A total synthesis of xestodecalactone A and proof of its absolute stereochemistry: Interesting observations on dienophilic control with 1,3-disubstituted nonequivalent allenes

Article abstract of DOI:10.1021/ja064270e

A concise total synthesis of xestodecalactone A, utilizing a Diels-Alder strategy is described. The focal Diels-Alder reaction relied on an "ynoate" dienophile to rapidly assemble the required resorcylinic acid scaffold. During this study, Diels-Alder cycloaddition reactions involving 1,3-disubstituted nonequivalent allene dienophiles were studied, and some surprising results were encountered.

Full text of DOI:10.1021/ja064270e

Published on Web 10/07/2006
A Total Synthesis of Xestodecalactone A and Proof of Its
Absolute Stereochemistry: Interesting Observations on
Dienophilic Control with 1,3-Disubstituted Nonequivalent
Allenes
Toshiharu Yoshino,† Fay Ng,† and Samuel J. Danishefsky*,†,‡
Contribution from the Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000
Broadway, New York, New York 10027, and the Laboratory for Bioorganic Chemistry,
Sloan-Kettering Institute for Cancer Research, 1275 York AVenue, New York, New York 10021
Received June 16, 2006; E-mail: s-danishefsky@ski.mskcc.org
Abstract: A concise total synthesis of xestodecalactone A, utilizing a Diels-Alder strategy is described.
The focal Diels-Alder reaction relied on an “ynoate” dienophile to rapidly assemble the required resorcylinic
acid scaffold. During this study, Diels-Alder cycloaddition reactions involving 1,3-disubstituted nonequivalent
allene dienophiles were studied, and some surprising results were encountered.
Introduction
macrolactone, we envisioned the possibility of using our then
new Diels-Alder methodology to build the aromatic ring. For
A variety of natural products can be viewed in the context
of the fusion of a macrolactone moiety with a resorcinylic
aromatic ring.1 In most cases,2 the fusion encompasses the
carbons R and â to the lactonic carbonyl group and carbons 5
and 6 of the resorcinol. The resultant system, (cf. 1, Figure 1)
corresponds to a lactone based on an orsellinic acid format,
functionalized at its benzylic site (see asterisk) with a side chain
bearing a pendant ω-hydroxyl group. Classic examples of such
systems are the 12-membered orsellinic acid type lactone
lasiodiplodin3 and the 14-membered orsellinic acid macrolides
zearalenone4 and radicicol.5 Like radicicol, relatively new
members to this group such as 14-membered aigialomycin D,6
and hypothemycin7 also possess potentially useful antitumor
activity.
instance, in our lasiodiplodin synthesis,9 cycloaddition of a
synergisitic 1,1,3-trioxygenated diene 7 with â-alkylated pro-
piolic ester dienophile 8 led to 9 and, shortly thereafter, to the
target. Thus, in keeping with the broad classification b of Figure
1 (see dotted line), lasiodiplodin was built from an “ynoate”
disconnection. While occurring with tight regiospecific control,
such uncatalyzed Diels-Alder reactions of monoactivated
acetylenic dienophiles (bearing substitution at the nonactivated
acetylenic carbons) require rather high temperatures. This being
the case, they tend to occur not surprisingly in mediocre yields.
A more pleasing route to related substructures was realized
via Diels-Alder reaction between diene 7 and the highly
reactive allene dienophile 10 (Scheme 1). Following regiospe-
cific cycloaddition, elimination of one of the alkoxy groups from
the erstwhile C1 of 7, and aromatization (presumably of 11) a
hydroaromatic system (cf. 12) was in hand.10 Given the
symmetrical character of allene 10, chemoselectivity issues
As early as 1978, our group described the synthesis of
lasiodiplodin (2), employing a significant departure from the
then prevailing strategies for synthesizing benzofused macro-
lactones.8 As an alternative to starting with a prebuilt benzo
structure around which would be built the cycloaliphatic
(8) For selected references of other syntheses of lasiodiplodin: (a) Gerlach,
H.; Thalmann, A. HelV. Chim. Acta 1977, 60, 2866. (b) Takahashi, T.;
Kasuga, K.; Tsuji, J. Tetrahedron Lett. 1978, 4917. (c) Fink, M.; Gaier,
H.; Gerlach, H. HelV. Chim. Acta 1982, 65, 2563. (d) Braun, M.; Mahler,
U.; Houben, S. Liebigs Ann. 1990, 513. (e) Jones, G. B.; Huber, R. S.
