Total Synthesis of Berkeleylactone A. - ACS Publications

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Total Synthesis of Berkeleylactone A. Branislav Ferko, Marián Zeman, Michele Formica, Sebastián Veselý, Jana Dohá#ošová, Jan Moncol, Petra Olejníková, Dusan Berkes, Pavol Jakubec, Darren J. Dixon, and Olga Caletkova J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00850 • Publication Date (Web): 13 May 2019 Downloaded from http://pubs.acs.org on May 13, 2019

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The Journal of Organic Chemistry

Total Synthesis of Berkeleylactone A. Branislav Ferko, †, ‡ Marián Zeman, †Michele Formica, ‡ Sebastián Veselý, † Jana Doháňošová, † Ján Moncol, † Petra Olejníková, † Dušan Berkeš, † Pavol Jakubec, † Darren J. Dixon,*, ‡ Oľga Caletková,*, † †Faculty

of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 81237, Bratislava, Slovakia of Chemistry, University of Oxford, Chemistry Research Laboratory, Oxford, OX1 3TA UK

‡Department

ABSTRACT: The first total synthesis of the potent antibiotic Berkeleylactone A is described in 10 steps with an overall yield of 9.5%. A key step of our concise route is a late stage, highly diastereoselective, sulfa-Michael addition. The 16-membered macrocyclic lactone was formed via RCM and subsequent chemoselective reduction. The absolute stereochemical configuration was confirmed by single crystal X-ray analysis. Synthetic berkeleylactone A was tested against several MRSA strains and its potent antibacterial activity was verified.

INTRODUCTION The discovery and implementation of antibiotics in the early twentieth century was transformative to human health and a landmark event in medical history. In recent times the widespread use of antibiotics has led to their benefits being substantially reduced due to the rapid emergence and transmission of antibiotic-resistant strains. This resistance has resulted in the launch of substantial discovery programs into the development of new antibiotics with novel modes of action coupled with less opportunity for cross resistance.1A viable approach for new antibacterial compound discovery is through bacterial and fungal coculture. It has been shown, that “crosstalk” between microorganisms can activate silent gene clusters and lead to the formation of novel secondary metabolites.2 When Penicillium fuscum and Penicillium camembertii/clavigerum, two extremophilic fungi that were isolated from a single sample of surface water from Berkeley Pit Lake were cocultured, numerous bioactive metabolites not present in either pure culture, were evident. Among several new compounds obtained from this experiment, berkeleylactone A,3 a 16-membered macrolactone (Figure 1 (A)), showed the most potent antibacterial activity, especially against several MRSA strains.4 Owing to this valuable antibacterial activity, attractive molecular structure and lack of an existing synthetic strategy, we planned to design and realize a concise and convergent synthesis of berkeleylactone A that would enable us to prepare larger quantities of this natural product, as well as its analogues for further SAR studies. Herein we wish to report our findings.

Our synthetic plan (Figure 1 (B)) relied on a late stage diastereoselective sulfa-Michael addition,6 which would control the configuration of the newly formed stereogenic center at C2. For the formation of the 16-membered macrocyclic lactone 10, we envisaged a ring-closing metathesis7 followed by chemoselective reduction5g of the non-conjugated double bond. A

Macrolactone natural products

O HO

CO2H O

O

O

S

O

HO

A26771B ( 2)5 Known Antiobiotic [ also f ound in Berkeleylactone culture]

Retrosynthetic analysis

via key late-stage diastereoselective sulf a-Michael

RCM & reduction

Achmatowicz oxidation

Steglich esterif ication

O

CBS reduction HO S

sulf a-Michael HO

epoxide opening CO2H

O HO

O O

O O

O O

CO2H

Berkeleylactone A ( 1) Isolated 2017 [ strong antibiotic activity vs. (2)]

B

O

10

HS HO

CO2R'

Figure 1. Berkeleylactone A and antibiotic A26771B, both isolated from coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum.

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Scheme 1. (A) Macrocycle construction. (B) S-Nucleophile formation. (C) Sulfa-Michael study. (D) Reversibility study. (E) XRay structures A

Macrocycle construction

( a) MgBr

O MeO

O

O

N Me

( b) (R)-CBS (A) BH3Me2S 88 %, 99 % ee

O

O

4

82 %

TBSO

O

7 HO

O

DCC, DMAP 67 %

45 %

6

8

S-Nucleophile formation STr

( i) TrSH, NaH CO2K

73 %

HO

T r = triphenylmethyl

11

85 %

CO2H

( g) Grubbs I (B) then PtO2, H2

SH

( j) TFA, Et3SiH HO

12

H

CO2H

SH

OH

DCC, DMAP, 23%

PCy3

Ph Cl

Ru

O

Cl

RO

Ph

O O

PCy3

9: R = TBS

( h) TFA 89%

Grubbs I (B)

(R)-CBS (A)

O

HO

Ph

O N B Me

13a ( k) TMS

10: R = H

Key macrolactone

TMS

O

( l) TFA, Et3SiH 73 %

13b

Sulfa-Michael study

HS

O HO

NEt3 (x eq)

+ O

HO

CO2R

Time

HO

R-SH

x eq

Time (h)

dr

1 2 3 4 5 6

13a 13a 13a 13b 13b 13b

0 1.2 2.2 0 1.5 0.2

> 7 days 2 2 2 2 2

6.5 : 1 2.0 : 1 4.0 : 1 2:1 6:1 14 : 1

O O

10

Entry

O

O 13a or 13b

14

S HO

CO2R ( m) isolated

D

O

(f )

O

Achmatowicz oxidation

5b

( e) NaClO2, amylene 98 %

O H

4

69 %

4

O

C

OTBS

4

( c) TBS-Cl 93%

3

B

( d) NBS, NaHCO3 then pyridine, NaHCO3

OTBS

D

Reversibility study

85% 16:1 dr

O

( n) TFA 92% >20:1 dr

HO

O O

S HO

CO2H

Berkeleylactone A ( 1) 10 linear steps, 9.5% total yield

X-Ray structures

O HO 1

O O 1

S HO

NEt3

epi-1

CO2H natural pref erred

O HO

O O

S

epi-1

HO

Berkeleylactone A ( 1) [major diastereomer]

epi-1 [minor diastereomer]

