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Enantioselective Synthesis of Chiral Medium-Sized Cyclic Compounds via Tandem Cycloaddition/Cope Rearrangement Strategy Xing Gao, Miaoren Xia, Chunhao Yuan, Leijie Zhou, Wei Sun, Cheng Li, Bo Wu, Dongyu Zhu, Cheng Zhang, Bing Zheng, Dongqi Wang, and Hongchao Guo ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04590 • Publication Date (Web): 11 Jan 2019 Downloaded from http://pubs.acs.org on January 12, 2019
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Enantioselective Synthesis of Chiral Medium-Sized Cyclic Compounds via Tandem Cycloaddition/Cope Rearrangement Strategy Xing Gao,† Miaoren Xia,‡ Chunhao Yuan,† Leijie Zhou,† Wei Sun,† Cheng Li,† Bo Wu,† Dongyu Zhu,† Cheng Zhang,† Bing Zheng,† Dongqi Wang,‡ and Hongchao Guo*,† † ‡
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China Institute of High Energy Physics, Chinese Academy of Science, Beijing 100049, P. R. China
ABSTRACT: The nine-membered ring-bearing bicyclo[5.2.2]tetrahydrooxonines frameworks have enantioselectively been constructed via a tandem [3+2] cycloaddition/Cope rearrangement reaction of vinylethylene carbonates (VECs) with coumalates or pyrones. Under mild conditions, palladium-cataO O R1 (2.5 lyzed asymmetric tandem reaction of various subor 5.0 mol%) Pd2dba3•CHCl3 R stituted VECs and coumalates or pyrones proceeds O O + O L* (15 or 20 mol%) O O O O o P N L* = smoothly to produce the corresponding mediumCHCl3, 25 C, 24 h or 48 h O R R1 sized heterocyclic compounds in high yields with R2 R2 O very high enantioselectivities. Moreover, the reacup to 99% yield R2 R = cyclohexyl O up to 99% ee or (R)-1-phenylethyl tion on the gram scale and further diverse transforR1 H mations of the products were workable. The reacO tion mechanism was investigated through control experiments and DFT calculations, which show the reaction proceeds via a tandem [3+2] cycloaddition/Cope rearrangement pathway rather than via a [5+4] cycloaddition pathway. KEYWORDS: asymmetric catalysis, cycloaddition, Cope rearrangement, palladium catalysis, medium-sized cyclic compound
INTRODUCTION Medium-sized cyclic ether exists in a large number of biologically important natural products (Figure 1).1 (−)Ovatolide is isolated from a Thai medicinal plant used in folk medicine as a laxative, a febrifuge, and an astringent.1b Coleophomone family compounds displayed the interesting biological activities including antibiotic, antifungal action.1c (+)-Brasilenyne have been demonstrated to be potent feeding deterrent to fresh water fish.1d (−)-Isolaurallene is a biologically significant metabolite, from the red algae laurencia nipponica Yamada.1e Therefore, the development of novel approaches for construction of chiral medium-sized cyclic ether is always desirable. Me
HO OH
Me O
O
O NH
HO
O OH − ( )-Ovatolide
O
Me
Br O Me
Me OH O Coleophomone A
O
O
O Cl
(+)-Brasilenyne
H
H
·
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
ACS Catalysis
Br − ( )-isolaurallene
Figure 1. Bioactive Medium-Sized Cyclic Ethers
In many cases, medium-sized rings (7-11-membered rings) are particularly difficult to synthesize, due to their unfavourable
transannular interactions as well as entropy and enthalpy factors.2 Transition metal-catalyzed cyclization,3 organocatalytic annulation,4 ring-closing metathesis,5 ring expansion,6 etc. are general methods for synthesis of medium-sized rings. Although many strategies are available for synthesis of medium-ring compounds,7 construction of chiral nine-membered ring is still a challenging task. Traditional methods for synthesis of chiral nine-membered rings, such as Baeyer-Villiger ring expansion8 and Claisen rearrangement9 need substrate induction to achieve chiral control. Only limited synthetic methods for nine-membered cyclic compounds were accomplished through asymmetric catalysis.10 Trost,10a Zhao,10f Wang10b−10d and our group10e used metal-catalyzed formal [6+3] or [5+4] cycloaddition reaction to achieve synthesis of chiral nine-membered cyclic compounds (Scheme 1a). You exquisitely developed metal-catalyzed allylic dearomatization strategy to construct mediumsized rings (Scheme 1b).10g−10i The Cope rearrangement11 is a particularly useful tool for ring-expansion, and has often been used as a key step in synthesis of medium-sized cyclic compounds12 and total synthesis of natural products.13 Since the Cope rearrangement is both stereospecific and stereoselective as a result of a cyclic chair-like transition state, it is very suited for constructing chiral mediumring compounds. However, it is a formidable task to prepare ring-containing chiral 1,5-diene substrates for Cope rearrangement. Asymmetric cycloaddition reaction is one of the most efficient ways to access cyclic compounds.14 Among various cycloadditions, Pd-catalyzed cycloaddition reactions involving
