Subscriber access provided by UNIV OF NEBRASKA - LINCOLN
Communication
Palladium-Catalyzed Dynamic Kinetic Asymmetric Transformation of Racemic Biaryls: Axial-to-Central Chirality Transfer Liu Yang, Huayu Zheng, Lei Luo, Jiang Nan, Jingjing Liu, Yaoyu Wang, and Xinjun Luan J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b01285 • Publication Date (Web): 07 Apr 2015 Downloaded from http://pubs.acs.org on April 9, 2015
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 5
Journal of the American Chemical Society
1 2 3 4 6
5
Palladium-Catalyzed Dynamic Kinetic Asymmetric Transformation of Racemic Biaryls: Axial-to-Central Chirality Transfer 10
9
8
7
Liu Yang,† Huayu Zheng,† Lei Luo,† Jiang Nan, Jingjing Liu, Yaoyu Wang, and Xinjun Luan* 12
1
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an 710069, China
14
13
16
15 Supporting Information Placeholder
17 18
ABSTRACT: The first dynamic kinetic asymmetric trans-
20
formation of racemic biaryl substrates on the basis of axialto-central chirality transfer has been realized. Chiral Pd-NHC complexes were found to catalyze the dynamic kinetic asymmetric spiroannulation of 4-(2-bromoaryl)-naphthalen1-ols (or 2'-bromo-[1,1'-biphenyl]-4-ols) with internal alkynes, affording a series of enantioenriched spirocyclic products bearing an all-carbon quaternary stereocenter in good yields (up to 95%) with excellent enantioselectivities (up to 97% ee).
27
26
25
24
23
2
21
19
28 30
29 Dynamic kinetic asymmetric transformation (DYKAT) represents one of the most powerful and economical strategies for the synthesis of enantioenriched compounds in the field 1 of asymmetric synthesis. The key feature of DYKAT is the ability of converting both enantiomers of the racemic starting material into a single optically pure product with a theoretical yield of 100%. To date, great advances have been achieved in this area. Remarkably, a number of excellent catalytic and enzymatic DYKATs with racemic compounds 3 bearing sp stereocenters have been successfully realized 2-3 (Scheme 1A). Meanwhile, some fascinating transformations featuring the same concept have been implemented by using 4-6 racemic allenes or amides (Scheme 1B). Recently, the pursuits of more challenging DYKATs with dynamic mixtures of rapidly racemizing biaryls have gained significant progress. Several elegant examples were reported for accessing optical7 ly enriched biaryls via this strategy (Scheme 1C, left). However, DYKAT of an atropisomeric biaryl, with concomitant 3 creation of a new sp stereocenter by breaking the aromaticity of one aryl ring, remains a daunting challenge (Scheme 1C, right). Notably, asymmetric synthesis of compounds with central chirality from enantiopure biaryls on the basis of dearomatizing axial-to-central chirality transfer has been 8 dramatically limited, which is in part due to the need of high cost chiral biaryls. In contrast, DYKAT, allowing the direct use of readily available racemic biaryls, would become a more economical and desirable solution to this novel axialto-central stereochemical transformation.
60
59
58
57
56
5
54
53
52
51
50
49
48
47
46
45
4
43
42
41
40
39
38
37
36
35
34
3
32
31
catalyzed dearomatization of 2-naphthol derivatives with 9 alkynes. The synthetic value of these racemic reactions have been reflected by the capacity of transferring one biaryl scaffold into another spirocyclic framework bearing an allcarbon quaternary stereocenter, which offers a potential opportunity for enabling the DYKAT of biaryls via axial-tocentral chirality transfer. Along these lines, we speculated that the phenolic derivative 1, which interconvert rapidly between (R)-1 and (S)-1, would be an ideal candidate for the anticipated DYKAT (Scheme 2). Presumably, a chiral catalyst might be able to discriminate the enantiotopic faces of the phenolic ring in 1, and further differentiate the formation rates of 3 and ent-3. However, catalyst-controlled asymmetric dearomatization of phenolic derivatives being restricted from a single enantioface is very challenging, and to date, 10 only a handful of leading examples have been disclosed. Herein, we describe the successful execution of our design for a Pd(0)-catalyzed DYKAT of racemic 1. To the best of our knowledge, this work represents the first example of DYKAT of racemic biaryls on the basis of axial-to-central chirality transfer.
