Asymmetric Synthesis of Î±,Î²-Unsaturated Î´-Lactones through Copper

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Asymmetric Synthesis of #,#-Unsaturated #-Lactones through Copper(I)-Catalyzed Direct Vinylogous Aldol Reaction Hai-Jun Zhang, and Liang Yin J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Aug 2018 Downloaded from http://pubs.acs.org on August 30, 2018

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Journal of the American Chemical Society

Asymmetric Synthesis of α,β β-Unsaturated δ-Lactones through Copper(I)-Catalyzed Direct Vinylogous Aldol Reaction Hai-Jun Zhang, Liang Yin* CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China Supporting Information Placeholder ABSTRACT: A simple methodology for the asymmetric synthesis of chiral α,β-unsaturated δ-lactones was achieved by copper(I)-catalyzed direct vinylogous aldol reaction (DVAR) of β,γ-unsaturated esters and various aldehydes, including aromatic aldehydes, heteroaromatic aldehydes, α,βunsaturated aldehydes and aliphatic aldehydes. As for aromatic and heteroaromatic aldehydes, a one-pot reaction consisting of DVAR, isomerization of the unsaturated carbon-carbon double bond from (E)-form to (Z)-form and subsequent intramolecular transesterification was required to get the lactones in moderate to high yields with high enantioselectivity. As for α,β-unsaturated and aliphatic aldehydes, the DVAR proceeded directly to afford the lactones in moderate yields with high enantioselectivity. In the DVAR, various functional groups were well tolerated. Moreover, the methodology was nicely applicable to the aldehyde group distributed in natural products, derivatives of natural product and derivatives of drug molecules (Atomoxetine and Naproxen). The mechanism studies revealed that α-addition was reversible and not favored, which accounted for the excellent regioselectivity in the DVAR. The copper(I)-dienolate species generated through deprotonation was proposed to form an equilibrium with an allyl copper(I) species, which reacted with aldehydes to afford the DVAR products through a catalytic asymmetric allylation of aldehydes. Finally, the robustness of the present reaction was demonstrated by a gram-scale reaction and the utility of the present methodology was showcased by the formal asymmetric synthesis of ezetimibe and fostriecin.

INTRODUCTION The asymmetric vinylogous aldol reaction (VAR) is one of the most powerful reactions in stereoselective construction of δhydroxylated α,β-unsaturated carbonyl compounds,1,2 which are precursors in the synthesis of chiral α,β-unsaturated δ-lactones and related polyketide networks.3 Chiral α,β-unsaturated δ-lactone moiety is a prevalent structure unit in natural products,4 which plays an essential role in the biological activity, due to its potential to act as a Michael acceptor in the presence of protein functional groups.5 Moreover, chiral α,β-unsaturated δ-lactones served as versatile synthetic intermediates towards total synthesis of natural products with various biological activities and synthesis of pharmaceutically active artificial molecules.6 Due to the significance of optically active α,βunsaturated δ-lactones, there is a growing interest in the asymmetric construction of such compounds and thus various strategies were employed to construct chiral α,β-unsaturated δ-lactones.4,7 However, multiple steps were generally required to achieve the asymmetric synthesis of such molecules.4 Therefore, convenient and stepeconomical synthetic methods are highly desired. In the catalytic asymmetric VAR with cyclic nucleophiles, no matter what dienolsilanes,8 metal dienolates9 or dienolates generated with organocatalysts10 were employed, VAR afforded γ-adduct exclusively. However, in the VAR with linear nucleophiles, linear dienolsilanes were generally employed due to its natural tendency to favor the γaddition,3d,3f,11 and such VAR was recognized as the Mukaiyama vinylogous aldol reaction (MVAR).12,13 Prominent examples were uncovered by Denmark group (Scheme 1a).14 Lewis base activation of Lewis acids,15 which was developed by professor Denmark, enabled highly regio- and enantioselective MVARs. Unfortunately, stoichiometric SiCl4 was indispensable and resulted in stoichiometric silicon waste. Later, Curti, Zanardi, Casiraghi and coworkers successfully applied this catalytic system to very challenging asymmetric Mukai-

