Total synthesis of O-methylsterigmatocystin using N-alkylnitrilium salts and carbonyl-alkene interconversion in a new xanthone synthesis

Article abstract of DOI:10.1021/jo990099w

A general strategy is described for the preparation of substituted xanthones and embodied in the preparation of (±)-O-methylsterigmatocystin (OMST), the most advanced, known intermediate in the biosynthesis of aflatoxin. The essential features of this approach are the reaction of N- alkylnitrilium salts with activated aromatic rings, and protection of the derived xanthones as their corresponding alkenyl xanthenes. The latter are readily synthesized by reaction with n-butyllithium and dehydration. The resulting stabilization of the xanthone nucleus enables a wide range of chemical modification reactions to be carried out, and a facile and unusual cleavage of the alkene with peracid restores the desired xanthone. Compatibility of these operations with the preparation of the sensitive dihydrobisfuran is exemplified in the synthesis of OMST.

Full text of DOI:10.1021/jo990099w

4050
J . Org. Chem. 1999, 64, 4050-4059
Tota l Syn th esis of O-Meth ylster igm a tocystin Usin g
N-Alk yln itr iliu m Sa lts a n d Ca r bon yl-Alk en e In ter con ver sion in a
New Xa n th on e Syn th esis
Linda K. Casillas and Craig A. Townsend*
Department of Chemstry, The J ohns Hopkins University, Baltimore, Maryland 21218
Received J anuary 20, 1999
A general strategy is described for the preparation of substituted xanthones and embodied in the
preparation of (()-O-methylsterigmatocystin (OMST), the most advanced, known intermediate in
the biosynthesis of aflatoxin. The essential features of this approach are the reaction of
N-alkylnitrilium salts with activated aromatic rings, and protection of the derived xanthones as
their corresponding alkenyl xanthenes. The latter are readily synthesized by reaction with
n-butyllithium and dehydration. The resulting stabilization of the xanthone nucleus enables a wide
range of chemical modification reactions to be carried out, and a facile and unusual cleavage of the
alkene with peracid restores the desired xanthone. Compatibility of these operations with the
preparation of the sensitive dihydrobisfuran is exemplified in the synthesis of OMST.
Sch em e 1
In tr od u ction
Aflatoxin B1 (7, AFB1) is an environmental carcinogen
produced by certain species of the fungal genus Aspergil-
lus and has worldwide consequences for human and
animal health.1 Its biosynthesis requires at least 15 steps
from norsolorinic acid (1) and proceeds through formation
of the characteristic dihydrobisfuran present in versicol-
orin A (2).2 Oxidative cleavage and rearrangement of the
anthraquinone nucleus of 2 gives demethylsterigmato-
cystin (3, DMST) which is sequentially O-methylated to
sterigmatocystin (4, ST) and O-methylsterigmatocystin
(5, OMST)3-5 Recent biochemical and genetic evidence
suggests that a single cytochrome P-450 converts 5 to
AFB1 (7).6 It is known that C-11 (•) in 5 is lost as CO2,
but the mechanism of this intriguing process is un-
known.7 To account for the oxidation state of this frag-
ment and the required ring cleavage and skeletal rear-
rangement to aflatoxin, we have proposed a biogenetic
hypothesis involving two cycles of oxidation.2,7,8 The
proposed product of the first oxidative cycle is 11-
hydroxy-O-methylsterigmatocystin (6, Scheme 1), which
putatively undergoes a second oxidation to lead on to ring
cleavage, rearrangement, and decarboxylation to AFB1
(7).
the biosynthesis. To investigate its proposed intermediacy
in the conversion of OMST (5) to AFB1 (7), syntheses of
both 5 and 6 are required. It could be anticipated at the
outset that a successful synthetic plan would provide a
general route to the xanthone nucleus compatible with
later elaboration of the sensitive dihydrobisfuran ring
system (a masked dialdehyde), introduction of isotopic
label, and maintence of the hydroquinone oxidation state
of the A-ring in 6. We describe a new synthesis of
xanthones that meets these demands and takes advan-
tage of the high electrophilicity of N-alkylnitrilium salts.
In addition, a central tactic of xanthone protection was
developed whereby the xanthone carbonyl is masked as
a double bond to allow side chain elaboration under
diverse reaction conditions. Scission of the olefin can be
carried out subsequently in an especially facile manner
to return the xanthone product in high yield. This
strategy should prove useful in future syntheses of
11-Hydroxy-O-methylsterigmatocystin (6) is unknown
as a natural product and may exist only transiently in
* Address correspondence to this author. Tel: 410-516-7444. Fax:
410-516-8420. e-mail: Townsend@jhunix.hcf.jhu.edu.
(1) Kensler, T. W.; Groopman, J . D. In Molecular Mechanisms of
Chemical and Radiation Carcinogenesis; Sipes, I. G., McQueen, C. A.,
Gandolfi, A. J ., Eds.; Pergammon Press: Oxford, 1997; pp 201-223.
(2) Minto, R. E.; Townsend, C. A. Chem. Rev. 1997, 97, 2537-2555.
(3) Cleveland, T. E.; Lax, A. R.; Lee, L. S.; Bhatnagar, D. Appl.
Environ. Microbiol. 1987, 53, 1711-1713.
(4) Yabe, K.; Ando, Y.; Hashimoto, J .; Hamasaki, T. Appl. Environ.
Microbiol. 1989, 55, 2172-2177.
(5) Keller, N. P.; Dischinger, J ., H. C.; Bhatnagar, D.; Cleveland, T.
E.; Ullah, A. H. Appl. Environ. Microbiol. 1993, 59, 479-484.
(6) Prieto, R.; Woloshuk, C. P. Appl. Environ. Microbiol. 1997, 63,
1661-1666.
(7) Chatterjee, M.; Townsend, C. A. J . Org. Chem. 1994, 59, 4424-
4429.
(8) Watanabe, C. M. H.; Townsend, C. A. J . Org. Chem. 1996, 61,
1990-1993.
10.1021/jo990099w CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/06/1999

Total Synthesis of O-Methylsterigmatocystin
J . Org. Chem., Vol. 64, No. 11, 1999 4051
Sch em e 2
Sch em e 3
higher yielding than Ullmann ether syntheses, the most
prevalent strategy for xanthone synthesis is acylation
first followed by cyclization to form the biaryl ether. The
xanthone skeleton can also be formed from two aryl
components in one step by either a combined Friedel-
Crafts/aryl condensation,22,23 or by aryl anion addition
to salicylaldehyde followed by reduction to the xanthene
and eventual oxidation to the xanthone (Tanase method).24
Some less conventional methods of xanthone synthesis
are also known.25,26 These generalized approaches are
shown in Scheme 2.
complex xanthone-based natural products which are of
broader importance for their demonstrated biological and
pharmacological properties, e.g., antileukemic, anti-
inflammatory, antimicrobial, tuberculostatic, and CNS
activites.9,10 We illustrate these developments in the
synthesis of a representative group of benzophenone
ketimines and in a total synthesis of (()-O-methylsterig-
matocystin (5).
Traditional xanthone syntheses involve the connection
of two aryl fragments to form the internal pyranone ring
(Scheme 2).11,12 The carbonyl connection can be formed
by three reaction types: (1) Friedel-Crafts acylation and
variants;13-15 (2) biaryl ester migration, such as the Fries
rearrangement;16,17 or (3) aryl anion addition to a benzoyl
chloride.18 The ether linkage can be formed intermolecu-
larly by the Ullmann method,10,19 or intramolecularly by
an SNAr mechanism16,20 or Smiles rearrangement.14,21
Because intermolecular acylation reactions are generally
At the outset of this project, we applied some of the
standard methods of xanthone synthesis. Unfortunately,
these proved to be inadequate for the preparation of
xanthone precursors to 5 and 6. For example, when
methyl 2,6-dihydroxy-4-methoxybenzoate (8), a phloro-
glucinol-based nucleus, was subjected to Friedel-Crafts
conditions (AlCl3, ZnCl2, Me3SiCl) in the presence of a
benzoyl chloride, a low yield of O-and C-acylated (9)
products was isolated (Scheme 3), and the major product
was the undesired ester 10. Under Vilsmeier-Haack
conditions, only the O-acylated product 10 was isolated.
The standard Houben-Hoesch27 procedure provided no
product at all.28 The presence of a methyl ester decreased
the ring nucleophilicity to such an extent that standard
acylating electrophiles were inefficient. For the acylation
reaction to proceed, a more suitable electrophile was
required. Ideally, we sought a simple procedure that
(20) Sato, H.; Dan, T.; Onuma, E.; Tanaka, H.; Koga, H. Chem.
Pharm. Bull. 1990, 38, 1266-1277.
(9) Bennett, G. J .; Lee, H. Phytochemistry 1989, 28, 967-998.
(10) J ackson, W. T.; Boyd, R. J .; Froelich, L. L.; Gapinski, D. M.;
Mallett, B. E.; Sawyer, J . S. J . Med. Chem. 1993, 36, 1726-1734.
(11) Roberts, J . C. Chem. Rev. 1961, 61, 591-605.
(12) Afzal, M.; Al-Hassan, J . M. Heterocycles 1980, 14, 1173-1205.
(13) Mehta, G.; Shah, S. R.; Venkateswarlu, Y. Tetrahedron 1994,
50, 11729-11742.
(21) Pfister, J . R. J . Heterocycl. Chem. 1982, 19, 1255-1256.
(22) Ho, D. K.; McKenzie, A. T.; Byrn, S. R.; Cassady, J . M. J . Org.
Chem. 1987, 52, 342-347.
(23) Scannell, R. T.; Stevenson, R. J . Heterocycl. Chem. 1986, 23,
857-859.
