Total synthesis of (±)-cavicularin: Control of pyrone diels-alder regiochemistry using isomeric vinyl sulfones

Article abstract of DOI:10.1021/ol303390a

An intramolecular pyrone Diels-Alder reaction-elimination retro-Diels-Alder cascade of a vinyl sulfone was used in the synthesis of cavicularin, a molecule possessing conformational chirality. The vinyl sulfone substitution pattern allowed for regiocontrol in the Diels-Alder cascade event.

Full text of DOI:10.1021/ol303390a

ORGANIC
LETTERS
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Vol. XX, No. XX
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Total Synthesis of (()-Cavicularin:
Control of Pyrone DielsÀAlder
Regiochemistry Using Isomeric
Vinyl Sulfones
Peng Zhao and Christopher M. Beaudry*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis,
Oregon 97331, United States
christopher.beaudry@oregonstate.edu
Received December 11, 2012
ABSTRACT
An intramolecular pyrone DielsÀAlder reactionÀelimination retro-DielsÀAlder cascade of a vinyl sulfone was used in the synthesis of
cavicularin, a molecule possessing conformational chirality. The vinyl sulfone substitution pattern allowed for regiocontrol in the DielsÀAlder
cascade event.
Macrocyclic bis(bibenzyls) are a class of over 70 biolo-
gically active natural products isolated from liverwort
species.1 With a few exceptions, all of these natural prod-
ucts fall into two structural classes: (1) C,D-ring diaryl-
ether substructure 1 (Figure 1) and (2) C,D-ring biaryl
substructure 2. Members of this family are differentiated
by the oxygenation pattern of their core, and most do not
possess sp3-hybridized stereogenic carbon atoms. One C,
D-biaryl member of this family, cavicularin,2 has a fasci-
nating (and unique) molecular architecture including a
dihydrophenanthrene motif. This macrocyclic structure
imparts severe strain to the molecule, and as a result, the
B ring is significantly distorted (ca. 15°) from planarity.
Cavicularin exists in stable chiral conformations, it is
highly strained, and a member of an interesting class of
biologically active molecules. For these reasons, and be-
cause of our ongoing interest in conformationally chiral
molecules,3 we decided to develop a chemical synthesis of
cavicularin.
The unique molecular architecture of cavicularin also
attracted attention from the synthetic community. In the
inaugural synthesis, Harrowven et al. used an intramolec-
ular radical addition to build the strained macrocyclic
architectureofthe natural product.4 Baranand co-workers
have also completed a synthesis of the natural product
using a pyrone DielsÀAlder strategy.5
Figure 1. Macrocyclic bis(bibenzyl) natural products.
ꢀ
ꢀ
(1) (a) Keseru, G. M.; Nogradi, M. Nat. Prod. Rep. 1995, 12, 69–75.
(b) Asakawa, Y.; Toyota, M.; Hashimoto, T.; Tori, M.; Nagashima, F.;
Harinantenaina, L. Heterocycles 2008, 76, 99–127.
(2) Toyota, M.; Yoshida, T.; Kan, Y.; Takaoka, S.; Asakawa, Y.
Tetrahedron Lett. 1996, 37, 4745–4748.
(4) (a) Harrowven, D. C.; Woodcock, T.; Howes, P. D. Angew.
Chem., Int. Ed. 2005, 44, 3899–3901. (b) Kostiuk, S. L.; Woodcock,
T.; Dudin, L. F.; Howes, P. D.; Harrowven, D. C. Chem.;Eur. J. 2011,
17, 10906–10915.
(3) Salih, M. Q.; Beaudry, C. M. Org. Lett. 2012, 14, 4026–4029.
r
10.1021/ol303390a
XXXX American Chemical Society