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zwitterionic allylpalladium intermediates are appealing methods for synthesis of chiral 1,5-diene substrates.15 The zwitterionic intermediates from vinyloxiranes,16 vinylethylene carbonates,17 vinylaziridines,18 vinyloxazolidinone,19 vinylcyclopropanes20 and vinyl benzoxazinones21 typically behaved as a versatile synthon to furnish ring formation with a remaining carbon-carbon double bond appending to a ring. Therefore, this type of reaction offers an excellent approach to ring-containing chiral 1,5-diene substrates for Cope rearrangement, as shown in Scheme 1c. Herein, we present our initial attempt on the use of a tandem [3+2] cycloaddition/Cope rearrangement strategy in the synthesis of chiral medium-ring heterocycles. Scheme 1. Synthesis of Chiral Nine-Membered Cyclic Compounds a) Formal [6+3] and [5+4] cycloaddition (Trost, Zhao, Wang and our group) R' +
4
R'
R''
X
[Pd] or [Cu]
4X
R'' O
+
O
[Pd]
3
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ligand (entry 3), affording 3aa in 58% yield with 56% ee. Further screening a series of axially chiral phosphoramidite ligands had a remarkable improvement in yield and enantioselectivity (entries 3−8). Studies with BINOL-based chiral phosphorus amidite ligands L3−L8 showed that the steric bulkiness of the substituent at nitrogen atom has a large impact on both reactivity and enantioselectivity. A moderate and good enantioselectivities was achieved with the piperidine-substituted ligand L4. The noncyclic amine-derived chiral ligand L5 afforded the product 3aa in 60% yield and 70% ee. The employment of ligand L6, resulted in a moderate yield but an amazing 95% ee (entry 6). In search for more effective ligands, it was found that 59% yield and 93% ee were obtained with the use of diisopropyl-substituted ligand L7 after 12 h (entry 7). Both yield and ee were increased to 84% and 99%, respectively, when dicyclohexylamine-derived ligand L8 was used (entry 8). Using CHCl3 as the solvent instead of CH2Cl2 offered better results, affording the product 3aa in 92% yield with 99% ee (entry 9). Increasing the ligand loading marginally raised the yield to 95% (entry 10). According to the above screening, the optimized reaction conditions were established as: using the combination of Pd2dba3•CHCl3 (2.5 mol%) and chiral ligand L8 (15 mol%) as the catalyst in CHCl3 at room temperature.
3
NR
N R
b) Allylic dearomatization of indole (You)
Table 1. Optimization of the Reaction Conditions Domino annulation of VEC 1a with Methyl Coumalate 2aa
R'N
OCO2Me
N R' R
*
[Pd]
R O
HN
N
Ph
+
O
c) Our strategy O X
O
R [Pd]
[Pd] X
X R
Cope rearrangement
L2
PPh2
Ph
Ph
O P N O
O P N O
X
RESULTS AND DISCUSSION Initially, the reaction between VEC 1a and methyl coumalate 2a, which has widely been used in organic synthesis,22 was chosen as the model reaction, and various achiral ligands were examined as the catalyst (see Table S1 in Supporting Information). PPh3 proved to be the optimal choice and afforded the product 3aa in 57% yield. Early efforts for asymmetric variant were focused on the screening of classical chiral di- or monophosphine ligands. We commenced our investigation using Pd2dba3•CHCl3 (2.5 mol%)/BINAP (L1) as catalyst system. However, the expected reaction did not work well under this reaction conditions (Table 1, entry 1). Pleasingly, when (R, R, R) -(+)-Ph-SKP23 (L2) was used as ligand, the reaction was stirred for 72 h to give the desired product 3aa in 92% ee, albeit with 12% yield (entry 2). To our delight, the reaction proceeded smoothly with the use of Feringa’s phosphoramidite L324 as a
CO2Me
O
− ( )-3aa
O P N O
L3
L4
O P N O
O P N O
Ph
Ph
L5
R
O O
O P N O
O O Ph2P
L1
cycloaddition
X = O, NR', or CR''2
CO2Me
PPh2 PPh2
R
Ph
o
25 C, solvent
2a
1a
O
or X R
(2.5 mol%) Pd2dba3•CHCl3 (10 mol%) L*
O
O
L6
L7
L8
(%)b
ee (%)c
entry
ligand
solvent
time (h)
yield
1
L1
CH2Cl2
72
14
14e
2
L2
CH2Cl2
72
12
92e
3
L3
CH2Cl2
12
58
56
4
L4
CH2Cl2
48
53
80
5
L5
CH2Cl2
12
60
70
6
L6
CH2Cl2
24
44
95
7
L7
CH2Cl2
12
59
93
8
L8
CH2Cl2
24
84
99
9
L8
CH2Cl2
24
92
99
10d
L8
CHCl3
24
95
99
aUnless
noted otherwise, the reaction of 1a (0.15 mmol), 2a (0.10 mmol), Pd2dba3•CHCl3 (2.5 mol%) and ligand (5 mol% for diphosphines, 10 mol% for phosphoramidites) was performed at 25 °C in 1 mL of solvent under indicated reaction conditions. bIsolated yield. cDetermined by chiral HPLC analysis. dThe reaction was carried out with 15 mol% of ligand. e(+)-3aa was obtained.