CO2H

(A) Macrocycle construction. (a) RMgBr (2 eq), THF, 0 °C-rt. (b) (R)-CBS (A, 35 mol%), BH3·DMS (1.36 eq), THF, -40 °C, 4 h. (c) TBSCl (1.08 eq), DMAP (0.2 eq), imidazole (2.5 eq), DMF, 0 °C-rt, 5 h. (d) NBS (1.2 eq), NaHCO3 (2 eq), acetone, H2O, -50 °C, 5 h. then pyridine (1 eq), NaHCO3 (2 eq), rt, 2.5 h. (e) NaClO2 (1.5 eq), amylene (5 eq), tBuOH, phosphate buffer, H2O, rt, 4 h. (f) DCC (1.2 eq), DMAP (10 mol%), DCM, 0 °C-rt, 2 h. (g) Grubbs I (B, 25 mol%), DCM (0.002 M), rt, 4.5 h, then PtO2 (20 mol%), H2 (1 atm), rt, 4 h. (h) TFA (excess), DCM, 0-4 °C. 24 h. (B) S-nucleophile formation (i) TrSH (1.33 eq), NaH (1.33 eq), THF, 0 °C-rt, 14 h. (k) Et3SiH (3 eq), TFA, DCM, 30 min. (l) DCC (2 eq), DMAP (1 eq), DCM, 0 °C, 18.5 h. (C) Sulfa-Michael study (m) NEt3 (20 mol%), DCM, rt, 2 h. (n) TFA, DCM, 0 °C, 15 h. (D) Reversibility study between natural product and epimer. dr (%) is displayed as percentage of compound 1 in a mixture of 1 and epi-1 over time.

RESULTS AND DISCUSSION Weinreb amide8 3 was prepared in excellent yield from furan2-carboxylic acid and used without further purification in the addition of hexenylmagnesium bromide9 furnishing desired ketone 4 (Scheme 1 (A)). This structure was reduced using borane dimethylsulfide complex together with 10 mol% (R)-2-methyl-CBSoxazaborolidine catalyst yielding alcohol 5 in good yield (88%)

and excellent enantioselectivity (99% ee).10 TBS protection11 of the hydroxyl group, subsequent Achmatowicz oxidation12 using N-bromosuccinimide, and then double bond isomerization catalyzed by pyridine in aqueous solution delivered aldehyde 6.13 (R)-Hept-6-en-2-ol 7 was prepared by the opening of (R)propylene oxide with the corresponding cuprate14. Aldehyde 6 was further oxidized with sodium chlorite to the corresponding carboxylic acid which was then submitted to the DCC/DMAP


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The Journal of Organic Chemistry promoted coupling15 with alcohol 7, furnishing key intermediate 8 in good yield. Ring-closing metathesis using Grubbs 1st generation catalyst was carried out in dichloromethane at a concentration of 0.002 M, and subsequent selective reduction of the non-conjugated double bond was carried out in the same pot, by swapping the argon atmosphere for one of hydrogen and adding a platinum (IV) oxide as catalyst. The choice of the catalyst was based on previous results on analogous substrate.5g Finally trifluoroacetic acid mediated TBS deprotection afforded key macrolactone product 10. Having developed a robust route to electrophile 10, we turned our attention to the synthesis of the thiol nucleophilic component (Scheme 1 (B)) which was founded on a regioselective epoxide ring opening of oxirane-2-carboxylate 11. Potassium (R)-oxirane-carboxylate 11 was prepared from L-serine,16 and subsequently treated with in situ prepared sodium triphenylmethylthiolate.17 A subsequent acidic deprotection afforded the desired acid 13a in 85% yield. With the key building blocks in hand the late stage sulfaMichael addition to form the remaining stereogenic center was explored. Our initial investigation showed a significant impact of the amount of base employed on the reaction diastereoselectivity. When nucleophile 13a was used, the Rconfigured diastereomer was formed as the major epimer (Scheme 1 (C)). In fact the highest dr of 6.5:118 was obtained without any added base (Scheme 1 (C), entry 1). Despite this the reaction was slow and even after 7 days full conversion was not achieved. With a small excess of base, the reaction was rapid and a dr of approximately 2:1 was recorded. With a larger amount of base (2.2 eq) the dr improved to approximately 4:1. Unfortunately, due to the near identical polarity of the final products, it was impossible to separate diastereomers 1 and epi1 by flash column chromatography. Despite this, semipreparative reverse phase HPLC allowed us to successfully separate both epimers, of which absolute stereochemical configurations were confirmed by single-crystal X-ray diffraction analysis19 (see SI for details). The lack of reactivity/diastereoselectivity was attributed to the free acid functionality, and therefore these results naturally led us to investigate the comparative performance of protected analogues of carboxylic acid 13a. After a survey of protecting groups, TMS-ethanol-derived ester delivered a significant increase in diastereoselectivity coupled with downstream deprotection compatibility with the macrolactone architecture. Steglich coupling and subsequent selective deprotection of trityl provided us with desired TMSE protected nucleophile 13b (Scheme 1 (B)). Interestingly, when the sulfa-Michael addition was carried out with 13b, an inverse trend of the influence of the amount of base on diastereomeric ratio was observed.20 Without base, the reaction proceeded faster compared to when using unprotected thiol 13a, with full conversion after only 2 hours and dr 2:1. With 0.2 eq of base, the dr increased to 14:1, but when 1.5 eq of base was used, the dr dropped to 6:1. The best of these highly diastereoselective reaction conditions was then exploited for the preparation of berkeleylactone A; where the resulting mixture of diastereomeric products was readily separated by flash column chromatography. After deprotection and crystallization, berkeleylactone A 1 was obtained as a single diastereoisomer, with no recourse to HPLC for purification. By this reaction sequence, we prepared the desired natural product in two steps from 10 in excellent yield (82%) and diastereoselectivity (>20:1).

In alignment with previous reports on electron poor Michael acceptors21 the variation of the reaction dr with the molar equivalents of base suggested that the sulfa-Michael addition was reversible. In order to elucidate this, we separately subjected both epimers 1 and epi-1 to the reaction conditions, and epimerization in the presence of base was monitored by HPLC. Indeed after ~7 days, the dr of both reaction mixtures converged to ~80:20, with berkeleylactone A 1 as the thermodynamically preferred epimer (Scheme 1 (D)). The antibacterial activity of berkeleylactone A 1, as well as its 2-epimer epi-1, electrophiles 9, 10 and nucleophile 13a was evaluated against one model S. aureus (MSSA) and two S. aureus isolates (MRSA). The obtained MIC100 values [µg/ml] are summarized in (Table 1). Whilst nucleophile 13a was found to be inactive, all of the other compounds examined were found to exhibit a significant bacteriostatic effect on selected strains. Interestingly no difference in activity was observed between tested compounds, berkeleylactone A 1,4 its 2-epimer epi-1 and electrophile 10.5n Our preliminary microbicidal tests indicated that only berkeleylactone A 1 exhibits significant bactericidal effect on tested S. aureus MB17 strain. We believe that the presented efficient synthesis will be the appropriate platform for further improvement of antibacterial properties and investigation into the as of yet unknown mode of action. Table 1. Antibacterial activity of tested compounds characterized by MIC value [µg/ml]. Comp .

