Copper-Catalyzed Stille Cross-Coupling Reaction and Application in the Synthesis of the Spliceostatin Core Structure

the Synthesis of the Spliceostatin Core Structure

Article

Copper-Catalyzed Stille Cross-Coupling Reaction and Application in

Arun K. Ghosh,* Joshua R. Born, Anne M. Veitschegger, and Melissa S. Jurica

Cite This: https://dx.doi.org/10.1021/acs.joc.0c00976

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sı Supporting Information

ABSTRACT: An eﬃcient palladium-free Stille cross-coupling

reaction of allylic bromides and functionalized organostannylfuran

using catalytic copper halide has been developed. The coupling

reaction was optimized using CuI and low catalyst loading (down

to 5 mol %). The reaction was conveniently carried out at ambient

temperature in the presence of inorganic base to aﬀord the

coupling product in good-to-excellent yields. The utility of this

reaction was demonstrated in the synthesis of a furan with sensitive functionalities. A sulfolene moiety was utilized as a masking

group for the sensitive diene. Noyori asymmetric reduction, Achmatowicz reaction, and Kishi reduction steps converted sulfolene to

a highly substituted tetrahydropyran intermediate used in the synthesis of the highly potent antitumor agents, spliceostatins, and

their derivatives.

19−23

INTRODUCTION

chemistry and biology of spliceostatin derivatives,

■

sought to develop a convergent synthesis of the core structure

of spliceostatin A and further FR901464 derivatives using Stille

cross-coupling as the key reaction. In particular, we planned to

explore the potential of the Pd-free, copper-catalyzed reaction

under mild reactions. Herein, we report a highly eﬃcient Cu-

catalyzed Stille cross-coupling reaction of organostannane

derivative and (E)-5-bromo-3-methylpenta-1,3-diene. The

resulting coupling product was converted to spliceostatin key

subunit for the synthesis of important bioactive structural

variants. Extensive structure−activity relationship studies have

shown the importance of the tetrahydropyran and diene

The Stille cross-coupling reaction is one of the most powerful

and widely used carbon−carbon bond forming reactions in

organic synthesis. Because of stability and functional group

tolerance of stannanes, broad scope of reaction partners, and

high degree of chemoselectivity, the Stille reaction has been

extensively employed in natural product as well as

pharmaceutical research. The Stille cross-coupling reactions

of organic electrophiles and organostannanes are traditionally

carried out in the presence of various palladium catalysts.

Eﬀective catalytic methods to carry out these reactions at

ambient temperature using palladium catalysts under mild and

green reaction conditions are limited, and because of the

−5

−8

22−27

moieties of spliceostatins and their structural derivatives.

costly nature of palladium, other catalysts are desired.

Interestingly, the Pd-catalyzed Stille reaction in the presence

of the cocatalytic amount of the copper catalyst has been

RESULTS AND DISCUSSION

■

For initial investigation, we prepared multigram quantities of

organostannane derivative, as shown in Scheme 2. Commer-

cially available 2-acetalylfuran (1) was converted to organo-

stannane derivative 2 in a two-step sequence. The reaction of

10,11

shown to improve otherwise sluggish reactions.

To this

end, copper was sought to catalyze the process on its own, and

early work in this area includes the report of Liebeskind and

Allred who reported an eﬃcient Stille coupling of stannanes

and vinyl iodide using stoichiometric amounts of copper

-acetylfuran with ethylene glycol and catalytic amount of p-

TsOH in reﬂuxing toluene using a Dean−Stark apparatus to

(

Scheme 1, ﬁrst entry). Kang and co-workers in 1997

eliminate generated water aﬀorded the corresponding

reported Stille coupling of vinyl stannanes and vinyl iodides in

dioxolane derivative. Deprotonation of the resulting furan

the presence of 10 mol % CuI at >100 °C (second entry).

derivative with nBuLi in tetrahydrofuran (THF) at −78 °C

followed by the reaction with nBu SnCl provided organo-

Takeda and co-workers reported the coupling of vinyltin

with allyl chloride using stoichiometric CuI at room temper-

ature in 1995, which led to a mixture of isomers due to poor

Received: April 23, 2020

regiocontrol (third entry). These reactions represent early

development of the palladium-free, copper-catalyzed Stille

reaction. However, the use of stoichiometric copper, higher

reaction temperature, directing groups, harsh reaction

conditions, and lack of regioselectivity limit the scope and

15−18

utility of these reactions.

In our continuing interest in the

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Scheme 1. Selected Prior Cu-Catalyzed Stille Reactions and

Present Work

Table 1. Optimization of the Cu-Catalyzed Reaction of

a b

Stannane 2 and Allyl Bromide

entry

catalyst (mol %)

additive (10 mol %) % yield 3 ratio 3:4

CuI (50)

CuCN (50)

CuI (50)

CuBr·DMS (50)

Cu(ACN) BF (5)

Na CO₃

5:1

≫20:1

10:1

>>20:1

>20:1

>10:1

>15:1

>20:1

Na CO₃

CuI (5)

Na CO₃

CuCl (5)

CuOAc (5)

(CuOTf) ·PhH (5)

None

Na CO₃

Li CO₃

Cs CO₃

Cu O (5)

Cs CO₃

4:1

>20:1

CuTC (5)

CuI (5)

Cs CO₃

Reaction time of 3−120 h depending on the desired product and

scale of reaction. Solvents used: DMSO/THF (3:1) for entries 1−3,

DMF for entries 4−15. Ratio determined by H NMR (400 MHz).

Yield of ketone 5. Gram scale; ND = not determined.

:1, as determined by H NMR (400 MHz). These products

were diﬃcult to separate by silica gel chromatography. We

chose to add carbonate additives to inhibit the protodestanny-

lation reaction to form byproduct 4 by sequestering any

adventitious acid formed in the system. Interestingly, the

combined yield of products 3 and 4 as well as the ratio was

improved when the order of addition was modiﬁed by the

addition of mixture of stannane, Na CO , and allyl bromide to

a ﬂame-dried ﬂask containing CuI under an argon atmosphere

at 23 °C (entry 2). The use of CuCN as the catalyst resulted in

lower yield (entry 3). The choice of CuI (0.5 equiv) in

dimethylformamide (DMF) aﬀorded improvement of both the

yield and ratio of 3:4 (entry 4). CuBr·DMS (0.5 equiv)

furnished comparable results as CuI (entries 4 and 5). We then

supported that the copper salts were needed for the reaction by

a control experiment without CuI, which resulted in no cross-

coupling products. We subsequently observed that the cross-

coupling reaction could be carried out eﬀectively using lower

catalyst loading (entry 6). Using 5 mol % CuI and Na CO

Scheme 2. Cu-Catalyzed Stille Cross-Coupling Reactions of

Organnostannane and Allyl Bromide

(

0.1 equiv), the cross-coupling reaction was carried out at 23

C for 3.5 h. This condition resulted in 89% yield of desired

coupling product 3 along with a very small amount of

protodestannylated byproduct 4 ( H NMR ratio > 20:1, entry

). The use of 5 mol % CuCl in DMF with or without various

carbonate additives was then tested and resulted in good

results, albeit the ratio of products 3:4 decreased when no

additive was present (entries 8−11). The use of Cs CO

resulted in a very good yield of product 3 and only a small

amount of protodestannylated product 4 (ratio > 20:1),

presumably because of increased solubility of Cs CO in DMF

stannane 2 in 64% yield over two steps. For our investigation,

we ﬁrst attempted Cu-catalyzed cross-coupling of 2 with allyl

bromide under a variety of reaction conditions. The results are

shown in Table 1. The cross-coupling reaction was carried out

by dissolving stannane 2 in a mixture (3:1) of dimethyl

sulfoxide (DMSO) and THF at 23 °C. To this solution, CuI

(entry 11). The ketone product 5 formed likely due to the

counter acids (entries 12 and 13). Catalytic Cu O (5 mol %)

