Stereoselective Synthesis of the ABC Ring System of

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Stereoselective Synthesis of the ABC Ring System of Aspterpenacids Shengling Xie, Pan Ren, Jieping Hou, Chengqing Ning, and Jing Xu J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 31 Oct 2018 Downloaded from http://pubs.acs.org on October 31, 2018

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The Journal of Organic Chemistry

Stereoselective Synthesis of the ABC Ring System of Aspterpenacids Shengling Xie,∥,a Pan Ren,∥,a,b Jieping Hou,a Chengqing Ning*,a,c and Jing Xu*,a a Department

of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, Guangdong,

China. b

School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, China

c

SUSTech Academy for Advanced Interdisciplinary Studies, Shenzhen, Guangdong, China

O

O

O

H

H

O

O

H

R

OH H COOH

Aspterpenacid A, R = OAc, 1S Aspterpenacid B, R = OH, 1R

Abstract: Aspterpenacids A and B are sesterterpenoids that possess a unique and highly congested 5/3/7/6/5 fused ring system. These compounds also contain a sterically encumbered isopropyl trans-hydrindane motif and a cyclopropane motif bearing two quaternary centers, which make them remarkably challenging synthetic targets. Herein, we report the successful construction of the key highly-substituted ABC ring system in a stereoselective manner.

Sesterterpenoids are a small family of terpenes, that commonly

the Trauner group accomplished an impressive asymmetric

have complex chemical architectures and intriguing biological

synthesis of nitidasin.13 Recently, our group also achieved the

activities, such as anti-inflammatory, anticarcinogenic, and

first and enantiospecific synthesis of astellatol.14 Encouraged

antimicrobial

activities.1,2

Isopropyl

trans-hydrindane

by these endeavor, we now report recent efforts toward the

sesterterpenoids are a major class of sesterterpenoids that,

synthesis

contain isopropyl- or isopropenyl-substituted trans-hydrindane

aspterpenacids.

motifs as common include

features.3

aspterpenacids,4

of

Representative compounds

retigeranic acids,5 astellatol,6 and

nitidasin7 (Figure 1). These isopropyl trans-hydrindane sesterterpenoids also commonly possess a highly congested ring system containing various stereocenters, including several quaternary and/or tetra-substituted carbon centers, that presents a significant synthetic challenge. Another obvious challenge is also presented by the well-known problematic trans-hydrindane motif3,8 of these unique sesterterpenoids. Unsurprisingly, the total synthesis of these sesterterpenoids have long attracted the attetion of synthetic chemists.9 The pioneering synthesis of retigeranic acid A was achieved by the Corey,8 Paquette,10 Hudlicky,11 and Wender12 groups. In 2014, ACS Paragon Plus Environment

the

challenging

ABC

ring

moiety

of

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

H

OAc

H

OH H

R

Page 2 of 9

Co/Rh/Pd mediated cyclization & directed hydrogenation

C

H

OH H COOH

OH H COOH

H

aspterpenacid A

7

A

H

aspterpenacid B

H

B

OH H COOH

Acylation

H

HO2C

4

H H

OH H

HO

endo-phytic fungus Aspergillus terreus H010 by Huang and She in 2016.4 These compounds possess a unique highly system

featuring

a

cyclopropane motif bearing two quaternary centers and a sterically encumbered isopropyl trans-hydrindane moiety. Our retrosynthetic analysis of these aspterpenacids is shown in 1.

We

envisaged

that

the

challenging

trans-hydrindane motif of aspterpenacids could be constructed from intermediate 1 via a metal-mediated cyclization reaction, such as Pauson–Khand reaction or enyne cycloisomerization reaction, and directed hydrogenation, similar to chemistry

the procedure of Danishefsky et al.15 The 1,2-reduction of 4 afforded allylic alcohol 7. Initially, the attempted coupling of 7 and diazo ketoacid 8 was unsuccessful.16 Therefore, alcohol 7 was reacted with the diketene first to afford ketoester 10 in 84% yield. Treatment of 10 with 4-acetamidobenzenesulfonyl azide (p-ABSA) afforded the desired diazoketoester. Various intramolecular cyclopropanation conditions were tested on substrate 9. However, all metal-catalysts tested under these conditions, including Rh2(OAc)4, Rh2(Ooct)4, Cu(acac)2, and Cu(TBSal)2, did not afford even trace amounts of desired compound 3. The presence of the terminal alkyne was thought to deactivate the catalysts.

