Enantioselective annulations

Despite the structural relationship between ginkgolide B and bilobalide, retrosynthetic analysis of the latter produced a totally different collection of sequences. A successful synthesis of bilobalide was implemented using a plan which depended on stereochemical and FG-based strategies. A process for enantioselective synthesis was based on an initial enantioselective Diels-Alder step in combination with a novel annulation method. 

Tlie constrLiction of carbocydic cotnpoutidi by ring-annulation procedures frequently plays a prominent role in total syntliesis. Tlie tolerance of various functional groups in tlie zinc reagents employed in copper-catalyzed asymmetric 1,4-additions fornis tlie basis for tliree novd catalytic enantioselective annulation metliods discussed bete. 

The titanocene dichloride complexes derived from the camphor- and pinene-annulated ligands 126 and 127 were tested as enantioselective hydrogenation catalyst and using 2-phenylbutene as substrate 2-phenylbutane was obtained with ee up to 34% [148, 149]. 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

Organocatalytic annulation of phthalazinium iodide 51 in the presence of (2A,5A)-2,5-dibenzylpyrrolidine furnished optically active (l,9,llM)-tetrahydro-l//-pyrido[2,l-tf]phthalazine 52 with high diastereo- and enantioselectivities (Equation 8) <2005AGE6058>. 

In summary, we have demonstrated the first efficient enantio-selective alkylation via phase transfer catalysis. This alkylation was expanded to include an enantioselective Robinson annulation. The methodology was developed for the preparation of either enantiomer. Finally, our kinetic studies have provided additional mechanistic insight into the chiral PT alkylation. 

In the first method, a dialkylzinc reagent bearing an acetal moiety at the d-posi-tion is used (Scheme 7.25(b)). The catalytic 1,4-addition is followed by acetal hydrolysis and aldol cyclization of the 4-substituted cycloalkanone, affording 6,6- (92), 6,7-, (93) and 6,8- (94) annulated ring systems with high enantioselectivities (>96% ees) [80]. In addition, dimethyl-substituted decalone 95, with a structure frequently found in natural products, is readily obtained in enantiomerically pure form. 

Scheme 7.25. Annulation methodology a) Hajosh-Parrish version of the Robinson annulation, b) catalytic enantioselective annulation with functionalised organozinc reagents.

Bicyclo[4.3.0]nonenes, thanks to their frequent appearance in natural products, are other important targets for novel annulation methodology. A six-membered ring-annulation to cyclopentenones has yet to be developed, the main reason for this being that, until very recently, the levels of enantioselectivity in catalytic 1,4-additions to 2-cyclopentenone were too low for a synthetically useful procedure. However, a highly enantioselective annulation of a five-membered ring to 2-cyclo-hexenone has been developed (Scheme 7.26) [80]. 

Scheme 7.26. Catalytic enantioselective annulations of five-membered rings.

The method involves a regioselective, trans-diastereoselective, and enantioselective three-component coupling, as shown in Scheme 7.26. In this case, the zinc enolate resulting from the 1,4-addition is trapped in a palladium-catalyzed allyla-tion [64] to afford trans-2,3-disubstituted cyclohexanone 96. Subsequent palladium-catalyzed Wacker oxidation [82] yields the methylketone 97, which in the presence of t-BuOK undergoes an aldol cyclization. This catalytic sequence provides the 5,6-(98) and 5,7- (99) annulated structures with ees of 96%. 

Scheme 7.27. Catalytic enantioselective annulations using RCM (ring-closing metathesis).

On the basis of their earlier aromatic annulation strategy (see Scheme 5.64) (596), Shin and Ogasawara reported the first enantioselective total synthesis of carbazo-quinocins A (272) and D (275) (639). The required methyl-substituted secondary chiral stereogenic center of the alkyl side chain at C-1 of carbazoquinocins A and D was introduced starting from the O-benzyl (R)-glycidol (R)-897. 

The product in entry 1 of Scheme 2.10 is commonly known as the Wieland-Miescher ketone and is a useful starting material for the preparation of steroids and terpenes. The Robinson annulation to prepare this ketone can be carried out enantioselectively by using the amino acid L-proline to form an enamine intermediate. The 5-enantiomer of the product is obtained in high enantiomeric excess.89 This compound and the corresponding product obtained from cyclopentane-1,3-dione90 are key intermediates in the enantiose-lective synthesis of steroids.91... 

Like the cWo-derivative, acetals may be formed using a similarly structured exo-annulated MBF-OH43. Conformational analysis can be carried out to determine the absolute configuration of compounds of a similar structure as with the endo-annulated reagent. Differences in chemical shift of the same hydrogens and carbons are similar and reveal that other acetals may be equally useful for enantioselectivity studies. 

Enantioselective annulation of (A)-2c with l-bromo-4-chlorobutane gives the hexahy-drobenzo[a]quinolizine in good chemical and excellent optical yield12. 

In 1992, Trost and his co-workers investigated desymmetrization of cyclic w j-o-diesters with lithium sulfonyl-methylenenitronate as a nucleophile in the presence of Trost s ligand 118, where the corresponding cyclic compounds are obtained with an excellent enantioselectivity via intramolecular cyclization (Scheme 15),103,103a Asymmetric cyclopropanation and lactone annulation are achieved according to this protocol (Scheme Nitroalkanes can also be employed as carbon-centered nucleophiles in lieu of malonates (Scheme 17). ... 

A wide range of a,p-unsaturated aldehydes, including 3-alkyl derivatives, undergo /V-heterocyclic carbene (NHC)-catalyzed annulations with A -sulfonyl ketimines under mild conditions to provide bicyclo[3.2.0]lactams 194 with outstanding dia-stereo- and enantioselectivity (Scheme 70) [101]. This concise route to p-lactams... 

Formation of the Wieland-Miescher ketone via an enantioselective Robinson annulation represents but one interesting example.91... 

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