Synthesis. Initially, modification of CH2OH or other related functional groups in properly functionalized cis-1,2-disubstituted cyclobutanes (used previously for the preparation of trans isomers ) was suggested as a main route towards target building blocks cis-1 and cis-2, thus leading to commercially available anhydride 3 as the key starting material (Figure ). As shown below, this strategy performed well only in case of methylsubstituted cyclobutanes (cis-1a/cis-2a); intermediates of the corresponding reaction sequence also were useful for the synthesis of CH2F-substituted compounds cis-1b/cis-2b. For the remaining derivatives, an alternative approach was necessary. Following the selected strategy, lactone 3 was treated with iPrOH or tBuOH, which produced monoesters cis-4 and 5 in nearly quantitative yields (Scheme 1). Since we also aimed at the preparation of hereto unreported isomers trans-1a and trans-2a, base-promoted isomerization of isopropyl ester cis-4 was performed, cleanly giving trans-disubstituted cyclobutane trans-4 in high yield. With significant amounts of esters 4 in hands, target cis-and trans-isomeric Me-substituted cyclobutanes 1a/2a were prepared using a series of simple chemical transformations (Scheme 2). Thus, reduction of either cis-4 or trans-4 with BH3•Me2S gave corresponding alcohols, which were immediately transformed into mesylates 6 in high yields. Further nucleophilic substitution of the mesylate moiety with NaI produced iodides cis-7 and trans-7 in 72% and 75% yield, respectively. Reductive dehalogenation with subsequent hydrolysis of the ester moiety gave target carboxylic acids cis-2a and trans-2a as pure diasteromers in up to 97% yield over 2 steps on up to 145-g scale in a single run. Next, a modified Curtius rearrangement with further N-deprotection gave amine hydrochlorides cis-1a and trans-1a in 65 and 69% yield over 2 steps on up to 33 g scale. Several other 2-methylcyclobutyl-containing building blocks were also prepared from carboxylic acids cis-/trans-2a. In particular, reduction of cis-/trans-2a with BH3•Me2S gave in alcohols cis-8 and trans-9 (93 and 96% yield) that were transformed to corresponding bromides cis-9 and trans-9 by the Appel reaction. Reaction of cis-/trans-8 with MsCl gave corresponding mesylates 10 that produced hydrochlorides cis-11 and trans-11 upon reaction with NaN3 and subsequent reduction of the intermediate azides with LiAlH4 in satisfactory 48 and 40% yield (over 2 steps). Following the strategy developed previously for the trans-1,2disubstituted cyclobutane derivatives, we tested the deoxofluorination protocols for carboxylic acid cis-4, alcohol cis-12 (prepared from cis-4 by reduction with BH3•Me2S complex), and aldehyde cis-13 (prepared by Swern oxidation of cis-12) (Scheme 3). Unfortunately, none of the standard nucleophilic fluorination protocols were successful with these substrates. Instead, rapid decomposition of the starting compounds was observed, likely due to the close proximity of the ester functionality, resulting in complex mixtures of products with traces of HF elimination products detected by 1 H NMR spectra. Therefore, alternative strategies were necessary to prepare the target fluoroalkylsubstituted cyclobutanes. Scheme 2. Synthesis of building blocks cis-/trans-1a, cis-/trans-2a, cis-/trans-8, cis-/trans-9, and cis-/trans-11 (DPPAdiphenyl phosphoroyl azide). Scheme 3. Attempted synthesis of fluoroalkyl-substituted cis-1,2-disubstituted cyclobutanes via deoxo(y)fluorination reactions.