Modified Julia-Kocienski reagents for a stereoselective introduction of

Subscriber access provided by Kaohsiung Medical University

Modified Julia-Kocienski reagents for a stereoselective introduction of trisubstituted double bonds: a formal total synthesis of Limazepine E and Barmumycin Guna Sakaine, and Gints Smits J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00643 • Publication Date (Web): 11 Apr 2018 Downloaded from http://pubs.acs.org on April 11, 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 29 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

Modified Julia-Kocienski reagents for a stereoselective introduction of trisubstituted double bonds: a formal total synthesis of Limazepine E and Barmumycin Guna Sakaine and Gints Smits*

Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, Latvia, LV-1006

*[email protected] N N N N R

Ph OH MeO

OH

O MeO

+

O

N

H

MeO2C

N CO2 H H t rans-4-Hydroxy-L-proline Isovanillic acid

N O

Ph SO2 Et

O

Julia-K ocienski O ol ef inati on

OH

O

N

MeO

H

MeO

N

H N

O R= Ph R=

N

E-/Z- 89:11 E-/Z- 97:3

O Limazepine E

cHex cHex

cHex

Abstract: A formal total synthesis of pyrrolo[1,4]benzodiazepine (PBD) anticancer antibiotic family member Limazepine E is described. The synthesis features a stereoselective introduction of trisubstituted double bond using novel sterically demanding Julia-Kocienski reagents, allowing significantly reduce the number of linear steps. The potential of the newly developed reagents has also been demonstrated by the formal total synthesis of Barmumycin.

Limazepine E 6 was isolated in 2009 from Micrococus sp. strain ICBB 81771 and belongs to a broad and expanding family of pyrrolo[1,4] benzodiazepine (PBD) natural products. Many PBD class members posses anticancer activity owing to their ability to covalently bind to the minor grove of DNA.2–4 A number of PBDs as well as

1 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 29

their antibody drug conjugates (ADC) have been evaluated as anticancer agents and are currently undergoing clinical trials.5

Figure 1. Representative examples of PBD natural products containing C2 alkylidene group.

Most PBDs possess a right-hand twisted three ring system, furthermore several naturally occurring PBD contain a C2 alkylidene group, some examples are shown in Figure 1.1,6–9 Importantly, it has been shown that a C2 double bond significantly increases the anticancer activity.10 Although total synthesis of Limazepine E11 6 and several related (E)-2-ethylidene PBDs12–15 have been reported, a stereoselective introduction of C2 alkylidene group still poses a considerable challenge. Moreover, the classical olefination methods (Wittig and Julia-Kocienski) lack selectivity or give the undesired Z- isomer predominantly.12,16–18 An alternative method for an Eselective introduction of trisubstituted double bond was introduced based on stereoselective

Ireland-Claisen

rearrangement,11,19

however

the

desired

3-

ethylidenproline building block was obtained in a linear sequence of 9 steps. Herein, we report a concise formal total synthesis of Limazepine E employing new sterically demanding Julia-Kocienski reagents for a stereoselective introduction of C2 alkylidene substituent.


Page 3 of 29 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


Our retrosynthetic analysis (Scheme 1) was based on a late stage introduction of the trisubstituted double bond, followed by selective C11 carbonyl reduction. The prerequisite ketone 8 could be easily constructed from inexpensive and readily available starting materials – isovanillic acid and trans-4-hydroxy-L-proline, followed by an oxidation of the intermediate dilactam 9.

Scheme 1. Retrosynthetic analysis of Limazepine E

The synthesis started with conversion of isovanilic acid into the corresponding nitrobenzoic acid 10 (Scheme 2). The latter was coupled with trans-4-hydroxy-Lproline producing the intermediate 11 in a good yield.18 Hydrogenation of the amide 11, followed by treatment with benzaldehyde dimethyl acetal at elevated temperature furnished the alcohol 12, which after oxidation gave the ketone 12 necessary for C2 olefination studies.

Scheme 2. The synthesis of ketone 13.



Page 4 of 29

With the ketone 13 in hand we began our studies for the stereoselective introduction of the trisubstituted double bond at C2 position (Table 1).

Table 1. Julia-Kocienski reagent screening for the olefination of ketone 3.[a]

Entry

Base

Yield

E-/Z-

LiHMDS

66%

50:50[b]

2

NaHMDS

16%

55:45[b]

3

KHMDS

nr

-

LiHMDS

13%

50:50[b]

NaHMDS

10%

50:50[b]

KHMDS

nr

-

LiHMDS

73%

73:27[c]

8

NaHMDS

67%

80:20[c]

9

KHMDS

75%

89:11[c]

10

LiHMDS

63%

56:44[c]

1

4

Sulfone 14 14a

14b

5 N

6 7

14c


Page 5 of 29 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


14d

11

N N N N tBu

12

NaHMDS

53%

77:23[c]

KHMDS

54%

89:11[c]

[a] 13: 0.055 mmol, 14: 0.110 mmol, Base: 0.110 mmol, THF (0.3 mL), -78 oC to rt. [b] Determined by 1H NMR. [c] Determined by HPLC.

Our

previous

studies18

determined

the

high

potential of

Julia-Kocienski

olefination20,21 for this transformation. In order to find the optimal olefination reagents the classical benzothiazolyl sulfone 14a,22 2-piridyl sulfone 14b23 and tetrazole sulfones24 14c25 and 14d were synthesized and subjected to olefination reaction with the ketone 13 in the presence of three different bases - Li, Na and KHMDS (Table 1). Whereas sulfones 14a and 14b (Entry 1 - 6) lack stereoselectivity and reactivity (Yields 0 – 66%), the tetrazole sulfones 14c and 14d delivered the desired product 15 in 53% - 75% yield and good stereoselectivity using KHMDS as a base (Entry 9 and 12).

