Ethers retrosynthetic analysis

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 16).

ANSWER We are using a Williamson Ether synthesis, so we will need to start with an alcohol and an alkyl halide to form the ether linkage. Working backwards (retrosynthetic analysis), we get the following ... 

The only other functional group is the conjugated unsaturated ester. This functionality is remote from the stereocenters and the ketone functionality, and does not play a key role in most of the reported syntheses. Most of the syntheses use cyclic starting materials. Those in Schemes 13.4 and 13.5 lead back to a para-substituted aromatic ether. The syntheses in Schemes 13.7 and 13.8 begin with an accessible terpene intermediate. The syntheses in Schemes 13.10 and 13.11 start with cyclohexenone. Scheme 13.3 presents a retrosynthetic analysis leading to the key intermediates used for the syntheses in... 

Ishikawa and coworkers reported a synthesis of ( )-0-methylkinamycin C (54) [32, 33]. Their retrosynthetic analysis is shown in Scheme 3.9. It was envisioned that 54 could be derived from the dihydroindanone 55 by D-ring oxygenation, installation of the diazo substituent, and oxidation of the protected hydroquinone function. The dihydroindanone 55 was envisioned to arise from the enol ether 56, itself formed from an endo Diels-Alder reaction between the indenone 59 and the diene 58. 

Scheme 4. Retrosynthetic Analysis and Synthesis of Trihydroxydecipiadiene 30 then H 52% b [(CH3)2N]2CHO-t-C4H9, 100% c CH3OH, TsOH, 92% d DIBAL-H ether then CH3OH, Dowex-50W-X-8-H + then PCC 87% See ref. 79 f HC1, H20, THF then Ph3PC(CH3)C02CH3, PhCH3, 100° then DIBAL-H, ether 56%...

Scheme 15. Retrosynthetic Analysis and Synthesis of Methyl Trisporate B a C4H9Li then 43 then KH/THF followed by TMS-C1, C5H5N, ether 70% b FVT, 95% CH3OH, HC(OCH,)3, HC1, 68% d CH3MgBr, (dppp)NiCl2, THF, 75% HC1, H20, CH3CN, 100% f See Ref. 975...

The result of the retrosynthetic analysis of rac-lO is 2-hydroxyphenazine (9) and the terpenoid unit rac-23, which may be linked by ether formation [29]. The rac-23 component can be dissected into the alkyl halide rac-24 and the (E)-vinyl halide 25. A Pd(0)-catalyzed sp -sp coupling reaction is meant to ensure both the reaction of rac-24 and 25 and the ( )-geometry of the C-6, C-7 double bond. Following Negishi, 25 is accessible via carboalumination from alkyne 27, which might be traced back to (E,E)-farnesyl acetone (28). The idea was to produce 9 in accordance with one of the methods reported in the literature, and to obtain rac-24 in a few steps from symmetrical 3-methyl-pentane-1,5-diol (26) by selective functionalization of either of the two hydroxyl groups. 

Some illustrative examples from the field of polyquinanes are the synthesis of some derivatives of bicyclo[3.3.0]octane 6 (Scheme 6.7) [12] [15] -which have been used in the total syntheses of coriolin, hirsutic acid and quadrone- and the synthesis of triquinacene 7 and some of its derivatives. The retrosynthetic analysis of perhydrotriquinacene-l,4,7-trione (7a) is shown in Scheme 6.7bis. In the actual synthesis the hydroxy groups must be protected either as trialkylsilyl ethers or more conveniently as benzyl ethers [16] [17]. 

Chiu s retrosynthetic analysis of the pseudolaric acids proposed a simple intermediate incorporating a bridging ether, similar to that used by Dauben and McMills. Cleavage of the ether bridge further reduced the problem to a tandem ylide formation-cycloaddition through a simple acyclic ot-diazoketone with a tethered olefin (Scheme 4.45). 

Retrosynthetic analysis of hirsutin 108 led to the tetrahydro-/i-carboline (3R)-aldehyde 116, Meldrum s acid 35 and the enol ether 117 via the retrosynthetic intermediates 113-115 (Scheme 5.20) [34]. 

You can immediately spot the 1,3 relationship in this analogue of the antidepressant, nisoxetine, but, unfortunately, it can t be disconnected straight back to an amino-alcohol because that would require nucleophilic substitution on an electron-rich aromatic ring. We have to disconnect the ether on the other side, giving an alkyl chloride, nisoxetine analogue retrosynthetic analysis Me(... 

As suggested by the retrosynthetic analysis (Scheme 4) described above, there are three pathways to methylene bridged glycoluril dimers -namely - 1) two equivalents of glycoluril cyclic ether (e.g. 12), 2) two equivalents of glycoluril NH compound (e.g. 13) with added... 

When furan is considered in the light of a retrosynthetic analysis it can be seen to derive from a double enol ether and can, therefore, be dissected retroanalytically in two ways (I, II) according to the following scheme ... 

The synthetic implications of this chapter are discussed via retrosynthetic analysis with three problems. The targets are ether 163, nitrile 164, and ether 165, with the designated starting material shown in each case. Ether 163 must be made from 1-pentene, and it is clear that analyzing both molecules leads to the conclusion that no new C-C bonds must be made. All five carbon atoms of 1-pentene are found in 163. It is also clear that a C-0 bond must be made at C2 of 1-pentene. What is the source of OMe Either an alcohol must be made and then OH must be converted to OMe, or OMe must be incorporated directly. In either case, methanol is the source of OMe. 

The second problem prepares ethoxybenzene (21 phenetole) from benzene, and the retrosynthetic analysis is 21 19 => 42 benzene. Because 21 is an ether, the most likely precursor is phenol (19), which is prepared from aniline (23) via the diazonium salt. Aniline is derived from nitrobenzene (42), which is prepared directly from benzene. Therefore, the synthesis is that shown in the following illustration. 

Rethinking suitable methods for the construction of a tertiary alkyl-aryl ether, 1 settled on an asymmetric allylation approach. The Trost ligand was known to favor formation of the branched adduct from unsymmetrical allyl donor substrates, and phenols had been successfully employed as nucleophiles. Accordingly, a retrosynthetic analysis suggested that a differentially protected dopa derivative 4 was required as the nucleophilic component, to be combined with a functionahzed isoleucine derivative containing either a branched (3a) or linear (3b) allyl donor component (Fig. 2). My first postdoc, Phihp Chan, embarked on the synthesis of such functionalized isoleucines in 2000 we were both rather green ... 

Example 5.6 Propose the retrosynthetic analysis and then synthesis of cyclic ether TM 5.6. 

For the retrosynthesis of the isoxazole system (see Fig. 5.12), it is essential that the heterocycle possesses the functionality of an oxime and of an enol ether, and that C-3/C-5 are at the oxidation level of a carbonyl function. Therefore, a logical retrosynthetic route (a - c) leads by way of the monoxime 2 to the 1,3-diketone and hydroxylamine. If the retrosynthetic operation a to d is generalized, one arrives at the 4,5-dihydroisoxazole 1. Its analysis, according to a retroanalytically permitted cycloreversion, leads to an alkene unsubstituted by a leaving group and to a nitrile oxide 3. These fragments represent the two components of a 1,3-dipolar cycloaddition. 

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