Asymmetric total synthesis of (+)-tolterodine, a new muscarinic receptor antagonist, via copper-assisted asymmetric conjugate addition of aryl Grignard reagents to 3-phenyl-prop-2-enoyl-oxazolidinones
Asymmetric total synthesis of (+)-tolterodine, a new muscarinic receptor antagonist, via copper-assisted asymmetric conjugate addition of aryl Grignard reagents to 3-phenyl-prop-2-enoyl-oxazolidinones
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DOI：
10.1021/jo981259r
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发表时间：
1998-10-30
影响因子：
3.6
通讯作者：
Österlund, K
中科院分区：
文献类型：
--
作者：
Andersson, PG;Schink, HE;Österlund, K
托特罗定（图1）是一种新的和有效的竞争性毒蕈碱受体拮抗剂。该药物用于治疗急迫性尿失禁和其他膀胱过度活动症状。1已经证明，在麻醉猫体内，托特罗定对膀胱的作用比对唾液腺的作用更明显。2临床试验表明，这种选择性似乎也发生在人体中。3然而，这种有利的特征不能归因于对单一毒蕈碱受体亚型的选择性。具有两个芳基连接到手性中心的结构元素，如具有R构型的托特罗定，是不寻常的，并且在化学文献中很少有报道涉及这些类型的二芳基化合物的不对称合成。[4]回顾过去，有几种方法可以解决这个问题。一种有吸引力的方法是使用一些手性配体-金属络合物催化双键的不对称氢化，如等式1所示。另一方面，将各种亲核试剂共轭加成到与手性助剂相连的R1-不饱和酸衍生物上是不对称合成中的一种众所周知的方法（式2）。例如，恶唑烷酮已广泛用于这方面，并且也容易获得。因此，通过选择这种方法，我们可以使用容易获得的起始材料和可靠的合成路线来制备所需的底物。
Tolterodine (Figure 1) is a new and potent competitive muscarinic receptor antagonist. The drug is intended for the treatment of urinary urge incontinence and other symptoms of bladder overactivity. 1 It has been shown that Tolterodine has a more pronounced action on the urinary bladder than on salivary glands in vivo in the anaesthetised cat. 2 This selectivity also seems to occur in humans as demonstrated in clinical trials. 3 However, this favorable profile cannot be attributed to selectivity for a single muscarinic receptor subtype. The structural element with two aryl groups attached to a chiral center, as in Tolterodine, which has the R configuration, is unusual, and few reports in the chemical literature deal with asymmetric synthesis of these types of diaryl compounds. 4 Retrosynthetically, there are several ways to approach this problem. One attractive way would be catalytic asymmetric hydrogenation of a double bond, as pictured in eq 1, using some chiralligand-metal complex. However, this requires control of the double bond configuration in the preceding steps, which is not a trivial problem.On the other hand, conjugate additions of various nucleophiles to R,-unsaturated acid derivatives attached to a chiral auxiliary is a well-known methodology in asymmetric synthesis (eq 2). Oxazolidinones, for example, have been extensively used in this context and are also easily obtained. 5 Thus, by choosing this approach we could use readily available starting materials and reliable synthetic routes for the preparation of the desired substrates.