The observation that molecular complexity, gauged by the fraction of sp³ carbon atoms and the presence of stereocenters, correlates with higher success rates in the preclinical phases of drug development, lies at the foundation of the so-called “escape from flatland” strategy in medicinal chemistry.¹ In this context, the quest for diversely substituted tridimensional scaffolds that can act as bioisosteres of aromatic groups and lead to improved affinities and pharmacokinetic properties has resulted in an upsurge of interest for strained ring systems.² Whilst the importance of cyclopropanes is well established,³ the conformationally restricted cyclobutyl fragment can likewise address some of the hurdles encountered during small-molecule drug development.⁴ Whereas 1,3-substituted achiral cyclobutanes have often been the privileged structures, several examples of bioactive trisubstituted cyclobutanes, with vicinal aryl and alkyl substitution and a heteroatom, can be found in patents from pharmaceutical industries, as illustrated in Figure 1.⁵ Hence, expanding the chemical space of substituted chiral cyclobutanes should likely stimulate a greater use of these scaffolds in medicinal chemistry.⁶ Recent years have witnessed substantial efforts in the development of enantioselective synthetic routes toward cyclobutanes, with the functionalization of preformed unsaturated four-membered carbocycles⁷ such as cyclobutenes⁸ or cyclobutenones^{9-11, 12-16} emerging as one possible attractive strategy.

Prochiral cyclobutenones have been involved in catalytic transformations leading to enantioenriched cyclobutenes or cyclobutanones, amenable to further derivatization (Scheme 1A). Most of the reported transformations are conjugate addition reactions, including the copper-catalyzed hydrosilylation (Equation 1) or the alkylation with diorganozinc reagents (Equation 2), which produce cyclobutenyl phosphates, after phosphorylation of the enolate intermediate.⁹ The scope of the copper-catalyzed hydrosilylation was further extended to gem-disubstituted cyclobutenones followed by hydrolysis or bromination of the silyl enol ether. In the latter case, subsequent nickel or cobalt-catalyzed Negishi cross-coupling reactions enabled the introduction of an additional substituent at the α-position of the carbonyl group (Equation 3).¹⁰ The copper-catalyzed conjugate borylation, which is actually the first reported enantioselective conjugate addition to cyclobutenones, allows access to densely substituted β-boryl cyclobutanones (Equation 4).¹¹ As an alternative to transition metal-catalyzed reactions, the biocatalyic conjugate reduction of cyclobutenones using ene-reductases has also been disclosed (Equation 5).¹² Recently, the asymmetric transfer hydrogenation (ATH)¹⁶ of cyclobutenediones, catalyzed by Noyori-lkariya ruthenium complexes, was reported and the outcome depended on the substituents and conditions.¹³ In the case of 4-aryl-3-alkylcyclobutenediones, regioselective conjugate ATH was observed and the resulting products were isolated in the form of enol esters. With a higher catalyst loading and LiCl as additive, the reaction progressed further by successive ATH of the carbonyl groups at C2 and C1, with dynamic kinetic resolution at C4. Cyclobutane-1,2-diols were obtained albeit with moderate diastereoselectivities (Equation 6).¹³ When the alkyl chain was replaced by a β-styryl substituent, successive ATH of the carbonyl groups at C2 and C1 took place and afforded cis-cyclobutene-1,2-diols (Equation 7).¹³

Despite these developments, the enantioselective reduction of the carbonyl group of simple cyclobutenones has not yet been reported.⁷ The known ability of some cyclobuten-1-ols, or metal alkoxides derived thereof, to undergo electrocyclic ring-opening may have deterred research efforts in this area.¹⁷ Herein we report our investigations on the reactivity of gem-dichloro-cyclobutenones in ATH catalyzed by Noyori-Ikariya type complex and unveil a new reductive allylic substitution-ATH cascade leading to 2-chlorocyclobuten-1-ols with high optical purities, as well as postfunctionalization reactions to demonstrate the synthetic utility of these building blocks (Scheme 1B).

