Myers’ alkylation

The synthetic strategy is based on Yamaguchi macrolactonization, metal alkynylide addition at C17, Mukaiyama-aldol Prins reaction of vinyl ether 219 with aldehyde 218 forming 2,6-d5-tetrahydropyran, Hosomi-Sakurai reaction giving 2,6-tran5-tetrahydropyran, asymmetric center formation via Myers alkylation at C12 and Noyori reduction at C15 and C3 (Scheme 47). 

TABLE 2.3 Myers Alkylation with P-Branched Primary Alkyl Iodides... 

Utilization of Myers Alkylation with Other Electrophiles Pseudoephedrine carboxamides were also used as pronucleophile with a wide variety of electrophiles. Rapidly after his seminal paper, Myers explored the possibihty of using epoxides as electrophiles [38], Surprisingly, the approach of the epoxide occurred from the opposite face of the enolate compared to alkyl halides (Scheme 2.38). 

Conclusion The Myers alkylation appears year after year to be a simple and robust method to create new carbon-carbon bonds in a highly diastereoselective fashion even with complex precursors. As such, this alkylation process is undoubtedly an unavoidable method in the modem toolbox of the synthetic organic chemist. 

Cylindrocyclophane A [85] In 20(X), Smith and coworkers achieved the total synthesis of cylindrocyclophanes A (123) and F (124). Their strategy relied on a dimerization by metathesis (Scheme 2.67) [85], This family of natural products presents an unusual 22-membered [7,7]-paracyclophane structure. Concerning the synthesis of cylindrocyclophane A, two stereogenic centers are controlled by a Myers alkylation, while the monomer (125) is obtained from three different fragments, namely, the product of the Myers alkylation 126, cyclobutenone 127, and the silylated ynol 128 bearing a stereogenic center controlled by an Evans alkylation. 

The authors proposed an approach where the macrolactone would be formed by a ring closing alkyne metathesis (RCAM) [97] of diyne 161. This RCAM precursor would in turn be obtained by the reunion of the northern fragment 162 and the southern fragment 163, for which a Myers alkylation was envisioned to control one of the stereogenic centers (Scheme 2.75). 

To introduce the third stereogenic center, an additional Myers alkylation was performed using hydroxamide 179 and iodide 180 (Scheme 2.78). The resulting alkylated product 181, obtained in high yield and excellent diastere-oselectivity, was then converted to the corresponding alcohol 182 through a reductive cleavage of the chiral auxiliary. 

Pironetin [101] In 2001, Keck and coworkers described the total synthesis of (-)-pironetin 185 [101], an immunosuppressant natural product, which also exhibits a potent cytotoxicity due to the inhibition of the tubulin polymerization [102]. Their strategy relied on a late-stage construction of the 5-lactone and an aldolization between silyl enol ether 187 and aldehyde 188 to build the polypropionate side chain (Scheme 2.79). A Myers alkylation was envisioned for the control of the C4 stereogenic center. 

The synthesis of the C3-C6 fragment 186 started with a variant of the Myers alkylation using acrylamide 189 (Scheme 2.80). Deprotonation under standard conditions... 

The group of Yadav exploited the hidden symmetry included in a main portion of the natural product (Scheme 2.82) [105]. Their strategy revolved around a key Myers alkylation between propionamide 25 and iodide 193 corresponding to the C1-C7 fragment of the natural product, which would in turn be obtained starting from meso oxabicycle 194. 

Chiral oxazolines were the first ehiral auxiliaries used for asymmetrie enolate alkylations. Subsequent studies led to the development of a number of other ehiral auxiliaries (34-38) ineluding those reported by Evans, Myers, Enders, Sehollkopf, and others, whieh are now widely used in asymmetrie synthesis. Although these new auxiliaries frequently provide higher yields and enantioseleetivities than the oxazolines originally developed by Meyers, the pioneering work of Meyers laid the groundwork for these later studies. 

A simple and atom-economical synthesis of hydrogen halide salts of primary amines directly from the corresponding halides, which avoids the production of significant amounts of secondary amine side products, has been described by researchers from Bristol-Myers Squibb [227]. Microwave irradiation of a variety of alkyl halides or tosylates in a commercially available 7 m solution of ammonia in methanol at 100-130 °C for 15 min to 2.5 h followed by evaporation of the solvent provided the corre-... 

The utility of chiral oxazoline enolates in asymmetric synthesis has elegantly been demonstrated by Myers (106,120). The stereoselective aldol condensations of these enolates have been examined in a hmited number of cases (eq. [107]) (32,121). Assuming that the enolate formed has the geometry indicated in 164 (120b), the diastereoselection observed for both the aldol condensation and the previously reported alkylations favors electrophile attack on the Re face as indicated. In contrast, the unsubstituted enolate 163b exhibits significantly poorer diastereoface selection with a range of aldehydes (eq. [108]) (121). 

The actual synthesis (Scheme 21) started with the stereoselective alkylation of Myers hydroxy-amide 131 [40] followed by reductive removal of the auxiliary to give 132 in high yield and enantioselectivity. Wittig olefination furnished enoate 133, which was then elaborated into the (E)-l-acetoxy-diene 129 using... 

Bristol-Myers Squibb in partnership with Otsuka has recently marketed aripiprazole for the treatment of schizophrenia. The synthesis (Scheme 20) begins with acylation of 3-methoxyaniline followed by Friedel-Crafts ring closure to give quinolinone 67. Hydrogenation provides dihydroquinolinone 68, which is treated with 1,4-dibromobutane in the presence of K2CO3 to afford 69. Compound 69 was treated with Nal and then alkylated with 2,3-dichlorophenylpiperazine to give aripiprazole (5). 

In the laboratory of T.F. Jamison, the synthesis of amphidinolide T1 was accomplished utilizing a catalytic and stereoselective macrocyclization as the key step. ° The Myers asymmetric alkylation was chosen to establish the correct stereochemistry at the C2 position. In the procedure, the alkyl halide was used as the limiting reagent and almost two equivalents of the lithium enolate of the A/-propionyl pseudoephedrine chiral auxiliary was used. The alkylated product was purified by column chromatography and then subjected to basic hydrolysis to remove the chiral auxiliary. 

The neurotoxic lipopeptide (+)-kalkitoxin was prepared by J.D. White et al., who installed one of the stereocenters via the Myers asymmetric alkylation followed by reductive workup to obtain the enantiopure primary alcohol. 

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