Highly Diastereoselective Intramolecular Asymmetric Oxidopyrylium-olefin [5 + 2] Cycloaddition and Synthesis of 8-Oxabicyclo[3.2.1]oct-3-enone Containing Ring Systems

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Highly Diastereoselective Intramolecular Asymmetric

Oxidopyrylium-oleﬁn [5 + 2] Cycloaddition and Synthesis of

8‑Oxabicyclo[3.2.1]oct-3-enone Containing Ring Systems

Arun K. Ghosh* and Monika Yadav

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ABSTRACT: We have the investigated base mediated asymmetric intramolecular

oxidopyrylium-alkene [5 + 2]-cycloaddition reaction which resulted in the synthesis

of functionalized tricyclic ring systems containing an 8-oxabicyclo[3.2.1]octane

core. Intramolecular cycloaddition constructed two new rings, three new

stereogenic centers, and provided a tricyclic cycloadduct with high diastereose-

lectivity and isolated yield. We incorporated an α-chiral center and an alkoxy alkene

tether on the substrates and examined the eﬀect of the size of alkyl groups and

alkene tether length on diastereoselectivity. The requisite substrates for the

oxidopyrylium-alkene cycloaddition reaction were synthesized in a few steps

involving alkylation of optically active α-hydroxy amide, furyllithium addition, reduction of resulting ketone, and Achmatowicz

reaction followed by acylation of a lactol intermediate. We have proposed stereochemical models for the [5 + 2] cycloaddition

reaction via the oxidopyrylium ylide. Interestingly, the alkoxy substituent on the stereocenter and the chain length are responsible for

the degree of stereoselectivity of the cycloadduct.

INTRODUCTION

■

The oxidopyrylium-alkene [5 + 2] cycloaddition reaction has

emerged as an important synthetic method for the

construction of complex seven-membered ring systems.¹⁻⁴

This reaction provides convenient access to a wide variety of

highly functionalized seven-membered ring structures contain-

ing an oxygen bridge. Over the years, the development of new

strategies and reaction protocols led this cycloaddition

chemistry to become a reliable strategy for the synthesis of a

diverse class of 8-oxabicyclo[3.2.1]octane heterocycles. Inter-

estingly, these heterocyclic structural motifs are inherent to a

wide variety of bioactive natural products.⁴⁻⁶Furthermore,

these heterocyclic intermediates have been exploited in the

design and synthesis of functionalized seven-membered ring

compounds in medicinal chemistry.⁷⁻⁹Representative exam-

ples include phorbol (1, Figure 1), a tumor-promoting agent

that works through activation of protein kinase C.^10,11

Resiniferatoxin (2) found in resin spurge shows extraordinary

irritant properties.^12,13Englerin B (3) and intricarene (4)

possess very potent anticancer activity with medicinal

potential.^14,15Wender and co-workers elegantly utilized the

intramolecular oxidopyrylium-alkene [5 + 2] cycloaddition

reaction in the total synthesis of phorbol and (+)-resin-

iferatoxin.^16,17Nicolaou and co-workers reported a racemic

total synthesis of englerin A and englerin B utilizing the [5 + 2]

cycloaddition.¹⁸Trauner and co-workers reported a biomi-

metic synthesis of (+)-intricarene using an intramolecular [5 +

2] cycloaddition.¹⁹A number of recent reviews highlighted

Figure 1. Natural products containing functionalized seven-

membered and 8-oxabicyclo [3.2.1] octane core.

Received: March 12, 2021

Published: May 20, 2021

https://doi.org/10.1021/acs.joc.1c00600

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important developments and applications of these cyclo-

addition reactions in organic synthesis.^4,6,20

access to structurally intriguing oxabicyclo[3.2.1]octane

heterocyclic ring systems. We recently incorporated a variety

of similar stereochemically deﬁned cyclic ether-derived ligands

and structural templates in the design of exceptionally potent

HIV-1 protease inhibitors.³⁵⁻³⁷Herein, we report our studies

on an asymmetric intramolecular cycloaddition reaction of the

oxidopyrylium ylide bearing an α-chiral center and a number of

alkoxy-alkene tethers for construction of ﬁve- to seven-

membered ring systems. We have examined the eﬀect of

diﬀerent alkyl groups and alkene tether lengths of the alkoxy

substituents on diastereoselectivity. Various cycloaddition

substrates and stereochemically deﬁned tricyclic cycloadducts

were synthesized eﬃciently in optically active form.

Among many developments, the generation of oxidopyry-

lium ylide through the elimination of the acetate or benzoate

derivative of a 6-hydroxy-2H-pyran-3(6H)-one, which can be

derived from an Achmatowicz reaction, greatly facilitated the

use of oxidopyrylium-alkene [5 + 2] cycloaddition in synthesis.

In 1980, Hendrickson and Farina ﬁrst reported that

acetoxypyranone can be used as a precursor to generate the

oxidopyrylium ylide by elimination of the acetate group.^21,22

Later, Sammes and co-workers reported an intramolecular

oxidopyrylium cycloaddition of 5 by using DBN as a base to

provide cycloadduct 6 as shown in Figure 2.^23,24The

RESULTS AND DISCUSSION

■

Our tentative plan for the asymmetric oxidopyrylium-alkene [5

+ 2] cycloadditions for substrates containing an α-chiral center

is shown in Scheme 1. We planned to synthesize various O-

alkylated optically active Weinreb amides (12) from optically

active α-hydroxy amides (11). Reaction of furyllithium is

expected to provide the corresponding ketone, which, upon

reduction, would provide alcohol 13 with some degree of

diastereoselectivity. The stereochemistry and diastereomeric

ratio are inconsequential, as the stereocenter will be destroyed

Scheme 1. Asymmetric Oxidopyrylium-alkene [5 + 2]

Cycloaddition of Substrates Containing an α-Alkoxy

Stereocenter

Figure 2. Prior works on intramolecular and asymmetric oxidopyry-

lium-alkene [5 + 2] cycloaddition of substrates containing an α-chiral

center.

oxidopyrylium-alkene cycloaddition can incorporate multiple

stereogenic centers in the cycloadducts. A number of reports of

asymmetric catalytic oxidopyrylium cycloaddition reactions

using organocatalysts have appeared in the literature.²⁵⁻²⁸

Prior to that, a number of asymmetric intramolecular

oxidopyrylium-alkene cycloadditions have been reported

where the oxidopyrylium ylide possessed at least an α-chiral

center. The stereochemical outcome of the cycloadduct was

dictated by the substituent in the existing α-chiral center.

During the synthesis of (+)-phorbol (1), Wender and co-

workers carried out an asymmetric cycloaddition of acetate

derivative 7 to provide cycloadduct 8 as a single diastereomer

in 79% yield.¹⁶Trivedi and co-workers reported an asymmetric

cycloaddition of acetate derivative 9 to provide cycloadduct 10

with very high diastereoselectivity (dr 97%).²⁹Several other

oxidopyrylium-alkene cycloadditions have been reported with

high selectivity in the literature.³⁰⁻³⁴We became interested in

the oxidopyrylium-alkene cycloaddition reaction to provide

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during the formation of pyrylium ylide. The alcohol mixture

will be converted to acetoxy dihydropyranone derivative 14,

the oxidopyrylium precursors. Base catalyzed elimination of

acetate from 14 would generate the oxidopyrylium ylide which

would undergo intramolecular [5 + 2]-cycloaddition with a

tethered alkene substituent to provide cycloadducts diaster-

eoselectively. Presumably, cycloaddition would proceed

through the transition states shown in 15a and 15b. Transition

state 15a is preferred over 15b due to competing nonbonded

interactions between the alkyl group and the alkoxy group of

the pyrylium ylide in the transition-state 15b. Tricyclic

diastereomer 16 with depicted stereochemistry would be

expected as the major product, and diastereomer 17 would be

the minor product. In this case, the new ﬁve-membered ring

will place the alkyl substituent in a pseudoequatorial

orientation as shown in Scheme 1. The size of the alkyl

substituents is expected to inﬂuence the degree of diaster-

eoselectivity. Also, varying the size of the alkene tethers would

enable the reaction to proceed through six- and seven-

membered ring systems. The stereochemical outcome is

expected to be similar, as the reaction will proceed through a

similar transition state as 15a. We planned to examine the

eﬀect of the R-substituents and alkoxy tether length on

diastereoselectivity.

ketones with sodium borohydride in MeOH at −78 °C for 1 h

aﬀorded the furfuryl alcohols 13a (7:1, 84%), 13b (9:1, 85%),

13c (3:1, 83%), and 13d (1.2:1, 73%) over two steps as a

mixture of diastereomers. The diastereomers were not

separable by ﬂash column chromatography and were carried

forward as a mixture for the subsequent reactions. The

diastereomeric ratio and stereochemistry of the new chiral

center are not important, as the chiral center will eventually be

destroyed during the formation of oxidopyrylium ylide. The

depicted anti-stereochemistry of the major isomer is based

upon the chelation control model reported for the reduction of

α-alkoxy ketones.⁴⁰

Initially, the one-carbon homologue of the O-allyl tether was

synthesized using the furfuryl alcohol 13a as outlined in

Scheme 3. Hydroboration of alkene 13a with dicyclohexyl

Scheme 3. Synthesis of Furan Derivative 13e

Our synthesis of variously substituted furan derivatives 13a−

d is shown in Scheme 2. Weinreb amides 11a−d were

Scheme 2. Synthesis of Furan Derivatives 13a−d

borane at 0 °C in THF for 2 h followed by oxidation of the

resulting borane with NaBO₃·4H₂O at 23 °C for 12 h aﬀorded

the diol 18 in 88% yield.⁴¹Diol 18 was obtained as a mixture

(1:5, syn/anti) of diastereomers, which were separated by ﬂash

column chromatography over silica gel. The major isomer was

carried forward for the next reaction. Selective oxidation of the

primary alcohol of diol 18 was carried out by treatment with

0.1 equiv of TEMPO and 1.2 equiv of bis(acetoxy)-

iodobenzene (BAIB) in THF at 0° to 23 °C for 9 h to give

the aldehyde in 74% yield.⁴²Incorporation of the terminal

oleﬁn was achieved by Wittig reaction of the aldehyde with the

methyltriphenylphosphonium ylide generated by treating 5

equiv of methyltriphenylphosphonium bromide with 4.5 equiv

of t-BuOK to provide alkene derivative 13e in 30% yield.⁴³

Overall, this route was less than satisfactory and resulted in a

poor yield of the desired O-homoallyl furfuryl alcohol 13e.

Therefore, we examined an alternative and more convergent

approach to synthesize O-homoallyl furfuryl alcohols via direct

alkylation of the α-hydroxy esters.

Direct O-alkylation of Weinreb amides with homoallyl

bromides or iodides under various O-alkylation conditions did

not provide satisfactory yield of the alkylated products.

Therefore, we utilized a modiﬁed procedure using alkenyl

triﬂates.⁴⁴As shown in Scheme 4, reaction of α-hydroxy esters

19a−b with t-BuOK and 3-butenyl triﬂate in THF at −20 °C

for 30 min provided O-alkylated products 20a and 20b in 47%

and 54% yields, respectively. Similarly, O-alkylation of 19b

with 4-pentenyl triﬂate aﬀorded alkylated product 20c in 84%

prepared from the optically active ester as described

previously.³⁸Treatment of alcohols 11a−d with NaH in

THF at −20 °C for 30 min followed by reaction with

allylbromide for 12−14 h provided O-alkylated products 12a

(87%), 12b (87%), 12c (88%), and 12d (69%) in good

yields.³⁹Reaction of Weinreb amides 12a−d with 2-lithiofuran,

generated in situ with furan and n-BuLi at −78 °C, aﬀorded the

corresponding ketone derivatives. Reduction of the resulting

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Scheme 4. Synthesis of Furan Derivatives 13f−h

Table 1. Synthesis of Cycloaddition Precursors,

Acetoxypyranone

a b

,

yield. Various alkylated ester derivatives 20a−c were converted

to the corresponding Weinreb amide derivatives 12f−h by

treatment with 4.0 equiv of AlMe₃and 4.0 equiv of

methoxymethylamine hydrochloride in THF at 23 °C for 24

h in good yields (12f, 75%; 12g, 65%; 12h, 80%). Reaction of

these Weinreb amides 12f−h with 2-lithiofuran as described in

Scheme 4 resulted in the corresponding ketones, which upon

reduction with NaBH₄in MeOH at −78 °C for 1 h as

described before, furnished alcohols 13f (3:1 mixture, 84%),

13g (1:1 mixture, 80%), and 13h (1.8:1 mixture, 73%) in good

yields over two steps. These diastereomeric alcohols were not

separated, and the mixtures were carried forward for the

subsequent reactions.

Various furfuryl alcohols 13a−h were then converted to

acetoxy-pyranone derivatives 14a−h, and the results are shown

in Table 1. Achmatowicz rearrangement of the furfuryl alcohols

13a−h were carried out by treatment of alcohols with a

catalytic amount of KBr (0.1 equiv), NaHCO₃(0.5 equiv), and

oxone (1.5 equiv) at 0 °C in a mixture (4:1) of THF and water

to provide the corresponding lactol.^45,46Reactions of the

resulting lactols with acetyl chloride in the presence of pyridine

in CH₂Cl₂at 0 °C for 30 min aﬀorded acetoxypyranone

derivatives 14a−h in good yields after silica gel chromatog-

raphy (55−92%).