Synlett 1993, 367. (f) Brachen, F.; Schulte, B. J. Chem. Soc., Perkin Trans.
1 1996, 2619. (g) Furstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B.
J. Org. Chem. 2000, 65, 7990. For selected references of syntheses of
zearalenone: (h) Vlattas, I.; Harrison, I. T.; Tokes, L. Fried, J. H.; Cross,
A. D. J. Org. Chem. 1968, 33, 4176. (i) Girotra, N. N.; Wendler, N. L. J.
Org. Chem. 1969, 34, 3192. (j) Corey, E. J.; Nicolaou, K. C. J. Am. Chem.
Soc. 1974, 96, 5614. (k) Massamune, S.; Kamata, S.; Schilling, W. J. Am.
Chem. Soc. 1975, 97, 3515. (l) Takahashi, T.; Kasuga, K.; Takahashi, M.;
Tsuji, J. J. Am. Chem. Soc. 1979, 101, 5072. (m) Rao, A. V. R.; Deshmukh,
M. N.; Sharma, G. V. M. Tetrahedron 1987, 43, 779. (n) Hitchcock, S.
A.; Pattenden, G. Tetrahedron Lett. 1990, 31, 3641. For selected references
on other syntheses of radicicol: (o) Tichkowsky, I.; Lett, R. Tetrahedron
Lett. 2002, 43, 4003. For synthesis of hypothemycin: (p) Selles, P.; Lett,
R. Tetrahedron Lett. 2002, 43, 4627.
† Columbia University.
‡ Sloan-Kettering Institute for Cancer Research.
(1) Omura, S., Ed. Macrolide Antibiotics: Chemistry, Biology, and Practice,
2nd ed.; Academic Press: San Diego, CA, 2002.
(2) Betina, V. Mycotoxins. Chemical, Biology and EnVironmental Aspects;
Elsevier: Amsterdam, 1989.
(3) For structure and isolation: (a) Aldridge, D. C.; Galt, S.; Giles, D.; Turner,
W. B. J. Chem. Soc. (C) 1971, 1623. (b) Lee, K.-H.; Hayashi, N.; Okano,
M.; Hall, I. H.; Wu, R.-Y.; McPhail, A. T. Phytochemistry 1982, 21, 1119.
(4) For structure and isolation: (a) Stob, M.; Baldwin, R. S.; Tuite, J.; Andrews,
F. N.; Gillette, K. G. Nature 1962, 196, 1318. (b) Urry, W. H.; Wehrmeister,
H. L.; Hodge, E. B.; Hidy, P. H. Tetrahedron Lett. 1966, 3109.
(5) For structure and isolation: (a) Delmotte, P.; Delmotte-Plaquee, J. Nature
1953, 171, 344. (b) Ayer, W. A.; Lee, S. P.; Tsunda, A.; Hiratsuka, Y.
Can. J. Microbiol. 1980, 26, 766.
(6) For structure and isolation: Isaka, M.; Suyarnsestakorn, C.; Tanticharoen,
M.; Kongaseree, P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
(7) For structure and isolation: (a) Nair, M. S. R.; Carey, S. T. Tetrahedron
Lett. 1980, 21, 2001. (b) Nair, M. S. R.; Carey, S. T.; James, J. C.
Tetrahedron 1981, 37, 2445. (c) Agatsuma, T.; Takahashi, A.; Kabuto, C.;
Nozoe, S. Chem. Pharm. Bull. 1993, 41, 373.
