Construction of the cyclophane core of the hirsutellones via a RCM strategy

Article abstract of DOI:10.1021/ol100692x

Construction of the highly strained [10]-paracyclophane core of the hirsutellones has been completed via an effective RCM strategy.

Full text of DOI:10.1021/ol100692x

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2504-2507
Construction of the Cyclophane Core of
the Hirsutellones via a RCM Strategy§
Mingzheng Huang,† Liqiang Song,† and Bo Liu*,†,‡
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College
of Chemistry, Sichuan UniVersity, Chengdu 610064, China, and Key Laboratory of
Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
CAS, 345 Lingling Road, Shanghai 200032, China
chembliu@scu.edu.cn
Received March 24, 2010
ABSTRACT
Construction of the highly strained [10]-paracyclophane core of the hirsutellones has been completed via an effective RCM strategy.
Despite that cyclophanes have been extensively synthesized
and evaluated due to their unique physical and chemical
properties for decades,1 examples on isolation and total synthesis
of cyclophane-containing natural products are rare, which
include haouamines A,2 sanjoinine G1,3 acerogenin A,4 lon-
githorone A,5 cylindrocyclophane A,6 etc. Recently, a family
of natural products named hirsutellones A-F were reported,
some of which show antimycobacterial activity.7 Their novel
structures (Figure 1) are very similar to those of GKK1032s,8
pyrrocidines,9 and pyrrospirones.10 Interestingly, all of them
contain a highly stained paracyclophane core embracing a bent
benzene ring.
† Sichuan University.
(5) For isolation, see: (a) Fu, X.; Hossain, M. B.; Schmitz, F. J.; van
der Helm, D. J. Org. Chem. 1997, 62, 3810–3819. (b) Fu, X.; Hossain, M. B.;
van der Helm, D.; Schmitz, F. J. J. Am. Chem. Soc. 1994, 116, 12125–12126.
For total synthesis, see: (c) Layton, M. E.; Morales, C. A.; Shair, M. D.
J. Am. Chem. Soc. 2002, 124, 773–775. (d) Morales, C. A.; Layton, M. E.;
Shair, M. D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12036–12041.
(6) For isolation, see: (a) Moore, B. S.; Chen, J.-L.; Patterson, G. M.;
Moore, R. E.; Brinen, L. S.; Kato, Y.; Clardy, J. J. Am. Chem. Soc. 1990,
112, 4061. (b) Moore, B. S.; Chen, J.-L.; Patterson, G. M.; Moore, R. E.
Tetrahedron 1992, 48, 3001. For total synthesis, see: (c) Smith, A. B., III;
Adams, C. M.; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 2001, 123,
5925–5937, and references therein. (d) Hoye, T. R.; Humpal, P. E.; Moon,
B. J. Am. Chem. Soc. 2000, 122, 4982–4983.
‡ Shanghai Institute of Organic Chemistry.
§ Dedicated to Prof. Wei-Shan Zhou on the occasion of his 87th birthday.
(1) (a) Cyclophanes; Keehn, P. M., Rosenfeld, S. M., Eds.; Academic:
New York, 1983. (b) Vo¨gtle, F. Cyclophane Chemistry; Wiley: New York,
1993. (c) Cyclophanes; Diedrerich, F., Ed.; The Royal Society of Chemistry:
Cambridge, 1991. (d) Weber, E. Top. Curr. Chem. 1994, 172, 1. (e) Modern
Cyclophane Chemistry; Gleiter, R., Hopf, H., Ed.; Wiley: Germany, 2004.
(2) For isolation, see: (a) Garrido, L.; Zubia, E.; Ortega, M. J.; Salva, J.
J. Org. Chem. 2003, 68, 293–299. For total synthesis, see: (b) Burns, N. Z.;
Jessing, M.; Baran, P. S. Tetrahedron 2009, 65, 6600–6610, and references
therein. (c) Baran, P. S.; Burns, N. Z. I. J. Am. Chem. Soc. 2006, 128,
3908–3909. (d) Burns, N. Z.; Krylova, I. N.; Hannoush, R. N.; Baran, P. S.
J. Am. Chem. Soc. 2009, 131, 9172–9173. (e) Burns, N. Z.; Baran, P. S.
Angew. Chem., Int. Ed. 2008, 47, 205–208, and references therein.
(3) For isolation, see: (a) Han, B. H.; Park, M. H.; Han, Y. N.
Phytochemistry 1990, 29, 3315–3319. (b) Han, B. H.; Park, J. H. Pure Appl.
Chem. 1989, 61, 443–448. For total synthesis, see: (c) Temal-Laib, T.;
Chastanet, J.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 583–590, and references
therein.
(7) (a) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai,
S.; Thebtaranonth, Y. Tetrahedron 2005, 61, 5577–5583. (b) Isaka, M.;
Prathumpai, W.; Wongsa, P.; Tanticharoen, M. Org. Lett. 2006, 8, 2815–
2817.
(8) (a) Koizumi, F.; Hasegawa, A.; Ando, K.; Ogawa, T.; Hara, M. Jpn.
Kokai Tokkyo Koho 2001, JP 2001247574. (b) Hasegawa, A.; Koizumi, F.;
Takahashi, Y.; Ando, K.; Ogawa, T.; Hara, M.; Yoshida, M. 43rd
Symposium on the Chemistry of Natural Products, Symposium Papers;
Osaka, 2001; pp 467-472.
(9) He, H.; Yang, H. Y.; Bigelis, R.; Solum, E. H.; Greenstein, M.;
Carter, G. T. Tetrahedron Lett. 2002, 43, 1633–1636.
(4) For isolation, see: (a) Nagai, M.; Kubo, M.; Fujita, M.; Inoue, T.;
Matsuo, M. J. Chem. Soc., Chem. Commun. 1976, 338–339. For total
synthesis, see: (b) Gonzalez, G. I.; Zhu, J. J. Org. Chem. 1999, 64, 914–
924, and references therein.
10.1021/ol100692x  2010 American Chemical Society
Published on Web 05/06/2010