Following the synthesis of acetoxypyranone derivatives, we

carried out the cycloaddition reaction with a mixture of

diastereomers of (S)-phenyl acetoxypyranone 14a under

various reaction conditions (Table 2). Initially, we attempted

the [5 + 2]-cycloaddition reaction without any base under

thermal conditions in acetonitrile at 80 °C and in toluene at

110 °C, respectively. However, no cycloadduct was formed

when CH₃CN was used as a solvent (entry 1) and a complex

mixture of unidentiﬁed products was obtained when

a

b

Reactions were carried out on 0.2 to 3 mmol scale. Yields are

calculated for two steps.

acetoxypyranone 14a was heated in toluene (entry 2). We

then screened diﬀerent amine bases with varying equivalents in

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Table 2. Initial Optimization of [5 + 2]-Cycloaddition Reaction Conditions of Acetoxypyranone 14a

a

Entry

Base

Equivalents

Solvent

Temp (°C)

Time (h)

Diastereomeric ratio

Yield (%) 16a

1

2

3

4

5

6

7

8

9

No base

DABCO

−

CH₃CN

PhMe

80

110

60

80

22

12

11

12

24

−

9:1

10:1

−

10:1

0

complex mix

56

69

89

complex mix

0

b

2.0

4.0

−

CH₃CN

c

NMP

d

DBU

e

Pyridine

DBN

f

SiO₂

CH₃CN

44

a

b

c

d

1

Diastereomeric ratios were determined via H NMR. DABCO = 1,4-Diazabicyclo-[2.2.2]octane. NMP = N-Methylpyrrolidine. DBU = 1,8-

Diazabicyclo[5.4.0]undec-7-ene, Recovered 14a (78%). DBN = 1,5-Diazabicyclo[4.3.0]non-5-ene.

e

f

CH₃CN at 60 °C under an argon atmosphere. Treatment of

acetoxypyranone 14a with 2.0 equiv of 1,4-diazabicyclo-

[2.2.2]octane (DABCO) in acetonitrile at 60 °C for 12 h

aﬀorded the cycloadduct 16a (CCDC 2025567) as the major

diastereomer in 56% yield (entry 3). Interestingly, increasing

the equivalents of base to 4.0 improved the yield to 69%, but

the diastereomeric ratio remained the same (entry 4). N-

Methylpyrrolidine (NMP) aﬀorded the best yield and

diastereomeric ratio of the cycloadduct 16a (entry 5). DBN,

DBU, and pyridine mediated cycloaddition reactions were

ineﬃcient (entries 6−8). To our surprise, heating the slurry of

acetoxypyranone 14a in silica gel (8x wt) provided the

cycloadduct in moderate yield and excellent diastereoselectiv-

ity (entry 9).

cycloadduct 16b was later crystallized in hexanes/EtOAc (4/1)

solution, and the absolute stereochemistry was unambiguously

determined by X-ray crystallography (CCDC 2025568).⁴⁷The

2-D NMR correlations are consistent with the X-ray crystal

structure of 16b. More detailed NMR and X-ray studies

including the ORTEP diagram of 16b and other structures are

shown in the Supporting Information. This result shows that

the stereochemical outcome of [5 + 2] cycloaddition reaction

can be inﬂuenced by the existing chirality of the substrate.

We investigated the eﬀect of the alkyl groups on the

stereoselectivity. The cycloaddition reaction proceeded well

with acetoxypyranones 14c and 14d containing the isopropyl

and methyl substituents, respectively. The diastereoselectivity

and yield of the cycloadduct were reduced as compared to the

phenyl derivative (entries 3 and 4). Surprisingly, the presence

of a methyl group on the alkene tether gave a slightly better

diastereoselectivity compared to the bulkier isopropyl group.

To conﬁrm the stereochemistry of the minor isomer, we

separated both isomers 16c (major) and 16c (minor) by

HPLC using a chiral column (CHIRALPAK-IC). As shown in

Scheme 5, Luche reduction of 16c (minor) using NaBH₄and

CeCl₃at 0 °C for 1 h furnished allylic alcohol 21 as a single

isomer in 75% yield (Scheme 5).

We also carried out stereochemical assignment of the

alcohol 21 by 2D-NMR experiments (Figure 4). The complete

assignment of all protons and carbons was achieved by

proton−proton (NOESY and COSY) and proton−carbon

(HMQC) correlation experiments (please see Supporting

Information). Our structural assignment was not conclusive

due to the lack of correlation between protons H_c−H_d.

However, the X-ray crystallography of compound 21 showed

that protons H_cand H_dare not in proximity and supported the

correlation between proton H_cand H_e. The absolute

stereochemistry of alcohol 21 was assigned by X-ray

crystallography (CCDC 2064460; please see Supporting

Information).⁴⁷

We then conducted cycloadditions of various other

substrates using 4 equiv of NMP as shown in entry 5, Table

2, and the results are shown in Table 3. We ﬁrst investigated O-

allyl tethered alkenes on the acetoxypyranone derivatives to

examine the scope of chirality transfer from the substrates.

Cycloaddition of acetoxy-pyranone 14a provided cycloadduct

16a in 89% yield. The diastereofacial selectivity was very high,

1

and the diastereomeric ratio (10:1) was determined using H

NMR analysis. Separation of the diastereomers via column

chromatography proved to be diﬃcult due to the similar R_f

values of the two diastereomers in many diﬀerent solvent

systems.

We have also prepared (R)-phenyl acetoxypyranone 14b

from (R)-mandelic acid and subjected it to [5 + 2]

cycloaddition under similar conditions. This resulted in

cycloadduct 16b in 74% yield and showed a similar

diastereomeric ratio (10:1). The relative stereochemistry of

1

the major diastereomer of 16b was initially established by H

NMR NOESY and COSY experiments. Since the absolute

stereochemistry of proton H_ccomes from the chiral starting

material, (R)-mandelic acid, we can assign the relative

stereochemistry of protons H_fand H_ifrom H_c. A COSY

experiment was done ﬁrst to assign the protons coupled to H_f

and H_irespectively. The results of the observed COSY and

NOESY correlation are summarized in Figure 3. The strong

NOESY correlations between H_c−H_e, H_e−H_f, and H_f−H_h

provided evidence for the assigned stereochemistry of H_f.

Similarly, the observed NOESY correlations between H_d−H_g

and H_g−H_isupports the assigned stereochemistry of H_i. The

We further investigated the stereochemical eﬀect of

increasing the tether length to form six- and seven-membered

rings containing alkyl substituents. The reaction of O-

homoallyl acetoxypyranone 14e with a phenyl substituent in

the presence of 4 equiv of NMP for 4 h resulted in cycloadduct

16e in 60% yield and diastereoselectivity was excellent (>19:1

by ¹H NMR analysis of the crude reaction products).

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Table 3. Intramolecular [5 + 2] Cycloaddition with Oxidopyrylium Ion and the Terminal Alkene

a

b

Reactions were carried out using N-methylpyrrolidine, NMP (4.0 equiv), in CH₃CN (0.02 M) at 60 °C. The diastereomeric ratios were

c

1

determined by H NMR. Reaction was carried out at 150 °C with 1.5 equiv of N-methyl pyrrolidine as base.

Cycloaddition reaction of homoallyl derivative 14f with an

isopropyl substituent proceeded well to provide cycloadduct

16f in 84% yield and excellent diastereoselectivity (>19:1).

Similarly, homoallyl derivative 14g with a methyl substituent

aﬀorded cycloadduct 16g in 79% yield with similar

diastereoselectivity as the other homoallyl derivatives (entries

5−7).

We then investigated the cycloaddition of acetoxypyranone

14h with a ﬁve carbon alkenyloxy tether containing a methyl

substituent. The results are shown in Table 4. Initial

cycloaddition attempt with 1.5 equiv of NMP in CH₃CN at

23 °C for 24 h, resulted in no cycloaddition product (entry 1).

We then carried out the cycloaddition in the presence of 4

equiv of NMP in CH₃CN at 60 °C for 4 h (entry 2). These

conditions resulted in a complex mixture of products (entry 2).

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The reaction temperature was increased to 80 °C, and after 6

h, cycloadduct 16h was obtained in 26% yield and 10% of the

1

starting material 14h was recovered (entry 3). The H NMR

analysis revealed that 16h was formed in a highly

diastereoselective manner (>19:1 by ¹H NMR analysis).

Intramolecular cycloaddition reactions that form seven-

membered rings are in general less reactive due to unfavorable

entropy. To overcome the entropic factors, we decided to carry

out the cycloaddition reaction at higher temperatures (entries

4−8). Reaction of 14h at 120 °C in the presence of 1.5 equiv

of NMP in CH₃CN in a sealed tube provided the cycloadduct

16h in 49% yield and excellent diastereoselectivity (>19:1 by

¹H NMR) (entry 4). The corresponding reaction in the

presence of 2.0 equiv of NMP resulted in a slight decrease in

the yield of the cycloadduct (entry 5). A further increase of

reaction temperature to 150 °C in a sealed tube for 4 h

provided cycloadduct 16h in 47% yield (entry 6). The

cycloaddition proceeded a bit more eﬃciently in the presence

of 1.5 equiv of NMP at 150 °C for 3 h which resulted in

complete consumption of starting material and yielded 16h in

59% yield (entry 8). We also examined the cycloaddition

reaction of 14h with 1.5 equiv of 2,2,6,6-tetramethylpiperidine

in CH₃CN at 150 °C (entry 7), as reported by Mei and co-

workers.⁴⁸This condition resulted in the formation of

cycloadduct 16h in 58% isolated yield.

Figure 3. Representative ¹H NMR COSY and NOESY correlations of

compound 16b.

Scheme 5. Synthesis of Allylic Alcohol 21

To explain the stereochemical outcome of the [5 + 2]-

cycloaddition of chiral substrate containing an alkoxy oleﬁn

tether, we proposed stereochemical models shown in Figure 5.

Figure 4. Representative ¹H NMR COSY and NOESY correlations of

alcohol 21.

Table 4. Temperature Screening for [5 + 2]-Cycloaddition

Reaction of Acetoxypyranone 14h

ab

,

Entry

Base (equiv)

Temp (°C)

Time (h)

Yield (%) 16h

1

2

3

4

5

6

7

8

NMP (1.5)

NMP (4.0)

NMP (1.5)

NMP (2.0)

TMP (1.5)

NMP (1.5)

23

60

80

120

150

24

4

6

4

19

3

No product

complex

26

49

45

47

58

59

Figure 5. Representations of transition states of ﬁve-membered and

six-membered fused cycloadducts.

Treatment of acetoxyhydropyranones 14 with base will lead to

the formation of the aromatic oxidopyrylium ion 15 containing

an α-chiral center bearing an alkyl substituent and an alkoxy

tether with a terminal alkene. The O-allyl chain with the phenyl

group will adopt a transition-state 15a where the bulky phenyl

group would occupy a pseudoequatorial position in the

envelope conformation of the developing ﬁve-membered

ring.^49,50The alkyl groups on the tether act as a stereochemical

handle to orient the pyranone ring at the bottom so that the

terminal alkene can approach from the top face. As the

a

Product 16h shows excellent diastereoselectivity (>19:1 by ¹H NMR

analysis). Yields refer to isolated product after chromatography.

CH₃CN was used as solvent. NMP, N-Methylpyrrolidine; TMP,

2,2,6,6-tetramethylpiperidine.

b

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chromatography was performed using silica gel, 230−400 mesh, 60

Å pore diameter. Isolated yields and yields based on the recovered

starting material (brsm) were determined following puriﬁcation.

Proton Nuclear Magnetic Resonance NMR (¹H NMR) spectra and

carbon nuclear magnetic resonance (¹³C NMR) spectra were

recorded on Bruker AV-III-400HD and Bruker AVIII-800 spectrom-

eters. Chemical shifts for protons are reported in parts per million and

are references to the NMR solvent peak (CDCl₃: δ 7.26). Chemical

shifts for carbons are reported in parts per million and are referenced

to the carbon resonances of the NMR solvent (CDCl₃: δ77.16). Data

are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet,

quint = quintet, sep = septet, m = multiplet, dd = doublet of doublets,

ddd = doublet of doublet of doublets, dddd = doublet of doublet of

doublets of doublets, td = triplet of doublets, dq = doublet of quartets,

qd = quartet of doublets, dt = doublet of triplets, brs = broad singlet.

All coupling constants are measured in hertz (Hz). Optical rotations

were measured on a Rudolph’sAUTOPOL-III automatic digital

polarimeter with a sodium lamp and are reported as follows: [α]λ

T °C (c = g/100 mL, solvent). High-resolution mass spectrometry

(HRMS) spectra were recorded under positive electron spray

ionization (ESI+) and positive atmospheric pressure chemical

ionization (APCI+) conditions using an LTQ Orbitrap Mass

Spectrometer at the Purdue University Department of Chemistry

Mass Spectrometry Center and an Agilent 6550 Q-TOF LC/MS

instrument at the Purdue University Analytical Mass Spectrometry

Facility.

General Procedure A: Synthesis of Weinreb Amides 11a−d.

To a solution of the indicated α-hydroxy ester (1.0 equiv) and N-

methyl-O-methyl hydroxylamine hydrochloride (1.5 equiv) in THF

(0.3 M) at −20 °C was added isopropylmagnesium chloride (2.0 M

solution in THF, 4.0 equiv). The reaction mixture was warmed to 0

°C and stirred for 2−5 h at the same temperature. A solution of satd

NH₄Cl was added, and the layers were separated. The aqueous phase

was extracted with CH₂Cl₂(3×), and the combined organic extracts

were dried over Na₂SO₄and concentrated in vacuo. Puriﬁcation by

silica gel column chromatography aﬀorded the desired Weinreb

amide.

(S)-2-Hydroxy-N-methoxy-N-methyl-2-phenylacetamide (11a).

The reaction was conducted according to the general procedure A

with methyl (S)-(+)-mandelate (4.86 g, 29.30 mmol), N-methyl-O-

methyl hydroxylamine hydrochloride (4.30 g, 44.0 mmol), and

isopropylmagnesium chloride (59.0 mL, 2.0 M solution in THF,

117.20 mmol) in THF (100 mL) for 2 h. Puriﬁcation by silica gel

column chromatography (10% EtOAc/hexanes) aﬀorded the Weinreb

amide 11a (4.96 g, 87% yield) as a colorless oil. Experimental data are

consistent with the data reported in the literature.⁵¹

(R)-2-Hydroxy-N-methoxy-N-methyl-2-phenylacetamide (11b).

