Letter pubs.acs.org/OrgLett
Pd-Catalyzed Regioselective Asymmetric Addition Reaction of Unprotected Pyrimidines to Alkoxyallene Soyeong Kang, Seok Hyeon Jang, Juyeol Lee, Dong-gil Kim, Mijin Kim, Wook Jeong, and Young Ho Rhee* Department of Chemistry, Pohang University of Science and Technology, 77 Cheongam-Ro, Pohang, Kyungbuk 37673, Republic of Korea S Supporting Information *
ABSTRACT: Catalytic asymmetric synthesis of N-heterocyclic glycosides free of protecting and directing groups is reported. The key reaction is highlighted by the atom-efficient and regioselective addition of unprotected pyrimidines to highly functionalized alkoxyallene. Numerous acyclic and cyclic N-heterocyclic glycosides are accessed with minimal formation of organic byproducts. The synthetic utility of the reaction is demonstrated by the first catalytic asymmetric synthesis of anticancer pharmaceutical (−)-Tegafur and stereoselective synthesis of an oxepane nucleoside derivative.
nucleophiles and the delicate regiocontrol between the nitrogen atoms make this task extremely challenging. Conventional chemical N-glycosylations (such as the Vorbrüggen reaction) require extensive use of protecting groups on N-heterocycles and activating groups on the glycosyl moiety. In addition, conventional approaches rely heavily on the substrate-based stereocontrol that needs directing groups. Thus, the ideal atomefficient N-glycosylation reaction free of protecting, activating, and directing groups still remains to be determined. Here, we report de novo N-glycosidic bond formation of pyrimidine nucleophiles employing Pd-catalyzed atom-efficient asymmetric addition of unprotected pyrimidines to alkoxyallene as the key stereocontrol event. The reaction establishes a general synthetic protocol for the acyclic N-glycosides, which cannot be readily prepared by conventional methods. In addition, various cyclic derivatives can also be accessed by combining the key reaction with metal-catalyzed ring-closing-metathesis (RCM).5,6 This sequential metal catalysis accomplishes a systematic and versatile synthetic protocol for highly valuable pyrimidine glycosides with minimal generation of organic waste. The value of this method is demonstrated by the first catalytic asymmetric synthesis of anticancer pharmaceutical Tegafur and stereoselective synthesis of an oxepane nucleoside derivative. Rutjes reported a highly efficient Pd-catalyzed addition reaction of amide nucleophiles and alcohols to alkoxyallene.7 We recently reported an asymmetric version of this reaction, which led to the development of conceptually new azacycle8 and carbohydrate synthesis9 upon combination with the RCM
N-Heterocyclic glycosides, particularly pyrimidine nucleosides and their analogs, represent a highly important class of chemical compounds because of their significant biological activities and essential roles in physiological processes (Scheme 1).1,2 Thus, developing highly efficient and stereoselective synthesis of these compounds has attracted significant attention over the past decades.3,4 However, ill-defined properties of pyrimidine Scheme 1. De Novo Synthesis of Biologically Significant Pyrimidine N-Glycosides
Received: July 28, 2017 Published: August 16, 2017 © 2017 American Chemical Society
4684
DOI: 10.1021/acs.orglett.7b02332 Org. Lett. 2017, 19, 4684−4687
Letter
Organic Letters Scheme 2. Scope of Acyclic Pyrimidine Glycosidea
reaction.10,11 Compared with these precedents, the current reaction is fundamentally more challenging because the reaction requires an ene-alkoxyallene substrate that can induce undesired reactions12 (such as cycloisomerization of enallenes). In addition, the poor solubility and metal-coordinating ability of unprotected pyrimidines may potentially affect the stereo- and regioselectivity of the reaction. In fact, the use of unprotected pyrimidines and other related N-heterocycles is very limited in metal catalysis13,14 including the metal-catalyzed asymmetric hydrofunctionalization15 and asymmetric allylic substitution reactions.16−18 Our concern was justified when we initially tested thymine with alkoxyallene 1a (Table 1). Performing the reaction in Table 1. Preliminary Test of Thymine with Alkoxyallene 1a
a
a
entry
solvent
additive
time
1 2 3 4 5
CH2Cl2 CH2Cl2 acetone DMF pyridine
none Et3N Et3N Et3N K3PO4
1 1 24 5 1
yield (2a-T, 2a′)a
