WO2003106438A1 - Synthesis of diazonamide "a" core - Google Patents

Abstract

Using a novel samarium (II)-based macrocyclization cascade reaction, the entire highly strained ABCDEF aromatic core of diazonamide "A" and several novel analogies thereof are constructed.

Description

SYNTHESIS OF DIAZONAMIDE "A" CORE

Description

Technical Field:

The invention relates to diazonamide "A" and to macrocyclization cascade reactions employable for synthesizing same. More particularly, the invention relates to analogs of the aromatic core of diazonamide "A" and to samarium (II) based hetero pinacol macrocyclization cascade reactions.

Background: In 1991 , Fenical and Clardy disclosed the structure of diazonamide A (1 ,

Figure 1 ), a secondary metabolite isolated from the colonial ascidian Diazona chinensis, whose unprecedented molecular architecture includes a cyclic polypeptide backbone, a strained halogenated heteroaromatic core trapped as a single atropisomer, and a lone quaternary center at the epicenter of the two major macrocyclic subunits (N. Lindquist, et al. J. Am. Chem. Soc. 1991 , 113, 2303-2304). Significant synthetic efforts have been directed towards diazonamide A by a number of laboratories around the world because of the unique challenges posed by this structural framework, its impressive in vitro cytotoxicity, and the inability to harvest additional material from the original source (Magnus, P.; et al. Tetrahedron Lett. 2001, 42, 7193-7196; Vedejs, E.; et al. Org. Lett. 2001 , 3, 2451-2454; Li, J.; et al. Angew. Chem. 2001 , 113, 2754-2757; Angew. Chem. Int. Ed. 2001, 40, 2682-2685; Wipf, P.; Methot, J.-L. Org. Lett. 2001 , 3, 1261-1264; Kriesberg, J. D.; et al. Tetrahedron Lett. 2001 , 42, 627-629; Radspieler, A.; Liebscher, J. Synthesis 2001 , 745-750; Fuerst, D. E.; et al. Org. Lett. 2000, 2, 3521-3523; Chen, X.; et al. Angew. Chem. 2000, 112, 967-970; Angew. Chem. Int. Ed. 2000, 39, 937-940; Vedejs, E.; Wang, J. Org. Lett. 2000, 2, 1031-1032; Vedejs, E.; Barba, D. A. Org. Lett. 2000, 2, 1033-1035; Magnus, P.; Mclver, E. G. Tetrahedron Lett. 2000, 41, 831-834; Chan, F.; et al. Tetrahedron Lett. 2000, 41, 835-838; Lach, F.; Moody, C. J. Tetrahedron Lett. 2000, 41, 6893-6896; Bagley, M. C; et al. Tetrahedron Lett.

2000, 41, 6897-6900; Bagley, M. C; et al. Tetrahedron Lett. 2000, 41, 6901-6904; Hang, H. C; et al. Synthesis 1999, 398-400; Magnus, P.; Kreisberg, J. D. Tetrahedron Lett. 1999, 40, 451-454; Boto, A. et al. Tetrahedron Lett. 1998, 39, 8167-8170; Wipf, P.; Yokokawa, F. Tetrahedron Lett. 1998, 39,

2223-2226; Jeong, S.; et al. J. Org. Chem. 1998, 63, 8640-8641 ; Moody, C. J.; et al. J. Chem. Soc. Perkin Trans. 1 1997, 2413-2419; Konolpelski, J. P.; et al. Synlett 1996, 609-611 ; Moody, C. J.; et al. Pure Appl. Chem. 1994, 66, 2107-2110). However, despite much progress, a route to this fascinating compound still remains elusive.

