Total synthesis of ( - )-cylindrocyclophanes A and F exploiting the reversible nature of the olefin cross metathesis reaction

Article abstract of DOI:10.1021/ja0106164

Efficient total syntheses of the C₂-symmetric ( - )-cylindrocyclophanes A and F (1a and 1f) have been achieved. The initial strategy featured the use of a common advanced intermediate to assemble in stepwise fashion the required macrocycle of 1f, exploiting in turn a Myers reductive coupling followed by ring-closing metathesis. In a second-generation strategy, a remarkable cross olefin metathesis dimerization cascade was discovered and exploited to assemble the requisite [7,7]-paracyclophane macrocycles of both 1a and 1f from dienyl monomers. The successful syntheses also featured the effective use of the Danheiser annulation to construct substrates for both the Myers reductive coupling and the metathesis dimerizations strategies. Finally, the Kowalski two-step chain homologation of esters to siloxyalkynes proved superior over the original one-step protocol.

Full text of DOI:10.1021/ja0106164

J. Am. Chem. Soc. 2001, 123, 5925-5937
5925
Total Synthesis of (-)-Cylindrocyclophanes A and F Exploiting the
Reversible Nature of the Olefin Cross Metathesis Reaction
Amos B. Smith, III,* Christopher M. Adams, Sergey A. Kozmin, and Daniel V. Paone
Contribution from the Department of Chemistry, Monell Chemical Senses Center, and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
ReceiVed March 7, 2001
Abstract: Efficient total syntheses of the C2-symmetric (-)-cylindrocyclophanes A and F (1a and 1f) have
been achieved. The initial strategy featured the use of a common advanced intermediate to assemble in stepwise
fashion the required macrocycle of 1f, exploiting in turn a Myers reductive coupling followed by ring-closing
metathesis. In a second-generation strategy, a remarkable cross olefin metathesis dimerization cascade was
discovered and exploited to assemble the requisite [7,7]-paracyclophane macrocycles of both 1a and 1f from
dienyl monomers. The successful syntheses also featured the effective use of the Danheiser annulation to
construct substrates for both the Myers reductive coupling and the metathesis dimerizations strategies. Finally,
the Kowalski two-step chain homologation of esters to siloxyalkynes proved superior over the original one-
step protocol.
A wide variety of bridged aromatic compounds, known as
cyclophanes,1,2 have become available as a result of extensive
research over the past 50 years. The unique physical and
chemical properties of cyclophanes, a direct result of their
unusual architecture, vary considerably on the basis of size and
constitution.3 Notably, larger cyclophanes possess intramolecular
cavities suitable for the formation of inclusion complexes,
leading to applications in host-guest chemistry3a,c,4 and mimicry
of natural enzymes.3a,c,5
Despite the structural diversity of synthetic cyclophanes,
naturally occurring paracyclophanes were not reported until
1990, when Moore and co-workers disclosed the isolation of
cylindrocyclophane A (1a) and nostocyclophane D (2).6a Five
additional members of the cylindrocyclophane family (1b-f)
were then reported in 1992.6b Interestingly, these 22-member
[7,7]-paracyclophanes were found to be the major cytotoxic
components in three different strains of the terrestrial blue-green
algae Cylindrospermum lichenforme,6a displaying in vitro cy-
totoxicity against the KB and LoVo tumor cell lines (IC50 2-10
µg/mL).6a,b
Initially, detailed NMR analysis, in conjunction with high-
resolution mass spectrometry, permitted structural assignments,
including the relative stereochemistry of cylindrocyclophane A
(1a).6a An X-ray structure of nostocyclophane D (2), exploiting
the anomalous dispersion of chlorine, revealed the absolute
stereochemistry of (-)-2 and, by implication, the same absolute
stereochemistry for (-)-1a.6a The latter was confirmed by the
Mosher ester NMR protocol.6b,7,8
Biosynthetically, the [7,7]-paracyclophane skeleton of the
cylindrocyclophanes was envisioned to arise via dimerization
of two identical resorcinol fragments, presumably involving
electrophilic aromatic substitution at C(2), with an olefin appro-
priately positioned in the side chain (Scheme 1).6 Feeding
2
experiments with H-, 13C-, and 18O-labeled sodium acetate in
Scheme 1
(5) (a) Benson, D. R.; Valentekovich, R.; Diederich, F. Angew. Chem.,
Int. Ed. Engl. 1990, 2, 191. (b) Habicher, T.; Diederich, F.; Gramlich, V.
HelV. Chim. Acta 1999, 82, 1066. (c) Mattei, P.; Diederich, F. HelV. Chim.
Acta 1997, 80, 1555. (d) Marti, T.; Peterson, B. R.; Fu¨rer, A.; Mordasini-
Denti, T.; Zarske, J.; Jaun, B.; Diederich, F. HelV. Chim. Acta 1998, 81,
109.
(6) (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.
(7) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
(8) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(1) Smith, B. H. Bridged Aromatic Compounds; Academic Press: New
York, 1964.
(2) Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1951, 73, 5691.
(3) (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 Chem-
istry: Cambridge, 1991. (d) Weber, E. Top. Curr. Chem. 1994, 172, 1.
(4) (a) Cerrini, S.; Giglio, E.; Mazza, F.; Pavel, N. V. Acta Crystallogr.,
Sect. B 1979, B35, 2605. (b) Hyatt, J. A.; Duesler, E. N.; Curtin, D. Y.;
Paul, I. C. J. Org. Chem. 1980, 45, 5074. (c) Weber, E.; Vo¨gtle, F. Top.
Curr. Chem. 1981, 98, 1. (d) Gabard, J.; Collet, A. J. Chem. Soc., Chem.
Commun. 1981, 1137. (e) Vo¨gtle, F.; Mu¨ller, W. M. Angew. Chem., Int.
Ed. Engl. 1982, 21, 147.
10.1021/ja0106164 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/05/2001

5926 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Smith et al.
C. lichenforme cultures suggested that the dimerization precur-
sors arise via successive polyketide synthase-mediated Claisen
condensations, followed by appropriate modifications. One
acetyl-CoA starter unit and eight malonyl-CoA fragments would
be required.
Synthetic Analysis. Exploitation of the proposed biosynthetic
pathway, 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 disconnections at C(4-5) and C(17-18) (Scheme 2).9
the total synthesis of (-)-cylindrocyclophanes A and F (1a and
1f).12 During the course of this synthetic venture, we discovered
a remarkable cross olefin metathesis dimerization cascade (vide
infra). An alternative elegant approach to (-)-cylindrocyclo-
phane A (1a) was also recently reported by Hoye and co-
workers.13
Synthesis of Siloxyalkyne 12: Modification of the Kow-
alski Protocol. At the outset, we required a reliable preparation
of (-)-12 (Scheme 4), the requisite siloxyalkyne for the
Scheme 4
Scheme 2
The approach would entail dimerization of two identical
fragments (3), involving initial bimolecular coupling between
the appropriate X and Y functional groups, followed by
intramolecular cyclization. By employing the proper dilution
conditions, dimerization should comprise the dominant reaction
pathway. Such an approach would take full advantage of the
C2 symmetry offered by the cylindrocyclophane skeleton. In
addition, the requisite stereogenic centers at C(1), C(2), and C(7)
could be securely installed in the acyclic precursor 3 prior to
construction of the macrocycle. Importantly, this strategy would
permit significant flexibility in fragment coupling and thereby
minimize end game manipulations. We further envisioned that
the common resorcinol 3 could arise via Danheiser annulation10
of cyclobutenone 4 with siloxyalkyne 6 (Scheme 3). This
Danheiser annulation. The method developed by Kowalski and
co-workers,11 requiring ester (-)-11, appeared particularly
attractive. Toward this end, Evans asymmetric alkylation14 of
known imide (+)-815 with allyl bromide proceeded in 77% yield
(de > 98%).16 Removal of the chiral auxiliary with basic lithium
peroxide, followed by alkylation with ethyl iodide and K2CO3,
furnished ester (-)-11 (93%, two steps). Initial studies exploiting
the original one-pot Kowalski homologation11 of ester (-)-11
revealed the process to be highly dependent on scale, the quality
of the reagents, and temperature control. The yields of (-)-12
varied substantially, ranging from 20 to 60%. The lability of
the siloxyalkyne also proved challenging during chromato-
graphic purification.
Scheme 3
A two-step modification of the Kowalski protocol,11 amenable
to scale-up, was therefore explored. The first step entailed
conversion of ester (-)-11 to dibromoketone (+)-13, employing
CH2Br2 and LiTMP; yields ranged from 72 to 80% (Scheme
5). Subsequent treatment of the lithium enolate of (+)-13 with
n-BuLi at -78 °C resulted in facile rearrangement; silylation
of the resulting ynolate with TIPSOTf then furnished the
siloxyalkyne (-)-12 in 92-100% yield, after bulb-to-bulb
distillation.
strategic transform would permit the efficient, stereocontrolled
installation of the highly congested C(7) stereogenic center.
Cyclobutenone 4 in turn would readily derive from ethoxy enone
5, while siloxyalkyne 6 would be constructed via a Kowalski
chain homologation11 starting with ester 7 (vide infra). Herein
we describe the evolution of synthetic studies that resulted in a
highly efficient unified strategy for the construction of the
cylindrocyclophane family of natural products, illustrated by
Danheiser Annulation: Assembly of Resorcinol (+)-20.
With a reliable protocol established for the preparation of
(12) For preliminary accounts of this work, see: (a) Smith, A. B., III;
Kozmin, S. A.; Paone, D. V. J. Am. Soc. Chem. 1999, 121, 7423. (b) Smith,
A. B., III; Kozmin, S. A.; Adams, C. M.; Paone, D. V. J. Am. Chem. Soc.
2000, 122, 4984. (c) For the preparation of related unnatrural [7,7]-
paracyclophanes, see: (i) Schubert, W. B.; Sweeney, W. A.; Latourette, H.
K. J. Am. Chem. Soc. 1954, 76, 6462. (ii) Staab, H. A.; Matzke, G.; Frieger,
C. Chem. Ber. 1987, 120, 89. (iii) Mascal, M.; Kerdelhue, J.-L.; Batsanov,
A. S.; Begley, M. J. J. Chem. Soc., Perkin Trans. 1 1996, 1141.
(13) Hoye, T. R.; Humpal, P. E.; Moon, B. J. Am. Soc. Chem. 2000,
122, 4982.
(9) Paone, D. V., Ph.D. Dissertation, University of Pennsylvania, 1998.
(10) (a) Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49, 1670. (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.
(14) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(11) (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.
(15) Imide (+)-10 was prepared in 97% yield from the (1S,2R)-(+)-
norephedrine-derived oxazolidinone and hexanoyl chloride (n-BuLi, THF,
-78 °C).
(16) The structural assignment to each new pure compound is in accord
1
with its IR, H and 13C NMR, and high-resolution mass spectra.

