A Chlorine-Atom-Controlled Terminal-Epoxide-Initiated Bicyclization Cascade Enables a Synthesis of the Potent Cytotoxins Haterumaimides J and K

Abstract

Haterumaimide J (hatJ) is reportedly the most cytotoxic member of the lissoclimide family of labdane diterpenoids. The unusual functional group arrangement of hatJ-C18 oxygenation and C2 chlorination-resisted our efforts at synthesis until we adopted an approach based on rarely studied terminal epoxide-based cation-π bicyclizations that is described herein. Using the C2chlorine atom as a key stereocontrol element and a furan as a nucleophilic terminator, the key structural features of hatJ were rapidly constructed. The 18-step stereoselective synthesis features applications of chiral pool starting materials, and catalyst-, substrate-, and auxiliary-based stereocontrol. Access to hatJ and its acetylated congener hatK permitted their biological evaluation against aggressive human cancer cell lines. Our laboratory has been investigating the chemistry and biology of the potently cytotoxic labdane diterpenoids in the lissoclimide family. 1-3 Nearly two dozen such natural products were isolated from sea squirts as described by the groups of Malochet-Grivois/Roussakis, 4 Ueda/Uemura, 5 and Schmitz. 6 Among these compounds, many of which were named haterumaimides, several showed potent cytotoxicity against the P388 murine leukemia cell line (Figure 1); dichlorolissoclimide (1) and chlorolissoclimide (2) were also very active against KB cells and non-small-cell lung cancer, 4b,c and were later shown by Pelletier and co-workers to be inhibitors of eukaryotic translation. 7 With the Alexanian group, we completed semisyntheses of haterumaimide Q (3) and chlorolissoclimide from sclareolide, featuring in the latter case a selective radical C-H chlorination reaction to install the salient C2-halogen atom. 1,8 In a separate report focused more on the biological properties of these *

Cobalt‐Catalyzed Hydrogen‐Atom Transfer Induces Bicyclizations that Tolerate Electron‐Rich and Electron‐Deficient Intermediate Alkenes

“…Although biosynthetically the oxidation of this carbon center surely occurs post‐cyclization, it would be strategically valuable to incorporate these functional groups prior to cyclization in the laboratory setting. This idea is in line with our broader program to extend the range of functionalized substrates in stereocontrolled polycyclizations . We presumed that this C20 “handle” would prove advantageous in subsequent applications to molecules such as 1 , 2 , and the many other diterpenoids with an oxidized C20 that is also frequently part of a ring structure.…”

Total Syntheses of (+)-Stemarin and the Proposed Structures of Stemara-13(14)-en-18-ol and Stemara-13(14)-en-17-acetoxy-18-ol

“…Coupling of allylic bromide (+)- 20 (93% ee) with the organolithium reagent derived from treatment of 18 with n -BuLi proceeded smoothly to give epoxide 17 in 87% yield . After extensive optimization, we were pleased to find that by exposure of 17 to BF 3 ·OEt 2 in toluene at −78 °C for 1 h, the desired tricycle 21 could be obtained in 45% yield. ,, As a comparison, other Lewis acids such as Et 2 AlCl, TiCl 4 , InBr 3 , FeCl 3 , Bi­(OTf) 3 , TMSOTf, and Ph 4 PBF 4 either gave no reaction or caused significant decomposition of the starting material. Under Mitsunobu conditions, the hydroxyl group at C3 was successfully eliminated to produce the corresponding alkene, which then underwent dedithianation at C7 with PhI­(CF 3 CO 2 ) 2 and CaCO 3 at 0 °C to deliver ketone 22 in 74% yield over two steps.…”

Cobalt‐Catalyzed Hydrogen‐Atom Transfer Induces Bicyclizations that Tolerate Electron‐Rich and Electron‐Deficient Intermediate Alkenes

“…Theu se of substoichiometric quantities of oxidant was not tolerated (entry 2), and different silanes, including the "Ruben-silane" [14] (entries 3a nd 4), did not significantly improve the outcome.F or its convenience and low price,TMDSO was chosen as the preferred silane.Other single-electron oxidants,including Cu(OTf) 2 and CAN, led to decomposition (not shown, see the Supporting Information). Fortuitously,asmall solvent screen revealed that carrying out the reaction in HFIP led to significantly improved yields (entries [4][5][6][7][8]. Ascreen of afew different catalysts (entries 8-10) revealed that only C1 gave full conversion in 3hours.…”

“…Although biosynthetically the oxidation of this carbon center surely occurs post-cyclization, it would be strategically valuable to incorporate these functional groups prior to cyclization in the laboratory setting.T his idea is in line with our broader program to extend the range of functionalized substrates in stereocontrolled polycyclizations. [7] We presumed that this C20 "handle" would prove advantageous in subsequent applications to molecules such as 1, 2,a nd the many other diterpenoids with an oxidized C20 that is also frequently part of aring structure.These synthesis endeavors themselves were largely discouraged by recent attractive, closely related successes by Li and co-workers, [8] who included as econdary allylic ether function at this position in aC arreira-type enantioselective polycyclization, [4b] and Ma and coworkers, [9] who used ad ifferent scaffold-building strategy to make nitrile compounds related to 4b.H owever,a so ur studies unfolded, we were surprised to discover conditions for Co-catalyzed HAT-initiated (HAT = hydrogen-atom transfer) dialkenylarene bicyclizations with ar ather broad scope, including the intriguing tolerance of either aC 20 electrondonating methyl group (3a)o ra ne lectron-withdrawing nitrile (3b). These results and some preliminary mechanistic investigations are the subject of this report.…”