Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C-H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.
Coupling of C9
-
14 (4) and C15
-
21 (5a) fragments to produce the
cis-trisubstituted olefin was achieved using Suzuki-type coupling
conditions employed by Marshall (5a/tert-BuLi/B-OMe-9-BBN
added to 4/Cs2CO3/Pd(dppf)2). The terminal (Z)-diene moiety
was attached to aldehyde 10 by using a sequential Nozaki−Hiyama allylation and Peterson olefination sequence; careful
monitoring of the disappearance of both diastereomeric β-hydroxysilanes was found to be essential for achieving a high yield.
In the oxidation of alcohols 12 and 16 to 13 and 7, respectively,
using iodobenzene diacetate and TEMPO, addition of a trace
of water was found to be crucial for complete conversion. The
C8
-
9 (Z)-olefin functionality was introduced on to aldehyde 13
using a Still−Gennari HWE reaction. Subsequent carbamate
installation at C-19 followed by a reduction/oxidation sequence
gave the title fragment C7
-
24 (7) ready to be coupled with the
C1
-
6 fragment, which is described in Part 2 of this series.
A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.
Smith's procedure of preparing fragment C15
-
21 (5) from
common precursor 3 was optimized. The ease of plant operations made this six-step route successful for the production of
several kilograms of this fragment with high purity.
An
expansive data set containing 33 substrates, 36 unique monophosphine
ligands, and two solvents was produced for the NiCl2·6H2O catalyzed aryl (pseudo)halide borylation with tetrahydroxydiboron
for a total of 1632 reactions. Exploratory data analysis revealed
excellent reaction performance with simple triarylphosphines (P(p-F-Ph)3 and P(p-Anis)3) and mixed aryl-alkyl phosphines (PPh2Cy), in addition
to the previously established high performance with Cy-JohnPhos. The
data were used to train machine learning models that predicted out
of sample reaction performance with a root-mean-square error of 18.4.
The important features extracted from the models identified three
phosphine parameters that offered reliable reactivity thresholds for
identifying optimal ligand performance. The predictive models showed
reasonable performance for predicting reaction yields employing ligands
not included in model training, while the important feature boundaries
accurately classified the performance of 10 of the 12 external ligands
examined.
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