Explorations of caffeic acid derivatives: Total syntheses of rufescenolide, yunnaneic acids C and D, and studies toward yunnaneic acids A and B

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Explorations of Caﬀeic Acid Derivatives: Total Syntheses of

Rufescenolide, Yunnaneic Acids C and D, and Studies toward

Yunnaneic Acids A and B

Daniel R. Griﬃth,^†Lorenzo Botta,^†Tyler G. St. Denis,^†and Scott A. Snyder*^,†,‡

^†Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, New York 10027, United States

^‡Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States

S

* Supporting Information

ABSTRACT: Yunnaneic acids A−D, isolated from the roots of

Salvia yunnanensis, are hexameric (A and B) and trimeric (C and D)

assemblies of caﬀeic acid that feature an array of synthetically

challenging and structurally interesting domains. In addition to

being caﬀeic acid oligomers, yunnaneic acids A and B are formally

dimeric and heterodimeric adducts of yunnaneic acids C and D.

Herein we report the ﬁrst total syntheses of yunnaneic acids C and

D featuring the formation of their bicyclo[2.2.2]octene cores in a

single step from simple precursors via an oxidative dearomatiza-

tion/Diels−Alder cascade that may have biogenetic relevance. In

addition, exploitation of the key intermediate resulting from this

cascade reaction has enabled rapid access to the structurally related

caﬀeic acid metabolite rufescenolide through an unexpected Lewis

acid-mediated reduction. Finally, we report the results of extensive

model studies toward forming the dimeric yunnaneic acids A and B. These explorations indicate that the innate reactivities of the

monomeric fragments do not favor spontaneous formation of the desired dimeric linkages. Consequently, enzymatic involvement

may be required for the biosynthesis of these more complex family members.

that exposure of molecules such as hydroxyketone 7 to various

acids and bases led to unsymmetrical dimer 8 in good yield.^4b

Its spirocycle, as veriﬁed by X-ray crystallography, closely

resembles that found within both yunnaneic acids A and B.

Given this result, as well as our successful and controlled

preparation of several members of the helicterin class,^4bwe

wanted to determine whether we could prepare this group of

oligomers as well. Careful analysis of these oligomers revealed,

however, that despite some structural similarities to the

helicterins, a number of critical diﬀerences exist between

these two families of molecules, such that the yunnaneic acids

present a wholly unique, and potentially more diﬃcult, set of

synthetic challenges.

For instance, unlike helicterin B, which we prepared via a

homodimerization of a single hydroxyketal, and spirocyclic

dimer 8, whose precursor was a single hydroxyketone, reaching

yunnaneic acid A (4) requires the controlled union of two

diﬀerent monomeric fragments. Yunnaneic acid B (5) presents

a similar challenge in that, although it formally comprises two

molecules of yunnaneic C (3), mechanistically the dimerization

requires selective hydration of one of the carbonyls of the

diketone starting material followed by nucleophilic attack onto

INTRODUCTION

■

Plants throughout the world convert caﬀeic acid (also known as

dihydroxycinnamic acid) into an array of structurally distinct

natural products. Among these, some of the most stereochemi-

cally dense and complex family members include the yunnaneic

acids. These compounds, including 2−5 (Figure 1), were

isolated from the roots of Salvia yunnanensis,¹a plant found in

southern China that has been used in traditional folk medicine.²

Little to no information, however, is known about their speciﬁc

bioactivity or mode of action. Formally, compounds 2 and 3 are

trimers and 4 and 5 are hexamers of caﬀeic acid, though they

also could be considered products arising by the merger of

caﬀeic acid with the caﬀeic acid-derived natural product

rosmarinic acid (1). Moreover, as can be noted upon careful

inspection, the structure of yunnaneic acid B (5) contains two

units of yunnaneic acid C, while yunnaneic acid A (4) contains

one molecule each of yunnaneic acid C (2) and D (3).

Over the course of the past several years, our group has

cultivated an interest in developing strategies for the rapid,

eﬃcient, and selective synthesis of members of oligomeric

natural product families,³including not only polyphenols⁴but

also other molecule classes such as alkaloids.⁵Indeed, it was

during one of these studies toward the related natural product

helicterin B (6) (Scheme 1) that the yunnaneic acids ﬁrst

caught our attention when, in eﬀorts to make its core, we found

Received: October 16, 2013

Published: December 13, 2013

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Scheme 1. Structure of Helicterin B (6), an Oligomeric

Natural Product with Pseudo-C₂Symmetry, and an

Unforeseen Dimerization of a Model Precursor under Basic

Conditions

Figure 1. Structures of the caﬀeic acid derivatives yunnaneic acids.

a nonhydrated diketone. Thus, in either case, the union of two

subtly diﬀerent monomers is required, a challenging proposi-

tion given that multiple additional reactive pathways can be

envisioned to aﬀord unwanted side products. Additionally,

while the two classes possess the same overall components in

their bicyclo[2.2.2]octene cores, likely arising from a Diels−

Alder reaction between two derivatives of caﬀeic acid (vide

infra), the substituents decorating their bicycles diﬀer in both

regio- and stereochemistry. The cores typical of the helicterins

are formally endo Diels−Alder products, which we constructed

previously via a retro-Diels−Alder/Diels−Alder cascade process

under thermodynamic control, while the yunnaneic acids

formally reﬂect exo Diels−Alder adducts. Thus, a successful

synthesis of these molecules would require an entirely unique

synthetic approach. In particular, a way had to be found to

overcome the stereo- and regiochemistry commonly observed

in Diels−Alder reactions leading to bicyclo[2.2.2]octenes.

Herein we report our studies to access this unique group of

caﬀeic acid oligomers, eﬀorts leading to the ﬁrst total syntheses

of yunnaneic acids C and D as well as the structurally related

metabolite rufescenolide. To solve these compounds’ core

regio- and stereochemical challenges, we employed a modiﬁed

Wessely oxidation/intramolecular Diels−Alder cascade, which

allowed us to forge the bicyclo[2.2.2]octene core in a single

step.⁶This process may suggest a unique biogenetic hypothesis

for their formation, one diﬀerent from that proposed in the

literature;¹it also may constitute the most complex example of

such a process to date. In addition, we discuss our explorations

into the dimerization behavior of model versions of the

monomeric natural products. These studies suggest that the

innate reactivities of these monomers do not favor the

spontaneous and selective formation of the naturally occurring

dimers. As a result, formation of the requisite bonds in nature

may require enzymes.

RESULTS AND DISCUSSION

■

1. Monomer Retrosynthesis, Strategic Considerations,

and Preliminary Synthetic Studies. As noted above, the

core bicyclic domain of the yunnaneic acid monomers C (2)

and D (3) potentially arises in nature via a Diels−Alder

reaction. The key question, however, is just how that exo-

selective event occurs. The original isolation team posited

elements of the idea shown in Scheme 2, wherein

dearomatization of rosmarinic acid (1), either to 9 or to 11,

aﬀords a diene that can then react with the double bond within

caﬀeic acid to deliver yunnaneic acids C (2) and D (3). In the

latter case, the alcohol-bearing chiral center within 11 could

control the facial presentation of the two fragments to aﬀord

enantiopure material,⁷while in the former enzymes would

likely be needed for chiral control since the lone stereogenic

center within 1 is quite remote from the reactive center.

However, why such a union would be exo-selective and proceed

with the requisite regiocontrol is unclear without invoking a

“Diels−Alderase” enzyme.⁸An alternative hypothesis, adapted

from a similar pathway proposed by Tezuka for the biosynthesis

of the helicterin natural products,⁹would involve the union of

radicals as shown in the lower part of Scheme 2 to generate 14,

with enol attack then leading to yunnaneic acid C (2).

However, one could object to such a pathway¹⁰on the grounds

that an intermediate such as 14 could easily rearomatize; attack

by oxygen instead of carbon after such a rearomatization event

could lead to lithospermic acid (16), a related natural product¹¹

that has been the subject of much recent synthetic interest.¹²

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Scheme 2. Potential Biogenetic Hypotheses for the Synthesis of Yunnaneic Acids C (2) and D (3) as Well as a Possible

Connection to the Related Natural Product Lithospermic Acid (16)

Scheme 3. Retrosynthetic Analysis of the Yunnaneic Acid Monomers via a Distinct Diels−Alder Approach

Our laboratory approach to the yunnaneic acids was

predicated on the idea that a Diels−Alder reaction could well

be the key to the core, but in order to eﬀect an exo-selective

event, an intramolecular variant¹³of that reaction would be

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needed rather than the intermolecular version shown in

Scheme 2. As shown in Scheme 3, we hoped to tether the

dienophile portion to a masked ortho-benzoquinone (MOB),

which could then undergo a [4 + 2]-cycloaddition with the

appropriate regio- and stereochemistry. In addition to being a

powerful and simplifying retrosynthetic disconnection, such a

transformation in the forward sense would result in a tricyclic

product (17) containing the latent 1,2-diketone of 2 (a reactive

domain whose instability could pose chemoselectivity problems

if carried through several steps unmasked) having one carbonyl

protected as a ketal, potentially allowing for chemoselective

reduction of the unprotected ketone to access the alcohol

moiety found in 3.

Scheme 4. Preliminary Synthetic Studies toward Yunnaneic

Acid C

a

Initial eﬀorts along these lines focused on the use of

hypervalent iodine to eﬀect an oxidative dearomatization of a

suitably functionalized phenol followed by a spontaneous

intramolecular Diels−Alder reaction. Indeed, such trans-

formations have been reported previously, albeit on less

complex substrates with nucleophiles/dienophiles that could

be used as the reaction solvent.¹⁴Unfortunately, our attempts

to adapt such conditions to our system with pieces of general

ﬂavor 18 and 19 failed, with intractable mixtures of products

being the only result, even when large excesses (up to 20 equiv)

of the dienophilic carboxylic acid or more reactive hypervalent

iodine sources [such as PhI(OC(O)CF₃)₂] were used. A major

roadblock to the success of this approach may well have been

the insolubility of the carboxylic acid in the solvents commonly

used for these transformations.

