Dimethyltitanocene:  From Millimole to Kilomole

Payack, Joseph F.; Huffman, Mark A.; Cai, D.; Hughes, David L.; Collins, Paul C.; Johnson, Brian K.; Cottrell, and Ian F.; Tuma, Linda D.

doi:10.1021/op034180j

Cited by 36 publications

(14 citation statements)

References 13 publications

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“…Metal alkylidenes are key intermediates in many prominent chemical reactions, such as C–H activation, olefination reactions, 1 and catalytic alkene and alkane metathesis. 2 – 4 These compounds are commonly generated by deprotonation of a metal alkyl, 5 carbene transfer or α-H abstraction from [M](CH 2 R) 2 species.…”

Section: Introductionmentioning

confidence: 99%

Metal alkyls programmed to generate metal alkylidenes by α-H abstraction: prognosis from NMR chemical shift

et al. 2018

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Section: Introductionmentioning

confidence: 99%

Metal alkyls programmed to generate metal alkylidenes by α-H abstraction: prognosis from NMR chemical shift

et al. 2018

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“…Without isolation, this material was subjected to triple benzyl ether protection with 2,4,6-tris(benzyloxy)-1,3,5-triazene (TriBOT) 48 giving lactone 30 as a single diastereomer (the minor meso diastereomer from the double AD reaction does not undergo the lactonization reaction) in 62% yield over two steps. Petasis methylenation 49 , 50 of both carbonyls gave bis enol ether 31 in 55% yield, both setting up a hydroboration/ B -alkyl Suzuki reaction for the allyl sidechain introduction and converting the methyl ester to a methyl ketone in masked form. Chemo- and diastereoselective hydroboration of 31 with 9-borabicyclo[3.3.1]nonane (9-BBN) 51 was followed by B -alkyl Suzuki coupling 52 with vinyl bromide 32 and acidic hydrolysis of the methyl enol ether to deliver the fully elaborated F-ring methyl ketone 33 in 49% yield.…”

Section: Resultsmentioning

confidence: 99%

Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

et al. 2018

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Spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody–drug conjugates and other targeted delivery approaches. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access. Using uniquely enabling direct complex fragment coupling crotyl- and alkallylsilylation reactions, we report a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is characterized by GI50 values in the low picomolar range, and a proof-of-concept result that the C(15) acetate may be replaced with linker functional group-bearing esters with only minimal reductions in potency.

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“…Without isolation, this material was subjected to triple benzyl ether protection with 2,4,6-tris(benzyloxy)-1,3,5-triazene (TriBOT) (44) giving lactone 30 as a single diastereomer (the minor meso diastereomer from the double AD reaction does not undergo the lactonization reaction) in 62% yield over 2 steps. Petasis methylenation (45,46) of both carbonyls gave bis enol ether 31 in 55% yield, both setting up a hydroboration/B-alkyl Suzuki reaction for the allyl sidechain introduction and converting the methyl ester to a methyl ketone in masked form. Chemo-and diastereoselective hydroboration of 31 with 9-borabicyclo[3.3.1]nonane (9-BBN) (47) was followed by B-alkyl Suzuki coupling (48) with vinyl bromide 32 and acidic hydrolysis of the methyl enol ether to deliver the fully elaborated F-ring methyl ketone 33 in 49% yield.…”

mentioning

confidence: 99%

Design, 22-step synthesis, and evaluation of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

Leighton¹,

Lm²,

Ma³

et al. 2018

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With an average GI50 value against the NCI panel of 60 human cancer cell lines of 0.12 nM, spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody-drug conjugates and other targeted delivery approaches. It is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive, however, and its development requires more efficient and step-economical synthetic access. Using novel and uniquely enabling direct complex fragment coupling alkallyl- and crotylsilylation reactions, we have developed a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is equipotent with the natural product, and have used that synthesis to establish that the C(15) acetate may be replaced with a linker functional group-bearing ester with only minimal reductions in potency.<br><div><br></div>

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Dimethyltitanocene: From Millimole to Kilomole

Cited by 36 publications

References 13 publications

Metal alkyls programmed to generate metal alkylidenes by α-H abstraction: prognosis from NMR chemical shift

Metal alkyls programmed to generate metal alkylidenes by α-H abstraction: prognosis from NMR chemical shift

Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

Design, 22-step synthesis, and evaluation of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

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