cis-2,3-Disubstituted

Subscriber access provided by - Access paid by the | UCSB Libraries

Article

Stereocontrolled Synthesis of trans/cis-2,3-Disubstituted Cyclopropane 1,1-Diesters and Applications in the Syntheses of Furanolignans Yue Shen, Jun Chai, Gaosheng Yang, Wenlong Chen, and Zhuo Chai J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01798 • Publication Date (Web): 17 Sep 2018 Downloaded from http://pubs.acs.org on September 17, 2018

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 12 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

Stereocontrolled Synthesis of trans/cis-2,3-Disubstituted Cyclopropane 1,1-Diesters and Applications in the Syntheses of Furanolignans Yue Shen,†,‡ Jun Chai,† Gaosheng Yang,*,† Wenlong Chen† and Zhuo Chai† †

Key Laboratory of Functionalized Molecular Solids, Ministry of Education, Anhui Key Laboratory of Molecule-Based Materials (State Key Laboratory Cultivation Base), College of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, China ‡ Traditional Chinese Medicine College, Bozhou University, Bozhou, Anhui 236800, China Supporting Information Placeholder

TOC: ABSTRACT: A new Michael addition/intramolecular alkylation sequence of (Z)-3-(2-bromo-3-arylacryloyl)oxazolidin-2-ones and malonates was developed. By a simple switch of the reaction conditions including the base promoter, solvent and reaction temperature, both the cis and trans isomers of a series of oxazolidinone-containing 2,3-disubstituted cyclopropane-1,1-diesters could be obtained in good-to-excellent yields and with excellent diastereoselectivity. The utility of the cyclopropane products was demonstrated in the diastereoselective syntheses of (±)-urinaligran and a stereoisomer of (±)-virgatusin involving the AlCl3-promoted [3 + 2] annulation with veraldehyde or piperonal as the key step.

INTRODUCTION The chemistry of donor–acceptor (D–A) cyclopropanes has been a flourishing field to spawn many efficient methods for the construction of diverse useful molecular skeletons.1 In this realm, the cyclopropane 1,1-diesters, especially 2monosubstituted-1,1-diester cyclopropanes,2 have been the mostly studied type of D–A cyclopropanes. On the other hand, the synthesis and application of densely substituted D–A cyclopropanes have recently attracted considerable attentions leading to not only expanded product scope with rich structural diversity and complexity but also the discovery of some interesting novel reactivity, as examplified by recent intensive studies on 2,3-disubstituted cyclopropane 1,1-diesters.3,4 The development of efficient synthetic methods for D–A cyclopropanes has been undoubtedly of fundamental importance for this chemistry. In this regard, the Michael initiated ring closure (MIRC) strategy is a particularly useful approach to 2,3-disubstituted cyclopropane 1,1-diesters. In general, methods following such a strategy could be classified into two kinds by the standard that either the Michael acceptor or the Michael donor contains the 1,1-diester moiety. The former system typically utilizes β-substituted methylidenemalonates as Michael acceptor and various ylides including sulfur, phos-

phorous and arsonium as Michael donor.5 The latter system usually involves the addition of 2-halomalonates to α,βunsaturated aldehydes/ketone or nitroolefins.6 However, all of theses systems are restricted to the syntheses of trans-2,3disubstituted cyclopropane 1,1-diesters, and the development of methods enabling diastereoselective syntheses of cis-2,3disubstituted cyclopropane 1,1-diesters remains a significant challenge.7 Moreover, our previous studies have shown that the cis-isomers tend to bear better reactivity in relevant Lewis acid-mediated ring-opening reactions of such cyclopropanes to give products with complementary stereochemistries.3b, 4 Our group have developed a cascade Michael addition/intramolecular alkylation reaction of α-bromochalcones and diethyl malonate, which provided the first access to the thermodynamically less favored cis-isomers of diethyl 2-aroyl3-phenyl-cyclopropane-1,1-diesters (Scheme 1).8 However, such a system suffers from not only the poor diastereoselectivity and moderate yield but also a rather limited convertibility of the 2-aroyl group to other useful structures. Given this, we presumed that a judicious choice of reaction conditions (kinetic vs thermodynamic) may enable better stereocontrol over the cis/trans ratio; and replacing the aroyl group with a synthetically versatile oxazolidine-2-one group would enhance 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 2 of 12

potential of utility of the resultant D–A cyclopropanes. Herein, we report the details of this study.

3

DMAP

DMSO

25

24

0

4

pyridine

DMSO

25

24

0

Scheme 1. Syntheses of 2,3-Disubstituted-1,1-Diester Cyclopropanes via MIRC

5

DBU

DMSO

25

4

82c (19:1)

9

Cs2CO3

DMF

–35

48

91c (19:1)

10

Cs2CO3

DMF

–20

48

85c,d (>19:1)

11

Cs2CO3

DMF

–20

48

87c,e (19:1)

12

Cs2CO3

toluene

–20

40

89 (6:1)

13

Cs2CO3

THF

–20

40

93 (2.8:1)

RESULTS AND DISCUSSION Our study began with the screen of reaction conditions for the model reaction between (Z)-3-(2-bromo-3phenylacryloyl)oxazolidin-2-one 1a and diethyl malonate 2a (Table 1). First, several organic and inorganic bases were tested in the reaction (entries 1–5). In the presence of K2CO3, the desired cyclopropane products were obtained in excellent combined yield but with a poor diastereoselectivity (entry 1). While Et3N, DMAP and pyridine were found to be ineffective promoters for this reaction, the more basic DBU could effect the reaction to provide the almost diasteremerically pure trans3aa in a high yield within 4.0 h (entries 2–5). Then we turned our attention to further improve the yield and selectivity for the synthesis of the thermodynamically less stable cis-3aa. Not unexpectedly, the diastereoselectivity favorable for the formation of cis-3aa could be improved significantly by performing the reaction at a lower temperature (entry 6). Using DMF as solvent enables further lowering the reaction temperature to –20 oC and an excellent diastereoseletivity (19:1) could be achieved (entry 7). The use of a stronger base (Cs2CO3) not only greatly enhanced the reaction efficiency but also led to a slightly better diastereoselectivity (entry 8). Further lowering the reaction temperature, reducing the amount of either 2a or the base, and the use of other solvents such as toluene, THF and CH2Cl2 or performing the reaction in a solvent-free fashion all led to inferior results (entries 9–15). Notably, the oxazolidine-2-one group in 1 is crucial for the excellent diastereoselectivity favoring the cis cyclopropane product (see Scheme S1 in the Supporting Information for a direct comparison with α-bromo chalcone), while we are unable to provide a rationale for this effect at present.

14

Cs2CO3

CH2Cl2

–20

40

91 (2.2:1)

15

Cs2CO3

–

–20

40

96 (4.3:1)

a Reaction scale: 0.3 mmol. bIsolated yield of the mixture of the two cis/trans isomers. The ratio of cis:trans is determined by 1H NMR analysis of the crude reaction mixture. cIsolated yield of the pure major isomer product. d2.0 equiv of 2a was used. e1.0 equiv of Cs2CO3 was used.

Table 2. Preparation of trans-3a

entry

1 (Ar)

2

t (h)

trans-3 (yield %)b

1

1a (Ph)

2a

4

3aa (82)

2

1a (Ph)

2b

5

3ab (82)

3

1b (4-FC6H4)

2a

5

3ba (81)

4

1c (4-ClC6H4)

2a

5

3ca (81)

5

1d (3-ClC6H4)

2a

5

3da (80)

6

1e (4-BrC6H4)

2a

4

3ea (78)

7

1f (4-MeC6H4)

2a

5

3fa (81)

8

1g (4-MeOC6H4)

2a

5

3ga (81)

9

1h (3-MeOC6H4)

2a

4

3ha (73)

10

1i (3,4-(MeO)2C6H3)

2a

5

3ia (80)

11

1j (3,4,5-(MeO)3C6H2) 1k (3,4-(OCH2O)2C6H3)

2a

5

3ja (79)

2a

5

3ka (78)

12 a

Table 1. Screen of Reaction Conditionsa

entry

base

solvent

T (oC)

1 2

t (h)

yield (cis:trans)b

K2CO3

DMSO

Et3N

DMSO

25

4

95% (1.7:1)

25

24

0

Reaction scale: 0.5 mmol. bIsolated yield of the pure product.

With the optimum reaction conditions in hand (Table 1, entry 5), we then probed the substrate scope with regard to the synthesis of trans-3aa (Table 2). Diethyl or dimethyl malonate are almost equally effective in the reaction (entries 1 and 2). A series of 1 bearing different substitutents on the benzene ring of the Ar group were examined in the reaction, and generally good yields of the corresponding products were obtained. Neither the electronic nature nor the positions of the substituents on the benzene ring showed consistent trend of influence on the reaction (entries 3–12). Notably, substrates 1i–1k bearing multiple electron-donating groups are also well-tolerated in this reaction. Also of note is that in all of the cases examined,


Page 3 of 12 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 trans cyclopropane products were isolated in almost diastereomerically pure form. Subsequently, the reaction scope with regard to the formation of cis-3aa was investigated (Table 3). Under the optimized reaction conditions (Table 1, entry 8), the corresponding cyclopropane products were generally obtained in excellent yields and with excellent diastereoselectivity. Similar to the formation of corresponding trans cyclopropanes, no obvious substituent effect related to the electronic nature and/or positions of the substituents on the benzene ring of the Ar group was observed, except that the presence of an electrondonating group at the para position seemed to be favorable in terms of diastereoselectivity (entries 3–8). Substrates 1i–1k bearing multiple electrondonating groups also participated well in the reaction to provide the corresponding cis cyclopropanes in excellent yields and diastereoselectivity (entries 10– 13). The reaction efficiency was also inert to a change in the ester group (R) of the malonates 2 from an ethyl to a methyl group (entries 2 and 13). The relative configuration of the product cis-3ha was confirmed by X-ray crystallographic analysis (see Figure S1 in the Supporting Information).9 Unfortunately, our attempts to realize enantioselective syntheses of cis-3 by introducing chiral oxazolidinone (Evans auxiliaries) into 1 led to a diasetereomeric mixture of very poor dr value (around 1:1, see Scheme S2 in the Supporting Information).

