Amino alkoxide

Based on these reports, we started investigation of the asymmetric addition of acetylide to pMB protected 5, mainly in the presence of chiral P-amino alcohols. Many types of chiral amines were also screened (e.g., diamines, diethers), and it was soon found that addition of P-amino alkoxides effectively induced enantiose-lectivity on the addition. Since the best result was obtained with a stoichiometric amount of chiral amino alcohols, we focused our screen on readily available chiral P-amino alcohols and the results are summarized in Table 1.2. 

Pyrroles and indoles have one further unique mode of lateral lithiation—deprotonation of an Af-methyl group (also an a lithiation). The reaction works particularly weU with an aldehyde director, temporarily protected as the a-amino alkoxide 565 (Scheme 228)°° . 

In addition to the parent heterocycle, both AT,N-diethyl-l-methylpyr-role-3-carboxamide and l-methylpyrrole-3-carboxaldehyde have been selectively a-lithiated in the 2-position (85TL6213 87JOC104), the latter compound via the intermediacy of an a-(Af-methylpiperazino) alkoxide (Scheme 6). The a-amino alkoxide is formed in situ, via the addition of... 

Comins and Killpack have also investigated the lithiation of a small number of N-protected indole-3-carboxaldehydes, using lithium N-methyl-piperazide to form the a-amino alkoxide, and found that decomposition occurred with the A -benzenesulfonyl, N-ter/-butoxycarbonyl, and A -di-methylcarbamyl derivatives (87JOC104). Success was achieved with the N-methoxymethyl derivative 19, although no attempt was made to subsequently remove the normally difficult to hydrolyze methoxymethyl protecting group. Therefore the real viability of this method as a route to... 

N-Methylindole-2-carboxaldehyde also undergoes /8-lithiation, after in situ conversion to its a-amino alkoxide with lithium A-methylpiperazide, and the resulting 3-lithio species has been successfully alkylated with methyl iodide (Scheme 22)(87JOC104). However, when the same reaction was repeated using N,A(,A -trimethylethylenediamine as the amine com-... 

Addition of A/ -forrnyl-/V,/V,/V -trimethylethylenediamine to 21 yields a-amino alkoxide 22. A further directed ortho metalation takes place by coordination of nBuLi to the ethylenediamine moiety and subsequent deprotonation. As result intermediate 6 is formed. 

In 1999, Nozaki and co-workers were the first to report an asymmetric copolymerization, catalysed by a chiral amino-alkoxide zinc complex 15 (Table 6) and producing optically active PCHC with 70% ee (measured by hydrolysing the copolymer and analysing the resulting diol using chiral GC) [138,148], The crystal structure of the catalyst, reported subsequently, showed a dimeric structure it was unclear whether the dimer was maintained during the copolymerization [148], In the solid state, the zinc-zinc distance in the catalyst was determined to be 3.00 A (vs. ca. 4 A, for the loosely bound BDI zinc dimers). 

Complexing with chromium tricarbonyl provided activation of the aromatic ring for nucleophilic substitution of a fluorine atom with j6-amino-alkoxides and then for rearrangements of the initially formed products. Thus,... 

A practical six-step synthesis of (S)-camptothecin was developed by D.L. Comins and co-workers." In order to prepare the DE ring fragment, 2-methoxypyridine was Iithiated at C3 with mesityllithium and treated with A/-formyl-A/,A/, A/ -trimethyl ethylenediamine to form an -amino alkoxide in situ. In the same pot, the addition of n-BuLi brought about a directed lithiation at C4 to afford a dianion, which was trapped with iodine and treated with NaBHVCeCIs to give the desired 4-iodo-2-methoxy-3-hydroxymethyl pyridine in 46% yield. 

An interesting protection of an aldehyde group in a lithiation reaction is to convert it to a-amino alkoxide. The alkoxide, here, is the ortho directing group... 

A three-step synthesis of cerpegin (118) was described by Hong and Comina (235). Lithiation of 2-methoxypyridine (361) with mesityllithium followed by the addition of N-formyl-A/,lV, 7V -trimethylethylenediamine (362) gave an a-amino alkoxide which was treated with n-butyl lithium. The resulting dianion 363 was reacted with cerium chloride followed by acetone to yield, after acidification, the lactol 364. Oxidation with PCC gave 365, which was treated with methyl iodide at 145°C to afford 118 (Scheme 43) (235). The overall yield was 34%. 

Trialkylsilicon, germanium or tin derivatives have been introduced at position 5 of thiophene-2-carbaldehyde via lithiation <92S954>. The first step is the protection of the aldehyde as the amino-alkoxide by reaction with lithium A(-methylpiperazide (LNMP). Subsequent treatment with BuLi followed by R MCl and hydrolysis by cold brine gave the desired products. 

The group of Collum, inspired by highly selective acetyUde additions to ketones (see below), performed lithium phenylacetyhde additions to PhCHO, mediated by the camphor-derived amino alkoxide 21 in THF at -78°C [80]. Variations of the alkoxide acetyUde ratio revealed changes in the sense of enantiose-lectivity and the highest enantioselectivity (78% ee) was observed at a ratio of 1 3. 

Reaction in THP at 50 kHz followed by lithiation of the intermediate a-amino-alkoxide on its ortho position and quenching with electrophiles provide ortho-substituted benzaldehydes in a one-step protocol. 

Scheme 18.49 Oxo-bridged aluminium amino-alkoxides investigated by Kim et al ...

The tertiary amide group (CONR2) is a widely used DMG but it usually requires further derivatisation ° to convert it to a reactive functional group however, it readily participates in intramolecular cyclisation reactions to form lactones/ Tertiary amides have also been converted to ketones through an intermediary a-amino alkoxide that plays the role of the DMG (Scheme 11.3). 

In the list of moderate DMGs, the ot-amino alkoxide group is of particular interest as it serves as a masked aldehyde conveniently effecting a one-pot ort/zo-alkylation of aromatic aldehydes (Scheme 11.5). ... 

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