S. aureus CCM 3953 [a]

S. aureus MB21 strain [b]

S. aureus MB17 strain [b]

MIC100

MBC100

MIC100

MBC100

MIC100

MBC100

1

5[c]

10[d]

5

100

5

5

epi-1 9 10 13a

5 5 5 >100

10 10 10 >100

10 >100 5 >100

100 >100 100 >100

5 >100 5 >100

100 >100 100 >100

[a] Czech collection of microorganisms, methicillin-sensitive [b] MRSA - methicillin-resistant Staphylococcus aureus, resistant to penicillin, cefoxitin, erythromycin, chloramphenicol, and ciprofloxacin. [c] MIC100 values [µg/ml] (determined according to the EUCAST method by broth microdilution. [d] MBC100 values [g/ml] (minimum bactericidal concentration- determined according to the EUCAST method by broth microdilution).

CONCLUSION To conclude, the first enantioselective synthesis of berkeleylactone A 1, starting from commercially available amide 3 in 10 steps and a 9.5% yield has been achieved. We have also prepared its 2-epimer epi-1. The absolute stereochemical configuration of both final products were confirmed by single crystal X-ray analysis. In antimicrobial testing, both epimers were found to exhibit potent antibacterial activity against several MRSA strains, as was Michael acceptor 10. We have also found an alternative route affording the desired product via a highly diastereoselective sulfa-Michael addition, without the need for HPLC separation. This concise, efficient and convergent synthesis represents a solid base for the preparation of a large and divergent collection of berkeleylactone analogues for future SAR studies.


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EXPERIMENTAL SECTION Unless otherwise noted all the chemicals were purchased from commercial sources and used without further purifications. Dry DCM and THF were dried over 4Å molecular sieves overnight, distilled and stored over dried 4Å molecular sieves. Nbromosuccinimide was crystallized from water prior to use. Potassium (R)-oxirane-2-carboxylate was prepared according to literature procedure.16 Column chromatography was carried out using Silica 60A, particle size 20-45 micron, Davisil, purchased from Fisher Chemicals. All reactions were followed by thin-layer chromatography (TLC) where practical, using Macherey-Nagel’s pre-coated TLC sheets POLYGRAM SIL G/UV254 which were visualized under UV light (254 nm) or by staining with aqueous basic potassium permanganate or cerium molybdate solutions as appropriate. MPLC separations were performed using Büchi Sepacore flash chromatography system, HPLC separation was performed on Varian system using Macherey-Nagel VP 250/10 Nucleodur Phenyl-Hexyl 5 µm column. HPLC analyses were performed on Varian system using Macherey-Nagel EC 250/4 Nucleodur Phenyl-Hexyl 5 µm column. All 1H and 13C NMR spectra were recorded using a Varian INOVA 300 MHz, Bruker AVIII HD 400 MHz and/or Varian VNMRS 600 MHz spectrometers. Chemical shifts () are given in parts per million (ppm). 1H NMR chemical shift scale is referenced to TMS internal standard (0 ppm) or solvent residual peak (=2.50 ppm for DMSO-d6 and 7.26 ppm for CDCl3). 13C NMR chemical shift scale is referenced to solvent residual peak (39.52 ppm for DMSO-d6 and 77.16 ppm for CDCl3). Coupling constants (J) are given in Hertz (Hz). The multiplicity of 1H NMR signals is reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, bs = broad singlet. Optical rotations were recorded using an JASCO P-2000 polarimeter; [α]D values are reported in deg cm3 g-1dm1; concentration (c) is given in g/100 ml at 589 nm. HRMS were measured using Thermo Scientific mass spectrometer with Orbitrap analyzer and HESI and APPI ionization or on Bruker μTOF mass spectrometer with ESI ionization. 1-(furan-2-yl)hept-6-en-1-one (4) Preparation of Grignard reagent: Magnesium turnings (2.2 eq; 142 mmol; 3.45 g) were heated with iodine (50 mg) under argon atmosphere until purple fumes occurred. After cooling to RT the solution of 6-bromohex-1-ene (2 eq; 129 mmol; 21.0 g) in dry THF (132 ml) was added dropwise over 50 min, keeping the temperature below boiling point of THF. The reaction mixture was then stirred at RT for 1 h. Weinreb amide 3 was prepared from furan-2-carboxylic acid according to literature procedure.8 Amide 3 (64.5 mmol; 10.0 g) was dissolved in dry THF (130 ml) under argon atmosphere and cooled to 0 °C. The solution of Grignard reagent was added to this mixture dropwise over 1 hour. The reaction mixture was stirred at 0 °C for another 40 minutes and for 2 hours at RT. Then it was diluted with water (200 ml) and extracted twice with diethyl ether (100 ml). Combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography with gradient: 0% to 10% EtOAc in hexanes. Product was isolated as a yellow oil. (9.50 g; 82 % yield). Rf = 0.49 (Hexanes: EtOAc = 9:1) 1H NMR (300 MHz, CDCl , 25 °C): δ[ppm] = 1.42-1.53 (m, 3 2H), 1.69-1.80 (m, 2H), 2.05-2.15 (m, 2H), 2.79-2.86 (m, 2H), 4.95 (ddt, J= 1.2, 2.1, 10.2 Hz, 1H), 5.01 (ddt, J= 1.6, 2.1, 17.1 Hz, 1H), 5.81 (ddt, J= 6.7, 10.2, 17.1 Hz, 1H), 6.53 (dd, J= 1.7, 3.6 Hz, 1H), 7.17 (dd, J= 0.8, 3.6 Hz, 1H), 7.57 (dd, J=

