Stereoselective Michael-alkylation and Michael-oxidation reactions of chiral 1,3-dioxolanones

Tetrahedron: Asymmetry 28 (2017) 803–808

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Stereoselective Michael-alkylation and Michael-oxidation reactions of chiral 1,3-dioxolanones Hao-Chun Liao, Kuan-Jen Yao, Yi-Chou Tsai, Biing-Jiun Uang ⇑ Department of Chemistry, National Tsing Hua University, No. 101, Sec 2, Kuang-Fu Rd, Hsinchu City 30013, Taiwan

a r t i c l e

i n f o

Article history: Received 17 March 2017 Revised 13 April 2017 Accepted 24 April 2017 Available online 19 May 2017

a b s t r a c t A highly diastereoselective Michael-alkylation/oxidation methodology has been developed for the synthesis of optically active a-hydroxy-1,5-diester subunits. Inverse stereochemistry at the C20 position could be achieved by using a Michael acceptor equipped with a suitable group followed by a highly stereoselective protonation. This methodology has been applied to the enantioselective synthesis of the upper fragment of (+)-retusine. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction The control of multiple stereogenic centers in a molecule is a challenge to organic synthesis. Optically active a-hydroxy acids1 are common subunits in many natural products and therapeutics. It is important to develop a methodology that could construct chiral a-hydroxy acid skeletons for natural product synthesis. Previously, the preparation of chiral 1,3-dioxolanones from glycolic acid and their a-alkylation had been reported by Pearson et al.,2a Ley et al.,2b and our group.2c Diastereoselective Michael addition reactions using a-hydroxyacids as Michael donors have been examined as a method for introducing a-substituents.3 Intramolecular Michael-alkylation4 or Michael-aldol5 reactions have been explored. However, intermolecular Michael-alkylation or Michael-aldol reactions are rare.6 Moreover, stereoselective synthesis of a-hydroxy-1,5-diacids with multiple stereogenic centers has not been explored. The building of a-hydroxy-1,5-diacids subunits that contain three contiguous stereogenic centers through a Michael-alkylation or Michael-oxidation remains as a challenge. As a result, we decided to explore the alkylation and oxidation reaction of chiral dioxolanone 1 after a Michael reaction. A concise and highly enantioselective synthesis of the upper fragment of (+)-retusine7 using this methodology is also reported. 2. Results and discussion In our previous studies, we demonstrated that Michael reactions of 1,3-dioxolanones 1 with a,b-unsaturated esters could give the Michael adducts 2 or 3 with excellent diastereoselectivity ⇑ Corresponding author. Tel.: +886 3 5715131 33410; fax: +886 3 5711082. E-mail address: [email protected] (B.-J. Uang). http://dx.doi.org/10.1016/j.tetasy.2017.05.002 0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

(Scheme 1).3a We then used this for constructing a-hydroxy acid subunits with three contiguous stereogenic centers from a Michael-alkylation or a Michael-oxidation reaction. Initially, we conducted the Michael-hydroxylation reaction from chiral dioxolanone 1a with methyl crotonate followed by treatment with Davis reagent 48 in a one-pot reaction. However, only trace amounts of desired product 5a were obtained; Michael adduct 2a (R2 = CH3) was obtained as the major product. We next studied the C20 -hydroxylation of Michael adduct 2a with 4. The results are summarized in Table 1. Treatment of Michael adduct 2a with LDA (1.2 equiv) at 100 °C followed by a slow addition of 4 (1.2 equiv) and warmed to 78 °C for 5 h gave the desired product 5a as a single diastereoisomer in 34% yield with a 46% recovery of 2a (entry 1). There is no appreciable yield when the hydroxylation was conducted under elevated temperatures, although the diastereoselectivity remained excellent (entries 2–4). An attempt to increase the yield of 5a by increasing the amount of 4 to 2 equiv resulted in only 17% yield with 66% recovery of 2a (entry 5). We surmised that more than one half of starting 2a was recovered might be due to not easily removable moisture in the Davis reagent. We then conducted the deprotonation of 2a with 3 equiv of LDA at 78 °C followed by the addition of 4 (2 equiv) at the same temperature for 5 h and obtained the desired product 5a in 40% yield along with a side product, vide infra (entry 6). When the amount of 4 was increased to 3 equiv and the reaction time was prolonged to 24 h, 5a was obtained in 53% yield with a similar side product (entry 7). This undesired side product might have arisen from the addition of the enolate from 2a to N-benzylidenebenzenesulfonamide, the decomposed product of 4, as judged from the AB pattern at d 7–8 region of its NMR spectrum, although it could not be fully purified due to inseparable impurities. When the reaction was conducted by treating 2a with 1.5 equiv of LDA