ospecific [3 + 2] annulation of a chiral trans-2,3-disubsituted1,1-diester cyclopropane with piperonal as lynchpin reaction in a five-step synthesis of (+)-virgatusin.3a Having established an efficient diastereoselective way to the oxazolidinonecontaining D–A cyclopropanes cis-3, we then became interested in exploring their reactivity for the construction of such densely substituted 2,5-diaryltetrahydrofuran structures. First, we screened the conditions for the [3 + 2] annulation between the cyclopropane cis-3kb and veratral (Table 4, entries 1–10). Under the promotion of 1.0 equiv of AlCl3 in CH2Cl2, the desired product 4a could be obtained in excellent yields as a single diastereomer in the presence of 10.0 equiv of the aldehyde (entry 2). In general, the reactivity of this oxalidinonecontaining cis-2,3-disubstituted cyclopropane in such a reaction seems to be inferior to its counterparts containing an aroyl group used in our previous studies, in which typically only 0.5 equiv. of AlCl3 and 5.0 equiv of the aldehyde were required to give excellent yields.4 Varying the reaction solvent failed to improve the result. Notably, the use of a catalytic amount of Lewis acids including Sc(OTf)3 and Al(OTf)3 led to no reaction. Piperonal was more reactive under the optimum reactions to deliver the desired product 4b in 92% yield as a single diastereomer within 2 hours (entry 11). Table 4. Screen of Reaction Conditions for the [3 + 2] Annulation of cis-3kb With Veratral/Piperonala

Table 3. Preparation of cis-3a

entry

1 (Ar)

2

drb

cis-3 (yield %)c

entry

Lewis (equiv)

1

1a (Ph)

2a

>19:1

3aa (92)

1

2

1a (Ph)

2b

>19:1

3ab (93)

3

1b (4-FC6H4)

2a

15.7:1

acid

solvent

t (h)

4a/4b (yield %)b

AlCl3 (1.5)

CH2Cl2

2

4a (91)

2

AlCl3 (1.0)

CH2Cl2

4

4a (91)

3ba (87)

3

AlCl3 (1.0)

CH2Cl2

24

4a (80)

AlCl3 (0.5)

CH2Cl2

80

4a (71)

AlCl3 (1.0)

CHCl3

9

4a (89)

4

1c (4-ClC6H4)

2a

15.7:1

3ca (88)

4

5

1d (3-ClC6H4)

2a

19:1

3da (90)

5

3ea (96)

6

AlCl3 (1.0)

CCl4

24

4a (87)

AlCl3 (1.0)

DCE

4.5

4a (91)

6

1e (4-BrC6H4)

2a

15.7:1

7

1f (4-MeC6H4)

2a

19:1

3fa (91)

7

8

1g (4-MeOC6H4)

2a

>19:1

3ga (91)

8

AlCl3 (1.0)

toluene

48

4a (0)

3ha (87)

9

Sc(OTf)3 (0.1)

CH2Cl2

48

4a (0)

3ia (93)

10

Al(OTf)3 (0.1)

CH2Cl2

3ja (90)

11

48 2

4b (92)

9 10 11

1h (3-MeOC6H4)

2a

1i (3,4-(MeO)2C6H3)

2a 2a

15.7:1 >19:1 19:1

12

1j (3,4,5-(MeO)3C6H2) 1k (3,4-(OCH2O)2C6H3)

2a

19:1

3ka (90)

13

1k (3,4-(OCH2O)2C6H3)

2b

19:1

3kb (90)

a

Reaction scale: 0.5 mmol. bDetermined by 1H NMR analysis of the crude reaction mixture. cIsolated yield of the pure product.

(–)-Virgatusin and (+)-urinaligran belong to a large family of furanolignans bearing interesting biological and pharmaceutical activities such as antioxidant, antimicrobial, antiinflammatory and anticancer activities,10 and considerable attention has been paid to their syntheses.3a,11 In particular, Johnson and co-workers have succeeded in utilizing the stere-

a

AlCl3 (1.0)

CH2Cl2

4a (0)

b

Reaction scale: 0.5 mmol. Isolated yield of the pure product.

Subsequently, we embarked on the elaboration of the products 4 to (±)-urinaligran and a stereoisomer of (±)-virgatusin (Scheme 2). Reduction of 4 with LiBH4 was followed by spontaneous intramolecular lactonization to provide 5 in good yields. Subjecting 5 to the conditions of the Krapcho decarboxylation reaction led to the selective loss of the sterically less encumbered lactone carbonyl to give 6, which were reduced to the diols 7 in high yields. Methylation of 7 with NaH and CH3I furnished 8a, a stereoisomer of (±)-virgatusin, and (±)-urinaligran 8b in excellent yields, respectively.



Scheme 2. Syntheses of (±)-Urinaligran and a Stereoisomer of (±)-Virgatusin O O N

O

O

CO2Me CO2Me O

O 4a: R = Me 4b: R = -CH2-

O

O

OR O

O O

OMe O

O O

(1) NaH (10.0 eq) THF, rt, 0.5 h (2) CH3I (10.0 eq) OR THF, rt, 1 h

OR 7a: R = Me (91%) 7b: R = -CH2- (92%)

MeO

OMe

OH O

OR 6a: R = Me (69%) 6b: R = -CH2- (68%) MeO

OR 5a: R = Me (71%) 5b: R = -CH2- (71%) HO

LiAlH4 (4.0 eq) THF, rt

OMe

O 8a (92%) OMe a stereoisomer of ( )-virgatusin

O

O O

to cis-2,3-disubstituted cyclopropane-1,1-diesters in high yields and excellent stereoselectivity. The reactivity of the cis D–A cyclopropane products in Lewis acid-promoted [3 + 2] annulation with aryl aldehydes was probed, which led to concise diastereoselective syntheses of two furanolignan compounds.

OR

OR

O

reflux, 24 h

O

CO2Me

HO

NaCl (8.0 eq) DMSO / H2O

O

OR O

O CO2Me

LiBH4 (1.0 eq) THF, rt, 8 h

Page 4 of 12

O 8b (93%) ( )-urinaligran

Very recently, we have observed that γ-butyrolactone fused cyclopropanes could be more reactive than their parent 2,3disubstituted cyclopropanes in Lewis acid-mediated annulation with carbonyls and heterocumulenes.12 For example, the cyclopropane 9, which could be prepared via a cascade process involving organocatalytic Michael addition-initiated cyclopropanation/reduction/lactonization between cinnamonaldehyde and 2-bromomalonate, is highly efficient in the [3 + 2] annulation with benzaldehyde to provide the densely substituted γ-butyrolactone fused tetrahydrofuran 10 in excellent yield and diastereoselectivity (Scheme 3). Given this, we then reasoned that the use of corresponding γ-butyrolactone fused cyclopropanes, which could be readily available from the product cis-3, might lead to an alternative efficient catalytic way to the useful γ-butyrolactone fused tetrahydrofuran products such as 5a and 5b. Using the simple cis-3ab as an example, we first realized the transformation of cis-3ab to 11 with a moderate yield via reduction with LiBH4. Surprisingly, as compared to the cyclopropane 9, the cyclopropane 11 demonstrated much poorer reactivity in the annulation with benzaldehyde under similar reaction conditions: the desired product 5c was only obtained in 21% yield even after a prolonged reaction time at a higher reaction temperature while most starting materials remained intact. Scheme 3. Conversion of cis-3ab to γ-Butyrolactone Fused Cyclopropane 11 and Reactivity Comparison

CONCLUSION In summary, we have developed a MIRC strategy-based method that enables access to both the cis and trans isomers of oxazolidinone-containing 2,3-disubstituted cyclopropane-1,1diesters in a controllable and highly diastereoselective way. This work represents the first example enabling direct access

EXPERIMENTAL SECTION General Information. All reactions were carried out with flame-dried Schlenk-type glassware using a Schlenk line. All the 3-cinnamoyloxazolidin-2-ones 12a–k used were synthesized following a literature procedure method as described in the Supporting Information (SI). All the other reagents were purchased from commercial suppliers and purified by standard techniques. Flash column chromatography was performed using silica gel (200–400 mesh). For thin-layer chromatography (TLC), silica gel plates (HSGF 254) were used and compounds were visualized by irradiation with UV light. 1H NMR (500/300 MHz) and 13C NMR (125/75 MHz) spectra were recorded in CDCl3. All chemical shifts (δ) are given in ppm relative to TMS (δ = 0 ppm) as internal standard. Data are reported as follows: chemical shift, multiplicity, coupling constants and integration. Melting points were uncorrected. IR spectra were reported in frequency of absorption (cm-1). High resolution mass spectral (HRMS) data were obtained with an ionization mode of APCI or ESI and a TOF analyzer. General Procedure for the Syntheses of (Z)-3-(2-Bromo3-arylacryloyl)oxazolidin-2-one (1). A suspension of 3cinnamoyloxazolidin-2-ones 12a–k (10 mmol) in CCl4 (20 mL) was stirred until a homogeneous solution was formed. Bromine (11 mmol, 1.758 g) was added dropwise to the above solution at 0 ºC (at –30 ºC for 12j) and the resulting mixture was slowly warmed up to room temperature and stirred for 2 h. The solution was then cooled down to 0 ºC, filtered and washed with ice-cold CCl4 (3 × 20 mL). The crude dibromide thus obtained was used in the next reaction without further purification. To a solution of the dibromide in toluene (40 mL) was added DBU (12 mmol) at room temperature. The reaction mixture was stirred at rt until full conversion of the dibromide was achieved (monitored by TLC). Upon completion, the reaction mixture was diluted with 20 mL of H2O and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (2 × 50 mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to yield a crude product. The crude product was purified by column chromatography to provide the desired products 1a–k. (Z)-3-(2-Bromo-3-phenylacryloyl)oxazolidin-2-one (1a). Purified by column chromatography (petroleum ether/ethyl acetate = 15/1) to afford a white solid in 53% yield (1.6 g, 5.3 mmol). Mp: 173–174 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.80–7.72 (m, 2H), 7.46–7.36 (m, 4H), 4.51 (t, J = 7.8 Hz, 2H), 4.12 (t, J = 7.8 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ 165.8, 152.0, 136.7, 133.6, 129.8, 128.4, 111.9, 62.4, 43.4. HRMS (APCI-TOF, m/z) calcd for C12H11BrNO3 [M + H]+: 295.9917, found: 295.9914. (Z)-3-(2-Bromo-3-(4-fluorophenyl)acryloyl)oxazolidin-2one (1b). Purified by column chromatography (petroleum ether/ethyl acetate = 12/1) to afford a white solid in 39% yield (1.2 g, 3.9 mmol). Mp: 154–155 ºC. 1H NMR (CDCl3, 500


Page 5 of 12 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


MHz): δ 7.82–7.73 (m, 2H), 7.35 (s, 1H), 7.16–7.06 (m, 2H), 4.51 (t, J = 7.9 Hz, 2H), 4.12 (t, J = 7.9 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ 165.6, 163.3 (d, 1JC–F = 251.2 Hz), 152.1, 135.6, 131.8, 129.7, 115.6 (d, 2JC–F = 21.8 Hz), 111.7, 62.4, 43.3. 19F NMR (CDCl3, 470 MHz): δ 140.7. HRMS (APCITOF, m/z) calcd for C12H10BrFNO3 [M + H]+: 313.9823, found: 313.9821.

ether/dichloromethane = 15/1) to afford a white solid in 53% yield (1.7 g, 5.3 mmol). Mp: 134–135 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.41–7.27 (m, 4H), 6.99–6.90 (m, 1H), 4.55–4.46 (m, 2H), 4.16–4.08 (m, 2H), 3.83 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 165.7, 159.4, 152.1, 136.6, 134.7, 129.4, 122.5, 115.9, 114.5, 112.0, 62.4, 55.4, 43.3. HRMS (APCI-TOF, m/z) calcd for C13H13BrNO4 [M + H]+: 326.0022, found: 326.0016.

