H), 2.38 (t, J ) 7.4 Hz, 2H), 2.05 (br s, 1H), 1.77-1.82 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 173.64, 61.57, 58.26, 55.34, 51.46,
33.33, 30.70, 21.20. Enantiomeric excess was determined by converting
epoxy alcohol 45 to its Mosher ester using the general technique.52 In
the event, (-)-(R)-Mosher’s chloride (53.0 mg, 0.210 mmol) in
pyridine (0.1 mL) was added to a solution of 25.8 mg (0.148 mmol) of
45 in pyridine (0.2 mL). After the typical workup, the solution was
1
O-Methyl Frondosin B (16). A solution of Diels-Alder adduct 43
(31.9 mg, 0.0890 mmol), AIBN (15.0 mg, 0.0910 mmol) and n-Bu3-
SnH (500 µL, 1.85 mmol) in toluene (2 mL) was heated at 110 °C for
1.5 h. After being cooled to room temperature, the solution was
concentrated and subjected to flash column chromatography (5%
EtOAc-hexane) to afford O-methyl frondosin B 16 (16.3 mg, 58%):
concentrated under vacuum. H NMR analysis of the crude diastere-
omeric mixture of the Mosher ester indicated that 45 was formed in
84% ee.
(+)-Methyl 6-R, 7-dihydroxy-5R-methyl heptanoate (48). A solu-
tion of 898 mg (5.15 mmol) of methyl (-)-5(S), 6(S)-epoxy-7-
hydroxyheptanoate (47) in 3 mL of CH2Cl2 was added dropwise over
a 30-min period to a 1.46 M solution of AlMe3 (54.0 mmol) in
hexanes-CH2Cl2 (2.7:1 by vol) at -78 °C. The resulting white mixture
was stirred at -78 °C for 3 days before carefully quenching with 5
mL of saturated, aqueous NaF. The mixture was allowed to warm and
was then filtered through a scintered glass funnel. The white aluminum
salts were washed with excess EtOAc (250 mL) and extracted with
additional EtOAc for 4 days via a Soxhlet extractor. The organic extracts
were combined and concentrated under vacuum. The crude residue was
purified by flash chromatography (80% EtOAc-hexane) to yield 593
1
IR (film) 2927, 1591, 1473, 1204, 1035 cm-1; H NMR (CDCl3, 500
MHz) δ 7.28 (d, J ) 8.8 Hz, 1H), 7.15 (d, J ) 2.5 Hz, 1H), 6.79 (dd,
J ) 8.8 Hz, 2.5 Hz, 1H), 3.83 (s, 3H), 3.15-3.22 (m, 1H), 2.57 (t, J
) 5.9 Hz, 2H), 2.09-2.18 (m, 3H), 1.70-1.73 (m, 2H), 1.56-1.64
(m, 3H), 1.34 (d, J ) 6.9 Hz, 3H), 1.091 (s, 3H), 1.088 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 160.0, 155.2, 149.0, 144.4, 129.3, 123.8,
116.6, 110.84, 110.77, 105.3, 56.1, 39.5, 38.7, 35.7, 34.6, 30.5, 29.0,
27.9, 26.1, 20.0, 19.7; HRMS (FAB) [M + H]+ calcd for C21H26O2,
310.1933; found, 310.1928.
mg (60%) of a clear oil: [R]27 ) +11.2 (c 0.580, CHCl3); IR (film)
(+)-(R)-O-Methyl Frondosin B (16). The titled compound was
prepared in a similar manner as the racemate of O-methyl frondosin B
D
1
3414 (br), 2954, 2877, 1738, 1459, 1249, 1171, 1058 cm-1; H NMR
(16): [R]25 ) +9.6 (c 0.355, CHCl3). The enantiomeric purity was
D
(CDCl3, 400 MHz) δ 3.70-3.74 (m, 1H), 3.68 (s, 3H), 3.49-3.53 (m,
2H), 2.28-2.35 (m, 2H), 1.72-1.75 (m, 1H), 1.53-1.62 (m, 3H), 1.22-
1.26 (m, 1H), 0.90 (d, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 174.36, 75.88, 64.62, 51.56, 35.66, 34.04, 31.75, 21.88, 15.22; MRMS
(EI) [M + H]+ m/z calcd for C9H18O4, 191.1283; found, 191.1278.