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ACS Catalysis Table 2. Scope of Coumalates and VECsa
Unfortunately, alkyl-substituted VECs (1x and 1y) failed to yield the desired product.
(2.5 mol%)
O
Pd2dba3•CHCl3 L8 (15 mol%)
O
O
Ar
+ O
O 1
CO2
R1 = Et R1 = Ph R1 = Bn R1 = (CH2)4Cl
O O
CO2R1
O
R2 = H R2 = Me R2 = OMe R2 =F R2 = Cl R2 = Br R2 = CN 3ga R2 = CF3 3ha R2 = Ph 3ia 3aa 3ba 3ca 3da 3ea 3fa
68%, 99% ee 73%, 99% ee 54%, 99% ee 84%, 99% ee
CO2Me
O R2 R2 =F 82%, 99% ee R2 = Cl 71%, 99% eed 3pa R2 = OMe 88%, 99% ee 3qa
3oa
O O
75%, 99% ee
3wa
O CO2Me O O 83%, 64% ee
S 3ua
R2 = Me 3ja R 3ka 2 = OMe R2 =F 3la R 3ma 2 = Cl R2 = Br 3na
O
91%, 99% ee 81%, 99% ee 81%, 99% ee 81%, 98% eeb 63%, 99% ee
Ph
O +
Ph
o
O
COPh
25 C, solvent
O O
COPh
O 5aa
4a
1a Ph
O P N O
O P N O
O P N O
O O
CO2Me
3va
L10
O P N O
O P N O
L12
L13
L11
Ph O P N O Ph
CO2Me
O Ph
L9 CO2Me
O F 75%, 97% ee 3sa
F
O CO2Me O R3 O 3xa R3 = Me, NRe 3 3ya R = t-Bu, NR
O O
O O
CO2Me
95%, 99% ee
(2.5 mol%) Pd2dba3•CHCl3 (15 mol%) L*
CO2Me
Ph
75%, 99% ee
O O O
CO2Me
O
O O
R2
95%, 99% ee 91%, 99% ee 94%, 99% ee 84%, 98% eeb 77%, 99% ee c 62%, 99% ee 72%, 98% eeb 83%, 97% eeb 87%, 99% ee
O
Cl
Table 3. Optimization of the Reaction Conditions for Domino Annulation of VEC 1a with Pyrones 4aa
O
O O
Cl
3ra
2-Nap
CO2Me
CO2R1
O 3
O
R2
O O
3ta
O O
Ar
2 O O
3ab 3ac 3ad 3ae
o
CHCl3, 25 C, 24 h
R1
L14
80%, 87% ee
entry
ligand
solvent
time (h)
yield (%)b
ee (%)c
1
L8
CHCl3
24
71
75
2
L6
CHCl3
48
31
91
3
L7
CHCl3
45
53
37
4
L9
CHCl3
48
37
61
5
L10
CHCl3
48
NRe
-
6
L11
CHCl3
48
NR
-
7
L12
CHCl3
60
54
75
8
L13
CHCl3
48
51
85
9
L14
CHCl3
48
50
50
10
L6
CH2Cl2
48
26
95
11
L6
toluene
48
trace
NDe
12
L6
PhCF3
48
trace
ND
13d
L6
CHCl3
48
73
92
X-ray structure of 3ea
aUnless
noted otherwise, the reaction of 1 (0.15 mmol), 2 (0.10 mmol), Pd2dba3•CHCl3 (2.5 mmol%) and L8 (15 mol%) was performed in 1 mL of CHCl3 for 24 h. ee was determined by chiral HPLC analysis. bThe reaction temperature was 40 °C. cThe reaction was carried out at 40 °C for 48 h. dPhCF3 was used as the solvent. eNo reaction.
The scope of VECs was next explored under the optimal reaction conditions (Table 2). The reaction of coumalates 2 and a range of VECs 1 gave products 3 with good to excellent yield and excellent enantioselectivities. Gratifyingly, all kinds of ester group in coumalates could be tolerated (3ab−3ae). In general, VECs containing electron-donating substituents on the aromatic group did not bring noticeable effects the reaction (Table 2, 3ba, 3ca, 3ja, 3ka, 3qa). In comparison, electronwithdrawing groups on the phenyl ring of VECs (3fa, 3ga, 3na) led to a slightly lower yield of the product. The position of the substituents doesn’t have certain effect on enantioselectivity. A range of VECs containing different groups (R2) at ortho, meta, para-position of the phenyl ring performed well in this reaction to deliver the corresponding cyclic products (Table 2, 3aa−3qa) in good to excellent yields and with excellent enantioselectivities (mostly 99% ee). The absolute configuration was unambiguously confirmed by single-crystal X-ray diffraction analysis of the product 3ea.17 Meaningfully, the reactions of 3,4-dichlorophenyl-substituted VEC 2r or 2,4difluorophenyl-substituted VEC 2s also proceeded smoothly to afford the corresponding 3ra or 3sa in high yields with excellent enantioselectivities. In addition, both the VEC 1t bearing naphthyl and the thienyl-substituted VEC 1u were workable, furnishing the desired products in good yields with high enantioselectivities. Noticeably, styryl-substituted VEC 1v and vinyl-substituted VEC 1w could successfully undergo the reaction, thus providing the products 3va and 3wa in good yields with moderate to good enantioselectivities, respectively.
