A concise approach to the dalesconol skeleton

Article abstract of DOI:10.1021/ol2015847

A rapid approach to the skeleton of dalesconol A and B, unprecedented immunosuppressants, has been achieved through a convergent strategy featuring a carbocation-mediated dearomatization-cyclization and a following one-pot consecutive operation.

Full text of DOI:10.1021/ol2015847

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4494–4497
A Concise Approach to the Dalesconol
Skeleton
Yukai Fan,a Pengju Feng,a Mao Liu,a Hongjie Pan,a and Yian Shi*,a,b
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China, and Department of Chemistry, Colorado State University, Fort Collins,
Colorado 80523, United States
yian@lamar.colostate.edu
Received June 13, 2011
ABSTRACT
A rapid approach to the skeleton of dalesconol A and B, unprecedented immunosuppressants, has been achieved through a convergent strategy
featuring a carbocation-mediated dearomatizationꢀcyclization and a following one-pot consecutive operation.
Polyketides dalesconol A and B (Scheme 1) were initially
isolated by Tan and co-workers in 2008 from Daldinia
eschscholzii, and they were revealed to possess promising
immunosuppressive activity, which is comparable to that
of clinically used cyclosporine A, but with a significantly
have an unprecedented carbon skeleton with seven fused
5-, 6-, and 7-membered rings. All these features make
dalesconol A and B attractive synthetic targets. During
the course of our synthetic studies toward dalesconol A
and B, Snyder and co-workers reported the first and
elegant total synthesis of these natural products.3 Herein,
we wish to report our own synthetic approach to the
skeleton of dalesconol A and B (compound 3 in Scheme 1).
One of our retrosynthetic plans is shown in Scheme 1.
The 7-membered ring ketone in 3 was envisioned to form
via an intramolecular Michael addition of spiro enone 4.
Compound 4 might be obtained through a dearomatiza-
tionꢀcyclization process from an intermediate such as 5,
which could be constructed by coupling of 6, 8, and 9.
The synthesis of fragments 8 and 9 is described in
Scheme 2. Both 8 and 9 can be obtained from 11, which
can be prepared on a multigram scale from commercially
available 10. Heating 10 in melted potassium hydroxide at
260 °C gave naphthalene-1,8-diol in 73% yield.3,4
Naphthalene-1,8-diol was monomethylated with MeI
superior selectivity index (SI) (1, IC50 = 0.16 μg mLꢀ1
,
SI > 500; 2, IC50 = 0.25 μg mLꢀ1, SI > 320; cyclosporine
A, IC50 = 0.06 μg mLꢀ1, SI = 187).1 It was found that the
racemates of 1 and 2 have better immunosuppressive
activity than that of their enantiomers. These compounds
were also isolated by She, Lin, and co-workers from a
marine-based endophytic fungus (Sporothrix sp. #4335)
and named sporothrin A and B.2 Compound 1 was found
to be a potent acetylcholine esterase (AChE) inhibitor. In
addition, both 1 and 2 showed modest antitumor activity
against hepG2 cell lines. These biological activities make 1
and 2 attractive lead compounds for the development of
pharmaceutical agents. Structurally, dalesconol A and B
a Chinese Academy of Sciences.
b Colorado State University.
(3) Snyder, S. A.; Sherwood, T. C.; Ross, A. G. Angew. Chem., Int.
Ed. 2010, 49, 5146.
(4) (a) Erdmann, H. Justus Liebigs Ann. Chem. 1888, 247, 345.
(b) Parker, K. A.; Iqbal, T. J. Org. Chem. 1980, 45, 1149. (c) Andersen,
N. G.; Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1996, 61, 9556.
(1) (a) Zhang, Y. L.; Ge, H. M.; Zhao, W.; Dong, H.; Xu, Q.; Li,
S. H.; Li, J.; Zhang, J.; Song, Y. C.; Tan, R. X. Angew. Chem., Int. Ed.
2008, 47, 5823. (b) Zhang, Y. L.; Zhang, J.; Jiang, N.; Lu, Y. H.; Wang,
L.; Xu, S. H.; Wang, W.; Zhang, G. F.; Xu, Q.; Ge, H. M.; Ma, J.; Song,
Y. C.; Tan, R. X. J. Am. Chem. Soc. 2011, 133, 5931.
(2) Wen, L.; Cai, X.; Xu, F.; She, Z.; Chan, W. L.; Vrijmoed, L. L. P.;
Jones, E. B. G.; Lin, Y. J. Org. Chem. 2009, 74, 1093.
~
(5) Carreno, M. C.; Garcıa Ruano, J. L.; Sanz, G.; Toledo, M. A.;
Urbano, A. Synlett 1997, 1241.
r
10.1021/ol2015847
Published on Web 08/01/2011
2011 American Chemical Society

