Formal Total Synthesis of Pericoannosin A | The Journal of Organic

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Formal Total Synthesis of Pericoannosin A Mark G Fulton, Jeanette L Bertron, Carson W Reed, and Craig W Lindsley J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01846 • Publication Date (Web): 22 Aug 2019 Downloaded from pubs.acs.org on August 23, 2019

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The Journal of Organic Chemistry

Formal Total Synthesis of Pericoannosin A

Mark G. Fulton,† Jeanette L. Bertron,† Carson W. Reed,† and Craig W. Lindsley†,‡* †

Department of Chemistry, ‡ Vanderbilt Center for Neuroscience Drug Discovery and Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States

Corresponding Author's E-mail Address: [email protected]

Table of Contents

O H

H 8 steps

O

known

NH

O H

OTBS 21.7% overall

OH

H

H

Pericoannosin A

ABSTRACT

A concise formal total synthesis of pericoannosin A, by the synthesis of an advanced intermediate of pericoannosin A, was achieved in eight steps from commercially available isoprene in 21.7% overall yield. Key transformations for this expedited route include an enantioselective organocatalytic Diels-Alder reaction to construct the C ring, a diastereoselective reduction (under Felkin-Ahn control), and a hydroboration/oxidation sequence for chain homologation.

This work represents the second synthetic

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effort towards pericoannosin A, the only reported natural product based on a hexahydro-1H-isochromen-5isobutylpyrrolidin-2-one core.

In 2015, Dai and co-workers reported on the isolation, from the fungus Periconia sp. F31, and characterization of a new polyketide synthase-nonribosomal peptide synthase (PKS-NRPS) hybrid metabolite named pericoannosin A (1), possessing a previously undescribed hexahydro-1H-isochromen-5isobutylpyrrolidin-2-one skeleton (Figure 1).1 Other natural products within this family displayed a broad spectrum of biological activity,2 and 1 was no exception. In addition to the novel carbon skeleton, 1 also

H

OH

O

6

NH

O H

7 21

H

H 4 OH

O 2

1

A

NH

20

C 10 B 3 O H15 16 18 17 11 19 9 H 13 14

Pericoannosin A (1)

22

1

Figure 1. Structure of pericoannosin A (1) and numbering convention.

displayed weak anti-HIV activity (IC50= 69 M), warranting the total synthesis of 1 as well as unnatural analogs for further biological evaluation.1 While in the midst of our synthesis campaign, Lücke, Kalesse and co-workers reported on the first, and only, total synthesis of 1 in 2018.3 Due to similarities between the two routes in the endgame strategy, we elected to halt our campaign, and report our synthetic efforts, which yielded a concise formal total synthesis of 1.


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In 2018, Lücke, Kalesse and co-workers reported their total synthesis of Pericoannosin A in a 15 step (17 steps from known compounds) longest linear sequence.3 Their retrosynthesis was predicated on the formation of the unique lactol moiety last, which could be formed from an aldol-oxidation sequence to form the necessary 1,3 dicarbonyl species 2, which was our plan as well. Importantly, our routes converged on a common, advanced intermediate aldehyde 3 (Scheme 1). Lücke, Kalesse and co-workers assembled 3 via a Diels-Alder reaction employing a substrate-tethered Evans oxazolidinone 4 to install the stereochemistry,4 but a competing 1,4-addition diminished the yield. A chiral Evans oxazolidinone was also employed to establish the stereochemistry at C11 via an aldol reaction. Overall, the published route to 3 required 13 steps (11 steps LLS) from commercial materials in ~10.7% overall yield starting from tiglic aldehyde 5.3

Scheme 1. Lücke, Kalesse and co-workers’ retrosynthesis to arrive at 3.3

aldol reaction H

OH

O NH

O

NTeoc Diels-Alder

O H

O H

homologation

H

O

OTBS

H

OTBS

H

H

lactol formation

1

2 O O

O

3

HWE O

N OTBS

Bn glycolate aldol 4


5


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Scheme 2. Our retrosynthetic analysis for 3. enantioselective, organocatalytic Diels-Alder O H

homologation (olefination/oxidation)

H

O OTBS

H

O

O

diastereoselective reduction (Felkin-Ahn)

H

+

O

OEt

OEt

ketone synthesis 3

6

7

8

While a Diels-Alder reaction was a key component of our approach to form the C ring of 1, we employed distinct chemistries en route to 3, as highlighted in our retrosynthetic analysis of 3 (Scheme 2). We envisioned an enantioselective, organocatalytic Diels-Alder reaction5 to form the C ring intermediate 6, derived from commercial 7 and isoprene (8). Moreover, we planned on utilizing substrate control for a highly diastereoselective reduction (Felkin Ahn control)6 to set the C11 stereochemistry, and a facile hydroboration/oxidation sequence to install the C3 aldehyde. If successful, the lack of steps to install and remove chiral auxiliaries would greatly expedite the route to 3.