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H.-C. Liao et al. / Tetrahedron: Asymmetry 28 (2017) 803–808 O 2'

LDA, THF, −100 oC O i Pr NO S 2 2

R1

anti-selective

iPr

−100 → −78

O

2

O 2

α ,β-unsaturated esters o C,

R1 R

O

2NO2 S

30 min, then

O

O

O

R1 = Me

dr > 99:1 O

3h R1 = H

1a R1 = Me 1b R 1 = H

O

O

syn-selective O

i

Pr2 NO2 S

R1

R2

O 3

dr > 99:1

Scheme 1. Michael addition of the enolate from chiral dioxolanone 1 to a,b-unsaturated esters.

Table 1 C20 -hydroxylation of the Michael adduct 2a

O HO

2'

O i

Pr2 NO2S

5

O

1'

O

1. LDA , T1 , 1 h 2. Davis reagent

O

T1 → T2

O

iPr

2a

a b c

2NO2 S

O

O O

2'

S

N

O

O 5

1'

4

O O

Davis reagent

5a

Entry

T1 (°C)

T2 (°C)

4 (equiv)

LDA (equiv)

Reaction time (h)

2a recovered (%)

1 2 3 4 5 6 7 8b

100 100 100 100 100 78 78 78

78 65 55 40 78 78 78 78

1.2 1.5 1.5 1.5 2 2 3 3

1.2 1.2 1.2 1.2 1.2 3 3 1.5

5 5 5 5 5 5 24 24

46 52 58 56 66 —c —c 8

5a yield (%) 34 37 17 3 17 40 53 82

dea (%) >98 >98 >98 >98 >98 >98 >98 >98

No second isomer has been detected by 400 MHz 1H NMR spectroscopic analysis of the crude product. Davis reagent was added in 5 min. Not recovered.

at 78 °C followed by the addition of 4 (3 equiv) in 5 min, after stirring at 78 °C for 24 h, the desired product 5a was obtained in 82% yield as a single isomer with a recovery of 2a in 8% (entry 8). Decreasing the addition time for 4 had substantially reduced the formation of the side product. The stereochemistry of 5a was unambiguously assigned as (5R,10 S,20 S) by single crystal X-ray analysis of 6, the O-acetylated product of 5a (Fig. 1).9 Encouraged by the excellent diastereoselectivity obtained from the C20 -hydroxylation, we next investigated the substrate scope of the C20 -alkylation, or amination. The results are summarized in Table 2. For the alkylation or amination of 2a or 2b, only 1.2 equiv of LDA were required with 4 equiv of alkyl halides (entries 1–4) or

O O O

O H

2' 1'

5

O

O O

O S

N

O 6

Figure 1. The absolute stereochemistry of 6 was confirmed by X-ray analysis.

3 equiv of nitrosobenzene (entry 5), because moistures in these reagents could be removed effectively. Among the examples, moderate to good yields with excellent diastereoselectivities were observed. The stereochemistry was confirmed as (5R,10 S,20 S) at C5, C10 and C20 by single crystal X-ray crystallographic analysis of 5b. 10 Retusine 7 is an alkaloid isolated from Crotalaria retusa L.7 Several Crotalaria retusa are grown in China, Australia and United States and their leaves are used for treating fevers and wounds.7f Although retusine 7 has been shown to be active against HeLa cells, as an antitumor agent for cervical cancer and skin cancer,7b–d the synthesis of retusine has not been reported yet. With the successful stereochemical control at C20 , we tried to extend our methodology for the synthesis of the upper fragment of (+)-retusine. The retrosynthetic analysis of (+)-retusine 7 is shown in Scheme 2. In principle, (+)-retusine could be synthesized by the connection of ()-platynecine with diester 5b0 . Diester 5b0 could be synthesized from the methylation of 2a or the Michael addition of 1a with tiglate followed by protonation. Herein we report our synthesis of the upper fragment of (+)-retusine 7, the a-hydroxy-1,5-diester subunit, with the control of three contiguous stereogenic centers. The stereochemistry at C12, C13 and C14 of the a-hydroxy1,5-diester subunit in (+)-retusine 7 is (12R,13S,14R), which corresponds to the stereochemistry at C5, C10 and C20 of 5b0 , the

