Technical Procedures for the Synthesis of Carotenoids and RelatedCompounds from 6-0x0-isophorone. I. Modification of the Kienzfe-Mayer-Synthesis of (3S, 3'S)-Astaxanthin SummaryAn efficient synthesis of (3S, 3's)-astaxanthin (la) in high yield and optical purity starting from (4R, 6R)-4-hydroxy-2,2,6-trimethylcyclohexanone (4) is reported. The absolute configuration of la, previously derived from ORD. data, has been confirmed by X-ray analysis of 5, a derivative of 6-0x0-isophorone (2). The key features of the improved synthesis are the two-step conversion of 4 to the key intermediate (4S)-2,6,6-trimethyl-4-hydroxy-2-cyclohexen-1-one (14), a new method for the partial reduction of the sterically hindered triple bond of (S)-6-hydroxy-3-(5-hydroxy-3-methyl-3-penten-l-ynyl)-2,4,4-trimethyl-2-cyclohexen-1-one (32), and Wittig olefination of the dialdehyde l,6-dimethyl-1,3, Soctatrienedial (38) using phosphonium salt 37 with a free hydroxyl group.

Dedicated to Dr. Otto Isler on the occasion of his 80th birthday (23.1V.90) Starting from the readily available, optically active (4R)-hydroxy-2,2,6-trimethylcyclohexanone (Z), a new technical synthesis of (3R,3'R)-zeaxanthin is described. According to a completely new C,+C2+C4 = C,, scheme, the ketone 2 was protected, ethynylated with Li-acetylide, and the C, ,-intermediate 6 was acetylated, followed by dehydration. The product 10 was protected, deprotonated, and subsequently reacted with methyl vinyl ketone to provide the C,,-propargylate 13. Reduction in situ of 13 with Vitride yielded the olefinic C,,-alcohol 11 which was transformed into the known C,,-Wittig salt 3. A double Wittig reaction of this salt with the C,,-dialdehyde 4 afforded nature-identical zeaxanthin (1).Introduction. -In the foregoing publication [ 11, we described a new technical synthesis of (3R,3'R)-zeaxanthin (1) starting from the optically active hydroxy-ketone 2 [2] (cf. Scheme). Using this C,-building block and the vitamin-A intermediate (E)-3-methylpent-2-en-4-yn-1-01 (C,-synthon [3]), we prepared the C,,-ally1 alcohol 11 which was converted in three additional steps into the known olefinic C,,-Wittig salt 3 [l] [4-61. Subsequent 'double Wittig reaction' of 3 with the C,,-dialdehyde 4 [7] provided (3 R,3'R)-zeaxanthin (1). SchemeHELVETICA CHIMICA ACTA ~ Vol. 73 (1990) 869In this publication, we describe a completely new approach to the known C,, salt 3 [l] again from ketone 2 but applying a new C,+C,+C, building scheme. In comparison with the former synthesis [ 11, the overall yield of 3 from 2 was increased from 43 YO up to 72 YO.Furthermore, the new approach avoids such problematical steps as the dehydration and hydrogenation of only moderately stable CIS-intermediates.Results and Discussion. -The OH group of 2 was first protected in situ with isopropenyl methyl ether, and the resulting THF solution of the IPM-ketone 5 was then treated with 2 equiv. of freshly prepared Li-acetylide in liquid ammonia (Scheme). After an acidic workup, the crude diol6 [8] [9] was obtained in almost quantitative yield with a purity of more than 98 YO. GLC analysis of this material revealed the presence of ca. 3 YO of the other C,-diastereoisomer [lo]. After acetylation of this crude material with Ac,O in pyridine or in the presence of 1% DMAP, the resulting monoacetate 7 [9] was used directly without purification in the following dehydration step. According to a previously described method on a similar vitamin-A intermediate [I 11 [12], we used as a catalyst 10 mol-YO of CuSO, in boiling o-xylene. The catalyst could be easily removed afterwards by simple filtration and recycled. A detailed investigation of this dehydration step showed that, contrary to [I I] [12], no reaction took place in boiling toluene, and we were not able to find any other suitable catalyst. All the common catalysts (Brmstedor Lewis acids etc.) gave rise to complex mixtures in which the major products were derived from hydration of the triple bond (cf Rupe reaction).Effic...

A New Access to 2,6,6-Trimethylcyclohexa-2,4dienone from COxoisophorone 2,6,6-Trimethylcyclohexa-2,4-dienone (l), a versatile starting material for the preparation of some carotenoids and several natural products, was efliciently (73 YO yield) prepared from oxoisophorone 3. After conversion of 3 to the alcohol 4 or the acetate 5, H 2 0 was eliminated (4-1) under acidic distillative conditions, whereas AcOH could be eliminated (5-+1) under Pd(0) catalysis.

SummaryStarting from 6-0x0-isophorone (2) a new concept for a seven-step synthesis of (3RS,3'RS)-astaxanthin (1) has been developed. As a key feature of the new approach, the oxidation state of astaxanthin (1) is adjusted already at an early stage of the synthesis. Thus, manipulation on more complex intermediates later in the synthesis is reduced to a minimum. Acetonide 10 or dimer 13 represent the key intermediates of this concept (Scheme 2). The whole sequence has been run on a kg scale with an overall yield of 52% (s. Scheme 5).1. Einleitung. -Kurzlich berichteten wir [l] iiber die Modifizierung einer von Kienzle & Muyer [2] beschriebenen Synthese von (3S, 3's)-Astaxanthin (la) zu einem effizienten, technisch anwendbaren Verfahren. Daran unbefriedigend geblieben war die durch den prinzipiellen Syntheseplan bedingte, relativ hohe Stufenzahl (14). Wir beschreiben nun ein vollig neues Synthesekonzept, welches ebenfalls ausgehend von 6-0x0-isophoron3) (= 3,5,5-Trimethyl-2-cyclohexen-1,4-dion; 2) in nur 7 Stufen und in der hohen Gesamtausbeute von >50% zum (3RS,3'RS)-Astaxanthin (1) fuhrt.

Ausgehend von Oxoisophoron (I) wird über die Intermediären (II) und (III) das Derivat (IV) synthetisiert und der Hydrierung unterworfen; Acetalisierung des dabei gebildeten Diolengemischs (V) +(VI) liefert das Acetonid (VII), aus dem durch Kupplung mit dem Acetylid (VIII) und Hydrolyse des gebildeten tertiären Alkohols das Dihydroxyketon (IX) erhalten wird.