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Full details of an enantioselective total synthesis of (+)-duocarmycin A (1) are described in which a solution to the control of the relative and absolute stereochemistry of the remote stereocenters is provided. Catalytic asymmetric dihydroxylation of 15 was employed to introduce the absolute stereochemistry required for the activated cyclopropane, and a diastereoselective Dieckmann-type condensation of 61 was employed to control the absolute stereochemistry of the C6 quaternary center. The complementary diastereoselectivity of a thermodynamic versus kinetic condensation of 61 permitted the divergent synthesis of (+)-duocarmycin A or epi-(+)-duocarmycin A from common intermediates. Final introduction of the reactive cyclopropane was accomplished by transannular spirocyclization of the mesylate 44 upon treatment with base or directly from the corresponding free alcohol itself, duocarmycin D1 (42), upon Mitsunobu activation. Notably, the asymmetric dihydroxylation of 15 employing (DHQD)2-PHAL/(DHQ)2-PHAL wa...

The comparative solvolysis reactivity, regioselectivity, and stereochemistry of N -BOC-DSA ( 4 ) and N -BOC-DA ( 5 ), simple derivatives of the DNA alkylation subunits of duocarmycin SA and A, are detailed. Most important of the observations is the substantially greater reactivity of 5 versus 4 (16x), the modest regioselectivity of both 4 (6.5-4:1) and 5 (1.5:1), and the establishment that the abnormal ring expansion solvolysis proceeds by S N 2 addition to the activated cyclopropane with clean inversion of the reacting center stereochemistry.

A quantitative Hammett study of the magnitude of the electronic effects of a C7 substituent on the functional reactivity of N-BOC-CBI (5, RH), its impact on biological properties, details of the mechanism of the acid-catalyzed nucleophilic addition to the activated cyclopropane, and its implications on the origin of the DNA alkylation selectivity of this class of agents is detailed.

Cyclization of a variety of substituted olefinic ketones in the presence of samarium (II) iodide has been studied. The authors further investigated noncyclized byproducts formed in this reaction.

Intramolecular nucleophilic acyl substitution reactions involving a broad range of halo substituted carboxylic acid derivatives have been accomplished in excellent yield employing samarium(II) iodide as the reductive coupling agent. Although particular substrates cyclized most effectively in THF in the presence of tripiperidinophosphine oxide, carboxylic acid esters, the focus of this report, cyclize equally well without such an additive in the presence of a catalytic quantity of iron(III) complexes. Thus a comprehensive series of halo substituted esters were cyclized in excellent yield to the corresponding 4-, 5-, and 6-members carbocycles. The reaction is extremely mild and selective as demonstrated by experiments wherein alkyl chlorides, acetals, and olefins remain completely intact under the reaction conditions. In addition to introducing a convenient procedure for preparing stereodefined spirocyclic systems, a new ring expansion sequence has been developed that appears extremely general for the preparation of various ring systems

Samarium(II) iodide (SmI 2 ) has been successfully employed as a reductive coupling agent for the intramolecular Barbier-type synthesis of bicyclo[m.n.1]alkan-1-ols. Thus, a variety of 3-(ω-iodoalkyl)cycloalkanones, upon treatment with SmI 2 and a catalytic quantity of iron complex in tetrahydrofuran (THF), provide the title compounds in excellent yields. The reaction is quite general for the construction of diverse bicyclic ring systems, including the highly strained bicyclo[2.1.1]hexan-1-ol

Samarium (II) iodide in the presence of HMPA effectively promotes the intramolecular coupling of unactivated olefinic ketones by a reductive ketyl-olefin radical-cyclization process. The reaction is quite for the formation of 5- and 6-membered carbocycles and even provides modest yields in less facile cyclization processes as evidenced by the generation of methylcyclooctanol via an 8-endo cyclization. Sequential radical cyclization-intermolecular nucleophilic addition/substitution process set the SmI 2 reaction apart from its radical-chain,photochemical, and electrochemical counterparts

Intramolecular nucleophilic acyl substitution reactions involving a broad range of halo substituted carboxylic acid derivatives have been accomplished in excellent yield employing samarium(II) iodide as the reductive coupling agent. Although particular substrates cyclized most effectively in THF in the presence of tripiperidinophosphine oxide, carboxylic acid esters, the focus of this report, cyclize equally well without such an additive in the presence of a catalytic quantity of iron(III) complexes. Thus a comprehensive series of halo substituted esters were cyclized in excellent yield to the corresponding 4-, 5-, and 6-members carbocycles. The reaction is extremely mild and selective as demonstrated by experiments wherein alkyl chlorides, acetals, and olefins remain completely intact under the reaction conditions. In addition to introducing a convenient procedure for preparing stereodefined spirocyclic systems, a new ring expansion sequence has been developed that appears extremely general for the preparation of various ring systems

Cyclization of a variety of substituted olefinic ketones in the presence of samarium (II) iodide has been studied. The authors further investigated noncyclized byproducts formed in this reaction.

