Cyclization precursors

The formation of five- (362) and six- (581) membered vinylogous lactams and pyrroles by intramolecular enamine acylations has been accomplished in some examples by formation of the cyclization precursor through an initial enamine exchange (362). 

In the initial step, neocarzinostatine 8 (simplified structure) is converted to the cyclization precursor 9, which contains a cumulated triene unit. The reaction... 

It is important to note here that both of the 5-exo radical cyclizations (133—>132—>131, Scheme 27) must proceed in a cis fashion the transition state leading to a strained mms-fused bicy-clo[3.3.0]octane does not permit efficient overlap between the singly occupied molecular orbital (SOMO) of the radical and the lowest unoccupied molecular orbital (LUMO) of the alkene. The relative orientation of the two side chains in the monocyclic radical precursor 134 is thus very significant because it dictates the relationship between the two outer rings (i. e. syn or anti) in the tricyclic product. The cis-anti-cis ring fusion stereochemistry of hirsutene would arise naturally from a cyclization precursor with trans-disposed side chain appendages (see 134). 

From 152, the synthesis of the tandem radical cyclization precursor 155 only requires a few manipulations of the two side chains. 

Aldol reaction of keto-acid 21 with aldehyde 10 and esterification of the resulting acids with alcohol 22 led rapidly to cyclization precursor 23 and its 6S,7R-diastereomer (not shown). RCM using ruthenium initiator 3 (0.1 equiv) in dichloromethane (0.0015 M) at 25 °C afforded macrolactones 24a and 24b in a 1.2 1 ratio. Deprotection and epoxidation of the desired macrolactone, 24a, afforded epothilone A (4) via 25a (epothilone C) (Scheme 5). Varying a number of reaction parameters, such as solvent, temperature and concentration, failed to improve significantly the Z-selectivity of the RCM. However, in the context of the epothilone project, the formation of the E-isomer 24b could actually be viewed as beneficial since it allowed preparation of the epothilone A analog 26 for biological evaluation. 

Overman s group [71,72] enlisted an intramolecular Heck reaction to form a quaternary center in their efforts toward ( )-gelsemine. When the cyclization precursor 70 was submitted to the ligandless conditions [Pd2(dba)3, Et3N] in the weakly coordinating solvent toluene, the quaternary center was formed as a 9 1 ratio of diastereomers (72 71 = 89 11). Addition of a silver salt in polar solvent THF completely reversed the sense of asymmetric induction in the cyclization reaction (72 71 = 3 97). 

Among early reported Pd-catalyzed reactions, the Mori-Ban indole synthesis has proven to be very useful for pyrrole annulation. In 1977, based on their success of nickel-catalyzed indole synthesis from 2-chloro-fV-allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [122]. Compound 102, easily prepared from 2-bromo-lV-acetylaniline and methyl bromocrotonate, was adopted as the cyclization precursor. Treatment of 102 with Pd(OAc)2 (2 mol%), Ph3P (4 mol%) and NaHCQ3... 

An intramolecular Heck cyclization strategy was developed for the construction of indole and benzofuran rings on solid support [82], enabling rapid generation of small-molecular libraries by simultaneous parallel or combinatorial synthesis. Sn2 displacement of resin-bound y-bromocrotonyl amide 97 with o-iodophenol 96 afforded the cyclization precursor 98. A subsequent intramolecular Heck reaction using Jeffery s ligand-free conditions furnished, after double bond tautomerization, the resin-bound benzofurans, which were then cleaved with 30% TFA in CH2CI2 to deliver the desired benzofuran derivatives 99 in excellent yields and purity. 

Ugi reaction of acid 88 with isonitrile 85, isobutyraldehyde and isopropylamine furnished dipeptide 89 in 67% yield. Similar Ugi reactions with other components afforded linear cyclization precursors in yields up to 98%. The final macrocyclization was not straightforward (no similar reactions were described in literature), but after optimization of the reaction conditions (varying base, solvent, concentration and reaction time) cyclopeptide alkaloid analogue 90 was obtained in 96% yield after treatment with K2CO3 and catalytic 18-crown-6 in acetone. 

