Metodologías para medir el posicionamiento, basadas en el consumidor

Ketoamides

1.4 Summary and Outlook

The biological importance and synthetic utility of -keto acids and their derivatives has led to the development of various methods for their preparation. While there are a number of practical procedures in place for the synthesis of achiral -keto esters, a general synthetic method for the introduction of a stereocenter at the -position remains elusive. The current strategies that are available to access this important class of compounds, particularly asymmetric methods, suffer from several major drawbacks. With the exception of Wang and Trost, the reaction scopes are restricted to alkyl substituents at the -position due to the vulnerability of enolization at this site. From a practicality standpoint, in many cases, the - keto ester moiety is not introduced in the key asymmetric CC bond forming step and

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significant functional group manipulation to reveal the -keto ester is required, and/or the starting materials are not readily available. The methods described in the following chapters seek to address these deficiencies by introducing three simple reagents that function as glyoxylate anion equivalents to provide access to diverse classes of -stereogenic -keto esters. Additionally, the facile racemization of these substrates is capitalized on in the development of the first dynamic kinetic resolution of -keto esters.

22 References

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(3) Li, Z.; Patil, G. S.; Golubski, Z. E.; Hori, H.; Tehrani, K.; Foreman, J. E.; Eveleth, D. D.; Bartus, R. T.; Powers, J. C. J. Med. Chem. 1993, 36, 3472.

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(8) Kang, Q.; Zhao, Z. A.; You, S. L. Adv. Synth. Catal. 2007, 349, 1657. (9) Wieland, T. Chem. Ber. 1948, 81, 314.

(10) Weinstock, L. M.; Currie, R. B.; Lovell, A. V. Synth. Commun. 1981, 11, 943. (11) Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1981, 46, 211.

(12) Hojo, M.; Masuda, R.; Sano, H.; Saegusa, M. Synthesis 1986, 137. (13) Tietze, L. F.; Meier, H.; Voss, E. Synthesis 1988, 274.

(14) Arnold, Z. Synthesis 1990, 39.

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(16) Meyer, B.; Kogelberg, H.; Koll, P.; Laumann, U. Tetrahedron 1989, 30, 6641. (17) Meyers, A. I.; Tait, T. A.; Comins, D. L. Tetrahedron Lett. 1978, 19, 4657. (18) Corey, E. J.; Seebach, D. Angew. Chem. Int. Ed. Engl. 1965, 4, 1077.

(19) Reutrakul, V.; Nimgirawath, V.; Prapnsiri, V.; Srikirin, Y. J. Sci. Soc. Thailand

1982, 8, 215.

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(27) Estenne, G.; Saroli, A.; Doutheau, A. J. Carbohydrate Chemistry, 1991, 10, 181. (28) Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Am. Chem. Soc. 1997,

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(33) Xian, M.; Alaux, S.; Sagot, E.; Gefflaut, T. J. Org. Chem. 2007, 72, 7560. (34) Thompson, W.; Buhr, C. A. J. Org. Chem. 1983, 48, 2769.

(35) Coutrot, P.; El Gadi, A. Synthesis, 1984, 115.

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(37) Komiyama, T.; Takaguchi, Y.; Tsuboi, S. Synthetic Communications 2006, 36, 265. (38) He, S. W.; Lai, Z.; Yang, D. X.; Hong, Q.; Reibarkh, M.; Nargund, R. P.; Hagmann,

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(39) Enders, D.; Dyker, H.; Raabe, G. Angew. Chem. Int. Ed. Engl. 1992, 31, 618.

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(41) Tyrell, E.; Skinner, G. A.; Janes, J.; Milsom, G. Synlett, 2002, 1073.

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CHAPTER TWO

CATALYTIC NUCLEOPHILIC GLYOXYLATION OF ALDEHYDES

2.1 Introduction

2.1.1 Umpolung Reactivity

The term umpolung is defined as “any process by which the normal alternating donor and acceptor reactivity pattern of a chain, which is due to the presence of O or N heteroatoms, is interchanged.”1

This concept was first introduced by Seebach to describe the latent electronic character at carbon in a heteroatom substituted framework, in which the inductive polarization of the more electronegative heteroatom (O, N, etc.) places a + on the

ipso carbon and a - on the -position (Figure 2-1). 2 The incorporation of-bonds allows further delocalization of the partial charges via resonance to more remote sites. Based on this analysis, the normal polarity mode of carbonyls provides access to -hydroxy carbonyl (aldol reaction), -amino carbonyl (Mannich reaction), and 1,5-dicarbonyl (Michael reaction) motifs. However, access to the complementary class of products, -hydroxy carbonyl, - amino carbonyl, and 1,4-dicarbonyls, requires an inversion of the standard polarity of carbonyl reagents (electrophilic to nucleophilic). As acyl anions and other umpolung reagents are often not stable or accessible (i.e. an acyl anion cannot be generated by deprotonation of an aldehyde), it is often necessary to mask umpoled functionality with a synthetically equivalent group.

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Figure 2-1. Normal vs. Umpolung Reactivity

The conversion of an aldehyde into an umpolung reagent is typically accomplished through dithiane3 and protected cyanohydrin4 derivatives (Scheme 2-1). The two anion- stabilizing sulfur atoms of dithiane 2.1 and the electron-withdrawing properties of the nitrile in 2.2 allow these intermediates to be converted to the corresponding -carbanion (2.3 and 2.4) with a strong base; this renders the electrophilic carbonyl carbon nucleophilic. The intermediate carbanion can then react with an electrophile and the deprotection of the dithiane or cyanohydrin regenerates the initially present carbonyl functionality in 2.5, yielding the formal acylation of an electrophile. While these tactics have proven to be useful in a number of circumstances, they lack the step economy and convenience of their enolate counterparts (generated from a normal polarity mode).

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