Alkylation natural product synthesis

Alkylations of 4-cyano-l,3-dioxanes (cyanohydrin acetonides) represent a highly practical approach to syn-l,3-diol synthesis. Herein we present a comprehensive summary of cyanohydrin acetonide chemistry, with particular emphasis on practical aspects of couplings, as well as their utility in natural product synthesis. Both 4-acetoxy-l,3-dioxanes and 4-lithio-1,3-dioxanes have emerged as interesting anri-l,3-diol synthons. The preparation and utility of these two synthons are described. 

Stork first demonstrated the utility of protected cyanohydrins as acyl anion equivalents in 1971 [2]. The acetal-protected cyanohydrin 8 was transformed into the corresponding anion with LDA in THF/HMPA, which was then alkylated with a range of alkyl halides, including secondary bromides (Scheme 2). A mild acidic hydrolysis yielded a cyanohydrin, which provided the ketone after treatment with base. The Stork cyanohydrin alkylation and its variants have become important methods in natural product synthesis [3,4]. 

Most often, the application of cyanohydrin acetonide couplings to a natural product synthesis calls for coupling with a primary alkyl halide. This has proven successful in every instance. However, on occasion, alkylations of more hindered epoxides or hindered alkyl halides are desirable. These reactions are less dependable. 

The cyanohydrin acetonide method has been a valuable tool in natural product synthesis. The first reported demonstration of this strategy was the total synthesis of (-)-roxaticin [29]. In this approach, treatment of cyanohydrin 57 with an excess of the C2-symmetrical dibromide 58 provided 59, without overalkylation (Scheme 6). A second alkylation involving cyanohydrin 60 gave 61 in excellent yield. (-)-Roxaticin was accessed in ca. 10 steps from tetraacetonide 62. 

The Sonogashira reaction is a transition metal-catalyzed coupling reaction which is widely used for the preparation of alkyl-, aryl- and diaryl-substituted acetylenes (Table 4.7) [120]. This reaction is a key step in natural product synthesis and is also applied in optical and electronic applications. Sonogashira reactions involve the use of an organic solvent with a stoichiometric portion of a base for capturing the... 

A number of nitro compounds used in natural product synthesis have been prepared by the nitration of alkyl halides. Some recent examples are summarized in Table 2.4. 

This chapter is divided into four major sections. The first (Section 2.1) will deal with the structure of both alkoxy and silyl nitronates. Specifically, this section will include physical, structural, and spectroscopic properties of nitronates. The next section (Section 2.2) describes the mechanistic aspects of the dipolar cycloaddition including both experimental and theoretical investigations. Also discussed in this section are the regio- and stereochemical features of the process. Finally, the remaining sections will cover the preparation, reaction, and subsequent functionalization of silyl nitronates (Section 2.3) and alkyl nitronates (Section 2.4), respectively. This will include discussion of facial selectivity in the case of chiral nitronates and the application of this process to combinatorial and natural product synthesis. 

Recently, both enantiomeric forms of callosobruchusic acid (170), a pheromone of the azuki bean weevil, Callosobruchus chinensis L., which induces the male to extrude his genital organ and to attempt copulation, were synthesized by Mori et al.178), applying Evan s alkylation method in natural product synthesis as the key step. Thus, (S)-prolinol propionamide was converted to its enolate (164) by treatment with LDA. 

As already demonstrated in the previous natural product synthesis, the alkylation of 2,2-dimethyl-l,3-dioxan-5-one SAMP/RAMP hydrazones is a reliable tool with which to synthesize chiral 4-substituted 2,2-dimethyl-l,3-dioxan-5-ones in gram quantities and with high enantiomeric excesses [68]. Thus, after metalla-tion of the RAMP hydrazone (R) -96 the corresponding lithio azaenolate was alkyl-... 

Sn2 ring opening by attack of a nucleophile on an ethenyl substituent (e.g. Scheme 60) has assumed importance in natural products synthesis (80JCS(P1)2084, cf. 81JA5969). The cyclopentene oxide (63) is a versatile synthon for alkylated, functionalized cyclopentanes (Scheme 61) (81JA2112). 

S. R. Chemler, D. Trauner, S. J. Danishefsky, The R-Alkyl Suzuki-Miayura Cross-Coupling Reaction Development, Mechanistic Study, and Applications in Natural Product Synthesis, Angew. Chem. Int. Ed. Engl. 2001, 40, 4544-4568. 

