Oppolzer aldol reaction

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

After two years working as a postdoctoral fellow under Dr. H.-P. Husson (Institut de Chimie de Substance Naturelles, CNRS, Gif-sur-Yvette, France) (CNRS methods in asymmetric synthesis) (1984-85), he worked as an associate researcher under Professor Wolfgang Oppolzer (Departement de Chimie Organique, Geneve, Suisse) (aldol reaction) (1986) and was a visiting professor at the Department of Chemistry, Duke University, NC, working with Professor Fraser-Reid (free radical chemistry annulated furanoses formal total synthesis of phyllathocin). 

Oppolzer et al. used (2M)-bornanc-10, 2-sultam as an effective chiral auxiliary to achieve a highly enantioselective syn-aldol reaction17 (Scheme 2.1p). Treatment of A-propionylsultam (46) with dibutylboron triflate and Hunig s base at -5°C in CH2CI2 followed by addition of aldehydes at -78° C provided, after a simple crystallization, the pure vyn-aldols 47a. It is noteworthy that no anti-aldol product was observed in the aldol reactions with any of the aldehydes. From the1 nuclear magnetic resonance (NMR) study, it was confirmed that the boron... 

Oppolzer et al. completed an asymmetric synthesis of (-)-denticulatin A (48) by using a syn-aldol methodology as a key feature18 (Scheme 2.1r). The diethyl-boron enolate of N-propionyIbomanesultam (46-ent) obtained from diethylboron triflate and Hunig s base underwent a highly stereoselective aldol reaction with the mes o-dialdchydc 49 to furnish the lactols 50 in 74% yield as a 2 1 epimeric mixture. When the lactols 50 were treated with 1, 2-ethanedithiol in the presence... 

In an effort toward the enantioselective synthesis of the natural product lasono-lide A (52), Shishido et al. used Oppolzer et al. s syn-aldol method to access a key intermediate (55)19 (Scheme 2.1s). Aldol reaction of the boron enolate of 46 with... 

A good example is the first step in a synthesis of the natural product himalchene by Oppolzer and Snowden. Even though the ester and the aldehyde are both crowded with substituents, the aldol reaction works well with the lithium enoiate of the ester. The cyclic mechanism ensures that the enoiate adds directly to the carbonyl group of the aldehyde and not in a conjugate (Michael) fashion. 

The first enantioselective total synthesis of (-)-denticulatin A was accomplished by W. Oppolzer. The key step in their approach was based on enantiotopic group differentiation in a meso dialdehyde by an aldol reaction. In the aldol reaction they utilized a bornanesultam chiral auxiliary. The enolization of A/-propionylbornane-10,2-sultam provided the (Z)-borylenolate derivative, which underwent an aldol reaction with the meso dialdehyde to afford the product with high yield and enantiopurity. In the final stages of the synthesis they utilized a second, double-dlastereoditferentiating aldol reaction. Aldol reaction of the (Z)-titanium enolate gave the anf/-Felkin syn product. The stereochemical outcome of the reaction was determined by the a-chiral center in the aldehyde component. 

The use of these auxiliaries in anti aldol reactions has been described, though not by generation of the anticipated ( )-enolate. Instead, the typical (Z)-enolate is formed, and then precomplexation of a Lewis acid with the reacting aldehyde diverts the reaction away from a cyclic transition state [23]. The contrasting stereochemical trends of the catalyzed and non-catalyzed reactions are evident in an early approach to muamvatin (Scheme 9-13) [24]. Alternatively, Oppolzer has reported the Lewis acid catalyzed anti aldol reaction of a silyl enol ether derived from sultam 38 [25]. In general, however, this methodology has seen limited use in the synthesis of complex natural products. 

In the middle of the 198O s some silyl enolates derived from homochiral esters were reported to enable highly enantioselective synthesis of aldols [106]. Later, Oppolzer et al. disclosed the utility of camphor sultam as a chiral auxiliary for asymmetric aldol reactions [107]. Braun et al. have recently achieved high levels of asymmetric induction in the aldol reaction of ketones with homochiral silyl enolate 43 (Scheme 10.38) [108]. 

Since conjugate (Michael) addition and Diels-Alder reactions use a,p-unsat united carbonyl compounds, asymmetric versions of these reactions could use the auxiliaries that we have seen in aldol reactions in the form of 118 and 119. Diels-Alder reactions work very well with these unsaturated amides and also with amides 121 derived from Oppolzer s chiral sultam14 120, prepared simply from camphorsulfonyl chloride. 

Oppolzer and coworkers [147, 454] have developed a class of reagents based on the enantiomeric bomane-2,10-sultam skeleton 1.133. These chiral auxiliaries are easily prepared from the enantiomeric 10-camphosulfonic adds [455]. Saturated or a,P-unsaturated TV-acylsultams 1.134, occasionally prepared from Af-silyl precursors [396], have been used very frequently. Asymmetric alkylations, animations and aldol reactions of enolates or enoxysilane derivatives of 1.134 (R = R CH2) [147, 404, 407, 456-460] are highly selective. The a,(3-unsaturated TV-acylsultams 1.134 (R = R R"C=CH) suffer highly stereoselective organocuprate 1,4-additions [147, 173], cyclopropanations [461], [4+2] and [3+2] cydoadditions [73,276,454,462], OSO4 promoted dihydroxylations [454,463] and radical addi-... 

