Total synthesis of (-)-cylindrocyclophane F [10]

Full text of DOI:10.1021/ja991538b

J. Am. Chem. Soc. 1999, 121, 7423-7424
7423
Scheme 1
Total Synthesis of (-)-Cylindrocyclophane F
Amos B. Smith, III,* Sergey A. Kozmin, and Daniel V. Paone
Department of Chemistry, Monell Chemical Sciences Center,
and Laboratory on the Structure of Matter, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104
ReceiVed May 10, 1999
The cylindrocyclophanes A-F, recently isolated by Moore and
co-workers from Cylindrospermum licheniforme,1 comprise a
unique family of natural products possessing a 22-membered
[7,7]-paracyclophane ring. Although a wide variety of cyclophanes
have been prepared2,3 since their initial synthesis by Cram and
Steinberg in 1951,4 the cylindrocyclophanes represent the first
examples isolated from a natural source. Structural assignments,
including complete relative and absolute stereochemistry, were
based on extensive NMR studies1b in conjunction with CD
spectroscopy and X-ray crystallography.1a In addition to their
novel architecture, the cylindrocyclophanes display in vitro
cytotoxicity against the KB and LoVo tumor cell lines.1a
Captivated both by the structure and the promising biological
profile, we initiated a program directed at their synthesis. Herein,
we disclose the first total synthesis of (-)-cylindrocyclophane F
(1).
Application of two versions of the Kowalski ester chain homolo-
gation9,10 (vide infra) would provide access to siloxy acetylene 5
and iodide 9; the latter, in turn, would be coupled with known
ethoxycyclobutenone 811 to furnish 6.
From the outset we planned to take advantage of the C2
symmetry of the cylindrocyclophane skeleton (Scheme 1).
Disconnection at the C(4-5) and C(17-18) σ linkages revealed
resorcinol 4 as a possible common advanced intermediate for
iodide 2 and tosyl hydrazone 3. For cyclophane assembly we
envisioned a two-step process,5 involving union of 2 and 3 via
reductive alkylation a la Myers,6 followed by a ring-closing
metathesis (RCM).7 Resorcinol 4, possessing the requisite ste-
reogenic centers securely installed, would, in turn, be constructed
from fragments 5 and 6 via a Danheiser benzannulation.8
Our point of departure entailed alkylation of (+)-1012 (>98%
de) with allyl bromide (Scheme 2),13 followed by removal of the
Scheme 2
(1) (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.
(2) For the preparation of related [7, 7]-paracyclophanes, see: (a) Schubert,
W. B.; Sweeney, W. A.; Latourette, H. K. J. Am. Chem. Soc. 1954, 76, 5462.
(b) Staab, H. A.; Matzke, G.; Frieger, C. Chem. Ber. 1987, 120, 89. (c) Mascal,
M.; Kerdelhue, J.-L.; Batsanov, A. S.; Begley, M. J. J. Chem. Soc., Perkin
Trans. 1 1996, 1141.
chiral auxiliary and conversion to ester (-)-714 (72% yield, three
(3) (a) Keehn, P. M., Rosenfeld, S. M., Eds. Cyclophanes; Academic
Press: New York, 1983. (b) Vogtle, F. Cyclophane Chemistry; Wiley: New
York, 1993.
steps). Best results for the initial Kowalski ester homologation9
(4) Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1951, 73, 5691.
(5) To date all attempts to prepare the macrocycle in one step by a variety
of dimerization processes have been unsuccessful. Paone, D. V. Ph.D.
Dissertation, University of Pennsylvania, 1998.
(6) Myers, A. G.; Movassaghi, M. J. Am. Chem. Soc. 1998, 120, 8891.
(7) For recent reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (c)
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037. (d)
Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(8) (a) Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49, 1672. (b)
Danheiser, R. L.; Gee, S. K., Perez, J. J. J. Am. Chem. Soc. 1986, 108, 806.
(c) Danheiser, R. L.; Nishida, A.; Savariar, S.; Trova, M. P. Tetrahedron Lett.
1988, 29, 4917. (d) Danheiser, R. L.; Casebier, D. S.; Huboux, A. H. J. Org.
Chem. 1994, 59, 4844.
(9) (a) Kowalski, C. J.; Haque, M. S.; Fields, K. W. J. Am. Chem. Soc.
1985, 107, 1429. (b) Kowalski, C. J.; Lal, G. S.; Haque, M. S. J. Am. Chem.
Soc. 1986, 108, 7127. (c) Kowalski, C. J.; Lal, G. S. J. Am. Chem. Soc. 1988,
110, 3693. (d) Kowalski, C. J.; Reddy, R. E. J. Org. Chem. 1992, 57, 7194.
(10) For a review of ynolate anions, see: Shido, M. Chem. Soc. ReV. 1998,
27, 367.
(11) Wasserman, H. H.; Piper, J. U.; Dehmlow, E. V. J. Org. Chem. 1973,
38, 1451.
(12) Imide (+)-10 was prepared in 97% yield from (1S,2R)-(+)-norephe-
drine derived oxazolidinone and hexanoyl chloride (n-BuLi, THF, -78 °C).
(13) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(14) The structural assignment given to each new pure compound is in
1
accord with its IR, H, and 13C NMR, and high-resolution mass spectra.
10.1021/ja991538b CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/27/1999