Many synthetic approaches derive from two distinct retrosynthetic analyses of the diazonamide problem, viz., 1.) an initial synthesis of the peptide framework (the AG macrocycle) with late-stage closure of the C₁₆-C₁₈ bond, or alternatively, 2.) an early introduction of the C₁₆-C₁₈ biaryl axis followed by a macrocyclization event to form the crucial C₂₉-C₃₀ linkage with subsequent A-ring oxazole synthesis. Although advanced synthetic intermediates have proven recalcitrant in the face of intensive efforts to forge the C₁₆-C₁₈ bond in the former approach (Li, J.; et al. Angew. Chem. 2001 , 113, 2754-2757; Angew. Chem. Int. Ed. 2001 , 40, 2682-2685), the overall viability of the latter retrosynthetic blueprint has been verified based on studies in which a highly convergent route to 3 (Figure 1 ) was developed by calling upon the power of the Suzuki and Homer-Wadsworth-Emmons (HWE) reactions to generate the C₁₆-C₁₈ biaryl linkage and the C₂₉-C₃₀ alkene, respectively (Nicolaou, K. C; et al. Angew. Chem. 2000, 112, 3615-3620; Angew. Chem. Int. Ed. 2000, 39, 3473-3478). In addition, an approach in which C_2g-C₃₀ bond formation was accomplished by Dieckmann condensation also realizes this goal (Vedejs, E.; et al. Org. Lett.

2001, 3, 2451-2454). The elaboration of the previously synthesized 3 is disclosed herein to the complete ABCDEF macrocycle as well as the development of a novel and concise hetero pinacol macrocyclization cascade sequence induced by Sml₂/HMPA which enables access to the parent 12-membered diazonamide model system 2 (Figure 1 ) in only sixteen linear steps. Summary:

Using a novel samarium(ll)-based macrocyclization cascade reaction, the entire highly strained ABCDEF aromatic core of diazonamide "A" and several novel analogs thereof can be constructed.

One aspect of the invention is directed to an analog of diazonamide "A" represented by the following structure:

In the above structure, R₁ and R₂ are each radicals independently selected from the group consisting of hydrogen and halide; R₃ is a radical selected from the group consisting of hydrogen, methyl, and MOM; R₄ is a radical selected from the group consisting of hydrogen and -OR₈, wherein R₈ is an alkyl group having from 1 to 6 carbons; R₅ is a radical selected from the group consisting of hydrogen and hydroxyl; R₆ and R₇ are each radicals independently selected from the group consisting of hydrogen and alkyls having from 1 to 6 carbons or together form a bridge represented by the following structure:

However, there is a proviso that, if R₆ and R₇ form the bridge, then the analog of diazonamide "A" is not identically diazonamide "A" itself. Preferred embodiments of this aspect of the invention are analogs of diazonamide "A" represented by the following structures:

Another aspect of the invention is directed to a process for performing a hetero pinacol macrocylization reaction. In the first step of the process, a bifunctional reactant having an oxime ether and an alkyl, vinyl, or ketyl radical is provided. Then, the oxime ether is coupled with the alkyl, vinyl, or ketyl radical by a samarium (II) based cascade reaction for cyclizing the bifunctional reactant and forming a ring having a size greater than seven. In a preferred mode of this process, the coupling step is represented by the following reductive cascade reaction:

[pinacol cyclization]

[N-0 cleavage]

Brief Description of Drawings:

Figure 1 illustrates the structure of diazonamide "A" and a retrosynthetic analysis of model system 2.

Figure 2 illustrates a scheme for the synthesis of an analog of the aromatic core of diazonamide "A," i.e., compound 8.

Figure 3 illustrates a scheme for the synthesis of advanced intermediates employable for constructing the aromatic core of diazonamide "A" and analogs thereof.

Figure 4 illustrates a macrocyclization scheme employing a pinacol coupling cascade sequence for synthesizing the aromatic core of diazonamide "A" and analogs thereof.

Figure 5 illustrates a scheme for the completing of the synthesis of the aromatic core of diazonamide "A" and analogs thereof, after the macrocylization procedure of Figure 4.