Although gem-dichlorocyclobutenones arguably constitute a readily accessible class of cyclobutenones,¹⁸ enantioselective reduction reactions of these strained substrates have not been reported. Our studies started by investigating the reactivity of dichlorocyclobutenone 1 a in ATH under rather classical conditions involving treatment with (R,R)-[Ru]-I (5 mol%) in the presence of HCO₂H/Et₃N (5:2) mixture as hydrogen donor (EtOAc, RT, 3 h).¹⁹ Complete conversion of 1 a was observed but none of the products arose from simple 1,4- or 1,2-reduction. Indeed, 2-chlorocyclobuten-1-ol 2 a was the major product, accompanied with 2-chlorocyclobutenone 3 a and acyclic alcohols 4 a and 4’a (2 a/3 a/4 a/4’a=69:14:14:3). We reasoned that ruthenium hydride [Ru*]-H (generated from precatalyst [Ru*]-Cl and HCO₂H/Et₃N) could trigger a reductive allylic substitution of one chlorine atom of dichlorocyclobutenone 1 a, in agreement with the known ability of these substrates to undergo S_N2’ reactions.²⁰ This would generate chlorocyclobutenone 3 a, effectively detected among the products, and regenerate precatalyst [Ru*]-Cl. Cyclobutenone 3 a would then undergo regioselective ATH leading to cyclobutenol 2 a and subsequent decarboxylation of the formate complex [Ru*]-OCHO would close the catalytic cycle. Electrocyclic ring-opening of 2 a would produce dienol 5 a which could tautomerize into aldehydes 6 a/6’a and subsequent reduction of the formyl group could explain the formation of alcohols 4 a/4’a. Because hydrogen transfer in the Noyori-Ikariya catalytic cycle does not involve a concerted process,²² the transient ruthenium alkoxide [Ru*]-2 a could undergo electrocyclic ring-opening and generate extended enolate [Ru*]-5 a, the protonation of which could also generate aldehydes 6 a/6’a (Scheme 2).

Encouraged by the high enantiomeric purity of cyclobutenol 2 a (ee=96%, 49% isolated yield)²¹ generated by this new allylic reduction-ATH cascade process from 1 a, alternative conditions were screened with the goal of optimizing the results and minimizing byproducts formation, in particular alcohols 4 a/4’a which are difficult to separate by flash column chromatography. With the hypothesis that a protic medium, by its capacity to engage in hydrogen bonding, could exert an influence on the enantioselectivity of the hydride addition to 3 a and on the proton transfer event in the ATH catalytic cycle (conversion of [Ru*]-2 a into 2 a),²² the use of an organic solvent-water mixture was considered. Sodium formate was then selected as the reductant in the presence of cetyltrimethylammonium bromide (CTAB) as phase transfer agent (Table 1). Rewardingly, these modifications almost entirely suppressed the formation of allylic alcohol 4 a and the best result was obtained in an EtOAc/H₂O mixture affording 2 a in high enantiomeric excess (ee>99%) (entry 1), although THF and CH₂Cl₂ were also satisfactory (entries 2 and 3). In the absence of catalyst, no conversion of substrate 1 a was observed thereby highlighting the requirement of the ruthenium complex in the reductive allylic substitution (entry 4). Whilst the replacement of the η⁶-(p-cymene) ligand of ruthenium by a mesitylene (catalyst [Ru]-II, entry 5) did not substantially affect the reactivity, other sulfonyl substituents than tosyl on the nitrogen atom of the ligand have a more significant impact. The reaction did not reach completion with the mesyl-substituted catalyst [Ru]-III and alcohol 7 a resulting from the direct ATH of the carbonyl group of 1 a was now detected as byproduct (entry 6). With the (pentafluorophenyl)sulfonyl-substituted catalyst [Ru]-IV, chlorocyclobutenone 3 a was the only newly formed product (entry 7), although subsequent ATH leading to 2 a eventually occurred by extending the reaction time (RT, 18 h) (entry 8). Other catalysts were also screened but none of them outpassed the simpler [Ru]-I complex (see the Supporting Information, Table S1).

Table 1. Reactivity of dichlorocyclobutenone 1 a under ATH conditions.