(

0.5 equiv) and carbonate additive Na CO (0.1 equiv) were

also showed a good yield of product 3; however, CuTC (5 mol

%) provided a poor yield of desired product 3 and

protodestannylated derivative 4 was obtained in larger amount

(entries 14 and 15). Based on our survey of various Cu(I)

catalysts, additives, and reaction of 5 mol % CuOAc or

Cu(OTf)·PhH in the presence of a Cs CO additive that

added, followed by allyl bromide (2 equiv). The resulting

mixture was stirred at 23 °C for 4.5 h. The reaction resulted in

3% yield of desired dioxolane derivative 3 along with a small

amount of protodestannylated byproduct 4. The ratio of

desired product 3 and protodestannylated byproduct 4 was

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

resulted in mainly the conditions, it was concluded that CuI (5

mol %) in the presence of Cs CO additive (0.1 equiv) would

Scheme 4. Cu-Catalyzed Stille Reactions of

Organnostannane and Bromo Diene 6

provide the best result, as this condition eﬀectively suppressed

the formation of the protodestannylated product. This reaction

was carried out and resulted in 90% yield of our desired

product 3 on a gram scale (entry 16). It should be noted that

puriﬁcation of these compounds was achieved using a modiﬁed

procedure of Curran and co-workers. The reaction products

were passed through 10% K CO in silica plug several times in

a row to aﬀord compounds 3 and 5 without coeluting

tributyltin salts.

Following the optimization of the CuI-catalyzed cross-

coupling reaction with allyl bromide, we then focused on the

Cu-catalyzed cross-coupling reaction of stannane derivative 2

with (E)-5-bromo-3-methyl-penta-1,3-diene 6, as shown in

Scheme 3. The product 7 is the precursor for amine derivative

Scheme 3. Cu-Catalyzed Stille Cross-Coupling and

Synthetic Strategy of Tetrahydropyran Derivative 8 for

Spliceostatins

Table 2. Cu-Catalyzed Reaction of Stannane 2 and (E)-5-

a b

Bromo-3-methyl-penta-1,3-diene 6

additive

% yield

ratio

entry

(10 mol %)

solvent

DMF

DMSO/THF

(BRSM)

(E)-7:(Z)-7:11:4

Cs CO₃

10:3:2:4

>20:8:2:1

Cs CO₃

(

3:1)

Cs CO₃

DMF

10:4:1:4

. The amine derivative 8 can be readily converted to

19−23

Cs CO₃

THF

63 (87)

>20:1:1:2

>20:1:1:4

spliceostatins, thailanstatin, and their derivatives.

ceostatin derivatives have been shown to inhibit premessenger

RNA splicing in eukaryotic cells.

for the cross-coupling reaction, stannane 2 and Cs CO were

Spli-

DMF/THF

(

1:3)

31−33

As shown in Scheme 4,

Cs CO₃

MeCN

>20:1:1:1

mixed together in DMF at 23 °C. To this mixture was then

added CuI (5 mol %) under an argon atmosphere at 23 °C,

followed by bromide 6. The reaction mixture was stirred at 23

Reaction time of 24−96 h depending on the desired product and

scale of reaction. Ratio determined via NMR. Ketone products

formed. CuI added last. >0.1 equiv Cs CO added. Multigram

scale. Yield of ketone (E)-12 over two steps, decagram scale. BRSM

°C for 48 h. This reaction condition resulted in a mixture of

products, which include desired coupling product 7 as a E/Z

mixture, the γ-alkylated product 11, and protodestannylated

product 4 (Table 2, entry 1).

= based on the recovered starting material.

The H NMR (400 MHz) analysis determined that ratios of

E)-7:(Z)-7:11:4 to be 5:1.5:1:2. This product mixture could

ketone products were formed exclusively because of depro-

tection of the dioxolane-protecting group. Otherwise, we

deprotected the dioxalane group by exposure of the mixture to

the catalytic amount of p-TSA in acetone at 23 °C for 2 h.

Changing the order of addition as before and adding a mixture

of stannane 2, Cs CO , and bromide 6 to ﬂame-dried CuI (5

(

not be separated by silica gel chromatography. The identity of

E and Z isomers (E)-7 and (Z)-7 was determined by H NMR

NOESY experiments of their respective ketone derivatives (E)-

12 and (Z)-12.

In order to improve on the ratio of (E)-7 to the rest of the

mol %) however did not improve the ratio as it did in the prior

model substrate reaction (entry 3). Interestingly, the use of

THF as the solvent signiﬁcantly improved the E/Z ratio of the

coupling products (>20:1), but the reaction did not go to

completion. The combined yield of products was 87% based

undesired byproducts, another optimization was carried out.

The use of a mixture (3:1) of DMSO and THF as the solvent

resulted in a reduction of combined yield as well as reduction

of E/Z ratio (2.5:1) (entry 2). In this reaction condition, the

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

transition state shown in Figure 1 . The proposed Cu(III) η

Article

on the recovery of starting stannane 2 (entry 4). The

improvement of E/Z ratio is presumably due to solvent

ligation on the metal center, resulting in a square planar

Scheme 5. Optically Active Synthesis of the Functionalized

Tetrahydropyran Derivative 8

Figure 1. Plausible mechanism for the solvent coordination and E-

selective Cu-catalyzed Stille cross-coupling reaction.

allyl complexation resulting in the Z-isomer or the γ-alkylated

intermediate would be less stable or may not form, leading to

34−37

the majority (E)-isomer.