Total Synthesis of (-)-Cylindrocyclophanes A and F
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5927
Scheme 5
asymmetric crotylboration20 (vide infra). Execution of this plan
began with ozonolysis of alkene (+)-20 (Scheme 8); reduction
Scheme 8
siloxyalkyne (-)-12, we turned to the Danheiser annulation.10
In the event, siloxyalkyne (-)-12 underwent facile addition to
known stannyl cyclobutenone 18.17 Silylation, followed by
iododestannylation, afforded aryl iodide (+)-20 in 69% yield
for the three steps (Scheme 6). Notably, this reaction sequence
Scheme 6
of the derived aldehyde furnished alcohol (+)-23, which was
converted to thioester (+)-24 via a modified Mitsunobu
protocol21 (57% yield for three steps). Stille palladium-catalyzed
carbonylation19 followed by Brown crotylboration20 of the
resulting aldehyde and hydroxyl protection then yielded olefin
(+)-25 with excellent diastereoselectivity (de > 95%). Dimer-
ization substrate (+)-22 was then available via hydroboration
and conversion of the primary hydroxyl to the corresponding
iodide. Unfortunately, despite extensive efforts toward dimer-
ization of (+)-22, neither dimer 21 nor monocoupled products
were observed.
represents the first use of a stannyl-substituted cyclobutenone
in the Danheiser annulation to install an iodide on a resorcinol,
amenable for further elaboration via either metal-halogen
exchange or a Pd-mediated process.
Macrocyclization Strategies: The Thiolate Dimerization
Tactic. Our initial approach to the cylindrocyclophane macro-
cycle entailed dimerization via thiolate alkylations of two
identical acyclic precursors (22) (Scheme 7). Extrusion of sulfur
The Sulfone Alkylation Tactic. We next turned to the
prospect of a phenyl sulfone-iodide dimerization strategy.22,23
(Scheme 9). Disconnections of (-)-1 at C(4-5) and C(17-18)
Scheme 7
Scheme 9
(or sulfur dioxide)18 with concomitant olefin formation, followed
by hydrogenation, was then envisioned to provide the requisite
macrocycle. Dimerization precursor 22 in turn would arise from
aryl iodide 20 via Stille carbonylation19 followed by Brown
would furnish sulfone 27, which was envisioned to arise from
aryl iodide 28. Toward this end, ozonolysis of (-)-11, followed
by reduction and conversion of the resulting alcohol to sulfide
(17) Liebeskind, L. S.; Stone, G. B.; Zhang, S. J. Org. Chem. 1994, 59,
7917.
(18) This strategy is commonly employed in the construction of unnatural
cyclophanes: see refs 3a,b.
(19) (a) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108,
452. (b) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 7175.
(20) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(21) (a) Loibnen, H.; Zbiral, E. HelV. Chim. Acta 1976, 59, 2100. (b)
Mitsunobu, O. Synthesis 1981, 1.

5928 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Smith et al.
Scheme 10
Design of a Low-Risk, Stepwise Strategy. Although the
Danheiser annulation10 permitted rapid and efficient access to
a variety of fully functionalized resorcinol fragments, our
inability to effect dimerization prompted a revision of the initial
strategy. The goal was to devise a low-risk approach to the less
substituted cylindrocyclophane F (1f), which in turn would
permit exploration of the key macrocyclization process (Scheme
12). Accordingly, the plan was to assemble the cyclophane via
Scheme 12
(+)-29, proceeded in 80% yield for three steps (Scheme 10).
Homologation11 again proceeded to give siloxyalkyne (+)-30.24
The latter was subjected to annulation10 with stannyl cy-
clobutenone 18,17 followed directly by silylation to furnish aryl
stannane (+)-31. Iododestannylation and palladium-catalyzed
carbonylation19 completed the four-step sequence to aldehyde
(+)-32; the overall yield was 71%. Oxidation of sulfide (+)-
32 provided sulfone (+)-33 (Scheme 11). Brown crotylbora-
a two-step process involving union of iodide 37 with hydrazone
38, exploiting the reductive alkylation protocol developed by
Myers and Movassaghi.25 Ring-closing metathesis (RCM) would
then furnish the macrocyclic skeleton.26 The synthesis of
resorcinol 36, a common precursor for 37 and 38, would again
employ the Danheiser annulation.10
Scheme 11
Resorcinol 36: The Common Precursor. We began with
the preparation of ester (-)-40 (Scheme 13). Again, the two-
Scheme 13
step homolgation,11 in this case with known ester (-)-39,27
proved superior to the original one-pot method. Reduction of
(-)-40 and protection of the primary hydroxyl as a MOM ether
were followed by hydrogenolysis and conversion of the revealed
hydroxyl to iodide (+)-41. Generation of the corresponding
organolithium (t-BuLi, 2 equiv) and addition to ethoxy cy-
clobutenone 4228 furnished cyclobutenone (+)-43 in 73% yield.
With both cyclobutenone (+)-43 and siloxyalkyne (-)-12 in
hand, annulation, followed by treatment with TBAF,10 proceeded
tion20 (dr 11:1) and protection of the resulting hydroxyl furnished
(+)-34 in 71% yield for the two steps. Hydroboration, tosylation,
and SN2 displacement with NaI completed construction of
iodosulfone (-)-27, the prospective dimerization substrate.
Unfortunately, despite our best efforts, macrocyclization could
not be achieved.
(24) The integrity of the stereogenic center in (-)-5 was established via
derivatization and subsequent NMR analysis. Paone, D. V., Ph.D. Disserta-
tion, University of Pennsylvania, 1998.
(25) Myers, A. G.; Movassaghi, M. J. Am. Chem. Soc. 1998, 120, 8891.
(26) For recent reviews on the use of the RCM reaction in organic
synthesis, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (c) Wright,
D. L. Curr. Org. Chem. 1999, 3, 211. (d) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012.
(22) (a) Takayanagi, H.; Uyehara, T.; Kato, T. J. Chem. Soc., Chem.
Commun. 1978, 359. (b) For an in-depth review of sulfone chemistry, see:
Simpkins, N. S. In Sulphones in Organic Synthesis; Baldwin, J. E., Magnus,
P. D., Eds.; Tetrahedron Organic Chemistry Series 10; Pergamon: New
York, 1993.
(27) Widmer, U. Synthesis 1987, 6, 568.
(23) Boekman, R. K.; Yoon, S. K.; Heckendorn, D. K. J. Am. Chem.
Soc. 1991, 113, 9682.
(28) Wasserman, H. H.; Piper, J. U.; Dehmlow, E. V. J. Org. Chem.
1973, 38, 1451.

Total Synthesis of (-)-Cylindrocyclophanes A and F
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5929
Scheme 14
Scheme 16
smoothly to yield the tetrasubstituted resorcinol in 71% for the
two steps (Scheme 14). Methylation then furnished (+)-36, the
common precursor.
Stepwise Construction of the Paracyclophane Skeleton.
To set the stage for macrocyclization, (+)-36 was converted to
iodide (-)-37 and hydrazone (+)-38, the requisite coupling
partners (Scheme 15). For (-)-37, the sequence entailed removal
Scheme 15
Total Synthesis of Cylindrocyclophane F (1f). Hydrogena-
tion of macrocycle (-)-47 followed by BBr3 liberation32 of the
phenolic hydroxyl groups afforded (-)-cylindrocyclophane F
(1f), identical in all respects with a sample of the natural material
(Scheme 17).33 Our first-generation synthesis of (-)-1f pro-
ceeded in 20 steps with an 8.3% overall yield.
of the MOM moiety and transformation of the resulting primary
hydroxyl to the iodide (91%, two steps). Alternatively, dihy-
droxylation of the olefin, followed by oxidative cleavage,
furnished the requisite aldehyde, which was converted to the
hydrazone followed by silylation25 (72%, three steps). Coupling
of (-)-37 and (+)-38 employing the Myers protocol25 entailed
generation of the organolithium reagent from iodide (-)-27 and
addition of the hydrazone (Scheme 16); the coupled product
(+)-44 was isolated in 73% yield. Quantitative removal of the
MOM group under acidic conditions followed by Dess-Martin
oxidation29 and Wittig30 methylenation (88%, three steps) then
provided diene (-)-46, the required ring-closing metathesis
precursor. Pleasingly, treatment of a dilute solution of (-)-46
(0.004 M, CH2Cl2, 20 °C) with the Grubbs ruthenium catalyst31a
(6 mol %) furnished the desired paracyclophane (-)-47 in
88% yield as a white crystalline solid. NMR analysis re-
vealed exclusive formation of the E-olefin. Subsequently,
the structure of macrocycle (-)-47 was secured via single-
crystal X-ray analysis. The solid-state conformation of (-)-47
features a highly ordered [7,7]-paracyclophane ring system,
with the parallel, aromatic rings separated by ca. 7.65 Å and
the hydrocarbon linkers in their fully extended conforma-
tion.
Scheme 17
Discovery of a Remarkable Cross Olefin Metathesis
Dimerization. Encouraged by both the high efficiency and
stereoselectivity of the ring-closing metathesis, we revisited our
original strategy for assembly of the cyclophane skeleton:
dimerization of an advanced C20 intermediate, now by cross
olefin metathesis. To our knowledge, this tactic had not been
exploited previously in natural product total synthesis.34 The
strategy called for simultaneous disconnection of macrocycle
48 at C(4-5) and C(17-18); incorporation of the requisite
(29) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(30) (a) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44. (b)
Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
(31) (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’Reagan, M. J. Am. Chem. Soc.
1990, 112, 3875.
(32) Combes, S.; Finet, J.-P. Synth. Commun. 1997, 27, 3769.
(33) We thank Professor Moore (University of Hawaii) for a generous
sample of authentic (-)-cylindrocyclophane F (1f).

5930 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Smith et al.
Table 1. Cross Metathesis Dimerization Studies
Scheme 18
catalyst
(mol %)
reaction time,
temperature
product yielda
(%)
entry
solvent
1
2
3
4
5
A (15)
A (20)
B (15)
B (15)
C (30)
CH2CI2
CH2CI2
CH2CI2
C6H6
25 h, 20 °C
75 h, 20 °C
4 h, 40 °C
27 h, 40 °C
2 h, 20 °C
55
61
48
58
72
C6H6
a Refers to isolated yield after chromatographic purification.
terminal olefins revealed diene 49 (Scheme 18). Assembly of
49 would again rely on the Danheiser annulation,10 in this case
involving cyclobutenone 50 and siloxyalkyne 12. Importantly,
this strategy held the promise of significant improvement in
overall efficiency. To begin, known alcohol (+)-5135 (Scheme
19) was converted to iodide (+)-52 via a Mitsunobu21-like
Scheme 19
Schrock catalyst (C),31c however, proved most effective,
furnishing (-)-48 in 72% in 2 h at 20 °C. It is noteworthy that
the alternative “head-to-head” dimerization products were not
detected in these experiments. We will return later to a
discussion of this remarkable dimerization reaction. Continuing
with the synthesis, heterogeneous hydrogenation of diene (-)-
48 (Scheme 20), followed by cleavage of the methyl ether
Scheme 20
process36 (82% yield). Metal-halogen exchange with t-BuLi
in ether at -78 °C, followed by addition to the ethoxy
cyclobutenone, furnished cyclobutenone (+)-50 in 62%. An-
nulation10 with siloxyalkyne (-)-12, desilylation with TBAF,
and methylation then led to the fully functionalized dimerization
substrate (-)-49 in 63% yield for the three steps. To our delight,
treatment of diene (-)-49 with Grubbs catalyst A31a (15 mol
%; Table 1) for 25 h at ambient temperature provided paracy-
clophane (-)-48 in 55% yield. Moreover, only the E,E-isomer
was observed. With 20 mol % of catalyst and a longer reaction
time (72 h), (-)-48 was produced in 61% yield. The perhy-
droimidazolidine catalyst (B), recently introduced by Grubbs
and co-workers,31b also promoted the dimerization with similar
efficiency when performed at 40 °C for 4 h in benzene. The
linkages with BBr3, then completed the synthesis of (-)-
cylindrocyclophane F (1f), which was identical in all respects
with an authentic sample33 as well as with the sample from our
first-generation synthesis. As anticipated, the second-generation
synthesis of (-)-cylindrocyclophane F (1f) proved more ef-
ficient, requiring only 11 steps with a 22% overall yield,
compared to our first synthesis (20 steps, 8.3% overall yield).
Return to (-)-Cylindrocyclophane A (1a). With a success-
ful second-generation synthesis of (-)-1f, we returned to the
more elaborate (-)-cylindrocyclophane A (1a), with the ex-
pectation that the metathesis dimerization strategy could be
extended to this target, thereby providing a unified approach to
this family of natural products. Accordingly, disconnection of
macrocycle 54 at C(4-5) and C(17-18) revealed alcohol 55,
which could be constructed from aryl iodide 56 (Scheme 21).
(34) 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) Schregenberger, C.; Seebach, D. Tetrahedron Lett. 1984,
25, 5881. (c) White, J. D.; Vedananda, T. R.; Kang, M.; Choudrhy, S. C.
J. Am. Chem. Soc. 1986, 108, 8105. (d) Paterson, I.; Yeung, K.-S.; Ward,
R. A.; Cumming, J. G.; Smith, J. D. J. Am. Chem. Soc. 1994, 116, 9391.
(e) 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. (f) Paterson, I.; Lombart, H. G.; Allerton, C. Org. Lett. 1999, 1, 19.
(g) Boger, D. L.; Ledeboere, M. W.; Kume, M. J. Am. Chem. Soc. 1999,
121, 1098. (h) Degnan, A. P.; Meyers, A. I. J. Am. Chem. Soc. 1999, 121,
2762.
(35) (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.
(36) Garegg, P. J.; Samuelsson B. J. Chem. Soc., Chem. Commun. 1979,
978.