• ^[a] Determined by analysis of the crude material by ¹H NMR spectroscopy. ^[b] ee (7 a)=98%. ^[c] Reaction time 18 h.

Additional experiments were conducted to shed light on the effect of the reaction conditions. Cyclobutene 2 a does not undergo electrocyclic ring-opening into enal 6 a at an appreciable rate at RT at the time scale of the experiments. The lower proportion of alcohols 4 a/4’a under the optimized conditions in EtOAc/H₂O compared to the preliminary experiment using HCO₂H/Et₃N in EtOAc was attributed to a faster protonation of the transient ruthenium alkoxide [Ru*]-2 a, which is more prone to electrocyclic ring-opening than cyclobutenol 2 a itself.²³

Under optimized conditions (Table 1, entry 1), cyclobutenol 2 a (ee=99.2%) was isolated in 96% yield and could be prepared on large scale (4.0 g, 22 mmol) with no adverse effect on the yield and enantiomeric purity (94%, ee=99%) (Scheme 3). The catalytic loading could be decreased to 1 mol% at the expense of a longer reaction time (24 h) and a lower isolated yield of 2 a (78%, ee=99%) due to the required separation from byproducts 4 a/4’a. The absolute configuration of 2 a was assigned by X-ray diffraction analysis of the corresponding crystalline acetate 8.²⁴ A deuterium labeling experiment with DCO₂Na produced the dideuterated cyclobutenol [D₂]-2 a as an equimolar mixture of diastereomers (ee>99%). This result indicates that the allylic substitution of the chlorine atom of 1 a by the ruthenium hydride complex proceeds in a stereorandom manner, whereas subsequent ATH of [D]-3 a is highly face selective. The observed stereochemical outcome of the ATH appears to be consistent with a preferential hydrogen transfer on the si face of chlorocyclobutenone 3 a through transition state model TS-I, which may be more favorable than TS-I’ suffering from lone pair repulsion between the chlorine atom and the sulfonyl group, and possibly a steric interaction between the methylene unit and the arene.²⁵ Interestingly, comparison was made with the methyl-substituted cyclobutenone 9, which turned out to be less reactive than chlorocyclobutenone 3 a in ATH and provided cyclobutenol 10 with low enantiomeric purity (ee=53%) (Scheme 3).²⁶

The scope of the allylic reduction-ATH cascade was explored with various β-substituted dichlorocyclobutenones 1 b-1 r (Scheme 4). The transformation accommodates substituents at the para position of the aromatic group, regardless of their electronic properties (electron-donating Me, OMe or electron-withdrawing CF₃, CO₂Me, F), or a chlorine atom at the meta position, as shown with the formation of products 2 b–2 g with high enantiomeric purities. A slight drop of enantioselectivity was noted in the case of the p-methoxy substituted 2 c (ee=93%) and the lower but still satisfactory yields of 2 f (82%) and 2 g (81%) were due to the required separation of the alcohols byproducts 4 f/4 g arising from electrocyclic ring-opening and reduction. A naphthyl group was also tolerated, as shown, with the formation of 2 h, as well as diversely disubstituted aromatic groups (meta and para positions) as illustrated with the formation of products 2 i, 2 j and 2 k (82–99%). The transformation is also compatible with heteroaromatic substituents derived from thiophene, benzofuran or N-Boc indole and led to the corresponding chlorocyclobutenols 2 l-2 n in high enantiomeric purities. For substrates 1 o and 1 p having an ortho-substituted aromatic group, chlorocyclobutenols 2 o (63%) and 2 p (49%) arising from the allylic reduction-ATH cascade were isolated in modest yields and were accompanied by dichlorocyclobutenols 7 o (31%) and 7 p (46%) (also formed with high enantiomeric purities, configuration assigned by analogy with 7 r, vide infra). The steric demand of the ortho substituent presumably retards the rate of the allylic reduction of the C−Cl bond in 1 o and 1 p by the ruthenium hydride and hence direct ATH of their carbonyl group is now competing. Alkyl-substituted cyclobutenones were previously identified as problematic substrates in S_N2’ reactions^{15, 20a, 27} and this was confirmed with 1 q possessing a phenethyl chain which led to gem-dichlorocyclobutenol 7 q (<70% yield) contaminated by unidentified byproducts. In the case of the cyclohexyl-substituted cyclobutenone 1 r, a regioselective direct 1,2-reduction of the carbonyl group took place delivering exclusively dichlorocyclobutenol 7 r (81%, ee=99%), the configuration of which was assigned by X-ray diffraction analysis²⁴ (Scheme 4). The allylic reduction of gem-dichlorocyclobutenones may involve a stepwise process (addition of a ruthenium hydride followed by β-elimination of a chlorine atom) which could explain the observed difference of reactivity between aryl- and alkyl-substituted substrates.