We then attempted the coupling

reaction in a mixture (3:1) of THF and DMF using 0.2 equiv

of Cs CO as the additive. This condition provided an

excellent yield of coupling products with a signiﬁcant

improvement of E/Z ratio (>20:1); however, the ratio of

reaction and Kishi reduction. Presumably, the protection of the

diene functionality will help to slow down the competing β-

elimination from the oxocarbenium ion intermediate. We

attempted masking diene with Na S O in a mixture (4:1) of

(E)-7 to 4 was still 5:1 (entry 5). The coupling reaction in

acetonitrile also provided excellent E/Z ratios, up to 94% yield

on a gram scale over a single step to yield (E)-7 or 85% over

two steps to yield the respective ketone (E)-12 as the sole

HFIP and water, as described by Larionov and co-workers.

detectable product by H NMR. These reaction conditions

However, these reaction conditions resulted in only 6% yield of

desired sulfolene derivative 18. Further improvement of this

reaction was then made by carrying out the reaction with

were reproducible on a decagram scale and required no

aqueous workup, simply following puriﬁcation using the

procedure described by Curran and co-workers.

sodium bisulﬁte in the presence of KHSO in a mixture (4:1)

With the successful Stille coupling of stannane 2 and

bromide 6, we then planned to convert product (E)-7 to

functionalized tetrahydropyran derivative 8. As shown in

Scheme 5, methyl ketone (E)-7 was subjected to Noyori

of dioxane and water. Sulfolene derivative 18 was obtained in

38,39

62% isolated yield (99% BRSM). Asymmetric reduction

18 using Noyori’s Ru-catalyst 14 in the presence of Et N and

formic acid aﬀorded optically active alcohol 19. However,

alcohol 19 turned out to be very unstable; thus, we were

unable to determine its optical purity at this step. We therefore

decided to carry forward the subsequent Achmatowicz reaction

steps. Accordingly, treatment of crude alcohol 19 with oxone

38,39

asymmetric reduction

using the RuCl(mesitylene)[(R,R)-

Ts-DPEN] (1 mol %) catalyst in the presence of Et N and

formic acid at 50 °C for 12 h to aﬀord optically active alcohol

40,41

15 in 99% yield. Achmatowicz reaction

of 15 with tert-

butylhydroperoxide and vanadyl acetylacetonate provided the

corresponding dihydropyran hemiacetal. Subjection of the

resulting hemiacetal with Kishi reduction with excess of

and KBr in the presence of NaHCO as greener Achmatowicz

conditions provided the corresponding dihydropyran hemi-

acetal. This hemiacetal too turned out to be unstable, and we

Et SiH in the presence of triﬂuoroacetic acid (TFA) in CH Cl

decided to carry out Kishi reduction and then remove the

sulfolene group. The results of this four-step sequence are

shown in Table 3. Initial reduction attempt of hemiacetal with

2 equiv of BF ·OEt in the presence of 2.5 equiv of Et SiH at

−78 °C resulted in the reduction product 20, which was

heated in toluene using an oil bath at 150 °C to aﬀord desired

enones 17 and 16 in 28% yield over four steps (entry 1). The

ratio of desired enone 17 and triene 16 was 10:1 as determined

at 0 °C to 23 °C resulted in triene derivative 16 as a major

product and a trace amount of desired reduction product 17.

Other attempts to carry out this reduction by using other

Lewis and Brønstead acids did not improve the desired

product yield for compound 17. We therefore devised an

alternate route involving the protection of diene in (E)-12 as a

sulfolene derivative ﬁrst and then carried out Achmatowicz

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Table 3. Synthesis of Enone 17 and Optimization of Kishi

Anomeric Reduction

8 in an optically active form. A sulfolene derivative was formed

using sodium bisulﬁte to mask the diene functionality during

the Achmatowicz reaction and subsequent oxo-carbenium ion-

mediated reduction step. Noyori’s RuCl(mesitylene)[(R,R)-

Ts-DPEN] catalyst (1 mol %) was utilized to provide an

optically active alcohol for the described Achmatowicz

reaction. Further scope and utility of sulfolene formation

using sodium bisulﬁte is being investigated. The resulting

pyranone derivative was converted to highly functionalized

tetrahydropyran intermediate 8. This was previously converted

to FR901464 derivatives, which exhibited very potent

inhibition of spliceosome with possible clinical application as

an anticancer therapeutic.

acid (equiv), Et SiH

yield

ratio

entry

(equiv)

temp

−78 °C

(4 steps)

17:16

BF ·Et O (2),

28%

10:1

Et SiH (2.5)

BF ·Et O (1.2),

−78 °C

24%

>20:1

Et SiH (1.2)

BF ·Et O (3),

−78 °C to 0 °C

−45 °C

Degraded

33%

Et SiH (3)

TFA (15), Et SiH

2:1

(

10)

BF ·Et O (5),

−60 °C to −45 °C

20%

>20:1

Et SiH (5)

TFA (2), Et SiH (6) −78 °C

60%

1:>20

>10:1

EXPERIMENTAL SECTION

BF ·Et O (2),

−78 °C

■

Et SiH (6)

All chemicals and reagents were purchased from commercial suppliers

and used without further puriﬁcation unless otherwise noted. THF

was distilled from Na/benzophenone prior to use. All reactions were

performed in oven-dried round-bottom ﬂasks, followed by ﬂame-

drying under vacuum in the case of moisture-sensitive reactions. The

ﬂasks were ﬁtted with a rubber septa and kept under a positive

pressure of argon. A cannula was used for transferring moisture-

sensitive liquids. Heated reactions were carried out using an oil bath

on a hot plate equipped with a temperature probe. TLC analysis was

conducted using glass-backed thin-layer silica gel chromatography

plates (60 Å, 250 μm thickness, F-254 indicator). Flash chromatog-

raphy was done using a 230−400 mesh, a 60 Å pore diameter silica

gel. Organic solutions were concentrated at 30−35 °C on rotary

evaporators capable of achieving a minimum pressure of ∼25 Torr

and further concentrated on a Hi-vacuum pump capable of achieving

Ratio determined via NMR. Reacted for 7 h. ND = not determined.

by H NMR (400 MHz) analysis. We then carried out further

optimization of the Kishi reduction step. We lowered the

equivalences of the Lewis acid and reductant, obtaining enone

7 as the sole reaction product at −78 °C, however with a

slight reduction of yield to 24% for four steps (entry 2). When

the reaction was warmed to 0 °C, there was complete

degradation of the product (entry 3). Kishi reduction using a

Brønsted acid at −45 °C in lieu of a Lewis acid resulted in 33%

yield and a 2:1 mixture of 17:16 (entry 4). Letting the reaction

warm only slightly as well as increasing the number of

equivalences of the reducing agent decreased the yield but

maintained excellent selectivity (entry 5). The corresponding

reaction in the presence of Brønsted acid at −78 °C for 7 h

only resulted in triene product 17 (entry 6). The Kishi

reduction with 2 equiv of BF ·Et O and 6 equiv of Et SiH at

a minimum pressure of ∼4 Torr. H NMR spectra were recorded on

00, 500, and 800 MHz spectrometers. C NMR spectra were

recorded at 100, 125, and 200 MHz on the respective NMRs.