aUnless
noted otherwise, the reaction of 1a (0.15 mmol), 4a (0.10 mmol), Pd2dba3•CHCl3 (2.5 mol%) and ligand (15 mol%) was stirred in 1.0 mL of solvent under indicated reaction conditions. bIsolated yield. cDetermined by chiral HPLC analysis. dThe reaction was carried out with 5% Pd and 20% of ligand. eNR: no reaction; ND: no detection.
Following exploration of the substrate scope of VECs, we attempted to develop asymmetric domino annulation of pyrones. Under the optimized conditions for the reaction of VEC 1 with methyl coumalates 2 (see Table 1, 2), the catalytic asymmetric domino annulation of pyrone 4a with VEC 1a was investigated (Table 3). Unfortunately, the dicyclohexylamine-derived ligand L8, which had proven to be very effective in annulation of VECs 1 and coumalate 2, gave the desired cycloadduct 5aa in 71% yield with 75% ee (Table 3, entry 1). Therefore, those similar phosphoramidite ligands to L8 were reevaluated. With the use of L6 as the ligand, the product 5aa was obtained with 91% ee, albeit in moderate yield (entry 2). Both yield and ee were moderate when the bis(iso-propyl)-substituted L7 was used (entry 2). H8-BINOL-based phosphorus amidite ligand L9 resulted in a similar yield and a lower ee, compared with its template
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Ligand L6 (entry 4). In order to achieve satisfactory yield and ee, more chiral phosphoramidite ligands were prepared and evaluated. The ligands L10 and L1125 with large substituents at nitrogen atom did not promote the reaction (entries 5–6). The dicycloalkylamine derived phosphoramidite ligands L12 and L1326 was also prepared, which delivered high ees (75 and 85%) but moderate yields (54 and 51%) (entries 7–8). Both moderate yield and moderate ee were obtained when diphenylamine-derived ligand L14 was employed (entry 9). According to the above screening results, we turned back the ligand L6 for further optimization. Using L6, the impact of the solvent was next examined. Compared with chloroform, the results from dichloromethane, toluene, and trifluorotoluene were disappointing (entries 10–12). To our delight, increasing the catalyst loading furnished the product 5aa in a good yield with excellent enantioselectivity (entry 13). In the light of the above screening, the optimal reaction conditions were determined as follows: using Pd2dba3•CHCl3 (5 mmol%) /L6 (20 mol%) as the catalyst in CHCl3 at 25 °C.
based polycyclic heterocycles (6) with excellent diastereoselectivities and enantioselectivities. Their [3+2] cycloaddition reaction with nitrilimines was also very successful under mild reaction conditions, producing hexahydro-1H-10,4-(epoxymethano)oxo-nino[3,4-c]pyrazol-12-ones (7) in 63−90% yields with uniform 99% ee and excellent diastereoselectivities. Further treatment of the product 3 with azomethine ylides in the presence of AgOAc and PPh3 in CH2Cl2 at room temperature led to the tetrahydropyrrole-fused nine-membered ethers (8) in 56−99% yields and 98−99% ee. Bromination of the product 3aa resulted in a interesting octahydro-1,6(epoxymethano)isobenzofuran-8-one derivative 9a in 66% yield with 99% ee. The configurations of the derivatives (6−9) were unambiguously confirmed by single-crystal X-ray diffraction analysis.27 Scheme 2. The Scaled-up Reaction and Further Elaborations of the Products. O
Table 4. Scope of Pyronesa O
O
Ph
O
+
O
O O
Ph
Ph
o
CHCl3, 25 C, 48 h
O O
Ph
O
5af 79%, 97% ee
O
O O
R2
O
Ph
O
O O
R 5ab 2 = 4-MeC6H4 R 5ac 2 = 4-EtC6H4 R 5ad 2 = 4-n-PrC6H4 R 5ae 2 = 4-i-PrC6H4
5ag 80%, 83% ee
TsN
78%, 93% ee 70%, 94% ee 50%, 95% eeb 80%, 93% eeb
O
Ph
O O
O +
N
5ah 99%, 98% ee
aUnless
noted otherwise, the reaction of 1a (0.15 mmol), 4a (0.10 mmol), Pd2dba3•CHCl3 (5 mmol%) and L6 (20 mol%) was performed in 1 mL of CHCl3 at 25 °C for 48 h. ee was determined by chiral HPLC analysis. bThe reaction time was 24 h.