Our synthetic approach to cavicularin also focused on
the use of a DielsÀAlder cascade to form the nonplanar B
ring (Scheme 1). DielsÀAlder-retro-DielsÀAlder cascades
to build phenyl rings are well precedented,6 including the
elegant synthesis of the strained-ring alkaloid haouamine
by Baran and Burns.7 The regiochemistry of the DielsÀ
Alder addition must be controlled in the cyclization event,
because there are two regiochemical outcomes of the
cascade. Cavicularin displays a para-substituted B-ring,
which requires formation of a bond between C6 and C5
(cavicularin numbering). DielsÀAlder addition with the
undesired regiochemistry would give a meta-substituted
B-ring (vide infra). Intermolecular pyrone DielsÀAlder
reactions often give mixtures of regioisomeric products,8
and we suspected that the constraints of the molecular
architecture would not be sufficient to guarantee forma-
tion of the desired regioisomer in the DielsÀAlder event.
Accordingly, we planned to use an alkyne equivalent
functional group with suitable electronic bias to favor
formation of the desired regioisomer. Of the various
alkyne-equivalent functional groups for DielsÀAlder reac-
tions,9 a vinyl sulfone (3) was selected as a substrate. The
electronic bias of the sulfone was anticipated to induce the
desired bond formation between the electrophilic C5 atom
of the vinyl sulfone and the nucleophilic C6 atom of the
pyrone. Vinyl sulfones have been used as alkyne equiva-
lents in pyrone DielsÀAlder reactions.10 Intermediate 3
was envisioned to arise from differentially functionalized
dihydrophenanthrene 4.
Our initial attempt at the synthesis of 4 began with
benzaldehyde 5 (Scheme 2).11 Wittig olefination of 5 with
the ylide derived from known benzyl bromide 612 gave
substituted stilbene 7 as a single geometrical isomer. The
stereochemistry of the stilbene was assigned as Z based on
the coupling constant (3JHH = 8 Hz) ofthe vinylic protons.
Reduction of the alkene in the presence of the aryl bro-
mides was accomplished using in situ generated diimide to
yield dibromide 8.13
Scheme 2. First-Generation Dihydrophenanthrene Synthesis
Reductive cyclization of 8 using Stille or Ullman condi-
tions14 gave only trace amounts of the desired dihydrophen-
anthrene 9. Attempts to improve the yield of the intra-
molecular coupling were not successful. Cyclization of
Z-configured 7 using such conditions led to dehalogenation
of the starting material without formation of any detect-
able phenanthrene product. Similarly, Wurtz-type condi-
tions failed to advance either 7 or 8 to cyclized products.
The second-generation synthesis of dihydrophenan-
threne 4 builds on a related strategy reported by Castle
(Scheme 3).15 Isovanillin derivative 5 was olefinated to
produce bromostyrene 10. Intermediate 10 was trans-
formed into coupling partner 12 using standard condi-
tions. Suzuki coupling of boronic ester 12 and bromide 13
(prepared from the corresponding benzaldehyde16) led to
biphenyl 14. Ring-closing metathesis gave a phenanthrene,
which underwent partial reduction of the phenanthrene
and hydrogenolysis of the benzyl ether to produce the
corresponding phenol. Activation of the phenol as the
Scheme 1. Retrosynthetic Analysis of Cavicularin
(5) (a) Dam, J. H., Ph.D. Thesis, Technical University of Denmark,
2009. (b) Gulder, T.; Dam, J. H.; Baran, P. S. Abstracts of Papers, Western
Regional Meeting of the American Chemical Society, Las Vegas, NV,
Sept 23À27, 2008.
(6) Gulder, T.; Baran, P. S. Nat. Prod. Rep. 2012, 29, 899–934.
(7) Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908–
3909.
(12) (a) Berger, D. M.; Birnberg, G.; DeMorin, F.; Dutia, M.; Powell,
D.; Wang, Y. D. Synthesis 2003, 11, 1712–1716. (b) Fukuyama, Y.;
Yaso, H.; Mori, T.; Takahashi, H.; Minami, H.; Kodama, M. Hetero-
cycles 2001, 54, 259–274.
(13) (a) Marshall, J. A.; Gung, W. Y. Tetrahedron 1989, 45, 1043–
1052. (b) Dewey, R. S.; van Tamelen, E. E. J. Am. Chem. Soc. 1961, 83,
3729.
(14) For reviews, see: (a) Farina, V.; Krishnamurthy, V.; Scott, W. J.
Org. React. 1997, 50, 1–652. (b) Nelson, T. D.; Crouch, R. D. Org. React.
2004, 63, 265–555.
(15) Jones, S. B.; He, L.; Castle, S. L. Org. Lett. 2006, 8, 3757–3760.
(16) Kobayashi, S.; Okimoto, K.; Imakura, Y. Chem. Pharm. Bull.
1982, 30, 1567–1573.
(8) Woodard, B. T.; Posner, G. H. Adv. Cycloaddition 1999, 5, 47–83.
(9) For example: (a) Ono, N.; Kamimura, A.; Kaji, A. Tetrahedron
Lett. 1986, 27, 1595–1598. (b) Anderson, W. K.; Dewey, R. H. J. Am.
Chem. Soc. 1973, 95, 7161–7162. (c) Danishefsky, S.; Prisbylla, M. P.;
Hiner, S. J. Am. Chem. Soc. 1978, 100, 2918–2920.
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12, 1275–1276. (b) Pratt, A. J.; Rendle, P. M.; Steel, P. J. Aust. J. Chem.
2011, 64, 945–950.
(11) Prepared from 2-bromo-3-hydroxy-4-methoxybenzaldehyde:
(a) Hamann, P. R.; Toth, J. E.; Fuchs, P. L. J. Org. Chem. 1984, 49,
3865–3867. (b) Natarajan, S.; Rajeswari, S.; Chandrasekaran, S.; Pai,
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Chem. Incl. Med. Chem. 1982, 21, 95–97.
B
Org. Lett., Vol. XX, No. XX, XXXX