(Z)-3-(2-Bromo-3-(4-chlorophenyl)acryloyl)oxazolidin-2one (1c). Purified by column chromatography (petroleum ether/dichloromethane = 12/1) to afford a white solid in 52% yield (1.7 g, 5.2 mmol). Mp: 125–126 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.70 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 4.56–4.47 (m, 2H), 4.16–4.08 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ 165.5, 152.0, 135.7, 135.3, 131.0, 128.7, 112.6, 62.5, 43.3. HRMS (APCI-TOF, m/z) calcd for C12H10BrClNO3 [M + H]+: 329.9527, found: 329.9525.

(Z)-3-(2-Bromo-3-(3,4dimethoxyphenyl)acryloyl)oxazolidin-2-one (1i). Purified by column chromatography (petroleum ether/dichloromethane = 10/1) to afford a white solid in 51% yield (1.8 g, 5.1 mmol). Mp: 127–128 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.53 (s, 1H), 7.39 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.50 (t, J = 7.8 Hz, 2H), 4.11 (t, J = 7.8 Hz, 2H), 3.92 (s, 6H). 13 C NMR (CDCl3, 125 MHz): δ 166.0, 152.2, 150.7, 148.6, 137.4, 126.2, 124.6, 112.4, 110.8, 109.5, 62.4, 56.0, 43.6. HRMS (APCI-TOF, m/z) calcd for C14H15BrNO5 [M + H]+: 356.0128, found: 356.0129.

(Z)-3-(2-Bromo-3-(3-chlorophenyl)acryloyl)oxazolidin-2one (1d). Purified by column chromatography (petroleum ether/dichloromethane = 12/1) to afford a white solid in 53% yield (1.8 g, 5.3 mmol). Mp: 124–125 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.75 (s, 1H), 7.63–7.57 (m, 1H), 7.40–7.32 (m, 2H), 7.29 (s, 1H), 4.52 (t, J = 7.9 Hz, 2H), 4.12 (t, J = 7.9 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ 165.4, 152.0, 135.3, 134.8, 134.4, 129.70, 129.66, 129.4, 127.8, 113.4, 62.5, 43.2. HRMS (APCI-TOF, m/z) calcd for C12H10BrClNO3 [M + H]+: 329.9527, found: 329.9524. (Z)-3-(2-Bromo-3-(4-bromophenyl)acryloyl)oxazolidin-2one (1e). Purified by column chromatography (petroleum ether/dichloromethane = 10/1) to afford a white solid in 51% yield (1.9 g, 5.1 mmol). Mp: 141–142 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.62 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.30 (s, 1H), 4.51 (t, J = 7.9 Hz, 2H), 4.11 (t, J = 7.9 Hz, 2H). 13 C NMR (CDCl3, 125 MHz): δ 165.5, 152.0, 135.3, 132.5, 131.7, 131.1, 124.0, 112.7, 62.4, 43.3. HRMS (APCI-TOF, m/z) calcd for C12H10Br2NO3 [M + H]+: 373.9022, found: 373.9019. (Z)-3-(2-Bromo-3-(p-tolyl)acryloyl)oxazolidin-2-one (1f). Purified by column chromatography (petroleum ether/dichloromethane = 15/1) to afford a white solid in 50% yield (1.6 g, 5.0 mmol). Mp: 110–111 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.69 (d, J = 7.9 Hz, 2H), 7.38 (s, 1H), 7.22 (d, J = 7.9 Hz, 2H), 4.49 (t, J = 7.8 Hz, 2H), 4.11 (t, J = 7.8 Hz, 2H), 2.37 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 165.9, 152.1, 140.2, 137.1, 130.7, 129.9, 129.2, 110.8, 62.4, 43.4, 21.5. HRMS (APCI-TOF, m/z) calcd for C13H13BrNO3 [M + H]+: 310.0073, found: 310.0075. (Z)-3-(2-Bromo-3-(4-methoxyphenyl)acryloyl)oxazolidin-2one (1g). Purified by column chromatography (petroleum ether/dichloromethane = 12/1) to afford a white solid in 50% yield (1.6 g, 5.0 mmol). Mp: 134–135 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.80 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 6.93 (d, J = 8.0 Hz, 2H), 4.49 (t, J = 8.0 Hz, 2H), 4.10 (t, J = 8.0 Hz, 2H), 3.84 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 166.1, 161.0, 152.2, 137.3, 131.9, 126.0, 113.9, 109.4, 62.4, 55.4, 43.6. HRMS (APCI-TOF, m/z) calcd for C13H13BrNO4 [M + H]+: 326.0022, found: 326.0023. (Z)-3-(2-Bromo-3-(3-methoxyphenyl)acryloyl)oxazolidin-2one (1h). Purified by column chromatography (petroleum

(Z)-3-(2-Bromo-3-(3,4,5trimethoxyphenyl)acryloyl)oxazolidin-2-one (1j). Purified by column chromatography (petroleum ether/dichloromethane = 8/1) to afford a white solid in 50% yield (1.9 g, 5.0 mmol). Mp: 123–124 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.17 (s, 1H), 6.48 (s, 2H), 4.44–4.31 (m, 2H), 4.06–3.95 (m, 2H), 3.84 (s, 3H), 3.81 (s, 6H). 13C NMR (CDCl3, 125 MHz): δ 165.8, 153.0, 152.2, 139.6, 137.0, 128.7, 110.9, 107.4, 62.4, 61.0, 56.2, 43.5. HRMS (APCI-TOF, m/z) calcd for C15H17BrNO6 [M + H]+: 386.0234, found: 386.0236. (Z)-3-(3-(benzo[d][1,3]dioxol-5-yl)-2bromoacryloyl)oxazolidin-2-one (1k). Purified by column chromatography (petroleum ether/dichloromethane = 10/1) to afford a white solid in 52% yield (1.8 g, 5.2 mmol). Mp: 139– 140 ºC. 1H NMR (CDCl3, 500 MHz): δ 7.51 (d, J = 1.4 Hz, 1H), 7.33 (s, 1H), 7.20 (dd, J = 8.1, 1.2 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.02 (s, 2H), 4.49 (t, J = 7.8 Hz, 2H), 4.10 (t, J = 7.8 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ 166.0, 152.1, 149.1, 147.7, 137.0, 127.5, 126.0, 109.8, 109.2, 108.4, 101.6, 62.4, 43.5. HRMS (APCI-TOF, m/z) calcd for C13H11BrNO5 [M + H]+: 339.9815, found: 339.9813. General Procedure for the Syntheses of Diethyl trans-2(2-oxooxazolidine-3-carbonyl)-3-arylcyclopropane-1,1dicarboxylate (trans-3). A solution of (Z)-3-(2-bromo-3arylacryloyl)oxazolidin-2-ones 1a−k (0.5 mmol), malonate 2a−b (1.5 mmol) and DBU (0.75 mmol) in DMSO (5 mL) was stirred at 25 ºC until the reaction was finished (monitored by TLC). Upon completion, the reaction mixture was diluted with 5 mL of H2O and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed twice with water, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude product, which was analyzed by 1H NMR to determine the diastereoselectivity (cis:trans). The crude product was purified by column chromatography to provide the trans-3. Diethyl trans-2-(2-oxooxazolidine-3-carbonyl)-3phenylcyclopro pane-1,1-dicarboxylate (trans-3aa). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a colorless oil in 82% yield (154 mg). 1H NMR (500 MHz, CDCl3): δ 7.37 (d, J = 7.2 Hz, 2H), 7.32–7.20 (m,



3H), 4.70 (d, J = 7.5 Hz, 1H), 4.51–4.42 (m, 2H), 4.35–4.25 (m, 2H), 4.10–4.02 (m, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.69 (d, J = 7.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.6, 166.3, 165.2, 153.5, 133.0, 128.9, 128.3, 127.7, 62.2, 62.0, 61.8, 45.4, 42.9, 37.2, 30.4, 14.1, 13.7. HRMS (ESI-TOF, m/z) calcd for C19H22NO7 [M + H]+: 376.1391, found: 376.1392 Dimethyl trans-2-(2-oxooxazolidine-3-carbonyl)-3phenylcyclopro pane-1,1-dicarboxylate (trans-3ab). Purified by column chromatography (petroleum ether/ethyl acetate = 11/1) to afford a colorless oil in 82% yield (142 mg). 1H NMR (500 MHz, CDCl3): δ 7.37 (d, J = 7.4 Hz, 2H), 7.33–7.22 (m, 3H), 4.71 (d, J = 7.5 Hz, 1H), 4.47 (t, J = 8.0 Hz, 2H), 4.06 (t, J = 8.0 Hz, 2H), 3.84 (s, 3H), 3.70 (d, J = 7.5 Hz, 1H), 3.45 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 168.6, 166.9, 165.6, 153.5, 132.8, 128.8, 128.4, 127.8, 62.2, 53.2, 52.8, 45.2, 42.9, 37.5, 30.5. HRMS (ESI-TOF, m/z) calcd for C17H18NO7 [M + H]+: 348.1078, found: 348.1077. Diethyl trans-2-(4-fluorophenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (trans-3ba). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a white solid in 81% yield (159 mg). Mp: 122–123 ºC. 1H NMR (500 MHz, CDCl3): δ 7.41–7.33 (m, 2H), 7.03–6.95 (m, 2H), 4.65 (d, J = 7.5 Hz, 1H), 4.51–4.44 (m, 2H), 4.34–4.24 (m, 2H), 4.10–4.03 (m, 2H), 3.99–3.90 (m, 2H), 3.64 (d, J = 7.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.3, 166.2, 165.1, 162.3 (d, 1JC–F = 246.3 Hz), 153.6, 130.6, 128.8, 115.2 (d, 2JC–F = 21.7 Hz), 62.2, 62.1, 62.0, 45.3, 42.9, 36.4, 30.6, 14.1, 13.8. 19F NMR (470 MHz, CDCl3): δ –115.0. HRMS (ESI-TOF, m/z) calcd for C19H21FNO7 [M + H]+: 394.1297, found: 394.1300. Diethyl trans-2-(4-chlorophenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (trans-3ca). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a colorless oil in 81% yield (166 mg). 1H NMR (300 MHz, CDCl3): δ 7.37–7.22 (m, 4H), 4.64 (d, J = 7.5 Hz, 1H), 4.52–4.42 (m, 2H), 4.36–4.22 (m, 2H), 4.11–4.01 (m, 2H), 4.01–3.90 (m, 2H), 3.63 (d, J = 7.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 168.2, 166.1, 165.0, 153.5, 133.6, 131.5, 130.3, 128.4, 62.2, 62.1, 62.0, 45.2, 42.8, 36.4, 30.5, 14.0, 13.8. HRMS (ESI-TOF, m/z) calcd for C19H21ClNO7 [M + H]+: 410.1001, found : 410.1005. Diethyl trans-2-(3-chlorophenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (trans-3da). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a colorless oil in 80% yield (164 mg). 1H NMR (500 MHz, CDCl3): δ 7.38 (s, 1H), 7.31–7.21 (m, 3H), 4.64 (d, J = 7.5 Hz, 1H), 4.48 (t, J = 8.1 Hz, 2H), 4.35–4.24 (m, 2H), 4.11–4.01 (m, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.65 (d, J = 7.5 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.2, 166.0, 165.0, 153.5, 135.1, 134.1, 129.6, 129.2, 128.0, 127.2, 62.3, 62.2, 62.1, 45.2, 42.8, 36.3, 30.5, 14.1, 13.8. HRMS (ESI-TOF, m/z) calcd for C19H21ClNO7 [M + H]+: 410.1001, found: 410.1002. Diethyl trans-2-(4-bromophenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (trans-3ea). Puri-