(24) Pillai, R. K. M.; Naiksatam, P.; J ohnson, F.; Rajagopalan, R.;
Watts, P. C.; Cricchio, R.; Borras, S. J . Org. Chem. 1986, 51, 717-
723.
(14) Elix, J . A.; Gaul, K. L.; J iang, H. Aust. J . Chem. 1993, 46, 95-
110.
(15) Ruske, W. In Friedel-Crafts and Related Reactions; Olah, G.
A., Ed.; Interscience Publishers: J ohn Wiley & Sons: New York, 1964;
pp 383-497.
(25) Lown, J . W.; Sondhi, S. M.; Mandal, S. B.; Murphy, J . J . Org.
Chem. 1982, 47, 4304-4310.
(26) Sandifer, R. M.; Bhattacharya, A. K.; Harris, T. M. J . Org.
Chem. 1981, 46, 2260-2267.
(16) Horne, S.; Rodrigo, R. J . Org. Chem. 1990, 55, 4520-4522.
(17) Finnegan, R. A.; Merkel, K. E. J . Org. Chem. 1972, 37, 2986-
2989.
(27) Spoerri, P. E.; DuBois, A. S. in The Hoesch Synthesis; Bachman,
W. E., Fieser, L. F., Blatt, A. H., J ohnson, J . R., Eds.; J ohn Wiley &
Sons: New York, 1949; pp 388-412.
(28) Aryl anion addition to benzonitriles, benzamides, and Vilsmeier-
type benzimidoyl chlorides were similarly unsuccessful.
(18) Elix, J . A.; Portelli, V. J . Aust. J . Chem. 1990, 43, 1773-1778.
(19) Kelly, T. R.; J agoe, C. T.; Li, Q. J . Am. Chem. Soc. 1989, 111,
1, 4522-4524.

4052 J . Org. Chem., Vol. 64, No. 11, 1999
Casillas and Townsend
completion at room temperature.32 Unfortunately, this
method was not widely applicable because the N-meth-
ylnitrilium triflates were difficult to prepare and readily
hydrolyzed on exposure to air, and, moreover, they could
not be generated from benzonitriles containing electron-
withdrawing groups. This work, however, did demon-
strate the application of alkylnitrilium salts in inter-
molecular electrophilic aromatic acylation reactions.
Realizing the potential of this reaction among the
limited known options for xanthone synthesis, we sought
to develop this method for electophilic aromatic substitu-
tion reactions. By selecting a relatively stable and easily
handled N-alkylnitrilium salt, the imino-acylation reac-
tion was found to be widely applicable in the synthesis
of various imines, some of which were subsequently
converted to xanthones. We illustrate this method in the
total synthesis of both OMST by way of xanthone 13, and
of xanthone 20 (eq 1), which can be similarly converted
to 11-hydroxy-O-methylsterigmatocystin (6).
Sch em e 4
could be readily applied to the synthesis of various
xanthone targets including xanthone 13 (Scheme 4)
which was selected as a preliminary synthetic target in
the preparation of OMST (5).
Meerwein demonstrated as early as 1955 that nitriles
can be activated by N-alkylation in the presence of Lewis
acids to become highly electrophilic nitrilium salts.29 Most
of the literature surrounding the application of these
N-alkylnitrilium salts has focused on the use of amino
and hydroxy nucleophiles in the synthesis of imidate
esters and heterocycles. The reactions of N-alkylnitrilium
salts with carbon nucleophiles has been limited to in-
tramolecular reactions of electron rich aromatics to make
quinazolines,30 or intermolecular reactions with indole,
pyrrole,31 1,3-dimethoxybenzene,32 anisole,33,34 and thio-
phene.35
The acylation reaction of alkylnitrilium salts surpasses
the Houben-Hoesch acylation method owing to the
enhanced electrophilicity of the intermediate. The pro-
tonated nitrile generated under Houben-Hoesch condi-
tions exists in only low concentrations (pKa ∼ -10). In
contrast, Meerwein’s alkylated nitrilium ion is the prin-
cipal reactive species in solution, and so it is a signifi-
cantly more potent electrophile than the corresponding
nitrile36 or the related imidoyl chloride.37
Resu lts a n d Discu ssion
The synthesis of O-methylsterigmatocystin (5) was
initiated by intermolecular imino-acylation of methyl 2,6-
dihydroxy-4-methoxybenzoate 838 by the N-isopropyl-
nitrilium salt prepared from 2-fluoro-6-methoxy benzo-
nitrile 11 and SbCl5 in 2-chloropropane and methylene
chloride. Benzophenone ketimine 12 was isolated in 92%
yield (Scheme 4). Imine 12 was extraordinarily resistant
to hydrolysis under both acidic and alkaline conditions,
presumably due to the very strong hydrogen-bonding
interaction between the imine and the peri-phenol. The
1H NMR spectrum of this compound revealed the excep-
tional strength of this interaction by the appearance of
the peri-phenolic hydrogen signal at approximately 18
ppm. In keeping with this observation, the 15N NMR
spectrum of 12 indicated an abberant hybridization for
the supposed imine nitrogen. The 15N signal resonates
at 135 ppm relative to nitromethane as internal standard
(380 ppm). This chemical shift, together with the N-H
(isopropyl) coupling constant (J NH ) 8 Hz) suggests the
existence of a significant tautomeric equilibrium between
the phenol-imine (12a ) and the keto-enamine (12b)
form.39,40 The predominance of the latter tautomer could
explain the hydrolytic stability of this imine. However,
the imine became susceptible to hydrolysis after intra-
molecular ether formation. In the presence of excess K2-
CO3 in dry refluxing acetonitrile,41 the hydrogen-bonded
phenol was freed to undergo nucleophilic substitution
Booth et al. reported the first intermolecular imino-
acylation of 1,3-dimethoxybenzene, by N-methylnitrilium
triflates in good yield (86%), although the reaction
required excess reagents and several days to reach
(29) Meerwein, H.; Laasch, P.; Mersch, R.; Spille, J . Chem. Ber.
1956, 89, 209-224.
(30) Meerwein, H.; Laasch, P.; Mersch, R.; Nentwig, J . Chem. Ber.
1956, 89, 224-238.
(31) Eyley, S. C.; Giles, R. G.; Heaney, H. Tetrahedron Lett. 1985,
26, 4649-4652.
(32) Booth, B. L.; J ibodu, K. O.; Proenc¸a, M. F. J . Chem. Soc.,
Commun. 1980, 1151-1153.
(33) Booth, B. L.; Noori, G. F. M. J . Chem. Soc., Perkin Trans. 1
1980, 2894-2900.
(38) Koreeda, M.; Dixon, L. A.; Hsi, J . D. Synlett 1993, 8, 555-556.
(39) Lichter, R. L. In Nitrogen Nuclear Magnetic Resonance Spec-
troscopy; Lambert, J . B., Riddell, F. G., Eds.; D. Reidel Publishing
Company: Boston, 1983; pp 207-244.
(40) Levy, G. C.; Lichter, R. L. Nitrogen-15 NMR Spectroscopy;
Wiley-Interscience: New York, 1979.
(34) Kopach, M. E.; Gonzalez, J .; Harman, W. D. J . Am. Chem. Soc.
1991, 113, 8972-8973.
(35) Rappoport, Z., Ed.;The Chemistry of the Cyano Group; Inter-
science Publishers: London, 1970.
(36) Fry, J . L.; Ott, R. A. J . Org. Chem. 1981, 46, 602-607.
(37) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279-1300.
(41) Boger, D. L.; Borzilleri, R. M. Bioorg., Med. Chem. Lett. 1995,
5, 1187-1190.

Total Synthesis of O-Methylsterigmatocystin
J . Org. Chem., Vol. 64, No. 11, 1999 4053
Ta ble 1. Rep r esen ta tive Nitr iliu m Acyla tion Rea ction sa
forming the corresponding xanthone imine. Addition of
aqueous methanol and continued heating promoted hy-
drolysis of the imine to provide xanthone 13 in good yield.
Some model imino-acylations were performed to es-
tablish the scope of this reaction (Table 1). In general,
the N-alkylnitrilium salts were formed in situ by reaction
of the appropriate benzonitrile with SbCl5 in the presence
of excess 2-chloropropane in methylene chloride. Various
aromatic nucleophiles were introduced, and imino acy-
lation was carried out at the appropriate temperature
(0 f 40 °C) depending on the nucleophilicity of the
aromatic substrate. This procedure led to the formation
of stable benzophenone ketimines.
The highly electron-rich aromatic rings, entries 1-3,
proceeded very smoothly to the corresponding imines 16,
17, and 18 in 3 h or less at room temperature. In the
case of trimethoxybenzene, the reaction was extremely
rapid at 0 °C. This procedure was not found to be suitable
for the acylations of phenol, anisole, or methylsalicylate
in under 20 h. Entry 4 represents the key acylation step
in this synthesis and highlights the relative reactivities
of both the nucleophilic and the electrophilic partners in
this reaction. Acylation of 8 requires considerably more
time due to the electron-withdrawing nature of the ester
substituent. Entry 5 demonstrates the enhanced electro-
philicity of a benzonitrile 1542 bearing an electron-
withdrawing pivaloate (Piv). The acylation of 8 occurs
much faster and at room temperature as compared to the
reaction between benzonitrile 11 and 8 (entry 4).43 It can
been seen that the alkylnitrilium acylation reaction
tolerates a fairly wide range of steric hindrance as well
as varying electronic properties of both the electrophile
and the nucleophile. The imines 12 and 19 were then
cyclized as described above and hydrolyzed to provide the
corresponding xanthones 13 and 20 (Scheme 4 and eq 1,
respectively).
