The enantioselective total synthesis of the rearranged spongian diterpenoid (−)‐macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the
The enantioselective total synthesis of the rearranged spongian diterpenoid (−)‐macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the
- Award ID(s):
- 1661612
- NSF-PAR ID:
- 10135473
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 59
- Issue:
- 15
- ISSN:
- 1433-7851
- Page Range / eLocation ID:
- p. 6268-6272
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract cis ‐2,8‐dioxabicyclo[3.3.0]octan‐3‐one moiety. The strategy involves a late‐stage fragment coupling between a tertiary carbon radical and an electrophilic butenolide resulting in the stereoselective formation of vicinal quaternary and tertiary stereocenters. A stereoselective Mukaiyama hydration that orients a pendant carboxymethyl side chaincis to the bulky octahydronapthalene substituent was pivotal in fashioning the challenging concave‐substitutedcis ‐dioxabicyclo[3.3.0]octanone fragment. -
more » « less
Abstract Quaternary carbons are useful motifs in chemical synthesis but can be challenging to prepare using many chemical methods. Here, we report a stereoselective synthesis of
β ‐quaternary lactams using flavin‐dependent ‘ene’‐reductases via a 5‐exo‐trig radical cyclization. The products are formed in moderate to good levels of enantioselectivity using an ‘ene’‐reductase variant fromZymomonas mobilis . This method highlights the opportunity for biocatalysis to form quaternary centers using non‐natural reactions. -
more » « less
Abstract Trifluoromethyl‐substituted cyclopropanes (CF3‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of
trans ‐CF3‐CPAs, stereoselective production of correspondingcis ‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis ofcis ‐CF3‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin fromAeropyrnum pernix (Ape Pgb) can catalyze this unusual reaction at preparative scale with low‐to‐excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron‐carbenoid and substrates to adopt a pro‐cis near‐attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3‐CPAs for drug discovery. -
more » « less
Abstract Trifluoromethyl‐substituted cyclopropanes (CF3‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of
trans ‐CF3‐CPAs, stereoselective production of correspondingcis ‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis ofcis ‐CF3‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin fromAeropyrnum pernix (Ape Pgb) can catalyze this unusual reaction at preparative scale with low‐to‐excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron‐carbenoid and substrates to adopt a pro‐cis near‐attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3‐CPAs for drug discovery. -
more » « less
Abstract The chemical synthesis of molecules with closely packed atoms having their bond coordination saturated is a challenge to synthetic chemists, especially when three-dimensional control is required. The organocatalyzed asymmetric synthesis of acyclic alkenylated, alkynylated and heteroarylated quaternary carbon stereocenters via 1,4-conjugate addition is here catalyzed by 3,3´-bisperfluorotoluyl-BINOL. The highly useful products (31 examples) are produced in up to 99% yield and 97:3 er using enediketone substrates and potassium trifluoroorganoborate nucleophiles. In addition, mechanistic experiments show that the (
Z )–isomer is the reactive form, ketone rotation at the site of bond formation is needed for enantioselectivity, and quaternary carbon formation is favored over tertiary. Density functional theory-based calculations show that reactivity and selectivity depend on a key n→π* donation by the unbound ketone’s oxygen lone pair to the boronate-coordinated ketone in a 5-exo-trig cyclic ouroboros transition state. Transformations of the conjugate addition products to key quaternary carbon-bearing synthetic building blocks proceed in good yield.