Table 2. Solvent screening[a]

Entry

Solvent

Yield

E-/Z- [a]

1

DMF

53%

77:26

2

DME

10%

84:16

3

DCM

34%

89:11

4

Toluene

44%

60:40



5

Et2O

24%

Page 6 of 29

82:18

[a] 13: 0.055 mmol, 14d: 0.110 mmol, KHMDS: 0.110 mmol, Solvent (0.3 mL), -78 o

C to rt. [b] Determined by HPLC

In order to fine-tune the reaction conditions we further focused on the solvent screening (Table 2). Out of five different solvents examined only DCM (entry 3) delivered stereoselectivity comparable to the previously employed THF (Table 1, entry 12), albeit accompanied by decrease in reactivity. Next we speculated that the sterical effect of the Julia-Kocienski reagent 14 may have a decisive impact on stereochemical outcome of the reaction. To verify this hypothesis we synthesized several undescribed bulky Julia-Kocienski reagents and subjected to the olefination reaction (Table 3).

Table 3. Alternative Julia-Kocienski reagent screening for the olefination of ketone 13.[a]


Page 7 of 29 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


Entry

1

2

3

Sulfone 14 14e

14f

Yield

E-/Z- [b]

68%

83:17

67%

94:6

58%

88:12

nr

-

63%

95:5

60%

97:3

30%

88:12

iPr iPr

14g tBu tBu

tBu

4

14h

t Bu

tBu

cPent

5

14i

cPent

cPent cHex

6

14j

cHex

cHex Ph

7

14k

Ph

Ph

[a] 13: 0.055 mmol, 14: 0.110 mmol, KHMDS: 0.110 mmol, THF (0.3 mL), -78 oC to rt. [b] Determined by HPLC

To our delight, all sulfones except 14h produced the desired alkene 15 with a good stereoselectivity. The lack of reactivity on the part of 14h was attributed to the excessive sterical build-up. The best result in olefination of ketone 13 was obtained with (2,4,6-tricyclohexylphenyl)-tetrazole sulfone 14j (Entry 6) furnishing the desired alkene 15 with E-/Z- ratio as high as 97:3.



With the dilactam 15 in hand, the total synthesis of Limazepine E 6 can be accomplished in one step according to the published route.11 Importantly, the newly developed methodology allows to obtain Limazepine E 6 in 9 steps (LLS) compared to 12 steps previously reported11 and enables late stage modification of the C2 position. Our newly developed modification of Julia-Kocienski olefination was further applied to on the formal total synthesis of Barmumycin 19 (Scheme 3).

Scheme 3. Formal total synthesis of Barmumycin 19.

The formal total synthesis was started with an oxidation of the literature known prolinol derivative 1626 to give the desired ketone 17 in a high yield. Next, the Julia – Kocienski olefination of the substrate 18 was examined with the newly developed sulfone 14j and the classical 14c as a reference. Gratifyingly, 14j provided significantly higher stereoselectivity (E-/Z- 3:1) than 14c (E-/Z- 2:1). The obtained prolinole derivative 18 can be further converted into Barmumycin by a literature known sequence.27 In summary, we have developed a new modification of Julia-Kocienski olefination employing novel sterically demanding aryltetrazole sulfones for a stereoselective introduction of trisubstituted double bonds. The superiority of these modified Julia8 ACS Paragon Plus Environment

Page 8 of 29

Page 9 of 29 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


Kocienski reagents over the literature known sulfones has been demonstrated in the formal total synthesis of Limazepine E 6 and Barmumycin 19. Further studies on the scope of the described olefination are ongoing in our laboratory.

Experimental Section

General Experimental Details. All reactions were performed under an atmosphere of argon unless otherwise indicated. Reagents and starting materials were obtained from commercial sources and used as received. The solvents were purified and dried by standard procedures prior to use; petroleum ether of boiling range 60–80 °C was used. Flash chromatography was carried out using Merck Kieselgel (230–400 mesh). NMR spectra were recorded on Varian Mercury (400 MHz) and Bruker (300 MHz) spectrometers. Chemical shift values are referenced against residual protons in the deuterated solvents, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). Infrared spectra were recorded in the range 4000-500 cm-1 as a film. HRMS were obtained on Micromass AutoSpec Ultima Magnetic sector mass spectrometer (TOF). Optical rotations were measured using Perkin Elmer 141 polarimeter. Melting points were determined using Stanford Research System MPA100 Automated Melting Point Apparatus and are uncorrected. Chromatographic analysis were performed on Waters 2695 Separations Module (UV visible detector Waters 2489), Chiralpak IC-1 column (4.6 x 250 mm), 30% IPA/70% Hex, flow rate 1 mL/min.

(8R,9aS)-8-hydroxy-3-methoxy-1-phenyl-7,8,9,9a-tetrahydro-1H-2-oxa-6a,10adiazabenzo[cd]cyclopenta[g]azulene-6,10-dione 12



The title compound was prepared according the literature procedure starting from 10, 1.52 g (45% in 3 steps).18 1

H NMR 300 MHz, CDCl3: δ 7.57 (1H, d, J = 8.9 Hz), 7.32-7.46 (6H, m), 6.84 (1H,

d, J = 8.9 Hz), 4.53-4.59 (1H, m), 4.41 (1H, t, J = 7.7 Hz), 4.25 (1H, td, J = 12.7, 2.2 Hz), 3.97 (3H, s), 3.53 (1H, dd, J = 12.7, 4.0 Hz), 2.78-2.88 (1H, m), 2.25-2.35 (1H, m);

13

C NMR 100 MHz, CDCl3: δ 169.4, 166.3, 146.7, 137.8, 136.5, 130.0, 128.9,

128.3, 126.0, 124.0, 113.7, 110.8, 95.5, 68.7, 58.0, 56.8, 54.9, 35.9; IR (film) 3397, 1685, 1636 cm-1; m.p. 110-113 oC; [α]D20 = 338.40 (c = 0.1, CHCl3); HRMS (+ESI) calculated for C20H19N2O5 [M+H+] 367.1294 found 367.1295.