Detailed Description:

Shortly after the disclosure of 3 (Nicolaou, K. C; et al. Angew. Chem. 2000, 112, 3615-3620; Angew. Chem. Int. Ed. 2000, 39, 3473-3478), it was established that the final A-ring oxazole of the diazonamide skeleton could be fashioned from the C₂₉-C₃₀ olefinic residue by following a four step sequence as delineated in Figure 2. First, exposure of 3 to KMn0₄ in acetic anhydride (Sharpless, K. B; et al. J. Am. Chem. Soc. 1971, 93, 3303-3304) led to the formation of a diketone, which was then transformed to 6 by selective conversion of the more activated and less sterically hindered carbonyl group to its corresponding methoxime derivative. Significantly, although dihydroxylation of the alkene in 3 could readily be achieved using stoichiometric amounts of Os0₄ activated by quinuclidine (He, F.; et al. J. Am. Chem. Soc. 1999, 121, 6771-6772; Corey, E. J.; et al. J. Am. Chem. Soc. 1996, 118, 7851-7852), the resulting diol proved highly unstable as it decomposed rapidly both in solution and during isolation, which led to the near exclusive formation of benzofuran side products by the cyclofragmentation pathway observed frequently in this type of system (Nicolaou, K. C; et al. Angew. Chem. 2000, 112, 1135-1138; Angew. Chem. Int. Ed. 2000, 39, 1093-1096). With 6 in hand, the oxime function was reductively cleaved through hydrogenolysis in acidified methanol (M. Hudlicky, Reductions in Organic Chemistry, ACS Monograph 188, American Chemical Society, 1996, pp. 149-189). Subsequent in situ acetylation of the resultant amine using AcCI furnished acetamide 7. Finally, formation of the desired oxazole ring in 8 was achieved from 7 by Gabriel-Robinson cyclodehydration initiated by p-TsOH in refluxing benzene (50 % yield) (Parsons, R. L.; Heathcock, C. H. J. Org. Chem. 1994, 59, 4733-4734); significantly, no other condition screened proved equally effective for this oxazole formation (Use of Martin's sulfurane as well as variants of the Gabriel-Robinson cyclodehydration such as PPh₃/CI₆C₂ Et₃N (see Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604-3606) failed to deliver the desired compound. In a related system, p-TsOH in toluene was the reported condition employed for oxazole formation (see Wipf, P.; Methot, J.-L. Org. Lett. 2001, 3, 1261-1264)).

Overall, although the above route proved successful for completion of the aromatic core of diazonamide A, the relatively modest yields observed for initial HWE closure to generate 3 as well as for diketone formation suggested that it would be potentially challenging to process sufficient material by using the developed sequence to complete the total synthesis of diazonamide A in the context of a fully elaborated G ring. As such, a second-generation strategy was sought to prepare model system 2 (Figure 1). Disclosed herein is a hetero pinacol coupling reaction employable for fashioning a fully functionalized C_2g-C₃₀ bond directly suitable for A-ring oxazole formation (5, Figure 1) from a percursor aldehyde-oxime (4). Since the pioneering efforts from the groups of Corey, Hart, and Bartlett (Corey, E. J.; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821-2824; Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1631-1633; Bartlett, P. A.; et al. J. Am. Chem. Soc. 1988, 110, 1633-1634), which established oximes as highly competent radical acceptors in reductive cyclizations, numerous examples of hetero pinacol coupling reactions of alkyl, vinyl, and ketyl radicals with oxime ethers have been reported in both inter-(Hanamoto, T.; Inanaga, J. Tetrahedron Lett. 1991 , 32, 3555-3556; Miyabe, H.; et al. Tetrahedron Lett. 1998, 39, 631-634) and intramolecular (For selected examples, see: Riber, D.; et al. J. Org. Chem. 2000, 65, 5382-5390; Keck, G. E.; et al. J. Am. Chem. Soc. 1999, 121, 5176-5190; Keck, G. E.; et al. J. Org. Chem. 1999, 64, 4465-4476; Tormo, J.; Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 201 -202; Miyabe, H.; et al. J. Org. Chem. 1998, 63, 4397-4407; Keck, G. E.; Wager, T. T. J. Org. Chem. 1996, 61, 8366-8367; Kiguchi, T.; et al. Tetrahedron Lett. 1995, 36, 253-256; Camps, P.; et al. Liebigs Ann. 1995, 523-535; Shono, T.; et al. J. Org. Chem. 1994, 59, 1730-1740; Naito, T.; et al. Tetrahedron Lett. 1994, 35, 2205-2206; Marco-Contelles, J.; et al. Tetrahedron Lett. 1991 , 32, 6437-6440) contexts. However, this variant of the pinacol reaction appears to have not yet been successfully applied in a macrocyclization reaction to generate a ring size greater than seven, despite precedent for medium-size ring formation in related systems in which dialdehydes were employed (Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745-777; Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321-3354; Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307-338; Skrydstrup, T. Angew. Chem. 1997, 110, 355-357; Angew. Chem. Int. Ed. Engl. 1997, 36, 345-347). As such, the diazonamide problem offered a unique and challenging test for the power of this synthetic methodology.