To obviate this problem, we next pursued a strategy of

tethering the dienophile to the phenol prior to dearomatization

via an ester linkage in the form of 23 (Scheme 4). This material

was prepared in two steps by an initial selective allylation of

catechol 20 at the 4-position and coupling of the remaining

phenol with acid 21, followed directly by deallylation under Pd-

catalyzed conditions. To our dismay, the only observable

reaction product when 23 was subjected to PhI(OAc)₂in

MeOH was solvent-initiated cleavage of the side chain. Thus,

we next pursued a more robust tether in the form of an ether

(i.e., 24). To our delight, when this variant was subjected to

PhI(OAc)₂in the presence of water (MeOH could also be

used) in 1,4-dioxane at 80 °C, the phenol underwent a smooth

dearomatization and Diels−Alder reaction in the same pot,

furnishing three new bonds and delivering tricycle 26 in 67%

yield. Although this step proceeded well, the preceding

Mitsunobu and deallylation reactions aﬀorded disappointing

product yields; indeed, it is perhaps unsurprising that selective

deallylation of a substrate containing two allylic ethers proved

troublesome.¹⁵Nevertheless, we could obtain suﬃcient

amounts of Diels−Alder product 26 to pursue its elaboration

into model versions of yunnaneic acids C and D.

a

Reagents and conditions: (a) NaH (1.05 equiv), KI (0.1 equiv), allyl

bromide (2.0 equiv), DMF, −50→25 °C, 16 h, 57%; (b) DCC (1.5

equiv), DMAP (0.1 equiv), 21 (1.5 equiv), CH₂Cl₂, 24 h; Pd(PPh₃)₄

(0.5 equiv), AcOH, 36 h, 67% (two steps); (c) DIAD (1.5 equiv),

Ph₃P (1.5 equiv), 22 (1.2 equiv), THF, 0→25 °C, 24 h; Pd(OAc)₂

(0.2 equiv), Ph₃P (0.4 equiv), Et₂NH, THF, H₂O, 25 °C, 1 h, 26%

(two steps); (d) PhI(OAc)₂(1.1 equiv), H₂O, 1,4-dioxane, 75 °C, 5

min, 67%; (e) Me₄NBH(OAc)₃(3.0 equiv), AcOH, MeCN, 25 °C, 16

h, 77%; (f) TEMPO (0.1 equiv), PhI(OAc)₂(1.1 equiv), CH₂Cl₂, 25

°C, 3 h, 60%; (g) NaClO₂(5.0 equiv), NaH₂PO₄·2H₂O (10.0 equiv),

2-methyl-2-butene (10.0 equiv), t-BuOH, H₂O, 25 °C, 2 h; (h)

TMSCHN₂(2.0 equiv), THF, MeOH, 0 °C, 30 min, 62% (two steps);

(i) Dess−Martin periodinane (4.0 equiv), NaHCO₃(7.5 equiv),

CH₂Cl₂, 0→25 °C, 2 h, 35%. DIAD = diisopropyl azodicarboxylate;

DCC = N,N-dicyclohexylcarbodiimide; TEMPO = 2,2,6,6-tetrame-

thylpiperidin-1-oxyl free radical.

Our next experiments focused on opening the cyclic

hemiketal within 26 and oxidizing the liberated primary alcohol

in hopes of aﬀording 28 directly. Unfortunately, no acid,

oxidant, or combination thereof screened proved equal to the

task, including those shown to be successful with similarly

“locked” hemiketal groups.¹⁶Our analysis of this outcome was

that perhaps it was too challenging to establish any eﬀective

equilibrium between the open and closed forms in this case

because of the apparent high kinetic barrier to formation of the

likely unstable diketone found in the open form. Consequently,

we wondered whether we could work around this problem by

reducing the neighboring ketone, a process that would make

opening of the hemiketal more facile and provide a

hydroxyketone intermediate that would not present the same

potential instability issues as the corresponding diketone.

In the event, reduction of 26 with Me₄NBH(OAc)₃aﬀorded

triol 27. This material presumably resulted from initial

reduction of the ketone from the exo face followed by rupture

of the hemiketal and a second reduction event directed by the

endo-disposed alcohol.¹⁷From here, the model version of

yunnaneic acid C (i.e., 28) was accessed via (1) selective

oxidation of the primary alcohol,¹⁸(2) Pinnick oxidation of the

resulting aldehyde, (3) esteriﬁcation of the newly formed

carboxylic acid with TMSCHN₂, and (4) oxidation of the trans-

diol with Dess−Martin periodinane. Despite the ability to

ﬁnally access this compound, however, the developed route

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clearly had a number of drawbacks, including excessive

nonstrategic redox manipulation,¹⁹low yield in the ﬁnal diol

oxidation step (35%), and a lack of obvious inroads to the

desired hydroxyketone regio- and stereochemistry pertinent to

yunnaneic acid D.

often involved performing the initial oxidation, solvent removal,

and dissolution in a higher-boiling solvent followed by

prolonged heating, this reaction occurred spontaneously and

rapidly at ambient temperatureneither the dearomatized

intermediate nor the starting material could be detected by

TLC analysis immediately after addition of the phenol.

2. Development of an Eﬃcient and Scalable Route to

the Monomeric Yunnaneic Acids: Model Studies and the

Total Synthesis of Yunnaneic Acids C and D. In light of

these ineﬃciencies, we reconsidered our initial goal of obtaining

the desired Diels−Alder adduct directly from an appropriate

carboxylic acid (dienophile) and phenol (latent diene) as

retrosynthetically deﬁned in Scheme 3 and initiated anew a

search for an oxidizing agent that could eﬀect such a

transformation. A promising candidate was Pb(OAc)₄, a

reagent known to dearomatize appropriately substituted

phenols to MOB ketals in a process known as the Wessely

oxidation.²⁰Furthermore, it has been shown that replacement

of the acetate ligands on the Pb(IV) center with an α,β-

unsaturated carboxylate could result in a dearomatization event

followed by a Diels−Alder reaction to generate a tricyclic

product of the type that we sought.^6,21To our delight, this

protocol could be adapted to our system.

With the success of this protocol, we hoped that the newly

formed tricycle would prove more amenable to the

manipulations necessary to form the cores of yunnaneic acids

C and D. Pleasingly, the γ-methoxylactone of 25 proved far

more labile than the hemiketal of 26 (cf. Scheme 4), and the

desired hydrolysis proceeded in good yield upon exposure to

aqueous TFA to aﬀord the model version of yunnaneic acid C

(i.e., 33) in 73% yield after 16 h of stirring. The desired

hydroxyketone core of yunnaneic acid B could be formed

following a nonselective reduction of the carbonyl group in 25

with NaBH(OAc)₃, which proceeded with 1.2:1 diastereose-

lectivity slightly favoring the desired isomer; the identity of

these diastereomers was determined by the observation of an

NOE between the α-hydrogen of the newly installed alcohol

and the benzylic hydrogen as well as crystallographic analysis of

structures obtained following subsequent steps (vide infra).

Following careful separation of the two diastereomers, the exo

alcohol 31 was subjected to the same acidic conditions as above

to form the desired hydroxyketone matching that found in

yunnaneic acid D, leading to 32. As one measure of the overall

eﬃciency of the developed sequences, several hundred

milligrams of each model compound could be obtained from

a single material batch, ample supplies for subsequent

dimerization studies in pursuit of yunnaneic acids A and B

(vide infra).

In the event, addition of phenol 29 (Scheme 5) to a solution

of Pb(OAc)₄and 7.0 equiv of carboxylic acid 21 in 1,4-dioxane

at 25 °C resulted in the nearly instantaneous formation of the

desired product 25, which was isolated in 69% yield.

Interestingly, whereas previous reports^6,21of these reactions

Scheme 5. Successful Approach to Yunnaneic Acid C and D

a

Core Structures 32 and 33

With model work complete, our next task was to translate the

developed approach to fully functionalized materials. A key

consideration was identifying an appropriate array of protecting

groups that would allow us to readily access and eﬃciently

isolate the highly polar ﬁnal natural products but would be

suﬃciently robust to survive the intervening reaction

conditions. As shown in Scheme 6, our key material was

phenol 34, a rosmarinic acid derivative synthesized readily in

large quantity over the course of seven straightforward steps

(see the Supporting Information). We selected benzyl ether

and allyl ester protecting groups following several rounds of

exploration, as both were used in a previously reported

synthesis of rosmarinic acid.²²Pleasingly, upon application of

the dearomatization protocol, the desired Diels−Alder adduct

36 was obtained in a reasonable yield of 50%, albeit as a 1:1

mixture with its inseparable diastereomer (structure not

drawn). This result, similar to that observed in our Diels−

Alder reaction leading to the core of the helicterins,^4breveals

that the lone chiral center within 34 is seemingly too remote to

dictate the facial presentation of the reactive partners in an

absolute sense; therefore, nature might need to deploy an

enzyme to achieve an appropriate chiral environment to

produce the single antipode observed. Nevertheless, despite the

absence of selectivity observed in our reaction, the event

constitutes, to the best of our knowledge, the most complex

example of an oxidative dearomatization/Diels−Alder cascade

aﬀording a nondimeric adduct in which the diene and

dienophile are not tethered prior to the reaction.²³

a

Reagents and conditions: (a) 21 (7.0 equiv), Pb(OAc)₄(1.1 equiv),

In order to complete the syntheses of yunnaneic acids C and

D, we needed a method to separate the mixture of two

diastereomers aﬀorded by the Diels−Alder reaction. To our

dismay, no solvent system proved capable of doing so, even

CH₂Cl₂, 25 °C, 1 h; then 1,4-dioxane, 25 °C, 30 min; then 29 (1.0

equiv), 25 °C, 5 min, 69%; (b) NaBH(OAc)₃(5.0 equiv), THF,

AcOH, 25 °C, 3 h, 71%; (c) TFA, H₂O, CH₂Cl₂, 25 °C, 3 h, 95%; (d)

TFA, H₂O, CH₂Cl₂, 25 °C, 16 h, 73%. TFA = triﬂuoroacetic acid.

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when preparative TLC or semipreparative HPLC was used.

Fortunately, treatment of the Diels−Alder product with

NaBH(OAc)₃, as in the model system (cf. Scheme 5), eﬀected

a clean reduction of the ketone, resulting in four diastereomers

(two exo alcohols and two endo alcohols) that could be

separated by careful preparative TLC. The two undesired endo

alcohols could then be oxidized back to the ketone via a Ley−

Griﬃth oxidation²⁴and carried forward to yunnaneic acid C

(2) and an epimer of its enantiomer by (1) debenzylation

under Lewis acidic conditions, (2) palladium-catalyzed deal-

lylation, and (3) acid-mediated rupture of the γ-methoxylac-

tone. The exo alcohols could be subjected to a similar sequence

to aﬀord yunnaneic acid D (3). In each case, comparison of the

spectra for each of the diastereomers made assignment of the

correct material facile, with several signiﬁcant diﬀerences

observed for the incorrect diastereomer; for the natural

products themselves, all of the spectral data were in accordance

with those reported previously.²⁵Thus, the ﬁrst total syntheses

of yunnaneic acids C and D were completed in 13 steps and 12

steps, respectively.

