Lepadiformine, synthesis

Reports on total synthesis of naniral products using nitrones papers are as follows marine alkaloid lepadiformine fRef 92 and fi-lactam antibiotics fRef 93, ... 

Perhydropyrido[l,2-A][l,2]oxazines have been utilized as key intermediates in a stereospecific total syntheses of (—)-pumiliotoxin C and 5-< />z-pumiliotoxin C <1996J(P1)1113>, and the marine alkaloids (—)-lepadins A, B, and C and macrocyclic dilactones, (+)-azimine and (+)carpaine <20000L2955, 2001JOC3338, 2003OL3839>. In the total synthesis of the marine alkaloids ( )-fasicularin and ( )-lepadiformine, perhydro[l,2]oxazino[3,2 /]quinolines were used to control the stereochemistry <2000JA4583, 2000TL1205>. 

Short Syntheses of (+)-Cylindricine and Formal Synthesis of (-)-Lepadiformine... 

The BINAL-H enantioselective reduction of o.,(j-conjugatcd ketones was used in the total synthesis of (—)-lepadiformine (20), which exhibits moderate cytotoxic activities against various tumor cell lines8 (Scheme 4.3g). A solution of 21 in toluene... 

The analogous intramolecular 1,3-dipolar cycloaddition of the cyclic nitrone 155, in an attempt to get to intermediates useful for the synthesis of the cylindricine or lepadiformine natural products, unexpectedly gave by lb/3a bonding the bridged cycloadduct oxazocine 117 in 49% yield with total diastereocontrol. From this reaction, the fused cycloadduct through la/3b bonding (41%) was also isolated (Equation 8) <2000TA2625>. 

S.M. Weinreb and co-workers were surprised to find that the convergent stereoselective synthesis of marine alkaloid lepadiformine resulted in a product that gave a totally different NMR spectra than the natural product. This finding led to the revision of the proposed structure of lepadiformine. In the final stages of the synthesis, they exposed a tricyclic piperidone intermediate to Ciemmensen conditions to remove the ketone functionality. Under these conditions the otherwise minor elimination product (alkene) was formed predominantly however, it was possible to hydrogenate the double bond to give the desired alkane. 

During the total synthesis of the marine alkaloid (+)-lepadiformine by S.M. Weinreb et al., one of the key bicyclic N-acyliminium salt intermediates was subjected to a nucleophilic attack by an organocuprate. ° The resulting allyidimethylsilyl derivative was then treated under the Fieming-Tamao oxidation conditions to afford the corresponding hydroxymethyl compound in excellent yield. 

The stereoselective total synthesis of ( )-lepadiformine was accomplished in the laboratory of S.M. Weinreb. The introduction of the hexyl chain in a stereoselective fashion was achieved by a Grignard reaction to an iminium salt during the last steps of the synthetic sequence. The iminium salt was generated in situ from an a-amino nitrile with boron trifluoride etherate, and the addition of hexylmagnesium bromide gave a 3 1 mixture of alkylated products favoring the desired stereoisomer. Removal of the benzyl group completed the total synthesis. 

Werner, K. M., De los Santos, J. M., Weinreb, S. M., Shang, M. A Convergent Stereoselective Synthesis of the Putative Structure of the Marine Alkaloid Lepadiformine via an Intramolecular Nitrone/1,3-Diene Dipolar Cycloaddition. J. Org. Chem. 1999, 64, 686-687. 

Abe, H., Aoyagi, S., Kibayashi, C. First Totai Synthesis of the Marine Aikaioids ( )-Fasicuiarine and ( )-Lepadiformine Based on Stereocontroiied intramoiecuiar Acyinitroso-Dieis-Alder Reaction. J. Am. Chem. Soc. 2000,122,4583-4592. 

Total synthesis and its role in structure elucidation of lepadiformine, alkaloid of marine invertebrates 03ACR59. 

Total synthesis of bioactive tricyclic marine alkaloids with A-heterocyclic fragments, lepadiformine, and related compounds 03BCJ2059. 

Weinreb and co-workers made use of a nucleophilic hyroxymethyl equivalent in the synthesis of the marine alkaloid lepadiformine.46 A highly stereoselective addition to a-methoxybenzamide 56 was achieved using the silylmethyl cuprate derived from Grignard reagent 57. Exposure of 58 to Fleming oxidation conditions provided 59 in high yield. 

Total synthesis of tricyclic marine alkaloids (—)-lepadiformine, (+)-cylin-dricine C, and (—)-fasicularin 07Y805. 

Lepadiformine is a not-too-complicated tricyclic alkaloid, which finds some attention in the synthetic community [31], The first synthesis hy Funk [32] constructs the rings sequentially (Scheme 11.24). The functionality initially needed to facilitate the Diels-Alder addition has been cleverly used to build the pyrrolidine ring. 

Lepadiformine nevertheless continues to be a target of synthetic endeavours [41, 42, 43, 44]. Perhaps the study of the syntheses presented here will encourage the reader to come up with shorter or more efficient proposals for this and other compounds. Their presentation was intended to give the reader the chance of enjoying the art of synthesis. 

Scheme 11.27 Lepadiformine synthesis proposed by R. W. Hoffmann-group...

In 2006, Shibasaki and co-workers [91] developed phase-transfer-catalyzed asymmetric Michael addition of glycine Schiff base 237 and dienone 238 to afford dienone 240 in 84% isolated yield and 82% ee for the total synthesis of (+)-cylin-dricine C (242) and a formal synthesis of (—)-lepadiformine (244), using a chiral two center organocatalyst 239 (TaDiAS Tartrate-derived Di-Ammonium Salt) (Scheme 17.41). (+)-cylindricine C (242) was achieved three steps from 240 using... 

SCHEME 17.41. Phase-transfer catalyzed synthesis of (-t-)-cylindricine C (242) and (—)-lepadiformine (244). 

Mihara H, Shibuguchi T, Kuramochi A, Ohshima T, Shibasaki M (2007) Short Synthesis of (-t)-Cylindricine C and Formal Total Synthesis of (-)-Lepadiformine. Heterocycles 72 421... 

Fig. 29 Ciufolini s synthesis of aza-spirocycles from para- and ort/io-phenolic sulfonamides and desymmetrization en route to the synthesis of a lepadiformine analogue...

In contrast to the previous examples, the preferred formation of linear aldehydes was the main target in some syntheses to construct a cyclic derivative with an appropriate ring size in the next step or for simply elongating a carbon chain. The linear aldehydes are the proper intermediates for the synthesis of indolizidine alkaloids [11], the tricyclic marine alkaloid lepadiformine [12], ACE inhibitors such as MDL 27210 and its analogues [13,14], and bryostatin, a remarkably potent anticancer agent [15]. Rhodium complexes of bisphosphite ligands provide one of the best known classes of linear-selective hydroformylation catalysts for simple ot-olefins. Except for the lepadiformine intermediate, where hydroformylation was carried out in the presence of the Rh(acac)(CO)2/P(OPh)3 catalyst system, in other... 

As will be discussed, our pivotal intramolecular aza-[3+3] cycloaddition was remarkably efficient in providing the tricyclic scaffold of (—)-cylindricine C 384 and that of putative (—)-lepadiformine 389 (or (—)-4-deoxo-2-epi-cylindricine C) [170b,[198], yet this route could not be implemented in our synthesis of (—)-lepadiformine 385. To reconcile this, we devised a unified strategy to synthesize (—)-lepadiformine and (+)-cylindricines C-E (386-388) that... 

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