(9aS)-3-methoxy-1-phenyl-9,9a-dihydro-1H-2-oxa-6a,10adiazabenzo[cd]cyclopenta[g]azulene-6,8,10(7H)-trione 13 The title compound was prepared according the literature procedure from 12, 1.320 g (82%).18 1

H NMR 400 MHz, CDCl3: δ 7.63 (1H, d, J = 8.8 Hz), 7.34-7.46 (6H, m), 6.90 (1H,

d, J = 8.8 Hz), 4.68 (1H, dd, J = 10.7, 4.4 Hz), 4.49 (1H, d, J = 20.2 Hz), 4.00 (3H, s), 3.86 (1H, d, J = 20.2 Hz), 3.65 (1H, dd, J = 20.2, 4.4 Hz), 2.92 (1H, dd, J = 20.2, 10.7 Hz); 13C NMR 100 MHz, CDCl3: δ 206.8, 168.1, 165.9, 147.2, 137.9, 136.2, 130.2, 129.0, 128.2, 125.9, 124.2, 113.0, 111.3, 95.4, 56.8, 56.4, 53.4, 37.3; IR (film) 1762, 1694, 1635 cm-1; m.p. 116-119 oC; [α]D20 = 403.20 (c = 0.1, CHCl3); HRMS (+ESI) calculated for C20H17N2O5 [M+H+] 365.1137 found 365.1138.

1-(tert-Butyl)-5-(ethylsulfonyl)-1H-tetrazole 14d 14d was synthesized starting from commercially available tert-butyl isothiocyanate.


Page 10 of 29

Page 11 of 29 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


NaN3 (596 mg, 9.163 mmol, 1.00 equiv) was dissolved in H2O (4 mL) and heated up to 100 oC. Then a solution of tert-butyl isothiocyanate (1056 mg, 9.163 mmol, 1.00 equiv) in i-PrOH (4 mL) was added dropwise and the reaction mixture was stirred for 4 h at this temperature followed by 16 h at room temperature. After that 1.4 mL of conc. HCl was diluted with 4 mL of H2O and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated and the crude product was partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(tert-butyl)-1H-tetrazole-5-thiol was dissolved in EtOH (7 mL) and KOH (615 mg, 10.995 mmol, 1.20 equiv) was added, the resulting mixture was stirred for 30 min at room temperature. After that EtBr (1572 mg, 10.079 mmol, 1.10 equiv) was added dropwise and the stirring was continued for next 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(tert-butyl)-5-(ethylthio)-1H-tetrazole was dissolved in DCM (22 mL) and NaHCO3 (3.848 g, 45.81 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (6.79 g, 27.49 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for the next 2 h, then organics were separated and aqueous phase extracted twice with DCM. The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column



Page 12 of 29

chromatography (Eluent: EtOAc/petroleum ether 0:1 -> 1:2). The title compound was obtained as a yellowish solid (800 mg, 40% in 3 steps). 1

H NMR 400 MHz, CDCl3: δ 3.84 (2H, q, J = 7.4), 1.86 (9H, s), 1.55 (3H, t, J = 7.4);

13

C NMR 100 MHz, CDCl3: δ 154.6, 65.4, 51.5, 29.6, 7.1; IR (film) 2997, 2933,

1329, 1158 cm-1; HRMS (+ESI) calculated for C7H14N4O2NaS [M+Na] 241.0735 found 241.0732; m.p. 53 – 55 oC.

1-((3s,5s,7s)-Adamantan-1-yl)-5-(ethylsulfonyl)-1H-tetrazole 14e 14e

was

synthesized

starting

from

commercially

available

1-

isothiocyanatoadamantane. NaN3 (168 mg, 2.586 mmol, 1.00 equiv) was dissolved in H2O (1 mL) and heated up to 100 oC. Then a suspension of 1-isothiocyanatoadamantane (500 mg, 2.586 mmol, 1.00 equiv) in i-PrOH (1 mL) was added dropwise and the reaction mixture was stirred 4 h at this temperature followed by 16 h at room temperature. Additional NaN3 (168 mg, 2.586 mmol, 1.00 equiv), H2O (2 mL) and dioxane (2 mL) were added and the reaction mixture was stirred overnight at 100 oC, then cooled. After that 0.35 mL of conc. HCl was diluted with 1 mL H2O and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated, and the crude product was partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-((3s,5s,7s)-adamantan-1-yl)-1H-tetrazole-5-thiol was dissolved in EtOH (15 mL) and KOH (189 mg, 3.362 mmol, 1.30 equiv) was added, the resulting mixture was stirred for 30 min at room temperature. After that EtBr (338 mg, 3.104 mmol, 1.20 equiv) was added dropwise and the stirring was continued for next 16 h at


Page 13 of 29 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


room temperature. Additional KOH (145 mg, 2.586 mmol, 1.00 equiv) and EtBr (282 mg, 2.586 mmol, 1.00 equiv) were added and the reaction mixture was stirred for next 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-((3s,5s,7s)-adamantan-1-yl)-5-(ethylthio)-1H-tetrazole was dissolved in DCM (15 mL) and NaHCO3 (1.09 g, 12.93 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (1.91 g, 7.76 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for the next 2 h, then organics were separated and aqueous phase extracted twice with DCM. The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 1:9 -> 1:1). The title compound was obtained as a white solid (435 mg, 57% in 3 steps). H NMR 400 MHz, CDCl3: δ 3.84 (2H, q, J = 7.4), 2.48 (6H, d J = 3.1), 2.31 (3H, s), 1.75 – 1.85 (6H, m), 1.55 (3H, t, J = 7.4); 13C NMR 100 MHz, CDCl3: δ 153.9, 66.3, 51.7, 41.9, 35.6, 29.9, 7.30; IR (film) 2943, 2916, 1339 cm-1; HRMS (+ESI) calculated for C13H21N4O2S [M+H+] 297.1385 found 297.1371; m.p.104 – 107 oC.

1-(2,6-Diisopropylphenyl)-5-(ethylsulfonyl)-1H-tetrazole 14f 14f was synthesized starting from commercially available 1,3-diisopropyl-2isothiocyanatobenzene.