DielsÀAlder cascade, we constructed alternative sub-
strates 19 and 20 (Scheme 5). These substrates were con-
veniently prepared from related boronic ester 2120 and
dihydrophenanthrene 4, using a similar synthetic strategy.
Coupling of 4 and 21 gave tetracycle 22. Subjection of 22 to
BCl3 induced removal of both the TBS and iPr groups.
Addition of the phenol to 18 gave 23. Alcohol 23 was
oxidized to the corresponding aldehyde and olefinated to
prepare vinyl sulfone 19. Alkyne 20 was prepared from 23
by oxidation and subsequent homologation using the
Ohira-Bestmann reagent.21 These alternative DielsÀAlder
cascade substrates would be used to test our hypothesis
that the substitution of the vinyl sulfone would control the
regiochemistry of the DielsÀAlder cascade.
Scheme 3. Second-Generation Dihydrophenanthrene Synthesis
Scheme 5. Synthesis of Alternate DielsÀAlder Substrates
triflate (4) was uneventful. Coupling of 4 withboronic ester
15 (prepared in 5 steps from m-anisaldehyde)17 proceeded
in high chemical yield to give tetracycle 16.
Scheme 4. Synthesis of Key DielsÀAlder Substrate 3
In the event, we were pleased to find that the key cascade
reaction generated the cavicularin skeleton (Scheme 6).
DielsÀAlder substrate 3 was heated to 240 °C using
microwave irradiation. The isolated product was methyl
cavicularin (24), produced in high yields as a single regio-
isomer. Presumably, DielsÀAlder cycloaddition occurs
first giving 25. Elimination of phenylsufinic acid gives inter-
mediate 26. Intermediate 26 undergoes a retro DielsÀ
Alder with loss of CO2 to give 24. The precise order of
the elimination events is inconsequential, and no inter-
mediates or byproducts were isolated or observed in this
Functional group manipulation gave the key DielsÀAlder
substrate (Scheme 4). Claisen-like condensation of 16 gave
a phosphonate, which underwent HornerÀWadsworthÀ
Emmons reaction with formaldehyde to give vinyl sulfone
17.18 A one-pot procedure involving generation of the
phosphonate and in situ treatment with paraformalde-
hyde gave superior yields of the vinyl sulfone compared to
the two-step procedure. Removal of the isopropyl ether19
and addition to chloropyrone 18 gave the desired cy-
cloaddition cascade substrate 3.
(18) Clasby, M. C.; Craig, D.; Slawin, A. M. C.; White, A. J. P.;
Williams, D. J. Tetrahedron 1995, 51, 1509–1532.
(19) Okano, K.; Okuyama, K.Ài.; Fukuyama, T.; Tokuyama, H.
In order to test our hypothesis that the substitution of
the vinyl sulfone would control the regiochemistry of the
Synlett 2008, 13, 1977–1980.
(20) Prepared in
Information.
5 steps from m-iodoanisole. See Supporting
(21) (a) Ohira, S. Synth. Commun. 1989, 19, 561–564. (b) Roth, G. J.;
Liepold, B.; Mueller, S. G.; Bestmann, H. J. Synthesis 2004, 59–62.
(17) See Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
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Interestingly, whenisomeric vinyl sulfone19was heated,
the key cascade reaction occurred, but only the undesired
regioisomer 27was produced. This result indicated that the
regiochemistry of the DielsÀAlder addition reaction was
influenced by the electronics of the substrate and was not
solely dependent on the constraints of the intramolecular
tether. When the less electronically biased alkyne substrate
20 was heated, a mixture of regioisomers 27 and 24 was
produced. Furthermore, longer reaction times were re-
quired for full consumption of the starting material, which
is consistent with an electronically less-activated substrate.
In summary, we have synthesized the conformationally
chiral macrocyclic bis(bibenzyl) natural product cavicular-
in. Our synthetic strategy features a pyrone DielsÀAlder
reaction to construct the strained B-ring of the natural
product. A vinyl sulfone served as an alkyne equivalent
dienophile that controlled the regiochemical outcome of
the DielsÀAlder reaction. To the best of our knowledge,
this is the first example of complete regiocontrol in the
DielsÀAlder reaction of a pyrone using a vinyl sulfone.
Efforts toapply our synthetic strategytoother macrocyclic
bis(bibenzyl) natural products and to develop an enantio-
selective synthesis of cavicularin are underway in our
laboratory.
Scheme 6. Synthesis of Cavicularin and its Regioisomer
Acknowledgment. The authors gratefully acknowledge
financial support from Oregon State University.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds
reaction. The desired regioisomer 24 was produced as
the sole isolable product. Demethylation using stan-
dard conditions completed the synthesis of cavicularin.
The spectral data (e.g., 1H, 13C NMR) of synthetic
cavicularin was identical to that reported for the nat-
ural substance.
1
including depiction of their H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
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