The reaction was conducted according to the general procedure A

with methyl (R)-(−)-mandelate (5.30 g, 31.90 mmol), N-methyl-O-

methyl hydroxylamine hydrochloride (4.60 g, 47.85 mmol), and

isopropylmagnesium chloride (63.80 mL, 2.0 M solution in THF,

127.60 mmol) in THF (100 mL) for 2 h. Puriﬁcation by silica gel

column chromatography (10% EtOAc/hexanes) aﬀorded the Weinreb

amide 11b (5.60 g, 90% yield) as a colorless oil. Experimental data are

consistent with the data reported in the literature.⁵²

bulkiness of the alkyl substituent (R-group) on the side chain

decreases, the preference of 15a over the alternative

diastereomeric transition state would also decrease and that

would lead to lower diastereoselectivity for the cycloadducts.

For [5 + 2] cycloaddition with a homoallyl side chain, the

stereochemical outcome can be rationalized using a six-

membered chair transition-state 15e similar to that suggested

by Wender and co-workers.¹⁶The phenyl group will be in the

equatorial position and will block the bottom face, so that the

approach of the alkene will occur from the top face as shown in

transition state 15e. The formation of a six-membered

transition state 15e is dominant in controlling the stereo-

chemistry and therefore gives rise to formation of cycloadducts

with high diastereoselectivity. The observed high diastereose-

lectivity for cycloadduct 16h with a seven-membered ring may

be due to the formation of a similar dominant pseudo chairlike

transition state as 15e for the six-membered ring as shown.

CONCLUSION

■

In summary, we investigated [5 + 2] intramolecular

oxidopyrylium-alkene cycloaddition reactions containing an

α-chiral center on the alkene tether. The presence of the α-

chiral center directed the formation of three new chiral centers

in the 8-oxabicyclo[3.2.1]octane core containing ﬁve- to seven-

membered fused oxacyclic rings with high diastereoselectivity.

These cycloadditions proceeded with good to excellent yields.

The degree of diastereoselectivity for the allyloxy tether is

dependent upon the size of the alkyl group for the formation of

the 6−5−5 tricyclic ring systems. The phenyl substituent

showed very good diastereoselectivity; however, both methyl

and isopropyl groups showed lower diastereoselectivity. For

cycloaddition substrates containing a homoallyloxy tether, the

reaction proceeded with very good yields and excellent

diastereoselectivity for methyl, isopropyl, and phenyl sub-

stituents. The stereochemical outcome of the cycloaddition

reaction was rationalized using stereochemical models. The

1

product stereochemistry was assigned by extensive H NMR

and X-ray crystallographic studies. For allyloxy derivatives, the

cycloaddition reaction presumably proceeded through an

envelope conformation with substituents oriented in a

pseudoequatorial position. For the cycloaddition with homo-

allyloxy tethers, the reaction presumably proceeded with a

chairlike transition state with the substituent on the α-chiral

center oriented equatorially, avoiding competing nonbonded

interactions. Various cycloaddition substrates were synthesized

eﬃciently from optically active starting materials. Further

utilization of this asymmetric cycloaddition reaction in the

synthesis of bioactive compounds in medicinal chemistry is

being explored.

(S)-2-Hydroxy-N-methoxy-3-methyl-N-methylbutanamide (11c).

The reaction was conducted according to the general procedure A

with (S)-methyl 2-hydroxy-3-methylbutanoate⁵³(1.80 g, 13.64

mmol), N-methyl-O-methyl hydroxylamine hydrochloride (2.0 g,

20.46 mmol), and isopropylmagnesium chloride (27.30 mL, 2.0 M

solution in THF, 54.56 mmol) in THF (50 mL) for 4 h. Puriﬁcation

by silica gel column chromatography (20% EtOAc/hexanes) aﬀorded

the Weinreb amide 11c (1.47 g, 67% yield) as a yellow oil.

Experimental data are consistent with the data reported in the

literature.³⁹

(S)-2-Hydroxy-N-methoxy-N-methylpropanamide (11d). The

reaction was conducted according to the general procedure A with

(S)-(−)-ethyl lactate (1.0 g, 8.50 mmol), N-methyl-O-methyl

hydroxylamine hydrochloride (1.24 g, 12.75 mmol), and isopropyl-

magnesium chloride (17.0 mL, 2.0 M solution in THF, 34 mmol) in

EXPERIMENTAL SECTION

■

All chemicals were purchased from commercial suppliers and were

used as received unless otherwise stated. Anhydrous solvents were

obtained as follows: anhydrous tetrahydrofuran and diethyl ether were

distilled from sodium metal under argon, anhydrous dichloromethane

was dried via distillation from calcium hydride, DMF was dried

overnight over barium oxide followed by vacuum distillation, and

anhydrous methanol was distilled from activated magnesium under

argon. All other solvents were reagent grade. All moisture-sensitive

reactions were carried out under an argon atmosphere in either ﬂame

or oven-dried (120 °C) glassware. Stainless steel syringes and cannula

were used to transfer air- or moisture-sensitive liquids. TLC analysis

was conducted using glass-backed thin-layer silica gel chromatography

plates (60 Å, 250 μm thickness, F254 indicator). Column

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THF (28 mL) for 5 h. Puriﬁcation by silica gel column

chromatography (30% EtOAc/hexanes) aﬀorded the Weinreb

amide 11d (1.0 g, 89% yield) as a colorless oil. Experimental data

are consistent with the data reported in the literature.⁵⁴

134.5, 117.4, 70.4, 61.3, 32.5, 17.8. HRMS (ESI/Q-TOF) m/z: [M +

H]⁺calcd for C₈H₁₆O₃N 174.1125; found 174.1126.

General Procedure C: O-Alkylation of α-Hydroxy Esters

20a−c. A ﬂame-dried round-bottom ﬂask was charged with 18-

crown-6 (0.1 equiv) and potassium tert-butoxide (1.0 M solution in

THF, 1.1 equiv) in freshly distilled THF (0.3 M) at −20 °C. To this

mixture, a solution of the α-hydroxy ester (1.0 equiv) in freshly

distilled THF (1.0 M) was added dropwise. The reaction mixture was

stirred for 10 min followed by addition of but-3-en-1-yl triﬂuoro-

methanesulfonate or pent-4-en-1-yl triﬂuoromethanesulfonate (1.3−

1.5 equiv) in one portion at −20 °C. After 20 min, the reaction was

quenched with a satd solution of NH₄Cl and extracted with EtOAc

(3×). The combined organic layers were dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. Puriﬁcation of crude by

silica gel column chromatography aﬀorded the O-alkylated product.

Methyl (S)-2-(But-3-en-1-yloxy)-3-methylbutanoate (20a). The

reaction was conducted according to the general procedure C with

(S)-methyl 2-hydroxy-3-methylbutanoate⁵³19a (2.0 g, 15.15 mmol),

18-crown-6 (400 mg, 1.52 mmol), potassium tert-butoxide (1.0 M

solution in THF, 23.0 mL, 22.70 mmol, 1.5 equiv), and but-3-en-1-yl

triﬂuoromethanesulfonate⁵⁵(4.60 g, 22.70 mmol). Puriﬁcation by

silica gel column chromatography (5% EtOAc/hexanes) aﬀorded

compound 20a in 47% isolated yield (1.32 g, 61% brsm) as a colorless

oil. [α]_D²⁴−45.3 (c 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 5.81

(ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.12−4.99 (m, 2H), 3.73 (s, 3H),

3.63 (dt, J = 9.2, 6.6 Hz, 1H), 3.57 (d, J = 5.8 Hz, 1H), 3.32 (dt, J =

9.1, 6.9 Hz, 1H), 2.34 (dtd, J = 8.7, 6.8, 5.3 Hz, 2H), 2.10−1.96 (m,

1H), 0.94 (d, J = 2.0 Hz, 3H), 0.93 (d, J = 2.0 Hz, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 173.0, 134.8, 116.3, 84.4, 70.2, 51.5, 33.9,

31.5, 18.6, 17.7. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺calcd for

C₁₀H₁₈O₃Na 209.1148; found 209.1152.

General Procedure B: O-Allylation of α-Hydroxy Amides

12a−d. To a suspension of sodium hydride (60% dispersion in oil,

1.5 equiv) in dry DMF (0.6 M) at −20 °C was added a 0.3 M solution

of the Weinreb amide (1.0 equiv) in dry DMF dropwise via cannula.

The reaction mixture was stirred for an additional 30 min, followed by

addition of allyl bromide (1.5 equiv) in one portion. The resulting

yellow suspension was then warmed to −10 °C and stirred for 12−14

h. The reaction was quenched by the addition of satd NH₄Cl and

allowed to warm to 23 °C. The thick white suspension was then

diluted with EtOAc and washed with cold H₂O (5×). The combined

aqueous layers were back extracted with EtOAc (2×). The combined

organic layers were washed with brine, dried over Na₂SO₄, and

concentrated under reduced pressure. Puriﬁcation by silica gel column

chromatography aﬀorded the O-allylated product.

(S)-2-(Allyloxy)-N-methoxy-N-methyl-2-phenylacetamide (12a).

The reaction was conducted according to the general procedure B

with NaH (60% dispersion in oil, 308 mg, 7.60 mmol), Weinreb

amide 11a (1.0 g, 5.10 mmol), and allyl bromide (660 μL, 7.70

mmol). Puriﬁcation by silica gel column chromatography (20%

EtOAc/hexanes) aﬀorded compound 12a (1.04 g, 87% yield) as a

24

1

white amorphous solid. [α]_D+82.3 (c 1.5, CHCl₃). H NMR (400

MHz, CDCl₃) δ 7.44−7.37 (m, 2H), 7.33−7.23 (m, 3H), 5.91 (ddt, J

= 17.3, 10.4, 5.8 Hz, 1H), 5.29−5.14 (m, 3H), 4.08−3.95 (m, 2H),

3.39 (s, 3H), 3.10 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

171.0, 136.6, 134.2, 128.4, 128.4, 128.0, 117.7, 77.6, 70.1, 60.9, 32.3.

HRMS (ESI/Q-TOF) m/z: [M + H]⁺calcd for C₁₃H₁₈O₃N

236.1281; found 236.1283.

Ethyl (S)-2-(But-3-en-1-yloxy)propanoate (20b). The reaction was

conducted according to the general procedure C with (S)-(−)-ethyl

lactate 19b (2.0 g, 16.94 mmol), 18-crown-6 (450 mg, 1.69 mmol),

potassium tert-butoxide (1.0 M solution in THF, 18.60 mL, 18.60

mmol), and but-3-en-1-yl triﬂuoromethanesulfonate⁵⁵(4.49 g, 22.02

mmol). Puriﬁcation by silica gel column chromatography (10%

EtOAc/hexanes) aﬀorded compound 20b in 54% isolated yield (1.55

g, 75% brsm) as a colorless oil. [α]_D²⁴−37.9 (c 0.9, CHCl₃). ¹H NMR

(400 MHz, CDCl₃δ 5.82 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.18−4.97

(m, 2H), 4.25−4.14 (m, 2H), 3.95 (q, J = 6.8 Hz, 1H), 3.63 (dt, J =

9.0, 6.8 Hz, 1H), 3.41 (dt, J = 8.9, 6.9 Hz, 1H), 2.44−2.27 (m, 2H),

1.39 (d, J = 6.9 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 173.3, 134.7, 116.4, 74.9, 69.4, 60.7, 34.0, 18.5,

14.1. HRMS (ESI/Q-TOF) m/z: [M + H]⁺calcd for C₉H₁₇O₃

173.1172; found 173.1171.

(R)-2-(Allyloxy)-N-methoxy-N-methyl-2-phenylacetamide (12b).

The reaction was conducted according to the general procedure B

with NaH (60% dispersion in oil, 1.60 g, 40.77 mmol), Weinreb

amide 11b (5.30 g, 28.18 mmol), and allyl bromide (3.50 mL, 40.77

mmol). Puriﬁcation by silica gel column chromatography (20%

EtOAc/hexanes) aﬀorded compound 12b (5.60 g, 87% yield) as a

white amorphous solid. [α]_D−83.5 (c 1.3, CHCl₃). H NMR (400

MHz, CDCl₃) δ 7.42−7.36 (m, 2H), 7.31−7.21 (m, 3H), 5.89 (ddt, J

= 17.2, 10.3, 5.8 Hz, 1H), 5.28−5.11 (m, 3H), 4.07−3.92 (m, 2H),

3.37 (s, 3H), 3.08 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

171.0, 136.6, 134.2, 128.4, 128.3, 128.0, 117.7, 77.5, 70.1, 60.9, 32.2.

HRMS (ESI/Q-TOF) m/z: [M + H]⁺calcd for C₁₃H₁₈O₃N

236.1282; found 236.1281.

24

1

(S)-2-(Allyloxy)-N-methoxy-N,3-dimethylbutanamide (12c). The

reaction was conducted according to the general procedure B with

NaH (60% dispersion in oil, 893 mg, 22.32 mmol), Weinreb amide

11c (2.40 g, 14.88 mmol), and allyl bromide (2.0 mL, 22.32 mmol).

