The First Efficient Synthesis and Optical Resolution of Monosubstituted Cyclotribenzylenes

Abstract

A new and high yielding synthetic route to monosubstituted cyclotribenzylenes 6 via the cyclocondensation of benzene with a suitably monosubstituted diol 20, obtained from ozonolysis of the corresponding dibenzosuberene precursor 19, was developed for the first time! The dibenzosuberene itself could be readily prepared in large quantities from inexpensive starting materials in five steps. Using this synthetic approach, a mono bromosubstituted cyclotribenzylene 12a was synthesized on large scale. Another four monosubstituted cyclotribenzylenes 21-24 were also prepared either via bromine/lithium exchange followed by subsequent quenching with external electrophiles or a copper mediated reaction with cyanide. These molecules adopt a rigid crown conformation as shown by X-ray analysis and temperature dependent NMR studies. The barrier to inversion is quite high, requiring temperatures well above 120 °C before inversion takes place. Futhermore, such monosubstituted cyclotribenzylenes are planar chiral and after optical resolution, using HPLC, we were able to obtain the first planar chiral C1-symmetric cyclotribenzylenes in form of the optically pure enantiomers of 12a, the CD spectra of which are exact mirror images over the entire spectral range.

Key words

carbocycles - cyclophanes - CD spectroscopy - planar chirality

References

• 2a Steed JW. Atwood JL. In Supramolecular Chemistry   Wiley; Chichester: 2000. 
• 2b Lehn J.-M. In Supramolecular Chemistry, Concepts and Perspectives   VCH; Weinheim: 1995. 
• 2c Vögtle F. In Supramolecular Chemistry   Wiley & Sons; Chichester: 1991. 
• 3a Sato T. Uno K. J. Chem. Soc., Chem. Commun.  1972,  579 
• 3b Sato T. Uno K. J. Chem. Soc., Perkin Trans. 1  1973,  895 
• 4 For a general review on cyclophanes see: Vögtle F. In Cyclophane Chemistry   Wiley & Sons; Chichester: 1993. 
• 5 Diedrich F. Angew. Chem., Int. Ed. Engl.  1988,  27:  362 
• 6 For a comprehensive review on the synthesis and properties of cyclotriveratrylenes see: Collet A. Tetrahedron  1987,  43:  5725 
• 7 For an extensive review see: Collet A. Dutasta J.-P. Lozach B. Canceil J. Top. Curr. Chem.  1993,  165:  103 
• 8 Sato T. Akima T. Uno K. J. Chem. Soc., Perkin Trans. 1  1973,  891 
• 9 Yamato T. Sakaue N. J. Chem. Res. (M)  1997,  12:  2614 
• 10 Tellenbröker J. Kuck D. Angew. Chem. Int. Ed.  1999,  38:  919 
• For further synthetic approaches to unsubstituted cyclotribenzylene 1 see:
• 11a Lee WY. Sim W. Choi KD. J. Chem. Soc., Perkin Trans. 1  1992,  881 
• 11b Kodomari M. Taguchi S. J. Chem. Res. (S)  1996,  240 
• 11c Yamamoto T. Sakaue N. Furusawa T. Tashiro M. Surya Prakash GK. Olah GA. J. Chem. Res. (S)  1991,  242 
• 11d Canceill J. Collet A. Gottarelli G. J. Am. Chem. Soc.  1984,  106:  5997 
• 11e Canceill J. Collet A. J. Chem. Soc., Chem. Commun.  1983,  1145 
• For other similar low yielding multi-step approaches to diol 4 see also:
• 12a Lee WY. Park CH. Kim YD. J. Org. Chem.  1992,  57:  4074 
• 12b Bergmann ED. Pelchowicz Z. J. Am. Chem. Soc.  1953,  75:  4281 
• 13 Platzek J. Snatzke G. Tetrahedron  1987,  43:  4947 
