Optically active trialkynyl(phenyl)methane: synthesis and determination of its absolute configuration by vibrational circular dichroism (VCD) and optical rotatory dispersion (ORD)

Article abstract of DOI:10.1002/ejoc.201000076

Both enantiomers of an optically active trialkynyl(phenyl)methane (the key building blocks in the construction of a stable expanded cubane) have been prepared. The strategy involved the resolution of a racemic intermediate by means of HPLC on a chiral stationary phase. The absolute configuration of this intermediate was unambiguously assigned by using vibrational circular dichroism (VCD) and optical rotatory dispersion (ORD), in combination with density functional theory (DFT) calculations.

Full text of DOI:10.1002/ejoc.201000076

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000076
Optically Active Trialkynyl(phenyl)methane: Synthesis and Determination of
Its Absolute Configuration by Vibrational Circular Dichroism (VCD) and
Optical Rotatory Dispersion (ORD)
Boris Buschhaus,[a] Vito Convertino,[a] Pablo Rivera-Fuentes,[a]
José Lorenzo Alonso-Gómez,[b] Ana G. Petrovic,[b] and François Diederich*[a]
Keywords: Alkynes / Chiral methanes / Chiral resolution / Optical rotatory dispersion / Vibrational circular dichroism
Both enantiomers of an optically active trialkynyl(phenyl)-
methane (the key building blocks in the construction of a
stable expanded cubane) have been prepared. The strategy
involved the resolution of a racemic intermediate by means
of HPLC on a chiral stationary phase. The absolute configu-
ration of this intermediate was unambiguously assigned by
using vibrational circular dichroism (VCD) and optical rota-
tory dispersion (ORD), in combination with density functional
theory (DFT) calculations.
(EC), bearing methoxy groups as substituents in the corners
(Figure 1a).[2] The synthesis of the octamethoxy-EC con-
Introduction
The geometrically defined expansion of molecules by in- sisted of the sequential construction of the corners, edges,
sertion of buta-1,3-diyne-1,4-diyl fragments into C–C single and faces of the cube. Unfortunately, the use of racemic
bonds has been a topic of research in our group for nearly corner modules led to very low overall yield; a consequence
20 years. This approach to new carbon-rich molecules has of the formation of inseparable mixtures of diastereoiso-
rendered a plethora of “expanded” polyacetylenes [the mers during the edge- and face-forming steps. To circum-
poly(triacetylene)s], arenes, annulenes, radialenes, and radia- vent this problem, the synthesis of an optically active, asym-
annulenes.[1] The application of this concept to the third metrically silyl-protected methyl trialkynylmethyl ether was
dimension led to the synthesis of the first expanded cubane developed.[3]
Figure 1. Expanded cubanes: (a) octamethoxy derivative; (b) octaphenyl derivative.
A serious problem associated with octamethoxy-EC,
which prevented production of larger materials quantities
and full exploration of its physical properties, is its high
instability: it explodes upon scraping. However, the stabili-
ties of a series of expanded polyhedranes were investigated
theoretically by using a combination of isodesmic, group
additivity, and molecular mechanics methods.[4] These stud-
[a] Laboratorium für Organische Chemie, ETH Zürich
Hönggerberg, HCI, 8093 Zurich, Switzerland
Fax: +41-44-632-1109
E-mail: diederich@org.chem.ethz.ch
[b] Department of Chemistry, Columbia University
10027 New York, USA
Fax: +1-212-932-1289
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000076.
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Optically Active Trialkynyl(phenyl)methane
ies revealed that most of the strain energy rests in the rela-
tively flexible buta-1,3-diyne-1,4-diyl edges, therefore ex-
panded derivatives are in fact less strained, and structurally
Results and Discussion
The synthesis of the trialkynyl(phenyl)methane is de-
more stable than their unexpanded counterparts. In this picted in Scheme 1. The initial step involved the cross-cou-
sense, the unexpected instability of the octamethoxy-EC pling of ethynyltriisopropylsilane (1) to ethyl 3-phenylpro-
can be explained in terms of an alternate decomposition piolate (2) in the presence of Pd(OAc)2 and tris(2,6-dimeth-
pathway. Mass spectrometry revealed the successive loss of oxyphenyl)phosphane (TDMPP) to provide the enynoate 3
up to eight methoxy groups in both the positive and nega- in high yield (84%).[6] The next step was the reduction of
tive ion mode, leading to the proposal of a polar mecha- ester 3 to alcohol 4 by using DIBAL-H in THF, followed
nism involving highly unstable nonplanar tripropargyl by epoxidation with m-chloroperbenzoic acid (MCPBA) to
ions.[2] To hinder this decomposition pathway, a different afford the racemic epoxide (Ϯ)-5. At this stage, several
substituent in the corner module is required. An alternative asymmetric epoxidation procedures were tried to obtain 5
building block is a trialkynyl(phenyl)methane, as a precur- in optically pure form and high yields (see the Supporting
sor of an octaphenyl-EC (Figure 1b), which is expected to Information); however, all of them proved to be strategi-
be more stable than the octamethoxy derivative.