To pursue this idea, the requisite synthetic fragments were prepared as shown in Figure 3, commencing from the previously reported lactone 9 (prepared in nine steps from known starting materials) (Nicolaou, K. C; et al. Angew. Chem. 2000, 112, 3615-3620; Angew. Chem. Int. Ed. 2000, 39, 3473-3478). Complete reduction of the lactone with LiBH₄ was followed by the smooth formation of dihydrobenzofuran 10 in 95 % yield upon heating the resultant diol with 1 ,1-carbonyldiimidazole in THF at reflux, a result which has been previously reported in related systems except under far more forcing conditions (Stafford, J. A.; Valvano, N. L. J. Org. Chem. 1994, 59, 4346-4349. Although the formation of a seven-membered carbamate upon reaction with 1 ,1-carbonyldiimidazole would be expected, it appears that, in this particular case, the formation of five-membered rings is favored exclusively based on considerations of ring strain.). Subsequent conversion of 10 to boronate 11 was then achieved in 70 % yield by using the conditions developed by Ishiyama et al.( J. Org. Chem. 1995, 60, 7508-7510). For the purposes of this model study, lactone 9 was also accessed through initial reaction of mandelic acid 12 with 2-bromophenol 13 using Padwa's method (Padwa, A.; et al. J. Am. Chem. Soc. 1975, 97, 1837-1845), followed by facile elaboration of 14 to 9 (The addition of HCHO was achieved using the protocol reported by Kobayashi, S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590-3596. For a related example, see: Bernardelli, P.; et al. J. Am. Chem. Soc. 2001 , 123, 9021-9032), which enabled the synthesis of boronate 11 in just six linear synthetic operations.

Next, the previously reported indole-oxazole 15 (Nicolaou, K. C; et al. Angew. Chem. 2000, 112, 3615-3620; Angew. Chem. Int. Ed. 2000, 39, 3473-3478) (available in six steps from 4-bromoindole) was protected as its MOM ether 16 in 94 % yield by a standard protocol. In a final series of steps, 11 and 16 were smoothly coupled by using [Pd(dppf)CI₂] and K₂C0₃ in DME at 105 °C

(Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508-7510) to afford 17 in 66 % yield. Finally, a tandem deprotection-oxidation sequence cleanly provided an intermediate dialdehyde, with the more activated benzylic aldehyde selectively engaged as a methyloxime ether upon exposure to excess methoxylamine hydrochloride in DMSO (75 % overall for three steps). With 18 in hand, the stage was set to attempt the critical hetero pinacol macrocyclization. In assessing reaction conditions to initially screen, the power of Sml₂ (Namy, J. L.; et al. Nouv. J. Chem. 1977, 1, 5-7; Girard, P.; et al. J. Am. Chem. Soc. 1980, 102, 2693-2698) seemed uniquely suited for the present purposes. Also, reports of Sml₂-induced scission of the N-0 bond of oximes (Keck, G. E.; et al. Tetrahedron 1999, 55, 11755-11772; Chiara, J. L; et al. J. Org. Chem. 1996, 61, 359-360; Keck, G. E.; et al. Tetrahedron Lett. 1995, 36, 7419-7422) were consistent with the possibility that a cascade sequence involving macrocyclization followed by in situ N-0 cleavage could be effected to generate an amino alcohol such as 5 (Figure 1) directly. However, only one isolated example of reductive cyclization with subsequent oxime cleavage in the presence of Sml₂ is reported in the literature (Marco-Contelles, J.; et al. J. Org. Chem. 1997, 62, 7397-7412). For a preliminary disclosure of the same reductive coupling/N-0 cleavage and an example with altered protecting groups, see Chiara, J. L.; et al. J. Org. Chem. 1995, 60, 6010-6011 ; Bobo, S.; et al. Synlett 1999, 1551-1554, in which the use of a large excess of Sml₂ ,(6.0 equiv) followed by prolonged treatment with deoxygenated H₂0 (The role of H₂0 is either as a proton source or, more likely, as a donor ligand which increases the reducing power of Sml₂. For leading references, see: Hanessian, S.; Girard, C. Synlett Λ 994, 861-862; Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008-5010) led to an amino alcohol product. There are no other reports of amino alcohol products arising from Sml₂-induced reductive cyclization, in which typically only three to four equivalents of Sml₂ are employed. It is disclosed herein that only through the use of a gross excess of Sml₂ in conjunction with a donor ligand additive such as HMPA does the desired cascade sequence proceed.