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0.8, 1.7 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3, 25 °C): δ [ppm] = 23.9, 28.6, 33.6, 38.4, 112.2, 114.8, 116.9, 138.6, 146.3, 152.9, 189.7. Mass Spectrometry: HRMS-HESI (m/z): Calcd for C11H15O2 [M+H]+, 179.1067. Found, 179.1068. (S)-1-(furan-2-yl)hept-6-en-1-ol (5a) Ketone 4 (5.6 mmol; 1.0 g) was dissolved in THF (10 ml) under argon atmosphere and cooled to -40 °C. (R)-2-methyl-CBSoxazaborolidine catalyst (0.35 eq; 1.96 mmol; 1.96 ml; 1M in toluene) and borane dimethyl sulfide complex (1.36 eq; 7.6 mmol; 3.8 ml; 2M in THF) were mixed together and stirred under argon atmosphere at RT for 30 minutes. Then, this mixture was cooled to -40 °C and it was added dropwise to the solution of ketone. After 4 hours, the reaction mixture was quenched by dropwise addition of aqueous saturated solution of NH4Cl (35 ml), which was extracted with ethyl acetate (2 x 35 ml) and DCM (35 ml). Combined organic layers were washed with brine (35 ml), dried over Na2SO4, filtered and concentrated in vacuo. Crude product was purified by flash chromatography with gradient: 0% to 10% EtOAc in hexanes. Alcohol 5a was isolated as a colorless oil. (903 mg; 88 % yield). Rf = 0.28 (Hexanes: EtOAc = 9:1) 1H NMR (300 MHz, CDCl , 25 °C): δ [ppm] = 1.25-1.52 (m, 3 4H), 1.79-1.90 (m, 2H), 1.98 (bs, 1H), 2.01-2.10 (m, 2H), 4.66 (t, J= 6.8 Hz, 1H), 4.93 (dddt, J= 0.4, 1.2, 2.1, 10.2 Hz, 1H), 4.99 (dddt, J= 0.4, 1.6, 2.1, 17.1 Hz, 1H), 5.79 (ddt, J= 6.7, 10.2, 17.1 Hz, 1H), 6.21-6.23 (m, 1H), 6.32 (dddd, J= 0.4, 0.4, 1.8, 3.2 Hz, 1H), 7.36 (ddd, J= 0.4, 0.9, 1.8 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3, 25 °C): δ [ppm] = 25.1, 28.8, 33.7, 35.5, 67.9, 105.9, 110.2, 114.6, 138.9, 142.0, 157.0. [α]D25 = −8.91 (c = 0.099, CHCl3). Mass Spectrometry: HRMS-HESI (m/z): Calcd for C11H17O2 [M+H]+, 181.1223. Found, 181.1222. (S)-tert-butyl((1-(furan-2-yl)hept-6-en-1-yl)oxy)dimethylsilane (5b) Alcohol 5a (22.8 mmol; 4.1 g), imidazole (2.5 eq; 56.9 mmol; 3.87 g) and DMAP (0.2 eq; 4.55 mmol; 556 mg) were dissolved in DMF (20 ml) under argon atmosphere and the reaction mixture was cooled to 0 °C. TBDMSCl (1.1 eq, 24.6 mmol, 3.71 g) was added portionwise to this mixture within 10 minutes. The reaction mixture was allowed to warm to RT and it was stirred for 5 hours. Then it was diluted with water (100 ml) and extracted with diethyl ether (3 x 80 ml). Combined organic layers were washed with brine (80 ml), dried over Na2SO4, filtered and concentrated in vacuo. Crude product was purified by flash chromatography with hexanes. Product 5b was isolated as colorless oil (6.2 g; 93% yield). Rf = 0.92 (Hexanes: EtOAc = 97:3) 1H NMR (300 MHz, CDCl , 25 °C): δ [ppm] = -0.07 (s, 3H), 3 0.04 (s, 3H), 0.87 (s, 9H), 1.23-1.46 (m, 4H), 1.69-1.88 (m, 2H), 1.99-2.08 (m, 2H), 4.66 (dd, J= 6.1, 7.0 Hz, 1H), 4.92 (ddt, J= 1.2, 2.2, 10.2 Hz, 1H), 4.98 (ddt, J= 1.6, 2.0, 17.2 Hz, 1H), 5.79 (ddt, J= 6.7, 10.2, 17.1 Hz, 1H), 6.13-6.16 (m, 1H), 6.29 (dd, J= 1.8, 3.2 Hz, 1H), 7.33 (dd, J= 0.9, 1.8 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl , 25 °C): δ [ppm] = -4.9, -4.7, 3 18.4, 25.1, 26.0, 28.9, 33.9, 36.9, 68.6, 105.7, 110.1, 114.4, 139.1, 141.3, 157.7. [α]D25 = −48.3 (c = 0.179, CHCl3). Mass Spectrometry: HRMS-HESI (m/z): Calcd for C17H31O2Si [M+H]+, 295.2088. Found, 295.2096 (S,E)-5-((tert-butyldimethylsilyl)oxy)-4-oxoundeca-2,10-dienal (6) 5b (2.35 mmol; 691 mg) was dissolved in a mixture of acetone: water (10:1; 42 ml) and the solution was cooled to -50 °C. NaHCO3 (2 eq; 4.70 mmol; 394 mg) and NBS (1.2 eq; 2.82


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The Journal of Organic Chemistry mmol; 501 mg;) were added to this mixture. After 5 hours stirring at this temperature the solution of NaHCO3 (2 eq; 4.70 mmol; 394 mg) in water (8 ml) and pyridine (1 eq; 2.35 mmol; 186 mg; 0.19 ml) were added to the reaction mixture, which was allowed to warm to RT. After 2.5 hours the reaction mixture was diluted with saturated solution of NaHCO3 (67 ml) and extracted with Et2O (2 x 70 ml). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Crude product was purified by flash chromatography with gradient: 0% to 3% EtOAc in hexanes. Aldehyde 6 was isolated as a yellow oil. (503 mg; 69 % yield). Rf = 0.25 (Hexanes: EtOAc = 97:3) 1H NMR (300 MHz, CDCl , 25 °C): δ [ppm] = 0.03 (s, 3H), 3 0.09 (s, 3H), 0.92 (s, 9H), 1.25-1.46 (m, 4H), 1.60-1.76 (m, 2H), 1.99-2.10 (m, 2H), 4.21 (dd, J= 5.6, 7.3 Hz, 1H), 4.94 (ddt, J= 1.2, 2.1, 10.2 Hz, 1H), 4.99 (ddt, J= 1.6, 2.1, 17.2 Hz, 1H), 5.78 (ddt, J= 6.7, 10.2, 17.1 Hz, 1H), 6.93 (dd, J= 7.6, 16.0 Hz, 1H), 7.37 (d, J= 16.0 Hz, 1H), 9.78 (d, J= 7.6 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl , 25 °C): δ [ppm] = -4.8, -4.7, 3 18.3, 24.3, 25.8, 28.7, 33.6, 34.7, 78.5, 114.8, 138.6, 138.6, 140.6, 193.2, 201.5. [α]D25 = -44.8 (c = 0.105, CHCl3). Mass Spectrometry: HRMS-HESI (m/z): Calcd for C17H31O3Si [M+H]+, 311.2037. Found, 311.2048. (S,E)-(R)-hept-6-en-2-yl 5-((tert-butyldimethylsilyl)oxy)-4oxoundeca-2,10-dienoate (8) Aldehyde 6 (1.61 mmol; 0.50 g) was dissolved in tert-butanol (6 ml), phosphate buffer (pH = 3.6; 3.05 ml) and 2-methyl-2butene (5 eq; 8.05 mmol; 565 mg; 0.85 ml) were added, followed by solution of NaClO2 (1.5 eq; 2.42 mmol; 218 mg) in water (3.05 ml). After stirring for 4 hours at RT, the reaction mixture was acidified with 1M HCl to pH = 4. Most of the solvent was evaporated and solution was diluted with EtOAc (15 ml) and brine (11 ml). Aqueous layer was extracted twice with EtOAc (20 ml). Combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Crude product was isolated as a yellow oil. (519 mg; 98 % yield). Rf = 0.06 (Hexanes: EtOAc = 97:3) Crude carboxylic acid (1.48 mmol; 483 mg) was dissolved in DCM (24 ml) and the mixture was cooled to 0 °C. DCC (1.2 eq; 1.78 mmol; 366 mg), alcohol 7 (1.1 eq; 1.63 mmol; 186 mg) and DMAP (0.1 eq; 0.148 mmol; 16.6 mg) were added to the reaction mixture, which was stirred at 0 °C for 30 minutes and at RT for 1.5 hours. Solvent was concentrated in vacuo and product was isolated by flash chromatography with gradient: 0% to 2% EtOAc in hexanes. Product 8 was obtained as a yellow oil (418 mg; 67 % yield). Rf = 0.39 (Hexanes: EtOAc = 97:3) 1H NMR (300 MHz, CDCl , 25 °C): δ [ppm] = 0.02 (s, 3H), 3 0.06 (s, 3H), 0.92 (s, 9H), 1.26 (d, J= 6.3 Hz, 3H), 1.27-1.76 (m, 10H), 1.99-2.12 (m, 4H), 4.16 (dd, J= 5.4, 7.3 Hz, 1H), 4.91-5.06 (m, 5H), 5.78 (ddt, J= 6.7, 10.2, 17.1 Hz, 1H), 5.79 (ddt, J= 6.7, 10.2, 17.1 Hz, 1H), 6.77 (d, J= 15.9 Hz, 1H), 7.49 (d, J= 15.9 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3, 25 °C): δ [ppm] = -4.8, -4.8, 18.3, 20.0, 24.4, 24.7, 25.8, 28.7, 33.6, 33.6, 34.6, 35.4, 72.2, 78.5, 114.7, 115.0, 132.4, 135.0, 138.4, 138.7, 165.2, 201.7. [α]D25= - 37.4 (c = 0.21, CHCl3). Mass Spectrometry: HRMS-HESI (m/z): Calcd for C24H43O4Si [M+H]+, 423.2925. Found, 423.2923. (6S,16R,E)-6-((tert-butyldimethylsilyl)oxy)-16methyloxacyclohexadec-3-ene-2,5-dione (9) Ester 8 (1.45 mmol; 613 mg) was dissolved in dry DCM (730 ml) under argon atmosphere. Grubbs catalyst 1st generation22

