The Organoalkali Route to Vitamin A and β-Carotene

Abstract

The reductive cleavage of methyl vinyl-β-ionyl ether (1) or the deprotonation of 3,2Ј,6Ј,6Ј-tetramethyl-5-(1-cyclohexenyl)-1,3-pentadiene (2) gives rise to an organometallic C 15 species that combines selectively with a variety of electrophiles at the terminal chain position. Its reaction with aldehydes, however, is less clean. In particular, (E)-β-formyl-2-butenyl acetate gives the expected adduct 7a and, after dehydration, vitamin A acetate only in poor yield. The same is true for the analogous reaction with 2,7-dimethyl-2,4,6-octa-3-Methoxy-3-methyl-1-(2,6,6-trimethyl-1-cyclohexenyl)-1,4-pentadiene (1), quantitatively obtained by the treatment of vinyl-β-ionol with sodium hydride and methyl iodide in tetrahydrofuran or with dimethyl sulfate in the presence of sodium hydroxide under phase-transfer conditions, is readily cleaved by lithium metal or sodium/potassium alloy. The resulting heptatrienyl-type organometallic C 15 entity [1Ϫ3] can be trapped by standard electrophiles to afford, for example, the hydrocarbon 3, the silane 4 or the alcohol 5. As we have found more recently, the same C 15 species can be generated conveniently by the deprotonation of 3-methyl-5-(2,6,6-trimethyl-1-cyclohexenyl)-1,3-pentadiene (2) with sec-butyllithium or the superbasic mixture of butyllithium and potassium tert-butoxide. The required triene is easily prepared by a Wittig olefination of (E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexenyl)-2-butenal, [4Ϫ5] the key building block in the Isler/Hoffmann-LaRoche syntheses of vitamin A [5Ϫ7] and β-carotene. [7Ϫ8] (E)-3-Formyl-2-butenyl acetate is, along with vinyl-β-ionol, the major component of the Pommer/BASF route [9Ϫ10] to vitamin A. When this aldehyde was allowed to react with the organometallic C 15 species, regardless of [a] 3903 triendial, which ultimately affords β-carotene. Vitamin A acetate can also be prepared, this time in moderate yield, by functionalization through consecutive deprotonation, borylation, oxidation and acetylation of a C 20 pentaene hydrocarbon having the required skeleton. Both the C 15 and the C 20 organometallic key intermediates adopt spontaneously a zigzag-like outstretched conformation which, upon electrophilic trapping, directly and exclusively leads to the all-(E) configuration.

Pentadienyl Type Lithium and Potassium Species: The Regioselectivity of their Reactions with Electrophiles

“…The metalation of 5-methyl-1,4-hexadiene with sec-butyllithium or superbasic mixed metal reagent followed by treatment with chlorotrimethylsilane invariably produced stereomixtures suggesting the coexistence of a "W-conformer" and an "S-conformer". 19 On the contrary, a neat "W-structure" can be attributed to the organometallic species generated by metalation of 2,6-dimethyl-2,5-heptadiene with "LIC-KOR" in tetrahydrofuran. Although its condensation with chlorotrimethylsilane mainly takes place at the 4-position (51% of isomer 6) and only to a small extent (6%) at the 2-position, the exclusive transconfiguration of the latter isomer 7 has been unequivocally established (Scheme 4).…”

First Modular Synthesis of Dissymmetric Biaryldiphosphine Ligands Allowing Tunable Steric and Electronic Effects

“…Crystallization from methanol (50 mL) gave the diphosphine as colorless cubes; yield: 7.9 g (56 %); mp 170-171 8C; 1 2,6,6'-Tribromo-2'-methoxy-1,1'-biphenyl (5) Butyllithium (0.10 mol) in hexanes (63 mL) was added at À75 8C to a solution of 2,2',6,6'-tetrabromo-1,1'-biphenyl (47 g, 0.10 mol) in tetrahydrofuran (500 mL). The mixture was consecutively treated with fluorodimethoxyborane· diethyl ether [52,53] (19 mL, 16 g, 0.10 mol), a 3.0 M aqueous solution of sodium hydroxide (36 mL) and 30 % aqueous hydrogen peroxide (10 mL, 3.6 g, 0.10 mol). The reaction mixture was neutralized at 25 8C with 2.0 M hydrochloric acid (100 mL) and extracted with diethyl ether (3 100 mL).…”

“…The residue was subjected to purification by silica gel chromatography (cyclohexane as eluent) to obtain the title compound as yellowish oil; yield: 4.1 g (63 %); 1 2',6-Dibromo-6'-(trimethylsilyl)-1,1'-biphenyl-2-ol (12) At À75 8C butyllithium (50 mmol) in hexanes (32 mL) was added to a solution of silane (15) (23 g, 50 mmol) in tetrahydrofuran (200 mL). The mixture was consecutively treated with fluorodimethoxyborane·diethyl ether [52,53] The same silane 12 was obtained in a 84 % yield (3.36 g), when solution of acetal 14 (4.5 g, 10 mmol) in tetrahydrofuran (20 mL) was treated with a 3.0 M hydrochloric acid (20 mL) for 2 h. The racemic silane 12 was separated into its enantiomers by preparative chromatography using a chiral stationary phase. The column used was CHIRALCEL OD 20 mm, the mobile phase was n-heptane/2-butanol = 100: Trimethyl(2',6,6'-tribromo-1,1'-biphenyl-2-yl)silane (15) At À75 8C, butyllithium (0.10 mol) in hexanes (63 mL) was added to a solution of 2,2',6,6'-tetrabromo-1,1'-biphenyl (47 g, 0.10 mol) in tetrahydrofuran (500 mL).…”

n-Butyllithium-Potassium t-Butoxide

“…35 This preference has been used in the synthesis of Vitamin A and β-carotene. 52 Two important issues arise when functional groups are present on the alkene moiety: their compatibility with the superbase metalation, and their effect on the regio-and stereochemical outcome of the reaction (eq 7).…”