Scheme 6. Total Synthesis of Yunnaneic Acids C (2) and D

(3)

a

Two aspects of this synthetic endgame deserve further

comment. First, a set of two orthogonal protecting groups for

the four phenolic groups and the ester proved necessary

because it was found that the side-chain carboxylic acid needed

to remain protected while the benzyl ethers were cleaved; when

the free acid was present under the debenzylation conditions,

signiﬁcant side-chain cleavage was observed. Second, yunnaneic

acid D was found to isomerize readily, presumably to a diﬀerent

hydroxyketone stereo- and/or regioisomer, upon standing in

the presence of residual acid that lingered following the ﬁnal

ketal-opening step. In fact, this isomerization occurred even

during the course of attempted removal of trace acids such as

TFA via coevaporation. Thus, the selection of an appropriate

acid in this ﬁnal step was crucial, with HCl proving to be ideal

in that it was suﬃciently strong to eﬀect the unmasking of the

desired ketone while easy enough to remove in the course of a

standard, nonbasic aqueous workup.

3. Total Synthesis of Rufescenolide. While our work on

the yunnaneic acids was proceeding, the isolation of the unique

natural product rufescenolide (41) (Scheme 7) from the

Scheme 7. Total Synthesis of Rufescenolide (41) from

a

Intermediate 31

a

Reagents and conditions: (a) 35 (7.0 equiv), Pb(OAc)₄(1.1 equiv),

CH₂Cl₂, 25 °C, 1 h; then 1,4-dioxane, 25 °C, 30 min; then 34 (1.0

equiv), 25 °C, 5 min, 50%; (b) NaBH(OAc)₃(5.0 equiv), AcOH,

THF, 25 °C, 82% (1.5:1 37:38); (c) BCl₃(8.0 equiv), CH₂Cl₂, −78

°C, 5 min; (d) Pd(PPh₃)₄(5 mol %), Meldrum’s acid (1.5 equiv),

THF, 25 °C, 15 min, 55% (two steps); (e) HCl, H₂O, CH₂Cl₂, 25 °C,

2 h, 95%; (f) TPAP (5 mol %), NMO (2.0 equiv), 4 Å molecular

sieves, CH₂Cl₂, 0 °C, 1 h, 67%; (g) BCl₃(8.0 equiv), CH₂Cl₂, −78 °C,

79%; (h) Pd(PPh₃)₄, 10 mol % Meldrum’s acid (1.5 equiv), THF, 25

°C, 15 min; (i) TFA, H₂O, CH₂Cl₂, 25 °C, 16 h, 50% (two steps).

DMAP = 4-dimethylaminopyridine, NMO = N-methylmorpholine-N-

oxide, TPAP = tetra-n-propylammonium perruthenate. For 34 and 35,

see the Supporting Information.

a

Reagents and conditions: (a) TMSOTf (3.0 equiv), Et₃SiH (20

equiv), CH₂Cl₂, 25 °C, 2.5 h, 54% (39), 25% (40); (b) BBr₃(6.0

equiv), CH₂Cl₂, 0 °C, 10 min, 55%.

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Scheme 8. Proposed Mechanism for the Transformation of 31 to 40

Brazilian shrub Cordia rufescens was reported.²⁶Rufescenolide is

In addition, this synthesis reinforces the potential value of the

intramolecular Diels−Alder product as a key intermediate for

the controlled assembly of a number of diﬀerent related natural

products. In addition to providing access to compounds 2, 3,

and 41 as described in this work, an intermediate with the

general structure of 46 could potentially lead to the synthesis of

both yunnaneic acids E (47) and F (48) as well (see Scheme

9).²The versatility of such an intermediate, when juxtaposed

with the proposed biosynthesis and the isolation of tricyclic

rufescenolide (41), could suggest that from a biogenetic

perspective, nature might deploy the enantiocontrolled syn-

thesis of a core like 46 as a means to accomplish the

stereocontrolled preparation of a number of target molecules.

4. Explorations into the Dimerization Behavior of

Model Yunnaneic Acid Compounds. With a concise route

to the monomeric natural products established, our attention

now turned to their dimerization into yunnaneic acids A (2)

and B (3). As discussed above, both of these events are formally

heterodimerizations and were expected to be quite challenging

relative to the homodimerizations we had previously accom-

plished within the helicterin program, not only because of the

mixed dimerization requirement but also because of the open

question of whether the free carboxylic acid substituent on the

core is a critical component. Indeed, its ability to potentially

attack the neighboring ketone or to hydrogen bond with

various substituents could play a critical role in success, as could

potentially protecting that group to remove such additional

properties. Thus, we felt that we needed to explore both

options overall.

In assessing some starting points for investigation, we were

mindful not only of our own studies with the helicterins but

also a number of additional literature precedents, work which

globally indicates that each template often requires unique and

speciﬁc conditions for dimerization to be achieved. For

instance, one additional example of a self-dimerization of a

hydroxyketone comes in the form of the union of two

molecules of salicortin (49) to form idesolide (50) (Scheme

10). Iwabuchi^30aand Kuwahara^30bindependently were able to

eﬀect this dimerization in 2010 under basic conditions; while

assuring to our work in that such an event could take place, it

also provides a cautionary tale in that extensive earlier studies

by the Snider group^30chighlighted alternate reaction pathways

a caﬀeic acid derivative with a structure remarkably similar to

that of model Diels−Alder product 25 (cf. Scheme 5) and is, to

our knowledge, the only bridged polycyclic caﬀeic acid natural

product containing a lactone. This target piqued our interest

not only because of rufescenolide’s structural homology to the

readily available 25 but also because of the resulting

implications for the biosynthesis of the yunnaneic acids.

Indeed, one could imagine that the bicyclo[2.2.2]octene

motif could conceivably arise in nature via an intramolecular

Diels−Alder reaction, which may explain the unusual regio- and

stereochemistry of the aryl and carboxyl substituents on the

bicycles of the yunnaneic acids.²⁷Given this resemblance, we

wondered whether we could utilize 25 and/or its reduced

variant 31 to achieve a concise synthesis of rufescenolide (41).

To accomplish this goal, we required a method to replace the

methoxy group of the γ-methoxylactone within the core with a

hydrogen atom. One potential way to eﬀect such a trans-

formation would be to react the γ-methoxylactone with a

suitable Lewis acid in the presence of a hydride source to

intercept the intermediate oxacarbenium ion (structure not

shown). However, the success of such an approach seemed

unlikely because the lactone oxygen within the tricyclic system

of 25 or 31 is unlikely to eﬀectively stabilize the necessarily

nonplanar carbocation generated by abstraction of the methoxy

group by the Lewis acid. Thus, it was with only a modest hope

for success that we attempted to apply such a protocol to the

synthesis of rufescenolide. Despite these reservations, however,

we found that upon reaction of 31 with TMSOTf and Et₃SiH,²⁸

the desired reduced product (i.e., 40) could be obtained in 54%

yield along with the C₂-symmetric dimer 39 (25% yield,

structure veriﬁed by X-ray crystallography). The overall

mechanism for this transformation is not currently deﬁnitive;

for now, we would posit that ring opening to form an

oxacarbenium ion resembling 42, followed by the intermediates

shown in Scheme 8, could be one pathway where similar steps

from the dimer of 42 would account for the formation of 39. In

any event, rufescenolide was then obtained from 40 in 55%

yield following deprotection of the phenolic methyl ethers

through 10 min of exposure to BBr₃in CH₂Cl₂at 0 °C. Overall,

this synthesis required just four steps from phenol 29.²⁹

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Scheme 9. Potential Ability To Utilize Intermediate 46 To

Access All Members of the Yunnaneic Acid Family as Well as

Related Structures

Scheme 10. Dimerization Studies into the Natural Product

Idesolide (50) via a Hydroxyketone Precursor

Scheme 11. Selected Examples of Diketone Dimerizations

that did not lead to the dimer. One challenge in this case could

be that there exists a high kinetic barrier for dimerization,

especially compared with an alternative aromatization pathway

leading to 51. These studies also highlight the importance of

concentration, as success was achieved only under solvent-free

conditions.

In terms of more direct precedent, speciﬁcally diketone

dimerizations as needed for yunnaneic acid B, there are three

major examples that reﬂect such processes (Scheme 11). The

ﬁrst, observed by Scharf and Kuesters,³¹formed the reactive

1,2-diketone moiety in situ through acidic hydrolysis of the

carbonate within 52, leading to a minor amount (10−20%

yield) of dimer 54 in the same pot. A similar dimerization was

observed by Klinotova³²when simple exposure of terpene

derivative 55 to silica gel aﬀorded 56 along with another

dimeric regioisomer (structure not shown) in 49% yield.

However, to highlight the speciﬁcity of such an event, it is

clearly substrate-dependent in that many other 1,2-diketones,

including our own for the model yunnaneic acid core, do not

undergo such facile dimerization when exposed to silica gel.

Finally, in what is an example of a yunnaneic acid A-type

dimerization, Yates and Langford³³showed that treatment of

diketone 57 with 0.5 equiv of MeLi could aﬀord 58, which then

reacted with the remaining 57 in solution to aﬀord mixed dimer

59 in 21% yield. Thus, this precedent provided a conceptual

underpinning for what we hoped to achieve for the

heterodimerization needed in our case.