Because little information is available on the reactivity of (chloro)cyclobutenols with a substitution pattern similar to that of 2 a, several postfunctionalization reactions were investigated from this compound (Scheme 5). A Mitsunobu reaction with DPPA afforded azide 11, which was involved in a copper-catalyzed (3+2)-cycloaddition with a terminal alkyne to produce triazole 12. Cyclobutenol 2 a was also converted to glycolate 13 which was engaged in an Ireland-Claisen rearrangement.²⁸ After enolization with Me₃SiCl and KMHDS, heating in THF at reflux was required to trigger the [3,3]-sigmatropic rearrangement and after hydrolysis and subsequent formation of the methyl ester, chlorocyclobutene 14 bearing a quaternary stereocenter was obtained (dr=7:1, 83%).²⁹ Functionalization of the C−Cl bond turned out to be challenging because of the propensity of 2 a and derivatives thereof to undergo thermal electrocyclic ring-opening. After protection of 2 a as the tert-butyldiphenylsilyl ether 15, reductive dechlorination could be accomplished under palladium-catalyzed conditions, using HCO₂H/Et₃N mixture as reducing agent, to afford 16 in 98% yield. Hydroboration of cyclobutene 16 with BH₃ ⋅ THF proceeded with low stereocontrol and produced a mixture of secondary alcohols from which the major cyclobutanol diastereomer 17 (32%), presumably corresponding to addition on the less-hindered face of the olefin, was isolated. Attempts at implementing Suzuki-Miyaura cross-coupling reactions from 15 (or acetate 8) were complicated by the concomitant electrocyclic ring-opening of the products.³⁰ However, introduction of an aryl group was smoothly accomplished by a palladium-catalyzed Corriu-Kumada cross-coupling,³¹ as illustrated with the formation of diarylcyclobutene 18 (85%). Iron-catalyzed cross-coupling reactions with Grignard reagents³² nicely serve for the introduction of alkyl groups and afforded methyl- and ethyl-substituted cyclobutenes 19 (98%) and 20 (93%), respectively, and even 21 bearing an isopropyl group albeit in lower yield (33%). Subsequent hydrogenation of the tetrasubstituted olefin in cyclobutene 19, which required the use of pressurized hydrogen gas, was conveniently achieved under flow conditions using a H-Cube^® device. After desilylation, trisubstituted cyclobutanol 22, arising from preferential hydrogen addition on the less-hindered face of 19 was obtained (dr=6:1, 81%), a suitable precursor of a GPR120 modulator^{5a, 13} (see Figure 1). Hydrogenation of cyclobutene 23 (synthesized from 19 by desilylation and a Mitsunobu reaction), possessing the sterically demanding N(Boc)Ts group, proceeded with excellent diastereocontrol and provided amino-cyclobutane derivative 24 bearing three contiguous stereocenters³³ (Scheme 5).

In summary, a new allylic reduction-ATH cascade from 3-(hetero)aryl gem-dichlorocyclobutenones, catalyzed by a Noyori-Ikariya ruthenium complex, was discovered that provides an efficient entry to (chloro)cyclobutenols with high enantiomeric purities. The results contribute to complement the repertoire of enantioselective catalytic transformations involving cyclobutenones and to expand the substrate scope of the ATH of ketones to new classes of strained substrates, while unveiling the ability of the involved ruthenium catalysts to trigger other reductive transformations. Postfunctionalization reactions demonstrate the synthetic utility of the (chloro)cyclobutenols as building blocks for targeting other classes of diversely substituted four-membered rings.

