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Progress Toward the Total Synthesis of Hamigerans C and D: A Direct Approach to an Elaborated 6-7-5 Carbocyclic Core

The hamigeran family of natural products has been the target of numerous synthetic efforts due to its biological activity and interesting structural properties. Herein we disclose our efforts toward the synthesis of hamigerans C and D, unique among the initially isolated members due to their 6-7-5 carbocyclic core. Our approach directly targets this tricyclic motif by sequential Negishi and Heck coupling reactions, yielding an advanced intermediate with all necessary carbons and sufficient functionality poised for completion of the synthesis of these two natural products.


Introduction
The hamigeran family of natural products was isolated in 1999 from marine sponge Hamigera tarangaensis by Cambie and coworkers (Scheme 1). 1 While all four members of the family possess moderate cytotoxicity in P-388 leukemia cells (IC 50 = 31.6, 13.5, 16.0 and 8.0 μM for hamigerans A, B, C and D, respectively), hamigeran B (2) displays 100% in vitro inhibition against both Herpes and Polio viruses.
Due to this attractive biological activity and the synthetically challenging 6-6-5 tricyclic structure bearing three consecutive stereocenters on the congested A-ring, hamigeran B has been the target of continual efforts of many synthetic organic chemists. Hamigeran B (along with hamigeran A and several analogs) was first synthesized in 2003 by Nicolaou and coworkers 2,3 and since has succumbed to a number of syntheses, 2,3,4,5,6,7,8,9,10,11,12,13,14 including epimeric and formal syntheses. In contrast, at the outset of our studies no synthesis of hamigeran C or hamigeran D (3 and 4), which share a unique 6-7-5 tricyclic core, had been reported. This dearth in syntheses is presumably due to the relative scarcity of methods for the synthesis of seven-membered rings as compared to their six-membered counterparts. Hamigeran D has been synthesized recently by Gao and coworkers via a biomimetic skeletal rearrangement from a 6-6-5 tricycle, 15 and thus our strategy of directly targeting the sevenmembered ring structure remains unique (vide infra).
The Stoltz group has developed a method for the asymmetric synthesis of γ-quaternary acylcyclopentenes (Scheme 2, 10) by a retro-aldol/aldol condensation sequence resulting in a two-carbon contraction of vinylogous esters of cycloheptenone (13). 16 The versatility of this intermediate and the excellent scalability of this sequence inspired us to pursue the synthesis of natural products with cores containing densely-functionalized cyclopentanes with quaternary carbon stereocenters, making hamigerans C and D ideal targets.