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H.-C. Liao et al. / Tetrahedron: Asymmetry 28 (2017) 803–808 Table 2 Substrate scope of diastereoselective C20 -funtionalization O R'

2'

O

5

Pr 2NO2 S

O

1. LDA , -78 oC, 1 h

R

O

i

O

1'

2. reagent, -78 o C, T

O

iPr

a

+

R

R

Reagent

T (h)

R0

Me 2a Me 2a Ph 2b Ph 2b Me 2a

MeI Allyl iodide MeI Allyl iodide Nitrosobenzene

14 7 24 14 16

Me (b) Allyl (c) Me (d) Allyl (e) N(OH)Ph (f)

R

O

i

Pr2 NO2S

5

1 2 3 4 5

O

O

1'

O

entry

O

R'

O

5

O

2NO2 S

2a or 2b

b

O 2'

O 5'

Yield (%) 68 82 91 77 75

Recovery (%) of 2a or 2b

dr (5:50 )a

17 13 —b 10 —b

>99:1 40:1 >99:1 >99:1 >99:1

Ratio of purified products. Not recovered.

H3 C O

OH CH 3 13 12

O

O

CH3 HO

(R)

14

O

H O

(R)

H OH

iPr NO S 2 2

N

O

1'

5

+

O O

N 5b'

(−)-platynecine

(+)-retusine 7

2'

O

stereoselective Michael-protonation

stereoselective methylation

O O iPr NO S 2 2

O

O

O iPr NO S 2 2

O 1a

O O 2a

Scheme 2. Retrosynthetic analysis for the synthesis of (+)-retusine.

To invert the stereochemistry of 5b at C20 , we studied the Michael addition of 1a with methyl tiglate followed by a stereoselective protonation. Product 5b0 should be obtained as the major product if protonation of the enolate from Michael addition of 1a with methyl tiglate follows the same manner as that on C20 -methylation of the enolate from 2a. The results for Michael addition of 1a with methyl tiglate followed by protonation are summarized in Table 3. When the Michael addition of 1a with methyl tiglate

C20 -epimer of 5b. Therefore the search for conditions that would allow for an (R)-configuration at C20 of 5b was necessary. Attempts to use LiBr11 or HMPA12 as an additive in the Michael-alkylation reaction to invert stereochemistry at C20 were not successful. Methylation of 2a in the presence of LiBr (2 equiv) or HMPA (1 equiv) showed no significant change of product composition and 5b was obtained as a single diastereoisomer in 64% and 60% yields respectively, with no sign of a second isomer. Table 3 Michael addition of 1a with methyl tiglate followed by protonation

O 2'

1. LDA , −100 oC, 30 min

O i

Pr 2NO2 S

2.

O O

O

O iPr NO S 2 2

O

1a

5

1'

O

O O 5b'

−100 → −78 °C

a

Entry

Reaction time (h)

Proton source

Yield (%)

Ratio (5b0 :5b)a

1 2 3 4 5

16 21 18 19 30

1% oxalic acid Benzensulfonamide MsNHtBu 8 9 9

66 45 66 64 57

4.4:1 9:1 10:1 >99:1 >99:1

The ratio was determined by 400 MHz 1H NMR spectral analysis of the crude product.