Optically active ethyl 3-hydroxybutanoate is a very useful chiral building block for natural product synthesis. Some applications are shown in Table I. Alkylation of doubly deprotonated ethyl 3-hydroxybutanoate gives branched structures of the following type ... 

Alkyl substituted a-lithiodihydrofurans 599-602 and a-lithiodihydropyrans 603-606 have been used for natural product synthesis. They are prepared by deprotonation of the corresponding DHF or DHP derivatives with f-BuLi in THF at —78 to 0 °C. Lithiated DHP 606 has been prepared by tin-lithium transmetallation starting from the hemiacetal 607, by successive transformation into the sulfone 608907 and the stannane 60 9908 (Scheme 163). 

After the intense use of concerted reactions for natural product synthesis, the related metal-catalyzed cyclizations gained ground in the 1980s and 1990s. Several authors demonstrated the effectiveness of these reaction types for the synthesis of dendrobine (82). Takano et al. and Zard et al. used the Pauson-Khand reaction as a key step for their EPC-synthesis efforts (144,165,166). Mori et al. relied on the more stable zirkonacycle in a related key step (167-169), while Trost et al. employed a palladium-catalyzed alkylation as well as a palladium-catalyzed ene reaction as key steps (170). Takano s efforts ended with the tricyclic skeleton of dendrobine, whereas Mori and Trost finished their formal EPC-syntheses with intermediates of Kende s and Roush s racemic S3mtheses, respectively. Both completed dendrobine synthesis would have necessitated more than 20 steps. 

In a second part, the reactivity of a-phenylselanyl enolates, derived from ketones, esters, lactones and a,/i-unsatm ated carbonyl compounds, is discussed. Alkylation, aldolisation and Michael reactions are considered as the use of selenium-stabilized carbanions in the natural product synthesis. Others a-fimctionalyzed species are also presented. 

A direct and satisfactory procedure for tertiary alkyl-alkynyl coupling has been developed by Negishi and Baba, who used trialkynylaluminums readily obtainable from the corresponding alkynyllithiums and anhydrous AICI3 [92]. For instance, tris(l-hexynyl)aluminum underwent a remarkably clean reaction with 1-adamantyl bromide to produce cross-coupled product 96 in 96 % yield. It is noteworthy that the reaction enables novel geminal alkyl-alkynylation of ketones this reaction should find a considerable application in natural product synthesis (Sch. 60). 

Alkoxycyclopropanes are commonly prepared from alkyl enol ethers by one of the Simmons-Smith modifications (see Chapter 7). According to Wenkert and coworkers they are cleaved by strong acids to the a-methylated carbonyl compound, thus establishing an overall a-methylation of a ketone or an aldehyde (equation 64). This method has often been used for natural product synthesis (e.g. valerane " ). 

Nogano and co-workers [3] reported similar examples of asymmetric induction for natural product synthesis using protected sugars and a variety of R MgX, where X = C1, Br, or 1. In Table 2, entries 3 and 4, the tetralose carbonyl can also contain in the Ri position an ether, ester, urethane, alkyl, or aryl group [13]. The authors reported the diastereometer ratio from the R substrate and the labeled carbon-2 varied from 80 20 to 10 90 (2S/2R). The variability was controlled by the nature of the nucleophile, the solvent, and the temperature. The authors rationalized the product distribution based on chelation of the metal and steric bulk of the reactants, favoring the R-isom.er. 

Chemler, S. R., Trauner, D., Danishefsky, S. J. The B-alkyl Suzuki-Miyaura cross-coupling reaction development, mechanistic study, and applications in natural product synthesis. Angewandte Chemie, International Edition 2001,40,4544-4568. 

Aldol condensations of more complex aldehydes are often sufficiently slow to allow successful alkylation reactions. There are numerous examples of aldehyde enolate methylations in the field of natural product synthesis. As shown in Scheme 29, the methylation of a tricyclic aldehyde, which was employed in the synthesis of ( )-rimuene, provides an illustrative case. As expected for an exocyclic enolate intermediate such as (61), the methyl group was introduced equatorial to the six-membered ring with a high degree of stereoselectivity. a-Alkylated aldehydes may be prepared efficiently by alkylations of enamines, Schiff base anions, hydrazone anions and other methods. A discussion of this methodology is provided in Section 1.1.5. 

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