established in our synthesis of astellatol14. The installation of a methyl group at the C-7 position should deliver compound 1 from 2. The seven-membered ring in 2 should be accessible from alkyne 3 via a gold-catalyzed Conia–ene reaction. Finally, sequential

reduction/acylation/intramolecular

cyclopropanation of 4 would furnish the congested skeleton of key compound 3. The C-7 methyl group is planned to be introduced at rather late stage because early stage introduction would most likely produce the opposite stereochemistry in the cyclopropanation corresponding

step,

while

intermolecular

the

2

alkyne 6 (Scheme 2), which was converted into ketone 4 using

Aspterpenacids A and B were isolated from the mangrove

ring

O

H

Our synthetic attempts started from commercially available

Figure 1. Isopropyl trans-hydrindane sesterterpenoids.

fused

3

Conia-ene reaction

Scheme 1. Retrosynthetic analysis of aspterpenacids.

nitidasin

5/3/7/6/5

Intramolecular H cyclopropanation

O H

O

astellatol

O

O O

retigeranic acid B

H

O

O

O

H

HO2C

retigeranic acid A

Scheme

1

aspterpenacid A, R = OAc, 1S aspterpenacid B, R = OH, 1R

H

congested

O H CO2H

H

H

H

Methylation

feasibility

cyclopropanation

of

the

is

also

uncertain.

ACS Paragon Plus Environment

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O

Ref. 15

MeOH, 0oC, 15 min, 98%

HO 6

4 O

O

O

HO

OH

N2

O

O

OH

n-BuLi, TMSCl

TMS

THF, -78 oC, 5 h, 87%

7

O

O TMS

p-ABSA, Et3N

N2

O

DMAP, CH2Cl2 rt, 8 h, 79%

11

O

O

O

8

various conditions

7

OH

NaBH4, CeCl3 7H2O

O

O

TMS

N2

MeCN, rt, 2 h, 98% 12

9

13 TMS

O OH O

O

O

DMAP, CH2Cl2 rt, 8 h, 84%

7

Cu(TBSal)2 (10 mol%)

O p-ABSA, Et3N

10

MeCN, rt, 2h, 98%

O

O

PhMe, 110 oC, 3 h, 25%

TBAF, THF

14

O various cyclopropanation conditions

O

Conia-ene

TBSOTf, Et3N

O

O

CH2Cl2, rt, 2 h, 88%

N2

H OTBS

O H

9

3

O 3

H

O

O O

55 oC, 8 h, 88%

O H

O

O

15

O

O

O

H 16

Scheme 3. Synthetic efforts toward tetracyclic compound

Scheme 2. Synthetic efforts toward compound 3.

16.

Therefore, the terminal alkyne in compound 7 was protected

These unsuccessful Conia–ene cyclization attempts forced us

with a TMS group to afford compound 11 (Scheme 3). The

to reconsider our strategy (Scheme 4). From readily available

secondary alcohol was also silylated in the reaction, but then

diketone 17,18 an olefination and reduction sequence afforded

deprotected during the acidic workup. Acylation of 11

compound 19 in racemic form. Following the same

furnished ketoester 12, which was subjected to the

transformations described earlier, 19 was acylated, diazolated,

diazo-transfer reaction under the same p-ABSA conditions to

and subjected to Cu-catalyzed cyclopropanation conditions to

afford diazoketoester 13. Although most cyclopropanation

successfully afford tricyclic compound 22. Methylenation

conditions were unsuccessful, in the presence of Cu(TBSal)2

under Eschenmoser’s conditions yielded diene 23. The initially

yield.16

attempted ring-closing metathesis (RCM) of substrate 23 was

Removal of the TMS group using TBAF smoothly furnished

unsuccessful. However, after reducing ketone 23, the

key compound 3, which contained the critical cyclopropane

corresponding allylic alcohol smoothly underwent RCM to

motif bearing two quaternary centers. An intramolecular

afford compound 24 as a mixture of two diastereomers.

gold-catalyzed Conia–ene reaction between the silyl enol ether

Subsequent Ley oxidation afforded key compound 2 bearing

(10 mol%), compound 14 was isolated in 25%

and alkyne moieties of

1517

was expected to afford the desired

the desired aspterpenacid ABC ring system.

seven-membered ring via a 7-exo-dig cyclization. However, all attempts to prepare desired product 16 under various

In summary, we have developed a facile synthesis of the

conditions were unsuccessful. The theoretical calculation for

sterically encumbered ABC ring system of aspterpenacids, a

reasoning the failed attempts is currently under investigation

rare type of sesterterpenoid. Our strategy features an

and will be reported in due course.

intramolecular cyclopropanation to form the B ring and an RCM reaction to form the C ring, and paves the way for the total synthesis of aspterpenacids. Notably, accessing the asymmetric synthetic route should be feasible because the asymmetric reduction of compound 18 would be readily achieved

via


a

Corey–Bakshi–Shibata

reduction19

or


Page 4 of 9

asymmetric hydrogenation.20 Further efforts toward the total

singlet; d, doublet; t, triplet; dt, double triplet; dq, double

synthesis of aspterpenacids are currently underway in our

quartet; ddd, doublet of double doublet; ddt, doublet of double

laboratory and will be reported in due course.

triplet; m, multiplet. High-resolution mass spectra (HRMS) were recorded on a Thermo Scientific Q Exactive Hybrid

O

O

NaBH4, CeCl3.7H2O

THF, 0 oC, 4h, 80%

17

O DMAP

O

Ph3PCH3Br, n-BuLi

O

O

Quadrupole-Orbitrap mass spectrometer.

