Lithium borohydride, reduction

Brimble and coworkers176 studied the asymmetric Diels-Alder reactions of cyclopentadiene with chiral naphthoquinones 272 bearing different chiral auxiliaries. The highest endo and facial selectivities were obtained using zinc dichloride as the Lewis acid catalyst and (—)-pantolactone as the chiral auxiliary. Thus, the reaction between cyclopentadiene and 272 afforded a 98 2 mixture of 273 and 274 (equation 76). The chiral auxiliary was removed easily by lithium borohydride reduction. 

A convenient method for the specific introduction of 2H or 3h (or both) into a molecule is by ketone reduction with labeled metal hydride. Beale and MacMillan (10) have utilized this method for the preparation of GAs labeled at the 1, 2 or 3 positions from GA3 or GA7 (Figure 12). One point of interest is the lithium borohydride reduction of the enone formed by manganese dioxide oxidation of GA3 or GA7. When the reaction is carried out in anhydrous tetrahydrofuran it proceeds in two steps. Initially the lithium enolate is formed which incorporates a proton at carbon-2 from the acid used in the work-up, forming the 3 ketone. This ketone is reduced to the 3 -alcohol by the borohydride which is decomposed more slowly than is the lithium enolate. Thus it is possible to introduce two different labels in a single reaction. 

In considering this question, we noted the following. It seemed to us that Choi, in his earlier 1991 disclosure of the lithium borohydride reduction of diethyl 2-phenylmalonate, may well have produced boron intermediates falling within the Johnson et al. intermediate patent claims. If this were so, then the Johnson et al. patent claims to boron intermediates would be invalid if they were the same as the boron intermediates previously produced by Choi. In short, the Johnson et al. claims would be open to attack as lacking novelty. We investigated. We undertook a boron NMR analysis of the following fully reduced solutions ... 

In non-hydroxylic solvents, the effects of the cation co-ordination become important, particularly if the cation is Li+ or Zn + 2. Lithium borohydride reductions of cyclohexanone, in THF, for example, are strongly inhibited by addition of the stoichiometric amount of the lithium specific [2.1.1]cryptand (Handel and Pierre, 1975). In the reduction of a,P-unsaturated ketones, lithium borohydride shows a strong selectivity for 1,2-addition (D Incan et al., 1982a,b) but in the presence of the cryptand, conjugate addition is favoured indeed, the selectivity is then indistinguishable from tetrabutyl-ammonium borohydride (D lncan and Loupy, 1981 Loupy and Seyden-Penne, 1979, 1980). 

Two large-scale syntheses were reported by Quaedflieg et al. at Tibotec.31 Chiral synthon 20, obtained from ascorbic acid, was converted to a,p-unsaturated ester 21 in 92% yield and E/Z ratio was > 95 5. Michael addition of nitromethane to 21 was carried out with DBU as base to provide 22 in 80% yield and a syn/anti ratio of 5.7 1. A Nef reaction then converted 22 to a mixture of lactone 23 (major, 56%) (a/p = 3.8 1) and ester 24 (minor). The a-23 was obtained via recrystallization in isopropanol (37%), with high enantiomeric purity (> 99%). Isomerization of P-23 followed by recrystallization in isopropyl alcohol gave an additional 9% yield of a-23. It is interesting that most of 24 remained in the aqueous layer. Lithium borohydride reduction of a-23 followed by acid-catalyzed cyclization resulted in (-)-ll. 

In 1972 Link and Bernauer (69) published a synthesis of (+)-isopilosine and of (+)-pilocarpine, and then obtained (—)-epiisopilosine as a by-product. The readily available ester 53 was converted in two steps to the aldehyde (54), which on Stobbe condensation with succinic ester gave the half-ester acid salt 55. Lithium borohydride reduction followed by prolonged acid treatment gave ( )-pilosinine [( )-32], together with 2,3-dehydropilosin-... 

A starting material for the synthesis of 9 is the 7-methoxymethyl ether of fraxetin (41), which was prepared by different workers using alternative methods. Tanaka et al. found it convenient to prepare it from fraxetin (35) by dropwise addition of a solution of chloromethyl methyl ether to a solution of 35 in a suspension of sodium hydride in THF. The reaction of this fraxetin derivative 41 with ethyl 2-bromo-3-(4-benzyloxy-3-methoxyphenyl)-3-oxopropionate (40) yielded an ether (42), which on lithium borohydride reduction yielded a mixture of diastereomers with threo- and erythro-Aio %, 43. Cyclization of this compound with sulphuric acid (5%) afforded cleomiscosin A monoacetate (44), which gave cleomiscosin A (9) on mild alkaline... 

Blumenfeld and Gallop (1962b) have used lithium borohydride reduction, with subsequent chromatographic separation of the amino alcohols produced, to identify the carboxyl donor of the ester links previously found by Gallop et al. (1959) using hydroxylamine and hydrazine. The peaks obtained on the chromatogram for the two products in question, namely homoserine and /3-amino-7-hydroxybutyric acid, are very small, but nonetheless seem to establish that a- and /3-carboxyl groups of aspartic acid participate in the hydroxylamine-sensitive links. 