yama hypervinylogous aldol reaction of aldehydes.16 In 2011, List group also developed an efficient asymmetric MVAR by using a chiral disulfonimide as the catalyst.17 However, the MVAR of aliphatic aldehydes suffered from unsatisfactory yields and enantioselectivity. In the catalytic asymmetric aldol reaction with linear metal dienolates generated through deprotonation, α-addition occurred preferentially.18 For example, in 2018, Shibasaki and Kumagai reported two direct asymmetric aldol reactions of β,γ-unsaturated thioamides and β,γ-unsaturated acetamide in the presence of copper(I) catalyst.18b,18c In these two cases, regio- and enantioselectivity were excellent and diastereoselective were high in most substrates. However, only a small quantity of VAR products (γ-adducts) were obtained. While in the case of linear copper(I)-dienolates generated through transmetalation with dienolsilanes, γ-addition dominated the reaction with aldehydes, which was a catalytic asymmetric MVAR reported by Campagne group (Scheme 1b).19 In this reaction, linear products were symbiotically produced with α,β-unsaturated δ-lactones. In the viewpoint of the atom economy,20 it is highly desirable to obtain lactones only (or mainly) with high enantioselectivity. Moreover, Krische reported a conceptually different but very effective method to generate the linear metal dienolate, starting from a γ-OBoc ethyl crotonate (Scheme 1c).21 A series of vinylogous aldol products was produced in good to excellent regioselectivity with high to excellent enantioselectivity. Scheme 1. Prior Arts in VAR and Our Work

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Journal of the American Chemical Society (a) Denmark's Catalytic Asymmetric MVAR

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

OTBS

O + SiCl4 + R'

OR

OH

organo-catalysis ref 14a

H

O

R'

OR

(b) Campagne's Catalytic Asymmetric MVAR O OTMS

[Cu]-Tol-BINAP

O

OH

O

+ OR

R'

O

ref 19e

H

R'

OR R'

Page 2 of 10

through deprotonation. However, due to the relatively high pKa value of γ-protons in crotonate, it is very difficult to perform its deprotonation with organic base. Therefore, β,γ-unsaturated ester was utilized instead to form the copper(I)-dienolate complex more easily with organic base in the presence of copper(I) complex due to the lower pKa value of α-protons.24 We embarked on the investigation of DVAR by using benzyl β,γ-unsaturated ester (1a) and benzaldehyde (2a) as the model substrates (Table 1).

mixtures generated

Table 1. Optimization of DVAR of β,γγ-Unsaturated esters and Benzaldehyde Catalyzed by Copper(I)-Bisphosphine Complexa

(c) Krische's Catalytic Asymmetric VAR O

O

OH

iridium-catalysis

O

+

BocO

OEt

R'

ref 21

H

R'

OEt

(d) Jiang's Catalytic Asymmetric DVAR

O

+ R'

O

R

R'

ref 22c

N R"

OR

R

organo-catalysis

O

O N R"

CN

+ R'

H

R' = aryl, vinyl

THF (0.1 M), T

Ph

12 h

OR

b

b

c

ee (LP)

ee (CP)c

1/1

-8%

82%

1/0.9

-7%

86%

-

-

-

0

-

-

-

rt

19

>20/1

20%

-

Barton's Base

rt

69

1/1.6

11%

90%

(R,R)-Ph-BPE

Barton's Base

rt

82

1/1.5

39%

-94%

(R,Rp)-TANIAPHOS

Barton's Base

rt

88

1/1.9

-58%

80%

Bn (1a)

(R)-DTBM-SEGPHOS

Barton's Base

rt

98

1/2.1

88%

87%

10

Ph (1b)

