Synthesis, formal total

Boger developed his pyridine synthesis out of a need to eonstruet a pentasubstituted pyridine in an approach to the formal total synthesis of antitumor antibiotic streptonigrin 44. The requisite triazine 48 was produeed by using this methodology in an iterative sense with two different aza-heteroeyeles. Reaetion of thioamidate 46 with tetrazine 47, in a eyeloaddition/eyeloreversion sequenee, afforded 1,2,4-triaziene 48. Exposure of enamine 49 to 48 resulted in the formation of 50. This compound was elaborated into a eompound that intereepted Kende s synthesis of 44. ... 

The iodocyclization of 1,4-dihydropyridines was used as the key step for the formal total synthesis of Sempervirine (327) as shown in Scheme 102 (99JOC2997). 

A formal total synthesis of the prostaglandin involved unmasking of an isoxazoline ring by hydrogenation over W-2 Raney Ni/BCl3/MeOH, H2O to reveal a -hydroxyketone. It was necessary in this case to deactivate the Raney... 

In March 1976, M.A. Wuonola and R.B. Woodward accomplished the conversion of cobyric acid (4) to vitamin B12 (1). The total synthesis of vitamin B12 can thus be claimed, see reference Id, footnote 11, p. 1420. The formal total synthesis of 1 had been accomplished in 1973. 

Also, a novel RCM-based approach to the 6-aza[3.2.1]bicyclooct-3-ene 103, and hence a formal total synthesis of the antitumor antibiotic (-)-peduncular-ine (104) (Scheme 20), was recently disclosed by Martin s group [70]. Initial ex-... 

Scheme 20 RCM-based construction of key intermediate 103 in a formal total synthesis of the antitumor antibiotic peduncularine (104) [70]...

Regioselective Beckmann rearrangements were used as key steps in the synthesis of phosphonoalkyl azepinones (Scheme 36) [43b] and in a formal total synthesis of the protein kinase C inhibitor balanol (Scheme 37) the optically active azide 197 derived from cyclohexadiene mono-oxide was converted into ketone 198 in several steps. After preparation of the oxime tosylates 199 (2.3 1 mixture), a Lewis acid mediated regioselective Beckmann rearrangement gave the lactams 200 and 201 in 66% and 9% yield, respectively. Lactam 201 underwent a 3-e im-ination to give additional 200, which served as a key intermediate in a balanol precursor synthesis (Scheme 37) [43 cj. 

Trost, B.M. Zhang, Y. (2006) Molybdenum-Catalyzed Asymmetric AUylation of 3-Alkyloxindoles Application to the Formal Total Synthesis of (—)-Physostigmine. Journal of the American Chemical Society, 128,4590M591. 

The consistent observation of the arylated products with 92% ee confirms that the enantioselectivity of the asymmetric deprotonation was preserved during the transmetalation with ZnCl2 and retained during the Pd-catalyzed coupling. In fact, the Negishi coupling with 3-bromopyridine (entry 16) was performed at 60 °C, and still provided 26m in 92% ee, which constitutes a formal total synthesis of (R)-nicotine [27]. 

Krapcho and Vivelo have described a new formal total synthesis of tropinone (124) and ( )-cocaine (98) (94). Cycloaddition of IV-methylpyrrole (182) and acetylenedicarboxylic acid leads to 183, which is hydrogenated to 184. The diacid mixture 184 is refluxed in MeOH/HCl to yield the diester mixture 185. Addition of this to an excess of metallic sodium in liquid ammonia at — 78°C leads to the N-methylpyrrolidine derivative 186 (cf. 95), whose diethyl analog 147 has earlier been converted to tropinone (124) and (+)-cocaine (98) (78-80) (Scheme 13). 

Reaction of 2-129 with NaCN followed by treatment with NaH and TIPSC1 led to the anthracene 2-130 in 68% yield (Scheme 2.30). The desired lactam 2-131 was then obtained by reduction of the cyano group and ring closure using CoCl2/ NaBH4. Quite recently, this procedure has also been used for a formal total synthesis of tetracenomycin [63]. 