7424 J. Am. Chem. Soc., Vol. 121, No. 32, 1999
Communications to the Editor
were obtained via a modified two-step sequence, in which the
initial dibromoketone was isolated and then subjected to rear-
rangement at -78 °C. This protocol, leading to siloxy acetylene
(-)-514 in 80% yield,15 proved superior to the one-pot process.9a
A second Kowalski homologation was employed for the
preparation of cyclobutenone 6 (Scheme 3). In this case, ester
(-)-1216 was chain extended to (-)-13.14 Conversion to iodide
(+)-9 was then achieved by reduction of (-)-13, protection of
the resulting alcohol (MOMCl, Hu¨nig’s base), hydrogenolysis of
the benzyl ether, and iodination (I2, PPh3, imidazole). Generation
of the organolithium reagent from iodide (+)-9 [t-BuLi (2 equiv),
ether-pentane] and addition to ethoxycyclobutenone 8,11 afforded
cyclobutenone (+)-614 in 73% yield after acidic workup.
Elaboration of the paracyclophane skeleton began with the
Myers reductive coupling6 of hydrazone (+)-3 employing the
organolithium reagent generated from iodide (-)-2 (Scheme 5);
coupled product (+)-1514 was obtained in 73% yield. Removal
of the MOM group (HCl, MeOH-THF, 60 °C), followed by
Dess-Martin oxidation17 and Wittig methylenation, then afforded
(-)-17, the substrate for the ring-closing metathesis. To our
delight, treatment of a dilute solution of (-)-17 (0.004 M, CH2-
Cl2, 20 °C) with the Grubbs ruthenium catalyst7 (6 mol %)
furnished the desired paracyclophane (-)-1814 in 88% yield.
Interestingly, only the E isomer was observed (>95%). That (-)-
18 possessed the [7,7]-paracyclophane skeleton was established
via X-ray crystallographic analysis. The solid-state confomation
of (-)-18 features a highly ordered [7,7]-paracyclophane ring
system with the aromatic rings parallel and separated by ∼7.65
Å.18 Hydrogenation of (-)-18 (Pd/C, EtOAc), followed by BBr3
liberation19 of the phenolic hydroxyl groups, afforded (-)-
cylindrocyclophane F (1), identical in all respects [500 MHz 1H
and 125 MHz 13C NMR, HRMS, optical rotation, and Rf (TLC;
three solvent systems)] to the natural material.20
Scheme 3
Scheme 5
To construct the tetrasubstituted resorcinol 4, we turned to the
Danheiser benzannulation8 (Scheme 4). Heating (-)-5 and (+)-6
at 80 °C for 2 h in toluene and then treating with TBAF afforded
(+)-1414 in 71% yield. Methylation (MeI, K2CO3, 2-butanone)
then furnished (+)-4,14 the common precursor for coupling
partners (-)-2 and (+)-3.
Scheme 4
In summary, the first total synthesis of (-)-cylindrocyclophane
F has been achieved in 20 steps and 8.3% overall yield. Progress
toward the synthesis of other members of this family of natural
cyclophanes will be reported in due course.
To set the stage for paracyclophane assembly, removal of the
MOM group from (+)-4 and iodination (I2, PPh3, imidazole) led
to (-)-2;14 alternatively, oxidative cleavage of the olefin (OsO4,
NMO; NaIO4) afforded the corresponding aldehyde, which was
converted to labile TBS-protected tosyl hydrazone (+)-3
(TsNHNH2, THF; TBSOTf, Et3N, THF)6 in 72% yield for 3 steps.
Acknowledgment support was provided by the National Institutes of
Health (National Institute of General Medical Sciences) through Grant
GM 29028. This article is dedicated to Professor Virgil Boekelheide,
colleague and friend, on the occasion of his 80th birthday.
(15) The integrity of the chiral center in (-)-5 was established rigorously.
Paone, D. V. Ph.D. Dissertation, University of Pennsylvania, 1998.
(16) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57, 5292.
(17) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(18) Carroll, P. J. University of Pennsylvania, unpublished results.
(19) Combes, S.; Finet, J.-P. Synth. Commun. 1997, 27, 3769.
(20) We thank Professor Moore (University of Hawaii) for a generous
sample of authentic (-)-cylindrocyclophane F.
Supporting Information Available: Spectroscopic data for 1-18
and X-ray data for (-)-18 as well as representative experimental
procedures. This material is available free of charge via the Internet at
http://pubs.acs.org.
JA991538B