Enals reduction

For successful substrate activation, an acid proves to be crucial, in this case provided by the imidazolidinone tri-fluoroacetic acid (TFA)-salt. Eventually, the conditions depicted in Scheme 32.3 turned out to be ideal for enal reductions. 

Although the C-3 stereocenter in 6 may be susceptible to epimer-ization in the presence of a basic organolithium reagent, enal 6 condenses smoothly in the desired and expected way with lithio sul-fone 5 at -78 °C to give, after quenching with acetic anhydride, a stereoisomeric mixture of acetoxy sulfones (see 35, Scheme 7). ( ,E,7f)-Triene 36 is then unveiled on reduction of the stereoisomeric acetoxy sulfones with 5 % sodium amalgam (77 % overall yield from 6).3... 

Starting from 63, the carbonylation may proceed via coordination and insertion of CO into the vinyl-C-Pd bond to provide an a,P-unsaturated acyl complex. This complex reacts with (ArY) 2, and subsequently the C-Y bond is formed by reductive elimination to give 64 (Scheme 7-14). Because the compound 64 could be directly converted into the corresponding enal 65 by the Pd-catalyzed reduction with BujSnH, this sequence is synthetically equivalent to the regio- and stereoselective thioformy-lation and selenoformylation of alkynes (Eq. 7.49) [53, 54]. 

Scheme 21 Catalytic [3 + 2] reductive cycloadditions of enals and alkynes...

Although the titanium-based methods are typically stoichiometric, catalytic turnover was achieved in one isolated example with trialkoxysilane reducing agents with titanocene catalysts (Scheme 28) [74], This example (as part of a broader study of enal cyclizations [74,75]) was indeed the first process to demonstrate catalysis in a silane-based aldehyde/alkyne reductive coupling and provided important guidance in the development of the nickel-catalyzed processes that are generally more tolerant of functionality and broader in scope. 

Ethylhexan-1 -ol is a useful building block for the pharmaceutical, food, cosmetic and chemical industries. The reduction of 2-ethylhex-2-enal to CS )-2-ethylhexan-l -ol by baker s... 

Williams and Rastetter also accomplished an elegant synthesis of ( )-hyalodendrin (83) in 1980 [39]. Beginning with the sarcosine anhydride-derived enolic aldehyde 78, silyl protection of the enal enabled alkylation of the glycine center with benzyl bromide and thiolation using LDA and monoclinic sulfur a la Schmidt. After protection of the thiol with methylsulfenyl chloride and deprotection of the silyl ether, the enol was sulfenylated with triphenylmethyl chlorodisulfide to afford bis(disulfide) 82 as a 2 1 mixture of diastereomers favoring the anti isomer. Reduction of the disulfides with sodium borohydride and oxidation with KI3 in pyridine afforded ( )-hyalodendrin (83) in 29 % yield (Scheme 9.4). 

Perhaps the most elusive variant of the aldol reaction involves the addition of metallo-aldehyde enolates to ketones. A single stoichiometric variant of this transformation is known [29]. As aldolization is driven by chelation, intramolecular addition to afford a robust transition metal aldolate should bias the enolate-aldolate equilibria toward the latter [30, 31]. Indeed, upon exposure to basic hydrogenation conditions, keto-enal substrates provide the corresponding cycloal-dol products, though competitive 1,4-reduction is observed (Scheme 22.7) [24 d]. 

Very few enzyme-catalysed reactions involving the reduction of alkenes have achieved any degree of recognition in synthetic organic chemistry. Indeed the only transformation of note involves the reduction of a, (3-unsaturated aldehydes and ketones. For example, bakers yeast reduction of (Z)-2-bromo-3-phenylprop-2-enal yields (S)-2-bromo-3-phenylpropanol in practically quantitative yield (99 % ee) when a resin is employed to control substrate concen-tration[50]. Similarly (Z)-3-bromo-4-phenylbut-3-en-2-one yields 2(5), 3(,S)-3-bromo-4-phenylbutan-2-ol (80% yield, >95% ee)[51]. Carbon-carbon double bond reductases can be isolated one such enzyme from bakers yeast catalyses the reduction of enones of the type Ar—CH = C(CH3)—COCH3 to the corresponding (S)-ketones in almost quantitative yields and very high enantiomeric excesses[52]. 

