A Convenient Stereoselective Synthesis of (1R,2S,3R,4S)‐3‐(Neopentyloxy)isoborneol

Abstract

A convenient preparation of (1 R,2S,3R,4S)-3-(neopentyloxy)isoborneol (= (1 R,2S,3R,4S)-3-(2,2-dimethylpropoxy)-I ,7,7-trimethylbicyclo[2.2.l]heptan-2-ol; la), a valuable chirdl auxiliary, is described. The synthesis iiivolves six steps starting from the readily available camphorquinone ( 5 ) and gives l a in 48% overall yield. The key step is the chemoselective hydrolysis of the less hindered 3,3-dioxolane moiety in the camphorquinone diacetal 4.

Regioselective Short Synthesis of Epiisoborneol Neopentyl Ether as Chiral Auxiliary: An Absolute Configuration Reset

“…[77,79] 11 Oxidation of (+)-5 with PCC in CH 2 Cl 2 afforded quantitatively (À )-14 ([α] D 20 = À 88.52, c = 0.5, EtOH) (for enantiomers, see Scheme 3). The analyses of (À )-14 are identical with those of the literature, [67] at the exception of the carbonyl 13 C-NMR resonance at 218.2 ppm (s), in our case. Oxidation of (+)-4 with PCC in CH 2 Cl 2 afforded similarly (+)-9 ([α] D 20 = + 153.3, c = 1.0, CHCl 3 ) (for enantiomers, see Scheme 2).…”

“…Angyal and Young, [37] as well as Takeshita and Kitajima, [40] sug-Scheme 5. Attempted synthesis of (À )-23. i) SeO 2 , Ac 2 O, 90 % yield; [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] ii) KHMDS, 1-phenyl-[N-toluylsulfonyl]oxaziridine, À 78 °C, 70 % yield; [87] iii) L-Selectride, THF, À 78 °C, 90 % yield; [88][89][90] iv) Zn, AcOH, 99 % yield of a 6 : 4 mixture, v) LiAlH 4 , Et 2 O, 20 °C, 75 % yield; vi) pivaldehyde, pentane, TsOH, 20 °C, 24 h, 60 % yield; vii) DIBAH, toluene, À 40 to 40 °C, 76 % crude yield, 14 % isolated; viii) PCC, CH 2 Cl 2 , 20 °C, 5 h, 99 % yield; ix) 50 % H 2 SO 4 , 96 % yield, [48] or 3 M HCl, EtOH, 93 % yield; [73] x) t BuOK, t BuOH, 20 °C, 64-72 h, 98 % yield, 1 : 1 to 6 : 4 endo/exo; xi) Na, i PrOH, Na 2 HPO 4 , 20 °C, 95 % yield, 48 : 29 : 23 mixture; xii) 50 % H 2 SO 4 , 93 % yield, [68] or 2 M HCl, MeOH, 67 % yield; [69] xiii) NaBH 4 , EtOH, 0 °C, 84 % yield as a 7 : 3 endo/exo mixture; [67] xiv) MesCl, Et 3 N, CH 2 Cl 2 , 0 °C, 3 h, 52 % yield. 14 For acylation, see Ref.…”

“…[104] In fact, despite absence of 1 H-NMR coupling evidence for their C(3)-H, they nevertheless obtained the endo-isomer in view of the typical resonances of their C(2), C(3), C(4) and C(5) nucleus exhibited in their 13 C-NMR analysis (by comparison with Ref. [67], for example). This inadvertence partially explains the poor induced diastereoselectivity observed in their case.…”

“…Opening of this resulting unreported crude acetal (À )-22 (DIBAH, À 40°to 40 °C, 76 % yield) afforded a 7 : 3 mixture of the main unreported hydroxy-ether (À )-23, and its known minor regioisomer 3-endo-neopentyloxy borneol (À )-24. [67] Unfortunately and disappointingly, the separation by preparative column chromatography proved to be particularly tedious and unsatisfactory, as both compounds were isolated in 14 %, and 6 % yield, respectively. We then tried to take advantage of the rapid epimerization, 19 but when either the pure exo-ketols (+)-(1R,3R,4S)-17, or (À )-(1S,3S,4R)-18a were alkylated by neopentyl mesylate (1.0 mol.-equiv.…”

“…50 % H 2 SO 4 , 60 °C, 94 % yield, [45] ) to the corresponding 3exo-neopentyloxy epicamphor (À )-9, prior to the ultimate stereoselective reduction to the desired epiisoborneol derivative (À )-4 (NaBH 4 , MeOH, 0 °C, 80 % yield, [45,46] ). 7 In several chemical transformations, its counterpart (À )-5 was found slightly superior, 8 and fifteen years later, this motivated Pericàs and Riera et al to report an even longer seven step regioselective synthesis (Scheme 3), [67] based on the tedious bisacetalization towards (+)-10, (ethylene glycol, TsOH, cyclohexane, 89 % yield after recycling the monoacetals (+)-6, [17,21,68,69] ). In their case, the key step was the sterically more accessible already known regioselective mono-deprotection to keto-acetal (À )-11 (4 M HCl, EtOH, reflux, 93 % yield, [68,69] ).…”