Enals, 1,4-additions

From a mechanistic standpoint, ammonia serves two functions 1) it behaves as a base to catalyze an aldol reaction between 2 equivalents of 31 to generate the corresponding enal 33, and 2) it is the source of nitrogen for the resultant pyridyl ring. This occurs through formation of enamine 34 with a third equivalent of 31. The Michael addition of 34 to 33 followed by cyclization gives rise to 32. 

Chromatography. A number of HPLC and TLC methods have been developed for separation and isolation of the brevetoxins. HPLC methods use both C18 reversed-phase and normal-phase silica gel columns (8, 14, 15). Gradient or iso-cratic elutions are employed and detection usually relies upon ultraviolet (UV) absorption in the 208-215-nm range. Both brevetoxin backbone structures possess a UV absorption maximum at 208 nm, corresponding to the enal moeity (16,17). In addition, the PbTx-1 backbone has an absorption shoulder at 215 nm corresponding to the 7-lactone structure. While UV detection is generally sufficient for isolation and purification, it is not sensitive (>1 ppm) enough to detect trace levels of toxins or metabolites. Excellent separations are achieved by silica gel TLC (14, 15, 18-20). Sensitivity (>1 ppm) remains a problem, but flexibility and ease of use continue to make TLC a popular technique. 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

Domino Michael/aldol processes, which are initiated by the addition of a halide to an enone or enal, have found wide attention. They are valuable building blocks, as they can be easily converted into a variety of extended aldols via subsequent SN2 reactions with nucleophiles or a halide/metal exchange. As an example, a-haloalkyl- 3-hy-droxy ketones such as 2-76 have been obtained in very good yields and selectivities by reaction of enones 2-71 with nBu4NX in the presence of an aldehyde 2-74 and TiCl4as described by the group of Shinokubo and Oshima (Scheme 2.16) [24]. 

Diastereoselective conjugate addition of nucleophiles to enones, enals, and enoates occurs with high stereocontrol and constitutes a powerful method in stereoselective synthesis.185... 

Within Hymenoptera, pheromones produced by workers in social colonies are the best studied across many genera, principally in ants [6], with those eliciting trail following most extensively studied. The distinct behavior and the relative ease of the bioassay have resulted in chemical identifications in many species [ 113,114]. Those that have been recently identified are listed in Table 5. In addition, several alarm and recruitment signals have recently been identified. Many of the compounds recently identified in ants have previously been reported as trail or alarm pheromones in other ant species. For example, methyl 4-methylpyrrole-2-carboxylate 64, 3-ethyl-2,5-dimethylpyrazine 65, (9Z)-hexadec-9-enal 66,4-methylheptan-3-ol 67, and methyl 6-methylsalicy-late 68 have been identified as trail pheromone components, and heptan-2-one 69,4-methylheptan-3-one 70, formic acid 71, undecane 61,4-methylheptan-3-ol 67, methyl 6-methylsalicylate 68, and citronellal 72 have been identified as alarm pheromone components [6]. The use of the same chemicals across genera, with some used for very different functions, is an interesting phenomenon. 

A ruthenium(n)-indenyl complex, which is an efficient catalyst for the isomerization of allylic alcohols, is also an effective catalyst for the isomerization of propargylic alcohols to both a,/3-enals and a,/ -enones (Scheme 57).96 In this reaction, the addition of 20—40 mol% InClj is highly effective. The reaction exhibits extraordinary chemoselectivity and a variety of functional groups are unaffected, which allows a highly efficient synthesis of dienals (R1 =Me2C = CH, R2 = H). 

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]. 

Insertion of carbon monoxide into Csp2—Zr bonds occurs readily at ambient temperatures or below to produce a,(5-unsaturated, reactive acyl zirconocene derivatives [27—29]. Early work by Schwartz demonstrated the potential of such intermediates in synthesis [5d], as they are highly susceptible to further conversions to a variety of carbonyl compounds depending upon manipulation. More recently, Huang has shown that HC1 converts 16 to an enal, that addition of a diaryl diselenide leads to selenoesters, and that exposure to a sulfenyl chloride gives thioesters (Scheme 4.11) [27,28]. All are obtained with (F)-stereochemistry, indicative of CO insertion with the expected retention of alkene geometry. 

Conjugate additions to enals and enones.1 ClSi(CH,)3/HMPT markedly accelerates the Cu(I)-catalyzed conjugate addition of Grignard reagents to enals, enones, and unsaturated esters. The conjugate addition of organocopper reagents is also facilitated. 

Coupling of vinyl iodides with aldehydes (12, 137). Further study1 of this 1,2-addition of alkenylchromium compounds to aldehydes to form allylic alcohols indicates that the reaction is applicable to a-alkoxy and a,(i-bisalkoxy aldehydes by use of a solvent other than DMF, which can promote elimination to an enal. A wide number of other functional groups can also be accommodated. Both vinyl iodides and p-iodo enones can be used as precursors to the alkenylchromium reagent. The reaction is only modestly diastereoselective, but the stereochemistry of a disubstituted vinyl iodide is retained. 

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. 

In the phosphonium salt synthesis, the addition reaction of tertiary phosphines to activated alkenes has been reported (Scheme 3). PPh3 is added to electron-deficient alkenes such as enones or enals at the p-position in the presence of acids.4 The reaction of styrenes with phosphine has recently been reported by Okuma, which gave Markovnikov adducts.5 Although no catalyzed reactions of... 

One of the first synthetic applications of organoboranes in radical chemistry is the conjugate addition to enones (Scheme 23, Eq. 23a) and enals reported by Brown [58-61]. Addition to -substituted enones and enals are not spontaneous and initiation with the oxygen [62], diacetyl peroxide [63], or under irradiation [63] is necessary (Eq. 23b). A serious drawback of this strategy is that only one of the three alkyl groups is efficiently transferred, so the method is restricted to trialkylboranes derived from the hydroboration of easily available and cheap alkenes. To overcome this limitation B-alkylboracyclanes have been used but this approach was not successful for the generation of tertiary alkyl radicals [64,65]. 

The modified Brown-Negishi and the B-alkylcatecholborane conjugate additions described above are limited to enone and enal radical traps. Other... 

Chlorotrimethylsilane-accelerated divinylcuprate addition to enal 61, followed by a Wittig olefination, provided enoate 62 as a single stereoisomer in excellent yield (Scheme 6.10) [23]. The enoate 62 could be transformed in further steps into olivin (63), the aglygon of olivomycin. 

Scheme 6.10. Stereoselective cuprate addition to enal 61 the key step to A/ards the synthesis of olivin. (TBS = t-butyidimethylsilyl, TMS = trimethylsilyl)...

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