OH

Compound 7. To a solution of compound 4 (5.0 g, 37.3

MeOH, 0 oC, 10min, 98%

18 O

O

O

p-ABSA, Et3N

O

NH4Cl (30 mL) was then added and the reaction mixture was

MeCN, 2h, 98%

O

with H2O (100 mL) and extracted with EtOAc (2×100 mL).

1. Et3N, TMSOTf, DCM, 0 oC 2. Eschenmoser's salt, DCM, 0 oC O

22

O

O

combined organic phase was dried over MgSO4, filtered,

H O 23

concentrated, and purified by column chromatography

Various x RCM conditions O

O

H

(petroleum ether/EtOAc, 5:1) to afford compound 7 (4.97 g, O

O

TPAP, NMO CH2Cl2, rt HO

81%

O

H 2

Scheme 4. Synthesis of the aspterpenacid ABC ring system.

reactions were conducted under a nitrogen atmosphere and anhydrous conditions. Tetrahydrofuran (THF) was distilled from sodium-benzophenone under an argon atmosphere. Dichloromethane (DCM) was distilled from calcium hydride. Reactions were monitored by thin-layer chromatography (TLC; GF254) using plates supplied by Yantai Chemicals (China) and visualized under UV or by staining with an ethanolic solution of phosphomolybdic acid, cerium sulfate, or

iodine.

J = 17.4, 15.3, 7.6, 4.8 Hz, 2H), 2.12 (s, 1H), 1.95 (s, 1H), 1.67 (ddt, J = 12.3, 7.9, 4.2 Hz, 1H) ppm; 13C{1H} NMR (100 17.3 ppm; HRMS-ESI (m/z): [M+H]+ calcd for C9H13O

General Information. Unless otherwise mentioned, all

solution,

1H), 4.65 (d, J = 7.3 Hz, 1H), 2.45–2.30 (m, 5H), 2.23 (dddd,

MHz, CDCl3) δ 144.4, 128.5, 84.6, 78.6, 68.7, 34.0, 29.7, 27.3,

■ EXPERIMENTAL SECTION

KMnO4

98%) as a colorless oil. TLC Rf = 0.3 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 5.60 (s,

24

basic

The organic layer was sequentially washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The

3. MeI, DCM, rt 76%

H

1. NaBH4, CeCl3.7H2O MeOH, 10min, 98% 2. Grubbs2nd cat., PhMe 80 oC, 3h, 94%

concentrated under reduced pressure. The residue was diluted

21

O

0 ℃. NaBH4 (2.1 g, 55.9 mmol) was then added carefully, followed by stirring for 5 min at room temperature. Aqueous

N2

20

PhMe, 110 oC, 3 h, 27%

(18.0 g, 48.5 mmol) and the mixture was stirred for 5 min at

O

DCM, rt, 8h, 84%

Cu(TBSal)2 (10 mol%)

mmol)15 in MeOH (100 mL) at 0 ℃ was added CeCl3·7H2O

19

Flash

column

chromatography was performed using silica gel (particle size, 0.040–0.063 mm). NMR spectra were recorded on Bruker AV400 or AV500 MHz instruments and calibrated using residual undeuterated chloroform in CDCl3 (δH = 7.26 ppm, δC = 77.0 ppm) as internal reference. The following abbreviations were used to describe signal multiplicities: s,

137.0961; found 137.0960. Compound 10. To a solution of compound 7 (2.0 g, 14.7 mmol) in dry CH2Cl2 (120 mL) at room temperature was added DMAP (179.4 mg, 1.5 mmol) and the mixture was stirred for 5 min. Diketene (1.5 g, 17.6 mmol) was carefully added, and the resulting mixture was stirred for 8 h at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc, 20:1) to afford compound 10 (2.7 g, 84%) as a yellow oil. TLC Rf = 0.60 (silica gel, petroleum ether/EtOAc = 8:1); 1H NMR (400 MHz, CDCl3) δ 5.81 (s, 1H), 5.77–5.67 (m, 1H), 3.45 (s, 2H), 2.51–2.42 (m, 1H), 2.41–2.27 (m, 6H), 2.26 (s, 3H), 1.95 (s, 1H), 1.87–1.75 (m, 1H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ 200.7, 167.3,

140.2, 132.1, 84.0, 82.4, 68.8, 50.5, 30.9, 30.4, 30.3, 27.4, 17.2 ppm; HRMS-ESI (m/z): [M+H]+ calcd for C13H17O3221.1172; found 221.1169.