(9) Danishefsky, S. J.; Etheridge, S. J. J. Org. Chem. 1979, 44, 4716.
(10) Danishefsky, S.; Yan, C.-F.; Singh, R. K.; Gammill, R. B.; McCurry, P.
M.; Fritsch, N.; Clardy, J. J. Am. Chem. Soc. 1979, 101, 7001.
9
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J. AM. CHEM. SOC. 2006, 128, 14185-14191
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A R T I C L E S
Yoshino et al.
Figure 1. Structure of lasiodiplodin and its synthesis.
Alder reaction of an “ynolide” type dienophile 15 with a
dimedone-derived 1,3-dioxygenated diene 14 leading to resor-
cinylic scaffold 17.15
The research described herein was addressed to reaching a
related, but different class of fused resorcinylic macrolides of
the general type 18 (Figure 3). In these target systems, a keto
rather than an ester group is presented at the benzylic position.
The ester bond corresponds to a macrolide of a formal
phenylacetic acid. These macrolides have received much interest
in agrochemical and pharmaceutical settings.1 Sporostatin
represents a 10-membered phenylacetic macrolactone macrolide
that exhibits anti-cancer activity.16 A representative of a 12-
membered phenylacetic macrolactone is curvularin as well as
its metabolites.17 The curvalarin macrolides apparently stem
from varied oxidation levels at the C11 and C12 position
Figure 2. Radicicol and its synthetic strategy.
Scheme 1. Diels-Alder Cycloaddition of Symmetrical Allene
Dienophile
(12) (a) For an overview of Hsp90 and its emerging role in cancer treatment:
Chiosis, G.; Vilenchik, M.; Kim, J.; Solit, D. Drug DiscoVery Today 2004,
9, 881. (b) For radicicol-Hsp90 binding: Roe, S. M.; Prodromou, C.;
O’Brien, R.; Ladbury, J. E.; Piper, P. W.; Pearl, C. H. J. Med. Chem. 1999,
42, 260. (c) For geldanamycin-Hsp90 binding: Stebbins, C. E.; Russo,
A. A.; Schneider, C.; Rosen, N.; Haitl, F. U.; Pavletich, N. P. Cell 1997,
89, 239. (d) For AAG-Hsp90 binding (AAG, a derivative of geldanamycin,
is the first Hsp90 inhibitor to enter clinical trials): Schulte, T. W.; Neckers,
L. M. Cancer Chemother. Pharmacol. 1998, 42, 273. For selected references
on Hsp90 inhibitors: (e) Llauger, L.; He, H.; Kim, J.; Aguirre, J.; Rosen,
N.; Peters, U.; Davies, P.; Chiosis, G. J. Med. Chem. 2005, 48, 2892. (f)
Chiosis, G.; Lucas, B.; Shtil, A.; Huezo, H.; Rosen, N. Bioorg. Med. Chem.
2002, 10, 3555. (g) Kuduk, S. C.; Harris, C. R.; Zheng, F. F.; Sepp-
Lorenzino, L.; Ouerfelli, O.; Rosen, N.; Danishefsky, S. J. Bioorg. Med.
Chem. Lett. 2000, 10, 1303.
which could arise from nonidentically substituted double bonds
in allenes had not been addressed in these earlier studies.
Initially, we had hoped to exploit cycloaddition chemistry of
the type described above to accomplish the synthesis of a
fascinating analogue of radicicol 4, bearing a cyclopropane in
place of an epoxide (13) and congeners thereof (Figure 2).11
Such targets were of interest to us, in light of the high affinity
binding of the parent radicicol with the chaperone protein
Hsp90.12 Unfortunately, early projected applications of these
findings to reach radicicol or some key analogues such as 13
failed to meet our requirements, owing to breakdowns after the
successful Diels-Alder reactions.13 Eventually, the synthesis
of 13 in the radicicol-like series was solved by recourse to the
broad logic of disconnection b implied in Figure 1.14 Central to
implementing this more elegant strategy was the retro Diels-
(13) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J.