Ogasawara and coworkers have also published a complete series of threefold anionic domino reactions, all of which are based on an initial retro-aldol process. For instance, starting from chiral bicyclo[3.2.1]octenone 2-437, a formal total synthesis of (-)-morphine (2-445) [233] has been successfully performed (Scheme 2.103) [234]. Transformation of 2-437 into the substrate 2-488, necessary for the domino reaction, was achieved in seven linear steps. The domino process was then initiated by simply refluxing a solution of 2-438 in benzene in the presence of ethy-... 

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]. 

Nicolaou and coworkers used this approach also for the synthesis of hamigerans A and B [30], as well as of several of their epimers [29, 31]. The group of Kraus succeeded in a formal total synthesis of the anticancer agent podophyllotoxin 5-103 from 5-100 [32] (Scheme 5.19) [33]. The method allows a rapid access to the central core 5-102 via 5-101. 

Liu, J.J., Hsu, C.C. and Wong, C.-H. (2004) Sequential aldol condensation catalyzed by DERA mutant Ser238Asp and a formal total synthesis of atorvastatin. Tetrahedron Letters, 45, 2439-2441. 

The reactivity of ethyl cyclopropylideneacetate (52b) has been exploited by Spitzner and Sawitzki in a new (formal) total synthesis of the diterpene ( + )-isoeremolactone 80 (Scheme 16) [25]. The key step of the synthesis is the addition of the enantiomerically pure dienolate 78 to the reactive acrylate 52b, to give a single isomer 79 in 92% yield. 

The Pictet-Spengler reaction has also seen much use in the synthesis of lavendamycin methyl ester. Both Hibino [31] and Behforouz [32] used it as a key step in their syntheses of this molecule (Fig. 10). In Hibino s synthesis, /i-methyltryptophan ethyl ester 27 was condensed with quinoline aldehyde 28 to give the corresponding lelrahydro- -carbohnc, which was aromatized by heating with palladium on carbon in xylenes, giving /1-carboline 29 in 75% yield. A five-step sequence (which included conversion to the methyl ester for easier comparison with known compounds) yielded bromoquinone 24 in 27% yield for the five steps. This completed Hibino s formal total synthesis of lavendamycin methyl ester, since this was the same intermediate used in Kende s synthesis. 

This asymmetric isomerization was successfully applied to the formal total synthesis of 7-hydroxycalamenene and 7-hydroxycalamenal, two naturally occurring sesquiterpenes in the cadinene family (Scheme 30).52... 

These studies paved the way for numerous synthetic applications, in particular total syntheses. Thus, the low-tech PtCl2, PtCl4, or PtBr4 systems, as named by Fiirstner, proved superior and more reliable compared to Trost s TCPCtfe system288 for the reactions of the cyclooctene substrate as shown in Scheme 81.300 These reactions, which could be run in a multi-gram scale, proved useful, for instance, for the formal total synthesis of streptorubine B. Similarly, a formal total synthesis of roseophilin was devised, based on a nearly quantitative transformation of an enyne moiety into a bicyclic diene system (Scheme 81).301... 

A key reaction in the formal total synthesis of (-)-mycalamide A involved the intermolecular ruthenium-catalyzed Alder-ene reaction between 157 and 158 to give the dienoate 159 (Scheme 35).94 This regioselective reaction provided a 63% yield of 159, which was subsequently transformed to a key building block 160 which was taken on to (-)-mycalamide A. 

Zhang68 has applied the cyclization of esters to the formation of a-methylene-y-butyrolactones, thus offering a novel and enantioselective entry to these substructures. The importance of this unsaturated lactone is evidenced by its ubiquitous presence in nearly a third of all naturally occurring secondary metabolites. The Alder-ene reaction has been applied to a formal total synthesis of (+)-pilocarpine, a leading therapeutic reagent for the treatment of narrow and wide glaucoma. Zhang intersected Btichi s synthetic intermediate (i )-181 (Scheme 47) in only two steps with a 99% ee and a 91% overall yield. In comparison, Biichi synthesized (i )-181 in five steps with a 92% ee and a 20% overall yield. 