Some of our initial eﬀorts began with protected forms of our

key compounds (e.g., 60 and 25 in Scheme 12) in terms of

both the exo-disposed acids and the ketone domains, largely to

get a sense of their reactivities. For instance, we were pleased to

ﬁnd early on that compound 60 could dimerize to the same

type of core as in the helicterins under conditions we developed

previously (i.e., BF₃·OEt₂) because this result indicated that

these compounds should have dimerization behavior similar to

that observed in the helicterin program. Thus, we moved onto

heterodimerization attempts, hoping that the formation of an

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a

Scheme 12. Iniital Dimerization Experiments Using

Protected Carboxylic Acids

Scheme 13. Mixed Dimerization Experiments

a

Reagents and conditions: (a) BF₃·OEt₂(4.0 equiv), CH₂Cl₂, 0 °C, 30

min, 36%; (b) TFA, H₂O, CH₂Cl₂(4:1:5), 25 °C, 3 h, <5%.

oxacarbenium ion derived from 60 (or a suitably protected

derivative) could be followed by attack of the alcohol of an

appropriate hydroxyketone to form a yunnaneic acid A-type

heterodimer. However, despite the initial success in eﬀecting

homodimerization of 60, the only other deﬁnitive outcome of

our work with this molecule and related compounds was the

unexpected formation of homodimer 39, the same material

observed in our rufescenolide synthesis, which was formed as a

very minor product upon treatment of 31 with aqueous TFA.³⁴

Turning next to alternate approaches for reaching yunnaneic

acid A, we treated model monomer pairs 32 and 33 or 62 and

28 (Scheme 13) with an array of acids and bases. In all cases,

these events led to either complex mixtures, recovered starting

materials, or the selective and unproductive dimerization of the

hydroxyketone component to form what we propose to be

structure 63.³⁵In the example shown where NaH was used as

the base, the diketone appeard to decompose under the

strongly basic conditions, and we noted that the same dimeric

product (i.e., 63) was obtained when hydroxyketone 62 alone

was treated with NaH. Indeed, these dimerization reactions

failed in all variants of polar aprotic solvents, while nonpolar

solvents proved to be incapable of dissolving the starting

materials.

Thus, in an eﬀort to obviate these problems, we turned next

to protic but non-nucleophilic solvents. We found that

1,1,1,3,3,3-hexaﬂuoro-2-propanol (HFIP) was unique in

providing the proper conditions to eﬀect pseudodimerization

of 32 and 33, aﬀording a rather unstable dimer alongside a

second dimer formed in smaller amounts that likewise proved

unstable. Although such instability hampered our ability to

characterize these dimers directly, immediate esteriﬁcation of

the crude dimerization products with TMSCHN₂increased

their stability and enabled far easier isolation of the dimers of

interest. Although they could not be crystallized into materials

suitable for X-ray diﬀraction, their brominated counterparts

(formed by exposure to 4 equiv of NBS at 25 °C for 14 h)

proved amenable to crystallization. X-ray analysis of those

materials revealed that our dimeric compounds, following

derivatization, were 64 and 65. Unfortunately, neither structure

matched that reported for yunnaneic acid A. Although we had

indeed achieved the selective union of the two distinct

monomers with no apparent homodimerization, it was found

a

Reagents and conditions: (a) NaH (10 equiv), THF, 0→25 °C, 30

min, 15%, 52% b.r.s.m.; (b) HFIP, 3 Å molecular sieves, CH₂Cl₂, 25

°C, 14 h; (c) TMSCHN₂(4.0 equiv), Et₂O, MeOH, −78 °C, 30 min,

26% (two steps), 4:1 64:65; (d) NBS (4.0 equiv), MeCN, 25 °C, 80%.

HFIP = hexaﬂuoro-2-propanol, NBS = N-bromosuccinimide.

that in the case of the major product 64, the wrong carbonyl of

the diketone had been engaged by the hydroxyketone. In the

case of the minor product 65, the desired carbonyl had

undergone attack, but the wrong pair of enantiomers had

reacted, resulting in a compound that was diastereomeric to the

natural product.

Application of similar conditions to diketones such as 66

(Scheme 14) alone, in hopes of aﬀording the yunnaneic acid B

core, also aﬀorded a mixture of dimers, albeit in lower yield. As

was the case with the heterodimers discussed above, these

compounds proved rather unstable. Nevertheless, one of these

dimers, 67, was characterized by X-ray crystallography when an

appropriately brominated diketone was subjected to the same

dimerization conditions.³⁶Once again, we had obtained a dimer

whose structure did not match that of the natural product. In

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a

Scheme 14. Diketone Dimerization Experiments

EXPERIMENTAL SECTION

■

General Procedures. Reactions were carried out under an argon

atmosphere with dry solvents under anhydrous conditions, unless

otherwise stated. Dry methylene chloride (CH₂Cl₂), diethyl ether

(Et₂O), and tetrahydrofuran (THF) were obtained by passing

commercially available predried, oxygen-free formulations through

activated alumina columns; triethylamine (Et₃N) was distilled from

KOH; acetone, methanol (MeOH), and dimethylformamide (DMF)

were purchased in anhydrous form and used as received. Yields refer to

chromatographically and spectroscopically (¹H and ¹³C NMR)

homogeneous materials, unless otherwise stated. Reagents were

purchased at the highest commercial quality and used without further

puriﬁcation, unless otherwise stated. Reactions were magnetically

stirred and monitored by thin-layer chromatography (TLC) carried

out on silica gel plates (60F-254) using UV light and an aqueous

solution of cerium ammonium sulfate and ammonium molybdate and

heat as visualizing agents. Preparative TLC was carried out on 0.50

mm silica gel plates (60F-254). Silica gel (60 Å, academic grade,

particle size 40−63 μm) was used for ﬂash column chromatography.

NMR spectra were recorded on 300 MHz, 400 MHz, and 500 MHz

spectrometers and calibrated using residual undeuterated solvent as an

internal reference. The following abbreviations are used to explain

multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =

multiplet, br = broad, app = apparent. IR spectra were recorded on an

FT-IR spectrometer. High-resolution mass spectra (HRMS) were

recorded using fast atom bombardment (FAB) with Xe as the carrier

gas and m-nitrobenzyl alcohol as the matrix on a double-focusing

sector-type mass spectrometer. Optical rotations were recorded on a

digital polarimeter.

a

Reagents and conditions: (a) HFIP, 50 °C, 16 h, 5%.

this case, rather than attack of a water molecule on the diketone

as required, the pendant carboxyl group had attacked the

ketone, followed by attack of the resulting hemiketal oxygen on

a second diketone molecule. Furthermore, ketalization had

occurred on the undesired carbonyl of the diketone (syn to the

carboxyl group). Unfortunately, X-ray-quality crystals of the

other two isolated dimers from these experiments have proven

elusive. Interestingly, the carboxylic acid of the diketone

appears to be critical to the success of these HFIP-mediated

dimerizations; the analogous methyl ester does not react.

Globally, our dimerization studies show that the appropriate

monomers can be made to engage with each other to aﬀord

cores reminiscent of the yunnaneic acids under very speciﬁc

reaction conditions, but in no case did we observe the correct

connectivities corresponding to the natural products. What this

body of results may suggest is that nature uses enzymes to help

guide the union of the two pieces; in other words, it seems

unlikely that these dimers are artifacts of the isolation team’s

eﬀorts, given that spontaneous and/or facile dimerizations were

not observed with any of our materials. If true, this statement

has interesting implications for the biosynthesis of these

oligomers, since it implies that extra energy may be required to

form the requisite bonds when there are clearly additional

reaction pathways that are open to these types of reactive

pieces.

(E)-Methyl 3-(4-(Allyloxy)-3-hydroxyphenyl)acrylate (S1).

(E)-Methyl 3-(3,4-dihydroxyphenyl)acrylate (20) (0.890 g, 4.59

mmol, 1.0 equiv) was dissolved in DMF (24 mL), and solid KI

(0.083 g, 0.50 mmol, 0.1 equiv) was added at 25 °C. The resultant

solution was then cooled to −50 °C, and NaH (60% dispersion in

mineral oil, 0.193 g, 5.20 mmol, 1.05 equiv) was added. After the

resultant yellow solution was stirred for 5 min at −50 °C, allyl bromide

(0.75 mL, 9.9 mmol, 2.0 equiv) was added, and the reaction mixture

was allowed to gradually warm to 25 °C and then stirred for an

additional 16 h. Upon completion, the reaction mixture was poured

into 1 M HCl (50 mL) and extracted with Et₂O (3 × 50 mL). The

combined organic layers were then washed with water (3 × 50 mL),

dried (MgSO₄), ﬁltered, and concentrated. The resultant crude

product was puriﬁed by ﬂash column chromatography (silica gel,

hexanes:EtOAc, 9:1→1:1) to give phenol S1 (0.605 g, 57% yield, 4.5:1

mixture of regioisomers favoring the 3-hydroxy isomer) as a white

solid alongside the diallylated compound (0.228 g, 18% yield) and

recovered starting material (0.120 g, 13% yield). [Note: drawn

structures of all of these additional compounds are provided in the

Supporting Information.] S1: R_f= 0.31 (hexanes:EtOAc, 4:1); IR

(ﬁlm) ν_max3387, 2960, 2865, 1694, 1629, 1609, 1580, 1504, 1426,

1316, 1267, 1163, 1123, 1023, 979, 934, 860, 800 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ 7.62 (d, J = 16.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H),

7.03 (dd, J = 8.5, 2.0 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.32 (d, J =

16.0 Hz, 1H), 6.12−6.04 (m, 1H), 5.69 (s, 1H), 5.44 (dd, J = 17.5, 1.5

Hz, 1H), 5.37 (dd, J = 10.5, 1.0 Hz, 1H), 4.67 (app dt, J = 4.0, 1.5 Hz,

1H), 3.82 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.7, 147.5,

146.1, 144.7, 132.3, 128.2, 121.6, 118.7, 115.9, 113.3, 111.9, 69.8, 51.6;

CONCLUSION

■

We have developed the ﬁrst total syntheses of yunnaneic acids

C and D through an oxidative dearomatization/Diels−Alder

cascade on a complex substrate that completely controls the

relative stereo- and regiochemistry of the carbon substituents

on the bicyclic core. Furthermore, this strategy would appear to

be applicable to the synthesis of other caﬀeic acid metabolites

(as exempliﬁed by our total synthesis of rufescenolide) and

highlights the value of a single, versatile intermediate in

aﬀording a number of diﬀerent natural product structures in a

controlled manner.⁴Moreover, the processes developed for the

monomer syntheses are readily scalable, allowing for extensive

studies of their dimerization. Such experiments have shown that

although it is possible to selectively couple the monomeric

diketone and hydroxyketone, the structures formed in nature

do not seem commensurate with the innate reactivities of the

monomers. This outcome may point to some kind of enzymatic

assistance for nature’s dimerization process. In any event, on

the basis of what has been achieved in the present work, studies

of the biochemical properties of our natural products, and,

potentially of more importance, unnatural analogues and

synthetic intermediates, can now begin in earnest and will be

reported in due course.

+

HRMS (FAB) calcd for C₁₃H₁₄O₄[M]⁺234.0892, found 234.0904.

