Ketopinic acid

Submitted by Paul D. Bartlett and L. H. Knox 1 Checked by John D. Roberts 

The camphorsulfonyl chloride is the crude product obtained as described on p. 14. If it is not carefully dried, it should be oxidized reasonably promptly after its preparation. The oxidation is conveniently carried out in 100-g. portions. Several reactions can easily be carried out in parallel. 

The checker found it convenient to use a rotary evaporator at this point. 

An additional small crop of crystals may be obtained by concentration of the mother liquor. The checker observed m.p. 240-242°. 

L-Ketopinic acid has been prepared by oxidation of bornyl chloride with nitric acid at 20°2 or with perbenzoic acid in acetic acid 3 from 10,10-dinitrocamphan-2-ol4 or apocamphan-2-ol-l-carboxylic acid5 with alkaline permanganate and from the oxidation of 10-camphorchlorosulfoxide, obtained from 10-camphorsulfonyl chloride by the action of pyridine, with potassium permanganate.6 The present procedure represents a simplification of the latter and gives as high an overall yield.7 

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Since then, optically active a-aminophosphonates have been obtained by a variety of methods including resolution, asymmetric phosphite additions to imine double bonds and sugar-based nitrones, condensation of optically active ureas with phosphites and aldehydes, catalytic asymmetric hydrogenation, and 1,3-dipolar cycloadditions. These approaches have been discussed in a comprehensive review by Dhawan and Redmore.9 More recent protocols involve electrophilic amination of homochiral dioxane acetals,10 alkylation of homochiral imines derived from pinanone11 and ketopinic acid,12 and alkylation of homochiral, bicyclic phosphonamides.13... 

D,L-10-Camphorsulfonyl chloride may be oxidized to ketopinic acid (p. 55). The optically active forms of the sulfonyl chloride are useful for resolving alcohols and amines into optical antipodes. 

Ketopinic acid is of interest as a /3-keto acid which fails to decarboxylate readily. It may be converted to apocamphane-1-carboxylic acid. ... 

Oxidation, of D,L-10-camphorsulfonyl chloride to D,L-ketopinic acid with potassium permanganate, 46, 55... 

Recently, compounds of this type were also prepared by the stereoselective alkylation of a lithiated (LDA) chiral camphor-based phosphonoglycine imine with high selectivity (82— >99% ee). When using ( + )-ketopinic acid, S -configurated a-amino-a-alkyl diethylphospho-nates w crc obtained95. 

With ketopinic acid (5B)46 as chiral auxiliary during the alkylation of benzylimine 6B no improvement in selectivity was observed (d.r. 1 99-43 57)47. 

A camphor-based 3-acyl-2-oxazolidinone has also been used for diastereoselective alkylations66. The A-acylated auxiliary 18 is prepared in three steps from 7,7-dimethyl-2-oxobicy-clo[2.2.1]heptane-l-carboxylic acid (ketopinic acid, 17)67. Deprotonation by lithium diiso-propylamide in tetrahydrofuran at — 78 °C and subsequent alkylation with activated halides [(bromo- or (iodomethyl)benzene, 3-bromo- or 3-iodopropene] furnished moderate to good yields of alkylation products in high diastereomeric ratios (>97 3 by H NMR). With added hexamethylphosphoric triamide the alkylation yields are increased and bromoalkanes also give satisfactory yields. The diastereomeric ratios are, however, much lower (d.r. 70 30 to 85 15)67. 

Camphorsulfonyl chloride has been used as a chiral starting material for the synthesis of a number of products such as ketopinic acid (eq 9), which has been used to resolve alcohols and hemiacetals, ... 

Camphor imines prepared from (+ )-camphor and ( > or (R)-a-phenylethylamine have been reduced with sodium borohydride to yield exclusively the endo- and coco-product, respectively59. An imine prepared from ketopinic acid ethyl ester and benzylamine has been reduced with excess diisobutylaluminum hydride to give the e.w-amino alcohol exclusively61. 

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