Chemical shifts are reported in parts per million and referenced to the

deuterated residual solvent peak (CDCl , 7.26 ppm for H and 77.16

−

78 °C for 7 h resulted in desired enone 16 in 60% over four

ppm for C). NMR data are reported as δ value (chemical shift), J-

value (Hz), and integration, where s = singlet, br s = broad singlet, d =

doublet, t = triplet, q = quartet, p = quintet, m = multiplet, dd =

doublet doublets, and so on. Optical rotations were recorded on a

digital polarimeter. Low-resolution mass spectra (LRMS) spectra

were recorded using a quadrupole LCMS under positive electrospray

steps and good ratio (>10:1, entry 7). We were able to support

the cis-relationship via 2D NMR correlation of H and H in

enone 17 and determine its ee to be >98% via chiral HPLC

coming from the desymmetrization at the Noyori reduction

step (see Supporting Information ). Enone 17 was then

converted to tetrahydropyran derivative 8 in a two-step

^s^e^q^u^eⁿ^c^eⁱⁿ^v^o^l^vⁱⁿ^g⁽¹⁾^r^e^a^c^tⁱ^oⁿ^o^f¹⁷^wⁱ^t^h^t^h^e^Lⁱ^C^u^M^e2

complex at −78 °C for 2 h and (2) reductive amination of

the resulting ketone with NaBH(OAc)₃and ammonium

ionization (ESI ). High-resolution mass spectrometry (HRMS)

spectra were recorded at the Purdue University Department of

Chemistry Mass Spectrometry Center. These experiments were

performed under ESI and positive atmospheric pressure chemical

ionization (APCI ) conditions using an Orbitrap XL Instrument.

acetate in the presence of TFA at 23 °C for 44 h to furnish

in 82% over two steps. Tetrahydropyran derivative 8 was

obtained as a single diastereomer (>20:1 by H NMR analysis)

and has been previously transformed into spliceostatins and

their bioactive derivatives.

19−23

CONCLUSIONS

Tributyl(5-(2-methyl-1,3-dioxolan-2-yl)furan-2-yl)stannane

■

(

2). To a two-neck oven-dried 1 L round-bottom ﬂask, furyl dioxolane

In conclusion, we have investigated the Cu-catalyzed Stille

cross-coupling reaction of a functionalized furanyl stannane

derivative and allylic bromides using a variety of reaction

conditions. We have examined a variety of Cu(I) salts and

inorganic bases as additives in a range of solvent systems. The

use of catalytic CuI (5 mol %) in the presence of Cs CO in

12.9 g, 117 mmol, 1.0 equiv) was dissolved in freshly distilled THF

195 mL), followed by tetramethylethylenediamine (40 mL, 269

mmol, 2.3 equiv) and cooled to −78 °C. n-Butyl lithium (1.6 M in

hexane, 95 mL, 152 mmol, 1.3 equiv) was added slowly, changing the

color of the reaction from gold to orange and then dark green. The

ﬂask was warmed to a range of −40 °C to −20 °C for a duration of

.5 h. At this time, the ﬂask was cooled back to −78 °C. In a separate

DMF or CH CN at room temperature provided very good-to-

ﬂask, tributyltin chloride (ClSnBu , 41.3 mL, 152 mmol, 1.3 equiv) in

excellent yields of coupling products. Of particular note, the

reaction of the functionalized furanyl stannane derivative 2

with (E)-5-bromo-3-methyl-1,3-pentadiene 6 proceeded

smoothly to provide an excellent yield of the corresponding

coupling product with diene (E)-7. The diene product was

converted to a highly functionalized tetrahydropyran derivative

freshly distilled THF (195 mL) was cooled to −78 °C as well and

cannulated into the reaction ﬂask at the same temperature. The ﬂask

turned brown with a golden fringe to orange. The reaction was

allowed to warm slowly to ambient temperature over the course of 20

h. The dark orange solution was quenched with saturated NaHCO₃

(300 mL), extracted with diethyl ether three times, washed with brine,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

δ 154.6, 142.5, 110.0, 106.6, 104.9, 65.3, 24.5.

Article

dried over Na SO , and concentrated under reduced pressure. The

92%). TLC: silica gel (10% ethyl acetate/hexane) R = 0.39. H NMR

crude material was puriﬁed via column chromatography using

(400 MHz, CDCl ): δ 7.37 (t, J = 1.3 Hz, 1H), 6.32−6.30 (m, 2H),

Harrowven and co-workers’ procedure (10% K CO /silica sta-

4.07−3.99 (m, 4H), 1.74 (s, 3H). C{ H} NMR (100 MHz, CDCl ):

tionary phase) and a 2−10% ethyl acetate/hexane gradient. Furyl

organostannyl dioxolane 2 was isolated as a brown oil (31.9 g, 61%).

TLC: silica gel (20% ethyl acetate/hexane) R = 0.47. H NMR (500

MHz, CDCl ): δ 6.44 (d, J = 3.1 Hz, 1H), 6.30 (d, J = 3.1 Hz, 1H),

.06−4.00 (m, 4H), 1.75 (s, 3H), 1.59−1.53 (m, 6H), 1.35−1.30 (m,

13 1

H), 1.14−1.00 (m, 6H), 0.89 (t, J = 7.3 Hz, 9H). C{ H} NMR

(200 MHz, CDCl ): δ 161.2, 159.2, 121.7, 106.3, 105.1, 65.2, 29.1,

9,22

7.3, 24.4, 13.8, 10.3. HRMS-APCI (+) m/z: calcd for C H O Sn

1-(5-Allylfuran-2-yl)ethan-1-one (5).

Clear oil, 26 mg.

TLC: silica gel (10% ethyl acetate/hexane) R = 0.24. H NMR (400

[

M + H] , 441.1755; found, 441.1762.

Stille Cross-Coupling of Stannane 2 and Allyl Bromide. To a

MHz, CDCl ): δ 7.11 (d, J = 3.5 Hz, 1H), 6.19 (d, J = 3.5 Hz, 1H),

.93 (ddt, J = 16.8, 10.1, 6.7 Hz, 1H), 5.22−5.16 (m, 2H), 3.47 (d, J =

two-neck oven-dried round-bottom ﬂask containing furyl organo-

stannyl dioxolane 2 (1.0 equiv) and solvent (0.1 M), additive (0.1

equiv) and Cu(I) catalyst (5−50 mol %) were added. Allyl bromide

.7 Hz, 2H), 2.43 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ

86.4, 159.6, 151.9, 132.4, 119.2, 118.3, 108.8, 33.0, 25.9. LRMS-ESI

(+) m /z : 151.1 [M + H] .

(

2.0 equiv) was then added neat. After the reaction via TLC analysis

3−120 h depending on the desired product and scale of reaction),

saturated KF (0.1 M) was added and stirred for a few minutes. The

quenched reaction was then diluted with ethyl acetate, extracted three

times with the said solvent, washed with brine/saturated LiCl, dried

with Na SO , and concentrated under reduced pressure. The crude

(E)-5-Bromo-3-methylpenta-1,3-diene (6). To a one-neck

material was then passed through a 10% K CO /silica plug using

oven-dried 250 mL round-bottom ﬂask, diene alcohol 23 was

dissolved in diethyl ether (Et O, 94 mL, 0.27 M) and cooled to 0

°C. Tribromophosphine (1.3 mL, 13.9 mmol, 0.55 equiv) was added

fuming occurred), and the reaction was stirred for 1.5 h at 0 °C. The

reaction was then quenched with brine (100 mL), brought to ambient

temperature, and extracted with ether three times. The organic layer

was dried over Na SO and concentrated under reduced pressure on

ice. The crude material was then diluted with cold hexane, ﬁltered

through a cotton plug to remove majority of the phosphine oxide, and

concentrated again under reduced pressure on ice to yield diene

bromide 6 as a yellow liquid (4 g, >99%) and was used without

0% ethyl acetate/hexane as the eluent. Allyl furyl dioxolane 3 and

protodestannylated byproduct 4 coeluted, and thus, the ratios were

calculated via H NMR. Allyl furyl ketone 5 was isolable, if formed.

