Computational planning of the synthesis of complex natural products.

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years1-7. However, the field has progressed greatly since the development of early programs such as LHASA1,7, for which reaction choices at each step were made by human operators. Multiple software platforms6,8-14 are now capable of completely autonomous planning. But these programs 'think' only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary15,16 and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program's knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships17,18, allowing it to 'strategize' over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization.

Distinct cognitive and discriminative stimulus effects of ketamine enantiomers in rats.

Although (S)-ketamine was approved for use in treatment-resistant depression in 2019, new preclinical findings suggest that (R)-ketamine might produce better efficacy and tolerability relative to (S)-ketamine. Here we evaluated the effects of (R)-, (S)-, and (R,S)-ketamine on executive functions as measured in the attentional set shifting task (ASST) and on their discriminative stimulus effects in rats. Earlier data demonstrated that cognitive flexibility is compromised by (R,S)-ketamine, but the effects of enantiomers in rats are unknown. Separate cohorts of rats were tested in ASST and trained to discriminate either (R,S)-ketamine, (S)-ketamine, or (R)-ketamine (all at 10 mg/kg) from saline; in order to maintain the discrimination, a higher (R)-ketamine dose (17.5 mg/kg) was subsequently instituted. In ASST, all three forms increased the trials to criterion measure at reversal learning and extra-dimensional set-shifting phases. However, in contrast to (R)- and (S)-ketamine, (R,S)-ketamine prolonged the mean time to complete a single trial during early stages, suggesting increased reaction time, and/or unspecific side-effects related to motor or motivational impairments. In the drug discriminations, all rats acquired their respective discriminations between drug and saline. In (R,S)-ketamine-trained rats, (R)-ketamine and (S)-ketamine only partially substituted for the training dose of (R,S)-ketamine. Further, (R)-ketamine did not fully substitute in rats trained to (S)-ketamine. The data suggest more serious cognitive deficits produced by (R,S)-ketamine than its enantiomers. Furthermore, (R,S)-ketamine and its isomers share overlapping but not isomorphic discriminative stimulus effects predicting distinct subjective responses to (R)- vs. (S)-ketamine in humans.

Synthesis of ß-lactams via diastereoselective, intramolecular Kinugasa reactions.

Intramolecular Kinugasa reactions on in situ generated carbohydrate-derived alkynylnitrones are described. The effects of the length of chains, their mutual configuration, influence of experimental conditions on product distribution and feasibility of the ß-lactam ring construction were studied. Intramolecular reactions proceed with high stereoselectivity to provide in each case one product only. The cycloadducts from tartaric acid were converted into the corresponding non-racemic 4-acetoxy azetidinones in good yields.

Stereoselective Synthesis of the Equatorial Glycosides of Legionaminic Acid.

The synthesis of a legionaminic acid donor from N-acetylneuraminic acid in 15 steps and 17% overall yield is described. Activation of the adamantanyl thioglycoside in the donor with N-iodosuccinimide and trifluoromethanesulfonic acid in dichloromethane and acetonitrile at -78 °C in the presence of primary, secondary and tertiary alcohols affords the corresponding glycosides in excellent yield and good to excellent equatorial selectivity. In particular, coupling to the 4-OH of a suitably protected neuraminic acid derivative affords a disaccharide that closely resembles the glycosidic linkage in the polylegionaminic acid from the lipopolysaccharide of the Legionella pneumophila virulence factor. A straightforward deprotection sequence enables conversion of the protected glycosides to the free N,N-diacetyllegionaminic acid glycosides.

Organocatalytic Synthesis of Higher-Carbon Sugars: Efficient Protocol for the Synthesis of Natural Sedoheptulose and d-Glycero-l-galacto-oct-2-ulose.

Herein we report a short and efficient protocol for the synthesis of naturally occurring higher-carbon sugars-sedoheptulose (d-altro-hept-2-ulose) and d-glycero-l-galacto-oct-2-ulose-from readily available sugar aldehydes and dihydroxyacetone (DHA). The key step includes a diastereoselective organocatalytic syn-selective aldol reaction of DHA with d-erythrose and d-xylose, respectively. The methodology presented can be expanded to the synthesis of various higher sugars by means of syn-selective carbon-carbon-bond-forming aldol reactions promoted by primary-based organocatalysts. For example, this methodology provided useful access to d-glycero-d-galacto-oct-2-ulose and 1-deoxy-d-glycero-d-galacto-oct-2-ulose from d-arabinose in high yield (85 and 74 %, respectively) and high stereoselectivity (99:1).

Amine-catalyzed direct aldol reactions of hydroxy- and dihydroxyacetone: biomimetic synthesis of carbohydrates.

This article presents comprehensive studies on the application of primary, secondary, and tertiary amines as efficient organocatalysts for the de novo synthesis of ketoses and deoxyketoses. Mimicking the actions of aldolase enzymes, the synthesis of selected carbohydrates was accomplished in aqueous media by using proline- and serine-based organocatalysts. The presented methodology also provides direct access to unnatural L-carbohydrates from the (S)-glyceraldehyde precursor. Determination of the absolute configuration of all obtained sugars was feasible using a methodology consisting of concerted ECD and VCD spectroscopy.