Acetylenic allenophanes: An asymmetric synthesis of a bis(alleno)- bis(butadiynyl)-metacyclophane

Article abstract of DOI:10.1002/anie.200500484

(Chemical Equation Presented) A cyclophane with allene and acetylene bridges has been prepared as a single enantiomer. This acetylenic allenophane (see structure) was synthesized by a series of palladium- and copper-mediated coupling reactions. The allene

Full text of DOI:10.1002/anie.200500484

Angewandte
Chemie
Asymmetric Synthesis
Acetylenic Allenophanes: An Asymmetric
Synthesis of a Bis(alleno)-bis(butadiynyl)-meta-
cyclophane**
Matthew D. Clay and Alex G. Fallis*
We have an ongoing interest in the design and synthesis of
novel cyclophanes, many of which contain a twisted con-
formation that imparts helical chirality[1] to the assembled
molecule.[2] This helical chirality is a consequence of the
number, type, and combination of unsaturated linkages
present in these molecules. The synthesis and design of
cyclophanes[3] and cage compounds with high carbon content
in novel shapes and supramolecular geometries[4] continues to
be a topic of current interest.
Allenes are a unique family of organic molecules because
of their diverse chemistry, axial chirality, and synthetic
versatility,[5] and so investigations into allene-containing
natural products and their total syntheses continue to
increase.[6] Furthermore, medical applications for these com-
pounds include employing them as inactivators of monoamine
oxidase.[7]
In contrast, cyclophanes that have only allene bridges
(termed allenophanes)[8] have received little attention and the
only reported example was prepared as a mixture of
diastereomers.[8] A related family of cyclophanes comprises
structures that contain both allene and acetylene bridges.
These acetylenic allenophanes should also possess interesting
properties. Herein, we report the first asymmetric synthesis of
an acetylenic allenophane that contains two allene bridges.
This compound appears to be the first cyclophane of this
general class.
Scheme 1. An acetylenic allenophane.
We devised a strategy to an acetylenic allenophane related
to 16 based on the dimerization of desilylated 15 (see
Scheme 4). We[9a] and others[9b] observed previously that the
separation of the alkyne termini dictates whether the intra- or
intermolecular product dominates. Molecular modeling stud-
ies have strongly suggested that the intermolecular product is
favored when the termini separation is greater than 7 ꢀ.[9c] In
the case of 15, the calculated alkyne separation of 8.87 ꢀ[10]
indicated that the intramolecular product 16 should be
preferred.
We initially examined the allene preparation used by
Myers and Zheng for the synthesis of an allenophane in which
R2 groups are hydrogen atoms (Scheme 1).[11] This asymmet-
ric method had the advantage that the allene precursor, a
secondary propargyl alcohol, was readily available through
the addition of an acetylide to an aldehyde.[12] Initially, ortho-
amino substituents at the aryl ring were chosen to aid
solubility, but this idea had to be abandoned because electron
donation from the lone pair of electrons on the nitrogen atom
in the ortho-amino substituent leads to the formation of
cumulene-type intermediates during allene formation
(Scheme 2), and so tert-butyl groups were selected instead.
The general structure of an acetylenic
allenophane is depicted in Scheme 1. The
R1 substituents aid solubility: the absence of
similar groups in the previously prepared
allenophane[8] limited its solubility and pre-
vented a full investigation into its properties.
The R2 substituents may be hydrogen atoms
or alkyl groups, depending on the method
selected to synthesize the allene moiety. The
number of acetylene bridges may also be
varied.
Scheme 2. Proposed mechanism for the formation of allene A because of ortho-amino aryl
substituents.
Unfortunately, the procedure of Myers and Zheng afforded a
disappointing yield of 18%.
[*] M. D. Clay, Prof. Dr. A. G. Fallis
Department of Chemistry
An attractive alternative for the generation of asymmetric
allenes employs an SN2’ addition of an organocuprate to a
propargyl acetate.[13] This method allows fully substituted
allenes to be synthesized, but requires the asymmetric
synthesis of a tertiary propargyl alcohol. Reported methods
University of Ottawa
10 Marie Curie, Ottawa, Ontario, K1N 6N5 (Canada)
Fax: (+1)613-562-5170
E-mail: afallis@science.uottawa.ca
[**] We are grateful to the National Sciences and Engineering Research
Council of Canada (NSERC) for financial support of this research.
We thank H. Foucault and L. Barriault (University of Ottawa) for
assistance with the molecular modeling studies. M.D.C. also thanks
the NSERC, OGS, and University of Ottawa for graduate scholar-
ships.
for the preparation of this species are limited to examples that
utilize the asymmetric addition of a zinc acetylide to a
ketone[14] or the asymmetric addition of an alkyl zinc to a
ketone.[15] Unfortunately, the asymmetric addition of dime-
thylzinc to the ketone precusor of 13 failed (see Scheme 4).
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DOI: 10.1002/anie.200500484
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Similarly, the combination of the zinc acetylide to the
A Sonogashira coupling between 1-bromo-3-iodo-5-tert-
butylbenzene (5)[17] and (triisopropylsilyl)acetylene smoothly
generated aryl bromide 6 in 99% yield. A lithium–halogen
exchange followed by quenching of the resulting anion with
