United States Patent (19) 11 Patent Number: 6,111,125 John Et Al
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USOO6111.125A United States Patent (19) 11 Patent Number: 6,111,125 John et al. (45) Date of Patent: Aug. 29, 2000 54 PREPARATION OF (1R,4S)-4-HYDROXY-1,2,2- -continued (Ia) TRIMETHYLCYCLOPENTYL METHYL KETONE AND DERVATIVES AND O STEREOSOMERS OF THIS COMPOUND ls 75 Inventors: Michael John, Ludwigshafen; Udo Rheude, Otterstadt; Joachim Paust, Neuhofen; Joachim Meyer, Maxdorf, all of Germany OR (R = H) 73 Assignee: BASF Aktiengesellschaft, Ludwigshafen, Germany which is required for preparing the red dye capSorubin which is in demand, Starts from 2, 2, 6 - 21 Appl. No.: 08/398,643 trimethylcyclohexanones of the general formula II 22 Filed: Mar. 3, 1995 (II) 30 Foreign Application Priority Data Mar. 7, 1994 DE Germany ............................. 44 07:464 (51) Int. Cl. .................................................. C07F 7/08 52 U.S. Cl. .......................... 556/436; 556/437; 556/482; 549/215; 549/546; 568/361; 568/377; 568/667; stOR 568/823: 568/825 58 Field of Search ..................................... 549/546, 215; 556/437, 482, 436; 568/361, 377,667, where R is hydrogen or a protective group, via the novel 823, 825 intermediates of the general formulae V and VI (V) 56) References Cited U.S. PATENT DOCUMENTS 5,155.243 10/1992 Fujiwa et al. ........................... 549/546 5,382,676 1/1995 Kuwana et al. ... 549/541 5,424,460 6/1995 Duhamel et al. .... ... 549/546 5,565,489 10/1996 Kaneko et al. .. ... 514/475 5,801,123 9/1998 Sakai et al. 504/291 r (VI) OTHER PUBLICATIONS J. Chem. Soc. 1961, 004019 f. Helv. Chim. Acta 66, 7 (1983) No. 192, pp 1939-60 J. Mol Struct. 226 (1992) pp. 91-92. Quim Nova 14 (1991) pp. 22–25. Carrotinoid Chem. Biochem. Proc. Int. Symp. Carotenoids, 6th Meeting, Date 1981, pp. 71-86, edited by Britten G. Goodween T.W., Pergamon, Oxford. Primary Examiner Paul F. Shaver by diastereoselective epoxidation and reaction of the result Attorney, Agent, or Firm-Keil & Weinkauf ing 7-Oxabicyclo4.1.0heptanes of the general formula VIII 57 ABSTRACT (VIII) A pro c e SS for preparing 4-hydroxy-1,2,2- O trimethylcyclopentyl methyl ketones of the general formula I, in particular of the (1R,4S)-4-hydroxy-1,2,2- trimethylcyclopentyl methyl ketone of the formula Ia (I) OR (R = H or protective group) with Lewis acids and, where appropriate, removal of the protective group. Also claimed are the novel intermediates of the formula V and their (1S) and (1R) isomers and those OR of the formula VIII as well as their (1R,3S,6S), (1S,3S,6R) (R = H) and (1R,3R,6S) isomers. 11 Claims, No Drawings 6,111,125 1 2 PREPARATION OF (1R,4S)-4-HYDROXY-1,2,2- TRIMETHYLCYCLOPENTYL METHYL (I) KETONE AND DERVATIVES AND O STEREOSOMERS OF THIS COMPOUND ls The invention relates to a process for the preparation of (1R,4S)-4-hydroxy-1,2,2-trimethylcyclopentyl methyl ketone and O-protected derivatives as essential precursors for the red dye capSorubin, which is in demand, and of HO Stereoisomers of this compound, and to novel precursors of 10 the general formulae V and VIII. CapSorubin is, like capsanthin and cryptocapsin, a pig It is an object of the present invention to develop a way ment of red paprika (Capsicum annuum) and has the fol of preparing (1R,4S)-4-hydroxy-1,2,2-trimethylcyclopentyl lowing Structure: methyl ketone and derivatives Starting from an easily obtain OH O 4naanene-Yen-4N4N4\" HO (3S, 5R, 3'S, 5R)-Capsorubin It is thus characteristic of this red pigment that cyclo- able Starting material in the minimum number of reaction pentanol units are present in the molecule. The complicated Steps which can easily be carried out industrially. Stereochemistry of the capSorubin end groups is unusual for 30 We have found that this object is achieved by a process carotenoids and was not definitively elucidated until the for preparing 1,2,2-trimethylcyclopentyl methyl ketone 1960s (cf. J. Chem. Soc. 1961 4019 ff.). derivatives of the general formula I The good coloring effect of capsorubin meant that early (I) attempts were made to prepare it by Synthesis. The first 35 O Synthesis of optically inactive capSorubin was achieved by Weedon (cf. Pure Appl. Chem. 14 (1967) 265–78) in a Sequence of 8 reaction Stages, the last Step being an aldol condensation of 2 equivalents of racemic 4-hydroxy-1,2,2- trimethylcyclopentyl methyl ketone with one equivalent of 40 the Co-dialdehyde crocetindialdehyde. OR Once the Synthesis of an appropriate cyclopentylcar boxylic ester with a center of chirality had Succeeded in 4 where R is hydrogen or alkyl, aryl, arylmethyl, trialkylsilyl, Stages starting from (+)-camphor (cf. Acta Chem. Scand. B triarylsilyl, alkylarylsilyl, alkoxyalkyl, tetrahydropyranyl, 28 (1974) 492-500), as well as the preparation of the 45 arylmethyloxycarbonyl, alkanoyl or benzoyl, preferably optically active end group of capSorubin from (3R)-3- hydrogen or tert-butyl, isopropyl, benzyl, alkylbenzyl, hydroxy-3-cyclocitral (cf. Pure Appl. Chem. 51 (1979) 2-napthyl methyl, tert-butyl dimethylsily 1, 535-64), the way was free for synthesizing optically active enzoylNyay, or methoxyisopropyl tetrahydropyranyl, which comprises ethoxyethyl, acetyl, capsorubin (cf. Helv. Chim. Acta 66 (1983) 1939–60). 