(E)-Methyl 3-(3-(((E)-3-(3,4-Dimethoxyphenyl)allyl)oxy)-4-

hydroxyphenyl)acrylate (24).³⁷To a solution of allyl ether S1

(0.380 g, 1.60 mmol, 1.0 equiv), (E)-3-(3,4-dimethoxyphenyl)prop-2-

en-1-ol (21) (0.373 g, 1.90 mmol, 1.2 equiv), and Ph₃P (0.628 g, 2.40

mmol, 1.5 equiv) in THF (16 mL) at 0 °C was added DIAD (0.47 mL,

2.40 mmol, 1.5 equiv). The resultant orange solution was then allowed

to warm slowly to 25 °C and stirred for 24 h. Upon completion, the

reaction mixture was concentrated directly, and the resultant oil was

puriﬁed by ﬂash column chromatography (silica gel, hexanes:EtOAc,

7:3→1:1) to give the desired Mitsunobu product as a colorless oil.

Pressing forward, this new intermediate was dissolved in THF (7.5

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mL), and Ph₃P (0.135 g, 0.51 mmol, 0.4 equiv) and H₂O (1.4 mL)

were added sequentially at 25 °C. Et₂NH (3.75 mL, 36 mmol, 22.5

equiv) was then added, and the solution became yellow-green in color.

Next, Pd(OAc)₂(0.057 g, 0.26 mmol, 0.2 equiv) was added at 25 °C,

and during the next few minutes of stirring, the solution became very

dark green in color. The reaction mixture was then stirred for an

additional 1 h at 25 °C. Upon completion, the reaction contents were

concentrated directly, and the resultant residue was then diluted with

EtOAc (40 mL) and washed with H₂O (50 mL) and brine (50 mL).

The organic layer was then dried (MgSO₄), ﬁltered, and concentrated

to give a dark-green oil. This crude material was then puriﬁed by ﬂash

column chromatography (silica gel, hexanes:Et₂O, 1:1→2:3) to give

phenol 24 (0.150 g, 26% yield over two steps) as an oﬀ-white solid.

24: R_f= 0.32 (hexanes:EtOAc, 3:2); IR (ﬁlm) ν_max3359, 2951, 2932,

1698, 1601, 1511, 1438, 1262, 1158, 1108, 1025 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 7.62 (d, J = 15.6 Hz, 1H), 7.10−7.07 (m, 2H), 6.98−

6.93 (m, 3H), 6.84 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H),

6.32−6.24 (m, 2H), 6.02 (br s, 1H), 4.77 (d, J = 6.0 Hz, 2H), 3.92 (s,

3H), 3.89 (s, 3H), 3.80 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

168.6, 150.4, 150.1, 149.2, 146.8, 145.8, 135.3, 129.9, 127.9, 124.0,

122.0, 121.0, 116.1, 115.9, 112.1, 112.0, 109.9, 70.9, 56.9, 56.8, 52.5;

HRMS data could not be obtained because of the lability of the allylic

ether.

disappearance of the red color of the solution. After the mixture was

stirred at 25 °C for an additional 2 min, ethylene glycol (0.160 mL,

2.61 mmol, 1.1 equiv) was added, resulting in the formation of a thick

colorless slurry that was stirred vigorously at 25 °C for 20 min. Upon

completion, the reaction contents were concentrated directly, and the

resulting oﬀ-white solid was suspended in EtOAc and ﬁltered. The

solid residue was then rinsed with EtOAc (3 × 15 mL) and ﬁltered.

The combined ﬁltrates were then washed with saturated aqueous

NaHCO₃(3 × 50 mL) and brine (50 mL), dried (MgSO₄), ﬁltered,

and concentrated to give a yellow oil. This crude residue was puriﬁed

by ﬂash column chromatography (silica gel, hexanes:EtOAc, 7:3→2:3)

to give the desired Diels−Alder adduct 25 (0.675 g, 69% yield) as a

pale-yellow foam along with the undesired compound (E)-methyl 3-

(3-acetoxy-3-methoxy-4-oxocyclohexa-1,5-dien-1-yl)acrylate (S2)

(0.074 g, 12% yield) as a yellow oil. [Note: the excess carboxylic

acid could be recovered from the aqueous layer by acidifying it to pH 2

and extracting twice with EtOAc.]

25: R_f= 0.44 (hexanes:EtOAc, 1:1); IR (ﬁlm) ν_max2951, 2839,

1

1792, 1747, 1710, 1633, 1515, 1314, 1193, 1024, 916 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ 7.40 (d, J =15.5 Hz, 1H), 6.72 (d, J = 8.5 Hz,

1H), 6.49 (s, 1H), 6.37 (m, 2H), 6.23 (d, J = 16 Hz, 1H), 4.13 (d, J =

5 Hz, 1H), 3.82−3.73 (m, 10H), 3.71−3.61 (m, 4H), 3.27 (d, J = 5

Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 195.3, 172.9, 166.6, 149.0,

148.7, 140.4, 137.1, 133.5, 131.0, 119.6, 119.3, 111.2 (2C), 99.5, 56.3,

55.9 (2C), 53.9, 52.0, 47.4, 44.9, 43.9; HRMS (FAB) calcd for

(E)-Methyl 3-(8-(3,4-Dimethoxyphenyl)-7a-hydroxy-7-oxo-

2,3,3a,6,7,7a-hexahydro-3,6-methanobenzofuran-4-yl)acrylate

(26). A solution of PhI(OAc)₂(0.052 g, 0.16 mmol, 1.1 equiv) in

CH₂Cl₂(0.5 mL) was added dropwise under an ambient atmosphere

to a suspension of phenol 24 (0.054 g, 0.15 mmol, 1.0 equiv) in 1,4-

dioxane/H₂O (2:1, 1.5 mL) at 75 °C. The resultant dark-red solution

was stirred at 75 °C for 5 min and then cooled to 25 °C. The reaction

mixture was then diluted with EtOAc (10 mL) and washed with

saturated aqueous NaHCO₃(10 mL), and the aqueous layer was then

extracted with EtOAc (2 × 5 mL). The combined organic layers were

then dried (MgSO₄), ﬁltered, and concentrated to give a brown oil.

Puriﬁcation of this crude residue by ﬂash column chromatography

(silica gel, hexanes:EtOAc, 1:1) aﬀorded the desired Diels−Alder

product 26 (0.039 g, 67% yield) as a pale-yellow oil. 26: R_f= 0.20

(hexanes:EtOAc, 1:1); IR (ﬁlm) ν_max3421, 2953, 1741, 1631, 1516,

1438, 1314, 1256, 1178, 1144, 1026 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 7.43 (d, J = 15.6 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.54 (d,

J = 2.4 Hz, 1H), 6.47 (dd, J = 8.4, 2.0 Hz, 1H), 6.29−6.21 (m, 2H),

4.38 (dd, J = 8.0, 3.2 Hz, 1H), 4.11 (s, 1H), 3.93 (d, J = 8.0 Hz, 1H),

3.85 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.73 (dd, J = 4.0, 2.0 Hz, 1H),

3.51 (dd, J = 7.2, 2.4 Hz, 1H), 3.43 (br s, 1H), 2.82 (br s, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ 200.6, 167.0, 148.9, 148.3, 141.2, 139.1,

133.6, 131.9, 119.7, 118.9, 111.4, 111.2, 96.4, 73.8, 55.9 (2C), 53.8,

+

C₂₂H₂₂O₈[M]⁺414.1315, found 414.1302.

S2: R_f= 0.65 (hexanes:EtOAc, 1:1); IR (ﬁlm) ν_max2953, 1707,

1

1691, 1436, 1248, 1168, 1104, 1087, 1014, 977, 822 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ 7.36 (d, J = 16.5 Hz, 1H), 7.17 (d, J = 10 Hz,

1H), 6.41 (s, 1H), 6.28 (d, J = 10 Hz, 1H), 6.24 (d, J = 16 Hz, 1H),

3.81 (s, 3H), 3.50 (s, 3H), 2.14 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

δ 190.6, 169.6, 166.4, 141.3, 137.1, 136.2, 132.7, 126.9, 120.6, 92.7,

51.9, 51.6, 20.4; HRMS data could not be obtained because the

product was not suﬃciently stable, but an [M + H]⁺peak at m/z

267.11 was observed via LRMS (FAB).

(E)-Methyl 3-(8-(3,4-Dimethoxyphenyl)-7-hydroxy-7a-me-

thoxy-2-oxo-2,3,3a,6,7,7a-hexahydro-3,6-methanobenzofur-

an-4-yl)acrylate (31) and (E)-Methyl 3-(8-(3,4-Dimethoxyphen-

yl)-7-hydroxy-7a-methoxy-2-oxo-2,3,3a,6,7,7a-hexahydro-3,6-

methanobenzofuran-4-yl)acrylate (S3). Diels−Alder adduct 25

(0.630 g, 1.52 mmol, 1.0 equiv) was dissolved in THF/AcOH (1:1, 14

mL). NaBH(OAc)₃(1.61 g, 7.61 mmol, 5.0 equiv) was added at 25

°C, and the resultant yellow solution was stirred at 25 °C for 3 h.

Upon completion, an aqueous solution of Rochelle’s salt (0.5 M, 38

mL) was added, and the mixture was stirred for an additional 20 min at

25 °C, after which time it was carefully poured into saturated aqueous

NaHCO₃(50 mL; CAUTION: vigorous bubbling was observed) and

extracted with EtOAc (50 mL). The organic layer was then washed

with saturated aqueous NaHCO₃(50 mL), and the combined aqueous

layers were re-extracted with EtOAc (2 × 50 mL). The combined

organic layers were then dried (MgSO₄), ﬁltered, and concentrated to

give a colorless oil. Puriﬁcation of this crude residue by ﬂash column

chromatography (silica gel, CH₂Cl₂:Et₂O, 19:1→9:1) gave exo alcohol

31 (0.228 g, 36% yield) as a white solid and endo alcohol S3 (0.221 g,

35% yield) as a cloudy, colorless oil.

+

51.9, 47.2, 45.9, 44.8; HRMS (FAB) calcd for C₂₁H₂₂O₇[M]⁺

386.1366, found 386.1370.

