Homoallylic alcohols from aldehydes

Transmetalation of cinnamyl and crotyl tributyltin reagents by SnCl2 in acetonitrile has been proposed to explain the predominant formation of anti homoallylic alcohols from aldehydes (Table 23) [41]. In contrast, the syn adducts predominate when these reactions are conducted in CH2CI2. The exchange reaction in acetonitrile was confirmed by the quantitative formation of BusSnCl. Presumably the putative allylic SnCl species is stabilized by complexation with acetonitrile (Eq. 25). 

Allylation. Formation of homoallylic alcohols from aldehydes and the title reagent is possible in aqueous media, ... 

HOFFMAN - YAMAMOTO Stereoselective adylations Synthesis of syn or anti homoallylic alcohols from Z or E crotylboronate and aldehydes (Hoffman) or of syn homoallylic alcohols from crotylstannanes, BF3 and aldehydes (Yamamoto)... 

The approach to polyketide synthesis described in Scheme 5.2 requires the relatively nontrivial synthesis of acid-sensitive enol acetals 1. An alternative can be envisioned wherein hemiacetals derived from homoallylic alcohols and aldehydes undergo dia-stereoselective oxymercuration. Transmetallation to rhodium could then intercept the hydroformylation pathway and lead to formylation to produce aldehydes 2. This proposal has been reduced to practice as shown in Scheme 5.6. For example, Yb(OTf)3-cata-lyzed oxymercuration of the illustrated homoallyhc alcohol provided organomercurial 14 [6]. Rhodium(l)-catalyzed hydroformylation of 14 proved successful, giving aldehyde 15, but was highly dependent on the use of exactly 0.5 equiv of DABCO as an additive [7]. Several other amines and diamines were examined with variation of the stoichiometry and none proved nearly as effective in promoting the reaction. This remarkable effect has been ascribed to the facilitation of transmetallation by formation of a 2 1 R-HgCl DABCO complex and the unique properties of DABCO when both amines are complexed/protonated. 

Several methods promoted by a stoichiometric amount of chiral Lewis acid 38 [51] or chiral Lewis bases 39 [52, 53] and 40 [53] have been developed for enantioselective indium-mediated allylation of aldehydes and ketones by the Loh group. A combination of a chiral trimethylsilyl ether derived from norpseu-doephedrine and allyltrimethylsilane is also convenient for synthesis of enan-tiopure homoallylic alcohols from ketones [54,55]. Asymmetric carbonyl addition by chirally modified allylic metal reagents, to which chiral auxiliaries are covalently bonded, is also an efficient method to obtain enantiomerically enriched homoallylic alcohols and various excellent chiral allylating agents have been developed for example, (lS,2S)-pseudoephedrine- and (lF,2F)-cyclohex-ane-1,2-diamine-derived allylsilanes [56], polymer-supported chiral allylboron reagents [57], and a bisoxazoline-modified chiral allylzinc reagent [58]. An al-lyl transfer reaction from a chiral crotyl donor opened a way to highly enantioselective and a-selective crotylation of aldehydes [59-62]. Enzymatic routes to enantioselective allylation of carbonyl compounds have still not appeared. 

Table 1 Homoallylic alcohols from aryl aldehydes...

From the range of synthetic applications of Brown s pinene-derived allyl- and crotylborane reagents illustrated in these selected examples, it is clear that they are excellent reagents for the synthesis of chiral homoallylic alcohols from chiral and achiral aldehydes alike. That so many researchers have applied these reagents in their research also attests to the great utility of these reagents in organic synthesis. 

Compared with well-established electrophilic it-allylpalladium chemisty, the catalytic asymmetric reaction via umpolung of jt-allylpalladium has received very limited exploration [93]. Zhou and co-workers investigated the Pd-catalyzed asymmetric umpolung allylation reactions of aldehydes [22a, 94], activated ketones [95], and imines [96] by using chiral spiro ligands (5)-18e, (S)-17c, and (5)-17a, respectively. One representative example is that of the Pd/(5)-18e-catalyzed umpolung allylation of aldehydes with allylic alcohols and their derivatives, which provided synthetically useful homoallylic alcohols from readily available allylic alcohols, with high yields and excellent enantioselectivities (Scheme 33). 