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H.-C. Liao et al. / Tetrahedron: Asymmetry 28 (2017) 803–808

followed by the addition of 1% aqueous oxalic acid, 5b0 was obtained as the major product, although the diastereoselectivity was moderate (entry 1). It was found that quenching of the Michael adduct with a bulkier and weaker acidic proton source such as sulfonamides could afford 5b0 as the major product with very high diastereoselectivity (entries 2–4). The best proton source for diastereoselective protonation was sulfonamide 9 (entry 4). There was a slight decrease in the yield after prolonging reaction time (entry 5). Diester 5b0 is a potential precursor for the synthesis of natural product (+)-retusine 7 when coupled with ()-platynecine. A plausible mechanism for the highly diastereoselective Michael-alkylation/hydroxylation of 1a is depicted in Scheme 3. The first Michael reaction was not considered to undergo chelated transition state,13 because chelated-T1 could not perform the Michael addition thoroughly and chelated-T2 was unfavorable due to the steric repulsion between the ester and the methyl group at C5. The Michael acceptor was proposed to approach the enolate of 1,3-dioxolanone from the si face due to the steric hindrance

between Michael acceptor and N,N-diisopropylsulfonamido (R) group. There are two possible orientations for the Michael addition, namely T1 and T2. The T1 approach is unfavorable for the Michael addition due to the steric repulsions between bornane skeleton and the ester group as well as two methyl groups at C5 and C10 . After Michael addition reaction, alkylating agent or Davis reagent approaches the enolate T4, generated from Michael addition, from the si face to give 5 as the major product. In principle, the Michael addition of dioxolanone 1a with methyl tiglate followed by protonation should follow the same mechanism to afford 5b0 as the major product. 3. Conclusions We have developed a highly diastereoselective Michael-alkylation/oxidation/protonation methodology for the asymmetric synthesis of a-hydroxy-1,5-diester units in a highly stereocontrol manner. The unique molecular structure of T4 provides the opportunity for C20 functionalization in a highly diastereoselective manner.

OMe R1

R1 Me

O R

O

MeO

O

O

Li

O

R

chelated-T 1

O

R1

Me

O

Me R

O

OLi

O

unfavorable

R1

Me OM

O

OM

O

Me

R1

O

Me

O

Li O

chelated-T 2

O O

O

O Me

O

O

R T1

T3

R = SO2 N iPr2

O R1 O Me R

O

O O

R1

O Me

Me

O Me

O

OLi

O

favorable

Me

R1

O

OM

OM

R

O

O

T2

T4

R 2-X

Me

O

si T4

R1 = H

O O

OLi Me

H

R

O 5

H+

si T4

O O

R 1 = Me R

O OLi

Me

Me

O

T4a

Me

O

O

reagent

O

R

O

R2

si face attack

Me

proton source

O T4b

Me

si face attack

O O

O

R

Me

O O 5b'

Scheme 3. A plausible mechanism for the Michael-alkylation/oxidation reaction of 1a.

H.-C. Liao et al. / Tetrahedron: Asymmetry 28 (2017) 803–808

The corresponding products contain three contiguous stereogenic centers with one tertiary alcohol. These products are valuable for the synthesis of biologically active natural products and therapeutics. 4. Experimental 4.1. General 1

