Oppolzers’ sultam

From the Oppolzer sultam by exchange AllylOH, Ti(OR)4, 67-95% yield. 

Oppolzer sultam-like chiral auxiliary (e.g., Xc in 304) has been studied in Diels-Alder cycloaddition reactions (Scheme 43) <2003JP0700>. The TiCU-promoted reaction of dienophile 304 and 1,3-cyclopentadiene 305 in DCM is complete within 18h and excellent diastereoselectivity of product 306 is observed. The same reaction in the absence of Lewis acid provides product 306 in very low yield. However, switching to trifluoroethanol as the solvent, the cycloaddition reaction proceeds to completion, albeit with slightly diminished levels of diastereoselectivity for Diels-Alder adduct 306. Surprisingly, the use of hexane as the solvent affords the opposite (23, J 31-diastereomer of 306 as the major product. 

During the course of the Baylis-Hillman-reaction two stereocenters are formed, one of which remains in the Baylis-Hillman-product. An obvious concept for the development of an asymmetric version of the reaction represents the use of an enantiomerically pure acrylic acid derivative. The use of enantiomerically pure menthyl acrylates resulted, but only in certain cases, to respectable diastereomeric excesses [21]. A significant improvement was reported in 1997 by Leahy and coworkers who used the Oppolzer-sultame as a chiral auxiliary in DABCO-catalyzed Baylis-Hillman-reactions (Scheme 2) [22]. In this reaction, the... 

Scheme 2. Diastereoselective Baylis-Hillman-reaction using Oppolzer sultam (Leahy et al).

Similar acryloyl imidazolidinones have been used in the asymmetric 1,4-addition of organomagnesium compounds in the presence of a Lewis acid. The diastereoselectivity is variable and was found to be highly depending on the nature of all the reaction participants.227 A symmetric fumaramide, obtained from the camphor-derived Oppolzer sultam, adds Grignard reagents, yielding after hydrolysis monosubstituted succinic acids with up to 90% ee (Scheme 73).228... 

The control of the C8 stereocenter was achieved by alkylation directed by an auxiliary at C7 involving Oppolzer sultams, Enders hydrazones and Evans oxazolidinones (Scheme 5 l-IIl, resp.). Either the corresponding propionate [14, 37] or propionaldehyde [13, 16] equivalents were alkylated with an alkyl iodide representing the principal part of the northern half of epothilones (Scheme 5 1, II), or C-8 of a sui-table chain was methylated diastereoselec-tively (Scheme 5 III, IV). 

An asymmetric permanganate-promoted oxidative cyclization of 1,5-dienes using a chiral phase-transfer catalyst was recorded <2001AGE4496>, and a diastereoselective permanganate-mediated oxidative cyclization with an Oppolzer sultam has been employed in the total synthesis of m-solamin <20020L3715>. In a metal-oxo-mediated approach to the synthesis of 21,22-di- /)7-membrarollin based on the use of a camphor-derived Oppolzer sultam as... 

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. 

Stereoselective oxidative dimerization of cinnamyl derivatives bearing an Oppolzer sultam as chiral auxiliary has been performed both enzymatically (HRP/H2O2) and by chemical means with Ag20. This method provides an enantioselective access to dehydrodiconiferyl ferulate (Equation 148) <2001T371>. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

The Oppolzer sultam 35-1 (Scheme 35, reaction (101) [84] reacts with even higher stereoselectivies and is easier to remove. The main domains of the Oppolzer sultam are conjugate 1,4-additions or simple double bond additions [Scheme 35, reactions (102) and (103)] [85], which show diastereoselectivities of >95% in most cases. Scheme 36 presents examples of persistent, restorable and selfimmolative auxiliaries which are all based on amino acids or amino alcohols, finders RAMP-SAMP [86] is attached to ketones or aldehydes in form of a hydrazone 36-1 which is used for highly stereoselective electrophilic a-alkyla-tions. After the reaction the auxihary is removed via ozonolysis which generates the nitrosamine 36-2 first. In an ensuing step this is reduced to the original auxiliary. In Schollkopf s bislactim ether alkylations [Scheme 36, reaction (105)]... 

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-... 

Table 5. Asymmetric additions of the Oppolzer sultam enolates. The Path column indicates the product configuration and the proposed transition structure from Scteme 5.14.

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

Scheme 4.18 Application of Oppolzer sultams 91 and enf-91 in enolate alkylations.

Scheme 4.103 Amination of Oppolzer sultams 92 by reaction of the potassium enolates with nitroso compound 486. Cleavage of the auxiliary and model 491 as a rationale of the stereochemical outcome.

The general applicability of the Oppolzer sultam as a practical chiral auxiliary in the preparation of enantiomerically... 

SCHEME 2.112 Oppolzer sultam-directed asymmetric synthesis of iyn-aldol products. 

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. 

Another widely used auxiliary for the asymmetric a-alkylation of carboxylic acids is the camphor-based Oppolzer sultam. Initial studies of this auxiliary in the alkylation of carboxylic acids employed LiHMDS for eno-late formation. Unfortunately, deprotonation with this base was not entirely selective for the carbonyl a-position and competing deprotonation at C-10—a to the SO2 group— also occurred (Scheme 7.33). This problem was remedied through the use of either -BuLi or NaHMDS. 

The Oppolzer sultam has been used extensively in the total synthesis of a variety of complex natural products, including epothilone and (-l-)-pumiliotoxin... 

Pumiliotoxin B was isolated from the skin secretions of the Panamanian frog Dendrobates pumilio and has been shown to disrupt neuromusclar transmissions by affecting sodium and calcium concentrations. Manaviazar et al. used the Oppolzer sultam in the total synthesis of... 

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