A and 3-Alkoxy aldehydes

Results of reactions of chiral a-methyl aldehydes and several chiral crotyl- and allyl-boron reagents are summarized in Tables 8 and 9. It is apparent from these data that the Brown (Ipc)2B(crotyl) and (Ipc)2B(allyl) reagents (51), (52) and (219) consistently give excellent results for the synthesis of each product diastereomer (Table 8, entries 3-6, 11, 16, 20, and 24 Table 9, entries 1,2, 10 and 18). This is true also for their reactions with chiral a- and 3-alkoxy aldehydes (Scheme 49).i. i4S-i50 Thg tartrate crotylboronates (18) and (19) also display excellent selectivity in the synthesis of crotyl diastereomers (136), (137) and (139) (Table 8, entries 7,10,13,17,25 and 28), but are much less selective for the syndesis of crotyl diastereomer (138), especially from -alkoxy-substituted aldehydes such as (253). Tartrate allylboronate (224) is also less effective than (Ipc)2Ballyl (219) for the synthesis of (257) and (258) in Table 9, and of (266) and (267) in Scheme 49.Substantial improvements in selectivity have been realized by using the taitramide-based allylboronate (228), and the results with this reagent (Table 9, entries 4, 7, 9, 12, 14, 17, 20 and 22) compare very favorably with those obtained with (219). The data... 

TlClamfF Aldol/chelating with a- and 3-alkoxy aldehydes cis anti-Cram products with chelatable aldehydes, trans Cram pr ucts with nonchelatable aldehydes... 

Results of the asymmetric 2-propenylborations of several chiral a- and /i-alkoxy aldehydes are presented in Table 11 74a-82 84. These data show that diisopinocampheyl(2-propenyl)borane A and l,3-bis(4-methylphenylsulfonyl)-4,5-diphenyl-2-propenyl-l,3,2-diazaborolidine C exhibit excellent diastereoselectivity in reactions with chiral aldehydes. These results are in complete agreement with the enantioselectivity of these reagents in reactions with achiral aldehydes (Section 1.3.3.3.3.1.4.). In contrast, however, the enantioselectivity of reactions of the tartrate 2-propenylboronate B (and to a lesser extent the tartrate (/i)-2-butenylhoronate)53b is highly... 

The potential for coordination depends on the oxy substituents.82 Alkoxy substituents are usually chelated, whereas highly hindered silyloxy groups usually do not chelate. Trimethylsiloxy groups are intermediate in chelating ability. The extent of chelation also depends on the Lewis acid. Studies with a-alkoxy and (3-alkoxy aldehydes with lithium enolates found only modest diastereoselectivity.83... 

The 2,6-dideoxy-L-arabino-hexoside (28) and the, 6-dideoxy-3-0 -methyl-D-xylo-hexoside (29) have been synthesized from the major isomers generated by coupling a- and g-alkoxy-aldehydes (30) and... 

Additions of non-stereogenic enolsilanes to a-methyl-3-alkoxy aldehyde 8 were reported to proceed with high selectivity. Chelation control was obtained with TiCl4 due to the formation of the 1 1 complex 9 which was shown to be quite rigid and essentially conformationally locked. Similarly to other cases discussed above the acetate derived silyl ketene acetal was found much less selective than the thioacetate. ... 

Brazeau JF, Mochirian P, Prevost M, Guindon Y. Stereopentads derived from a sequence of Mukaiyama aldolization and free radical reduction on a-methyl-(3-alkoxy aldehydes a general strategy for efficient polypropionate synthesis. J. Org. Chem. 2009 74 64-74. 

The tartrate ester modified allylboronates, the diisopropyl 2-allyl-l,3,2-dioxaborolane-4,5-di-carboxylates, are attractive reagents for organic synthesis owing to their ease of preparation and stability to storage71. In the best cases these reagents are about as enantioselective as the allyl(diisopinocampheyl)boranes (82-88% ee with unhindered aliphatic aldehydes), but with hindered aliphatic, aromatic, a,/l-unsaturated and many a- and /5-alkoxy-substituted aldehydes the enantioselectivity falls to 55-75% ee71a-b... 

In each instance, the silyl enol ether approaches anti to the methyl substituent on the chelate. This results in a 3,4-syn relationship between the hydroxy and alkoxy groups for a-alkoxy aldehydes and a 3,5-anti relationship for (3-alkoxy aldehydes with the main chain in the extended conformation. 

A. y-Oxygen-Substituleel Stannanes. Oxygenated allylic stannanes have been synthesized and used advantageously in several types of syntheses. Both a- and y-alkoxy and silyloxy stannane can be prepared by several complementary methods.177 C-y-Alkoxy and silyloxy allylic stannanes react with aldehydes to give primarily syn... 

A number of other useful modifications of the intramolecular Williamson synthesis have been developed. Reaction of a,a-dialkyl-/3-tosyloxy aldehydes and ketones with potassium cyanide or with sodium alkoxide gives the corresponding 2-cyano- or 2-alkoxy-oxetanes... 