Page 6 of 12

fied by column chromatography (petroleum ether/ethyl acetate = 9/1) to afford a colorless oil in 78% yield (177 mg). 1H NMR (500 MHz, CDCl3): δ 7.42 (d, J = 8.4 Hz, 2H), 7.31– 7.22 (m, 2H), 4.64 (d, J = 7.5 Hz, 1H), 4.47 (t, J = 8.0 Hz, 2H), 4.35–4.25 (m, 2H), 4.10–4.02 (m, 2H), 4.00–3.91 (m, 2H), 3.61 (d, J = 7.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.2, 166.1, 165.0, 153.5, 132.1, 131.4, 130.7, 121.8, 62.3, 62.13, 62.06, 45.2, 42.9, 36.4, 30.5, 14.1, 13.8. HRMS (ESI-TOF, m/z) calcd for C19H21BrNO7 [M + H]+: 454.0496, found: 454.0498. Diethyl trans-2-(2-oxooxazolidine-3-carbonyl)-3-(ptolyl)cyclopro pane-1,1-dicarboxylate (trans-3fa). Purified by column chromatography (petroleum ether/ethyl acetate = 11/1) to afford a colorless oil in 81% yield (158 mg). 1H NMR (300 MHz, CDCl3): δ 7.30–7.22 (m, 2H), 7.09 (d, J = 7.8 Hz, 2H), 4.66 (d, J = 7.5 Hz, 1H), 4.52–4.41 (m, 2H), 4.34–4.24 (m, 2H), 4.10–4.02 (m, 2H), 3.99–3.88 (m, 2H), 3.65 (d, J = 7.5 Hz, 1H), 2.30 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 168.6, 166.4, 165.2, 153.5, 137.3, 129.8, 128.9, 128.7, 62.2, 62.0, 61.8, 45.4, 42.8, 37.0, 30.4, 21.1, 14.0, 13.7. HRMS (ESI-TOF, m/z) calcd for C20H24NO7 [M + H]+: 390.1547, found: 390.1548. Diethyl trans-2-(4-methoxyphenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (trans-3ga). Purified by column chromatography (petroleum ether/ethyl acetate = 9/1) to afford a colorless oil in 81% yield (164 mg). 1H NMR (500 MHz, CDCl3): δ 7.28 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.63 (d, J = 7.4 Hz, 1H), 4.45 (t, J = 8.0 Hz, 2H), 4.33–4.21 (m, 2H), 4.08–3.99 (m, 2H), 3.98–3.88 (m, 2H), 3.76 (s, 3H), 3.61 (d, J = 7.4 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.6, 166.4, 165.2, 159.0, 153.5, 130.0, 124.8, 113.6, 62.2, 61.9, 61.8, 55.2, 45.4, 42.8, 36.7, 30.5, 14.0, 13.8. HRMS (ESI-TOF, m/z) calcd for C20H24NO8 [M + H]+: 406.1496, found: 406.1497. Diethyl trans-2-(3-methoxyphenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (trans-3ha). Purified by column chromatography (petroleum ether/ethyl acetate = 9/1) to afford a colorless oil in 73% yield (148 mg). 1H NMR (500 MHz, CDCl3): δ 7.19 (t, J = 7.8 Hz, 1H), 7.01–6.92 (m, 2H), 6.83–6.76 (m, 1H), 4.67 (d, J = 7.5 Hz, 1H), 4.50– 4.43 (m, 2H), 4.34–4.25 (m, 2H), 4.10–4.01 (m, 2H), 3.99– 3.90 (m, 2H), 3.79 (s, 3H), 3.67 (d, J = 7.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.5, 166.3, 165.2, 159.5, 153.5, 134.5, 129.3, 121.2, 114.2, 113.8, 62.2, 62.0, 61.8, 55.3, 45.3, 42.9, 37.2, 30.5, 14.0, 13.7. HRMS (ESI-TOF, m/z) calcd for C20H24NO8 [M + H]+: 406.1496, found: 406.1497. Diethyl trans-2-(3,4-dimethoxyphenyl)-3-(2-oxooxazolidine3-carbonyl)cyclopropane-1,1-dicarboxylate (trans-3ia). Purified by column chromatography (petroleum ether/ethyl acetate = 8/1) to afford a colorless oil in 80% yield (174 mg). 1H NMR (300 MHz, CDCl3): δ 6.98–6.87 (m, 2H), 6.81–6.72 (m, 1H), 4.62 (d, J = 7.4 Hz, 1H), 4.50–4.40 (m, 2H), 4.34–4.21 (m, 2H), 4.08–3.99 (m, 2H), 3.99–3.89 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.60 (d, J = 7.4 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 168.5, 166.4, 165.2, 153.6, 148.6, 148.4, 125.3, 121.1, 112.0, 110.7, 62.2, 62.0, 61.8, 55.9, 55.8, 45.3, 42.8, 37.0, 30.6, 14.0, 13.8.


Page 7 of 12 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


HRMS (ESI-TOF, m/z) calcd for C21H26NO9 [M + H]+: 436.1602, found: 436.1605. Diethyl trans-2-(2-oxooxazolidine-3-carbonyl)-3-(3,4,5trimethoxyphenyl)cyclopropane-1,1-dicarboxylate (trans-3ja). Purified by column chromatography (petroleum ether/ethyl acetate = 6/1) to afford a yellow solid in 79% yield (184 mg). Mp: 125–126 ºC. 1H NMR (500 MHz, CDCl3): δ 6.65 (s, 2H), 4.62 (d, J = 7.4 Hz, 1H), 4.52–4.43 (m, 2H), 4.37–4.24 (m, 2H), 4.11–4.02 (m, 2H), 4.02–3.92 (m, 2H), 3.85 (s, 6H), 3.81 (s, 3H), 3.62 (d, J = 7.4 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.4, 166.4, 165.2, 153.6, 153.1, 137.6, 128.6, 106.1, 62.3, 62.1, 61.9, 60.8, 56.2, 45.3, 42.9, 37.6, 30.8, 14.1, 13.8. HRMS (ESI-TOF, m/z) calcd for C22H28NO10 [M + H]+: 466.1708, found: 466.1709. Diethyl trans-2-(benzo[d][1,3]dioxol-5-yl)-3-(2oxooxazolidine-3-carbonyl)cyclopropane-1,1-dicarboxylate (trans-3ka). Purified by column chromatography (petroleum ether/ethyl acetate = 7/1) to afford a colorless oil in 78% yield (164 mg). 1H NMR (500 MHz, CDCl3): δ 6.90–6.82 (m, 2H), 6.73 (d, J = 8.6 Hz, 1H), 5.93 (s, 2H), 4.60 (d, J = 7.4 Hz, 1H), 4.51–4.42 (m, 2H), 4.34–4.22 (m, 2H), 4.10–3.94 (m, 4H), 3.60 (d, J = 7.4 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.5, 166.3, 165.2, 153.5, 147.6, 147.2, 126.7, 122.4, 109.4, 108.1, 101.1, 62.2, 62.0, 61.9, 45.4, 42.9, 37.0, 30.8, 14.1, 13.9. HRMS (ESI-TOF, m/z) calcd for C20H22NO9 [M + H]+: 420.1289, found: 420.1288. General Procedure for the Syntheses of Diethyl cis-2-(2oxooxazolidine-3-carbonyl)-3-arylcyclopropane-1,1dicarboxylate (cis-3). Under an argon atmosphere, to a stirred solution of (Z)-3-(2-bromo-3-arylacryloyl)oxazolidin-2-ones 1a−k (0.5 mmol) and malonate 2a−b (1.5 mmol) in anhydrous DMF (5 mL) was added Cs2CO3 (0.75 mmol) at –20 ºC. Stirring was continued until the reaction was finished (monitored by TLC). Upon completion, the reaction mixture was diluted with 5 mL of H2O and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed twice with water, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude product, which was analyzed by 1H NMR to determine the diastereoselectivity (cis:trans). The crude product was purified by column chromatography to provide the cis-3. Diethyl cis-2-(2-oxooxazolidine-3-carbonyl)-3phenylcyclopropane -1,1-dicarboxylate (cis-3aa). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a colorless oil in 92% yield (173 mg). 1H NMR (500 MHz, CDCl3): δ 7.37 (d, J = 7.1 Hz, 2H), 7.30–7.20 (m, 3H), 4.43 (t, J = 8.0 Hz, 2H), 4.35–4.26 (m, 2H), 4.18–4.09 (m, 2H), 4.06–3.95 (m, 2H), 3.79 (d, J = 9.8 Hz, 1H), 3.45 (d, J = 9.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 169.0, 166.3, 165.4, 153.5, 131.8, 130.3, 127.7, 127.3, 62.6, 62.2, 61.6, 42.7, 41.3, 36.6, 31.9, 14.0, 13.8. HRMS (ESI-TOF, m/z) calcd for C19H22NO7 [M + H]+: 376.1391, found: 376.1394. Dimethyl cis-2-(2-oxooxazolidine-3-carbonyl)-3phenylcyclopro pane-1,1-dicarboxylate (cis-3ab). Purified by column chromatography (petroleum ether/ethyl acetate = 11/1)