Having secured a new and effective synthesis of
xanthones, we proceeded to the elaboration of OMST (5)
from 13. In the synthesis of complex xanthones with
functionalized aliphatic or aromatic side chains, the
xanthone core is usually constructed relatively late in the
synthesis. This strategy is exemplified in the syntheses
of cervinomycin,19 bikaverin,44 O-methylsterigmato-
cystin,45 and its saturated tetrahydrobisfuran analogue,
dihydro-OMST,16 and linear pyranoxanthones.46 While
the reasons for this strategy are unstated, delaying
formation of the xanthone minimizes potential side
reactions at the xanthone carbonyl, which is known to
be susceptible to hydride reduction24,47 and to nucleophilic
attack by alkyl-48 and aryllithium49 reagents. In those
(43) O-Acylation of the nitrilium species blocks unwanted reactions
and enhances electrophilicity. It should be noted that entry 5 was
carried out with a 2.5-fold excess of the nucleophile to increase the
rate of reaction and the net yield. At 1:1 stoichiometry we found that
prolonged exposure of this nitrilium salt, and possibly the imine
product 19, to the acidic reaction conditions caused removal of the
pivaloate ester and side reactions initiated by that unprotected phenol.
(44) Bekaert, A.; Andrieux, J .; Plat, M. Tetrahedron Lett. 1992, 33,
2805-2806.
(45) Rance, M. J .; Roberts, J . C. Tetrahedron Lett. 1970, 2799-2802.
(46) Kondedeshmukh, R. S.; Paradkar, M. V. Synth. Commun. 1994,
24, 659-664.
(47) Wechter, W. J . J . Org. Chem. 1963, 28, 2935-2936.
(48) Halton, B.; Cooney, M. J .; Boese, R.; Maulitz, A. H. J . Org.
Chem. 1998, 63, 1583-1590.
(49) Martin, J . C.; Smith, R. G. J . Am. Chem. Soc. 1964, 86, 2252-
2256.
(42) The synthesis of 15 will be described in a future publication.

4054 J . Org. Chem., Vol. 64, No. 11, 1999
Casillas and Townsend
Sch em e 5
22
cases when a hydride reductant (LiAlH4 or diisoamyl-
borane45) had been used in the presence of a functional-
ized xanthone, only low yields of desired product were
obtained, presumably because of competitive reduction
of the xanthone carbonyl.
With a xanthone carbonyl protection/deprotection
method apparently in hand, the methyl ester of 21 was
converted to the aldehyde 23 by a two-step LiAlH4/
TPAP52 redox sequence and then subjected to the one-
pot, multistep geminal disubstitution procedure of Mar-
tin53 which has been further developed in this labora-
tory.54,55 Aldehyde 23 was introduced into a solution of
the lithium anion of diethyl 1-(N-benzylidenamino)-
methylphosphonate. The resulting azadiene 24 was
treated with n-butyllithium to generate an intermediate
metalloenamine. Alkylation with ethyl bromoacetate
followed by mild acid hydrolysis produced aldehyde 25.
Treatment of this aldehyde with TIPS triflate promoted
rapid and specific cyclization with concomitant loss of the
SEM protecting group to form the diastereomeric furanyl
TIPS acetals, 26.56 The pendant ethyl ester was cleanly
reduced to alcohol 27. With all the necessary hydride
reduction reactions having been carried out, the xanthone
carbonyl could be reestablished by oxidative cleavage of
the butylene group.
A broadly applicable synthesis of xanthones, however,
would construct the xanthone core first followed by
completion of the desired structure. Vulnerability of side
chains to the imino-acylation reaction conditions dictate
such a plan of attack, particularly in the case of the
sensitive dihydrobisfuran present in 5 and 6. For bio-
synthetic experiments, the late introduction of label could
be advantageously carried out in side chain positions. To
achieve this order of synthesis, a method was needed to
both protect the xanthone carbonyl and allow its efficient
regeneration at a later stage.
Reduction of xanthones to the corresponding xanthenes
proceeds readily, but the products are prone to autoxi-
dation. Alternatively, ketalization was considered but
never achieved. Finally, the ready reactivity of the
xanthone carbonyl with alkyllithium reagents was turned
to advantage.49,48 Dehydration of the adduct of the SEM-
protected xanthone 14 and n-BuLi was extremely facile
during the course of silica gel chromatography forming
butylene 21 (Scheme 5). Literature precedents for xan-
thone formation by oxidative cleavage of an alkyl xan-
thene derivative are limited50,51 and involved hot, alkaline
KMnO4sconditions far too vigorous for the envisioned
synthesis. Notwithstanding, treatment of 21 with NaIO4
and catalytic OsO4 in aqueous dioxane proceeded smoothly
to regenerate the xanthone 14.
As before, NaIO4/catalytic OsO4 and, alternately, care-
ful low-temperature ozonolysis were attempted to re-form
the xanthone nucleus. In both cases, the starting material
was readily consumed, but both the mass recovery and
product yield were disappointingly low and variable. A
milder strategy was envisioned in which the butylene
(52) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(53) Martin, S. F.; Phillips, G. W.; Puckette, T. A.; Colapret, J . A.
J . Am. Chem. Soc. 1980, 102, 5866-5872.
(54) Graybill, T. L.; Pal, K.; McGuire, S. M.; Brobst, S. W.; Townsend,
C. A. J . Am. Chem. Soc. 1989, 111, 8306-8308.
(55) Graybill, T. L.; Casillas, E. G.; Pal, K.; Townsend, C. A.,
manuscript in preparation.
(56) Townsend, C. A.; Whittamore, P. R. O.; Brobst, S. W. J . Chem.
Soc., Chem. Commun. 1988, 726-728.
(50) Granoth, I.; Kalir, A. J . Org. Chem. 1973, 38, 841-843.
(51) Kimura, M.; Okabayashi, I. Chem. Pharm. Bull. 1987, 35, 136-
141.

Total Synthesis of O-Methylsterigmatocystin
J . Org. Chem., Vol. 64, No. 11, 1999 4055
acetates.45,57-59 More recently, analogous phenyl sulfox-
ides have undergone thermal elimination to afford the
dihydrobisfuran substructure.54,55 We elected to examine
selenoxide elimination and prepared the mixed phenyl-
selenoacetals 31 using the method of Lallemand.60 Oxi-
dation with m-CPBA at 0 °C61 proceeded in 15 min to
give a single spot on TLC coincident with OMST (5). The
1H NMR spectrum revealed that another product in
addition to OMST had been formed with identical mobil-
ity on silica gel; the m-chlorobenzoyloxyacetal. This side
reaction was also observed by Lallemand in the formation
of a similar enol ether.62 Notwithstanding, HPLC puri-
fication readily provided pure OMST (5), which was
spectroscopically identical to an authentic sample.63,64
Sch em e 6
Con clu sion
The use of N-alkylnitrilium salts as aromatic acylating
reagents under relatively mild reaction conditions has
been demonstrated. This method has been utilized to
synthesize a variety of imines which can be converted to
the corresponding xanthones. Application of this new
approach has been demonstrated in the total synthesis
of O-methylsterigmatocystin (5), a late intermediate in
aflatoxin biosynthesis. In addition, a new carbonyl pro-
tecting group has been developed that greatly expands
the tolerance of the xanthone nucleus to chemical modi-
fication. The protected alkenyl xanthene is easily formed
by the addition of n-butyllithium and dehydration pro-
moted by silica gel chromatography. The butylene group
can be efficiently cleaved to restore the parent xanthone
using m-CPBA in a mild, one-step deprotection reaction.
Together, these construction and protection tactics pro-
vide a general strategy for the synthesis of complex
xanthone natural products.
group was to be oxidized to a xanthenyl spiroepoxide.
After acid-catalyzed oxirane hydrolysis, it was hoped that
the resultant diol could be cleaved with either NaIO4 or
Pb(OAc)4. The reagent chosen to carry out the initial
epoxidation was m-CPBA. Unexpectedly, the reaction of
xanthene 27 with excess m-CPBA in the presence of 4 Å
molecular sieves formed xanthone 28 rapidly and exclu-
sively (Scheme 5). The product was easily recognizable
owing to the strong blue fluorescence of the xanthone
intermediates on TLC under long- and short-wave UV
irradiation.
Exp er im en ta l P r oced u r es
Melting points were determined in open capillaries and are
uncorrected. 1H and 13C NMR spectra were recorded at 300 or
400 MHz and are referenced to CDCl3 (7.26 and 77.0 ppm),
acetone-d6 (2.04 and 29.9 ppm), or CD2Cl2 (5.32 and 54.0 ppm)
as indicated by the individual experiments. High and low
resolution mass spectra were recorded at 70 eV in EI+, CI+,
or FAB operating modes. Combustion analyses were performed
by Atlantic Microlab, Inc. (Norcross, GA). Flash chromatog-
raphy was performed on EM silica gel 60 (230-400 mesh). A
ratio of 25-100:1 silica gel/crude product by weight and flow
rates of 1-2 in/min were normally employed for flash columns.
Thin-layer chromatography was performed on glass plates
containing fluorescent indicator, visualized by UV and 20%
ethanolic solution of phosphomolybdic acid reagent. Reagents
were supplied by Aldrich Chemical Co. All nonaqueous reac-
tions were performed in flame-dried glassware under a positive
atmosphere of dry N2 or Ar. All solvents were dried and
Mechanistically it is important to note that the olefin
present in 27 is a multiply vinylogous enol ether. On the
basis of 1H NMR studies of a model xanthene-butylene
cleavage reaction, we propose that the first equivalent
of peracid forms the epoxide 32, followed by an intramo-
lecular oxirane opening with participation of the xan-
thene oxygen (Scheme 6). The resulting cationic inter-
mediate 33 is quenched by remote addition of a second
equivalent of m-CPBA. This â-hydroxy peracyl inter-
mediate 34 can be cleaved to form the xanthone 28 and
butyraldehyde with the concomitant loss of m-chloroben-
zoate. When the model butylene-xanthene was treated
with only 1 equiv of m-CPBA, the reaction was arrested
at approximately 50% conversion. In fact, more than 2
equiv of oxidant are required to drive the reaction to
completion due to competitive oxidation of butyraldehyde.