by an intramolecular Diels-Alder reaction (IMDA) from 3.
One of the key steps is to constitute the paracyclophane core
effectively, which might be realized through two strategies.
On one hand, an ambitious ketene-trapping/IMDA tandem
strategy (strategy A) was devised to install three rings in
one step, in which the highly reactive ketene generated in
situ acts as an important reaction intermediate from 4a. On
the other hand, cleavage at the trans- double bond in the
cyclophane core of 3 would give the ring closing metathesis
(RCM) precursor 4b (strategy B). Following the retrosyn-
thetic analysis, we evaluated these synthetic strategies,
respectively, with simplified model substrates.
In our previous communication, to promptly test the
feasibility of the tandem reaction (strategy A), we applied a
model substrate by omitting one six-membered ring; how-
ever, the desired ketene trapping toward formation of
paracyclophane did not work, although the intramolecular
Diels-Alder reaction occurred smoothly.12b It suggested that
the formation of the strained paracyclophane core be the most
important and difficult puzzle. To fully address the possibility
of a current ketene-trapping strategy, we synthesized com-
pounds 9a-9d from the known compound 5 via routine
procedures (Scheme 2).15 Theoretically, compounds 9a-9d,
with sufficient rotational flexibility, might show different
reactivity in the intramolecular ketene-trapping step based
on their different steric and electric properties. In fact, to
our disappointment, no desired [10]-paracyclophane could
be detected by heating the cyclization precursors 9a-9d
either in a sealed tube or with a Dean-Stark trap. We
speculated that such failure be ascribed to the ring strain of
[10]-paracyclophane since a less strained [14]-paracyclo-
phane with similar structure was successfully constructed by
employing the same ketene-trapping tactic in a recent total
synthesis of macrocidin A.16
Figure 1. Structures of the hirsutellones.
The structural novelty and interesting bioactivity of the
hirsutellones have attracted the attention of synthetic chem-
ists. The Nicoloau group achieved an elegant total synthesis
of hirsutellone B in 2009, which featured an epoxide opening/
Diels-Alder cascade to form the 6-5-6 fused tricyclic
motif and the construction of a cyclophane core through a
Ramberg-Ba¨cklund reaction.11 In addition, the Sorensen
group and our group proposed a very similar ketene-trapping/
IMDA cascade strategy independently (Scheme 1).12 From
Scheme 1. Retrosynthetic Analysis toward the Hirsutellones
To circumvent this obstacle, we turned our attention to
the RCM protocol, which has been employed to construct
the [16]-paracyclophane core of the turrianes by the Fu¨rstner
group17 and to make a [12]-paracyclphane of longithorone
A by the Zhu group.4 Thus, compounds 11a and 11b were
prepared conveniently from the known compound 5, and both
were subsequently subjected to the RCM conditions in a
highly diluted solution of DCM or toluene, with Grubbs first
or second generation catalysts or Hoveyda-Grubbs second
generation catalyst.18 However, very low conversion was
(10) Shiono, Y.; Shimanuki, K.; Hiramatsu, F.; Koseki, T.; Tetsuya, M.;
Fujisawa, N.; Kimura, K. Bioorg. Med. Chem. Lett. 2008, 18, 6050–6053.
(11) Nicolaou, K. C.; Sarlah, D.; Wu, R. T.; Zhan, W. Angew. Chem.,
Int. Ed. 2009, 48, 6870–6874.
(12) (a) Tilley, S. D.; Reber, K. P.; Sorensen, E. J. Org. Lett. 2009, 11,
701–703. (b) Huang, M.; Huang, C.; Liu, B. Tetrahedron Lett. 2009, 50,
2797–2800.
(13) Oikawa, H. J. Org. Chem. 2003, 68, 3552–3557.
(14) Snider, B. B.; Neubert, B. J. J. Org. Chem. 2004, 69, 8952–8955.
(15) For preparation of compound 5, see: (a) Boyle, T. P.; Bremner,
J. B.; Coates, J.; Deadman, J.; Keller, P. A.; Pyne, S. G.; Rhodes, D. I.
Tetrahedron 2008, 64, 11270–11290. (b) Bayardon, J.; Sinou, D. Tetra-
hedron: Asymmetry 2005, 16, 2965–2972.
(16) For isolation, see: (a) Graupner, P. R.; Carr, A.; Clancy, E.; Gilbert,
J.; Bailey, K. L.; Derby, J.-A.; Gerwick, B. C. J. Nat. Prod. 2003, 66, 1558–
1561. For total synthesis, see: (b) Yoshinari, T.; Ohmor, K.; Schrems, M. G.;
Pfaltz, A.; Suzuki, K. Angew. Chem., Int. Ed. 2010, 49, 881–885.
(17) Fu¨rstner, A.; Stelzer, F.; Rumbo, A.; Krause, H. Chem.sEur. J.
2002, 8, 1856–1871.
a biogenic viewpoint,13,7b the hirsutellones are able to be
transformed from a key intermediate 1, which could be
obtained from compound 2 following Snider’s methodol-
ogy.14 The 5-6 fused ring substructure can be constructed
Org. Lett., Vol. 12, No. 11, 2010
2505

