Synthesis of the Macrocycles

The first report dealing with the synthesis of a macrocyclic tri-chothecene, albeit a non-natural product, originated from Tamm s laboratory in 1978 (22). Three years later, Still and Ohmizu synthesized the first naturally occurring macrocyclic trichothecene verrucarin A (37) (133). Since 1981, the increased availability of verrucarol (82) (150), the sesquiter-penoid backbone for most of the macrocycles, has stimulated work in this area and culminated in Still s recent syntheses (135) of baccharin B5 (59) and roridin E (47), the most complex trichothecenes synthesized to date. Sandwiched between these landmark syntheses have been equally exciting studies initiated by Tamm (verrucarin A and 3a-hydroxyverrucarin A (106), Fraser-Reid and Jarvis (verrucarin J) (42) and Roush (verrucarin J and 

As model studies represented most of the early activity in the synthesis of macrocyclic trichothecenes and, in addition, contributed a number of important precedents for future synthetic endeavors, the syntheses of these systems will be outlined first. 

Reaction of the verrucarinic acid derivative (247) with verrucarol (82), mediated by DCC and 4-N,N-dimethylaminopyridine (DMAP), yielded the monoester (250) by exclusive acylation at C-15. A similar esterification procedure attached the muconic acid (249) to C-4. Following desilylation the seco acid (251) was cyclized (52%) and deacetylated to yield verrucarin A (37). When alternative conditions for the esterification of acid (249) were employed, partial isomerization of the , Z-isomer (251) to an E,E-isomer was observed. However, lactonization of this mixture produced only the natural E,Z-macrocyclic (37) as the E,E-isomer failed to cyclize. Such reactivity differences have been observed with other trichothecanoid macrocycles (22, 148), although, as shall be seen, E,E-macrocycles can be prepared if so desired 115, 121). 

Nearly identical routes to the hydroxy ester (264) have been developed independently by Roush and by Trost (722,144). Selective opening of the trans-cpoxidc (262) gave alcohol (263) with correct relative stereochemistry at C-2 and C-3. Subsequent conversion to the hydroxy ester (264) was straightforward. Successful resolution of alcohol (263) allows this route to be used for the synthesis of chiral material (144). 

A tin-mediated ene reaction on the chiral glyoxylate ester (265, R = chiral group) has yielded the verrucarinic acid precursor (266) as virtually a single enantiomer (168). The selectivity of this metallo-ene process stands in sharp contrast to the proto-ene reaction (129) which produces a mixture of diastereomers (267) and (268) in low yield. 

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Various organotin reagents react with acyl and aroyl halides under mild conditions without decarbonylation to give carbonyl compounds[390,39l]. Alkyl- or alkenyltin reagents react with acyl and aroyl chlorides to give ketones[548.733,734]. One example is the preparation of the a,/3-dnsaturated 7-keto esters 860 and 861, carried out under a CO atmosphere[735]. The reaction has been applied intramolecularly to the synthesis of the macrocyclic keto... 

Pyrazolecarbinols can be dehydrated to vinylpyrazoles, (438) — (446) (72JHC1373), or transformed into chloromethyl derivatives (81T987). Compound (440 R = CH2C1) thus prepared is the starting material for the synthesis of the macrocycles (226)-(228) (Section 4.04.2.1.2(vi)). Vinyl- and ethynyl-pyrazoles have been extensively studied (B-76MI40402) and many vinylpyrazoles are polymerized by free radical initiators. 

The synthesis of the macrocycle is outlined in Scheme 17. Union of the polyol segment 86 and polyene segment 107 proved difficult, presumably due to steric hindrance about the ester linkage. After a series of standard esterification protocols failed, it was found that this coupling could be accomplished in 70 % yield... 

It should be noted that while TE domains represent the most common solution in releasing macrocyclic NRPs and PKs, other pathways are known. For instance, in the biosynthesis of cyclosporine, the cyclization is proposed to be catalyzed by the most downstream C-domain [48]. Macrocyclization can also occur under reduction of a carbonyl group mediated by a reduction domain (R-domain) as proposed in the synthesis of the macrocyclic imine nostocyclopeptide [49]. The synthetic utility of these cyclization strategies has not yet been reported. 

The synthesis of the macrocycles 43 (Scheme 9) is an example of repetitive, highly stereoselective Diels-Alder reaction between bis-dienes 41 and bis-dienophiles 42, containing all oxo or methano bridges syn to one another. The consecutive inter- and intramolecular Diels-Alder reactions only succeed at high pressure. Obviously, both reactions are accelerated by pressure. The macrocycles are of interest in supramolecular chemistry (host-guest chemistry) because of their well-defined cavities with different sizes depending on the arene spacer-units. 

Grieco in the total synthesis of (—)-epothilone B 134 used a rhodium-catalyzed hydroboration as a key step in the synthesis of the macrocyclic ring (Figure 15).141 Completion of the synthesis of the C(3)-C(12) fragment was carried out using a rhodium-catalyzed hydroboration as the key step. 