Scheme 3. Organocatalytic Diels-Alder to deliver 6. F3C CF3 OTMS

N H2

CF3

ClO4 F3C

O +

EtO

8


O O

H2O, 4C, 16 hr 92%, 94% ee

O 7

H

9 10 mol%

H 6

OEt

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For the synthesis of 6, we were attracted to the work of Hayashi,7 wherein his lab developed methodology for asymmetric Diels–Alder reactions of α,β‐unsaturated aldehydes catalyzed by a diarylprolinol silyl ether salt in the presence of water.7 Fortunately, the catalyst 9 is available from Sigma,8 and we converted this organocatalyst to the requisite perchloric acid salt form according to literature procedure.7 In the event, 9 effectively catalyzed the Diels–Alder reaction between 7 and 8 to deliver C ring intermediate 6 in 92% yield and 94% ee (Scheme 3).9 Once 6 was in hand, we turned our attention to the conversion of the aldehyde moiety in 6 to the corresponding terminal olefin to set the stage for a final hydroboration/oxidation chain homologation sequence. After surveying several conditions (Table 1), a Wittig reaction with CH3PPh3Br and LHMDS as base at -78 oC (with slow warming to room temperature) provided the desired terminal olefin 10 in 73% yield and in >20:1 d.r (Table 1, entry 4).10 Importantly, this reaction was scalable, affording comparable yield and d.r. on a 1 gram scale (Table 1, entry 5).9

Table 1. Conditions surveyed to effect olefination of 6 to provide 10. H

O

H O

H

Conditions

O H

OEt

6

OEt

10

Conditionsa

Yield

d.r.

Rh(PPh3)3Cl, iPrOH, PPh3, TMSCHN2

65%

>20:1

CH3PPh3Br, KOtBu

55%

4:1

CH3PPh3Br, KHMDS

59%

10:1

CH3PPh3Br, LHMDS

73%

>20:1

CH3PPh3Br, LHMDSb

75%

>20:1

Reactions were conducted on 100 mg (0.5 mmol) scales. bReaction conducted on a 1 g (5 mmol) scale.

a



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Scheme 4. Formal total synthesis of pericoannosin A (1) by the synthesis of 3.

H O H

OEt

O P OEt nBuLi, OEt THF, -78 C, 3 hr 91%

H

H

O .

O H

Ba(OH)2 8H2O,

O P OEt EtO

O

THF, RT, 4 hr 81%

H

H

NOE 10

11

12

H

H DIBAL Toluene, -78 C, 15 min 80%, >20:1 d.r

OH H

TBSOTf, 2,6-Lutidine DCM, -78-0C, 0.5 hr 90%

13

OTBS H

14 OH

O

H 9-BBN then NaOH, H2O2 THF, 0-23 C, 2 hr 81%

H OTBS

H

DMP, NaHCO3 DCM, 0-23 C, 1.5 hr 73%

15

OTBS H

3

With 10 in hand, the formal total synthesis of pericoannosin A (1), via the synthesis of 3, required only six additional steps (Scheme 4). Treatment of 10 with excess lithated ethyl ethylphosphonate produced the desired Horner-Wadsworth-Emmons (HWE) substrate,11 β-ketophosphonate 11 in 81% yield. βKetophosphonate 11 then underwent an HWE reaction with acetaldehyde in the presence of a soft source of hydroxide, barium hydroxide octahydrate, to deliver the enone 12, harboring the correct E-olefin (conformed by multiple NOE studies) in 81% yield.9 Diastereoselective reduction of the enone carbonyl


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with DIBAL at -78 oC for 15 minutes proceeded under Felkin-Ahn control12-14 to afford the desired secondary alcohol 13 in 80% yield and >20:1 d.r., which was confirmed by Mosher ester analysis.15 While a second diastereomer was observed in the course of this reaction, the two diastereomers were readily separated by column chromatography, such that 13 was advanced as a single diastereomer. Next, protection of the chiral secondary alcohol as the TBS silyl ether 14 proceeded in 90% yield using TBSOTf and 2,6lutidine in DCM.