NaN3 (299 mg, 4.582 mmol, 1.00 equiv) was dissolved in H2O (2 mL) and heated up to 100 oC. Then a solution of 1,3-diisopropyl-2-isothiocyanatobenzene (1005 mg, 4.582 mmol, 1.00 equiv) in i-PrOH (2 mL) was added dropwise and the reaction mixture was stirred 4 h at this temperature followed by 16 h at room temperature. After that 0.7 mL of conc. HCl was diluted with 2 mL H2O and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated and the crude product was partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(2,6-diisopropylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (6 mL) and KOH (308 mg, 5.498 mmol, 1.20 equiv) was added, the resulting mixture was stirred for 30 min at room temperature. After that EtBr (549 mg, 5.040 mmol, 1.10 equiv) was added dropwise and the stirring was continued for next 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(2,6-diisopropylphenyl)-5-(ethylthio)-1H-tetrazole was dissolved in DCM (20 mL) and NaHCO3 (1.92 g, 22.91 mmol, 5.00 equiv) was added, followed by slow addition of 70% mCPBA (3.39 g, 13.75 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for the next 2 h, then organics were separated and aqueous phase was extracted twice with DCM. The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was


Page 14 of 29

Page 15 of 29 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


purified by flash column chromatography (Eluent: EtOAc/petroleum ether 0:1 -> 1:5 ). The title compound was obtained as a beige solid (900 mg, 61% in 3 steps). H NMR 400 MHz, CDCl3: δ 7.57 (1H, t, J = 7.8), 7.33 (2H, d J = 7.8), 3.71 (2H, q, J = 7.4), 1.97 – 2.07 (2H, m), 1.52 (3H, t, J = 7.4), 1.24 (6H, d, J = 7.0), 1.08 (6H, d, J = 7.0);

13

C NMR 100 MHz, CDCl3: δ 154.3, 146.2, 132.4, 128.6, 124.3, 50.7, 29.2,

25.3, 22.2, 6.9; IR (film) 2978, 2936, 1154 cm-1; HRMS (+ESI) calculated for C15H22N4O2NaS

[M+Na] 345.1361 found 345.1369; m.p. 90 – 93 oC.

1-(3,5-Di-tert-butylphenyl)-5-(ethylsulfonyl)-1H-tetrazole 14g 14g was synthesized starting from commercially available 3,5-di-tert-butylaniline. To a solution of 3,5-di-tert-butylaniline (230 mg, 1.12 mmol, 1.00 equiv) in DCM (6 mL) was added sat. aq. NaHCO3 (6 mL) and the resulting mixture was cooled to 0 oC. After addition of thiophosgene (167 mg, 1.456 mmol, 1.30 equiv) the reaction mixture was allowed to warm up to room temperature and vigorously stirred for next 5 h. After that water was added, the organic layer separated and aq. layer extracted with DCM (3x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1,3-di-tert-butyl-5-isothiocyanatobenzene was used in the next step without further purification. NaN3 (146 mg, 2.240 mmol, 2.00 equiv) was dissolved in H2O (3 mL) and heated up to 100 oC. Then a solution of 1,3-di-tert-butyl-5-isothiocyanatobenzene (277 mg, 1.120 mmol, 1.00 equiv) in dioxane (3 mL) was added dropwise and the reaction mixture was stirred 4 h at this temperature followed by 16 h at room temperature. After that 0.2 mL of conc. HCl was diluted with 0.6 mL H2O and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated and the crude product was partitioned between water and DCM. Organics were separated



and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(3,5-di-tert-butylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (7 mL) and KOH (144 mg, 2.576 mmol, 2.30 equiv) was added, the resulting mixture was stirred for 30 min at room temperature. After that EtBr (268 mg, 2.464 mmol, 2.20 equiv) was added dropwise and stirring was continued for next 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(3,5-di-tert-butylphenyl)-5-(ethylthio)-1H-tetrazole was dissolved in DCM (10 mL) and NaHCO3 (470 mg, 5.60 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (828 mg, 3.36 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for the next 2 h, then organics were separated and aqueous phase extracted twice with DCM. The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 0:1 -> 1:9. The title compound was obtained as a yellow solid (160 mg, 41% in 4 steps). H NMR 400 MHz, CDCl3: δ 7.63 (1H, s), 7.54 (2H, s), 3.77 (2H, q, J = 7.4), 1.56 (3H, t, J = 7.4), 1.37 (18H, s);

13

C NMR 100 MHz, CDCl3: δ 153.3, 153.0, 132.8,

125.3, 119.4, 51.0, 35.4, 31.4, 7.1; IR (film) 2965, 1341, 1153 cm-1; HRMS (+ESI) calculated for C17H26N4O2NaS [M+Na] 373.1674 found 373.1680; m.p. 55 – 57 oC.


Page 16 of 29

Page 17 of 29 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


5-(Ethylsulfonyl)-1-(2,4,6-tri-tert-butylphenyl)-1H-tetrazole 14h 14h was synthesized starting from 1,3,5-tri-tert-butyl-2-isothiocyanatobenzene.28 NaN3 (321 mg, 4.942 mmol, 5.00 equiv) was dissolved in H2O (3 mL), then 1,3,5-tritert-butyl-2-isothiocyanatobenzene (300 mg, 0.988 mmol, 1.00 equiv) and dioxane (6 mL) were added and the obtained mixture was stirred for 16 h at 150 oC. After cooling to ambient temperature, an aqueous solution of HCl (prepared from 0.5 mL of conc. HCl and 1.5 mL of H2O) was added to the reaction mixture. Volatiles were evaporated and the crude product was partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(2,4,6-tri-tert-butylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (3 mL) and KOH (83 mg, 1.482 mmol, 1.50 equiv) was added, the resulting mixture was stirred for 30 min at room temperature. After that EtBr (140 mg, 1.284 mmol, 1.30 equiv) was added dropwise and the stirring was continued for 16 h at room temperature. Additional KOH (83 mg, 1.482 mmol, 1.50 equiv) and EtBr (140 mg, 1.284 mmol, 1.30 equiv) were added and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo.