(

The same stationary phase for the plug could be used several times

before being replaced due to decreased ﬂow and blockage. *If a

change of addition was indicated, 2 was dissolved in the solvent,

followed by an additive and bromide. In a separate ﬂask, CuI was then

ﬂame-dried under vacuum to form a canary yellow color and then

cooled under argon, and the reaction ﬂask was cannulated to the

copper ﬂask and stirred. Equivalences, workup, and puriﬁcation all

remained the same.

further puriﬁcation. TLC: silica gel (10% ethyl acetate/hexane) R =

.66, clearly degrading on silica. H NMR (400 MHz, CDCl ): δ 6.38

(

ddd, J = 17.4, 10.7, 0.7 Hz, 1H), 5.78 (t, J = 8.9 Hz, 1H), 5.30 (d, J =

7.4 Hz, 1H), 5.12 (d, J = 10.7 Hz, 1H), 4.13 (d, J = 8.6 Hz, 2H),

.85 (d, J = 1.3 Hz, 3H). C{1H} NMR (100 MHz, CDCl ): δ 140.2,

39.9, 126.8, 114.9, 29.0, 11.6.

-(5-Allylfuran-2-yl)-2-methyl-1,3-dioxolane (3). Clear oil,

96 mg. TLC: silica gel (10% ethyl acetate/hexane) R = 0.40. H

NMR (400 MHz, CDCl ): δ 6.21 (d, J = 3.1 Hz, 1H), 5.97−5.87 (m,

H), 5.16−5.08 (m, 2H), 4.05−3.98 (m, 4H), 3.38 (dq, J = 6.6, 1.4

13 1

Hz, 2H), 1.72 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ 154.1,

53.1, 133.8, 117.1, 107.3, 105.9, 104.9, 65.2, 32.8, 24.5. HRMS-APCI

(

E)-1-(5-(3-Methylpenta-2,4-dien-1-yl)furan-2-yl)ethan-1-

(+) m /z : calcd for C H O [M + H] , 195.1016; found, 195.1018.

11 15 3

one (E)-7. To a two-neck oven-dried 100 mL round-bottom ﬂask,

furyl organostannyl dioxolane 2 (970 mg, 2.2 mmol, 1.0 equiv) was

dissolved in acetonitrile (MeCN, 15 mL). To this, Cs CO (143 mg,

.4 mmol, 0.2 equiv) was added. Diene bromide 6 (705 mg, 4.4

mmol, 2.0 equiv) in 7 mL of MeCN was then cannulated to the

reaction mixture, then copper(I)iodide (CuI, 21 mg, 0.1 mmol, 5 mol

) was added, and the reaction was stirred. After the reaction via

TLC analysis (24−96 h depending on the scale of reaction), it was

concentrated under reduced pressure. The crude material was puriﬁed

via column chromatography using Harrowven and co-workers’

-(Furan-2-yl)-2-methyl-1,3-dioxolane (4). To a one-neck

oven-dried 500 mL round-bottom ﬂask equipped with a Dean−Stark

apparatus and a reﬂux condenser, 2-acetyl furan 1 (10 g, 91 mmol, 1.0

equiv) was added, followed by benzene (PhH, 181 mL, 0.5 M). To

this, ethylene glycol (7.6 mL, 136 mmol, 1.5 equiv) and p-

toluenesulfonic acid monohydrate (PTSA·H O, 863 mg, 4.5 mmol,

mol %) were added sequentially, and the reaction was reﬂuxed at

50 °C in order to remove water. The reaction mixture changed to

golden color after several hours, and a dark maroon color was

developed overnight. After the reaction via TLC analysis (75 h), the

ﬂask was cooled to ambient temperature, and the reaction was

quenched with 1 M NaOH (200 mL), extracted with ethyl acetate

three times, dried with Na SO , and concentrated under reduced

pressure. The crude mixture was puriﬁed via silica column

chromatography using 10% ethyl acetate/hexane as the eluent.

Furyl dioxolane intermediate 4 was isolated as a brown liquid (12.8 g,

procedure (10% K CO /silica stationary phase) and 10% ethyl

acetate/hexane as the eluent. Dioxolane furyl diene (E)-7 was isolated

as a yellow liquid (479 mg, 94%). TLC: silica gel (10% ethyl acetate/

hexane) R = 0.39. H NMR (400 MHz, CDCl ): δ 6.41 (ddd, J =

17.4, 10.7, 0.7 Hz, 1H), 6.20 (d, J = 3.1 Hz, 1H), 5.89 (dt, J = 3.1, 1.0

Hz, 1H), 5.64 (t, J = 7.3 Hz, 1H), 5.16 (d, J = 17.4 Hz, 1H), 5.00 (d, J

= 10.7 Hz, 1H), 4.05−4.00 (m, 4H), 3.48 (d, J = 7.4 Hz, 2H), 1.80 (d,

J = 1.1 Hz, 3H), 1.72 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ

154.3, 153.0, 141.1, 136.1, 127.0, 111.9, 107.3, 105.5, 104.8, 65.2,

27.4, 24.4, 11.9. HRMS-APCI (+) m/z: calcd for C H O [M +

H] , 235.1329; found, 235.1332.

(2R,3R,5S,6S)-2,5-Dimethyl-6-((E)-3-methylpenta-2,4-dien-

9−23

1-yl)tetrahydro-2H-pyran-3-amine (8).

To an oven-dried 10

mL round-bottom ﬂask β-methyl, ketone 21 (30 mg, 0.14, 1.0 equiv)

The Journal of Organic Chemistry

J. Org. Chem. XXXX, XXX, XXX−XXX

[M + H] , 191.1067; found, 191.1069.

Article

NMR shifts could be determined. TLC: silica gel (20% ethyl acetate/

was dissolved in THF (2.88 mL, 0.05 M) and cooled to 0 °C.

hexane) R = 0.24. H NMR (400 MHz, CDCl ): δ 7.12−7.09 (m,

Ammonium acetate (NH OAc, 222 mg, 2.88 mmol, 20 equiv),

1H), 6.76 (ddd, J = 17.2, 10.8, 0.9 Hz, 1H), 6.17−6.15 (m, 1H), 5.54

(t, J = 7.6 Hz, 1H), 5.35−5.28 (m, 1H), 5.22−5.15 (m, 1H), 3.62−

3.58 (m, 2H), 2.49 (s, 3H), 1.88 (d, J = 1.3 Hz, 3H). HRMS-APCI

sodium triacetoxy borohydride [NaBH(OAc) , 152.6 mg, 0.72 mmol,

.0 equiv], and TFA (11 μL, 0.14 mmol, 1.0 equiv) were added

sequentially, and the reaction was warmed slowly to ambient

temperature. Fuming and bubbling were observed upon addition of

reagents. After TLC analysis indicated that the reaction was complete

(+) m /z : calcd for C H O [M + H] , 191.1067; found, 191.1068.