Puriﬁcation by silica gel column chromatography (20% EtOAc/

hexanes) aﬀorded compound 12c (2.62 g, 88% yield) as a colorless

Ethyl (S)-2-(Pent-4-en-1-yloxy)propanoate (20c). The reaction

was conducted according to the general procedure C with (S)-

(−)-ethyl lactate 19b (2.50 g, 21.19 mmol), 18-crown-6 (560 mg,

2.12 mmol), potassium tert-butoxide (1.0 M solution in THF, 23.30

mL, 23.50 mmol), and pent-4-en-1-yl triﬂuoromethanesulfonate⁵⁶

(6.90 g, 31.77 mmol). Puriﬁcation by silica gel column chromatog-

raphy (5% EtOAc/hexanes) aﬀorded compound 20c in 84% isolated

24

1

oil. [α]_D−30.5 (c 1.0, CHCl₃). H NMR (400 MHz, CDCl₃) δ

5.94−5.75 (m, 1H), 5.20 (dq, J = 17.3, 1.7 Hz, 1H), 5.10 (dq, J =

10.4, 1.5 Hz, 1H), 4.04 (ddt, J = 12.8, 5.2, 1.6 Hz, 1H), 4.00−3.87 (m,

1H), 3.79 (ddt, J = 12.8, 6.1, 1.4 Hz, 1H), 3.62 (s, 3H), 3.15 (s, 3H),

2.08−1.89 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.9 Hz,

3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.2, 134.6, 116.9, 80.4,

70.8, 61.1, 32.1, 30.8, 18.8, 18.0. HRMS (ESI/Q-TOF) m/z: [M +

H]⁺calcd for C₁₀H₂₀O₃N 202.1438; found 202.1438.

24

yield (3.32 g, 92% brsm) as a colorless oil. [α]_D−28.7 (c 1.2,

1

CHCl₃). H NMR (400 MHz, CDCl₃) δ 5.91−5.72 (m, 1H), 5.09−

4.89 (m, 2H), 4.29−4.10 (m, 2H), 4.01−3.86 (m, 1H), 3.63−3.48

(m, 1H), 3.44−3.31 (m, 1H), 2.26−2.06 (m, 2H), 1.80−1.62 (m,

2H), 1.39 (dd, J = 6.8, 1.2 Hz, 3H), 1.28 (td, J = 7.1, 1.1 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.4, 138.1, 114.7, 74.9, 69.5,

60.7, 30.1, 28.8, 18.6, 14.1. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺

calcd for C₁₀H₁₈O₃Na 209.1147; found 209.1149.

(S)-2-(Allyloxy)-N-methoxy-N-methylpropanamide (12d). The

reaction was conducted according to the general procedure B with

NaH (60% dispersion in oil, 680 mg, 16.90 mmol), Weinreb amide

11d (1.50 g, 11.27 mmol), and allyl bromide (1.50 mL, 16.90 mmol).

Puriﬁcation by silica gel column chromatography (20% EtOAc/

hexanes) aﬀorded compound 12d (1.33g, 69% yield) as a colorless oil.

General Procedure D: Synthesis of Weinreb Amides 12f−h.

To a solution of N-methyl-O-methyl hydroxylamine hydrochloride

(4.0 equiv mmol) in CH₂Cl₂(0.1 M) was added trimethylaluminum

(2.0 M solution in n-hexane, 4.0 equiv) at −10 °C. The resulting clear

solution was stirred for 1 h at 23 °C and then cooled to −10 °C. To

the reaction mixture was cannulated a solution of O-alkylated ester

(1.0 equiv) in CH₂Cl₂(1.0 M), and the reaction mixture was slowly

warmed to 23 °C over 1 h. After 24 h, the reaction was quenched by

adding a satd potassium sodium tartrate solution at 0 °C, and the

24

1

[α]_D−69.8 (c 0.8, CHCl₃). H NMR (400 MHz, CDCl₃) δ 6.02−

5.83 (m, 1H), 5.26 (ddq, J = 17.2, 4.8, 1.6 Hz, 1H), 5.17 (ddq, J =

10.3, 4.2, 1.5 Hz, 1H), 4.38 (q, J = 6.4 Hz, 1H), 4.17−4.03 (m, 1H),

3.95−3.83 (m, 1H), 3.68 (d, J = 5.3 Hz, 3H), 3.19 (d, J = 5.2 Hz,

3H), 1.45−1.30 (m, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.7,

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resulting mixture was warmed to 23 °C. After 1 h, the mixture was

ﬁltered through a pad of Celite and washed with CH₂Cl₂. The ﬁltrate

was extracted with CH₂Cl₂(2×). The combined organic layers were

dried over Na₂SO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation by

silica gel column chromatography aﬀorded the desired Weinreb

amide.

(S)-2-(But-3-en-1-yloxy)-N-methoxy-N,3-dimethylbutanamide

(12f). The reaction was conducted according to the general procedure

D with methyl (S)-2-(but-3-en-1-yloxy)-3-methylbutanoate 20a (500

mg, 2.69 mmol), N-methyl-O-methyl hydroxylamine hydrochloride

(1.05 g, 10.76 mmol), and trimethylaluminum (2.0 M solution in n-

hexane, 5.40 mL, 10.76 mmol) for 24 h. Puriﬁcation by silica gel

column chromatography (15% EtOAc/hexanes) aﬀorded the Weinreb

amide 12f (435 mg, 75% yield) as a colorless oil. [α]_D²⁴−25.3 (c 0.7,

CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 5.80 (ddt, J = 17.0, 10.2, 6.7

Hz, 1H), 5.10−4.96 (m, 2H), 3.89 (brs, 1H), 3.68 (s, 3H), 3.61−3.53

(m, 1H), 3.34−3.26 (m, 1H), 3.20 (s, 3H), 2.42−2.25 (m, 2H),

2.11−1.97 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.9 Hz,

3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.4, 135.0, 116.2, 81.7,

69.4, 61.2, 34.0, 32.2, 30.9, 18.7, 18.2. HRMS (ESI/Q-TOF) m/z: [M

+ H]⁺calcd for C₁₁H₂₂O₃N 216.1594; found 216.1594.

(2S)-2-(Allyloxy)-1-(furan-2-yl)-2-phenylethan-1-ol (13a). The

reaction was conducted according to the general procedure E with

furan (2.0 mL, 27.24 mmol), n-BuLi (1.6 M solution in hexane, 15.30

mL, 24.51 mmol), and (S)-2-(allyloxy)-N-methoxy-N-methyl-2-

phenylacetamide 12a (3.20 g, 13.62 mmol). Puriﬁcation by silica

gel column chromatography (20% EtOAc/hexanes) aﬀorded the furyl

ketone (2.90 g, 88% yield) as an amorphous white solid. [α]_D²⁴+25.3

1

(c 0.3, CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.57 (d, J = 1.7 Hz,

1H), 7.50 (d, J = 7.3 Hz, 2H), 7.39 (d, J = 3.6 Hz, 1H), 7.32 (dt, J =

13.8, 7.0 Hz, 3H), 6.54−6.44 (m, 1H), 5.95 (ddt, J = 16.1, 10.6, 5.7

Hz, 1H), 5.47 (s, 1H), 5.34−5.16 (m, 2H), 4.14−4.03 (m, 2H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 186.1, 150.4, 146.8, 136.0,

133.8, 128.6, 128.4, 127.4, 119.7, 118.0, 112.2, 83.6, 70.5. HRMS

(ESI/Q-TOF) m/z: [M + H]⁺calcd for C₁₅H₁₅O₃243.1016; found

243.1018.

The above furyl ketone (2.80 g, 11.86 mmol) was reduced with

NaBH₄(1.35 g, 35.58 mmol) in dry MeOH (60 mL) following the

general procedure E. Puriﬁcation by silica gel column chromatography

(10% EtOAc/hexanes) aﬀorded the furfuryl alcohol 13a (2.82 g, 95%

1

yield) as a colorless oil in a 7:1 diastereomeric ratio. H NMR (400

MHz, CDCl₃) δ 7.37 (dd, J = 1.8, 0.9 Hz, 1H), 7.34−7.29 (m, 3H),

7.27−7.23 (m, 2H), 6.30 (dd, J = 3.3, 1.8 Hz, 1H), 6.22−6.16 (m,

1H), 5.88−5.77 (m, 1H), 5.22−5.12 (m, 2H), 4.87 (d, J = 5.9 Hz,

1H), 4.71−4.67 (m, 1H), 4.00 (ddt, J = 13.0, 5.0, 1.6 Hz, 1H), 3.80

(ddt, J = 12.9, 6.1, 1.4 Hz, 1H), 2.32 (brs, 1H). ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 153.3, 141.6, 137.6, 134.3, 128.2, 128.1, 127.6, 117.0,

110.2, 107.8, 82.7, 71.2, 69.9. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺

calcd for C₁₅H₁₆O₃Na 267.0992; found 267.0992.

(S)-2-(But-3-en-1-yloxy)-N-methoxy-N-methylpropanamide

(12g). The reaction was conducted according to the general

procedure D with a slight modiﬁcation using ethyl (S)-2-(but-3-en-

1-yloxy)propanoate 20b (820 mg, 4.76 mmol), N-methyl-O-methyl

hydroxylamine hydrochloride (980 mg, 10.01 mmol), and trimethy-

laluminum (2.0 M solution in n-hexane, 5.0 mL, 10.01 mmol) for 24

h. Puriﬁcation by silica gel column chromatography (20% EtOAc/

hexanes) aﬀorded Weinreb amide 12g (575 mg, 65% yield) as a

(2R)-2-(Allyloxy)-1-(furan-2-yl)-2-phenylethan-1-ol (13b). The

reaction was conducted according to the general procedure E with

furan (810 μL, 11.06 mmol), n-BuLi (1.6 M solution in hexane, 6.20

mL, 9.95 mmol), and (R)-2-(allyloxy)-N-methoxy-N-methyl-2-

phenylacetamide 12b (1.30 g, 5.53 mmol). Puriﬁcation by silica gel

column chromatography (20% EtOAc/hexanes) aﬀorded the furyl

ketone (1.16 g, 89% yield) as an amorphous white solid. [α]_D²⁴−27.0

24

colorless oil. [α]_D−27.9 (c 0.4, CHCl₃). ¹H NMR (400 MHz,

CDCl₃) δ 5.89−5.72 (m, 1H), 5.16−4.94 (m, 2H), 4.33 (q, J = 6.8

Hz, 1H), 3.69 (s, 3H), 3.60−3.50 (m, 1H), 3.42−3.30 (m, 1H), 3.20

(s, 3H), 2.43−2.29 (m, 2H), 1.35 (dd, J = 6.7, 1.6 Hz, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 173.7, 134.8, 116.3, 72.5, 68.8, 61.3, 34.1,

32.2, 17.7. HRMS (ESI/Q-TOF) m/z: [M + H]⁺calcd for C₉H₁₈O₃N

188.1281; found 188.1280.

1

(c 1.8, CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.59−7.51 (m, 1H),

(S)-N-Methoxy-N-methyl-2-(pent-4-en-1-yloxy)propanamide

(12h). The reaction was conducted according to the general

procedure D with ethyl (S)-2-(pent-4-en-1-yloxy)propanoate 20c

(3.25 g, 17.47 mmol), N-methyl-O-methyl hydroxylamine hydro-

chloride (6.80 g, 69.89 mmol), and trimethylaluminum (2.0 M

solution in n-hexane, 35.0 mL, 69.89 mmol) for 24 h. Puriﬁcation by

silica gel column chromatography (15% EtOAc/hexanes) aﬀorded the

7.53−7.44 (m, 2H), 7.41−7.34 (m, 1H), 7.36−7.23 (m, 3H), 6.52−

6.41 (m, 1H), 6.03−5.86 (m, 1H), 5.47 (s, 1H), 5.36−5.23 (m, 1H),

5.25−5.16 (m, 1H), 4.17−4.04 (m, 2H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 186.0, 150.4, 146.8, 136.0, 133.8, 128.6, 128.4, 127.4, 119.

7, 118.0, 112.2, 83.6, 70.5. HRMS (ESI/Q-TOF) m/z: [M + H]⁺

calcd for C₁₅H₁₅O₃243.1016; found 243.1016.

24

The above furyl ketone (630 mg, 2.60 mmol) was reduced with

NaBH₄(300 mg, 7.80 mmol) in dry MeOH (13 mL) following the

general procedure E. Puriﬁcation by silica gel column chromatography

(10% EtOAc/hexanes) aﬀorded the furfuryl alcohol 13b (610 mg,

Weinreb amide 12h (2.80 g, 80% yield) as a colorless oil. [α]_D

−15.6 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 5.84−5.68 (m,

1H), 5.02−4.85 (m, 2H), 4.27 (q, J = 7.1, 6.7 Hz, 1H), 3.66 (t, J = 2.1

Hz, 3H), 3.52−3.40 (m, 1H), 3.35−3.23 (m, 1H), 3.16 (s, 3H),

2.13−2.01 (m, 2H), 1.73−1.59 (m, 2H), 1.35−1.27 (m, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.8, 138.1, 114.5, 72.4, 68.8,

61.3, 32.2, 30.1, 28.8, 17.7. HRMS (ESI/Q-TOF) m/z: [M + H]⁺

calcd for C₁₀H₂₀O₃N 202.1437; found 202.1437.

1

95% yield) as a colorless oil in a 9:1 diastereomeric ratio. H NMR

(400 MHz, CDCl₃) δ 7.37 (dd, J = 1.8, 0.9 Hz, 1H), 7.36−7.29 (m,

3H), 7.27−7.23 (m, 2H), 6.30 (dd, J = 3.2, 1.8 Hz, 1H), 6.23−6.15

(m, 1H), 5.83 (dddd, J = 17.2, 10.4, 6.1, 5.0 Hz, 1H), 5.26−5.10 (m,

2H), 4.88 (t, J = 5.9 Hz, 1H), 4.69 (d, J = 5.9 Hz, 1H), 4.00 (ddt, J =

13.0, 5.0, 1.6 Hz, 1H), 3.80 (ddt, J = 12.9, 6.1, 1.4 Hz, 1H), 2.40−2.28

(m, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.2, 141.7, 137.6,

134.2, 128.2, 128.1, 127.6, 117.0, 110.2, 107.8, 82.7, 71.2, 69.9.