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chromatography (petroleum ether/EtOAc, 25:1) to afford

mmol) and p-acetamidobenzensulfonyl azide (p-ABSA, 3.9 g,

compound 12 (3.3 g, 79%) as a yellow oil. TLC Rf = 0.64

16.3 mmol) in MeCN (150 mL) at 0 C was added

(silica gel, petroleum ether/EtOAc = 10:1); 1H NMR (500

triethylamine (5.7 mL, 40.9 mmol) dropwise. The reaction

MHz, CDCl3) δ 5.78 (s, 1H), 5.75–5.67 (m, 1H), 3.44 (s, 2H),

mixture was warmed to room temperature and stirred for 2 h.

2.45 (dddd, J = 15.6, 9.0, 4.5, 2.3 Hz, 1H), 2.41–2.22 (m, 9H),

The solvent was removed under reduced pressure and the

1.82 (ddt, J = 10.5, 8.4, 3.9 Hz, 1H), 0.13 (s, 9H) ppm; 13C{1H}

residue triturated with ether/hexanes (1:1, 200 mL). The

NMR ( MHz, CDCl3) δ 200.8, 167.3, 140.3, 132.1, 106.8, 85.1,

mixture was then filtered, concentrated, and purified by

82.5, 50.5, 31.0, 30.4, 30.3, 27.5, 18.8, 0.2 ppm; HRMS-ESI

column chromatography (petroleum ether/EtOAc, 20:1) to

(m/z): [M–H] calcd for C16H23O3Si291.1422; found 291.1425.

give compound 9 (3.3 g, 98%) as a colorless oil. TLC Rf

=


NMR (400


MHz, CDCl3) δ 5.84 (s, 1H), 5.83–5.78 (m, 1H), 2.47 (s, 4H),

14.4 mmol) in MeCN (150 ml) at 0 C was added Et3N (7.0

2.45–2.27 (m, 6H), 1.96 (t, J = 2.5 Hz, 1H), 1.91–1.82 (m, 1H)

mL, 35.9 mmol). The reaction mixture was warmed to room

0.73 (silica gel, petroleum ether/EtOAc = 8:1);

1H

NMR (100 MHz, CDCl3) δ 190.3, 161.6, 139.9,

temperature and stirred for 2 h. The solvent was then removed

132.5, 83.8, 82.8, 68.9, 31.2, 30.3, 28.4, 27.5, 17.3 ppm;

under reduced pressure and the residue triturated with

HRMS-ESI (m/z): [M+H]+ calcd for C13H15N2O3 247.1077;

ether/hexanes (1:1, 200 mL). The mixture was filtered,

found 247.1074.


ppm;

13C{1H}

Compound 11. To a stirred solution of compound 7 (2.0 g,

(petroleum ether/EtOAc, 25:1) to afford compound 13 (3.74 g,

14.7 mmol) in THF (150 mL) at 78 C was added n-BuLi

98%) as a colorless oil. TLC Rf = 0.74 (silica gel, petroleum

(2.4 M, 14.1 mL, 33.8 mmol) dropwise via cannula. The

ether/EtOAc = 10:1); 1H NMR (400 MHz, CDCl3) δ 5.83–5.76

resulting reaction mixture was stirred for another 2 h at 78 C.

(m, 2H), 2.46 (s, 4H), 2.43–2.35 (m, 3H), 2.35–2.24 (m, 3H),

Chlorotrimethylsilane (TMSCl, 4.0 g, 36.7 mmol) was then

1.89–1.80 (m, 1H), 0.12 (s, 9H) ppm;

added slowly via syringe. The reaction mixture was then

MHz, CDCl3) δ 190.4, 161.6, 140.0, 132.6, 106.5, 85.3, 82.9,

warmed to 0 C over 4 h, 2 N HCl (30 mL) was slowly added

31.2, 30.3, 28.4, 27.7, 18.9, 0.2 ppm; HRMS-ESI (m/z):

at 0 C, and the mixture was stirred for a further 30 min. The

[M+H]+, calcd for C16H23N2O3Si 319.1472; found 319.1470.