A mixture of the cis and trans xanthone alcohols 28
was efficiently oxidized to the diastereomeric aldehydes
29 with TPAP/NMO (Scheme 5). At this stage, the cis
and trans aldehydes could be separated for characteriza-
tion purposes, but, in general, they were carried on as a
mixture through the next reaction. Treatment of the
aldehydes 29 with TEA‚(HF)3 both removed the TIPS
group and promoted cyclization to the furofuran endo-
and exo-hemiacetals 30. The hemiacetals exist in equi-
librium with the phenolic dialdehyde.
(57) Rance, M. J .; Roberts, J . C. J . Chem. Soc. (C) 1971, 1247-1252.
(58) Bu¨chi, G.; Foulkes, D. M.; Kurono, M.; Mitchell, G. F.; Schneider,
R. S. J . Am. Chem. Soc. 1967, 89, 6745-6753.
(59) Bu¨chi, G.; Weinreb, S. M. J . Am. Chem. Soc. 1971, 93, 746-
752.
(60) Bouchard, H.; Soulie´, J .; Lallemand, J . Y. Tetrahedron Lett.
1991, 32, 5957-5958.
(61) Danheiser, R. L.; Choi, Y. M.; Menichincheri, M.; Stoner, E. J .
J . Org. Chem. 1993, 58, 322-327.
(62) Brunetie´re, A. P.; Lallemand, J . Y. Tetrahedron Lett. 1988, 29,
2179-2182.
(63) Cole, R. J .; Cox, R. H. Handbook of Toxic Fungal Metabolites;
Academic Press: New York, 1981; pp 1-127.
(64) Note that the 1H NMR spectral assignments we report for
OMST 5 are a correction of the original literature and have been
verified by NOE experiments conducted on analogous xanthones.
Classically, the hemiactetals 30 have been dehydrated
by flash vacuum pyrolysis of their corresponding

4056 J . Org. Chem., Vol. 64, No. 11, 1999
Casillas and Townsend
distilled immediately prior to use (THF and Et2O were distilled
from sodium/benzophenone ketyl, and CH2Cl2 and CH3CN
were distilled from CaH2).
8.3, 6.3 Hz, 1H), 6.62 (ddd, J ) 8.4, 8.4, 0.9 Hz, 1H), 6.54 (d,
J ) 8.4 Hz, 1H), 6.08 (s, 2H), 3.78 (s, 3H), 3.68 (s, 6H), 3.61 (s,
3H), 3.54 (m, J ) 6.2 Hz, 1H), 1.16 (d, J ) 6.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 161.3, 161.1 (d, J ) 247 Hz), 158.7
(d, J ) 6.8 Hz), 158.1, 153.0, 128.6 (d, J ) 10.5 Hz), 120.8 (d,
J ) 15.0 Hz), 108.7, 108.2 (d, J ) 23.2 Hz), 106.9 (d, J ) 3
Hz), 90.2, 56.2, 55.5, 55.1, 53.9, 23.3; IR (CHCl3) 3006, 2956,
1604, 1583, 1463 cm-1; MS (EI) m/e (rel inten) 361 (M+, 9),
318 (100), 303 (30); HRMS (EI) calcd for C20H24FNO4 (M+):
361.1689, found 361.1693.
2,4-Dih yd r oxy-6,6′-d im eth oxy-2′-flu or o-3-(m eth oxyca r -
bon yl)-ben zop h en on e-N-(2-m et h ylet h yl)k et im in e (12).
To a solution of 2-fluoro-6-methoxybenzonitrile 11 (6.5 g, 0.043
mol) and 2-chloropropane (32 mL, 0.35 mol) in 90 mL of dry
CH2Cl2 was added antimony(V) chloride (SbCl5, 65 mL, 0.065
mol, 1 M in CH2Cl2). The yellow solution was stirred at room
temperature for 2 h. A 0.5 M CH2Cl2 solution of ester 8 (9.4 g,
0.047 mol) was added via cannula, and the mixture was heated
to reflux for 60 h. The reaction was cooled, quenched by the
addition of 1 N NaOH, and extracted four times with 150 mL
portions of CHCl3. The organic extracts were concentrated to
a red oil and redissolved in 400 mL of ethyl acetate from which
all the imine was extracted into 500 mL of 10% HCl. The
aqueous solution was then neutralized with solid NaOH and
extracted four times with 100-mL portions of CHCl3, which
was dried over MgSO4, filtered, and concentrated under
vacuum to provide 15.5 g (92%) of pure 12 as a yellow solid.
In smaller scale reactions (<2 g), the workup was modified
such that the initial CHCl3 extract was purified by flash
chromatography (40% ethyl acetate/hexane). Vapor recrystal-
lization from ethyl acetate and hexane produced yellow rods:
2′-Flu or o-2,4,6′-tr im eth oxyben zop h en on e-N-(2-m eth yl-
eth yl)k etim in e (17). 1H NMR (400 MHz, CDCl3) δ 7.14 (ddd,
J ) 8.6, 8.5, 6.4 Hz, 1H), 7.08 (dd, J ) 8.2, 0.6 Hz, 1H), 6.65
(dd, J ) 8.5, 8.4 Hz, 1H), 6.60 (d, J ) 8.4 Hz, 1H), 6.44 (m,
2H), 3.78 (s, 3H,), 3.76 (s, 3H), 3.70 (s, 3H), 3.61 (m, J ) 6.5
Hz, 1H), 1.18 (d, J ) 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 160.7, 160.3 (d, J ) 246 Hz), 158.2 (d, J ) 7 Hz), 157.0, 156.3,
129.6 129.0 (d, J ) 10 Hz), 120.8 (d, J ) 18 Hz), 119.7, 108.3
(d, J ) 22 Hz), 106.9 (d, J ) 3 Hz), 104.0, 98.2, 56.1, 55.3,
55.2, 53.4, 23.4; IR (CHCl3) 3008, 2966, 2933, 1607, 1466 cm-1
;
MS (CI+ (NH3)) m/e (rel inten) 332 [(M + H)+], 100), 288 (5);
HRMS (CI) calcd for C19H23FNO3 [(M + H)+]: 332.1662, found
332.1656.
2,4-Dih yd r oxy-2′-flu or o-6′-m et h oxyb en zop h en on e-N-
1
1
mp 146-147°; Rf ) 0.30 (5% CH3CN/CH2Cl2); H NMR (300
(2-m eth yleth yl)k etim in e (18). H NMR (400 MHz, CDCl3)
MHz, acetone-d6) δ 17.87 (s, 1H), 13.0 (s, 1H), 7.47 (ddd, J )
8.4, 8.3, 6.9 Hz, 1H), 6.98 (d, J ) 8.4 Hz, 1H), 6.86 (dd, J )
8.9, 8.4 Hz, 1H), 5.56 (s, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.46
(m, 1H), 3.32 (s, 3H), 1.20 (d, J ) 6.2 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 178.2, 173.2, 172.2, 166.4, 161.8, 158.2 (d, J C-F
δ 7.43 (ddd, J ) 8.3, 8.3, 6.7 Hz, 1H), 6.81 (m, J ) 8.3, 7.6 Hz,
2H), 6.56 (d, J ) 8.8 Hz, 1H), 6.50 (d, J ) 2.4 Hz, 1H), 6.13
(dd, J ) 8.8, 2.4 Hz, 1H), 3.75 (s, 3H), 3.39 (m, J ) 6.3 Hz,
1H), 1.21 (d, J ) 6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
170.9, 163.4, 162.6, 159.2 (d, J ) 246 Hz), 157.3 (d, J ) 7 Hz),
132.2, 131.6 (d, J ) 10 Hz), 111.4, 109.8 (d, J ) 24 Hz), 108.1
(d, J ) 22 Hz), 106.6, 104.9, 56.1, 51.1, 23.5, 23.3; IR (CHCl3)
3582, 3020, 2972, 1615, 1470 cm-1; MS (EI) m/e (rel inten) 303
(M+, 100), 288 (38), 272 (60), 230 (35); HRMS (EI) calcd for
3
3
) 245 Hz), 156.3 (d, J C-F ) 7.8 Hz), 130.4 (d, J C-F ) 10.1
2
2
Hz), 113.1 (d, J C-F ) 20.2 Hz), 107.5 (d, J C-F ) 21.5 Hz),
106.0 (d, 4J C-F ) 3 Hz), 101.5, 98.1, 87.6, 55.9, 55.1, 52.0, 48.0,
23.0, 22.9; IR (CHCl3) 3001, 2966, 2860, 1630, 1617, 1572,
1548, 1090 cm-1; MS (EI) m/e (rel inten) 391 (M+, 75.7), 359
(100); HRMS (EI) calcd for C20H22FNO6 (M+): 391.1431, found
391.1435.
C
17H18FNO3 (M+): 303.1271, found 303.1275.