(

44 h), it was quenched with saturated NaHCO (3.0 mL), extracted

with ethyl acetate three times, washed with brine, dried with Na SO ,

and concentrated under reduced pressure. The crude material was

puriﬁed via silica column chromatography using 10% MeOH/DCM

as the eluent to yield amine 8 as a clear oil (24.8 mg, 82% yield) as the

sole detectable isomer via H NMR. TLC: silica gel [5% methanol/

1-(5-(3-Methylpenta-1,4-dien-3-yl)furan-2-yl)ethan-1-one

(13). Yellow oil, 20 mg. TLC: silica gel (20% ethyl acetate/hexane) R

dichloromethane (DCM)] R = 0.07. [α] −4.0 (c 0.708, CHCl ); H

NMR (400 MHz, CDCl ): δ 6.36 (dd, J = 17.4, 10.7 Hz, 1H), 6.05

= 0.24. H NMR (800 MHz, CDCl ): δ 7.11 (d, J = 3.5 Hz, 1H), 6.22

(

br s, 2H), 5.44 (t, J = 7.2 Hz, 1H), 5.10 (d, J = 17.3 Hz, 1H), 4.94 (d,

(d, J = 3.5 Hz, 1H), 6.04 (dd, J = 17.4, 10.5 Hz, 2H), 5.18 (d, J = 10.5

Hz, 2H), 5.04 (d, J = 17.4 Hz, 2H), 2.44 (s, 3H), 1.54 (s, 3H).

J = 10.7 Hz, 1H), 3.62 (br s, 1H), 3.52−3.44 (m, 1H), 3.09 (br s,

H), 2.40 (dt, J = 14.2, 6.7 Hz, 1H), 2.24 (dt, J = 15.1, 7.5 Hz, 1H),

C{ H} NMR (200 MHz, CDCl

): δ 186.7, 163.8, 152.3, 141.6,

.15 (d, J = 14.7 Hz, 1H), 2.02−2.00 (m, 1H), 1.80−1.72 (m, 4H),

118.3, 114.7, 108.6, 46.1, 26.0, 23.5. HRMS-APCI (+) m/z: calcd for

.26 (d, J = 6.6 Hz, 3H), 1.12 (d, J = 7.4 Hz, 3H). C{ H} NMR

(

H] .

100 MHz, CDCl ): δ 141.5, 135.8, 128.3, 111.2, 80.9, 75.1, 49.3,

5.6, 31.9, 28.6, 17.8, 14.5, 12.1. LRMS-ESI (+) m/z: 210.1 [M +

(

R,E)-2-Methyl-6-((E)-3-methylpenta-2,4-dien-1-ylidene)-

H-pyran-3(6H)-one (16). Orange amorphous solid, 10 mg. TLC:

R = 0.21 (silica gel, 10% ethyl acetate/hexane). H NMR (800 MHz,

(

E)-1-(5-(3-Methylpenta-2,4-dien-1-yl)furan-2-yl)ethan-1-

CDCl ): δ 6.98 (d, J = 9.8 Hz, 1H), 6.57−6.51 (m, 2H), 6.02 (d, J =

one (E)-12. To a two-neck oven-dried 500 mL round-bottom ﬂask,

CuI (215 mg, 1.1 mmol, 0.05 equiv) was ﬂame-dried under vacuum

until it formed canary yellow and then cooled under argon and diluted

with 75 mL of acetonitrile (MeCN). Cs CO (2.2 g, 6.8 mmol, 0.3

2.0 Hz, 1H), 5.98 (d, J = 9.8 Hz, 1H), 5.33 (d, J = 17.3 Hz, 1H),

.16 (d, J = 10.6 Hz, 1H), 4.64 (q, J = 7.0 Hz, 1H), 1.92 (d, J = 1.3

Hz, 3H), 1.49 (d, J = 6.9 Hz, 3H). C{ H} NMR (200 MHz,

CDCl ): δ 195.3, 147.3, 141.3, 141.1, 139.3, 124.9, 121.5, 116.0,

equiv) was then added, and the solution turned yellow/gold. To this,

stannane 2 (10 g, 23 mmol, 1.0 equiv) was dissolved in MeCN (75

mL) and added. Finally, bromide 6 (6.2 g, 39 mmol, 1.7 equiv) in 75

mL MeCN was then added, and the reaction was stirred. The reaction

slowly turned milky white and then teal. After the reaction via TLC

analysis (24−96 h depending on the scale of reaction), it was

concentrated under reduced pressure. The crude material was puriﬁed

via column chromatography using Harrowven and co-workers’

14.7, 78.0, 18.2, 12.4. HRMS-APCI (+) m/z: calcd for C H O [M

H] , 191.1067; found, 191.1068.

12 15 2

procedure (10% K CO /silica stationary phase) and 2−10% ethyl

acetate/hexane as the eluent. The fractions containing dioxolane furyl

diene (E)-7 were concentrated under reduced pressure and carried on

to the next step.

(2R,6S)-2-Methyl-6-((E)-3-methylpenta-2,4-dien-1-yl)-2H-

pyran-3(6H)-one (17). To a one-neck oven-dried 10 mL round-

bottom ﬂask, crude alcohol sulfolene 19 (80.6 mg assumed, 0.31

To a one-neck oven-dried 1 L round-bottom ﬂask, dioxolane furyl

diene (E)-7 (5.29 g, 22.6 mmol, 1.0 equiv) was dissolved in acetone

280 mL, 0.08 M), and p-toluenesulfonic acid monohydrate (4.7 g,

4.8 mmol, 1.1 equiv) was added. The reaction changed from yellow

to a greenish-gold color. After the reaction via TLC analysis (2 h), it

was concentrated under reduced pressure and puriﬁed via silica

column chromatography using 5% ethyl acetate/hexane as the eluent.

Ketone furyl diene (E)-12 was isolated as a yellow oil (3.58 g, 83−

5% over two steps depending on the scale). TLC: silica gel (20%

ethyl acetate/hexane) R = 0.24. H NMR (400 MHz, CDCl ): δ 7.09

d, J = 3.5 Hz, 1H), 6.39 (ddd, J = 17.4, 10.7, 0.7 Hz, 1H), 6.15 (dt, J

3.5, 1.0 Hz, 1H), 5.63 (dddd, J = 7.4, 6.8, 1.4, 0.7 Hz, 1H), 5.18 (d,

J = 17.2 Hz, 1H), 5.02 (d, J = 10.7 Hz, 1H), 3.55 (d, J = 7.4 Hz, 2H),

.42 (s, 3H), 1.80 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ

86.2, 159.8, 151.8, 140.7, 137.0, 125.2, 119.2, 112.6, 108.5, 27.7,

mmol, 1.0 equiv) was dissolved in a THF/H

0.1 M) and cooled to 0 °C. Potassium bromide (KBr, 3.7 mg, 0.03

mmol, 0.1 equiv), sodium bicarbonate (NaHCO , 13 mg, 0.16 mmol,

O mixture (2.5/0.6 mL,

(

0.5 equiv), and oxone (213 mg, 0.35 mmol, 1.1 equiv) were added

sequentially, and the reaction was stirred at 0 °C for 1.5 h. After the

reaction via TLC analysis, it was quenched with saturated NaHCO

(3 mL), extracted three times with ethyl acetate, washed with brine,

dried with Na SO , and concentrated under reduced pressure. The

crude material (clear oil) was then taken immediately for the next

reaction. TLC: silica gel (60% ethyl acetate/hexane) R = 0.30.

