Manzamines preparation

Marko, l.E. and Chesney, A. (1992) Towards the total synthesis of manzamines preparation and reactions of 2-methoxycarbonyl-l,3-butadienes and P-amino aldehydes, Synlett, 275-278. 

The central five-membered ring of Manzamine A (315), a member of a family of antileukimic and antibacterial marine polycyclic alkaloids, has been constructed using intramolecular azomethine ylide technology (88). Model studies on the construction of the central ABC rings, by condensation of the aldehyde 316 prepared by standard chemistry with sarcosine ethyl ester, furnished the desired ABC ring system as a single diastereoisomer in 45% yield (Scheme 3.105). 

Microbial bioconversion studies of manzamine A and ent-8-hydroxymanzamine A have shown that they can be metabolized by several microbial species.76 Preparative-scale fermentation of manzamine A with Fusarium oxysporium f. gladioli ATCC 11137 resulted in the isolation of the known ircinal A (61) as a major metabolite. Preparative-scale fermentation of enf-8-hydroxymanzamine A with Nocardia sp. ATCC 11925 and Fusarium oxysporium ATCC 7601 resulted in the isolation of the new major metabolite 12,34-oxamanzamine F (62). The latter metabolite showed no cytotoxicity against different cell lines (>10 pg/ml). 

Ethoxycarbonyl-l,3-dithiane (183), easily accessible from ethyl glyoxylate diethyl acetal, can be lithiated-alkylated to afford, after deprotection, a-ketoesters as exemplifies the product 184 (Scheme 53)237. This methodology has been used in the preparation of 3-deoxy-D-manno-2-octulosonic acid (KDO) derivatives238 and of the ABC ring system of manzamine A239. 

There are several reviews referring to manzamine alkaloids [7,31-35]. In this chapter, we will review the structure and source of manzamine alkaloids including the large-scale preparation of manzamine alkaloids for preclinical evaluation. We also discuss the detailed synthesis and bioactivities of manzamine alkaloids. 

Source and Large-scale Preparation of Manzamine Alkaloids... 

In 1998, Langlois et al. completed the third synthesis of manzamine C using a strategy based on Sila-Cope elimination (Scheme 8.9) [80]. In this approach, the key intermediate, piperidine derivative 146, was prepared in six steps from 2-methylpyr-idine 143. Oxidation of 146 afforded a mixture of diastereomeric N-oxides 147 and 148. Sila-Cope elimination of N-oxide 147 led to compound 149, while Cope elimination of N-oxide 148 led to compound 150. Oxidative cleavage of the N-O bond in 149 followed by treatment with N-chlorosucdnimide provided the chlor-oamine 153. Elimination, hydrolysis, ditosylation, and finally basic treatment of the ditosylate intermediate afforded the cyclic sulfonamide 124, which is the direct synthetic precursor of manzamine C [73]. 

The fourth approach to the synthesis of manzamine C involved a Ramberg-Backlund rearrangement in the key step for the preparation of the azacycloundecene ring [81[. Synthesis ofthis ring began with thecondensationof5-amino-l-pentanol 156... 

Using a Zincke-Bradsher convergent strategy for the synthesis of the ABE tricyclic core of Manzamine A, Magnier and Langlois reported the use of aqueous conditions to achieve, in one pot, the preparation of a naphthylpyridi-nium salt intermediate which underwent an inverse electron demand heterocyclic Diels-Alder cycloaddition with either ethyl vinyl ether or (Z)-l-ethoxy-... 

Most synthetic effort directed toward the manzamines has focused on the complex isoquinoline core (164), and none has succeeded in completing the preparation of one of the isoquinoline-bearing manzamines. 

In the preparation of (3-carbolines such as 165, aromatization of ring C has proved much more difficult from the PS tetrahydro-p-carboline intermediate than the BN dihydro-P-carboline intermediate (129, 123). Coupling 165 with macrocycle 166 yielded an amide which was reduced to the tertiary amine, manzamine C. 

A radical cyclization has been used by Hart, at The Ohio State University, to prepare the manzamine tricyclic core (139). Utilizing tri-w-butyltin hydride to mediate the cyclization of selenide 171, the desired stereochemistry of the octahydroisoquinoline ring (172) was established (Scheme 13) electrophilic catalysis generated the tricyclic intermediate 174. An anionic cyclization leading to a tricyclic intermediate is being developed by Marko, at the University of Sheffield, toward which he has recently reported a model study (140). 

Ring D (see Scheme 15) has been successfully appended to the tricyclic core by an olefin metathesis reaction (147). Treatment of 177, prepared largely by the method described in Scheme 11, with the ruthenium complex 178 (Cy3P = tricyclohexylphosphine) resulted in the ABCD ring system of the manzamines. 

Two other methods toward the manzamines have been reported recently. A preliminary report by Baldwin s group at Oxford of a biomimetic approach described the preparation of a key tricycle, which bears a resemblance to likely natural product precursors to the manzamines (153). A multistep synthesis from Overman s group at the University of California at Irvine, featuring an intermolecular Mannich reaction, starts from D-(-)quinic acid, thus setting the absolute stereochemistry (154). 

An intramolecular vinylogous amide photocycloaddition, retro-Mannich fragmentation and final Mannich cyclization cascade provided a useful method for the synthesis of the complex ABCE ring system [91], The preparation of the requisite photosubstrate is outlined in Scheme 28. After cluomatographic separation, the cis alcohol was irradiated and led to the formation of aminals in a 2 1 ratio. Equilibration studies of the Swem oxidation products revealed that exposure of the minor diketone to sodium methoxide in methanol effected conversion to the manzamine-unlike... 

A Diels-Alder Approach to Functionalized c/s-Hydroisoquinolines. Attemtpts to Prepare a Tricyclic Core of Manzamine A. Imbroisi, D. de O. and Simpkins, N. 

Mukai and co-workers used a reduction/cyclization cascade to prepare (-)-nakadomarin, a manzamine-related alkaloid with cytotoxic activity, inhibitor activity against cyclin-dependent kinase 4 (CDK-4), and anti-fungal and antibacterial activity. Treatment of the tetracyclic precursor with DIBAL-H followed by reaction with HCl led to the desired pentacyclic system in 41% yield. 

The first total synthesis of manzamine A was reported by Winkler and Axten in 1998 [18,19]. In their synthesis, a unique [2 + 2] photocycloaddition followed by retro Mannich/Mannich rearrangement furnished a 6/6/S/8 ring system in a highly stereospecific manner. The 13-membered ring was prepared by standard cyclization. 

Nishida and Nakagawa [80-82], Langlois [83,84], Simpkins [85] and Mara-zano [86,87] have used the intermolecular Diels-Alder reaction to synthesize the central core of manzamine A (Scheme 12). We have also demonstrated that an efficient Diels-Alder reaction using Danishefsky-type siloxydiene (125) followed by acid treatment resulted in a Michael reaction to give the chiral ABC ring intermediate (122) of manzamine A (Scheme 12). This intermediate was converted to 36-oxo-ircinal A (119) using sequential RCM to prepare the D- and E-rings. 

---