Subscriber access provided by ECU Libraries
Article
Access to multi-substituted 2(5H)-furanones using hydrogen bonding-promoted ring-closing metathesis and polyamine workup Kai Tan, Huan Yan, Pengbo Lu, Yuehui Liu, Ruigeng Ji, Zhongxian Liu, Ya-Min Li, Fu-Chao Yu, and Yuehai Shen J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 26 Feb 2019 Downloaded from http://pubs.acs.org on February 26, 2019
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 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 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.
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 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
Access to multi-substituted 2(5H)-furanones using hydrogen bonding-promoted ring-closing metathesis and polyamine workup Kai Tan, Huan Yan, Pengbo Lu, Yuehui Liu, Ruigeng Ji, Zhongxian Liu, Ya-Min Li, Fu-Chao Yu, Yuehai Shen* Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China. R1 O R3
HG-II, toluene
O R2
O
80 or 110 oC
O R1
R3 polyamine workup
OH
OH
R2
Up to 88% yield
- H bonding-promoted
26 examples
- Mechanistic insights - Facile Ru-removal
Abstract: Structurally complex 2(5H)-furanones are potentially challenging targets for ring-closing metathesis (RCM). A hydrogen bonding-guided RCM strategy was developed in this study to provide 3substituted and 3,4-disubstituted 2(5H)-furanones in moderate to high yields with broad functional group tolerance. A workup procedure using ethylenediamine-derived polyamines such as tetraethylenepentylamine was also established to effectively remove Ru residues in products. Introduction 2(5H)-Furanones are structure subunits often seen in synthetic intermediates1-2 and in some natural products with cardiotonic, anticancer and antifouling activities3-7 (Figure 1). Ru-catalyzed ring-closing metathesis (RCM) is one popular method for accessing 2(5H)-furanones. However, when the target C=C bonds are tri- or tetra-substituted, the increasing steric hindrance and electron-deficient nature of acryl moiety may prevent substrates from interacting with Ru carbene complex in a desired manner. While 2(5H)-furanones with a relatively small 3-/4-substituent can be obtained in high yields,8,9 2(5H)-furanones with a large 3-/4substituent or 3,4-disubstituted 2(5H)-furanones are often difficult targets.10,11 To overcome this problem, several terminal olefin-assisted RCM methods have been developed. Hoye and colleagues12 devised a relay RCM approach to synthesize 3,4-dimethyl-2(5H)-furanone. Li13 and Fernandes groups14 designed a ringopening/ring-closing metathesis cascade to construct asteriscunolides and similar bicyclic structures from advanced intermediates containing a cyclobut-1-enecarboxyl group. Meyer and Cossy15 also demonstrated that a cyclopropene-based metathesis cascade could be applied in constructing 2(5H)-furanones.
ACS Paragon Plus Environment
The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
( )3
O O
O
N
Page 2 of 28
Ph
Bn
OH
O
O
O
O O
O pandamarilactonine A
Bn
O
asteriscunolide A-D
car diotonic
Ph
maculalactone F
anticancer
antif ouling O
HO
O O
( )11
OH
OH
OH
O
( )10 O
murisolin
OAc sarcophytonolide H
anticancer
antif ouling
Figure 1. Representative 2(5H)-furanone natural products. Following the seminal works from Hoye,16 Forman17 and Hoveyda18 groups, hydrogen bonding has been recognized as a valuable control element for Ru-catalyzed olefin metathesis recently.19 Hydrogen bondingpromoted metathesis has been applied in total syntheses of natural products.20 To construct 5,6-dihydro-αpyrones, Matsuya20e and Hatakeyama20h groups have developed RCM methods of homoallyl 2(hydroxymethyl)acrylates catalyzed by the Stewart-Grubbs catalyst (SG) or the Hoveyda-Grubbs second generation catalyst (HG-II) (Scheme 1a). We have recently established RCM of sterically demanding homoallyl 2-(hydroxymethyl)acrylates, and revealed that Ru catalyst was directed to first interact with the electron-deficient, more hindered acrylic C=C bond by the OH-Cl hydrogen bond (Scheme 1b).21 These works demonstrated the potential of using 2-(hydroxymethyl)acryl moieties to construct lactone systems. Previous work: 5,6-dihydro--pyrone R O
R
O
O
O
SG or HG-II
(a)
toluene, 80 oC OH OH R1 O
HG-II toluene, 110 oC
R3
R1
O
O
R2
O
R3
R2
(b)
OH OH
This work: 2(5H)-furanone R1 O R3
O
O 2
R
HG-II, toluene 80 or 110 oC
OH
polyamine workup
O R1
3
R
(c) OH
R2
Scheme 1. 2-(Hydroxymethyl)acryl-assisted RCM.