to afford a colorless oil in 93% yield (162 mg). 1H NMR (500 MHz, CDCl3): δ 7.35 (d, J = 7.1 Hz, 2H), 7.32–7.20 (m, 3H), 4.48–4.38 (m, 2H), 4.08–3.94 (m, 2H), 3.85 (s, 3H), 3.82 (d, J = 9.9 Hz, 1H), 3.66 (s, 3H), 3.47 (d, J = 9.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 169.4, 166.2, 165.9, 153.6, 131.6, 130.1, 127.8, 127.4, 62.2, 53.5, 52.6, 42.7, 41.0, 36.9, 32.1. HRMS (ESI-TOF, m/z) calcd for C17H18NO7 [M + H]+: 348.1078, found: 348.1078. Diethyl cis-2-(4-fluorophenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (cis-3ba). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a colorless oil in 87% yield (171 mg). 1H NMR (500 MHz, CDCl3): δ 7.42–7.32 (m, 2H), 7.01–6.90 (m, 2H), 4.43 (t, J = 8.0 Hz, 2H), 4.34–4.23 (m, 2H), 4.18–4.08 (m, 2H), 4.06–3.94 (m, 2H), 3.77 (d, J = 9.8 Hz, 1H), 3.40 (d, J = 9.7 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.8, 165.2, 163.1, 162.1 (d, 1JC– 2 F = 246.4 Hz), 153.5, 132.1, 127.4, 114.6 (d, JC–F = 21.4 Hz), 62.6, 62.2, 61.7, 42.7, 41.3, 35.8, 31.8, 14.0, 13.8. 19F NMR (470 MHz, CDCl3): δ –115.0. HRMS (ESI-TOF, m/z) calcd for C19H21FNO7 [M + H]+: 394.1297, found: 394.1299. Diethyl cis-2-(4-chlorophenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (cis-3ca). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a white solid in 88% yield (180 mg). Mp: 112– 113 ºC. 1H NMR (500 MHz, CDCl3): δ 7.32 (d, J = 8.3 Hz, 2H), 7.25–7.19 (m, 2H), 4.43 (t, J = 8.1 Hz, 2H), 4.34–4.24 (m, 2H), 4.20–4.07 (m, 2H), 4.05–3.93 (m, 2H), 3.79 (d, J = 9.8 Hz, 1H), 3.39 (d, J = 9.8 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.7, 166.3, 165.2, 153.5, 133.3, 131.7, 130.3, 127.8, 62.7, 62.2, 61.7, 42.7, 41.3, 35.8, 31.8, 14.0, 13.8. HRMS (ESI-TOF, m/z) calcd for C19H21ClNO7 [M + H]+: 410.1001, found: 410.1004. Diethyl cis-2-(3-chlorophenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (cis-3da). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a colorless oil in 90% yield (184 mg). 1H NMR (500 MHz, CDCl3): δ 7.42 (s, 1H), 7.33–7.27 (m, 1H), 7.25– 7.16 (m, 2H), 4.44 (t, J = 8.0 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.22–4.11 (m, 2H), 4.08–3.94 (m, 2H), 3.79 (d, J = 9.8 Hz, 1H), 3.42 (d, J = 9.7 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.6, 166.2, 165.1, 153.5, 133.8, 133.5, 130.4, 128.8, 128.7, 127.5, 62.7, 62.2, 61.8, 42.7, 41.3, 35.7, 31.7, 14.0, 13.8. HRMS (ESI-TOF, m/z) calcd for C19H21ClNO7 [M + H]+: 410.1001, found: 410.1002. Diethyl cis-2-(4-bromophenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (cis-3ea). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a white solid in 86% yield (195 mg). Mp: 109– 110 ºC. 1H NMR (500 MHz, CDCl3): δ 7.39 (d, J = 8.5 Hz, 2H), 7.31–7.24 (m, 2H), 4.44 (t, J = 8.1 Hz, 2H), 4.35–4.24 (m, 2H), 4.19–4.09 (m, 2H), 4.06–3.94 (m, 2H), 3.80 (d, J = 9.7 Hz, 1H), 3.38 (d, J = 9.7 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.7, 166.2, 165.2, 153.5, 132.1, 130.8, 121.6, 62.7, 62.2, 61.8, 42.7, 41.3, 35.8, 31.7, 14.0, 13.8. HRMS (ESI-TOF, m/z) calcd for C19H21BrNO7 [M + H]+: 454.0496, found: 454.0499.



Diethyl cis-2-(2-oxooxazolidine-3-carbonyl)-3-(ptolyl)cyclo propane-1,1-dicarboxylate (cis-3fa). Purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford a white solid in 91% yield (177 mg). Mp: 98–99 ºC. 1 H NMR (500 MHz, CDCl3): δ 7.28–7.21 (m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 4.43 (t, J = 8.1 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 4.19–4.10 (m, 2H), 4.07–3.94 (m, 2H), 3.78 (d, J = 9.8 Hz, 1H), 3.42 (d, J = 9.8 Hz, 1H), 2.30 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.0, 166.3, 165.4, 153.5, 136.9, 130.1, 128.6, 128.4, 62.5, 62.1, 61.6, 42.7, 41.2, 36.4, 31.8, 21.1, 14.0, 13.8. HRMS (ESI-TOF, m/z) calcd for C20H24NO7 [M + H]+: 390.1547, found: 390.1548. Diethyl cis-2-(4-methoxyphenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (cis-3ga). Purified by column chromatography (petroleum ether/ethyl acetate = 9/1) to afford a colorless oil in 91% yield (184 mg). 1H NMR (500 MHz, CDCl3): δ 7.30 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.43 (t, J = 8.1 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 4.18–4.10 (m, 2H), 4.07–3.95 (m, 2H), 3.82–3.73 (m, 4H), 3.40 (d, J = 9.8 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.0, 166.4, 165.4, 158.7, 153.5, 131.4, 123.5, 113.1, 62.5, 62.1, 61.6, 55.2, 42.7, 41.2, 36.2, 31.9, 14.0, 13.8. HRMS (ESI-TOF, m/z) calcd for C20H24NO8 [M + H]+: 406.1496, found: 406.1494. Diethyl cis-2-(3-methoxyphenyl)-3-(2-oxooxazolidine-3carbonyl) cyclopropane-1,1-dicarboxylate (cis-3ha). Purified by column chromatography (petroleum ether/ethyl acetate = 9/1) to afford a white solid in 87% yield (176 mg). Mp: 123– 124 ºC. 1H NMR (500 MHz, CDCl3): δ 7.18 (t, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.82–6.75 (m, 1H), 4.43 (t, J = 8.1 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.20–4.10 (m, 2H), 4.08–3.94 (m, 2H), 3.82–3.74 (m, 4H), 3.44 (d, J = 9.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13 C NMR (125 MHz, CDCl3): δ 168.9, 166.2, 165.4, 159.0, 153.5, 133.2, 128.6, 122.6, 116.3, 112.9, 62.6, 62.2, 61.6, 55.2, 42.7, 41.3, 36.6, 32.0, 14.0, 13.8. HRMS (ESI-TOF, m/z) calcd for C20H24NO8 [M + H]+: 406.1496, found: 406.1506. Diethyl cis-2-(3,4-dimethoxyphenyl)-3-(2-oxooxazolidine-3carbonyl)cyclopropane-1,1-dicarboxylate (cis-3ia). Purified by column chromatography (petroleum ether/ethyl acetate = 8/1) to afford a colorless oil in 93% yield (202 mg). 1H NMR (500 MHz, CDCl3): δ 7.04 (d, J = 2.0 Hz, 1H), 6.95–6.86 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.48–4.38 (m, 2H), 4.34–4.25 (m, 2H), 4.21–4.08 (m, 2H), 4.06–3.94 (m, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.73 (d, J = 9.8 Hz, 1H), 3.41 (d, J = 9.8 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 169.0, 166.3, 165.5, 153.5, 148.2, 148.0, 124.0, 122.5, 114.0, 110.4, 62.5, 62.1, 61.6, 55.83, 55.75, 42.7, 41.3, 36.5, 32.2, 14.0, 13.9. HRMS (ESI-TOF, m/z) calcd for C21H26NO9 [M + H]+: 436.1602, found: 436.1604. Diethyl cis-2-(2-oxooxazolidine-3-carbonyl)-3-(3,4,5trimethoxy phenyl)cyclopropane-1,1-dicarboxylate (cis-3ja). Purified by column chromatography (petroleum ether/ethyl acetate = 6/1) to afford a colorless oil in 90% yield (209 mg). 1 H NMR (500 MHz, CDCl3): δ 6.71 (s, 2H), 4.49–4.38 (m, 2H), 4.36–4.26 (m, 2H), 4.24–4.15 (m, 1H), 4.15–4.08 (m, 1H), 4.07–3.94 (m, 2H), 3.82 (s, 9H), 3.69 (d, J = 9.8 Hz, 1H), 3.41 (d, J = 9.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.18 (t, J =