H NMR spectra were recorded with a Varian Mercury-400 (400 MHz) spectrometer. Data are reported as follows: chemical shift values referenced to CDCl3 (d = 7.24 ppm), multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet) and integration. 13C NMR spectra were recorded with a Varian Mercury-400 (100 MHz) spectrometer. Chemical shift values are referenced to CDCl3 (d = 77.00 ppm). HRMS data were recorded with mass spectrometers at the NSC Instrumentation Center at National Tsing Hua University. IR spectra were obtained with a Bomen MB 100FT spectrometer. Thin-layer chromatography was performed with silica gel G60 F254 (Merck) with short-wavelength UV light for visualization. Silica Gel 60 (particle size 63–200 lm, purchased from Merck) was used for column chromatography. 4.2. Experimental procedures and characterization data General procedure for hydroxylations: To a stirred solution of dry THF (0.76 mL) containing dry diisopropylamine (0.09 mL, 0.66 mmol) was added butyllithium (0.27 mL, 2.33 M in hexane, 0.62 mmol) at 0 °C under argon. After stirring for 30 min, the known Michael adduct 2a3e (200 mg, 0.41 mmol) in dry tetrahydrofuran (0.41 mL) was added to lithium diisopropylamide mixture dropwise at 78 °C for 20 min under argon. After stirring for 1 h at 78 °C, Davis reagent (4, 321 mg, 1.23 mmol) in dry THF (1.23 mL) was added dropwise at 78 °C for 5 min. The reaction was stirred at the same temperature for 24 h and quenched by the addition of 1% aq. oxalic acid (1 mL). The resulting mixture was neutralized to pH = 6–7 with 1% aq oxalic acid and extracted with EtOAc (3  20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired compound. 4.2.1. (1S,2S,50 R,100 S,200 S)-N,N-Diisopropyl{2-spiro-20 -[50 -(200 hydroxycarbomethoxy-100 -methylethyl)-50 -methyl-10 ,30 dioxolane-40 -one]-7,7-dimethylbicyclo[2.2.1]hept-1-yl} methanesulfonamide 5a The desired compound was prepared by the general procedure on a 0.41 mmol (200 mg) scale to give 5a (169 mg, 82%) as a white solid after silica gel column chromatography (EtOAc/hexanes, 1:3). dr >99:1. [a]25 D = +17.9 (c 1.0, CHCl3). Mp 64.7–66.6 °C. IR (KBr, film): 3512, 2963, 1787, 1739, 1334, 1138, 976 cm1. 1H NMR (400 MHz, CDCl3) d: 4.70 (d, J = 3.6 Hz, 1H), 3.76 (s, 3H), 3.70 (septet, J = 7.2 Hz, 2H), 3.26 (d, J = 14 Hz, 1H), 2.79 (d, 4.8 Hz, 1H), 2.63 (d, J = 14 Hz, 1H), 2.38–2.22 (m, 3H), 2.16–2.02 (m, 1H), 1.84–1.76 (m, 3H), 1.29 (s, 3H), 1.29 (s, 6H), 1.27 (s, 6H), 1.02 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.93 (s, 3H). 13C NMR (100 MHz, CDCl3) d: 174.8, 173.6, 115.7, 82.0, 68.7, 54.4, 52.8, 51.9, 50.4, 48.2, 46.3, 44.2, 41.6, 26.4, 25.6, 22.8, 21.8, 20.6, 20.1, 18.7, 7.4. HRMS (ESI) calcd for C24H41NNaO8S [M+Na]+: 526.2451, found: 526.2444. General procedure for alkylation and amination: To a stirred solution of dry THF (0.51 mL) containing dry diisopropylamine (0.07 mL, 0.53 mmol) was added butyllithium (0.21 mL, 2.33 M in hexane, 0.49 mmol) at 0 °C under argon. After stirring for 30 min, the known Michael adduct 23e (0.41 mmol) in dry tetrahydrofuran (0.41 mL) was added to lithium diisopropylamide mixture dropwise at 78 °C for 20 min under argon. After stirring for 1 h at

