[Structure: see text] A mild and efficient [3+2] nitrile oxide/olefin cycloaddition allows coupling of the highly functionalized naphthalene and isocoumarin hemispheres of purpuromycin. A rationale of the inability of advanced keto alcohols to spirocyclize is presented based upon a systematic examination of the electronic factors present in these systems and suggests that the biosynthesis of purpuromycin does not proceed through open-chain intermediates.

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In this laboratory experiment, upper-division undergraduate chemistry and biochemistry majors investigate amide-bond-forming reactions from a green chemistry perspective. Using hydrocinnamic acid and benzylamine as reactants, students perform three types of amide-forming reactions: an acid chloride derivative route; a coupling reagent promoted method; and a boric acid catalyzed condensation. After isolation of the common product, students assess the reactions using the 12 Principles of Green Chemistry and several green chemistry metrics: atom economy; reaction mass efficiency; process mass intensity; and the EcoScale. In addition to assessing what route is the greenest, students also compare the metrics to discern what aspects of green chemistry each metric captures. In order to extend sustainability to economic considerations, the projected "front-end" cost of synthesizing a kilogram of the amide is calculated based on data from each reaction. The experimental work is conducted over two 3 h laboratory periods.

A concise synthesis of naphthalene compounds for incorporation into a synthetic sequence for the rubromycin family of natural products is presented. These highly substituted naphthalenes are generated in seven and nine steps, respectively, from 2,4,5-trimethoxybenzaldehyde. Three ring-forming methods were explored and the controlled oxygenation of different positions was investigated to yield differentially substituted/protected systems. Key steps to the final products include a Stobbe condensation to form the ring system and a novel series of regioselective oxidations to introduce the required oxygen functionality. These naphthalene products incorporate orthogonal protecting groups and are suitable for combination with a variety of coupling partners.

The first catalytic, enantioselective addition of organozinc reagents to α-aldiminoesters is described. The use of a Lewis acid/Lewis base containing bifunctional catalyst preorganizes both reactive substrates to promote enantioselective addition over the racemic background reaction and alternative addition modes. Alcohol additives were found to enhance the enantioselection. The addition product was also found to cyclize with remaining substrate to provide imidazolidines.Optically active natural and nonnatural amino acids are versatile building blocks for a range of biologically important molecules. 1 Enantioselective addition to α-iminoesters as a route to the synthesis of important chiral amino acids has been achieved 2 via the iminoene reaction, 3 Friedel Crafts reaction, 4 enol ether addition 5 and enolisable ketone 6 and aldehyde 7 addition.In comparison, the enantioselective addition of unstabilized anions to α-iminoesters which provides entry to key congeners of α-amino acids has not been reported. While related diastereomeric processes have been forthcoming, 8 the enantioselective processes have proven more difficult. To date only enantioselective additions of stoichiometric allyl zinc reagents have appeared. 9 On the other hand, the corresponding aldimine additions have met with greater success. 10 α-Iminoesters are significantly more challenging due to their higher reactivity and the presence of a bicoordinate metal binding site ( Figure 1); both factors lead to substantial racemic background processes.We have previously reported the enantioselective addition of Et 2 Zn to α-ketoesters using salen-derived independent Lewis acid/Lewis base bifunctional catalysts. 11 In these systems, the electrophile coordinates to the Lewis acid, while the electronically decoupled Lewis base activates the nucleophile. These independent moieties facilitate enantioselective addition (Figure 2). Here we report the first enantioselective addition of organozinc reagents to α-iminoesters using these bifunctional catalysts. Our initial experiments showed that the addition of Et 2 Zn to α-ketiminoesters (Figure 3, R ≠ H) proceeded with poor regioselectivity, yielding 1,2-addition, 1,4-addition and reduction. A survey of prior work revealed similar regioselectivity problems. Mg, Al and Cu mediated alkylations have resulted in 1,4-additions, whereas Zn mediated additions lead to mainly 1,2-additions ( Figure 3). 12Upon screening aldiminoester substrates (Figure 3, R = H) against metal adducts of bifunctional salens 1-4, we found that PMP (para-methoxyphenyl) protected aldiminoester 6 gave only 1,2-addition (eq 1) and was chosen for further exploration. Pure 6 can be synthesized on a large scale by condensation of ethylglyoxylate and para-methoxyaniline and subsequent distillation. 13Importantly, treating 6 with Et 2 Zn at −40°C in the absence of catalyst led to the formation of significant racemic addition product within 2 h. Thus, these substrates are much more challenging than most aldehydes (no background reaction) ...

The synthesis of alpha,alpha-disubstituted alpha-amino acids by means of a three component coupling is reported. The coupling occurs through umpolung addition of organometallic reagents to the nitrogen of alpha-iminoesters. The resulting enolate intermediates subsequently react with electrophiles (aldehydes, imines, alpha,beta-unsaturated nitro, alkyl halides, acyl cyanides) to form a quaternary center. Tethering of the electrophile and nucleophile components provides cyclic alpha,alpha-disubstituted alpha-amino acid derivatives.