Reagent-Controlled Aldol Reactions

Important limitations were observed with regard to reagent control in reactions with highly sterically hindered aldehydes involving a chiral hydroxy function at the p position (Eq. 58) [43g]. When (S)-3f was used for 32, diastereo- and enantioselectivity were less satisfactory. When (l )-3f was used, however, the reaction proceeded more smoothly to give the corresponding aldols with moderate syn selectivity in 87 % yield. Each of the isomers obtained was almost enantiomericaUy pure. The spatial orienta-... 

Both these syntheses of oleandolide relied upon substrate-controlled aldol reactions of dipropionate reagents (5)-18 and ent-25. Substrate control is also evident in the way both groups incorporated the exocyclic epoxide with greater than 95% ds. While we chose to use macrocyclic control for this transformation, the Evans synthesis used acyclic stereocontrol and the directing influence of a nearby hydroxyl group. 

Reagents are available nowadays for acyl anions other than (4). Thus when Heathcock made the ketone (16), which he used in stereoselective aldol reactions, he needed a-hydroxy ketone (17), This required synthon (18) for which an acetylene is not a good choice as there are as yet no means of controlling the reglo-selectivity of hydration of (19). 

The aldol reaction is also important in the synthesis of more complex molecules and in these cases control of both regiochemistry and stereochemistry is required. In most cases, this is accomplished under conditions of kinetic control. In the sections that follow, we discuss how variations of the basic mechanism and selection of specific reagents and reaction conditions can be used to control product structure and stereochemistry. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

The aldol reaction between a chiral a-amino aldehyde 16 and an acetate derived enolate 17 creates a new stereogenic center and two possible diastereomers. Several different methods for the synthesis of statine derivatives following an aldol reaction have been reported most of them lead to a mixture of the (35,45)- and (3/ ,45)-diastereomers 18 (Scheme 3), which have to be separated by laborious chromatographic methods.[17 211 Two distinct approaches for stereochemical control have been used substrate control and reagent control. 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

The stereochemical course of the aldol reaction can be controlled by the judicious selection of the enolization reagents. Treatment of propionate esters with <7-Hex2BOTf and triethylamine produced anti-aldol products, and that of with Bu2BOTf and diisopropylethylamine selectively gave syn-aldol products after reaction with aldehydes (Equation (180)).684 685 Complementary anti- and yy/z-selective asymmetric aldol reactions were also demonstrated in structurally related chiral norephedrine-derived propionate esters (Equation (181)).686... 

It s not only Grignard reagents that will react with aldehydes or ketones to make alcohols enolates will too—we spent Chapters 27 and 26 discussing this reaction, the aldol reaction, its variants, and ways to control it. 

Two dialkyl boranes arc in common use. The bicyclic 9-borabicyclo[3.3.1] nonane (9-BBN), introduced in Chapter 34 as a reagent for diastereoselcctive aldol reactions, is a stable crystalline solid. This is very unusual for an alkyl borane and makes it a popular reagent. It is made by hydroboration of cyclo-octa-1,5-diene. The second hydroboration is fast because it is intramolecular but the third would be very slow. The regioselectivity of the second hydroboration is under thermodynamic control. 

Another control experiment was done to determine the importance of water in this oxidative cleavage reaction. Water was found to be a necessary reagent for the reaction to occur since no p-hydroxybenzaldehyde was obtained when the sodium salt of chlorostilbene 5b was heated in neat nitrobenzene with or without solid sodium hydroxide and a crown ether phase transfer catalyst. Another set of controls was done to evaluate the formation of p-hydroxybenzaldehyde by a nonoxidative reaction, such as the loss of X-PI1-CH2 in a retrograde-type Aldol reaction. No p-hydroxybenzaldehyde was formed when the chlorostilbene 5b was heated at 155 °C for 5 hours in the presence of 2N NaOH but without the presence of nitrobenzene and atmospheric oxygen. Finally, in all of the above control experiments, no oxidized cleavage products were observed from the nonphenolic side of the alcohols 4 or stilbenes 5 (Dershem, S. M., et al., Holzforschung, in press). 

The chiral borane 3f-mediated aldol reaction proceeds with a-chiral aldehydes in a reagent-controlled manner. Both enantiomers are obtained almost optically pure from one racemic aldehyde (Eqs 53 and 54) [43d]. 

A very short asymmetric synthesis of the bryostatin C1-C9 segment was achieved by use of three sequential 3f-promoted aldol reactions under reagent control [43f]. This synthetic methodology is based on the direct asymmetric incorporation of two acetate and one isobutyrate synthones into a framework (Sch. 1). 

The third step is an Evans aldol reaction and employs the enolate of 26 that is the enantiomer of 50 that was used in the previous aldol reaction. The stereochemistry of the reaction is entirely reagent-controlled. Can you draw the favored transition state and predict the stereochemical outcome of the reaction ... 

The linear synthesis of the title compound started from an enantiopure building block with one stereogenic center. The other six stereogenic centers were introduced by two reagent-controlled Evans aldol reactions, an unselective 1,3-dipolar cycloaddition with subsequent separation of the diastereomers, and a substrate-controlled epoxidation step. 

In a related manner, -keto imide 25 also functions as a versatile dipropionate reagent with three different stereoselective aldol reactions being reported by the Evans group (Scheme 9-9). Both syn aldol isomers, 26 and 27, are available from either the titanium or tin(II) enolates [14] and the anti adduct 28 can be accessed using the dicyclohexyl boron enolate [15], While a chiral auxiliary is present, it is the ketone a-stereocenter that controls the r-facial selectivity in these aldol reactions. 

The related lactate-derived ketones, 44 [27] and 45 [29], are useful auxiliaries for boron- and titanium-mediated syn aldol reactions, respectively (Scheme 9-14). The effect of the protecting group in both cases is notable. For ketone 44, the use of the boron chloride reagent unexpectedly afforded the syn adduct with good control... 

In Masamune s initial synthesis of the C -Cn polyacetate region of the bryo-statins (Scheme 9-37), the chiral reagents (S)- and (R)-53 were used to control the stereocenters at C3, C7 and Cn [36], The first of these reactions used R)-53 to set the C3 center in 115 and then two subsequent double asymmetric induction aldol reactions, to give 116 and 117, set the remaining stereocenters. 

Our synthesis of the C1-C7 fragment 227 of oleandolide started with a substrate-controlled tin-mediated aldol reaction of a-chiral ketone (5)-18 which afforded syn adduct 52 with 93% ds. This same transformation could also be achieved using reagent control with (Ipc)2BOTf, albeit with lower selectivity (90% ds). In a key step, treatment of the aldol adduct 52 with (-i-)-(Ipc)2BH led to controlled reduction of the C3 carbonyl together with stereoselective hydrobora-tion of the C -Cv olefin, affording the desired triol 228 with 90% ds. 

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