Total Synthesis of (-)-Cylindrocyclophanes A and F
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5931
Scheme 21
duction at high concentration after an extended reaction time
(84 h) provided the desired alcohol (+)-55 in 81% yield with
excellent diastereoselectivity (dr 19:1). Mosher ester analysis,7
employing the Kakisawa test,8 confirmed the absolute config-
uration at C(1). Silylation then led to the fully elaborated
dimerization substrate (+)-60. Since the Schrock catalyst (C)31c
(see Table 1) produced the best results in the dimerization of
(-)-49, we employed this catalyst. As anticipated, the desired
[7,7]-paracyclophane (+)-54 (Scheme 23) was obtained as the
Scheme 23
Toward this end, annulation10 of stannyl cyclobutenone 1817
with siloxyalkyne (-)-12 gave the corresponding aryl stannane,
which upon iododestannylation and desilylation furnished
resorcinol (+)-56 (Scheme 22); methylation led to iodide (-)-
Scheme 22
major product (77% yield). Again only the E,E-olefin isomer40
was observed. Desilylation with TBAF, followed by hydrogena-
tion (Adams’ catalyst), provided (-)-61. All that remained to
complete the construction of (-)-cylindrocyclophane A (1a) was
removal of the four phenolic methyl groups. Attempted depro-
tection of (-)-61 with BBr3 proved incompatible with the
benzylic hydroxyl groups, resulting in material decomposition.
Nucleophilic displacement appeared a more promising alterna-
tive. Indeed, treatment with PhSH41 in the presence of K2CO3
in a sealed tube at 215 °C afforded (-)-cylindrocyclophane A
(1a), identical in all respects with the spectral data and chiroptic
properties reported for the natural material.6b In summary, the
synthesis of (-)-cylindrocyclophane A (1a) required 16 steps
and proceeded in 8.1% overall yield.
Dimerization via Cross Olefin Metathesis.42 The unex-
pected efficiency and selectivity in the dimerization reactions
suggested that the [7,7]-paracyclophane skeleton is the ther-
modynamically more favored isomer. That is, a cascade of
reversible olefin metatheses drives the reaction toward formation
of the energetically most favorable isomer.43 This idea was
supported by recent work from the Grubbs,44 Hoveyda,45 and
Sanders46 laboratories implicating the reversible nature of the
olefin metathesis process. To explore this possibility from the
theoretical perspective, we carried out a series of Monte Carlo
conformational searches47 utilizing the MM2 force field48 to
determine the relative energies of the seven possible cyclic
dimers of (-)-49, including those having either seven methyl-
57. Installation of the side chain began with the formation of
the organolithium reagent derived from iodide (-)-57 (t-BuLi,
2 equiv); addition to the lithium alkoxide obtained from the
Myers amide (-)-5837 furnished ketone (+)-59.38 This tactic
represents a significant improvement in efficiency compared
to our previous approach for installation of the side chain, which
relied on carbonylation and crotylboration (Schemes 8 and 11).
We next explored the reduction of ketone (+)-59. To probe the
inherent substrate selectivity, we initially examined NaBH4 and
K-selectride; both reagents effected reduction without significant
stereoselectivity. To surmount the lack of inherent diastereofacial
bias, we turned to reduction with (+)-B-chlorodiisopinocam-
pheylborane [(+)-DIPCl], a reagent-controlled process.39 Re-
(40) The olefin geometry of desilylated (+)-54 was elucidated by NOESY
experiments.
(41) Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1997, 38, 8749.
(42) For an initial report, see: Smith, A. B., III; Adams, C. M.; Kozmin,
S. A. J. Am. Chem. Soc. 2001, 123, 990.
(37) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(38) We anticipated that (+)-59 would be a suitable dimerization
substrate; the resulting diketone could then be reduced stereoselectively
after formation of the macrocycle. However, all attempts at dimerization
of (+)-59 using the various conditions employed to dimerize (-)-41 (Table
1) resulted in polymeric products.
(43) For related work, see: Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.
Org. Lett. 2001, 3, 449.
(44) (a) Marsella, N. J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1101. (b) Lee, C. W.; Grubbs, R. H. Org. Lett.
2000, 2, 2145.
(45) Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.;
Hofilena, G. E.; Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302.
(46) Hamilton, D. G.; Feeder, N.; Teat, S. J.; Sanders, K. M. New J.
Chem. 1998, 22, 1019.
(39) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am.
Chem. Soc. 1988, 110, 1539.

5932 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Smith et al.
Scheme 24
Scheme 25
enes between the aromatic rings (48, 62, 63) or eight and six
(64-67) (Scheme 24). The calculations indicated that 48,
possessing the [7,7]-E,E-macrocyclic skeleton, is the lowest
energy isomer by ca. 2.6-4.7 kcal/mol relative to the other
possible dimers (Figure 1).49 To obtain experimental evidence
(-)-72 via acidic hydrolysis, Mitsunobu reaction21 with 1-phen-
yl-1H-tetrazole-S-thiol, and hydrogen peroxide oxidation pro-
moted by ammonium heptamolybdate tetrahydrate51 (83% yield,
three steps). Deprotonation of (-)-72 with KHMDS followed
by addition of aldehyde (+)-70 furnished (-)-69 in 74% yield
(E:Z > 15:1).
Scheme 26
Figure 1. Energy values for the lowest energy conformation of the
seven possible geometrical/constitutional isomers (see Scheme 25).
for the predicted reversible olefin metatheses cascade, we
prepared trienes 68 and 69 (Schemes 25 and 26), both pre-
disposed to form the [8,6]-macrocycle via RCM. The conversion
of 68 and 69 to the [7,7]-macrocycle (-)-48, instead of the
analogous RCM products, would provide clear evidence for the
proposed cascade. Wittig30 and Kocienski-modified Julia50
olefinations were envisioned to provide ready access to the
requisite Z- and E-trienes (-)-68 and (-)-69. The synthesis of
(-)-68 began with the previously prepared MOM ether (+)-
36. Acidic hydrolysis followed by Dess-Martin oxidation29
afforded the requisite aldehyde (+)-70. Similarly, treatment of
the previously prepared iodide (-)-37 (Scheme 15) with PPh3
in acetonitrile at reflux provided Wittig salt (-)-71 (94% yield).
With the coupling partners in hand, Wittig olefination of (-)-
71 (Scheme 25) with aldehyde (+)-70 furnished the Z-triene
(-)-68 (88% yield, Z:E > 15:1). Preparation of the E-isomer
(-)-69 (Scheme 26) began with conversion of (+)-36 to sulfone
In the event, despite the predisposition of the substrates to
form the [8,6]-cyclophane, trienes (-)-68 and (-)-69 afforded
only the [7,7]-E,E-paracyclophane (-)-48 (Scheme 27) in yields
ranging from 66 to 70% for the Grubbs catalyst (B) and from
75 to 81% for the more reactive Schrock catalyst (C). Presum-
ably, both substrates undergo a cascade of olefin metathesis
reactions which eventually leads, via a self-editing process, to
the [7,7]-E,E-paracyclophane skeleton.
Summary. We have devised and executed a highly efficient,
unified strategy to the cylindrocyclophane family of natural
products. The requisite resorcinol fragments were readily
constructed utilizing a combination of the Kowalski chain
homologation and Danheiser annulation. Assembly of the
(47) 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.
(48) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127.
(49) To simplify calculations, the butyl chains in isomers 48 and 62-
67 were replaced with methyl groups.
(50) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
(51) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140.