50 A. reacting a 2.2,6-trimethyl-1-cyclohexanone of the gen Another Successful route to optically active capSorubin eral formula II started from (+)-camphor (cf. J. Mol. Struct. 226 (1992) 91–96) or isophorone (cf. Quim. Nova 14 (1991) 22-25) as (II) Source of the optically active cyclopentyl unit and crocet- 55 O indialdehyde. The disadvantage of all the capSorubin Syn theses described to date is that the individual reaction Steps are too elaborate and thus unsuitable for industrial imple mentation. However, Since the aldol condensation, disclosed in 60 Helv. Chim. Acta 66 (1983) 1939–60, of (1R,4S)-4- OR hydroxy-1,2,2-trimethylcyclopentyl methyl ketone with cro cetindialdehyde can also be carried out quite well on the where R is hydrogen or one of the abovementioned industrial Scale, it was important for Synthesizing capSorubin radicals, with a methyl carbanion of the general for to develop a straightforward way of preparing (1R,4S)-4- 65 mula III hydroxy-1,2,2-trimethylcyclopentyl methyl ketone of the formula I or its O-protected derivatives. CH-M (III), 6,111,125 3 where M is Li, MgCl, MgBr or Mg, and converting the resulting 1,4-dihydroxy-1,2,2, 6 - (VIII) tetramethylcyclohexane derivative of the general for mula IV (IV) OH OR by reaction with Lewis acids and, where appropriate, OR elimination of the protective group on the oxygen in a conventional way into the 1,2,2-trimethylcyclopentyl 15 methyl ketones of the general formula I. where R is hydrogen or one of the abovementioned Although it was disclosed in Carotenoid Chem. Biochem. radicals, acid-catalyzed elimination of the tertiary Proc. Int. Symp. Carotenoids, 6th Meeting, Date 1981, pages hydroxyl group into a mixture of compounds of the 71-86, especially 78-79, Edited by: Britton G.; Goodwen T. formulae V and VI W., Pergamon, Oxford, that it is possible by epoxidation of optically active 1-acetoxy-3,4,5,5-tetramethyl-3- (V) cyclohexene derivatives to prepare optically active 3-acetoxy-7-Oxa-1,5,5,6-tetramethylbicyclo4.1.0heptanes and convert the latter by reaction with Lewis acids into 25 optically active 4-hydroxy-1,2,2-trimethylcyclopentyl methyl ketones, on the one hand the preparation described herein of the Starting compound from hydroxycyclocitral is OR industrially very elaborate, and on the other hand sufficient (VI) Stereocontrol of the reaction cannot be attained by the acetoxy group used as protective group in this case. To prepare the (1R,4S)-4-hydroxy-1,2,2- trimethylcyclopentyl methyl ketone of the general formula Ia 35 (Ia) OR O or else converting the 2,2,6-trimethyl-1-cyclohexanone ls s of the general formula II in a Wittig reaction with a 40 methylenetri-phenylphosphorane of the formula VII (CHS)P=CH, (VII) OR 45 directly into the compound of the general formula VI, where R is hydrogen, which is in particular demand as B. converting the resulting compound of the general capSorubin precursor, the procedure in the process according formula VI by acid-catalyzed double-bond isomeriza to the invention is such that in step C. a (1S)-3,4,5,5- tion into the compound of the general formula V, tetramethyl-3-cyclohexene derivative of the general formula C. epoxidizing the double bond in the compound of the 50 general formula V Va. (V) (Va) 55 OR OR 60 where R has the abovementioned meaning by reaction where R is tert-butyl, isopropyl, benzyl, alkylbenzyl, with peroxy acids, their Salts or hydroperoxides in a 2-naphthylmethyl or tert-butyldimethylsilyl, is stereoselec tively epoxidized, and in Step conventional way, and 65 D. converting the resulting 7-Oxabicyclo4.1.0 heptane D. the resulting (1R,3S,6S)-7-Oxabicyclo4.1.0heptane derivatives of the general formula VIII derivative of the general formula VIIIa 6,111,125 (VIIIa) (Va) OR is reacted with a Lewis acid, and Subsequently the where R is preferably tert-butyl, isopropyl, benzyl, protective group is eliminated in a conventional way. alkylbenzyl, 2-naphthyl methyl or tert The advantageous procedure according to the invention butyldimethylsilyl, is Stereoselectively epoxidized and for prep a ring (1R, 4S)-4-hydroxy-1, 2,2- 15 D. the resulting (1R,3S,6S)-7-Oxabicyclo4.1.0heptane trimethylcyclopentyl methyl ketone, which is provided with a protective group where appropriate, of the general formula derivative of the general formula VIIIa Ia (VIIIa) (Ia) O Lls s 25 OR where R has the meanings Stated under C.