(0.2 eq; 0.29 mmol; 239 mg) was added and the reaction mixture was stirred at RT for 2.5 hours. Second portion of Grubbs catalyst (0.05 eq; 72.5 µmol, 60 mg) was added and the reaction mixture was stirred for another 2 hours. The reaction mixture was put under H2 atmosphere for 30 min, swapped for argon atmosphere to add the catalyst PtO2 (0.2 eq; 0.29 mmol; 80 mg) and then swapped again for H2 atmosphere and stirred at RT for 4 hours. The crude reaction mixture was then filtered through the short plug of silica gel and the filtrate was concentrated in vacuo at RT. The Crude product was purified by flash chromatography with gradient: 0% to 3% EtOAc in hexanes. Product was isolated as a brown oil. (260 mg; 45 % yield). Rf = 0.33 (Hexanes: EtOAc = 97:3) 1H NMR (600 MHz, CDCl , 25 °C): δ [ppm] = 0.03 (s, 3H), 3 0.06 (s, 3H), 0.91 (s, 9H), 1.12-1.42 (m, 17H), 1.54-1.63 (m, 2H), 1.70-1.75 (m, 2H), 4.26 (t, J= 5.6 Hz, 1H), 5.07 (ddq, J= 3.3, 6.3, 8.1 Hz, 1H), 6.71 (d, J= 15.9 Hz, 1H), 7.45 (d, J= 15.9 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3, 25 °C): δ [ppm] = 4.84, -4.83, 18.3, 20.3, 22.4, 23.8, 25.8, 26.4, 27.3, 27.7, 27.7, 28.2, 33.7, 34.9, 72.6, 78.3, 131.7, 134.9, 165.2, 201.0. [α]D25 = -31.9 (c = 0.070, CHCl3). Mass Spectrometry: HRMSHESI (m/z): Calcd for C22H41O4Si [M+H]+, 397.2769. Found, 397.2771. (6S,16R,E)-6-hydroxy-16-methyloxacyclohexadec-3-ene-2,5dione (10) Protected lactone 9 (0.108 mmol; 43 mg) was dissolved in dry DCM (3.3 ml) under nitrogen atmosphere. The reaction mixture was cooled to 0 °C and TFA (0.33 ml) was added dropwise over 5 minutes period. The reaction mixture was then put into the fridge at 4 °C for 24 hours. The volatiles were evaporated in vacuo at RT and the crude product was purified by flash chromatography with gradient: 0% to 25% EtOAc in hexanes. Product 10 was isolated as a white solid (27.2 mg; 89 % yield). Rf = 0.32 (Hexanes: EtOAc = 5:1). Spectral data were in accordance with those previously reported. 5h (S)-2-hydroxy-3-(tritylthio)propanoic acid (12) Triphenylmethanethiol (5.5 g; 20 mmol) was dissolved in anhydrous THF (75 ml) under argon atmosphere, and the reaction mixture was cooled to 0 °C by an ice−water bath. NaH (60% dispersion in mineral oil; 800 mg; 20 mmol) was added carefully in several portions, and the resulting solution was stirred at 0 °C for an additional 15 min. Potassium (R)-oxirane2-carboxylate 11 (1.9 g; 15 mmol) was added in one portion, and the resulting reaction mixture was then gradually warmed to RT and was stirred for 14 hours before being poured into H2O (250 ml) and extracted with Et2O (3 x 100 ml). The Et2O layer was discarded, and the aqueous phase was acidified by 1N HCl to pH 3−4 (determined by pH strips) and was extracted with EtOAc (3 x 100 ml). The combined EtOAc layers were washed with brine and dried over anhydrous Na2SO4 and concentrated to provide crude product as a pale yellow viscous oil, which was crystallized from acetonitrile and dried in vacuo affording 12 (4.0 g, 73 %) as a white solid. Rf = 0.68 (DCM: MeOH = 1:1) 1H NMR (300 MHz, DMSO-d , 25 °C): δ [ppm] = 2.31-2.39 6 (m, 2H), 3.84 (dd, J= 5.7, 6.8 Hz, 1H), 5.63 (bs, 1H), 7.16-7.44 (m, 15H), 12.48 (bs, 1H); 13C{1H} NMR (75 MHz, DMSO-d6, 25 °C): δ [ppm] = 36.0, 65.8, 69.0, 126.7, 128.0, 129.1, 144.4, 173.8. Spectral data were in accordance with those previously reported.17 [α]D25 = -39.0 (c = 1.005, CHCl3), m.p. 99-101 °C.


