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The final stage of our studies corresponds to the formation of two cyclic olefin moieties, a macrocyclic and a cyclooctenyl structure, en route to stereoselective total synthesis of nakadomarin A. (–)-Nakadomarin A, a marine alkaloid of the manzamine family, was isolated from the sea sponge Amphimedon sp. in Okinawa.¹² It exhibits cytotoxic activity against murine lymphoma (L1210) with an IC50 value of 1.3 µg/mL, as well as inhibition of cyclin dependent kinase 4 (IC50 = 9.9 µg/mL). It also shows antimicrobial activity against the fungus Trichophyton mentagrophytes (MIC = 23 µg/mL) and Gram-positive bacterium Corynebacterium xerosis

(MIC = 11 µg/mL). Nakadomarin A possesses an 8/5/5/5/15/6 hexacyclic ring system and four stereogenic centers, including a quaternary one.

(37) Zhan, W.; Jiang, Y.; Brodie, P. J.; Kingston, D. G.; Liotta, D. C.; Snyder, J. P. Org. Lett. 2008, 10, 1065–1068.

Because of the biological activities and challenging structure of nakadomarin A, synthetic chemists made numerous efforts to access the alkaloid by chemical synthesis. Most of their approaches utilized alkene RCM to prepare the macrocyclic ring of nakadomarin A, albeit with relatively low efficiency (15–30 mol % Ru-based catalyst) and minimal or no stereoselectivity (~1:2–2:1 Z:E).³⁸ The first total synthesis of the target molecule was achieved by Nishida and co-workers in 2004 (Scheme 2.10).^38b Chiral lactam 2.51, prepared in ten steps from L-serine, was converted to triene 2.52 in 24 linear steps. Macrocyclic RCM with 20 mol % Grubbs 1^st generation catalyst delivered a mixture of olefin stereoisomers (Z:E = 36:64), from which Z-2.53 was isolated in 26% yield; reduction of bislactam with Red-Al resulted in the formation of nakadomarin A. Another RCM-based approach to its antipode, (+)-nakadomarin A, was reported by Kerr’s group in 2007.^38c Furan-containing 1,2-oxazine 2.54, available in seven steps from D-mannitol, was transformed to triene 2.55 in 19 linear steps. Treatment of 2.55 with 40 mol % Grubbs 1^st generation catalyst afforded macrocycle 2.56 in 66% yield as a mixture of olefin stereoisomers (Z:E = 3:5); subsequent reduction gave (+)-nakadomarin as a mixture of two olefin stereoisomers. Unfortunately, the Z and E olefin isomers of both lactam 2.56 and diamine 2.5 could not be separated under flash column chromatography or HPLC conditions.

(38) (a) Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc. 2003, 125, 7484–7485. (b) Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2004, 43, 2020–2023. (c) Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465–1469. (d) Jakubec, P.; Cockfield, D. M.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 16632–16633. (e) Cheng, B.; Wu, F.; Yang, X.; Zhou, Y.; Wan, X.; Zhai, H. Chem. Eur. J. 2011, 17, 12569–12572.

2.52 Scheme 2.10: Representative RCM Approaches to Nakadomarin A (2.5)

(-)-nakadomarin A

Due to the ineffective stereochemical control in the macrocyclic ring formation, as with epilachnene and epothilone C, synthetic routes using alkyne RCM/hydrogenation sequence have been studied (Scheme 2.11).³⁹ In 2010, Funk’s group demonstrated that the macrocyclic alkene of nakadomarin A could be accessed through alkyne RCM.^39a Methyl-substituted alkyne substrate 2.57 was prepared in 12 linear steps from D-pyroglutamic acid, which was then subjected to several different alkyne RCM systems. Schrock alkylidyne complex 2.32 in chlorobenzene, as well as the molybdenum nitride complex 2.58 was proved effective in this cyclization. After another 6 steps, alkyne RCM product 2.59 was converted to triene 2.60. The use of 100 mol % Grubbs 1^st generation catalyst was required for the cyclooctene ring formation;

reduction of bis-lactam afforded nakadomarin A in 58% yield over two steps. More recently, Dixon’s group has identified an alkyne RCM-based approach to the alkaloid.^36c RCM of diyne-diamide 2.61 was examined under various reaction conditions and the Mortreux alkyne metathesis system [100 mol % Mo(CO)6, p-chlorophenol in reflux toluene] delivered pentacyclic

