Stereochemistry reductions with hydrides

Mechanism, Stoichiometry and Stereochemistry of Reductions with Hydrides... 

In many cases also the reduction agent itself influences the result of the reduction, especially if it is bulky and the environment of the function to be reduced is crowded. A more detailed discussion of stereochemistry of reduction with hydrides is found in the section on ketones (p. 114). 

A stereoselective total synthesis of ( )-hirsutine has been developed by Brown et al. (179). Catalytic hydrogenation of hydroxycyclopentenone 327, prepared previously (180), afforded a mixture of isomeric diols 328, which were quantitatively cleaved by sodium periodate to supply 329. Reductive amination of 329 with tryptamine resulted in tetrahydropyridine 330, which upon treatment with aqueous methanol in the presence of hydrochloric acid gave indolo-[2,3-a]quinolizine 321 with pseudo stereochemistry. Conversion of 321 to ( )-hirsutine was accomplished in a similar manner by Wenkert et al. (161) via selective reduction with diisobutylaluminum hydride and methylation with methanol (179). 

Double bonds conjugated with benzene rings are reduced electrolytically [344] (p. 23). Where applicable, stereochemistry can be influenced by using either catalytic hydrogenation or dissolving metal reduction [401] (p. 24). Indene was converted to indane by sodium in liquid ammonia in 85% yield [402] and acenaphthylene to acenaphthene in 85% yield by reduction with lithium aluminum hydride in carbitol at 100° [403], Since the benzene ring is not inert toward alkali metals, nuclear reduction may accompany reduction of the double bond. Styrene treated with lithium in methylamine afforded 25% of 1-ethylcyclohexene and 18% of ethylcyclohexane [404]. 

On treatment with benzeneselenenyl chloride two olefinic urethanes (214 and 217) underwent cyclization to afford piperidine derivatives (215 and 218, respectively) having the cis stereochemistry. Their reduction with triphenyltin hydride gave the same product (216). Removal of the blocking group from the nitrogen gave ( )-isosolenopsin A (Ic) (Scheme 6) (392). 

Acyl-2-phenyloxazole derivatives undergo a reductive photocyclization in the presence of sodium borohydride to generate a bicychc oxazoline with a cis-fused pyridinone ring 307. The stereochemistry of the product is consistent with hydride attack from the less hindered surface of the cyclic intermediate 306. The oxazoline containing pyridinone is a key intermediate used for the synthesis of pseudodisto-mins 308 (Scheme 8.85, p. 415). ° ... 

The cyclic borates (758) are useful alternatives to benzanilides in the photochemical synthesis of phenanthridines. Irradiation, followed by reduction with lithium aluminum hydride, gives phenanthridines in good yield, the borate ring maintaining the correct stereochemistry (78CC884). 

The main methods of reducing ketones to alcohols are (a) use of complex metal hydrides (b) use of alkali metals in alcohols or liquid ammonia or amines 221 (c) catalytic hydrogenation 14,217 (d) Meerwein-Ponndorf reduction.169,249 The reduction of organic compounds by complex metal hydrides, first reported in 1947,174 is a widely used technique. This chapter reviews first the main metal hydride reagents, their reactivities towards various functional groups and the conditions under which they are used to reduce ketones. The reduction of ketones by hydrides is then discussed under the headings of mechanism and stereochemistry, reduction of unsaturated ketones, and stereochemistry and selectivity of reduction of steroidal ketones. Finally reductions with the mixed hydride reagent of lithium aluminum hydride and aluminum chloride, with diborane and with iridium complexes, are briefly described. 

Reduction of ketones. Reduction of ketones with metals in an alcohol is one of the earliest methods for effecting reduction of ketones, and is still useful since it can proceed with stereoselectivity opposite to that obtained with metal hydrides.1 An example is the reduction of the 3a-hydroxy-7-ketocholanic acid 1 to the diols 2 and 3. The former, ursodesoxycholic acid, a rare bile acid found in bear bile, is used in medicine for dissolution of gallstones. The stereochemistry is strongly dependent on the nature of the reducing agent (equation I).2 Sodium dithionite and sodium borohydride reductions result mainly in the 7a-alcohol, whereas reductions with sodium or potassium in an alcohol favor reduction to the 7p-alcohol. More recently3 reduction of 1 to 2 and 3 in the ratio 96 4 has been achieved with K, Rb, and Cs in f-amyl alcohol. Almost the same stereoselectivity can be obtained by addition of potassium, rubidium, or cesium salts to reductions of sodium in t-amyl alcohol. This cation effect has not been observed previously. 

Stereoselectivity in the reaction of acyclic ketone 270 is different from that of the cyclic ketone 256. The acetate in 271, prepared by reduction of the ketone 270 to alcohol with LiAlH and acetylation, was displaced with Me A1 from the exo side to give 272 with retention of the stereochemistry. No racemization of benzyl cation was observed. However, reaction of 270 with MeLi gave 274. The OH group of 274 was removed with hydride from the less hindered side as shown by 275 to give 276 with... 

The n.m.r. characteristics of the isopropylidene acetals of the four possible types of ring A primary, secondary 1,3-glycol systems, exemplified by serratriol (178), lycoclavanol (179), methyl hederagenate (180), and methyl 3-epihederagenate (181), have been tabulated, and provide a useful means of differentiation.132 The reactions of the primary monotosylates of these four types provide further confirmation of stereochemistry.133 With potassium t-butoxide the cis types (178) and (181) afforded oxetans whereas the trans types (179) and (180) were converted into A-seco-aldehydes (182). Appreciable amounts of alkyl oxygen fission products were obtained on lithium aluminium hydride reduction of the monotosylates of (178), (180), and (181), presumably via participation of the 3-hydroxy-group, e.g. (183). 