Page 8 of 12

7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.9, 166.2, 165.5, 153.5, 152.5, 137.4, 127.2, 107.8, 62.6, 62.2, 61.7, 61.5, 60.8, 56.1, 42.8, 41.4, 36.9, 32.6, 14.0, 13.9. HRMS (ESI-TOF, m/z) calcd for C22H28NO10 [M + H]+: 466.1708, found: 466.1709. Diethyl cis-2-(benzo[d][1,3]dioxol-5-yl)-3-(2oxooxazolidine-3-carbonyl)cyclopropane-1,1-dicarboxylate (cis-3ka). Purified by column chromatography (petroleum ether/ethyl acetate = 7/1) to afford a colorless oil in 90% yield (189 mg). 1H NMR (500 MHz, CDCl3): δ 6.96–6.83 (m, 2H), 6.71 (d, J = 8.1 Hz, 1H), 5.92 (s, 2H), 4.44 (t, J = 8.0 Hz, 2H), 4.29 (q, J = 7.0 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 4.07–3.95 (m, 2H), 3.76 (d, J = 9.8 Hz, 1H), 3.39 (d, J = 9.8 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.9, 166.3, 165.4, 153.5, 147.0, 146.8, 125.2, 123.9, 110.8, 107.6, 101.0, 62.6, 62.2, 61.7, 42.7, 41.3, 36.5, 31.9, 14.0, 13.9. HRMS (ESI-TOF, m/z) calcd for C20H22NO9 [M + H]+: 420.1289, found: 420.1289. Dimethyl cis-2-(benzo[d][1,3]dioxol-5-yl)-3-(2oxooxazolidine-3-carbonyl)cyclopropane-1,1-dicarboxylate (cis-3kb). Purified by column chromatography (petroleum ether/ethyl acetate = 8/1) to afford a colorless oil in 90% yield (176 mg). 1H NMR (CDCl3, 500 MHz): δ 6.87 (s, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 5.92 (s, 2H), 4.44 (t, J = 8.1 Hz, 2H), 4.09–3.94 (m, 2H), 3.83 (s, 3H), 3.77 (d, J = 9.8 Hz, 1H), 3.68 (s, 3H), 3.39 (d, J = 9.8 Hz, 1H). 13C NMR (CDCl3, 125 MHz): δ 169.3, 166.2, 165.9, 153.6, 147.1, 146.9, 124.9, 123.7, 110.6, 107.7, 101.0, 62.2, 53.6, 52.8, 42.7, 40.9, 36.7, 32.1. HRMS (ESI-TOF, m/z) calcd for C18H18NO9 [M + H]+: 392.0976, found: 392.0972. Procedure for the [3 + 2] Annulation of cis-3kb With Veratral/Piperonal. To a solution of cis-3kb (196 mg, 0.5 mmol), veratral (831 mg, 5 mmol) or piperonal (751 mg, 5 mmol) in 5.0 mL of dichloromethane was added AlCl3 (67 mg, 0.5 mmol). The reaction mixture was stirred at 30 °C and monitored by TLC. Upon completion, the reaction mixture was cooled down to room temperature followed by the addition of 2.0 mL of H2O. Then the mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic layers were washed twice with brine (2 × 10 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude products were purified by flash chromatography (petroleum ether/ethyl acetate = 1/1) to give the pure products 4. Dimethyl 5-(benzo[d][1,3]dioxol-5-yl)-2-(3,4dimethoxyphenyl)-4-(2-oxooxazolidine-3carbonyl)dihydrofuran-3,3(2H)-dicarboxylate (4a). Colorless oil, 91% yield (256 mg). 1H NMR (CDCl3, 500 MHz): δ 7.21 (d, J = 1.3 Hz, 1H), 7.18–7.09 (m, 2H), 6.97 (dd, J = 7.9, 1.4 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 5.98 (s, 2H), 5.72 (s, 1H), 5.55 (d, J = 8.9 Hz, 1H), 5.22 (d, J = 9.0 Hz, 1H), 4.42–4.27 (m, 2H), 4.03–3.91 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.73 (s, 3H), 3.29 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 171.7, 168.8, 168.4, 152.6, 149.1, 148.4, 148.2, 148.1, 131.7, 128.5, 121.2, 120.0, 110.53, 110.46, 108.2, 107.8, 101.2, 85.1, 84.6, 70.3, 61.7, 55.93, 55.88, 52.84, 52.80, 42.9. HRMS (ESI-TOF, m/z) calcd for C27H31N2O12 [M + NH4]+: 575.1872, found: 575.1871.


Page 9 of 12 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


Dimethyl 2,5-bis(benzo[d][1,3]dioxol-5-yl)-4-(2oxooxazolidine-3-carbonyl)dihydrofuran-3,3(2H)dicarboxylate (4b). Colorless oil, 92% yield (249 mg). 1H NMR (CDCl3, 500 MHz): δ 7.19 (d, J = 1.5 Hz, 1H), 7.12– 7.02 (m, 2H), 6.96 (dd, J = 8.0, 1.6 Hz, 1H), 6.82–6.74 (m, 2H), 5.98 (s, 2H), 5.94 (dd, J = 3.6, 1.4 Hz, 2H), 5.68 (s, 1H), 5.50 (d, J = 8.8 Hz, 1H), 5.21 (d, J = 8.9 Hz, 1H), 4.41–4.27 (m, 2H), 4.02–3.88 (m, 2H), 3.73 (s, 3H), 3.36 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 171.7, 168.7, 168.4, 152.7, 148.2, 148.1, 147.6, 147.2, 131.7, 129.7, 121.2, 121.0, 108.2, 108.0, 107.8, 101.2, 101.0, 85.0, 84.5, 70.3, 61.7, 56.1, 52.9, 52.8, 42.9. HRMS (APCI-TOF, m/z) calcd for C26H27N2O12 [M + NH4]+: 559.1559, found: 559.1566. Procedure for the Reduction of 4 to 5 Using LiBH4. In a glovebox, to a solution of the cyclopropane 4a (240 mg, 0.43 mmol) or 4b (233 mg, 0.43 mmol) in anhydrous THF (5.0 mL) was added LiBH4 (9.4 mg, 0.43 mmol) at rt and the resulting mixture was stirred for 8 hours. Then the reaction was quenched with saturated NH4Cl solution (2 mL). The reaction mixture was extracted with ethyl acetate (3 × 10 mL) and the combined organic layers were washed twice with brine (2 × 10 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude product. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 1/1) to afford the pure product 5a or 5b. Methyl 1-(benzo[d][1,3]dioxol-5-yl)-3-(3,4dimethoxyphenyl)-4-oxohexahydrofuro[3,4-c]furan-3acarboxylate (5a). Colorless oil, 71% yield (135 mg). 1H NMR (CDCl3, 500 MHz): δ 7.12–7.04 (m, 2H), 7.01 (d, J = 1.8 Hz, 1H), 6.95 (dd, J = 7.9, 1.5 Hz, 1H), 6.90–6.82 (m, 2H), 6.01 (s, 2H), 5.34 (s, 1H), 4.63 (d, J = 9.6 Hz, 1H), 4.39 (dd, J = 10.0, 6.0 Hz, 1H), 4.29 (d, J = 10.0 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.63 (dd, J = 9.4, 5.8 Hz, 1H), 3.30 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 173.4, 166.3, 149.2, 148.7, 148.43, 148.36, 131.3, 129.0, 120.7, 119.5, 110.7, 110.1, 108.4, 106.9, 101.4, 86.5, 85.2, 67.8, 67.4, 56.0, 55.9, 53.5, 53.0. HRMS (APCI-TOF, m/z) calcd for C23H26NO9 [M + NH4]+: 460.1602, found: 460.1605. Methyl 1,3-bis(benzo[d][1,3]dioxol-5-yl)-4oxohexahydrofuro[3,4-c]furan-3a-carboxylate (5b). Colorless oil, 71% yield (130 mg). 1H NMR (CDCl3, 500 MHz): δ 7.07 (s, 1H), 7.04–6.98 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.02 (s, 2H), 5.97 (d, J = 1.5 Hz, 2H), 5.31 (s, 1H), 4.60 (d, J = 9.6 Hz, 1H), 4.38 (dd, J = 10.0, 6.0 Hz, 1H), 4.28 (d, J = 10.0 Hz, 1H), 3.61 (dd, J = 9.5, 5.9 Hz, 1H), 3.36 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 173.4, 166.2, 148.42, 148.38, 147.8, 147.5, 131.1, 130.3, 120.8, 120.7, 108.4, 108.0, 107.4, 106.9, 101.4, 101.2, 86.4, 85.0, 67.8, 67.3, 53.5, 53.0. HRMS (APCI-TOF, m/z) calcd for C22H22NO9 [M + NH4]+: 444.1289, found: 444.1282. Procedure for the Decarboxylation of 5 to 6. A mixture of compound 5a (142 mg, 0.32 mmol) or 5b (140 mg, 0.33 mmol) and NaCl (150 mg, 2.56 mmol) in DMSO (10 mL) and water (1 mL) was heated at 100 °C for 24 h under an argon atmosphere. Then the mixture was cooled down to room temp, diluted with water (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by col-

umn chromatography (petroleum ether/dichloromethane = 1/1) to afford the pure product 6a or 6b. Methyl 5-(benzo[d][1,3]dioxol-5-yl)-2-(3,4dimethoxyphenyl)-4-(hydroxymethyl)tetrahydrofuran-3carboxylate (6a). Colorless oil in 69% yield (92 mg). 1H NMR (CDCl3, 500 MHz): δ 7.18 (d, J = 1.5 Hz, 1H), 7.02–6.89 (m, 3H), 6.86–6.76 (m, 2H), 5.97 (s, 2H), 5.19 (d, J = 8.7 Hz, 1H), 4.66 (d, J = 9.1 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.81–3.73 (m, 1H), 3.72–3.63 (m, 1H), 3.48 (dd, J = 8.7, 7.0 Hz, 1H), 3.23 (s, 3H), 2.95–2.82 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 172.9, 148.6, 148.5, 148.0, 147.6, 133.8, 130.8, 120.8, 119.1, 110.6, 109.9, 108.1, 107.5, 101.1, 82.9, 81.7, 61.5, 55.91, 55.88, 53.7, 52.4, 51.6. HRMS (ESI-TOF, m/z) calcd for C22H23O7 [M + H – H2O]+: 399.1438, found: 399.1437. Methyl 2,5-bis(benzo[d][1,3]dioxol-5-yl)-4(hydroxymethyl)tetra hydrofuran-3-carboxylate (6b). Colorless oil in 68% yield (89 mg). 1H NMR (CDCl3, 500 MHz): δ 7.16 (s, 1H), 6.97 (dd, J = 7.9, 1.2 Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.98 (s, 2H), 5.94 (s, 2H), 5.17 (d, J = 8.8 Hz, 1H), 4.65 (d, J = 9.1 Hz, 1H), 3.84–3.74 (m, 1H), 3.73–3.63 (m, 1H), 3.47 (dd, J = 8.6, 7.3 Hz, 1H), 3.29 (s, 3H), 2.92– 2.82 (m, 1H), 1.53–1.45 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 172.7, 148.0, 147.7, 147.4, 147.2, 133.6, 132.1, 120.8, 120.2, 108.2, 107.9, 107.5, 107.3, 101.1, 101.0, 82.8, 81.6, 61.5, 53.7, 52.4, 51.7. HRMS (APCI-TOF, m/z) calcd for C21H19O7 [M + H – H2O]+: 383.1125, found: 383.1118. Procedure for the Reduction of 6 to 7 Using LiAlH4. LiAlH4 (31 mg, 0.84 mmol) was added slowly to a solution of compound 6a (90 mg, 0.21 mmol) or 6b (89 mg, 0.22 mmol) in anhydrous THF (10 mL) at 0 °C under an argon atmosphere. After completion of the reaction, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/2) to afford the pure product 7a or 7b. 2-(Benzo[d][1,3]dioxol-5-yl)-5-(3,4dimethoxyphenyl)tetrahydro furan-3,4-diyl)dimethanol (7a). Brown oil, 91% yield (74 mg). 1H NMR (CDCl3, 500 MHz): δ 7.02 (d, J = 1.4 Hz, 1H), 6.97–6.87 (m, 3H), 6.84 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 5.97 (s, 2H), 5.11 (d, J = 8.6 Hz, 1H), 4.47 (d, J = 9.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.79–3.70 (m, 1H), 3.66–3.56 (m, 1H), 3.41–3.29 (m, 1H), 3.17–3.08 (m, 1H), 2.64–2.54 (m, 1H), 2.27–2.16 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 148.9, 148.5, 148.0, 147.5, 134.0, 131.3, 120.5, 118.7, 111.0, 109.7, 108.2, 107.0, 101.2, 82.6, 81.2, 63.8, 63.0, 55.9, 55.3, 55.2, 50.8. HRMS (ESI-TOF, m/z) calcd for C21H23O6 [M + H – H2O]+: 371.1489, found: 371.1488. 2,5-Bis(benzo[d][1,3]dioxol-5-yl)tetrahydrofuran-3,4diyl)dimeth anol (7b). Colorless oil, 92% yield (81 mg). 1H NMR (CDCl3, 500 MHz): δ 7.00 (d, J = 1.5 Hz, 1H), 6.94– 6.86 (m, 2H), 6.85–6.76 (m, 3H), 5.97 (s, 2H), 5.96 (s, 2H), 5.08 (d, J = 8.6 Hz, 1H), 4.45 (d, J = 9.4 Hz, 1H), 3.74 (dd, J = 10.5, 4.0 Hz, 1H), 3.60 (dd, J = 10.3, 8.7 Hz, 1H), 3.35 (dd, J = 10.6, 4.7 Hz, 1H), 3.16 (t, J = 10.1 Hz, 1H), 2.62–2.52 (m,



