Quaternary center synthesis

The utility of this method becomes apparent in a synthesis of 6, a precursor of pinguisone. This demonstrates that sterically hindered compounds can be easily synthesized in one step by a cis annulation, i.e., even those that have two adjacent quaternary centers, and three adjacent methyl groups41. The structure of 6 was confirmed by X-ray analysis46. 

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

In an approach towards a total synthesis of the marine ascidian metabolite pero-phoramidine (6/1-96) [55], Weinreb and coworkers developed a domino Heck/car-bonylation process [56]. This allowed construction of the C,E,F-ring system of 6/1-96, together with the C-20 quaternary center and the introduction of a functionality at C-4 (Scheme 6/1.25). Thus, reaction of 6/1-97 in the presence of catalytic amounts of Pd(OAc)2 and P(oTol)3 under a CO atmosphere in DMA/MeOH led to 6/1-98 in 77% yield. 

A microwave-driven Sonogashira coupling step is involved in the total synthesis of azaphilones, a structurally diverse family of natural products containing a highly oxygenated bicyclic core and a quaternary center. Porco and his colleagues have described the alkynylation of densely functionalized bromobenzaldehydes with... 

The asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[h]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. 

The asymmetric arylation of ketone enolates represents an attractive method for the preparation of optically active carbonyl compounds with a stereogenic quaternary center at the a-position to the carbonyl group. Such types of compounds are important intermediates for natural product synthesis. Replacement of BINAP by 109 provides... 

Subsequent examination of a tethered alkyne-VCP with rhodium(i) resulted in the first metal-catalyzed [5 + 2]-reaction. Excellent yields were obtained with a variety of substrates (Scheme 3) irrespective of the steric and electronic nature of the R1 group. Notably, quaternary centers are accessed in high yield. Since this first report, in-depth studies on catalysts, substrate scope, selectivity, and applications to total synthesis have been carried out. Work in this area has been reviewed.23-26... 

An application of copper-catalyzed propargylic etherification has been reported in the synthesis of ustiloxin D (Equation (63)).248 Here, a quaternary center was generated from the unprecedented reaction of a phenol with an ethynyl aziridine. 

Finally, the Nazarov reaction was used to build a quaternary center in a study aimed at the synthesis of a potential precursor of cephalotaxine <2000S2113>. 

A remarkable example is the combination of three pericyclic reactions for the synthesis of decalin frameworks with quaternary centers by a tandem oxy-Cope-ene-Claisen reaction shown in 163 [539] (Scheme 1.72). 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Sphydrofuran is a structurally unique secondary metabolite produced by a variety of Streptomycetes strains. The first total synthesis of this compound was based in the use of RAMA to catalyze the aldol addition of chloroacetaldehyde with DHAP that provides two of the three chiral centers of the target molecule. The third quaternary center was introduced via a highly diastereoselective Grignard addition of allylmagnesium bromide (Scheme 4.17) [41]. 

Recently, the oxygen-free neutral precursor to the pentalenolactone family of metabolites was isolated, identified as 759, and named pentalenene Annis and Paquette have since devised a synthesis of 759 which efficiently elaborates its ring junction quaternary center and three angularly fused cyclopentane rings Condensation... 

Synthesis of 16,16,16-trifluororetinal requires the constmction of a quaternary center bearing a CF3 group. For this, a Diels-Alder cycloaddition (cf. trifluoromethyl steroids) between a trifluoromethacrylate and a functionahzed diene has been conducted. The obtained adduct has been transformed further into the trifluoromethyl analogue of jS-cyclocitral (Figure 4.26). ... 

In summary, of the many chiral auxiliaries used in the asymmetric synthesis of carbonyl compounds via imines, those able to form a methoxymethyl-chclated azaenolate show the best enantioselectivities (see Tabic 7). The same is true for valine and im-leucine derivatives which form rigid chelates via their carboxyl groups. In particular, quaternary centers (see Table 6) and a-alkvl-/i-oxo esters arc effectively prepared using these chiral auxiliaries. 

A twofold intramolecular Heck reaction has been employed as a key step for the synthesis of the skeleton of the natural product (—)-chimonanthine 58 (Scheme 19). The synthetically most challenging structural features of this bispyrro-loindoline alkaloid are its two adjacent quaternary centers. They were both built up by intramolecular double-bond carbopalladations, which stereoselectively produced the pentacycle 57 from the f72-symmetrical bis[A-(2-iodophenyl)-cyclohexane-1,2-dicarboxamide 55 via the intermediate 56. The key intermediate 57 was thus obtained as a single enantiomer in 90% yield. 

The marine alkaloid (-)-norzoanthamine 3 suppresses bone loss in ovariectomized mice, and so is of interest as a lead to antiosteoporotic drugs. A substantial challenge in the assembly of 3 is the stereocontrolled construction of the C ring, with its three all-carbon quaternary centers. In the synthesis of 3 by Masaaki Mayashita of Hokkaido University (Science 2004,305,495), the and C rings were built and two of the three needed quaternary centers were set by the intramolecular Diels-Alder cyclization of 1 to 2. 

Samuel Danishefsky of Columbia University has also described (J. Am. Chem. Soc. 2005, 127, 8298) a total synthesis of 1, starting from the pyroglutamate derivative 10. Conjugate addition followed by alkylation established the lactam framework. Intramolecular cyclization of 12 gave 13, establishing the aminated quaternary center. The oxygenated quaternary center was then constructed by phenylselenyl-mediatcd cyclization of 14. The end game of this synthesis used the already-established cyclohexenyl zinc addition, which worked as well with 16 as it had with 7. 

Chiral 3,3-disubstituted cyclopentanones. Taber et al have extended a synthesis of cyclopentanones by a rhodium catalyzed intramolecular C—H insertion (11,459) to a synthesis of (+ )-a-cuparenone (3), which contains a chiral quaternary center. Thus the chiral a-diazo-p-keto ester 1, prepared by alkylation of a chiral oxazolidone (11, 379-381) on treatment with Rh2(OAc)4 is converted into 2 in 67% yield. This product is converted in several steps into (+ )-3. 

Constructing a quaternary center by the alkylation of azlactones has led to development of a new strategy for the synthesis of sphingosine analogs. The azlactone derived from alanine was alkylated with a gem-diacetate to give a 10.5 1 mixture of diastereomers both with 89% ee [191 ]. 

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