Supporting Information Summary

The authors have cited additional references within the Supporting Information.^34-44

Acknowledgments

Financial support from the ANR (ATHOMICS project, ANR-21-CE07-0038) is gratefully acknowledged.

中文翻译：

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从 gem-二氯环丁烯酮到环丁烯醇：揭开钌催化烯丙基还原-不对称转移氢化级联的面纱

通过sp ³碳原子的分数和立体中心的存在来衡量分子复杂性与药物开发的临床前阶段较高的成功率相关，这是药物化学中所谓的“逃离平原”策略的基础。¹ 在这种情况下，寻求可以充当芳香族基团的生物等排体并导致亲和力和药代动力学特性的多样化取代的三维支架导致了对应变环系统的兴趣激增。² 虽然环丙烷的重要性已得到充分证实，³ 但构象限制性环丁基片段同样可以解决小分子药物开发过程中遇到的一些障碍。⁴ 虽然 1,3-取代的手性环丁烷通常是特权结构，但在制药行业的专利中可以找到几个具有生物活性的三取代环丁烷的例子，具有邻近芳基和烷基取代以及杂原子，如图 1 所示。⁵ 因此，扩大取代手性环丁烷的化学空间可能会刺激这些支架在药物化学中的更多使用。⁶ 近年来，在开发针对环丁烷的对映选择性合成途径方面取得了重大努力，预先形成的不饱和四元碳水化合物^{环 7}（如环丁烯⁸ 或环丁烯酮^9-11、12-16）的功能化成为一种可能的有吸引力的策略。

原手性环丁烯酮参与催化转化，导致对映体富集的环丁烯或环丁酮，适合进一步衍生化（方案 1A）。大多数报道的转化是偶联物加成反应，包括铜催化的氢化硅烷基化反应（方程 1）或用二有机锌试剂进行烷基化反应（方程 2），它们在烯醇化物中间体磷酸化后产生环丁烯磷酸酯。⁹ 铜催化的氢化硅烷基化的范围进一步扩展到 gem 二取代的环丁烯酮，然后是硅烷基烯醇醚的水解或溴化。在后一种情况下，随后的镍或钴催化的 Negishi 交叉偶联反应能够在羰基的 α 位置引入额外的取代基（方程 3）。¹⁰ 铜催化的偶联硼酸化实际上是首次报道的对映选择性偶联物添加到环丁烯酮中，允许获得密集取代的 β-硼基环丁酮（方程式 4）。¹¹ 作为过渡金属催化反应的替代方案，还披露了使用烯还原酶对环丁烯酮进行生物催化偶联物还原（方程 5）。¹² 最近，报道了由 Noyori-lkariya 钌配合物催化的环丁烯二酮的不对称转移氢化 （ATH）¹⁶，结果取决于取代基和条件。¹³ 在 4-芳基-3-烷基环丁烯二酮的情况下，观察到区域选择性共轭物 ATH，所得产物以烯醇酯的形式分离。 在较高的催化剂负载量和 LiCl 作为添加剂的情况下，反应在 C2 和 C1 处通过羰基的连续 ATH 进一步进行，在 C4 处具有动态动力学分辨率。获得环丁烷-1,2-二醇，尽管具有中等的非对映选择性（方程 6）。¹³ 当烷基链被 β-苯乙烯基取代时，羰基在 C2 和 C1 处的连续 ATH 发生，并得到顺式-环丁烯-1,2-二醇（方程 7）。¹³

尽管有这些发展，但尚未报道简单环丁烯酮羰基的对映选择性还原。⁷ 一些环丁烯-1-醇或其衍生的金属醇盐的已知能力能够进行电循环开环，这可能阻碍了该领域的研究工作。¹⁷ 在此，我们报告了我们对 Gem-二氯-环丁烯酮在 Noyori-Ikariya 型复合物催化的 ATH 中反应性的研究，并揭示了一种新的还原烯丙基取代-ATH 级联反应，导致具有高光学纯度的 2-氯环丁烯-1-醇，以及功能后化反应，以证明这些结构单元的合成效用（方案 1B）。