The residue was purified by flash column

chromatography using petroleum ether and EtOAc as eluents. 212 mg (57% in 2 steps) of 5-(ethylthio)-1-(2,4,6-tri-tert-butylphenyl)-1H-tetrazole were isolated. The 5-(ethylthio)-1-(2,4,6-tri-tert-butylphenyl)-1H-tetrazole (212 mg, 0.566 mmol, 1.00 equiv) was dissolved in DCM (10 mL) and NaHCO3 (238 mg, 2.830 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (418 mg, 1.698 mmol,



3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h. Additional NaHCO3 (238 mg, 2.830 mmol, 5.00 equiv) and mCPBA (418 mg, 1.698 mmol, 3.00 equiv) were added and the stirring was continued overnight. Additional NaHCO3 (238 mg, 2.830 mmol, 5.00 equiv), mCPBA (418 mg, 1.698 mmol, 3.00 equiv) and DCM (15 mL) were added and the reaction mixture was stirred for 3 h at room temperature and then quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for the next 2 h, then organics were separated and aqueous phase extracted twice with DCM. The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 0:1 -> 1:5). The title compound was obtained as a beige solid (124 mg, 54%). The structure of the title compound was confirmed by XRay crystallography. H NMR 400 MHz, CDCl3: δ 7.53 (2H, s), 3.69 (2H, q, J = 7.4), 1.54 (3H, t, J = 7.4), 1.36 (9H, s), 1.05 (18H, s); 13C NMR 100 MHz, CDCl3: δ 156.6, 153.1, 146.8, 125.3, 125.1, 51.2, 37.9, 35.3, 32.1, 31.3, 6.5; IR (film) 2964, 1367, 1154 cm-1; HRMS (+ESI) calculated for C21H35N4O2S [M+H+] 407.2481 found 407.2475; m.p. 104 – 106 oC.

5-(Ethylsulfonyl)-1-(2,4,6-tricyclopentylphenyl)-1H-tetrazole 14i 14i was synthesized starting from 2,4,6-tricyclopentylaniline.29 To a solution of 2,4,6-tricyclopentylaniline (460 mg, 1.546 mmol, 1.00 equiv) in DCM (8 mL) was added sat. aq. NaHCO3 (8 mL) and the resulting mixture was cooled to 0 oC. After addition of thiophosgene (231 mg, 2.010 mmol, 1.30 equiv) the reaction mixture was allowed to warm up to room temperature and vigorously stirred


Page 18 of 29

Page 19 of 29 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


for next 5 h. After that water was added, the organic layer separated and aq. layer extracted with DCM (3x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1,3,5-tricyclopentyl-2isothiocyanatobenzene was used in the next step without further purification. NaN3 (201 mg, 3.092 mmol, 2.00 equiv) was dissolved in H2O (4 mL), then a solution of 1,3,5-tricyclopentyl-2-isothiocyanatobenzene (525 mg, 1.546 mmol, 1.00 equiv) in dioxane (4 mL) was added and the reaction mixture was stirred 4 h at 100 oC, then cooled. Additional NaN3 (201 mg, 3.092 mmol, 2.00 equiv), H2O (4 mL) and dioxane (4 mL) were added and the reaction mixture was stirred for 16 h at 100 oC, then cooled. After that 1 mL of conc. HCl was diluted with 3 mL H2O and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated and the crude product was partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(2,4,6-tricyclopentylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (6 mL) and KOH (120 mg, 2.146 mmol, 2.30 equiv) was added, the resulting mixture was refluxed for 1 h, then cooled. After that EtBr (224 mg, 2.053 mmol, 2.20 equiv) was added dropwise and the mixture was refluxed for 16 h. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography using petroleum ether and EtOAc as eluents. 406 mg (64% in 3 steps) of 5-(ethylthio)-1-(2,4,6-tricyclopentylphenyl)-1Htetrazole were isolated.



The 5-(ethylthio)-1-(2,4,6-tricyclopentylphenyl)-1H-tetrazole (400 mg, 0.974 mmol, 1.00 equiv) was dissolved in DCM (20 mL) and NaHCO3 (409 mg, 4.871 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (720 mg, 2.922 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 2 h. Additional 10 mL of DCM, NaHCO3 (205 mg, 2.436 mmol, 2.50 equiv), and mCPBA (360 mg, 1.461 mmol, 1.50 equiv) were added and the reaction mixture was stirred at room temperature for 16 h and then quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for the next 2 h, then organics were separated and aqueous phase extracted twice with DCM. The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 0:1 -> 1:5). The title compound was obtained as a beige solid (150 mg,35%). H NMR 400 MHz, CDCl3: δ 7.14 (2H, s), 3.69 (2H, q, J = 7.4), 2.99 – 3.08 (1H, m), 1.32 – 2.17 (26H, m), 1.51 (3H, t, J = 7.4);

13

C NMR 100 MHz, CDCl3: δ 154.5,

150.7, 143.9, 127.8, 123.5, 50.7, 46.4, 40.8, 36.6, 34.7, 33.9, 25.9, 25.9, 25.6, 6.8; IR (film) 2955, 1346, 1153 cm-1; HRMS (+ESI) calculated for C24H34N4O2NaS [M+Na] 465.2300 found 465.2285; m.p. 119 – 121 oC.

5-(Ethylsulfonyl)-1-(2,4,6-tricyclohexylphenyl)-1H-tetrazole 14j 14j was synthesized starting from 2,4,6-tricyclohexylaniline.29 To a solution of 2,4,6-tricyclohexylaniline (1490 mg, 4.388 mmol, 1.00 equiv) in DCM (23 mL) was added sat. aq. NaHCO3 (23 mL) and the resulting mixture was cooled to 0 oC. After addition of thiophosgene (656 mg, 5.714 mmol, 1.30 equiv) the reaction mixture was allowed to warm up to room temperature and stirred vigorously


Page 20 of 29

Page 21 of 29 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


for next 5 h. After that water was added, the organic layer separated and aq. layer extracted with DCM (3x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude (2-isothiocyanatobenzene1,3,5-triyl)tricyclohexane was used in the next step without further purification. NaN3 (570 mg, 8.776 mmol, 2.00 equiv) was dissolved in H2O (11 mL), then a solution of crude (2-isothiocyanatobenzene-1,3,5-triyl)tricyclohexane in dioxane (11 mL) was added and the reaction mixture was stirred 4 h at 100 oC, then cooled. Additional NaN3 (570 mg, 8.776 mmol, 2.00 equiv), H2O (11 mL) and dioxane (11 mL) were added and the reaction mixture was stirred at 100 oC for 16 h, then cooled. After that 3 mL of conc. HCl was diluted with 9 mL H2O and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated and the crude product was partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(2,4,6-tricyclohexylphenyl)-1H-tetrazole-5-thiol was dissolved in EtOH (30 mL) and KOH (566 mg, 10.092 mmol, 2.30 equiv) was added, the resulting mixture was refluxed for 1 h, then cooled. After that EtBr (1052 mg, 9.654 mmol, 2.20 equiv) was added dropwise and the reaction mixture was refluxed for the next 16 h. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography using petroleum ether and EtOAc as eluents. 1646 mg (83% in 3 steps) of 5(ethylthio)-1-(2,4,6-tricyclohexylphenyl)-1H-tetrazole were isolated.