Am. Chem. Soc. 2001, 123, 10903.
(14) Yang, Z.-Q.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 9602.
(15) For reviews on retro Diels-Alder reactions: (a) Rickborn, B. Org. React.
1998, 52, 1. (b) Ichihara, A. Synthesis 1987, 207. (c) Lasne, M.-C.; Ripoll,
J.-L. Synthesis 1985, 121. For examples of related retro-Diels-Alder
reactions: (d) Reference 14. (e) Geng, X.; Danishefsky, S. J. Org. Lett.
2004, 6, 413. (f) Yang, Z.-Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen,
N.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 7881.
(16) (a) Kinoshita, K.; Sasaki, T.; Awata, M.; Takada, M.; Yaginuma, S. J.
Antibiot. 1997, 50, 961. (b) Murakami, Y.; Ishii, A.; Mizuno, S.; Yaginuma,
S.; Uehara, Y. Anticancer Res. 1999, 19, 4145.
(17) (a) Musgrave, O. C. J. Chem. Soc. 1956, 4301. (b) Musgrave, O. C. J.
Chem. Soc. 1957, 1104. (c) Birch, A. J.; Musgrave, O. C.; Richards, R.
W.; Smith, H. J. Chem. Soc. 1959, 3146. (d) Lai, S.; Shizuri, Y.; Yamamura,
S.; Kawai, K.; Terada, Y.; Furukawa, H. Tetrahedron Lett. 1989, 30, 2241.
(e) Ghisalberti, E. L.; Rowland, C. Y. J. Nat. Prod. 1993, 56, 2175. (f)
Kusano, M.; Nakagami, K.; Fujioka, S.; Kawano, T.; Shimada, A.; Kimura,
Y. Biosci. Biotechnol. Biochem. 2003, 6, 1413.
(11) Yamamoto, K.; Gabaccio, R. M.; Stachel, S. J.; Solit, D. B.; Chiosis, G.;
Rosen, N.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 1280.
9
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Total Synthesis of Xestodecalactone A
A R T I C L E S
Figure 3. Structure of phenylacetic macrolactone macrolides.
Scheme 2. Proposed Synthesis of Phenylacetic Lactones
(curvularin numbering), and they have attracted interest in the
agrochemical arena. The larger, naturally derived 14-membered
macrolactones, y5-02-B and y5-02-C, are lead compounds in
the inhibition of neuropeptide Y receptor for anti-obesity
programs.18
to try to develop a broadly applicable capability to synthesize
phenylacetic lactones such as 18. In particular we hoped to
revisit the Diels-Alder reaction, this time directed to the
alternate phenylacetic acid lactone goal as exemplified by
xestodecalactone A.
The xestodecalactones A and B share the same carbon
backbone as sporostatin. Xestodecalactone B was shown to
exhibit antibacterial properties.19 This paper concerns itself with
the total synthesis of xestodecalactone A. These macrolides were
isolated by Bringmann and associates as a metabolite of
Penicillium cf. montanense from the marine sponge Xestospon-
gia exigua.19 An earlier synthesis of xestodecalactone A was
reported by Bringmann et al.20 Having successfully reached
radicicol and aigialomycin D, it was of interest for our laboratory
Results and Discussion
In contemplating a cycloaddition route to a potential seco
precursor of 18, we first wondered about the possibility of a
Diels-Alder reaction between an unsymmetrical allene system
31 and a diene of the acyclic type 29.21 Alternatively, we would
consider a cyclic diene such as 30 (Scheme 2), hoping to gain
access to the phenylacetic acid scaffold 32 as shown. At the
outset, we envisioned that the unsymmetrical allene would be
flanked by keto- and ester-type activating groups as implied in
31.
(18) Hanasaki, K.; Kamigaito, T.; JP 2000287697 A2 20001017 (Japanese).