Only two general methods have been developed for the synthesis of the macrocyclic annulenes.9 The first of these, developed by Sondheimer and co-workers, involves the oxidative coupling of a suitable terminal diacetylene to a macrocyclic polyacetylene of required ring size, using typically cupric acetate in pyridine. The cyclic compound is then transformed to a dehydroannulene, usually by prototropic rearrangement effected by potassium i-butoxide. Finally, partial catalytic hydrogenation of the triple bonds to double bonds leads to the annulene. 

Encapsulation of squaraine 23a in diastereomeric triptycene-based tetralactam macrocycles 24a and 24b was described in [61], The synthesis of the macrocyclic hosts was done by the reaction of pyridine-2,6-dicarbonyl dichloride and 2,7-diaminotriptycene in dry THF with Et3N. Macrocycles 24a and 24b readily form... 

In their synthesis of the macrocyclic hexapeptide bistratamide D, Meyers and co-workers prepared the tran -oxazoline 70 from the corresponding cw-oxazo-line 69 through several steps, the last of which was cyclization to the oxazoline using Burgess reagent. The net outcome is inversion of the stereocenter at the 5-position of the oxazoline (Scheme 8.25). 

The synthesis of didemnin A (60) consists of four main elements (1) construction of the Hyvpa-isostatine unit 52 (Scheme 9), (2) synthesis of the tetrapeptide unit, Z-Leu-Pro-(Me)Tyr(Me)-0-Boc-Thr-OH (57, Scheme 10), (3) synthesis of the macrocycle, and (4) addition of the A-methyl-D-leucine unit to form didemnin A (60, Scheme 11). 

Template reactions between malonaldehydes and diamines in the presence of copper(II), nickel(II) or cobalt(II) salts yield neutral macrocyclic complexes (equation 15).99-102 Both aliphatic102 and aromatic101 diamines can be used. In certain cases, non-macrocyclic intermediates can be isolated and subsequently converted into unsymmetrical macrocyclic complexes by reaction with a different diamine (Scheme ll).101 These methods are more versatile and more convenient than an earlier template reaction in which propynal replaces the malonaldehyde (equation 16).103 This latter method can also be used for the non-template synthesis of the macrocyclic ligand in relatively poor yield. A further variation on this reaction type allows the use of an enol ether (vinylogous ester), which provides more flexibility with respect to substituents (equation 17).104 The approach illustrated in equation (15), and Scheme 11 can be extended to include reactions of (3-diketones. The benzodiazepines, which result from reaction between 1,2-diaminobenzenes and (3-diketones, can also serve as precursors in the metal template reaction (Scheme 12).101 105 106 The macrocyclic complex product (46) in this sequence, being unsubstituted on the meso carbon atom, has been shown to undergo an electrochemical oxidative dimerization (equation 18).107... 

The coupling was extended to the synthesis of the macrocyclic lactone I containing a dienone group. In this case a stoichiometric amount of Pd(II) is necessary to effect ring closure.2... 

Carbonylative coupling of vinyl triflates with organotins (12, 470-471).3 The final step in a synthesis of the macrocyclic diterpene jatrophone (2) was effected by carbonylative coupling of a vinyl triflate with vinyltin catalyzed by bis(acetonitrile)-dichloropalladium. 

Scheme 4. Synthesis of the macrocyclic part (3) of sanglifehrin A (1) by Nicolaou et al.

The ring opening of rfr-azetidin-2-ones 323 with 2,2,6,6-tetramethylpiperidinyl-l-oxy (TEMPO) and sodium hypochloride furnished the ring expansion product isoxazolidinc-2,5-dionc 324, which is used in the synthesis of the macrocyclic antibiotic lysobactin (Equation 112) <2000PAC1763>. 

The synthesis of macrocycle 17 was optimized to 46 % overall yield of both isomers and 22 % overall yield of the meso isomer in nine steps. During this synthesis a method was developed to separate the pro-meso isomer from the pro-d/1 isomer of the amides. This method was very reproducible and there was good recovery of compound from the column. A method was also developed to separate the meso isomer from the d/1 isomer that resulted from isomerization of the meso isomer to a 1 1 mixture of meso and d/1 during the reduction of pro-meso to the meso isomer. However, this method was tedious and not very reproducible therefore care must be taken to prevent isomerization during the reduction of the amide. With an optimized synthesis of the macrocycle 17 at hand, enough macrocycle was made available to explore synthesis of the attachment of the side arm. 

The synthesis of the macrocycle 130a with the topology of a bacteriophin on the other hand required a high-dilution technique. A subsequent reduction to 130b followed by thermo-flash dehydrogenation gave bacteriophin 3, albeit in poor yield (0.2%). 

A stereoselective Michael addition was utilized in a synthesis of the macrocyclic polyamine alkaloid lunarine. The key intermediate was generated as shown below <02JCS(P1)1115>. 