HRMS (ESI/Q-TOF) m/z: [M + Na]⁺calcd for C₁₅H₁₆O₃Na

267.0992; found 267.0993.

(2S)-2-(Allyloxy)-1-(furan-2-yl)-3-methylbutan-1-ol (13c). The

reaction was conducted according to the general procedure E with

furan (1.80 mL, 24.88 mmol), n-BuLi (1.6 M solution in hexane, 14.0

mL, 22.39 mmol), and (S)-2-(allyloxy)-N-methoxy-N,3-dimethylbu-

tanamide 12c (2.39 g, 11.89 mmol). Puriﬁcation by silica gel column

chromatography (20% EtOAc/hexanes) aﬀorded the furyl ketone

(2.16 g, 87% yield) as a colorless oil. [α]_D²⁴−19.4 (c 0.4, CHCl₃). ¹H

NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 3.6

Hz, 1H), 6.57−6.49 (m, 1H), 5.95−5.80 (m, 1H), 5.25 (dq, J = 17.2,

1.6 Hz, 1H), 5.17 (dq, J = 10.3, 1.3 Hz, 1H), 4.09 (ddt, J = 12.7, 5.3,

1.5 Hz, 1H), 4.00 (d, J = 6.6 Hz, 1H), 3.88 (ddt, J = 12.7, 6.0, 1.3 Hz,

1H), 2.22−2.06 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8

Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.3, 151.3, 146.7,

General Procedure E: Synthesis of Furfuryl Alcohols 13a−h.

A ﬂame-dried round-bottom ﬂask was charged with furan (2.0 equiv)

and dry THF (0.2 M) under argon. The reaction ﬂask was then

cooled to 0 °C, and a solution of n-BuLi (1.6 M solution in hexane,

1.8 equiv) was added dropwise. The resulting mixture was stirred at

this temperature for 30 min and then cooled to −78 °C, followed by a

dropwise addition of the O-alkylated Weinreb amide (1.0 equiv)

solution in THF. After 1 h, the reaction was quenched with satd

NH₄Cl and extracted with EtOAc (2×). The organic phase was

washed with brine, dried over Na₂SO₄, and concentrated under

reduced pressure. The crude product was puriﬁed by silica gel column

chromatography.

The above furyl ketone (1.0 equiv) was dissolved in dry MeOH at

−78 °C followed by portionwise addition of NaBH₄(3.0 equiv). After

1 h, the reaction was quenched by water, the residue was diluted with

CH₂Cl₂, and the aqueous layer was extracted with CH₂Cl₂(3×). The

combined organic layers were dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. The crude product was puriﬁed

by silica gel column chromatography.

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134.1, 119.4, 117.4, 112.0, 87.9, 71.5, 32.1, 18.9, 18.2.HRMS (ESI/Q-

TOF) m/z: [M + H]⁺calcd for C₁₂H₁₇O₃209.1172; found 209.1173.

The above furyl ketone(2.10 g, 10.09 mmol) was reduced with

NaBH₄(1.15 g, 30.29 mmol) in dry MeOH (50 mL) following the

general procedure E. Puriﬁcation by silica gel column chromatography

(10% EtOAc/hexanes) aﬀorded the furfuryl alcohol 13c (2.0 g, 95%

mmol) and bis(acetoxy)iodobenzene (885 mg, 2.75 mmol) at 0 °C.

The reaction mixture was warmed to 23 °C over 1 h and continued to

stir at 23 °C. After 8 h, the reaction mixture was quenched with satd

Na₂S₂O₃and extracted with CH₂Cl₂(3×). The combined organic

layers were dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. Puriﬁcation by silica gel column chromatography

(5% EtOAc/CH₂Cl₂) aﬀorded the aldehyde (440 mg, 74% yield) as a

yellow oil.

1

yield) as a colorless oil in a 3:1 diastereomeric ratio. H NMR (400

MHz, CDCl₃) δ 7.37 (d, J = 3.9 Hz, 1H), 6.33 (d, J = 2.9 Hz, 2H),

5.80 (ddt, J = 16.5, 10.8, 5.4 Hz, 1H), 5.25−5.14 (m, 1H), 5.16−5.05

(m, 1H), 4.70 (d, J = 6.3 Hz, 1H), 4.04−3.85 (m, 1H), 3.82 (dd, J =

12.5, 5.6 Hz, 1H), 3.46−3.35 (m, 1H), 2.39 (brs, 1H), 1.98−1.83 (m,

1H), 0.97 (dd, J = 6.9, 1.9 Hz, 3H), 0.96−0.89 (m, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 154.6, 141.6, 134.9, 116.5, 110.3, 107.6,

86.1, 73.7, 68.3, 29.6, 19.7, 17.0. HRMS (ESI/Q-TOF) m/z: [M +

Na]⁺calcd for C₁₂H₁₈O₃Na 233.1148; found 233.1149.

To a suspension of methyltriphenylphosphonium bromide (2.50 g,

6.92 mmol) in Et₂O (25 mL) was added potassium tert-butoxide (1.0

M solution in THF, 6.20 mL, 6.21 mmol) at 0 °C. The resulting

yellow suspension was then warmed to 23 °C and stirred for 30 min.

The reaction mixture was cooled to −20 °C followed by addition of

the solution of the above aldehyde (360 mg, 1.38 mmol) in 15 mL of

Et₂O. After stirring at −20 °C for 2 h, the reaction was quenched with

satd NH₄Cl and extracted with Et₂O (3×). The combined organic

layers were dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. Puriﬁcation by silica gel column chromatography

(10% EtOAc/hexanes) aﬀorded the furfuryl alcohol 13e (105 mg,

(2S)-2-(Allyloxy)-1-(furan-2-yl)propan-1-ol (13d). The reaction

was conducted according to the general procedure E with furan (1.10

mL, 15.03 mmol), n-BuLi (1.6 M solution in hexane, 8.50 mL, 13.52

mmol), and (S)-2-(allyloxy)-N-methoxy-N-methylpropanamide 12d

(1.30 g, 7.51 mmol). Puriﬁcation by silica gel column chromatography

(20% EtOAc/hexanes) aﬀorded the furyl ketone (1.20 g, 89% yield)

24

1

30% yield) as a colorless oil. [α]_D+43.3 (c 0.3, CHCl₃). H NMR

(400 MHz, CDCl₃) δ 7.38−7.28 (m, 4H), 7.27−7.19 (m, 2H), 6.30

(dd, J = 3.3, 1.9 Hz, 1H), 6.18 (d, J = 3.3 Hz, 1H), 5.74 (ddt, J = 17.0,

10.2, 6.7 Hz, 1H), 5.09−4.95 (m, 2H), 4.84 (t, J = 5.6 Hz, 1H), 4.62

(d, J = 5.8 Hz, 1H), 3.50 (dt, J = 9.4, 6.6 Hz, 1H), 3.35 (dt, J = 9.4,

6.6 Hz, 1H), 2.38 (d, J = 6.0 Hz, 1H), 2.30 (qt, J = 6.6, 1.5 Hz, 2H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.3, 141.6, 137.8, 135.0,

24

1

as a colorless oil. [α]_D−68.7 (c 0.9, CHCl₃). H NMR (400 MHz,

CDCl₃) δ 7.62 (dd, J = 1.7, 0.7 Hz, 1H), 7.44 (dd, J = 3.6, 0.7 Hz,

1H), 6.55 (dd, J = 3.6, 1.7 Hz, 1H), 5.91 (ddt, J = 17.2, 10.4, 5.7 Hz,

1H), 5.27 (dq, J = 17.2, 1.6 Hz, 1H), 5.19 (dq, J = 10.4, 1.3 Hz, 1H),

4.49 (q, J = 6.9 Hz, 1H), 4.09 (ddt, J = 12.6, 5.4, 1.4 Hz, 1H), 3.96

(ddt, J = 12.6, 5.9, 1.3 Hz, 1H), 1.48 (d, J = 6.9 Hz, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 190.0, 150.3, 146.8, 134.0, 119.3, 117.6,

112.1, 78.3, 70.8, 18.9. HRMS (ESI/Q-TOF) m/z: [M + H]⁺calcd

for C₁₀H₁₃O₃181.0858; found 181.0859.

128.1, 128.0, 127.4, 116.3, 110.1, 107.7, 83.7, 71.2, 68.7, 34.0. HRMS

(ESI/Q-TOF) m/z: [M + Na]⁺calcd for C₁₆H₁₈O₃Na 281.1148;

found 281.1147.

(2S)-2-(But-3-en-1-yloxy)-1-(furan-2-yl)-3-methylbutan-1-ol

(13f). The reaction was conducted according to the general procedure

E with furan (605 μL, 8.26 mmol), n-BuLi (1.6 M solution in hexane,

7.50 mL, 7.45 mmol), and (S)-2-(but-3-en-1-yloxy)-N-methoxy-N,3-

dimethylbutanamide 12f (890 mg, 4.13 mmol). Puriﬁcation by silica

gel column chromatography (5% EtOAc/hexanes) aﬀorded the furyl

The above furyl ketone (1.10 g, 6.10 mmol) was reduced with

NaBH₄(700 mg, 18.30 mmol) in dry MeOH (30 mL) following the

general procedure E. Puriﬁcation by silica gel column chromatography

(10% EtOAc/hexanes) aﬀorded the furfuryl alcohol 13d (900 mg,

1

82% yield) as a colorless oil in a 1:1 diastereomeric ratio. H NMR

24

ketone (800 mg, 87% yield) as a yellow oil. [α]_D−81.4 (c 0.6,

(400 MHz, CDCl₃) δ 7.40−7.37 (m, 1H), 6.35−6.32 (m, 2H), 5.93−

5.86 (m, 1H), 5.33−5.22 (m, 2H), 4.81−4.72 (m, 1H), 4.48 (dd, J =

7.5, 3.1 Hz, 1H), 3.99−3.93 (m, 1H), 3.78 (d, J = 6.4 Hz, 1H), 2.57−

2.49 (m, 1H), 1.14 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 153.7, 141.7, 134.7, 116.9, 110.1, 107.0, 76.5, 70.3, 70.1,

14.5. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺calcd for C₁₀H₁₄O₃Na

205.0835; found 205.0835.

1

CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.61 (dd, J = 1.7, 0.8 Hz,

1H), 7.43 (dt, J = 3.6, 0.7 Hz, 1H), 6.53 (dd, J = 3.6, 1.7 Hz, 1H),

5.77 (ddt, J = 16.9, 10.0, 6.7 Hz, 1H), 5.12−4.94 (m, 2H), 3.88 (d, J =

6.9 Hz, 1H), 3.64−3.52 (m, 1H), 3.43−3.32 (m, 1H), 2.40−2.24 (m,

2H), 2.17−2.03 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.8

Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.4, 151.2, 146.7,

134.8, 119.4, 116.4, 112.0, 89.2, 70.1, 34.1, 32.1, 18.8, 18.4. HRMS

(ESI/Q-TOF) m/z: [M + H]⁺calcd for C₁₃H₁₉O₃223.1329; found

223.1329.

The above furyl ketone (665 mg, 2.99 mmol) was reduced with

NaBH₄(500 mg, 11.98 mmol) in dry MeOH (15 mL) following the

general procedure E. Puriﬁcation by silica gel column chromatography

(10% EtOAc/hexanes) aﬀorded the furfuryl alcohol 13f (645 mg,

96% yield) as a yellow oil in a 3:1 diastereomeric ratio. ¹H NMR (400

MHz, CDCl₃) δ 7.37 (dd, J = 1.8, 0.9 Hz, 1H), 6.36−6.31 (m, 2H),

5.85−5.72 (m, 1H), 5.13−4.98 (m, 2H), 4.72 (d, J = 5.9 Hz, 1H),

3.66−3.53 (m, 1H), 3.42−3.29 (m, 2H), 2.33−2.20 (m, 2H), 1.91−

1.72 (m, 1H), 0.97 (dd, J = 6.9, 1.3 Hz, 3H), 0.93−0.89 (m, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.6, 141.5, 135.4, 116.5,

110.3, 107.5, 86.9, 72.3, 68.5, 34.6, 29.8, 19.6, 17.4. HRMS (ESI/Q-

TOF) m/z: [M + Na]⁺calcd for C₁₃H₂₀O₃Na 247.1304; found

247.1306.

3-((1S)-2-(Furan-2-yl)-2-hydroxy-1-phenylethoxy)propan-1-ol

(18). To a ﬂame-dried ﬂask ﬂushed with argon was added cyclohexene

(4.0 g, 48.77 mmol) in 35 mL of THF at 0 °C followed by the

addition of borane dimethyl sulﬁde complex (2.30 mL, 24.37 mmol).