(R)-DTBM-SEGPHOS

Barton's Base

rt

98

1/1.6

88%

94%

11

Ph (1b)

(R)-DTBM-SEGPHOS

TEA

rt

70

1/0.6

89%

95%

12

Ph (1b)

(R)-DTBM-SEGPHOS

TMG

rt

96

1/1.4

86%

94%

13d

Ph (1b)

(R)-DTBM-SEGPHOS

Barton's Base

-20

98

1/1

95%

97%

14d,e Ph (1b)

(R)-DTBM-SEGPHOS

Barton's Base

-20

92

20/1 dr b 8a, 72%, 13/1 dr

6j, 63%, 87% ee O

O

8b, 58%, 16/1 dr

O

O

O O

O

O

N O

O 6o, 54%, 89% ee

6p, 59%, 90% ee

O

O

O O

8d, 62%, 7/1 dr b

O O

8e, 62%, 13/1 dr b O

O TBSO

O

O

O

O

O H 6q, 62%, 89% ee

6r, 65%, 91% ee

H

6s, 57%, >20/1 dr H

a1c,

0.6 mmol; 5, 0.4 mmol. Isolated yield reported. Enantioselectivity determined by chiralstationary-phase HPLC analysis. Diastereoselectivity determined by 1H NMR analysis of the reaction crude mixture.

TBSO

H

H O

H 8f, 61%, >20/1 dr

H

H 8g, 61%, >20/1 dr

ligand = (S,S)-Ph-BPE O

The substrate scope of aliphatic aldehydes was studied with 5 mol % complex of mesitylcopper(I) and (R,R)-Ph-BPE at room temperature (Table 3). Linear aliphatic aldehydes reacted with 1c smoothly to give the lactones (6a-6c) in moderate yields with satisfactory enantioselectivity. It is noteworthy that lactone 6a is a natural product, named as ()-massoia lactone.30 The α-branched aldehyde, as well as the cycloalkyl aldehydes, was also competent substrates to generate the lactones (6d-6g) in moderate yields and excellent enantioselectivity. In the cases of α,β-unsaturated aldehyde, the corresponding lactones (6h-6i) were isolated in moderate yields with acceptable enantioselectivity. Enantiomer of lactone 6h, named as goniothalamin, which exhibited a broad manifold of biological activities,31 is a known natural product.

O

O

O

O

O

ent-8c, 65%, 7/1 dr b 9a, 73%, 11/1 dr

O

9b, 65%, 11/1 dr O O

O

N O

O

9e, 62%, 11/1 dr b

ent-8d, 69%, >20/1 drb O

Furthermore, a series of aliphatic aldehydes bearing various functional groups was evaluated under the optimized reaction conditions. Phthalimide (6j), TBS-ether (6k), phenyl sulfone (6l), alkyl chloride (6m), ester (6n), terminal olefin (6o), internal alkyne (6p) and acetal (6q) were well tolerated under the present catalytic system. These versatile functional groups leave the spacious room for further elaboration of the structures in organic synthesis. It is particularly noteworthy that a methyl ketone moiety, which may lead to a competitive aldol reaction with the aldehyde moiety, did not disturb the DVAR in the present conditions. The corresponding lactone (6r) was isolated in 65% yield with 91% ee. Moreover, a chiral aldehyde containing TBSether of a secondary alcohol was employed in the DVAR. The reaction proceeded nicely to give the corresponding lactone (6s) in excellent stereoselectivty, which would lead to the enantiomer of natural product euscapholide (anti-inflammatory activity)32 through deprotection of the TBS-ether moiety. The absolute configurations of 6a, 6b, 6g, 6h and 6s were determined as shown in Table 3 through comparing their optical rotation values with reported data. The absolute configurations in other products were assigned tentatively by analogy.

