Imposing conformational restriction through a bicyclic system is an important design methodology in drug discovery that can improve the compound's potency, selectivity, physicochemical and/or metabolic profile, and this approach was implemented successfully for numerous bicyclic sultams. For the smallest representatives of the series, however, the above strategy may represent a considerable synthetic challenge. Such rigidification is well-studied for saturated heterocyclic amines (i.e., pyrrolidine) and to a lesser extent -for lactams (Figure ). Thus, 2,4-methanoproline (1) was isolated from natural sources as early as in 1980. Since then, numerous efficient approaches to the synthesis of 2,4-methanopyrrolidines were developed. Meanwhile, isosteric bridged bicyclic -sultam, 2-thia-3-azabicyclo[2.1.1]hexane 2,2-dioxide (2), remained unknown to date. Recently, we have reported the preparation of its isomer -2-thia-1-azabicyclo[2.1.1]hexane 2,2-dioxide (3), the smallest "Paquette's sultam". We anticipated that bicyclic system 4 could be constructed in an efficient and atom-economy manner through intramolecular photochemical [2 + 2] cycloaddition of appropriately substituted diene 5 (Scheme 1, A). Notably, intramolecular photochemical [2 + 2] cycloaddition was used to construct fused bicyclic sultams previously (Scheme 1, B); its application for the synthesis of bridged bicyclic systems was hereto unknown. Nevertheless, we have been inspired by the fact that a similar method was used to obtain 2,4-methanoproline 1 and other 2,4-methanopyrrolidines (Scheme 1, C). Based on these literature precedents, we have chosen intermediates 5a and 5b bearing an ester synthetic handle and phenyl substituent, respectively, for the preparation of target 2-thia-3-azabicyclo[2.1.1]hexane 2,2-dioxides. Compound 5a could be prepared on a large scale (over 100 g in a single run) in 39% overall yield starting from readily available serine methyl ester hydrochloride (6a) (Scheme 2). For intermediate 5b, somewhat longer reaction sequence was required due to the complications at the diene formation step. The key step -[2+2] cycloaddition -was performed by passing a highly diluted solution of 5a or 5b in MeCN (c = 16 mM) through a flow photoreactor upon irradiation at 365 nm in the presence of benzophenone at rt for 1 h. The cycloaddition was accompanied by polymerization, and after some optimization, we could achieve 55% yield of target product 4a on up to 40 g scale. As might be anticipated, the reaction was less efficient for the case of 5b, so that product 4b was obtained in 32% yield. Formation of fused regioisomers 12 was not observed at these conditions. The structure of sultam 4a was confirmed by X-Ray diffraction studies. We have tried to improve the above reaction sequence by implementing a much shorter approach to the synthesis of diene 5a (Scheme 3). Thus, 2-chloroethane-1-sulfonyl chloride was subjected to the reaction with p-methoxybenzylamine (PMBNH2) in the presence of Et3N to give vinyl sulfonamide 13 (63% yield). Further PPh3-mediated α-Umpolung addition of compound 13 to methyl propiolate proceeded smoothly to give required intermediate 5a in 80% yield. However, these yields were reproducible on up to 200mg scale and quickly diminished upon further scale-up attempt. Therefore, this alternative method can be useful for the rapid production of cycloadducts 4 in relatively small quantities. Nevertheless, a similar approach worked well for the preparation of dienes 5c and 5d (Scheme 4). This diene intermediates were obtained in 61-67% yield as mixtures of E and Z isomers (ca. 2:3 ratio). In the case of 5d, this mixture was separated by column chromatography (22% and 45% isolated yields, respectively). Notably, the subsequent flow photochemical [2 + 2] cycloaddition reaction of either isomer (E)-or (Z)-5d (or mixture thereof) gave cycloadduct 4d as a single diastereomer (59% yield). These results suggest non-synchronous biradical mechanism for the cycloaddition step, with possible formation of intermediates 14 and/or 15. Starting from a mixture of (E)-or (Z)-5c, compound 4c was obtained in 63% yield. Notably, the latter step could be performed on up to 25 g scale in a single run without considerable changes in the reaction outcome.