Total Synthesis of Capsanthin Using Lewis Acid-Promoted Regio- and Stereoselective Rearrangement of Tetrasubstituted Epoxide.

Abstract

The synthesis of capsanthin 1 was accomplished via the C 15 -cyclopentyl ketone 13 prepared by Lewis acid-promoted regioand stereoselective rearrangement of the epoxide 12.Key words capsanthin; tetrasubstituted epoxide; regio-and stereoselective rearrangement; total synthesis Previously, we reported 1) the first biomimetic type total synthesis of both crassostreaxanthin B 2 (Fig. 1) possessing a novel acyclic-tetrasubstituted olefinic end group and mytiloxanthin 3 containing a cyclopentyl enolic b-diketone group applying stereoselective rearrangement of tetrasubstituted epoxide.2) In these syntheses, we employed epoxides, in which substituents at the C-63) position were alkyl groups having an oxygen functional group as shown in Chart 1.Capsanthin 1 (Fig. 1), having a k-end group, is a main pigment of red paprika Capsicum annuum and has become the center of attention due to its strong antioxidant activities. 4) There has been only one report by Weedon's group 5) concerning its synthesis. Here, we describe the total synthesis of 1 via regio-and stereoselective rearrangement of the C 15 -epoxide 12 (Chart 3) having a conjugated olefinic group at C-6, which was efficiently derived from the optically active (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone. 6) It has been known that the rearrangement of the epoxide 4b 7) (Chart 2) only provided the flanoid 5b by opening of C-6-oxygen bond of the oxirane ring (route a) and subsequent migration of the 7,8-double bond, whereas that of the epoxide 4a 8) predominantly produced the cyclopentyl ketone 6a by cleavage of the oxirane ring at the C-5 position (route b) and successive ring contraction. It is considered that the selective cleavage of epoxide 4a at C-5 was promoted by destabilization of the cation at C-6 due to the electron deficiency of 7(b)-carbon on a,b-unsaturated carbonyl group.Thus, the reaction of epoxides 4c-e 9) having an olefinic group conjugated to a carbonyl group at C-6 (Chart 2) was investigated toward the synthesis of 1. As a result, treatment of the epoxide 4d with SnCl 4 was found to give predominantly the desired cyclopentyl ketone 6d (91%). On the other hand, the reaction of the epoxides 4c and 4e with SnCl 4 preferentially provided flanoids 5c (86%; 5,8-trans 10) : 5,8-cis 10) ϭ8 : 1) and 5e (53%; 5,8-trans : 5,8-cisϭ5 : 1). These results show that the direction of C-O bond cleavage in the oxirane ring depends upon both the length of conjugated double bond system and the electron-withdrawing ability of the substituent adjacent to the double bond.In order to synthesize 1, C 15 -epoxide 12 was prepared via stereo-controlled cross-coupling reaction of the vinylstannane 8 with the vinyl triflate 15 11) as shown in Chart 3. The known 12) terminal alkyne 7, prepared (62%) from (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone, 6) was heated at 130°C for 20 min with an excess amount (4 eq) of Bu 3 SnH in the presence of a catalytic amount of azobisisobutyronitrile (AIBN) 13) to give stereoselectively the E-vinylstannane 8 in 88% yield. Cross-coupling rea...

Carotenoids and Related Polyenes, Part 12 First Total Synthesis and Absolute Configuration of 3'-Deoxycapsanthin and 3,4-Didehydroxy-3'-deoxycapsanthin

“…HPLC analysis using a chiral column (CHIRALPAK AY-H; Daicel) revealed that the enantiomeric excess (ee) of the cyclopentyl ketone 6a (84% ee) remained almost unchanged during the rearrangement of C 15 -epoxy dienal 5a (94% ee). From the previous results, 8,9) the absolute stereochemistry of the newly formed C-5 chiral center in rearrangement product 6a was expected to be (R); however, its configuration was determined by an alternative synthesis from (ϩ)-(R)-camphonanic acid (11) 13) (Chart 2). Esterification of the acid 11 with TMSCHN 2 14) followed by reduction with LiAlH 4 gave the corresponding alcohol 12 15) (88%).…”

“…3-Deoxycapsanthin (1) To a solution of the phosphonium salt 20 8,9) (1.14 g, 2.0 mmol) and the all-E apocarotenal 17 (83 mg, 0.23 mmol) in MeOH (15 ml) was added NaOMe (1.0 M in MeOH; 3.0 ml, 3.0 mmol) at rt. After being stirred at rt for 3.5 h, Dowex 50 W-X8 (H ϩ ) (5 g) was added to the reaction mixture and this was stirred at rt for 5 min.…”

“…Preparative HPLC (PHPLC) provided the all-E isomer 17 (42%) and an isomeric mixture (18%), which thermodynamically isomerized while standing in ethereal solution at room temperature (rt) for 1 d to yield the desired all-E isomer 17 (7% from 6a). The stereochemistry of 17 was determined by comparison of its 1 H-NMR data with previously prepared 8,9) 3-hydroxycyclopentyl apocarotenal.…”

“…Wittig reaction of the C 25 -apocarotenal 17 with the C 15 -phosphonium salt 20 8,9) afforded a mixture of condensation products, which were separated by PHPLC to provide all-E 3Ј-deoxycapsanthin (1) (27%) and an isomeric mixture (20%). The latter was also transformed (6% from 17) into the desired all-E isomer by thermodynamic isomerization.…”

First Total Synthesis of Cucurbitaxanthin A Applying Regioselective Ring Opening of Tetrasubstituted Epoxides

“…From the previous results 4) in the reaction of epoxides 3a-e with an olefinic group at C-6 5) (Chart 2) with Lewis acid, we found that the direction of the oxirane ring cleavage depended upon both the length of conjugated double bond system and the electron-withdrawing ability of the substituents adjacent to the double bond. Epoxides 3a and 3d carrying a strong electron-withdrawing group (EWG) predominantly provided the cyclopentyl ketones 5a and 5d, respectively, via cleavage of the oxirane ring at the C-5 position (route b), whereas 5,6-epoxides 3b, 3c, and 3e only gave 5,8-epoxides 4b, 4c, and 4e, respectively, via opening of the C-6-oxygen bond of the oxirane ring (route a).…”