oxygen in 11 is conjugated with a π-orbital on the benzene
ring, making the two double bonds far away from each other.
The other is that excess enthalpy is required to overcome the
energy barrier for contorting the flat benzene ring to a bent ring,
a necessary conformation in the transition state.
Scheme 2
.
Ketene-Trapping Strategy to Construct the
[10]-Paracyclophane Core
Enlightened by the Collins group’s pioneering work on
exploitation of fluorophenyl-phenyl interactions for mac-
rocyclizations by metathesis,20 we anticipated that the above-
mentioned problems from direct RCM might be solved by
introducing an electron-deficient benzyl gearing element. On
one hand, steric repulsion between ester substitution at the
ortho position and the phenyl ether, as well as lp-π
interaction between ethereal oxygen and an electron-deficient
aryl ring, can break up the conjugation between ethereal
oxygen and the benzene ring. On the other hand, the flat
benzene structure might be partially distorted by π-π
stacking between electron-rich and electron-deficient aryl
rings in both the ground state and transition state. To access
the desired RCM precursor 17 from compound 13, various
formylation methods, such as the Vilsmeier-Haack reac-
tion21 and DMF/nBuLi,22 were tried, but did not work. In
fact, an important intermediate 14 toward the precursor of
RCM was prepared through titanium-mediated formylation,23
followed by reduction with sodium borohydride to faciliate
column chromatography (Scheme 4).24 However, since the
Scheme 4
.
Second Generation of RCM Strategy to Construct
the [10]-Paracyclophane Core
observed, and paracyclophane 12 could not be detected, even
though titanium(IV) isopropoxide was applied to mediate the
basic nitrogen atom of amides 11a and 11b and supposedly
to assist RCM (Scheme 3).19 We surmised that the abortion
Scheme 3
.
First Generation of the RCM Strategy to Construct
the [10]-Paracyclophane Core
25% yield of this transformation is quite unsatisfactory, we
developed a second synthetic route. Commercially available
Boc-L-tyrosine was treated by paraformaldehyde and borax
to afford compound 15, which was then selectively converted
to methyl ester and allyl phenyl ether in turn. After removal
of this direct RCM method should result from two vital factors.
One is that the lone electron pair on sp2-hybrided ethereal
2506
Org. Lett., Vol. 12, No. 11, 2010