Selective hydroboration of the terminal olefin, employing a slight excess of 9-

borabicyclo(3.3.1)nonane (9-BBN)16 in THF, followed by oxidation using hydrogen peroxide with 2M NaOH, yielded the desired primary alcohol 15 in 81% yield. Oxidation of the primary alcohol using DessMartin Periodinane (DMP) in DCM buffered with sodium bicarbonate,16 to neutralize the acetic acid byproducts and protect the very sensitive allylic silyl ether, proceeded smoothly to give the known aldehyde 3 in 73% yield, and completed the formal total synthesis of 1. The data collected for our 3 was in complete agreement with that reported by Lücke, Kalesse and co-workwers.3,9

In conclusion, we have completed a concise, formal total synthesis of pericoannosin A, by the synthesis of advanced intermediate 3, following a novel route that employed an organocatalytic Diels-Alder reaction, a

substrate-controlled

diastereoselective

reduction

(under

Felkin

Ahn

control)

and

a

hydroboration/oxidation sequence for chain homologation. This work diminishes the number of steps (8 versus 13 steps), while also improving the overall yield (10.7% versus 21.7% overall yield) of advanced intermediate 3, utilizing commercial starting materials.

EXPERIMENTAL SECTION

General methods. All reactions were carried out employing standard chemical techniques under inert atmosphere. Solvents used for extraction, washing, and chromatography were HPLC grade. All reagents were purchased from commercial sources and were used without further purification. Analytical HPLC was performed on an Agilent 1200 LCMS with UV detection at 215 nm along with ELSD detection and electrospray ionization, with all final compounds showing > 95% purity and a parent mass ion consistent with the desired structure. All NMR spectra were recorded on a 400 MHz Brüker AV-400 instrument. 1H chemical shifts are reported



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as δ values in ppm relative to the residual solvent peak (CDCl3 = 7.26, C6D6=7.16). Data are reported as follows: chemical shift, multiplicity (br. = broad, s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet), coupling constant (Hz), and integration. 13C chemical shifts are reported as δ values in ppm relative to the residual solvent peak (CDCl3 = 77.16, C6D6=128.06). High resolution mass spectra were obtained on an Agilent 6540 UHD Q-TOF with ESI source. Automated flash column chromatography was performed on an Isolera One by Biotage.

ethyl (1S,6S)-6-formyl-3-methyl-cyclohex-3-ene-1-carboxylate (6). To a 100 mL round-bottom flask at 4

oC

containing ethyl (E)-4-oxobut-2-enoate 7 (3.53 mL, 28.1 mmol, 1 eq) and [bis[3,5-

bis(trifluoromethyl)phenyl]-[(2S)-pyrrolidin-1-ium-2-yl]methoxy]-trimethyl-silane perchlorate 9 (981 mg, 1.4 mmol, 0.05 eq) in water (30 mL) was added isoprene 8 (8.43 mL, 84 mmol, 3 eq) with stirring. After 48 hours, the reaction mixture was quenched with saturated sodium bicarbonate (20 mL), then extracted with ether (3x75 mL), and the organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo onto silica gel. Crude product was purified using Teledyne ISCO Combi-Flash system (solid loading, 40G column, 0-25% Hex/EtOAc) to yield ethyl (1S,6S)-6-formyl-3-methylcyclohex-3-ene-1-carboxylate 6 (5.2 g, 26.4 mmol, 94% yield) as a clear oil. 1H-NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 5.38 (bs, 1H), 4.19-4.07 (m, 2H), 2.91-2.76 (m, 2H), 2.37-2.24 (m, 2H), 2.14-2.01 (m, 1H), 1.64 (s, 3H), 1.27-1.17 (m, 3H) ppm; 13C-NMR (100 MHz, CDCl3) δ 202.8, 174.5, 133.0, 118.4, 60.9, 47.4, 39.8, 31.5, 24.3, 23.3, 14.3 ppm; ESI-HRMS: m/z calc for C11H17O3 [M+H]+: 197.1172, found: 197.1175; [α]D20 = +58.2 (c 1.0, CHCl3); Rf = 0.24 (Hex:EtOAc 20:1). ethyl

(1S,6R)-3-methyl-6-vinyl-cyclohex-3-ene-1-carboxylate

(10).