(19) Edrada, R. A., Heubes, M.; Brauers, G., Wray, V.; Berg, A.; Grafe, U.;
Wohlfarth, M.; Muhlbacher, J.; Schaumann, K.; Sudarsono; Bringmann,
G.; Proksch, P. J. Nat. Prod. 2002, 65, 1598.
(20) Bringmann, G.; Lang, G.; Michel, M.; Heubes, M. Tetrahedron Lett. 2004,
45, 2829.
(21) For Diels-Alder reactions with allenes: Murakami, M.; Matsuda, T.
Cycloadditions of Alenes In Modern Allene Chemistry; Krause, W., Hashmi,
A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; Chapter 12, p 727.
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Yoshino et al.
Figure 4. Regiochemical studies with unsymmetrical allenes.
As a first approximation, we expected there to be considerable
regioselection in the cycloaddition of acyclic diene 29 or cyclic
diene 30 with allene 31. At this stage we were viewing a mixed
allene such as 31 in the context of its presenting two distinct
dienophiles, i.e., an R,â-unsaturated ketone and R,â-unsaturated
ester. In the case at hand it was projected that such a reaction
would provide predominantly cycloadduct 32. This prediction
was based on the perception that 32 would arise from the ketone
moiety being the dominant activator in the cycloaddition of
allene 31. Of course, this cycloaddition could produce an
alternative product, 33. The potentially competitive product 33
would have arisen from dienophilic “control” by the ester rather
than by the ketone moiety in 31. Since it was assumed that the
vinyl ketone group within 31 would be dominant, it was
expected 32 would be the major product. This expectation
seemed to follow from the elegant work of Rawal and associates.
It had been demonstrated that the Rawal diene (45) reacts
approximately 10 times faster with methyl vinyl ketone than
with methyl acrylate.22 Given our supposition that the outcome
of the mixed allene Diels-Alder could be predicted by reference
to the relative reactivities of the individual acrylyl-type dieno-
philes, control by the vinyl ketone was confidently expected.
To our surprise, the cycloaddition of diene 34 (1.5 equiv)
and mixed allene 3523 (neat, ambient temperature) furnished a
1-to-1 mixture of adducts 36 and 37 (Figure 4) in unoptimized
38% yield. The mixture was not separated into its components,
but we could readily discern and assign the key features of the
spectra of each product in the mixture.24 It was possible to
increase its ratio (1:1.6 36/37), employing solvents such as PhH,
PhMe, and CHCl3. The combined yields of these products were
increased to approximately 60%. Similarly, cycloaddition of
acyclic diene 38 (2.0 equiv) and allene 35 (neat, ambient
temperature) provided a 1-to-1 mixture of adducts 39 and 40.
(23) For preparation of allene 35: In a two-step process, dehydroacetic acid
was unraveled to methyl 3,5-dioxohexanoate (preparation see: Solladie,
G.; Colobert, F.; Denni, D. Tetrahedron: Asymmetry 1998, 9, 3081)
followed by treatment with freshly prepared DMC (generated from 1,3-
dimethyl-2-imidazolidinone) providing allene 35 (DMC protocol: Node,
M.; Fujiwara, T.; Ichihashi, S.; Nishide, K. Tetrahedron Lett. 1998, 39,
6331). For preparation of allene 42: Similarly, commercially available tert-
butylacetoacetate was extended to tert-butyl 3,5-dioxohexanoate, and
treatment with DMC furnished allene 42.
(22) Kozmin, S. A.; Green, M. T.; Rawal, V. H. J. Org. Chem. 1999, 64, 8045.
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Total Synthesis of Xestodecalactone A
A R T I C L E S
Figure 5. Diels-Alder reaction with mixed allenes.