2,4-Dih yd r oxy-6,6′-d im eth oxy-2′-flu or o-3-(m eth oxyca r -
b o n y l)-3′-p iv a lo y lb e n zo p h e n o n e -N -(2-m e t h y le t h y l)-
k etim in e (19). Rf ) 0.6 (2%MeOH/CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 17.00 (brs, 1H), 13.21 (s, 1H), 7.08 (dd, J )
8.8, 8.4 Hz, 1H), 6.69 (dd, J ) 9.2, 1.2 Hz, 1H), 5.54 (s, 1H),
4.00 (s, 3H), 3.75 (s, 3H), 3.46 (m, 1H), 3.36 (s, 3H), 1.35 (s,
9H), 1.23 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 178.2, 176.3,
173.3, 172.5, 166.5, 160.8, 153.5 (d, 6 Hz), 150.0 (d, J ) 247
Hz), 132.3 (d, J ) 14 Hz), 123.7, 114.5 (d, J ) 18 Hz), 105.6
(d, J ) 3 Hz), 101.6, 98.1, 88.0, 56.2, 55.4, 52.2, 48.3, 39.0,
27.0, 23.3, 23.0; IR (CHCl3) 3032, 2984, 1752, 1630, 1571, 1550
cm-1; MS (EI) m/e (rel inten) 491 (M+, 40), 459 (100), 375 (15);
HRMS (EI) calcd for C25H30FNO8 (M+): 491.1955, found
491.1960;
1,8-Dim eth oxy-3-h ydr oxy-4-(m eth oxycar bon yl)-9H-xan -
th en -9-on e (13). Imine 12 (13.85 g, 35.4 mmol) and K2CO3
(48.95 g, 354 mmol) were stirred at reflux in 1770 mL of dry
CH3CN for 19 h. Hydrolysis was accomplished by adding 600
mL of a 1:1 H2O/MeOH solution and stirring at reflux for an
additional 4 h. The reaction mixture was acidified to pH ∼ 6
with concentrated HCl, and the CH3CN and CH3OH were
removed under vacuum. The residual aqueous layer was
extracted repeatedly with CHCl3. The organic layer was then
washed with brine, dried over MgSO4, filtered, and adsorbed
onto 60 g of silica gel. The preadsorbed residue was purified
by flash chromatography (5% CH3OH/CH2Cl2) to afford 8 g
(68%) of 13 as a white powder. Recrystallization from cold CH2-
Cl2 produced fine white needles: mp 227-229 °C; Rf ) 0.45
3,5-Dih ydr oxy-1,8-dim eth oxy-4-(m eth oxycar bon yl)-9H-
xa n th en -9-on e (20). A suspension of 19 (1 g, 2.04 mmol), K2-
65
1
CO3 (5.6 g, 40.36 mmol), KF‚Al2O3 (0.33 g, 2.04 mmol), and
(5% CH3OH/CH2Cl2); H NMR (300 MHz, CDCl3) δ 12.54 (s,
18-crown-6 (0.05 g, 0.2 mmol) in 200 mL of dry CH3CN was
heated to reflux and stirred for 6 h. A 1:1 mixture of CH3OH/
H2O (200 mL) was added and the resulting solution stirred at
reflux for 1 h then overnight at room temperature. The
reaction mixture was concentrated to an orange residue,
dissolved in 100 mL of 1 N HCl and 300 mL of CH2Cl2, and
extracted three times with 100 mL portions of CH2Cl2. The
organic extracts were dried over MgSO4, filtered, and concen-
trated under vacuum. Purification by flash chromatography
(2.5% CH3OH/10% CH3CN/CH2Cl2) afforded 0.53 g (75%) of
20 as a white solid: mp 244-245° (dec); Rf ) 0.2 (2% MeOH/
1H), 7.52 (t, J ) 8.3 Hz, 1H), 6.98 (d, J ) 8.4 Hz, 1H), 6.78 (d,
J ) 8.3 Hz, 1H), 6.35 (s, 1H), 4.06 (s, 3H), 3.98 (s, 3H), 3.97 (s,
3H); 13C NMR (75 MHz, pyridine-d5) δ 174.06, 170.14, 167.2,
165.4, 160.8, 158.2, 157.2, 134.5, 114.5, 110.2, 108.7, 107.4,
97.9, 96.5, 56.8, 56.7, 53.0; IR (CHCl3) 3006, 2953, 1652, 1583,
1115, 1079 cm-1; MS (EI) m/e (rel inten) 330 (M+, 65.39), 298.1
(100); HRMS (EI) calcd for C17H14O7 (M+): 330.0740, found
330.0743; 330. Anal. calcd for C17H14O7: C, 61.82; H, 4.27.
Found: C, 61.82; H, 4.28.
Gen er a l P r oced u r e for Nitr iliu m Acyla tion Rea ction :
2′-F lu or o-2,4,6,6′-tetr a m eth oxyben zop h en on e-N-(2-m eth -
yleth yl)k etim in e (16). To a solution of 11 (0.11 g, 0.072
mmol) and 2-chloropropane (0.7 mL, 7.2 mmol) in 2 mL of dry
CH2Cl2 was added antimony(V) chloride (0.9 mL, 0.9 mmol).
The yellow solution was stirred at room temperature for 30
min. The mixture was then cooled to 0 °C, and solid 1,3,5-
trimethoxybenzene (0.12 g, 0.72 mmol) was added. After 15
min, the reaction was quenched by the addition of 2 N NaOH
and extracted three times with CH2Cl2. The organic portion
was washed with 1.8 M Rochelle’s salt and dried with brine
followed by MgSO4. The mixture was filtered and concentrated
under vacuum to provide 0.26 g (99%) of pure 16 as a yellow
sticky solid: 1H NMR (400 MHz, CDCl3) δ 7.09 (ddd, J ) 8.3,
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 12.38 (s, 1H), 7.18 (d,
J ) 8.9 Hz, 1H), 6.70 (d, J ) 8.9 Hz, 1H), 6.38 (s, 1H), 5.80
(brs, 1H), 4.10 (s, 3H), 3.99 (s, 3H), 3.92 (s, 3H); 13C NMR (100
MHz, DMSO-d6/pyridine-d5) δ 173.6, 168.1, 164.7, 163.7, 156.7,
151.6, 145.3, 139.8, 119.7, 114.4, 107.2, 106.7, 98.1, 95.3, 56.2,
55.8, 52.0; IR (CHCl3) 3534, 3009, 1652, 1582, 1483 cm-1; MS
(EI) m/e (rel inten) 346 (M+, 75), 314 (100), 299 (78); HRMS
(EI) calcd for C17H14O8 (M+): 346.0689, found 346.0691. Anal.
calcd for C17H14O8: C, 58.96; H, 4.05. Found: C, 58.72; H, 4.08.
(65) Schmittling, E. A.; Sawyer, J . S. J . Org. Chem. 1993, 58, 3229-
3230.

Total Synthesis of O-Methylsterigmatocystin
J . Org. Chem., Vol. 64, No. 11, 1999 4057
1,8-Dim et h oxy-4-(m et h oxyca r b on yl)-3-[2-(t r im et h yl-
silyl)eth oxym eth oxy]-9H-xa n th en -9-on e (14). Procedure
1: 2-(Trimethylsilyl)ethoxymethyl chloride (SEMCl, 4.3 mL,
24.1 mmol) was added dropwise to a 0 °C mixture of 13 (5.3 g,
16.1 mmol) and diisopropylethylamine (DIPEA, 5.3 g, 30.5
mmol) in 230 mL of dry CH2Cl2 and stirred for 2 h while
warming to room temperature. Saturated aqueous NH4Cl was
added, and the resulting mixture was extracted with 50-mL
portions of cold 5% HCl, 5% NaHCO3, and brine. The organic
portion was dried over MgSO4, filtered, and concentrated
under vacuum. Purification by flash chromatography (2.5%
CH3OH/10% CH3CN/CH2Cl2) afforded 6.73 g (91%) of 14 as a
yellow solid: mp 128-129 °C; Rf ) 0.6 (2.5% CH3OH/10% CH3-
CN/CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.44 (t, J ) 8.4 Hz,
1H), 6.85 (d, J ) 8.4 Hz, 1H), 6.71 (d, J ) 8.4 Hz, 1H), 6.60 (s,
1H), 5.30 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H), 3.75
(t, J ) 8.3 Hz, 2H), 0.91 (t, J ) 8.3 Hz, 2H), 0.03 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 174.4, 164.6, 162.3, 159.9, 158.8,
156.1, 154.4, 133.5, 112.9, 108.8, 108.1, 105.8, 104.5, 93.2, 92.8,
66.7, 56.1, 55.9, 55.1, 17.6, -1.7; IR (CHCl3) 3012, 2950, 1726,
1652, 1471 cm-1; MS (EI) m/e (rel inten) 460 (M+, 28), 402
(100), 387 (62); HRMS (EI) calcd for C23H28O8Si (M+) 460.1553,
found 460.1554. Anal. calcd for C23H28O8Si: C, 60.0; H, 6.09.
Found: C, 59.98; H, 6.18.
Procedure 2: To a 7 mL solution of 21 (72 mg, 0.144 mmol)
in dioxane/H2O (1:1) were added a 2.5 wt % solution of OsO4
in 2-methyl-2-propanol (0.1 mL, 0.01 mmol) and NaIO4 (46 mg,
0.216 mmol). After stirring for 24 h, another 20 mg (0.95 mmol)
of NaIO4 and 1 mL of pyridine were added. The reaction was
quenched after 48 h by the addition of 5 mL of 10% Na2SO3,
and the mixture was diluted with 10 mL of CH2Cl2. After
extracting with 5-mL portions of 10% Na2SO3 and brine, the
organic portion was dried over MgSO4, filtered, and concen-
trated under vacuum. Purification by flash chromatography
(10% CH3CN/CH2Cl2) afforded 52 mg (79%) of 14.