尽管 gem-二氯环丁烯酮可以说是一类容易获得的环丁烯酮，但尚未报道这些菌株底物的对映选择性还原反应¹⁸。我们的研究首先调查了二氯环丁烯酮 1 a 在 ATH 中的反应性，在相当经典的条件下，包括 （R，R）-[Ru]-I （5 mol%） 在 HCO₂H/Et₃N （5：2） 混合物作为氢供体 （EtOAc， RT， 3 h） 存在下处理。¹⁹ 观察到 1 a 的完全转化，但没有一个产物是由简单的 1,4- 或 1,2 还原产生的。事实上，2-氯环丁烯-1-醇 2 a 是主要产物，伴有 2-氯环丁烯酮 3 a 和无环醇 4 a 和 4'a （2 a/3 a/4 a/4'a=69：14：14：3）。我们推断，氢化钌 [Ru*]-H（由预催化剂 [Ru*]-Cl 和 HCO₂H/Et₃N生成）可以触发二氯环丁烯酮 1 a 的一个氯原子的还原烯丙基取代，这与这些底物发生 S_N2' 反应的已知能力一致。²⁰ 这将生成氯环丁烯酮 3 a，在产物中有效检测到，并再生预催化剂 [Ru*]-Cl。然后环丁烯酮 3 a 将经历区域选择性 ATH，导致环丁烯醇 2 a，随后甲酸盐复合物 [Ru*]-OCHO 的脱羧将关闭催化循环。 2 a 的电循环开环会产生二醇 5 a，二醇 5 a 可以互变异构化成醛 6 a/6'a，随后甲酰基的还原可以解释醇 4 a/4'a 的形成。由于 Noyori-Ikariya 催化循环中的氢转移不涉及协同过程，²² 瞬时醇钌 [Ru*]-2 a 可以发生电循环开环并产生延伸的烯醇酸盐 [Ru*]-5 a，其质子化也可以产生醛 6 a/6'a（方案 2）。

这种新的烯丙基还原-ATH 级联工艺从 1 a 产生环丁烯醇 2 a（ee=96%，分离产率 49%）²¹ 的高对映体纯度，筛选了替代条件，以优化结果并最大限度地减少副产物的形成，特别是醇类 4 a/4'a它们难以通过 Flash 柱色谱分离。假设质子介质通过其参与氢键的能力，可以对 3 a 中氢化物添加的对映选择性和 ATH 催化循环中的质子转移事件（将 [Ru*]-2 a 转化为 2 a）产生影响，²² 考虑了有机溶剂-水混合物的使用。然后在十六烷基三甲基溴化铵 （CTAB） 作为相转移剂存在下选择甲酸钠作为还原剂（表 1）。值得一提的是，这些修饰几乎完全抑制了烯丙基醇 4 a 的形成，并且在 EtOAc/H₂O 混合物中获得了最佳结果，该混合物在高对映体过量 （ee>99%） 中提供 2 a（条目 1），尽管 THF 和 CH₂Cl₂ 也令人满意（条目 2 和 3）。在没有催化剂的情况下，没有观察到底物 1 a 的转化，从而突出了钌配合物在还原烯丙基取代中的需要（条目 4）。 虽然用均三甲苯（催化剂 [Ru]-II，条目 5）取代钌的η⁶-（对环烯烃）配体没有实质性影响反应性，但除甲苯磺酰基外，其他磺酰取代基对配体氮原子的影响更显着。使用甲氧基取代催化剂 [Ru]-III 未完成反应，现在将羰基 1 a 的直接 ATH 产生的醇 7 a 检测为副产物（条目 6）。使用（五氟苯基）磺酰基取代的催化剂 [Ru]-IV，氯环丁酮 3 a 是唯一新形成的产物（条目 7），尽管随后通过延长反应时间（RT，18 小时）最终导致 2 a的 ATH（条目 8）。还筛选了其他催化剂，但没有一种催化剂超过更简单的 [Ru]-I 复合物（参见支持信息，表 S1）。

Table 1. Reactivity of dichlorocyclobutenone 1 a under ATH conditions.