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(S)-2-hydroxy-3-mercaptopropanoic acid (13a) Acid 12 (4.2 mmol; 1.53 g) was dissolved in DCM (24 ml) and triethylsilane (3 eq; 12.6 mmol; 2.01 ml) was added in one portion. The reaction mixture was cooled to 0 °C and trifluoroacetic acid (2.4 ml) was added dropwise. After 30 min the reaction mixture was concentrated in vacuo resulting white solid. The crude product was washed 4 times with hexanes to remove triphenylmethane and dried in vacuo yielding 13a (436 mg, 85 %) as a white solid. Rf = 0.48 (DCM: MeOH = 1:1) 1H NMR (600 MHz, DMSO-d , 25 °C): δ [ppm] = 2.22 (t, J= 6 8.2 Hz, 1H), 2.67 (ddd, J= 6.1, 8.4, 13.5 Hz, 1H), 2.77 (ddd, J= 4.6, 8.0, 13.3 Hz, 1H), 4.10 (dd, J= 4.6, 6.0 Hz, 1H), 5.49 (bs, 1H), 12.60 (bs, 1H); 13C{1H} NMR (150 MHz, DMSO-d6, 25 °C): δ [ppm] = 28.3, 71.1, 173.7. [α]D25 = 20.3 (c = 0.93, MeOH). m.p. 67-69 °C. Mass Spectrometry: HRMS-HESI (m/z): Calcd for C3H6O3SNa [M+Na]+, 144.9930. Found, 144.9931 (S)-2-(trimethylsilyl)ethyl 2-hydroxy-3-mercaptopropanoate (13b) Acid 12 (1.11 mmol; 405 mg) and DMAP (1 eq; 1.11 mmol; 136 mg) were dissolved in DCM (5 ml) under argon atmosphere and the reaction mixture was cooled to 0 °C. 2(Trimethylsilyl)ethanol (4 eq; 4.44 mmol, 636 µl) was added followed by the solution of DCC (2 eq; 2.22 mmol; 460 mg) in DCM (4 ml). The reaction mixture was stirred at 0 °C for 30 min and then at RT for 18 h. The crude reaction mixture was filtered through the Celite, washed with DCM and concentrated in vacuo. Crude product was purified by flash chromatography with gradient: 50% to 75% DCM in pentane. Product was isolated as a colorless oil (119 mg; 23%). Rf = 0.44 (Hexanes: EtOAc = 5:1) Ester (0.236 mmol; 110 mg) was dissolved in DCM (5 ml) and triethylsilane (3 eq; 0.708 mmol; 113 µl) was added in one portion. The reaction mixture was cooled to 0 °C and trifluoroacetic acid (6 eq; 1.42 mmol; 108 µl) was added dropwise. After 30 min at 0 °C the reaction mixture was concentrated in vacuo and crude product was purified by flash chromatography with gradient: 0% to 33% EtOAc in hexanes. Product 13b was isolated as a colorless oil. (38 mg; 72 % yield). Rf = 0.38 (Hexanes: EtOAc = 5:1) 1H NMR (400 MHz, CDCl , 25 °C): δ [ppm] = 0.06 (s, 9H), 3 1.02-1.08 (m, 2H), 1.62 (dd, J= 7.9, 9.6 Hz, 1H), 2.85 (ddd, J= 4.5, 9.6, 14.0 Hz, 1H), 2.96 (ddd, J= 3.8, 7.9, 14.0 Hz, 1H), 3.18 (d, J= 5.4 Hz, 1H), 4.31 (dd, J= 7.7, 9.6 Hz, 2H), 4.39 (q, J= 4.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3, 25 °C): δ [ppm] = 1.4, 17.6, 29.0, 64.9, 70.6, 173.0. [α]D25 = -9.98 (c = 0.65, CHCl3). Mass Spectrometry: HRMS-ESI (m/z): Calcd for C8H17O3SSi [M-H]-, 221.0673. Found, 221.0671. Berkeleylactone A (1) and 2-epi-berkeleylactone A (epi-1). Electrophile 10 (0.057 mmol, 16 mg) was dissolved in DCM (1.2 ml) followed by the addition of nucleophile 13a (1.2 eq; 0.068 mmol; 8.3 mg) and Et3N (5 eq; 0.29 mmol; 40 µl). The reaction mixture was stirred for 2 h at RT, concentrated and separated by preparative reverse phase HPLC (Macherey-Nagel VP 250/10 Nucleodur Phenyl-Hexyl 5 µm column, mobile phase: CH3CN:H2O, 1:1, 0.1 v/v % HCOOH, flow 2 ml/min, tR (1) = 22 min, tR (epi-1) = 25 min). After lyophilization berkeleylactone A 1 (14.5 mg, 63 %) and 2-epi-berkeleylactone A epi-1 (5.7 mg, 25 %) were obtained as white solids. Both

