Matched aldol reaction

During the total synthesis of rhizoxin D by J.D. White et al., an asymmetric aldol reaction was utilized to achieve the coupling of two key fragments. " The aldol reaction of the aldehyde and the chiral enolate derived from (+)-chlorodiisopinocampheylborane afforded the product with a diastereomeric ratio of 17-20 1 at the CIS stereocenter. During their studies. White and co-workers also showed that the stereochemical induction of the chirai boron substituent and the stereocenters present in the enolate reinforce each other thus representing a matched aldol reaction. 

As previously mentioned, certain methyl ketone aldol reactions enable the stereocontrolled introduction of hydroxyl groups in a, 5-anti relationship (Scheme 9-7) [9], and this was now utilized twice in the synthesis. Hence, methyl ketones 48 and 98 were converted to their respective Ipc boron enolates and reacted with aldehydes 97 and 99 to give almost exclusively the, 5-anti aldol adducts 100 and 101, respectively (Scheme 9-34). In the case of methyl ketone 48, the j -silyl ether leads to reduced stereoinduction however, this could be boosted to >97%ds with the use of chiral ligands. In both examples, the y9-stereocenter of the aldehyde had a moderate reinforcing effect (1,3-syn), thus leading to triply matched aldol reactions. Adducts 100 and 101 were then elaborated to the spiro-acetal containing aldehyde 102 and ketone 103, respectively. 

Evans-Tishchenko reaction 41) gave the benzoate 28. Functional group manipulation then gave the aldehyde 29. A matched aldol reaction ( 3) between aldehyde 29 and the ( )-enolate 30 (derived from ketone 21), which presumably proceeds via TS 31, provided the anti adduct 32 ( 8% ds). This was then elaborated into the stannane 17. In this way, the introduction of the 6 contiguous stereocenters was achieved with essentially complete control. 

Now, we examine the interaction of chiral aldehyde (-)-96 with chiral enolate (S )-lOOb. This aldol reaction gives 104 and 105 in a ratio of 104 105 > 100 1. Changing the chirality of the enolate reverses the result Compound 104 and 105 are synthesized in a ratio of 1 30 (Scheme 3-38).66 The two reactions (—)-96 + (S )-lOOb and (—)-96 + (7 )-100b are referred to as the matched and mismatched pairs, respectively. Even in the mismatched pair, stereoselectivity is still acceptable for synthetic purposes. Not only is the stereochemical course of the aldol reaction fully under control, but also the power of double asymmetric induction is clearly illustrated. 

Carefully matched acid and base catalysis has been used to select the pyrrolidine-p-nitrophenol combination as an efficient organocatalyst for direct aldol reactions.108... 

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. 

On the basis of Kiyooka s working hypothesis for the aldol reaction mechanism, the reduction proceeds via by an intramolecular hydride transfer this is accelerated by matching between the chirality of the promoter and that of the newly formed aldol (Eq. 50). An alternative mechanism without chelation is also possible, and involves hydride delivery to the preferred O-silyl oxocarbenium ion conformer (Eq. 51). 

The stereochemical outcome of an aldol reaction involving more than one chiral component is consistent with the rule of approximate multiplicativity of diastereofacial selectivities intrinsic to the chiral reactants. For a matched case, the diastereoselectivity approximates (substrate DS) X (reagent DS). For a mismatched case, the diastereoselectivity is (substrate DS) (reagent DS). Double asymmetric induction also can be used to enforce the inherent facial selectivity of a chiral aldehyde, as shown below. 

In the Evans synthesis of the polypropionate region (Scheme 9-45), the boron-mediated anti aldol reaction of -ketoimide ent-25 with a-chiral aldehyde 145 afforded 146 with 97% ds in what is expected to be a matched addition. Adduct 146 was then converted into aldehyde 147 in readiness for union with the C -Cs ketone. This coupling was achieved using the titanium-mediated syn aldol reaction of enolate 148 leading to the formation of 149 with 97% ds. 

In our synthesis, iterative aldol reactions of dipropionate reagent (R)-18 allowed for the control of the C3-C10 stereocenters (Scheme 9-72) [89]. Hence, a tin-mediated, syn aldol reaction followed by an anti reduction of the aldol product afforded 270. Diol protection, benzyl ether deprotection and subsequent oxidation gave aldehyde 271 which reacted with the ( )-boron enolate of ketone (/ )-18 to afford anti aldol adduct 272. While the ketone provides the major bias for this reaction, it is an example of a matched reaction based on Felkin induction from the... 