Results and Discussion
Studies toward the syntheses of hamigerans C and D were initiated during our investigations of the asymmetric synthesis of γ-quaternary acylcyclopentenes. 16 From acylcyclopentene 10, we were able to assemble the 6-7-5 carbocyclic core of hamigerans C and D (Scheme 2, 18) in good overall yield over four synthetic steps, featuring two sequential Heck crosscoupling reactions.
Notably lacking on tricycle 18, however, is substitution on the aromatic C-ring and any functional handle on the benzannulated cycloheptyl B-ring of the natural products. The latter is due to the (E)-selectivity in the coupling of 10 with o-iodophenol. The resulting olefin must be hydrogenated in order to perform the second Heck coupling, resulting in loss of the otherwise useful olefin moiety. As such, we envisioned a retrosynthetic strategy that would allow us to perform the first cross-coupling reaction to yield a (Z)-olefin with an appropriately substituted aromatic ring (Scheme 1, 7). Such a strategy would allow us to obtain a tricyclic intermediate (6) with all of the necessary functional handles in place to advance toward the total syntheses of both of these natural products.
Our first synthetic efforts were directed toward synthesis of Negishi coupling partners 8 and 9. We desired a differentially protected orcinol derivative, as one phenol group would need to be deprotected and converted to an aryl triflate for the planned Heck cross-coupling, while the other phenol would need to be robustly protected as a methyl ether to be revealed late in the synthesis as the phenol present in hamigeran C or the phenol precursor to the oxazine moiety of Hamigeran D. Synthesis of the O-methyl-O′-tetrahydro-2-pyranylorcinol 8 was accomplished by dimethylation and mono-demethylation of orcinol (19), 17 followed protection as a THP ether in 64% yield over three steps (Scheme 3).
The synthesis of (Z)-vinyl iodide 9 was accomplished by a novel sequence from acylcyclopentene 10. Following the established procedure for ketal protection of the enone, 16 the resulting diene could be selectively ozonolyzed to yield aldehyde 21 in 71% yield over 2 steps. However, yields obtained using the (Z)-iodomethylenation procedure reported by Stork 18 proved unreliable upon several repeated experiments (Table 1).
While mass-balance for this transformation was consistent, varying amounts of starting material contaminated by deprotection side-products were reisolated, with yields of the desired vinyl iodide 9 ranging from 33-67% (Table 1, entry 1). Moreover, the 5:1 ratio of Z:E isomers (as determined by integration of the terminal vinyl proton in the 1 H NMR spectrum) could not be separated by chromatography through silica gel, alumina, or silver nitrate-impregnated silica gel with a wide variety of eluent combinations. As unreacted starting material appeared to be a major cause of loss for the yield in this transformation, we considered that, given the quaternary center proximal to the aldehyde of 21, nucleophilic approach by the Wittig reagent was extremely hindered. We reasoned that the Wittig reagent was instead acting as a base, deprotonating the α-position of 21 to yield an unreactive enolate.
Raising the temperature of addition in this reaction to 40 °C and maintaining that temperature throughout the reaction yielded a consistent boost in yield (66-87%) without any detriment to the (Z)-selectivity (Table 1, entry 2). Reaction at 30 °C also appeared to be an improvement, though longer reaction times resulted in increased appearance of side products resulting from deprotection of the ketal (entry 3). By increasing the temperature to 50 °C and performing the reaction in benzene, we were able to achieve a good yield, but noted a dramatic decrease in selectivity from 5:1 to 1.3:1 in favor of the (Z)-olefin. (entry 4).
Satisfied with the improved yields obtained by performing the reaction with an addition temperature of 40 °C, we sought to improve the (Z)-selectivity by modifying the nature of the Wittig reagent. We imagined that modification of the aggregation state of the deprotonated Wittig salt by modifying the counterion or base used or by chelation of the counterion by hexamethylphosphoramide (HMPA), could benefit the selectivity of the reaction.
Unfortunately, substitution of sodium hexamethyldisilylamide (HMDS) for lithium or potassium HMDS (Table 2, entries 2 and 4) both resulted in a decrease in selectivity for the desired (Z)-olefin, as did addition of HMPA (entry 3) or the use of sodium t-butoxide (entry 5). Moreover, tuning of the sterics of the Wittig reagent itself by substituting (iodomethyl)triphenylphosphonium iodide for the less bulky (bromomethyl)triphenylphosphonium bromide (entry 6) or (iodomethyl)tri-nbutylphosphonium iodide (entry 7) also resulted in a decrease in selectivity. To our surprise, the more sterically-hindered (iodomethyl)tri-o-tolylphosphonium iodide gave a modest selectivity of 0.9:1 in favor of the undesired (E)-olefin (entry 8). As such, we returned to our initial conditions and proceeded with our synthetic studies.
With the proposed Negishi cross-coupling partners in hand, we began investigations of this reaction. We anticipated being able to affect a selective deprotonation of 8 orthoto the two ether substituents with n-butyllithium, followed by transmetallation with zinc(II) chloride to afford the Negishi coupling partner for vinyliodide 9 (Scheme 3).
Gratifyingly, this reaction proceeded in good yield to afford 22 as a single product with respect to the deprotonation of 8, though still as a mixture of olefin isomers. Removal of both acetal and THP protecting groups proceeded smoothly using Montmorillonite K-10 clay in methanol at 50 °C, the crude product of which was >95% pure by 1 H NMR and could be used directly in the following step. We also found that triflation of the intermediate phenol could be affected using trifluoromethanesulfonyl anhydride and DMAP over a slightly longer reaction time but without loss of yield when compared to the more costly Comins' reagent (N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide)), furnishing the desired aryl triflate 7 in 55-62% yield over three steps from Negishi coupling partners 8 and 9. At this point, the minor olefin isomer had also been removed over the course of purification and isolation steps, or had otherwise isomerized to the major isomer due to exposure to light and/or heat. Aryl triflate 7 was subjected to conditions developed for the model Heck reaction (Scheme 2), modified to be run in a microwave reactor, providing tricycle 6 in 88% yield on 0.12 mmol scale (Scheme 3). However, upon scale up, cleavage of the triflate caused a significant decrease in yield, and a large amount of an undesired acylated side-product was obtained. Further improvements to this Negishi-Heck sequence, including attempts at performing the steps in a one-pot cascade fashion using Pd and Ni catalysis, have been the subject to ongoing research in our group.
With functionalized tricyclic core of hamigerans C and D (6) in hand, we sought to pursue the selective functionalization of the disubstituted olefin. A number of dihydroxylation and epoxidation conditions including AD-mix, stoichiometric osmium tetroxide, and m-CPBA all failed to provide the desired product. Epoxidation of the disubstituted alkene 6 was finally affected in a mixture of aqueous bleach and dichloromethane with (R,R)-Mn(salen) epoxidation catalyst 23 to afford epoxide 24 in 89% yield and a 7.5-10:1 ratio of inconsequential diastereomers (Scheme 3).
Treatment of 24 with catalytic gold(III) chloride in dry acetone 19 directly yielded protected diol 25 in 74% yield as a single diastereomer, although the stereochemistry of the B-ring substituents has eluded definitive determination. The final carbon of hamigerans C and D could be installed by submitting acetal 25 to Wittig conditions, yielding desired compound 26. Diene 26 represents the most advanced intermediate we have synthesized to date, and completion of the synthesis of hamigerans C and D requires hydrogenation of the diene moiety, deprotection and oxidation of the B-ring diol, bromination and demethylation of the aromatic C-ring. Synthesis of hamigeran C would require installation of the acetoxy group on the B-ring, and completion of hamigeran D would occur by completion of the oxazine Dring.
In conclusion, we have achieved the synthesis of the 6-7-5 tricyclic core of hamigerans C and D via a unique strategy of directly targeting synthesis of the seven-membered ring via sequential Negishi and Heck cross-coupling reactions. Our targeted synthesis is made catalytically enantioselective by application of our asymmetric alkylation/ring-contraction strategy for synthesis of chiral acylcyclopentenes. Our advanced intermediates possess the requisite carbons and functionality for elaboration to both of these targets, and research into the remaining steps is underway in our group.
For experimental procedures, please see accompanying supporting information.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material. Duquette  Structures of first four identified members of the hamigeran family of natural products, and retrosynthetic analysis of hamigerans C and D.  Temperature and solvent optimization studies for yield and selectivity in olefination reaction.  Table 2 Phosphonium ylide and base optimization studies for selectivity in olefination reaction.