1H), 2.24–2.15 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 148.0, 147.8, 147.6, 147.1, 134.0, 133.9, 132.6, 120.5, 119.8, 108.25, 108.18, 107.0, 101.2, 101.1, 82.6, 81.2, 63.8, 63.0, 55.4, 50.7. HRMS (APCI-TOF, m/z) calcd for C20H21O7 [M + H]+: 373.1282, found: 373.1278. Procedure for the Methylation of 7 to 8 Using MeI. Under an argon atmosphere, to an ice-cooled solution of diol 7a (30 mg, 0.077 mmol) or 7b (81 mg, 0.2 mmol) in anhydrous THF (10 mL) was added NaH (31 mg, 0.77 mmol for 7a; 80 mg, 2 mmol for 7b, 60% dispersion in mineral oil). The resultant suspension was stirred for 30 min before the dropwise addition of CH3I (0.48 mL, 0.77 mmol for 7a; 1.01 mL, 2 mmol for 7b). The resulting reaction solution was stirred at room temperature for 2.5 h before the addition of 5.0 mL of H2O. After concentration of the reaction mixture, the residue was dissolved in 20 mL of CH2Cl2 and 20 mL of H2O and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to afford the pure product 8a or 8b. 5-(3,4-Dimethoxyphenyl)-3,4-bis(methoxymethyl)tetrahydrofuran-2-yl)benzo[d][1,3]dioxole (8a). Brown oil, 92% yield (29.5 mg). 1H NMR (CDCl3, 500 MHz): δ 7.04 (d, J = 1.3 Hz, 1H), 6.99–6.90 (m, 3H), 6.84 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 5.96 (s, 2H), 5.09 (d, J = 7.3 Hz, 1H), 4.71 (d, J = 8.1 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.58–3.46 (m, 2H), 3.36 (s, 3H), 3.07 (s, 3H), 3.04 (d, J = 9.0 Hz, 1H), 2.97–2.89 (m, 1H), 2.66–2.57 (m, 1H), 2.35–2.25 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 148.6, 148.1, 147.8, 147.0, 135.6, 131.4, 120.1, 118.6, 110.7, 109.8, 108.1, 107.0, 101.0, 82.7, 81.5, 73.2, 73.0, 59.1, 58.7, 55.9, 51.2, 46.6. HRMS (APCITOF, m/z) calcd for C23H29O7 [M + H]+: 417.1908, found: 417.1899. (±)-Urinaligran (8b). Dark red oil, 93% yield (75 mg). 1H NMR (CDCl3, 500 MHz): δ 7.02 (d, J = 1.5 Hz, 1H), 6.97– 6.89 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.82–6.75 (m, 2H), 6.02–5.90 (m, 4H), 5.04 (d, J = 7.3 Hz, 1H), 4.69 (d, J = 8.0 Hz, 1H), 3.57–3.45 (m, 2H), 3.35 (s, 3H), 3.08 (s, 3H), 3.07– 3.01 (m, 1H), 3.01–2.93 (m, 1H), 2.64–2.52 (m, 1H), 2.33– 2.21 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 147.8, 147.4, 147.0, 146.6, 135.6, 132.7, 120.0, 119.6, 108.1, 107.9, 107.1, 107.0, 101.0, 100.9, 82.6, 81.4, 73.2, 73.0, 59.1, 58.6, 51.4, 46.5. HRMS (APCI-TOF, m/z) calcd for C22H25O7 [M + H]+: 401.1595, found: 401.1594. Procedure for the Conversion of cis-3ab to 11. In a glovebox, to a solution of the cyclopropane cis-3ab (240 mg, 0.69 mmol) in anhydrous THF (5.0 mL) was added LiBH4 (7.5 mg, 0.35 mmol) at rt and the resulting mixture was stirred for 8 hours. Then the reaction was quenched with saturated NH4Cl solution (2 mL). The reaction mixture was extracted with ethyl acetate (3 × 10 mL) and the combined organic layers were washed with brine (2 × 10 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude product. The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 10/1) to afford the γ-butyrolactone fused cyclopropane 11 as a colorless oil in 53% yield (85 mg). Methyl 2-oxo-6-phenyl-3-

Page 10 of 12

oxabicyclo[3.1.0]hexane-1-carboxylate (11). 1H NMR (CDCl3, 500 MHz): δ 7.41–7.29 (m, 5H), 4.39 (dd, J = 10.0, 5.3 Hz, 1H), 4.11 (d, J = 10.0 Hz, 1H), 3.90 (s, 3H), 3.61 (d, J = 8.5 Hz, 1H), 3.06 (dd, J = 8.5, 5.2 Hz, 1H). 13C NMR (CDCl3, 125 MHz): δ 169.3, 167.6, 130.5, 129.2, 129.1, 128.4, 63.8, 53.2, 36.1, 34.8, 33.3. HRMS (ESI-TOF, m/z) calcd for C13H13O4 [M + H]+: 233.0808, found: 233.0804. Procedure for the [3 + 2] Annulation of 11 with Benzaldehyde. To a solution of the γ-butyrolactone fused cyclopropane 11 (85 mg, 0.37 mmol), benzaldehyde (43 mg, 0.41 mmol) in 5.0 mL of dichloromethane was added Sc(OTf)3 (4.5 mg, 0.0092 mmol). The reaction mixture was stirred at 70 °C for 72 h. Upon completion (monitored by TLC), the reaction mixture was cooled down to room temperature followed by the addition of 2.0 mL H2O. Then the mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic layers were washed with brine (2 × 10 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (petroleum ether/ethyl acetate = 10/1) to give the pure product 5c as a colorless oil in 21% yield (26 mg). Methyl 4-oxo-1,3diphenylhexahydrofuro[3,4-c]furan-3a-carboxylate (5c). 1H NMR (CDCl3, 500 MHz): δ 7.60–7.51 (m, 4H), 7.50–7.30 (m, 6H), 5.44 (s, 1H), 4.74 (d, J = 9.6 Hz, 1H), 4.44–4.32 (m, 2H), 3.73–3.65 (m, 1H), 3.22 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 173.4, 166.2, 137.6, 136.7, 129.2, 129.1, 128.7, 128.2, 127.0, 126.7, 86.8, 85.3, 68.2, 67.4, 53.7, 52.8. HRMS (ESI-TOF, m/z) calcd for C20H22NO5 [M + NH4]+: 356.1492, found: 356.1496.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. X-ray crystallographic data and structures for cis-3ha and 1a, copies of 1H, 13C NMR spectra for all new compounds (PDF) X-ray crystallographic data for cis-3ha (CIF) X-ray crystallographic data for 1a (CIF)

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interest. ACKNOWLEDGMENT Financial support of this project from the NNSFC (Nos. 21672005, 21472001, 21172002) and the Natural Science Research Fund for Universities in Anhui Province (KJ2017A709) is gratefully appreciated.

REFERENCES 1.

For selected recent reviews: (a) Pagenkopf, B. L.; Vemula, N. Cycloadditions of Donor–Acceptor Cyclopropanes and Nitriles. Eur. J. Org. Chem. 2017, 2561–2567. (b) Meazza, M.; Guo, H.; Rios, R. Synthetic Applications of Vinyl Cyclopropane Opening. Org. Biomol. Chem. 2017, 15, 2479–2490. (c) Reissig, H.-U.; Werz, D. B. (Guest Editorial), Special Issue: Chemistry of Donor-Acceptor Cyclopropanes and Cyclobutanes. Israel J. Chem. 2016, 56, 365−577. (d) Schneider, T. F.; Kaschel, J.; Werz, D. A


Page 11 of 12 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

2.

3.

4.

5.