With the optimal reaction conditions established, delightedly, with the use of L6 as chiral ligand, the pyrones 4 also displayed excellent reactivity as coumalates did. As indicated in the Table 4, for the aryl substituted pyrones, the corresponding products (5aa−5af) were obtained in moderate to good yields with high to excellent enantioselectivities. The electron-donating and electron-withdrawing groups on the phenyl ring did not show significant different effect on the reactions, and all the tested pyrones afforded the corresponding products (5aa−5af) in satisfactory results. Notably, the 2-furan substituted pyrone 4g carried out the reaction to produce the product 5ae in high yield and good enantioselectivity. Using the cyano-substituted pyrone (4h) as the substrate, the reaction still occurred to give bridged cyclic product 5ah in 99% yield and 98% ee. Following exploration on the substrate scope, the model reaction was performed on the gram-scale under the optimal reaction conditions, giving the product 3aa in 90% yield with 99% ee (Scheme 2). With the medium-sized heterocycles in hand, we next turned our attention to investigate their selective transformations (Scheme 2). These chiral nine-membered heterocyclic compounds performed 1,3-dipolar cycloaddition with C, N-cyclic azomethine imines at 60 °C to give quinazoline-
CO2Me
o
CHCl3, 25 C, 24 h
O O O
Ph
CO2Me
3aa 1.35 g, 90%, 99% ee
2a (0.77 g, 5 mmol)
R2 CO2Me
O O O
TsN
CO2Me
N N
R2
N
o
o
CCl4, 0 C to rt, 3 h
O
O
CO2Me
R3
3 (99% ee)
N
H N
Br CO2Me
Br O H O
Ph
9a
R1
Cl N Ph
O Br2
O O O
DCE, 60 C
=Ph H, 7 h, 6a R2 99%, 99% ee R = Cl, 72 h, 75%, 99% ee 6b 2
CN
O
2.5 mol% Pd2dba3•CHCl3 15 mol% L8
O
N
O
R3
O
O Cl
R1
5
O
Ph O 5aa 73%, 92% ee
Ph
1a (1.43 g, 7.5 mmol)
O O
4
1a
Ph
R1
O O
(5 mol%) Pd2dba3•CHCl3 L6 (20 mol%)
O
Page 4 of 9
66% yield, 99%ee
CO2Me
MeO2C
NH
N Ph
Et3N, CH2Cl2, rt, 6 h
O
R1 7a R1 = R3 = Ph, 90%, 99% ee 7b R1= Ph, R3 = 3-ClC6H4, 63%, 99% ee 7c R1 = 3-BrC6H4, R3 = Ph, 71%, 99% ee 7d R1 = 4-BrC6H4, R3 = Ph, 79%, 99% ee
R4
R4 10 mol% AgOAc 15 mol% PPh3 CH2Cl2, rt, 8 h
O
O
CO2Me O
R1
8a R1 = R4 = Ph, 99%, 99% ee 8b R1 = 4-ClC6H4, R4 = Ph, 90%, 99% ee 8c R1 = 3-BrC6H4, R4 = Ph, 90%, 98% ee 8d R1 = 4-BrC6H4, R4 = Ph, 95%, 99% ee 8e R1 = Ph, R4 = 4-ClC6H4, 76%, 98% ee 8f R1 = Ph, R4 = 4-BrC6H4, 56%, 98% ee
In order to shed light on the reaction mechanism, some control experiments had been carried out (Scheme 3). During reaction optimization, when we monitored the reaction by TLC, an unknown intermediate was always observed. In order to prove that it is a [3+2] cycloadduct, the reaction was stopped in 40 min and the intermediate was isolated as yellow oil. The NMR data revealed that the intermediate was an expectant [3+2] cycloaddition product 10aa. The compound 10aa was very unstable and quickly converted to the ring-expansion product 3aa via Cope rearrangement. Under catalysis of racemic catalyst Pd/Ph3P, the [3+2] cycloadduct 10aa’, which is a diastereomer of the intermediate 10aa, was obtained in 23% yield, and it did not perform Cope rearrangement to give the product 3aa. When unsubstituted vinylethylene carbonate (1z) was used under the optimal conditions, the reaction produced two diastereomers (10za and 10za’) of [3+2] cycloadduct in moderate yields with good enantioselectivity, rather than nine-membered product. Both the compound 10za and 10za’ are stable at room temperature or even 110 °C, and did not perform Cope rearrangement. Its relative configuration was determined by X-ray analysis.27
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Page 5 of 9 Scheme 3. Control Experiments.
+
1a
2a
2.5 mol% Pd2dba3•CHCl3 15 mol% L8 o CHCl3, 25 C, 40 min
O
CO2Me CO2Me Ph +
O H
O
O
O O
Ph
10aa, 83% yield 99% ee, >20:1 dr
3aa, trace
CDCl3, rt, 24 h 100% conv., 99% ee
2a
CO2Me
O
5.0 mol% Pd2dba3•CHCl3 20 mol% PPh3
CO2Me Ph +
O H
o
CH2Cl2, 25 C, 26 h
O
O
Figure 2. The Optimized Geometries of the Intermediate B and the Numbering of Key Atoms.