Total Synthesis of (-)-Cylindrocyclophanes A and F
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5933
was cooled to 0 °C and treated with n-BuLi (2.5 M in hexanes; 6.72
mL, 16.8 mmol), and this yellow LiTMP solution was immediately
added dropwise via an addition funnel to the ester solution over a 25
min period. After 20 min, the reaction was quenched by slow addition
to a 1.2 M aqueous solution of HCl (50 mL), extracted with hexanes
(2 × 50 mL), washed with water (30 mL), dried over MgSO4, filtered,
and concentrated. The product was purified by flash chromatography
on silica gel (hexanes/Et2O, 50:1; 20:1) to afford 1.76 g (80% yield)
of the desired dibromoketone as a light yellow oil: [R]20D +22.3 (c )
3.00, CHCl3); IR (CHCl3) 3080 (w), 2960 (s), 2930 (m), 2940 (s), 2860
Scheme 27
(m), 1735 (s), 1640 (w), 1470 (w), 1440 (w), 1150 (w), 920 (w) cm-1
;
1H NMR (500 MHz, CDCl3) δ 5.88 (s, 1 H), 5.74 (dddd, J ) 17.7,
14.5, 7.3, 7.3 Hz, 1 H), 5.08 (m, 2 H), 3.10 (dddd, J ) 7.5, 7.5, 6.0,
6.0 Hz, 1 H), 2.41 (ddd, J ) 14.7, 7.3, 7.3 Hz, 1 H), 2.29 (ddd, J )
12.8, 6.1, 6.1 Hz, 1 H), 1.73 (m, 1 H), 1.53 (m, 1 H), 1.30 (m, 4 H),
0.89 (t, J ) 7.0 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 198.1, 134.6,
117.8, 46.9, 43.4, 37.2, 31.9, 29.3, 22.6, 13.8.
Siloxyalkyne (-)-12. A solution of dibromoketone (1.50 g, 4.78
mmol) in THF (27 mL) was cooled to -78 °C. In a separate flask, a
solution of hexamethyldisilazane (HMDS) (1.21 mL, 5.70 mmol) in
THF (27 mL) was cooled to 0 °C and treated with n-BuLi (2.5 M in
hexanes; 2.0 mL, 5.0 mmol), and this colorless LHMDS solution was
immediately added dropwise via addition funnel to the dibromoketone
solution over a 25 min period. The reaction mixture was stirred for 20
min at -78 °C and treated with n-BuLi (2.5 M in hexanes; 4.2 mL,
10.5 mmol) via syringe. After 30 min, freshly distilled TIPSOTf (1.39
mL, 5.18 mmol) was added. The reaction mixture was allowed to warm
to 0 °C, cooled to -78 °C, quenched with saturated aqueous NaHCO3
(50 mL), extracted with hexanes (2 × 50 mL), dried over MgSO4,
filtered, and concentrated. The product was purified by bulb-to-bulb
distillation (0.1 mmHg, oven temperature 80-120 °C) to afford 1.48
macrocycle was performed by olefin metathesis. Having secured
initial access to the [7,7]-paracyclophane skeleton by ring-
closing metathesis, we discovered a remarkably efficient cross
metathesis dimerization process which culminated in the ef-
ficient total syntheses of both (-)-cylindrocyclophane A (16
steps) and (-)-cylindrocyclophane F (11 steps). Importantly,
the conversion of (-)-68 and (-)-69 to (-)-48 establishes that
the cross metathesis dimerization process can lead selectively
to the thermodynamically most stable member of a set of
structurally related isomers. This self-editing process has
important strategic implications for the design and implementa-
tion of future synthetic strategies.
g (100% yield) of (-)-12 as a colorless oil: [R]25 -6.2° (c 0.81,
D
CHCl3); IR (CHCl3) 2960 (m), 2280 (s), 1640 (w) cm-1; 1H NMR (500
MHz, CDCl3) δ 5.88 (dddd, J ) 17.1, 10.1, 7.0, 7.0 Hz, 1 H), 5.03
(dd, J ) 17.1, 2.1 Hz, 1 H), 5.00 (dd, J ) 10.1, 1.1 Hz, 1 H), 2.31-
2.26 (m, 1 H), 2.16-2.12 (m, 2 H), 1.48-1.21 (m, 9 H), 1.12 (d, J )
7.3 Hz, 18 H), 0.89 (t, J ) 7.3 Hz, 3 H); 13C NMR (125 MHz, CDCl3)
δ 137.2, 115.5, 88.2, 40.7, 35.4, 33.6, 30.5, 29.6, 22.6, 17.4, 14.1, 11.9;
high-resolution mass spectrum (CI, NH3) m/z 309.2624 [(M + H)+;
calcd for C19H37OSi, 309.2613].
Iodide (+)-52. To a solution of known alcohol (+)-5135 (1.05 g,
10.5 mmol) in Et2O (20 mL) and acetonitrile (6 mL) at 0 °C were
added triphenylphosphine (2.88 g, 11 mmol), imidazole (748 mg, 11
Experimental Section52
(52) Materials and Methods. Reactions were carried out in oven- or
flame-dried glassware under an argon atmosphere, unless otherwise noted.
All solvents were reagent grade. Diethyl ether and tetrahydrofuran (THF)
were freshly distilled from sodium/benzophenone under argon. Dichlo-
romethane, benzene, and diisopropylamine were freshly distilled from
calcium hydride. Triethylamine was distilled from calcium hydride and
stored over potassium hydroxide. Anhydrous pyridine, dimethylformamide,
and dimethyl sulfoxide were purchased from Aldrich and used without
purification. n-Butyllithium and tert-butyllithium were purchased from
Aldrich and standardized by titration with diphenylacetic acid. Except as
indicated otherwise, reactions were magnetically stirred and monitored by
thin-layer chromatography with 0.25-mm E. Merck precoated silica gel
plates. Flash chromatography was performed with silica gel 60 (particle
size 0.040-0.062 mm) supplied by E. Merck. Yields refer to chromato-
graphically and spectroscopically pure compounds, unless otherwise stated.
Melting points were determined on a Bristoline heated-stage microscope
or Thomas-Hoover apparatus and are corrected. Infrared spectra were
recorded with a Perkin-Elmer model 283B spectrometer with polystyrene
as external standard. Proton NMR spectra were recorded on a Bruker AM-
500 spectrometer. Carbon-13 NMR spectra were recorded on a Bruker AM-
500. Chemical shifts are reported relative to internal tetramethylsilane (δ
0.00), chloroform (δ 7.24), methanol (δ 3.34), or dimethyl sulfoxide (δ
2.54) for 1H and either chloroform (δ 77.0), benzene (δ 128.0), or methanol
(δ 49.9) for 13C. Optical rotations were obtained with a Perkin-Elmer model
241 polarimeter. High-resolution mass spectra were measured at the
University of Pennsylvania Mass Spectrometry Service Center on either a
VG Micromass 70/70H or a VG ZAB-E spectrometer. Microanalyses were
performed by Robertson Laboratories, Madison, NJ. Single-crystal X-ray
structures were determined at the University of Pennsylvania with an Enraf
Nonius CAD-4 automated diffractometer. High-performance liquid chro-
matography (HPLC) was performed with a Ranin component analytical/
semipreparative system.
Second-Generation Synthesis of (-)-Cylindrocyclophane F (1f).
Ethyl Ester (-)-11. Potassium carbonate (45.6 g, 330 mmol) and
iodoethane (42 mL, 528 mmol) were added to a solution of acid (-)-
10 (20.65 g, 132 mmol) in acetone (380 mL) and water (20 mL), and
the mixture was heated to 75 °C. After 3 h, the reaction was cooled to
room temperature, diluted with water (600 mL) and 10% HCl (50 mL),
extracted with dichloromethane (3 × 500 mL), washed with brine (300
mL), dried over MgSO4, filtered, and concentrated to provide (-)-11
(23.2 g, 96% yield) as a yellow oil: [R]20D -8.8° (c 1.21, CHCl3); IR
(CHCl3) 3020 (s), 2960 (m), 2940 (m), 2860 (w), 1730 (s), 1510 (w),
1470 (w), 1445 (w), 1380 (w), 1205 (s), 1185 (s), 1030 (m), 920 (m),
720 (s), 670 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.74 (dddd, J )
17.2, 10.2, 7.0, 7.0 Hz, 1 H), 5.05 (dd, J ) 17.1, 1.8 Hz, 1 H), 5.00
(dd, J ) 10.2, 1.1 Hz, 1 H), 4.13 (q, J ) 7.1 Hz, 2 H), 2.43-2.32 (m,
2 H), 2.25-2.19 (m, 1 H), 1.65-1.58 (m, 1 H), 1.51-1.44 (m, 1 H),
1.33-1.23 (m, 4 H), 1.25 (t, J ) 7.1 Hz, 3 H), 0.88 (t, J ) 7.0 Hz, 3
H); 13C NMR (125 MHz, CDCl3) δ 175.68, 135.64, 116.48, 60.03,
45.34, 36.49, 31.53, 29.44, 22.55, 14.31, 13.87; high-resolution mass
spectrum (CI, NH3) m/z 185.1547 [(M + H)+; calcd for C11H21O2,
185.1541].
Anal. Calcd for C11H20O2: C, 71.70; H, 10.94. Found: C, 71.53; H,
10.62.
Dibromoketone (+)-13. A solution of ester (-)-11 (1.29 g, 7.00
mmol) and dibromomethane (3.04 g, 17.5 mmol) in THF (30 mL) was
cooled to -78 °C. In a separate flask, a solution of 2,2,6,6-
tetramethylpiperidine (TMP) (3.18 mL, 18.9 mmol) in THF (30 mL)