After treatment of aldehyde-oxime 18 with a premixed complex of 9.0 equiv of Sml₂ and 36.0 equiv of HMPA in THF at ambient temperature for 1 hour, followed by quenching with aqueous NH₄CI, extraction, solvent removal, and subsequent peptide coupling with a DMF solution of AcOH, EDC, and HOBt, the formation of compound 22 as a mixture of stereoisomers in 25 % overall yield (Figure 4) was observed. It is disclosed herein that initial exposure of 18 to Sml₂/HMPA leads to the generation of diradical intermediate 19, which then cyclizes to provide 20. The presence of excess Sml₂ complexed with HMPA then effected N-0 cleavage, which first led to intermediate 21 , and then provided the desired amino alcohol upon workup which was trapped as its acetamide 22. As such, each step in the cascade proceeded in an average yield of 63 %. Although one could also envision solely the generation of a ketyl radical which then engaged the oxime directly to provide 20, the isolation of noncyclized material with both the aldehyde and oxime reduced suggests that diradical 19 cannot be excluded. In accordance with earlier reports exploring aldehyde-oximes, (Riber, D.; et al. J. Org. Chem. 2000, 65, 5382-5390), (Miyabe, H.; et al. J. Org. Chem. 1998, 63, 4397-4407) the macrocyclization did not proceed at all in the absence of HMPA. Significantly, when the ratio of HMPA Sml₂ was reduced from 4:1 to 2:1 (still with 9.0 equiv of Sml₂), 22 was observed along with significant amounts of cyclized product with the N-0 linkage firmly intact, indicating that the presence of a suitable donor ligand in conjunction with excess Sml₂ is the critical combination required for reliable oxime cleavage after reductive cyclization. Moreover, these results suggest that in cases where one wishes to effect only N-0 cleavage, the addition of HMPA might greatly facilitate the transformation in cases which prove difficult or low-yielding with Sml₂ alone (Keck, G. E.; et al. Tetrahedron 1999, 55, 11755-11772), (Keck, G. E.; et al. Tetrahedron Lett 1995, 36, 7419-7422). This proposition, along with an exploration of the generality of this cascade sequence, is the subject of current investigations. Finally, one should note that the final peptide coupling is a highly general reaction and L-valine amino acids bearing Fmoc, Boc, and Cbz protecting groups were readily coupled in yields comparable to those obtained with AcOH. This procedure represents a step forward in terms of overall synthetic utility, since previous reports have only indicated that products from Sml₂ reactions could be trapped directly with simple acylating reagents.

After the desired cascade sequence, oxidation of 22 to ketoamide 23 was smoothly effected with Dess-Martin periodinane in 94 % yield. As shown in Figure 5, formation of the A-ring oxazole was then accomplished by heating 23 in neat POCI₃ at 70 °C for 2 h, providing 24 and 25 in a ratio of 2.4:1 and in an overall yield of 65 % (Although POCI₃/DMF has been reported several times for oxazole formation from ketoamides, use of neat POCI₃ is far more rare. For one example, see: Dow, R. L. J. Org. Chem. 1990, 55, 386-388). The formation of 25 was significant in that it indicated that MOM cleavage was far more facile with the heterocyclic skeleton completed, since numerous synthetic precursors such as 16 were recovered unscathed under these reaction conditions (In one particularly instructive example, remote substituents played a critical role in the ease of MOM cleavage from an indole substrate: Meyers, A. I.; et al. J. Org. Chem. 1991, 56, 2960-2964). Simply treating 25 with aqueous NaOH in THF (Macor, J. E.; et al. Tetrahedron Lett. 1997, 38, 1673-1676) then readily effected the expulsion of formaldehyde which led to the fully deprotected diazonamide skeleton 26. Additionally, the A-ring oxazole could also be fashioned from 23 with pTsOH in refluxing benzene, albeit in lower yield with prolonged reaction times, whereas the use of the Burgess reagent in refluxing THF (Brain, C. T.; Paul, J. M. Synlett 1999, 1642-1644) afforded 24 exclusively in comparable yield to that obtained with POCI₃.

