Double stereodifferentiation examples

Scheme 2.5 gives some additional examples of double stereodifferentiation. Entry 1 combines the steric (Felkin) facial selectivity of the aldehyde with the facial selectivity of the enolate, which is derived from chelation. In reaction with the racemic aldehyde, the (R)-enantiomer is preferred. 

Scheme 2.5. Examples of Double Stereodifferentiation in Aldol and Mukaiyama...

In Entry 5, the aldehyde is also chiral and double stereodifferentiation comes into play. Entry 6 illustrates the use of an oxazolidinone auxiliary with another highly substituted aldehyde. Entry 7 employs conditions that were found effective for a-alkoxyacyl oxazolidinones. Entries 8 and 9 are examples of the application of the thiazolidine-2-thione auxiliary and provide the 2,3-syn isomers with diastereofacial control by the chiral auxiliary. 

With unhindered aldehydes such as cyclohexanecarboxaldehyde, the diastereoselec-tivity is higher than 95%, with the F-boronate giving the anti adduct and the Z-boronate giving the syn adduct. Enantioselectivity is about 90% for the F-boronate and 80% for the Z-boronate. With more hindered aldehydes, such as pivaldehyde, the diastere-oselectivity is maintained but the enantioselectivity drops somewhat. These reagents also give excellent double stereodifferentiation when used with chiral aldehydes. For example, the aldehydes 3 and 4 give at least 90% enantioselection with both the E- and Z-boronates.43... 

Effective double stereodifferentiation is possible in intramolecular C-H insertion.199 For example, catalytic decomposition of enantiopure (lY,2Y)-diazoacetate 74 by Rh2(4A-MEOX)4 directed the reaction toward the preferential formation of y-lactone (lY)-75, whereas the corresponding reaction catalyzed by Rh2(4i -MEOX)4 prefers initially forming y-lactone (lY)-76 (Equation (66)). Similarly, treatment of (lY,2i )-diazoacetate 77 with Rh2(5A-MEPY)4 or Rh2(4i -MPPIM)4 gave (lY)-78 or (lY)-79, respectively (Equation (67)).199... 

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. 

The descriptors of relative topicity are used in Iwo different ways as they may be derived from inter- or intramolecular combinations. It is prescribed that the descriptor of the former precedes that of the latter combinations nevertheless, extended strings of descriptors can be quite cumbersome. In order to help readability, brackets are added that contain the mfromolecular relative topicities, in accordance with the extension of the Izumi Tai terms described in Section 1.1.3.1. Such brackets are particularly helpful when examples of double stereodifferentiation are to be described (see Section 1.2.2.5.). The SP system is also a powerful tool here its application to the examples previously displayed in Section 1.2.2.5. is straightforward ... 

The latter example shows that in selecting the matched pair ent-185 and acetal 186, an astonishing high level of double stereodifferentiation can be obtained, affording 187 as a single product. A Lewis acid (TMSOTf) is necessary to activate the acetal functionality. 

Intramolecular C-H insertions of aryldiazoacetates have been effectively achieved with high asymmetric induction by using either Rh2(S-DOSP)4[13] or Rh2(S-PTLL)4[14] as catalyst. An impressive recent example is a key step (18 to 19) in the synthesis of (-)-ephedradine A (20) (Scheme 8) [15]. In this particular case, a double stereodifferentiation with a chiral catalyst and auxiliary gave the best asymmetric induction. 

Thought experiment III in Figure 3.27 provides an example of how such a double stereodifferentiation can be used to increase stereoselectivity. The two competing hy-... 

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 asymmetric hydroxylation of ester enolates with N-sulfonyloxaziridines has been less fully studied. Stereoselectivities are generally modest and less is known about the factors influencing the molecular recognition. For example, (/J)-methyl 2-hydroxy-3-phenylpropionate (10) is prepared in 85.5% ee by oxidizing the lithium enolate of methyl 3-phenylpropionate with (+)-( ) in the presence of HMPA (eq 13). Like esters, the hydroxylation of prochiral amide enolates with N-sulfonyloxaziridines affords the corresponding enantiomerically enriched a-hydroxy amides. Thus treatment of amide (11) with LDA followed by addition of (+)-( ) produces a-hydroxy amide (12) in 60% ee (eq 14). Improved stereoselectivities were achieved using double stereodifferentiation, e.g., the asymmetric oxidation of a chiral enolate. For example, oxidation of the lithium enolate of (13) with (—)-(1) (the matched pair) affords the a-hydroxy amide in 88-91% de (eq 15). (+)-(Camphorsulfonyl)oxaziridine (1) mediated hydroxylation of the enolate dianion of (/J)-(14) at —100 to —78 °C in the presence of 1.6 equiv of LiCl gave an 86 14 mixture of syn/anti-(15) (eq 16). The syn product is an intermediate for the C-13 side chain of taxol. 

Oxa-Diels-Alder reactions between l-oxy-3-silyloxybuta-1,3-dienes and aromatic aldehydes (either component being attached to a carbohydrate auxiliary) have been investigated by Stoodley et al. [109,110], drawing on the pioneering work of the Danishefsky group [111,112]. For example, the reaction of the carbohydrate-linked diene 143 with p-nitrobenzaldehyde in the presence of Eu(III) catalysts gave dihydropyrans 144-147 [109] (Scheme 10.47). When the chiral Eu complexes (- -)-Eu(hfc)3 and (—)-Eu(hfc)3 were used, double stereodifferentiation was... 