New Golden Age for Donor–Acceptor Cyclopropanes. Angew. Chem., Int. Ed. 2014, 53, 5504–5523. (e) Cavitt, M. A.; Phun, L. H.; France, S. Intramolecular Donor–Acceptor Cyclopropane Ring-Opening Cyclizations. Chem. Soc. Rev. 2014, 43, 804–818. (f) de Nanteuil, F.; De Simone F.; Frei, R.; Benfatti, F.; Serrano, E.; Waser, J. Cyclization and Annulation Reactions of NitrogenSubstituted Cyclopropanes and Cyclobutanes. Chem. Commun. 2014, 50, 10912–10928. (g) Campbell, M. J.; Johnson, J. S.; Parsons, A. T.; Pohlhaus, P. D.; Sanders, S. D. ComplexityBuilding Annulations of Strained Cycloalkanes and C=O π Bonds. J. Org. Chem. 2010, 75, 6317–6325. For very recent examples with 2-monosubstituted-1,1-diester cyclopropanes: (a) Ivanov, K. L.; Bezzubov, S. I.; Melnikov, M. Y.; Budynina, E. M. Donor–Acceptor Cyclopropanes as orthoQuinone Methide Equivalents in Formal (4+2)-Cycloaddition to Alkenes. Org. Biomol. Chem. 2018, 16, 3897–3909. (b) Richmond, E.; Vuković, V. D.; Moran, J. Nucleophilic Ring Opening of Donor–Acceptor Cyclopropanes Catalyzed by a Brønsted Acid in Hexafluoroisopropanol. Org Lett. 2018, 20, 574–577. (c) Das, S.; Daniliuc, C. G.; Studer, A. Lewis Acid Catalyzed Stereoselective Dearomative Coupling of Indolylboron Ate Complexes with Donor–Acceptor Cyclopropanes and Alkyl Halides. Angew. Chem., Int. Ed. 2018, 57, 4053–4057. (d) Saha, A.; Bhattacharyya, A.; Talukdar, R.; Ghorai, M. K. Stereospecific Syntheses of Enaminonitriles and β-Enaminoesters via Domino Ring-Opening Cyclization (DROC) of Activated Cyclopropanes with Pronucleophilic Malononitriles. J. Org. Chem. 2018, 83, 2131–2144. (e) Kreft, A.; Jones, P. G.; Werz, D. B. The Cyclopropyl Group as a Neglected Donor in Donor–Acceptor Cyclopropane Chemistry. Org Lett. 2018, 20, 2059–2062. (f) Augustin, A. U.; Jones, P. G.; Werz, D. B. Formal Insertion of Thioketenes into Donor–Acceptor Cyclopropanes by Lewis Acid Catalysis. Org Lett. 2018, 20, 820–823. (g) Irwin, L. C.; Renwick, C. R.; Kerr, M. A. Nucleophilic Opening of Donor–Acceptor Cyclopropanes with Indoles via Hydrogen Bond Activation with 1,1,1,3,3,3-Hexafluoroisopropanol. J. Org. Chem. 2018, 83, 6235–6242. (h) Ivanova, O. A.; Chagarovskiy, A. O.; Shumsky, A. N.; Krasnobrov, V. D.; Levina, I. I.; Trushkov, I. V. Lewis Acid Triggered Vinylcyclopropane–Cyclopentene Rearrangement. J. Org. Chem. 2018, 83, 543–560. For examples with trans-2,3-disubstituted-1,1-diester cyclopropanes: (a) Sanders, S. D.; Ruiz-Olalla, A.; Johnson, J. S. Total Synthesis of (+)-Virgatusin via AlCl3-Catalyzed [3+2] Cycloaddition. Chem. Commun. 2009, 5135–5137. (b) Yang, G.; Shen, Y.; Li, K.; Sun, Y.; Hua Y. AlCl3-Promoted Highly Regio- and Diastereoselective [3+2] Cycloadditions of Activated Cyclopropanes and Aromatic Aldehydes: Construction of 2,5-Diaryl3,3,4-trisubstituted Tetrahydrofurans. J. Org. Chem. 2011, 76, 229–233. (c) Xing, S.; Li, Y.; Li, Z.; Liu, C.; Ren, J.; Wang, Z. Lewis Acid Catalyzed Intramolecular [3+2] Cross-Cycloaddition of Donor–Acceptor Cyclopropanes with Carbonyls: A General Strategy for the Construction of Acetal[n.2.1] Skeletons. Angew. Chem., Int. Ed. 2011, 50, 12605–12609. (d) Thangamani, M.; Srinivasan, K. Lewis Acid-Mediated Ring-Opening Reactions of trans-2-Aroyl-3-styrylcyclopropane-1,1-dicarboxylates: Access to Cyclopentenes and E,E-1,3-Dienes. J. Org. Chem. 2018, 83, 571–577. For an example with cis-2,3-disubstituted-1,1-diester cyclopropanes: Yang, G.; Sun, Y.; Shen, Y.; Chai, Z.; Zhou, S.; Chu, J.; Chai, J. cis-2,3-Disubstituted Cyclopropane 1,1-Diesters in [3+2] Annulations with Aldehydes: Highly Diastereoselective Construction of Densely Substituted Tetrahydrofurans. J. Org. Chem. 2013, 78, 5393–5400. (a) Krief, A.; Provins, L.; Froidbise, A. Diastereoselective Synthesis of Dimethyl Cyclopropane-1,1-dicarboxylates from a γAlkoxy-Alkylidene Malonate and Sulfur and Phosphorus Ylides. Tetrahedron Lett. 1998, 39, 1437–l440. (b) Jiang, H.; Deng, X.; Sun, X.; Tang, Y.; Dai, L. -X. Highly Stereoselective Synthesis

of Trisubstituted Vinylcyclopropane Derivatives via Arsonium Ylides. J. Org. Chem. 2005, 70, 10202–10205. (c) Appel, R.; Hartmann, N.; Mayr, H. Scope and Limitations of Cyclopropanations with Sulfur Ylides. J. Am. Chem. Soc. 2010, 132, 17894– 17900. 6. (a) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. Organocatalytic Enantioselective Cascade Michael-Alkylation Reactions: Synthesis of Chiral Cyclopropanes and Investigation of Unexpected Organocatalyzed Stereoselective Ring Opening of Cyclopropanes. J. Am. Chem. Soc. 2007, 129, 10886–10894. (b) Ibrahem, I.; Zhao, G.-L; Rios, R.; Vesely, J.; Sundén, H.; Dziedzic, P.; Córdova, A. One-Pot Organocatalytic Domino Michael/α-Alkylation Reactions: Direct Catalytic Enantioselective Cyclopropanation and Cyclopentanation Reactions. Chem. Eur. J. 2008, 14, 7867–7879. (c) Fan, R.; Ye, Y.; Li, W.; Wang, L. Efficient Stereoselective Synthesis of Nitrocyclopropanes by the Oxidative Cyclization of Michael Adducts of Nitroolefins with Activated Methylene Compounds. Adv. Synth. Catal. 2008, 350, 2488–2492. (d) Xuan, Y.; Nie, S.; Dong, L.; Zhang, J.; Yan, M. Highly Enantioselective Synthesis of Nitrocyclopropanes via Organocatalytic Conjugate Addition of Bromomalonate to α,β-Unsaturated Nitroalkenes. Org. Lett. 2009, 11, 1583–1586. (e) Selvi, T.; Srinivasan, K. Boron Trifluoride Mediated Ring-Opening Reactions of trans-2-Aryl-3nitro-cyclopropane-1,1-dicarboxylates. Synthesis of Aroylmethylidene Malonates as Potential Building Blocks for Heterocycles. J. Org. Chem. 2014, 79, 3653–3658 and references cited therein. 7. For selected examples on the synthesis of 2,3-disubstituted cyclopropane-1,1-diester with other strategies: (a) González-Bobes, F.; Fenster, M. D. B.; Kiau, S.; Kolla, L.; Kolotuchin, S.; Soumeillant, M. Rhodium-Catalyzed Cyclopropanation of Alkenes with Dimethyl Diazomalonate. Adv. Synth. Catal. 2008, 350, 813–816. (b) Goudreau, S. R.; Marcoux, D.; Charette, A. B. General Method for the Synthesis of Phenyliodonium Ylides from Malonate Esters: Easy Access to 1,1-Cyclopropane Diesters. J. Org. Chem. 2009, 74, 470–473. (c) Nishimura, T.; Maeda, Y.; Hayashi, T. Asymmetric Cyclopropanation of Alkenes with Dimethyl Diazomalonate Catalyzed by Chiral Diene–Rhodium Complexes. Angew. Chem., Int. Ed. 2010, 49, 7324–7327. (d) Deng, C.; Liu, H.-K.; Zheng, Z.-B.; Wang, L.; Yu, X.; Zhang, W.; Tang, Y. Copper-Catalyzed Enantioselective Cyclopropanation of Internal Olefins with Diazomalonates. Org. Lett. 2017, 19, 5717–5719. 8. Sun, Y.; Yang, G.; Shen, Y.; Chai, Z. Stereoselective Cyclopropanation of α-Bromochalcone with Diethyl Malonate Promoted by K2CO3. Tetrahedron 2013, 69, 2733–2739. 9. CCDC 1854392 (1a), and CCDC 1854393 (cis-3ha) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. 10. (a) Teponno, R. B.; Kusari S.; Spiteller, M. Recent Advances in Research on Lignans and Neolignans. Nat. Prod. Rep. 2016, 33, 1044–1092. (b) Cunha, W. R.; Andrade e Silva, M. L. R.; Veneziani, C. S.; Ambrosio, S. R.; Bastos, J. K. in Lignans: Chemical and Biological Properties, Phytochemicals—A Global Perspectives of Their Role in Nutrition and Health, Rao, V., Ed.; InTech Publishers: Rijeka, 2012; pp 213–234. 11. For a recent review on the synthesis of tetrahydrofurans: (a) de la Torre, A.; Cuyamendous, C.; Bultel-Poncé, V.; Durand, T.; Galano, J.-M.; Oger, C. Recent Advances in the Synthesis of Tetrahydrofurans and Applications in Total Synthesis. Tetrahedron 2016, 72, 5003–5025. For selected examples on the synthesis of virgatusin: (b) Martinet, S.; Méou A.; Brun, P. Access to Enantiopure 2,5-Diaryltetrahydrofurans–Application to the Synthesis of (–)-Virgatusin and (+)-Urinaligran. Eur. J. Org. Chem. 2009, 2306–2311. (c) Matcha, K.; Ghosh, S. A Stereocontrolled



Approach for the Synthesis of 2,5-Diaryl-3,4-disubstituted Furano Lignans Through a Highly Diastereoselective Aldol Condensation of an Ester Enolate with an α-Chiral Center: Total Syntheses of (–)-Talaumidin and (–)-Virgatusin. Tetrahedron Lett. 2008, 49, 3433–3436. (d) Akindele, T.; Marsden, S. P.; Cumming, J. G. Stereocontrolled Assembly of Tetrasubstituted Tetrahydrofurans: A Concise Synthesis of Virgatusin. Org. Lett. 2005, 7, 3685–3688. (e) Yamauchi, S.; Okazaki, M.; Akiyama, K.; Sugahara, T.; Kishida, T.; Kashiwagi, T. First Enantioselective Synthesis of (–)- and (+)-Virgatusin, Tetra-substituted Tetrahydrofuran Lignan. Org. Biomol. Chem. 2005, 3, 1670–1675. (f) Yoda, H.; Mizutani, M.; Takabe, K. First Total Synthesis of Tetrasubstituted Tetrahydrofuran Lignan, (–)-Virgatusin. Tetrahedron Lett. 1999, 40, 4701–4702 and ref. 3a. 12. (a) Feng, M.; Yang, P.; Yang, G.; Chen, W.; Chai, Z. FeCl3‑ Promoted [3+2] Annulations of γ-Butyrolactone Fused Cyclopropanes with Heterocumulenes. J. Org. Chem. 2018, 83, 174– 184. (b) Shen, Y.; Yang, P.-F.; Yang, G.; Chen, W.-L.; Chai, Z. Lewis Acid-Catalyzed Enantiospecific [3+2] Annulations of γButyrolactone Fused Cyclopropanes with Aromatic Aldehydes: Synthesis of Chiral Furanolignans. Org. Biomol. Chem. 2018, 16, 2688–2696. (c) Yang, P.; Shen, Y.; Feng, M.; Yang, G.; Chai, Z. Lewis Acid Catalyzed [3+2] Annulation of γ-Butyrolactone Fused Cyclopropane with Aldehydes/Ketones. Eur. J. Org. Chem. 2018, 4103–4112.


Page 12 of 12

cis-2,3-Disubstituted

Recommend Documents