Assembly of (-)-cylindrocyclophanes A and F via remarkable olefin metathesis dimerizations [3]

Full text of DOI:10.1021/ja000430p

4984
J. Am. Chem. Soc. 2000, 122, 4984-4985
called for disconnection of macrocycle 2 at C(4-5) and C(17-
18); incorporation of the requisite terminal olefins revealed diene
3 (Scheme 1). Assembly of 3 would again rely on Danheiser
Assembly of (-)-Cylindrocyclophanes A and F via
Remarkable Olefin Metathesis Dimerizations
Amos B. Smith, III,* Sergey A. Kozmin,
Christopher M. Adams, and Daniel V. Paone
Scheme 1
Department of Chemistry, Laboratory for Research on the
Structure of Matter, and Monell Chemical Senses Center
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
ReceiVed February 4, 2000
A fascinating array of architecturally complex natural products
arise via dimerization.1 The vast majority of these structures
involve assembly via carbon-heteroatom linkages (e.g., ester,
amide, etc.), giving rise to macrocyclic lactones and lactams often
possessing C2-symmetry. Dimerization via carbon-carbon bond
formation, a relatively rare event, not surprisingly furnishes
particularly attractive synthetic targets. The cylindrocyclophanes
A-F represent such a case.2 These unique naturally occurring
22-membered carbocyclic [7,7]-paracyclophanes,3 isolated by
Moore and co-workers from Cylindrospermum licheniforme,2b are
postulated to arise biosynthetically via dimerization involving
electrophilic aromatic substitution at C(2) of a 5-substituted
resorcinol with an olefin appropriately positioned in the side
chain.2c
annulation,6 in this case involving cyclobutenone 4 and siloxy
acetylene 5, the latter prepared in our first-generation synthesis.5
We envisioned this approach to hold considerable promise for
significant improvement in overall efficiency.
Our point of departure for cylindrocyclophane F (1b) involved
conversion of known alcohol (+)-67 to iodide (+)-78 (Scheme
2). Treatment of this iodide with t-BuLi in ether at -78 °C,
Scheme 2
From the retrosynthetic perspective, exploitation of the above
biomimetic strategy, while appealing, appeared difficult due to
both regio- and stereochemical issues associated with bond
formation at C(7) and C(20). We therefore explored an alternate
tactic involving olefin metathesis4 to close the [7,7]-paracyclo-
phane skeleton.5 This approach led to cylindrocyclophane F (1b),
the first member of the family to succumb to total synthesis.
Encouraged by the high efficiency of the ring-closing metathesis
(RCM) process, we recently explored the feasibility of assembling
the C2-symmetric cyclophane skeletons for both cylindrocyclo-
phanes A and F via olefin metathesis dimerization, a tactic not
previously exploited in natural product total synthesis.4 The plan
followed by addition of the resultant organolithium to ethoxy
cyclobutenone,9 furnished cyclobutenone (+)-88 in 62% yield.
Danheiser annulation6 was then achieved by heating a solution
of (+)-88 and siloxy acetylene (-)-95 for 2 h at 80 °C. Treatment
of the reaction mixture with TBAF, followed after chromatog-
raphy by methylation (MeI, K2CO3, 2-butanone), led to diene (-)-
11.8
For cylindrocyclophane A (1a), Danheiser annulation of stannyl
cyclobutenone 1210 with siloxyacetylene (-)-9,5 followed by
iododestannylation and desilylation, furnished resorcinol (+)-13;8
methylation then gave iodide (-)-14.8 The iodide was next
metalated with t-BuLi and the lithium alkoxide obtained from
(1) For representative syntheses of dimeric natural products, see: (a) Corey,
E. J.; Hua, D. H.; Pan, B.-C.; Seitz, S. P. J. Am. Chem. Soc. 1982, 104, 6818.
(b) White, J. D.; Vedananda, T. R.; Kang, M.; Choudhry, S. C. J. Am. Chem.
Soc. 1986, 108, 8105. (c) Paterson, I.; Yeung, K.-S.; Ward, R. A.; Cumming,
J. G.; Smith, J. D. J. Am. Chem. Soc. 1994, 116, 9391. (d) Nicolaou, K. C.;
Patron, A. P.; Ajito, K.; Richter, P. K.; Khatuya, H.; Bertinato, P.; Miller, R.
A.; Tomaszewski, M. J. Chem. Eur. J. 1996, 2, 847. (e) Paterson, I.; Lombart,
H. G.; Allerton, C. Org. Lett. 1999, 1, 19. (f) Boger, D. L.; Ledeboer, M. W.;
Kume, M. J. Am. Chem. Soc. 1999, 121, 1098.
(2) (a) Moore, B. S.; Chen, J.-L.; Patterson, G. M.; Moore, R. M.; 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.
(c) Bobzin, S. C.; Moore, R. E. Tetrahedron 1993, 49, 7615.
(3) (a) Cyclophanes; Keehn, P. M., Rosenfeld, S. M., Eds.; Academic: New
York, 1983. (b) Vogtle, F. Cyclophane Chemistry; Wiley: New York, 1993.
(c) For pioneering work on paracyclophanes, see: Cram, D. J.; Steinberg,
H.; J. Am. Chem. Soc. 1951, 73, 5691.
(4) For recent reviews of RCM in organic synthesis, see: (a) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413. (b) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (c) Schmalz, H.-G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1833. (d) Grubbs, R. H.; Miller, S. J.; Fu, G.