Scheme 3. Evaluation of Dienophiles 51 and 53
The unusual regiochemical outcome was even more pronounced
in the reaction of cyclic diene 41 (1.8 equiv) and dienophile
4223 (80 °C, 2 h; Et3N, PhMe, 140 °C). A ca. 1:3 mixture of
adducts 43 and 44 was obtained. Curiously, the cycloaddition
reaction of diene 45 (1.5 equiv) and allene 35 did give a 2.3-
to-1 mixture of adducts 46 and 47 in 60% yield. In this instance,
the product ratio reflected apparent control by the ketonic
dienophile function. Apparently the high reactivity of the Rawal
diene 45 tilts the sense of the mixed allene Diels-Alder reaction
to more nearly reflect the behavior of its acrylyl ketone- and
acrylyl ester-activated subcomponents.22 It will be recalled that
in our earlier radicicol synthesis,13 the cycloaddition of diene
38 with unsymmetrical allene 48 had provided a 4 to 1 mixture
of adducts 49 and 50, favoring the aromatic benzoate 49. Though
the predominance of 49 was consistent with the anticipated
dienophilic dominance by the R,â-unsaturated ester relative to
that of the vinyl chloride segment of the mixed allene,13 the
rather modest observed ratio of 49:50 with allene 48 did not
reflect the far greater dienophilicity of an acrylate ester relative
to that of a vinyl chloride.
Scheme 4. Synthesis of Compound 62a
With the benefit of retrospection, it is now recognized that
the reactivity patterns in the case of separate ester and ketonic
dienophiles need not be not translatable to the more subtle case
of the mixed allene. Thus, in the mixed allene case, the â-carbon
of the dienophile is common to the two actiVating groups. The
key reactivity difference between the individual ketone- and
ester-based dienophiles must be at their R- rather than their
â-olefinic carbons (cf. R and R′). In the separate dienophile
model (Figure 5, i vs ii), the different activating functions impact
primarily on the reactivity of the â-carbon of the two olefins.
By contrast, in the mixed allene cycloaddition, the central (sp)
carbon is, at once â- to both activating groups. Here, the pivotal
question is really the “cyclizing affinities” of the presumably
more closely balanced R-carbons of the ester and ketonic
moieties (see iii and iV). The effect of the activating group on
the cyclizing character of the R-carbon in the mixed allene may
well hinge on the venerable but still unresolved issue of levels
of synchroneity in the Diels-Alder reaction.25 The mixed allene
a Reagents and conditions: a) nBuLi, HCHO, THF; b) Dess-Martin
periodinane, CH2Cl2, 81% over 2 steps; c) CBr4, PPh3, CH2Cl2, 86%; d)
TBDPSCl, imidazole, DMF, rt, overnight, 99%; e) DIBAL-H, CH2Cl2, -78
°C, 15 min, 94%; f) (EtO)2POCH2CO2Et, LiCl, DBU, MeCN, rt, overnight,
90%; g) H2, 10% Pd/C, EtOAc, rt, 2.5 h, quant.; h) MeNH(OMe)-HCl,
iPrMgCl, THF, -20 °C, 30 min 96%.
dienophile case may well constitute a unique opportunity to
study the more subtle chemoselectivies and directivities of
R-carbons in Diels-Alder dienophiles.
(24) The inseparable mixture of 36/37 was selectively reduced (sodium
borohydride) to give alcohol 37A and unreacted isomer 36. On the basis
of its proton NMR spectroscopic pattern (the benzylic methylene protons
were each a dd, and the geminal proton of alcohol was a complex multiplet),
alcohol 37A was determined to arise from reduction of 37. The alcohol
was oxidized (TPAP/NMO) back to ketone 37. It was then readily
discernible which proton NMR peak of the Diels-Alder adducts mixture
belong to which product, particularly the benzylic methylene, methyl ketone
(acetyl), and methyl ester. These three distinct peaks in the NMR were
subsequently used to determine the ratios of Diels-Alder products.