zinc bromide generated an organozinc intermediate, which
was coupled with vinyl iodide 7[18] to generate the tert-
butyldimethylsilyl (TBS) ether 8, also in 99% yield. Selective
cleavage of the TBS group followed by Sharpless asymmetric
epoxidation of the allylic alcohol provided the allylic epoxy
alcohol 9 in 93% yield (88% ee).[19] Initially, the ring opening
of 9 was examined with various aluminum hydride reagents.
In each case, the epoxide was cleaved readily, however,
despite a literature precedent[20] the resulting diol was
partially racemized. This occurred presumably through a
Payne rearrangement[21] of the epoxy alcohol. Therefore, the
ring opening of the epoxide was postponed until a later stage
in the synthesis.
appropriate acetophenone to generate 13 directly was also
unsuccessful. This failure was likely due to the steric
encumbrance of the tert-butyl solubilizing groups as well as
the inherent poor electrophilicity of the ketones employed.
Consequently, a new strategy was developed to construct
these tertiary propargyl alcohols.
We designed a method in which the requisite stereogenic
centers could be installed by using a Sharpless asymmetric
epoxidation (Scheme 3). Oxidation of epoxy alcohol 2 should
Scheme 3. An asymmetric synthetic route to tertiary propargyl
alcohols.
Oxidation of 9 with the Dess–Martin periodinane gave an
aldehyde in 89% yield, which was subsequently converted
into a terminal alkyne with the Ohira reagent (93%). The
epoxide in 10 was opened cleanly on exposure to L-selectride
to provide tertiary propargyl alcohol 11, and no lowering of
enantiomeric excess was detected (HPLC analysis). This
sequence for the conversion of an epoxide into a tertiary
afford the desired aldehyde 3, which upon exposure to the
reagent developed by Ohira[16] would give an epoxy alkyne
that could undergo ring opening with a suitable hydride
reagent to yield the desired tertiary propargyl alcohol 4. The
synthetic pathway that was developed is given in Scheme 4.
Scheme 4. Synthesis of acetylenic allenophane 16. Reagents and conditions: a) (triisopropylsilyl)acetylene, [PdCl2(PPh3)2], CuI, Et3N, THF, RT, 16 h
(99%); b) 1. 6, tBuLi, THF, ꢀ788C, 5 min; 2. ZnBr2, THF, ꢀ78!08C, 30 min; 3. 7, [Pd(PPh3)4], THF, RT, 16 h, (99%); c) 10% HCl, THF, RT, 4 h
(79%); d) [Ti(OiPr)4], l-DIPT, tBuOOH, 4-ꢀ molecular sieves, CH2Cl2, ꢀ50!208C, 16 h (93%, 88% ee); e) Dess–Martin periodinane, CH2Cl2, RT,
30 min (89%); f) Ohira reagent, K2CO3, MeOH, 08C!RT, 90 min (93%); g) L-selectride, THF, 08C, 10 min (88%); h) 12, [PdCl2(PPh3)2], CuI,
Et3N, THF, RT, 16 h (51%); i) Ac2O, DMAP, pyridine, CH2Cl2, RT, 24 h (85%); j) CH3MgBr, LiBr, CuI, THF, 08C, 2 h (74%); k) TBAF, THF, 08C,
10 min (98%); l) addition of 15 to a solution of Cu(OAc)2 in pyridine/diethyl ether (3:1) over 6 h, RT, total time: 8 h (40%). l-DIPT=diisopropyl
l-tartrate, L-selectride=lithium tri-sec-butylborohydride, DMAP=4-dimethylaminopyridine, TBAF=tetrabutylammonium fluoride,
TIPS=triisopropylsilyl, Ac=acetyl.
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propargyl alcohol was easily completed within one day in an
overall yield of 73%. A Sonogashira reaction between 11 and
aryl iodide 12 (prepared through a lithium–halogen exchange
of 6 followed by quenching with iodine) generated the
propargyl alcohol 13 in 51% yield. A modification of the
standard Sonogashira coupling conditions failed to increase
the yield.[22]
Acetylization of 13 with acetic anhydride gave acetate 14
in 85% yield. As anticipated, (S)-allene 15 was formed
through the addition of 14 to the organocuprate generated
from a mixture of CH3MgBr, LiBr, and CuI (74% yield).
Removal of the triisopropylsilyl groups with TBAF generated
the terminal bisalkyne 15 in 98% yield with 83% ee. This
indicated that there was minimal racemization during gen-
eration of the allene. The slow addition of (S)-15 to a solution
of Cu(OAc)2 in pyridine and diethyl ether afforded the
desired (S,S)-acetylenic allenophane 16 in 40% yield. The
desilylation–dimerization sequence could also be conducted
in a one-pot procedure, but the isolation of 16 was more
difficult because of the presence of several highly fluorescent
impurities. Unfortunately, crystals of 16 suitable for X-ray
crystallographic studies could not be obtained; however,
molecular modeling studies revealed the unique conforma-
tion of this cyclophane:[23] Figure 1a illustrates the chirality of
16, whereas Figure 1b reveals its helical nature.
Figure 3. CD spectrum of 16.
allenes with which to compare the spectra of our acetylenic
allenophane.[24] Nevertheless, the typical “fingerprint” pattern
for acetylenes with bands at 295, 313, and 335 nm is apparent
in the UV/Vis spectrum. Major signals at 263 and 270 (sh) nm
were observed in the CD spectrum that may have arisen from
the through-space interactions of the phenyl rings.
In conclusion, a novel single-enantiomer acetylenic alle-
nophane 16 has been synthesized by a series of palladium- and
copper-mediated coupling reactions. A new protocol was
developed that allowed the stereochemistry of the allene to be
controlled by the use of a Sharpless asymmetric epoxidation
and a tertiary a-hydroxyethyne intermediate. We are cur-
rently investigating the scope and synthetic utility of this
reaction sequence for other targets.
Received: February 8, 2005
Published online: May 20, 2005
Keywords: alkynes · allenes · asymmetric epoxidation ·
.
cyclophanes · diynes
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