The resulting white slurry was stirred at 0 °C for 3 h before the

addition of a solution of furfuryl alcohol 13a (1.72 g, 7.17 mmol) in

8.0 mL of THF. The reaction mixture was slowly warmed to 23 °C

and stirred for 2 h. Oxidation of the resulting dicyclohexylborinate

was achieved by adding 0.3 M water and sodium perborate

tetrahydrate (11.03 g, 71.70 mmol) at 0 °C. The resulting mixture

was stirred for 12 h at 23 °C and then extracted with ethyl acetate

(3×). The combined organic layers were dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. Puriﬁcation by silica gel

column chromatography (1% MeOH/CH₂Cl₂) aﬀorded the diol 18

(1.60 g, 88% yield) as a white amorphous solid in a 5.4:1

diastereomeric ratio. The diastereomers were separated via column

24

1

(2S)-2-(But-3-en-1-yloxy)-1-(furan-2-yl)propan-1-ol (13g). The

reaction was conducted according to the general procedure E with

furan (630 μL, 8.64 mmol), n-BuLi (1.6 M solution in hexane, 5.0

mL, 8.08 mmol), and (S)-2-(but-3-en-1-yloxy)-N-methoxy-N-methyl-

propanamide 12g (540 mg, 2.88 mmol). Puriﬁcation by silica gel

column chromatography (8% EtOAc/hexanes) aﬀorded the furyl

chromatography. Anti-diol: [α]_D+62.2 (c 0.9, CHCl₃). H NMR

(400 MHz, CDCl₃) δ 7.43−7.37 (m, 1H), 7.39−7.28 (m, 3H), 7.25

(dt, J = 7.5, 1.4 Hz, 2H), 6.32 (dd, J = 3.3, 1.8 Hz, 1H), 6.18 (d, J =

3.2 Hz, 1H), 4.78 (d, J = 6.2 Hz, 1H), 4.61 (d, J = 6.2 Hz, 1H), 3.69

(td, J = 5.7, 2.2 Hz, 2H), 3.64−3.54 (m, 1H), 3.52−3.41 (m, 1H),

2.16 (brs, 2H), 1.83−1.72 (m, 2H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 153.0, 142.0, 137.7, 128.4, 128.2, 127.3, 110.2, 108.1, 84.5,

71.1, 68.8, 61.8, 31.8. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺calcd

for C₁₅H₁₈O₄Na 285.1097; found 285.1097.

24

ketone (465 mg, 83% yield) as a yellow oil. [α]_D−20.8 (c 1.1,

1

CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 1.7 Hz, 1H),

7.41 (d, J = 3.6 Hz, 1H), 6.52 (dd, J = 3.6, 1.7 Hz, 1H), 5.76 (ddt, J =

17.1, 10.3, 6.7 Hz, 1H), 5.14−4.93 (m, 2H), 4.40 (q, J = 6.9 Hz, 1H),

3.54 (dt, J = 9.0, 6.8 Hz, 1H), 3.44 (dt, J = 9.0, 6.8 Hz, 1H), 2.41−

2.26 (m, 2H), 1.43 (d, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz,

(1S,2S)-2-(But-3-en-1-yloxy)-1-(furan-2-yl)-2-phenylethan-1-ol

(13e). To a solution of the above anti-diol 18 (600 mg, 2.29 mmol) in

anhydrous CH₂Cl₂(10 mL) were added TEMPO (36 mg, 0.23

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CDCl₃) δ 190.1, 150.3, 146.7, 134.7, 119.4, 116.5, 112.1, 79.3, 69.3,

34.1, 18.8. HRMS (ESI/Q-TOF) m/z: [M + H]⁺calcd for C₁₁H₁₅O₃

195.1015; found 195.1016.

chromatography (10% EtOAc/hexanes) aﬀorded an inseparable

mixture of diastereomers of acetoxypyranone 14a (340 mg, 92%

yield over 2 steps) as a cream color amorphous solid. H NMR (400

1

The above furyl ketone (400 mg, 2.0 mmol) was reduced with

NaBH₄(230 mg, 6.0 mmol) in dry MeOH (10 mL) following the

general procedure E. Puriﬁcation by silica gel column chromatography

(10% EtOAc/hexanes) aﬀorded the furfuryl alcohol 13g (375 mg,

96% yield) as a yellow oil in a 1:1 diastereomeric ratio. ¹H NMR (400

MHz, CDCl₃) δ 7.41−7.33 (m, 1H), 6.38−6.26 (m, 2H), 5.89−5.73

(m, 1H), 5.17−5.01 (m, 2H), 4.44 (d, J = 7.8 Hz, 1H), 3.80−3.59 (m,

2H, superimposed by peak corresponding to the minor isomer), 3.44

(dq, J = 9.2, 6.7 Hz, 1H), 3.17 (brs, 1H), 2.40−2.28 (m, 2H), 1.05 (d,

J = 6.2 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.8, 142.1,

135.1, 116.8, 110.1, 108.0, 77.7, 71.7, 68.5, 34.3, 15.6. HRMS (ESI/

Q-TOF) m/z: [M + Na]⁺calcd for C₁₁H₁₆O₃Na 219.0992; found

219.0993.

(2S)-1-(Furan-2-yl)-2-(pent-4-en-1-yloxy)propan-1-ol (13h). The

reaction was conducted according to the general procedure E with

furan (1.73 mL, 23.88 mmol), n-BuLi (1.6 M solution in hexane,

13.50 mL, 21.49 mmol), and (S)-N-methoxy-N-methyl-2-(pent-4-en-

1-yloxy)propanamide 12h (2.40 g, 11.94 mmol). Puriﬁcation by silica

gel column chromatography (5% EtOAc/hexanes) aﬀorded the furyl

ketone (2.0 g, 81% yield) as a yellow oil. [α]_D²⁴−14.9 (c 0.6, CHCl₃).

¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, J = 1.7, 0.7 Hz, 1H), 7.37

MHz, CDCl₃) δ 7.35−7.25 (m, 5H, superimposed by peak

corresponding to the minor isomer), 6.79 (dd, J = 10.3, 3.6 Hz,

1H), 6.47 (d, J = 3.7 Hz, 1H), 6.07−6.01 (m, 1H), 5.90 (dddd, J =

17.0, 10.4, 6.4, 5.1 Hz, 1H), 5.26−5.09 (m, 2H), 5.08 (d, J = 2.8 Hz,

1H), 4.95 (d, J = 2.8 Hz, 1H), 4.07−3.91 (m, 1H), 3.87−3.70 (m,

1H), 2.10 (d, J = 2.4 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃)) δ

192.6, 169.2, 141.9, 136.0, 134.2, 128.6, 128.2, 128.0, 127.8, 117.4,

87.2, 79.4, 79.3, 69.9, 20.9. HRMS (ESI/LTQ) m/z: [M + Na]⁺calcd

for C₁₇H₁₈O₅Na 325.1046; found 325.1050.

6-((R)-(Allyloxy)(phenyl)methyl)-5-oxo-5,6-dihydro-2H-pyran-2-

yl Acetate (14b). The reaction was conducted according to the

general procedure F with furfuryl alcohol 13b (600 mg, 2.45 mmol),

KBr (30 mg, 0.25 mmol), NaHCO₃(103 mg, 1.23 mmol), and oxone

(2.95 g, 1.8 mmol) to aﬀord the desired hydroxypyranone. The

acetylation reaction was conducted according to the general

procedure using crude hydroxypyranone (637 mg, 2.45 mmol),

pyridine (431 μL, 4.90 mmol), and acetyl chloride (265 μL, 3.67

mmol) in CH₂Cl₂(8 mL). Puriﬁcation by silica gel column

chromatography (10% EtOAc/hexanes) aﬀorded an inseparable

mixture of diastereomers of acetoxypyranone 14b (405 mg, 55%

1

yield over 2 steps) as a cream color amorphous solid. H NMR (400

MHz, CDCl₃) δ 7.46−7.19 (m, 5H, superimposed by peak

corresponding to the minor isomer), 6.78 (dd, J = 10.3, 3.7 Hz,

1H), 6.47 (d, J = 3.6 Hz, 1H), 6.03 (d, J = 10.3 Hz, 1H), 5.89 (dddd, J

= 17.0, 10.3, 6.4, 5.0 Hz, 1H), 5.27−5.12 (m, 2H), 5.12−5.04 (m,

1H), 4.95 (d, J = 2.8 Hz, 1H), 4.07−3.93 (m, 1H), 3.82 (ddt, J = 12.9,

6.4, 1.3 Hz, 1H), 2.09 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

192.7, 169.3, 141.9, 135.9, 134.1, 128.6, 128.2, 128.0, 127.8, 117.5,

87.2, 79.3, 79.2, 69.9, 20.85. HRMS (ESI/LTQ) m/z: [M + Na]⁺

calcd for C₁₇H₁₈O₅Na 325.1046; found 325.1049.

6-((S)-1-(Allyloxy)-2-methylpropyl)-5-oxo-5,6-dihydro-2H-pyran-

2-yl Acetate (14c). The reaction was conducted according to the

general procedure F with furfuryl alcohol 13c (200 mg, 0.95 mmol),

KBr (12 mg, 0.1 mmol), NaHCO₃(40 mg, 0.48 mmol), and oxone

(877 mg, 1.43 mmol) to aﬀord the desired hydroxypyranone. The

acetylation reaction was conducted according to the general

procedure using the crude hydroxypyranone (215 mg, 0.95 mmol),

pyridine (167 μL, 1.90 mmol), and acetyl chloride (102 μL, 1.43

mmol) in CH₂Cl₂(1.5 mL) for 30 min. Puriﬁcation by silica gel

column chromatography (10% EtOAc/hexanes) aﬀorded an insepa-

rable mixture of diastereomers of acetoxypyranone 14c (198 mg, 78%

over 2 steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.89 (dd,

J = 3.6, 2.0 Hz, 1H), 6.54 (d, J = 3.8 Hz, 1H), 6.22−6.17 (m, 1H),

5.95−5.83 (m, 1H), 5.30−5.19 (m, 1H), 5.16−5.07 (m, 2H), 4.68 (d,

J = 2.3 Hz, 1H), 4.16 (ddt, J = 12.7, 5.4, 1.4 Hz, 1H), 4.01 (ddt, J =

13.7, 6.8, 1.3 Hz, 1H, superimposed by peak corresponding to the

minor isomer), 3.57 (dd, J = 8.5, 2.3 Hz, 1H), 2.09 (s, 3H), 1.04−

0.99 (m, 1H), 0.99−0.94 (m, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 193.8, 169.3, 140.9, 134.8, 128.8, 116.7, 87.0, 84.4, 77.0,

72.2, 29.4, 20.8, 19.5, 19.2. HRMS (ESI/Q-TOF) m/z: [M + Na]⁺

calcd for C₁₄H₂₀O₅Na 291.1203; found 291.1202.

(dd, J = 3.6, 0.8 Hz, 1H), 6.50 (dd, J = 3.6, 1.7 Hz, 1H), 5.72 (ddt, J =

16.9, 10.2, 6.6 Hz, 1H), 5.01−4.80 (m, 2H), 4.35 (q, J = 6.9 Hz, 1H),

3.46 (dt, J = 9.1, 6.5 Hz, 1H), 3.36 (dt, J = 9.1, 6.6 Hz, 1H), 2.05 (tdt,

J = 8.0, 6.4, 1.4 Hz, 2H), 1.74−1.56 (m, 2H), 1.40 (d, J = 6.9 Hz,

3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 190.1, 150.3, 146.7, 137.9,

119.2, 114.7, 112.0, 79.2, 69.3, 30.0, 28.8, 18.8. HRMS (ESI/Q-TOF)

m/z: [M + H]⁺calcd for C₁₂H₁₇O₃209.1171; found 209.1172.

The above furyl ketone (175 mg, 0.84 mmol) was reduced with

NaBH₄(96 mg, 2.52 mmol) in dry MeOH (4.2 mL) following the

general procedure E. Puriﬁcation by silica gel column chromatography

(10% EtOAc/hexanes) aﬀorded the furfuryl alcohol 13h (160 mg,

90% yield) as a yellow oil in a 2:1 diastereomeric ratio. ¹H NMR (400

MHz, CDCl₃) δ 7.35 (dd, J = 6.2, 1.7 Hz, 1H), 6.39−6.22 (m, 2H),

5.88−5.70 (m, 1H), 5.10−4.87 (m, 2H), 4.43 (d, J = 7.5 Hz, 1H),

3.77−3.47 (m, 2H), 3.38 (dt, J = 9.1, 6.5 Hz, 1H), 3.19 (brs, 1H),

2.09 (dq, J = 15.1, 6.7 Hz, 2H), 1.76−1.49 (m, 2H), 1.03 (d, J = 6.2

Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.4, 142.0, 138.1,

114.8, 110.1, 107.8, 77.4, 71.6, 68.5, 30.3, 29.0, 15.6. HRMS (ESI/Q-

TOF) m/z: [M + Na]⁺calcd for C₁₂H₁₈O₃Na 233.1149; found

233.1148.

General Procedure F: Synthesis of Acetoxypyranone via

Achmatowicz Rearrangement 14a−h. To a stirring solution of

furfuryl alcohol (1.0 equiv) in a 4:1 mixture of THF/H₂O (0.1 M) at

0 °C were added KBr (0.1 equiv), NaHCO₃(0.5 equiv), and oxone

(1.5 equiv). After the reaction mixture was stirred at 0 °C for 1−4 h,

the reaction was quenched by addition of satd NaHCO₃solution. The

mixture was extracted with EtOAc (3×), washed with brine, dried

over anhydrous Na₂SO₄, ﬁltered, and concentrated under reduced

pressure. The crude hydoxypyranone was used directly for the

subsequent reaction without puriﬁcation. To a solution of the crude

hydroxypyranone (1.0 equiv) in CH₂Cl₂at 0 °C were added pyridine

(2.0 equiv) and acetyl chloride (1.5 equiv). The resulting solution was

stirred for 30 min, and then the reaction was quenched by water and

extracted with CH₂Cl₂(3×). The combined organic layers were

washed with brine, dried over Na₂SO₄, ﬁltered, and concentrated

under reduced pressure. Puriﬁcation by silica gel column chromatog-

raphy aﬀorded the desired acetoxypyranone.

