Benzo[b]pyran, or chroman, is one of the most important oxygencontaining heterocyclic systems found in numerous natural products, as well as marketed and investigational drugs. Among them, 2-substituted chromans are especially notable: their naturally occurring representatives include tocopherols (vitamin E), tetrahydrocannabinols, and various 2-arylchroman (flavan) derivatives, e.g., apiforol and luteoforol (Figure ). Many classic studies in this area are related to 2-arylchromane derivatives, a subclass of flavonoid natural products. With an increased interest to sp -enriched compounds (i.e., those having higher fraction of sp -hybrid carbon atoms) in drug discovery observed in the last decades, 2-((hetera)cyclo)alkylchromanes and their spirocyclic analogs become very promising chemotypes and synthetic targets. Some of them have already paved their way to medicinal chemistry, e.g. calanolide A, an experimental HIV-1 reverse transcriptase inhibitor, potent beta-secretase 1 (BACE-1), indoleamine 2,3-dioxygenase-1 (IDO1), or cholesteryl ester transfer protein (CETP) inhibitors (Figure ). To ensure the presence of a synthetic handle suitable for further synthetic modifications in the target molecules, we have turned our attention to sp -enriched 2-substituted chroman-4-ols as promising building blocks for drug discovery (Scheme 1, A). Since these compounds have one or two chiral centers, a method for their synthesis should consider their preparation in enantioenriched form. A major part of the known approaches is based on asymmetric catalytic hydrogenation (Scheme 1, B). A major drawback of these methods is the use of expensive catalysts, sometimes with limited accessibility. On the contrary, approaches based on the enzymatic resolution of racemates are in general relatively cheap, easy to scale-up, and can provide both enantiomers of the compound, which is beneficial at the early stages of drug discovery projects. While enzymatic kinetic resolution was reported for (aryl-substituted) flavanols, to the best of our knowledge, it was not used for their sp 3 -enriched counterparts. In this work, we report a convenient multigram preparation of enantioenriched 2-((hetera)cyclo)alkyl)chroman-4-ols and their spirocyclic analogs through enzymatic resolution (Scheme 1, C). We demonstrate that depending on the size of the substituent(s) at the C-2 position, enzymatic acetylation (promoted by Burkholderia Cepacia lipase, Amano PS) or enzymatic hydrolysis (promoted by porcine liver esterase, PLE) is optimal to obtain cisisomeric chromanols with over 99% ee. Finally, we illustrate the synthetic utility of the synthesized chiral alcohols by performing model Mitsunobu reactions and further transformations, eventually leading to enantioenriched trans-isomeric chromanols and the corresponding primary aminesvaluable building blocks for medicinal chemistry.