and K2CO3, and subsequently regioselectively brominated
with NBS3,5 in 95% and 97% yield, respectively. Upon
protection with a MOM group (97% yield),3 compound 11
was treated with n-BuLi and DMF to provide aldehyde 12
in 83% yield.3 Fragment 8 was formed in 87% yield by a
regioselective bromination of 12 with NBS in DMF at
room temperature.6 Alternatively, compound 11 was pro-
tected with chlorotriisopropylsilane to provide 13 in 85%
yield,7 which was then boronated with pinacolborane,
triethylamine, and Pd(PPh3)4 at 90 °C to afford fragment
9 in 85% yield.8 Fragment 6 was prepared from o-bro-
moacetophenone in 97% yield by ketalization.9
Scheme 2. Synthesis of Compounds 8 and 9
Scheme 1. Retrosynthetic Analysis of the Dalesconol Skeleton
Scheme 3. Synthesis of Compound 3
The synthesis of dalesconol skeleton 3 is outlined in
Scheme 3. Fragments 8 and 9 were combined to give com-
pound 7 in 53% yield via SuzukiꢀMiyaura coupling with
10 mol % Pd(PPh3)4 in the presence of Na2CO3.8,10
Reacting aldehyde 7 with the anion generated from com-
pound 6 by halogenꢀlithium exchange led to the formation
of alcohol 5a, which cyclized smoothly with concomitant
deprotection of the methoxy ketal11 to give two diastereo-
isomers 4a and 4b (4a:4b = 1.14:1) in 86% yield upon
treatment with silica gel. The structures of 4a and 4b were
confirmed by X-ray diffraction (Figures 1 and 2). Further
studies showed that 4a and 4b behaved differently toward
the subsequent intramolecular Michael addition reaction.
No cyclization was observed for 4a under various re-
action conditions. However, to our delight, 4b was readily
(6) Mallory, F. B.; Mallory, C. W.; Butler, K. E.; Lewis, M. B.; Xia,
A. Q.; Luzik, E. D., Jr.; Fredenburgh, L. E.; Ramanjulu, M. M.; Van,
Q. N.; Francl, M. M.; Freed, D. A.; Wray, C. C.; Hann, C.; Nerz-
Stormes, M.; Carroll, P. J.; Chirlian, L. E. J. Am. Chem. Soc. 2000, 122,
4108.
(7) (a) Landi, J. J., Jr.; Ramig, K. Synth. Commun. 1991, 21, 167. (b)
Couladouros, E.; Strongilos, A. T. Tetrahedron Lett. 2000, 41, 535.
(8) (a) Thompson, A. L. S.; Kabalka, G. W.; Akula, M. R.; Huffman,
J. W. Synthesis 2005, 547. (b) Babudri, F.; Cardone, A.; Cioffi, C. T.;
Farinola, G. M.; Naso, F.; Ragnib, R. Synthesis 2006, 1325.
(9) Wang, S.; Morrow, G. W.; Swenton, J. S. J. Org. Chem. 1989, 54,
5364.
(11) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J. M. Synthesis
1978, 63.
(10) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41, 512.
Org. Lett., Vol. 13, No. 17, 2011
4495