1,8-Dim et h oxy-4-(m et h oxyca r b on yl)-3-[2-(t r im et h yl-
silyl)eth oxym eth oxy]-9H-xa n th en e-∆9,δ-bu ta n e (21). To a
cooled (-78 °C) solution of ester 14 (86 mg, 0.187 mmol) in 4
mL of THF was added n-butyllithium (0.35 mL, 0.7 M solution
in hexanes). After 10 min, tartaric acid (0.5 mL of 1 M soln)
and ethyl acetate (3 mL) were added, and the reaction mixture
was warmed to room temperature. The mixture was extracted
with saturated NH4Cl and brine, dried over MgSO4, filtered,
and concentrated under vacuum. The residue was purified by
flash chromatography (10% acetone/1% acetic acid/CHCl3) to
provide 21 as a roughly 1:1 mixture of E/Z olefins (0.072 g,
77%). Trituration with hexanes afforded a white solid. All the
butylene-masked xanthone compounds that follow exist as
inseparable mixtures of E/Z isomers which have been arbi-
trarily designated as A and B in the 1H NMR spectra: mp 107-
108.5°; Rf ) 0.56 (20% ethyl acetate/hexane); 1H NMR (300
MHz, CDCl3) δ 7.19 (t, J ) 8.2 Hz, 1H, B), 7.08 (t, J ) 8.2 Hz,
1H, A), 6.71 (m, 4H, A/B), 6.59 (s, 1H, B), 6.57 (s, 1H, A), 6.23
(dd, J ) 7.3. 7.0 Hz, 1H, A), 6.15 (dd, J ) 7.3, 7.2 Hz, 1H, A),
5.26 (s, 2H, A), 5.24 (s, 2H, B), 3.97 (s, 3H, A), 3.95 (s, 3H, B),
3.86 (s, 6H, A), 3.86 (s, 6H, B), 3.78 (m, 4H, A/B), 2.26 (m, 2H,
A/B), 1.83 (m, 2H, A/B), 1.41 (m, 4H, A/B), 0.94 (t, J ) 8.3 Hz,
4H, A/B), 0.89 (t, J ) 7.3 Hz, 3H, A), 0.87 (t, J ) 7.3 Hz, 3H,
B), 0.01 (s, 18H, A/B); 13C NMR (100 MHz, CDCl3) δ 165.9,
157.4, 157.2, 155.8, 155.7, 155.3, 154.9, 154.1, 153.3, 153.0,
151.4, 133.8, 133.7, 128.1, 126.8, 117.9, 116.9, 114.3, 111.4,
109.2, 108.9, 108.6, 106.5, 106.3, 106.1, 94.7, 94.3, 93.9, 93.7,
93.5, 66.6, 66.5, 55.9, 55.8, 55.4, 55.3, 52.3, 33.3, 22.7, 18.0,
14.0, -1.4; IR (CHCl3) 3013, 2953, 1724, 1613 cm-1; MS (EI)
m/e (rel inten) 500 (M+, 28), 442 (12), 427 (31), 411 (68), 385
(100); HRMS (EI) calcd for C27H36O7Si (M+) 500.2230, found
500.2237. Anal. calcd for C27H36O7Si: C, 64.80; H, 7.20.
Found: C, 64.80; H, 7.35.
was filtered, and the filtrate was concentrated to afford 0.24
g (>99%) of 22 as a mixture of E/Z isomers as a light yellow
oil, which needed no further purification: Rf ) 0.33 (20% ethyl
acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 7.20 (t, J ) 8.2
Hz, 1H, B), 7.10 (t, J ) 8.2 Hz, 1H, A), 6.80 (dd, J ) 8.5, 8.3
Hz, 2H, A/B), 6.69 (d, J ) 8.3 Hz, 2H, A/B), 6.59 (s, 1H, B),
6.58 (s, 1H, A), 6.23 (dd, J ) 7.1 Hz, 1H, A), 6.16 (dd, J ) 7.3,
7.0 Hz, 1H, B), 5.29 (d, J ) 2.4 Hz, 2H, A), 5.26 (s, 2H, B),
4.88 (s, 1H, A), 4.86 (s, 1H, B), 3.86 (s, 6H, A/B), 3.85 (s, 12H,
A/B), 3.78 (m, 4H, A/B), 2.28 (m, 4H, A/B), 1.85 (m, 2H, A/B),
1.41 (m, 4H, A/B), 0.97 (t, J ) 8.3 Hz, 4H A/B), 0.89 (t, J ) 7.3
Hz, 3H, A), 0.87 (t, J ) 7.3 Hz, 3H, B), 0.01 (s, 18H, A/B); 13
C
NMR (100 MHz, CDCl3) δ 156.1, 155.9, 155.8, 155.7, 155.69,
155.0, 154.9, 153.7, 153.5, 152.2, 133.3, 133.1, 127.9, 126.7,
118.3, 117.2, 114.5, 111.4, 110.6, 110.2, 108.9, 108.6, 108.5,
106.4, 105.9, 94.9, 94.0, 93.8, 93.6, 66.5, 55.7, 55.2, 54.3, 33.2,
22.6, 17.9, 14.0, 13.9, -1.5; IR (CHCl3) 3600, 3010, 2946, 1615,
1061 cm-1; MS (EI) m/e (rel inten) 472 (M+, 47), 399 (18), 357
(17), 324 (85); HRMS (EI) calcd for C26H36O6Si (M+) 472.2281,
found 472.2286. Anal. calcd for C26H36O6Si: C, 66.07; H, 7.63.
Found: C, 66.09; H, 7.75.
1,8-D im e t h o x y -4-fo r m y l-3-[2-(t r im e t h y ls ily l)e t h -
oxym eth oxy]-9H-xa n th en e-∆9,δ-bu ta n e (23). To a room
temperature solution of alcohol 22 (240 mg, 0.513 mmol) in
25 mL of CH2Cl2 were added 4 Å molecular sieves (480 mg, 2
g/g) and N-methylmorpholine N-oxide (96 mg, 0.82 mmol).
After 20 min, TPAP (11 mg, 0.0308 mmol) was added, and the
mixture stirred for 30 min. The mixture was concentrated
under vacuum. Purification by flash chromatography provided
230 mg of E and Z 23 (96%) as a yellow oil: Rf ) 0.42 (20%
1
ethyl acetate/hexane); H NMR (300 MHz, CDCl3) δ 10.55 (s,
1H, A), 10.54 (s, 1H, B), 7.23 (t, J ) 8.3 Hz, 1H, B), 7.13 (t, J
) 8.2 Hz, 1H, A), 6.85 (dd, J ) 8.9, 7.3 Hz, 2H, A/B), 6.72 (d,
J ) 8.2 Hz, 2H, A/B), 6.61 (s, 1H, B), 6.59 (s, 1H, A), 6.25 (dd,
J ) 7.2, 7.1 Hz, 1H, A), 6.13 (dd, J ) 7.3, 7.1 Hz, 1H, B), 5.36
(s, 2H, A), 5.33 (s, 2H, B), 3.92 (s, 6H, A/B), 3.88 (s, 6H, A/B),
3.83 (m, 4H, A/B), 2.28 (m, 2H, A/B), 1.80 (m, 2H, A/B), 1.39
(m, 4H, A/B), 0.96 (dt, J ) 9.4, 6.8 Hz, 4H, A/B), 0.88 (t, J )
7.4 Hz, 3H, A), 0.87 (t, J ) 7.3 Hz, 3H, B), 0.004 (s, 18H, A/B);
13C NMR (100 MHz, CDCl3) δ 187.1, 187.0, 160.7, 160.6, 160.1,
159.0, 157.7, 156.0, 155.6, 155.5, 154.6, 153.0, 134.0, 133.8,
128.3, 127.0, 117.3, 116.7, 114.2, 111.1, 109.3, 108.9, 108.7,
108.6, 108.2, 106.7, 106.3, 94.2, 93.6, 93.5, 93.4, 66.9, 66.8, 55.9,
55.7, 55.5, 55.4, 55.3, 33.3, 33.1, 22.6, 22.5, 17.9, 13.9, -1.5;
IR (CHCl3) 3010, 2950, 1674, 1590, 1065, cm-1; MS (EI) m/e
(rel inten) 470 (M+, 20), 412 (18), 397 (46), 381 (77), 355 (100);
HRMS (EI) calcd for C26H34O6Si (M+) 470.2125, found 470.2117.
Anal. calcd for C26H34O6Si: C, 66.38; H, 7.23. Found: C, 65.70;
H, 7.28.
1,8-Dim eth oxy-4-(eth yl-3′-for m ylp r op a n oa te)-3-[2-(tr i-
m eth ylsilyl)eth oxym eth oxy]-9H-xan th en e-∆9,δ-bu tan e (25).
To a cooled (-78 °C) solution of diethyl 1-(N-benzylidenamino)-
methylphosphonate66,67 (1.02 g, 4.5 mmol) in 23 mL of dry THF
was added n-butyllithium (3.2 mL, 1.4 M in hexanes, 4.5 mmol)
over 12 min. This solution stirred at -65 °C for 1 h. After the
resulting lithium benzylidenaminomethylphosphonate was
cooled to -78 °C, a solution of aldehyde 23 (1.7 g, 3.77 mmol)
in 10 mL of dry THF was added via cannula over 3 min. After
50 min, the mixture was allowed to stir at room temperature
for 1.5 h. The reaction mixture was then cooled to -78 °C,
and nBuLi (3.8 mL, 1.4 M) was added over 4 min. After 2.5 h,
ethyl bromoacetate (2.5 mL, 22.62 mmol) was added to the
-78 °C mixture, which was then allowed to warm to room
temperature over 1.5 h. The reaction was quenched by the
addition of 10 mL of 1 M aqueous tartaric acid and stirred for
1 h. The mixture was extracted with 10-mL portions of cold
5% HCl (2×), 5% NaHCO3 (2×), and brine, dried over MgSO4,
filtered, and concentrated under vacuum. The residue was
purified by flash chromatography (10% ethyl acetate/hexane)
to give 1.23 g (57%) of 25, a yellow oil, as a mixture of E and
1,8-Dim eth oxy-4-(h ydr oxym eth yl)-3-[2-(tr im eth ylsilyl)-
eth oxym eth oxy]-9H-xa n th en e-∆9,δ-bu ta n e (22). To a 0 °C
solution of ester 21 (254 mg, 0.51 mmol) in 15 mL of Et2O was
added LiAlH4 (20 mg, 0.558 mmol). After 20 min, the reaction
was quenched by cautious addition of NaSO4‚10H2O. The
mixture was diluted with Et2O and ethyl acetate and stirred
overnight at room temperature. The resulting white precipitate
(66) Yamauchi, K.; Mitsuda, Y.; Kinoshita, M. Bull. Chem. Soc. J pn.