5934 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Smith et al.
mmol), and iodine in three portions (2.67 g, 10.5 mmol in total). The
reaction was allowed to reach room temperature and stirred for 2 h,
passed through a pad of silica (pentane/Et2O 5:1), and concentrated
via rotary evaporation (bath temperature 15 °C). Bulb-to-bulb distillation
(oven temperature 50-80 °C, 20 mmHg) afforded (+)-52 (1.8 g, 82%
Macrocycle (-)-48. General Procedure for Metathesis Dimer-
ization. A degassed solution (ca. 0.02 M) of diene (-)-49 (0.05 mmol)
was treated with the metathesis catalyst (15-34 mol %). The resulting
homogeneous solution was stirred at ambient temperature for the time
period indicated in Table 1; concentration under reduced pressure led
to the product that was purified by flash chromatography on silica gel.
yield): [R]25 +6.3° (c 1.4, CHCl3); IR (CHCl3) 3060 (w), 2960 (s),
D
For (-)-48: [R]25 -91° (c 0.80, C6H6); IR (CHCl3) 2960 (m), 1600
2800 (s), 1640 (m), 1450 (m), 2800 (s), 1440 (m), 1380 (m), 1320
D
1
(s), 1580 (s), 1450 (m), 1100 (m) cm-1; H NMR (500 MHz, CDCl3)
1
(m), 1190 (s), 990 (s), 910 (s) cm-1; H NMR (500 MHz, CDCl3) δ
δ 6.06 (s, 2 H), 6.00 (s, 2 H), 5.15 (br dd, J ) 14, 10 Hz, 2 H), 5.09
(br dd, J ) 14, 9 Hz, 2 H), 3.77 (s, 6 H), 3.73 (s, 6 H), 3.40 (m, 2 H),
2.61 (ddd, J ) 12.6, 12.6, 10.4 Hz, 2 H), 2.27 (m, 2 H), 2.00 (m, 2 H),
1.78 (m, 2 H), 1.63-1.55 (m, 4 H), 1.50-1.42 (m, 1 H), 1.40-1.08
(m, 14 H), 0.80 (dd, J ) 13.5, 11.4 Hz, 2 H), 0.83 (t, J ) 7.0 Hz, 6
H), 0.57 (d, J ) 6.5 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ 159.2,
158.1, 141.7, 131.9, 129.5, 117.9, 107.1, 104.2, 56.5, 55.1, 41.6, 41.5,
36.9, 35.2, 35.1, 33.6, 30.7, 22.9, 19.9, 14.1; high-resolution mass
spectrum (CI, CH4) m/z 605.4552 [(M + H)+; calcd for C40H61O4,
605.4569].
5.73 (dddd, J ) 17.2, 10.1, 7.1, 7.1 Hz, 1 H), 5.08 (m, 2 H), 3.23 (dd,
J ) 5.1, 9.6 Hz, 1 H), 3.15 (dd, J ) 6.0, 9.6 Hz, 1 H), 2.14 (ddd, J )
13.9, 6.8, 6.8 Hz, 1 H), 2.03 (ddd, J ) 13.9, 6.9, 6.9 Hz, 1 H), 1.58
(m, 1 H), 1.0 (d, J ) 6.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
135.8, 116.9, 40.6, 34.6, 20.3, 16.6.
Cyclobutenone (+)-50. A solution of iodide (+)-52 (210 mg, 1.00
mmol) in Et2O (2 mL) was cooled to -78 °C and treated slowly with
t-BuLi (1.7 M in pentane, 1.0 mL, 1.7 mmol). The resulting white
suspension was stirred for 45 min and then treated with ethoxy
cyclobutenone (90 mg, 0.8 mmol) in Et2O (2 mL). The reaction mixture
was allowed to warm to 20 °C and quenched with 1.2 M aqueous HCl
(15 mL). The resulting mixture was diluted with Et2O (40 mL),
transferred into a separatory funnel, and vigorously shaken for 2 min.
The aqueous layer was extracted with Et2O (50 mL). Combined organic
layers were washed with saturated aqueous NaHCO3, dried over MgSO4,
filtered, and concentrated. The product was purified by flash chroma-
tography on silica gel (pentane/Et2O, 3:1) to afford 81 mg (67% yield)
of (+)-50 as a colorless oil: [R]25D +15 ° (c 1.3, CHCl3); IR (CHCl3)
(-)-Cylindrocyclophane F. A solution of macrocycle (-)-48 (38
mg, 0.062 mmol) in ethyl acetate (6 mL) was hydrogenated in the
presence of 10% Pd/C (100 mg) under 1 atm of hydrogen for 20 h.
Filtration of the reaction mixture through a plug of silica gel, followed
by removal of volatiles under reduced pressure, afforded 38 mg of the
desired product (quantitative yield) as a white solid. A solution of the
hydrogenation product (5.5 mg, 0.009 mmol) in CH2Cl2 (150 µL) was
treated slowly with BBr3 (1.0 M in CH2Cl2, 60 µL, 0.06 mmol) at 20
°C. The resulting dark red solution was stirred for 2.5 h, diluted with
CH2Cl2 (5 mL), and quenched with water (1 mL). The resulting mixture
was extracted with CH2Cl2 (3 × 10 mL), dried over MgSO4, filtered,
and concentrated. The product was purified by flash chromatography
on silica gel (hexane/ethyl acetate, 4:1) to afford 4.2 mg (84%) of (-)-
cylindrocyclophane F (1f) as an amorphous solid identical in all respects
to a sample of the natural material33 [500 MHz 1H NMR and 125 MHz
13C NMR, HRMS, optical rotation, and TLC (three solvent systems)]:
[R]25D -70° (c 0.2, MeOH); 1H NMR (500 MHz, CD3OD) δ 6.00 (br
s, 2 H), 5.97 (br s, 2 H), 3.14-3.06 (m, 2 H), 2.57 (dd, J ) 13.1, 3.8
Hz, 2 H), 2.00-1.88 (m, 4 H), 1.82 (dd, J ) 13.1, 11.4 Hz, 2 H),
1.60-1.54 (m, 2 H), 1.52-0.90 (m, 22 H), 0.80-0.73 (m, 4 H), 0.93
(d, J ) 6.6 Hz, 6 H), 0.81 (t, J ) 7.1 Hz, 6 H), 0.64 (m, 2 H); 13C
NMR (125 MHz, CD3OD) δ 158.3, 157.1, 140.9, 116.2, 110.0, 108.1,
45.8, 36.8, 36.7, 36.7, 35.5, 34.9, 31.7, 30.6, 30.1, 23.9, 20.8, 14.5;
high-resolution mass spectrum (CI, NH3) m/z 553.4235 [(M + H)+;
calcd for C36H57O4, 553.4256].
1
3000 (m), 1760 (s), 1580 (s) cm-1; H NMR (500 MHz, CDCl3) δ
5.87 (s, 1 H), 5.74 (m, 1 H), 4.98-5.20 (m, 2 H), 3.12 (m, 2 H), 2.57
(ddd, J ) 16.3, 5.8, 1.0 Hz, 1 H), 2.36 (ddd, J ) 16.3, 7.9, 1.0 Hz, 1
H), 2.10-2.05 (m, 1 H), 2.04-1.97 (m, 1 H), 1.93-1.85 (m, 1 H),
0.95 (d, J ) 6.6 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 187.7, 180.1,
136.0, 135.1, 116.8, 50.9, 41.0, 38.7, 30.9, 19.6; low-resolution mass
spectrum (CI, CH4) m/z 151 [(M + H)+; calcd for C10H15O, 151.1].
Resorcinol (+)-53. A solution of siloxyalkyne (-)-12 (385 mg, 1.25
mmol) and cyclobutenone (+)-50 (220 mg, 1.47 mmol) in toluene (2
mL) was heated to 100 °C. After 2 h, the reaction mixture was cooled
to 0 °C, diluted with THF (10 mL), and treated with TBAF (1.5 mL,
1.0 M in THF). The resulting solution was stirred for 15 min at ambient
temperature and quenched with 1.2 M HCl (1.5 mL), diluted with water
(50 mL), and extracted with Et2O (2 × 50 mL). The combined organic
layers were dried with MgSO4, filtered, concentrated, and purified by
flash chromatography on silica gel (hexanes/Et2O, 2:1) to afford 261
mg (69% yield) of (+)-53 as a colorless oil: [R]25 +3.0° (c 1.5,
D
Synthesis of (-)-Cylindrocyclophane A (1a). Resorcinol (+)-56.
A degassed solution of siloxyalkyne (-)-12 (375.0 mg, 1.22 mmol)
and cyclobutenone 18 (542.0 mg, 1.52 mmol) in toluene (2.9 mL) was
heated to 100 °C for 2 h. The resulting dark brown mixture was cooled
to ambient temperature, diluted with Et2O (50 mL), washed twice with
saturated aqueous NaHCO3 (25 mL), dried over MgSO4, filtered, and
concentrated to give a brown oil. Flash chromatography (hexanes/ethyl
acetate, 60:1) using deactivated silica gel [prepared by thoroughly
mixing silica (90 g) and water (18 mL)] gave the desired monosilylated
aryl stannane as an oil (691.0 mg, 85% yield). A solution of stannane
(355 mg) prepared as described above in CH2Cl2 (8.5 mL) was treated
dropwise with iodine (7.0 mL, 0.075 M in CH2Cl2) until the starting
material was consumed. The progress of the reaction was monitored
by TLC. The reaction mixture was diluted with saturated aqueous Na2-
S2O3 (5 mL) and water (20 mL), extracted with CH2Cl2 (3 × 20 mL),
dried with MgSO4, filtered, and concentrated to give an oil. Flash
chromatography on silica gel (1% f 6% ethyl acetate in hexanes)
afforded the unstable monoprotected aryl iodide as an oil (184.4 mg,
77% overall yield for two steps) which was used immediately in the
next step.
CHCl3); IR (CHCl3) 3600 (s), 3300 (m), 2960 (m), 1620 (s), 1580 (s),
1
1420 (m) cm-1; H NMR (500 MHz, CDCl3) δ 6.13 (s, 2 H), 5.7-
5.82 (m, 2 H), 4.98-5.03 (m, 2 H), 4.90 (br d, J ) 20.1 Hz, 1 H), 4.74
(s, 2 H), 3.18-3.12 (m, 1 H), 2.60 (m, 1 H), 2.50-2.42 (m, 2 H), 2.22
(dd, J ) 13.4, 8.1 Hz, 1 H), 2.1 (m, 1 H), 1.93-1.85 (m, 2 H), 1.80-
1.65 (m, 2 H), 1.35-1.10 (m, 4 H), 0.85 (d, J ) 6.7 Hz, 3 H), 0.84 (t,
J ) 7.2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 154.8, 140.6, 138.3,
137.3, 115.9, 115.1, 114.7, 109.4, 42.5, 40.9, 38.1, 36.0, 34.5, 32.9,
30.4, 22.8, 19.3, 14.0; high-resolution mass spectrum (CI, CH4) m/z
303.2318 [(M + H+); calcd for C20H31O2, 303.2324].
Diene (-)-49. To a solution of (+)-53 (205 mg, 0.68 mmol) in
2-butanone (2.0 mL) was added K2CO3 (1.0 g, 7.2 mmol) and methyl
iodide (1.74 mL, 27.9 mmol). The reaction was heated at reflux for 21
h, diluted with Et2O (40 mL), filtered, and concentrated. Flash
chromatography (hexanes/Et2O, 5:1) afforded (-)-49 (203 mg, 91%
yield) as a colorless oil: [R]25 -2.8 ° (c 2.7, CHCl3); IR (CHCl3)
D
1
2960 (m), 1600 (s), 1580 (s), 1120 (m) cm-1; H NMR (500 MHz,
CDCl3) δ 6.22 (s, 2 H), 5.73 (m, 1 H), 5.60 (dddd, J ) 17.0, 10.0, 6.9,
6.9 Hz, 1 H), 4.92 (m, 2 H), 4.81 (d, J ) 17.0 Hz, 1 H), 4.72 (d, J )
10.0 Hz, 1 H), 3.66 (s, 6 H), 3.24 (m, 1 H), 2.50 (dd, J ) 13.4, 6.2 Hz,
1 H), 2.47-2.40 (m, 1 H), 2.35-2.27 (m, 1 H), 2.24 (dd, J ) 13.4,
8.1 Hz, 1 H), 2.07-2.00 (m, 1 H), 1.86-1.65 (m, 3 H), 1.54-1.47
(m, 1 H), 1.25-0.90 (m, 5H), 0.79 (d, J ) 6.6 Hz, 3 H), 0.73 (t, J )
7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 159.1, 140.0, 139.2,
137.4, 118.8, 115.8, 114.0, 105.5, 56.0, 43.6, 41.0, 38.3, 35.0, 34.8,
32.9, 30.4, 22.8, 19.3, 14.1; high-resolution mass spectrum (CI, CH4)
m/z 331.2625 [(M + H)+; calcd for C22H35O2, 331.2637].
A solution of the iodide prepared above (165 mg, 0.328 mmol) in
THF (3.3 mL) was cooled to 0 °C. In a separate flask, tetrabutylam-
monium fluoride (TBAF) (1.0 M in THF; 1.28 mL, 1.28 mmol) was
added to glacial acetic acid (75.0 µL, 1.30 mmol) and stirred for 5
min. The aryl iodide solution was then treated with the TBAF solution
(0.957 M in AcOH/THF, 0.45 mL, 0.41 mmol). After 15 min at 0 °C,
the reaction mixture was allowed to warm to ambient temperature over
a 10 min period, quenched with saturated aqueous NH4Cl (20 mL) and