O

O

O

H H TBSO

H H

H 9f, 63%, >20/1 dr

H O

H

H 9g, 64%, >20/1 dr

1c, 0.6 mmol; 7, 0.4 mmol. Isolated yield reported. Diastereoselctivity determined by 1H NMR analysis of the reaction crude mixture. bDiastereoselectivity determined by chiralstationary-phase HPLC analysis. a

The present methodology was successfully extended to chiral natural products, natural product derivatives and a derivative of drug molecule Atomoxetine, all of which contain an aldehyde moiety (Table 4). In the presence of 5 mol % mesitylcopper(I) and 5 mol % (R,R)-PhBPE or (S,S)-Ph-BPE, (-)-perillaldehyde and (-)-myrtenal reacted smoothly with 1c to afforded the lactones (8a, 8b, 9a and 9b) in moderate yields with high diastereoselectivity. It is noteworthy that the copper catalyst derived from (R,R)-Ph-BPE exhibited slightly better

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asymmetric induction. Both (-)-citronellal and (+)-citronellal were suitable substrates, which afforded all four enantiomers of the lactone (8c, 8d, ent-8c and ent-8d) in moderate yields. However, in the case of 8d and ent-8c, the diastereoselectivity was moderate due to the unsatisfactory optical purity of commercially available (+)-citronellal. Moreover, an aldehyde derived from drug molecule Atomoxetine, which is used to treat attention deficit hyperactivity disorder, was applicable under the present reaction conditions. Lactones 8e and 9e were generated in moderate yields with high diastereoselectivity. DVAR of two steroidal molecules (7f and 7e) bearing an aldehyde group, which derived from (+)-lithocholic acid, resulted in lactones (8f, 8g, 9f and 9g) in good yields with excellent diastereoselectivity. The stereochemistry of product 9f was determined as shown in Table 4 by X-ray diffraction analysis (for details, see SI). The stereochemistry of other products was assigned by analogy. Scheme 3. Catalytic Asymmetric DVAR via Dynamic Kinetic Resolution

3. Insights to the Reaction Mechanism and Proposed Reaction Pathway. The catalytic asymmetric DVARs of benzaldehyde and 4butenoate 1a and 1b at room temperature are presented in Scheme 5. When 1a was used, 3aa was generated in 32% yield with 88% ee while 4a was produced in 66% yield with 87% ee (Scheme 5A). In the case of 1b, 3ba was obtained in 38% yield with 88% ee while 4a was obtained in 60% yield with 94% ee. It is interesting to note that 4a (94% ee) showed higher ee than 3ba (88% ee). When we submitted the racemic lactone 4a to the present conditions of DVAR, 4a was recovered quantitatively without any change in its ee (Scheme 5B). This observation indicated that the pathway to form 4a was not reversible. Scheme 5. Catalytic Asymmetric DVARs of Benzaldehyde with 1a and 1b (1H NMR Yields Are Given)

DVAR of chiral aldehyde 7h derived from Naproxen, which was suspicious to racemize under basic conditions, furnished lactone 8h in 88% yield with 11/1 dr based on the 1H NMR analysis of the crude mixture (Scheme 3A). Fortunately, the diastereoisomers were separated successfully by column chromatography to deliver pure 8h in 73% yield with >20/1 dr and 97% ee. When (S,S)-Ph-BPE was employed instead of (R,R)-Ph-BPE, ent-8h of 81% ee was produced in 73% yield with 1.8/1 dr based on the 1H NMR analysis of the crude mixture (Scheme 3B). It was evident that racemization of 7h occurred under the present basic reaction conditions, which resulted in the formation of ent-8h. We reasoned that if racemic aldehyde 7h was used, a dynamic kinetic resolution might occur to generate the chiral lactone 8h. In DVAR of 1c and rac-7h, lactone 8h was isolated in 66% yield with >20/1 dr and 94% ee (Scheme 3C). Finally, the more easily available crotonates (vs β,γ-unsaturated esters) were tried under the present reaction conditions. As shown in Scheme 4, both methyl crotonate and phenyl crotonate were completely inert in the presence of 5 mol % Cu(CH3CN)4PF6, (R)-DTBMSEGPHOS and Barton’s Base. Even by increasing the amount of Barton’s Base from 5 mol % to 1 equiv, methyl crotonate remained intact. In the case of phenyl crotonate, only slight decomposition was observed and no desired VAR products were detected. Clearly, Barton’s Base was not strong enough to achieve the deprotonation process at the γ-position of crotonates. Scheme 4. DVAR of Methyl Crotonate and Phenyl Crotonate with Benzaldehyde

