Overall Preparation Scheme

we optimized our new process and the process improvements are summarized as follows  

1) Drug supply needs for the project were supported by providing 1 at short notice. 

2) The overall yield of 1 was improved to 10% in 16 chemical steps with the longest linear sequence as ten steps. 

3) A newly developed asymmetric nucleophilic addition of malonate to 7i-allyl Mo complex was the cornerstone for this preparative campaign. 

4) A better diastereoselectivity with Cu-catalyzed cyclopropanation was discovered. 

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The overall preparation scheme of functionalized metal polymer complex is summarized in Figure 11.3. 

Sheridan and co-workers reported a novel photo-assisted [5 + 2 + 2]-reaction based on the reactions of 77S-cyclodienyl Mn complexes160,161 or Cr complexes162 and two alkynes. Decomplexation of the metal gives cycloadducts in moderate to good overall yields (Scheme 66, Equation (42), and Scheme 67). It should be noted that the authors refer to this reaction as a [5 + 2]-, [3 + 2]- or a [5 + 2]-, homo-[5 + 2]-reaction. This reaction leads to the formation of impressively complex tricyclic products that would be otherwise difficult to prepare with step economy. 

The diazotization of o-diaminobenzene derivatives is the most common synthetic route to benzo-triazoles. Triazolo[6,7- /]phthalide (791) is synthesized in a seven-step sequence from phthalide in 24% overall yield as shown in Scheme 159. Triazolo[6,7-c ]dihydrocoumarin is similarly prepared in nine steps from dihydrocoumarin in 20% overall yield <92JHC1519>. Benzo[l,2-tf 4,5-tf jbistriazole (795) is synthesized from w-dichlorobenzene in five steps and 54% overall yield (Scheme 160). The hydrogenation of (792) is carried out in ethanol to give (793), which, without isolation, is diazotized at 0°C to afford diacetyl bistriazole (794) in 96% yield <86JOC979>. 

Conjugate addition of dialkylcuprates to the homochiral dioxinone (57), prepared from (/ )-3-hydroxy-butyric acid (56), produces single diastereomers (58), which can be hydrolyzed to the homochiral products (59).60 61 The overall process (Scheme 22) constitutes an example for self-regeneration of a stereogenic center . Interestingly, the high stereoselectivity can not be attributed to simple steric effects. 

This approach was used by Panek et al. [76] as a key step in the enantioselective synthesis of methyl-L-callipeltose 156 (Northern-part of Callipeltoside A [77]). Starting from enantioenriched allylsilane 154, acetal 156 was prepared in eight steps and 23% overall yield (Scheme 13.52). 

The alternative disconnection to CH3 and HCCH2CH2CH2CH3 reveals a plausible approach to 2-hexanol but is inconsistent with the requirement of the problem that limits starting materials to four carbons or fewer. The five-carbon aldehyde would have to be prepared first, making for a lengthy overall synthetic scheme. 

Analogs of Zefirov s reagent have been prepared from (diacetoxyiodo)ben-zene and some strong acids according to the general overall equation (Scheme 12) [48]. 

Starting from ethyl (iS )-lactate, rhodinose was prepared in four steps, with 31% overall yield (Scheme 57).272 Chelation-controlled addition of the Grignard... 

Trifluoromethyl-P-lactam 63 was prepared in racemic form via a ketene-imine [2 + 2] cycloaddition, following previously published methods81 with modifications.46 The subsequent oxidative cleavage of PMP, acylation of NH with (f-Boc)20, hydrogenolysis over Pd/C, and protection as 1-ethoxyethyl ether gave N-f-Boc-P-lactam 63 in good overall yield (Scheme 13). 

Finally, a synthesis of a chiral azodicarboxamide containing a bridging binaphtyl moiety was described by Vederas and co-workers, and electrophilic amination reactions of achiral ester enolates were performed [53]. The chiral azocarboxamide 105 containing a binaphtyl group was prepared by an intramolecular cyclization between the bis-(A-methylamine) of 2,2-dimethyl-1,1 -binaphtyl 103 and N,N -bis(azidocarbonyl)hydrazine 104 followed by oxidation with IV-bromosuccinimide (NBS) and pyridine in 15 % overall yield (Scheme 48). 

Deoxytazettine neomethide (31), a key degradation product of tazettine, has been prepared (Scheme 4).11 The biphenyl derivative (28), obtained in low yield by Ullman condensation, was converted into the cyano-oxepin (29) in two steps (34% overall yield). Reduction gave the amine (30), which upon resolution followed by reductive methylation provided a sample of (—)-deoxytazettine neomethide (31) that was identical (including optical rotation) with the degradation product of tazettine. 

The dioxoerythrinan (19), earlier prepared by a concerted intermolecular alkylation of the 7/ -mesylate (18b),15 has now been synthesized from homoveratrylamine (17) in 35% overall yield (Scheme 2).16 This is useful as an intermediate in the preparation of alkaloids of the dienoid type.15,16... 

An ingenous method for the preparation of the lateral macrobicycles has been developed by Newkome and co-workers 30). The method consists on bis-quatemization of the macrocycles 25 with bis(2-iodoethoxy)ethane (26) in boiling acetonitrile to afford the bis-quaternary salts 27 in ca. 40% yield. Those were not isolated, but directly demethylated with L-selectride to form the desired macrobicycles 28 in a 40 % overall yield (Scheme 4). 

Benzodiazepines 392 are generally prepared from the appropriately o-disubstituted benzene (e.g., 0-phenylenedia-mine) and a 1,3-bis carbon electrophile (Scheme 210) . For example, acetylated derivatives of BaylisHillman adducts 393 derived from ethyl acrylate and aromatic or heteroaromatic aldehydes readily react with 0-phenylenediamine under the influence of base to provide l,4-benzodiazepin-2-ones 394 in good overall yields (Scheme 211) <2006S4205>. 

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