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compounds were further crystallized by vapor diffusion using petrolether and chloroform. berkeleylactone A (1): Rf = 0.32 (MeOH: DCM = 4:10) [α]D25 = 101.0 (c = 0.105, CHCl3), lit4 [α]D25 = 0.5 (c = 0.170, CHCl3). m.p. 119-121 °C. Mass Spectrometry: HRMS-HESI (m/z): Calcd for C19H32O7SNa [M+Na]+, 427.1761. Found, 427.1768. 2-epi-berkeleylactone A (epi-1): Rf = 0.32 (MeOH: DCM = 4:10) [α]D25 = -20.0 (c = 0.095, CH3CN). m.p. 105-107 °C. Mass Spectrometry: HRMS-HESI (m/z): Calcd for C19H33O7S [M+H]+, 405.1942. Found, 405.1941. Assignment of 1H NMR and 13C NMR signals of final products based on 2D COSY, HSQC, HMBC spectra is summarized in Table S1. in Supporting information Berkeleylactone A (1) To the mixture of electrophile 10 (0.04 mmol; 11.3 mg) and Et3N (0.2 eq; 0.008 mmol; 1.11 µl) in DCM (1 ml) at RT, the solution of nucleophile 13b (1.1 eq; 0.044 mmol; 9.8 mg) in DCM (0.7 ml) was added. The reaction mixture was monitored by TLC (DCM:EtOAc = 4:1) and after consumption of starting material (2 hours) was concentrated under reduced pressure. The crude reaction mixture (dr 14:1) was purified by column chromatography (9 % to 15 % EtOAc in DCM) affording 1b as a colorless oil (17.3 mg; 85%; dr 16:1). Rf = 0.4 (pentane:EtOAc = 1:1) 1H NMR (400 MHz, CDCl , 25 °C): δ [ppm] = 0.05 (s, 9H), 3 0.94-1.06 (m, 3H), 1.15-1.50 (m, 17H), 1.53-1.63 (m, 1H), 1.81-1.89 (m, 2H), 2.74 (ddd, J= 0.6, 6.0, 18.4 Hz, 1H), 2.96 (dd, J= 5.7, 14.3 Hz, 1H), 3.24 (dd, J= 3.8, 14.4 Hz, 1H), 3.25 (dd, J= 8.4, 18.4 Hz, 1H), 3.34 (d, J= 5.2 Hz, 1H), 3.43 (d, J= 5.6 Hz, 1H), 4.03 (dd, J= 6.0, 8.4 Hz, 1H), 4.25-4.32 (m, 2H), 4.33-4.38 (m, 1H), 4.45 (ddd, J= 3.8, 5.5, 5.5 Hz, 1H), 4.925.01 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3, 25 °C): δ [ppm] = -1.4, 17.6, 20.0, 20.9, 23.1, 25.4, 26.1, 26.7, 26.9, 27.0, 32.7, 34.7, 35.9, 41.2, 41.3, 64.8, 70.7, 72.7, 76.2, 172.0, 173.0, 209.0. To the solution of substrate 1b (0.034 mmol; 17 mg) in DCM (4 ml) was added TFA (800 µl) at 0 ˚C. The reaction mixture was put into the fridge and after 15 hours volatiles were removed under reduced pressure. The crude mixture was crystallized in a two vial system (chloroform/pentane) yielding a colorless crystals of Berkeleylactone A 1 (12.6 mg; 92%).

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Synthetic procedures and full characterization data of compounds (PDF)

AUTHOR INFORMATION Corresponding Author * Email: [email protected] * Email: [email protected] ORCID Ján Moncoľ: 0000-0003-2153-9753 Darren J. Dixon: 0000-0003-2456-5236 Oľga Caletková: 0000-0001-6296-7266


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The Journal of Organic Chemistry Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We are grateful to Dr. Jamie Leitch for help in the preparation of this manuscript. We are also thankful to students David Scherhafer, Alica Ištoková and Barbora Janíková for their contribution to this synthesis. This research was conducted with the support of the MŠVVaŠ of the Slovak Republic within the Research and Development Operation Programme for the project "University Science Park of STU Bratislava" (ITMS project no. 26240220084) cofounded by the European Regional Development Fund. B. F. is thankful to the Slovak Academic Information Agency (SAIA) for his research mobility grant. M. F. is grateful to the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship. This work was supported by the Slovak Research and Development Agency under contract number No APVV-16-0258

REFERENCES (1) a) Wright, P. M.; Seiple, I. B.; Myers, A. G. The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery. Angew. Chem. Int. Ed. 2014, 53, 8840-8869; b) Moloney, M. G. Natural Products as a Source for Novel Antibiotics. Trends Pharmacol. Sci., 2016, 37, 689701. (2) Giddings, L.-A.; Newman, D. J. Bioactive Compounds from Marine Extremophiles, in Springer Briefs in Microbiology; Extremophilic Bacteria (Eds.: S. M. Tiquia-Arashiro, M. Mormile), Springer, Heidelberg, 2015; pp. 4-39. (3) Berkeleylactone A, although the trivial name suggests, is not structurally related to berkelic acid which was also isolated from the Berkeley Pit Lake. Isolation: Stierle, A. A.; Stierle, D. B.; Kelly, K. Berkelic Acid, A Novel Spiroketal with Selective Anticancer Activity from an Acid Mine Waste Fungal Extremophile. J. Org. Chem. 2006, 71, 5357-5360; Structure correction: Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.; Goddard, R.; Fürstner, A. A Synthesis‐Driven Structure Revision of Berkelic Acid Methyl Ester. Angew. Chem. Int. Ed. 2008, 47, 8450-8454. (4) Stierle, A. A.; Stierle, D. B.; Decato, D.; Priestley, N. D.; Alverson, J. B.; Hoody, J.; McGrath, K.; Klepacki, D. The Berkeleylactones, Antibiotic Macrolides from Fungal Coculture. J. Nat. Prod. 2017, 80, 1150-1160. (5) Isolation: Michel, K. H.; Demarco, P. V.; Nagarajan, R. The isolation and structure elucidation of macrocyclic lactone antibiotic, A26771 B. J. Antibiot. 1977, 30, 571-575. For syntheses of optically active (-)-A26771B, see: a) Tatsuta, K.; Nakagawa, A.; Maniwa, S.; Kinoshita, M. Stereospecific total synthesis and absolute configuration of a macrocyclic lactone antibiotic, A26771B. Tetrahedron Lett. 1980, 21, 1479-1482; b) Tatsuta, K.; Amemiya, Y.; Kanemura, Y.; Kinoshita, M. Total Synthesis of a Macrocyclic Lactone Antibiotic A26771B and Its Isomers Using Carbohydrates. Bull. Chem. Soc. Jpn. 1982, 55, 32483253; c) Quinkert, G.; Küber, F.; Knauf, W.; Wacker, M.; Koch, U.; Becker, H.; Nestler, H. P.; Dürner, G.; Zimmermann, G.; Bats, J. W.; Egert, E. Synthese des Makrolid-Antibiotikums (-)-A26771B mit Photolactonisierung als Schlüsselreaktion und Computersimulation als effektive Optimierungshilfe. Helv. Chim. Acta 1991, 74, 1853-1923; d) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. A General Approach to Enantiomerically Pure Methylcarbinols. Asymmetric Synthesis of Antibiotic (-)-A26771B and the WCR Sex Pheromone. J. Org. Chem. 1993, 58, 7789-7796; e) Nagarajan, M. Boc20 Mediated Macrolactonisation: Formal Chemoenzymatic Synthesis of Macrolide Antibiotic (-)-A26771B. Tetrahedron Lett. 1999, 40, 1207-1210; f) Kobayashi, Y.; Okui, H. An Efficient Synthesis of Antibiotic (-)A26771B. J. Org. Chem. 2000, 65, 612-615; g) Lee, W.-W.; Shin, H. J.; Chang, S. A rapid formal synthesis of the macrolide (-)-A26771B. Tetrahedron: Asymmetry 2001, 12, 29-31; h) Gebauer, J.; Blechert, S. Synthesis of -Unsaturated--keto Lactones via Sequential Cross Metathesis-Lactonization: A Facile Entry to Macrolide Antibiotic (-)A26771B. J. Org. Chem. 2006, 71, 2021-2025; i) Reddy, C. R.; Suman,