However, when racemic 3ba was submitted to the present conditions, 85% 3ba was recovered in 16% ee and 4a was obtained in 15% yield with 86% ee (Scheme 5C). The reaction of racemic 3aa gave the similar results, which revealed that the pathway to form 3aa or 3ba was reversible. More interestingly, the retro-DVAR of (R)-3aa or (R)3ba was favored. Thus, more (S)-3aa or (S)-3ba remained in the reaction mixture. These results indicated that a low efficient kinetic resolution possibly existed in the retro-DVAR of racemic 3aa or 3ba. The retro-DVAR of 3aa or 3ba occurred to give benzaldehyde and corresponding dienolates, which afforded (R)-γ-adduct with a (Z)-olefin through the copper(I)-catalyzed DVAR. Then, (Z,R)-γ-adduct transformed to (R)-4a through irreversible intramolecular transesterification. Since α-adduct was not observed in the catalytic asymmetric DVAR, we tried to explore the reason. In order to get some insights, we prepared racemic α-adduct 10aa according to a reported procedure with modification.33 Then, it was submitted to the present catalytic asymmetric reaction conditions (Scheme 5D). Surprisingly, α-adduct


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completely consumed. 4a was obtained in 79% yield with 85% ee and 3aa was obtained in 19% yield with 71% ee. This observation clearly pointed out that the α-addition of 1 with aromatic aldehydes was reversible and unfavored in the present basic reaction conditions. Scheme 6. Catalytic Asymmetric DVARs of Hexan-1-al with 1c under Two Different Reaction Conditions (1H NMR Yields Are Given)

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was observed (Scheme 6C). In order to get further insights to the mechanism, the mixed cross-over reaction of benzaldehyde and racemic 12ca (dr = 1/1) was performed in the reaction conditions of catalytic asymmetric DVAR with (R)-DTBM-SEGPHOS as the ligand (Scheme 7C). Interestingly, three products were obtained, including 3ca (12% yield, 78% ee), 6a (18% yield, 76% ee) and 4a (56% yield, 83% ee). These results indicated the DVAR of aromatic aldehyde proceeded preferentially in the presence of aliphatic aldehyde. Moreover, it is interesting to note that 4-butenoic acid ester of but-2-yn-1ol (1c) led to more CP (4a) than 4-butenoic acid ester of phenol (1b) in the DVAR of aromatic aldehyde with (R)-DTBM-SEGPHOS as the ligand (Scheme 7A vs Scheme 5A). Even in the DVAR of aliphatic aldehyde 5a and 1c with (R)-DTBM-SEGPHOS as the ligand, no LP (11ca) was generated (Scheme 7B). Scheme 7. Catalytic Asymmetric Cross-Over DVAR (1H NMR Yields Are Given)