The stereochemistry at positions 3,15, and 20 is preserved in alloyo-himbone (LXIV) and its reduction product, alloyohimbane (3a, 15a,20a-yohimbane, LXV), of which several syntheses have been reported (Volume VII, p. 58) (30). In a recent synthesis, tryptamine (XXVI) was condensed with 4-methoxyhomophthalic anhydride (LXVI) to the amide LXVII. This in the five stages shown was converted to LXVIII and the latter, through another series of reactions, converted to LXX consisting of two epimers which were separable. Tosylation of the hydroxyl and ultimate reduction with lithium aluminum hydride generated alloyohimbane (LXV) (31). 

Epoxidation of oxonine 93 with dimethyldioxirane, followed by reduction with diisobutylaluminium hydride (DIBAL-H), resulted in a separable mixture of alcohols 95 and 96, and the side product 94 (Scheme 16). Each of the isomers was submitted to Swern oxidation and sequential stereoselective reduction with L-selectride to achieve desired stereochemistry of the products 97 and 98. Formation of the side product 94 was explained by Lewis acidity of DIBAL-H and confirmed by treatment of oxirane derived from 93 with another Lewis acid, AlMe3, to produce oxocine aldehyde 99 in 35% isolated yield <1997CL665>. Similar oxidative synthetic sequence was utilized for the synthesis of functionalized oxonines as precursors of (-l-)-obtusenyne <1999JOG2616>. 

The stereochemistry of the major adduct was elucidated by H NMR and by conversion to the known 3/i-nitrocholestane. The corresponding aziridine could not be prepared, since the reduction with lithium aluminum hydride or zinc gave 2-cholestene, and treatment with iron(II) sulfate and hydrochloric acid gave starting material only. 

The same photoaddition takes place with N-nitrosodimethylamine. The stereochemistry of both the Ar,Af-dimethyl-2-nitroso-1-cyclohexanamine and 2-[hydroxy(nitroso)amino]-AT V-di-methyl-l-cyclohexaneamine was established by reduction with lithium aluminum hydride and A -acetylation to give both rrans -/V-acctyl-/Vr, Ar-dimethyl-l,2-cyclohexanediamine ( H NMR). 

Table 5 Stereochemistry of Reduction of 4-f-ButylcycIohexyliminium Salts and other Cyclohexyl Imines with Hydride Reagents... 

The mechanism and stereochemistry of the reduction with metal hydride has been dealt with in many articles. It may be stated in general that the structure of the oxirane and the nature of the reducing agent exert great effects on the rate and pathway of the reaction. 

Acetylation and reduction with sodium borohydride of (106a) led to (109) dehydrated to (110). Lithium aluminium hydride reduction of the oxiran ring of (110) afforded the tertiary alcohol (111) identical to N-isobutyrylbuxaline F, isolated from Buxus balearica whereby structure and stereochemistry were established. 

Homer and Balzer had earlier reported 32) that reduction of optically active phosphine oxides with either trichlorosilane (HSiCls), HSiClj/pyridine, or HSiCls/N, N-diethylaniline affords phosphines with overall retention of configuration, whereas reduction with HSiCls/triethylamine affords phosphine with inversion of configuration at phosphorus. In summary, it was suggested 32) that this difference in overall stereochemistry of reduction reflected a difference in the mode of hydride transfer from silicon to phosphorus intra- and intermolecular hydride transfer led to retention and inversion, respectively. The essential features of these mechanistic rationalizations are represented by Eq. (3). The intramolecular hydride transfer mechanism ), which may include pseudorotation (see Sect. 3) if intermediate phospho-HSiClj + O=PR3 - 0 PRj PRj + [ClsSiOH]... 

A transannular route to 1-substituted pyrrolizidines has recently been reported by Wilson and Sawicki. The lactam (79) was prepared by Beckmann rearrangement of the oxime p-toluenesulfonate of cyclohept-4-enone. Reduction with lithium aluminum hydride gave the amine (80), which on treatment with bromine yielded the 1-bromopyrrolizidine (81) in one stereospecific step (95%). The stereochemistry of the product corresponds to a disfavored exo-mode of cyclization by attack of the nitrogen on the bromonium ion. Further modification of this route to produce naturally occurring alkaloids would appear feasible, but has not yet been reported. 

N. G. Gaylord, Reduction with Complex Metal Hydrides. Interscience, New York (1956) H. C. Brown, Boranes in Organic Chemistry, Cornell Univ. Press, Ithaca, NY (1972), pp 209-250 H. 0. House, Modem Synthetic Reactions, Benjamin, New York (1972), p 49 Chem Soc Rev 5 23 (1976) Tetr 35 449 (1979) (stereochemistry and mechanism) Topics Stereochem 11 53 (1979) (stereochemistry) JACS 103 4540 (1981) (stereochemistry of cyclohexanone reductions) J. Seyden Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis, VCH-Lavoisier (1991), Chpt 2 Comprehensive Organic Synthesis, Eds. B. M. Trost and I. Fleming, Pergamon, Oxford (1991), Vol 8, Parts 1.1 and 1.7 TL 34 5483 (1993) (stereochemistry) ... 

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