Acetals disconnection

Norwegian spruce, is an acetal. Disconnection reveals two 1,4-relatlonships (58), either of which could be connected by an acetylene. 

Further into the skeleton is another hidden carbonyl group 85 masked as a hemiacetal rather than an acetal. Disconnection there shows up an enol 86 and conversion of the enol into the aldehyde gives the simplest structure we have yet seen 87 without any rings at all. Indeed if we redraw that structure in a more conventional way 88, we can see that it is one continuous piece... 

The Grignard reagent from (41) has been widely used in synthesis. We recognise a bromide and an acetal disconnecting the acetal reveals a j3-bromo aldehyde available by Michael addition of Br" to acrolein (42)... 

Place 5 mi. of ethyl acetate in a 100 ml. round-bottomed flask, and add about 50 ml. of 10% sodium hydroxide solution, together with some fragments of ungiazed porcelain. Fit the flask with a reflux water-condenser, and boil the mixture gently over a wire gauze for 30 minutes. Now disconnect the condenser, and fit it by means of a bent delivery-tube (or knee-tube ) to the flask for direct distillation (Fig. 59, or Fig. 23(0), p. 45). Reheat the liquid, and collect the first 10 ml. of distillate, which will consist of a dilute aqueous solution of ethanol. Confirm the presence of ethanol by the iodoform test Test 3, p. 336). 

Since (A) does not contain any other functional group in addition to the formyl group, one may predict that suitable reaction conditions could be found for all conversions into (A). Many other alternative target molecules can, of course, be formulated. The reduction of (H), for example, may require introduction of a protecting group, e.g. acetal formation. The industrial synthesis of (A) is based upon the oxidation of (E) since 3-methylbutanol (isoamyl alcohol) is a cheap distillation product from alcoholic fermentation ( fusel oils ). The second step of our simple antithetic analysis — systematic disconnection — will now be exemplified with all target molecules of the scheme above. For the sake of brevity we shall omit the syn-thons and indicate only the reagents and reaction conditions. 

Diethyl 3-oxoheptanedioate, for example, is clearly derived from giutaryl and acetic acid synthons (e.g. acetoacetic ester M. Guha, 1973 disconnection 1). Disconnection 2 leads to acrylic and acetoacetic esters as reagents. The dianion of acetoacetic ester could, in prin-ciple,be used as described for acetylacetone (p. 9f.), but the reaction with acrylic ester would inevitably yield by-products from aldol-type side-reactions. 

Bonds between carbon and various heteroatoms (e.g. O, N, S, P) which are easily generated synthetically are strategic for disconnection. Specific bonds in this category are ester, amide, imine, thioether, and acetal. 

Recognising an acetal Is a problem for many chemists in raining. Molecule (1) Is obviously an acetal, and the first disconnection is easy to write... 

Recognising the acetal in frontalin (3), a pheromone of the western pine beetle," is not so easy. Nevertheless, it is Important to look for the two oxygen atoms joined to the same carbon atom ( in 3a) and disconnect the acetal before considering any other steps. 

Recognise the acetal in the following TMs and carry out the first disconnection. 

Answer There are two acetals here Either could be disconnected first, though not both, since problems of chemoselectivity would arise, Since we have already made piperonal (9) (page T 9) we shall use that as an intermediate. 

Answer Friedel-Crafts disconnection reveals 1,2-diX compound (21) easily made from thiol (22) and chloro-acetic acid. Thiol (22) can be made by the thiourea route (p T 37 ). 

The last one requires a 1,1-dlX disconnection of the acetal before the 1,3-dlX disconnection can be raade. 

Frontalin (18), the pheromone of the western pine beetle, is an acetal (atom has two single bonds to oxygen). Disconnection reveals diol ketone (19). 

Example Diol (20) was used on page 45 to make an acetal. It Is a 1,3-dlol so could be derived from 6-hydroxy aldehyde (21) and a simple disconnection follows Analysis... 

Answer Disconnecting the acetal reveals a 1,3-di hydroxy compound (24) which can be made by the reaction we have Just met from CH O and aldehyde (2h), an obvious Die s-Alder product. 

The compound is an acetal and disconnection of this reveals pinacol (30), made from available acrolein. 

Disconnection of the acetals leads nowhere but a,P disconnection (21a) gives symmetrical (22). This is a 1,6-dicarbonyl compound and can be reconnected to (23). Removal of the acetals now reveals a Diels-Alder adduct (24). 

The first disconnection must be of the acetal to reveal two identical 1,5-relationships (23). Disconnection of these would require a change of oxidation level to, say (24), and the addition of activating groups (25). 

Acetylcyclohexanone. Method A. Place a mixture of 24-6 g. of cyclohexanone (regenerated from the bisulphite compound) and 61 g. (47 5 ml.) of A.R. acetic anhydride in a 500 ml. three-necked flask, fitted with an efficient sealed stirrer, a gas inlet tube reaching to within 1-2 cm. of the surface of the liquid combined with a thermometer immersed in the liquid (compare Fig. II, 7, 12, 6), and (in the third neck) a gas outlet tube leading to an alkali or water trap (Fig. II, 8, 1). Immerse the flask in a bath of Dry Ice - acetone, stir the mixture vigorously and pass commercial boron trifluoride (via an empty wash bottle and then through 95 per cent, sulphuric acid) as fast as possible (10-20 minutes) until the mixture, kept at 0-10°, is saturated (copious evolution of white fumes when the outlet tube is disconnected from the trap). Replace the Dry Ice-acetone bath by an ice bath and pass the gas in at a slower rate to ensure maximum absorption. Stir for 3 6 hours whilst allowing the ice bath to attain room temperature slowly. Pour the reaction mixture into a solution of 136 g. of hydrated sodium acetate in 250 ml. of water, reflux for 60 minutes (or until the boron fluoride complexes are hydrolysed), cool in ice and extract with three 50 ml. portions of petroleum ether, b.p. 40-60° (1), wash the combined extracts free of acid with sodium bicarbonate solution, dry over anhydrous calcium sulphate, remove the solvent by... 

As shown in Scheme 4.16, the retrosynthetic process proceeds as follows i) FGI (substitution of the unconjugated aldehyde by an acetal group and the conjugated double bond by an OH group) ii) retro-aldol disconnection of the 1,3-C system iii) "reconnection" of the resulting 1,6-D system to a 6-membered ring iv) FGI (substitution of the double bond by an OH group and the acetal by a carbonyl... 

In one case report a 37-year-old male maintenance fitter was accidentally exposed to a large cloud of hot acetic acid while disconnecting a pressurized pump. The patient suffered first-degree burns on the hands and face and developed progressive dyspnea. At 3 months there were persistent extensive crackles in the basal area of the lungs, widespread bronchial inflammatory changes, and diffuse moderate interstitial pneumonitis that promptly improved after treatment with corticosteroids and bronchodilators. 

Dauben s group utilized the same retrosynthetic disconnections, but chose to add more functionality to the cycloaddition precursor. From a simple frawi-disubstituted cyclopentane, Dauben used an aldol reaction of a cyclopropylvinyl aldehyde to prepare the cycloaddition precursor. The diazo-substituted (3-ketoester was completed using a Roskamp-Padwa coupling followed by diazo-transfer. Addition of rhodium acetate to the diazo substituted p-ketoester 179 led to an excellent 86% yield of the correct diastereomer (Scheme 4.42). 

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