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T1 - Total synthesis of Brevetoxin A

Before concluding this chapter, it should be noted that many synthetic studies have been reported by laboratories around the world since we completed the total synthesis of CTX3C (1) in 2001. However, only one total synthesis of CTX1B (3) aside from our synthesis has been completed, by the Isobe group in 2009., Neither the total synthesis of other ciguatoxin congeners nor the successful preparation of anti-CTX monoclonal antibodies has been reported to date.

Having secured the reliable reaction conditions for constructing the left-hand side chain, the final stage of the total synthesis of 1 was executed as shown in . Reductive removal of the benzyl group from 43 with LiDBB was followed by reprotection as the TBS group to give silyl ether 48. Selective removal of the primary TBDPS group from 48 in the presence of the three TBS groups was successfully carried out according to the procedure of Nakata and co-workers, leading to primary alcohol 49 in 73% yield after three recycles. Oxidation of 49 with Dess–Martin periodinane followed by treatment of the resulting aldehyde with the Ohira–Bestmann reagent (K2CO3, MeOH) produced an alkyne, which was then methylated with n-butyllithium/methyl iodide to provide alkyne 50 in excellent overall yield. At this stage, the robust TBS protecting groups were replaced with the easily removable TES ethers. Thus, alkyne 50 was treated with HF•pyridine, and the resulting triol was reprotected with TESOTf and triethylamine to give tris-TES ether 51. Regioselective silylcupration of 51 with (Me2PhSi)2Cu(CN)Li2 delivered the desired vinylsilane 52 in an approximately 9:1 regioselectivity. The regiochemistry of 52 was confirmed by the characteristic pattern of the olefinic proton (dd, J = 7.0, 7.0 Hz). Conversion of 52 to vinyl iodide 3, required for the projected Stille coupling, was performed on exposure to N-iodosuccinimide (NIS) in MeCN/THF (4:1) at room temperature. Under these reaction conditions, isomerization of the olefin stereochemistry partially occurred and ca. 6:1 mixture of (E)-vinyl iodide 3 and its (Z)-isomer, along with small amounts of regioisomers, were produced in 99% combined yield from 51. The (E)-geometry of 3 was tentatively assigned because it is well-known that the iododesilylation generally proceeds with retention of configuration, and this was later confirmed by characterization of the cross-coupled product 53 (vide infra). Without separation of these isomers, the crucial Stille coupling was carried out under the established conditions. Thus, cross-coupling of 3 with vinyl stannane 5b in the presence of the Pd2(dba)3/Ph3As/CuTC catalyst system in THF/DMSO (1:1) at room temperature proceeded smoothly to furnish (E,E)-diene 53 in 63% yield as a single stereoisomer, after purification by flash chromatography. The stereochemistry of the diene system was unequivocally established by NOE experiments as shown.


The Total Synthesis of the Spirovetivane Phytoalexin, "

Inoue, "Total Synthesis and Functional Evaluation of Fourteen Stereoisomers of Yaku’amide B.

N2 - A formal total synthesis of hemibrevetoxin B (1) is described. Intramolecular allylation of α-chloroacetoxy ether 10, prepared from carboxylic acid 11 and alcohol 12, was carried out with MgBr2·OEt2 to give 27. Ring-closing metathesis of 27 furnished tetracycle 29, which was converted to a known synthetic intermediate 9, to complete a formal total synthesis of 1.

AB - A formal total synthesis of hemibrevetoxin B (1) is described. Intramolecular allylation of α-chloroacetoxy ether 10, prepared from carboxylic acid 11 and alcohol 12, was carried out with MgBr2·OEt2 to give 27. Ring-closing metathesis of 27 furnished tetracycle 29, which was converted to a known synthetic intermediate 9, to complete a formal total synthesis of 1.

Inoue, "Total Synthesis of Crotophorbolone,"

Approaches to marine-derived polycyclic ether natural products: first total synthesis of the asbestinins and a convergent strategy for Brevetoxin A

Inoue, "Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine,"

Inoue, "Total Synthesis of Four Stereoisomers of (4,7,10,12,16,18)-14,20-Dihydroxy-4,7,10,12,16,18-docosahexaenoic Acid and Their Anti-inflammatory Activities,"

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The Total Synthesis of the Spirovetivane Phytoalexin, (±)-Lubiminol"

Inoue, "A Convergent Total Synthesis of Ouabagenin,"

Inoue, "Total Synthesis of Four Stereoisomers of (5,8,10,14)-12-Hydroxy-17,18-epoxy-5,8,10,14-eicosatetraenoic Acid and Their Anti-Inflammatory Activities," , , 8320-8332.