13C{1H}

NMR (125

reaction mixture was extracted with Et2O (3 × 100 mL) and

Compound 14. A solution of Cu(TBSal)2 (39.4 mg, 0.094

the combined organic layers were washed with saturated

mmol) in toluene (2.4 mL) was heated to 110 C under an

aqueous NaHCO3 and brine, dried over MgSO4, and

argon atmosphere. A warm solution of diazo compound 13

concentrated in vacuo to afford compound 11 (2.66 g, 87%) as

(200.0 mg, 0.628 mmol) in toluene (20 mL) was then added

a colorless oil. TLC Rf = 0.58 (silica gel, petroleum

dropwise over 30 min and the reaction was monitored by TLC

NMR (400 MHz, CDCl3) δ 5.61 (s,

(EtOAc/hexanes, 1:5). After 100 min, the reaction mixture was

1H), 4.69 (s, 1H), 2.47–2.34 (m, 5H), 2.34–2.25 (m, 1H),

allowed to cool to ambient temperature and concentrated. The

2.24–2.15 (m, 1H), 1.78 (s, 1H), 1.74–1.65 (m, 1H), 0.13 (s,

residue was purified by flash chromatography (petroleum

ether/EtOAc = 10:1);

9H) ppm;

13C{1H}

1H

NMR (100 MHz, CDCl3) δ 144.7, 128.8,

ether/EtOAc, 25:1) to afford compound 14 (45.6 mg, 25%) as

107.6, 85.2, 78.7, 34.1, 29.8, 27.6, 19.2, 0.2 ppm; HRMS-ESI

a yellow oil. TLC Rf = 0.48 (silica gel, petroleum ether/EtOAc

(m/z): [M+H]+ calcd for C12H21OSi 209.1356; found209.1353.

= 5:1); 1H NMR (500 MHz, CDCl3) δ 4.98 (s, 1H), 2.88 (d, J =

Compound 12. To a solution of compound 11 (3 g, 14.4

6.3 Hz, 1H), 2.55 (s, 3H), 2.36–2.25 (m, 3H), 2.09–2.00 (m,

mmol) in CH2Cl2 (150 mL) at room temperature was added

3H), 1.94 (ddd, J = 14.3, 8.0, 6.3 Hz, 1H), 1.84–1.76 (m, 1H),

DMAP (175.9 mg, 1.4 mmol) and the mixture was stirred for 5

0.15 (s, 9H) ppm;

min. Diketene (1.5 g, 17.3 mmol) was carefully added and the

172.7, 105.1, 86.7, 85.5, 60.0, 50.0, 43.3, 38.7, 30.6, 24.4, 24.3,

resulting mixture was stirred for 8 h at room temperature and

18.4, 0.0 ppm; HRMS-ESI (m/z): [M+H]+ calcd for

then concentrated. The residue was purified by column

C16H23O3Si 291.1411; found 291.1406.


13C{1H}

NMR 125 MHz, CDCl3) δ 199.6,


Page 6 of 9

Compound 3. To a solution of compound 14 (300 mg, 1.03

and stirred for 30 min. A solution of compound 17 (2 g, 13.1

mmol) in THF (10 mL) and H2O (3 mL) was added

mmol)18 in THF (10 mL) was then added dropwise via syringe

tetrabutylammonium fluoride (TBAF) solution (1.3 mL, 1.0 M

and the mixture was warmed to room temperature and stirred

in THF) and AcOH (3 mL) at 0 C. The reaction mixture was

for 4 h. The reaction mixture was quenched with saturated

stirred for 8 h at 55 C, quenched with H2O, and extracted with

aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL).

EtOAc. The combined organic extracts were washed with

The combined organic extracts were washed with water, dried

brine, dried over MgSO4, filtered, and concentrated. The

over MgSO4, and concentrated in vacuo. The residue was

residue was purified by column chromatography (petroleum

purified by column chromatography (petroleum ether/EtOAc,

ether/EtOAc, 15:1) to afford compound 3 (198.5 mg, 88%) as

15:1) to afford compound 18 (1.6 g, 80%) as a colorless oil.

a colorless oil. TLC Rf = 0.42 (silica gel, petroleum ether/

TLC Rf = 0.61 (silica gel, petroleum ether/EtOAc = 5:1); 1H

EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 4.97 (s, 1H),

NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 4.72 (s, 1H), 4.68 (s,

2.87 (d, J = 6.4 Hz, 1H), 2.55 (s, 3H), 2.36–2.25 (m, 3H),

1H), 2.56 (tt, J = 4.8, 2.2 Hz, 2H), 2.43–2.35 (m, 2H), 2.36–

2.14–2.06 (m, 1H), 2.06–1.92 (m, 4H), 1.86–1.76 (m, 1H) ppm;

2.28 (m, 2H), 2.20 (dd, J = 9.5, 5.6 Hz, 2H), 1.73 (s, 3H) ppm;

13C{1H}

13C{1H}

NMR (100 MHz, CDCl3) δ 199.7, 172.6, 85.1, 82.5,

NMR (100 MHz, CDCl3) δ 210.1, 157.7, 145.9, 145.0,

70.3, 59.8, 49.9, 43.4, 38.7, 30.6, 24.4, 23.9, 17.1 ppm.