(39) (a) Nilson, M. G.; Funk, R. L. Org. Lett. 2010, 12, 4912–4915. (b) Kyle, A. F.; Jakubec, P.; Cockfield, D. M.;

Cleator, E.; Skidmore, J.; Dixon, D. J. Chem. Commun. 2011, 47, 10037–10039. (c) Jakubec, P.; Kyle, A. F.; Calleja, J.; Dixon, D. J. Tetrahedron Lett. 2011, 52, 6094–6097.

structure 2.62 in 36% yield. Subsequent three steps led to the formation of nakadomarin A in 20% yield. Attempts to perform alkyne RCM of the possibly more strained pentacyclic intermediate 2.63 that contains two Lewis basic tertiary amines, with either one equivalent of Mo- or W-based alkylidynes 2.32 or 2.58, including the more recently developed variations, were unable to promote the formation of nakadomarin A.^36c The strong resistance of the diyne in regards to cyclization illustrates the sensitivity of alkyne metathesis catalysts towards basic functionalities as well as the higher level of ring stain associated with cycloalkyne than the Scheme 2.11: Representative Alkyne RCM Approaches to Nakadomarin A (2.5) 23#456789#:%5;+<

2.5.b  Z-­‐Selective  Macrocyclic  RCM  Approaches  to  (–)-­‐Nakadomarin  A

Because of the aforementioned difficulties among the alkyne RCM approaches to nakadomarin A, as well as those discussed in the cases of epilachnene and epothilone C, study of olefin metathesis-based strategies towards nakadomarin A offers a distinct advantage. The relatively low stereoselectivities gained from previous RCM studies broach the question as to

whether it can be addressed through the use of our Mo- or W-based MAP complexes. In collaboration with Dixon’s research group, we planned to prepare the fifteen-membered ring through RCM followed by the construction of the aza-cyclooctene moiety. Thereby the polycyclic structure of nakadomarin A provides the opportunity for investigations of whether the eight-membered ring can be generated through RCM in the presence of the relatively sensitive macrocycle and without significant diminution of the stereochemical purity of the macrocyclic alkene. Such investigations would allow us to establish if the MAP complexes can be involved in stereoselective formation of polycyclic compounds and the presence of one or more macrocyclic Z alkenes can be tolerated while additional rings are being formed.

N

Scheme 2.12: Approach to RCM Substrate 2.74

2.66

As depicted in Scheme 2.12, synthesis of tetracyclic diene substrate 2.74 begins with a diastereoselective formation of nitro ester 2.67 through a Michael addition of furanyl nitro olefin 2.64 (available in four steps) with chiral nucleophile 2.65, catalyzed by a bi-functional

organocatalyst.^38d A three-component nitro-Mannich/lactamization cascade reaction with 5-hexen-1-amine and formaldehyde in reflux methanol affords 2.68. Reductive removal of the nitro group is achieved with AIBN and tributyltin hydride.⁴⁰ To access the tetracyclic structure of the alkaloid through an N-acyliminium cyclization, switching of the protecting group is required:

acid-catalyzed methanolysis followed by an exhaustive Boc protection delivers 2.71 in two steps.

Selective delivery of one hydride to 2.71 by superhydride, leads to the formation of hemiaminal 2.72. Acylation followed by the treatment with (+)-camphorsulfonic acid furnishes a highly diastereoselective iminium cyclization to give tetracyclic diene 2.74.

2.75

Table 2.5: Catalytic RCM for Stereoseletive Total Synthesis of Nakadomain A ^a

a Reactions were carried out in benzene or toluene under an atmosphere of nitrogen gas or a vacuum, as noted. ^b Complexes 2.26 and 2.28 were prepared before use; Alkylidene 2.24 and 2.25 were synthesized in situ from the corresponding bis-pyrrolide and aryl alcohol. ^c Conversion and Z:E ratios were determined by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures; ^d Yields of purified products.