To

a

suspension

of

methyltriphenylphosphonium bromide (2.01 g, 5.61 mmol, 1.1 eq) in THF (17 mL) at 0 °C was added LHMDS (1M in THF, 5.35 mL, 5.35 mmol, 1.05 eq) dropwise. The reaction was stirred for 40 minutes at this temperature, then cooled to -78 °C and a solution of ethyl (1S,6S)-6-formyl-3-methyl-cyclohex-3-ene1-carboxylate 6 (1 g, 5.10 mmol, 1 eq) was added slowly. The cooling bath was removed and the reaction


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was stirred for 10 minutes at this temperature before a solution of saturated NH4Cl (30 mL) and ether (30 mL) were added. The layers were separated and the aqueous was extracted with ether (3x30 mL), then the organics were pooled, dried over magnesium sulfate, filtered, and concentrated in vacuo. Crude product was purified by column chromatography (EtOAc/Hex, 0-20%) to yield ethyl (1S,6R)-3-methyl-6-vinylcyclohex-3-ene-1-carboxylate 10 (751 mg, 3.87 mmol, 75%) as a clear oil in >20:1 d.r. 1H-NMR (400 MHz, CDCl3) δ 5.75-5.66 (m, 1H), 5.38 (m, 1H), 5.06 (dd, J = 17.1, 1.5 Hz, 1H), 4.97 (dd, J = 10.2, 1.7 Hz, 1H), 4.11 (qd, J = 7.1, 1.4 Hz, 2H), 2.49-2.41 (m, 2H), 2.32-2.26 (m, 1H), 2.15-2.09 (m, 2H, 1.95-1.87 (m, 1H), 1.67 (bs, 3H), 1.24 (t, J = 7.2 Hz, 3H) ppm; 13C-NMR (100 MHz, CDCl3) δ 175.4, 140.8, 132.1, 119.8, 115.2, 60.2, 45.9, 40.9, 32.8, 31.2, 23.3, 14.5; ESI-HRMS: m/z calc for C12H19O2 [M+H]+: 195.1380, found: 195.1381; [α]D20 = +53.6 (c 0.65, CHCl3); Rf = 0.48 (Hex:EtOAc 20:1).

2-diethoxyphosphoryl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]propan-1-one

(11).

To

a

solution of diethyl ethylphosphonate (1.28 g, 7.72 mmol, 3 eq) in THF (12.9 mL) at -78 oC was added nBuLi (1.77M in hexanes, 3.68 mL, 7.46 mmol) dropwise. The reaction was stirred for 1 hour at this temperature, then ethyl (1S,6R)-3-methyl-6-vinyl-cyclohex-3-ene-1-carboxylate 10 (500 mg, 2.57 mmol, 1 eq) in THF (3.2 mL) was added slowly and the reaction was stirred an additional 1.5 hours at the same temperature. The reaction was quenched by addition of saturated NH4Cl (30 mL), then allowed to warm to room temperature and the mixture was extracted with ether (3x60 mL). The organics were dried over magnesium sulfate, filtered, and then concentrated in vacuo and crude product was purified using column chromatography (0-50% EtOAc/Hex) to yield 2-diethoxyphosphoryl-1-[(1S,6R)-3-methyl-6-vinylcyclohex-3-en-1-yl]propan-1-one (740 mg , 2.35 mmol, 91% yield) as a clear oil as a ~3:1 mixture of methyl diastereomers. Analytical data are given for the mixture of diastereomers (signals are described as major (mj) and minor (mn) where it can be determined, otherwise given as a mix (mix)). 1H-NMR (400 MHz, CDCl3): 5.64 (m, 1.36H, mix), 5.33 (m, 0.35H, mn), 5.27 (m, 1H, mj), 4.99 (d, J = 17.2 Hz, 0.38H, mn), 4.93 (d, J = 17.1 Hz, 1H, mj), 4.88 (d, J = 10.2 Hz, 1.56H, mix), 4.05 (sep, J = 7.2 Hz, 6.3H, mix), 3.25 (q, J = 7.1 Hz, 0.19H, mn), 3.18 (qd, J = 26.5, 6.9 Hz, 1H, mj), 2.99 (td, J = 19.9, 5.5 Hz, 1.35H, mix), 2.53-



