Asymmetric total synthesis of cylindrocyclophanes A and F through Cyclodimerization and a Ramberg-Baecklund Reaction

Article abstract of DOI:10.1002/anie.201003500

(Figure Presented) Two make a cycle: A Ramberg-Baecklund reaction was employed to form the macrocyclic carbon skeleton of the marine natural products cylindrocyclophanes A and F in an asymmetric synthesis through a head-to-tail dimerization approach (see scheme).

Full text of DOI:10.1002/anie.201003500

Angewandte
Chemie
DOI: 10.1002/anie.201003500
Natural Product Synthesis
Asymmetric Total Synthesis of Cylindrocyclophanes A and F through
Cyclodimerization and a Ramberg–Bꢀcklund Reaction**
K. C. Nicolaou,* Ya-Ping Sun, Henry Korman, and David Sarlah
With their appealing architectures and unique chemical and
physical properties, the bridged class of aromatic compounds
known as cyclophanes (e.g. parent [7.7]paracyclophane,
Scheme 1) have been inspiring chemists ever since their
total synthesis,[4–6] with two total syntheses of such molecules,
both employing head-to-tail cyclodimerizations.[4,5] The total
synthesis of cylindrocyclophanes A (1) and F (2) by Smith
et al.[4] involved an elegant cross metathesis/ring-closing
metathesis (CM/RCM) dimerization to cast the moleculeꢁs
[7.7]paracyclophane framework (see bis(olefin) I and its
precursor II, Scheme 2a). The total synthesis of cylindrocy-
clophane A by Hoye et al.[5] exploited a dimerization based
on a double Horner–Emmons reaction to construct a
[7.7]paracyclophane intermediate from a suitable precursor
(structures III and IV, Scheme 2b). Herein we describe our
own head-to-tail dimerization approach to access this class of
compounds based on the Ramberg–Bꢂcklund olefination
reaction to generate [7.7]paracyclophane intermediate 3 from
Scheme 1. Structures of parent [7.7]paracyclophane and cylindrocylo-
phanes A (1) and F (2).
introduction by Cram and Steinberg almost 60 years ago.[1] To
the designed cyclophanes[2] were later added naturally occur-
ring compounds, beginning in 1990 when Moore et al.
reported the isolation of cylindrocyclophane A (1,
Scheme 1) and its siblings from a blue–green algae belonging
to Cylindrospermum licheniforme Kꢀtzing (ATTC 29204).[3a]
Two years later, the same research group isolated cylindro-
cyclophane F (2) from the same algae.[3b] These 22-membered
[7.7]paracyclophanes exhibit potent cytotoxicity against the
KB and LoVo tumor cell lines (IC50 = 2–10 mgmLꢀ1).
The unique molecular architectures and important bio-
logical properties of the cylindrocyclophane natural products
elicited considerable research activities directed toward their
[*] Prof. Dr. K. C. Nicolaou, Dr. Y.-P. Sun, H. Korman, D. Sarlah
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 N. Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry,
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
Fax: (+1)858-784-2469
[**] We thank Dr. D. H. Huang and Dr. L. Pasterneck for assistance with
the NMR spectroscopy measurements, and Dr. Siuzdak for mass
spectrometry measurements. Financial support for this work was
provided by the National Institute of Health (USA) and The Skaggs
Institute for Research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003500.
Scheme 2. Cyclodimerization approaches to cylindrocyclophanes:
a) Smith et. al.;[4] b) Hoye et. al.;[5] c) this work.
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precursor 4 (Scheme 2c) that culminated in asymmetric total
syntheses of cylindrocyclophanes A (1) and F (2).
From a strategic perspective, it would be most desirable to
construct the C2-symmetric cyclophane structural motif of
these molecules through dimerization, preferably head-to-
tail, of two identical fragments. To this end, our approach
envisioned a Ramberg–Bꢂcklund reaction of sulfone 5 as
shown retrosynthetically in Scheme 3. Disassembly of 5 led to
bifunctional monomeric unit 4, which was traced back to aryl
bromide 6 through asymmetric functionalization.
Scheme 4. Enantioselective construction of bifunctional monomeric
unit 4. Reagents and conditions: a) nBuLi (1.3 equiv), THF, ꢀ78!