Cyclizations. A stereocontrolled synthesis of trisubstituted tetrahydropyrans by condensation of homoallylic alcohols with aldehydes is developed. Treatment of THP ethers derived from unsaturated alcohols with triflic acid leads to oxygen heterocycles. ... 

Allylation. Active barium is generated by reduction of Bah with 2 equivalents of Li biphenylide in THF at room temperature. Allylic chlorides are converted to the allylbarium reagents, which can be used to effect allylation with excellent regio- and stereoselectivities. r/ireo-Homoallylic alcohols from a y-selective reaction with aldehydes are obtained. ... 

Hoffmann has published full details of his diastereoselective synthesis of homoallylic alcohols from crotyl boronates (c/. 4, 149) and aldehydes (Scheme 24). In results consistent with the rationalization presented above, -boronates gave rhreo-alcohols and Z-boronates gave the erythro-diastereomer with virtually complete diastereoselectivity, i.e. threo erythro ratios in the products mirroring the E Z ratio in the starting boronates. A full account has also appeared of work by the same group on addition of chiral allylboronates such as (33) to aldehydes to produce optically active homoallylic alcohols (Scheme 25) cf. 3, 143), with approx. 70% e.e. in the case of saturated aldehydes and having the configumtion as illustrated. "... 

The 2-oxonia [3,3]sigmatropic rearrangement was also used by Ramachandran ti al. to explain their observation on the synthesis of 4-substituted homoallylic alcohols from crotylboronates [292]. The products from the ln(OTf)3 catalyzed reaction of crotylboronates and aldehydes were observed to be highly dependent on temperature, with the kinetic 2-substituted homoallylic alcohol exclusively observed at low temperature and the thermodynamic 4-substituted product observed at room temperature. This is provided that there is an excess of aldehydes, with less than stoichiometric amounts giving product mixtures (Figure 8.134). These results are consistent with the oxonia [3,3]sigmatropic rearrangement mechanism. The procedure was found to be useful for a variety of alkyl and aryl aldehydes. 

The 4-hydroxy-1-alkene (homoallylic alcohol) 81 is oxidized to the hetni-acetal 82 of the aldehyde by the participation of the OH group when there is a substituent at C3. In the absence of the substituent, a ketone is obtained. The hemiacetal is converted into butyrolactone 83[117], When Pd nitro complex is used as a catalyst in /-BuOH under oxygen, acetals are obtained from homoallylic alcohols even in the absence of a substituent at C-3[l 18], /-Allylamine is oxidized to the acetal 84 of the aldehyde selectively by participation of the amino group[l 19],... 

Allylboron compounds have proven to be an exceedingly useful class of allylmetal reagents for the stereoselective synthesis of homoallylic alcohols via reactions with carbonyl compounds, especially aldehydes1. The reactions of allylboron compounds and aldehydes proceed by way of cyclic transition states with predictable transmission of olefinic stereochemistry to anti (from L-alkene precursors) or syn (from Z-alkene precursors) relationships about the newly formed carbon-carbon bond. This stereochemical feature, classified as simple diastereoselection, is general for Type I allylorganometallicslb. 

Treatment of allyl bromides with the complex obtained from tin(II) chloride and the disodium salt of diethyl 2,3-dihydroxybutanedioate gives an intermediate which reacts with aldehydes to provide homoallylic alcohols with 50-65% ee. Lower enantiomeric excesses were obtained with bulky aldehydes and for allylstannanes with y-substituents. Pentacoordinated allyltin complexes may be involved97. 

The complex 8, formed by the addition of 2-propenylmagnesium chloride to 7, adds to aromatic aldehydes, 1-alkanals, a-branched and unbranched alkanals uniformly from the 7 c-face leading to hoinoallylic alcohols with 88-94% ee35 (Method A). After hydrolytic workup, both components can be recycled. Allyl complexes 10, generated from 9, prefer 67-attack and lead to the ent-homoallylic alcohols with excellent enantioselectivity36 (Method B) (Table 8). 