Total Synthesis of (-)-Cylindrocyclophanes A and F
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5935
water (5 mL), extracted with ethyl acetate (3 × 20 mL), dried over
MgSO4, filtered, and concentrated. Flash chromatography on silica gel
(2% f 5% ethyl acetate in hexanes) gave (+)-56 (98 mg, 88% yield)
as a pale yellow oil: [R]20D +4.87° (c 0.575, CHCl3); IR (CHCl3) 3560
(s), 3285 (m), 2945 (s), 2925(s), 2845 (s), 1760 (w), 1635 (w), 1595
(s), 1405 (s), 1320 (m), 1135 (m), 1015 (s), 940 (w), 910 (m), 825 (s),
570 (w) cm-1; 1H NMR (500 MHz, CDCl3) δ 6.67 (s, 2 H), 5.69 (dddd,
J ) 17.1, 10.1, 7.1, 7.1 Hz, 1 H), 4.97 (d, J ) 17.1 Hz, 1 H), 4.87 (d,
J ) 10.1, 1 H), 4.73 (s, 2 H), 3.13 (dddd, J ) 9.4, 9.4, 6.0, 6.0 Hz, 1
H), 2.56 (m, 1 H), 2.40 (m, 1 H), 1.84 (dddd, J ) 13.4, 9.9, 9.9, 5.3
Hz, 1 H), 1.63 (m, 1 H), 1.20 (complex m, 4 H), 0.82 (t, J ) 7.2 Hz,
3 H); 13C NMR (125 MHz, CDCl3) δ 155.78, 137.83, 117.87, 117.57,
115.48, 89.47, 37.78, 36.01, 32.60, 30.36, 22.74, 14.03; high-resolution
mass spectrum (CI, CH4) m/z 347.0508 [(M + H)+; calcd for C14H20O2I,
347.0508].
Alcohol (+)-55. To neat (+)-B-chlorodiisopinocampheylborane [(+)-
DIPCl] (103 mg, 0.321 mmol) was added a solution of (+)-59 (57
mg, 0.166 mmol) in THF (0.30 mL). Once the solution became
homogeneous by stirring, the reaction was placed at 0 °C for 10 h and
then allowed to warm to room temperature. After 86 h at room
temperature, the reaction was diluted with Et2O (5.5 mL) and transferred
to a larger flask. The solution was them stirred vigorously, and
diethanolamine (100 mg, 0.952 mmol) was added to yield a white
precipitate. After 1 h, 45 min, the reaction was filtered through a pad
of Celite, diluted with Et2O (25 mL) and washed with 1 N NaOH (2 ×
15 mL) and brine (15 mL), dried over MgSO4, filtered, and concen-
trated. Purification via flash chromatography (3% f 7% ethyl acetate
in hexanes) gave (+)-55 (43 mg, 0.124 mmol, 81% yield, dr 19:1) as
a colorless oil: [R]20D +5.4° (c 0.725, CHCl3); IR (CHCl3) 3585 (m),
3065 (m), 2940 (s), 2925 (s), 2835 (m), 1635 (m), 1605 (m),1580 (s),
1455 (s), 1420 (s), 1360 (m), 1310 (w), 1230 (w), 1190 (w), 1130 (s),
990 (m), 980 (w), 910 (s), 820 (w), 620 (w) cm-1; 1H NMR (500 MHz,
C6D6) δ 6.47 (s, 2 H), 5.94 (dddd, J ) 17.1, 10.1, 7.0 Hz, 1 H), 5.74
(dddd, J ) 17.1, 10.2, 7.1, 7.1 Hz, 1 H), 5.10 (d, J ) 17.0 Hz, 1 H),
5.00 (m, 2 H), 4.94 (d, J ) 10.2 Hz, 1 H), 4.32 (dd, J ) 2.8, 4.6 Hz,
1 H), 3.78 (dddd, J ) 9.1, 9.1, 6.1, 6.1 Hz, 1 H), 3.42 (s, 6 H), 2.88
(m,1 H), 2.68 (m,1 H), 2.21 (m,1 H), 2.15 (m,1 H), 1.86 (complex m,
3 H), 1.40 (m, 2 H), 1.31 (m, 2 H), 1.22 (d, J ) 3.01 Hz, 1 H), 1.01
(d, J ) 6.4 Hz, 3 H), 0.85 (t, J ) 6.9 Hz, 3 H); 13C NMR (125 MHz,
C6D6, 65 °C) δ 159.57, 143.73, 139.26, 137.64, 120.87, 115.93, 114.50,
103.21, 77.82, 55.50, 40.83, 38.98, 38.46, 35.84, 33.58, 31.01, 23.20,
14.39, 14.18; high-resolution mass spectrum (CI, CH4) m/z 345.2424
[(M - H)+; calcd for C22H33O3, 345.2430].
Aryl Iodide (-)-57. To a solution of resorcinol (+)-56 (130 mg,
0.375 mmol) in 2-butanone (1.2 mL) were added K2CO3 (520 mg, 3.76
mmol) and methyl iodide (2.0 mL, 32.1 mmol). This solution was
vigorously stirred and heated at 64 °C for 22.5 h. The reaction was
then allowed to cool to room temperature and diluted with Et2O (25
mL) and water (25 mL). The layers were separated, and the aqueous
layer was extracted with Et2O (2 × 15 mL). The combined organic
layers were then washed with brine (15 mL), dried over MgSO4, and
concentrated. Purification via flash chromatography (0% f 2.5% ethyl
acetate in hexanes) gave (-)-57 (125 mg, 0.334 mmol, 89% yield) as
a colorless oil: [R]20 -2.54° (c 0.59 CHCl3); IR (CHCl3) 3060 (w),
D
2990 (m). 2950 (s), 2840 (s), 1635 (w), 1570 (s), 1460 (s), 1400 (s),
1365 (m), 1300 (w), 1275 (w), 1230 (m), 1170 (m), 1130 (s), 1100 (s),
990 (w), 950 (w), 905 (m), 810 (s), 570 (w) cm-1; 1H NMR (500 MHz,
CDCl3) δ 6.80 (s, 2 H), 5.62 (dddd, J ) 17.1, 10.1, 7.1, 7.1 Hz, 1 H),
4.88 (d, J ) 17.1 Hz, 1 H), 4.79 (d, J ) 10.1 Hz, 1 H), 3.74 (s, 6 H),
3.31 (dddd, J ) 9.3, 9.3, 6.4, 6.4 Hz, 1 H), 2.47 (m, 1 H), 2.35 (m, 1
H), 1.75 (dddd, J ) 13.2, 9.9, 9.9, 5.2 Hz, 1 H), 1.55 (m, 1 H), 1.22
Triethyl Silyl Ether (+)-60. To a solution of (+)-55 (33 mg, 0.095
mmol) in CH2Cl2 (2.1 mL) at 0 °C was added 2,6-lutidine (60 µL,
0.609 mmol), followed by triethylsilyl trifluoromethanesulfonate
(TESOTf) (54 µL, 0.238 mmol). After 15 min, the reaction was
quenched with saturated aqueous NaHCO3 (18 mL), extracted with CH2-
Cl2 (3 × 10 mL), dried over MgSO4, filtered, and concentrated to a
clear oil. Purification via flash chromatography (1% Et2O in hexanes)
(m, 2 H), 1.10 (m, 1 H), 1.00 (m, 1 H), 0.79 (t, J ) 7.3 Hz, 3 H); 13
C
NMR (125 MHz, CDCl3) δ 159.42, 138.59, 121.32, 114.46, 114.11,
90.32, 55.91, 37.90, 35.05, 32.58, 30.30, 22.76, 14.05; high-resolution
mass spectrum (CI, CH4) m/z 375.0804 [(M + H)+; calcd for C16H24O2I,
375.0821].
gave (+)-60 (40 mg, 0.087 mmol, 92% yield) as a colorless oil: [R]20
D
+29.7° (c 0.525, CHCl3); IR (CHCl3) 3060 (w), 2930 (s), 2850 (s),
1635 (m), 1605 (m), 1570 (s), 1460 (s), 1420 (s), 1375 (m), 1305 (m),
1235 (m), 1185 (w), 1135 (s), 1095 (s), 1000 (m), 910 (s), 835 (m),
Ketone (+)-59. To a solution of known amide (-)-58 (259 mg,
0.991 mmol) in THF (1.9 mL) at -78 °C was added tert-butyllithium
(1.7M in pentane, 0.585 mL, 0.994 mmol). In a separate flask, to a
solution of aryl iodide (-)-57 (141 mg, 0.377 mmol) in THF (2.2 mL)
at -78 °C was added tert-butyllithium (1.7M in pentane, 0.455 mL,
0.774 mmol). The amide solution was then transferred dropwise via
cannula to the aryl iodide solution and allowed to stir for 7 min at
-78 °C. The reaction was then brought to -20 °C for 10 min, and
then to 0 °C for 7 min, at which time diisopropylamine (0.50 mL, 3.57
mmol) was added and allowed to stir for 5 min. The reaction was then
quenched with 10% v/v aqueous acetic acid (5 mL) and diluted with
Et2O (15 mL), the layers were separated, and the aqueous layer was
extracted with Et2O (10 mL). The combined organic layers were washed
with 50% aqueous NaHCO3 (2 × 10 mL) and saturated aqueous
NaHCO3 (10 mL), dried over MgSO4, filtered, and concentrated.
Purification via flash chromatography (1% ethyl acetate in hexanes)
1
805 (w); H NMR (500 MHz, C6D6) δ 6.56 (s, 2 H), 5.92 (dddd, J )
17.1, 10.1, 7.1, 7.1 Hz, 1 H), 5.78 (dddd, J ) 17.2, 10.2, 7.3, 7.3 Hz,
1 H), 5.05 (m, 3 H), 4.94 (d, J ) 10.1 Hz, 1 H), 4.50 (d, J ) 5.1 Hz,
1 H), 3.77 (dddd, J ) 9.2, 9.2, 6.1, 6.1 Hz, 1 H), 3.46 (s, 6 H), 2.87
(m, 1 H), 2.67 (m, 1 H), 2.30 (m, 1 H), 2.16 (dddd, J ) 14.2, 9.8, 9.8,
4.8 Hz, 1 H), 1.88 (complex m, 3 H), 1.38 (m, 2 H), 1.28 (m, 2 H),
1.10 (d, J ) 6.2 Hz, 3 H), 0.96 (t, J ) 7.9 Hz, 9 H), 0.86 (t, J ) 6.9
Hz, 3 H), 0.59 (q, J ) 7.8 Hz, 6 H); 13C NMR (125 MHz, C6D6, 65
°C) δ 159.4,143.9, 139.2, 137.9, 120.9, 115.8, 114.4, 103.8, 79.7, 55.5,
42.2, 39.0, 38.3, 35.9, 33.5, 31.0, 23.2, 15.0, 14.2, 7.0, 5.6; high-
resolution mass spectrum (CI, CH4) m/z 459.3284 [(M - H)+; calcd
for C28H47O3Si, 459.3294].
Macrocycle (+)-54. To a solution of (+)-60 (28 mg, 0.0608 mmol)
in degassed benzene (5.0 mL) was added a solution of Schrock’s catalyst
(0.1 M in benzene, 1.3 mL, 0.0205 mmol), yielding a brown solution.
After 1.25 h, the reaction was quenched with saturated aqueous NH4-
Cl (2 mL), diluted with Et2O (20 mL), washed consecutively with
saturated aqueous NH4Cl (10 mL), saturated aqueous NaHCO3 (10 mL),
and brine (10 mL), dried over MgSO4, filtered, and concentrated.
Purification via flash chromatography (0.25% f 1% ethyl acetate in
hexanes) gave (+)-54 (20 mg, 0.023 mmol, 77% yield) as a white
gave (+)-59 (88 mg, 0.255 mmol, 68% yield) as a colorless oil: [R]20
D
+23.7° (c 0.7, CHCl3); IR (CHCl3) 3060 (w), 2960 (s), 2840 (m), 1670
(s), 1635 (m), 1570 (s), 1455 (s), 1410 (s), 1370 (m), 1300 (s), 1230
(m), 1190 (m), 1130 (s), 985 (m), 940 (w), 910 (m), 850 (w), 565 (br,
1
w) cm-1; H NMR (500 MHz, CDCl3) δ 7.10 (s, 2 H), 5.79 (dddd, J
) 17.1, 10.1, 6.9, 6.9 Hz, 1 H), 5.63 (dddd, J ) 17.1, 10.1, 7.1, 7.1
Hz, 1 H), 5.05 (d, J ) 17.1 Hz, 1 H), 5.01 (d, J ) 10.1 Hz, 1 H), 4.89
(d, J ) 17.1 Hz, 1 H), 4.79 (d, J ) 10.1 Hz, 1 H), 3.82 (s, 6 H), 3.44
(complex m, 2 H), 2.54 (m, 2 H), 2.41 (ddd, J ) 6.9, 13.9, 6.9 Hz, 1
H), 2.19 (ddd, J ) 7.4, 14.4, 7.4 Hz, 1 H), 1.81 (dddd, J ) 13.3, 9.9,
9.9, 5.2 Hz, 1 H), 1.60 (dddd, J ) 13.1, 10.5, 5.8, 5.8 Hz, 1 H), 1.24
(complex m, 2 H), 1.20 (d, J ) 6.9 Hz, 3 H), 1.13 (m,1 H), 1.01 (m,1
H), 0.80 (t, J ) 7.2 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 203.25,
159.28, 138.66, 136.27, 135.49, 127.60, 116.86, 114.81, 104.55, 56.04,
40.65, 38.09, 38.04, 35.73, 32.77, 30.57, 22.98, 17.50, 14.25; high-
resolution mass spectrum (CI, CH4) m/z 345.2426 [(M + H)+; calcd
for C22H33O3, 345.2430].
solid: mp 176-178 °C, [R]20 +22.0° (c 0.20, CHCl3); IR (CHCl3)
D
3000 (m), 2940 (s), 2870 (s), 2350 (w), 1730 (m), 1610 (m), 1590 (s),
1450 (s), 1420 (s), 1380 (m), 1300 (w), 1240 (s), 1140 (s), 1115 (s),
1100 (s), 1000 (m), 965 (w), 905 (m), 845 (m), 820 (w) cm-1; 1H NMR
(500 MHz, CDCl3) δ 6.50 (s, 2 H), 6.05 (s,2 H), 5.01 (complex m, 4
H), 4.13 (d, J ) 5.3 Hz, 2 H), 3.7 (s,6 H), 3.65 (s,6 H), 3.28 (m, 2 H),
2.52 (ddd, J ) 8.1, 12.5, 12.5 Hz, 2 H), 2.14 (ddd, J ) 12.9, 4.5, 4.5
Hz, 2 H), 1.81 (m,2 H), 1.64 (m,2 H), 1.51 (m,2 H), 1.17 (complex
m,10 H), 1.00 (m, 2 H), 0.79 (q, J ) 8.0 Hz, 18 H), 0.61 (d, J ) 5.6
Hz, 6 H), 0.43 (m, 18 H); 13C NMR (125 MHz, CDCl3) δ 159.4, 157.7,
143.0, 131.0, 128.9, 119.4, 104.0, 102.9, 80.4, 56.5, 55.3, 42.3, 36.8,