1975, 48, 3285-3286.
(67) Ratcliffe, R. W.; Christensen, B. G. Tetrahedron Lett. 1973, 46,
4645-4648.

4058 J . Org. Chem., Vol. 64, No. 11, 1999
Casillas and Townsend
Z isomers: Rf ) 0.48 (20% ethyl acetate/hexane); 1H NMR (300
MHz, CDCl3) δ 9.60 (m, 2H, A/B), 7.25-7.13 (m, 1H, B), 7.13-
7.0 (m, 1H, A), 6.8-6.7 (m, 4H, A/B), 6.64 (s, 1H, B), 6.61 (s,
1H, A), 6.25-6.12 (m, 2H, A/B), 5.30 (s, 2H, A), 5.29 (s, 2H,
B), 4.65-4.58 (m, 2H, A/B), 4.25-4.05 (m, 4H, A/B), 3.86 (s,
6H, A/B), 3.7-3.8 (m, 4H, A/B), 3.3-3.1 (m, 2H, A/B), 2.55-
2.35 (m, 2H, A/B), 2.35-2.25 (m, 2H, A/B), 1.9-1.75 (m, 2H,
A/B), 1.5-1.3 (m, 4H, A/B), 1.2 (m, 6H, A/B), 0.98-0.86 (m,
10H, A/B), 0.004 (s, 18H, A/B); 13C NMR (100 MHz, CDCl3) δ
199.9, 199.7, 172.3, 156.1, 155.9, 155.9, 155.7, 154.9, 154.8,
153.4, 133.7, 133.5, 128.4, 128.2, 126.9, 118.2, 117.1, 114.4,
111.4, 109.1, 108.9, 108.8, 108.6, 106.6, 1061, 105.6, 105.3,
105.2, 94.3, 93.5, 93.3, 93.1, 66.6, 66.5, 60.4, 55.8, 55.3, 44.5,
44.4, 33.4, 33.3, 22.7, 18.0, 17.9, 14.1, 14.0, -1.4; IR (CHCl3)
3012, 2958, 1723, 1465, 1058, cm-1; MS (EI) m/e (rel inten)
570 (M+, 49), 512 (15), 483 (75), 481 (67), 455 (100); HRMS
(EI) calcd for C31H42O8Si (M+) 570.2649, found 570.2660. Anal.
calcd for C31H42O8Si: C, 65.26; H, 7.37. Found: C, 65.06; H,
7.41.
5,7-Dim eth oxy-1-(eth oxyca r bon ylm eth yl)-2-[tr is(1-m e-
t h ylet h yl)silyloxy)]-6H-fu r o[2,3-c]xa n t h en e-∆6,δ-b u t a n e
(26). Aldehyde 25 (1 g, 1.88 mmol) and triethylamine (0.4 mL,
3 mmol) were combined in 25 mL of dry THF and cooled to 0
°C. Triisopropylsilyl trifluoromethylsulfonate (TIPSOTf, 2.3
mL, 2.25 mmol) was added dropwise and the mixture stirred
for 4 h while warming to room temperature. The reaction was
quenched by the addition of N,N-dimethylethanolamine (0.6
mL, 5.63 mmol) and extracted with 10-mL portions of cold 5%
HCl, 5% NaHCO3, and brine, and dried over MgSO4, filtered,
and concentrated under vacuum. The residue was purified by
flash chromatography (5% ethyl acetate/hexane) to provide
0.97 g (86%) of a colorless oil, 26, as a mixture of 4 isomers:
E and Z, and cis and trans acetals: Rf ) 0.57 (10% ethyl
acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 7.20 (t, J ) 8.2
Hz, 1H, B), 7.10 (t, J ) 8.2 Hz, 1H, A), 6.80-6.75 (m, 2H, A/B),
6.68 (d, J ) 8.2 Hz, 2H, A/B), 6.27 (s, 1H, B), 6.25 (s, 1H, A),
6.18-6.12 (m, 2H, A/B), 5.97-5.89 (m, 2H, A/B), 4.2-4.05 (m,
4H, A/B), 3.86 (s, 3H, A/B), 3.83 (s, 3H, OCH3, A/B), 3.75-3.6
(m, 2H, H-1, A/B), 2.9-2.75 (m, 2H, (HCHCO2), A/B), 2.6-2.4
(m, 2H, A/B), 2.4-2.2 (m, 2H, A/B), 1.9-1.8 (m, 2H, A/B), 1.55-
1.3 (m, 4H, A/B), 1.3-1.0 (m, 48H, A/B), 0.90 (t, J ) 7.4 Hz,
3H, A), 0.89 (t, J ) 7.2 Hz, 3H, B); 13C NMR (100 MHz,
acetone-d6) δ 171.7, 160.4, 159.0, 158.1, 157.9, 156.9, 156.8,
155.8, 154.3, 152.5, 151.0, 133.3, 133.0, 129.2, 127.9, 119.6,
118.4, 115.4, 111.3, 109.7, 109.4, 109.1, 108.3, 107.8, 107.4,
107.2, 106.9, 91.4, 91.3, 90.8, 90.6, 61.0, 56.4, 56.1, 55.8, 55.6,
47.2, 47.1, 36.9, 36.5, 34.0, 23.4, 18.2, 18.1, 14.4, 14.3, 13.0,
12.8, 12.7; IR (CHCl3) 3007, 2930, 1730, 1635, 1091 cm-1; MS
(FAB) m/e (rel inten) 596 (M+, 54), 565 (16), 539 (21), 479 (22);
HRMS (EI) calcd for C34H48O7Si (M+) 596.3169, found 596.3177.
Anal. calcd for C34H48O7Si: C, 68.46; H, 8.05. Found: C, 67.99;
H, 8.42.
5,7-Dim et h oxy-1-(h yd r oxyet h yl)-2-[t r is(1-m et h ylet h -
yl)silyloxy)]-6H-fu r o[2,3-c]xa n th en e-∆6,δ-bu ta n e (27). Li-
AlH4 (8.4 mg, 0.22 mmol) was added to a 0 °C solution of ester
26 (80 mg, 0.138 mmol) in 7 mL of dry Et2O. After warming
to room temperature over 1 h, NaSO4‚10H2O was added
cautiously, and the suspension stirred for 1 h. The mixture
was filtered, and the filtrate was concentrated under vacuum
to afford 76 mg (99%) of 27 as a mixture of E/Z and cis/trans
isomers as a faint yellow oil requiring no further purification:
Rf ) 0.49 (20% ethyl acetate/hexane); 1H NMR (300 MHz,
CDCl3) δ 7.20 (t, J ) 8.2 Hz, 1H, B), 7.10 (t, J ) 8.2 Hz, 1H,
A), 6.83-6.74 (m, 2H, A/B), 6.69 (d, J ) 8.2 Hz, 2H, A/B), 6.30
(s, 1H, B), 6.28 (s, 1H, A), 6.21-6.13 (m, 2H, A/B), 5.85-5.82
(m, 2H, A/B), 3.86 (s, 6H, B), 3.83 (s, 6H, A), 3.75-3.65 (m,
4H, A/B), 3.6-3.35 (m, 2H, A/B), 2.4-2.0 (m, 4H, A/B), 2.0-
1.75 (m, 4H, A/B), 1.5-1.28 (m, 4H, A/B), 1.1-1.05 (m, 42H,
A/B), 0.89 (t, J ) 7.3 Hz, 6H, A/B); 13C NMR (100 MHz,
acetone-d6) δ 160.6, 159.3, 159.2, 157.8, 157.7, 157.6, 157.5,
157.3, 157.1, 156.9, 156.0, 154.5, 152.6, 151.2, 133.0, 132.9,
129.2, 127.9, 120.1, 118.7, 115.7, 111.5, 109.9, 109.5, 109.2,
108.9, 108.4, 107.8, 107.2, 105.4, 104.6, 104.3, 104.1, 101.7,
91.5, 90.8, 90.7, 89.7, 61.5, 60.7, 60.3, 56.5, 56.3, 55.9, 55.7,
48.3, 43.5, 43.2, 43.1, 36.1, 35.9, 34.2, 34.1, 23.5, 18.4, 18.3,
18.2, 14.4, 13.1, 12.9; IR (CHCl3) 3615, 3005, 2946, 2868, 1633,
1486, 1088 cm-1; MS (EI) m/e (rel inten) 554 (M+, 14), 380 (45),
349 (68), 323 (100); HRMS (EI) calcd for C32H46O6Si (M+)
554.3064, found 554.3068. Anal. calcd for C32H46O6Si: C, 69.31;
H, 8.30. Found: C, 69.12; H, 8.29.