807

78 °C, alkyl iodide (1.64 mmol) or nitrosobenzene (132 mg, 1.23 mmol) in dry THF (1.64 mL) was added dropwise at 78 °C for 20 min. The reaction was then stirred at 78 °C for the required time and quenched by the addition of 1% aq oxalic acid (1 mL). The resulting mixture was neutralized to pH 6–7 with 1% aq. oxalic acid and extracted with EtOAc (3  20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired compound. 4.2.2. (1S,2S,50 R,100 S,200 S)-N,N-Diisopropyl{2-spiro-20 -[50 -(200 carbomethoxy-100 -methylpropyl)-50 -methyl-10 ,30 -dioxolane-40 one]-7,7-dimethylbicyclo[2.2.1]hept-1-yl}methanesulfonamide 5b The desired compound was prepared by the general procedure on a 0.41 mmol (200 mg) scale to give 5b (140 mg, 68%) as a white solid after silica gel column chromatography (EtOAc/hexanes, 1:6). dr >99:1. [a]25 D = +3.4 (c 1.0, CHCl3). Mp 127.0–129.6 °C. IR (KBr, film): 2974, 1793, 1736, 1334, 1198, 1137, 977 cm1. 1H NMR (400 MHz, CDCl3) d: 3.70 (septet, J = 6.8 Hz, 2H), 3.64 (s, 3H), 3.20 (d, J = 14.0 Hz, 1H), 2.86–2.80 (m, 1H), 2.65 (d, J = 14.0 Hz, 1H), 2.60–2.50 (m, 1H), 2.40–2.30 (m, 1H), 2.30–2.10 (m, 3H), 1.85– 1.78 (m, 3H), 1.49 (s, 3H), 1.28 (s, 6H), 1.27 (s, 6H), 1.13 (d, J = 7.2 Hz, 3H), 1.01 (s, 3H), 0.97 (d, J = 7.2 Hz, 3H), 0.94 (s, 3H). 13 C NMR (100 MHz, CDCl3) d: 176.2, 174.0, 116.3, 83.0, 54.7, 52.0, 51.8, 50.4, 48.2, 46.8, 44.4, 39.8, 38.2, 26.4, 25.5, 22.8, 21.9, 20.8, 20.1, 19.4, 12.8, 10.4. HRMS (ESI) calcd for C25H43NNaO7S [M +Na]+: 524.2658, found: 524.2653. 4.2.3. (1S,2S,50 R,100 S,200 S)-N,N-Diisopropyl{2-spiro-20 -[50 -(200 -allylcarbomethoxy-100 -methylethyl)-50 -methyl-10 ,30 -dioxolane-40 one]-7,7-dimethylbicyclo[2.2.1]hept-1-yl}methanesulfonamide 5c The desired compound was prepared by the general procedure on a 0.41 mmol (200 mg) scale to give 5c0 (4 mg, 2%) and 5c (173 mg, 80%) as a light yellow paste after silica gel column chromatography (EtOAc/hexanes, 1:6). dr = 40:1. [a]25 D = +2.3 (c 1.0, CHCl3). IR (KBr, film): 2950, 1793, 1735, 1334, 1138, 977 cm1. 1H NMR (400 MHz, CDCl3) d: 5.80–5.65 (m, 1H), 5.05– 4.96 (m, 2H), 3.71 (septet, J = 6.8 Hz, 2H), 3.63 (s, 3H), 3.19 (d, J = 13.6 Hz, 1H), 2.78 (m, 1H), 2.66 (d, J = 13.6 Hz, 1H), 2.50–2.39 (m, 1H), 2.38–2.33 (m, 3H), 2.33–2.10 (m, 3H), 1.85–1.78 (m, 3H), 1.51 (s, 3H), 1.29 (s, 6H), 1.27 (s, 6H), 1.03 (d, J = 6.8 Hz, 3H), 1.01 (s, 3H), 0.94 (s, 3H). 13C NMR (100 MHz, CDCl3) d: 174.8, 173.7, 135.4, 116.6, 116.3, 82.9, 54.6, 51.9, 51.5, 50.4, 48.2, 46.7, 44.2, 44.2, 40.0, 32.1, 26.3, 25.4, 22.8, 21.8, 20.7, 20.0, 19.4, 11.0. HRMS (ESI) calcd for C27H45NNaO7S [M+Na]+: 550.2818, found: 550.2804. 4.2.4. (1S,2S,50 R,100 R,200 S)-N,N-Diisopropyl{2-spiro-20 -[50 -(200 carbomethoxy-100 -phenylpropyl)-50 -methyl-10 ,30 -dioxolane-40 one]-7,7-dimethylbicyclo[2.2.1]hept-1-yl}methanesulfonamide 5d The desired compound was prepared by the general procedure on a 0.36 mmol (200 mg) scale to give 5d (185 mg, 91%) as a white solid after silica gel column chromatography (EtOAc/hexanes, 1:6). dr >99:1. [a]27 D = +1.9 (c 2.0, CHCl3). Mp 65.1–65.5 °C. IR (KBr, film): 2971, 2951, 2879, 1791, 1733, 1335, 1136, 977 cm1. 1H NMR (400 MHz, CDCl3) d: 7.32–7.17 (m, 5H), 3.68 (s, 3H), 3.63 (septet, J = 6.8 Hz, 2H), 3.07 (d, J = 14 Hz, 1H), 3.06–3.00 (m, 1H), 2.65– 2.59 (m, 1H), 2.52 (d, J = 14 Hz, 1H), 2.28–2.17 (m, 1H), 2.23–2.00 (m, 2H), 1.83–1.74 (m, 2H), 1.47 (s, 3H), 1.44–1.34 (m, 2H), 1.21 (d, J = 6.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 6H), 0.93 (d, J = 6.8 Hz, 3H), 0.89 (s, 3H), 0.86 (s, 3H). 13C NMR (100 MHz, CDCl3) d: 176.5, 173.7, 136.5, 131.0, 127.9, 127.1, 116.3, 82.0, 54.5, 53.2, 51.9, 51.7, 50.4, 48.1, 46.1, 45.5, 38.9, 26.3, 25.6, 22.7, 21.8, 20.7, 19.9,

