Keto acid reduction with borohydride

Keto acids can be dehydrated to enol lactones (Section III,A,1). They may also undergo esterification with alcohols e.g., /V-methylhydrasteine (104) in methanol at room temperature gave the expected keto ester 126 (R + R = CH2, R1 = CH3) (5,87). Sodium borohydride reduction of keto acid 104 supplies the saturated y-lactone 132 identical with that obtained from enol lactone 98 (5). 

Borohydride reduction of the keto acid (318) yields the lactone (319), which is converted into the y-chloro ester (320) by successive treatment with thionyl chloride and ethanol. Treatment of 320 with potassium ferf-butoxide yields the trans ester (203 It = C02Et).466- 620... 

Conversion of (107) into the dimethyl acetal (108) with trimethyl orthoformate and Rexyn 101, followed by pyrolytic elimination in refluxing o-xylene, gave (109). Treatment of (109) with n-butyl-lithium and C02 in THF, followed by hydrolysis, afforded the keto-acid (110). Reduction of (110) with borohydride, followed by dehydration with phosphoric acid and esterification, gave (111). 

Berberine has been converted into a mixture of a- and /3-hydrastines, in the proportions 1 2 oxidation with potassium ferricyanide produced dimeric oxy-bisberberine, which with methanolic hydrochloric acid yielded the betaine (91). Hydration of this, followed by N-methylation, yielded the keto-ester (92), which gave a- and /3-hydrastines on reduction with sodium borohydride and subsequent hydrolysis.100 The photo-oxidation of tetrahydroberberine methiodide to allo-cryptopine has been reported.101... 

Hydrastine has been prepared by the hydrogenolysis of the 1-phenyl-l/f-5-tetrazolyl ether of (—)-a-narcotoline,154 and in the racemic form by the reductive cyclization of the quaternary salt of the keto-acid (53) that is obtained from oxidoberberine (51) as described above.133 The lactone (80), prepared by the dye-sensitized photo-oxidation of oxidonorcoralyne followed by reduction with sodium borohydride and from 6 -acetylpapaveraldine by oxidation with hypo-bromite followed by reduction, has been TV-methylated and reduced with sodium borohydride to an isomer of cordrastine.133 Cordrastine itself has been synthesized by the electrolytic reduction of a mixture of the iminium salt (81) and bromomeconine (82), a process that has been shown to be of general applicability to the synthesis of alkaloids of this group.155... 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

Metal-alcohol reductions have also been used in the stereoselective reduction of 3a-hydroxy-7-keto-cholanic acid (26) to the commercially important equatorial 7 3-ol (27). These reductions have been carried out with several alkali metals in secondary and tertiary alcohols, where reduction with K in tertiary alcohols is more stereoselective than Na-isopropyl alcohol. These reductions afford the equatorial alcohol as the major product in good yield, in contrast to sodium borohydride reduction, which provides the axial alcohol (28) almost exclusively. 

A ketone added to the aged solution is reduced effectively, but a carboxylic acid or ester is not reduced. This weak hydride donor is thus useful for the selective reduction of a keto acid to the corresponding hydroxy acid. Both intermolecular 2md intramolecular competition experiments with tetrakis-(N-dihydropyridyl)-aluminate showed that diaryl ketones are more reactive to this reagent than either dialkyl or aralkyl ketones. This relationship is the opposite of that found by H. C. Brown for reduction with sodium borohydride in isopropyl alcohol, where the order of reactivity is acetone > acetophenone > benzophenone. 

Toward this end, exposure (9 h) of dienophile (284) to 5.0 equiv. of dienoic acid (285) in 3.0 M LiClOr-diethyl ether gave rise in 72% yield to crystalline keto acid (286), a which was reduction with sodium borohydride in methanol at 0°C by treatment with concentrated hydrochloric acid afforded the crystalline tetracyclic alcohol (287). To set the stage for the inversion of configuration at C(9), tetracyclic alcohol (287) was transformed into tetracyclic enone (291), via tetracyclic ketone (290), which was readily available by a five-step sequence from (287) described above [133],... 

The enantiomerically pure 2,3-unsaturated aldonic lactone 2 was prepared following Sharpless asymmetric dihydroxylation of 2-vinylfuran to give 1 (Scheme 1). The chain-extended aldonolactones 4 and 5 were prepared from the P-keto ester 3 by use of a diastereoselective reduction with either d- or L-tartaric acid in conjuction with sodium borohydride (Scheme 2). Reaction of Meldrum s acid (5a) with D-aldopentoses and hexoses gave 3,6-anhydro-2-deoxy-aldono-... 

To construct tricycHc compound 275, they first employed sodium boro-hydride to reduce the keto group to furnish alcohol 273. The terminal olefin was then converted to an alcohol via a two-step protocol employing oxidation with osmium tetroxide and sodium periodate followed by reduction with sodium borohydride to furnish diol 274, which underwent acid mediated lactonization. Dess—Martin oxidation of the remaining secondary alcohol then led to the desired tricyclic lactone 275. 

Confirmative evidence of the proposed structure was obtained from partial synthesis of hyocholic acid [Hsia et al. (30)]. An important intermediate in the synthesis was 3a,6a-dihydroxy-7-keto-5 -cholanic acid (VII, Fig. 2), first prepared by Takeda et al. (35). The 3 - and 6a-hydroxyl groups in VII were established by the formation of hyodeoxycholic acid (IX) after hydrogenolysis of the ethylenedithioketal derivative (VIII) with Raney nickel. Hyocholic acid was obtained from VII either by reduction with sodium borohydride or by hydrogenation in the presence of platinum both methods were known to produce the axially oriented 7a-hydroxy from 7-keto bile acids [Mosbach et al. (36) Iwasaki (37)]. More direct evidence for the la-hydroxyl group in hyocholic acid was found in a later study [Hsia et al. (8)], when hyocholic acid was derived from bromohydrin acetate XII (Fig. 3),... 

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