of Boc protection, the free amine was transformed to amide
14 by coupling 4-pentenoic acid. The RCM precursor 17
was thus obtained by converting the hydroxylmethyl group
in 14 to an acid and then esterifying it with 3,5-di(trifluo-
romethyl) benzyl alcohol. While application of Grubbs first
generation catalyst did not result in any conversion, using
20 mol % loading of Grubbs second generation catalyst
smoothly promoted the formation of [10]-paracyclophanes
18a and 18b,25 by refluxing 17 in dichloromethane for 24 h.
It is worth noting that compounds 18a and 18b are a pair of
rotamers since the small cavity of [10]-paracyclophanes
restricts free rotation along the central axis across the benzene
ring. The geometric configuration of the double bond in these
two rotamers was determined to be E-form from the coupling
constants, which is crucial for the following intramolecular
Diels-Alder reaction to install the proper stereocenters in
total synthesis of the hirsutellones.
In summary, a synthetic method to construct the [10]-
paracyclophane skeleton of hirsutellones via RCM was
established successfully. Total synthesis of the hirsutellones
with this strategy is underway in our laboratory.
(18) For recent reviews on RCM reaction, see: (a) McReynolds, M. D.;
Dougherty, J. M.; Hanson, P. R. Chem. ReV. 2004, 104, 2239–2258. (b)
Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592–
4633. (c) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–
1923. (d) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003. (e) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
34, 18–29. (f) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
(19) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871–874.
(20) (a) Collins, S. K.; El-Azizi, Y.; Schmitzer, A. R. J. Org. Chem.
2007, 72, 6397–6408. (b) El-azizi, Y.; Schmitzer, A.; Collins, S. K. Angew.
Chem., Int. Ed. 2006, 45, 968–973.
Acknowledgment. We appreciate the financial support from
NSFC (20702032, 20872098), the Ministry of Education of
China (NCET, IRT0846), and National Basic Research Program
of China (973 Program, 2010CB833200). We also thank
Analytical & Testing Center of Sichuan University for NMR
recording and State Key Laboratory of Biotherapy for HRMS
determination.
(21) Agarwal, A. K.; Johnson, A. P.; Fishwick, W. G. Tetrahedron 2008,
64, 10049–10054.
(22) Yu, X.; Scheller, D.; Rademacher, O.; Wolff, T. J. Org. Chem.
2003, 68, 7386–7399.
Supporting Information Available: Experimental pro-
cedures, characterization data for new compounds, and
selected copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) Liao, X. W.; Liu, W.; Dong, W. F.; Guan, B. H.; Chen, S. Z.; Liu,
Z. Z. Tetrahedron 2009, 65, 5709–5715.
(24) The desired aldehyde was unable to be isolated from the crude
reaction mixture without treatment with NaBH4.
(25) For a hydrogen-bond directing synthesis of chiral [10]-paracyclo-
phane, see: Mori, K.; Ohmori, K.; Suzuki, K. Angew. Chem., Int. Ed. 2009,
48, 5638-5641.
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