The Catalytic Enantioselective Total Synthesis ..
The enantioenriched lactam products formed by our catalytic asymmetric alkylation chemistry are envisioned to be of broad utility in synthetic chemistry. To illustrate this point, lactam 3 can be transformed into the Aspidosperma alkaloid (+)-quebrachamine by modification of a previous route that employed a chiral auxiliary. Additionally, cleavage of the N-Bz group of lactam 3 produces chiral lactam 24, a compound previously used as a racemate in the synthesis of rhazinilam, a microtubule-disrupting agent that displays similar cellular characteristics to paclitaxel ()., Finally, reduction of lactam 24 produces the C(3)-quaternary piperidine (25) and demonstrates access to the corresponding amine building blocks.
2011), The Catalytic Enantioselective Total Synthesis of ..
In summary, we have reported the first method for catalytic enantioselective alkylation of monocyclic 5-, 6-, and 7-membered lactam enolate derivatives to form α-quaternary and α-tetrasubstituted tertiary lactams. The reaction discovery process was enabled by parallel screening of reaction parameters and led to the identification of a sterically and electronically tuned system for highly enantioselective alkylation. We have applied this method to the catalytic asymmetric synthesis of key intermediates previously employed for the construction of Aspidosperma alkaloids. Finally, the asymmetric products formed in this investigation are envisioned to be widely useful as building blocks for the preparation of range of nitrogen containing heterocycles in materials science, medicinal chemistry and natural products synthesis.
Beyond piperidinones, we have demonstrated that pyrrolidinones and caprolactams are also exceptional substrate classes, furnishing heterocycles 10–13 in excellent yield and ee (). Additionally, morpholine-derived product 14, containing a C(α)-tetrasubstituted tertiary center, is produced in 91% yield and 99% ee. C(α)-Fluoro substitution is readily introduced into the 1,3-dicarbonyl starting material and is viable in the enantioselective reaction leading to fluoropyrrolidinone 12 (86% yield, 98% ee) and fluoropiperidinone 15 (89% yield, 99% ee). Moreover, N-Bz glutarimides serve as outstanding substrates smoothly reacting to provide cyclic imides 16 and 17 in high yield and enantioselectivity. Finally, alteration of the N-Bz group is possible (), giving lactams with an N-acetyl group (18), N-carbamates (19 and 20), and a variety of N-aroyl derivatives (21–23).
"Catalytic enantioselective total synthesis of (+) ..
Liphagal (1), a selective inhibitor of PI3K α, has been isolated from the marine sponge collected in Dominica. The “liphagane” meroterpenoid carbon skeleton of liphagal (1) is new. A biomimetic total synthesis has been used to confirm the constitution of liphagal (1) and support a proposed biogenesis.
The catalytic enantioselective total synthesis of (+)-liphagal
Herein, we report the first catalytic enantioselective total synthesis of (+)-liphagal.Retrosynthetically, we envisioned simplification of the aromatic ring of liphagal to dimethoxybenzofuran 2, a known precursor to the natural product (). Disconnection of the tetracycle along the benzofuran moiety led back to α-bromoaryl dienone 3.
The catalytic enantioselective total synthesis of ..
Judicious choice of tetracyclic hydrogenation substrate 21 established the critical trans-[6-7] ring fusion and enabled completion of the total synthesis.
The Catalytic Enantioselective Total Synthesis of (+) ..
Herein we report the first enantioselective total synthesis of (+)-dichroanone, confirming the absolute configuration of the natural product. This protecting group-free route features the first application of our enantioselective Tsuji allylation in the context of a natural product total synthesis. Additionally, this 11-step preparation of the molecule from commercial material features a novel Kumada-aromatization strategy and a rapid sequence for the conversion of a phenol to a hydroxy--benzoquinone.