C. Acc. Chem. Res. 1995, 28, 446.
(5) Smith, A. B., III; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 1999,
121, 7423.
(6) (a) Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49, 1670. (b)
Danheiser, R. L.; Nishida, A.; Savariar, S.; Trova, M. P. Tetrahedron Lett.
1988, 29, 4917.
(7) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737. (b) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc.
1988, 110, 2506.
(8) The structural assignment to each new compound is in accord with its
1
IR, H and 13C NMR, and mass spectroscopic analysis.
(9) Wasserman, H. H.; Piper, J. U.; Dehmlow, E. V. J. Org. Chem. 1973,
38, 1451.
(10) Liebeskind, L. S.; Stone, G. B.; Zhang, S. J. Org. Chem. 1994, 59,
7917.
10.1021/ja000430p CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/06/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 20, 2000 4985
the Myers amide (-)-1511 added to furnish, as anticipated, a
ketone which was reduced with (+)-B-chlorodiisopinocamphey-
lborane (dr ) 19:1)12 to give alcohol (+)-16.8 Protection of the
benzylic hydroxyl (TESOTf, 2,6-lutidine) completed construction
of diene (+)-17 (Scheme 3).8
the metathesis reaction and the low-energy nature of the all-trans
“head-to-tail” dimer.14
Heterogeneous hydrogenation of diene (-)-18 (Scheme 4),
followed by cleavage of the methyl ethers with BBr3, then
Scheme 4
Scheme 3
completed the synthesis of (-)-cylindrocyclophane F (1b), which
1
was identical in all respects [500-MHz H and 125-MHz 13C
NMR, HRMS, optical rotation, and TLC (three solvent systems)]
with an authentic sample.15 As anticipated, the second-generation
synthesis of (-)-cylindrocyclophane F (1b) proved more efficient
(11 steps; 22% overall yield) compared to our first synthesis (20
steps; 8.3% overall yield), which employed a stepwise construc-
tion of the cyclophane skeleton.5
Completion of (-)-cylindrocyclophane A (1a) was next
achieved via desilylation (TBAF, THF) of (+)-19, hydrogenation
(Adams’ catalyst), and cleavage of methyl ethers (PhSH, K2CO3,
NMP, 215 °C) (Scheme 5).16 The synthesis required 16 steps and
With both (-)-11 and (+)-17 in hand, we turned to the required
dimerizations. Treatment of diene (-)-11 with Grubbs catalyst
A13a (15 mol %; Table 1) for 25 h at ambient temperature led to
paracyclophane (-)-188 in 55% yield. Interestingly, only the E,E
isomer was observed. With 20 mol % of catalyst and a longer
reaction time (72 h; entry 2) (-)-18 was produced in 61% yield.
The perhydroimidazolidine catalyst (B), recently introduced by
Grubbs,13b also promoted the dimerization with similar efficiency
at 40 °C for 4 h in benzene. The Schrock catalyst (C)13c proved
most reactive, furnishing (-)-18 in 72% in 2 h at 20 °C. Even
higher efficiency (77% yield, entry 6) was obtained when the
latter conditions were applied to diene (+)-17, required for
cylindrocyclophane A (1a). It is noteworthy that the alternative
“head-to-head” dimerization products were not detected in these
experiments, presumably indicative of the reversible nature of
Scheme 5
proceeded in 8.1% overall yield.17 (-)-Cylindrocyclophane A (1a)
was identical in all respects with the literature spectral data [500-
MHz 1H and 125-MHz 13C NMR, HRMS] and chiroptic
properties.2b,17
Table 1
In summary, dimerization via the ring-closing metathesis
provides a remarkably efficient tactic for assembly of the
cylindrocyclophane [7,7]-paracyclophane skeleton.
Acknowledgment. We thank Professor Grubbs for a generous sample
of ruthenium complex B, Professor Hoye for the exchange of spectral
data, and Professor Kozlowski for useful comments regarding molecular
modeling. Support was provided by the National Cancer Institute through
Grant CA 19033.
Supporting Information Available: Spectroscopic data for 1-19,
as well as representative experimental procedures (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA000430P
(14) (a) A Monte Carlo conformational search (Macro Model 6.0)14b using
the MM2 force field14c indicated that the lowest energy conformation of the
[7,7]-cyclophane system was 3.3 kcal mol-1 lower than the minimum energy
conformation found for [6,8]-cyclophane corresponding to the alternative
“head-to-head” dimerization product. (b) Mohamadi, F.; Richards, N. G. J.;
Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson,
T.; Still, W. C. J. Comput. Chem. 1990, 11, 440. (c) Allinger, N. L. J. Am.
Chem. Soc. 1977, 99, 8127.
(15) We thank Professor Moore (University of Hawaii) for a generous
sample of authentic (-)-cylindrocyclophane F.
(16) Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1997, 38, 8749.
(17) For an alternative synthetic strategy leading to the synthesis of
cylindrocyclophane A (1a), see the preceding communication in this issue:
Hoye, T. R.; Humpal, P. E.; Moon, B. J. Am. Chem. Soc. 2000, 122, 4982-
4983.
(11) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(12) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am. Chem.
Soc. 1988, 110, 1539.
(13) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953. (c) Schrock, R. R.; Murdzek, J. S.;
Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem. Soc. 1990,
112, 3875.