Coupling to both termini of the 2-methyl-2-propcnyl residue occurs when the complex 5, formed from the iodo compound 4 and stiver tetratluoroborate, is allowed to react with an excess of aldehyde, giving rise to diastcreomerically pure 4-fluoro-2,4,6-trisubstituted tetrahy-dropyrans 617. The details of the reaction and, as well, the origin of stereoselectivity is unclear at present. It would not be surprising if the reaction is restricted to those aldehydes leading in the first step to homoallylic alcohols capable of forming mesomerically highly stabilized carb-enium ions on solvolysis. 

Indium-mediated allylation of an unreactive halide with an aldehyde132 was used to synthesize an advanced intermediate in the synthesis of antillatoxin,133 a marine cyanobacteria (Lyngbya majus-cula) that is one of the most ichthyotoxic compounds isolated from a marine plant to date. In the presence of a lanthanide triflate, the indium-mediated allylation of Z-2-bromocrotyl chloride and aldehyde in saturated NH4C1 under sonication yielded the desired advanced intermediate as a 1 1 mixture of diastereomers in 70% yield. Loh et al.134 then changed the halide compound to methyl (Z)-2-(bromomethyl)-2-butenoate and coupled it with aldehyde under the same conditions to yield the desired homoallylic alcohol in 80% yield with a high 93 7 syn anti selectivity (Eq. 8.55). 

Mg. Li and co-worker first reported magnesium-mediated Barbier-Grignard allylation of benzaldehyde in water (Eq. 8.73).172 Recently, a study was completed in which some water-tolerant allylating agents were prepared in situ from allylmagnesium chloride and various metallic salts reacted with aldehydes in THF-FLO to afford the desired homoallylic alcohols.173... 

Pb. Homoallylic alcohols can be obtained from allylation of aldehydes and ketones with allyl bromide promoted by metallic lead in aqueous media.176... 

Iridium-catalyzed transfer hydrogenation of aldehyde 73 in the presence of 1,1-dimethylallene promotes tert-prenylation [64] to form the secondary neopentyl alcohol 74. In this process, isopropanol serves as the hydrogen donor, and the isolated iridium complex prepared from [Ir(cod)Cl]2, allyl acetate, m-nitrobenzoic acid, and (S)-SEGPHOS is used as catalyst. Complete levels of catalyst-directed diastereoselectivity are observed. Exposure of neopentyl alcohol 74 to acetic anhydride followed by ozonolysis provides p-acetoxy aldehyde 75. Reductive coupling of aldehyde 75 with allyl acetate under transfer hydrogenation conditions results in the formation of homoallylic alcohol 76. As the stereochemistry of this addition is irrelevant, an achiral iridium complex derived from [Ir(cod)Cl]2, allyl acetate, m-nitrobenzoic acid, and BIPHEP was employed as catalyst (Scheme 5.9). 

Fluorinated dihydropyrans 16 are readily derived from aldehydes via the homoallyl alcohols 15. A second allylation is a prelude to a RCM (Scheme 7) <00CC607>. 

Starting from 2,4,6-octatriene and pivaldehyde, the conjugated homoallylic alcohol 8 is obtained as the sole product. Cycloheptatriene-derived complexes react with aldehydes and C02 to afford mixtures of the isomeric 1,3- and 1,4-cycloheptadienyl carbinols or acids, respectively. Interestingly, analogous reactions with methyl chloroformate or dimethyl carbamoyl chloride produce the conjugated dienyl ester 9 or amide 10 as unique products [19,20]. 

The above interesting approach to the asymmetric allyltitanation reaction does, however, have a limitation. Thus, L-glucose is much more expensive that the D-form and, consequently, homoallylic alcohols of the opposite configuration cannot easily be obtained by this method. In an attempt to induce the opposite si face selectivity, other acetonide derivatives of monosaccharides from the xylose, idose, and allose series were tested [42b,42c], The enantiofacial discrimination was, however, much lower than that with DAGOH and both re and si face selective additions to aldehydes were observed. 

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