ꢀ308C, 0.5 h, pentanal (2.0 equiv), 08C, 1 h; b) TEMPO (0.15 equiv),
BAIB (1.2 equiv), CH2Cl2, 238C, 12 h, 76% over two steps; c) vinyl
bromide 8 (2.0 equiv), tBuLi (4.1 equiv), Et2O, ꢀ78!238C, 0.5 h,
ketone 7, ꢀ78!08C, 0.5 h; d) PDC (3.0 equiv), M.S. (4 ꢀ), CH2Cl2,
238C, 3 h, 48% (64% brsm) over two steps; e) (S)-CBS (0.3 equiv),
catecholborane (2.0 equiv), toluene, ꢀ78!08C, 12 h; f) Crabtree’s
catalyst (9 mol%), H2 (50 atm), CH2Cl2, 238C, 4 h, 65% yield over two
steps, 93% ee, d.r.>20:1; g) MsCl (1.1 equiv), Et3N (1.2 equiv), THF,
08C, 0.5 h; then super-H (4.0 equiv), THF, 808C, 4 h; then TBAF
(3.0 equiv), THF, 08C, 1 h, 73%; h) PPh3 (1.8 equiv), DIAD (1.8 equiv),
THF, 08C, 20 min; then AcSH (1.7 equiv) and alcohol 11, 08C, 1 h;
i) TsOH (0.2 equiv), AcOH/H2O (7:1), 238C, 1 h; j) MsCl (1.5 equiv),
Et3N (2.0 equiv), CH2Cl2, 08C, 0.5 h, 76% over three steps. BAIB=bi-
s(acetoxyiodo)benzene, brsm=based upon recovered starting mate-
rial, CBS=Corey–Bakshi–Shibata catalyst, DIAD=diisopropyl azodicar-
boxylate, Ms=mesyl, M.S.=molecular sieves, PDC=pyridinium
dichromate, TBAF=tetrabutylammonium fluoride, TEMPO=2,2,6,6-
tetramethylpiperidine-1-oxyl, THF=tetrahydrofuran, super-
Scheme 3. Retrosynthetic analysis of cylindrocylophanes A (1) and F
(2). Ac=acetyl, TBS=tert-butyldimethylsilyl.
The enantioselective construction of the bifunctional
precursor 4 commenced with bromide 6[7] and proceeded as
depicted in Scheme 4. Thus, addition of lithiated 6 (nBuLi) to
pentanal and subsequent oxidation of the resulting alcohol
with TEMPO/BAIB furnished benzylic ketone 7 in 76%
overall yield. Reaction of the latter compound with the vinyl
lithium derived from 8 (tBuLi) and subsequent PDC-medi-
ated oxidative allylic transposition of the resulting allylic
alcohol gave vinyl ketone 9 (64% yield over two steps).[8]
Enantioselective reduction of 9 with (S)-CBS furnished the
expected chiral allylic alcohol (95% ee), which underwent
hydroxy-directed hydrogenation (CH2Cl2, 50 atm of H2) in
the presence of Crabtreeꢁs catalyst (9 mol%)[9] to afford
alcohol 10 in 65% yield and 93% ee (d.r. > 20:1). Deoxyge-
nation of the latter intermediate was achieved through its
mesylate, which reacted with superhydride (super-H =
LiBEt3H) to generate, after desilylation (TBAF), benzylic
alcohol 11 in 73% overall yield. Mitsunobu reaction of 11
with AcSH (Ph3P, DIAD) and subsequent desilylation
(TsOH, AcOH, H2O) and mesylation (MsCl, Et3N) led to
the desired thioacetate mesylate 4 in 76% overall yield.
H=LiBEt3H, Ts=para-toluenesulfunyl.
