Horeau’s method

Preparative-scale fermentation of papaveraldine, the known benzyliso-quinoline alkaloid, with Mucor ramannianus 1839 (sih) has resulted in a stereoselective reduction of the ketone group and the isolation of S-papaverinol and S-papaverinol M-oxide [56]. The structure elucidations of both metabolites were reported to be based primarily on ID and 2D NMR analyses and chemical transformations [56]. The absolute configuration of S-papaverinol has been determined using Horeau s method of asymmetric esterification [56]. The structures of the compounds are shown in Fig. 7. 

Another method for determining the absolute configurations of secondary alcohols is Horeau s method, which is based on kinetic resolution. As shown in Scheme 1-14, an optically active alcohol reacts with racemic 2-phenylbutanoic anhydride (54), and an optically active 2-phenylbutanoic acid (52) is obtained after hydrolysis of the half-reacted anhydride. 

The procedure is widely applicable and highly reliable. For example, the configuration of bicyclo[2.2.2]oct-5-ene-2-carboxylic acid (6) was correctly assigned applying Horeau s method to bicyclo[2.2.2]octan-2-ol (7) derived from 6. Conversely, on the basis of the octant rule, the wrong sign for the Cotton effect of 8 was predicted (see p 430)235. 

It has been reported that Horeau s method can be applied to micromolar quantities of secondary alcohols, if the enantiomeric composition of the remaining 2-phenylbutanoic anhydride is determined by means of gas chromatography. To the acylation mixture an optically active amine [(+)-(R)-l-phenylethanamine] is added which reacts rapidly with the excess of 2-phenylbutanoic anhydride. The resulting diastereomeric amides are then characterized by GLC. The amine salts of 2-phenylbutanoic acid do not interfere. Success is dependent upon rapid amide formation (without significant resolution of the anhydride by the amine)236. The application of this method to (+)-(A/)-binaphthol (9) is shown237. 

Despite the many successful applications of Horeau s method, it should be remembered that fundamentally it is an empirical method it may not always be clear-cut which of the groups in 2 (see p 457) is the more bulky188. 

For chemical correlations of planar chiral cyclophanes with centrochiral derivatives for the purpose of applying Horeau s method IOO), see the following section. 

The chirality (—)(R) for 23 (and 20 derivatives thereof), as deduced by kinetic resolution S4,1kinetic resolution of 2-phenylbutanoic anhydride with optically active carbinols) 100) to the two epimeric carbinols (—)-92 and (+)-93 derived from (—)-23 via (—)-91 and... 

In analogy to 23, the chiralities of [2.2]meta- and [10]paracyclophanecarboxylic acids were also deduced from the results of kinetic resolutions 40-77>. For the application of Horeau s method, (—)-[10]paracyclophanecarboxylic acid (14) was transformed by stereoselective hydrogenation and subsequent sodium borohydride reduction of an intermediate cyclohexanone into the (—)-cis-cyclohexanol 94 which on reaction with racemic 2-phenylbutanoic anhydride afforded a 15% excess of the Ievorotatory acid thereby proving (in agreement with the kinetic resolution of the anhydride of 14, vide supra) the chirality (5) for (—)-14 and all its derivatives 40). Optical comparison with dioxa[10]paracyclophanecarboxylic acid (16) confirmed this result63,108). 

The chirality of methano[10]anulene-2-carboxylic acid (96) was derived from results of a kinetic resolution as outlined for cyclophanes in Section 2.9.3. The reaction of the anhydride of 96 with (—)-l-phenylethylamine as well as the kinetic resolution of 102 (unambiguously correlated with 96 via the acetyl derivative 99) with (+)-2-phenylbutanoic anhydride (Horeau s method) — affording an excess of (+)-carbinol 102 — led to the assignment of the descriptor (S) to (+ )-96 and all its derivatives U7). 

The absolute configuration of (-)-spiro[4.4]nonane-l,6-dione was determined by application of Horeau s method of optical rotations.[45] In support of the assignment, and with greater certainty, the Exciton Chirality Rule was applied to the bis-p-dimethylamino-benzoate of the cis,trans-diol obtained following reduction of the diketone. The cis,trans-diol is readily distinguished by NMR from the C2-symmetry cis,cis and rrans,rrans-diols. Since the cis,trans-diol dibenzoate from the (-)-dione exhibits a (-) exciton chirality CD, it follows that the absolute configuration of the dione is that shown in Figure 37. The absolute stereochemistry is easily determined by CD. 

Hydroxysedamine (174), 3-hydroxyallosedamine (175) and 3-hydroxynorallosedamine (176) were isolated from Sedum acre and their structures were determined by MS, IR, lH and 13c NMR and chemical transformations [449]. Treatment of 176 with aqueous HCHO/KOH gave a tetrahydro 1,3-oxazine. Spectroscopic analysis of the oxazine and application of Horeau s method provided the relative and absolute configurations of 176, respectively [449]. 

LiAlH4 reduction of the above oxazine provided 175 with known absolute configuration, given the above application of Horeau s method. 3-Hydroxyallosedamine was readily converted with TsCl/CHCl3, followed by strong base, into a tetrahydrofuran derivative, confirming the position of the 3-hydroxyl group in 176 and 175 [449]. 

Spectroscopic analysis of the diacetyl derivative of 174 was used to determine its structure. The structure was confirmed by a synthesis of 174 [and 175 and 176] involving the cycloaddition reaction of styrene and a nitrone. Resolution of an intermediate and application of Horeau s method before completion of the synthesis provided the absolute configuration of 174 [449]. In a recent synthesis of (-)-174, a key step utilized the hydroboration of an appropriately substituted enecarbamate to introduce the 5-hydroxyl group [450]. 

The stereochemistry of minovincinine (40d) and 11-methoxyminovincinine (40e) has been settled510 6 by Horeau s method [for C(20)] and by interconversions with the corresponding minovindnes (40f and g) (for the other centres). The 2,16-dihydro-alcohols (40h and i) spontaneously lactonize. 

A, Ozonolysis to lactone 114 or 129 of known configuration B, correlation studies C, asymmetric synthesis with peroxy acids of known configuration D, circular dichroism studies E, Horeau s method. 

The nature of the side chain in eupomatenoid-11 (7.5a) was determined by spectroscopy and confirmed by oxidation of the compound to a substituted propanone. Conversion into eupomatenoid-3 (7.3c) by substitution of the alcoholic OH by Cl and dehydrohalogenation established the additional structural features. The absolute configuration was determined as R by Horeau s method (722). 

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