(E)-Methyl 3-(8-(3,4-Dimethoxyphenyl)-7a-methoxy-2,7-

dioxo-2,3,3a,6,7,7a-hexahydro-3,6-methanobenzofuran-4-yl)-

acrylate (25). Solid Pb(OAc)₄(95%, 1.20 g, 2.61 mmol, 1.1 equiv)

was suspended in toluene (5 mL), and the suspension was

concentrated directly to remove any residual AcOH. The resultant

light-brown solid was then dissolved in CH₂Cl₂(33 mL), and 3,4-

dimethoxycinnamic acid (22) (3.45 g, 16.6 mmol, 7.0 equiv) was

added at 25 °C, yielding an orange suspension. After the reaction

mixture was stirred at 25 °C for 30 min, the suspension was

concentrated directly. Upon complete removal of the solvent, the ﬂask

was back-ﬁlled with argon by attaching a balloon to the air inlet of the

rotary evaporator. The resultant orange solid was then suspended in

toluene (15 mL) and concentrated directly to remove any residual

AcOH resulting from ligand exchange. This azeotroping procedure

was then repeated. The subsequent orange solid was then resuspended

in CH₂Cl₂(33 mL), and the above procedure (i.e., stirring for 30 min,

concentration, and azeotroping) was repeated. After the ﬁnal

azeotrope was performed, the orange solid was dissolved in anhydrous

1,4-dioxane (33 mL), and the resulting deep-red solution was stirred at

25 °C for 30 min. A solution of (E)-methyl 3-(4-hydroxy-3-

methoxyphenyl)acrylate (29) (0.493 g, 2.37 mmol, 1.0 equiv) in

1,4-dioxane (3 mL) was then added via syringe, resulting in rapid

31: R_f= 0.34 (hexanes:EtOAc, 3:7); IR (ﬁlm) ν_max3505, 2949,

1

1777, 1713, 1634, 1518, 1351, 1256, 1197, 1025, 929 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ 7.44 (d, J = 16.0 Hz, 1H), 6.70 (d, J = 8.0 Hz,

1H), 6.54 (d, J = 6.5 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 6.38 (dd, J =

8.5, 2.0 Hz, 1H), 6.08 (d, J = 16 Hz, 1H), 4.11 (app t, J = 3.5 Hz, 1H),

3.89 (d, J = 4.5 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.58

(s, 3H), 3.45 (app dt, J = 7.0, 3.0 Hz, 1H), 3.36 (br s, 1H), 2.90 (dd, J

= 4.5, 2.0 Hz, 1H), 2.51 (d, J = 4.0 Hz, 1H); ¹³C NMR (125 MHz,

CDCl₃) δ 174.0, 167.0, 148.8, 148.2, 141.5, 139.8, 133.3, 132.9, 119.5,

117.0, 111.2, 111.1, 109.8, 74.2, 55.9, 52.9, 51.9, 47.8, 47.3, 44.2, 40.4;

+

HRMS (FAB) calcd for C₂₂H₂₄O₈[M]⁺416.1471, found 416.1465.

S3: R_f= 0.34 (hexanes:EtOAc, 3:7); IR (ﬁlm) ν_max3477, 3059,

2993, 2951, 2844, 1780, 1716, 1633, 1605, 1518, 1255, 1203, 1175,

1026, 948, 735 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.38 (d, J = 16.0

Hz, 1H), 6.69 (d, J = 10.0 Hz, 1H), 6.51−6.49 (m, 2H), 6.36 (dd, J =

98

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8.0, 2.0 Hz, 1H), 6.09 (d, J = 16 Hz, 1H), 3.86 (dd, J = 5.0, 2.0 Hz,

1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.68 (app t, J = 2.5 Hz,

1H), 3.62 (d, J = 2.0 Hz, 1H), 3.47 (s, 3H), 3.15 (app dt, J = 7.0, 3.0

Hz, 1H), 2.98 (dd, J = 5.0, 2.0 Hz, 1H), 2.92 (d, J = 5.5 Hz, 1H); ¹³C

NMR (125 MHz, CDCl₃) δ 173.9, 167.1, 148.8, 148.1, 141.4, 139.2,

134.3, 133.6, 119.6, 117.8, 111.5, 111.0, 107.7, 72.3, 55.9, 52.1, 51.9,

with 1 M HCl (3 × 140 mL) and brine (140 mL), dried (MgSO₄),

ﬁltered, and concentrated to give a yellow oil (S4), which was carried

forward without further puriﬁcation. Next, S4 was dissolved in

CH₂Cl₂/MeOH (1:1, 160 mL) at 25 °C, and solid NaOMe (0.750 g,

13.9 mmol, 1.0 equiv) was added. The resulting dark-yellow solution

was stirred at 25 °C for 4.5 h. Upon completion, the reaction mixture

was poured into saturated aqueous NH₄Cl (600 mL) and extracted

with EtOAc (3 × 600 mL). The combined organic layers were then

washed with brine (600 mL), dried (MgSO₄), ﬁltered, and

concentrated. The resultant crude white solid was puriﬁed by ﬂash

column chromatography (silica gel, hexanes:EtOAc, 7:3→3:2) to give

methyl (E)-3-(3,4-bis(benzyloxy)phenyl)acrylate (S5) (4.93 g, 95%

yield over three steps) as a white solid along with methyl (R)-3-(3,4-

bis(benzyloxy)phenyl)-2-hydroxypropanoate (S6) (4.41 g, 81% yield

over three steps) as a white crystalline solid. S6: R_f= 0.60

(hexanes:EtOAc, 1:1); [α]²_D²= +7.8 (c = 0.5, CHCl₃); IR (ﬁlm) ν_max

3480, 3066, 3032, 2926, 1733, 1606, 1589, 1512, 1459, 1427, 1265,

1218, 1137, 1091, 1020, 736, 696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)

δ 7.46−7.31 (m, 10H), 6.89 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 2.0 H,

1H), 6.74 (dd, J = 8.4, 2.0 Hz, 1H), 5.17 (s, 2H), 5.16 (s, 2H), 4.42

(ddd, J = 6.4, 4.4, 2.0 Hz, 1H), 3.74 (s, 3H), 3.05 (dd, J = 14.0, 4.4 Hz,

1H), 2.89 (dd, J = 14, 6.4 Hz, 1H), 2.63 (d, J = 6.4 Hz, 1H); ¹³C NMR

(100 MHz, CDCl₃) δ 174.5, 148.8, 148.1, 137.5, 137.4, 129.7, 128.5,

127.8 (2C), 127.4 (2C), 122.5, 116.7, 115.1, 71.3, 52.4, 40.1; HRMS

+

48.1, 47.5, 42.7, 39.8; HRMS (FAB) calcd for C₂₂H₂₄O₈[M]⁺

416.1471, found 416.1454.

(1R,2R,3S,4R)-3-(3,4-Dimethoxyphenyl)-8-hydroxy-6-((E)-3-

methoxy-3-oxoprop-1-en-1-yl)-7-oxobicyclo[2.2.2]oct-5-ene-

2-carboxylic Acid (32). Reduction product 31 (0.200 g, 0.49 mmol,

1.0 equiv) was suspended in CH₂Cl₂(2.5 mL), and then H₂O (1.25

mL) and TFA (1.25 mL) were added sequentially at 25 °C. After the

resultant colorless, cloudy mixture was vigorously stirred at 25 °C for 3

h, the reaction contents were concentrated directly to give a white

solid, from which residual TFA was removed by further coevaporations

with toluene (2 × 5 mL) to aﬀord the desired hydroxy ketone 32

(0.196 g, 99%), which was carried forward without further puriﬁcation.

32: R_f= 0.19 (CH₂Cl₂:MeOH, 9:1); IR (ﬁlm) ν_max3395, 2948, 2913,

2841, 1713, 1630, 1590, 1517, 1314, 1255, 1144, 1025 cm⁻¹; ¹H NMR

(500 MHz, CD₃OD) δ 7.44 (d, J = 16.0 Hz, 1H), 6.89−6.79 (m, 3H),

6.74 (dd, J = 8.5, 2.0 Hz, 1H), 6.22 (d, J = 15.5 Hz, 1H), 4.09 (d, J =

2.5 Hz, 1H), 3.83−3.78 (m, 10H), 3.67 (d, J = 4.0 Hz, 1H), 3.26 (app

dt, J = 4.0, 2.0 Hz, 1H), 2.82 (dd, J = 5.5, 2.5 Hz, 1H); ¹³C NMR (125

MHz, CD₃OD) δ 177.3, 171.6, 167.5, 149.0, 148.0, 141.1, 140.3, 136.8,

136.2, 119.3, 117.1, 111.7 (2C), 71.4, 55.1, 55.0, 51.1, 50.9, 50.8, 46.5,

31.3; HRMS (FAB) calcd for C₂₁H₂₂O₈Na⁺[M + Na]⁺425.1212,

found 425.1213.

+

(FAB) calcd for C₂₄H₂₄O₅[M]⁺392.1624, found 392.1624.

Chiral alcohol S6 (3.99 g, 10.2 mmol, 1.0 equiv) was dissolved in

THF/MeOH/H₂O (3:1:1, 50 mL) at 25 °C. The resultant mixture

was cooled to 0 °C, and solid LiOH (0.600 g, 14.3 mmol, 1.4 equiv)

was added. The ice bath was then removed, and the mixture was

heated to 45 °C and stirred under an ambient atmosphere for 6 h.

Upon completion, the reaction mixture was cooled to 25 °C, poured

into 1 M HCl (160 mL), and extracted with EtOAc (3 × 150 mL).

The combined organic layers were then dried (MgSO₄), ﬁltered, and

concentrated. The resultant crude white solid was dissolved in DMF

(40 mL), and K₂CO₃(2.20 g, 15.9 mmol, 1.5 equiv) and allyl bromide

(1.40 mL, 15.87 mmol, 1.5 equiv) were added sequentially at 25 °C.

The reaction mixture was then stirred at 25 °C for 2 h before being

poured into 1 M HCl (160 mL) and extracted with Et₂O (3 × 80 mL).

