Modern Organic Synthesis an Introduction

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Modern Organic Synthesis an Introduction G. S. Zweifel M. H. Nantz W.H. Freeman and Company Chapter 1 Synthetic Design • What is an ideal or viable synthesis, and how does one approach a synthetic project? • The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps) and selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity). • This chapter outlines strategies for the synthesis of target molecules based on retrosynthetic analysis. 1 1.1 Retrosynthetic Analysis Basic Concept The symbol signifies a reverse synthetic step and is called atransform. The main transforms are disconnections, or cleavage of C-C bonds, and functional group interconversions (FGI) Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions(FGI). Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE). Synthetic design involves two distinct steps (1) Retrosynthetic analysis (2) Subsequent translation of the analysis into a “forward direction” synthesis. Chemical bonds can be cleaved heterolytically, homolytically, or through concerted transform. 2 Donor and Acceptor Synthons Acceptor synthon Æ carbocation (electrophilic) Donor synthon Æ carbanion (nucleophilic) Table 1.1 Common Acceptor Synthon Synthetic equivalents Common Acceptor Synthon Synthetic equivalents 3 Table 1.2 Common Donor Synthons Common Donor Synthon Synthetic equivalents Retrosynthetic Analysis A Synthesis A 4 Retrosynthetic Analysis B Synthesis B Alternating Polarity Disconnections The presence of a heteroatom in a molecule imparts a pattern of electrophilicity and nucleophilicity to the atom of the molecule. The concept of alternating polarities or latent polarities (imaginary chargies) often enables one to identify the best positions to make a disconnection within a complex molecule. Functional groups may be classified as follows. E class: Groups conferring electrophilic character to the attached carbon (+): -NH2, -OH, -OR, =O, =NR, -X (halogens) G class: Groups conferring nucleophilic character to the attached carbon (-): -Li, -MgX, -AlR2, -SiR3 A class: Functional groups that exhibit ambivalent character (+ or -): -BR2, C=CR2, CCR3, -NO2, N, -SR, -S(O)R, -SO2R 5 Consonant Pattern: Positive charge are placed at carbon atom bonded to the E class groups. Dissonant Pattern: One E class is bonded to a carbon with a positive charge, whereas the other E class group resides on a carbon with a negative charge. Alternating Polarity Disconnections Consonant Simple synthesis Dissonant One Functional Group Analysis 6 Synthesis Two Functional Groups In a 1,3-Relationship Analysis 7 Synthesis (path a) Synthesis (path b) 8 Two Functional Groups in 1,4-Relationship The α-carbon in this synthon requires an inversion of polarity (umpolung in German) from the negative (-) polarity normally associated with a ketone α-carbon. Analysis α-bromoketone Enolate cannot be used because of the formation of an epoxy ketone (Darzens condensation). Instead, enamine is used. Synthesis 9 Analysis Umpolung Synthesis 10.

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Protokoll Handledarmöte 2020-02-14
http://www.diva-portal.org Postprint This is the accepted version of a paper published in Organic Letters. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. Citation for the original published paper (version of record): Colas, K., dos Santos, A C., Mendoza, A. (2019) i-Pr2-NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions Organic Letters, 21(19): 7908-7913 https://doi.org/10.1021/acs.orglett.9b02899 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-175818 i-Pr2NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addi- tion of Grignard Reagents to Carboxylate Anions Kilian Colas, A. Catarina V. D. dos Santos and Abraham Mendoza* Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory, 106 91 Stockholm (Sweden) Supporting Information Placeholder direct Grignard - carboxylate coupling 1 R MgX + i-Pr2NMgCl•LiCl 1 MgX ( ) R * CO2 i-Pr i-Pr L L O [Mg] N O ideal ( ) * Mg Li (*) sources 1 1 2 R O Cl R R R2 L O ketone [proposed structure] products base R1 OH [in-situ from commercial] ◾ >30 examples ◾ scalable ◾ facile isotopic-labelling ABSTRACT: The direct preparation of ketones from carboxylate anions is greatly limited by the required use of organolithium reagents or activated acyl sources that need to be independently prepared. Herein, a specific magnesium amide additive is used to activate and control the addition of more tolerant Grignard reagents to carboxylate anions.
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