2.43 (m, 0.35H, mn), 2.33-2.22 (m, 1.36H, mix), 2.22-2.14 (m, 1H, mj), 2.14-1.82 (m, 5.39H, mix), 1.59 (bs, 4.62H, mix), 1.26 (q, J = 7.3, 10H, mix), 1.17 (dd, J = 17.5, 7.0 Hz, 3.76H, mix), 0.27 (t, J = 7.2 Hz, 0.22H, mn) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 209.9 (d, J = 3.9 Hz, mj), 208.5 (d, J = 4.0 Hz, mn), 145.5 (mn), 141.1 (mn), 104.4 (mj), 132.8 (mj), 131.5 (mn), 120.5 (mn), 118.9 (mj), 115.9 (mj), 115.0 (mn), 62.7 (d, J = 6.8 Hz, mj), 62.6 (d, J = 6.9 Hz, mn), 62.5 (d, J = 6.8 Hz, mj), 62.4 (d, J = 6.8 Hz, mn), 53.3 (mj), 51.8 (mn), 49.7 (mj), 48.4 (mj), 46.6 (mn), 45.3 (mn), 43.1 (mj), 39.0 (mn), 33.3 (mn), 32.2 (mj), 31.8 (mj), 30.8 (mn), 23.3 (mj), 23.3 (mn), 16.5 (d, J = 5.3 Hz, mj), 16.4 (d, J = 5.8 Hz, mj), 11.5 (d, J = 6.5 Hz, mn), 9.8 (d, J = 6.1 Hz, mj) ppm; ESI-HRMS: m/z calc for C16H28O4P [M+H]+: 315.1720, found: 315.1720; Rf = 0.27 (Hex:EtOAc 2:1).

(E)-2-methyl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]but-2-en-1-one (12). To a solution of 2diethoxyphosphoryl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]propan-1-one 11 (1.2 g, 3.84 mmol, 1.2 eq) in THF (16 mL) at 0 oC was added barium hydroxide octahydrate (1.01 g, 3.2 mmol, 1 eq) and acetaldehyde (180 μL, 3.2 mmol, 1 eq) at 0 oC. The reaction was warmed to room temperature overnight, then diluted with ether (60 mL) and filtered. The organics were removed in vacuo, then crude product was purified using column chromatography (0-60% EtOAc/Hex, high gradient used to recover excess starting material) to yield (E)-2-methyl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]but-2-en-1-one 12 (528 mg, 2.58 mmol, 81% yield) as a clear oil. Olefin geometry was confirmed by 1D nOE analysis (see supporting information). 1H-NMR (400 MHz, CDCl3) δ 6.70 (q, J = 6.4 Hz, 1H), 5.55 (m, 1H), 5.35 (m, 1H), 4.92 (d, J = 17.1 Hz, 1H), 4.83 (dd, J = 10.9, 1.0 Hz, 1H), 3.27 (td, J = 10.7, 5.3 Hz, 1H), 2.50-2.41 (m, 1H), 2.17-2.07 (m, 2H), 1.95-1.87 (m, 2H), 1.83 (d, J = 6.9 Hz, 3H), 1.72 (s, 3H), 1.62 (s, 3H) ppm; 13C-NMR

(100 MHz, CDCl3) δ 205.2, 141.0, 139.4, 136.9, 132.8, 119.8, 114.8, 44.9, 40.8, 34.5, 31.4, 23.3,

14.9, 11.2 ppm; ESI-HRMS: m/z calc for C14H21O [M+H]+: 205.1587, found: 205.1587; [α]D20 = +63.8 (c 1.14, CHCl3); Rf = 0.348 (Hex:EtOAc 50:1).