cally inconvenient. The racemic epoxy alcohol (Ϯ)-5 was
Herein, we report the synthesis and optical resolution of protected by using tBuMe2SiCl to deliver derivative (Ϯ)-6.
an asymmetrically silyl-protected trialkynyl(phenyl)meth- Compound (Ϯ)-6 underwent Yamamoto rearrangement[7]
ane and the determination of its absolute configuration by in the presence of methylaluminum bis(4-bromo-2,6-di-tert-
vibrational circular dichroism (VCD)[5] and optical rotatory butylphenoxide) (MABR) to give aldehyde (Ϯ)-7. Corey–
dispersion (ORD).
Fuchs dibromoolefination gave (Ϯ)-8, which was trans-
Scheme 1. Synthesis of optically pure trialkynyl(phenyl)methane. Reagents and conditions: (a) Pd(OAc)2, TDMPP, benzene, 20 °C, 24 h,
84%; (b) DIBAL-H, THF, –78 °C, 3 h, 95%; (c) m-CPBA, Na2HPO4, CH2Cl2, 0 °C, 2 h, 75%; (d) tBuMe2SiCl, imidazole, CH2Cl2, 0–
20 °C, 24 h, 95%; (e) MABR, CH2Cl2, –78 °C, 45 min, 67%; (f) PPh3, CBr4, CH2Cl2, 0 °C, 3 h, 93%; (g) nBuLi, THF, –78 °C, 2 h, 95 %;
(h) TFA/H2O (9:1), CH2Cl2, 0 °C, 45 min, 100%; (i) nBuLi, Me3SiCl, THF, –78 °C, 2 h, then HCl 1 , THF, –78 °C, 20 min, 72%; (j)
DMP, CH2Cl2, 0 °C, 12 h, 74%; (k) PPh3, CBr4, CH2Cl2, 0 °C, 3 h, 83%; (l) nBuLi, THF, –78 °C, 3 h, 73%. TDMPP = tris(2,6-dimeth-
oxyphenyl)phosphane, DIBAL-H = diisobutylaluminium hydride, m-CPBA = m-chloroperbenzoic acid, MABR = methylaluminum bis(4-
bromo-2,6-di-tert-butylphenoxide), TFA = trifluoroacetic acid, DMP = Dess–Martin periodinane.
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F. Diederich et al.
SHORT COMMUNICATION
formed into dipropargyl derivative (Ϯ)-9 in good yields.[8]
The VCD spectrum of alcohol 10 was measured in dry
The key intermediate (Ϯ)-10 was obtained by removal of CCl4 at a concentration of 0.14 . Infrared spectroscopy
the SiMe2tBu protecting group. The enantiomers (+)-10 shows only marginal association of 10 at this concentration
and (–)-10 were obtained in enantiomerically pure form af- (see the Supporting Information). VCD and ORD data
ter resolution by HPLC on a chiral stationary phase were also calculated at the B3LYP/6-31G(d) level of theory.
(WHELK-O1, for details see the Supporting Information). The VCD curve calculated for the ensemble of (S)-10,[12]
The last steps of the synthesis were the Dess–Martin oxi- and the spectrum measured for (–)-10 are shown in Fig-
dation of (+)-10 to give aldehyde (+)-11,[9] a second Corey– ure 3. The calculated Cotton effects 1 and 2 correlate well
Fuchs olefination to furnish the intermediate (–)-12, and in sign and frequency with the experimental ones. Cotton
subsequent elimination to yield the final compound (+)-13. effects 3, 4, and 5 are shifted to higher wavenumbers, and
The pure enantiomers (–)-11, (+)-12, and (–)-13 were ob- the relative intensities of 4 and 5 are not well reproduced.
tained similarly by starting from (–)-10 (for experimental Equivalent results were obtained when optimization and
details, see the Supporting Information). Enantiomers (+)- harmonic vibrational analysis (including VCD) were per-
13 and (–)-13 were obtained as colorless oils that are stable
under ambient laboratory conditions.
Despite their high optical purity (Ն 99% ee), compounds
10, 11, 12, and 13 featured electronic circular dichroism
(ECD) spectra with very weak Cotton effects, which could
not be distinguished from noise. This lack of Cotton effects
in the measurable range precludes the determination of the
absolute configuration by direct comparison of the calcu-
lated and experimental ECD traces.
