CHAPTER V SYNTHESIS, RESOLUTION AND VCD ANALYSIS OF THE FIRST
V- 2.6.4 Generation of the Enantiopure Bowls
N N O
R1 R2
Raney Ni
(RC,RS)-109a: R1=Ph; R2=nPr
MeOH, 80%
N N
O
R2 S
O p-Tol
R1
(SC,RS)-109b: R1=nPr; R2=Ph
(S)-107a: R1=Ph; R2=nPr (R)-107a: R1=nPr; R2=Ph Equation V-2. Generation of the non-racemic bowl (S)-107a and (R)-107a.
To confirm this stereochemical analysis, each separated diastereomers was then treated with Raney nickel in methanol under inert atmosphere at room temperature to remove the sulfoxide fragment. Filtration of the crude over celite, evaporation of the solution, and further flash chromatography over silica gel afforded two fractions in good overall yields (80%) of which the enantiomeric purity could be checked by analytical CSP-HPLC using chiralpak AD-H (ee > 98%). From 109a and (+)-109b, the (–)-(S)-107a and (+)-(R)-107a was obtained respectively. This indicates that (+)-109a is the (+)-(RC,RS)-109a diastereomer and (+)-109b the (+)-(SC,RS)-109b.
V-3 Conclusion
Herein, using simple organic synthetic transformations, we have reported the synthesis of a novel racemic diazaoxatricornan derivative. The enantiomers of which were readily separated by chiral stationary phase chromatography. The absolute configuration of (–)-(S)-107a was determined by a comparison of the experimental and theoretical VCD spectra. A posteriori, the initial selection of Me, Ph and n-Pr as substituents R’, R1 and R2 seems to have been ideal for the purposed study as it has allowed to establish the feasibility of the synthetic protocol, the efficiency of CSP-HPLC as a resolution method and the global chemical stability of the chiral cup-like molecule 107a – things that were not completely obvious at the start of the study.
Finally, concerning a large scale resolution of such molecules, the addition of the well known chiral sulfoxide turned out to be unfortunately inefficient. Low overall yields and no separation of the diastereomers could be obtained on regular column chromatography. The separation could be however effectively achieved using again preparative CSP-HPLC. Then, treatment of each diastereomer in presence of Raney nickel afforded (–)-(S)-107a and (+)-(R)-107a with good enantioselectivities (> 98%).
All in all, this isolation of (–)-(S)-107a and (+)-(R)-107a constitutes thus the first report of a non-racemic closed-capped chiral bowl molecule for which the chirality is due only to the intrinsic dissymmetry of the central core of the structure.
V-4 Perspectives
Any chiral object is expected to have an optical activity and display vibrational and possibly electronic circular dichroism.50 However, enantiomerically pure compounds that do not show any optical activity in the ordinarily accessible UV/Vis spectral range (200-800 nm) are known and have been termed cryptochiral.51 Classical examples of such molecules are compounds 110 to 113 detailed in Figure V-22.52 The chirality originates from a very small chemical difference between two or more substituents attached to a central stereogenic carbon atomor to a rotational axis (in the
50 Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New York, 1994;.
51 Mislow, K.; Bickart, P. Isr. J. Chem. 1977, 15, 1-6.
52 Ten Hoeve, W.; Wynberg, H. J. Org. Chem. 1980, 45, 2754-2763. Wynberg, H.; Hulshof, L. A. Tetrahedron 1974, 30, 1775-1782. Sanderson, W. A.; Mosher, H. S. J. Am. Chem. Soc. 1966, 88, 4185-4190. Wynberg, H.; Hekkert, G. L.; Houbiers, J. P.
M.; Bosch, H. W. J. Am. Chem. Soc. 1965, 87, 2635-2639. Mislow, K.; Graeve, R.; Gordon, A. J.; Wahl, G. H., Jr. J. Am. Chem.
Soc. 1964, 86, 1733-1741. Fischer, H. O. L.; Baer, E. Chem. Rev. 1941, 29, 287-316.
Chapter V. Synthesis, Resolution and VCD Analysis of the First Enantiopure Diazaoxatricornan Derivative
specific case of 113). For compounds 110 and 111, it is quite likely that the lack of optical activity is linked to the conformational mobility in the acyclic hydrocarbon chains.53 Highly rigid chiral compounds, completely devoid of any conformational issues, tend to possess rather strong chiroptical properties – even if constituted of saturated hydrocarbons only (e.g., 114, Figure V-23).54
OH
DH
H C15H31OCO
OCOC15H31 OCOC11H23
CD3 CH3 D3C
H3C
110 111
112 113
Figure V-22. Classical Examples of Cryptochiral Molecules.
For cryptochiral compounds displaying single (or degenerate) conformations such as 111 and 113, the discrimination of the substituents around the stereogenic element tends to rely on an isotopic labeling to minimize to the extreme the distinction of the substituents.55
114
Figure V-23. Chemical Formula of Triangulane Trispiro[2.0.0.2.1.1]nonane 114.
Finally and as already mentioned, cryptochiral molecules tend to possess sp3 carbon and hydrogen atoms only. Compound 111, and dendritic derivatives recently reported by Meijer and collaborators,56 are in that sense exceptional as they possess a
53 Recently, it was shown that the hidden cryptochirality of compounds 110 can be distinguished using an elegant asymmetric autocatalysis protocol. See Kawasaki, T.; Tanaka, H.; Tsutsumi, T.; Kasahara, T.; Sato, I.; Soai, K. J. Am. Chem. Soc. 2006, 128, 6032-6033.
54 It is for instance the case of triangulane trispiro[2.0.0.2.1.1]nonane reported by de Meijere and coworkers:de Meijere, A.;
Khlebnikov, A. E.; Kostikov, R. R.; Kozhushkov, S. I.; Schreiner, P. R.; Wittkopp, A.; Yufit, D. S. Angew. Chem., Int. Ed. Engl.
1999, 38, 3474-3477.
55 Recently, it was shown that (R)-[2H1, 2H2, 2H3]-neopentane could be distinguished in ROA experiments. See Haesler, J.;
Schindelholz, I.; Riguet, E.; Bochet, C. G.; Hug, W. Nature 2007, 446, 526-529.
56 Peerlings, H. W. I.; Struijk, M. P.; Meijer, E. W. Chirality 1998, 10, 46-52.
large number of oxygen atoms in their framework. The presence of the heteroatoms in these molecules is probably compensated by the rotational freedom as described previously. In this context, the existence of a cryptochiral molecule that would be (i) highly rigid, (ii) constituted of an extended unsaturated framework, and (iii) of which the chirality would be directly linked to the presence of different types of heteroatoms (or their substituents), would be an important novelty; the isolation and absolute configuration assignment of the enantiomers being, most probably, also a challenging task.
For this purpose one can now tell that tricornan derivatives of type 107 may constitute an interesting platform. They can be easily synthesized and resolved in few steps. They are good synthetic answers to statements (i) to (iii) and do not exhibit strong manifestations of molecular chirality (e.g., VCD and optical rotation).
Compounds 115 to 117 (vide infra Figure V-24) have thus a good chance to be cryptochiral. In this prospect, the isolation of the enantiomers of 107a then constitutes a first effective step towards the preparation of a cryptochiral molecule with “all the wrong” properties.
N N N
Hex nOct
n
nPr
115 116 117
N N O
D3C CH3
N N O
Hex nOct
n
Figure V-24. Towards Cryptochiral Molecules of the Tricornan Families.