Returning to the xestodecalactone problem, we took note of
the possibility of building a dienophile of the type 51 to gain
access to the seco-phenylacetic macrolactone scaffold was
equally unproductive (Scheme 3). Unfortunately such structures
are converted virtually instantaneously to their allenic tautomers
(51 f 52).26 In a similar vein, we explored the possibility of
utilizing an unsymmetrical allene wherein the ester functionality
was masked as an ortho ester group (cf. 53).27 However cyclo-
(26) Unpublished results by T. Yoshino. For seminal work on this type of
transformation: Jones, E. R. H.; Mansfield, G. H.; Whiting, M. C. J. Chem.
Soc. 1954, 3208.
(25) For seminal discussions on the mechanism of the Diels-Alder reaction,
concerted or stepwise: (a) Woodward, R. B.; Katz, R. B. Tetrahedron 1959,
5, 70. (b) Berson, J. A.; Mueller, W. A. J. Am. Chem. Soc. 1961, 83, 4947.
(27) Unpublished results by T. Yoshino.
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Yoshino et al.
Scheme 5. Completion of Synthesis of Xestodecalactone Aa
a Reagents and conditions: a) neat, 180 °C, 79%; b) H2SO4, MeOH, 59%; c) LiOH, H2O, THF; d) PPh3, DEAD, PhMe, THF, rt, 2 day, 54% over 2 steps;
e) BCl3, CH2Cl2, -78 °C to room temperature, 4 h, 58%.
additon of allene 53 and acyclic diene 38 or cyclic diene 41
produced complex mixtures. We suspect that some of the com-
plexity may well have arisen from reactions which occurred
after the cycloaddition event. Unlike the case of doubly activated
allene 31, the tautomerization en route to aromatizations after
cycloaddition of 53 are less facile, and other chemistry intervenes.
A Total Synthesis of Xestodecalactone A. Following the
difficulties described above, we retreated to a substantially
revised, less ambitious, but in the end, successful strategy to
reach the specific target, xestodecalactone A.20 Our program
sought to address several matters of importance. The overriding
issue was to develop a more concise Diels-Alder-based strategy
for reaching phenylacetic acid lactones. Moreover, at the time
the synthesis was undertaken, there was no clear basis for
assigning the absolute configuration of the xestodecalactones.
At the time, we sought to answer this question as well, though
in the interim, this problem was indeed solved by Bringmann
and associates through their total synthesis of xestodecalactone
A.20 Herein, we relate our total synthesis of xestodecalactone
A, which was accomplished by a variation of the type-b ynoate
dienophile logic (cf. lasiodiplodin, Scheme 1). We also con-
firmed the Bringmann assignment of absolute stereochemistry
of xestodecalactone A.
Our synthesis commenced with the known bromo ortho ester
5428 (Scheme 4). Chain extension as shown afforded aldehyde
55 which was converted to dibromo building block 56. In a
parallel series of experiments, the known (3S)-hydroxybutyrate
was protected as shown (cf. 57) en route to aldehyde 58.
Roush-Masamune modified Horner-Wadsworth-Emmons29
chain extension to 59 was followed by catalytic reduction of
the double bond of 59 to afford 60. The latter lent itself to
conversion to the Weinreb-type amide 61.30 At this stage, a key
coupling step was accomplished. Treatment of 56 under Corey-
Fuchs conditions31 generated a lithioacetylide intermediate which
did indeed couple with the Weinreb-type amide 61 to afford
the acetylenic ketone 62. Unlike the case of acetylene 51 which
reverts to mixed allene 52, ynoate 62 is a stable compound.
A variety of cyclohexadienes were screened as to their
effectiveness as dienes in Diels-Alder reactions with 62. In
the end, we settled on compound 64 to optimize the requirement
of stability to the harsh conditions which would be required
for the upcoming Diels-Alder reaction, and eventual convert-
ability to the required resorcinol. Compound 64 was prepared
in a straightforward fashion from dimedone as shown.
