Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin

Savage, Scott A.; McClory, Andrew; Zhang, Haiming; Cravillion, Theresa; Lim, Ngiap‐Kie; Masui, Colin; Robinson, Sarah J.; Han, Chong; Ochs, Christoph; Rege, Pankaj D.; Gosselin, Francis

doi:10.1021/acs.joc.8b01551

Cited by 21 publications

(14 citation statements)

References 18 publications

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“…54 The formation of the ( E )-alkene in 16 by the treatment of 15 with tosyl chloride and lithium tert -butoxide is also successfully predicted. 55…”

Section: Resultsmentioning

confidence: 99%

Molecular Transformer: A Model for Uncertainty-Calibrated Chemical Reaction Prediction

et al. 2019

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Organic synthesis is one of the key stumbling blocks in medicinal chemistry. A necessary yet unsolved step in planning synthesis is solving the forward problem: Given reactants and reagents, predict the products. Similar to other work, we treat reaction prediction as a machine translation problem between simplified molecular-input line-entry system (SMILES) strings (a text-based representation) of reactants, reagents, and the products. We show that a multihead attention Molecular Transformer model outperforms all algorithms in the literature, achieving a top-1 accuracy above 90% on a common benchmark data set. Molecular Transformer makes predictions by inferring the correlations between the presence and absence of chemical motifs in the reactant, reagent, and product present in the data set. Our model requires no handcrafted rules and accurately predicts subtle chemical transformations. Crucially, our model can accurately estimate its own uncertainty, with an uncertainty score that is 89% accurate in terms of classifying whether a prediction is correct. Furthermore, we show that the model is able to handle inputs without a reactant–reagent split and including stereochemistry, which makes our method universally applicable.

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“…54 The formation of the ( E )-alkene in 16 by the treatment of 15 with tosyl chloride and lithium tert -butoxide is also successfully predicted. 55…”

Section: Resultsmentioning

confidence: 99%

Molecular Transformer: A Model for Uncertainty-Calibrated Chemical Reaction Prediction

et al. 2019

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“…Iwasawa and co-workers have reported the stereodefined synthesis of E-and Z-isomers of tamoxifen (Scheme 16). [40] The synthetic approach to E-tamoxifen started from Cu-catalyzed coupling of (E)-1-bromo-2-iodoalkene (78) and tributyl(phenyl) tin (79) in the presence of CuTC afforded 80 with full retention of stereochemistry in 63% yield which is an important intermediate for the synthesis of tamoxifen. Compound 80 was further reacted with p-anisylboronic acid under Suzuki crosscoupling reaction afforded 81 in 83% yield.…”

Section: Formation Of C-c Bondmentioning

confidence: 99%

“…Savage et al . reported the synthesis of GDC‐0810, a tamoxifen derivative involving Claisen condensation, stereoselective lithium tert ‐butoxide assisted enolyzation‐tosylation, Heck and Suzuki‐Miyaura cross couplings as main steps (Scheme ) . The synthesis involved the Claisen condensation of phenylacetic acid 330 and methyl 4‐bromobenzoate in the presence of NaHMDS under cryogenic conditions afforded 330 a .…”

Section: Synthesis Of Tamoxifen Analoguesmentioning

confidence: 99%

“…On the other hand, compounds 329 c and 329 d exhibited better potency than compounds 329 a and 329 b. These synthesized compounds showed promising biological activity irrespective of presence of E and Z isomers.Savage et al reported the synthesis of GDC-0810, a tamoxifen derivative involving Claisen condensation, stereoselective lithium tert-butoxide assisted enolyzation-tosylation, Heck and Suzuki-Miyaura cross couplings as main steps (Scheme 65) [78]. The synthesis involved the Claisen condensation of phenylacetic acid 330 and methyl 4-bromobenzoate in the presence of NaHMDS under cryogenic conditions afforded 330 a. Interestingly, changing base from NaHMDS to NaH resulted in the elimination of cryogenic conditions.…”

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confidence: 99%

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Recent Advances in the Synthesis of Tamoxifen and Analogues in Medicinal Chemistry

et al. 2020

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Tamoxifen is one of the important tricyclicethylene moieties and recognized as an important drug candidate because of extensive applications in the field of medicinal and pharmaceutical chemistry. Recently, ample attention is given to this analogue by organic and medicinal chemistry community due to its successful utilization for the inhibition of estrogen receptor in MCF-7 breast cancer cell lines. Due to its structural character, tamoxifen is also useful in material chemistry. The synthesis of tamoxifen and its anlogues is desirable from easily available chemicals as an important drug candidate. Here, we report a review on various synthetic schemes for tamoxifen and its anlogues employing use of different strategies such as formation of CÀ C, C=C and C�C bonds, CÀ H functionalization, addition to alkynes, insertion reaction, nucleophilic substitution and addition reactions, elimination reaction, reductive couplings etc.

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“…Several approaches have been developed previously that can excite individual overlapping signals, but they all suffer from complications and for routine use all require long experiment times. They include two-step experiments that excite a well-resolved signal and then use targeted transfer of magnetization to the proton of interest, [4][5][6][7] and multi-dimensional approaches such as HSQC-NOESY, [8] which exploits the high resolution of the 13 C spectrum. A more direct way to selectively observe a single site from within multiple overlapping signals is the chemical shift selective filter (CSSF), [9][10][11][12] which is the starting point for the method presented here.…”

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confidence: 99%

Single‐Scan Selective Excitation of Individual NMR Signals in Overlapping Multiplets

et al. 2020

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2D NMR is an immensely powerful structural tool but it is time‐consuming. Targeting individual chemical groups by selective excitation in a 1D experiment can give the information required far more quickly. A major problem, however, is that proton NMR spectra are often extensively overlapped, so that in practice only a minority of sites can be selectively excited. Here we overcome that problem using a fast, single‐scan method that allows selective excitation of the signals of a single proton multiplet even where it is severely overlapped by other multiplets. The advantages of the method are illustrated in a selective 1D NOESY experiment, the most efficient way to determine relative configuration unambiguously by NMR. The new approach presented here has the potential to broaden significantly the applicability of selective excitation and unlock its real potential for many other experiments.

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Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin

Cited by 21 publications

References 18 publications

Molecular Transformer: A Model for Uncertainty-Calibrated Chemical Reaction Prediction

Molecular Transformer: A Model for Uncertainty-Calibrated Chemical Reaction Prediction

Recent Advances in the Synthesis of Tamoxifen and Analogues in Medicinal Chemistry

Single‐Scan Selective Excitation of Individual NMR Signals in Overlapping Multiplets

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