ACS Paragon Plus Environment
Page 3 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
On the other hand, removing Ru residue from the product of metathesis reactions is often a significant challenge, especially for the manufacturing of active pharmaceutical ingredients.22 As summarized in several recent reviews,23 numerous methods have been developed to solve this issue. These methods could be roughly categorized into optimized workups using quenching reagents or absorptive materials,23a,c and applying tailordesigned catalysts with ligands facilitating separation.23a,b However, as the workup procedures were usually developed on a case-by-case basis, and the modified Ru catalysts are seldom commercially available, new methods for removal of Ru residue are still in demand. In this study, we investigated the 2-(hydroxymethyl)acryl-assisted RCM approach for constructing multisubstituted 2(5H)-furanones for the first time, and found that hydrogen bonding effect significantly promote the RCM reactions (Scheme 1c). Meanwhile, to remove Ru impurities from the product, a workup protocol using ethylenediamine-derived polyamines was also established. Results and discussion Despite the wide use of RCM in 2(5H)-furanone synthesis, we noticed that hydrogen bonding effect, which might enhance reactions of difficult substrates as shown in our previous work,21 had never been investigated in this system.24 Therefore, we carried out a preliminary study to test if a pre-installed allylic hydroxyl group can promote the RCM reaction of substituted allyl acrylates (Table 1). In the presence of Hoveyda-Grubbs 2nd generation catalyst (HG-II, 1 mol%), methyl-substituted diene substrate 1 converted to RCM product 2 slowly, providing 63% yield after 2.5 hours at 80 oC with significant amount of compound 1 remained unreacted (entry 1). In contrast, the reaction of 2-(hydroxymethyl)acrylate 3aa was complete in 0.5 h and gave 2(5H)-furanone 4aa in 74% isolated yield (entry 2). Capping the allylic hydroxyl of compound 3aa with TBS or acetyl group (entries 3 and 4) sharply slowed the ring-closing process, resulting incomplete conversions and 40% and 54% yields after 2.5 hours. A comparison among non-alcohol substrates 1, 3aa-TBS and 3aa-Ac demonstrates that RCM reactions become more difficult with larger substituents on the acrylic moiety. However, the fact that the reaction of alcohol 3aa proceeded much faster than other three compounds clearly suggests that the allylic hydroxyl group accelerates the reaction, presumably through hydrogen bonding with one of the chloride ligands in Ru catalyst.17,18,21 Table 1. Verification of hydrogen bonding effect a
ACS Paragon Plus Environment
The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
n
Pr
O
O
O
HG-II (1 mol%)
Page 4 of 28
O n
Pr
toluene 80 oC, 2.5 h
R
a
R
Entry
Substrate
Product
R
Convb (%)
Workup
Yieldc (%)
1
1
2
H
70
Silica
63
2
3aa
4aa
OH
100
TEPA-silica
74
3
3aa-TBS
4aa-TBS
OTBS
50
Silica
40
4
3aa-Ac
4aa-Ac
OAc
60
Silica
54
The reaction was carried out at 0.25 mmol scale in toluene (3 mL) under nitrogen. b Estimated by TLC. c Isolated yields.
One concern for the RCM of allyl 2-(hydroxymethyl)acrylate 3aa is that, unlike reactions of the non-alcohol substrates, HG-II catalyst decomposed into many fluorescent by-products. Similar by-products have been detected previously in RCM of homoallyl 2-(hydroxymethyl)acrylate substrates, and repeated column separation was used for product purification.21 However, in this study column chromatography could not afford pure RCM products. Several known workup protocols23a were tested but met with no success. Fortunately, we found that treating the crude mixture with ethylenediamine (EDA) followed by column chromatography could get rid of the by-products effectively. As EDA has an unpleasant odor and could produce an irritating mist while exposed to humid air, several EDA-derived polyamines, i.e. diethylenetriamine (DETA), triethylenetetramine (TETA) and tetraethylenepentylamine (TEPA), were tested and found equally effective. Among them, TEPA has the highest molecular weight, thus was chosen for the reaction workup (entry 2, Table 1). Dimethylamine failed to clean up Ru by-products, suggesting that the primary amino groups might be responsible for the effect. A quick filtration through a short pad of silica gel after adding TEPA was necessary (see Experimental section for details), as product 4aa could react slowly with TEPA, presumably though a conjugate addition.25 Aqueous partitioning after adding EDA or polyamines was also tested, but gave lower yields as the product is soluble in the aqueous phase. It is worthy to note that although EDA, EDA-derived polyamines or the polymer-bound forms are widely used in complexing with transitional metals, their use in workup of olefin metathesis reactions is nearly unknown. To the best of our knowledge, an EDA workup procedure developed by Roche researchers26 for manufacturing hepatitis C virus protease inhibitor danoprevir is the only disclosed example so far. Together, these works demonstrated that EDA and EDA-derived polyamines are reliable Ru scavengers for metathesis reaction workup.