6-((S)-1-(Allyloxy)ethyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl Ace-

tate (14d). The reaction was conducted according to the general

procedure F with furfuryl alcohol 13d (330 mg, 1.81 mmol), KBr (27

mg, 0.22 mmol), NaHCO₃(76 mg, 0.90 mmol), and oxone (1.85 g,

3.01 mmol) to aﬀord the desired hydroxypyranone. The acetylation

reaction was conducted according to the general procedure using the

crude hydroxypyranone (360 mg, 1.81 mmol), pyridine (318 μL, 3.62

mmol), and acetyl chloride (195 μL, 2.71 mmol) in CH₂Cl₂(5 mL)

for 30 min. Puriﬁcation by silica gel column chromatography (10%

EtOAc/hexanes) aﬀorded an inseparable mixture of diastereomers of

6-((S)-(Allyloxy)(phenyl)methyl)-5-oxo-5,6-dihydro-2H-pyran-2-

yl Acetate (14a). The reaction was conducted according to the

general procedure F with furfuryl alcohol 13a (300 mg, 1.23 mmol),

KBr (15 mg, 0.12 mmol), NaHCO₃(52 mg, 0.62 mmol), and oxone

(1.1 g, 0.1.85 mmol) to aﬀord the desired hydroxypyranone. The

acetylation reaction was conducted according to the general

procedure using the crude hydroxypyranone (320 mg, 1.23 mmol),

pyridine (216 μL, 2.46 mmol), and acetyl chloride (132 μL, 1.85

mmol) in CH₂Cl₂(4 mL) for 30 min. Puriﬁcation by silica gel column

1

acetoxypyranone 14d (260 mg, 60% over 2 steps) as a yellow oil. H

NMR (400 MHz, CDCl₃) δ 6.90 (td, J = 10.1, 3.5 Hz, 1H), 6.54 (d, J

= 3.5 Hz, 1H), 6.16 (d, J = 10.3 Hz, 1H), 5.93−5.81 (m, 1H), 5.16−

5.03 (m, 2H), 4.66 (d, J = 2.1 Hz, 1H), 4.14−3.91 (m, 3H,

superimposed by peak corresponding to the minor isomer), 2.07 (s,

3H), 1.14 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

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193.7, 169.2, 142.0, 134.7, 128.7, 116.9, 87.2, 77.7, 73.9, 70.0, 20.8,

14.3. HRMS (ESI/LTQ) m/z: [M + Na]⁺calcd for C₁₂H₁₆O₅Na

263.0890; found 263.0892.

mmol) in CH₂Cl₂(3.0 mL) for 50 min. Puriﬁcation by silica gel

column chromatography (10% EtOAc/hexanes) aﬀorded a mixture of

diastereomers of acetoxypyranone 14h (163 mg, 64% yield over 2

steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.94−6.86 (m,

1H), 6.53 (d, J = 3.7 Hz, 1H), 6.21−6.13 (m, 1H), 5.83−5.65 (m,

1H), 4.94−4.85 (m, 2H), 4.29−4.23 (m, 1H), 4.08 (dd, J = 7.0, 2.8

Hz, 1H), 3.56−3.38 (m, 2H), 2.07 (d, J = 1.3 Hz, 3H), 2.03−1.93 (m,

2H), 1.66−1.58 (m, 2H), 1.24 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 193.8, 169.1, 142.3, 138.1, 129. 1, 114.6, 87.2,

79.7, 74.2, 68.4, 30.1, 28.8, 20.8, 15.2. HRMS (ESI/LTQ) m/z: [M +

Na]⁺calcd for C₁₄H₂₀O₅Na 291.0203; found 291.0207.

General Procedure G: Synthesis of the Cycloadducts 16a−

h. To a stirred solution of the acetoxypyranone (1.0 equiv) in

CH₃CN (0.02 M) at 23 °C was added N-methylpyrrolidine (4.0

equiv), and the resulting mixture was heated to 60−150 °C in an oil

bath. After 3−24 h, the mixture was concentrated, and the residue was

puriﬁed by silica gel column chromatography aﬀorded the desired

cycloadduct.

(3S,3aS,7S,8aS)-3-Phenyl-1,7,8,8a-tetrahydro-3H,4H-3a,7-

epoxycyclohepta[c]furan-4-one (16a). The reaction was conducted

according to the general procedure G with acetoxypyranone 14a (100

mg, 0.33 mmol) and N-methylpyrrolidine (138 μL, 1.32 mmol) in

CH₃CN (12.7 mL) at 60 °C for 12 h. Puriﬁcation by silica gel column

chromatography (20% EtOAc/hexanes) aﬀorded the cycloadduct 16a

(71 mg, 89% yield, dr = 10:1) as a crystalline white solid. The puriﬁed

compound was dissolved in ethyl acetate and hexanes and was

allowed to crystallize at 23 °C for 5 days. ¹H NMR (800 MHz,

CDCl₃) δ 7.47 (d, J = 7.4 Hz, 2H), 7.37−7.26 (m, 3H), 7.15 (dd, J =

9.7, 4.3 Hz, 1H), 6.01 (d, J = 9.7 Hz, 1H), 5.56 (s, 1H), 5.05−4.98

(m, 1H), 4.22 (t, J = 8.6 Hz, 1H), 4.08 (dd, J = 9.3, 3.4 Hz, 1H),

2.97−2.89 (m, 1H), 2.33 (dd, J = 12.1, 8.9 Hz, 1H), 2.16 (dt, J = 12.0,

6.1 Hz, 1H). ¹³C{¹H} NMR (200 MHz, CDCl₃) δ 194.9, 151.8,

135.6, 127.8, 127.8, 126.7, 126.7, 97.7, 80.0, 76.7, 71.9, 46.5, 36.4.

HRMS (APCI/LTQ) m/z: [M + H]⁺calcd for C₁₅H₁₅O₃243.1016;

found 243.1014.

6-((S)-(But-3-en-1-yloxy)(phenyl)methyl)-5-oxo-5,6-dihydro-2H-

pyran-2-yl Acetate (14e). The reaction was conducted according to

the general procedure G with furfuryl alcohol 13e (50 mg, 0.19

mmol), KBr (2.5 mg, 0.02 mmol), NaHCO₃(8.2 mg, 0.1 mmol), and

oxone (145 mg, 0.23 mmol) to aﬀord the desired hydroxypyranone.

The acetylation reaction was conducted according to the general

procedure using the crude hydroxypyranone(53 mg, 0.19 mmol),

pyridine (25 μL, 0.29 mmol), and acetyl chloride (20 μL, 0.29 mmol)

in CH₂Cl₂(1.0 mL) for 3 h. Puriﬁcation by silica gel column

chromatography (15% EtOAc/hexanes) aﬀorded a separable mixture

of anti/syn-acetoxypyranone 14e (36 mg, 60% yield over 2 steps) as a

colorless oil in 3:1 diastereomeric ratio. anti-Acetoxypyranone 14e:

¹H NMR (400 MHz, CDCl₃) δ 7.36−7.21 (m, 5H), 6.79 (dd, J =

10.3, 3.6 Hz, 1H), 6.48 (dd, J = 3.6, 0.6 Hz, 1H), 6.06 (dd, J = 10.3,

0.7 Hz, 1H), 5.79 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.10−4.97 (m,

3H), 4.92 (d, J = 2.8 Hz, 1H), 3.45 (ddt, J = 32.7, 9.3, 6.8 Hz, 2H),

2.35 (dq, J = 7.0, 1.5 Hz, 2H), 2.11 (s, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 192.8, 169.3, 141.9, 136.3, 134.9, 128.6, 128.3, 127.9,

127.8, 116.4, 87.3, 80.5, 79.4, 68.8, 34.0, 20.9. HRMS (ESI/LTQ) m/

z: [M + Na]⁺calcd for C₁₈H₂₀O₅Na 339.1203; found 339.1208.

6-((S)-1-(But-3-en-1-yloxy)-2-methylpropyl)-5-oxo-5,6-dihydro-

2H-pyran-2-yl Acetate (14f). The reaction was conducted according

to the general procedure G with furfuryl alcohol 13f (100 mg, 0.45

mmol), KBr (5.0 mg, 0.04 mmol), NaHCO₃(19.0 mg, 0.22 mmol),

and oxone (330 mg, 0.54 mmol) to aﬀord the desired hydroxypyr-

anone. The acetylation reaction was conducted according to the

general procedure using the crude hydroxypyranone (107 mg, 0.45

mmol), pyridine (78 μL, 0.89 mmol), and acetyl chloride (48 μL, 0.67

mmol) in CH₂Cl₂(1.5 mL) for 30 min. Puriﬁcation by silica gel

column chromatography (15% EtOAc/hexanes) aﬀorded a mixture of

diastereomers of acetoxypyranone 14f (82 mg, 65% yield over 2

steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.91 (d, J = 3.7

Hz, 1H), 6.58−6.52 (m, 1H), 6.28−6.18 (m, 1H), 5.88−5.75 (m,

1H), 5.14−5.01 (m, 2H), 4.69 (d, J = 2.1 Hz, 1H), 3.72−3.64 (m,

1H), 3.48−3.40 (m, 2H), 2.34−2.28 (m, 2H), 2.24−2.19 (m, 1H),

2.14 (s, 3H), 1.10−0.86 (m, 6H, superimposed by peak

corresponding to the minor isomer). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 193.7, 169.2, 140.9, 135.2, 128.8, 116.1, 87.7, 84.9, 79.0,

70.6, 34.3, 29.4, 20.7, 19.7, 19.2. HRMS (ESI/Q-TOF) m/z: [M +

Na]⁺calcd for C₁₅H₂₂O₅Na 305.1360; found 305.1357.

(3R,3aR,7R,8aR)-3-Phenyl-1,7,8,8a-tetrahydro-3H,4H-3a,7-

epoxycyclohepta[c]furan-4-one (16b). The reaction was conducted

according to the general procedure G with acetoxypyranone 14b (170

mg, 0.56 mmol) and N-methylpyrrolidine (235 μL, 2.25 mmol) in

CH₃CN (22 mL) at 60 °C for 12 h. Puriﬁcation by silica gel column

chromatography (20% EtOAc/hexanes) aﬀorded the cycloadduct 16b

(100 mg, 74% yield, dr = 10:1) as a crystalline white solid. The

puriﬁed compound was dissolved in ethyl acetate and hexanes and

1

was allowed to crystallize at 23 °C for 5 days. H NMR (800 MHz,

6-((S)-1-(But-3-en-1-yloxy)ethyl)-5-oxo-5,6-dihydro-2H-pyran-2-

yl Acetate (14g). The reaction was conducted according to the

general procedure G with furfuryl alcohol 13g (55 mg, 0.28 mmol),

KBr (4 mg, 0.03 mmol), NaHCO₃(12 mg, 0.14 mmol), and oxone

(210 mg, 0.34 mmol) to aﬀord the desired hydroxypyranone. The

acetylation reaction was conducted according to the general

procedure using the crude hydroxypyranone (59 mg, 0.28 mmol),

pyridine (50 μL, 0.55 mmol), and acetyl chloride (30 μL, 0.41 mmol)

in CH₂Cl₂(1.0 mL) for 40 min. Puriﬁcation by silica gel column

chromatography (10% EtOAc/hexanes) aﬀorded a mixture of

diastereomers of acetoxypyranone 14g (53 mg, 75% yield over 2

steps) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.94−6.88 (m,

1H), 6.63 (dd, J = 3.4, 0.7 Hz, 1H), 6.22−6.15 (m, 1H), 5.86−5.72

(m, 1H), 5.11−4.91 (m, 2H), 4.29−4.26 (m, 1H), 4.14−4.09 (m,

1H), 3.58−3.50 (m, 2H), 2.24−2.18 (m, 2H), 2.09 (s, 3H), 1.28 (d, J

= 6.5 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 193.8, 169.1,

142.3, 134.9, 129.2, 116.2, 87.3, 79.8, 74.4, 69.3, 34.1, 20.8, 15.2.

HRMS (ESI/LTQ) m/z: [M + Na]⁺calcd for C₁₃H₁₈O₅Na 277.1046;

found 277.1050.

5-Oxo-6-((S)-1-(pent-4-en-1-yloxy)ethyl)-5,6-dihydro-2H-pyran-

2-yl Acetate (14h). The reaction was conducted according to the

general procedure G with furfuryl alcohol 13h (200 mg, 0.95 mmol),

KBr (11.0 mg, 0.1 mmol), NaHCO₃(40.0 mg, 0.48 mmol), and

oxone (700 mg, 1.14 mmol) to aﬀord the desired hydroxypyranone.

The acetylation reaction was conducted according to the general

procedure using the crude hydroxypyranone (215 mg, 0.95 mmol),

pyridine (170 μL, 1.90 mmol), and acetyl chloride (100 μL, 1.43

CDCl₃) δ 7.47 (d, J = 7.6 Hz, 2H), 7.36−7.26 (m, 3H), 7.15 (dd, J =

9.7, 4.3 Hz, 1H), 6.01 (d, J = 9.7 Hz, 1H), 5.56 (s, 1H), 5.02 (dd, J =

6.7, 4.2 Hz, 1H), 4.22 (t, J = 8.7 Hz, 1H), 4.08 (dd, J = 9.2, 3.4 Hz,

1H), 2.96−2.90 (m, 1H), 2.33 (dd, J = 12.0, 8.9 Hz, 1H), 2.16 (dt, J =

12.3, 6.3 Hz, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 194.9, 151.8,

135.6, 127.8, 127.8, 126.7, 126.7, 97.7, 80.0, 76.7, 71.9, 46.5, 36.4.

HRMS (APCI/LTQ) m/z: [M + H]⁺calcd for C₁₅H₁₅O₃243.1016;

found 243.1018.