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(E,1S)-2-methyl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]but-2-en-1-ol (13). To a solution of (E)-2-methyl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]but-2-en-1-one 12 (528 mg, 2.58 mmol, 1 eq) in Toluene (10.6 mL) at -78 oC was added DIBAL (1M in toluene, 3.51 mL, 3.51 mmol, 1.34 eq) dropwise, turning the reaction yellow. The mixture was stirred for 5-15 minutes (monitored by TLC), then quenched by addition of methanol (3.5 mL) and saturated Rochelle's salt (20 mL), then allowed to warm to room temperature and diluted further with Rochelle's salt (75 mL) and ether (75 mL). The mixture was stirred vigorously at room temperature for 2 hours, forming two distinct layers, then the organics were separated and the aqueous was extracted with ether (3x50mL). The organics were pooled, dried over magnesium sulfate, filtered, and concentrated in vacuo, then crude product was purified using column chromatography (0-20% EtOAc/Hex) to yield (E,1S)-2-methyl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3en-1-yl]but-2-en-1-ol 13 (424 mg, 2.06 mmol, 80% yield) as a clear oil. 1H-NMR (400 MHz, CDCl3) δ 5.95 (ddd, J = 17.5, 10.1, 8.0 Hz, 1H), 5.39 (q, J = 6.44 Hz, 1H), 5.32 (m, 1H), 5.11 (d, J = 17.2 Hz, 1H), 4.99 (dd, J = 10.4, 0.8 Hz, 1H), 3.87 (d, J = 8.8 Hz, 1H), 2.43 (p, J = 7.3 Hz, 1H), 2.15 (m, 1H), 2.01-1.89 (m, 2H), 1.82-1.72 (m, 2H), 1.63-1.55 (m, 9H), 1.53-1.43 (m, 1H) ppm; 13C-NMR (100 MHz, CDCl3) δ 144.1, 136.7, 132.6, 122.9, 119.3, 114.0, 80.8, 41.2, 39.9, 30.7, 23.8, 13.2, 10.7 ppm; ESI-HRMS: m/z calc for C14H22 [M+H]+[-H2O]: 189.1638, found: 189.1640; [α]D20 = +24.2 (c 1.21, CHCl3); Rf = 0.296 (20:1 Hex:EtOAc). Mosher ester analysis was performed as described by Hoye, et al.15 Briefly, to a solution of (E,1S)-2-methyl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]but-2-en-1-ol (10 mg, 0.05 mmol) and (R)-(-)-alpha-methoxy-alpha-trifluoromethyl acetic acid {(R)-Mosher’s acid} (35.18 mg, 0.15 mmol, 3.1 eq) in DCM (0.75 mL) at 23 oC was added 1,3-dicyclohexylcarbodiimide (31.0 mg, 0.15 mmol, 3.1 eq) and 4-dimethylaminopyridine (18.4 mg, 0.15 mmol, 3.1 eq). The reaction was stirred overnight at room temperature, then diluted with DCM (1 mL) and filtered through a plug of celite, washing with DCM (3x2 mL). The solvent was removed in vacuo, then crude product was purified using silica gel chromatography (0-10% EtOAc/Hex) to yield [(E,1S)-2-methyl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]but-2enyl] (2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoate (20 mg, 0.047 mmol, 98% yield) as a clear oil. 1H-NMR

(400 MHz, CDCl3) δ 7.53-7.45 (m, 2H), 7.40-7.36 (m, 3H), 5.80 (ddd, J = 17.3, 10.1, 7.6 Hz,



1H), 5.58 (qd, J = 6.8, 1.1 Hz, 1H), 5.34 (m, 1H), 5.30 (d, J = 9.9 Hz, 1H), 4.99 (td, J = 17.1, 1.4 Hz, 1H), 4.94 (m, 1H), 3.54 (d, J = 1.0 Hz, 3H), 3.20 (m, 1H), 2.38-2.32 (m, 1H), 2.25-2.16 (m, 1H), 2.04-1.99 (m, 1H), 1.99-1.89 (m, 4H), 1.77-1.70 (m, 2H), 1.62-1.59 (m, 3H), 1.59-1.57 (m, 3H), 1.37 (s, 3H), 1.36-1.17 (m, 5H). The S-Mosher ester product was synthesized in an analogous fashion using (S)-(-)-alpha-methoxyalpha-trifluoromethyl acetic acid (16 mg, 0.038 mmol, 78%). 1H-NMR (400 MHz, CDCl3) δ 7.52-7.47 (m, 2H), 7.42-7.35 (m, 3H), 5.75 (ddd, J = 17.2, 10.4, 7.5 Hz, 1H), 5.65 (qd, J = 6.7, 1.1 Hz, 1H), 5.37-5.31 (m, 2H), 4.89-4.87 (m, 1H), 4.87-4.82 (m, 1H), 3.53 (d, J = 1.1 Hz, 3H), 2.22-2.12 (m, 1H), 2.12-2.06 (m, 1H), 2.01-1.91 (m, 2H), 1.89-1.83 (m, 1H), 1.65 (dd, J = 6.8, 0.8 Hz, 3H), 1.57 (s, 3H), 1.56 (d, J = 9.4 Hz, 3H).

