Double stereodifferentiation in aldol reactions

THE DOUBLE STEREODIFFERENTIATION IN ALDOL REACTIONS TBSO 0 OH TBSO 0 OH... 

In Step D another thiazoline chiral auxiliary, also derived from cysteine, was used to achieve double stereodifferentiation in an aldol addition. A tin enolate was used. The stereoselectivity of this reaction parallels that of aldol reactions carried out with lithium or boron enolates. After the configuration of all the centers was established, the synthesis proceeded to P-D lactone by functional group modifications. 

BLA 28 is very useful in the double stereodifferentiation of aldol-type reactions of chiral imines [41], Reaction of (5)-benzylidene-a-methylbenzylamine with trimethyl-silyl ketene acetal derived from tert-butyl acetate in the presence of (R)-28 at -78 °C for 12 h provides the corresponding aldol-type adduct in 94 % de (Eq. 78). Including phenol in the reaction mixture does not influence the reactivity or the diastereoselec-tivity. The aldol-type reaction using yellow crystals of (R)-28.(5)-benzylidene-a-methylbenzylamine PhOH proceeds with unprecedented (> 99.5 0.5) diastereoselec-tivity (Eq. 79). In general, 28 is a more efficient chiral Lewis acid promoter than 27. 

Heathcock has demonstrated the utility of double stereodifferentiation to enhance 1,2-diastereoselectivity in aldol reactions. ... 

Subsequently, Evans examined double-stereodifferentiating titanium enolate aldol reactions [59]. Both the aldehyde and the enolate contained a and j5 stereogenic centers. In aldol reactions bet veen these substrates the enolate can adopt either a matched or mismatched relationship vith the aldehyde. Several possible scenarios vere investigated. As sho vn in Scheme... 

Double stereodifferentiation in syn aldol reaction. ( 28% of an anti diastereomer also isolated.)... 

Double stereodifFerentiation in aminoindanol-derived anti aldol reaction. 

In 1995, Evans et al. reported on the double stereodifferentiation in Mukaiyama aldol reaction to produce polypropionate compounds (Scheme 8.34)." " -enol silane 233... 

The synthesis in Scheme 13.37 also used a me,ro-3,4-dimethylglutaric acid as the starting material. Both the resolved aldehyde employed in Scheme 13.36 and a resolved half-amide were successfully used as intermediates. The configuration at C(2) and C(3) was controlled by addition of a butenylborane to an aldehyde (see Section 9.1.5). The boronate was used in enantiomerically pure form so that stereoselectivity was enhanced by double stereodifferentiation. The allylic additions carried out by the butenylboronates do not appear to have been quite as highly stereoselective as the aldol condensations used in Scheme 13.37, since a minor diastereoisomer was formed in the boronate addition reactions. 

Scheme 2.6 provides an overall view of our strategy towards solving this problem. As depicted, our late generation synthesis embraces three key discoveries that were crucial to its success. We anticipated that the difficult Cl-Cll polypropionate domain could be assembled through a double stereodifferentiating aldol condensation of the C5-C6 Z-metalloenolate system B and chiral aldehyde C. Two potentially serious problems are apparent upon examination of this strategy. First was the condition that the aldol reaction must afford the requisite syn connectivity between the emerging stereocenters at C6-C7 (by uk addition) concomitant with the necessary anti relationship relative to the resident chirality at C8 (by Ik diastereoface addition). Secondly, it would be necessary to steer the required aldol condensation to C6 in preference to the more readily enolizable center at C2. 

In order to test these assumptions Heathcock prepared different chiral ketones. Thus, the aldol condensation of the fructose-derived ketone and the acetonide of (/ )-glyceraldehyde gave poor results in the double stereodifferentiation, since an almost equal mixture of the two jyn-aldols 68a and 68b were obtained. However, the reaction with the (5)-aldehyde gave only one syn adduct (69a) (Scheme 9.22) ... 

Up to this point, we have considered primarily the effect of enolate geometry on the stereochemistry of the aldol condensation and have considered achiral or racemic aldehydes and enolates. If the aldehyde is chiral, particularly when the chiral center is adjacent to the carbonyl group, the selection between the two diastereotopic faces of the carbonyl group will influence the stereochemical outcome of the reaction. Similarly, there will be a degree of selectivity between the two faces of the enolate when the enolate contains a chiral center. If both the aldehyde and enolate are chiral, mutual combinations of stereoselectivity will come into play. One combination should provide complementary, reinforcing stereoselection, whereas the alternative combination would result in opposing preferences and lead to diminished overall stereoselectivity. The combined interactions of chiral centers in both the aldehyde and the enolate determine the stereoselectivity. The result is called double stereodifferentiation,67... 