O O
Ph
( )-3aa, 63% yield ( )-10aa' 23% yield, >20:1 dr
X O O
O
+
2a
2.5 mol% Pd2dba3•CHCl3 15 mol% L8
TS[3+2]R
O
O O H
o
CHCl3, 25 C, 18 h
Table 5. The Transition States of Cycloadditions.a
CO2Me
+
O
10za
1z
31% yield, 72% ee
O H
CO2Me O
10za' 43% yield, 67% ee
Scheme 4. A Plausible Reaction Mechanism. TS[5+4]
Pd(0)
O
O CO2Me Ph
O H
O
Ph
O 1a
Cope Rearrangement
O H
CO2Me Ph Pd/Ln
O
O O O
Ph
O O O D
Ph [3+2] pathway
Ph A
CO2Me O
[5+4] pathway
O O H
Pd/Ln O
C Pd/Ln
TS[3+2]S
CO2Me
3aa
CO2Me
d 2.184 2.205 2.350 C1 C3 C4 C6 Bond d C1–C6 2.432 3 Pd–C 2.257 Pd–C7 3.306 C1 C3 C4 C6 Bond d C3–C4 2.369 Pd–C1 Pd–C6 2.252 C1 C3 C4 C6 Pyramidalization
O 10aa
O
Bond C3–C4 Pd–C1 Pd–C6 Pyramidalization
+
1a
Pyramidalization
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ACS Catalysis
O
MBO 0.401 0.494 0.416 17.4 18.8 21.6 17.7 MBO 0.251 0.440 12.8 7.7 0.8 14.0 MBO 0.332 0.454 0.5 15.2 20.1 19.6
aThe
CO2Me 2a
[3+2] Cycloaddition at the re-face (TS[3+2]R), [5+4] Cycloaddition (TS[5+4), and [3+2] Cycloaddition at the si-face (TS[3+2]S) with Key Geometric Parameters Distance (d in Å), Mayer Bond Order (MBO), and Pyramidalization (in degree).
Pd/Ln O Ph B
Computational Investigations. On the basis of control experiments, previous reports,11, 15, 17 and density functional theory (DFT) calculations, as shown in Scheme 4, a plausible mechanism was proposed. In the presence of Pd catalyst, vinylethylene carbonate 1a performs ring-opening to afford the zwitterionic allylpalladium intermediate A, which attacks methyl coumalate 2a to give the intermediate B. Subsequent intramolecular annulation and protonation led to a [3+2] annulation product 10aa, which underwent a Cope rearrangement to produce the final product 3aa. The direct [5+4] cycloaddition pathway was unfavorable.
According to experimental data reported above, Ar-substituted VEC (1a) afforded an [3+2] cycloaddition product that could easily convert to the product with a nine-membered ring while the unsubstituted VEC (1z) could only give the [3+2] product (10za and 10za’) with moderate diastereoselectivity (Scheme 3). This stimulated us to hypothesize that the presence of the Ar substituent is key to the stereoselectivity of the [3+2] cycloaddition and the following Cope rearrangement. The [3+2] cycloaddition starts from the nucleophilic addition of the zwitterionic allylpalladium intermediate A to coumalate (Scheme 4), which leads to the intermediate B. The optimized geometry of this intermediate B is shown in Figure 2. In this model intermediate, the catalyst Pd-L8 is used with the binaphthyl group mimicked by a biphenyl group to save computational cost and labelled as Pd-Ph. The prototype ligand was denoted as L8 and the biphenyl analogue as L8-Ph in Table 6.
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CO2Me
O PdLn O O Ph LnPd
Ph
TS[5+4] 23.8 [23.1]
CO2Me O O O Ph B [5+4] 16.3
PdLn Me O
TS[3+2]R 19.4 [19.2]
[16.4]
C -1.6 [-2.6]
2
4
Me O
7
O
O
PdLn
6
5
Me O O
O
O
-PdLn
10aa -3.5 [1.7]
3aa -13.4 [-8.2]
OO O O H
CO2Me Ph
O O
O Ph
O
LnPd
CO2Me
O
CO2Me
-PdLn
PdLn
O
O
O 3aa' 0.7 [1.1]
Ph
O
TSCope 16.3 [22.3]
O O
Ph
1
Ph
O
LnPd
B 0.0 [0.0] Ph 3
O O
O
TS[3+2]S LnPd 23.5 Ph [23.1]
O
CO2Me
O
CO2Me O O
O Ph
O
B' 19.9 [19.7]
C' 10.3 [8.9] PdLn
O
B 0.0 [0.0] Ph
O H 1
2
3 5
6
4
Me O
O O
CO2Me Ph
PdLn 7
O
O
O
- PdLn O
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kcal/mol (see Figure 3), and produces 10aa, which works as the precursor compound in the Cope rearrangement. The Cope rearrangement is featured by the concerted cleavage of C3–C4 and formation of C1–C6 bonds via a chair-like transition state TSCope as shown in Figure 4. The TSCope displays significant dissociative character in view of the C3–C4 and C1–C6 bond distances, which are measured as 2.56 and 2.61 Å respectively, and the charge discretization between the atom pair C3 (0.07e) and C4 (–0.23e). These charge carriers holding opposite charge are stabilized by the phenyl and the ester groups bound to them to convoy the Cope rearrangement under ambient condition. Energetically, the activation energies to the tandem [3+2] cycloaddition/Cope rearrangement pathway were calculated to be 19.4 and 19.8 kcal/mol for the sequential elementary step, respectively, and both are exothermic by 1.6 and 9.9 kcal/mol, respectively. This indicates that the pathway is feasible kinetically under experimental condition and favourable thermodynamically. As seen in Figure 3, the free energy of TSCope is lower than that of TS[3+2]R by 3.1 kcal/mol, indicating that the [3+2] cycloaddition is the rate-determining step. In contrast, for the [3+2] cycloadduct 10za without the Ar substituent from the unsubstituted substrate 1z (Scheme 3), the activation energy to the Cope rearrangement was raised to 28.9 kcal/mol and the reaction was endothermic by 4.2 kcal/mol, suggesting that for the unsubstituted substrate 1z, the formation of the nine-membered ring is unfavourable both kinetically and thermodynamically.