The 5-(ethylthio)-1-(2,4,6-tricyclohexylphenyl)-1H-tetrazole (1646 mg, 3.636 mmol, 1.00 equiv) was dissolved in DCM (100 mL) and NaHCO3 (1527 mg, 18.180 mmol, 5.00 equiv) was added followed by slow addition of mCPBA (2689 mg, 10.908 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h. Additional 40 mL of DCM, NaHCO3 (764 mg, 9.090 mmol, 2.50 equiv), and mCPBA (1345 mg, 5.454 mmol, 1.50 equiv) were added and the reaction mixture was stirred at room temperature for 16 h and then quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The obtained biphasic mixture was stirred vigorously for the next 2 h, then organics were separated and aqueous phase extracted twice with DCM. The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 1:10 -> 1:4). The title compound was obtained as a beige solid (600 mg, 34%). H NMR 400 MHz, CDCl3: δ 7.10 (2H, s), 3.70 (2H, q, J = 7.4), 2.52 – 2.61 (1H, m), 0.95 – 1.98 (32H, m), 1.49 (3H, t, J = 7.4);

13

C NMR 100 MHz, CDCl3: δ 154.2,

151.9, 144.6, 126.5, 123.4, 50.6, 44.9, 40.0, 35.7, 34.4, 32.4, 27.0, 26.9, 26.7, 26.2, 26.0, 7.1; IR (film) 2929, 1348, 1150 cm-1; HRMS (+ESI) calculated for C27H40N4O2NaS [M+Na] 507.2770 found 507.2779; m.p. 155 – 158 oC.

5-(Ethylsulfonyl)-1-(5'-phenyl-[1,1':3',1''-terphenyl]-4'-yl)-1H-tetrazole 14k 14k was synthesized starting from commercially available 2,4,6-triphenylaniline. To a solution of 2,4,6-triphenylaniline (300 mg, 0.933 mmol, 1.00 equiv) in DCM (5 mL) was added sat. aq. NaHCO3 (5 mL) and the resulting mixture was cooled to 0 oC. After addition of thiophosgene (140 mg, 1.213 mmol, 1.30 equiv) the reaction mixture was allowed to warm up to room temperature and vigorously stirred for next 5 h.


Page 22 of 29

Page 23 of 29 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


After that water was added, the organic layer separated and aq. layer extracted with DCM (3x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 2'-isothiocyanato-5'-phenyl-1,1':3',1''-terphenyl was used in the next step without further purification. NaN3 (121 mg, 1.866 mmol, 2.00 equiv) was dissolved in H2O (3 mL), then a solution of crude 2'-isothiocyanato-5'-phenyl-1,1':3',1''-terphenyl in dioxane (3 mL) was added and the reaction mixture was stirred 4 h at 100 oC followed by 16 h at room temperature. After that 0.2 mL of conc. HCl was diluted with 0.6 mL H2O and the resulting solution was added dropwise to the reaction mixture. Volatiles were evaporated and the crude product was partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 1-(5'-phenyl-[1,1':3',1''-terphenyl]-2'-yl)-1H-tetrazole-5-thiol was dissolved in EtOH (6 mL) and KOH (120 mg, 2.146 mmol, 2.30 equiv) was added, the resulting mixture was stirred for 30 min at room temperature. After that EtBr (224 mg, 2.053 mmol, 2.20 equiv) was added dropwise and the stirring was continued for the next 16 h at room temperature. The reaction mixture was then evaporated and the crude product partitioned between water and DCM. Organics were separated and aq. layer extracted with DCM (3 x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude 5-(ethylthio)-1-(5'-phenyl-[1,1':3',1''-terphenyl]-2'-yl)-1H-tetrazole was dissolved in DCM (10 mL) and NaHCO3 (392 mg, 4.665 mmol, 5.00 equiv) was added followed by slow addition of 70% mCPBA (690 mg, 2.799 mmol, 3.00 equiv) under vigorous stirring. The resulting slurry was stirred at room temperature for 16 h and then quenched by addition of sat. aq. solution of Na2S2O3 and NaHCO3. The



obtained biphasic mixture was stirred vigorously for the next 2 h, then organics were separated and aqueous phase extracted twice with DCM. The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 1:9 -> 1:1). The title compound was obtained as a white solid (345 mg, 79% in 4 steps). H NMR 400 MHz, CDCl3: δ 7.77 (2H, s), 7.70 – 7.74 (2H, m), 7.41 – 7.53 (3H, m), 7.24 – 7.33 (10 H, m), 2.83 (2H, q, J = 7.4), 0.97 (3H, t, J = 7.4); 13C NMR 100 MHz, CDCl3: δ 153.6, 144.6, 141.2, 139.2, 136.8, 129.2, 129.1, 128.9, 128.7, 128.6, 128.5, 128.3, 127.6, 50.6, 6.1; IR (film) 1348, 1152 cm-1; HRMS (+ESI) calculated for C27H23N4O2S

[M+H+] 467.1542 found 467.1534; m.p. 118 – 121 oC.

(9aS)-8-ethylidene-3-methoxy-1-phenyl-7,8,9,9a-tetrahydro-1H-2-oxa-6a,10adiazabenzo[cd]cyclopenta[g]azulene-6,10-dione 15 General procedure for the olefination of ketone 13 : To a solution of the sulfone 14 (0.110 mmol, 2.00 equiv) in dry THF (0.3 mL) under Ar atmosphere KHMDS (1M solution in THF, 0.11 mL, 0.110 mmol, 2.00 equiv) was added at -78 oC and the resulting mixture was stirred for 15 min at this temperature, then a solution of the ketone 13 (20 mg, 0.055 mmol, 1.00 equiv) in dry THF (0.4 mL) was added dropwise. The reaction mixture was stirred for 40 min at -78 oC and then warmed up to room temperature (~ 15 min) and quenched with sat. aq. NH4Cl and extracted with DCM (3x). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 4:6 -> 7:3). Major isomer (E-15): 1H NMR 400 MHz, CDCl3: δ 7.58 (1H, d, J = 9.0 Hz), 7.327.45 (6H, m), 6.85 (1H, d, J = 9.0 Hz), 5.48-5.57 (1H, m), 4.52 (1H, d, J = 15.5 Hz),