(-)-Methyl 5(R)-methyl-6-heptynoate (44). A mixture of methyl
(-)-6(R), 7-dihydroxy-5(R)-methyl heptanoate (1.58 g, 8.30 mmol) and
NaIO4 (2.70 g, 12.6 mmol) in 60 mL of THF:H2O (1:1 v:v) was stirred
at 25 °C for 2 h. The volatile components were removed via rotary
evaporation, and the aqueous layer was extracted with five 60-mL
portions of Et2O. The ethereal extracts were combined, dried (MgSO4),
and concentrated under reduced pressure to afford crude methyl 5-(R)-
methyl-6-oxohexanoate, which was immediately used in the next step
without further purification. A solution of 1.37 g (9.13 mmol) of
determined by CSP HPLC [hexane at 1.0 mL/min; tR (major enanti-
omer) ) 11.4 min, tR (minor enantiomer) ) 21.9 min]. The enantiomeric
purity was determined to be 86% (i.e., er ) 93:7).
Frondosin B (1). A solution of EtSH (400 µL, 5.40 mmol) in DMF
(3 mL) was cooled to 0 °C and treated with NaH (60% in mineral oil,
204 mg, 5.10 mmol). The solution was stirred at room temperature for
30 min. This NaSEt solution (2.3 mL, ∼3.4 mmol) was added to a
solution of O-methyl frondosin B 16 (52.6 mg, 0.169 mmol) in DMF
(1 mL), and the mixture was heated at 140 °C for 3 h. After being
cooled to room temperature, the solution was quenched with saturated
aqueous NH4Cl and diluted with EtOAc (60 mL). The organic layer
was washed with H2O and brine, dried (Na2SO4), and concentrated.
Flash column chromatography (10% EtOAc-hexane) gave frondosin
B 1 (47.3 mg, 94%). IR (film) 3370, 2928, 1620, 1589, 1461, 1374,
1
1197 cm-1; H NMR (CDCl3, 400 MHz) δ 7.22 (d, J ) 8.7 Hz, 1H),
(52) Mosher, H. S.; Dull, D. L.; Dale, J. A. J. Org. Chem. 1969, 34,
2543.
7.11 (d, J ) 2.5 Hz, 1H), 6.70 (dd, J ) 8.7 Hz, 2.5 Hz, 1H), 4.81 (s,

Absolute Configuration of Frondosin B
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1889
dimethyl (diazomethyl)phosphonate in 10.0 mL of THF was added to
a 0.90 M solution (-78 °C) of potassium t-butoxide (9.13 mmol) in
THF. The yellow solution was stirred at -78 °C for 5 min and a solution
of crude methyl 5-(R)-methyl-6-oxohexanoate in 1.5 mL of THF was
added dropwise over a 30-min period. Gas evolution was observed
within 5 min. The orange mixture was stirred overnight at -50 °C.
The orange mixture was concentrated to ∼1 mL and then purified by
column chromatography (5% EtOAc-hexane) to give 915 mg (71%)
reactions between alkyne 44 and iodophenol 45 (Table 1) were
conducted in a similar manner as described above using either
tetramethylguanidine (Table 1, entry 1) or piperidine (Table 1, entry
2) as an amine base.
(-)-(R)-Methyl Ester 50. A dry, one-necked, 50-mL, round-
bottomed flask was charged, under argon, with (-)-7-(2-hydroxy-5-
methoxy-phenyl)-5(R)-methyl-hept-6-ynoic acid methyl ester (51) (1.38
g, 4.99 mmol), DMF (16.0 mL), triethylamine (1.40 mL, 10.1 mmol),
bis(triphenylphoshpine) palladium (II) chloride (123 mg, 0.175 mmol),
and copper (I) iodide (127 mg, 0.667 mmol). The dark brown solution
was warmed to 50 °C and stirred for 18 h. The solution was allowed
to cool and then was quenched with 15 mL of H2O. The aqueous layer
was extracted with EtOAc (3 × 30 mL and 2 × 20 mL). The combined
organic extracts were washed with H2O (5 × 25 mL) and brine (1 ×
25 mL), dried (MgSO4), and concentrated under reduced pressure. Flash
chromatography (5-10-20% EtOAc-hexanes gradient) yielded 843
of the volatile alkyne: [R]27 ) -23.0 (c 0.160, CHCl3); IR (film)
D
3295, 2970, 2934, 2874, 1740, 1454, 1375, 1292, 1167 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 3.68 (s, 3H), 2.42-2.48 (m, 1H), 2.34 (t, J ) 7.5
Hz, 2H), 2.05 (d, J ) 2.3 Hz, 1H), 1.73-1.86 (m, 2H), 1.20-1.50 (m,
2H), 1.19 (d, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 173.91,
88.46, 68.54, 51.50, 35.98, 33.76, 25.46, 22.65, 20.87; MRMS (EI)
m/z calcd for C9H14O2, 154.0994; found, 154.0984.