The key step in the formal total synthesis of ( )-brefeldin A utilized the acid catalyzed ring opening of (289) to (290) 99>. 

Lactam 299 has later been synthesized by another route from ethyl trans-5-ethyl-2-oxo-4-piperidineacetate and 3-chloroacetylindole, which represents a new formal total synthesis of ( )-dihydrocorynantheine and related alkaloids (104). 

Another formal total synthesis of ( )-yohimbine has been worked out by Wenkert et al. (229) by preparing O-methylhexadehydroyohimbine (420), which was first prepared by Kametani and co-workers (224-226) as a key intermediate toward ( )-yohimbine. In Wenkert s approach, pyridinium salt 427 was y-alkylated with acetoacetic ester anion. The product 428 then underwent intramolecular condensation, affording tetracyclic quinone 429. Methylation of 429... 

Ninomiya and co-workers have also published a formal total synthesis of ( )-yohimbine (230). Photocyclization of unstable enamide 431, obtained from har-... 

In Baldwin s formal total synthesis of haliclamines A and B, a Suzuki coupling of 3-bromopyridine was the central operation [52], Chemoselective hydroboration of diene 66 employing 9-BBN occurred at the less hindered terminal olefin. Suzuki coupling of the resulting alkylborane with 3-bromopyridine then furnished alkylpyridine 67 as a common intermediate for the synthesis of haliclamines A and B. 

G. Macdonald, L. Alcaraz, N. J. Lewis, R. J. K. Taylor, Asymmetric Synthesis of the mC7N Core of the Manu-mycin Family Preparation of (+)-MT 35214 and a Formal Total Synthesis of (-)-Alsamyciri , Tetrahedron Lett. 1998, 39, 5433-5436 and references therein. 

After two years working as a postdoctoral fellow under Dr. H.-P. Husson (Institut de Chimie de Substance Naturelles, CNRS, Gif-sur-Yvette, France) (CNRS methods in asymmetric synthesis) (1984-85), he worked as an associate researcher under Professor Wolfgang Oppolzer (Departement de Chimie Organique, Geneve, Suisse) (aldol reaction) (1986) and was a visiting professor at the Department of Chemistry, Duke University, NC, working with Professor Fraser-Reid (free radical chemistry annulated furanoses formal total synthesis of phyllathocin). 

In Bettolo and co-workers approach to (+)-methyl trachyloban-18-oate (16), enone 13 was subjected to a photocycloaddition with 1,2-propadiene (1) to afford the [2 + 2]-cycloadduct 14 as a single product in 67% yield (Scheme 19.3) [5]. The addition proceeded exclusively from the /3-face. The resulting exocyclic olefin was eventually converted to a ketone using osmium tetroxide and NaI04 and taken on to 15, constituting a formal total synthesis of 16. 

Scheme 19.3 A formal total synthesis of (+)-methyl trachyloban-18-oate.

In another approach to periplanone B by Cauwberghs and De Clercq, an intramolecular Diels-Alder reaction of furan-allene 122 afforded a mixture of two exo adducts 123 and 124 and an endo adduct (not pictured) in 90% yield and a 5 4 1 ratio (Scheme 19.23) [28], Refluxing the mixture in mesitylene (N2, 164 °C) afforded a 2 1 equilibrium mixture of 123-124 through a cydoreversion process. The Diels-Alder adduct 123 was converted to 125 via a series of synthetic manipulations, which constituted a formal total synthesis of periplanone B (126). 

This tandem intramolecular silylformylation/Sakurai reaction has successfully been applied in a formal total synthesis of mycoticin A [75]. The scope and utility of these reactions was expanded to (Z)- and (E)-crotyl groups leading to the stereospecific incorporation of both anti and syn propionate units into the growing polyol chain (Scheme 21) [76]. 

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