D.; Rao, N. N. Alkyne-Assisted Approach to the Formal Synthesis of Antibiotic Macrolide (-)-A26771B. Synlett 2012, 272-274; j) Persich, P.; Llaveria, J.; Lhermet, R.; de Haro, T.; Stade, R.; Kondoh, A.; Fürstner, A. Increasing the Structural Span of Alkyne Metathesis. Chem. Eur. J. 2013, 19, 13047-13058; k) Chatterjee, S.; Sharma, A.; Chattopadhyay S. Chemoenzymatic Synthesis of the Macrolide Antibiotic (-)-A26771B. RSC Adv. 2014, 4, 42697-42705; l) Saidhareddy, P.; Shaw, A. K. Glycal Approach to the Synthesis of Macrolide (-)-A26771B. RSC Adv. 2015, 5, 29114-29120. For the macrolactam analogues, see: m) Canova, S.; Lépine, R.; Thys, A.; Baron, A.; Roche, D. Synthesis and biological properties of macrolactam analogs of the natural product macrolide (-)-A26771B. Bioorg. Med. Chem. Lett. 2011, 21, 4768-4772. For syntheses of racemic (±)-A26771B, see: n) Trost, B. M.; Brickner, S. J. Palladium-Assisted Macrocyclization Approach to Cytochalasins: A Synthesis of Antibiotic A26771B. J. Am. Chem. Soc. 1983, 105, 568-575, and references cited therein. (6) a) Farley, A. J.; Sandford, C.; Dixon, D. J. Bifunctional Iminophosphorane Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α-Substituted Acrylate Esters. J. Am. Chem. Soc. 2015, 137, 15992-15995; b) Yang, J.; Farley, A. J.; Dixon, D. J. Enantioselective Bifunctional Iminophosphorane Catalyzed SulfaMichael Addition of Alkyl Thiols to Unactivated β-Substituted-α,βUnsaturated Esters. Chem. Sci. 2017, 8, 606-610. (7) Fürstner, A. Olefin Metathesis and Beyond. Angew. Chem., Int. Ed. 2000, 39, 3012-3046; (b) Trnka, T. M.; Grubbs, R. H. The Development of L2X2Ru=CHR Olefin Metathesis Catalysts: An Organometallic Success Story. Acc. Chem. Res. 2001, 34, 18-29; (c) Kotha, S.; Sreenivasachary, N. Catalytic metathesis reaction in organic synthesis. Ind. J. Chem. B, 2001, 40, 763-780. (8) Peixoto, P. A.; Boulangé, A.; Leleu, S.; Franck, X. Versatile Synthesis of Acylfuranones by Reaction of Acylketenes with αHydroxy Ketones: Application to the One-Step Multicomponent Synthesis of Cadiolide B and Its Analogues. Eur. J. Org. Chem. 2013, 16, 3316-3327. (9) Nahm, S.; Weinreb, S. M. N-Methoxy-N-methylamides as effective acylating agents. Tetrahedron Lett. 1981, 22, 3815-3818. (10) General CBS reduction: Corey, E. J.; Bakshi, R. K.; Shibata, S. Highly Enantioselective Borane Reduction of Ketones Catalyzed by Chiral Oxazaborolidines. Mechanism and Synthetic Implications. J. Am. Chem. Soc. 1987, 109, 5551-5553. On a homologous substrate: Jammula, S. R.; Anna, V. R; Tatina, S.; Krishna, T.; Sreenivas, B. Y; Pal, M. A new strategy for accessing (S)-1-(furan-2-yl)pent-4-en-1-ol: a key precursor of Ipomoeassin family of compounds and C1-C15 domain of halichondrins. Tetrahedron Lett. 2016, 57, 3924-3928. (11) Corey, E. J.; Venkateswarlu, A. Protection of Hydroxyl Groups as tert-Butyldimethylsilyl Derivatives. J. Am. Chem. Soc. 1972, 94, 6190-6191. (12) Achmatowicz, O.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.; Zamojski, A. Synthesis of methyl 2,3-dideoxyDL-alk-2-enopyranosides from furan compounds. A general approach to the total synthesis of monosacharides. Tetrahedron 1971, 27, 19731996. (13) On a homologous substrate: (a) Prasad, K. R.; Pawar, A. B. Enantioselective Formal Synthesis of Palmerolide A. Org. Lett. 2011, 13, 4252-4255.; (b) Fürstner, A.; Nagano, T. Total Syntheses of Ipomoeassin B and E. J. Am. Chem. Soc., 2007, 129, 1906–1907. (c) Nagano, T.; Pospíšil, J.; Chollet, G.; Schulthoff, S.; Hickmann, V.; Moulin, E.; Herrmann, J.; Müller, R.; Fürstner, A. Total Synthesis and Biological Evaluation of the Cytotoxic Resin Glycosides Ipomoeassin A–F and Analogues. Chem. Eur. J. 2009, 15, 9697-9706. (14) Leijondahl, K.; Borén, L.; Braun, R.; Bäckvall, J.-E. Enzymeand Ruthenium-Catalyzed Dynamic Kinetic Asymmetric Transformation of 1,5-Diols. Application to the Synthesis of (+)Solenopsin A. J. Org. Chem. 2009, 74, 1988-1993. (15) Neises, B.; Steglich, W. Simple Method for the Esterification of Carboxylic Acids. Angew. Chem. Int. Ed. 1978, 17, 522-523. (16) Petit, Y.; Larchevêque, M. Ethyl glycidate from (S)-serine: ethyl (R)-(+)-2,3-epoxypropanoate. Org. Synth. 1998, 75, 37-39. (17) Liu, F.; Mayer, J. P. An Fmoc Compatible, O to S ShiftMediated Procedure for the Preparation of C-Terminal Thioester Peptides. J. Org. Chem. 2013, 78, 9848-9856.


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(18) dr determined by HPLC; there was no significant change in dr during 48 h monitoring. (19) CCDC 1896863 (1) and 1896864 (epi-1∙0.5H2O) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre. (20) The reaction diastereomeric ratio was determined by 1H NMR analysis. The minor diastereoisomer was not isolated and the 1H NMR signals were tentatively assigned. (21) For reversible sulfa-Michael additions, see: Krenske, E. H.; Petter, R. C.; Houk, K. N. Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines. J. Org. Chem. 2016, 81, 11726-11733, and references cited therein. For a review on thiol Michael additions in synthesis, see: (j) Enders, D.; Lüttgen, K.; Narine, A. A. Asymmetric Sulfa-Michael Additions. Synthesis, 2007, 959-980. (22) The amount of the catalyst used for the complete conversion of the starting material was strongly dependent on the quality of the catalyst. Only 0.05 eq. of the high-quality catalyst was necessary for the full conversion, however there was no significant improvement of the reaction yield.


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Total Synthesis of Berkeleylactone A. - ACS Publications

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