5936 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Smith et al.
36.7, 35.7, 33.4, 30.6, 22.8, 14.3, 14.1, 6.8, 4.9; high-resolution mass
spectrum (ES+) m/z 887.6025 [(M + Na)+; calcd for C52H88O6NaSi2,
887.6017].
(+)-36 (35 mg, 0.105 mmol) in CH2Cl2 (1.9 mL) was added pyridine
(50 µL, 0.620 mmol). The reaction was placed at 0 °C, and Dess-
Martin periodinane (103 mg, 0.242 mmol) was added. The reaction as
placed at room temperature and stirred for 2.5 h, at which time it was
quenched with saturated aqueous NaHCO3 (1.0 mL) and saturated
aqueous Na2SO3 (1 mL), diluted with CH2Cl2 (10 mL), washed
consecutively with saturated aqueous NaHCO3 (4.0 mL) and brine (4.0
mL), and then dried over MgSO4. Purification via flash chromatography
(47% Et2O in hexanes) gave (+)-70 (31 mg, 91% yield) as a yellow
oil: [R]20D + 9.7° (c 0.48, C6H6); IR (CHCl3) 2950 (s), 2930 (s), 2840
(w), 1715 (s), 1600 (w), 1570 (m), 1450 (m), 1410 (m), 1125 (m),
1110 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 9.28 (t, J ) 1.7 Hz, 1
H), 6.23 (s, 2 H), 5.91 (dddd, J ) 17.1, 10.2, 7.2, 7.2 Hz, 1 H), 5.08
(m, 1 H), 4.92 (m, 1 H), 3.73 (dddd, J ) 9.2, 9.2, 6.2, 6.2 Hz, 1 H),
3.43 (s, 6 H), 2.84 (m, 1 H), 2.66 (m, 1 H), 2.34 (ddd, J ) 0, 1.2, 7.2
Hz, 1 H), 2.25 (ddd, J ) 0, 13.3, 7.3 Hz, 1 H), 2.13 (m, 2 H), 2.00
(ddd, J ) 16.5, 5.6, 1.6 Hz, 1 H), 1.84 (m, 1 H), 1.78 (m, 1 H), 1.35
(m, 4 H), 0.84 (t, J ) 7.0 Hz, 3 H), 0.79 (d, J ) 6.6 Hz, 3 H); 13C
NMR (125 MHz, C6D6) δ 200.5, 159.5, 139.32, 139.27, 119.4. 114.7,
105.6, 55.3, 50.4, 43.8, 39.0, 35.6, 33.5, 31.2, 31.0, 30.5, 30.2, 23.4,
23.3, 20.1, 20.0, 14.3; high-resolution mass spectrum (CI, CH4) m/z
333.2415 [(M + H)+; calcd for C21H33O3, 333.2430].
Diol (-)-61. To a solution of (+)-54 (13.5 mg, 0.0156 mmol) in
THF (0.65 mL) at 0 °C was added a solution of TBAF (1.0 M in THF,
105 µL, 0.105 mmol). The reaction was brought to room temperature
after 30 min, and after 90 min the reaction was quenched with NH4Cl
(5 mL), extracted with ethyl acetate (4 × 10 mL), dried over MgSO4,
filtered, and concentrated to a yellow solid. Purification via flash
chromatography (10% f 15% ethyl acetate in hexanes) gave (-)-61
(7 mg, 0.011 mmol 71% yield) as a white solid: mp 144-126 °C;
[R]20D -131.4° (c 0.50, CHCl3); IR (CHCl3) 3560 (m), 3000 (m), 2950
(s), 1605 (s), 1585 (s), 1460 (s), 1415 (s), 1385 (m), 1310 (m), 1235
(m), 1185 (m),1140 (s), 1115 (s), 1100 (s), 970 (s), 815 (w) cm-1; 1H
NMR (500 MHz, CDCl3) δ 6.57 (s, 2 H), 5.86 (s, 2 H), 5.28 (m, 2 H),
5.10 (m, 2 H), 3.78 (s, 6 H), 3.76 (s, 6 H), 3.47 (m, 2 H), 3.18 (m, 2
H), 2.62 (app q, J ) 12.3 Hz, 2 H), 2.31 (m, 2 H), 1.89 (m, 4 H), 1.81
(m, 2 H), 1.61 (m, 2 H), 1.41 (m, 2 H), 1.24 (m, 6 H), 1.11 (m, 2 H),
0.82 (t, J ) 7.0, 2 H), 0.78 (d, J ) 4.8, 2 H), 0.52 (d, J ) 6.9 Hz, 2
H); 13C NMR (125 MHz, CDCl3) δ 159.25, 158.51, 145.17, 132.65,
128.67, 118.86, 101.79, 101.05, 71.74, 56.34, 55.12, 39.50, 37.61, 36.86,
35.13, 33.22, 30.68, 22.86,14.10, 12.58; high-resolution mass spectrum
(ES+) m/z 659.4301 [(M + Na)+; calcd for C40H60O6Na, 659.4288].
(-)-Cylindrocyclophane A (1a). A solution of diol (-)-61 (6.5 mg,
0.010 mmol) in ethanol (2.1 mL) was hydrogenated in the presence of
a catalytic amount of PtO2 under 1 atm of H2 gas for 75 min. The
resulting mixture was diluted with ethyl acetate (25 mL), filtered
through a pad of Celite, and concentrated, to give the expected
hydrogenated product (6.5 mg, 0.010 mmol, quantitative yield) as a
Wittig Salt (-)-71. To a solution of iodide (+)-37 (10.0 mg, 0.0225
mmol) in acetonitrile (0.75 mL) was added triphenylphosphine (71 mg,
0.27 mmol). The reaction was heated at reflux for 7.5 h and then cooled
to room temperature and purified directly via flash chromatography
(5% f 10% ethyl acetate in hexanes to 5% MeOH in CH2Cl2), which
gave (-)-71 (15.0 mg, 94% yield) as a yellow amorphous solid: [R]20
D
-13.6° (c 0.25, CHCl3); IR (CHCl3) 3000 (m), 2950 (s), 2850 (m),
1610 (w), 1585 (m), 1465 (m), 1440 (s), 1240 (m), 1120 (s), 1000 (w),
910 (w), cm-1; 1H NMR (500 MHz, CDCl3) δ 7.74 (m, 9 H), 7.67 (m,
6 H), 6.31 (s 2 H), 5.61 (dddd, J ) 17.0, 10.1, 6.9, 6.9 Hz, 1 H), 4.87
(dd, J ) 1.5, 17.1 Hz, 1 H), 4.71 (dd, J ) 1.3, 10.1 Hz, 1 H), 3.72 (m,
1 H), 3.70 (s, 6 H), 3.56 (m, 1 H), 3.27 (ddd, J ) 15.1, 8.8, 6.5 Hz, 1
H), 2.56 (m, 1 H), 2.44 (m, 2 H), 2.36 (m, 1 H), 2.24 (m, 1 H), 1.64
(m, 3 H), 1.41 (m, 1 H), 1.21 (m, 4 H), 1.01 (d, J ) 6.6 Hz, 3 H), 0.76
(t, J ) 7.3 Hz, 3 H); 13C NMR (125 MHz, C6D6, 65 °C) δ 158.8,
139.1, 139.0, 135.0, 133.7, 133.6, 132.1, 132.0, 131.88, 130.5, 130.4,
128.5, 128.4, 119.0, 118.6, 117.9, 117.8, 114.1, 105.5, 56.1, 43.3, 38.2,
35.2, 35.1, 34.9, 32.8, 30.4, 28.81, 28.77, 22.8, 21.4, 21.0, 19.9, 14.0;
high-resolution mass spectrum (CI, CH4) m/z 579.3403 [(M - I)+; calcd
for C39H48O2P, 579.3391].
white powder: mp 195-197 °C; [R]20 -8.44° (c 0.32, CHCl3); IR
D
3690 (m), 2930 (s), 2855 (m), 1654 (w), 1603 (s), 1458 (m), 1420 (w),
1375 (w), 1136 (m), 979 (w), 838 (w) cm-1 1H NMR (500 MHz,
;
CDCl3) δ 6.53 (s, 2 H), 6.25 (s, 2 H), 3.96 (dd, J ) 2.3, 9.4 Hz, 2 H)
3.73 (s, 6 H), 3.70 (s, 6 H), 3.19 (m, 2 H), 1.82 (d, J ) 2.6 Hz, 2 H)
1.77 (m, 4 H), 1.54 (m, 4 H), 1.35 (m, 4 H), 1.23 (m, 4 H), 1.13 (m,
2 H), 1.07 (d, J ) 6.4 Hz, 6 H), 1.01 (m, 2 H), 0.82 (m, 4 H), 0.80 (t,
J ) 7.1 Hz, 6 H), 0.58 (complex m, 6 H); 13C NMR (125 MHz, CDCl3)
δ 160.07, 158.13, 142.68, 121.42, 106.06, 101.51, 81.24, 56.75, 55.58,
41.33, 35.62, 34.29, 33.70, 33.52, 30.60, 29.38,28.52, 22.86, 16.37,
14.09; high-resolution mass spectrum (ES+) m/z 663.4600 [(M + Na)+;
calcd for C40H64O6Na, 663.4601].
To a solution of the hydrogenation product (4.0 mg 0.00624 mmol)
in 1-methyl-2-pyrrolidinone (0.80 mL) was added anhydrous K2CO3
(4.5 mg, 0.033 mmol) followed by thiophenol (0.190 mL, 1.84 mmol).
The reaction vessel was sealed and heated to 215 °C for 6 h, at which
time it was diluted with ethyl acetate (15 mL) and pH 4 buffer (10
mL) The layers were separated, and the aqueous layer was saturated
with NaCl and extracted with ethyl acetate (4 × 15 mL), followed by
5% MeOH in CH2Cl2 (4 × 10 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated. The solvent and excess
of thiophenol were removed by bulb-to-bulb distillation (60 °C, 2
mmHg), leaving behind a yellow solid. Purification via flash chroma-
tography on silica gel (5% f 7% methanol in CH2Cl2) gave 3.1 mg
(85% yield) of (-)-cylindrocyclophane A (1a) as a white solid. The
spectroscopically pure sample was obtained upon reverse-phase HPLC
purification (70% MeCN/30% H2O) to yield (-)-cylindrocyclophane
A (1a) as a white solid (2.9 mg, 79% yield) that was identical in all
Z-Dimer (-)-68. To a solution of Wittig salt (-)-71 (56 mg, 0.089
mmol) in THF (1.30 mL) at -78 °C was added KHMDS (0.5 M in
toluene; 177 µL, 0.089 mmol). The resulting bright orange solution
was brought to 0 °C for 8 min and then returned to -78 °C. A solution
of aldehyde (+)-70 (22 mg, 0.067 mmol) in THF (0.70 mL) was then
added dropwise via cannula to the ylide. After 1.5 h, the reaction was
brought to 0 °C for 5 min, quenched with saturated aqueous NaHCO3
(5.0 mL), extracted with Et2O (3 × 7 mL), dried over MgSO4, filtered,
and concentrated. Purification via flash chromatography (1% f 5%
Et2O in hexanes) gave (-)-68 (35 mg, 88% yield, E/Z > 15:1) as a
colorless oil: [R]20D -19.0° (c 0.78, CHCl3); IR (film) 3072 (w), 2955
(s), 2913 (s), 2860 (m), 1637 (w), 1605 (m), 1573 (s), 1456 (m), 1414
1
(m), 1371 (w), 1212 (m), 1132 (s), 1110 (m) cm-1; H NMR (500
MHz, CDCl3) δ 6.28 (s, 4 H), 5.67 (dddd, J ) 17.3, 10.1, 7.4, 7.4 Hz,
2 H), 5.48 (dd, J ) 4.7, 4.7 Hz, 2 H), 4.91 (app d, J ) 17.2 Hz, 2 H),
4.79 (app d, J ) 10.1 Hz, 2 H), 3.73 (s, 12 H), 3.31 (m, 2 H), 2.58
(dd, J ) 13.4. 6.2 Hz, 2 H), 2.50 (dddd, J ) 13.9, 7.0, 7.0, 7.0 Hz, 2
H), 2.39 (m, 2 H), 2.28 (m, 2 H), 2.04 (app dt, J ) 10.0, 4.7, 4.7 Hz,
2 H), 1.87 (m, 2 H), 1.77 (m, 4 H), 1.57 (m, 2 H), 1.22 (m, 6 H), 1.04
(m, 2 H), 0.85 (d, J ) 6.6 Hz, 6 H), 0.80 (t, J ) 7.1 Hz, 6 H); 13C
NMR (125 MHz, C6D6, 65 °C) δ 159.6, 140.6, 139.4, 129.6, 119.6,
114.5, 106.0, 55.5, 44.3, 39.1, 36.0, 35.8, 34.9, 33.6, 31.0, 23.2, 19.8,
14.2; high-resolution mass spectrum (CI, CH4) m/z 633.4883 [(M +
H)+; calcd for C42H65O4, 633.4870].
Sulfone (-)-72. To a solution of the alcohol derived from acidic
hydrolysis of (+)-36 (15.0 mg, 0.045 mmol) in THF (0.50 mL) was
added 1-phenyl-1H-tetrazole-S-thiol (16 mg, 0.091 mmol). The reaction
was placed at 0 °C, and then triphenylphosphine was added (18.0 mg,
0.069 mmol), followed by diethyl azodicarboxylate (13 µL, 0.082
1
respects to the reported literature data [500 MHz H NMR and 125
MHz 13C NMR, HRMS]: mp 276-278 °C; [R]20 -20.7° (c 0.14,
D
1
MeOH); H NMR (500 MHz, DMSO) δ 8.55 (s, 2 H), 8.52 (s, 2 H),
6.16 (s, 2 H), 5.94 (s, 2 H), 4.83 (d, J ) 1.9 Hz, 2 H), 3.56 (dd, J )
9.5, 3.7 Hz, 2 H) 3.06 (m, 2 H), 1.89 (m, 2 H), 1.81 (m, 2 H), 1.44 (m,
2 H), 1.36 (m, 2 H), 1.30 (m, 2 H), 1.26 (m, 2 H),1.23 (m, 2 H), 1.16
(m, 2 H), 1.09 (m, 2 H), 1.02 (m, 2 H), 0.97 (d, J ) 6.4 Hz, 6 H), 0.86
(m, 2 H), 0.77 (t, J ) 7.2 Hz, 6 H), 0.70 (m, 2 H), 0.62 (m, 2 H), 0.57
(complex m, 4 H); 13C NMR (125 MHz, CD3OD) δ 158.9, 157.0, 143.9,
117.8, 109.0, 105.1, 81.9, 42.1, 36.9, 35.5, 35.3, 34.9, 31.7, 30.7, 29.9,
23.9, 17.0, 14.5; high-resolution mass spectrum (ES+) m/z 607.3956
[(M + Na)+; calcd for C36H56O6Na, 607.3975].
The Cross Olefin Metathesis Dimerization Process: Aldehyde
(+)-70. To a solution of the alcohol dervied from acidic hydrolysis of