Treatment of aldehyde ent-91c with R,R)-2 9 resulted in the stereoselective (selectivity = 9 1) formation of adduct enf-105c, via the mismatched double asymmetric reaction discussed previously (Eq. (11.17)). Aldehyde 251, derived in two steps from olefin e r-105c, underwent an asymmetric aldol reaction [206] with the boron enolate of 252, generating adduct 253 stereoselectively. Adduct 253 was converted in five steps to aldehyde 254, which underwent a matched double asymmetric reaction with (S,S)-219, affording stereoheptad 255 in 90% yield (selectivity =>98 2). Adduct 255 was then elaborated to aldehyde 256, which was directly submitted to the matched double asymmetric reaction with R,R)-2 9, affording the advanced adduct 257 (selectivity=>98 2), which was converted in seven steps to the C(l)-C(13) fragment 250 of (-t-)-damavaracin D. 

These aldols have all had just one chiral centre in the starting material. Should there be more than one, double diastereomeric induction produces matched and mismatched pairs of substrates and reagents, perfectly illustrated by the Evans aldol method applied to the syn and anti aldol products 205 themselves derived from asymmetric aldol reactions. The extra chiral centre, though carrying just a methyl group, has a big effect on the result. The absolute stereochemistry of the OPMB group is the same in both anti-205 and yvn-205 but the stereoselectivity achieved is very different. The matched case favours Felkin selectivity as well as transition state 201 but, with the mismatched pair, the two are at cross purposes. It is interesting than 1,2-control does not dominate in this case.33... 

Stork and coworkers [624e] have introduced enamines as a nucleophilic substitute of enols, and a few asymmetric aldol reactions have been performed with enamines. Scolastico and coworkers [1311] have reacted morpholine enamines with chiral oxazolidine 1.84 (EWG = Ts), and in some cases they obtained higher sdectivities than those obtained from enoxysilanes ( 6.9.3) (Figure 6.102). Chiral enamines derived from pyrrolidine 1.64 (R = MeOCI ) react with acyliminoesters of chiral alcohols at -100°C [1313], Double diastereodifferentiation is at work so that from matched reagents, for example the pyrrolidine enamine and iminoester 6.126 shown in Figure 6.102, P-keto-a-aminoesters are obtained with a high diastereo- and enantioselectivity. The esters of either enantiomer of menthol or of achiral alcohols give mediocre asymmetric induction. 

Since the stereochemical outcome of the aldol reaction with these enolates is predictable from the above results, selection of either (5)-(29b) or (R)-(29b) for a matched or mismatched pair can easily be made. Thus, in the reaction of chiral aldehyde (24) with (5)-(29b) (matched) the product ratio exceeds 1(X) 1, favoring formation of (33), whereas when reagent (R)-(29b) is used, (34) l omes the predominant product with a respectable stereoselection (mismatched) (Scheme 24). Compared to the ratios observed for the reaction with an achiral enolate (Scheme 22), it is clear that the facial selectivity of the enolates dictates the 3,4-stereochemistry of the aldol reaction and either the 2,3-jy -3,4-an or 2,3-syn-3,4-syn units can be constructed in a predictable manner. 

Paterson et have prepared the enolate of 3-pentanone, an achiral ketone, with (-( )- or (-)-IpcaBOTf and have found that its aldol reactions with various aldehydes proceed with high syn.anti ratios (>9 1) and respectable enantioselectivities (5 1-20 1) (Scheme 44). High degrees of asymmetric induction are noted with unhindered aldehydes, llie combination of the chiral ethyl ketone (104) and (-t-)-Ipc2BOTf constitutes a matched pair, which enhances the diastereofacial selectivity of the resulting enolate (compared to that obtained with an achiral boron reagent), and provides via aldol reactions high... 

A binaphthol-derived chiral titanium(iv) complex effectively catalyzes the Mukaiyama aldol reaction in SCCHF3 or scC02. It was found that the chemical yield and enantioselectivity of the reaction in supercritical fluids could be tuned by changing the supercritical fluids (scCHFs vs. SCCO2) and adjusting the matched polarities by varying the pressure of CHF3 (Scheme 39). 

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