Amphidinolide

The examples shown throughout this chapter demonstrate that RCAM is a powerfril 

Further advances in catalyst development are likely to improve the uptake and applicability of the RCAM strategy. In particular, the design of a catalyst system that mediates effective RCAM of terminal alkynes under mild conditions with good functional group tolerance is extremely desirable and would have great effect on the synthetic impact of this already highly employable reaction. 

18 For a recent report on the use of terminal alkynes in alkyne metathesis see Coutelier, O., Nowogrocki, G., Paul, 

De Souza, D., Turet, L., Fenster, M.D.B., Parra-Rapado, L, Wirtz, C., Mynott, 

45 For an example, see the recent advances in platinum and gold activation of alkynes Fiirstner, A. and Davies, 

---

In some cases, if necessary, a C(3)-regioselective addition of cuprate can be accomplished by the use of a sterically demanding protecting group - such as an -OTr or -OMMTr group - on C(l), as described in the synthesis of the polypropionate segment present in (-)-amphidinolide P and (+)-amphidinolide K [54]. 

Scheme 38 Regioselective RCM of heptaene 193 in Maleczka s synthesis of the structure 195 proposed for amphidinolide A [96a]...

Scheme 39 Influence of a remote substituent on efficiency and stereochemistry of the RCM step in Fiirstner s total synthesis of amphidinolide T4 (199) [98a] and amphidinolide T3 (12-epf-199) [98b]...

In Ghosh s enantioselective total synthesis of the cytotoxic marine macrolide (+)-amphidinolide T1 (318) [143], the C1-C10 fragment 317 was constructed by CM of subunits 315 and 316 (Scheme 62). The reaction mediated by catalyst C (5 mol%) afforded in the first cycle an inconsequential 1 1 mixture of (E/Z)-isomeric CM products 317 in 60% yield, along with the homodimers of 315 and 316. The self-coupling products were separated by chromatography and exposed to a second metathesis reaction to provide olefins 317 in additional 36% yield [144]. 

Scheme 62 Efficient coupling of fragments 315 and 316 via CM in Ghosh s total synthesis of the cytotoxic marine macrolide amphidinolide T1 (318) [143]...

The Stille reaction has been successfully applied to a number of macrocyclic ring closures.207 In a synthesis of amphidinolide A, the two major fragments were coupled via a selective Stille reaction, presumably governed by steric factors. After deprotection the ring was closed by coupling the second vinyl stannane group with an allylic acetate.208... 

Entries 4 and 5 are examples of use of the Sakurai reaction to couple major fragments in multistage synthesis. In Entry 4 an unusual catalyst, a chiral acyloxyboronate (see p. 126) was used to effect an enantioselective coupling. (See p. 847 for another application of this catalyst.) Entry 5 was used in the construction of amphidinolide P, a compound with anticancer activity. 

Inter- and intramolecular ruthenium-catalyzed Alder-ene reactions were utilized to synthesize the proposed structures of amphidinolide A.98 Conversion of dienyne 163 into pentaene 164 was accomplished in 46% yield with the products obtained as a 3.5 1 mixture of the branched to linear forms (Scheme 39). It is notable that the Cp variant of the ruthenium catalyst 64 was used for the intermolecular Alder-ene reaction. Conversion of 164 into protected amphidinolide A was performed using high dilution conditions with the normal catalyst to give a 58% yield of the macrolide which was then deprotected to provide the natural product. 

Kjelleberg S, Steinberg P (2001) Surface waters in the sea. Microbiol Today 28 134-135 Knaggs AR (2003) The biosynthesis of shikimate metabolites. Nat Prod Rep 20 119-136 Kobayashi J, Ishibashi M, Nakamura H, Ohizumi Y, Yamasu T, Sasaki T, Flirata Y (1986) Amphidinolide-A an antineoplastic macrolide from the marine dinoflagellate Amphidinium sp. Tetrahedron Lett 27 5755-5758... 

Other procedures using TPAP/NMO/PMS/CH Cl include steps in the synthesis of (+)-altholactone (lactol to lactone) [78] antheliolide A [168] the AChE inhibitor (+)-arisugacin A and B (primary alcohol to aldehyde step also) [83] the marine macrolide amphidinolide T1 [169] the alkaloid (+)-batzelladine D cf. mech. 

Amphidinolide T4 285, another member of the amphidinolide family containing a saturated 19-membered lactone... 

The iron-catalyzed addition of Grignard reagents to propargylic epoxides developed by Furstner and Mendez allows one to prepare a yw-allenol, which is an important intermediate for the synthesis of a precursor of the amphidinolide X (Scheme 67). 

SCHEME 81. Synthesis of amphidinolide T1 via Pd-catalyzed acylation of an alkylzinc derivative... 

The amphidinolides are a class of structurally diverse and physiologically potent natural products. The key step in the total synthesis of enantiomerically-pure amphidinolide T l 3 recently reported (J. Am. Chem. Soc. 2004,126,998) by Timothy Jamison of , the Ni-mediated cyclization of 1 to 2, clearly illustrates the power of organometallic C-C bond formation in organic synthesis. 

From aryl halide 110 From alcohol 156 Protection 100, 101, 144 Amino acid from hydroxy acid 40 Amphidinolide synthesis 50,94 Anatoxin synthesis 82 Aromatic ring construction 171,191 Aromatic ring substitution 10,18,19,21, 48, 54, 65,69, 104, 108, 110, 111, 120, 122,138, 149, 164, 171, 174, 175, 190,205... 

---