110.6, 35.7, 34.7, 26.6, 23.0, 22.5 ppm. HRMS-ESI (m/z):

HRMS-ESI (m/z): [M+H]+ calcd for C13H15O3 219.1016; found

[M+H]+ calcd for C10H15O 151.1117; found 151.1117.

219.1010.


Compound 15. To a solution of compound 3 (300.0 mg, 1.4

mmol) in MeOH (70 mL) at 0 C was added CeCl3·7H2O

mmol) and triethylamine (417.0 mg, 4.1 mmol) in CH2Cl2 (15

(11.2 g, 30.0 mmol) and the mixture was stirred for 5 min.

mL) at 0 C was added TBSOTf (445.6 mg, 2.1 mmol),

NaBH4 (1.0 g, 26 mmol) was then carefully added, followed

followed by stirring for 2 h. The reaction mixture was diluted

by stirring for 5 min at room temperature. The resulting

with CH2Cl2 and washed with cold sodium bicarbonate. The

reaction mixture was quenched with aqueous NH4Cl (30 mL)

organic layer was dried over MgSO4, concentrated, and the

and concentrated under reduced pressure. The resulting residue

residue was washed with dry ether to remove the insoluble

was diluted with H2O (100 mL) and extracted with EtOAc (2 ×

triethylammonium triflate salt. The combined ether solution

100 mL). The organic layer was sequentially washed with

was then concentrated and underwent chromatography on

saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The

basic alumina (pH 9.0–9.5) using hexane as the eluent to

organic phase was dried over anhydrous MgSO4, filtered,

afford compound 15 (402.2 mg, 88%) as a yellow oil. TLC Rf


NMR


(400 MHz, CDCl3) δ 4.89 (s, 1H), 4.45 (d, J = 2.0 Hz, 1H),


4.39 (d, J = 1.8 Hz, 1H), 2.35 (td, J = 7.3, 2.7 Hz, 3H), 2.29–

ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 5.56 (s,

2.18 (m, 1H), 2.13 (dt, J = 13.2, 6.6 Hz, 1H), 2.06–1.94 (m,

1H), 4.71 (d, J = 6.7 Hz, 2H), 4.66 (s, 1H), 2.47–2.37 (m, 1H),

3H), 1.80 (dt, J = 14.8, 7.6 Hz, 1H), 1.77–1.69 (m, 1H), 0.90

2.35–2.14 (m, 6H), 1.74 (s, 3H), 1.70 (ddd, J = 13.0, 8.8, 4.2

= 0.59 (silica gel, petroleum ether/EtOAc = 20:1);

(s, 9H), 0.21 (d, J = 5.3 Hz, 6H) ppm;

13C{1H}

1H

NMR (100

Hz, 1H), 1.42 (d, J = 6.1 Hz, 1H) ppm;

13C{1H}

NMR (100

MHz, CDCl3) δ 174.0, 150.7, 95.0, 85.5, 83.3, 69.6, 52.2, 46.9,

MHz, CDCl3) δ 146.0, 145.9, 127.5, 110.1, 79.1, 36.0, 34.2,

39.7, 36.6, 26.7, 25.8, 23.9, 18.2, 16.8, 4.4, 5.0 ppm.

29.8, 26.4, 22.6 ppm. HRMS-ESI (m/z): [M+H]+ calcd for

HRMS-ESI (m/z): [M+H]+ calcd for C19H29O3Si 333.1880;

C10H17O153.1274; found153.1271.

found 333.1871. Compound

Compound 20. To a solution of compound 19 (2 g, 13.1 18.

To

a

solution

of

mmol) in dry CH2Cl2 (100 mL) was added DMAP (0.16 g, 1.3

methyltriphenylphosphonium bromide (9.4 g, 26.2 mmol) in

mmol) and the mixture was stirred for 5 min at room

THF (100 mL) at 78 C was added n-BuLi (2.4 M, 10.4 mL,

temperature. Diketene (1.2 g, 14.4 mmol) was carefully added

25.0 mmol) dropwise. The reaction was then warmed to 0 C

and the resulting reaction mixture was stirred for 8 h at room


Page 7 of 9 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


temperature and then concentrated. The resulting residue was

42.9, 38.6, 36.0, 30.4, 24.4, 23.4, 22.2 ppm. HRMS-ESI (m/z):


[M+H]+ calcd for C14H19O3 235.1329; found 235.1326.