(3S,3aS,7S,8aS)-3-isopropyl-1,7,8,8a-tetrahydro-3H,4H-3a,7-

epoxycyclohepta[c]furan-4-one (16c). The reaction was conducted

according to the general procedure G with acetoxypyranone 14c (190

mg, 0.71 mmol) and N-methylpyrrolidine (295 μL, 1.41 mmol) in

CH₃CN (27 mL) at 60 °C for 12 h. Puriﬁcation by silica gel column

chromatography (15% EtOAc/hexanes) aﬀorded the cycloadduct 16c

24

(129 mg, 88% yield, dr = 2:1) as a yellow oil. 16c (major): [α]_D

1

+38.6 (c 0.3, CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.17 (dd, J =

9.8, 4.3 Hz, 1H), 5.98 (d, J = 9.8 Hz, 1H), 5.01 (dd, J = 6.6, 4.3 Hz,

1H), 4.01−3.93 (m, 2H), 3.84 (dd, J = 9.2, 3.2 Hz, 1H), 2.74−2.66

(m, 1H), 2.22 (dd, J = 12.0, 8.9 Hz, 1H), 2.05−1.90 (m, 2H), 1.06 (d,

J = 6.6 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 195.4, 151.6, 126.7, 96.8, 84.6, 76.4, 71.4, 47.2, 36.2, 28.0,

24

1

20.3, 19.1. 16c (minor): [α]_D−116.4 (c 0.2, CHCl₃). H NMR

(400 MHz, CDCl₃) δ 7.16 (dd, J = 9.7, 4.4 Hz, 1H), 6.00 (d, J = 9.5

Hz, 1H), 5.11 (d, J = 4.9 Hz, 1H), 4.29 (t, J = 8.2 Hz, 1H), 3.44 (t, J =

9.1 Hz, 1H), 3.28 (d, J = 10.4 Hz, 1H), 2.82 (dp, J = 9.6, 6.4 Hz, 1H),

2.66 (p, J = 7.8 Hz, 1H), 1.93 (t, J = 5.4 Hz, 2H), 1.01 (d, J = 6.6 Hz,

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3H), 0.81 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

195.7, 150.8, 128.0, 97.0, 93.1, 79.5, 72.7, 49.8, 31.9, 26.5, 20.3,

19.2.HRMS (APCI/LTQ) m/z: [M + H]⁺calcd for C₁₂H₁₇O₃

209.1172; found 209.1174.

Puriﬁcation by silica gel column chromatography (20% EtOAc/

hexanes) aﬀorded the cycloadduct 16h (46 mg, 59% yield, dr >19:1)

as a white amorphous solid. ¹H NMR(400 MHz, CDCl₃) δ 7.28−7.20

(m, 1H), 5.89 (dd, J = 9.8, 0.8 Hz, 1H), 4.85 (q, J = 4.2 Hz, 1H), 4.25

(q, J = 6.5 Hz, 1H), 3.90 (dd, J = 11.5, 5.9 Hz, 1H), 3.65−3.49 (m,

1H), 2.33−2.18 (m, 1H), 2.03−1.92 (m, 3H), 1.90−1.77 (m, 2H),

1.69 (q, J = 9.1, 6.9 Hz, 1H), 1.23 (dd, J = 6.4, 0.8 Hz, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 198.4, 153.0, 125.8, 92.7, 73.7, 71.6, 40.8,

35.6, 29.0, 26.3, 18.3. HRMS (APCI/LTQ) m/z: [M + H]⁺calcd for

C₁₂H₁₇O₃209.1172; found 209.1174.

(3S,3aS,7S,8aS)-3-Methyl-1,7,8,8a-tetrahydro-3H,4H-3a,7-

epoxycyclohepta[c]furan-4-one (16d). The reaction was conducted

according to the general procedure G with acetoxypyranone 14d (75

mg, 0.31 mmol) and N-methylpyrrolidine (130 μL, 1.25 mmol) in

CH₃CN (12 mL) at 60 °C for 12 h. Puriﬁcation by silica gel column

chromatography (20% EtOAc/hexanes) aﬀorded the cycloadduct 16d

1

(25 mg, 45% yield, dr = 4:1) as a colorless oil. H NMR (400 MHz,

(3S,3aS,4S,7R,8aR)-3-Isopropyl-4,7,8,8a-tetrahydro-1H,3H-3a,7-

epoxycyclohepta[c]furan-4-ol (21). To a solution of the cycloadduct

16c (minor) (20 mg, 0.10 mmol) in a 4:1 mixture of MeOH/CH₂Cl₂

(5 mL) at 23 °C was added CeCl₃·7H₂O (54 mg, 0.14 mmol). After

stirring for 30 min the reaction mixture was cooled to 0 °C and

sodium borohydride (4.0 mg, 0.10 mmol) was added. After 1 h, the

reaction was quenched with H₂O and extracted with ethyl acetate

(3×). The combined organic layers were washed with brine, dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

Puriﬁcation by silica gel column chromatography (25% EtOAc/

hexanes) aﬀorded the allylic alcohol 21 (15.0 mg, 75% yield, dr

CDCl₃) δ 7.17 (dd, J = 9.8, 4.3 Hz, 1H), 5.97 (d, J = 9.7 Hz, 1H),

5.01 (dd, J = 6.4, 4.4 Hz, 1H), 4.43 (q, J = 6.4 Hz, 1H), 3.98 (dd, J =

9.2, 8.0 Hz, 1H), 3.84 (dd, J = 9.3, 3.0 Hz, 1H), 2.81−2.69 (m, 1H),

2.27 (dd, J = 12.0, 8.9 Hz, 1H), 2.05 (dt, J = 12.2, 6.2 Hz, 1H), 1.28

(d, J = 6.4 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 195.0,

151.9, 126.6, 96.7, 76.4, 74.9, 71.8, 46.0, 36.5, 12.8. HRMS (APCI/

LTQ) m/z: [M + H]⁺calcd for C₁₀H₁₃O₃181.0859; found 181.0860.

(1S,4aR,6S,9aS)-1-Phenyl-4,4a,5,6-tetrahydro-1H-6,9a-epoxy-

cyclohepta[c]pyran-9(3H)-one (16e). The reaction was conducted

according to the general procedure G with acetoxypyranone 14e (25

mg, 0.08 mmol) and N-methylpyrrolidine (33 μL, 0.32 mmol) in

CH₃CN (4.0 mL) at 60 °C for 4 h. Puriﬁcation by silica gel column

chromatography (20% EtOAc/hexanes) aﬀorded the cycloadduct 16e

24

1

>19:1) as a white amorphous solid. [α]_D+25.3 (c 0.1, CHCl₃). H

NMR(400 MHz, CDCl₃) δ 5.99 (dd, J = 9.7, 3.9 Hz, 1H), 5.49 (dd, J

= 9.7, 2.0 Hz, 1H), 4.86 (s, 1H), 4.74 (t, J = 5.0 Hz, 1H), 4.18 (t, J =

8.4 Hz, 1H), 3.39 (t, J = 8.7 Hz, 1H), 3.26 (p, J = 7.4 Hz, 2H), 2.10

(dq, J = 12.6, 6.4 Hz, 1H), 2.01 (dd, J = 11.6, 8.1 Hz, 1H), 1.76 (dt, J

= 12.0, 6.3 Hz, 1H), 1.68 (s, 1H), 1.03 (t, J = 6.9 Hz, 6H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 133.0, 127.7, 94.2, 91.1, 80.1, 72.4, 68.2,

43.8, 36.6, 27.3, 20.1, 19.8. HRMS (APCI/LTQ) m/z: [M + H]⁺

calcd for C₁₂H₁₉O₃211.1329; found 211.1328.

1

(12 mg, 60% yield, dr >19:1) as a white amorphous solid. H NMR

(400 MHz, CDCl₃) δ 7.43−7.36 (m, 2H), 7.36−7.19 (m, 4H), 5.91

(dd, J = 9.8, 1.2 Hz, 1H), 5.50 (s, 1H), 4.86−4.77 (m, 1H), 4.10

(ddd, J = 11.7, 4.6, 2.3 Hz, 1H), 3.65 (td, J = 11.9, 1.7 Hz, 1H), 2.24

(qd, J = 9.0, 7.4, 5.2 Hz, 1H), 2.13 (dd, J = 12.3, 8.1 Hz, 1H), 2.00

(ddt, J = 12.3, 7.2, 4.1 Hz, 2H), 1.80−1.65 (m, 1H). ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 197.1, 155.3, 138.3, 127.9, 127.7, 127.6, 126.7,

87.7, 77.2, 71.3, 66.4, 39.8, 35.1, 30.4. HRMS (APCI/LTQ) m/z: [M

+ H]⁺calcd for C₁₆H₁₇O₃257.1172; found 257.1173.

(1S,4aR,6S,9aS)-1-Isopropyl-4,4a,5,6-tetrahydro-1H-6,9a-

epoxycyclohepta[c]pyran-9(3H)-one (16f). The reaction was con-

ducted according to the general procedure G with acetoxypyranone

14f (50 mg, 0.18 mmol) and N-methylpyrrolidine (75 μL, 0.71

mmol) in CH₃CN (9.0 mL) at 60 °C for 24 h. The reaction mixture

was concentrated, and the residue was washed with 1 N HCl. The

mixture was extracted with EtOAc (3×), washed with brine, dried

over anhydrous Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation by

silica gel column chromatography (15% EtOAc/hexanes) aﬀorded the

cycloadduct 16f (33 mg, 84% yield, dr >19:1) as a white amorphous

solid. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J = 9.8, 4.8 Hz, 1H),

6.02 (d, J = 9.8 Hz, 1H), 4.82 (dd, J = 7.6, 4.8 Hz, 1H), 4.01 (d, J =

7.9 Hz, 1H), 3.97−3.84 (m, 1H), 3.47−3.29 (m, 1H), 2.16−1.96 (m,

2H), 1.96−1.77 (m, 3H), 1.58−1.41 (m, 1H), 1.01 (d, J = 6.7 Hz,

3H), 0.79 (d, J = 6.9 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

197.9, 154.3, 126.7, 86.8, 80.5, 71.0, 65.7, 39.5, 35.7, 30. 9, 30.6, 20.2,

19.5. HRMS (APCI/LTQ) m/z: [M + H]⁺calcd for C₁₃H₁₉O₃

223.1329; found 223.1331.

(1S,4aR,6S,9aS)-1-Methyl-4,4a,5,6-tetrahydro-1H-6,9a-epoxy-

cyclohepta[c]pyran-9(3H)-one (16g). The reaction was conducted

according to the general procedure G with acetoxypyranone 14g (50

mg, 0.20 mmol) and N-methylpyrrolidine (82 μL, 0.79 mmol) in

CH₃CN (10 mL) at 60 °C for 18 h. Puriﬁcation by silica gel column

chromatography (20% EtOAc/hexanes) aﬀorded the cycloadduct 16g

(30 mg, 79% yield, dr >19:1) as a white amorphous solid. ¹H

NMR(400 MHz, CDCl₃) δ 7.43 (dd, J = 9.7, 4.8 Hz, 1H), 5.98 (d, J =

9.7 Hz, 1H), 4.87−4.79 (m, 1H), 4.40 (q, J = 6.5 Hz, 1H), 3.89 (ddd,

J = 11.6, 4.6, 2.3 Hz, 1H), 3.50−3.38 (m, 1H), 2.17−2.01 (m, 2H),

1.99−1.85 (m, 2H), 1.61−1.46 (m, 1H), 1.19 (d, J = 6.5 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 197.4, 155.7, 126.6, 87.3, 71.3,

ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00600.

¹H and ¹³C NMR spectra for all new compounds, HPLC

data, and X-ray crystallographic data (PDF)

Accession Codes

CCDC 2025567−2025568 and 2064460 contain the supple-

mentary crystallographic data for this paper. These data can be

obtained free of charge via www.ccdc.cam.ac.uk/data_request/

cif, or by emailing data_request@ccdc.cam.ac.uk, or by

contacting The Cambridge Crystallographic Data Centre, 12

Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

■

Corresponding Author

Arun K. Ghosh − Department of Chemistry and Department

of Medicinal Chemistry, Purdue University, West Lafayette,

Indiana 47907, United States; orcid.org/0000-0003-

2472-1841; Email: akghosh@purdue.edu

Author

Monika Yadav − Department of Chemistry and Department of

Medicinal Chemistry, Purdue University, West Lafayette,

Indiana 47907, United States; orcid.org/0000-0003-

3772-2317

71.2, 65.8, 39.7, 34.1, 30.5, 16.8. HRMS (APCI/LTQ) m/z: [M +

H]⁺calcd for C₁₁H₁₅O₃195.1016; found 195.1017.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00600

(1S,5aR,7S,10aS)-1-Methyl-3,4,5,5a,6,7-hexahydro-1H,10H-

7,10a-epoxycyclohepta[c]oxepin −10-one (16h). The reaction was

conducted according to the general procedure G with acetoxypyr-

anone 14h (100 mg, 0.37 mmol) and N-methylpyrrolidine (58 μL,

0.56 mmol) in CH₃CN (19 mL) in a sealed tube for 3 h at 150 °C.

Notes

The authors declare no competing ﬁnancial interest.

8140

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J. Org. Chem. 2021, 86, 8127−8142

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(20) Min, L.; Liu, X.; Li, C.-C. Total Synthesis of Natural Products

with Bridged Bicyclo[m.n.1] Ring Systems via Type II [5 + 2]

Cycloaddition. Acc. Chem. Res. 2020, 53, 703−718.

ACKNOWLEDGMENTS

■

Financial support of this work was provided by the National

Institutes of Health (Grant AI150466). The authors would like

to thank Anando Ghosh (graphic designer) for his help with

cover art design. NMR and Mass Spectrometry were all

performed using shared resources which are partially supported

by the Purdue Center for Cancer Research through an NIH

grant (P30CA023168).

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1700634.

8142

https://doi.org/10.1021/acs.joc.1c00600

J. Org. Chem. 2021, 86, 8127−8142

Article Doi

Highly Diastereoselective Intramolecular Asymmetric Oxidopyrylium-olefin [5 + 2] Cycloaddition and Synthesis of 8-Oxabicyclo[3.2.1]oct-3-enone Containing Ring Systems

DOI: 10.1021/acs.joc.1c00600

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Article abstract of DOI:10.1021/acs.joc.1c00600

Full text of DOI:10.1021/acs.joc.1c00600

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