Allylmetallic reagents The ally] anions obtained by reductive metallation of ally I phenyl sulfides with lithium l-(dimethy amino)naphthalenide (LDMAN, 10, 244) react with a, 3-enals to give mixtures of 1,2-adducts. The regioselectivity can be controlled by the metal counterion. Thus the allyllithium or the allyltitanium compound obtained from either 1 or 2 reacts with crotonaldehyde at the secondary terminus of the allylic system to give mainly the adduct 3. In contrast the allylcerium compound reacts at the primary terminus to form 4 as the major adduct. 

Addition with carbonyl compoundsThese reagents form 1,2-adducts with carbonyl compounds at -65° in high yield without enolization or reduction. 1,2-Adducts are also formed from a,0-enones or -enals. Yields are generally over 90%. 

Conjugate hydrogenation. The combination of zinc and NiCl2 (9 1) effects conjugate reduction of a,(3-enones in an aqueous alcohol in which both the enone and product are completely soluble. Ultrasound increases the rate and the yields. Presumably the salt is reduced to a low-valent form that is absorbed on the zinc. No reduction takes place with a 1 1 Zn-NiCl2 couple. The method is not applicable to a,(3-unsaturated enals. Isolated double bonds are also reduced by this method, but this hydrogenation can be inhibited by addition of ammonia or triethylamine. 

Complex hydrides have been used rather frequently for the conjugate reduction of activated dienes92-95. Just and coworkers92 found that the reduction of a,ft-unsaturated ketene 5,5-acetals with lithium triethylborohydride provided mixtures of 1,4- and 1,6-reduction products which were transformed into enals by treatment with mercuric salts (equation 27). Likewise, tetrahydro-3//-naphthalen-2-ones can be reduced with L-Selectride to the 1,6-reduction products93 -95 this reaction has been utilized in the stereoselective synthesis of several terpenes, e.g. of (/ )-(—)-ligularenolide (equation 28)95. Other methods for the conjugate reduction of acceptor-substituted dienes involve the use of methylcopper/diisobutylaluminum hydride96 and of the Hantzsch ester... 

Cordova has described a reductive Mannich protocol that proceeds with high chemo-, diastereo- and enantioselectivity [179]. Conjugate reduction of p,p-disub-stituted enal 118 with Hantzsch ester 119 in the presence of 30 (10 mol%) and benzoic acid (10 mol%) (63 h, -20 °C) followed by addition of a-iminoglyoxylate 120 and stirring for a further 24 h gave the product (121) with excellent levels of relative and absolute stereocontrol (10 1-50 1 dr 95-99% ee) (Scheme 49). 

Asymmetric reduction of a,/l-unsaturated aldehydes with transition metal catalysts has not yet proven ready for widespread industrial application. One area, namely the chiral reduction of enals to yield chiral alcohols using bakers yeast has been... 

Lithio-l-methoxycyclopropane can be generated by reductive lithiation of 1-methoxy-l-phenylsulfanylcyclopropane with lithium 1-dimethylaminonaphthalenide (Method A)146,147 or lithium 4,4 -di-f< r/-butylbiphenylide (Method B)148 in tetrahydrofuran at — 78 °C. 1-Lithio-l-methoxycyclopropanc reacts with enones and enals to produce 1-methoxycyclo-propanemethanols, which rearrange to vinylcyclobutanones 1 using tetrafluoroboric acid in tetrahydrofuran (Method C) 146,147 or triflic anhydride in the presence of 2,6-di-f 77-butyl-4-methylpyridine in dichloromethane (Method D).148 The latter method avoids destruction of acid-sensitive products (Table 11). 

Reduction of enediones. 1,4-Encdioncs and 4-oxo-2-alkenals are reduced to saturated 1,4-dicarbonyl compounds in nearly quantitative yield by a large excess of Nal-HCl (1 1) in acetone. The method is ineffective with butenedioic acids and 3,/J-enones and a,/J-enals. 

A third approach to the preparation of allyl lluorovinyl ethers is the reaction of an allylic alcohol with trifluoroacetaldehyde, as illustrated by an alternative synthesis of 37a.17 Cinnamyl alcohol (47) forms with trifluoroacetaldehyde a hemiacetal, which is converted into bromide 48 via the mesy late. Reductive elimination affords 37a, which undergoes Claisen rearrangement within one hour in refluxing carbon tetrachloride to give 2,2-difluoro-3-phenylpent-4-enal (38a).17... 

This system when catalyzed by ZnCl2 can effect conjugate reduction of a,p-enones and -enals.2... 

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