2-[(1R,6S)-6-[(E,1S)-1-[tert-butyl(dimethyl)silyl]oxy-2-methyl-but-2-enyl]-4-methyl-cyclohex-3-en-1yl]ethanol (14). To a solution of (E,1S)-2-methyl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]but-2en-1-ol 13 (101 mg, 0.49 mmol, 1 eq) in DCM (2.45 mL) at -78 oC was added 2,6-lutidine (0.29 mL, 2.45 mmol, 2 eq) and tert-butyldimethylsilyl trifluoromethylsulfonate (0.21 mL, 0.93 mmol, 1.5 eq). This was then warmed to 0ºC for 30 minutes, at which point TLC analysis confirmed formation of desired product. The reaction was quenched by addition of water (5 mL) and the aqueous was extracted with DCM (3x5 mL). The organics were pooled, passed through a phase separator, and concentrated in vacuo, then crude product was purified using column chromatography (100% Hex) to yield tert-butyl-dimethyl-[(E,1S)-2methyl-1-[(1S,6R)-3-methyl-6-vinyl-cyclohex-3-en-1-yl]but-2-enoxy]silane 14 (141 mg, 0.44 mmol, 90% yield) as a clear oil. 1H-NMR (400 MHz, CDCl3) δ 5.89 (ddd, J = 17.3, 10.2, 7.2 Hz, 1H), 5.34-5.26 (m, 2H), 5.02 (d, J = 17.3 Hz, 1H), 4.95 (d, J = 10.3 Hz, 1H), 3.86 (d, J = 9.6 Hz, 1H), 2.73-2.66 (m, 1H), 2.242.14 (m, 1H), 1.96-1.85 (m, 2H), 1.79-1.70 (m, 1H), 1.58 (d, J = 6.7 Hz, 3H), 1.56-1.51 (m, 6H), 0.87 (s, 10H), 0.01 (s, 3H), -0.06 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3) δ 143.7, 137.7, 132.3, 122.2, 118.9, 112.9, 79.6, 41.2, 35.4, 28.0, 26.3, 26.1, 25.9, 24.2, 18.4, 13.2, 10.8, -2.7, -4.3, -5.1 ppm; ESI-HRMS: m/z calc for C20H37OSi [M+H]+: 320.2535, found: 320.2525; [α]D20 = -14.50 (c 1.03, CHCl3); Rf = 0.826 (100% Hexanes).


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2-[(1R,6S)-6-[(E,1S)-1-[tert-butyl(dimethyl)silyl]oxy-2-methyl-but-2-enyl]-4-methyl-cyclohex-3-en-1yl]ethanol (15). To a solution of tert-butyl-dimethyl-[(E,1S)-2-methyl-1-[(1S,6R)-3-methyl-6-vinylcyclohex-3-en-1-yl]but-2-enoxy]silane 14 (272 mg, 0.85 mmol) in THF (4.24 mL) at 0 °C was added 9BBN solution (0.5M in THF, 3.39 mL, 1.7 mmol) dropwise. The reaction was warmed to room temperature and stirred for 30 minutes, at which point TLC analysis indicated consumption of starting materials. The reaction was again cooled to 0 °C and a premixed solution of hydrogen peroxide (30 wt%, 1.11 mL, 10.87 mmol) and aqueous sodium hydroxide (2M, 1.24 mL, 2.47 mmol) was added slowly. The reaction was warmed to room temperature and stirred for 1.5 hours, then diluted with brine (10 mL) and extracted with ether (3x15 mL). The organics were pooled, dried over magnesium sulfate, filtered, and concentrated in vacuo, then crude product was purified using column chromatography (0-20% EtOAc/Hex) to yield 2[(1R,6S)-6-[(E,1S)-1-[tert-butyl(dimethyl)silyl]oxy-2-methyl-but-2-enyl]-4-methyl-cyclohex-3-en-1yl]ethanol 15 (234 mg, 0.69 mmol, 81% yield) as a clear oil. 1H-NMR (400 MHz, CDCl3) δ 5.30-5.23 (m, 2H), 3.80 (d, J = 10.0 Hz, 1H), 3.72-3.63 (m, 2H), 2.21-2.12 (m, 2H), 1.94-1.85 (m, 1H), 1.76-1.65 (m, 2H), 1.65-1.61 (m, 1H), 1.59-1.52 (m, 9H), 1.50 (s, 3H), 0.85 (s, 9H), 0.00 (s, 3H), -0.07 (s, 3H) ppm; 13CNMR (100 MHz, CDCl3) δ 137.8, 131.6, 122.3, 118.9, 79.8, 61.8, 39.9, 37.0, 27.4, 26.5, 24.1, 18.4, 13.1, 10.5, -4.3, -5.1 ppm; ESI-HRMS: m/z calc for C20H38O2SiNa [M+Na]+: 361.2533, found: 361.2539; [α]D20 = -13.60 (c 0.75, CHCl3); Rf = 0.478 (6:1 Hex:EtOAc).