• 
  ^[a] 通过 ¹H NMR 波谱分析粗料测定。^[b] ee （7 a）=98%。^[c] 反应时间 18 h。

进行了额外的实验以阐明反应条件的影响。在实验的时间尺度上，环丁烯 2 a 在 RT 下不会以可观的速率电循环开环成烯醛 6 a。与在 EtOAc 中使用 HCO₂H/Et₃N 的初步实验相比，在 EtOAc/H₂O 中优化条件下醇 4 a/4'a 的比例较低，这归因于瞬时钌醇盐 [Ru*]-2 a 的质子化速度更快，它比环丁烯醇 2 a 本身更容易发生电环开环。²³

在优化条件下（表 1，条目 1），以 96% 的产量分离出环丁烯醇 2 a （ee=99.2%），并且可以大规模制备 （4.0 g， 22 mmol），对产量和对映体纯度 （94%，ee=99%） 没有不利影响（方案 3）。由于需要与副产物 4 a/4'a 分离，因此催化负载量可以降低到 1 mol%，但代价是反应时间较长（24 h）和较低的分离产率为 2 a（78%，ee=99%）。2 a 的绝对构型是通过对相应的结晶乙酸盐 8 进行衍射分析分配的。²⁴ 用 DCO₂Na 进行氘标记实验，产生二元化的环丁烯醇 [D₂]-2 a，作为非对映异构体 （ee>99%） 的等摩尔混合物。该结果表明，1 a 的氯原子被钌氢化物络合物的烯丙基取代以立体随机方式进行，而随后的 [D]-3 a 的 ATH 具有高度的面选择性。观察到的 ATH 立体化学结果似乎与氯环丁烯酮 3 a 通过过渡态模型 TS-I 在 si 面上的优先氢转移一致，这可能比 TS-I' 更有利，TS-I' 在氯原子和磺酰基之间发生孤对排斥，并且可能在亚甲基单元和芳烃之间发生空间相互作用。²⁵ 有趣的是，与甲基取代的环丁烯酮 9 进行了比较，结果证明它在 ATH 中的反应性低于氯环丁烯酮 3 a，并且提供了对映体纯度低的环丁烯醇 10 （ee=53%）（方案 3）。²⁶

用各种 β 取代的二氯环丁烯酮 1 b-1 r 探索烯丙基还原-ATH 级联反应的范围 （方案 4）。该转化在芳香族基团的对位容纳取代基，无论它们的电子性质如何（供电子 Me、OMe 或吸电子 CF₃、CO₂Me、F）或间位的氯原子，如形成具有高对映体纯度的产物 2 b-2 g 所示。在对甲氧基取代 2 c （ee=93%） 的情况下，对映选择性略有下降，并且 2 f （82%） 和 2 g （81%） 的产量较低但仍然令人满意，这是由于需要分离醇类副产物 4 f/4 g，这是由于电环开环和还原产生的。如图所示，萘基也可耐受 2 h 的形成，以及多种二取代的芳香族基团（meta 和 para 位置），如产物 2 i、2 j 和 2 k （82-99%） 的形成所示。该转化还与衍生自噻吩、苯并呋喃或 N-Boc 吲哚的杂芳族取代基相容，并导致相应的氯环丁烯醇 2 l-2 N 具有高对映体纯度。 对于具有邻位取代芳香族基团的底物 1 o 和 1 p，由烯丙基还原-ATH 级联反应产生的氯环丁烯醇 2 o （63%） 和 2 p （49%） 以中等产量分离，并伴有二氯环丁烯醇 7 o （31%） 和 7 p （46%） （也具有高对映体纯度，通过与 7 r 类比分配的构型， 视频 infra）。邻位取代基的空间位位需求可能延缓了氢化钌在 1 o 和 1 p 中 C-Cl 键的烯丙基还原速率，因此它们的羰基的直接 ATH 现在正在竞争。烷基取代的环丁烯酮先前在 S_N2' 反应^{15、20a、27} 中被确定为有问题的底物，这被证实为 1 q 具有苯乙基链，导致 gem-二氯环丁烯醇 7 q（<70% 产率）被未鉴定的副产物污染。在环己基取代的环丁烯酮 1 r 的情况下，羰基的区域选择性直接 1,2-还原发生，仅产生二氯环丁烯醇 7 r （81%，ee=99%），其构型由 X 射线衍射分析²⁴ 分配（方案 4）。gem-二氯环丁烯酮的烯丙基还原可能涉及一个逐步过程（添加钌氢化物，然后β消除氯原子），这可以解释观察到的芳基和烷基取代底物之间的反应性差异。