Samarium (II) iodide in the presence of HMPA effectively promotes the intramolecular coupling of unactivated olefinic ketones by a reductive ketyl-olefin radical-cyclization process. The reaction is quite for the formation of 5- and 6-membered carbocycles and even provides modest yields in less facile cyclization processes as evidenced by the generation of methylcyclooctanol via an 8-endo cyclization. Sequential radical cyclization-intermolecular nucleophilic addition/substitution process set the SmI 2 reaction apart from its radical-chain,photochemical, and electrochemical counterparts

Samarium(II) iodide (SmI 2 ) has been successfully employed as a reductive coupling agent for the intramolecular Barbier-type synthesis of bicyclo[m.n.1]alkan-1-ols. Thus, a variety of 3-(ω-iodoalkyl)cycloalkanones, upon treatment with SmI 2 and a catalytic quantity of iron complex in tetrahydrofuran (THF), provide the title compounds in excellent yields. The reaction is quite general for the construction of diverse bicyclic ring systems, including the highly strained bicyclo[2.1.1]hexan-1-ol

We have compared the antitumor activities of SP500263, a novel next-generation selective estrogen receptor modulator (SERM), tamoxifen, and raloxifene side-by-side in in vitro and in vivo MCF-7 breast cancer models. In vitro, SP500263 acted as an antiestrogen and potently inhibited estrogen-dependent MCF-7 proliferation with IC(50) values in the nanomolar range. SP500263 also strongly inhibited MCF-7 proliferation in the absence of estrogen at all of the concentrations tested. To investigate the antitumor activity of SP500263 in animals, athymic nude mice were implanted with MCF-7 tumor in the presence of a tumor growth-supporting sustained release estrogen pellet. Treatment was initiated after tumors were established. SP500263, administered for 28 days through daily i.p. dosing, effectively reduced estrogen-stimulated tumor growth at 3 and 30 mg/kg. SP500263 was as efficacious as tamoxifen and superior to raloxifene at the corresponding doses. Maximum efficacy was reached with the 30 mg/kg dose. The observed effects were highly significant. SP500263 represents a member of a novel series of SERMs that is structurally unrelated to SERMs currently on the market or in clinical development. The experiments described herein demonstrate that SP500263 is efficacious in the MCF-7 proliferation assay and in a murine model of breast cancer.

Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.

The synthesis of 7-methoxy-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (MCBI), a substituted CBI derivative bearing a C7 methoxy group para to the C4 carbonyl, is described in efforts that establish the magnitude of potential electronic effects on the chemical and functional reactivity of the agents. The core structure of the MCBI alkylation subunit was prepared by a modified Stobbe condensation/Friedel-Crafts acylation for generation of the appropriately functionalized naphthalene precursors (15 and 20) followed by 5-exo-trig aryl radical-alkene cyclization (24 --25, 32 --33) for completion of the synthesis of the 1,2-dihydro-3H-benz[e]indole skeleton and final Ar-3' alkylation of 28 for introduction of the activated cyclopropane. Two approaches to the implementation of the key 5-exo-trig free radical cyclization are detailed with the former proceeding with closure of 24 to provide 25 in which the required product functionalization was introduced prior to cyclization and the latter with Tempo trap of the cyclization product of the unfunctionalized alkene substrate 32 to provide 33. The latter concise approach provided the MCBI subunit and its immediate precursor in 12-13 steps in superb overall conversions (27-30%). Resolution of an immediate MCBI precursor and its incorporation into both enantiomers of 39-46, analogs of CC-1065 and the duocarmycins, are detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-MCBI (29) revealed that introduction of the C7 methoxy group accelerates the rate of solvolysis by only 1.2-1.06x. This remarkably modest effect is inconsistent with C4 carbonyl protonation as the slow and rate-determining step of solvolysis or acid-catalyzed nucleophilic addition but is consistent with a mechanism in which protonation is rapid and reversible followed by slow and rate-determining nucleophilic addition to the cyclopropane requiring both the presence and assistance of a nucleophile (S(N)2 mechanism). No doubt this contributes to the DNA alkylation selectivity of this class of agents and suggests that the positioning of an accessible nucleophile (adenine N3) and not C4 carbonyl protonation is the rate-determining step controlling the sequence selectivity of the DNA alkylation reaction. This small electronic effect on the solvolysis rate had no impact on the solvolysis regioselectivity, and stereoelectronically-controlled nucleophilic addition to the least substituted carbon of the activated cyclopropane was observed exclusively. For the natural enantiomers, this unusually small electronic effect on functional reactivity had little or no perceptible effect on their DNA alkylation selectivity, efficiency, and relative rates or on their biological properties. Perceptible effects of the C7 methoxy substituent on the unnatural enantiomers were observed and they proved to be 4-40x more effective than the corresponding CBI-based unnatural enantiomers and comparable in cytotoxic potency with the MCBI natural enantiomers. This effect is most consistently rationalized not by a C7 methoxy substituent effect on functional reactivity but rather through introduction of additional stabilizing noncovalent interactions which increase the unnatural enantiomer DNA alkylation efficiency and further stabilize its inherently reversible DNA alkylation reaction.