CO2Me O H
Ph O
10aa' -4.4 [-0.6]
Figure 3. The Gibbs Free Energy Profiles (in kcal/mol) of [3+2] (re-face) and [5+4] (top), and [3+2] (si-face) (bottom) Cycloaddition Reactions in Dichloromethane. Data in Parentheses Are Obtained in Gas Phase. Figure 4. The Transition State of the Cope Rearrangement As shown in Figure 2, in the intermediate B, the Pd atom builds dative bonds with the allyl group in a η3 manner and the C6 of coumalate. This offers two possible pathways to produce the final bicyclo[5.2.2]tetrahydro-oxonine, i.e. the tandem [3+2] cycloaddition/Cope rearrangement and the direct [5+4] cycloaddition pathways. We have found the stationary points in the elementary steps along these routes, and the structures of the transition states with key geometric parameters are shown in Table 5. The corresponding Gibbs free energy profiles are plotted in Figure 3. Along the [3+2] cycloaddition pathway, as shown in Table 5, the benzylic carbon atom (C3) attaches to the C4 atom which is next to the ester substituent via a transition state (TS[3+2]R) with a C3–C4 distance of 2.184 Å. This value is much longer than the value of 1.598 Å in the [3+2] cycloaddition product C (Scheme 4), indicating that the interaction between C3 and C4 is rather weak in the transition state. In C, the formation of C3–C4 bond closes a five-membered ring, and expels the PdL catalyst from the clap region constituted by the allyl group and the coumalate ring to prepare for the Cope rearrangement. The detachment of PdL catalyst from C is thermodynamically favourable by 1.9
Table 6. The Difference in the Activation Energies (kcal/mol) to the [3+2] (re-face) and that to the [5+4] or the [3+2] (siface) Cycloaddition at B3LYP/BS1(PCM) level Ligand ∆G[5+4]-∆G[3+2]R ∆G[3+2]S-∆G[3+2]R L8-Ph +4.4 (+3.8)a +4.1 (+4.2)a TMP +1.4 +1.5 L8-Me +3.3 +3.5 L8 +4.3 (+4.1)a +3.6 (+4.0)a a Data in parentheses are from energy refinement by single point calculations at B3LYP/BS2(PCM) with zero-point, thermal and entropic corrections obtained at B3LYP/BS1(PCM) level included. When proceeding along the [5+4] cycloaddition pathway, the intermediate B need loose its contact with the PdL catalyst in order to release the C1 and C6 positions to make the way for nine-membered ring closure. This costs substantial energy which was calculated to be 16.3 kcal/mol, and an additional energy of 7.5 kcal/mol is demanded to approach the transition state, leading to a higher free energy of TS[5+4] than TS[3+2]R by
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ACS Catalysis 4.4 kcal/mol at the B3LYP/BS1(PCM) level. The energy refinement with a larger basis of BS2(PCM) gives a value of 3.8 kcal/mol. This suggests that the contribution of the [5+4] cycloaddition route to the final product is negligible compared to that of the tandem [3+2] cycloaddition/Cope rearrangement pathway. In the transition state TS[5+4], the Pd atom remains coordinated to the benzylic position and the bridging O atom of the coumalate ring. This in some sense enhances the nucleophilicity of C1 atom and assists the C1–C6 bond formation. The distance between C1 and C6 was calculated to be 2.432 Å, and the pyramidalization of the two atoms were 12.8○ and 14.0○, respectively, suggesting a rather early transition state. The calculated imaginary frequency was 209.1i cm–1, corresponding to the C1–C6 bond formation. We have also evaluated the influence of the ligand of the catalyst. The four ligands investigated here include the prototype model of L8, the simplified form of L8 by replacing the two cyclohexyl and the binaphthyl groups by methyl (L8-Me, MeO2PNMe2), the trimethyl phosphine (TMP), and the simplified form of L8 by replacing the binaphthyl skeleton with biphenyl skeleton (L8-Ph). As seen in Table 6, the simplification of the ligand does not eliminate the superiority of the tandem [3+2] cycloaddition/Cope rearrangement over the [5+4] route. However, it does, either replacing the cyclohexyl or the binaphthyl by methyl groups, cause noticeable attenuation of the predominance of the former route over the latter, which is consistent with the observations in experiment that L8 performed better than the other simpler ligands. As mentioned above, the reaction of Ar-substituted VEC with coumalate exhibited high enantioselectivity, i.e. the [3+2] cycloaddition occurred from the re-face of the benzylic position of VEC. The analysis of the structure of B shows that this is governed by the coordination mode of Pd atom. Here we prepared an isomer of B that the [3+2] cycloaddition