Scheme 1. Previous Work on DYKAT A. DYKAT of racemic compounds with central chirality
B. DYKAT of racemic non-biaryls with axial chirality
C. DYKAT of racemic biaryls with axial chirality
In this context, we embarked to develop a catalytic DYKAT of racemic biaryls to access a new type of enantioenriched 3 compounds bearing a sp stereocenter. This DYKAT proposal was originated from our recent studies on transition-metal-
ACS Paragon Plus Environment
Journal of the American Chemical Society Scheme 2. Design of a DYKAT of Configurationally Labile Biaryls via Axial-to-Central Chirality Transfer
2
1
Page 2 of 5
1a (1a') showed higher reactivity (89% yield), but the enantioselectivity dropped dramatically (29% ee) (entry 16).
Table 1. Optimization of the Reaction Conditions
3 4 5 6 7 8 9 10 1 12 13 14 16
15 11
31
30
29
28
27
26
25
24
23
2
21
20
19
18
17
To test the feasibility of our hypotheses, atropisomeric 1a and alkyne 2a were selected as the model substrates. The study commenced with a search for chiral Pd catalysts that can promote the anticipated DYKAT of 1a with 2a in an enantioselective manner. Much to our delight, a key breakthrough was ultimately achieved by identifying chiral Nheterocyclic carbenes (NHCs) L1-L5 as the effective ligands. These readily available C2-symmetric NHCs were pioneered by Grubbs and have proven to be excellent promoters for Ru12-13 catalyzed asymmetric ring-closing metathesis, while their use in Pd-catalyzed asymmetric transformations remains 14 underdeveloped. As shown in Table 1, the initial finding showed that the desired reaction proceeded in the presence t of Pd2(dba)3 (10 mol%), L1 (20 mol%), and NaO Bu (1.5 equiv) in toluene at 80 C, affording the spirocyclic product 3aa in 18% yield with 62% ee (entry 1). Encouraged by this primary observation, we attempted to improve the reaction performance by screening a variety of solvents, which revealed a significant impact on not only the catalytic activity of the Pd catalyst but also the stereocontrol of the spiroannulation of 1a with 2a (entries 2-5). In coordinating solvents THF and 1,4-dioxane, the reaction led to higher chemical yield (45%) and better enantioselectivity (90% ee) for 3aa, respectively. Taking 1,4-dioxane as the reaction solvent, several Pd sources were investigated (entries 69), and Pd(OAc)2 turned out to be the optimal catalyst precursor in terms of reactivity and enantioselectivity (53% yield, 91% ee). The reaction was then examined by using other bat t ses such as LiO Bu and KO Bu (entries 10-11), but none of t them could give comparable result as the run with NaO Bu. Subsequently, a series of NHC ligands, which incorporate a methyl, ethyl, cyclohexyl or phenyl group on the orthoposition of the aryl side chains, were assayed for the DYKAT of 1a (entries 12-15). The experimental results indicated that the alkyl-substituted NHCs (L2-L4) were generally effective, with the bulkier ligand showing the better catalytic outcome. However, L5 that bears an ortho-phenyl substituent was totally inactive towards the desired spiroannulation. Additionally, achiral NHC ligands such as SIPr and SIMes were also tested, but they could not enable the formation of 3aa at all. This observation illustrated that devising mono-ortho-alkylsubstituted aryl side chains in L1-L4 were crucial for the title transformation. Up to this point, the superior conditions for 1a could provide product 3aa in 53% yield with 91% ee (entry 9). Notably, the related attempt with the iodo-counterpart of
59
58
57
56
5
54
53
52
51
50
49
48
47
46
45
4
43
42
41
40
39
38
37
36
35
34
3
32
entry [Pd] L* base solvent yield (%)a ee (%)b t 1 Pd2(dba)3 L1 NaO Bu toluene 18 62 2 Pd2(dba)3 L1 NaOtBu DCE 22 55 t 3 Pd2(dba)3 L1 NaO Bu DME 8 73 4 Pd2(dba)3 L1 NaOtBu THF 45 40 5 Pd2(dba)3 L1 NaOtBu 1,4-dioxane 12 90 6 [Pd(allyl)Cl]2 L1 NaOtBu 1,4-dioxane 51 64 t 7 PdCl2 L1 NaO Bu 1,4-dioxane