Oppolzeds sultams 1.133 are also efficient auxiliaries in asymmetric aldol reactions [209,404,407,457,1271], Boron, titanium or Sn (IV) enolates of W-pro-pionoylsultams lead stereoselectively to either enantiomeric syn aldol at -78°C. These products are easily purified by fractional crystallization (Figure 6.83). After treatment with Li0H/H202 and CH2N2, syw-P-hydroxyesters are obtained with an excellent enantiomeric excess. The drawback of this method is the need to use an excess of aldehyde to obtain good chemical yields. As in the case of oxazolidi-... 

An interesting asymmetric aldol reaction utilizing enantiomerically homogeneous bomane sultam derived boron enolates has recently been reported by Oppolzer et al. The reaction of aldehydes with boron enolates (57), generated from acyl sultams (58) under standard enolization conditions (Pr 2NEt/Bu2BOTf/0 C), provides syn aldol products (59) with extremely high ratios of (59) to (60) as shown in Scheme 29. Results from the aldol reactions with representative aldehydes are summarized in... 

Scheme 3.69 Stereocontrol of Oppolzer sultam aldol reaction by choice of counter ion.

De Brabander et al. have reported a very rapid enantioselective synthesis of the Prelog-Djerassi lactonic acid through an asymmetric aldol reaction [88] (Scheme 44). The Oppolzer sultam-derived A-propionyl derivative 215 was used to desymmetrize meso-dialdehyde 216, and the diastereoselectivity was found to be 80 %. Oxidation of the resulting lactol 217 to lactone 218 was followed by oxidative removal of the chiral auxiliary. The unwanted diastereoisomer resulting from the aldol reaction was removed chromatographically after the oxidation step. 

The Oppolzer group has developed aldol reactions with amide enolates 140. The selectivities observed by this approach are good, and the four possible diastereomers 141-144 can be obtained by the appropriate selection of conditions (Scheme 10.30). Very often V-acylbornane-10,2-sultams 141-142 are solid materials that can be purified by simple crystallization. This approach is still used up to date. ... 

SCHEME 10.30. The use of the Oppolzer group auxihary in aldol reactions. 

Alternative routes to labeled anri-/3-hydroxy-a-amino acids of the a//o-threonine type are described in Section 11.3.9. They involve aldol reactions of haloacetyl-Evans and -Oppolzer auxiliaries to give iyn-/3-hydroxy-a-halo derivatives, whose a-halo groups are then inverted by nucleophilic displacement with azide ion. ... 

Helmchen [67] and Oppolzer [68] investigated and documented the use of camphor-derived auxiliaries in Mukaiyama aldol reactions. Silyl ketene acetals 106 and 108 participate in diastereoselective additions to aldehydes in the presence of TiCl4, affording adducts with up to 99 1 diastereoselectivity (Equations 7 and 8). 

Oppolzer has designed two approaches to modhephene, both of which are based on the high level of stereochemical control attainable in intramolecular thermal ene reactions. In the first (Scheme XCIV), a, jJ-unsaturated ketone 793 is obtained by aldol methodology and heated at 250 °C in toluene to produce 794 A methyl group and double bond are next introduced in standard fashion prior to arrival at the final sesquiterpene stage. 

Dianion aldol condensation reactions with Evans oxazolidinones or Oppolzer sultams as chiral auxiliaries have been demonstrated to be a useful method to generate the core skeleton of furofurans with diastereoselectivities of 5 1-20 1. Stereoselective total syntheses of the furofuran lignans (-l-)-eudesmin, (+)-yangambin, (—)-eudesmin, and (-)-yangambin according to this procedure have been reported (Equation 102) <2006TL6433>. 

Tandem radical addition-aldol-type reaction of a,/3-unsaturated oxime ethers bearing an Oppolzer sultam auxiliary leads to stereoselective incorporation of alkyl groups in the 5- and 3-positions in tetrahydrofurans (Scheme 77) <2005AGE6190>. The observed /ra r,/ra r-stereoselectivity was explained by invoking a cyclic six-membered ring transition state. 

Lange and his co-workers have reported a short, convenient approach to the sesquiterpene (—)-acorenone (170) centred about the stereoselective Michael addition of l-methoxybut-3-en-2-one to the less hindered face of the enamine (169) followed by aldol cyclization, ° and Oppolzer etal. have synthesized acorenone and several other members of the same sesquiterpene family by further elaboration of the cis,trans mixture of esters (171) formed, with 100% cndo-selectivity, during the intramolecular thermal ene reaction of the 1,6-diene (172). ... 

Typically, in these aldol additions sy -aldol adducts are formed, in which the chiral auxiliary induces the absolute configuration. The sultam methodology by Oppolzer is particularly useful as both enantiomeric aldols may be generated from the same auxiliary, by adjusting the reaction conditions (Scheme 3.69). Thus, in route A the enolborinate is generated and adduct 353 is formed [113]. If, however, in route B the lithium or the stannyl enolates are used the predominant aldol adduct is 355. The overaD selectivity of route B is lower than the one of route A. In addition to the formation of the syn-adducts 353 and 355, the two anti-diastereomers 354 and 356 are observed in small quantities for the lithium enolate whereas 354 is suppressed by using a tin enolate. 

---