2-Iodo-4-methoxyphenol (45). A solution of 5.23 g (23.4 mmol)
of diethyl carbamic acid (4-methoxyphenyl ester)53 and 2.10 mL of
N,N,N′,N′-tetramethylethylenediamine (25.7 mmol) in 250 mL of THF
was cooled to -78 °C, and 21.0 mL of a 1.20 M solution of sec-BuLi
(48.4 mmol) in cyclohexane was added dropwise over a 10-min period.
The resulting bright yellow solution was stirred at -78 °C for 1.5 h to
complete the directed ortho-lithiation and a saturated solution of iodine
in THF was added dropwise until an orange color persisted in the
reaction mixture. The orange mixture was stirred at -78 °C for 30
min before the addition of 50 mL of 10% aqueous sodium thiosulfate.
The cooling bath was then removed and the slurry was allowed to warm
to room temperature. The resulting mixture was washed with 50 mL
of water, dried (MgSO4), and concentrated under reduced pressure. The
crude diethyl carbamic acid (2-iodo-4-methoxyphenyl ester) was used
in the next step without purification. The crude diethyl carbamic acid
(2-iodo-4-methoxyphenyl ester) was dissolved in 70 mL of 2 N NaOH
and 70 mL of MeOH, and the solution was refluxed for 4 days. The
solution was cooled and then extracted with three 70-mL portions of
Et2O. The aqueous layer was acidified with concentrated HCl to ∼pH
2 and then extracted with five 70-mL portions of Et2O. The organic
layers that were extracted from the acidic layer were combined, dried
(Na2SO4), and concentrated under reduced pressure. Flash chromatog-
raphy (5% EtOAc-0.1% AcOH-hexane) afforded 2.92 g (50% from
the diethyl carbamyl ester) of the known54 iodophenol as a white
solid: mp 63.5-64.5 °C; 1H NMR (CDCl3, 400 MHz) δ 7.19 (d, J )
2.9 Hz), 6.91 (d, J ) 8.9 Hz, 1H), 6.84 (dd, J ) 8.9 Hz, 2.9 Hz,1H),
5.01(s, 1H), 3.75 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 153.86,
149.14, 122.60, 116.31, 115.09, 85.01, 55.93.
mg (61%) of benzofuran 50 as well as 114 mg (8%) of recovered
1
starting material (51): [R]27 ) -20.2 (c 0.104, CHCl3); H NMR
D
(CDCl3, 400 MHz) δ 7.30 (d, J ) 8.9 Hz, 1H), 6.97 (d, J ) 2.6 Hz,
1H), 6.81 (d, J ) 8.9 Hz, 2.6 Hz, 1H), 6.33 (s, 1H), 3.84 (s, 3H), 3.66
(s, 3H), 2.91-2.96 (m, 1H), 2.31-2.35 (m, 2H), 1.76-1.83 (m, 1H),
1.33 (d, J ) 6.9 Hz, 3H), 1.61-1.70 (m, 3H); 13C NMR (CDCl3, 100
MHz) δ 173.93, 164.05, 155.70, 149.49, 129.30, 111.47, 111.11, 103.21,
101.09, 55.94, 51.49, 34.79, 33.96, 33.47, 22.56, 18.95; MRMS (EI)
m/z calcd for C16H20O4, 276.1362; found, 276.1352.