由于关于具有类似于 2 a 的取代模式的（氯）环丁烯醇的反应性的信息很少，因此研究了该化合物的几个功能化后反应（方案 5）。Mitsunobu 与 DPPA 反应得到叠氮化物 11，其参与铜催化的 （3+2）-环加成反应与末端炔烃生成三唑 12。环丁烯醇 2 a 也被转化为乙醇酸盐 13，乙醇酸盐 13 参与 Ireland-Claisen 重排。²⁸ 用 Me₃SiCl 和 KMHDS 烯醇化后，需要在回流时在 THF 中加热以触发 [3,3] -σ 偏斜重排，在水解并随后形成甲酯后，获得了带有四元立体中心的氯环丁烯 14 （dr=7：1， 83%）。²⁹ C-Cl 键的功能化被证明是具有挑战性的，因为 2 a 及其衍生物倾向于发生热电循环开环。在以 2 a 作为叔丁基二苯基甲硅烷醚 15 进行保护后，可以在钯催化条件下完成还原脱氯，使用 HCO₂H/Et₃N 混合物作为还原剂，得到 16 比 98% 的收率。环丁烯 16 与 BH₃ ⋅ THF 的硼氢化反应以低立体控制进行，并产生仲醇混合物，从中分离出主要的环丁醇非对映异构体 17 （32%），可能对应于烯烃受阻较少的表面的添加。 从 15 （或乙酸盐 8） 实现 Suzuki-Miyaura 交叉偶联反应的尝试因产物的电循环开环而变得复杂。³⁰ 然而，芳基的引入是通过钯催化的 Corriu-Kumada 交叉偶联顺利完成的，³¹ 如二芳基环丁烯 18 （85%） 的形成所示。使用 Grignard 试剂³² 的铁催化交叉偶联反应很好地用于引入烷基，并分别得到甲基和乙基取代的环丁烯 19 （98%） 和 20 （93%），甚至 21 带有异丙基，尽管产率较低 （33%）。随后在环丁烯 19 中对四取代烯烃进行加氢，这需要使用加压氢气，使用 H-Cube^® 装置在流动条件下方便地实现。脱硅烷基化后，获得了三取代环丁醇 22，这是由于在 19 的受阻较少的表面上优先加氢而产生的 （dr=6：1， 81%），这是 GPR120 调节剂^{5a， 13} 的合适前体（见图 1）。具有空间要求 N（Boc）Ts 基团的环丁烯 23（通过脱硅烷基和 Mitsunobu 反应从 19 合成）的氢化以出色的非对映控制进行，并提供了带有三个连续立体中心³³ 的氨基-环丁烷衍生物 24（方案 5）。

总之，在 Noyori-Ikariya 钌复合物催化下，发现了一种由 3-（杂）芳基 gem-二氯环丁烯酮产生的新的烯丙基还原 ATH 级联反应，它为具有高对映体纯度的（氯）环丁烯醇提供了有效的进入。这些结果有助于补充涉及环丁烯酮的对映选择性催化转化，并将酮的 ATH 的底物范围扩展到新的应变底物，同时揭示了所涉及的钌催化剂触发其他还原转化的能力。功能后化反应证明了（氯）环丁烯醇的合成效用，作为靶向其他类别的不同取代的四元环的构建单元。

支持信息摘要

作者在支持信息中引用了其他参考文献。^34-44 岁

 确认

感谢 ANR（ATHOMICS 项目，ANR-21-CE07-0038）的财政支持。