A Stereospecific Synthesis of Vitamin A from 2,2,6‐Trimethyl‐cyclohexanone

Abstract

Summary. An efficient synthesis of all-(E) vitamin A acetate from 2,2,6-trimethyl-cyclohexanone has been achieved via the intermediacy of 1-(9-acetoxy-3,7-dimethyl-nona-3,5,7-trienl-ynyl)-Z, 2,6-trimethyl-cycIohexanol (25), readily prepared in high yield by allylic rearrangement of tertiary propenols with glacial acetic acid. The key step in the synthesis is the transformation of 25 to the unsaturated ketone 27 (9-acetoxy-3,7-dimethyl-l-(2,6,6-trimethyl-cycIohex-1-enyl)-nona-3,5,7-trien-Z-one) using a novel vanadium(V)-catalysed rearrangement reaction. The carbonyl in 27 affords the means for the essential isomerization of the adjacent double bond to the (E) isomer and the product is readily transformed into the polyene by reduction and elimination. An overall yield of 18-31 % of vitamin A acetate from 2,2,6-trimethyl-cyclohexanone has been realized.The synthesis of vitamin A (1) and its derivatives has been the subject of numerous investigations [l] since the structure elucidation of the vitamin by Karrer [2] in 1931. All of the synthetic routes which have achieved commercial prominence employ p-ionone as the common starting material, and there has been considerable recent effort at improved syntheses of @-ionone and its precursors [3]. Recent developments in the catalytic alkylation of phenols [4] and their conversion to cyclohexanones [5] encouraged us to investigate new routes to vitamin A utilizing 2,2,6-trimethyl-cyclohexanone (2) as a starting material. No study of this possibility has been published since the reports by Heilbron et al. [6] and Atteitburrow et al. [7] in the 1950's.In our approach (Scheme I ) it was considered to be essential to control the configuration about the 9 , l O double bond (numbering of 1) to produce the 9-(E) isomer and to effect any reductions with very high selectivity. We utilize anovelvanadium(V)-catalysed rearrangement of an ethynyl-substituted 2,2,6-trimethyl-cyclohexanol derivative (3) to produce an 8-0x0-compound (4). The carbonyl function is a convenient device for the important isomerization of the 9,lO double bond and is easily transformed into the polyene by reduction and dehydration. The rearrangement reaction, formally analogous to the Meyer-Sckuster [8] reaction, is effected by tris(triarylsily1)vanadate catalysts, discovered by Pauling [9] and improved by Pauling et al.

Synthesis of (−)‐Cubebol by Face‐Selective Platinum‐, Gold‐, or Copper‐Catalyzed Cycloisomerization: Evidence of Chirality Transfer and Mechanistic Insights

“…The 1 H NMR, 13 C NMR, and MS spectra are in perfect agreement with those reported. [5] (+)-2-[(3S,6R)-3-Isopropyl-6-methyl-1-cyclohexen-1-yl]acetaldehyde (15): Oxalyl chloride (4.88 g (3.31 mL), 38.5 mmol) was added at À78 8C to a solution of DMSO (4.29 g (3.91 mL), 55.0 mmol) in CH 2 Cl 2 (105 mL). After 15 min, a solution of 14 (4.66 g, 25.6 mmol) in CH 2 Cl 2 (30 mL) was added dropwise (in 20 min) at À70 8C.…”

“…The different diastereoface selectivities observed for the cycloisomerizations of 8 a and 8 b prompted us to examine the chirality transfer of the enantioenriched propargyl pivalates 23 and 27, readily accessible from aldehydes 20 [14] and 24 [15] (Scheme 5). Pt-or Cu-catalyzed rearrangement of 23 (95 % ee) afforded 28, which gave, after hydrolysis, ketone 29 with 57-61 % ee (Scheme 6, expt 1 and 2).…”

“…Starting from 21 (2.36 g, 10.0 mmol), 22 (2.90 g, 91 %; 95 % ee (see 23)) was obtained after concentration at 80 8C/0.1 mbar. [a] 20 D = À61.8 (c = 0.76 in CHCl 3 ); 1 H NMR (CDCl 3 ): d = 1.02 (s, 6 H), 1.20 (s, 9 H), 1.44 (m, 2 H), www.chemeurj.org 1.49 (s, 6 H), 1.57 (m, 2 H), 1.96 (m, 2 H), 2.16 (s, OH), 2.37 (m, 1 H), 2.44 (m, 1 H), 5.44 (br t, J = 3.8 Hz, 1 H), 5.50 ppm (dd, J = 8.3, 6.1 Hz, 1 H);13 C NMR (CDCl 3 ): d = 19.1 (t), 26.0 (t), 27.0 (3q), 28.0 (2q), 31.3 (2q), 34.0 (s), 36.8 (t), 38.7 (s), 39.5 (t), 63.2 (d), 65.0 (s), 80.2 (s), 89.7 (s), 124.5 (d), 138.8 (s), 177.4 ppm (s); MS: m/z (%): 218 (7) [M] + , 217 (7), 203 (29), 185 (10), 175 (13), 149(15), 133(16), 105 (10), 85(12), 57 (100), 41(19).…”

Isomerization of Propargylic Alcohols into α,β‐Unsaturated Carbonyl Compounds Catalyzed by the Sixteen‐Electron Allyl‐Ruthenium(II) Complex [Ru(η3‐2‐C3H4Me)(CO)(dppf)][SbF6]

“…Both type of reactions are generally carried out in acidic medium or using strong acids as catalysts, which often give rise to non-regioselective transformations. [4] Although more efficient and selective catalytic systems based on transition metal complexes, such as Ti(OR) 4 /CuCl/RCO 2 H, [5] Bu 4 NReO 4 /p-MeC 6 H 4 SO 3 H, [6] MoO 2 (acac) 2 /R 2 SO/ ArCO 2 H [7] and vanadium(V) oxides, [8] have been developed, elevated temperatures ( > 100 8C) and/or acidic conditions are still needed. With all these oxo-metal catalysts, the suggested key step in the catalytic cycle involves the formation of an allenyloxy intermediate generated by O-coordination of the propargylic alcohol to the metal and subsequent addition of the [M] ¼ O oxygen atom to the C(1) carbon atom of the alkyne ( [3,3]-sigmatropic rearrangement).…”

Tris(triphenylsilyl) Vanadate

“…2 Since this is an equilibrium process, the reaction is probably limited to cases where the starting allylic alcohol is considerably less stable than its allylic rearrangement product. As in the above case with propargylic alcohols, the reaction proceeds via a [3,3]-sigmatropic rearrangement. In some cases, minor amounts of alcohol oxidation products were also observed.…”