As for aliphatic aldehyde 5a, in the presence of 5 mol % mesitylcopper(I)-(R,R)-BPE, lactone 6a was obtained in 75% yield with 90% ee while linear product 11ca was observed in 21% yield with 40% ee (Scheme 6A). It should be noted that 6a had the opposite absolute configuration to 11ca. In order to explore the reason that only trace αadduct was observed, α-adduct34 was subjected to the present catalytic system with mesitylcopper(I)-(R,R)-BPE. α-Adduct 12ca converted to γ-adducts completely in 12 h (Scheme 6B). 6a was obtained in 53% yield with 90% ee and 11ca was generated in 20% yield with 39% ee, which perfectly matched with the results of the DVAR. Under the reaction conditions with 5 mol % Cu(CH3CN)4PF6-(R)-DTBMSEGPHOS-Barton’s Base, such a tendency was also observed (Scheme 6E). These experimental observations clearly demonstrated that the retro-aldol reaction of α-adduct also occurred in the cases of aliphatic aldehydes. It should be noted that the DVAR of aliphatic aldehyde 5a with (R)-DTBM-SEGPHOS gave 6a in higher yield without formation of 11ca than the reaction with (R,R)-Ph-BPE, albeit with lower enantioselectivity for 6a (Scheme 6D vs Scheme 6A).

Based on above experiment observations and literatures,19e,19f a plausible reaction pathway is proposed although speculative at this juncture (Scheme 8). In the presence of copper(I) complex U, deprotonation of A by base generates copper(I)-dienolate V, which forms an equilibrium with allyl copper(I) species W. The aldol reaction of V with aldehyde B would result in α-addition and finally lead to αadduct upon protonation, which was found to be reversible. αAddition would be disfavored in the presence of steric hindrance from the bulky bisphosphine ligand. The competitive allylation of B (γaddition) with W would furnish copper(I)-alkoxide X and Y through a formal vinylogous aldol reaction through a six-membered transition state. However, the pathway to X and Y is not controlled with selectivity, possibly because that W was not optically pure. Definitely, this allylation process is reversible in the case of aromatic aldehydes as demonstrated by above experimental observations. Protonation of Y with A would lead to linear product C and regenerate copper(I)dienolate V. On the other way, intramolecular transesterification of X irreversibly generates cyclic product D and releases copper(I) alkoxide/phenoxide, which transforms to copper(I)-dienolate V through deprotonation with A. Scheme 8. Proposed Mechanism for the Copper(I)-Catalyzed Asymmetric DVAR

Furthermore, no change was found in the reaction of racemic 11ca in the presence of 5 mol % mesitylcopper(I)-(R,R)-BPE or 20 mol % Cu(CH3CN)4PF6-(R)-DTBM-SEGPHOS-Barton’s Base (Scheme 6F). When racemic 11ca was subjected to the catalytic system with 20 mol % mesitylcopper(I)-(R,R)-BPE, a very weak kinetic resolution


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Journal of the American Chemical Society [Cu(I)]-base

O

P Cu(I)

OR

[Cu(I)]

*

U

P

H A O O R'

O[Cu(I)]

O R'

B

H

re rs ve ib le

OR

re ve rs ib le

copper(I)-dienolate (V) D (CP)

[Cu(I)]O

O A

R'

OR

base reversible

-adduct V

Z OH

O

O O

R'

OR

OR OR

C (LP) H A

O[Cu(I)]

[Cu(I)] allyl copper(I) species (W )

O O

R'

OR Y R'

O[Cu(I)] O

ar r om ev at ers ic ib a l le de in hy de s

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

R'

B

H

OR X

4. Application of the Present Methodology. The robustness of the present catalytic asymmetric DVAR was demonstrated by a gramscale reaction of para-F-benzaldehyde in the presence of 2 mol % Cu(CH3CN)4PF6, (R)-DTBM-SEGPHOS and Barton’s Base. para-FBenzaldehyde (0.993 g) reacted with phenyl 4-butenoate (1.946 g) to afford lactone 4g (1.143 g) in 74% yield with 95% ee (Scheme 9). Interestingly, lactone 4g was an advanced synthetic intermediate toward the synthesis of ezetimibe (Zetia®),6d which is a strong βlactamic cholesterol absorption inhibitor and is commercially available as a new drug for lowering plasma cholesterol levels. By following the literature synthetic route,6d ezetimibe could be synthesized from lactone 4g. Scheme 9. Application of the Present Catalytic Asymmetric DVAR in the Formal Asymmetric Synthesis of Ezetimibe