Compound 23. To a solution of compound 22 (200 mg,

1H

0.85 mmol) and Et3N (0.35 mL, 2.6 mmol) in CH2Cl2 (50 mL)

NMR (400 MHz, CDCl3) δ 5.73 (d, J = 6.8 Hz, 2H), 4.72 (s,

at 0 C was added TMSOTf (0.31 mL, 1.7 mmol) slowly. The

1H), 4.69 (s, 1H), 3.45 (s, 2H), 2.44 (dddd, J = 17.1, 8.8, 4.3,

resulting reaction mixture was stirred for 2 h at room

2.1 Hz, 1H), 2.38–2.32 (m, 1H), 2.28–2.14 (m, 8H), 1.81 (ddt,

temperature and then diluted with water (50 mL), extracted

J = 13.3, 7.7, 3.5 Hz, 1H), 1.72 (s, 3H) ppm;

NMR

with CH2Cl2 (3 × 25 mL), dried over MgSO4, and

(100 MHz, CDCl3) δ 200.7, 167.4, 145.4, 141.8, 130.9, 110.3,

concentrated. The residue was dissolved in CH2Cl2 (50 mL)

82.7, 50.5, 35.8, 30.9, 30.3, 30.3, 26.4, 22.5 ppm. HRMS-ESI

and Eschenmoser’s salt (393 mg, 2.1 mmol) was added at 0 C.

TLC Rf = 0.54 (silica gel, petroleum ether/EtOAc = 5:1);

(m/z):

[M+H]+

13C{1H}

calcd for C14H21O3 237.1485; found 237.1477.

The resulting mixture was then stirred for 2 h at room


temperature and then diluted with water (30 mL) and extracted


with CH2Cl2 (3 × 20 mL). The combined organic extracts were

12.7 mmol) in MeCN (100 ml) at 0 C was added Et3N (4.4

washed with brine and dried with MgSO4. The solvent was

mL, 31.8 mmol) dropwise. The reaction mixture was warmed

evaporated to give a grey–green oil that was then dissolved in

to room temperature and stirred for 2 h. The solvent was

CH2Cl2 (50 mL). To this solution was added MeI (0.16 mL,

removed under reduced pressure and the residue was triturated

2.6 mmol) and the mixture was stirred for 5 min. DBU (0.39

with ether/hexanes (1:1, 200 mL). The mixture was filtered,

mL, 2.6 mmol) was then added and the reaction mixture was


stirred for a further 1 h at room temperature. Aqueous


NaHCO3 (30 mL) was then added and the mixture was


extracted with CH2Cl2 (3 × 20 mL). The combined organic

NMR (400 MHz, CDCl3) δ 5.79 (d, J =

extract was washed with brine, dried with MgSO4,

4.0 Hz, 1H), 5.75 (s, 1H), 4.72 (s, 1H), 4.68 (s, 1H), 2.48 (s,


3H), 2.47–2.36 (m, 2H), 2.34 – 2.26 (m, 1H), 2.26–2.12 (m,

(petroleum ether/EtOAc, 15:1) to afford compound 23 (160

ether/EtOAc = 5:1);

1H

NMR (100

mg, 76%) as a colorless oil. TLC Rf = 0.41 (silica gel,

MHz, CDCl3) δ 190.4, 161.7, 145.2, 141.4, 131.3, 110.4, 83.1,

petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ

35.8, 31.2, 30.3, 28.4, 26.5, 22.5 ppm. HRMS-ESI (m/z):

7.30 (dd, J = 17.0, 10.4 Hz, 1H), 6.33 (dd, J = 17.0, 1.8 Hz,

[M+H]+ calcd for C14H19N2O3 263.1390; found 263.1382.

1H), 5.74 (dd, J = 10.4, 1.8 Hz, 1H), 4.84 (d, J = 3.1 Hz, 1H),

4H), 1.90–1.80 (m, 1H), 1.72 (s, 3H) ppm;

13C{1H}

Compound 22. To a hot solution (110 C) of Cu(TBSal)2

4.72 (s, 1H), 4.68 (s, 1H), 2.93 (d, J = 6.2 Hz, 1H), 2.36–2.26

(0.4 g, 0.95 mmol) in toluene (100 mL) was added a warm

(m, 1H), 2.15–1.77 (m, 7H), 1.67 (s, 3H) ppm; 13C{1H} NMR

solution of diazo compound 21 (2.5 g, 9.5 mmol) in toluene

(100 MHz, CDCl3) δ 190.2, 172.9, 144.0, 133.2, 129.2, 111.7,

(10 mL) dropwise over 30 min. The reaction was monitored by

85.2, 61.2, 49.9, 42.8, 38.7, 36.1, 24.4, 23.7, 22.2 ppm.