With the monomeric precursor 4 in hand, its dimerization
to [7.7]paracyclophane 3 and further functionalization to the
targeted cylindrocylophanes became possible, and indeed was
realized as demonstrated in Scheme 5. The much anticipated
cyclodimerization of 4 was brought about by treatment with
NaOMe in MeOH at ambient temperature and afforded the
corresponding macrocyclic bis(thioether), whose oxidation
with H2O2 in the presence of (NH4)6Mo7O24·4H2O furnished
macrocyclic bis(sulfone) 5 in 51% overall yield. Treatment of
sulfone 5 with alumina-impregnated KOH (KOH/Al2O3) in
the presence of CF2Br2 in CH2Cl2/tBuOH (1:1) at 0!238C led
to the expected bis(olefin) 3 in 70% yield (ca. EE/EZ = 12:1
before complete isomerization to EE-3 with [Pd-
(CH3CN)2Cl2]).[10] Dihydroxylation of the latter compound
with AD-mix-b (MeSO2NH2, tBuOH/H2O (2:1), ambient
temparature)[11] efficiently generated the corresponding
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zole), and led to dihydroxy compound 12 (50% yield over
three steps). Methylation of 12 (MsCl; then AlMe3),[13] and
subsequent removal of the methyl groups to reveal phenolic
groups (BBr3), all in one pot, secured cylindrocyclophane F
(2) in 71% overall yield. Oxidation of common intermediate
12 (DMP), followed by enol triflate formation (KHMDS,
Comins reagent) and subsequent Kumada-type coupling with
MeMgBr in the presence of [Fe(acac)3],[14] led to bis(olefin)
13 (74% yield over three steps, single geometrical isomer).
The latter compound served as a precursor in Hoyeꢁs total
synthesis of cylindrocyclophane A (hydroboration/deprotec-
tion).[5] The physical properties of synthetic 2 and 13 were in
accord with those previously reported in the literature.[3b,5]
The chemistry described here constitutes a short and
efficient total synthesis of cylindrocyclophane F (2) and a
formal total synthesis of cylindrocyclophane A (1) in their
naturally occurring enantiomeric forms. The asymmetry was
introduced through a CBS reduction of an enone and
subsequent hydroxy-directed hydrogenation employing the
Crabtree catalyst and deoxygenation. The crucial macro-
cyclodimerization was achieved through the use of a Ram-
berg–Bꢂcklund reaction, whose application to the synthesis of
complex molecules is on the rise.[15]
Received: June 8, 2010
Published online: July 12, 2010
Keywords: cyclodimerization · natural products · Ramberg–
.
Bꢁcklund reaction · total synthesis
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Scheme 5. Construction of [7.7]paracyclophane 3 and its conversion
into cylindrocylophanes A (1) and F (2). Reagents and conditions:
a) NaOMe (5.0 equiv), MeOH, 238C, 36 h; b) (NH4)6Mo7O24·4H2O
(0.3 equiv), H2O2 (aq, 35% w/w, 10.0 equiv), EtOH, 238C, 12 h, 51%
over two steps; c) CF2Br2 (5.0 equiv), KOH/Al2O3 (15% w/w, 2 g per
mmol), CH2Cl2/tBuOH (1:1), 0!238C, 2 h; then [Pd(CH3CN)2Cl2]
(0.3 equiv), 408C, 4 h, 70%; d) AD-mix-b, MeSO2NH2 (1.0 equiv),
tBuOH/H2O (2:1), 238C, 12 h; e) 1,1’-thiocarbonyldiimidazole
(10.0 equiv), toluene, 1258C, 5 h; f) AIBN (2.0 equiv), nBu3SnH
(10.0 equiv), toluene, 1008C, 1.5 h, 50% over three steps; g) MsCl
(5.0 equiv), Et3N (5.0 equiv), CH2Cl2, 08C, 0.5 h; then AlMe3
(5.0 equiv), 08C, 10 min; then BBr3 (10.0 equiv), 238C, 5 h, 71% one
pot; h) DMP (5.0 equiv), NaHCO3 (10.0 equiv), CH2Cl2, 238C, 1 h;
i) KHMDS (6.0 equiv), Comins reagent (6.0 equiv), THF, ꢀ788C, 1 h;
j) Fe(acac)3 (0.3 equiv), MeMgBr (10.0 equiv), THF/NMP (20:1), 08C,
1 h, 74% over three steps; for 13!1 see Ref. [5]. acac=acetylaceto-
nate, AIBN=2,2’-azobis(2-methylpropionitrile), DMP=Dess–Martin
periodinane, imid=imidazole, HMDS=hexamethyldisilazide.
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[10] T. Z. Chan, S. Fong, Y. Li, T. O. Man, C. D. Poon, J. Chem. Soc.
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Barton conditions (nBu3SnH, AIBN)[12] of its bis(thionocar-
bonate) (prepared by exposure to 1,1’-thiocarbonyldiimida-
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[11] E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schrꢃder, K. B.
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