2-[(1R,6S)-6-[(E,1S)-1-[tert-butyl(dimethyl)silyl]oxy-2-methyl-but-2-enyl]-4-methyl-cyclohex-3-en-1yl]acetaldehyde (3).To a solution of 2-[(1R,6S)-6-[(E,1S)-1-[tert-butyl(dimethyl)silyl]oxy-2-methyl-but2-enyl]-4-methyl-cyclohex-3-en-1-yl]ethanol 15 (88 mg, 0.26 mmol, 1 eq) in DCM (1.73 mL) at 0 oC was added sodium bicarbonate (131 mg, 1.56 mmol, 6 eq) and Dess-Martin Periodinane (165 mg, 0.39 mmol, 1.5 eq). The reaction was warmed to room temperature and stirred for 1.5 hours, at which point TLC analysis indicated full consumption of starting materials and formation of a more non-polar spot. The reaction was diluted with water (2 mL) and extracted with EtOAc (3x4 mL) and the organics were passed



through a phase separator and concentrated in vacuo. Crude product was purified using Teledyne ISCO Combi-Flash system (solid loading, 0-15% EtOAc/Hex) to yield 2-[(1R,6S)-6-[(E,1S)-1-[tertbutyl(dimethyl)silyl]oxy-2-methyl-but-2-enyl]-4-methyl-cyclohex-3-en-1-yl]acetaldehyde 3 (64 mg, 0.19 mmol, 73% yield) as a clear oil. 1H-NMR (400 MHz, C6D6) δ 9.50 (t, J = 2.0 Hz, 1H), 5.24-5.19 (m, 2H), 3.88 (d, J = 9.9 Hz, 1H), 2.85-2.77 (m, 1H), 2.33-2.24 (m, 1H), 2.10 (ddd, J = 16.3, 9.0, 2.2 Hz, 1H), 1.92 (ddd, J = 16.3, 5.4, 1.7 Hz, 1H), 1.77-1.59 (m, 4H), 1.53-1.49 (m, 6H), 1.45 (dd, J = 6.6, 0.9 Hz, 4H), 1.00 (s, 9H), 0.09 (s, 3H), 0.02 (s, 3H); 13C-NMR (100 MHz, C6D6) δ 200.9, 137.9, 131.5, 122.6, 118.9, 79.9, 48.3, 40.2, 27.5, 26.2, 25.0, 24.1, 18.5, 13.0, 10.5, -4.2, -5.0 ppm; ESI-HRMS: m/z calc for C20H36O2SiNa [M+Na]+: 359.2377, found: 359.2380; [α]D20 = -21 (c 1.0, CHCl3), lit: -31.5; Rf = 0.46 (20:1 EtOAc:Hex). Analytical data are in accordance with the literature.

ASSOCIATED CONTENT

Supporting Information 1H and 13C NMR spectra for new compounds. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]; Phone: 615-322-8700

ORCID Craig W. Lindsley: 0000-0003-0168-1445

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS


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C.W.L. thanks the William K. Warren Family and Foundation for funding the William K. Warren, Jr. Chair in Medicine and support of our programs.

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Formal Total Synthesis of Pericoannosin A | The Journal of Organic

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