The present methodology of DVAR was applied to the formal asymmetric synthesis of fostriecin (Scheme 10). Commercially available and cheap dimethyl D-malate (13) was selected as the starting material. Its partial reduction by borane and sodium borohydride and subsequent protection of the vicinal diol afforded 14 in 82% yield for two steps. Reduction of 14 with DIBAL-H and following Wittigolefination with the aldehyde moiety provided 15 in 81% yield for two steps. The similar synthetic approach from 15 to 16 was realized in 91% yield for three steps. The reduction of 16 with DIBAL-H and succedent Swern oxidation furnished 17 as the starting material for the key DVAR. The catalytic asymmetric DVAR of 17 gave 18 in 64% yield with 12/1 diastereoselectivity at room temperature. The total yield from dimethyl D-malate to advanced intermediate 18 reached 33%. Then, by following a reported synthetic approach,36 fostriecin could be accessed.

CONCLUSION

Fostriecin, which was a star molecule, exhibited impressive cytotoxicity towards a broad spectrum of cancer cell lines, including breast cancer, ovarian cancer, and leukemia. Therefore, extensive efforts from the chemical community have been dedicated to its asymmetric total synthesis.35 Although the phase I clinical trials with fostriecin were not continued due to its instability and the inconsistent purity of the samples from natural sources, the endeavors towards its asymmetric synthesis continued emerging. It is realized that the synthetic approaches provide an opportunity for searching potentially more stable analogues of fostriecin and obtaining sufficient sample with consistent purity.35 Thus, developing new and efficient synthetic approaches toward fostriecin are still valuable. Scheme 10. Application of the Present Catalytic Asymmetric DVAR in the Formal Asymmetric Synthesis of Fostriecin

In conclusion, a simple methodology for the rapid synthesis of chiral α,β-unsaturated δ-lactones was disclosed by using easily available starting materials in the presence of copper catalyst. This methodology enjoys broad substrate scope, including various aromatic aldehydes, heteroaromatic aldehydes, α,β-unsaturated aldehydes and aliphatic aldehydes. Interestingly, in the cases of aromatic and heteroaromatic aldehydes, a one-pot reaction involving DVAR, isomerization of the unsaturated carbon-carbon double bond from (E)-form to (Z)-form and subsequent intramolecular transesterification was carried out to obtain the lactones in good to high yields. Various functional groups, such as aryl halides (F, Cl, Br, I), methoxyl, methylthio, BPin, phthalimide, TBS-ether, sulfone, alkyl chloride, ester, terminal olefin, internal alkyne, acetal and ketone were well tolerated. Moreover, the methodology was successfully applied to natural products, natural product derivatives and derivatives of drug molecules, all of which contain an aldehyde group. In the proposed mechanism, an allyl copper(I) species, which forms an equilibrium with a copper(I)-dienolate species, was considered as the key intermediate to react with aldehydes to generate the chiral vinylogous products. The retro-aldol reaction of α-adducts indicated a reversible and unfavored α-addition process and was attributed to the reason that perfect regioselectivity was achieved in the present DVAR. Finally, the present methodology was applied in the formal asymmetric synthesis of ezetimibe and fostriecin. Further expansion of the vinylogous pronucleophiles, as well as application of the present DVAR in the asymmetric synthesis of complex natural products or medicinal molecules, is currently ongoing in our laboratory.



ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at: Crystallographic data for 9f (CIF) Experimental procedures, X-ray diffraction data for 9f, and spectroscopic data for all new compounds including 1H, 19F, and 13C NMR spectra (PDF)

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AUTHOR INFORMATION Corresponding Author

(7)

*[email protected]

ORCID Liang Yin: 0000-0001-9604-5198

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We gratefully acknowledge the financial support from the “Thousand Youth Talents Plan”, the National Natural Science Foundation of China (No. 21672235 and No. 21871287), the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB20000000), CAS Key Laboratory of Synthetic Chemistry of Natural Substances and Shanghai Institute of Organic Chemistry. Mr. Jun-Zhao Xiao from Shanghai Institute of Organic Chemistry is acknowledged for the check of reproducibility.