Page 24 of 29

Page 25 of 29 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


4.33 (1H, dd, J = 9.8, 3.1 Hz), 4.07 (1H, d, J = 15.5 Hz), 3.98 (3H, s), 3.57 (1H, d, J = 15.5 Hz), 2.68-2.80 (1H, m), 1.72 (3H, d, J = 7.0 Hz); Minor isomer (Z-15): 1H NMR 400 MHz, CDCl3: δ 7.59 (1H, d, J = 9.0 Hz), 7.317.46 (6H, m), 6.85 (1H, d, J = 9.0 Hz), 5.47-5.60 (1H, m), 4.44 (1H, d, J = 15.5 Hz), 4.26 (1H, dd, J = 9.8, 3.1 Hz), 4.15 (1H, d, J = 15.5 Hz), 3.98 (3H, s), 3.45 (1H, d, J = 15.5 Hz), 2.82-2.90 (1H, m), 1.64 (3H, d, J = 7.0 Hz)

(S)-tert-butyl

2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-oxopyrrolidine-1-

carboxylate 17 To a solution of tert-butyl (2S,4R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4hydroxypyrrolidine-1-carboxylate30 16 (1.24 g, 2.721 mmol, 1.00 equiv) in DCM (35 mL) was added DMP (1.73 g, 4.082 mmol, 1.50 equiv) and the resulting mixture was stirred at room temperature for 4 h. Additional DMP (577 mg, 1.361 mmol, 0.50 equiv) was added and the mixture was stirred for the next 16 h After being quenched by addition of at. aq. solution of Na2S2O3, the obtained biphasic mixture was stirred vigorously for the next 10 min, then organics were separated and aqueous phase extracted twice with DCM. The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Eluent: EtOAc/petroleum ether 4:1 -> 2:1). The title compound was obtained as a yellowish solid (1.14 g, 92%). H NMR 400 MHz, CDCl3: δ 7.53 – 7.68 (4H, m), 7.33 – 7.48 (6H, m), 4.41 (0.5H, d, J = 9.4)4.37 (0.5H, d, J = 9.4), 3.80 – 4.15 (3H, m), 3.52 (1H, t, J = 11.3), 2.65 – 2.83 (1H, m), 2.54 (1H, t, J = 19.2), 1.51 and 1.47 (together 9H, both s), 1.00 (9H, s); 13C NMR 100 MHz, CDCl3 (rotomers): δ 211.0, 210.3, 135.7, 132.8, 130.0, 128.0, 80.5, 66.5, 66.2, 55.8, 55.3, 54.3, 53.7, 41.0, 40.5, 28.6, 26.8, 19.2; IR (film) 2962, 2931,



1764, 1165, 1106 cm-1; [α]D20 = 11.84° (c = 1, CHCl3); HRMS (+ESI) calculated for C26H35NO4NaSi [M+Na] 476.2233 found 476.2234; m.p. 99 – 102 oC. The olefination of ketone 17 was conduced according to general olefination procedure, the obtained intermediate olefin was further subjeced to TBDPS protecting group cleavage: To a solution of olefin in THF (3 mL) was added TBAF x 3 H2O (139 mg, 0.440 mmol, 2 equiv) and the resulting mixture was stirred at room temperature for 16 h, then loaded on silica and purified by flash column chromatography (Eluent: EtOAc/petroleum ether 1:1 -> 1:0). The title compound was isolated as a yellow wax. 29 mg (58% in 2 steps) using sulfone 14c; 31 mg (62% in 2 steps) using sulfone 14j.

ASSOCIATED CONTENT Supporting Information General scheme for the synthesis of sulphones 14, ORTEP diagram of 14h, representative examples of HPLC plots used for determination of E-/Z- ratio in JuliaKocienski olefination of ketone 13 with sulphones 14 as well as copies of NMR spectrais available free of charge on ACS Publications website.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Notes The authors declare no competitive financial interest.


Page 26 of 29

Page 27 of 29 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


ACKNOWLEDGMENTS The authors acknowledge the Latvian Institute of Organic synthesis internal grant for G. Sakaine (IG-2017-05) and ERDF (PostDoc Latvia) project No.1.1.1.2/VIAA/1/16/243 for G. Smits for the financial support. We also thank Dr. S. Belyakov (LIOS) for X-ray crystallographic analyses.

REFERENCES (1)

Fotso, S.; Zabriskie, T. M.; Proteau, P. J.; Flatt, P. M.; Santosa, D. A.; Sulastri; Mahmud, T. Limazepines A−F, Pyrrolo[1,4]Benzodiazepine Antibiotics from an Indonesian Micrococcus Sp. J. Nat. Prod. 2009, 72, 690–695.

(2)

Kaur Gill, R.; Om Kaushik, S.; Chugh, J.; Bansal, S.; Shah, A.; Bariwal, J. Recent Development in [1,4]Benzodiazepines as Potent Anticancer Agents: A Review. Mini Rev. Med. Chem. 2014, 14, 229–256.

(3)

Gerratana, B. Biosynthesis, Synthesis, and Biological Activities of Pyrrolobenzodiazepines. Med. Res. Rev. 2012, 32, 254–293.

(4)

Hartley, J. A. The Development of Pyrrolobenzodiazepines as Antitumour Agents. Expert Opin. Investig. Drugs 2011, 20, 733–744.

(5)

Mantaj, J.; Jackson, P. J. M.; Rahman, K. M.; Thurston, D. E. From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs). Angew. Chem. Int. Ed. 2017, 56, 462–488.

(6)

Sato, S.; Iwata, F.; Yamada, S.; Kawahara, H.; Katayama, M. Usabamycins A– C: New Anthramycin-Type Analogues from a Marine-Derived Actinomycete. Bioorg. Med. Chem. Lett. 2011, 21, 7099–7101.