In a final study, exposure of 24 to 3.0 equiv of NCS in THF/CCI₄ (1 :1 ) at 55 °C for 10 h cleanly provided dichloro compound 27 as a single atropisomer along the C₂₄-C₂₆ biaryl axis. Formation of the ABCDEF macrocycle prior to chlorination was critical for the selectivity of this reaction, as chlorination of earlier synthetic intermediates such as 17 proceeded with equal facility, but provided a 1 :1 mixture of atropisomers which could not be interconverted in CD₃CN at 340 K over 30 min. Subsequent use of BBr₃ in CH₂CI₂ at -78 °C for 20 min led to the exclusive cleavage of the methyl ether linkage of the MOM protecting group in 27, which upon immediate treatment with aqueous NaOH completed the synthesis of 2 in just sixteen linear steps from known or commercially available starting materials (This protocol represents a new method for MOM cleavage on indoles, particularly for acid-sensitive substrates since typical deprotection procedures utilize HCl at elevated temperatures. Since previous reports have already established the acid-sensitivity of the aryl chlorine atoms on the diazonamide skeleton that bears a free indole (see Li, J.; et al. Angew. Chem. 2001, 113, 2754-2757; Angew. Chem. Int. Ed. 2001 , 40, 2682-2685), the ability to initially cleave the methyl ether only, followed by basic hydrolysis, is crucial for the survival of the chlorine substituents in 2.). Synthetic Protocols:

Figure 1 shows the structure of diazonamide A (1) and retrosynthetic analysis of model system used in this study.

Figure 2 illustrates the initial model studies which led to the complete heteroaromatic skeleton (8) of diazonamide A: a) KMn0₄ (6.0 equiv), Ac₂0, 0 °C, 2 h, 35 %; b) MeONH₂-HCI (20 equiv), EtOH, 25 °C, 12 h, 95 %; c) Pd/C (10 %, 2.0 equiv), H₂ (3.0 atm), TFA/MeOH (1 :20), 25 °C, 12 h; then AcCI (3.0 equiv), Et₃N (3.0 equiv), CH₂CI₂, 25 °C, 30 min, 80 %; d) p-TsOH, benzene, 80 °C, 20 h, 50 %. TFA=trifluoroacetic acid, p-TsOH=p-toluenesu!fonic acid.

Figure 3 shows the synthesis of key intermediate 18: a) LiBH₄ (8.0 equiv), THF, 25 °C, 4 h, 95 %; b) CDI (2.0 equiv), THF, reflux, 2 h, 95 %; c) BPD (1.2 equiv), [Pd(dppf)CI₂]»CH₂CI₂ (0.2 equiv), KOAc (3.0 equiv), DMSO, 90 °C, 6 h, 70 %; d) 12 (1.0 equiv), 13 (1.0 equiv), H₂S0₄ (70 % aq.), 45 min, 42% (95% based on recovered 13); e) Et₃N (3.0 equiv), TMSOTf (1.2 equiv), CH₂CI₂, 0 °C, 1 h; then HCHO (37 % in H₂0, 5.0 equiv), [Yb(OTf)₃] (0.1 equiv), THF, 25 °C, 24 h, 78 %; f) TBSCI (3.0 equiv), imidazole (6.0 equiv), DMF, 25 °C, 6 h, 95 %; g) NaH (2.0 equiv), THF, 0 °C, 5 min; then MOMCI (2.0 equiv), THF, 0 °C, 10 min, 94 %; h) 11 (1.0 equiv), [Pd(dppf)CI₂].CH₂CI₂ (0.2 equiv), K₂C0₃ (5.0 equiv), DME, 110 °C, 8 h, 66 %; i) TBAF (3.0 equiv), THF, 25 °C, 10 min, 93 %; j) Dess-Martin periodinane (3.0 equiv), NaHC0₃ (10 equiv), CH₂CI₂, 25 °C, 1 h, 88 %; k) MeONH₂«HCI (10 equiv), DMSO, 25 °C, 10 min, 91 %. CDI=1 ,1'-carbonyldiimidazole, BPD=bis(pinacolato)diboron, dppf=(diphenylphosphanyl)ferrocene, LiHMDS=lithium salt of 1 ,1 , 1 ,3,3, 3-hexa- methyldisilazane, TBS=tert-butyldimethylsilyl, TBDPS=tert-butyldiphenylsilyl, MOM=methoxymethyl, TBAF=tetrabutylammonium fluoride.

