Alcohol stereochemistry

This reaction was utilized to establish the vincinal amino alcohol stereochemistry required for the construction of key intermediates 251 and 252 for the synthesis of the natural product balanol 253 (Scheme... 

When a carboxylic acid is used as the nucleophile, simple ester hydrolysis releases the alcohol, providing an inversion of alcohol stereochemistry. 

CM Kao, M McPherson, R McDaniel, H Fu, DE Cane, C Khosla. Alcohol stereochemistry in polyketide backbones is controlled by the (3-ketoreductase domains of modular polyketide synthases. J Am Chem Soc 120 2478-2479, 1998. 

Saponification of the ester provided 39 as a cyclohexylamine salt. The functionalization at C4 and C5 to install the necessary vicinal aminoalcohol begins with a selective halolactonization reaction of 39 to give lactone 40, bearing the incorrect alcohol stereochemistry at C4, and a rather challenging stereochemistry at C5, which would require the amino group be installed with retention at the C5-Br bond. Both issues are remedied by treatment of 40 with lithium hydroxide to generate an intermediate epoxide with inversion at C5, which, upon acidification, opens with inversion at C4 to give the y-lactone 41.37... 

Previously documented methods for menthol inversion under standard Mitsunobu conditions (benzoic acid, PPha, diethyl azodicarboxylate) result in low yields4 (27%). More effective methods have been reported using extended reaction periods in refluxing toluene via a formic acid/N,N -dicyclohexylcarbodiimide-mediated transformation5 (20-92 hr, 80%). For hindered alcohols in general, representative methods for inverting alcohol stereochemistry necessitate conversion of the alcohol to... 

Inversion of Secondary Alcohol Stereochemistry (The Mitsunobu Reaction) 117... 

INVERSION OF SECONDARY ALCOHOL STEREOCHEMISTRY (THE MITSUNOBU REACTION)... 

White has also completed two syntheses of racemic methyl nonactate (154). The first approach controlled the C-8 alcohol stereochemistry, and the second provided a rapid entry into the ring system. The first sequence, outlined in Scheme 4.28, began with the opening of propylene oxide by 2-lithiofuran. The Friedel-Crafts acylation that followed also resulted in protection of the alcohol as the acetate to give 175 in 81% overall yield. Hydrogenation of the furan ring over rhodium on charcoal gave a 96% yield of tetrahydrofuran diastereomers... 

Scheme 18.33 Inversion of allylic alcohol stereochemistry via two T2.31 rearrangements. ...

Mitsunobu-like Processes. Triphenylphosphonium 3,3-dime-thyl-l,2,5-thiadiazolidine 1,1-dioxide (1) can be conveniently utilized as a stable source of [PhsP+J in the promotion of Mitsunobu-like processes. By analogy with the betaine generated by reaction of DEAD and triphenylphosphine, protonation of zwitterionic species 1 by an acidic component HX generates ion pair 2 which on subsequent reaction with an alcohol (ROH) affords oxyphosphonium species (3) and 3,3-dimethyl-1,2,5-thiadiazolidine-1,1-dioxide (4). Finally, Sn2 displacement reaction, occurring with Walden inversion of the alcohol stereochemistry, leads to the coupled product R-X and triphenylphosphine oxide (TPPO) (eq 1). 

SCHEME 5 Mitsunobu reaction with retention of alcohol stereochemistry. 

The Mitsunobu reaction is another method frequently used to invert alcohol stereochemistry [for a review see Mitsunobu, O. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products Synthesis 1981, 1-28]. An example is shown below. 

Recall that the goal was to arrive at aminoketone 56. The projected Mannich reaction requires that the amino group be on the concave face surface of the m-decalin ring system. Notice that the alcohol stereochemistry in 67 is set such that an 8 2 reaction at the carbinol center would establish the required stereochemistry in 56 [We will see another approach to establishing this stereochemistry shortly]. Tosylate formation followed by acetal hydrolysis provided 68, but treatment of this material with azide failed to give any of the desired 8 2 product. Treatment of 68 with methylamine, however, gave 56 in excellent yield. Given the results with azide, it is probable that this displacement occurs with intramolecular delivery the nucleophile via involvement of an N,W-acetal (69). The final Mannich reaction proceeded as anticipated to provide luciduline (55). 

The reaction of 204 with succinimide, triphenylphosphine, and diethyl azodicarboxylate (Et02CN=NC02Et) gave (after chromatography) a 20% yield of the diastereomer of 204 with inverted alcohol stereochemistry. Provide a mechanistic explanation for this observation. (Gephyrotoxin- 3)... 

Indium Lewis acids have garnered attention due to their mild reactivity and air and water stability. Both Li et al. and Chan and Loh have shown that In(III) complexes are suitable Lewis acids for Prins cyclizations [81, 82]. These reports prompted Loh and coworkers to embark on a synthesis of (+)-SCH 351488 that utilized this strategy (Scheme 40) [83]. Condensation of homoallylic alcohol 147 and aldehyde 148 in the presence of indium ttibromide and TMSBr gave 4-bromo THP 149 in 65 % overall yield as an inconsequential mixture of diastereomers (2,A-cisP,4 trans = 75 25). Complete retention of the homoallylic alcohol stereochemistry is responsible for the key 2,6-cis relationship in the product. Initial attempts to apply these same conditions to the B ring resulted in acetonide deprotection and no THP formation. Subsequent optimization revealed that indium triflate and TMSCl were competent additives to effect cyclization. Careful temperature control was required to suppress an undesired Prins side reaction. The combination of homoallylic alcohol 150 and aldehyde 151 in the presence of the appropriate Lewis acids at 78 °C, followed by warming to 0 °C for 4 h, led to the desired monomer precursor 152 in 42 % yield. 

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