**2. Results and Discussion**

This section may be divided by subheadings. It should provide a concise and precise description of the experimental results, their interpretation, and the experimental conclusions that can be drawn. In our earlier studies of the formal nucleophilic substitution of bromocyclopropanes, we have demonstrated several reaction modes that allow for efficient control of the diastereoselectivity of this transformation (Scheme 1). Thus, it was shown that the derivatives of 2-bromocyclopropylcarboxylic acid **4** produced achiral cyclopropene **5** upon treatment with base. The latter underwent in situ addition of nucleophiles to afford *trans*-cyclopropane **6**. The high diastereoselectivity of the addition was attributed to a base-assisted, thermodynamically driven epimerization of the tertiary carbon atom (C-1, mode **A**, Scheme 1) [59–63]. Alternative approaches to control the diastereoselectivity of the intermolecular nucleophilic substitution were also developed by utilizing 1,2,2-trisubstituted cyclopropanes as the starting materials. The first approach employs substrates bearing two substituents with significantly different steric demands (**7**, small RS, and large RL). The in situ generated achiral cyclopropene **8** undergoes nucleophilic attack at the least hindered face, resulting in selective formation of product **9** (Scheme 1, mode **B**) [62,63]. The second approach takes advantage of bromocyclopropane **10**, bearing a directing functionality (DG, typically carboxamide or carboxylic acid group) capable of efficient coordination to the potassium cation, which serves as a delivery vehicle for the nucleophilic counter-anion. Overall, the addition to the double bond of cyclopropene **11** proceeds in cis fashion, with respect to the directing functional group furnishing **12** with high diastereoselectivity (Scheme 1, mode **C**) [62,63]. The addition of a tethered alkoxide entity was also investigated; both *exo-trig* (Scheme 1, mode **D**) [64,65] and *endo*-*trig* (mode **E**) [66] modes efficiently provided the corresponding medium-size heterocycles **15** and **18**.

Attempts to extend this methodology beyond the trisubstituted cyclopropane substrates greatly amplify the challenge of controlling the stereoselectivity of the addition. Indeed, all the modes discussed above require the control of a single center only, since the two forming chiral centers are linked to each other. In 2013, we communicated on the realization of a more advanced strategy, involving two modes of diastereoselctivity control providing tetrasubstituted cyclopropyl ethers **23** (mode **F**, Scheme 2) [67]. The proof of concept of such a strategy was showcased on racemic bromocyclorporpanes **20**. We also demonstrated employing racemic substrates, i.e., that the relative configuration of the center at C-3 can be efficiently controlled by steric environment employing appropriate substituents RS, RL; thus, control of this step is related to mode **B**. Finally, relative configuration at C-1 was installed via the base-assisted epimerization of this center, in a process identical to the one, previously used in mode **A** (Scheme 2) [66,67]. We reasoned that the absolute configuration of the quaternary stereogenic center at C-2 in chiral non-racemic amide **20** would be preserved during the dehydrohalogenation/nucleophilic addition sequence, which can be used to access to enantiomerically enriched compounds **23**.

**Scheme 2.** "Dual" control of diastereoselectivity—a new mode of formal nucleophilic substitution of bromocyclopropanes.

In order to access the densely substituted enantiopure cyclopropanes, we have developed a very facile protocol for the chiral resolution of carboxylic acids **19**, utilizing the re-crystallization of racemic acids with cinchona alkaloids [68]. It was shown that a variety of enantiomerically enriched acids **19** with ee > 95% were available in multi-gram scale, in both enantiomeric forms after single crystallization of either cinchonine or cinchonidine salts. Enantiopure acids can easily be converted into amides **20**, as a precursor for enantioenriched cyclopropenes (Scheme 3).

**Scheme 3.** Preparation of homochiral 1-bromocyclopropylcarboxamides employed as starting materials in these studies.