Lithium borohydride reduction of C,oHg(BCl2)4, prepared from the interaction of B2CI4 with naphthalene, gave a 28% yield of CioHg(BH2)4. Infrared and NMR evidence support a structure containing distinct BH2 groups with no B—H—B bridges 117, 119). 

The cyclic anhydride was converted into the amide acid which on Hofmann rearrangement followed by lithium borohydride reduction on the ester gave a derivative of ip-amino-2a, 3a-dihydroxy-43-hydroxy-methylcyclopentane. Condensation of the amino-triol with 5-amino-4,6-dichloropyrimidine followed by ring closure with triethyl orthoformate gave the 6-chloropurine derivative which on treatment with ammonia gave 11. ... 

In contrast to the usual reaction of aromatic aldehydes with cyclic ketones o-nitrobenzaldehyde condenses with 17-ketones to produce good yields of seco-acids, a reaction which has been applied to the preparation of 16-oxa-steroids. Thus, 3 -hydroxy-5a-androstan-17-one or its acetate affords the seco-steroid (153), which can be oxidised either as the free acid by ozone and alkaline hydrogen peroxide to the diacid (155) or, as its methyl ester (154), with chromium trioxide to the monomethyl ester (156). Diborane reduction of the diacid (155) or lithium aluminium hydride reduction of the dimethyl ester (157) gave the trans-diol (158), cyclised with toluene-p-sulphonic acid to 16-oxa-androstan-3)5-ol (159) or, by oxidation with Jones reagent to the lactone (152) (as 3-ketone) in quantitative yield. This lactone could also be obtained by lithium borohydride reduction of the monomethyl ester (156), whilst diborane reduction of (156) and cyclisation of the resulting (151) afforded the isomeric lactone (150). The diacid (155) reacted with acetic anhydride to afford exclusively the cis-anhydride (161) which was reduced directly with lithium aluminium hydride to the cis-lactone (160) or, as its derived dimethyl ester (162) to the cis-diol (163) which cyclised to 16-oxa-14)5-androstan-3) -ol (164). 

Synthesis from L-threitol The L-threitol derivative 24, obtained from D-(-)-diethyl tartarate in three steps and 90% overall yield, was used as a starting material for the synthesis of nectrisine (1) (Scheme 5). " Swern oxidation of 24 produced the L-threose derivative 25, which was transformed into the aminonitrile 26 in 96% overall yield from 24, as an inseparable diastereomeric mixture. Removal of the silyl protecting group from 26 followed by oxidation of the resulting primary hydroxyl group with TPAP afforded the lactam 27, which was treated with sodium methoxide to produce the methyl ester 28 in 62% yield from 26. Lithium borohydride reduction of 28 afforded a chromatographically separable mixture of the lactams 29 and 30 in a ratio of 56 44 and 87% total yield. Silylation... 

The interesting conversion of nornarceine (181) into the rhoeadine analogues (187) and (188) has been carried out as shown in Scheme 9. Nornarceine (181), obtained from (— )-a-narcotine, was heated in base to afford the enamine (182) which readily cyclized in dilute acetic acid to the y-lactone (183). Upon standing, (183) was oxidized to the ketone (184). Lithium borohydride reduction led to the c/.s-acid (185). The derived ds-fused lactone (186) was then reduced to the hemi-acetal (187) which upon O-methylation with trimethyl orthoformate gave (188). The structure of the methiodide salt of (187) was confirmed by an X-ray analysis. The phthalideisoquinoline alkaloid (— )-bicuculline (189) was then converted into naturally occurring (+ )-rhoeadine (190) by an analogous route. Since (— )-bicuculline was obtained from (—)-)3-hydrastine, whose synthesis had been reported in 1950, this transformation represents the first total synthesis of a rhoeadine alkaloid. ... 

S. EtogoNzue, B. Bodo, and D. Molho. Lithium borohydride reduction of substituted phthalic anhydrides. Bull Mus. Natl. Hist. Nat., Sci. Phys.-Chim., 1977,14, 65. 

The syn selective reduction of ester 128 to alcohol 129 was accomplished by Grignard addition followed by lithium borohydride reduction. The reagents were added simultaneously since lithium borohydride does not compete with the Grignard reagent in the reaction with the ester 128. In contrast, the anti-product 120 was obtained by first reducing the ester with diisobutylalurninum hydride and subsequent Grignard addition. Both alcohols 129 and 130 were obtained as single isomers with the respective procedures. 

This was demonstrated by reacting the bacterial product with diazometh-ane, followed by lithium borohydride reduction and hydrolysis of the modified polymer to give exclusively r-amino-5-hydroxyvaleric acid.3... 

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