converted to dalesconol skeleton 3in overall 85% yield in one
pot via intramolecular Michael addition (2.0 equiv of
LiHMDS in THF at rt),12 removal of MOM (concentrated
HCl), and oxidation with DDQ.13 The structure of com-
pound 3 was established by X-ray diffraction (Figure 3).
The alkylative dearomatization of compound 5a is the
key step for the synthetic sequence, and its success is highly
dependent upon the protecting groups and acid catalysts
used. Various reaction conditions have been examined for
this step, and some of them are shown in Table 1. For ex-
ample, treating 5b with various acids, such as HCl, TsOH,
HOAc, led to a messy mixture (Table 1, entry 1). No
cyclization was observed when 5a was first desilylated with
TBAF and subsequently treated with n-Bu3P and DEAD
(Table 1, entry 2).14 However, the cyclization products 4a
and 4b were obtained in 51% yield when 5a was desilylated
and then treated with silica gel (Table 1, entry 3). Subse-
quently, it was found that a higher yield (86%) was
obtained when 5a was directly treated with silica gel in
CH2Cl2 at 40 °C (Table 1, entry 4). The dearomatiza-
tionꢀcyclization process likely proceeded via a carboca-
tion generated from the cleavage of the benzylic hydroxy
group assisted by the weakly acidic silica gel. In this
process, the FriedelꢀCrafts-type alkylation occurred at
the para-position of the OTIPS group to form the spiro
5-membered ring.15ꢀ19
Table 1. Studies on the Alkylative Dearomatization
Figure 1. X-ray structure of compound 4a.
protective
group
yield (%)
entry
1
5
reagent
Acida
(4aþ4b)
5b
R = MOM
R0 = MOM
R = TIPS
R0 = MOM
0
2
5a
TBAF
0
(n-Bu)3P
DEAD
3
4
5a
5a
R = TIPS
R0 = MOM
R = TIPS
R0 = MOM
TBAF
51
86
Silica gel
Silica gel
a Such as HCl, TsOH, HOAc.
Figure 2. X-ray structure of compound 4b.
In summary, we have developed a convergent and
concise synthetic approach to the dalesconol skeleton.
(12) (a) Takasu, K.; Mizutani, S.; Noguchi, M.; Makita, K.; Ihara,
M. J. Org. Chem. 2000, 65, 4112. (b) Kanoh, N.; Sakanishi, K.; Iimori,
E.; Nishimura, K.; Iwabuchi, Y. Org. Lett. 2011, 13, 2864.
(13) Interestingly, the product resulting from the removal of the
MOM group could also be oxidized to give compound 3 upon standing
in air for an extended period of time.
(14) Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem.
Soc. 1996, 118, 2301.
ꢀ
(15) For leading reviews on dearomatization, see: (a) Pouyegu, L.;
Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235. (b) Roche, S. P.;
Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068.
(16) For selected examples of acid-catalyzed dearomatization, see:
(a) Oshima, T.; Asahara, H.; Koizumi, T.; Miyamoto, S. Chem. Com-
mun. 2008, 1804. (b) Asahara, H.; Saito, K.; Ikuma, N.; Oshima, T.
J. Org. Chem. 2010, 75, 733.
Figure 3. X-ray structure of compound 3.
4496
Org. Lett., Vol. 13, No. 17, 2011

The key ring structure and the quaternary carbon are con-
structed via a carbocation-mediated alkylative dearomati-
zation and subsequent intramolecular Michael addition.
Further improvement of this strategy and its application
to the total synthesis of dalesconol A, B and their deriva-
tives as well as biological activity studies are currently
underway.
(17) For selected examples of alkylative dearomatization under basic
conditions, see: (a) Masamune, S. J. Am. Chem. Soc. 1961, 83, 1009.
(b) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921. (c) Baird, R.;
Winstein, S. J. Am. Chem. Soc. 2011, 133, 5931. (d) Nicolaou, K. C.;
Wu, T. R.; Kang, Q.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2009, 48,
3440. (e) Nicolaou, K. C.; Kang, Q.; Wu, T. R.; Lim, C. S.; Chen, D. Y.-K.
J. Am. Chem. Soc. 2010, 132, 7540.
Acknowledgment. The authors gratefully acknowledge
the National Basic Research Program of China (973
program, 2011CB808600) and the Chinese Academy of
Sciences for financial support.
(18) Forselectedexamplesofoxidativedearomatization,see:(a)Kita,Y.;
Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.; Eichhorn, J. J. Org.
Chem. 1996,61, 5857. (b) Simmons, E. M.; Hardin, A. R.; Guo, X.; Sarpong,
R. Angew. Chem., Int. Ed. 2008, 47, 6650. (c) Nicolaou, K. C.; Li, A.;
Edmonds, D. J.; Tria, G. S.; Ellery, S. P. J. Am. Chem. Soc. 2009, 131, 16905.
(19) For an example of palladium catalyzed dearomatization, see:
Nemoto, T; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu, M.;
Hamada, Y. Org. Lett. 2010, 12, 5020.
Supporting Information Available. Experimental pro-
cedure, characterization data, and X-ray structures of 4a,
4b, 3 along with NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
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