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19.9, 18.2. HRMS (ESI) calcd for C30H45NNaO7S [M+Na]+: 586.2814, found: 586.2819. 4.2.5. 3(1S,2S,50 R,100 R,200 S)-N,N-Diisopropyl{2-spiro-20 -[50 -(200 allylcarbomethoxy-100 -phenylethyl)-50 -methyl-10 ,30 -dioxolane-40 one]-7,7-dimethylbicyclo[2.2.1]hept-1-yl}methanesulfonamide 5e The desired compound was prepared by the general procedure on a 0.36 mmol (200 mg) scale to give 5e (163 mg, 77%) as a white solid after silica gel column chromatography (EtOAc/hexanes, 1:6). dr >99:1. [a]27 D = +2.3 (c 1.0, CHCl3). Mp 131.8–132.4 °C. IR (KBr, film): 2971, 2951, 2879, 1792, 1734, 1223, 1137, 1121, 978 cm1. 1 H NMR (400 MHz, CDCl3) d: 7.34–7.18 (m, 5H), 5.58–5.47 (m, 1H), 4.85 (d, J = 9.6 Hz, 1H), 4.68 (d, J = 16.4 Hz, 1H), 3.67 (s, 3H), 3.59 (septet, J = 6.8 Hz, 2H), 3.20–3.02 (m, 1H), 3.05 (d, J = 14 Hz, 1H), 2.64–2.56 (m, 1H), 2.52 (d, J = 14 Hz, 1H), 2.27–1.98 (m, 5H), 1.84–1.76 (m, 2H), 1.49 (s, 3H), 1.42–1.34 (m, 2H), 1.22 (d, J = 6.4 Hz, 6H), 1.21 (d, J = 6.8 Hz, 6H), 0.90 (s, 3H), 0.85 (s, 3H). 13 C NMR (100 MHz, CDCl3) d: 174.6, 173.5, 136.4, 133.8, 131.0, 127.9, 127.3, 117.1, 116.3, 82.1, 54.6, 52.3, 51.7, 51.6, 50.4, 48.1, 46.1, 44.5, 44.5, 36.3, 26.3, 25.6, 22.7, 21.8, 20.7, 20.1, 19.9. HRMS (ESI) calcd for C32H47NNaO7S [M+Na]+: 612.2971, found: 612.2971. 4.2.6. (1S,2S,50 R,100 S,200 S)-N,N-Diisopropyl{2-spiro-20 -[50 -(200 hydroxy(phenyl)-aminocarbomethoxy-100 -methylethyl)-50 methyl-10 ,30 -dioxolane-40 -one]-7,7-dimethylbicyclo[2.2.1]hept1-yl}-methanesulfonamide 5f The desired compound was prepared by the general procedure on a 0.41 mmol (200 mg) scale to give 5f (183 mg, 75%) as a light yellow solid after silica gel column chromatography (EtOAc/hexanes, 1:3). dr >99:1. [a]27 D = +6.3 (c 1.0, CHCl3). Mp 165.9– 166.2 °C. IR (KBr, film): 3443, 2971, 2952, 1781, 1740, 1336, 1138, 978 cm1. 1H NMR (400 MHz, CDCl3) d: 7.30–7.18 (m, 5H), 6.94–6.80 (m, 1H), 6.11 (s, 1H), 4.82 (d, J = 4 Hz, 1H), 3.71 (septet, J = 7.2 Hz, 2H), 3.62 (s, 3H), 3.31 (d, J = 13.6 Hz, 1H), 2.81–2.77 (m, 1H), 2.60 (d, J = 14 Hz, 1H), 2.40–2.28 (m, 2H), 2.12–2.02 (m, 1H), 1.88–1.76 (m, 3H), 1.62 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H), 1.27 (d, J = 6.4 Hz, 12H), 1.05 (s, 3H), 0.93 (s, 3H). 13C NMR (100 MHz, CDCl3) d: 174.4, 171.4, 151.5, 128.9, 121.2, 115.8, 114.4, 82.4, 77.3, 65.7, 54.5, 51.9, 50.7, 48.2, 46.4, 44.3, 39.9, 26.5, 25.8, 22.8, 21.8, 20.6, 20.2, 17.5, 11.3. HRMS (ESI) calcd for C30H46N2NaO8S [M+Na]+: 617.2873, found: 617.2868. 4.2.7. (1S,2S,50 R,100 S,200 R)-N,N-Diisopropyl{2-spiro-20 -[50 -(200 carbomethoxy-100 -methylpropyl)-50 -methyl-10 ,30 -dioxolane-40 one]-7,7-dimethylbicyclo[2.2.1]hept-1-yl}methanesulfonamide 5b0 To a stirred solution of dry THF (0.25 mL) containing dry diisopropylamine (0.09 mL, 0.68 mmol) was added butyllithium (0.27 mL, 2.33 M in hexane, 0.62 mmol) at 0 °C under argon. After stirring for 30 min, the dioxolanone 1a (200 mg, 0.52 mmol) in dry tetrahydrofuran (0.78 mL) was added to lithium diisopropylamide mixture dropwise at 100 °C for 20 min under argon. After stirring for 30 min at 100 °C, methyl tiglate (0.09 ml, 0.78 mmol) in dry THF (0.09 mL) was added dropwise at 100 °C for 20 min. The reaction was then warmed to 78 °C and stirred for 19 h. The reaction was quenched by the addition of sulfonamide 9 (213 mg, 0.78 mmol) in THF (1 mL) dropwise for 20 min. The resulting mixture was added H2O (10 mL) after 30 min and extracted with EtOAc (3  20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes, 1:5) to give 5b0 (167 mg, 64%) as a colorless paste. dr >99:1. [a]25 D = 15.7 (c 1.0, CHCl3). IR (KBr, film): 2972, 1792, 1735, 1335, 1186, 1138, 977 cm1. 1H NMR (400 MHz, CDCl3) d: 3.69 (septet, J = 6.8 Hz, 2H), 3.60 (s, 3H), 3.15 (d, J = 14.0 Hz, 1H),