(

To a one-neck oven-dried 10 mL round-bottom ﬂask, crude

hemiacetal (42.8 mg, 0.16 mmol, 1.0 equiv) was dissolved in DCM

(1.6 mL, 0.1 M) and cooled to −78 °C. To this, triethylsilane

(Et

(BF

SiH, 151 μL, 0.94 mmol, 6.0 equiv) and boron triﬂuoride etherate

·Et O, 39 μL, 0.31 mmol, 2.0 equiv) were added sequentially and

3 2

5.8, 12.0. HRMS-ESI (+) m/z: calcd for C H O Na [M + Na] ,

13.0886; found, 213.0885.

Z)-1-(5-(3-Methylpenta-2,4-dien-1-yl)furan-2-yl)ethan-1-

stirred at this temperature for at least 7 h. The reaction turned a dark

orange gold or orange pink color. The reaction was then removed

from the −78 °C bath and quenched slowly with the addition of

(

one (12). Yellow oil, 37 mg. Part of mixture of isomers, only H

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

saturated NaHCO (2 mL, bubbled violently). The organic layer was

then extracted with DCM ﬁve times, dried with Na SO , and

concentrated under reduced pressure. The crude material 20 (yellow

oil) was then taken immediately for the next reaction. TLC analysis

(R_f= 0.54, silica gel, 60% ethyl acetate/hexane) during the reaction

seems not to be reliable as it shows full conversion almost

immediately, but if analysis is carried out, TLC of the crude material

then shows the starting material (almost no conversion). It was found

that letting the reaction run for 7 h instead and then working it up

showed full conversion via crude TLC.

To a one-neck oven-dried 50 mL round-bottom ﬂask equipped

with a reﬂux condenser, the crude sulfolene enone 20 (40 mg

assumed, 0.16 mmol, 1.0 equiv) was dissolved in toluene (15.7 mL,

formic acid (HCO H, 89 μL, 2.4 mmol, 7.5 equiv) were added

sequentially, and the evolution of H gas was observed. [N-[(1R,2R)-

2-(Amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-

κN]chloro[(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-ruthenium (RuCl-

[(R,R)-TsDPEN](mesitylene), 2 mg, 0.003 mmol, 1 mol %) was

added last, and the reaction was heated in an oil bath to reﬂux (30

°C). After the reaction via TLC analysis (24−48 h), the solution was

cooled and concentrated down under reduced pressure and passed

.01 M) and heated in an oil bath to reﬂux (150 °C). After the

reaction via TLC analysis (3 h), the ﬂask was cooled to ambient

through 10% K CO /silica plug, using 65% ethyl acetate/hexane as

2 3

temperature and concentrated under reduced pressure. The crude

the eluent. The solution was concentrated down under reduced

pressure again, and the crude material 19 (clear oil) was then taken

immediately for the next reaction. Of particular note, for any transfer

of the crude mixture, ethyl acetate was found to be the most suitable

solvent. If the crude came into contact with DCM or deuterated

chloroform for the NMR analysis, it appeared to degrade very quickly

afterward before the next reaction could be carried out. NMR data

were recorded quickly in a single time; however, the sample degraded

before the material could be recovered and used in the next step. The

material was then puriﬁed via 10% K CO /silica chromatography

using 1−10% ethyl acetate/hexane as the gradient. Enone diene 17

was isolated as a yellow oil (18 mg, 60% over four steps, >10:1 ratio of

7:16, >98% ee). TLC: silica gel (10% ethyl acetate/hexane) R =

.20. [α]²+76.2 (c 0.362, CHCl ); H NMR (400 MHz, CDCl ): δ

.90 (d, J = 10.3 Hz, 1H), 6.39 (dd, J = 17.3, 10.6 Hz, 1H), 6.10 (d, J

10.2 Hz, 1H), 5.55 (t, J = 7.1 Hz, 1H), 5.16 (d, J = 17.4 Hz, 1H),

.01 (d, J = 10.7 Hz, 1H), 4.41 (t, J = 6.4 Hz, 1H), 4.09 (q, J = 6.5 Hz,

H), 2.60−2.50 (m, 2H), 1.78 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H).

use of a 10% K

opposed to traditional silica and celite plugs. HRMS data were

recorded as well. TLC: silica gel (60% ethyl acetate/hexane) R =

2 3

CO /silica plug appeared to less degrade 19 as

C{ H} NMR (100 MHz, CDCl ): δ 197.1, 150.8, 141.0, 137.2,

27.0, 126.2, 112.1, 77.3, 74.0, 33.8, 15.6, 12.2. HRMS-ESI (+) m/z:

.22. H NMR (400 MHz, CDCl ): δ 6.16−6.12 (m, 2H), 5.66 (br s,

calcd for C H O [M + H] , 193.1223; found, 193.1227.

H), 4.81 (q, J = 6.6 Hz, 1H), 3.82 (t, J = 6.4 Hz, 1H), 3.72−3.58 (m,

H), 3.29−3.07 (m, 2H), 2.14 (br s, 1H), 1.79 (br s, 3H), 1.50 (d, J =

.6 Hz, 3H). C{ H} NMR (100 MHz, CDCl ): δ (157.1, 157.0),

(

149.7, 149.6), 138.4, 118.0, (108.7, 108.7), (106.3, 106.2), (65.9,

5.8), (63.7, 63.6), 55.7, 26.9, (21.4, 21.3), 18.3. HRMS-ESI (+) m/z:

calcd for C H O SNa [M + Na] , 279.0662; found, 279.0665.

-(5-((3-Methyl-1,1-dioxido-2,5-dihydrothiophen-2-yl)-

methyl)furan-2-yl)ethan-1-one (18). A thick-walled sealed tube

reaction vessel was ﬁtted with a stir bar and septa. The apparatus was

ﬂame-dried under vacuum and then cooled under argon. Solvents

were prebubbled with argon for at least 10 min beforehand, and then

in a one-neck oven-dried round-bottom ﬂask, ketone furyl diene (E)-

2 (110 mg, 0.6 mmol 1.0 equiv) was dissolved in the freshly bubbled

:1 mixture of 1,4-dioxane and H O (2.9 mL, 0.2 M) and cannulated

to the sealed tube. KHSO₄(472 mg, 3.5 mmol, 6.0 equiv) and

(2R,5S,6S)-2,5-Dimethyl-6-((E)-3-methylpenta-2,4-dien-1-

19,21,22

yl)dihydro-2H-pyran-3(4H)-one (21).

