Retrosynthetic disconnection

The pentacyclic plant alkaloid camptothecin has been a popular synthetic target because of its antitumor activity. Retrosynthetic disconnection to tricyclic intermediate A and chiral lactone B followed from multistrategic planning. 

Otsuka K-76, a fungal product with strong anticomplement activity, was synthesized from the A/B bicyclic precursor of stemodin. The aromatic subunit was retrosynthetically disconnected to a symmetrical precursor. A surprising non-selectivity of olefinic hydroxylation by osmium tetroxide was noted. 

An application of this variation was put forward in the total synthesis of oc-talactin (Scheme 14). In retrosynthetic disconnection the macrolactone sim-... 

Both target compounds discussed in this review, kelsoene (1) and preussin (2), provide a fascinating playground for synthetic organic chemists. The construction of the cyclobutane in kelsoene limits the number of methods and invites the application of photochemical reactions as key steps. Indeed, three out of five completed syntheses are based on an intermolecular enone [2+2]-photocycloaddition and one—our own—is based on an intramolecular Cu-catalyzed [2+2]-photocycloaddition. A unique approach is based on a homo-Favorskii rearrangement as the key step. Contrary to that, the pyrrolidine core of preussin offers a plentitude of synthetic alternatives which is reflected by the large number of syntheses completed to date. The photochemical pathway to preussin has remained unique as it is the only route which does not retrosynthetically disconnect the five-membered heterocycle. The photochemical key step is employed for a stereo- and regioselective carbo-hydroxylation of a dihydropyrrole precursor. 

Synthetic transformations which are parts of total syntheses of natural products are outlined by a general retrosynthetic outline. For each retrosynthetic disconnection, suggest a reagent or short sequence of reactions which could accomplish the forward synthetic reaction. The proposed route should be diastereoselective but need not be enantioselective. 

Pitavastatin (3) was launched in 2003 and is currently marketed in Japan under the trade name Livalo . Like rosuvastatin and fluvastatin, pitavastatin is a completely synthetic HMG-CoA reductase inhibitor that was developed by Kowa, Nissan Chemical, and Sankyo (Sorbera et al., 1998). Multiple syntheses of pitavastatin have been reported and an exhaustive review of these efforts is beyond the scope of this text (Hiyama et al., 1995a, b Minami and Hiyama, 1992 Miyachi et al., 1993 Takahashi et al., 1993, 1995 Takano et al., 1993). Instead, we will focus our discussion on two related and innovative synthetic approaches that differ strategically from the routes we have previously examined for rosuvastatin and fluvastatin. These routes to pitavastatin employed palladium-mediated coupling reactions to install the 3,5-dihydroxyheptanoic acid side-chain. This key retrosynthetic disconnection is highlighted in Scheme 12.6, in which a suitable functionalized side-chain (52 or 53) is attached to the heterocyclic core of pitavastatin (51) through palladium-mediated coupling. 

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). 

Lycorine is an alkaloid that has attracted attention from both the synthetic community and pharmacologists. Prior synthetic approaches have included inter-and intramolecular Diels-Alder cycloaddition. Based on a similar retrosynthetic disconnection, Padwa and co-workers (106,109) chose to use a push-pull carbonyl ylide cycloaddition with a disubstituted pyrrolidinone core to generate a tricyclic substrate. The major difference for this synthetic smdy was the availability of a labile proton a to the carbonyl moiety (Scheme 4.53). 

Although a retrosynthetic disconnection of an a-branched aldehyde to give an alkyl group and a mesomerically stabilised a-carbanion suggests a synthesis based on this strategy, in practice it is not feasible. This is because the a-... 

A retrosynthetic disconnection of a simple 0-hydroxy ester gives the carbocation (8) and the carbanion (9). 

A retrosynthetic disconnection of the ester of a higher homologue [e.g. (14)] leads to the carbanion and the carbocation synthons (15) and (16) respectively. 

Retrosynthetic disconnection of a / -keto ester of the type R-COCH2-C02Et,... 

The retrosynthetic disconnection for the y-keto acid shown below generates an acyl anion synthon and a three-carbon carbocation. 

Three target molecules, namely, cyclopropyl methyl ketone (1), cyclobutane-carboxylic acid (2) and 3-benzylcyclobutanone (3), are used to illustrate appropriate retrosynthetic disconnection strategies that may be applied to devise suitable synthetic procedures for these compounds. 

A retrosynthetic disconnection for cyclobutanecarboxylic acid (2) gives rise to a synthon having the charge distribution shown in (7). 

Suitable retrosynthetic disconnections of 3-methylcyclopentane-l,2,4-trione may not be immediately obvious owing to the presence of the three carbonyl groups. However, disconnection in the manner shown gives the reagent equivalents diethyl oxalate and butan-2-one. 

A retrosynthetic disconnection in the case of each of these molecules gives a methylene group synthon, and benzylideneaniline and benzaldehyde from (7) and (8) respectively. 

By retrosynthetically disconnecting the butyl group from the carbon that bears the hydroxyl substituent, we see that the appropriate starting ketone is 2-butanone. 

Retrosynthetic disconnection of the nitrogen-carbon bond in thiazole 3.26 leads formally to enol 3.27 which is equivalent to ketone 3.28. This can be derived from haloketone 3.29 and thioamide 3.30. 

Retrosynthetic disconnection of generalised 1,2-azole 4.7 gives initially 4.8 which would exist as ketone 4.9. This in turn is clearly derived from 1,3-diketone 4.10. 

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

---