In the event, Diels-Alder reaction of alkyne 62 with optimal
diene 6432 proceeded smoothly at 180 °C to furnish resorcinylic
adduct 65 in 79% yield in a single step (Scheme 5). To complete
the synthesis of xestodecalactone A, acidolysis of 65 achieves
unmasking of the ester functionality concomitant with desily-
lation to afford seco-compound 66. A routine saponification to
the corresponding carboxylic acid was followed by Mitsunobu
reaction to secure macrolactone 67. Subsequent demethylation
indeed provided xestodecalactone A (20) which was identical
to an authentic sample of the natural product kindly provided
by Professor Bringmann.
At the time of the synthesis, the absolute configuration of
xestodecalactone A had been reported as being S19 (this was
later revised20). On the basis of the original assignment we
would have expected to reach ent-xestodecalactone A from our
precursor since the Mitsunobu reaction would have been
anticipated to proceed with its usual pattern of inversion of
stereochemistry (the stereocenter was fashioned from 3S-
hydroxybutyrate). Rather, we were both surprised and gratified
to find that our synthetic xestodecalactone A exhibits substan-
tially the same optical rotation as that reported by Bringmann
and colleagues,19 thereby confirming retrospectively their revised
(R) assignment. For additional comparative analysis (Scheme
6), methanolysis of macrolactone 67 to its acyclic ester 68
followed by benzoylation provided benzoate 69. In the same
vein, Mitsunobu precursor 66 was similarly converted to
benzoate 70. Compounds 69 and 70 gave opposite CD patterns.
Indeed, the Mitsunobu macrolactonization had proceeded as
expected with complete inversion of stereochemistry.
(28) For halogen-metal exchange: (a) Chandrasekhar, S.; Roy, C. D. Tetra-
hedron 1994, 50, 8099. For preparation of compound 54: (b) Stetter, H.;
Steinacker, K. H. Chem. Ber. 1953, 86, 790.
(29) Masamune, S.; Roush, W. R. Tetrahedron Lett. 1984, 25, 2183.
(30) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, J. J. Tetrahedron Lett. 1995, 36, 5461.
(32) The synthesis of diene 64 is described in Supporting Information.
Cycloaddition of dienophile 62 and siloxyl diene was unsuccessful.
(31) Corey, E. J.; Fuchs, P. C. Tetrahedron Lett. 1972, 3769.
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14190 J. AM. CHEM. SOC. VOL. 128, NO. 43, 2006

Total Synthesis of Xestodecalactone A
A R T I C L E S
Scheme 6. CD Spectroscopic Pattern of Compounds 69 and 70a
of active dienophiles (see Figure 5) otherwise dwarfed by the
major effects at the â-carbons. We expect that the chemose-
lection in the relative dienophilicity offers significant challenges
and opportunities for estimating the concertedness of cycload-
ditions of the Diels-Alder genre.
Subsequently an efficient synthesis of xestodecalactone A,
utilizing an “ynoate” dienophile, served to rapidly construct the
resorcylinic scaffold. This strategy is amenable to assembling
a broad range of biologically acive phenylacetic lactone
macrolides with pleasingly high convergence.
Acknowledgment. This work was supported in part by a grant
from the NIH (HL25848). T.Y. thanks Prof. Bringmann for an
authentic sample of xestodecalactone A and for providing its
spectroscopic data. Dr. Hideki Ishii is acknowledged for CD
measurements. Mr. Mingji Dai is acknowledged for helpful
discussions.
a Reagents and conditions: a) MeOH, K2CO3, reflux, 1 h, 64%; b) BzCl,
pyridine, 4-(dimethylamino)pyridine, rt, overnight.
Conclusion
In summary, we have learned through this research that the
Diels-Alder cycloaddition reaction involving an unsymmetrical
allene dienophile results with modest chemoselection in dif-
ficultly predictable ways. Though from a synthetic perspective
this was a disappointing finding, in retrospect it has considerable
potential teaching value in Diels-Alder reactions, in that it
allows for the examination of the subtle effects at the R-carbon
Supporting Information Available: Experimental procedures
and characterization data for compounds 55-67, xestodeca-
lactone A, and 68-70. This material is available free of charge
via the Internet at http://pubs.acs.org.
JA064270E
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