To a one-neck oven-

NaHSO (903 mg, 8.7 mmol, 15.0 equiv) were added to the reaction

dried 10 mL round-bottom ﬂask, copper (I) iodide (CuI, 108 mg,

0.56 mmol, 3.0 equiv) was ﬂame-dried under vacuum until it formed a

canary yellow color and then cooled under argon. Diethyl ether

vessel, and the tube was sealed and heated in an oil bath to the desired

temperature. After 24 h, the vessel was cooled down to 0 °C and

opened. If TLC analysis showed that the reaction was still in progress,

it was resealed and heated back up until the reaction was either

complete or if TLC analysis showed no further progression. The

(Et O, 1.0 mL) was then added, the solution was cooled to 0 °C, and

methyl lithium (MeLi, 3.1 M in diethyl ether, 371 μL, 1.15 mmol, 6.1

equiv) was added and stirred at 0 °C for 30 min. The reaction turned

from a yellow color to orange and then became clear. In a separate

ﬂask, enone diene 17 (12 mg, 0.06 mmol, 1.0 equiv) was dissolved in

reaction was then diluted with ethyl acetate (0.1 M) and H O (0.1

M) and extracted with ethyl acetate four times. Organic layers were

then washed with brine, dried with Na SO , and concentrated under

Et O (1.35 mL) and cooled to −78 °C. The solution of the starting

reduced pressure. The crude material was puriﬁed via silica gel

column chromatography using 10−70% ethyl acetate/hexane as the

gradient to recover any unreacted ketone furyl diene 12 and sulfolene

ketone 18 as clear yellow oils. Sulfolene ketone 18 was solidiﬁed to a

yellow white solid (92 mg, 6−62%, 6−>99% BRSM) once

material was then cannulated to the in situ formed Gilman reagent at

−78 °C and stirred. The reaction turned from a yellow to orange

yellow color and eventually grew darker over time. Hours later, it

developed a dark brown-green color. After the reaction via TLC

analysis (5 h), it was removed from the bath and quenched slowly

concentrated under reduced pressure with diethyl ether three times

with H

mixture was extracted with ethyl acetate three times, washed with

brine, dried with Na SO , and concentrated under reduced pressure.

O (2.5 mL) and brought to ambient temperature. The crude

iteratively. TLC: silica gel (60% ethyl acetate/hexane) R = 0.24. H

NMR (400 MHz, CDCl ): δ 7.11 (d, J = 3.5 Hz, 1H), 6.45 (dt, J =

.5, 0.8 Hz, 1H), 5.70 (tt, J = 3.1, 1.6 Hz, 1H), 3.94−3.85 (m, 1H),

The crude material was puriﬁed via silica column chromatography

using 5% ethyl acetate/hexane as the eluent. β-Methyl ketone 21 was

isolated as a clear yellow oil (34.5 mg, 91%). TLC: silica gel (10%

.77−3.61 (m, 2H), 3.35−3.19 (m, 2H), 2.43 (s, 3H), 1.85−1.83 (m,

H). ¹³C{ H} NMR (100 MHz, CDCl ): δ 186.2, 155.5, 152.2, 137.6,

19.1, 118.4, 111.2, 65.5, 55.9, 26.9, 26.0, 18.2. HRMS-ESI (+) m/z:

ethyl acetate/hexane) R

NMR H NMR (400 MHz, CDCl ): δ 6.39 (dd, J = 17.4, 10.7 Hz,

= 0.36. [α]

−19.6 (c 0.467, CHCl ); H

calcd for C H O SNa [M + Na] , 277.0505; found, 277.0502.

-((5-((R)-1-Hydroxyethyl)furan-2-yl)methyl)-3-methyl-2,5-

1H), 5.50 (t, J = 7.4 Hz, 1H), 5.14 (d, J = 17.3 Hz, 1H), 4.98 (d, J =

10.7 Hz, 1H), 3.96 (q, J = 6.5 Hz, 1H), 3.90 (td, J = 7.0, 1.7 Hz, 1H),

2.64 (dd, J = 15.2, 6.1 Hz, 1H), 2.48 (dt, J = 14.0, 6.7 Hz, 1H), 2.38−

2.25 (m, 3H), 1.78 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H), 0.98 (d, J = 7.0

dihydrothiophene-1,1-dioxide (19). To a one-neck oven-dried 10

mL round-bottom ﬂask equipped with a reﬂux condenser, ketone

sulfolene 18 (80 mg, 0.31 mmol, 1.0 equiv) was dissolved in DCM

(

3.1 mL, 0.1 M). Triethylamine (329 μL, 2.4 mmol, 7.5 equiv) and

Hz, 3H). C{ H} NMR (200 MHz, CDCl ): δ 208.9, 141.3, 136.1,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

28.1, 111.6, 79.7, 78.9, 46.9, 35.1, 31.6, 15.2, 13.3, 12.1. LRMS-ESI

Authors

+) m /z : 209.1 [M + H] .

Joshua R. Born − Department of Chemistry and Department of

Medicinal Chemistry and Molecular Pharmacology, Purdue

University, West Lafayette, Indiana 47907, United States

Anne M. Veitschegger − Department of Chemistry and

Department of Medicinal Chemistry and Molecular

Pharmacology, Purdue University, West Lafayette, Indiana

47907, United States

Melissa S. Jurica − Department of Molecular Cell and

Developmental Biology and Center for Molecular Biology of

RNA, University of California, Santa Cruz, Santa Cruz,

California 95064, United States

Ethyl (E)-3-Methylpenta-2,4-dienoate (22). To a two-neck

oven-dried 500 mL round-bottom ﬂask, MePPh Br (8.4 g, 23.5 mmol,

.07 equiv) was added with a stir bar and stirred under vacuum while

heating the ﬂask to 110 °C in an oil bath overnight. The ﬂask was

cooled under argon and then freshly distilled THF (157 mL, 0.14 M)

was added, followed by n-butyllithium (n-BuLi, 1.6 M in hexane, 15

mL, 24 mmol, 1.1 equiv) at −78 °C. The solution changed from white

slurry to golden. The ﬂask was then allowed to warm to 0 °C over the

course of an hour and then recooled to −45 °C, and ethyl-3-methyl-4-

oxocronate (3 mL, 22 mmol, 1.0 equiv) was added slowly. The

reaction changed from golden orange to pink. After 2 hours, the

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c00976

Notes

reaction was removed from a −45 °C bath and quenched with H O

150 mL), turning purple. The crude mixture was extracted three

(

The authors declare no competing ﬁnancial interest.

times with diethyl ether and then concentrated under reduced

pressure on ice because of product volatility. The crude mixture was

puriﬁed via a short silica plug using 5% diethyl ether/hexane as the

eluent. Diene ester 22 was isolated as a clear liquid. The product was

then used without any further puriﬁcation. TLC: silica gel (10% ethyl

ACKNOWLEDGMENTS

■

Financial support of this work was provided by the National

Institutes of Health (GM122279).

acetate/hexane) R = 0.24 H NMR (400 MHz, CDCl ): δ 6.40 (ddd,

J = 17.4, 10.6, 0.8 Hz, 1H), 5.79 (s, 1H), 5.61 (d, J = 17.4 Hz, 1H),

.38 (d, J = 10.6 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.27 (d, J = 1.2

Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H). C{ H} NMR (126 MHz,

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