The enantioselective version of a retro-[ 1,4]-Brook rearrangement was accomphshed as the subsequent reaction of enantioselective cyclocarbolithiation by Hoppe and colleagues (equation 111) . The cyclization precursor 179 was treated with s-BuLi/(—)-sparteine (24) in ether, providing the cyclized and silyl-rearranged product (/f,/f,/f)-180 in 58% yield as a single stereoisomer. 

Ester-tethered enyne systems cycloisomerized to give lactone products (Eq. 11) [24]. Eor example, enyne 6 reacted under the Alder-ene conditions of [Rh(COD)Cl]2/BlNAP/ AgSbEg to give the corresponding lactone (Eq. 11). Once again free hydroxyl groups on the allylic terminus were incorporated into the cyclization precursors and subjected to the Alder-ene conditions, which led to the exclusive formation of the tautomerized products in good yields and enantioselectivities (Eq. 12). 

Kappe et al. (103,104) approached dihydropyrimidines, a potent group of calcium channel modulators, through the use of an isomiinchnone-type cyclization. Kappe prepared the cyclization precursor 195 in the course of a three component Biginelli condensation process (Scheme 4.49). 

The chloromethylpyrimido[5,4-( ]-l,2,4-triazine 86 is an extremely versatile starting material (see Section 10.20.7.2, Equation 12) and was synthesized from the commercially available thiol 151 as shown in Scheme 25. Thus, 6 -methylation of compound 151 gave the sulfide 152, which was nitrosated to allow access to the nitroso-thiomethyl derivative 153. Nucleophilic substitution of the thiomethyl group by hydrazine gave the cyclization precursor 154, which underwent cyclization with chloroacetaldehyde diethyl acetal under acidic conditions to give the chloro-methylpyrimido[5,4-( ]-l,2,4-triazine 86 after workup with aqueous ammonia <2003BML2895>. 

As with any retrosynthetic analysis, once potential strategies are identified, one must address the problems posed by each route. In the present synthesis, such questions arise as Are the planned cyclizations likely to succeed Will the two cyclizations be conducted together or separately In what order will they occur How will the stereochemistry of the methyl group be controlled By what method will the cyclizations be conducted and what will the actual cyclization precursor(s) be How will the precursors be prepared The answers to these questions will help determine the selection of a practical synthetic pathway. 

The hydrogen atom transfer method is most useful for electrophilic radicals (for example, malonate, acetoacetate, etc.). Because radicals are generated from C—H bonds, the preparation of cyclization precursors by alkylation is routine. The hydrogen atom transfer method is very good for conducting slow cyclizations. In addition reactions, the hydrogen donor is typically used in large excess relative to the acceptor to facilitate H-transfer however, cyclizations must use different conditions because the H-donor and the alkene acceptor are in the same molecule. 

Their most detailed investigations focused on the Heck cyclization of iodide 18.1c to form oxindole 17.3a (Scheme 8G.18) [38a,b]. A chiral-amplification study [47] established that the catalytically active species is a monomeric Pd-BINAP complex, a conclusion also corroborated by NMR studies by Amatore and co-workers [42d,43], In addition, two possibilities for the enantioselective step of the neutral pathway were easily eliminated [38a], Oxidative addition was precluded as the enantioselective step, because iodides cyclize with very different enantioselectivities in the presence of Ag(I) salts. A scenario where migratory insertion is reversible and [l-hydridc elimination is the enantioselective step was also ruled out, because this is not consistent with the dependence of enantioselectivity on the geometry of the double bond of the cyclization precursor. 

Below are shown a few examples of the types of complex structures that can be assembled by intramolecular free-radical cyclization. Note the presence of a great many polar functional groups present in the cyclization substrates which are compatible with the process. While the examples shown do not need protecting groups, a great number of other free-radical cyclizations are known which have unprotected alcohols, carbonyl groups, and carboxylic acids in the cyclization precursor. 

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