(7)

Oh, M.; Jang, J.-H.; Choo, S.-J.; Kim, S.-O.; Kim, J. W.; Ko, S.-K.; Soung, N.K.; Lee, J.-S.; Kim, C.-J.; Oh, H.; Hong, Y.-S.; Ueki, M.; Hirota, H.; Osada, H.; Kim, B.-Y.; Ahn, J.-S. Boseongazepines A–C, Pyrrolobenzodiazepine Derivatives from a Streptomyces Sp. 11A057. Bioorg. Med. Chem. Lett. 2014, 24, 1802–1804.

(8)

Kariyone, K.; Yazawa, H.; Kohsaka, M. The Structures of Tomaymycin and Oxotomaymycin. Chem. Pharm. Bull. 1971, 19, 2289–2293.

(9)

Shimizu, K.-I.; Kawamoto, I.; Tomita, F.; Morimoto, M.; Fujimoto, K. Prothracarcin, a novel antitumor antibiotic. J. Antibiot. 1982, 35, 972–978. 27 ACS Paragon Plus Environment


(10) Gregson, S. J.; Howard, P. W.; Corcoran, K. E.; Barcella, S.; Yasin, M. M.; Hurst, A. A.; Jenkins, T. C.; Kelland, L. R.; Thurston, D. E. Effect of C2-Exo Unsaturation on the Cytotoxicity and DNA-Binding Reactivity of Pyrrolo[2,1c][1,4]Benzodiazepines. Bioorg. Med. Chem. Lett. 2000, 10, 1845–1847. (11) Smits, G.; Zemribo, R. The Exocyclic Olefin Geometry Control via Ireland– Claisen Rearrangement: Stereoselective Total Syntheses of Barmumycin and Limazepine E. Org. Lett. 2013, 15 (17), 4406–4409. (12) Mori, M.; Uozumi, Y.; Kimura, M.; Ban, Y. Total Syntheses of Prothracarcin and Tomaymycin by Use of Palladium Catalyzed Carbonylation. Tetrahedron 1986, 42, 3793–3806. (13) Langley, D. R.; Thurston, D. E. A Versatile and Efficient Synthesis of Carbinolamine-Containing Pyrrolo[1,4]Benzodiazepines via the Cyclization of N-(2-Aminobenzoyl)Pyrrolidine-2-Carboxaldehyde Diethyl Thioacetals: Total Synthesis of Prothracarcin. J. Org. Chem. 1987, 52, 91–97. (14) Sakaine, G.; Zemribo, R.; Smits, G. The First Total Synthesis of Usabamycins a and C. Tetrahedron Lett. 2017, 58, 2426–2428. (15) Smits, G.; Zemribo, R. One-Step Preparation of Pyrrolo[1,4]Benzodiazepine Dilactams: Total Synthesis of Oxoprothracarcin, Boseongazepines B and C. Synlett 2015, 2272–2276. (16) Junutula, J.; Jammalamadaka, V. Isoquinolidinobenzodiazepines. WO/2016/149546, September 23, 2016. (17) Howard, P. W.; Gregson, S.; Taylor, P. W.; Thurston, D. E.; Hadjivassileva, T. S. Pyrrolobenzodiazepines. WO2005085260 (A1), September 15, 2005. (18) Sakaine, G.; Smits, G.; Zemribo, R. Late Stage Fe(CO)5 Promoted Double Bond Migration: Total Synthesis of Limazepines C and D. Tetrahedron Lett. 2015, 56, 4767–4769. (19) Smits, G.; Kinens, A.; Zemribo, R. Ireland–Claisen Rearrangement of 6Methylene-1,4-Oxazepan-2-Ones. Eur. J. Org. Chem. 2015, 2015, 6701–6709. (20) Dumeunier, R.; Markó, I. E. The Julia Reaction. In Modern Carbonyl Olefination; Takeda, essor T., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA, 2003; pp 104–150. (21) Plesniak, K.; Zarecki, A.; Wicha, J. The Smiles Rearrangement and the Julia– Kocienski Olefination Reaction. In Sulfur-Mediated Rearrangements II; Topics in Current Chemistry; Springer, Berlin, Heidelberg, 2006; pp 163–250. 28 ACS Paragon Plus Environment

Page 28 of 29

Page 29 of 29 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


(22)

Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. A direct synthesis of olefins by reaction of carbonyl compounds with lithio derivatives of 2-[alkyl- or (2′alkenyl)- or benzyl-sulfonyl]-benzothiazoles. Tetrahedron Lett. 1991, 32,

1175–1178. (23) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856–878. (24) Blakemore, P. R.; Cole, W. J.; Kocieński, P. J.; Morley, A. A Stereoselective Synthesis of trans-1,2-Disubstituted Alkanes Based on the Condensation of Aldehydes with Metallated 1-Phenyl-1H-tetrazol-5-yl Sulfones. Synlett 1998, 26–28. (25) Hoefle, G.; Richter, W. Novel Macrocycles for the Treatment of Cancer. WO2004007492 (A1), January 22, 2004.

(26)

Vermote, A.; Brackman, G.; Risseeuw, M. D. P.; Coenye, T.; Van Calenbergh, S. Novel hamamelitannin analogues for the treatment of biofilm related MRSA infections-A scaffold hopping approach. Eur. J. Med. Chem.

2017, 127, 757–770. (27) Lorente, A.; Pla, D.; Cañedo, L. M.; Albericio, F.; Álvarez, M. Isolation, Structural Assignment, and Total Synthesis of Barmumycin. J. Org. Chem. 2010, 75, 8508–8515. (28) Habib, N. S.; Rieker, A. Metathesis of Aryl Isothiocyanates: A Novel Method for the Synthesis of Sterically Hindered Aryl Isothiocyanates. Synthesis 1984,, 825–827. (29) Savka, R.; Plenio, H. Metal Complexes of Very Bulky N,N′‐Diarylimidazolylidene N‐Heterocyclic Carbene (NHC) Ligands with 2,4,6‐Cycloalkyl Substituents. Eur. J. Inorg. Chem. 2014, 6246–6253. (30) Vermote, A.; Brackman, G.; Risseeuw, M. D. P.; Coenye, T.; Van Calenbergh, S. Novel Hamamelitannin Analogues for the Treatment of Biofilm Related MRSA Infections–A Scaffold Hopping Approach. Eur. J. Med. Chem. 2017, 127, 757–770.


Modified Julia-Kocienski reagents for a stereoselective introduction of

Recommend Documents