ACS Paragon Plus Environment
Page 5 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
The reaction conditions for RCM of compound 3aa were then optimized (Table 2). Increasing the loading of HG-II to 2 mol% gave a significantly improved 88% yield (entry 2). However, 5 mol% loading of HG-II gave slightly lower 82% yield (entry 3) because increased amounts of Ru by-products made the purification more difficult. Lowering the temperature to 40 oC slowed the reaction significantly, requiring 6 hours to reach full conversion and the isolated yield decreased to 76% (entry 4), while the reaction at 110 oC gave a lower yield (entry 5), too. In addition, benzoquinone (BQ) additive was also tested as BQ is known to be able to prevent the decomposition of ruthenium catalysts during olefin metathesis.27 However, adding 3 mol% of BQ did not further improve the results (entry 6). In fact, a slightly lower 84% yield was obtained as the purification became difficult due to similar polarities of BQ and product 4aa. An interesting and welcoming pattern of this system is that reactions at lower concentrations gave similar yields. Comparing with reactions of homoallyl 2(hydroxymethyl)acrylates,21 RCM of compound 3aa proceeded significantly faster and no competitive self metathesis (SM) product could be detected by TLC. Table 2. Optimization of RCM condition a n
Pr
O
OH
a
HG-II toluene
O
additive temperature
3aa
O
O n
Pr
OH
4aa
Entry
HG-II (mol%)
Temp (oC)
Time (h)
BQ (mol%)
Yieldb (%)
1
1
80
2.5
0
74
2
2
80
2
0
88
3
5
80
2
0
82
4
2
40
6
0
76
5
2
110
2
0
82
6
2
80
2
3
84
The reaction was carried out at 0.25 mmol scale in toluene (3 mL) under nitrogen. b Isolated yields.
The substrate scope of this hydrogen bonding-promoted RCM was then investigated under the optimized reaction condition (Table 2, entry 2), and the results for constructing 3-substituted 2(5H)-furanones are summarized in Table 3. For substrates with a simple 2-(hydroxymethyl)acryl moiety (R1 = H) and various alkyl R2 group, the RCM reactions proceeded fast and gave good to high yields (entries 1 to 7). Large alkyl R2 groups, such as i-butyl and cyclohexyl groups, tend to slow down the reactions (entries 3 and 4). For these slower reactions, more catalyst and BQ additive were necessary for obtaining high yields. Introducing alkyl R1 group into the substrates was found well tolerated in this RCM reaction (entries 9-21), although the
ACS Paragon Plus Environment
The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 6 of 28
reactivity drops as the size of R1 group increases. For example, among the substrates with a cyclohexyl R2 group (i.e., 3ad, 3bd, 3cd and 3fd), 3ad gave 79% yield with 2 times of 2 mol% loading of HG-II (entry 4), while phenethyl-bearing 3fd gave only 51% yield with more catalyst (entry 20). It is worthy of note that glyceraldehyde acetonide-derived substrate series (i.e., 3ag, 3bg, 3cg, 3dg, 3eg and 3fg), with a 2,2-dimethyl1,3-dioxolan-4-yl substituent that was previously found superior for the RCM of homoallyl 2(hydroxymethyl)acrylates,17 were relatively sluggish in this system (entries 7, 14, 16, 17, 18 and 21). However, with higher catalyst loadings, moderate to high yields could still be obtained in most cases. Table 3. Substrate scope for constructing 3-substituted 2(5H)-furanones a R2
O
O
O
HG-II
R1
oC
OH
80 toluene
3
O R2
1
R
OH
4
HG-II
Time
BQ
Conv b
Yield c
(mol%)
(h)
(mol%)
(%)
(%)
Pr
2
2
0
100
88
Pr
2
1.5
0
100
82
Bu
2x2
2
3
100
83
H
Cy
2x2
2.5
3
90
79
4ae
H
Bn
2
2.5
2
100
79
3af
4af
H
phenethyl
2
2.5
2
100
83
3ag
4ag
H
2
3.5
3
80
64
Ph
2
1.5
3
90
~80 d
Entry
Substrate
Product
R1
R2
1
3aa
4aa
H
n
2
3ab
4ab
H
i
3
3ac
4ac
H
i
4
3ad
4ad
5
3ae
6 7
O O
8
3ah
4ah
H
9
3ba
4ba
Me
n
Pr
2x2
4
2
100
78
10
3bc
4bc
Me
i
Bu
2x2
3
3
80
67
11
3bd
4bd
Me
Cy
2x3
3
3
70
56
12
3be
4be
Me
Bn
2
3
2
95
72
13
3bf
4bf
Me
phenethyl
2
2.5
3
95
72
14
3bg
4bg
Me
2
3.5
3
60
47
2x3
3
3
70
66
2x3
3
2
80
72
2x3
3
2
60
54
3x3
10
8