Of particular concern with a-hydroxy carbonyl compounds is the stereochemistry of the hydroxy group attached to the stereogenic carbon because biological activity is often critically dependent on its orientation. A-Sulfonyloxaziridines have played a prominent role in the stereoselective synthesis of this key structural element (Scheme 25). Enantiomerically and diastereomerically enriched materials have been prepared by (1) the hydroxylation of chiral nonracemic enolates with racemic A-sulfonyloxaziridines, for example (63a) (2) the asymmetric hydroxylation of prochiral enolates with enantiopure A-sulfonyloxaziridines and (3) a combination of the first two, double stereodifferentiation. 

As pointed out in an earlier section, the ees for the asymmetric hydroxylation of acyclic enolates derived from a-branched carbonyl compounds is often low because of the difficulty in generating a specific enolate geometric isomer as well as poor enantiofacial discrimination between the re and si faces of the enolate (Scheme 25). In one example of a double stereodifferentiation process, the asymmetric oxidation of a chiral enolate, was successfully employed to circumvent these difficulties <87JOC5288>. For the matched pair, (—)-(179) and oxaziridine (—)-(114), the de was 88-91% (Equation (43)) whereas with the mismatched pair, (—)-(179) and (+)-(114), the de dropped to 48.4%. The pyrrolidine methanol chiral auxiliary in (180) was removed without racemization by basic hydrolysis affording nonracemic atrolactic acid in 70-89% yield. 

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... 

Scheme 47 shows a case 2 example for double stereodifferentiation, the problem being to reduce enone 47-1 preferentially to alcohol 47-2 or 47-3 [110]. The substrate control (DIBAH or L-selectride) is essentially zero, so that the chiral hydride donor must do the job. It can be seen that BINAL-H [ 111 ] is ineffective whereas diborane plus the CBS catalyst [112] shows a very pronounced reagent control so that either one of 47-2 and 47-3 may be generated selectively for the formation of 47-3 the reagent control is much higher than for 47-2, which is surprising in view of the low substrate control of the process. 

When chiral substituted pyrrolidines are utilized as substrates, opportunities exist for double stereodifferentiation, kinetic resolution, and catalyst differentiation. A striking example of double stereodifferentiation was provided by substrate 141, in which the R enantiomer underwent smooth C-H insertion in 85% yield and >94% de to afford product 142, but no observable reaction occurred with the S enantiomer (Scheme 33). 

Asymmetric induction from a stereocenter in a chiral group bound to N has also been studied, and good to excellent levels of relative diastereoselection have been observed (Scheme 35). Interestingly, incorporation of a N-phenethyl unit of appropriate absolute stereochemistry into (214) resulted in substantially improved selectivity for the 1,3-syn product diastereomer (compare results with 210, Scheme 34) 120b jhis is an example of double stereodifferentiation, a synthetic strategy that is discussed in Section 1.1.5. 

We have examined a purely logical way in which the "Cram s rule problem" can be attacked — double stereodifferentiation. For example, either reactant in an aldol condensation can be chiral and exhibit diastereoface selectivity. Suppose we have an aldehyde which reacts with achiral enolates to give the two possible erythro adducts in a 10 1 ratio ... 

We have also observed double stereodifferentiation when one of the chiral elements is a reactant and the other is the solvent. One example of this phenomenon is shown below for the condensation... 

There are a few examples of unbridged metallocenes which are stereoselective by site control. Examples have been reported with substituted cy-clopentadienyl, indenyl, and fluorenyl ligands, the latter being apparently the most stereoselective. The biscyclopentadienyl system C2-ITI (Chart 16) produces, at low polymerization temperature (—50 °C), a low molecular weight, low isotactic PP mmmm = 51%) with a double stereodifferentiating mechanism, partly site control (27%, b = 0.96) partly chain-end control (73%, p = 0.79). The related, but much bulkier, rac-[Cp-CH(Ph)CH2(9-BBN)]2ZrCl2 (Q-II-Z) produced at —50 °C a more isotactic PP mmmm = 75%), with predominance of site control (67%, b =... 

Double stereodifFerentiation was used to achieve enantioselective enolborination of chiral ketones by reaction with chlorobis(isopinocampheyl)borane (DIPCl) in the presence of a chiral amine [69]. As an example, reaction of excess ( )-94 with IPC2BCI and sparteine at —78°C produced 95 regioselectively with a 90% ee (evaluated after oxidation into diadds). 

This is a very good example where the inherent selectivity of the enolate overrides the inherent selectivity of the aldehyde with the 6(R),7(S)-configuration resulting from double stereodifferentiation using the aldehyde with the (S)-configuration. On the other hand, the same reaction with (R)-phenylpropionaldehyde 31 yielded two diastereomers 32 and 33 in a ratio of 40 1 and 77% yield as shown in Scheme 7.10 [26]. 

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. 

A few examples showcasing double stereodifferentiation phenomena are outlined below. In the case of crotylation of a-alkoxy-substituted aldehyde 72, Roush observed a reversal of facial selectivity with either enantiomer of the chiral ( )-crotylboronate reagent 29 (Scheme 5.13) [48]. Similarly, Brown found that the pinene-derived crotyl boranes 76 and 77 provide access to all four stereotriads 78-81 with impressive stereoselectivity with use of either the ( )- or the (Z)-crotyl reagent (Scheme 5.14) [77]. 

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