A systematic study of methyl ketone aldol additions with a-alkoxy and o ,/5-bisalkoxy aldehydes has been undertaken, under non-chelating conditions.130 With a single a-alkoxy stereocentre, diastereoselectivity generally follows Cornforth/polar Felkin-Anh models. With an additional /5-alkoxy stereocentre, 7r-facial selectivity is dramatically dependent on the relative configuration at a- and /3-centres if they are anti, high de results, but not if they are syn. A model for such acyclic stereocontrol is proposed in which the /5-alkoxy substituent determines the position in space of the a-alkoxy relative to the carbonyl, thus determining the n-facial selectivity. 

Stereoselective additions to chiral a- and -alkoxy aldehydes. Lewis-acid-catalyzed additions of enol silyl ethers to chiral ct-alkoxy or (3-alkoxy aldehydes can proceed with high 1,2- and 1,3-asymmetric induction. Moreover, the sense of induction can be controlled by the Lewis acid. Thus BF, which is nonchelating, can induce diastereo-... 

In the Type II allylation reactions of a-methyl-/i-alkoxy aldehydes, the principles of 1,2- and 1,3-asymmetric induction both contribute to the reaetion diastereo-selectivity. Evans and co-workers have explained the stereoehemical outcome of these reactions in terms of a merged 1,2- and 1,3-asymmetric induction model [931- For example, the 2,3-anti aldehyde 135 reacts with allyl- and methallyltri-n-butylstannanes 98, generating the Felkin homoallylic alcohols 136 with >99 1 diastereoselectivity (Eq. (11.8)) [93]. 

Additions to a,3-dialkoxy aldehydes (protected glyceraldehydes) are complicated by the possibility of chelation involving either the a or 3 alkoxy group. With 2,3-0-isopropylideneglyceraldehyde (62 equations 21 and 22) and Znh as catalyst, a preponderance of the 3-chelated complex (63) was obtained with consequent formation of the C-3,C-4 anti compounds as major isomers (Table 13, entries 1-3 Table 14,... 

Masamune and coworkers have examined the facial selectivity of the (Z)-lithium enolates of 3-penta-none and ethyl cyclohexyl ketone with a series of (3-alkoxy aldehydes having stereocenters at both the a-and 3-position (equation 110 Table 18).61 In the six-membered chelate, the methyl and R1 groups are on the same side of the ring, and it may be seen from the data in Table 18 that the nature of R1 influences the facial preference of the chiral aldehyde. Another example of this effect is seen in equation (54). 

TiCU-mediated addition of silyl enol ether (95) to chiral a-amino aldehyde (94) was reported to proceed with good chelation control, albeit in poor yield (equation 28).84 Effective chelation control was also reported in the TiCU-mediated reactions of chiral a-alkoxy and 3-alkoxy acyl cyanides (96) and (97) with silyl enol ether (95 equations 29 and 30)696,85 Reaction of acyl cyanide (97) with the ( )-silyl enol ether (93) gave a single stereoisomer as a result of complete chelation control and syn simple stereoselection (equation 31).85 Additions of silyl enol ethers and silyl ketene acetals to (-)-menthyl phenyl-glyoxylate and pyruvate were reported to proceed with moderate facial selectivity the best result (84 16) is shown in equation (32).86... 

In the field of chiral electrophiles, diastereoselective additions of enolsilanes to chiral a-fluoro-a-methyl-p-alkoxy aldehydes,152 a-methyl aldehydes,137 a-alkoxy aldehydes,137 a, 3-dialkoxy aldehydes138 and a-methyl-p-alkoxy aldehydes153 were reported to proceed with good stereocontrol following Felkin-Anh or chelation models (c/. Section 2.4.4.1). Very good selectivities were reported in the addition of enolsilanes to chiral imines,154-156 particularly those derived from carbohydrates (Scheme 17 and 18).155,56... 

The hydrolysis of the acetal moiety and the elimination of the alkoxy group generally proceed under strongly acidic conditions. This is a weakness of the method, especially in the case of carotenoids, because it may cause isomerization and even decomposition of the products [5]. Milder conditions are achieved by the use of acetic acid/sodium acetate or formic acid [18], or formic acid/sodium formate [14]. Mild acidic hydrolysis (e.g. with dilute phosphoric acid) removes selectively the acetal group, thereby yielding the free 3-alkoxy-aldehyde [11,19]. 

The nucleophilic addition of pinacolone enolsilane 1 to 5j -a-methyl-P-alkoxy aldehydes 2, promoted by Lewis acids, is highly stereoselective. Thus, when SnCU was employed, aldols 3 were obtained preferentially with selectivities higher than 95 5. Instead, the stereoisomers 4 were isolated with nearly total stereoselectivity when Mc2A1C1 (2 eq) was used to promote the reaction (Scheme 19. la and b). ... 

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