N

(40) (a) Ono, N.; Miyake, H.; Tamura, R.; Kaji, A. Tetrahedron Lett. 1981, 22,1705–1707. (b) Tormo, J.; Hays, D.

S.; Fu, G. C. J. Org. Chem. 1998, 63, 5296–5307.

With sufficient amount of 2.74 in hand, we then examined the macrocyclic RCM reactions to form the fifteen-membered ring (Table 2.5). As indicated by the data in entries 1 and 2 of Table 2.5, both Ru-based catalysts readily convert 2.74 to macrocycle 2.75 with reasonable efficiency, but favoring the undesired E isomer (62% and 64% E selectivity, respectively). Mo-based MAP complexes, such as 2.24 and 2.25, affords the formation of macrocycle 2.75 but with only 55% and 69% Z selectivity, respectively (entries 3 and 4, Table 2.5). By stopping the reaction at an earlier time point, when RCM proceeds to 45% conversion, the Z olefin of 2.75 is formed in only 72% stereoselectivity, suggesting a relatively lower kinetic selectivity provided by the catalyst (entry 5, Table 2.5). Similarly, reaction with tungsten complex 2.28 shows no significant selectivity (55% Z, entry 6, Table 2.5). In contrast, the sterically more demanding tungsten alkylidene 2.26, on the other hand, again occurs as the source of a facile and uniquely stereoselective catalyst, delivering the desired pentacycle 2.75 in 90% yield and with 97% Z selectivity (entry 7, Table 2.5). When the catalyst loading is reduced to 2 mol %, Z-2.75 is still obtained in 75% yield and with the same stereoselectivity (entry 8, Table 2.5).

Surprisingly, under conditions routinely used for typical chemical transformations (0.1 M vs high dilution required for RCM, entries 9 and 10, Table 2.5), RCM furnishes 2.75 in 52%

yield and 94% Z selectivity. Reduced pressure is no longer necessary when cyclization is performed at 0.1 M concentration. Otherwise, the desired macrocycle is obtained in a lower yield and selectivity (39% yield and 90% Z under 7 torr vaccum, entry 9, Table 2.5). Because homo-dimerization of diene 2.74 probably becomes predominant reaction pathway at a higher concentration, highly reactive methylidene complex, raised by ethylene generated from the reaction, converts the homocoupled byproduct to the monomeric diene 2.74, thus may increase the yield of desired ring closure. The slightly lower Z selectivity observed under vacuum (90% Z

vs 94% Z, entries 9 and 10, Table 2.5) possibly comes from RCM process involving the alkylidene derived from the terminal alkene of the homocoupled byproduct. It is possible that the latter pathway to 2.75, involving cyclization onto an internal olefin, can be less Z-selective than the RCM process involving two terminal alkenes of diene 2.74. It is consequently as a result of several delicate reactivity preferences that Z-selective RCM of diene 2.74 can be achieved efficiently with complex 2.26 as the catalyst.

To further understand the special reactivity profile of complex 2.26, as what we have studied in epothilone C RCM, we subjected samples of fifteen-membered macrocycle 2.75 (97%

Z) to a solution of Mo-based methylidene 2.41 and W-based methylidene 2.42. As in the case of

Mo complex, substantial loss of Z selectivity is detected within one hour (from 97% Z to 82% Z).

In the case of tungsten complex, in contrast to the epothilone C precursor, where alkene isomerization is undetected (cf. Scheme 2.8), tungsten methylidene complex leads to a slight erosion of Z:E ratio (from 97:3 to 93:7). It is likely that, as a result of diminished steric hindrance and a higher degree of angle strain of pentacyclic structure of 2.75, a stronger preference towards ring-opening/ring-closing process might exist, lowering the stereochemical purity of Z olefin.

Considering that the reaction time is at least two hours (entry 7, Table 2.5), it is possible that some part of 3% E olefin generated from RCM is the result of post-RCM isomerization, rather than any imperfection in kinetic selectivity. The above scenarios emphasize the unique challenges associated with an efficient and highly Z-selective RCM route to the polycyclic compounds.

2.5.c   Synthesis   of   the   Cyclooctene   Ring   of   Nakadomarin   A   through   Catalytic