The combined organic layers were washed with H₂O (5 × 80 mL),

dried (MgSO₄), ﬁltered, and concentrated to give allyl (R)-3-(3,4-

bis(benzyloxy)phenyl)-2-hydroxypropanoate (S7) (4.08 g, 96% yield)

as a white solid of suﬃcient purity to press forward without further

puriﬁcation. S7: R_f= 0.44 (hexanes:EtOAc, 1:1); [α]²_D²= +16.9 (c =

0.5, CHCl₃); IR (ﬁlm) ν_max3421, 3034, 2945, 1726, 1592, 1519, 1454,

1429, 1386, 1270, 1251, 1241, 1229, 1168, 1140, 1024 cm⁻¹; ¹H NMR

(400 MHz, CDCl₃) δ 7.40−7.32 (m, 10H), 6.90 (d, J = 8.0 Hz, 1H),

6.87 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.0, 1.6 Hz, 1H), 5.96−5.86 (m,

1H), 5.35 (dd, J = 17.2, 1.2 Hz, 1H), 5.17 (s, 2H), 5.16 (s, 2H), 4.68−

4.59 (m, 2H), 4.44 (dd, J = 10.4, 5.6 Hz, 1H), 3.07 (dd, J = 14.0, 4.4

Hz, 1H), 2.95 (dd, J = 14.0, 6.8 Hz, 1H), 2.69 (d, J = 6.0 Hz, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ 173.8, 148.8, 148.1, 137.5, 137.4, 131.5,

129.6, 128.5 (2C), 127.8 (2C), 127.4, 127.3, 122.6, 119.2, 118.7, 115.2,

(1R,2R,3S,4R)-3-(3,4-Dimethoxyphenyl)-6-((E)-3-methoxy-3-

oxoprop-1-en-1-yl)-7,8-dioxobicyclo[2.2.2]oct-5-ene-2-carbox-

ylic Acid (33). Diels−Alder adduct 25 (0.240 g, 0.58 mmol, 1.0

equiv) was dissolved in CH₂Cl₂(2.5 mL), and then H₂O (1.25 mL)

and TFA (1.25 mL) were added sequentially at 25 °C. After the

resultant mixture was vigorously stirred at 25 °C for 16 h, the reaction

contents were concentrated directly to give a yellow oil, from which

residual TFA was removed by further coevaporations with toluene (2

× 5 mL). Puriﬁcation of the resultant crude yellow oil by ﬂash column

chromatography (silica gel, CH₂Cl₂:MeOH, 97:3→19:1) gave

diketone 33 (0.170 g, 73% yield) as a yellow foam. 33: R_f= 0.61

(CH₂Cl₂:MeOH, 9:1); IR (ﬁlm) ν_max3385, 3056, 3002, 2954, 2831,

1793, 1740, 1717, 1634, 1518, 1258, 1197, 1145, 1026 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 7.32 (d, J = 16.0 Hz, 1H), 6.66 (d, J = 8.5 Hz,

1H), 6.44 (br s, 1H), 6.35−6.31 (m, 2H), 6.17 (d, J = 15.5 Hz, 1H),

4.01 (dd, J = 4.0, 1.5 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H),

3.74−3.68 (m, 2H), 3.19 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ

166.8, 149.1, 148.8, 139.8, 138.4, 133.4, 120.1, 119.5, 111.3, 56.0, 55.4,

+

52.1, 48.6, 44.7, 40.1; HRMS (FAB) calcd for C₂₁H₂₀O₈[M]⁺

400.1158, found 400.1190.

(R)-1-(Allyloxy)-3-(3,4-bis(benzyloxy)phenyl)-1-oxopropan-

2-yl (E)-3-(4-Hydroxy-3-methoxyphenyl)acrylate (34). Rosmar-

inic acid (1) (5.00 g, 13.9 mmol, 1.0 equiv) was dissolved in THF/

MeOH (10:1, 110 mL) at 25 °C, and the resultant solution was cooled

to −78 °C. TMSCHN₂(2.0 M in Et₂O, 6.6 mL total, 0.95 equiv) was

then added at −78 °C in 0.55 mL portions every 5 min until the

complete volume had been added. The low-temperature bath was then

removed, and the reaction mixture was allowed to warm to 25 °C,

during which time the solution turned a brown color. The solution was

then stirred for an additional 1 h at 25 °C. Upon completion, the

reaction was quenched by the addition of glacial AcOH (∼3 drops; no

bubbling was observed, indicating complete consumption of the

TMSCHN₂), and the mixture was concentrated directly. The resultant

crude brown oil was ﬁltered through a pad of silica gel, eluting with

CH₂Cl₂/MeOH (9:1), and the ﬁltrate was concentrated directly. The

resulting brown foam was then dissolved in DMF (70 mL), and solid

K₂CO₃(11.5 g, 83.4 mmol, 6.0 equiv) and benzyl bromide (9.9 mL,

83.4 mmol, 6.0 equiv) were added sequentially at 25 °C. The reaction

suspension was then heated to 55 °C and stirred vigorously at that

temperature for 16 h. Upon completion, the reaction contents were

cooled to 25 °C, poured into 1 M HCl (140 mL), and extracted with

Et₂O (3 × 140 mL). The combined organic layers were then washed

+

71.4, 71.3, 66.2, 40.0; HRMS (FAB) calcd for C₂₆H₂₆O₅[M]⁺

418.1780, found 418.1793.

To a solution of crude alcohol S7 (4.08 g, 9.76 mmol, 1.0 equiv)

and (E)-3-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)acrylic

acid (S8) (9.00 g, 29.3 mmol, 3.0 equiv, prepared according to the

method of Snyder and Kontes^4b) in CH₂Cl₂(55 mL) at 25 °C were

sequentially added DMAP (1.91 g, 15.6 mmol, 1.6 equiv) and EDCI

(3.74 g, 19.5 mmol, 2.0 equiv). The resulting yellow solution was then

stirred at 25 °C for 3 h. Upon completion, the reaction mixture was

diluted with EtOAc (165 mL) and washed with 1 M HCl (165 mL)

and brine (165 mL). The organic layer was then dried (MgSO₄),

ﬁltered, and concentrated to give the desired intermediate as a viscous

yellow oil. Pressing forward without any additional puriﬁcation, this

crude yellow oil was dissolved in THF (60 mL) and cooled to 0 °C,

and AcOH (0.6 mL) and TBAF (1.0 M in THF, 29.3 mL, 29.3 mmol,

3.0 equiv) were added sequentially. The resulting solution was then

stirred for 1 h at 0 °C. Upon completion, the reaction mixture was

poured into 1 M HCl (180 mL) and extracted with EtOAc (180 mL).

99

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The organic layer was then washed with brine (180 mL), dried

(MgSO₄), ﬁltered, and concentrated. The resultant crude yellow solid

was puriﬁed by ﬂash column chromatography (silica gel, hexanes:E-

tOAc, 3:2) to give phenol 34 (4.97 g, 82% yield over four steps) as a

127.3, 127.2, 122.5, 120.6, 118.9, 118.5, 116.5, 115.0, 114.6, 99.1, 73.5,

71.6, 71.3 (2C), 71.1, 66.0, 60.4, 56.2, 54.4, 47.4, 44.9, 44.3, 36.9;

+

HRMS (FAB) calcd for C₅₉H₅₂O₁₂[M]⁺952.3459, found 952.3472.

36b: R_f= 0.75 (hexanes:EtOAc, 1:1); [α]²_D²= −4.0 (c = 1.0,

CHCl₃); IR (ﬁlm) ν_max3486, 3066, 3031, 2926, 2149, 1796, 1750,

1721, 1632, 1592, 1513, 1464, 1429, 1380, 1262, 1163, 1016, 920, 853,

737 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.44−7.42 (m, 6H), 7.39−

7.28 (m, 15H), 6.90−6.87 (m, 2H), 6.84−6.77 (m, 2H), 6.45 (d, J =

1.6 Hz), 6.38 (dd, J = 8.0, 1.6 Hz, 1H), 6.26−6.21 (m, 1H), 6.16 (d, J

= 16.0 Hz, 1H), 5.85 (ddt, J =17.2, 10.4, 5.6 Hz), 5.32−5.23 (m, 3H),

5.15−5.09 (m, 8H), 4.67−4.57 (m, 2H), 3.94 (dd, J = 5.2, 2.4 Hz,

1H), 3.74 (s, 3H), 3.71 (m, 1H), 3.61 (dd, J = 6.8, 2.8 Hz, 1H), 3.21−

3.07 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 195.3, 172.6, 169.2,

165.4, 148.9, 148.7, 148.6, 148.3, 141.5, 141.3, 137.2, 137.1, 136.9,

136.8, 134.1, 131.4 (2C), 128.9, 128.6, 128.5, 128.0, 127.9, 127.8,

127.4, 127.3, 127.2, 122.4, 120.6, 118.8, 118.5, 118.4, 116.5, 115.0

(2C), 114.6, 99.2, 73.6, 73.5, 71.6, 71.5, 71.3, 71.2, 71.1, 66.0 (2C),

60.4, 56.2, 56.1, 54.3, 47.4, 44.9, 44.1, 36.9; HRMS (FAB) calcd for

clear, pale-yellow oil. 34: R_f= 0.48 (hexanes:EtOAc, 1:1); [α]_D²²

=

+17.4 (c = 0.5, CHCl₃); IR (ﬁlm) ν_max3419, 3034, 1750, 1713, 1632,

1603, 1591, 1455, 1429, 1380, 1314, 1268, 1154, 1029, 984, 738, 697

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 15.6 Hz, 1H), 7.47−

7.30 (m, 10H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H),

6.95−6.90 (m, 3H), 6.83 (dd, J = 8.0, 2.0 Hz, 1H), 6.33 (d, J = 15.6

Hz, 1H), 5.93 (s, 1H), 5.92−5.85 (m, 1H), 5.39−5.27 (m, 2H), 5.26

(dd, J = 9.2, 1.2 Hz, 1H), 5.16 (s, 2H), 5.15 (s, 2H), 4.65−4.63 (m,

2H), 3.91 (s, 3H), 3.19−3.12 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)

δ 169.6, 166.4, 149.0, 148.3, 148.2, 146.8, 146.2, 137.4, 137.2, 131.5,

129.3, 128.5, 127.8, 127.8, 127.4, 127.3, 126.8, 123.4, 122.5, 118.8,

116.6, 115.2, 114.8, 114.4, 109.4, 72.9, 71.5, 71.4, 65.9, 56.0, 37.1;

+

HRMS (FAB) calcd for C₃₆H₃₄O₈[M]⁺594.2254, found 594.2250.

Diels−Alder Adduct 36. Pb(OAc)₄(3.77 g, 8.10 mmol, 1.1

equiv) was suspended in toluene (5 mL) and concentrated directly to

remove any trace/adventitious AcOH that might have been present.