Figure 4 shows the novel pinacol coupling cascade sequence to efficiently prepare ketoamide 23. a) Sml₂ (0.1 M in THF, 9.0 equiv), HMPA (36 equiv), THF, 25 °C, 1 h; then saturated aq. NH₄Cl, 25 °C, 1 h; solvent removal; then AcOH (3.0 equiv), EDC (3.0 equiv), HOBt (3.0 equiv), DMF, 25 °C, 4 h, 25 % overall, 63 % per synthetic operation in the cascade sequence; b) Dess-Martin periodinane (15 equiv), NaHC0₃ (50 equiv), CH₂CI₂, 25 °C, 1.5 h, 94 %. HMPA=hexamethyIphosphoramide, EDC = 3-(3-dimethylaminopropyl)-1- ethylcarbodiimide, HOBt = 1-hydroxy-1H- benzotriazole.

Figure 5 shows the completion of the synthesis of the fully elaborated heterocyclic skeleton 2 of diazonamide A (1). a) POCI₃, 70 °C, 2 h, 24/25 (2.4:1), 65 %; b) aq. NaOH (15 %, excess), THF, 25 °C, 10 min, 74 %; c) NCS (3.0 equiv), THF/CCI₄ (1:1 ), 55 °C, 8 h, 73 %; d) BBr₃ (1.0 M in CH₂CI₂, 2.0 equiv), CH₂CI₂, -78 °C, 20 min; then aq. NaOH (15 %, excess), THF, 25 °C, 10 min, 61 %.

Claims

What is claimed is:

1. An analog of diazonamide "A" represented by the following structure:

wherein:

R., and R₂ are each radicals independently selected from the group consisting of hydrogen and halide; R₃ is a radical selected from the group consisting of hydrogen, methyl, and MOM;

R₄ is a radical selected from the group consisting of hydrogen and -OR₈, wherein R₈ is an alkyl group having from 1 to 6 carbons; R₅ is a radical selected from the group consisting of hydrogen and hydroxyl; R₆ and R₇ are each radicals independently selected from the group consisting of hydrogen and alkyls having from 1 to 6 carbons or together form a bridge represented by the following structure:

with a proviso that, if R₆ and R₇ form the bridge, then the analog of diazonamide "A" is not identically diazonamide "A" itself.

2. An analog of diazonamide "A" according to Claim 1 represented by the following structure:

3. An analog of diazonamide "A" according to Claim 1 represented by the following structure:

4. An analog of diazonamide "A" according to Claim 1 represented by the following structure:

5. An analog of diazonamide "A" according to Claim 1 represented by the following structure:

6. An analog of diazonamide "A" according to Claim 1 represented by the following structure:

7. An analog of diazonamide "A" according to Claim 1 represented by the following structure:

8. A process for performing a hetero pinacol macrocylization reaction, the process comprising the following steps:

Step A: providing a bifunctional reactant having an oxime ether and an alkyl, vinyl, or ketyl radical; and then

Step B: coupling the oxime ether with the alkyl, vinyl, or ketyl radical by a samarium (II) based cascade reaction for cyclizing the bifunctional reactant of said Step A and forming a ring having a size greater than seven. rocess according to claim 10 wherein:

the coupling step of said Step B is represented by the following cascade reaction: