Total synthesis of (±)-rocaglamide via oxidation-initiated nazarov cyclization

Article

pubs.acs.org/joc

Total Synthesis of ( )-Rocaglamide via Oxidation-Initiated Nazarov

Cyclization

John A. Malona, Kevin Cariou, William T. Spencer, III, and Alison J. Frontier*

Department of Chemistry, University of Rochester, Rochester, New York 14627, United States

S

* Supporting Information

ABSTRACT: This article describes the evolution of a Nazarov

cyclization-based synthetic strategy targeting the anticancer, antiin-

flammatory, and insecticidal natural product ( )-rocaglamide. Initial

pursuit of a polarized heteroaromatic Nazarov cyclization to construct

the congested cyclopentane core revealed an unanticipated electronic

bias in the pentadienyl cation. This reactivity was harnessed in a suc-

cessful second-generation approach using an oxidation-initiated

Nazarov cyclization of a heteroaryl alkoxyallene. Full details of these

two approaches are given, as well as the characterization of undesired

reaction pathways available to the Nazarov cyclization product. A

sequence of experiments that led to an understanding of the unexpected

reactivity of this key intermediate is described, which culminated in the

successful total synthesis of (+)-rocaglamide.

bioactive characteristics. The compounds are potent insecticides^1a,3

INTRODUCTION

Several species of Aglaia, a genus of trees found primarily in the

tropical forests of Southeast Asia and on the Pacific Islands, have

■

and NF-κB inhibitors⁴and display remarkable anticancer activity.

Since King’s report describing the anticancer behavior of

rocaglamide, testing of an expanding array of both naturally

long been used by native populations for housebuilding, firewood,

occurring and synthetic rocaglamide derivatives in both in vitro and

tea fragrance, moth repellent, and as sources of medicinal sub-

in vivo models has revealed anticancer activity across a broad array

stances. In the latter role, their extracts have been valued as heart

of human cancer cell lines.¹Studies on the cellular mechanism of

stimulants and as treatments for fever, inflammation, diarrhea, and

injuries.¹In 1982, King and co-workers²isolated the compound

rocaglamide and its derivatives have shown that cyclopenta[b]-

benzofurans function through both cytostatic and cytotoxic modes

rocaglamide (1a, Figure 1) from the chloroform-soluble fraction of

of action, which can depend on both the derivative and the cell line.

Rocaglamide itself displays potent and selective cytotoxicity

through consistent activation of the p38 MAP kinase pathway

along with a long-term suppression of the survival MAP, an

extracellular signal-regulated kinase.^4dThis affects pro-apoptotic

bcl-2 proteins, triggering caspase-mediated apoptosis. This

effect is highly selective for abnormal lymphocytes over healthy

cells. Recently, rocaglamide was found to have a cytostatic effect

in T cells infected with HTLV-1 associated T-cell leukemia/

lymphoma. This is accomplished through inhibition of the

MEK-ERK-MNK1 signaling pathway, thereby inhibiting phos-

phorylation of eIF4E. This prevents de novo synthesis of c-FLIP,

a protein that causes resistance to receptor-mediated apoptosis.

In the same cell, upregulation of CD95L was also shown. CD95L

is a ligand which, when bound to the CD95 receptor, causes

apoptosis. Thus, rocaglamide sensitizes cancer cells to treat-

Figure 1. Rocaglamide and analogues.

ment with apoptosis-inducing ligands such as CD95L and

the extract of dried roots and stems of Aglaia elliptifolia.

Rocaglamide exhibited substantial antileukemic activity against

P388 lymphocytic leukemia in CDF₁mice with optimal T/C

values of ca. 156% at a nontoxic dose of 1.0 mg/kg. This natural

product was the first of a large series of cyclopenta[b]benzofurans

isolated from various Aglaia species over the subsequent years (e.g.,

1b−e; Figure 1), of which many were found to possess powerful

TRAIL.^5,6

The impressive biological profile of rocaglamide and the

cyclopenta[b]benzofurans as a whole has stimulated considerable

Received: December 8, 2011

Published: January 26, 2012

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effort toward their synthesis over the past 20 years. The primary

challenges in synthesizing them lay in the densely functionalized

core. In particular, the fused cyclopentane ring is composed of

five stereogenic carbons, of which the two fusion bond carbons

are fully substituted. This compact architecture has lent itself to a

variety of creative approaches toward its construction.

Scheme 1. First Generation Approach

The first, executed by Trost⁷and co-workers in 1990, used a

2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated

oxidative cyclization to form the rocaglamide skeleton as a single

diastereomer, which after a stereochemical correction and func-

tional group manipulations yielded (−)-rocaglamide. In addi-

tion to being the first synthesis of the natural product, it pro-

vided confirmation of its absolute stereochemical assignment. An

approach pioneered by Taylor⁸and Kraus⁹in the late 1980s and

early 1990s took advantage of a samarium(II) iodide-mediated

intramolecular pinacol coupling to form the cyclopentane ring.

Both quaternary fusion stereocenters were formed in the correct

relative configuration. This method provided the basis for several

later syntheses of rocaglamide and rocaglamide derivatives.¹⁰

More recently, Porco¹¹developed a [3 + 2] photocyclo-

addition to synthesize a cyclopenta[bc]pyran intermediate. This

approach was first attempted by Staunton, who obtained in-

correct regiochemistry of cycloaddition.¹²This skeleton type

is proposed^1a,13to be a key intermediate in the biosynthesis

of cyclopenta[b]benzofuran and benzo[b]oxepine flavaglines.

When subjected to base, this material underwent an α-ketol re-

arrangement to give a cyclopenta[b]benzofuran intermediate,

which was concisely elaborated to rocaglamide. Treatment of

the [3 + 2] product with lead tetraacetate formed the benzo-

[b]oxepine. This spectacularly concise and novel method of

accessing all three flavagline core types through a biomimetic

pathway was used in an enantioselective synthesis of roca-

glamide,¹⁴rocaglaol,¹⁴silvestrol,¹⁵and a variety of other natural

and unnatural rocagamide derivatives.¹⁶In 2009, our group

published an annotated study on the total synthesis of roca-

glamide which harnessed an oxidation-initiated Nazarov

cyclization.¹⁷In addition to the complete syntheses outlined

above, a number of other approaches have been used to con-

struct rocaglamide derivatives, including those published by

Feldman,¹⁸Umezawa,¹⁹Schoop,²⁰Ragot,²¹Magnus,²²and

Moser.²³

additional electron-donating groups of 3 to further enhance its

reactivity.

Scheme 2. Catalytic Nazarov Cyclization of a Benzofuryl

Vinyl Ketone

To explore this strategy, benzofurans of type 2 (Scheme 1)

were required. Vilsmeier formylation of 4,6-dimethoxybenzo-

furans reportedly occurs at the 7-position,²⁸so Friedel−Crafts

acylation was not a viable strategy for their preparation. Instead,

a cyclization/carbomethoxylation strategy was examined (eq 1).

RESULTS/DISCUSSION

■

First Generation Synthetic Strategy. The initial strategy

we envisioned for the synthesis of rocaglamide capitalized on

a Nazarov cyclization−oxyallyl cation trapping sequence,²⁴⁻²⁶

shown in Scheme 1. We planned to synthesize the requisite

Nazarov substrate 3 from benzofuran precursor 2. Lewis acid

activation of 3 would generate a pentadienyl cation of type I,

which after electrocyclization generates oxyallyl cation of type

II. Trapping of this intermediate with water^26ewould install the

tertiary hydroxyl group while retaining the adjacent stereocenters

formed via conrotatory Nazarov cyclization. Thus, planar benzo-

furan 3 would be converted to cyclopentanone 4 in one step, and

intermediate 4 has been converted by Trost et al. into

( )-rocaglamide.⁷

o-Alkynylphenol derivative 5, prepared via Sonagashira

coupling²⁹of 2-iodo-5-methoxyphenol and phenylacetylene,

could be efficiently converted into benzofuran methyl ester 6.³⁰

Optimistic that this approach would allow preparation of

an appropriately functionalized benzofuran, compounds of

type 8 were prepared via the protocol shown in Scheme 3.

2-Hydroxy-4,6-dimethoxybenzaldehyde³¹was O-alkylated with

(2-(chloromethoxy)ethyl)trimethylsilane (SEMCl) or

((chloromethoxy)methyl)benzene (BOMCl) in the presence of

DMAP and N,N-diisopropylethylamine in dichloromethane to furnish

the corresponding aryl ethers. These compounds were subjected to the

Bestmann−Ohira modification³²of the Seyferth−Gilbert homologa-

tion³³using dimethyl (1-diazo-2-oxopropyl)phosphonate and K₂CO₃

Nazarov substrate 3 was appealing as a starting point because

of its polarized nature: it was expected to exhibit enhanced

reactivity due to the low activation barrier for cyclization

observed when one olefin is electron-poor and the other is

electron-rich.²⁵Earlier work in our laboratory²⁷demonstrated

that benzofuran is a competent “vinyl nucleophile” in polarized

Nazarov cyclizations (Scheme 2), and we expected the

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diethyl ether, the cyanohydrin undergoes a Hoesch reaction³⁶

which after acidic hydrolysis provided a diphenolic benzofur-

anone. Dimethyl sulfate methylation of the free hydroxyl

groups yielded dimethylated benzofuranone 10. Treatment of

10 with vinyl magnesium bromide in the presence of cerium

chloride³⁷followed by elimination afforded 3-vinylbenzofuran

11. Wacker oxidation³⁸gave ketone 12. Claisen condensa-

tion with dimethyl carbonate gave the β-ketoester 13, and

Knoevenagel condensation yielded Nazarov substrate 3 as a

1:3.3 mixture of E/Z isomers.

Scheme 3. Preparation of Alkynes 8a and 8b

Despite extensive experimentation, the Nazarov cyclization/

trapping sequence could not be realized (Scheme 5). Various

catalysts (scandium(III) trifluoromethanesulfonate, aluminum

chloride, hydrochloric acid, boron trifluoride diethyl etherate)

were examined in the presence of water or sodium acetate,

which were intended to serve as nucleophiles capable of trap-

ping the oxyallyl cation.²⁶No cyclization products were detected

under any of the reaction conditions examined; the only trans-

formations observed were efficient isomerization of the E/Z

mixture to the Z-alkylidene β-ketoester isomer, retro-Knoevena-

gel condensation, and even retro-Claisen condensation to deliver

precursor ketone 12.

Strategy Revision: Adjusting the Reactivity of the

Pentadienyl Cation. Because none of the experiments on

alkylidene β-ketoester 3 ever showed any evidence of cyclization

chemistry, it was necessary to reevaluate our synthetic strategy.

It was apparent that the Lewis acid was activating 3 toward

nucleophilic attack by water, as evidenced by the isolation of the

retro-Knoevenagel product (Scheme 5), but no cyclization was

occurring. A report from the Magnus group in 2005 described

conrotatory cyclization of a different system, via ionization of a

mixed ketal (Scheme 6),^22,39which led us to view the reactivity

of 3 differently.

in methanol which provided terminal alkynes 7a and 7b.

Sonogashira coupling with 1-iodo-4-methoxybenzene fur-

nished internal alkynes 8a and 8b.

Unfortunately, the transformation performed in eq 1 was not

effective for electron-rich systems of type 8 after removal of the

protecting group. Reports of a related cycloisomerization by

Yamamoto³⁴and Furstner³⁵(eq 2) were then explored. Again,

̈

electron-rich alkynes 8 did not cyclize, even though these

reactions were highly efficient on systems with fewer electron-

donating groups.

This result suggests that the C1 terminus (see I; C4 sub-

stituent = EWG; Scheme 7) of the pentadienyl cation exhibits

electrophilic character, which is competent to react with the

nucleophilic α-position of the silyl enol ether (i.e., C5, the

nucleophilic terminus of the pentadienyl cation). Extrapola-

ting to our alkylidene β-ketoester substrate 3, we can more

accurately visualize the pentadienyl cation generated by Lewis

acid activation with a positive charge localized at the C1

terminus. The carbocation at C1 would be stabilized by both

oxygen and the p-methoxybenzyl group (Scheme 7). With an

electron-withdrawing ester at C4, C5 is also electrophilic,

and the system is not favorably polarized for cyclization.

However, polarization of the system would be restored if the

ester at C4 were replaced with an electron-donating

substituent (see I; C4 substituent = EDG), improving both

However, we found that modification of Yamamoto’s con-

ditions (eq 2, top) to include excess ((chloromethoxy)methyl)-

benzene induced cyclization of 8b to afford benzofuran 9 in 31%

yield (77% conversion) using 10 mol % platinum(II) chloride

(Table 1, entry 1). It was later discovered that gold(III) chloride

efficiently promoted the reaction (entry 2), but high catalyst

loading (25 mol %) was necessary for optimal results, and the

reaction did not scale well (entry 3).

Ultimately, Nazarov substrate 3 could be prepared from 2-

hydroxy-2-(4-methoxyphenyl)acetonitrile as shown in Scheme 4.

Upon stirring with phloroglucinol in hydrogen chloride−saturated

Table 1. Cycloisomerization of BOM-Protected Phenol 8b to Benzofuran 9

a

entry

conditions

conversion (%)

yield (%)

1

2

PtCl₂(10 mol %), COD BOMCl, PhCH₃

AuCl₃(25 mol %), COD BOMCl, PhCH₃

77

31

60

45

100

66

b

3

a

b

BOM = benzyloxymethyl. Results upon scaling up by a factor of 50.

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Scheme 4. Synthesis of Nazarov Precursor 3

Scheme 5. Subjection of 3 to Lewis Acidic Conditions

Scheme 7. Reactivity Paradigm for Electron-Rich Benzofuryl

Pentadienyl Cations

Scheme 6. Magnus: Nazarov Cyclization To Access the

Rocaglate Core

The reactivity of this pentadienyl cation was expected to be

similar to the Magnus system (Scheme 6), leading to cycli-

zation to a diosphenol of type 15. Unlike other methods for

generating pentadienyl cations for Nazarov cyclization, the

Lewis acid would not play a role as promoter or catalyst in

either activation of substrate 14 or cyclization of intermediate I.

Epoxidation of simple vinylallenes (Figure 2; X = H) as the first

step in a Nazarov cyclization sequence has been described pre-

viously⁴³and has been identified as part of a biosynthetic

pathway in the formation of prostanoids in plants and corals.⁴⁴

However, no examples of oxidation/cyclization of vinyl alkoxyallenes

(Figure 1; X = OR) had been disclosed.⁴⁵

kinetic reactivity and stability of the oxyallyl cation inter-

mediate (II; C4 substituent = EDG).

To pursue these ideas, we chose to explore a strategy

involving oxidation of a heteroaryl alkoxyallene.⁴⁰⁻⁴²Treat-

ment of an alkoxyallene of type 14 with an oxidant would

produce the target pentadienyl cation I (C4 substituent = O⁻),

either directly or via an intermediate allene oxide (Scheme 8).

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and isolation led to partial decomposition. The selectivity may

be attributed to the steric bulk of the electrophile, which reacts

at the terminal rather than the benzofuranylic position of the

allenyl anion (i.e., IV rather than III). On the basis of this find-

ing, we examined isomerization of 18c, hoping the steric bulk of

the o-methoxy group might discourage reprotonation at the pro-

pargylic position, but no isomerization was observed (entry 5).

Interestingly, we found that 18d, with no substitution at the

alkyne terminus, readily isomerized to the terminal allene 20

efficiently and in high yield in the presence of Triton B in

dimethyl sulfoxide⁴⁷(entry 7).

Scheme 8. New Synthetic Design: Generation of Pentadienyl

Cation via Oxidation of Alkoxyallene

When allenylsilane 19a was subjected to either m-

chloroperoxybenzoic acid (m-CPBA) or dimethyldioxirane

(DMDO), decomposition occurred. However, allenylstannane

19b underwent the desired Nazarov cyclization in the presence

of m-chloroperoxybenzoic acid with potassium carbonate in

dichloromethane/hexanes in 34% yield to give 15a as a single

diastereomer (Table 1, entry 1). However, ethyl ester 21 was

identified as the major product of the reaction. Solvent polarity,

oxidant, and reaction acidity were found to impact product

ratio (Table 3, entries 2−7). Optimal conditions were found to

be m-CPBA (3.5 equiv) in degassed N,N-dimethylformamide at

0 °C, providing the desired product 15a in 50% yield, with ester

21 as a minor byproduct (4.3:1 ratio; entry 5).

Interestingly, we found that DMDO-promoted cyclization of

terminal allene 20 even more efficiently, giving a 63% yield of

diosphenol 22 over two steps from the propargylic ether

precursor without any detectable ester byproduct (Scheme 10).

Although intermediate 22 lacks the phenyl group of the natural

product, it may be possible to synthesize rocaglamide derivatives

from this material through α-arylation chemistry.⁴⁸

Proposed Mechanism of Electrocyclization. Because

treatment of alkoxyallene 19b with m-CPBA leads to the forma-

tion of two products, a mechanistic hypothesis that accounts for

this behavior is required. Direct oxidation at the central carbon

of the allene 19b or epoxidation to the corresponding allene

oxide followed by ring-opening would give pentadienyl cation

23 (Scheme 11). Protodestannylation, most likely from the

α-stannyl ketone, would produce pentadienyl cation 24, relieving

the steric crowding at the terminal carbons of the pentadienyl

cation 23. Conrotatory electrocyclization of the enolate with

phenyl situated in an exo position provides 15a, which is the

only isomer observed in the product mixture.

Figure 2. Substituted vinylallenes.

In many cases, the isomerization of propargylic ethers to

alkoxyallenes is kinetically favored under basic conditions.⁴⁶

To this end, several propargylic ethers were synthesized ac-

cording to Scheme 9. Oxidative cleavage of 3-vinylbenzofuran

Scheme 9. Synthesis of Propargylic Ethers 18a−d

Ester 21 is thought to arise from oxidation at the benzo-

furanylic carbon, an electron-rich carbon center, to give

intermediate hemiketal 25, followed by expulsion of phenyl-

acetylene. Consistent with this proposal, it was also observed

that if the stannylallene were allowed to stand neat, prior to

exposure with m-CPBA, it was slowly transformed to ester 21.

Therefore, oxidation by adventitious oxygen may also account

for the formation of 21, which explains why this reaction

pathway is minimized in degassed solvent.

Completion of the Synthesis. Our next objective was to

convert intermediate 15a into the natural product, which required

installation of a hydroxyl group at the sp²carbon at the ring

junction, conversion of the enol ether into a hydroxy group,

and addition of an appropriate carbon unit to the ketone

(Scheme 12).

11 provided aldehyde 16, which was then treated with lithium

phenylacetylide or ethynylmagnesium bromide to form the cor-

responding propargylic alcohols 17a and 17b. O-Alkylation

then furnished target propargylic ethers 18a−d.

Contrary to expectations, no isomerization occurred using

base-catalyzed or -promoted allene isomerization conditions

for 18a (Table 2, entry 1). For this compound, there are two

possible isomers of the allenylanion intermediate (see III and

IV, Table 2), and the results indicate that protonation occurs

at the propargylic position rather than the allenyl position.

However, the lithium anion of 18a or 18b could be trapped

with chlorotrimethylsilane or tributyltin chloride to afford the

corresponding allenylsilane 19a or allenylstannanes 19b and

19c (entries 2−4). Allenylsilane 19a was prone to hydrolysis,

Unfortunately, attempts to functionalize 15a triggered an un-

expected cleavage of the ring C−O bond (Scheme 13). Thus,

exposure of ketone 15a to basic conditions, acidic conditions,

nucleophiles (sodium cyanide), or hydride reagents gave ring-

opened products, of which 26 and 27 are just two examples.⁴⁹

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ab

,

Table 2. Preparation of Alkoxyallenes from Propargylic Ethers

a

b

entry

substrate

R₁

R₂

Et

conditions

product (R₃)

yield (%)

1

2

3

4

5

6

18a

18b

18c

18d

Ph

H

A, B, C, D, E, F

c

−

Et

G

19a (SiMe₃)

19b (SnBu₃)

19c (SnBu₃)

c

40

95

94

−

Et

H

PMB

OMB

PMB

H

I, J, K, L, M

N

20 (H)

∼90

a

b

PMB = p-methoxybenzyl; OMB = o-methoxybenzyl. Conditions: (A) KOt-Bu, MeOH, THF. (B) MeLi, THF, and then MeOH. (C) MeLi, THF,

and then ZnCl₂and then NH₄Cl. (D) t-BuLi, THF, and then imidazole. (E) t-BuLi, THF, and then ZnCl₂and then NH₄Cl. (F) Triton B, DMSO,

50 °C. (G) 1.3 equiv of t-BuLi and then TMSCI, THF, −30 °C. (H) t-BuLi, Et₂O, −40 °C, and then Bu₃SnCl. (I) t-BuLi, THF, and then MeOH. (J)

t-BuLi, TMEDA, THF, and then MeOH. (K) t-BuLi, TMEDA, THF, and then t-BuOH. (L) t-BuLi, TMEDA, THF, and then 2,6-di-tert-butylphenol.

c

(M) t-BuLi, TMEDA, THF, and then imidazole. (N) Triton B (40% w/w MeOH), DMSO, 50 °C. Propargylic ether was isolated unchanged.

Table 3. Optimization of Oxidative Nazarov Cyclization

entry

solvent

oxidant

m-CPBA (1 equiv)

temp, °C

ratio (15a:21)

1

2

3

4

5

6

7

DCM/hexane (1:1)

toluene

r.t.

1:1.2

1:4

m-CPBA (1 equiv)

r.t.

DMF

m-CPBA (1 equiv)

r.t.

1.6:1

1:2

DMF

m-CPBA (1 equiv) p-TSA (5 mol %)

m-CPBA (3.5 equiv)

CF₃CO₃H

−10 to 0

0

DMF

4.3:1

1:6

DMF

−10 to 0

sulfolane

m-CPBA (3.5 equiv)

1.2:1

Scheme 10. Oxidation-Initiated Nazarov Cyclization of

Terminal Alkoxyallene 20

and ¹³C NMR data, we deduced that compounds 27, 28a, and

28b had the same carbon skeleton (see Supporting Information).

Then, the mixed ketal structure of 28a was determined by X-ray

crystallographic analysis, which led us to propose analogous

mixed ketal structures for 27 and 28b, as shown in Scheme 13. It

was also found that upon isolation and exposure to air, mixed

ketal 27 was converted to pyrone 29.

A proposed mechanism for the formation of reduction pro-

duct 27 is shown in Scheme 14. Stereoselective borohydride

reduction of 15a, due to the overwhelming steric influence of

the aryl groups,⁵¹would lead to enol ether 30. Once the enol

ether is no longer in conjugation with the ketone, it would be de-

stabilized and may collapse to expel the phenolate oxygen, leading

to intermediate 31. Intramolecular attack by the phenolate, under

neutral, anhydrous conditions, would then form mixed ketal 27,

as a single diastereomer. This process could also be viewed as

In one case, treatment of ketone 15a with 1,4-dia-

zabicyclo[2.2.2]octane (DABCO) led to 26 (Scheme 13),

while treatment with lithium triethyl borohydride gave an

initially unidentified compound 27. We found that 27 could be

functionalized with methyl chloroformate to give a carbonate

28a, or with Comin’s reagent⁵⁰to give a triflate 28b. From H

1

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Scheme 11. Proposed Mechanism for Oxidation-Initiated Nazarov Cyclization of 19a

Scheme 12. Remaining Manipulations To Synthesize

Rocaglamide from Intermediate 15a

(see 33, Scheme 15).⁵²Fragmentation of hydroperoxide 34

would produce ketene 35, which is set up to undergo 6π elec-

trocyclization to give the observed pyrone 29.

After finding that our preferred approaches for functionaliza-

tion of ketone 15a led to cleavage of the ring C−O bond, we

sought reaction conditions that would not generate an enolate

at the ketone α-position or activate the tetrahydrofuran oxygen

yet would still deliver a useful synthetic intermediate. Thus, we

explored oxidation protocols for installing the hydroxyl group

at C8b (see Scheme 12). Oxidation of 15a did not occur upon

treatment with DMDO, while oxidation with ceric ammonium

nitrate or DDQ led to a complex mixture of products. The

analogous p-methoxybenzyl ether 15b was prepared from 19c

(Scheme 16). We hypothesized that while oxidation of 15a

would produce reactive intermediate 36a, oxidation of 15b

might afford neutral intermediate 36b (Figure 3) Indeed, treat-

ment of 15b with DDQ effected both cleavage of the PMB

group and oxidation at carbon 8b, and diosphenol 37 was

isolated in 71% yield.

a concerted [1,3]-shift of the oxygen, converting 30 to 27

directly, without opening the ring.

Upon standing overnight, or rapidly in the presence of acid,

mixed ketal 27 is converted to pyrone 29 through a sequence

involving a net oxidation. One possible mechanism involves

hydrolysis of 27 to give ketone 32, followed by oxidation at

the α-position of the enol form by adventitious oxygen of 32

Scheme 13. Ring-Opening of Intermediate 15a

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Scheme 14. Proposed Mechanism for Formation of Hydride

Reduction Product 27

Scheme 16. Synthesis and DDQ Oxidation of 15b

Scheme 15. Proposed Mechanism for Formation of Pyrone

29

Figure 3. Putative intermediates generated upon oxidation of 15a and

15b.

Scheme 17. Installation of the α-Carbomethoxy Group

Treatment of 37 with N-(2-pyridyl)bis(trifluoro-

methanesulfonimide) provided triflate 38, and palladium-

catalyzed carbonylation in the presence of methanol installed

the ester to give 39 (Scheme 17). This completed assembly of

the carbon skeleton of the natural product.

Compound 39 could be transformed directly to β-ketoester

40 via hydrogenation in the presence of PtO₂. However,

purification of 40 obtained from the hydrogenation was difficult

and reaction results were erratic. More reliable outcomes were

obtained if hydrogenation was conducted on the trimethylsilyl

ether 41, followed by deprotection of β-ketoester 42 to give 40,

consistent with the findings of Trost⁷(Scheme 18).

( )-rocaglamide (1a) in 60% yield. All spectral data were identical

to literature values for the natural product.^10c

In summary, the total synthesis of ( )-rocaglamide was

achieved starting from benzofuranone 10. The key step was

oxidation-triggered Nazarov cyclization of the highly function-

alized alkoxyallene 19c to give 15b (Scheme 20). The adjacent

stereocenters of the rocaglamide system were created via con-

rotatory electrocyclization. However, due to an unexpected,

irreversible ring-opening, the Nazarov cyclization product could

not be functionalized using either acidic or basic conditions.

Ultimately, the requisite tertiary hydroxyl group was installed by

oxidation of 15b under neutral conditions, which allowed com-

pletion of the synthesis via Trost’s intermediate 39. Ongoing

work in the laboratory is focused on developing an enantioselective

Templated reduction with sodium triacetoxyborohydride yielded

aglafolin (1e) as a single diastereomer (Scheme 19). Saponification

of aglafolin gave rocagloic acid (1d) in 82% yield, which after

dicyclohexylcarbodiimide-mediated amide coupling yielded

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specified. Dry solvents were obtained from a solvent purification

system. Reagents were used as received unless otherwise specified.

n-Butyllithium was titrated periodically with diphenylacetic acid. Thin

layer chromatography was visualized with p-anisaldehyde/heat,

Scheme 18. Preparation of β-Ketoester 40 via

Hydrogenation of Alkylidene β-Ketoester 39

1

potassium permanganate/heat, vanillin/heat, or a UV lamp. H NMR

and ¹³C NMR spectroscopy were performed at ambient temperature.

Dimethyldioxirane (DMDO) was prepared according to the procedure

of Adam,⁵³and the concentration assayed by preparing an NMR sample

containing 5 μL of thioanisole and 50 μL of DMDO solution and

comparing relative peak areas of the aromatic protons of thioanisole and

its corresponding sulfoxide.

5-Methoxy-2-(2-phenylethynyl)phenol (5). In dry diethylamine

(15 mL), sparged with argon for 10 min, 2-iodo-5-methoxyphenol

(0.50 g, 2.0 mmol) was suspended. To the suspension, trans-

dichlorobis(triphenylphosphine)palladium(II) (7.0 mg, 0.0099 mmol)

and copper(I) iodide (3.8 mg, 0.020 mmol) were added. Phenyl-

acetylene (0.25 g, 2.40 mmol) was added via syringe, and the reaction

was stirred for 12 h at room temperature. The reaction was then

warmed to 45 °C and stirred for an additional 1.5 h. The reaction was

allowed to cool, whereupon the solvent was removed in vacuo. The

residue was taken up in dichloromethane (15 mL) and washed with

water (15 mL), and the organic layer was dried over Na₂SO₄, filtered

over an alumina plug, and concentrated. If a solid was isolated, it was tri-

turated with hexanes and vacuum filtered to afford 5-methoxy-2-(2-

phenylethynyl)phenol 5 (260 mg, 59%) as a gray powder, or the pure

material was obtained by flash chromatography using hexane/ethyl

acetate (6:1). IR (neat) cm⁻¹3450, 2220, 1616, 1504, 1245, 1145, 1022.

¹H NMR (400 MHz, CDCl₃) δ 7.61−7.57 (2H, m), 7.47−7.37 (4H,

m), 6.55 (1H, d, J = 2.4 Hz), 6.50 (1H, dd, J = 8.6, 2.4 Hz), 5.87 (1H, s,

broad), 3.86 (3H, s). ¹³C NMR (125 MHz, CDCl₃) δ 161.7, 158.0,

132.5, 131.5, 128.5, 122.8, 107.5, 102.1, 100.3, 95.3, 83.3, 55.5. HRMS

m/z calcd for C₁₅H₁₂O₂: [M + H⁺] 224.0832, found 224.0839.

Methyl 6-Methoxy-2-phenylbenzofuran-3-carboxylate (6). Alky-

nylphenol 5 (0.300 g, 1.34 mmol) was dissolved in a mixture of 7:3

methanol/tetrahydrofuran (85 mL). The solution was sparged with

carbon monoxide for 20 min. To the solution were added palladium(II)

iodide (48 mg, 0.13 mmol), thiourea (10 mg, 0.13 mmol), cesium car-

bonate (3.05 g, 9.37 mmol), and carbon tetrabromide (3.11 g, 9.37 mmol).

The flask was sealed and stirred under 1 atm of carbon monoxide at 50 °C

for 5 h. The reaction was allowed to cool and concentrated in vacuo. The

residue was extracted with dichloromethane (2 × 20 mL) and washed with

brine, and the organic layer was dried over Na₂SO₄and passed through a

silica plug. The filtrate was concentrated and the residue subjected to

flash column chromatography on silica gel using 2:1 dichloromethane/

hexanes to afford methyl 6-methoxy-2-phenylbenzofuran-3-carboxylate

6 (290 mg, 77%) as a white solid. IR (neat) cm⁻¹3063, 2999, 2950,

Scheme 19. Preparation of Natural Products Aglafolin,

Rocagloic Acid, and Rocaglamide from β-Ketoester 40

1

Scheme 20. Summary: Total Synthesis of Rocaglamide

2836, 1716, 1622, 1492, 1278, 1225, 1150, 1115, 1089, 767, 690. H

NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.7

Hz, 1H), 7.50−7.46 (3H, m), 7.07 (d, J = 2.2 Hz, 1H), 6.99 (dd, J =

8.7, 2.2 Hz, 1H), 3.94 (3H, s), 3.90 (3H, s). ¹³C NMR (100 MHz,

CDCl₃) δ 164.6, 159.9, 158.6, 154.8, 130.0, 129.3, 128.6, 128.2, 123.0,

120.3, 113.1, 108.7, 95.5, 55.8, 51.6. HRMS m/z calcd for C₁₇H₁₄O₄Na

[M + Na⁺] 305.0784, found 305.0784.

(2-((2-Ethynyl-3,5-dimethoxyphenoxy)methoxy)ethyl)-

trimethylsilane (7a). To a solution of 2-hydroxy-4,6-dimethoxyben-

zaldehyde³¹(1.00 g, 5.50 mmol), dry N,N-diisopropylethylamine

(1.15 mL, 6.60 mmol), and 4-(N,N-dimethylamino)pyridine

(732 mg, 0.550 mmol) in dry dichloromethane (18.3 mL) was

added (2-(chloromethoxy)ethyl)trimethylsilane (1.05 mL, 6.00 mmol)

slowly. The reaction was stirred at 40 °C for 3.5 h, and then N,N-diiso-

propylethylamine (1.91 mL, 11.0 mmol) and (2-(chloromethoxy)-

ethyl)trimethylsilane (1.94 mL, 11.0 mmol) were added. After

refluxing for 1.25 h, the reaction was diluted with dichloromethane

(150 mL). The solution was washed with a 10% w/w aqueous solution

of copper(II) sulfate (3 × 100 mL) and brine (40 mL), dried over an-

hydrous MgSO₄, filtered, and concentrated in vacuo to afford a residue

which was purified by flash chromatography on silica gel (90:10−50:50

hexanes/ethyl acetate) to afford 2,4-dimethoxy-6-((2-(trimethylsilyl)-

ethoxy)methoxy)benzaldehyde (1.09 g, 63%).

strategy for the synthesis of rocaglamide and its congeners and

investigation of the antiproliferative activity of this natural

product class.

EXPERIMENTAL SECTION

■

General Methods. Reactions were carried out in oven- or flame-

dried glassware under argon with magnetic stirring unless otherwise

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The aldehyde from the previous reaction (1.09 g, 3.50 mmol)

was dissolved in methanol (12 mL), and potassium carbonate (1.20 g,

8.75 mmol) was added. After cooling to 0 °C, a solution of dimethyl

(1-diazo-2-oxopropyl)phosphonate (1.34 g, 6.98 mmol) in methanol

(5.0 mL) was added slowly. The resulting slurry was stirred to room

temperature for 18 h at which time it was filtered and concentrated in

vacuo. The resulting oil was dissolved in ethyl acetate (130 mL) and

washed with saturated aqueous ammonium chloride (3 × 70 mL) and

brine (50 mL), dried over anhydrous MgSO₄, and concentrated in

vacuo to provide an oil which was purified by flash chromatography on

silica gel (99:1−85:15 hexanes/ethyl acetate) to afford (2-((2-ethynyl-

3,5-dimethoxyphenoxy)methoxy)ethyl)trimethylsilane 7a (430 mg,

2.1 Hz, 1H), 6.15 (d, J = 2.1 Hz, 1H), 5.36 (s, 2H), 4.76 (s, 2H), 3.87

(s, 3H), 3.78 (s, 3H), 3.48 (s, 1H).

1-((Benzyloxy)methoxy)-3,5-dimethoxy-2-((4-methoxyphenyl)-

ethynyl)benzene (8b). To an argon-sparged solution of alkyne 7b

(1.65 g, 5.50 mmol), 4-iodoanisole (983 mg, 4.20 mmol), dry tri-

ethylamine (1.76 mL, 12.6 mmol), and copper(I) iodide (160 mg,

0.84 mmol) in tetrahydrofuran (42 mL) was added tetrakis-

(triphenylphosphine)palladium(0) (485 mg, 0.42 mmol). The slurry

was stirred at room temperature for 12 h and then concentrated in

vacuo to remove most of the tetrahydrofuran. The residue was dis-

solved in ethyl acetate (200 mL), washed with a 10% w/w aqueous

solution of copper(II) sulfate (3 × 150 mL) and brine (90 mL), dried

over anhydrous MgSO₄, filtered, and concentrated in vacuo to afford a

residue which was purified by flash chromatography on silica gel

(98:2−75:25 hexanes/ethyl acetate) to afford 1-((benzyloxy)methoxy)-

3,5-dimethoxy-2-((4-methoxyphenyl)ethynyl)benzene 8b (1.5 g, 67%)

along with starting alkyne 7 (172 mg, 10% recovery). IR (neat) cm⁻¹

3000, 2950, 2840, 1608, 1575, 1512, 1454, 1335, 1245, 1160, 1065,

1

41%). H NMR (400 MHz, CDCl₃) δ 6.40 (d, J = 2.2 Hz, 1H),

6.16 (d, J = 2.2 Hz, 1H), 5.31 (s, 2H), 3.89 (s, 3H), 3.85−3.80 (m, 5H),

3.47 (s, 1H), 1.00−0.94 (m, 2H), 0.08−-0.03 (s, 10H).

(2-((3,5-Dimethoxy-2-((4-methoxyphenyl)ethynyl)phenoxy)-

methoxy)ethyl)trimethylsilane (8a). To an argon-sparged solution of

alkyne 7a (430 mg, 1.43 mmol), 4-iodoanisole (257 mg, 1.10 mmol),

dry triethylamine (0.46 mL, 3.30 mmol), and copper(I) iodide (54 mg,

0.29 mmol) in tetrahydrofuran (11 mL) was added tetrakis-

(triphenylphosphine)palladium(0) (165 mg, 0.14 mmol). The slurry

was stirred at room temperature for 14 h and then concentrated in

vacuo to remove most of the tetrahydrofuran. The residue was dis-

solved in ethyl acetate (100 mL), washed with a 10% w/w aqueous

solution of copper(II) sulfate (3 × 75 mL) and brine (60 mL), dried

over anhydrous MgSO₄, filtered, and concentrated in vacuo to afford a

residue which was purified by flash chromatography on silica gel

(98:2−86:14 hexanes/ethyl acetate) to afford (2-((3,5-dimethoxy-2-

((4-methoxyphenyl)ethynyl)phenoxy)methoxy)ethyl)trimethylsilane

8a (141 mg, 30%) along with starting terminal alkyne (191 mg, 44%

recovery). IR (neat) cm⁻¹2935, 2829, 1608, 1513, 1245, 1161, 1122,

1

1121, 831. H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8.7 Hz, 2H),

7.38−7.28 (m, 5H), 6.85 (d, J = 8.7 Hz, 2H), 6.41 (d, J = 2.1 Hz, 1H),

6.18 (d, J = 2.1 Hz, 1H), 5.36 (s, 2H), 4.80 (s, 2H), 3.88 (s, 3H), 3.81

(s, 3H), 3.79 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 161.8, 161.2,

159.9, 159.2, 137.1, 133.0, 128.5, 128.3, 127.9, 116.4, 113.8, 96.5, 96.2,

94.1, 92.9, 92.5, 80.5, 70.1, 56.1, 55.5, 55.3. HRMS m/z calcd for

C₂₅H₂₅0₅[M + H⁺] 405.1702, found 405.1712.

3-((Benzyloxy)methyl)-4,6-dimethoxy-2-(4-methoxyphenyl)-

benzofuran (9). To a solution of alkyne 8b (1.5 g, 3.7 mmol),

((chloromethoxy)methyl)benzene (0.1 mL, 0.74 mmol), and 1,5-

cyclooctadiene (0.36 mL, 3.0 mmol) in toluene (37 mL) was added

gold(III) chloride (280 mg, 0.93 mmol). The reaction was stirred for

16 h and then filtered through a short plug of silica gel, eluting with

dichloromethane (150 mL) and ethyl acetate (150 mL). The filtrate

was concentrated in vacuo to provide a residue which was purified by

flash chromatography on silica gel (98:2−82:18 hexanes/ethyl acetate)

to afford 3-((benzyloxy)methyl)-4,6-dimethoxy-2-(4-methoxyphenyl)-

benzofuran 9 (680 mg, 45%) along with starting alkyne 8b (523 mg,

34% recovery). IR (neat) cm⁻¹2928, 2914, 2840, 2178, 2161, 1597,

1

1074, 1008, 830. H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 8.9 Hz,

1H), 6.86 (d, J = 8.9 Hz, 1H), 6.39 (d, J = 2.2 Hz, 1H), 6.18 (d, J = 2.2

Hz, 1H), 5.31 (s, 2H), 3.89 (s, 3H), 3.84−3.70 (m, 2H), 3.65 (s, 6H),

1.03−0.94 (m, 2H), 0.00 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ

161.8, 161.1, 160.17, 159.2, 133.0, 116.6, 113.8, 96.5, 96.0, 94.1, 93.7,

92.3, 80.5, 66.5, 56.1, 55.4, 55.3, 18.1, −1.4. HRMS m/z calcd for

C₂₃H₃₁0₅Si [M + H⁺] 415.1941, found 415.1956.

1

1458, 1249, 1072, 1015, 821. H NMR (400 MHz, CDCl₃) δ 7.32−

7.26 (m, 2H), 7.17 (d, J = 8.8 Hz, 2H), 6.95−6.93 (m, 3H), 6.64

(d, J = 8.8 Hz, 2H), 6.43 (d, J = 2.1 Hz, 1H), 6.21 (d, J = 2.1 Hz, 1H),

5.24 (d, J = 7.1 Hz, 1H), 5.14 (d, J = 7.1 Hz, 1H), 4.43 (d, J = 11.8 Hz,

1H), 4.35 (d, J = 11.8 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.65 (s,

3H). ¹³C NMR (100 MHz, CDCl₃) δ 162.1, 158.7, 155.6, 137.1, 131.4,

128.9, 128.4, 128.3, 127.9, 127.7, 124.2, 113.5, 109.5, 93.1, 92.4, 91.7,

77.2, 69.5, 56.1, 55.4, 55.0. HRMS m/z calcd for C₂₅H₂₅0₅[M + H⁺]

405.1702, found 405.1703.

1-((Benzyloxy)methoxy)-2-ethynyl-3,5-dimethoxybenzene (7b).

To a solution of 2-hydroxy-4,6-dimethoxybenzaldehyde³¹(6.76 g,

37.0 mmol), dry N,N-diisopropylethylamine (19.4 mL, 111 mmol),

and 4-(N,N-dimethylamino)pyridine (451 mg, 3.70 mmol) in dry

dichloromethane (221 mL) was added ((chloromethoxy)methyl)-

benzene (15.5 mL, 111 mmol) slowly. The reaction was stirred

at room temperature for 12 h, and then N,N-diisopropylethylamine

(6.47 mL, 37.1 mmol) and ((chloromethoxy)methyl)benzene (5.15 mL,

37.1 mmol) were added. After refluxing for 1 h, the reaction was

diluted with dichloromethane (250 mL). The solution was washed

with a 10% w/w aqueous solution of copper(II) sulfate (3 × 200 mL)

and brine (70 mL), dried over anhydrous MgSO₄, filtered, and con-

centrated in vacuo to afford a residue which was purified by flash

chromatography on silica gel (90:10−50:50 hexanes/ethyl acetate)

to afford 2-((benzyloxy)methoxy)-4,6-dimethoxybenzaldehyde (7.3 g,

4,6-Dimethoxy-2-(4-methoxyphenyl)benzofuran-3(2H)-one (10).

Potassium cyanide (57.4 g, 881 mmol) was added to a stirred mixture

of distilled water (200 mL) and ethyl acetate (230 mL). Once the

KCN was dissolved, sodium bisulfite (NaHSO₃, 91.7 g, 881 mmol)

was added and stirring was continued. Note: The order of addition is

important; addition of KCN to a solution of NaHSO₃results in a violent

reaction. To this mixture was added freshly distilled p-anisaldehyde

(17.9 mL, 147 mmol), the flask was then sealed with an outlet, and the

mixture was stirred vigorously for 20 h. The reaction was poured

into 300 mL of distilled water and washed with distilled water (3 ×

200 mL) and then brine. The organic layer was dried over MgSO₄and

concentrated. The residue was dissolved in 150 mL of toluene, and

∼30 mL of hexanes was added with swirling. The solution was allowed

to stand, whereupon crystallization occurred. The product was filtered,

washed with hexane, and dried in vacuo to give 2-hydroxy-2-(4-

methoxyphenyl)acetonitrile (23.7 g, 99%) ¹H NMR (400 MHz,

CDCl₃) δ 7.46 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 4.48 (d,

J = 7.0 Hz, 1H), 3.84 (s, 3H), 2.74 (d, J = 7.0 Hz, 1H).

1

65%). H NMR (400 MHz, CDCl₃) δ 10.44 (s, 1H), 7.45−7.32 (m,

5H), 6.46 (d, J = 2.0 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 5.43 (s, 2H),

4.81 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H).

The aldehyde from the previous reaction (217 mg, 0.71 mmol) was

dissolved in methanol (2.2 mL), and potassium carbonate (215 mg,

1.56 mmol) was added. After cooling to 0 °C, a solution of dimethyl

(1-diazo-2-oxopropyl)phosphonate (230 mg, 1.28 mmol) in methanol

(1.3 mL) was added slowly. The resulting slurry was stirred to room

temperature over 14 h at which time it was filtered and concentrated in

vacuo. The resulting oil was dissolved in ethyl acetate (70 mL) and

washed with saturated aqueous ammonium chloride (3 × 70 mL) and

brine (50 mL), dried over anhydrous MgSO₄, and concentrated in

vacuo to provide an oil which was was purified by flash chro-

matography on silica gel (96:4−85:15 hexanes/ethyl acetate) to afford

1-((benzyloxy)methoxy)-2-ethynyl-3,5-dimethoxybenzene 7b (93 mg,

43%). ¹H NMR (400 MHz, CDCl₃) δ 7.40−7.27 (m, 5H), 6.42 (d, J =

To a three-necked flask containing dry diethyl ether (440 mL) were

added 2-hydroxy-2-(4-methoxyphenyl)acetonitrile (26.6 g, 163 mmol)

and phloroglucinol (20.6 g, 163 mmol, dried in vacuo 1 h @ 35 in. Hg,

100 °C). The flask was cooled to 0 °C with mechanical stirring. Dry

HCl (g) was bubbled through slowly for 1 h. After ∼30 min, a pre-

cipitate developed which could range in appearance from orange and

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sticky to off-white and free-flowing. Once a full 1 h of gas flow had

elapsed, the gas was stopped, the precipitate was scraped from the walls

of the reaction vessel, and the flask was refrigerated for 3 days. Once

removed from the cold, the supernatant was vacuum suctioned from the

flask and replaced with fresh diethyl ether. The precipitate was triturated

in this same manner several times with diethyl ether (3 × 300 mL). To

remove the residual ether that could not be removed by vacuum

suctioning, the flask was connected to a vacuum pump directly and

warmed until the precipitate was freely flowing. At this point, the

trituration with ether was repeated followed by an additional evacuation

on a pump. The resulting powder was then dissolved in 0.1 M HCl (aq)

(356 mL) and heated to 112 °C with a reflux condenser in place. The

solution was refluxed for ∼3 h, at which time a precipitate formed. The

reaction was cooled, the precipitate was filtered, washed with distilled

water, and dried in vacuo overnight to yield the diphenolic

oxygen atmosphere and warmed to 65 °C. After 4 h at this tem-

perature, the reaction was cooled, filtered over Celite (ethyl acetate),

and poured into distilled water. The aqueous layer was extracted with

ethyl acetate (3 × 25 mL), and the combined organic extracts were

washed with distilled water and brine and then dried over MgSO₄.

After filtration, the filtrate was concentrated and the resulting residue

was subjected to flash column chromatography (80:20 hexanes/ethyl

acetate) to give 1-(4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-

3-yl)methyl ketone 12 (135 mg, 93%). IR (neat) cm⁻¹3012, 2961,

2947, 2838, 1689, 1608, 1501, 1463, 1453, 1414, 1251, 1217, 1148,

1

1110. H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 8.8 Hz, 2H), 6.89

(d, J = 8.8 Hz, 2H), 6.60 (d, J = 1.6 Hz, 1H), 6.30 (d, J = 1.6 Hz, 1H),

3.81 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 2.57 (s, 3H). ¹³C NMR (100

MHz, CDCl₃) δ 199.8, 160.3, 159.6, 155.2, 153.3, 151.6, 128.7, 122.4,

117.1, 113.9, 110.6, 94.8, 88.0, 55.6, 55.5, 55.2, 32.3. HRMS m/z calcd

for C₁₉H₁₉O₅[M + H⁺] 327.1227, found 327.1230.

1

benzofuranone (11.25 g, 25%). H NMR (500 MHz, CD₃OD) δ 7.23

(d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.03 (d, J = 2.0 Hz, 1H),

5.94 (d, J = 2.0 Hz, 1H), 5.45 (s, 1H), 3.79 (s, 3H).

Methyl 3-(4,6-Dimethoxy-2-(4-methoxyphenyl)benzofuran-3-yl)-

3-oxopropanoate (13). In a two-neck round-bottom flask outfitted

with a Liebig condenser, sodium hydride (60% in mineral oil, 195 mg,

4.88 mmol) and potassium hydride (30% in mineral oil, 653 mg, 4.88 mmol)

were washed first with hexanes (3 mL) and then with dry tetra-

hydrofuran (3 mL) under argon. The hydride reagents were suspended in

dry tetrahydrofuran (50 mL), dimethyl carbonate (1.12 mL, 13.3 mmol)

was added via syringe, and the flask was warmed to 65 °C. Once at that

temperature, ketone 12 (1.45 g, 4.44 mmol), dissolved in dry tetra-

hydrofuran (15 mL), was added slowly. The reaction was refluxed until

the starting ketone was consumed, cooled to room temperature, and

quenched with a saturated aqueous solution of ammonium chloride. The

reaction was made acidic by the addition of 1 N HCl (aq) and poured

into distilled water (100 mL). The aqueous phase was extracted with ethyl

acetate (2 × 30 mL), and the combined organic extracts were washed

with distilled water and brine and then dried over MgSO₄. Filtration of

the organic phase, followed by concentration and chromatography (silica

gel, 85:15 hexanes/ethyl acetate), gave methyl 3-(4,6-dimethoxy-2-

(4-methoxyphenyl)benzofuran-3-yl)-3-oxopropanoate 13 (1.13 g, 66%).

IR (neat) cm⁻¹3010, 2955, 2838, 1738, 1667, 1608, 1501. ¹H NMR (400

MHz, CDCl₃) δ 7.84 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.68

(d, J = 2.0 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 4.04 (s, 2H), 3.91 (s, 3H),

3.86 (s, 3H), 3.85 (s, 3H), 3.66 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ

193.1, 168.0, 160.6, 159.7, 155.2, 153.8, 153.1, 129.2, 122.0, 115.8, 113.9,

110.0, 95.0, 88.1, 55.7, 55.3, 52.1, 50.2.

Once dry, the product of the above reaction was dissolved in

degassed acetone (300 mL, degassed by five vacuum/argon cycles

under stirring). This solution was cannulated to a suspension of di-

methyl sulfate (23.5 mL, 248 mmol) and potassium carbonate (34.3 g,

248 mmol) in 150 mL of degassed acetone, and the mixture was

refluxed under argon for 30 min. After this time, methanol (200 mL)

was added and the mixture was filtered (to remove the remaining

solids) and concentrated. The resulting solid was filtered, washed with

100 mL of methanol, and dried in vacuo overnight to give 4,6-

dimethoxy-2-(4-methoxyphenyl)benzofuran-3(2H)-one 10 (8.60 g,

1

69%) as a clear brown powder. H NMR (500 MHz, CDCl₃) δ 7.31

(d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.22 (d, J = 2.0 Hz, 1H),

6.04 (d, J = 2.0 Hz, 1H), 5.43 (s, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.79

(s, 3H); (lit.^8b¹H NMR).

4,6-Dimethoxy-2-(4-methoxyphenyl)-3-vinylbenzofuran (11). To

a stirred solution of benzofuranone 10 (10.3 g, 34.4 mmol) in dry

tetrahydrofuran (300 mL) at room temperature, vinylmagnesium

bromide (100 mL 1 M soln in tetrahydrofuran, 100 mmol) was added

rapidly via cannula. The reaction was stirred ∼15 min, until no starting

material remained, as judged by TLC. The reaction was quenched with

a saturated aqueous solution of ammonium chloride and made slightly

acidic by the addition of 1 N HCl (aq). The mixture was poured into

distilled water/ethyl acetate (100 mL/250 mL) and extracted. The

aqueous phase was extracted with ethyl acetate (100 mL), and the

combined organic extracts were washed successively with distilled

water and brine. The organic layer was dried over MgSO₄, filtered, and

concentrated. The crude material was redissolved in toluene (200 mL),

and p-toluenesulfonic acid (5 mg) was added. The reaction was stirred

briefly (no more than 7 min), until most material was converted to the

least polar product by TLC (R_f∼ 0.8, 80:20 hexane/ethyl acetate, blue

under UV). The reaction was filtered over a silica plug washing with

ethyl acetate and concentrated. The resulting residue was subjected to

flash column chromatography (75:25 hexane/ethyl acetate) to give

the desired 4,6-dimethoxy-2-(4-methoxyphenyl)-3-vinylbenzofuran 11

(7.11 g, 67%) as a white solid. Note: Prestirring the ketone at room

temperature for 2 h with 1.5 equiv of anhydrous cerium(III) chloride made

it possible to decrease the amount of Grignard reagent to 1.5 equiv but did

not increase the yield of the reaction.

Methyl 2-(4,6-Dimethoxy-2-(4-methoxyphenyl)benzofuran-3-

carbonyl)-3-phenylacrylate (3). β-Ketoester 13 (1.13 g, 2.93 mmol)

was dissolved in benzene (20 mL). To the solution, glacial acetic acid

(0.08 mL, 1.3 mmol), piperidine (0.03 mL, 0.3 mmol), and benz-

aldehyde (0.31 mL, 3.1 mmol) were added. The flask was fitted with a

Dean−Stark trap and Liebig condenser, and the reaction was heated to

110 °C. Once the reaction was finished (as determined by TLC), the flask

was cooled, and the reaction was poured into distilled water (50 mL),

diluted with ethyl acetate (50 mL), and extracted (2 × 25 mL). The

organic extract was washed with 1 N HCl (150 mL), a saturated

aqueous solution of sodium bicarbonate (200 mL), and brine. The

organic layer was dried over Na₂SO₄, filtered, and concentrated. The

resulting residue was subjected to flash chromatography (80:20

hexane/ethyl acetate) to yield methyl 2-(4,6-dimethoxy-2-(4-metho-

xyphenyl)benzofuran-3-carbonyl)-3-phenylacrylate 3 (1.24 g, 89%) as

a 1: 3.3 mixture of E/Z isomers. IR (neat) cm⁻¹3006, 2949, 2837,

IR (neat) cm⁻¹2997, 2953, 2938, 2905, 2835, 1618, 1591, 1501,

1

1729, 1651, 1615, 1502. H NMR (400 MHz, CDCl₃) δ 7.90 (d, J =

1250, 1148, 1113, 1103. H NMR (500 MHz, CDCl₃) δ 7.70 (d, J =

8.8 Hz, 2H, E), 7.79 (s, 1H, E), 7.74 (d, J = 9.2 Hz, 2H, Z), 7.37 (s,

1H, Z), 7.37−7.31 (m, 4H, Z + 3H, E), 7.15−7.09 (m, 1H, E), 6.98−

6.92 (m, 3H, Z + 2H, E), 6.70 (d, J = 2.0 Hz, 1H, Z), 6.50 (d, J = 2.0

Hz, 1H, E), 6.34−6.28 (m, 1H, E + Z), 3.90 (s, 3H, Z), 3.89 (s, 3H,

E), 3.87 (s, 3H, Z), 3.86 (s, 3H, E), 3.82 (s, 3H, Z), 3.80 (s, 3H, E +

Z), 3.78 (s, 3H, E). ¹³C NMR (100 MHz, CDCl₃) major isomer δ

191.1, 167.7, 160.2, 159.7, 155.1, 153.6, 152.3, 144.4, 136.1, 133.1,

131.2, 130.7, 129.4, 128.8, 128.1, 122.1, 114.2, 112.4, 94.9, 87.9, 55.8,

55.7, 55.3, 52.6. HRMS m/z calcd for C₂₈H₂₅O₇[M + H⁺] 473.1595,

found 473.1596.

8.5 Hz, 2H), 6.99−6.95 (m, 3H), 6.65 (d, J = 2.0 Hz, 1H), 6.35 (d, J =

2.0 Hz, 1H), 5.99 (dd, J = 17.5 Hz, 2.0 Hz, 1H), 5.40 (dd, J = 11.5 Hz,

2.0 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 6H). ¹³C NMR (125 MHz, CDCl₃)

δ 159.5, 158.9, 156.1, 154.6, 150.7, 129.2, 127.7, 123.9, 118.3, 114.3,

114.0, 111.6, 94.5, 88.0, 55.7, 55.4, 55.3. HRMS m/z calcd for

C₁₉H₁₈O₄[M⁺] 310.1200, found 310.1196.

1-(4,6-Dimethoxy-2-(4-methoxyphenyl)benzofuran-3-yl)methyl

Ketone (12). In a round-bottom flask, vinylbenzofuran 11 (0.139 g,

0.447 mmol) was dissolved in 10 mL of a 7:1 mixture of N,

N-dimethylformamide and distilled water. To this solution,

palladium(II) chloride (7.9 mg, 0.045 mmol) and copper(I) chloride

(49 mg, 0.049 mmol) were added. The reaction was placed under an

4,6-Dimethoxy-2-(4-methoxyphenyl)benzofuran-3-carboxalde-

hyde (16). To a stirred solution of vinylbenzofuran 11 (5.00 g, 16.1

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mmol) in acetone (240 mL) were added tert-butyl alcohol (35 mL)

and distilled water (12 mL), and the reaction vessel was flushed with

argon. To this solution was added N-methylmorpholine N-oxide

(3.60 g, 20.5 mmol) followed by osmium tetroxide (2.4 mL of a 4%

solution in H₂O, 0.4 mmol). The reaction was stirred at room temperature

for ∼3 h, until the starting material was consumed. The reaction was

concentrated to an oil via rotary evaporation and then diluted with

tetrahydrofuran (410 mL) and distilled water (150 mL). To this

solution, sodium periodate (7.50 g, 35.0 mmol) was added. The

reaction was stirred until the intermediary diol was converted to

aldehyde 16. Upon completion, the reaction was poured into a

saturated aqueous sodium thiosulfate solution and extracted with ethyl

acetate (2 × 200 mL). The organic extracts were combined and

washed several times with additional sodium thiosulfate until the

aqueous layer stopped developing a pink coloration. The organic

extract was washed with distilled water and brine and then dried over

MgSO₄. The organic phase was filtered and concentrated to yield

4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-3-carboxaldehyde 16

(5.05 g, quantitative), which was used without further purification. IR

(neat) cm⁻¹3003, 2966, 2941, 2910, 2887, 2835, 1674, 1622, 1597,

1539, 1497, 1350, 1313, 1250, 1150, 1107. ¹H NMR (400 MHz,

CDCl₃) δ 10.59 (s, 1H), 8.22 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz,

2H), 6.69 (d, J = 2.0 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 3.95 (s, 3H),

3.89 (s, 3H), 3.88 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 187.5,

161.5, 159.6, 158.4, 155.3, 154.6, 130.3, 121.9, 116.2, 113.8, 110.6,

95.5, 88.0, 55.8, 55.7, 55.4. HRMS m/z calcd for C₁₈H₁₇O₅[M + H⁺]

313.1071, found 313.1078; mp = 145 °C−149 °C.

¹H NMR (500 MHz, CDCl₃) δ 8.03 (d, J = 9.0 Hz, 2H), 7.23−7.17 (m,

3H), 7.13−7.07 (m, 2H), 7.00 (d, J = 7.2 Hz, 2H), 6.67 (d, J = 1.5 Hz,

1H), 6.36 (d, J = 1.5 Hz, 1H), 6.29 (s, 1H), 3.94 (s, 3H), 3.94−3.88

(m, 1H), 3.86 (s, 6H), 3.73−3.67 (m, 1H), 1.31 (t, J = 6.5 Hz, 3H).

¹³C NMR (125 MHz, CDCl₃) δ 159.8, 158.9, 155.3, 154.4, 152.7,

131.7, 130.0, 128.1, 128.0, 123.5, 122.9, 113.5, 112.6, 112.2, 94.6,

88.1, 87.5, 84.8, 64.0, 63.2, 55.8, 55.5, 55.4, 15.3. HRMS m/z

calcd for C₂₈H₂₆O₅Na [M + Na⁺] 465.1672, found 465.1666;

mp =98 °C−100 °C.

3-(1-(4-Methoxybenzyloxy)-3-phenylprop-2-ynyl)-4,6-dimethoxy-

2-(4-methoxyphenyl)benzofuran (18b). To a solution of propargylic

alcohol 17a (350 mg, 0.84 mmol) in N,N-dimethylformamide (7.1 mL)

at 0 °C was added sodium hydride (60% dispersion in mineral oil, 40 mg,

1.01 mmol) in one portion. The resulting suspension was stirred for 1 h at

0 °C over which time it turned red. p-Methoxybenzyl chloride (0.14 mL,

1.01 mmol) was added and the suspension stirred to room temperature

overnight. The reaction mixture was diluted with saturated aqueous

ammonium chloride (100 mL) and a 5% w/w aqueous solution of LiCl

(80 mL). The resulting aqueous mixture was extracted with ethyl acetate

(3 × 80 mL), and the combined organics were washed with a 5% w/w

aqueous solution of lithium chloride (3 × 90 mL) and brine, dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo. The resulting oil

was purified by flash chromatography on silica gel (95:5−60:40 hexanes/

ethyl acetate to provide 3-(1-(4-methoxybenzyloxy)-3-phenylprop-2-ynyl)-

4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran 18b (6.19 g, 96%) as

a thick yellow oil. IR (neat) cm⁻¹3002, 2956, 2936, 2906, 2834,

1

1611, 1507, 1464, 1249, 1149, 1113. H NMR (400 MHz, CDCl₃) δ

1-[4,6-Dimethoxy-2-(4-methoxyphenyl)benzofuran-3-yl]-3-phe-

nylprop-2-yn-1-ol (17a). Phenylacetylene (2.70 mL, 24.6 mmol) was

dissolved in 80 mL of dry tetrahydrofuran and cooled to −78 °C. To

this solution, n-butyllithium (11.0 mL of a 1.9 M solution in hexane,

20.9 mmol) was added dropwise under argon. The solution was stirred

for 10 min after which a solution of aldehyde 16 (5.05 g, 16.1 mmol)

in dry tetrahydrofuran (120 mL) was added via cannula. The reaction

was allowed to warm to room temperature and quenched with a

saturated aqueous solution of ammonium chloride. The mixture was

poured into distilled water, and the aqueous phase was made neutral

by the addition of 1 N HCl (aq). The mixture was extracted with ethyl

acetate (2 × 200 mL), and the combined organic extracts were washed

with brine. The organic layer was dried over Na₂SO₄and concentrated.

Precipitation in methyl tert-butyl ether afforded 1-[4,6-dimethoxy-2-

(4-methoxyphenyl)benzofuran-3-yl]-3-phenylprop-2-yn-1-ol 17a.

(5.20 g, 78%). IR (neat) cm⁻¹3474, 3003, 2935, 2836, 1621, 1597,

8.01 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.27−7.17 (m, 5H),

6.99 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 2.0 Hz,

1H), 6.35 (d, J = 2.0 Hz, 1H), 6.28 (s, 1H), 4.83 (d, J = 11.6 Hz, 1H),

4.75 (d, J = 11.6 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.86 (s, 6H). ¹³C

NMR (100 MHz, CDCl₃) δ 159.8, 159.2, 158.9, 155.4, 154.4, 152.8,

131.7, 130.1, 130.0, 128.7, 128.2, 128.1, 123.4, 122.9, 114.0, 113.7,

113.5, 112.4, 112.0, 94.6, 88.0, 87.2, 69.9, 62.3, 55.8, 55.4, 55.35, 55.3.

HRMS m/z calcd for C₃₄H₃₀O₆[M⁺] 534.2037, found 534.2051.

4,6-Dimethoxy-3-(1-((2-methoxybenzyl)oxy)-3-phenylprop-2-

yn-1-yl)-2-(4-methoxyphenyl)benzofuran (18c). To a solution of

propargylic alcohol 17a (350 mg, 0.84 mmol) in dry N,N-dime-

thylformamide (7 mL) at 0 °C was added sodium hydride (60% dispersion

in mineral oil, 41 mg, 1.0 mmol) in one portion. The deep orange

suspension was stirred for 30 min, after which o-methoxybenzyl chloride⁵⁴

(160 mg, 1.0 mmol) was added slowly. The mixture was stirred for 2.5 h

and then diluted with saturated aqueous ammonium chloride (150 mL)

and a 5% w/w aqueous solution of LiCl (80 mL). The resulting aqueous

mixture was extracted with dichloromethane (3 × 100 mL), and the

combined organics were washed with a 5% w/w aqueous solution of

lithium chloride (3 × 90 mL) and brine, dried over anhydrous MgSO₄,

filtered, and concentrated in vacuo. The resulting oil was purified by

flash chromatography on silica gel (95:5−60:40 hexanes/ethyl acetate

to provide 4,6-dimethoxy-3-(1-((2-methoxybenzyl)oxy)-3-phenylprop-

2-yn-1-yl)-2-(4-methoxyphenyl)benzofuran 18c (382 mg, 85%). IR

(neat) cm⁻¹2930, 2840, 1600, 1500, 1250, 1120, 1035, 753. ¹H NMR

(400 MHz, CDCl₃) δ 8.02 (d, J = 8.9 Hz, 2H), 7.45 (d, J = 7.4 Hz,

1H), 7.34−7.04 (m, 6H), 7.01−6.89 (m, 3H), 6.86 (d, J = 8.2 Hz, 1H),

6.65 (d, J = 1.9 Hz, 1H), 6.35 (s, 2H), 4.88 (dd, J = 58.3, 12.3 Hz, 1H),

3.85 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H). ¹³C NMR (125

MHz, CDCl₃) δ 159.8, 158.8, 157.4, 155.3, 154.5, 152.9, 131.7, 130.0,

129.5, 128.6, 128.1, 128.0, 126.6, 123.6, 120.4, 113.5, 112.6, 112.2,

110.1, 94.6, 88.0, 87.5, 85.2, 65.3, 63.0, 55.8, 55.4, 55.4, 55.3.

1

1501, 1255, 1146, 1111. H NMR (400 MHz, CDCl₃) δ 7.63 (d, J =

6.8 Hz, 2H), 7.40 (m, 2H), 7.28 (m, 3H), 7.03 (d, J = 6.8 Hz, 2H),

6.73 (d, J = 1.6 Hz, 1H), 6.45 (d, J = 1.6 Hz, 1H), 5.85 (d, J = 9.2 Hz,

1H), 4.63 (d, J = 9.2 Hz, 1H), 4.06 (s, 3H), 3.87 (s, 6H). ¹³C NMR

(125 MHz, CDCl₃) δ 160.0, 159.3, 156.2, 152.3, 149.7, 131.7, 129.3,

128.3, 128.2, 122.9, 122.8, 115.6, 114.3, 111.2, 95.0, 89.4, 89.1, 84.5,

57.6, 56.2, 55.9, 55.4. HRMS m/z calcd for C₂₈H₂₆O₅[M⁺] 414.1462,

found 414.1471; mp = 119 °C−121 °C.

3-(1-Ethoxy-3-phenylprop-2-ynyl)-4,6-dimethoxy-2-(4-

methoxyphenyl)benzofuran (18a). Propargylic alcohol 17a (3.70 g,

9.00 mmol) was dissolved in 60 mL of dry tetrahydrofuran, and potas-

sium hydride (0.740 g, 18.5 mmol, from the 30% suspension in mineral

oil which was washed three times with hexanes) was added. The re-

action was stirred for ∼5 min until steady gas evolution was observed.

At this point, ethyl iodide (2.22 mL, 27.8 mmol) was added and the re-

action stirred until the intermediary propargyl alcohol is consumed.

The excess potassium hydride was quenched by the addition of a

saturated aqueous solution of ammonium chloride, and the mixture was

poured into distilled water and made neutral by the addition of 1 N

HCl (aq). The mixture was extracted with ethyl acetate (2 × 100 mL),

and the combined organic extracts were washed successively with

distilled water and brine. The organic layer was dried over Na₂SO₄and

concentrated. The resulting residue was subjected to flash column

chromatography (80:20 hexane/ethyl acetate) to afford 3-(1-ethoxy-3-

phenylprop-2-ynyl)-4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran

18a (2.57 g, 64%). IR (neat) cm⁻¹2969, 2936, 2907, 2878, 2836, 1622,

1611, 1592, 1501, 1490, 1296, 1252, 1215, 1149, 1110, 1060, 1029.

1-(4,6-Dimethoxy-2-(4-methoxyphenyl)benzofuran-3-yl)prop-2-

yn-1-ol (17b). To ethynylmagnesium bromide (0.5 M in tetrahy-

drofuran, 1.8 mL, 0.88 mmol) at −78 °C was added a solution of

aldehyde 16 (250 mg, 0.8 mmol) in tetrahydrofuran (8 mL). After

addition, the cooling bath was removed and the reaction solution was

stirred at room temperature for 16 h. The solution was quenched with

saturated aqueous ammonium chloride (50 mL) and partially

concentrated in vacuo to remove tetrahydrofuran. Distilled water

(150 mL) was added, and then the mixture extracted with

dichloromethane (3 × 150 mL). The combined organic layers were

washed with brine (100 mL), dried over anhydrous MgSO₄, filtered,

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and concentrated in vacuo. The resulting orange residue was purified

by flash chromatography on silica gel (95:5−6:4 hexanes/ethyl acetate)

to provide 1-(4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-3-yl)-

prop-2-yn-1-ol 17b (85%). ¹H NMR (400 MHz, CDCl₃) δ 7.57

(d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 1.9 Hz, 1H),

6.43 (d, J = 1.9 Hz, 1H), 5.62 (dd, J = 11.6, 2.3 Hz, 1H), 4.63 (d, J =

11.6 Hz, 1H), 4.04 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 2.56 (d, J =

2.3 Hz, 1H).

deactivated with triethylamine) to afford tributyl(3-(4,6-dimethoxy-2-(4-

methoxyphenyl)benzofuran-3-yl)-3-ethoxy-1-phenylpropa-1,2-dien-1-yl)-

stannane 19b (1.57 g, 95%). This material was used without delay in

subsequent reactions.

Stannylallene 19b (1.55 g, 1.95 mmol) was dissolved in 20 mL of

degassed N,N-dimethylformamide, and m-chloroperoxybenzoic acid

(1.66 g of 77% m-CPBA, 7.41 mmol w/r/t m-CPBA) was added all at

once. The flask was flushed with argon and stirred. After ∼3 h, an

additional 1 equiv of m-CPBA was added and the reaction was stirred

until the starting allene was consumed (an additional 3 h). At this

time, the reaction was poured into a solution of sodium thiosulfate in

water and extracted with ethyl acetate (2 × 50 mL). The organic ex-

tracts were washed with a saturated aqueous solution of sodium bi-

carbonate twice, distilled water, and finally brine. The organic phase

was dried over MgSO₄, filtered, and concentrated to give an orange

residue. This was subjected to flash column chromatography (85:15

hexane/ethyl acetate). Note: fractions containing the desired product

appear orange/blue under UV light. This material was concentrated,

redissolved in the minimum amount of diethyl ether, and allowed to

stand. After a few moments, a precipitate developed and the diethyl

ether suspension was briefly refrigerated. After refrigeration, the

precipitate was filtered to yield pure (3S,3R)-1-ethoxy-6,8-dimethoxy-

3a-(4-methoxyphenyl)-3-phenyl-3,3a-dihydro-2H-cyclopenta[b]-

4,6-Dimethoxy-3-(1-((4-methoxybenzyl)oxy)prop-2-yn-1-yl)-2-(4-

methoxyphenyl)benzofuran (18d). To a solution of propargylic

alcohol 17b (218 mg, 0.64 mmol) in dry N,N-dimethylformamide

(5.4 mL) at 0 °C was added sodium hydride (60% dispersion in

mineral oil, 31 mg, 0.77 mmol) in one portion. The deep red sus-

pension was stirred for 45 min, after which p-methoxybenzyl chloride

(0.10 mL, 0.77 mmol) was added slowly. The mixture was stirred to

room temperature over 16 h and then diluted with saturated aqueous

ammonium chloride (70 mL) and a 5% w/w aqueous solution of lithium

chloride (80 mL). The resulting aqueous mixture was extracted with

ethyl acetate (3 × 150 mL), and the combined organics were washed

with a 5% w/w aqueous solution of lithium chloride (4 × 50 mL) and

brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo.

The resulting yellow residue was purified by flash chromatography on

silica gel (95:5−7:3 hexanes/ethyl acetate) to provide 4,6-dimethoxy-3-

(1-((4-methoxybenzyl)oxy)prop-2-yn-1-yl)-2-(4-methoxyphenyl)-

benzofuran 18d (125 mg, 42%) as a pale yellow tar. IR (neat) cm⁻¹3280,

3000, 2920, 2820, 1612, 1508, 1251, 1150. ¹H NMR (400 MHz, CDCl₃)

δ 7.89 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.9 Hz,

2H), 6.83 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 1.9 Hz, 1H), 6.30 (d, J = 1.9

Hz, 1H), 6.02 (d, J = 2.4 Hz, 1H), 4.69 (d, J = 11.5 Hz, 1H), 4.60 (d, J =

11.5 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 2.37

(d, J = 2.4 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 159.8, 159.2, 158.9,

155.4, 154.3, 152.5, 130.1, 129.7, 128.3, 123.1, 113.6, 113.5, 111.9, 111.7,

94.6, 87.9, 81.5, 73.6, 69.8, 61.6, 55.8, 55.4, 55.3. HRMS m/z calcd for

C₂₈H₂₆O₆Na [M + Na⁺] 481.1627, found 481.1631.

1

benzofuran-2-one 15a as a yellow powder (450 mg, 50%). H NMR

(400 MHz, CDCl₃) δ 7.14−7.08 (m, 5H), 6.91−6.85 (m, 2H), 6.59

(d, J = 7.2 Hz, 2H), 6.18 (d, J = 1.2 Hz, 1H), 6.04 (d, J = 1.2 Hz, 1H),

5.57 (s, 1H), 4.56−4.50 (m, 1H), 4.15−4.09 (m, 1H), 3.80 (s, 3H),

3.67 (s, 3H), 3.09 (s, 3H), 1.45 (t, J = 5.6 Hz, 3H). ¹³C NMR (100

MHz, CDCl₃) δ 198.4, 166.1, 165.6, 159.1, 157.8, 149.9, 144.9, 134.3,

132.0, 130.0, 127.8, 127.4, 127.0, 113.0, 104.7, 98.2, 93.0, 89.7, 68.4,

66.5, 55.9, 55.8, 55.1, 15.8. HRMS m/z calcd for C₂₈H₂₆O₆Na [M +

Na⁺] 481.1627, found 481.1631; mp = 131−135 °C. Ethyl ester 21

was isolated as a byproduct in varying ratios relative to ketone 15a,

depending on the reaction conditions employed. The structure was

1

(3-(4,6-Dimethoxy-2-(4-methoxyphenyl)benzofuran-3-yl)-3-((4-

methoxybenzyl)oxy)-1-phenylpropa-1,2-dien-1-yl)trimethylsilane

(19a). Alkyne 18a (30 mg, 0.068 mmol) was dissolved in 2 mL of dry

tetrahydrofuran and cooled to −40 °C. This solution was treated drop-

wise with tert-butyllithium (0.052 mL of a 1.7 M solution in pentane,

0.088 mmol) and stirred for 20 min. At this time, chlorotrimethylsilane

(12 μL, 0.0947 mmol) was added and after 3 min the reaction was

quenched with a saturated aqueous solution of ammonium chloride

(40 mL). The reaction was poured into distilled water (30 mL, ex-

tracted with ethyl acetate (3 × 25 mL), and the combined organic

extracts were washed with brine (30 mL). The organic layer was dried

over MgSO₄, filtered, and concentrated. The resulting residue was

subjected to flash column chromatography (6:1 hexanes/ethyl acetate)

to yield (3-(4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-3-yl)-3-

((4-methoxybenzyl)oxy)-1-phenylpropa-1,2-dien-1-yl)trimethylsilane

19a (14 mg, 40%) ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 9.2 Hz,

2H), 7.27−7.21 (m, 3H), 7.14−7.08 (m, 2H), 6.66 (d, J = 9.2 Hz,

2H), 6.65 (d, J = 2.0 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 3.86 (m, 5H),

3.82 (s, 3H), 3.81 (s, 3H), 1.46 (t, J = 8.4 Hz, 3H), 0.17 (s, 9H). ¹³C

NMR (100 MHz, CDCl₃) δ 203.0, 159.5, 158.0, 155.7, 154.0, 151.1,

138.9, 128.8, 127.6, 126.2, 124.6, 123.3, 117.5, 113.7, 112.9, 108.4,

94.3, 87.8, 64.0, 55.7, 55.2, 55.0, 15.1, −0.5.

(3S,3aR)-1-Ethoxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phe-

nyl-3,3a-dihydro-2H-cyclopenta[b]benzofuran-2-one (15a). Pro-

pargylic ether 18a (1.00 g, 2.26 mmol) was dissolved in 20 mL of dry

diethyl ether and cooled to −40 °C under argon. To this solution, tert-

butyllithium (1.46 mL, 1.7 M solution in hexanes, 2.49 mmol) was added

dropwise. With the addition of the base, the reaction color progressed

from light yellow to a deep brown. Upon completion of addition, the re-

action was stirred for 5 min, tributyltin chloride (0.74 mL, 2.7 mmol) was

added, and the reaction was allowed to warm to room temperature.

Upon the addition of the stannyl chloride, the color of the reaction

bleached back to yellow and eventually a white precipitate developed.

The magnetic stir bar was removed, the reaction was concentrated,

and the residue was taken up in hexanes and immediately subjected to

flash column chromatography (90:10 hexanes/ethyl acetate on silica

deduced based on H NMR: the chemical shifts were nearly identical

to those measured for methyl ester 7.

(3S,3aR)-6,8-Dimethoxy-1-((4-methoxybenzyl)oxy)-3a-(4-me-

thoxyphenyl)-3-phenyl-3,3a-dihydro-2H-cyclopenta[b]benzofuran-

2-one (15b). Propargylic ether 18b (2.6 g, 4.9 mmol) was dissolved in

70 mL of dry diethyl ether and cooled to −40 °C under argon. To this

solution tert-butyllithium (3.0 mL, 1.7 M solution in hexanes, 5.1 mmol)

was added dropwise. With the addition of the base, the reaction color

progressed from light yellow to a deep brown. The reaction was stirred

for 5 min, and then tributyltin chloride (1.5 mL, 5.6 mmol) was added.

Upon the addition of the stannyl chloride, the color of the reaction

bleached back to yellow and eventually a white precipitate developed.

The reaction was allowed to warm to room temperature, the magnetic

stir bar was removed, the reaction was concentrated, and the residue was

taken up in hexanes and immediately subjected to flash column chro-

matography (75:25 hexanes/ethyl acetate) to afford (3-(4-methox-

ybenzyloxy)-3-(4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-3-yl)-1-

phenylpropa-1,2-dienyl)tributylstannane 19c (3.8 g, 94%). This material

−1

was used without delay in subsequent reactions. IR (neat) cm 3002,

2952, 2921, 2836, 1917, 1612, 1506, 1464, 1247, 1146, 1109. ¹H NMR

(500 MHz, CDCl₃) δ 7.77 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H),

7.25−7.18 (m, 3H), 6.88 (d, J = 8.5 Hz, 2H), 7.10−7.08 (m, 2H), 6.79

(d, J = 9.0 Hz, 2H), 6.67 (d, J = 2.0 Hz, 1H), 6.36 (d, J = 2.0 Hz, 1H),

4.89 (d, J = 11.0 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 3.89 (s, 3H), 3.85

(s, 6H), 3.83 (s, 3H), 1.45−1.35 (m, 6H), 1.25−1.15 (m, 12H), 0.80

(t, J = 7.0 Hz, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 200.1, 159.4, 159.1,

158.9, 155.8, 154.2, 150.8, 140.4, 130.3, 130.1, 129.5, 128.9, 128.2, 128.1,

126.3, 123.5, 123.2, 116.5, 113.7, 113.0, 109.1, 94.3, 87.8, 70.2, 55.7,

55.3, 55.2, 46.2, 29.0, 27.2, 11.6. HRMS m/z calcd for C₃₄H₃₀O₆[M⁺]

534.2037, found 534.2051.

Stannylallene 19c (3.8 g, 4.6 mmol) was dissolved in 150 mL of

degassed N,N-dimethylformamide, and m-chloroperoxybenzoic acid

(4.50 g of 77% m-CPBA, 18.4 mmol w/r/t m-CPBA) was added all at

once. The flask was flushed with argon and stirred. After ∼3 h, an addi-

tional 1 equiv of m-CPBA was added and the reaction was stirred until

the starting allene was consumed (an additional 3 h). At this time, the

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2,4-dienone (26). Nazarov product 15a (59 mg, 0.00013 mmol) was

dissolved in 3 mL of dichloromethane. To this solution, 1,4-dia-

zabicyclo[2.2.2]octane (3 drops) was added. Upon addition of base,

the reaction immediately developed a dark coloration. The solvent was

removed via rotary evaporation, and the crude product was subjected to

flash column chromatography, eluting with 4:1 hexane/ethyl acetate to

give 2-ethoxy-3-(2-hydroxy-4,6-dimethoxyphenyl)-4-(4-methoxy-6,8-

dimethoxy-1-((4-methoxybenzyl)oxy)-3a-(4-methoxyphenyl)-3,3a-di-

hydro-2H-cyclopenta[b]benzofuran-2-one phenyl)-5-phenylcyclopenta-

2,4-dienone 26 as a dark brown oil (53 mg, 90%). ¹H NMR (400 MHz,

CDCl₃) δ 7.23−7.17 (m, 5H), 6.83 (d, J = 8.0 Hz, 2H), 6.63 (d, J = 8.0 Hz,

2H), 6.25 (d, J = 4.0 Hz, 1H), 5.83 (d, J = 4.0 Hz, 1H), 4.35−4.29

(m, 1H), 4.26−4.20 (m, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.06 (s, 3H),

1.29 (t, J = 5.0 Hz, 8H). ¹³C NMR (100 MHz, CDCl₃) δ 195.0(q),

162.6(q), 159.8(q), 158.5(q), 155.1(q), 142.9(q), 131.2(q), 130.1(CH),

15.6(CH₃), 129.5(CH), 128.1(CH), 127.0(CH), 126.7(q), 125.4(q),

118.8(q), 113.1(CH), 101.5(q), 94.2(CH), 92.1(CH), 67.9(CH₂), 55.5-

(CH₃), 55.3(CH₃), 55.2(CH₃).

reaction was poured into distilled water and extracted with ethyl acetate

(2 × 200 mL). The organic extracts were washed with distilled water

twice, a 10% solution of sodium thiosulfate, and finally brine. The

organic phase was dried over MgSO₄, filtered, and concentrated to give

an orange residue. This was subjected to flash column chromatography

(80:20 hexanes/ethyl acetate). Note: fractions containing the desired

product appear bright yellow under UV light. This material was con-

centrated, redissolved in the minimum amount of diethyl ether, and

allowed to stand. After a few moments, a precipitate developed and the

diethyl ether suspension was briefly refrigerated. After refrigeration, the

precipitate was filtered to yield pure (3S,3aR)-6,8-dimethoxy-1-((4-

methoxybenzyl)oxy)-3a-(4-methoxyphenyl)-3-phenyl-3,3a-dihydro-2H-

cyclopenta[b]benzofuran-2-one 15b as a yellow powder (960 mg,

38%). ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 8.4 Hz, 2H), 7.13−

7.07 (m, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.82 (m, 2H), 6.78 (d, J = 8.4

Hz, 2H), 6.48 (d, J = 8.8 Hz, 2H), 6.15 (d, J = 2.0 Hz, 1H), 6.04 (d, J =

2.0 Hz, 1H), 5.64 (d, J = 11.7 Hz, 1H), 5.38 (d, J = 11.7 Hz, 1H), 4.52

(s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 3.64 (s, 3H). ¹³C

NMR (100 MHz, CDCl₃) δ 198.6, 166.3, 165.6, 159.6, 159.0, 157.8,

151.3, 143.9, 134.4, 131.7, 130.3, 130.0, 129.7, 128.6, 127.8, 127.4,

127.0, 113.8, 112.8, 98.3, 93.0, 89.6, 72.6, 66.6, 55.8, 55.8, 55.27, 55.0.

HRMS m/z calcd for C₃₄H₃₁O₇[M + H⁺] 551.2064, found 551.2064;

mp =135 °C−139 °C.

4,6-Dimethoxy-3-(1-((4-methoxybenzyl)oxy)propa-1,2-dien-1-yl)-

2-(4-methoxyphenyl)benzofuran (20). To a solution of propargylic

ether 18d (177 mg, 0.386 mmol) in dimethyl sulfoxide (1.0 mL) was

added benzyltrimethylammonium hydroxide (40 wt %/wt in MeOH,

0.1 mL, 0.20 mmol). The red solution was warmed to 40 °C, stirred for

1 h, and then poured into water (70 mL). The aqueous solution was

extracted with ethyl acetate (3 × 80 mL), and the combined organics

were washed with brine, dried over anhydrous MgSO₄, filtered, and

concentrated in vacuo to provide 4,6-dimethoxy-3-(1-((4-

methoxybenzyl)oxy)propa-1,2-dien-1-yl)-2-(4-methoxyphenyl)-

benzofuran 20 as a red-orange oil which was brought to the Nazarov

cyclization step without delay. IR (neat) cm⁻¹2995, 2922, 2839, 2367,

2339, 1952, 1616, 1508, 1458, 1250, 1219, 1175, 1148, 1111, 1030.

¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 8.9 Hz, 2H), 7.35 (d, J =

8.6 Hz, 2H), 6.88 (dd, J = 12.6, 8.8 Hz, 4H), 6.62 (d, J = 1.8 Hz, 1H),

6.31 (d, J = 1.8 Hz, 1H), 5.41 (s, 2H), 4.79 (s, 2H), 3.85 (s, 3H), 3.84

(s, 3H), 3.83 (s, 3H), 3.79 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ

200.8, 159.4, 159.2, 159.0, 155.7, 154.2, 150.5, 129.9, 129.7, 127.9,

125.7, 123.4, 113.8, 113.7, 112.6, 107.9, 94.8, 88.8, 87.9, 77.2, 70.5,

55.8, 55.3, 55.3.

(2S,3S,3aS)-3a-Ethoxy-6,8-dimethoxy-1-(4-methoxyphenyl)-2-phenyl-

3,3a-dihydro-2H-cyclopenta[b]benzofuran-3-ol (27). Lithium triethylbor-

ohydride (0.42 mL of a 1 M solution in tetrahydrofuran, 0.42 mmol)

was diluted with dry tetrahydrofuran (6 mL) and cooled to −30 °C.

To this solution, Nazarov product 15a (60 mg, 0.013 mmol) in 2 mL

of dry tetrahydrofuran was added dropwise. The reaction was stirred

for ∼2 min and was then poured into a saturated aqueous solution

of sodium bicarbonate. The aqueous phase was extracted with ethyl

acetate, and the organic phase was washed with brine, dried over

MgSO₄, filtered, and concentrated to give (2S,3S,3aS)-3a-ethoxy-6,8-

dimethoxy-1-(4-methoxyphenyl)-2-phenyl-3,3a-dihydro-2H-

cyclopenta[b]benzofuran-3-ol 27 which was used crude for subsequent

reactions (40 mg, 67%). Column chromatography could be performed

with triethylamine-deactivated silica, eluting with 3:1 hexanes/ethyl

1

acetate. H NMR (500 MHz, CDCl₃) δ 7.43−7.37 (m, 5H), 7.25 (d,

J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.27 (d, J = 2.0 Hz), 6.18 (d,

J = 2.0 Hz, 1H), 4.63 (dd, J = 12.0 Hz, 8 Hz, 1H), 4.49 (d, J = 8.0 Hz,

1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.57−3.51 (m, 1H),

3.48−3.52 (m, 1H), 2.42 (d, J = 12.5 Hz, 1H), 1.00 (t, J = 7.0 Hz, 3H).

¹³C NMR (125 MHz, CDCl₃) δ 166.1(q), 163.42(q), 159.4(q),

155.3(q), 138.5(q), 134.9(q), 132.5(q), 130.5(CH), 130.2(CH),

129.6(q), 127.9(CH), 127.2 (CH), 117.0(q), 112.5(CH), 104.3(q),

92.8(CH), 89.1(CH), 77.2(CH), 62.2(CH), 59.2(CH₂), 55.8(CH₃),

55.4(CH₃), 55.1(CH₃), 15.07(CH₃).

(2S,3S,3aS)-3a-Ethoxy-6,8-dimethoxy-1-(4-methoxyphenyl)-2-

phenyl-3,3a-dihydro-2H-cyclopenta[b]benzofuran-3-yl Methyl Car-

bonate (28a). Mixed ketal 27 (35 mg, 0.075 mmol) was dissolved in

2 mL of dry tetrahydrofuran and cooled to −78 °C. n-Butyllithium

(0.06 mL of a 1.98 M solution in pentane, 0.113 mmol) was added

slowly, and the reaction was stirred for 2 min. After this time, freshly

distilled methyl chloroformate (0.012 mL, 0.150 mmol) was added.

The reaction was stirred for ∼3 min and was then poured into a satur-

ated aqueous solution of sodium bicarbonate. The aqueous phase was

extracted with ethyl acetate, and the organic phase was washed with

brine, dried over MgSO₄, filtered, and concentrated. The residue was

subjected to flash column chromatography (3:1 hexanes/ethyl acetate)

to give (2S,3S,3aS)-3a-ethoxy-6,8-dimethoxy-1-(4-methoxyphenyl)-2-

phenyl-3,3a-dihydro-2H-cyclopenta[b]benzofuran-3-yl methyl carbo-

nate 28a (40 mg, 90%). ¹H NMR (500 MHz, CDCl₃) δ 7.36−7.30 (m,

5H), 7.19 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 6.24 (s, 1H),

6.12 (s, 1H), 5.42 (d, J = 8.0 Hz, 1H), 4.72 (d, J = 8.0 Hz, 1H), 3.83

(s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 3.69 (s, 3H), 3.60−3.54 (m, 1H),

3.51−3.45 (m, 1H), 1.03 (t, J = 8.8 Hz, 3H).

(2S,3S,3aS)-3a-Ethoxy-6,8-dimethoxy-1-(4-methoxyphenyl)-2-

phenyl-3,3a-dihydro-2H-cyclopenta[b]benzofuran-3-yl Trifluoro-

methanesulfonate (28b). Mixed ketal 27 (69 mg, 0.15 mmol) was

dissolved in 4 mL of dry tetrahydrofuran and cooled to −78 °C.

n-Butyllithium (0.09 mL of a 2.5 M solution in pentane, 0.223 mmol)

was added slowly, and the reaction was stirred for 2 min. After this

time, 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine

(117 mg, 0.297 mmol) in 0.5 mL of dry tetrahydrofuran was added.

The reaction was stirred for ∼3 min without cooling after which silica

6,8-Dimethoxy-1-((4-methoxybenzyl)oxy)-3a-(4-methoxyphen-

yl)-3,3a-dihydro-2H-cyclopenta[b]benzofuran-2-one (22). To allene

20 (180 mg, 0.39 mmol) in acetone (HPLC grade, 3 mL) was added a

solution of dimethyldioxirane in acetone (0.084 M, 7.0 mL, 0.58

mmol) slowly. The yellow solution was stirred for 10 min, diluted with

water (60 mL), and partially concentrated in vacuo to remove acetone.

The resulting mixture was extracted with ethyl acetate (3 × 80 mL).

The organic layers were combined and washed with brine, dried over

anhydrous MgSO₄, filtered, and concentrated in vacuo. The resulting

orange residue was purified by flash chromatography on silica gel

(95:5−75:25 hexanes/ethyl acetate) to provide 6,8-dimethoxy-1-((4-

methoxybenzyl)oxy)-3a-(4-methoxyphenyl)-3,3a-dihydro-2H-

cyclopenta[b]benzofuran-2-one 22 (116 mg, 63% over two steps from

propargylic ether 18d) as a pale yellow tar. IR (neat) cm⁻¹2880, 2834,

1

1703, 1606, 1509, 1246, 1146, 1083, 1028, 812. H NMR (400 MHz,

CDCl₃) δ 7.38 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 6.85 (d,

J = 8.6 Hz, 2H), 6.70 (d, J = 8.9 Hz, 2H), 6.16 (d, J = 1.9 Hz, 1H), 6.01

(d, J = 1.9 Hz, 1H), 5.45 (d, J = 11.5 Hz, 1H), 5.27 (d, J = 11.5 Hz,

1H), 3.82 (s, 3H), 3.80 (s, 6H), 3.73 (s, 3H), 3.17 (d, J = 15.8 Hz,

1H), 2.86 (d, J = 15.8 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 199.5,

166.3, 165.8, 159.5, 159.1, 157.8, 154.6, 143.9, 134.3, 130.0, 129.6,

125.8, 113.8, 113.7, 104.5, 93.0, 92.9, 89.4, 72.8, 55.8, 55.7, 55.2, 55.2,

51.6. HRMS m/z calcd for C₂₈H₂₇O₇[M + H⁺] 475.1757, found

475.1753.

2-Ethoxy-3-(2-hydroxy-4,6-dimethoxyphenyl)-4-(4-methoxyp6,8-di-

methoxy-1-((4-methoxybenzyl)oxy)-3a-(4-methoxyphenyl)-3,3a-dihy-

dro-2H-cyclopenta[b]benzofuran-2-one phenyl)-5-phenylcyclopenta-

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gel was added. The reaction was concentrated, and the resulting

residue was subjected to flash column chromatography (4:1 hexanes/

ethyl acetate) to give (2S,3S,3aS)-3a-ethoxy-6,8-dimethoxy-1-(4-

methoxyphenyl)-2-phenyl-3,3a-dihydro-2H-cyclopenta[b]benzofuran-

3-yl trifluoromethanesulfonate 28b (84 mg, 95%) ¹H NMR

(400 MHz, CDCl₃) δ 7.42−7.36 (m, 5H), 7.16 (d, J = 8.4 Hz, 2H),

6.76 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 2.0 Hz, 1H), 6.14 (d, J = 2.0 Hz,

1H), 5.50 (d, J = 8.0 Hz, 1H), 4.67 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H),

3.79 (s, 3H), 3.70 (s, 3H), 3.58−3.52 (m, 1H), 3.49−3.43 (m, 1H),

1.01 (t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.0, 163.7,

159.6, 155.5, 136.0, 132.8, 132.5, 130.3, 130.1, 128.2, 128.0, 127.9,

115.7, 112.5, 103.4, 93.0, 89.2, 85.0, 60.5, 59.8, 55.7, 55.2, 55.0, 15.0.

3-(2-Hydroxy-4,6-dimethoxyphenyl)-4-(4-methoxyphenyl)-6-phe-

nyl-2H-pyran-2-one (29). The mixed ketal 27 was purified via flash

column chromatography on silica gel. The combined product-containing

fractions were evaporated in a round-bottom flask until a thin film remained.

The product containing flask was exposed to air for 12 h upon which time

the residue was resubjected to flash column chromatography (3:1 hexanes/

(3aS,8bR)-Methyl 8b-Hydroxy-6,8-dimethoxy-3a-(4-methoxy-

phenyl)-1-oxo-3-phenyl-3a,8b-dihydro-1H-cyclopenta[b]-

benzofuran-2-carboxylate (39). The enol triflate 38 (112 mg,

0.194 mmol) was dissolved in 4 mL of dry tetrahydrofuran. The

solution was saturated with carbon monoxide for 5 min whereupon

tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.048 mmol),

methanol (0.62 mL, 16 mmol), and N,N-diisopropylethylamine

(0.135 mL, 0.776 mmol) were added. The reaction was warmed to

65 °C for 6 h. Upon consumption of the starting material, the reaction

was poured into distilled water and extracted with ethyl acetate (3 ×

20 mL). The organic extract was washed with distilled water and then

brine. The organic layer was dried over MgSO₄, filtered, and con-

centrated. The resulting residue was subjected to flash column chro-

matography (50:50 hexanes/ethyl acetate) to yield (3aS,8bR)-methyl

8b-hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-1-oxo-3-phenyl-

3a,8b-dihydro-1H-cyclopenta[b]benzofuran-2-carboxylate 39 (69 mg,

79%) as a white solid. IR (neat) cm⁻¹3445, 2955, 2843, 1740, 1613,

1219, 1150. ¹H NMR (400 MHz, CDCl₃) δ 7.38−7.29 (m, 7H), 6.93

(d, J = 8.8 Hz, 2H), 6.13 (d, J = 2.0 Hz, 1H), 6.08 (d, J = 2.0 Hz, 1H),

3.82 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.24 (s, 1H).

¹³C NMR (100 MHz, CDCl₃) δ 196.2, 166.1, 164.2, 164.1, 160.9,

159.8, 158.5, 133.0, 131.6, 130.9, 129.4, 128.3, 127.5, 125.8, 114.1,

105.8, 98.5, 92.8, 88.6, 86.9, 55.6, 55.6, 52.5, 55.2. HRMS m/z calcd

for C₂₈H₂₄O₈[M⁺] 488.1466, found 488.1482; mp =189 °C−191 °C.

(2R,3S,3aR,8bR)-Methyl 8b-Hydroxy-6,8-dimethoxy-3a-(4-me-

thoxyphenyl)-1-oxo-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta-

[b]benzofuran-2-carboxylate (40). α,β-Unsaturated ester 39 (52 mg,

0.11 mmol) was dissolved in 10 mL of absolute ethanol, platinum

oxide (10 mg) was added, and the solution was saturated with hydro-

gen gas for 10 min and stirred at room temperature for 3 h. Upon

consumption of the starting material, the reaction was filtered over

Celite and the filtrate concentrated. The resulting residue was subjected

to flash column chromatography (50:50 hexanes/ethyl acetate) to yield

(2R,3S,3aR,8bR)-methyl 8b-hydroxy-6,8-dimethoxy-3a-(4-methoxy-

phenyl)-1-oxo-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]-

benzofuran-2-carboxylate 40 (33 mg, 65%). Note: purification of 40

obtained under these reaction conditions was difficult and reaction results

were erratic.

1

ethyl acetate) to yield pyrone 29 (84%). H NMR (400 MHz, CDCl₃)

δ 7.62 (s, 1H), 7.28−7.22 (m, 3H), 7.04−6.98 (m, 2H), 6.77 (d, J = 8.8

Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 6.12 (d, J = 2.0 Hz, 1H), 6.08 (s, 1H),

5.88 (d, J = 2.0 Hz, 1H), 3.72 (s, 3H), 3.68 (s, 3H), 3.43 (s, 3H).

(3aS,8bR)-2,8b-Dihydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-

3-phenyl-3a,8b-dihydro-1H-cyclopenta[b]benzofuran-1-one (37).

Nazarov product 15b (264 mg, 0.480 mmol) was dissolved in 5 mL

of dichloromethane. To this solution, 1 mL of distilled water was added

followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (489 mg,

2.16 mmol). The reaction was stirred at room temperature for 12 h.

Upon completion, the reaction was poured into distilled water and

extracted with ethyl acetate (2 × 20 mL). The organic layer was washed

exhaustively with distilled water to remove the excess DDQ. The

organic layer was then washed with brine, dried over MgSO₄, filtered,

and concentrated. The resulting residue was subjected to flash column

chromatography (60:40 ethyl acetate/hexanes) to yield (3aS,8bR)-2,8b-

dihydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phenyl-3a,8b-dihydro-

1H-cyclopenta[b]benzofuran-1-one 37 (158 mg, 71%) as a white solid.

1

IR (neat) cm⁻¹3432, 3315, 1710, 1598, 1512, 1500, 1393. H NMR

(3aS,8bR)-Methyl 6,8-Dimethoxy-3a-(4-methoxyphenyl)-1-oxo-

3-phenyl-8b-((trimethylsilyl)oxy)-3a,8b-dihydro-1H-cyclopenta[b]-

benzofuran-2-carboxylate (41). Alkylidene β-ketoester 39 (69 mg,

0.15 mmol) was dissolved in 3 mL of benzene. To this solution, N,N-

diisopropylethylamine (0.080 mL, 0.046 mmol) and 4-dimethylami-

nopyridine (2 mg, 0.015 mmol) were added. Chlorotrimethyl silane

(0.039 mL, 0.306 mmol) was added, and the reaction was stirred at

room temperature for 30 min. Upon consumption of the starting

material, the reaction was filtered over a plug of silica (ethyl acetate)

and the filtrate concentrated to yield 3aS,8bR)-methyl-6,8-dimethoxy-

3a-(4-methoxyphenyl)-1-oxo-3-phenyl-8b-((trimethylsilyl)oxy)-3a,8b-

dihydro-1H-cyclopenta[b]benzofuran-2-carboxylate 41 (83 mg, 96%).

(400 MHz, CDCl₃) δ 7.99 (d, J = 5.6 Hz, 2H), 7.37−7.29 (m, 5H), 6.88

(d, J = 6.8 Hz, 2H), 6.16 (d, J = 1.2 Hz, 1H), 6.06 (d, J = 1.2 Hz, 1H),

3.82 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 2.88 (broad s, 1H). ¹³C NMR

(100 MHz, CDCl₃) δ 195.6, 164.4, 161.7, 159.7, 158.7, 148.3, 132.9,

131.2, 130.7, 129.3, 128.3, 127.9, 113.9, 105.0, 98.0, 92.7, 88.8, 83.9, 55.7,

55.6, 55.2. HRMS m/z calcd for C₂₆H₂₂O₇Na [M + Na⁺] 469.1258,

found 469.1265; mp = 95−100 °C.

(3aS,8bR)-8b-Hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-1-

oxo-3-phenyl-3a,8b-dihydro-1H-cyclopenta[b]benzofuran-2-yl Tri-

fluoromethanesulfonate (38). Diosphenol 37 (105 mg, 0.235 mmol)

was dissolved in 4 mL of dry tetrahydrofuran and cooled to 0 °C under

argon. To this solution, freshly prepared potassium bis(trimethylsilyl)-

amide (0.59 mL of a 1 M solution in tetrahydrofuran, 0.59 mmol) was

added dropwise. The solution was stirred for 3 min whereupon 2-[N,N-

bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (168 mg, 0.47

mmol) was added slowly in 1 mL of dry tetrahydrofuran. The reac-

tion was stirred at 0 °C for 30 min and then poured into distilled water

(20 mL). The aqueous layer was extracted with ethyl acetate (3 ×

25 mL), and the combined organic extracts were washed with brine. The

organic layer was dried over MgSO₄, filtered, and concentrated. The

resulting residue was subjected to flash column chromatography (60:40

hexanes/ethyl acetate) to yield (3aS,8bR)-8b-hydroxy-6,8-dimethoxy-3a-

(4-methoxyphenyl)-1-oxo-3-phenyl-3a,8b-dihydro-1H-cyclopenta[b]-

benzofuran-2-yl trifluoromethanesulfonate 38 (112 mg, 83%) as a yellow

solid. IR (neat) cm⁻¹3445, 2940, 2843, 1740, 1624, 1597, 1512, 1427,

1

IR (neat) cm⁻¹2959, 2932, 2917, 2847, 1740, 1597, 1427, 1219. H

NMR (400 MHz, CDCl₃) δ 7.34−7.32 (m, 3H), 7.27−7.23 (m, 4H),

6.91 (d, J = 9.2 Hz, 2H), 6.11 (d, J = 2.0 Hz, 1H), 6.06 (d, J = 2.0 Hz,

1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), −0.03

(s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 194.6, 164.5, 164.3, 159.7,

161.0, 158.7, 133.5, 131.7, 130.3, 129.1, 128.3, 128.2, 126.9, 113.6,

106.6, 99.1, 92.5, 89.2, 88.5, 55.5, 55.3, 55.1, 52.3, 1.0. HRMS m/z

calcd for C₃₁H₃₂O₈Si [M⁺] 560.1861, found 560.1874.

(2R,3S,3aR,8bR)-Methyl 6,8-Dimethoxy-3a-(4-methoxyphenyl)-1-

oxo-3-phenyl-8b-((trimethylsilyl)oxy)-2,3,3a,8b-tetrahydro-1H-

cyclopenta[b]benzofuran-2-carboxylate (42). Silyl ether 41 (76 mg,

0.11 mmol) was dissolved in 15 mL of absolute ethanol, platinum

oxide (10 mg) was added, and the solution was saturated with hydro-

gen gas for 10 min and stirred at room temperature for 6 h. Upon

consumption of the starting material, the reaction was filtered over

Celite and the filtrate concentrated. The resulting residue was subjected

to flash column chromatography (80:20 hexane/ethyl acetate) to yield

(2R,3S,3aR,8bR)-methyl 6,8-dimethoxy-3a-(4-methoxyphenyl)-1-oxo-

3-phenyl-8b-((trimethylsilyl)oxy)-2,3,3a,8b-tetrahydro-1H-cyclopenta-

1

1215. H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 8.8 Hz, 2H), 7.43−

7.33 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 6.13 (d, J = 2.0 Hz, 1H), 6.08

(d, J = 2.0 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.03 (s, 1H). ¹³C NMR

(100 MHz, CDCl₃) δ 191.2, 164.7, 161.1, 160.1, 158.7, 152.7, 142.5,

131.8, 130.4, 128.8, 128.2, 127.6, 126.0, 114.3, 105.2, 97.1, 93.1, 88.9,

84.6, 55.8, 55.7, 55.3. HRMS m/z calcd for C₂₇H₂₁O₉F₃SNa [M + Na⁺]

601.0751, found 601.0734; mp =179 °C−183 °C.

1

[b]benzofuran-2-carboxylate 42 (42 mg, 55%). H NMR (500 MHz,

CDCl₃) δ 7.11−7.05 (m, 3H), 6.92 (d, J = 8.5 Hz, 2H), 6.80 (m, 2H),

1905

dx.doi.org/10.1021/jo202366c | J. Org. Chem. 2012, 77, 1891−1908

The Journal of Organic Chemistry

Article

6.64 (d, J = 8.5 Hz, 2H), 6.32 (d, J = 2.0 Hz, 1H), 6.08 (d, J = 2.0 Hz,

1H), 4.08 (d, J = 13.5 Hz, 1H), 3.94 (d, J = 13.5 Hz, 1H), 3.87 (s, 3H),

3.79 (s, 3H), 3.72 (s, 3H), 3.62 (s, 3H), −0.38 (s, 9H). ¹³C NMR

(125 MHz, CDCl₃) δ 201.2, 167.7, 165.1, 161.4, 159.4, 158.7, 135.8,

128.5, 128.0, 127.8, 127.0, 126.4, 112.6, 105.7, 99.7, 92.6, 89.6, 58.4, 56.4,

55.6, 55.3, 55.1, 52.7, 51.3, 0.6. HRMS m/z calcd for C₃₁H₃₄O₈SiNa

[M + Na⁺] 585.1915, found 585.1941; mp =155 °C−158 °C

(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 174.0, 164.1, 160.8, 158.6,

156.8, 136.8, 128.9, 127.8, 127.7, 126.6, 126.2, 112.7, 107.5, 101.8,

93.6, 92.6, 89.4, 79.3, 55.8, 55.7, 55.0, 54.9, 50.1 (lit.¹⁴).

Rocaglamide (1a). Rocagloic acid 1d (11 mg, 0.023 mmol) was

dissolved in 4 mL of dry dichloromethane. Dicyclohexylcarbodiimide

(12 mg, 0.058 mmol), 4-dimethylaminopyridine (19 mg, 0.15 mmol),

and dimethylamine hydrochloride (6 mg, 0.07 mmol) were added, and

the reaction was stirred at room temperature for 15 h. The reaction

was quenched with 1 N HCl and extracted with dichloromethane (2 ×

10 mL). The combined organic layers were washed with distilled water

and brine and then dried over MgSO₄. The organic phase was filtered and

concentrated, and the resulting residue was subjected to flash column

chromatography (ethyl acetate) to yield rocaglamide 1a as a white solid

(7 mg, 60%). Eventually rocaglamide can be recrystallized from dichloro-

methane/hexanes to give translucent crystals. IR (neat) cm⁻¹3500−3250,

2935, 2838, 1620, 1512, 1496. ¹H NMR (400 MHz, CDCl₃) δ 7.12 (dd,

J = 6.8, 2.0 Hz, 2H), 7.08−7.00 (m, 3H), 6.90−6.86 (m, 2H), 6.69 (dd, J =

6.8, 2.4 Hz, 2H), 6.29 (d, J = 2.0 Hz, 1H), 6.12 (d, J = 2.0 Hz, 1H), 4.94

(dd, J = 6.4, 2.0 Hz, 1H), 4.57 (d, J = 13.4 Hz, 1H), 4.07 (dd, J = 13.4,

6.4 Hz, 1H), 4.03 (bs, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.72 (s, 3H), 3.33

(s, 3H), 2.95 (s, 3H), 1.81 (s, 1H). ¹³C NMR (100 MHz, CDCl₃) δ

169.5, 163.9, 161.0, 158.6, 157.2, 137.6, 128.8, 127.7, 127.6, 127.1,

126.2, 112.7, 107.6, 101.7, 94.0, 92.5, 89.2, 78.5, 56.0, 55.6, 55.0,

47.7, 37.0, 35.7. HRMS m/z calcd for C₂₉H₃₁O₇NNa [M + Na⁺]

528.1993, found 528.1981; mp =119−121 °C (lit.^10c¹H NMR, ¹³C NMR,

HRMS, mp).

(2R,3S,3aR,8bR)-Methyl 8b-Hydroxy-6,8-dimethoxy-3a-(4-me-

thoxyphenyl)-1-oxo-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta-

[b]benzofuran-2-carboxylate (40). Silyl ether 42 (50 mg, 0.09 mmol)

was dissolved in 3 mL of dry methanol. To this solution, potassium

fluoride (100 mg, 1.7 mmol) was added. The reaction was stirred at

room temperature for 6 h after which the starting material was con-

sumed. The methanol solution was poured into saturated ammonium

chloride solution and extracted twice with ethyl acetate (2 × 25 mL).

The combined organic extracts were washed with distilled water and

brine and then dried over MgSO₄. The organic phase was filtered and

concentrated to yield (2R,3S,3aR,8bR)-methyl 8b-hydroxy-6,8-dime-

thoxy-3a-(4-methoxyphenyl)-1-oxo-3-phenyl-2,3,3a,8b-tetrahydro-1H-

cyclopenta[b]benzofuran-2-carboxylate 40 (45 mg, quantitative) which

was used without further purification. The compound was obtained

1

as a 1:1 to 3:1 mixture of the keto- and the enolic forms. H NMR

(400 MHz, CDCl₃) δ 10.60 (s, 1H, enol), 7.10−7.06 (m, 3H), 7.01 (d,

J = 9.2 Hz, 2H, enol), 6.95−6.91 (m, 3H), 6.68 (d, J = 9.2 Hz, 2H,

ketone), 6.53 (d, J = 9.2 Hz, 2H, enol), 6.35 (d, J = 2.0 Hz, 1H,

ketone), 6.19 (d, J = 2.0 Hz, 1H, enol), 6.11 (d, J = 2.0 Hz, 1H,

ketone), 6.05 (d, J = 2.0 Hz, 1H, enol), 4.48 (s, 1H, enol), 4.24 (d, J =

13.2 Hz, 1H, ketone), 3.88 (d, J = 13.2 Hz, 1H, ketone), 3.86 (s, 3H,

ketone), 3.83 (s, 3H, enol), 3.81 (s, 3H, ketone), 3.79 (s, 3H, enol),

3.71 (s, 3H, ketone), 3.66 (s, 3H, ketone), 3.65 (s, 3H, enol), 3.59 (s,

3H, enol). ¹³C NMR (100 MHz, CDCl₃) δ 203.4, 172.0, 170.1, 167.3,

165.0, 163.6, 161.0, 160.8, 158.9, 158.6, 158.5, 158.1, 138.9, 135.4,

129.1, 129.0, 128.0, 127.9, 127.7, 127.2, 127.0, 126.6, 113.2, 112.0,

106.1, 105.8, 102.3, 100.7, 99.3, 92.9, 92.4, 89.9, 89.1, 88.9, 88.5, 56.4,

56.9, 55.7, 55.6, 55.1, 54.9, 52.9, 51.9, 51.5. HRMS m/z calcd for

C₂₈H₂₆O₈Na [M + Na⁺] 513.1520, found 513.1524.

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H and ¹³C spectra for all new compounds, X-ray crystal struc-

ture coordinates and files for compounds 15a, 28a, 29, and 38

in CIF format. This material is available free of charge via the

Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: frontier@chem.rochester.edu.

■

Aglafolin (1e). Sodium borohydride (80 mg, 2.1 mmol) was slowly

and carefully added in 3 mL of glacial acetic acid. After the mixture was

stirred 30 min, the resulting solution was added to a solution of

β-ketoester 20 (25 mg, 0.050 mmol) in 1 mL of dry acetonitrile. The

reaction was stirred at room temperature for 15 h, poured into water,

and extracted with ethyl acetate (3 × 10 mL). The combined organic

layers were washed with distilled water (10 mL) and brine and then

dried over MgSO₄. The organic phase was filtered and concentrated,

and the resulting residue was subjected to flash column chromatog-

raphy (80:20 ethyl acetate/hexanes) to yield aglafolin 1e (14 mg, 56%)

as a single stereoisomer. IR (neat) cm⁻¹3483, 3005, 2951, 2839, 1744,

ACKNOWLEDGMENTS

■

We thank the National Institutes of Health (NIGMS R01

GM079364) and the ARRA (3R01 GM079364-03S2) for

funding this work. We are also grateful to Dr. William Brennessel

(University of Rochester) for solving structures by X-ray

crystallography, Dr. Sandip Sur (University of Rochester) for

assistance with NMR spectroscopy, and Dr. Alice Bergmann

(University of Buffalo) and Dr. Furong Sun (University of

Illinois at Urbana−Champaign) for carrying out high-resolution

mass spectroscopy. A.J.F. thanks Prof. Philip Magnus for helpful

discussions throughout this synthetic journey.

1

1601, 1501, 1439, 1250. H NMR (400 MHz, CDCl₃) δ 7.09 (d, J =

9.2 Hz, 2H), 7.07−7.01 (m, 3H), 6.88−6.81 (m, 2H), 6.65 (d, J = 9.2

Hz, 2H), 6.26 (d, J = 1.6 Hz, 1H), 6.10 (d, J = 1.6 Hz, 1H), 5.01 (dd,

J = 6.8, 1.2 Hz, 1H), 4.28 (d, J = 14.4 Hz, 1H), 3.88 (dd, J = 14.4,

6.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H), 3.63 (s, 3H),

3.62 (s, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 170.5, 164.1, 160.9,

158.7, 157.0, 136.9, 128.9, 128.3, 127.8, 127.7, 126.5, 112.7, 107.7,

101.9, 93.7, 92.6, 89.5, 79.5, 55.7, 55.6, 55.1, 55.0, 51.9, 50.4. HRMS

m/z calcd for C₂₈H₂₈O₈Na [M + Na⁺] 515.1676, found 515.1701;

mp = 89−91 °C.

Rocagloic Acid (1d). Aglafolin 1e (14 mg, 0.028 mmol) was dis-

solved in 6 mL of a 5:1 mixture of tetrahydrofuran and distilled water.

Lithium hydroxide (10 mg, 0.42 mmol) was added, and the reaction

was stirred at room temperature for 12 h. The mixture was diluted

with 20 mL of dichloromethane and washed with 10 mL of 1 N HCl,

and the organic layer was extracted with dichloromethane (2 × 5 mL),

dried over MgSO₄, filtered, and concentrated to yield rocagloic acid 1d

(11 mg, 82%) which was used without further purification. IR (neat)

cm⁻¹3600−3200, 2923, 2853, 1715, 1610, 1513, 1453. ¹H NMR (400

MHz, CDCl₃) δ 7.10 (d, J = 8.8 Hz, 2H), 7.14−7.00 (m, 3H), 6.93−

6.85 (m, 2H), 6.68 (d, J = 8.8 Hz, 2H), 6.29 (d, J = 2.0 Hz, 1H), 6.12

(d, J = 2.0 Hz, 1H), 5.06 (d, J = 6.4, Hz, 1H), 4.28 (d, J = 15.2 Hz,

1H), 4.07 (dd, J = 14.0, 6.4 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.72

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Total synthesis of (±)-rocaglamide via oxidation-initiated nazarov cyclization

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