The synthesis in Scheme 13.30 uses stereoselective aldol condensation methodology. Both the lithium enolate and the boron enolate method were employed. The enol derivatives were used in enantiomerically pure form, so the condensations are examples of double stereodifferentiation (Section 2.1.3). The stereoselectivity observed in the reactions is that predicted for a cyclic transition state for the aldol condensations. 

In a more complex scenario, the /J-substituents were also found to participate in partially matched or mismatched reactions577. Examples of double induction pave the route of polypropionate and polyketide synthesis and it was emphasized that the relative influence of the enolate or aldehyde component may be enhanced, depending on the coordinating metal employed in the double stereodifferentiating aldol reaction. Thus, it was found that, in spite of their modest synlanti selectivity, lithium enolates are effective in double stereodifferentiating aldol reaction578. In the matched and partially matched cases, lithium enolate face selectivity is opposite to that which is found for their boron or titanium counterparts. This is perfectly illustrated in a recent work by Roush and coworkers reporting a partial synthesis of Bafilomycin Aj (Scheme 122)579. 

The boron-aldol reaction of the p-methoxyben-zyl(PMB)-protected methylketone 16 proceeds with excellent 1,5-anti-selectivity (Scheme 4). In cases where the asymmetric induction is lower it may be improved by a double stereodifferential aldol reaction with chiral boron ligands [7]. The reason for this high stereoselectivity is currently unknown. Ab initio calculations suggest the involvement of twisted boat structures rather than chair transition structures [6]. 

But is isn t as simple as this. The stereochemistry of the enolisation depends also on the group on the other side of the carbonyl (phenyl in the above case). So, for example, while pentan-2-one gives mostly cis boron enolate 55, branched ketone 56 give mostly trans.13 The aldol reaction is immensely complicated as there are so many variables. However, all the fundamentals from cis and trans enolates to double stereodifferentiation can be found in a review by Heathcock.14... 

The aldol condensation, one of the oldest organic reactions, is emerging as a powerful method for control of relative and absolute stereochemistry in the synthesis of conformationally flexible compounds. Some of the research which has been carried out at Berkeley over the past five years is reviewed in this article. Points discussed are the factors that control simple erythro, threo diastereoselection, the use of double stereodifferentiation to influence the "Cram s rule" preference shown by chiral aldehydes, and some recent experiments that shed light on the role that the solvent and other nucleophilic ligands play in determining the stereochemistry of the reaction. 

Mukaiyama aldol reaction. Double stereodifferentiation using chiral reactants in the presence of BFj-OEt is observed, even though such a reaction adopts open transition... 

Diastereoselective aldol reactions have been extensively utilized in the synthesis of complex natural products, including macrolides [4] and ionophores [5]. In this context, iterative approaches are often exploited to append propionate units one at a time. This approach leads to double stereodifferentiation [6] in tvhich the reactant pairs can be either matched or mismatched . The chirality of the t vo reactants reinforce each other if they are matched. As a result, the diastereoselectivity is often higher than vould... 

In a later study Mulzer presented examples of double stereodifferentiating aldol reactions with (S)-C3 protected nucleophiles [35]. The same double TBSO-protected (S)-ethyl ketone 41 used before by Kalesse et al. gave 6 1 ratio in an aldol reaction with an a-(S)-chiral aldehyde 48 as a result of matching chirality (70% yield). Again, the major isomer 49 had the natural epothilone configuration at C6 and C7. 

Double stereodifFerentiating aldol reactions in the presence of the epoxide functionality by Mulzer et at. 

In a further series of experiments Danishefsky employed chiral ketones of type 59. Both enantiomers were available with high optical purity and could be involved in investigations in the double stereodifferentiating aldol reaction. However, the lithium anion of 59 (R = TBS) could not be effected in useful yield due to the sensitivity of the j5-silyloxy system to elimination. The less basic titanium enolate of 59 gave mixtures of diastereomers in moderate yields. The stereochemical outcome of these reactions showed that the configuration at C3 rather than C8 had a larger effect on the newly... 

Despite that, these undesired results from the dianion aldol reactions can be used to understand some principles of the double stereodifFerentiating reactions. The C3 protected series, such as Schinzer-type aldol reactions described before required the (S)-configuration at C3 to establish the (R)-configuration at C6 and the (S)-configuration at C7 with a similar a-chiral (S)-aldehyde. The matching chirality in the protected series corresponds to the mismatched case in the unprotected series of these double stereodifFerentiating aldol reactions. This disparity could be a result of different transition states. 

Heathcock and White" and Masamune et al." developed independently the double stereodifferentiation to enhance 1,2-diastereoselection in aldol condensations of chiral aldehydes. As shown in Scheme 8.32," Masamune et al. examined the effect of stereochemistry of an enolate and an aldehyde in asymmetric aldol reaction. Benzaldehyde, the achiral aldehyde, reacted with the chiral enolate S-207 to... 

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