Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2018, 20, 6534−6538
Macrolactonization of Alkynyl Alcohol through Rh(I)/Yb(III) Catalysis Wen-Wen Zhang,†,‡ Tao-Tao Gao,‡ Li-Jin Xu,*,† and Bi-Jie Li*,‡ †
Department of Chemistry, Renmin University of China, Beijing 100084, China Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100084, China
‡
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S Supporting Information *
ABSTRACT: A catalytic macrolactonization through oxidative cyclization of alkynyl alcohol by synergistic transition-metal and Lewis-acid catalysis was developed. Because the alkynyl alcohol substrates involved in this method are different from the seco acids that are used in conventional macrolactonization methods, the current method provides a strategically distinct entry to macrolactones. In addition to the operational simplicity, this macrolactonization protocol proceeds at relatively high concentration, precluding the need for high dilution or slow addition procedures.
M
carboxylic acid for the macrolactonization. Because an alkyne group is usually stable under many conditions,11 protection of the alkyne is not necessary during the synthesis. Therefore, this strategy provides the advantage of avoiding the multistep synthesis of the seco acids and tedious manipulation of the carboxylic acid (Scheme 1).
acrolactone structures exist in numerous natural products and bioactive molecules.1 Many of them have significant medicinal and biological activities. Due to the importance of the macrocyclic structures, a range of macrolactonization methods have been developed in the past decades.2 Among them, macrolactonization of seco-acid is a prominent strategy for the synthesis of macrolide, which has been practiced in a large number of total syntheses.3 However, there are several inherent limitations associated with traditional macrolactonization methods. For example, a stoichiometric amount of activating reagents are required for the activation of either the acid or the hydroxyl group.2,3 In addition, to minimize intermolecular dimerization, highly diluted conditions or slow addition protocols are required.4 These limitations continue to stimulate the development of novel methods for the synthesis of macrolactones. Transition metal catalyzed macrocyclization provides a distinct opportunity for the preparation of macrolactones.5 For example, ring-closing metathesis6 and cross-coupling reactions4d,f,7 enable efficient synthesis of macrolactones.8 Compared to these catalytic methods that construct the macrolactone through formation of the C−C bond of the backbone, strategies to synthesize macrolactone through transition metal catalyzed C−O bond formation have been rather limited.9 In 2006, White and co-workers reported a seminal work on Pd-catalyzed macrolactonization of alkenyl acid through C−H functionalization.9a−c Recently, the Breit group has developed a novel macrolactonization method through atom-economical Rh-catalyzed addition of carboxylic acid to unsaturated C−C bonds.9d,e Both of these methods involve the use of carboxylic acid as the cyclization precursor. The groups of Takahashi and Dai have achieved macrolactonization through Pd-catalyzed carbonylation reactions.9f−h The presence of a carboxylic acid in the cyclization precursor could complicate the synthesis. Usually the acid must be protected before functional group manipulation, and the protecting group needs to be removed before the macrolactonization event.3 In connection with our interest in alkyne functionalization,10 we sought to use alkyne as a surrogate of © 2018 American Chemical Society
Scheme 1. Macrolactonization of Alkyne
We envisioned that an oxidative macrolactonization of alkynyl alcohol could be achieved by transition metal catalysis through intermediacy of a ketene. Specifically, transition metal12 such as Rh13 and Ru14 could interact with the alkyne to afford a metal vinylidene (Scheme 2). Further oxygenation of the vinylidene complex would afford a ketene intermediate.14d−f,15 Intramolecular trapping of the ketene by the alcohol group would afford the macrolactone product.16 Although an Received: September 7, 2018 Published: October 10, 2018 6534
DOI: 10.1021/acs.orglett.8b02858 Org. Lett. 2018, 20, 6534−6538
Letter
Organic Letters
Table 1. Development of Catalytic Macrolactonizationa
Scheme 2. Proposed Macrolactonization of Alkynyl Alcohol
entry
elegant example of catalytic intermolecular oxidative esterification of alkyne has been developed by Lee and coworkers,15d a catalytic macrolactonization through oxidative alkyne functionalization is unknown.14a,b We report here a Rh and Yb-cocatalyzed cyclization of alkynyl alcohol for the synthesis of a range of macrolactones. Significantly, this macrolactonization method proceeds efficiently at relatively high concentration. High dilution or slow addition protocol is not necessary.4 Moreover, the alkynyl alcohol substrate involved in this method is distinct from the seco acids that are used in traditional macrolactonization. This method provides a possible alternative retrosynthetic planning to macrolactone molecules. We began our studies by testing the viability of the designed intramolecular lactonization from alkynyl alcohol (Scheme 3).
ligand
oxidant
1
Rh(COD)2OTf
N-Oxide 1
−
36
2
Rh(COD)2BF4
N-Oxide 1
−
39
3 4
Rh(COD)2BF4 Rh(COD)2BF4
N-Oxide 1 N-Oxide 1
− −
34 35
5b
Rh(COD)2BF4
N-Oxide 1
Zn(OTf)2
48
6b
Rh(COD)2BF4
N-Oxide 1
In(OTf)3
45
7b
Rh(COD)2BF4
N-Oxide 1
Yb(OTf)3
70
8b
Rh(COD)2BF4
(4-FC6H4)3P (4-FC6H4)3P Ph3P (4-MeOC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P
N-Oxide 1
AgOTf
42
N-Oxide 2
Yb(OTf)3