TLC (EtOAc/hexanes, 1:5). After 3 h, the reaction mixture

HRMS-ESI (m/z): [M+H]+ calcd for C15H19O3 247.1329;

was allowed to cool to ambient temperature, concentrated, and

found 247.1325.


Compound 2. To a solution of compound 23 (100 mg, 0.41


mmol) in MeOH (15 mL) at 0 C was added CeCl3·7H2O (227

TLC Rf = 0.38 (silica gel, petroleum ether/EtOAc = 5:1); 1H

mg, 0.61 mmol) and the reaction mixture was stirred for 5 min.

NMR (400 MHz, CDCl3) δ 4.79 (d, J = 1.6 Hz, 1H), 4.73 (s,

NaBH4 (20 mg, 0.53 mmol) was then added, followed by

1H), 4.67 (s, 1H), 2.82 (d, J = 6.4 Hz, 1H), 2.52 (s, 3H), 2.32–

stirring for 5 min at room temperature. The reaction mixture

2.23 (m, 1H), 2.09 (dddd, J = 14.5, 10.3, 6.3, 1.5 Hz, 1H),

was then quenched with aqueous NH4Cl (10 mL) and

2.03–1.77 (m, 6H), 1.67 (s, 3H) ppm;

13C{1H}

NMR (100

concentrated. The resulting residue was diluted with H2O (10

MHz, CDCl3) δ 199.4, 172.9, 144.0, 111.6, 84.9, 60.8, 49.9,

mL) and extracted with EtOAc (2 × 20 mL). The combined



Page 8 of 9

organic extracts were sequentially washed with saturated

Financial support from the National Natural Science Foundation of

aqueous NaHCO3 (10 mL) and brine (10 mL). The organic

China

phase was dried over MgSO4, filtered, and concentrated, and

Construction Program), SZSTI (JCYJ20170817110515599 and

the resulting residue was used directly in the next step.

KQJSCX2017072815423320), and the Shenzhen Nobel Prize

A solution of the as-obtained alcohol (50 mg, 0.201 mmol)

(No.

21402082

and

21772082),

SZDRC

(Discipline

Scientists Laboratory Project (C17213101) is greatly appreciated.

and Grubbs 2nd generation catalyst (17 mg, 0.020 mmol, 10 mol%) in toluene (30 mL) was heated to 80 °C for 3 h. The reaction mixture was then concentrated and purified by column chromatography (petroleum ether/EtOAc, 10:1→2:1)

■ REFERENCES [1]

to afford compound 24 (44 mg, 94%) as a colorless oil. To a suspension of compound 24 (40 mg, 0.18 mmol) in dry CH2Cl2 was added TPAP (6.5 mg, 0.018 mmol) and NMO

[2]

(42.3 mg, 0.36 mmol). The mixture was vigorously stirred for 2 h and then filtered through a pad of Celite. The filtrate was concentrated and purified by flash chromatography (petroleum ether/EtOAc, 2:1→1:1) to afford ketone 2 (32 mg, 81%) as a colorless oil. TLC Rf = 0.3 (silica gel, petroleum ether/EtOAc = 2:1); 1H NMR (400 MHz, CDCl3) δ 5.88 (s, 1H), 4.76 (d, J = 1.2 Hz, 1H), 2.74 (d, J = 6.5 Hz, 1H), 2.58–2.52 (m, 1H), 2.52–2.47 (m, 1H), 2.41–2.33 (m, 1H), 2.33–2.26 (m, 1H), 2.12 (ddd, J = 14.7, 6.1, 3.7 Hz, 1H), 2.09–2.03 (m, 1H), 2.00– 1.93 (m, 1H), 1.90 (s, 3H), 1.89–1.82 (m, 1H) ppm;

13C{1H}

[3]

NMR (100 MHz, CDCl3) δ 189.9, 170.1, 154.5, 127.8, 85.2, 53.4, 49.3, 40.7, 39.0, 34.0, 28.1, 25.3, 24.7 ppm; HRMS-ESI (m/z): [M+H]+ calcd for C13H15O3 219.1016; found 219.1009. ■ ASSOCIATED CONTENT Supporting Information 1H

[4]

[5]

and 13C NMR spectra of all new compounds

■ AUTHOR INFORMATION

[6]

Corresponding Author *E-mail: [email protected]; [email protected] ORCID Jing Xu: 0000-0002-5304-7350 Author Contributions

[7]

∥These

authors contributed equally. Notes The authors declare no competing financial interest.

[8]

■ ACKNOWLEDGEMENTS

[9]

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Stereoselective Synthesis of the ABC Ring System of

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