Total synthesis of CTX1B and 54-deoxyCTX1B.

Initial attempts to complete the synthesis of brevetoxin A from diol 16 focused on the formation of the A ring lactone followed by removal of the J ring benzyl ethers and functionalization of the J ring side chain. While the A ring lactone could be readily constructed by treatment of diol 16 with n-Pr4NRuO4, subsequent attempts to cleave the J ring benzyl ethers under a host of reductive or Lewis acidic conditions met with failure due to significant amounts of decomposition. Ultimately, a strategy involving the selective oxidation of tetraol 2 was examined. Unlike the A ring lactone derived from diol 16, the J ring benzyl ethers could be readily cleaved from diol16 itself to deliver tetraol 2. Thus, brevetoxin A (1) was accessed in three straightforward operations from diol 16 (). Reductive cleavage of the J ring benzyl ethers, and subsequent exposure of tetraol 2 to PhI(OAc)2 in the presence of catalytic TEMPO served to selectively form the A-ring lactone and the C44 aldehyde while leaving the axially-disposed C39 secondary alcohol unaffected. The unpurified decacyclic aldehyde 17 was treated with Eschenmoser′s salt in the presence of Et3N, to complete the synthesis of brevetoxin A (1). Synthetic brevetoxin A (1) was identical in all respects (1H and 13C NMR, IR, HRMS, [α]D) to an authentic sample.,

Models for the Total Synthesis of Laurenene and Silphinene"

In summary, the total synthesis of brevetoxin A was completed from aldehyde 6 and phosphine oxide 5 through a stereoselective Horner—Wittig olefination to assemble two advanced tetracycles. The uncommon cyclization of a medium ring mixed methyl ketal was accomplished and the mixed methyl ketal was assessed as a substrate for a reductive etherification of an oxocene. Ultimately, a sulfone-based approach proved superior and set the stage for a selective oxidation strategy of tetraol 2, allowing the completion of the second total synthesis of brevetoxin A (1).

Inoue, "Total Synthesis of (-)-4-Hydroxyzinowol,"

A different methodology was applied for the synthesis of the right wing segment (7) of CTX3C (1) ()., Yamaguchi esterification between alcohol 10 and carboxylic acid 11 produced ester 26. Construction of the J-ring from 26 by C-C bond formation was challenging due to steric hindrance at C42. Intramolecular carbonyl olefination, however, using Cp2Ti[P(OEt)3]2 developed by Takeda and co-worker successfully closed the six-membered J-ring to afford pentacycle 27. The stereoselective introduction of hydrogen at C42 and the oxygen functionality at C41 was also problematic. Dihydropyran 27 has a strong conformational bias for accepting the reagent from the α-face, since the sterically demanding LM-ring portion projects toward the β-face. For example, hydroboration of 27 led predominantly to the undesired stereoisomer with an α-hydrogen at C42.

Inoue, "Total Synthesis of Ryanodol,"

The synthetic strategy used for the first synthesis of ciguatoxin CTX3C (1), employing the RCM reaction and radical cyclization as key tactics, is illustrated in ., The size and complexity of this fused ether array led us to use a unified convergent strategy called the [X + 2 + Y] strategy., This strategy involved the coupling of the synthetic fragments followed by the construction of the two rings and introduction of the two stereocenters. The challenge lay in developing a reaction sequence to construct the new ethers of the requisite ring sizes in a stereoselective manner without affecting the preexisting functionalities. Consequently, we improved the convergence of the assembly in which four simple fragments (8, 9, 10, and 11) were coupled and further modified to form the CD-, JK-, and FG-rings. The comparably complex ABCDE- and HIJLKLM-ring systems (6 and 7, respectively) would be synthesized prior to the final coupling at the central region of the molecule. The four fragments (811) were prepared from the starting materials D-glucose (12), D-2-deoxyribose (16), and ()-()-benzylglycidol (17) (). The medium-sized ether rings (the A-, E-, and I-rings) were constructed using an RCM reaction (for example, 1314), which greatly simplified the synthesis of the fragments.

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