Total Synthesis of (-)-Cylindrocyclophanes A and F
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5937
mmol). The resulting yellow solution was brought to 20 °C and after
20 min diluted with Et2O (10 mL) and brine (5 mL), extracted with
Et2O (2 × 7 mL), dried over MgSO4, filtered, and concentrated.
Purification via flash chromatography (20% Et2O in hexanes) afforded
to 20 °C and allowed to stir for 19 h, quenched with H2O (1.0 mL),
diluted with Et2O (10 mL), washed successively with saturated aqueous
NH4Cl (4 mL) and brine (4 mL), dried over MgSO4, filtered, and
concentrated. Purification via flash chromatography (2% Et2O in
hexanes) gave (-)-69 (16.0 mg, 74% yield, E/Z > 15:1) as a colorless
oil: [R]20D -12.8° (c 0.40, CDCl3); IR (film) 2955 (s), 2923 (s), 2859
(m), 1637 (w), 1605 (m), 1573 (s), 1456 (m), 1419 (m), 1371 (w),
the thioether (0.21 mg, 95% yield) as a yellow oil: [R]20 - 24.0° (c
D
0.20, C6H6); IR (CHCl3) 3000 (m), 2950 (s), 2860 (m), 1640 (w), 1610
(s), 1590 (s), 1500 (s), 1465 (s), 1425 (s), 1280 (w), 1250 (m), 1130
1
1
(s), 1015 (w), 750 (s), 680 (s) cm-1; H NMR (500 MHz, CDCl3) δ
1212 (m), 1132 (s) cm-1; H NMR (500 MHz, C6D6) δ 6.34 (s, 4 H),
7.53 (m, 6 H), 6.28 (s, 2 H), 5.65 (dddd, J ) 17.3, 10.0, 7.4, 7.4 Hz,
1 H), 4.88 (app d, J ) 17.7 Hz, 1 H), 4.77 (app d, J ) 10.1 Hz, 1 H),
3.72 (s, 6 H), 3.46 (m, 1 H), 3.33 (m, 2 H), 2.59 (m, 1 H), 2.49 (dddd,
J ) 7.5, 7.5, 7.5, 7.5 Hz, 1 H), 2.38 (m, 2 H), 1.87 (m, 1 H), 1.75 (m,
1 H), 1.67 (m, 1H), 1.56 (m, 1 H), 1.22 (m, 2 H), 1.13 (m, 1 H), 1.02
(m, 1 H), 0.94 (d, J ) 6.6 Hz, 3 H), 0.78 (t, J ) 6.8 Hz, 3 H); 13C
NMR (125 MHz, C6D6, 63 °C) δ 159.6, 154.2, 139.8, 139.3, 134.6,
129.6, 127.54, 124.0, 119.8, 114.5, 106.0, 55.6, 43.9, 39.0, 36.6, 35.8,
34.5, 33.6, 31.7, 31.0, 23.2, 19.5, 14.2; high-resolution mass spectrum
(CI, CH4) m/z 495.2794 [(M + H)+; calcd for C28H39O2N4S, 495.2784].
To a solution of the thioether (11.0 mg, 0.022 mmol) in EtOH (1.5
mL) at 0 °C was added a solution of aqueous hydrogen peroxide and
ammonium heptamolybdate tetrahydrate [25.0 µL of a stock solution
of Mo7O24(NH4)6‚4H2O (240 mg, 0.19 mmol) in 30% w/v aqueous
hydrogen peroxide (1.0 mL)]. The reaction was allowed to warm to
20 °C and after 18.5 h was quenched with water (3.0 mL), extracted
with ethyl acetate (3 × 5.0 mL), dried with MgSO4, filtered, and
concentrated. Purification via flash chromatography (10% ethyl acetate
5.93 (dddd, J ) 17.2, 10.1, 7.2, 7.2 Hz, 2 H), 5.50 (app t, J ) 4.1 Hz,
2 H), 5.10 (app d, J ) 16.3 Hz, 2 H), 4.94 (app d, J ) 10.1 Hz, 2 H),
3.76 (dddd, J ) 9.1, 9.1, 6.6, 6.6 Hz, 2 H), 3.44 (s, 12 H), 2.86 (m, 2
H), 2.70 (m, 4 H), 2.34 (dd, J ) 13.3, 8.2 Hz, 2 H), 2.14 (m, 4 H),
1.95 (m, 2 H), 1.86 (m, 4 H), 1.36 (complex m, 8 H), 0.95 (d, J ) 6.6
Hz, 6 H), 0.85 (t, J ) 7.0 Hz, 6 H); 13C NMR (125 MHz, C6D6, 65 °C)
δ 159.6, 140.6, 139.4, 130.7, 119.6, 114.5, 106.0, 55.5, 44.1, 40.4, 39.1,
35.8, 35.7, 33.6, 31.0, 23.2, 19.7, 14.2; high-resolution mass spectrum
(CI, CH4) m/z 655.4677 [(M + Na)+; calcd for C42H64O4Na, 655.4702].
Macrocycle (-)-48 from Trienes (-)-68 and (-)-69. General
Procedure for Metathesis Reaction. A degassed solution (ca. 0.02
M) of triene (-)-69 (4.5 mg, 0.007 mmol) in degassed benzene (0.70
mL) was treated with the metathesis catalyst (32-35 mol %). The
resulting homogeneous solution was stirred for 60-75 min; concentra-
tion under reduced pressure led to the product, which was purified by
preparative TLC. All spectroscopic and chirooptic properties are
identical to those reported above for macrocycle (-)-48.
in hexanes) gave (-)-72 (10.0 mg, 87% yield) as a yellow oil: [R]20
Acknowledgment. Support was provided by the National
Institutes of Health (National Institute of General Medical
Sciences) through Grant GM-29028. In addition, we thank
Professor Grubbs (California Institute of Technology) for a
generous sample of ruthenium complex B, and Drs. George T.
Furst, Patrick J. Carroll, and Rakesh Kohli of the University of
Pennsylvania Spectroscopic Service Center for assistance in
securing and interpreting high-field NMR spectra, X-ray crystal
structures, and mass spectra, respectively. Finally, we thank
Professor Hoye for the exchange of spectral data and Professor
Kozlowski for useful advice and comments regarding molecular
modeling.
D
-21.3° (c 0.15, CDCl3); IR (film) 2983 (s), 2915 (s), 2859 (w), 1603
(m), 1573 (w), 1495 (w), 1456 (s), 1420 (m), 1339 (s), 1149 (s) cm-1
;
1H NMR (500 MHz, C6D6) δ 7.32 (m, 2 H), 6.88 (m, 3 H), 6.21 (s, 2
H), 5.93 (dddd, J ) 17.1, 10.1, 7.0, 7.0 Hz, 1 H), 5.10 (app d, J )
17.6 Hz, 1 H), 4.95 (app d, J ) 10.2 Hz, 1 H), 3.76 (dddd, J ) 9.1,
9.1, 6.0, 6.0 Hz, 1 H), 3.48 (s, 6 H), 3.38 (m, 1 H), 3.26 (m, 1 H), 2.88
(m, 1 H), 2.68 (dddd, J ) 7.1, 7.1, 7.1, 7.1 Hz, 1 H), 2.29 (dd, J )
13.5, 6.6 Hz, 1 H), 2.14 (m, 2 H), 1.86 (m, 2 H), 1.66 (m, 1 H), 1.60
(m, 1 H), 1.35 (m, 4 H), 0.85 (t, J ) 6.9 Hz, 3 H), 0.63 (d, J ) 6.5 Hz,
3 H); 13C NMR (125 MHz, C6D6, 63 °C) δ 159.4, 154.0, 138.9, 138.8,
133.4, 130.6, 129.1, 125.0, 119.7, 114.2, 105.5, 55.2, 54.4, 43.2, 38.6,
35.4, 33.6, 33.2, 30.6, 28.6, 22.9, 19.9, 13.8; high-resolution mass
spectrum (CI, CH4) m/z 549.2488 [(M + Na)+; calcd for C28H38O4N4-
SNa, 549.2511].
Supporting Information Available: Experimental proce-
dures and spectroscopic and analytical data for compounds 1a,
1f, 9-13, 19, 20, 22-25, 27, 29-34, 36-41, 43-53, 54-57,
59-61, 68-72 (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
E-Dimer (-)-69. To a solution of sulfone (-)-72 (18.0 mg, 0.034
mmol) in THF (0.90 mL) at -78 °C was added KHMDS (0.5 M in
toluene; 87 µL, 0.034 mmol), resulting in a bright yellow solution.
After 30 min, aldehyde (+)-70 (12.0 mg, 0.036 mmol), predissolved
in THF (0.70 mL), was added dropwise via cannula to the reaction
mixture and allowed to stir for 2 h, after which the reaction was brought
JA0106164