An Asymmetric Hydroformylation Catalyst that Delivers Branched Aldehydes from Alkyl Alkenes
An Asymmetric Hydroformylation Catalyst that Delivers Branched Aldehydes from Alkyl Alkenes
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DOI：
10.1002/anie.201108203
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Clarke, Matthew L.
中科院分区：
文献类型：
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作者：
Noonan, Gary M.;Fuentes, Jose A.;Clarke, Matthew L.
烯烃的对映选择性氢甲酰化反应可以同时生成一个新的C？C键，安装一个非常多功能的官能团，并从非常经济的试剂：烯烃、一氧化碳和氢中生成富含对映体的化合物。鉴于大规模生产非手性直链醛的先例，氢甲酰化可被视为工业化生产手性构建块的潜在理想反应。[1]然而，尽管经过数十年的研究努力，相对于不对称氢化等核心不对称生产方法，仍有更多的障碍需要克服。经过密集的研究工作，一系列催化剂现已面世，这些催化剂为模型底物(如苯乙烯)提供了良好的对映体过剩(Ee)。[2]现在，利用该技术制造与制药工业和有机合成相关的产品方面，有大量的研究和商业兴趣。[3]尽管有这些活性，但对支链醛的区域选择性控制充其量只是一个部分解决的问题。某些众所周知的底物，如苯乙烯，使支链醛具有大约10：1的典型区域选择性，可在提纯后使用，尽管需要更高的选择性。一些功能化的底物在催化剂的正确选择下表现出对支链醛的高度偏好，同时作为底物的可逆辅助剂和结合Rh的配体已经成功地应用于控制特定官能化烯烃的区域选择性。[4]一个完全悬而未决的问题代表着巨大的进步，那就是从RCH2CH=CH2类型的简单末端烷基烯烃控制生成支链手性醛。在这里，我们展示了实现这一总体目标的最重大进展，第一批催化反应结合了RCH2CH=CH2类型烯烃的显著区域选择性和对映体选择性。长期以来，我们一直对从烷基烯烃中获得支链醛感兴趣，但在没有任何真正的线索的情况下，我们将这些努力限制在筛选新型催化剂上，这些催化剂最初是为了解决羰化催化中的其他问题而设计的。在最近一项旨在进一步调整重要的不对称氢甲酰化配体Kelliphite和Ph-BPE的优异性能的研究项目中，我们考虑了一种混合非对称配体，它将呈现这两种配体的最佳性能，并可能从非C2对称中获得优势。亚膦-亚磷酸盐在氢甲酰化反应中引起了人们极大的兴趣，[2g，L-q]，尽管磷醇衍生物或使用±CH2O±主链的衍生物还没有得到很好的研究。[2N，p]我们倾向于称之为bobphos(“两个磷配体中最好的”)的配体，(Sax，S，S)-4，可以通过方案1中所示的路线从已知的前体1可靠地合成。[5]亚磷酸盐的偶联是通过Me3SiI活化(S)-2完成的；在DABCO作为碱和去保护剂的存在下，碘(S)-3和(S)-2约40：60的混合物与已知的前体1直接反应，纯化后得到(SAX，S，S)-4。(R)-2也制备了[5](RAX，S，S)-4。该配体在模型底物乙酸乙烯酯的氢甲酰化反应中进行了初步研究(方案2)。Bobphos在2.5bar压力下于608℃下4小时后转化率99%为醛；线性异构体仅在微量下可观察到(见辅助信息)，并且测得83%的ee。配体的另一个非对映异构体(RAX，S，S)-4是由手性二醇对映体制成的，给出了32%的…
Enantioselective hydroformylation of alkenes can simultaneously create a new CÀC bond, install a very versatile functional group, and produces enantiomerically enriched compounds from very economic reagents: an alkene, carbon monoxide, and hydrogen. Given the precedent for large-scale production of achiral linear aldehydes, hydroformylation can be viewed as potentially the ideal reaction for commercial production of chiral building blocks.[1] However, there have been far more hurdles to overcome relative to core asymmetric production methods such as asymmetric hydrogenation, despite decades of research effort. After intensive research effort, a range of catalysts that give good enantiomeric excess (ee) for model substrates (eg styrene) are now available.[2] There is now substantial research and commercial interest in making products of relevance to the pharmaceutical industry and organic synthesis using this technology.[3] Despite all this activity, the control of regioselectivity towards the branched aldehyde is at best only a partially resolved issue. Certain well-known substrates like styrene give the branched aldehyde with a typical regioselectivity of around 10: 1, which is usable after purification, although higher selectivity is desirable. Some functionalized substrates show a very high preference for the branched aldehyde with the correct choice of catalyst, and ligands that simultaneously act as reversible auxiliaries for the substrate and bind rhodium have been applied successfully to control regioselectivity for specific functionalized alkenes.[4] A completely unresolved issue that would represent a huge step forward is the controlled formation of branched chiral aldehydes from simple terminal alkyl olefins of type RCH2CH= CH2. Here we show the most significant progress yet towards this general goal, with the first catalytic reactions that combine significant regioselectivity and enantioselectivity for alkenes of type RCH2CH= CH2. We have had a long-standing interest in obtaining branched aldehydes from alkyl alkenes, but in the absence of any real leads have confined these efforts to screening novel catalysts that were originally designed to solve other problems in carbonylation catalysis. In one recent research project aimed at further tuning the excellent performance of the important asymmetric hydroformylation ligands, Kelliphite and Ph-bpe, we considered a hybrid non-symmetric ligand that would present the best of both these ligands, and might gain advantage from being non-C2 symmetric. Phosphine-phosphites have attracted much interest in hydroformylation,[2g, l–q] although phospholano derivatives or derivatives using aÀCH2OÀbackbone are not well studied.[2n, p] The ligand, that we have tended to refer to as bobphos (“best of both phosphorus ligands”),(Sax, S, S)-4, can be produced reliably by the route shown in Scheme 1 from the known precursor 1.[5] The phosphite coupling was accomplished by activating (S)-2 with Me3SiI; this does not proceed cleanly and the ca. 40: 60 mixture of iodide (S)-3 and (S)-2 was reacted directly with the known precursor 1 in the presence of DABCO as base and deprotecting agent to give, after purification,(Sax, S, S)-4.[5](Rax, S, S)-4 was also prepared from (R)-2.This ligand was initially examined in the hydroformylation of the model substrate, vinyl acetate (Scheme 2). Bobphos delivered> 99% conversion to aldehyde after 4 h at 2.5 bar pressure at 608C; the linear isomer was observable only in trace quantities (see Supporting Information) and an 83% ee was measured. The other diastereomer of the ligand,(Rax, S, S)-4 made from the opposite enantiomer of chiral diol, gave 32% ee of the …