Total Synthesis of -FR

As expected, some sequences also occur where a domino anionic/pericyclic process is followed by another bond-forming reaction. An example of this is an anionic/per-icyclic/anionic sequence such as the domino iminium ion formation/aza-Cope/ imino aldol (Mannich) process, which has often been used in organic synthesis, especially to construct the pyrrolidine framework. The group of Brummond [450] has recently used this approach to synthesize the core structure 2-885 of the immunosuppressant FR 901483 (2-886) [451] (Scheme 2.197). The process is most likely initiated by the acid-catalyzed formation of the iminium ion 2-882. There follows an aza-Cope rearrangement to produce 2-883, which cyclizes under formation of the aldehyde 2-884. As this compound is rather unstable, it was transformed into the stable acetal 2-885. The proposed intermediate 2-880 is quite unusual as it does not obey Bredf s rule. Recently, this approach was used successfully for a formal total synthesis of FR 901483 2-886 [452]. 

Scheme 11. The Ti-catalyzed asymmetric aldol renders both aldol adduct antipodes readily accessible, allowing Simon to complete the total synthesis of FR-901,228 (1996).

In the total synthesis of FR-900848 (1) published by Falck et al. a cyclopropane coupling strategy was successfully applied for the preparation of the tetracyclopropane backbone (Scheme 12) [38]. 

Danishefsky and co-workers exploited a 6-exo intramolecular vinylic Heck substitution reaction en route to a total synthesis of ( )-FR-900482 (76) (Scheme 6-12) [26]. The efficient conversion of aryl iodide 70 to tetracycle 71 is illustrative of the impressive functional-group tolerance displayed by the Heck reaction. During the development of this synthesis, attempts were made to introduce the oxygenation present at C —13 at an earlier stage [27]. Enol ethers 72 and 74 were prepared and subjected to Heck conditions. 

Ciufolini et al. (61) reported a facile assembly of the benzazocenone 307 as a part of the total synthesis of the antitumor alkaloids mitomycin C (309) and FR 900482 (310) based on intramolecular 1,3-dipolar cycloadditions of aryl azides with electron-rich alkenes (Scheme 9.61). Azide 305 was heated in refluxing toluene with a catalytic amount of K2CO3 to give the triazoline 306 in 55% yield. Irradiation of a solution of the triazoline 306 in wet THF with a sun lamp gave an 84% yield of the required benzazocene 308, which was converted to the target molecules 309 and 310. 

Cetusic JRP, Green IB FR, Graupner PR, Oliver MP (2002) Total Synthesis of Hecto-chlorin. Org Lett 4 1307... 

Perhydropyrido[l,2-fr][l,2]oxazine 10 was applied in the total synthesis of (-)-monomorine I, an indolizidine alkaloid, to control the stereoselectivity (09S655). 

With regard to the synthesis of the oligo-cyclo-propane natural product FR-900848 (1) multiple and consecutive cyclopropanation reactions using zinc carbenoids have been applied. Thus, in the total synthesis of 1 by Barrett et al. the Furu-kawa-procedure was used for the conversion of 52 into the biscyclopropane 53 (Scheme 11). [37] After bidirectional elongation of the molecule, another double cyclopropanation of diene 54 using Charette s catalyst gave tetracyclopro-pane 55 in 93 % yield as one stereoisomer only. Finally, the olefin 56 is cyclopropanated at -40 °C to yield the desired pentacyclopropane alcohol 57. Thus, all five cyclopropane rings of... 

The total synthesis of U-106305 (46) by Barret et al. [97] follows the same strategy as that of FR-900848 (45). In the synthesis of Charette and Lebel [98] the pentacyclopropane core (47) is prepared starting from the cyclopropane derived from trans-1,4-but-2-enediol by a tandem oxidation-Wittig olefination-reduction-cyclopropanation method. The Julia olefination of the corresponding monoaldehyde with benzothiazoylsulfone... 

The full structure and absolute configuration of FR 900848 104 has been determined to be (6R,8S,9R,11S,12S,14R,15S,17R) from X-ray crystallographic study [133]. Strategies for its enantioselective total synthesis are based on an iterative cyclopropanation [134], and on the use of chiral auxiliaries [135]. It has also been prepared by fermentation and isolated from cultures of Streptoverticillium fervens to be considered as an agrochemical microbicide [136]. 

The catalytic process has found successful application in several natural product total syntheses. In 1996, Simon reported a synthesis of the antitumor dep-sipeptide FR-9001,228 in which the aldol addition reaction of 168 and the ethyl acetate-derived enol silane furnished a key synthetic intermediate (Eq. 23). The enantioselective aldol addition reaction of 168 was conducted with 165 and its enantiomer ent-165 to separately provide both enantiomers of the aldol adducts 169 and 170 (Scheme 14). These were then utilized in the preparation of diastereomeric seco acids 171 and 172 [101]. Macrocyhzation of 172 through a Mitsonobu reaction yielded the desired natural product 173. 

The full structure and absolute stereochemistry of FR-900848 (45) has been recently described [90-92] together with the total synthesis [93,94] by Barret et al. and also by Falck et al [95], The first synthesis by Barret etal [93,94] started from mucondiol, which was cyclopropanated [96] in... 

Another patent by Fujisawa disclosed [31] the structure of FR-901375 from an extract of Pseudomonas chloroaphis No. 2522. While it is a likely H DAC inhibitor, no data have been reported in this regard and the decision seems to have been made to promote FK228 instead as the clinical candidate. In 2001, additional depsipeptide natural products, the spiruchostatins, were reported [32] by Shin-ya s group at the University of Tokyo and Yamanouchi Pharmaceuticals. These compounds were isolated from an extract of Pseudomonas sp. Q71576, on the basis of the ability to increase expression of luciferase driven by the plasminogen activator inhibitor (PAI-1) promoter. Given the structural similarity to FK228, the spiruchostatins were likely to be HDAC inhibitors and this was confirmed in a later patent [33] and in our biochemical studies (see below) with the natural product prepared by total synthesis. 

Papin, J., et al., The Scarabee Total Blockage Series Synthesis of the Interpretation, Nureth-4, 1, Karlsruhe, Germany, 0-13 October, 1989, FRS. 

Figure 9.12 Menthol-containing PCL nanoparticles dependence of size on total initial concentration in the acetone feed, at constant MR = 6 (menthol concentration ranges from 10 to 60 mg/mL). Quenched and non-quenched samples are shown, but it must be noted that without quenching particles generally have a non-monomodal distribution. FR = 100 mL/min (v. = 2.12 m/s), measured after synthesis and eventual quench in CIJM-dl.

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