5,7-Dim et h oxy-1-(a cet a ld eh yd e)-2-[t r is(1-m et h ylet h -
yl)silyloxy)]-6H-fu r o[2,3-c]xa n th en -6-on e (28). To a 10 mL
CH2Cl2 solution of alcohol 27 (30 mg, 0.054 mmol) were added
4 Å molecular sieves (250 mg) and m-CPBA (57-86%, 125 mg,
0.72 mmol). The reaction was quenched after 30 min by the
addition of 2 N NaOH. The mixture was extracted three times
with CH2Cl2, dried over MgSO4, and concentrated under
vacuum. The residue was purified by flash chromatography
(2-5% CH3OH/CH2Cl2) to afford 20 mg (68%) of xanthone 28:
1
Rf ) 0.26 (2.5% CH3OH/10% CH3CN/CH2Cl2); H NMR (300
MHz, CDCl3) δ 7.5 (t, J ) 8.3 Hz, 1H), 6.9 (d, J ) 8.2 Hz, 1H),
6.73 (d, J ) 8.3 Hz, 1H), 6.3 (s, 1H), 5.99 (d, J ) 1.3 Hz, 1H),
3.94 (s, 3H), 3.91 (s, 3H), 3.79 (m, 2H), 3.55 (t, J ) 6.4 Hz,
1H), 2.0 (m, 2H), 1.1-1.05 (m, 21H). Without further purifica-
tion, the crude alcohol 28 (25 mg, 0.044 mmol) was dissolved
in 2.2 mL of CH2Cl2 and treated with N-methylmorpholine
N-oxide (8.4 mg, 0.072 mmol) and 4 Å molecular sieves (50
mg). After 15 min, TPAP (0.95 mg, 0.0027 mol) was added to
the reaction. After 30 min, the reaction was concentrated
under vacuum and purified by flash chromatography (2% CH3-
OH/CH2Cl2) to afford 21 mg of the cis and trans aldehydes 29
(92%):
Cis furan: Rf ) 0.73 (5% CH3OH/CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 9.94 (s, 1H), 7.48 (t, J ) 8.3 Hz, 1H), 6.88 (d,
J ) 8.3 Hz, 1H), 6.76 (d, J ) 8.4 Hz, 1H), 6.35 (d, J ) 6.3 Hz,
1H), 6.31 (s, 1H), 4.13 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.25-
3.4 (m, 1H), 3.1-3.2 (m, 1H), 1.07 (m, 21H). trans furan: Rf
) 0.62 (5% CH3OH/CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 9.91
(s, 1H), 7.50 (t, J ) 8.2 Hz, 1H), 6.90 (d, J ) 8.0 Hz, 1H), 6.76
(d, J ) 8.6 Hz, 1H), 6.33 (s, 1H), 5.89 (s, 1H), 3.94 (m, 7H),
2.9-3.1 (m, 1H), 2.6-2.75 (m, 1H), 1.08 (m, 21H). 13C NMR
(100 MHz, acetone-d6) δ 201.2, 173.9, 164.1, 163.7, 161.2, 157.5,
154.4, 134.5, 114.7, 109.9, 109.5, 108.5, 107.5, 106.7, 91.6, 56.8,
45.7, 44.6, 18.23, 18.16, 12.9; IR (CHCl3) 3014, 2948, 2863,
2723, 1593, 1470, 1097 cm-1. MS (EI) m/e (rel inten) 512 (M+,
21), 441 (43), 310 (100); HRMS (EI) calcd for C28H36O7Si (M+)
512.2230, found 512.2235. Anal. calcd for C28H36O7Si: C, 65.63;
H, 7.03. Found: C, 64.82; H, 7.35.
6,8-Dih yd r oxy-2-h yd r oxy-7H-1,2-d ih yd r ofu r o[3′,2′:4,5]-
fu r o[2,3-c]xa n th en -7-on e; O-Meth ylster igm a tocystin Hy-
d r a te (30). To a 4 mL CH3CN/CH2Cl2 solution (1:1) of cis and
trans aldehydes 29 (25 mg, 0.048 mmol) was added 5 drops of
TEA‚(HF)3. After 8.5 h, the reaction mixture was purified by
flash chromatography (1-5% CH3OH/CH2Cl2) to provide 15
mg (88%) of 30 as a mixture of endo and exo hemiacetals and
open-form aldehydes in the form of a white solid: mp 238-
239 °C (dec); Rf ) 0.38 (5% CH3OH/CH2Cl2); 1H NMR (300
MHz, DMSO-d6) δ 9.61 (s, 1H), 7.55 (t), 7.53 (t, J ) 8.4 Hz,
1H), 7.0 (d), 6.96 (d, J ) 8.4 Hz, 1H), 6.95 (d), 6.80 (d, J ) 8.8
Hz, 1H), 6.45 (d, J ) 6 Hz, 1H), 6.42 (d), 6.38 (s), 6.35 (s, 1H),
6.30 (s), 6.26 (s), 5.90 (d), 5.59 (d, J ) 4.4 Hz, 1H), 5.40 (s,
1H), 4.15 (m), 3.86 (s, 3H), 3.82 (s, 3H), 3.61 (d, J ) 4 Hz, 1H),
2.6-1.9 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 200.5, 173.8,
173.6, 173.5, 163.1, 163.0, 162.0, 161.8, 160.0, 159.8, 159.5,
156.2, 156.0, 152.7, 152.6, 152.4, 133.7, 133.6, 133.5, 113.2,
112.9, 112.7, 110.4, 108.8, 108.7, 107.7, 107.4, 107.1, 106.2,
106.1, 105.5, 104.4, 99.8, 99.7, 98.8, 95.9, 95.3, 89.9, 89.8, 56.0,
55.8, 42.5, 42.1, 37.4, 35.0, 28.5; IR (CHCl3) 3684, 3599, 3023,
2928, 1705, 1598 cm-1. MS (EI) m/e (rel inten) 356 (M+, 100),
338 (44); HRMS (EI) calcd for C19H16O7 (M+) 356.0896, found
356.0899. Anal. calcd for C19H16O7: C, 64.04; H, 4.49. Found:
C, 62.31; H, 4.67. Second trial, found: C, 64.26; H, 5.55.
6,8-Dim et h oxy-7H -fu r o[3′,2′:4,5]fu r o[2,3-c]xa n t h en -7-
on e; O-Meth ylster igm a tocystin (5). To 5 mL of CH3CN
were added hemiacetal 30 (15 mg, 0.042 mmol), PhSeH (0.02
mL, 0.188 mmol), 4 Å molecular sieves (30 mg), and trace
Amberlyst 15 resin (about 10 beads). This suspension was
stirred at room temperature for 72 h. A small amount of the
hemiacetal 30 was still present, as observed by TLC, but this
is due to gradual hydrolysis of the selenoacetal on SiO2. The

Total Synthesis of O-Methylsterigmatocystin
J . Org. Chem., Vol. 64, No. 11, 1999 4059
reaction mixture was quickly filtered through a column of silica
gel (eluted with 5% CH3OH/CH2Cl2) providing 13 mg (62%) of
pure selenoacetal 31 (Rf ) 0.8, 5% CH3OH/CH2Cl2) along with
approximately 7 mg of product 31 mixed with hemiacetal 30.
To minimize the rapid product decomposition, 31 was carried
to the next reaction without characterization. A 0 °C solution
of 31 (10 mg, 0.02 mmol) in 2.6 mL of CH2Cl2 was treated with
4 Å molecular sieves (22 mg) and m-CPBA (57-86%, 11 mg,
0.065 mmol) in 0.8 mL CH2Cl2 (dried over sieves). After 20
min, the reaction was compared to an authentic sample of
OMST 5 by TLC and deemed complete. The mixture was
purified by flash chromatography (2-5% CH3OH/CH2Cl2) to
provide 3 mg (44%) of crude 5. Further purification was carried
out by HPLC to provide pure OMST 5 which was identical to
an authentic sample in all respects:63 HPLC: retention time
) 13.7 min on a Spherex 5 C18 column (Phenomenex, 250 ×
4.6 mm) eluted with 50% H2O (0.1% TFA)/CH3CN, 1 mL/min
flow rate; coinjection with authentic sample confirmed identity;
3H, OCH3), 3.90 (s, 3H, OCH3); UV λmax (CH3OH) nm: 236,
310; IR (CHCl3) 3020, 2927, 2853, 1598, 1473 cm-1. MS (EI)
m/e (rel inten) 338 (M+, 100), 323 (24), 309 (40); HRMS (EI)
calcd for C19H14O6 (M+) 338.0790, found 338.0794.
Ack n ow led gm en t. Financial support of the Na-
tional Institutes of Health (ES01670) is gratefully
acknowledged. Major instrumentation used was pur-
chased with grants from the NIH (NMR: RR 01934, RR
04794, RR 06468; MS: RR 02318) and the NSF (NMR:
PCM 83-03176). We thank Dr. E. G. Casillas for advice
during the course of the work, and Drs. D. Stoermer
and A. Basak for suggestions in the preparation of the
manuscript.
Su p p or tin g In for m a tion Ava ila ble: Reproductions of 1H
and 13C NMR spectra for compounds 12, 16-19, 23, 26, 28,
and 30. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
Rf ) 0.8 (5% CH3OH/CH2Cl2); H NMR (400 MHz, CDCl3) δ
7.53 (t, J ) 8.4 Hz, 1H, H-10), 7.00 (d, J ) 8.4 Hz, 1H, H-11),
6.81 (d, J ) 7.2 Hz, 1H, H-3a), 6.80 (d, J ) 8 Hz, 1H, H-9),
6.50 (t, J ) 2.4 Hz, 1H, H-2), 6.41 (s, 1H, H-5), 5.48 (t, J ) 2.4
Hz, 1H, H-1), 4.82 (dt, J ) 7,2, 1.6 Hz, 1H, H-12c), 3.94 (s,
J O990099W