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(27) With (R,R)-Ph-BPE as the ligand, the ester moiety was investigated. Three esters were identified as the best in terms of both the yield and the enantioselectivity. Considering the easy availability and the price, 4-butenoic acid ester of but-2-yn-1-ol was chosen for the further study of DVAR of aliphatic aldehydes.

(28) For some selected recent applications of mesitylcopper(I) in asymmetric catalysis, see: (a) Tamura, K.; Kumagai, N.; Shibasaki, M. Eur. J. Org. Chem. 2015, 2015, 3026–3031. (b) Weidner, K.; Sun, Z.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2015, 54, 6236– 6240. (c) Takada, H.; Kumagai, N.; Shibasaki, M. Org. Lett. 2015, 17, 4762–4765. (d) Wei, X.-F.; Xie, X.-W.; Shimizu, Y.; Kanai, M. J. Am. Chem. Soc. 2017, 139, 4647–4650. (e) Liu, Z.; Takeuchi, T.; Pluta, R.; Arteaga, F. A.; Kumagai, N.; Shibasaki, M. Org. Lett. 2017, 19, 710–713. (29) Study of the combination of copper sources and bases identified mesitylcopper(I) as the best catalyst in terms of yield of 6a. Mean-



while, LP (11ca) was obtained in 21% yield with 40% ee (Scheme 5A).

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(30) For the isolation and biological evaluation of (-)-massoia lactone, see: (a) Cavill, G. W. K.; Clark, D. V.; Whitefield, F. B. Aust. J. Chem. 1968, 21, 2819–2823. (b) Hashizume, T.; Kikuchi, N.; Sasaki, Y.; Sakata, I. Agr. Biol. Chem. 1968, 32, 1306–1309. (c) Barros, M. E. S.

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B.; Freitas, J. C. R.; Oliveira, J. M.; da Cruz, C. H. B.; da Silva, P. B. N.; de Araújo, L. C. C.; Militão, G. C. G.; da Silva, T. G.; Oliveira, R. A.; Menezes, P. H. Eur. J. Med. Chem. 2014, 76, 291-300. And more references cited there. For the isolation and biological evaluation of goniothalamin, see: (a) Jewers, K.; Davis, J. B.; Dougan, J.; Manchanda, A. H.; Blunden, G.; Kyi, A.; Wetchapinan, S. Phytochemistry 1972, 11, 2025–2030. (b) Wach, J.-Y.; Güttinger, S.; Kutay, U.; Gademann, K. Bioorg. Med. Chem. Lett. 2010, 20, 2843–2846. And more references cited there. (a) Dakeda, J. M.; Okada, Y.; Masuda, T.; Hirata, E.; Takushi, A.; Otsuka, H. Phytochemistry 1998, 49, 2565–2568. (b) Lee, H.-Y.; Sampath, V.; Yoon, Y. Synlett 2009, 249–252. Galatsis, P.; Millan, S. D.; Nechala, P.; Ferguson, G. J. Org. Chem. 1994, 59, 6643–6651. Racemic 12ca was prepared by the aldol reaction of 5a and 1c in the presence of catalytic mesitylcopper(I) and rac-BINAP. For details, see SI. For a leading review on the total synthesis of fostriecin and related natural products, see: Trost, B. M.; Knopf, J. D.; Brindle, C. S. Chem. Rev. 2016, 116, 15035–15088. And more references about fostriecin cited there. Li, D.; Zhao, Y.; Ye, L.; Chen, C.; Zhang, J. Synthesis 2010, 3325– 3331.


Asymmetric Synthesis of Î±,Î²-Unsaturated Î´-Lactones through Copper

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