This reaction was applied to the synthesis of the macrocyclic polyamine alkaloid celacinnine [65] a key step of this synthesis was the conversion of the bicyclic VIII/123 to nine-membered VIII/124, see Scheme VIII/23. 

The nickel ) complex of 92 cannot be prepared directly via the template method, but can be prepared by a transmetallation procedure. Synthesis of the macrocycle in the presence of one of the metal ions known to be effective as a template is followed by a metal exchange process in solution to insert the nickel ) ion. This cation exhibits a strong preference for the square planar, square pyramidal, and octahedral geometries 79). Thus the failure of the nickel ) cation to behave as a template ion in the synthesis of 92 is probably due to the disinclination of the metal to accommodate the pentagonal array of donor nitrogen atoms necessary for reaction to occur. 

A simple possibility for the synthesis of esters, the reaction of an acid chloride with an alcohol, was used by Schrage and Vogtle [58] for a two-step synthesis of the macrocycle 63 from the alcohol 61 and the acid chloride 62. Compound 63, an example from the field of host/guest chemistry, forms a cavity, as studied with CPK-models, which could include planar, aromatic guests. Crystals obtained from benzene/ -heptane point to a 1 2 stoichiometry of 63 and benzene according to NMR-spectroscopic data. However, whether this is a molecular inclusion complex or just a clathrate is not yet known. 

This procedure has been used by Roush and Blizzard [33] in the synthesis of the macrocyclic mycotoxin verrucarin J (55). Thus, seco acid 54 was treated with 2 equiv of pivaloyl chloride and 3 equiv of triethylamine in dichloromethane (0.01 M) and the resultant mixed anhydride was treated in situ with 4-pyrrolidinopyridine (4-PP) to effect the ring closure at 23 °C. Verrucarin J (55) was obtained in up to 60% yield (Scheme 17). The mixed pivalic anhydride method has also been applied, e.g. to the synthesis of verrucarin B [34] and 4-epiverrucarin A [35] as the key cyclization step. 

This procedure was developed by Yamaguchi and coworkers [36]. Yamada and coworkers [37] applied it to the synthesis of the macrocyclic pyrrolizidine alkaloids ( — )-integemmine and (—)-monocrotaline. For instance, in the synthesis of (—)-integerrimine 58) [37a], treatment of seco acid 56 with 1.1 equiv of... 

In the particular case of the synthesis of the 14-member i polyoxomacrolide narbonolide, direct cyclization through the activation of thiol ester failed and then the mixed phosphoric anhydride derived from diphenylphosphorochloridate was developed to effect cyclization by Masamune and coworkers [39]. Fukumoto et al. [40] applied this procedure to the synthesis of the macrocyclic alkaloid vertaline 63). Thus, seco acid 62 was treated with diphenyl phosphorochloridate and triethylamine followed by refluxing in benzene in the presence of DMAP at high dilution afforded 63 in 54% yield (Scheme 20). 

A further reaction mechanistically similar to the Mitsunobu reaction as shown in Scheme 26, with the use of AT,iV-dimethylformamide dineopentylacetal (80), can also be employed for macrolactonization [47]. Takei and coworkers [48] applied it to the synthesis of the macrocyclic antibiotic A26771B (55). As shown in Scheme 27, treatment of the linear precursor 82 with 80 in refluxing dichloromethane for 7 h afforded the lactone 83 (39% yield). 

Kurokawa and Ohfune [71] employ i DPPA in the synthesis of the hexapeptide echinocandin D 125). As shown in Scheme 42, the cyclization of the Unear peptide 124 was accomplished by DPPA to give 125 in 50% yield. There are more applications of DPPA in the synthesis of macrocycUc natural products [72]. DEPC is relatively less commonly used than DPPA. Kishi and coworkers [73] have successfully achieved the synthesis of the macrocyclic antibiotic rifamycin S using DEPC as a macrolactamization promoter. 

Other applications of this method include, e.g. the synthesis of the antibiotic A26771B (5i) [118] and the marine cembranolide isolobophytolide [119], Trost and Warner [120] reported that a-sulfonyl sulfones can also serve as the substrates of ir-allylpalladium complexes for macrocyclization. Furthermore, an a-hydroxy-carbonyl ketone was alkylated intramolecularly by a a-allylpalladium complex in the total synthesis of the macrocyclic sesquiterpene humulene [121]. 

Intramolecular photocyclization between the vinyl moieties of (189) occurs using 9,10-dicyanoanthracene as an electron transfer sensitizer. In general, the route leads to the moderately efficient synthesis of the macrocyclic ring system (190, 191). The stereoselectivity shown by the reaction is, in some instances, dependent on the solvent used. Thus with (189a, b, and c), the cis-isomers (190) were the major products with acetonitrile as solvent, but with benzene the frans-isomer (191) predominated. In the case of (189d, e, and f), the trans-isomers predominate with both solvents. 

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