Esters chemoselective reductions

The same starting material can also be employed to synthesize the antipode (i )-methanophenazine [(i )-lOj, as R)-3l may easily be transformed into lactone (S)-30 by chemoselective reduction of the ester functionality [43] and subsequent cyclization. 

The second synthetic approach to oidiolactone C (61) is summarized in Scheme 20. This route also commences with the ozonolysis of trans-communic acid 180. Now, when this compound was exposed to ozone in excess, keto aldehyde 187 was obtained in 76% yield. The key step in this approach was the y-lactone closure via chemoselective reduction of the lactone moiety on compound 189 through a SN2 mechanism. Compound 189 could be prepared by saponification of the corresponding methyl ester with sodium propanethiolate. Once the primary alcohol is oxidized, the completion of the synthesis of key lactone 103 only requires the allylic oxidation of the C-17 methyl with concomitant closure of the 8-lactone. This conversion was achieved with Se02 in refluxing acetic acid to give 103 in 51% yield. 

Chemoselective reduction of an ester. The ester group of 2 is reduced in high yield by 3 equivalents of 1 (1 equivalent to neutralize the acid group and 2 equivalents for reduction of the ester). 

Chemoselective reduction of methyl ester 7 to aldehyde 2 is possible with DIB AH. The metallatcd hemiacetal that results from addition of DIBAII to the carbonyl group of ail ester usually decomposes rapidly in polar solvents like THF to an intermediate aldehyde This then competes with the ester and, as a result of its higher clcctrophilicity. js reduced by DIBAH to an alcohol. However, ester 7 bears a methoxymethyl residue in its a-position, which stabilizes the metallated hemiacetal by chelate formation. Chelate complex 22 is protolytically cleaved by way of the hemiacetal only in the course of aqueous workup, so in this case the DIBAH reaction produces only aldehyde 2, not the alcohol (see also Chapter 3), DIBAH, THF, -78 C 100. ... 

Mechanisms of sodium borohydride reactions with primary, secondary, and tertiary amides have been investigated both at the B3LYP/6-31+- -G(d,p)//B3LYP/6-31G(d,p) and B3LYP/6-31++G(d,p)//HF/6-31G(d,p) levels of theory. The predicted structures of the key intermediates were then confirmed by experiment.317 For chemoselective reductions of a-substituted and aromatic esters with sodium borohydride, agreement between experimental results and theoretical computations at the B3LYP/6-31+-1-G(d,p)//HF/6-31G(d,p) levels of theory have been reported.318... 

Further improvements in the stereocontrol were achieved by changing the substitution pattern of the succinic anhydride 2-phenyl succinic anhydride (roc)-36 gave the best control giving the monosubstituted succinic ester (f )-37 and (S)-38 in 95% ee and 85% ee respectively (Scheme 9). Simple chemoselective reduction gave the corresponding y-lactones (R)-39 and (S)-40 in similar enantiomeric purity. 

The Cp2TiCl/H20 combination can also be used for the chemoselective reduction of aromatic ketones. The reaction discriminates between ketones and alkenes, between ketones and esters and, remarkably, between conjugated and non-conjugated ketones [80]. There is strong evidence that this reduction proceeds via ketyl-type radicals, which are finally reduced by H-atom transfer from 42 [81]. Under dry conditions, titanium-promoted ketyl radicals from aromatic ketones can be used for intermolecular and intramolecular cross-coupling of ketones [82], Thus, depending on whether water is added or not, complementary and versatile synthetic procedure protocols are available. 

Selective reduction of —COOH to —CHiOH. Chemoselective reduction of car-boxylic acids is possible by in situ conversion to the carboxymethyleneiminium salt by reaction with the Vilsmeier reagent (DMF and oxalyl chloride). This salt is then reduced with NaBH4 (2 equiv.) to the alcohol (equation I). Various functional groups are tolerated bromo, cyano, ester, and C=C (even when conjugated to COOH). 

Zinc-modified cyanoborohydride, prepared from anhydrous zinc chloride and sodium cyanoborohy-dride in the ratio 1 2 in ether, selectively reduced aldehydes and ketones but not acids, anhydrides, esters and tertiary amides. In methanol the reactivity paralleled the unmodified reagent. Zinc and cadmium borohydrides form solid complexes with DMF, which may prove to be convenient sources of the reducing agents.Aromatic and a,p-unsaturated ketones were reduced much more slowly than saturated ketones, so chemoselective reduction should be possible. 

Hydrostannation of carbonyl compounds with tributyltin hydride is promoted by radical initiation and Lewis or protic acid catalysis.The activation of the carbonyl group by the acidic species allows the weakly nucleophilic tin hydride to react via a polar mechanism. Silica gel was a suitable catalyst allowing chemoselective reduction of carbonyl groups under conditions that left many functional groups unchanged. Tributyltin triflate generated in situ from the tin hydride and triflic acid was a particularly efficient catalyst for the reduction of aldehydes and ketones with tributyltin hydride in benzene or 1,2-di-chloromethane at room temperature. Esters and ketals were not affected under these conditions and certain aldehydes were reduced selectively in preference to ketones. 

Alane (AIH3) and its derivatives have also been utilized in the reduction of carboxylic acids to primary alcohols. It rapidly reduces aldehydes, ketones, acid chlorides, lactones, esters, carboxylic acids and salts, tertiary amides, nitriles and epoxides. In contrast, nitro compounds and alkenes are slow to react. AIH3 is particularly useful for the chemoselective reduction of carboxylic acids containing halogen or nitro substituents, to produce the corresponding primary alcohols. DIBAL-H reduces aliphatic or aromatic carboxylic acids to produce either aldehydes (-75 °C) or primary alcohols (25 C) Aminoalu-minum hydrides are less reactive reagents and are superior for aldehyde synthesis. ... 

The reactivity of boranes is dominated by the desire to accept an electron pair into the empty p-orbital. Therefore boranes reduce electron-rich carbonyl groups fastest. In the context of carboxylic acid reduction a triacylborate 35 is formed first. Compared to, for example, ketones, esters are less electrophilic because of conjugation between the carbonyl group and the lone pair of the sp -hybridized oxygen atom. However, in the case of boron esters such as 35, the oxygen next to the boron has to share its lone pair between the carbonyl group and the empty p-orbital of the boron. This fact makes them considerably more reactive than normal esters and allows the chemoselective reduction of carboxylic acids in the presence of esters or acyl chlorides. 

The synthesis will be easier if we use esters instead of acids. Syntheses based on e disconnection a or b will be fine. We prefer a because the enone starting material is a di.xj acetone and very easily made (it can be bought). The best specific enolate is probably malonats there is no problem with the chemoselective reduction as NaBH4 reduces ketones but not The hydroxy-ester will cyclize on work-up. 

Lithium tri-t-butoxyaluminum hydride readily reduces aldehydes and ketones to the corresponding alcohols and reduces acid chlorides to aldehydes. Epoxides, esters, carboxylic acids, tert-amides, and nitriles are not, or only slowly, reduced. Thus, the reagent may be used for chemoselective reductions. ... 

The facile reduction of the -COOH group by BHj THF or BH3 SMej has been employed for chemoselective reductions of the carboxyl group in the presence of ester or lactone functionalities using a stoichiometric quantity of the borane. The carbonyl group in triacylboranes resembles the reactivity of an aldehyde or a ketone more than of an ester (ester resonance) due to electron delocalization from the acyl oxygen into the p orbital of boron. 

Step 2. Chemoselective reduction of the a-alkoxy ester Step 4. Ester enolate alkylation (5-exo-tet cyclization)... 

Esters are much less sensitive than ketones to Zn(BH4)2 or cyanoborohydrides [PSl], and the selective reduction of the ketone groups of a- and P-ketoesters can be accomplished without problems (Section 3.2.4). Moreover, Zn(BH4)2 in DME under sonication reduces acetates or cyclohexanecarboxylates while benzoates are left untouched [R3]. The chemoselective reduction of the acetate residue of 3.163 can be performed under these conditions (Figure 3.55). 

In steroids, the carbonyl group at C-3 is generally the most reactive and that on C-ll the least reactive enabling chemoselective reductions of polyoxosteroids5. The following example demonstrates this chemoselectivity, as well as excess formation of the thermodynamically more stable alcohol by the Meerwein-Ponndorf-Verley reduction of a 7,11-diketone 21l82. The acetic ester is cleaved under these conditions. 

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