• 14 A related approach was used by Renaud and coworkers. However, their route requires four steps and was rather low yielding with 58% yield at best: Renaud RN. Layton RB. Fraser RR. Can. J. Chem.  1973,  51:  3380 
• 15 This is in accordance with other reports in the literature; see e.g. for a double nitration of dibenzosuberenone: Campbell TW. Ginsig R. Schmid H. Helv. Chim. Acta  1953,  36:  1489 
• 16 Gringauz A. In Medicinal Chemistry   Wiley-VCH; New York: 1997. 
• 17a Thompson WJ. Anderson S. Britcher SF. Lyle TA. Thies JE. J. Med. Chem.  1990,  33:  789 
• 17b Weiler-Feilchenfeld H. Solomonovici A. J. Chem. Soc. B  1971,  869 
• 17c Jung ME. Miller SJ. J. Am. Chem. Soc.  1981,  103:  1984 
• 17d Inoue J. Cui Y.-S. Rodriguez L. Chen Z. Kador PF. Eur. J. Med. Chem. Chim. Ther.  1999,  34:  399 
• A regioisomer of this compound had been prepared earlier by Renaud in a very low yielding 12 step synthesis:
• 18a Fraser RR. Renaud RN. Can. J. Chem.  1971,  49:  746 
• 18b Renaud RN. Bovenkamp JW. Fraser RR. Capoor R. Can. J. Chem.  1977,  55:  2642 
• 19a Engelhardt EL. Zell HC. Saari WS. Christy ME. Colton CD. Stone CA. Stavorski JM. Wenger HC. Ludden CT. J. Med. Chem.  1965,  8:  829 
• 19b Remy DC. Rittle KE. Hunt CA. Anderson PS. Arison BH. Engelhardt EL. Hirschmann R. Clineschmidt BV. Lotti VJ. Bunting PR. Ballentine RJ. Papp NL. Flataker L. Witoslawski JJ. Stone CA. J. Med. Chem.  1977,  20:  1013 
• 19c Davis DA. de Paulis T. Janowsky A. Smith HE. J. Med. Chem.  1990,  33:  809 
• 20 Mikotic-Mihun Z. Dogan J. Litvic M. Cepanec I. Karminski-Zamola GM. Synth. Commun.  1998,  28:  2191 
• 21 Manning C. McClory MR. McCullough JJ. J. Org. Chem.  1981,  46:  919 
• 22a Slates HL. Wendler NL. J. Med. Chem.  1965,  8:  886 
• 22b Looker JJ. J. Org. Chem.  1966,  31:  3599 
• 23 Wendler NL, Taub D, and Hoffsommer RD. inventors; U. S. Patent  2,247,272. In analogy to a patented procedure:
• For various reductive work-up procedures after ozonolysis see:
• 25a Thiem J. In Houben-Weyl: Methoden der Organischen Chemie   Vol. VI/1a:  Thieme; Stuttgart: 1980.  p.853 
• 25b For the use of lithium boronate see also: Brown HC. Narasimhan S. Choi YM. J. Org. Chem.  1982,  47:  4702 
• 26 Flippin LA. Gallagher DW. Jalali-Araghi K. J. Org. Chem.  1989,  54:  1430 
• 27a Canceill J. Collet A. Gotarelli G. Plamieri P. J. Am. Chem. Soc.  1987,  109:  6454 
• 27b Canceill J. Collet A. New J. Chem.  1986,  10:  17 
• 27c Canceill J. Lacombe L. Collet A. J. Am. Chem. Soc.  1985,  107:  6993 
• 27d Canceill J. Collet A. Gabard J. Gotarelli G. Spada GP. J. Am. Chem. Soc.  1985,  107:  1299 
• 27e Collet A. J. Am. Chem. Soc.  1981,  103:  5912 

1

Former address: Institut für Organische Chemie, Universität zu Köln, Greinstrasse 4, 50939 Köln, Germany.

24

LiAlH₄ even in equimolar amounts at low temperatures caused substantial debromination and gave only 23%, at most, of the desired bromosubstituted diol 20. Other reducing agents such as sodium boronate or lithium boronate only gave complex product mixtures in which the desired diol 20 was only present in small amounts (according to TLC and GC-MS analysis), no matter which reaction conditions we tried (e.g. by variation of temperature and solvent, respectively). Borane in THF did not react at all.