may proceed at the si-face, which is denoted as B’, and evaluated the reactivity of this reaction channel. According to our calculations, the free energy of the transition state of the reaction at the si-face is higher than that at the re-face by 4.1 kcal/mol at the B3LYP/BS1(PCM) level (see Figure 3 and Table 6). Examination of the geometry indicates that there is substantial difference in the coordination mode of PdL with the annulated VEC and pyrone fragments between TS[3+2]S and TS[3+2]R: in the former, Pd atom loosely interacts with the phenyl ring in a η2 manner and the C6 position. This conformation helps to lock the two fragments to prepare for the C3–C4 bond formation, while loses the η3 interaction with the allyl group. This may largely minimize the pyramidalization of the C3 and C4 sites (15.2○ and 20.1○ respectively) which is enforced by the neighbouring phenyl and ester groups, but lacks direct contact with the reaction site to catalyse the [3+2] cycloaddition at the si-face. This explains the importance of the aromatic group in VEC to head into the [3+2] cycloaddition at the re-face with excellent enantioselectivity. CONCLUSIONS In conclusion, we have developed an efficient synthetic method to access chiral bicyclo[5.2.2]tetrahydrooxonine derivatives though Pd-catalyzed asymmetric tandem [3+2] cycloaddition/Cope rearrangement of VECs with coumalates or pyrones. The catalytic system displayed extremely excellent enantioselectivity and diastereoselectivity, and tolerated a broad scope of
VECs, coumalates and pyrones. This novel synthetic strategy opens a window for asymmetric synthesis of nine-membered cyclic ether, which are challenging to be accessed by other methods. In addition, the further conversions of the nine-membered heterocyclic compounds to several functionalized derivatives demonstrate the utility of the reaction for diversity-oriented synthesis. The mechanism for formation of the nine-membered ring via the reaction of vinylethylene carbonates with coumalates or pyrones was investigated in detail through DFT calculations. It revealed that the reaction proceeds via a tandem [3+2] cycloaddition/Cope rearrangement pathway rather than via a [5+4] cycloaddition pathway. The [3+2] cycloaddition is the rate-determining step. The current strategy is very appealing in synthetic chemistry since it provides a highly efficient approach for asymmetric synthesis of nine-membered rings. Further studies on application of tandem cycloaddition/Cope rearrangement strategy in medium-sized cyclic compounds are currently underway in our laboratory. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental procedure, characterization data, HPLC analysis data, NMR spectra, and X-ray crystallographic data (PDF).
AUTHOR INFORMATION Corresponding Author * E-mail:
[email protected] ORCID Xing Gao: 0000-0001-6254-2583 Cheng Zhang: 0000-0002-8760-8152 Hongchao Guo: 0000-0002-7356-4283 Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT This work is supported by the Natural Science Foundation of China (Nos. 21572264, 21871293) and the Program for Changjiang Scholars and the Innovative Research Team Project (No. IRT1042).
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Organocatalytic Enantioselective CrossVinylogous Rauhut-Currier Reaction of Methyl Coumalate with Enals. Angew. Chem. Int. Ed. 2018, 57, 9505−9509. (23) Wang, X.; Meng, F.; Wang, Y.; Han, Z.; Chen, Y. J.; Liu, L.; Wang, Z.; Ding, K. Aromatic spiroketal bisphosphine ligands: palladium-catalyzed asymmetric allylic amination of racemic Morita-Baylis-Hillman adducts. Angew. Chem. Int. Ed. 2012, 51, 9276−9282. (24) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Enantioselective Conjugate Addition of Dialkylzinc Reagents to Cyclic and Acyclic Enones Catalyzed by Chiral Copper Complexes of New Phosphorus Amidites. Angew. Chem. Int. Ed. 1996, 35, 2374−2376. (25) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. Catalytic asymmetric diamination of conjugated dienes and triene. J. Am. Chem. Soc. 2007, 129, 11688−11689. (26) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. A simple iridium catalyst with a single resolved stereocenter for enantioselective allylic amination. Catalyst selection from mechanistic analysis. J. Am. Chem. Soc. 2005, 127, 15506−15514. (27) CCDC 1860289, 1860290, 1860291, 1860292, 1878864, 1878862 and 1878863 for the compounds 3ea, 6a, 7c, 8b, 9a, 10za and 10za’ contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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