2.98–2.88 (m, 1H), 2.68 (d, J = 14.0 Hz, 1H), 2.33–2.25 (m, 1H), 2.22–2.12 (m, 2H), 2.03–1.94 (m, 1H), 1.86–1.66 (m, 4H), 1.52 (s, 3H), 1.27 (s, 6H), 1.26 (s, 6H), 1.17 (d, J = 7.2 Hz, 3H), 1.09 (d, J = 7.2 Hz, 3H), 0.97 (s, 3H), 0.93 (s, 3H). 13C NMR (100 MHz, CDCl3) d: 175.0, 173.8, 116.5, 82.9, 54.6, 51.8, 51.1, 50.1, 48.1, 46.6, 44.1, 43.4, 37.7, 26.2, 25.2, 22.7, 21.6, 20.6, 19.9, 19.8, 17.2, 10.7. HRMS (ESI) calcd for C25H43NNaO7S [M+Na]+: 524.2658, found: 524.2650. Acknowledgements We thank the Ministry of Science and Technology (Taiwan) for financial support (NSC 102-2113-M-007-009-MY3). A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.05. 002. References 1. For example see: (a) Evidente, A.; Lanzetta, R.; Capasso, R.; Vurro, M.; Bottalico, A. Phytochemistry 1993, 34, 999; (b) Evidente, A.; Capasso, R.; Abouzeid, M. A.; Lanzetta, R.; Vurro, M.; Bottalico, A. J. Nat. 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