Several derivatives of 10 were prepared in an attempt to
determine the absolute configuration by X-ray crystallo-
graphic methods. Unfortunately, all these derivatives were
oils, which could not be crystallized. Other attempts to cou-
ple strong chromophores, which could provide Cotton ef-
fects in the visible or near-UV range, failed.
In view of the impossibility of using ECD to determine
the absolute configuration of these molecules, we decided
to use a combination of VCD spectroscopy and ORD to
determine the absolute configuration of compound 10.[10]
In order to obtain the calculated spectra, we performed a
conformational search to identify the conformers that con-
tribute to the equilibrium properties, and assess their pop-
ulations in a Boltzmann ensemble (for details see the Sup-
porting Information). The conformational search was per-
formed by using a mixed Monte Carlo Multiple Minimum/
Low-Mode Conformational Search algorithm (for details
see the Supporting Information), followed by geometry op-
timization of the resulting conformers at the B3LYP/6-
31G(d) level of theory using Gaussian 03.[11] This further
Figure 3. Calculated IR (dashed line, upper graph), experimental
IR (solid line, upper graph), calculated VCD (dashed line, lower
refinement led to the three main conformers shown in Fig-
graph), and experimental VCD spectrum (solid line, lower graph).
Calculated frequencies were shifted by 0.97. For details and assign-
ment of the Cotton effects, see the Supporting Information.
ure 2. Their relative populations were determined by using
the computed Gibbs free energy.
Figure 2. Conformers of (R)-10 found at the B3LYP/6-31G(d) level of theory. The conformer populations (Boltzmann distribution) were
determined by using the computed Gibbs free energy at 298.15 K and 1 atm.
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Optically Active Trialkynyl(phenyl)methane
formed at the B3PW91/6-31G+(d) level of theory. Differ-
ences between calculated and experimental VCD spectra
can be attributed to the omission of conformers with minor
contributions, bad estimation of the conformer’s free en-
ergy, functional and/or basis set effects, and even to experi-
mental errors. However, the overall signature of the curve
calculated for the (S) structure is in qualitative agreement
with that measured for the (–) sample.
To support the assignment made by VCD, optical rota-
tion values at four different wavelengths were measured for
both enantiomers of 10 [(+)-10 at c = 9.6 m in n-hexane
and (–)-10 at c = 12.5 m] in CCl4, i.e. at low concentration
in the absence of any possible aggregation (see the Support-
ing Information). Comparison of the experimental and cal-
culated curves (Figure 4) shows conclusive results, which
confirm the assignment by VCD. Therefore, the absolute
configuration can be unambiguously assigned as (–)-(S)-10.
Since the asymmetric center is not altered in the subsequent
reactions (see Scheme 1), the absolute configuration of all
optically active material can be assigned: (–)-(R)-11, (+)-
(S)-12, and (–)-(S)-13.
Experimental Section
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, full characterization of all com-
pounds, aggregation studies of compound 10, and details about
calculations.
Acknowledgments
This work was supported by the Research Council of ETH Zurich,
a doctoral fellowship to P. R.-F. from the Stipendienfonds der
Schweizerischen Chemischen Industrie (SSCI), and a postdoctoral
fellowship to B. B. from the Deutsche Forschungsgemeinschaft. We
acknowledge the C4 Competence Center for Computational Chem-
istry at ETH Zurich and CESGA (Santiago de Compostela, Spain)
for the allocation of computational resources. We are grateful to
Prof. P. L. Polavarapu for facilitating the VCD measurements and
for discussions. A. G. P. and J. L. A.-G. thank Prof. N. Berova (Co-
lumbia University) for support and useful discussions. We grate-
fully acknowledge one of the referees of this communication for
very valuable comments.
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Figure 4. Experimental ORD curves of (+)-10 (c = 9.6 m in n-
hexane, triangles, black line) and (–)-10 (c = 12.5 m in n-hexane,
diamonds, black line). Calculated ORD values at the B3LYP/6-
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Conclusions
We accomplished the synthesis and optical resolution of
the asymmetrically silyl-protected trialkynyl(phenyl)meth-
anes (–)-(S)-13 and (+)-(R)-13. The absolute configuration
of the precursors (–)-(S)-10 and (+)-(R)-10 was unambigu-
ously determined by using VCD spectroscopy and ORD, in
combination with quantum chemical calculations. Future
work includes the synthesis of the octaphenyl-EC, which
could provide larger quantities of stable material to experi-
mentally study the interesting properties conceived for these
cage compounds.[2,4,13]
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[12] The calculated spectrum of (S)-10 was obtained by multiplying
the calculated spectrum of the ensemble of (R)-10 by –1.
Received: January 21, 2010
Published Online: March 17, 2010
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