1,4-Dioxamacrolides: Preparation and Sensory Properties

Abstract

The synthesis of 3-methyl-1,4-dioxacylopentadecan-2-one (12c) and 3-methyl-1,4-dioxacylohexadecan-2-one (12d), two new musk odorants, is described starting from methyl 2-bromopropionic acid (6b) and allylic alcohol, respectively. The key step of the synthesis is the ring-closing olefin metathesis (RCM) to the unsaturated 1,4-dioxamacrolides. Insight into the structure-odor relationship (SOR) is provided by the synthesis of ten related unsubstituted or methyl substituted oxamacrolides. Finally, a four step enantioselective synthesis of both (3R)-(+)- and (3S)-(-)-3-methyl-1,4-dioxacyclopentadecan-2-one as well as (3R)-(+)- and (3S)-(-)-3-methyl-1,4-dioxacyclohexadecan-2-one reveals that mainly the (3R)-(+) enantiomers are responsible for the powerful musky odor characteristic. Their synthesis starts from ethyl (2S)-2-hydroxy­propanoate (14) or isobutyl (2R)-2-hydroxypropanoate (15) which were treated under acidic conditions with allyl trichloroacetimidate (16), followed by titanate mediated transesterification, ring-closing olefin metathesis and hydrogenation.

Key words

macrocycles - metathesis - lactones - ring closure - musk odorants - fragrance - structure-odor relationship

References

• 1a Rimkus G. Brunn H. Ernährungs-Umschau  1996,  43:  442 
• 1b Rimkus G. Brunn H. Ernährungs-Umschau  1997,  44:  4 
• 2a Williams AS. Synthesis  1999,  1707 
• 2b Kraft P. Bajgrowicz JA. Denis C. Fráter G. Angew. Chem. Int. Ed.  2000,  39:  2980 ; Angew. Chem. 2000, 112, 3106
• 2c Saito H, and Onishi T. inventors; Jap. Patent  09202783.  1996; Chem. Abstr. 1997, 127, 220678
• 2d Mane M, and Ponge J.-L. inventors; Eur. Patent  818452.  1996; Chem. Abstr. 1998, 128, 140564
• 2e Munro D, and Stanley SC. inventors; Eur. Patent  841333.  1996; Chem. Abstr. 1998, 129, 4590
• 2f Bajgrowicz JA, Frater G, and Kraft P. inventors; Eur. Patent  859003.  1996; Chem. Abstr. 1998, 129, 175655
• 2g Bertram H.-J, Koch O, Wörner P, and Surburg H. inventors; Eur. Patent  862911.  ; Chem. Abstr. 1998, 129, 193539.
• 2h Fráter G, Helmlinger D, and Müller U. inventors; Eur. Patent  908455.  1998; Chem. Abstr. 1999, 130, 301508
• 2i Kraft P. inventors; Eur. Patent  884315.  1998; Chem. Abstr. 1999, 130, 52441
• 2j Körber A, Wörner P, and Surburg H. inventors; Eur. Patent  905222.  ; Chem. Abstr. 1999, 130, 257202
• 2k Yamamoto K, Matsuda H, and Yamazaki T. inventors; Jap. Patent  11124378.  ; Chem. Abstr. 1999, 130, 325158.
• 2l Surburg H, Sonnenberg S, Warnecke B, Tochtermann W, Rodefeld L, and Heinemann I. inventors; Ger. Patent  19801056.  1998; Chem. Abstr. 1999, 131, 87835
• 2m Watanabe S, Matsuda H, and Yamazaki T. inventors; Jap. Patent  00053675.  1998; Chem. Abstr. 2000, 132, 166135
• 2n Surburg H, Woerner P, Tochtermann W, and Lehmann J. inventors; Ger. Patent  19858728.  1999; Chem. Abstr. 2000, 133, 43455
• 2o Eh M, and Wörner P. inventors; Ger. Patent  19946128.  1999; Chem. Abstr. 2001, 134, 252366
• 3 Bauer K. Garbe D. Surburg H. Common Fragrance and Flavor Materials   Wiley-VCH; Weinheim: 1997. 
• 4a Stoll M. Rouvé A. Helv. Chim. Acta  1935,  18:  1087 
• 4b Theimer ET. Fragrance Chemistry - The Science of the Sense of Smell   Academic Press; New York: 1982. 
• 5 Berends W. Am. Perfum. Cosmet.  1965,  80:  35 
• 6 Kraft P. Cadalbert R. Synthesis  1998,  1662 
• 7a Nguyen ST. Grubbs RH. Ziller JW. J. Am. Chem. Soc.  1993,  115:  9858 
• 7b Nguyen ST. Johnson LK. Grubbs RH. Ziller JW. J. Am. Chem. Soc.  1992,  114:  3974 
• 7c Schwab P. France MB. Ziller JW. Grubbs RH. Angew. Chem., Int. Ed. Engl.  1995,  34:  2039 ; Angew. Chem. 1995, 107, 2179
• 8 Burke SD. Ng RA. Morrison JA. Alberti MJ. J. Org. Chem.  1998,  63:  3160 
• 9 Fürstner A. Langemann K. J. Am. Chem. Soc.  1997,  119:  9130 
• 10a Lipshutz BH. Pegram JJ. Tetrahedron Lett.  1980,  21:  3343 
• 10b Kalinowski H.-O. Crass G. Seebach D. Chem. Ber.  1981,  114:  477 
• 10c Mahler U. Devant RM. Braun M. Chem. Ber.  1988,  121:  2035 
• 10d Lipshutz BH. Moretti R. Crow R. Tetrahedron Lett.  1989,  30:  15 
• 10e Nemoto H. Takamatsu S. Yamamoto Y. J. Org. Chem.  1991,  56:  1321 
• 10f Gmeiner P. Junge D. J. Org. Chem.  1995,  60:  3910 
• 11a Grundler G. Schmidt RR. Carbohydr. Res.  1985,  135:  203 
• 11b Wessel H.-P. Iversen T. Bundle DR. J. Chem. Soc., Perkin Trans. 1  1985,  2247 
• 11c Schmidt RR. Angew. Chem., Int. Ed. Engl.  1986,  25:  212 ; Angew. Chem. 1986, 98, 213
• 11d Nakajima N. Horita K. Abe R. Yonemitsu O. Tetrahedron Lett.  1988,  29:  4139 
• 11e Meinjohanns E. Meldal M. Paulsen H. Bock K. J. Chem. Soc., Perkin Trans. 1  1995,  405 
• 11f Christoffers J. Rößler U. J. Prakt. Chem.  2000,  342:  654 
• 12a Schnurrenberger P. Züger MF. Seebach D. Helv. Chim. Acta  1982,  65:  1197 
• 12b Seebach D. Hungerbühler E. Naef R. Schnurrenberger P. Weidmann B. Züger M. Synthesis  1982,  138 
• 13 Kraft P. Fráter G. Chirality  2001,  13:  388 ; and references therein