(+)-(R)-Silyl Enol Ether 52. A mixture of 69.0 mg (0.282 mmol)
of (-)-(R)-ketone 33, 0.107 mL (0.843 mmol) of chlorotrimethylsilane,
and ∼200 mg of crushed molecular sieves in 1.4 mL of THF was cooled
to -40 °C, and 0.860 mL of a 0.98 M solution of LiHMDS (0.843
mmol) was added dropwise. The resulting dark yellow solution was
stirred at -40 °C for 1 h before quenching with 2.0 mL of saturated,
aqueous, NaHCO3. The layers were separated and the aqueous layer
was extracted with three 2-mL portions of EtOAc. The combined
organic extracts were washed with 2 mL of brine, dried (Na2SO4), and
concentrated under vacuum. The crude residue was purified by flash
chromatography (20% EtOAc-hexane) to give 66.6 mg (75%) of the
silyl enol ether as well as 7.4 mg (11%) of recovered starting material:
1
[R]27 ) +18.8 (c 1.13, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.47
D
(dd, J ) 8.9 Hz, 2.7 Hz, 1H), 7.29 (d, J ) 8.9, 1H), 6.85 (d, J ) 2.7
Hz, 1H), 5.28 (t, 6.5 Hz, 1H), 3.86 (s, 3H), 3.32 (six-line pattern, J )
7.0 Hz, 1H), 2.24-2.33 (m, 1H), 2.02-2.06 (m, 1H), 1.61-1.80 (m,
1H), 1.40 (d, J ) 7.0 Hz, 3H), 0.31 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 155.48, 148.58, 145.83, 128.34, 113.94, 113.09, 112.42, 111.05,
110.88, 110.68, 109.52, 104.94, 55.83, 35.17, 32.52, 22.38, 20.29, 0.23;
MRMS (FAB) m/z calcd for C18H24O3Si, 316.1495; found, 316.1485.
Alkynyl Phenol (51). A dry, one-necked, 50-mL, round-bottomed
flask was charged, under argon, with 2-iodo-4-methoxyphenol (45; 1.35
g, 5.40 mmol), DMF (16.0 mL), triethylamine (1.50 mL, 10.8 mmol),
bis(triphenylphoshpine) palladium (II) chloride (134 mg, 0.191 mmol),
and copper (I) iodide (134 mg, 0.704 mmol). The dark brown solution
was stirred for 20 min at 25 °C before the addition of methyl 5(R)-
methyl-6-heptynoate (47; 915 mg, 5.93 mmol). The solution was stirred
for 24 h at 25 °C and then was quenched with 15 mL of H2O. The
aqueous layer was extracted with EtOAc (3 × 30 mL and 2 × 20 mL).
The combined organic extracts were washed with H2O (5 × 25 mL)
and brine (25 mL), dried (MgSO4), and concentrated via rotary
evaporation. Flash chromatography (5-10-20% EtOAc-hexane)
yielded 1.38 g (93%) of 51 as well as 42.0 mg (3%) of benzofuran 50:
Acknowledgment. This work was supported by the National
Institutes of Health (Grant No: AI16943). M.W.C. gratefully
acknowledges the U.S. Army Breast Cancer Research Program
(DAMD17-98-1-8154). M.I. gratefully acknowledges the Uehara
Memorial Foundation for a postdoctoral fellowship. A.J.F.
gratefully acknowledges the American Chemical Society Or-
ganic Division and Merck & Co. for graduate fellowship
support. We thank Dr. George Sukenick of the MSKCC NMR
Core Facility (CA 08748, SKI core grant) and Dr. Yasuhiro
Itagaki of the Columbia University Mass Spectral Facility for
mass spectral analyses and K.H. Lee, Director, Natural Products
Laboratory, School of Pharmacy, University of North Carolina,
Chapel Hill, for HIV suppression studies.
[R]27 ) -29.0 (c 0.445, CHCl3); IR (film) 3442 (br), 2952, 2873,
D
1
1730, 1495, 1274, 1164 cm-1; H NMR (CDCl3, 400 MHz) δ 6.78-
6.87 (m, 3H), 5.62 (s, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 2.74 (six-line
pattern, J ) 6.9 Hz, 1H), 2.39 (t, J ) 7.2 Hz, 2H), 1.77-1.94 (m, 2H),
1.55-1.61 (m, 2H), 1.30 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 173.95, 152.87, 150.87, 116.59, 115.40, 115.27, 110.06, 101.19,
75.34, 55.80, 51.63, 36.17, 33.61, 26.62, 22.71, 21.09; MRMS (EI)
m/z calcd for C16H20O4, 276.1362; found, 276.1358. Exploratory
Supporting Information Available: Experimental proce-
dures and spectral character not involved in the most specific
total synthesis (general method, 1, 6-9, 11-14, 18-21, 30,
1
39) and H NMR spectral data for compounds (1, 16, 30, 33,
(53) 49 was prepared in 74% yield by an acylation reaction between
4-methoxy-1-phenol and diethyl cabamoyl chloride in pyridine at reflux:
Lustig, E.; Benson, W. R.; Dut, N. J. J. Org. Chem. 1967, 32, 851.
(54) Shashidhar, G. V. S.; Satyanarayana, N.; Sundaram, E. V. Indian
J. Chem. Sect. A. 1986, 25, 289.
34, 37, 39-43). This material is available free of charge via
the Internet at http://pubs.acs.org.
JA0021060