The resulting light-brown solid was then dissolved in CH₂Cl₂(100

mL), and (E)-3-(3,4-bis(benzyloxy)phenyl)acrylic acid (35) (18.5 g,

51.4 mmol, 7.0 equiv) was added at 25 °C. The resultant orange

suspension was then stirred vigorously at 25 °C for 30 min. Upon

completion, the suspension was concentrated directly. The ﬂask was

then back-ﬁlled with argon by attaching a balloon to the air inlet of the

rotary evaporator. The orange solid was then suspended in toluene (50

mL) and concentrated to remove any residual AcOH resulting from

ligand exchange. This azeotroping procedure was then repeated. The

orange solid was then resuspended in CH₂Cl₂, and the above

procedure (i.e., stirring for 30 min, concentration, azeotroping) was

repeated. Next, the orange solid was suspended in anhydrous 1,4-

dioxane (100 mL), and the resulting orange suspension was stirred at

25 °C for 30 min. A solution of (R)-1-(allyloxy)-3-(3,4-bis-

(benzyloxy)phenyl)-1-oxopropan-2-yl (E)-3-(4-hydroxy-3-

methoxyphenyl)acrylate (34) (4.37 g, 7.30 mmol, 1.0 equiv) in 1,4-

dioxane (10 mL) was then added via syringe, resulting in the

disappearance of the orange color of the original suspension and a

signiﬁcant thickening of the mixture. The reaction ﬂask was swirled

manually to ensure eﬃcient mixing, and ethylene glycol (0.5 mL, 8.87

mmol, 1.2 equiv) was then added at 25 °C. After the mixture was

vigorously stirred at 25 °C for 20 min, the reaction contents were

concentrated directly. The resulting white solid was then suspended in

EtOAc (50 mL) and ﬁltered. The solid residue was then thoroughly

rinsed with EtOAc (3 × 15 mL) and ﬁltered. The combined ﬁltrates

were then washed with brine (500 mL). The combined organic layers

were then dried (MgSO₄), ﬁltered, and concentrated. The resultant

crude yellow solid was then suspended in Et₂O (50 mL), ﬁltered, and

concentrated. The resultant crude yellow oil was puriﬁed by ﬂash

column chromatography (silica gel, hexanes:EtOAc, 4:1→3:2) to give

the desired Diels−Alder product 36 (3.45 g, 50% yield, ∼1:1 mixture

of inseparable diastereomers) as a clear, colorless oil. Separation of the

two diastereomers of the product proved to be possible after their

ketones were reduced to the corresponding alcohols. The separate

diastereomers were then oxidized to regenerate the ketones (vide

infra), and the ﬁnal individual spectra separately matched the

combined spectral information for the original mixture of diaster-

eomers generated from the Diels−Alder reaction of 34.

+

C₅₉H₅₂O₁₂[M]⁺952.3459, found 952.3472.

exo-Alcohol 37 and endo-Alcohol 38. Diels−Alder product 36

(2.1 g, 2.20 mmol) was dissolved in THF/AcOH (1:1, 20 mL).

NaBH(OAc)₃(2.3 g, 11.0 mmol, 5.0 equiv) was added at 25 °C, and

the resulting pale-yellow solution was stirred at 25 °C for 4 h. An

aqueous solution of Rochelle’s salt (0.5 M, 50 mL) was then added,

and the resultant mixture was stirred for 20 min, after which time it

was carefully poured into saturated aqueous NaHCO₃(100 mL;

CAUTION: vigorous bubbling was observed) and extracted with

EtOAc (100 mL). The organic layer was washed with saturated

aqueous NaHCO₃(100 mL), and the combined aqueous layers were

re-extracted with EtOAc (2 × 100 mL). The combined organic layers

were then dried (MgSO₄), ﬁltered, and concentrated. The resultant

crude colorless residue was puriﬁed by ﬂash column chromatography

(silica gel, CH₂Cl₂:Et₂O, 19:1→9:1) to give two pairs of diastereomers

(i.e., two exo alcohols and two endo alcohols), each as a clear colorless

oil (1.72 g total, 82% yield, ∼1.5:1 exo:endo). Each pair of

diastereomers was separated by preparative TLC in 30 mg batches

(CH₂Cl₂:Et₂O, 97:3, 4−5 developments per plate).

37a: R_f= 0.52 (CH₂Cl₂:Et₂O, 9:1); [α]²_D²= +94.3 (c = 0.95,

CHCl₃); IR (ﬁlm) ν_max3503, 3063, 3032, 2946, 2863, 1779, 1752,

1717, 1633, 1604, 1513, 1454, 1382, 1264, 1206, 1162, 1023, 931, 737,

697 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.43−7.28 (m, 21H), 6.88−

6.85 (m, 2H), 6.80−6.76 (m, 2H), 6.45 (d, J = 2.5 Hz, 1H), 6.42−6.39

(m, 2H), 6.06 (d, J = 16.0 Hz, 1H), 5.83 (ddt, J = 17.5, 10.5, 5.5 Hz,

1H), 5.32−5.21 (m, 3H), 5.14−5.06 (m, 8H), 4.61 (ddt, J = 12.0, 5.5,

1.0 Hz, 1H), 4.56 (ddt, J = 13.0, 5.5, 1.5 Hz, 1H), 4.07 (app t, J = 3.5

Hz, 1H), 3.78 (d, J = 4.5 Hz, 1H), 3.52 (s, 3H), 3.38 (app quintet, J =

3.0 Hz, 1H), 3.29 (br s, 1H), 3.15 (dd, J = 14.5, 5.0 Hz, 1H), 3.10 (dd,

J = 14.5, 3.0 Hz, 1H), 2.74 (dd, J = 4.5, 1.5 Hz, 1H), 2.34 (d, J = 4.5

Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 173.8, 169.3, 165.7, 149.0,

148.5, 148.4, 148.3, 142.7, 140.4, 137.3, 137.2, 137.1, 137.0, 133.8,

132.8, 131.4, 128.9, 128.6, 128.5 (3C), 127.9 (3C), 127.8, 127.4, 127.3

(2C), 127.2, 122.5, 120.6, 118.9, 116.7, 116.2, 115.2 (2C), 114.8,

109.7, 74.1, 73.3, 71.6, 71.4 (2C), 71.3, 66.0, 52.9, 47.8, 47.1, 44.2,

40.4, 37.0; HRMS (FAB) calcd for C₅₉H₅₄O₁₂⁺[M]⁺954.3615, found

954.3619.

37b: R_f= 0.52 (CH₂Cl₂:Et₂O, 9:1); [α]²_D²= −92.0 (c = 0.75,

CHCl₃); IR (ﬁlm) ν_max3523, 3032, 2949, 1779, 1717, 1632, 1512,

1

1261, 1205, 1161, 1140, 1080, 1020, 930, 738, 698 cm⁻¹; H NMR

36a: R_f= 0.75 (hexanes:EtOAc, 1:1); [α]²_D²= +24.7 (c = 0.5,

CHCl₃); IR (ﬁlm) ν_max3486, 3066, 3031, 2926, 2149, 1796, 1750,

1721, 1632, 1592, 1513, 1464, 1429, 1380, 1262, 1163, 1016, 920, 853,

737 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.44−7.40 (m, 6H), 7.40−

7.30 (m, 15H), 6.89−6.86 (m, 2H), 6.83−6.77 (m, 2H), 6.45 (d, J =

2.4 Hz, 1H), 6.25 (br d, J = 6.0 Hz, 1H), 6.19 (d, J = 16.0 Hz, 1H),

5.85 (ddt, J = 17.2, 10.4, 5.6 Hz, 1H), 5.34−5.22 (m, 3H), 5.17−5.06

(m, 8H), 4.65−4.54 (m, 2H), 3.93 (dd, J = 5.2, 2.0 Hz, 1H), 3.68 (s,

3H), 3.68 (m, 1H), 3.61 (dd, J = 6.8, 2.8 Hz, 1H), 3.19−3.08 (m, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 195.3, 172.6, 171.1, 169.2, 165.5,

148.9, 148.7, 148.6, 148.3, 141.5, 137.2, 137.1, 136.9 (2C), 136.8,

134.1, 131.4 (2C), 128.8, 128.6 (2C), 128.5, 127.9 (2C), 127.8, 127.4,

(500 MHz, CDCl₃) δ 7.46−7.30 (m, 21H), 6.92−6.90 (m, 2H), 6.84−

6.80 (m, 2H), 6.48 (d, J = 2.5 Hz, 1H), 6.45−6.41 (m, 2H), 6.07 (d, J

= 16.0 Hz, 1H), 5.87 (ddt, J = 17.5, 10.5, 6.0 Hz, 1H), 5.36−5.24 (m,

3H), 5.17−5.09 (m, 8H), 4.65−4.59 (m, 2H), 4.10 (app t, J = 3.5 Hz,

1H), 3.82 (d, J = 4.5 Hz, 1H), 3.59 (s, 3H), 3.41 (app quintet, J = 3.0

Hz, 1H), 3.32 (br s, 1H), 3.19 (dd, J = 14.5, 4.5 Hz, 1H), 3.12 (dd, J =

14.0, 8.5 Hz, 1H), 2.76 (d, J = 4.5, 1.5 Hz, 1H), 2.40 (d, J = 4.5 Hz,

1H); ¹³C NMR (125 MHz, CDCl₃) δ 173.9, 169.3, 165.7, 149.0,

148.5, 148.3 (2C), 142.6, 140.5, 137.3, 137.2, 137.1, 137.0, 133.8,

132.8, 131.4, 129.0, 128.5 (5C), 127.9, 127.8, 127.4, 127.3 (2C), 127.2

(2C), 122.5, 120.6, 118.9, 116.6, 116.2, 115.2 (2C), 114.8, 109.7, 74.1,

73.4, 71.6, 71.4 (2C), 71.3, 66.0, 53.0, 47.9, 47.0, 44.2, 40.3, 37.0.

100

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38a: R_f= 0.41 (CH₂Cl₂:Et₂O, 9:1); [α]²_D²= +79.6 (c = 0.75,

CHCl₃); IR (ﬁlm) ν_max3474, 3062, 3024, 2936, 1780, 1754, 1718,

Hz, 1H), 3.96 (d, J = 2.8 Hz, 1H), 3.46 (s, 3H), 3.22 (br s, 1H), 3.15

(dd, J = 6.0, 3.2 Hz, 1H), 3.03 (d, J = 12.4 Hz, 1H), 2.72 (dd, J = 14.4,

10.4 Hz, 1H), 2.65 (d, J = 4.0 Hz, 1H); ¹³C NMR (125 MHz, DMSO-

d₆) δ 175.4, 173.4, 166.6, 145.7, 145.5, 144.8, 144.1, 141.8, 140.4,

133.4, 133.2, 130.5, 129.4, 128.7, 120.0, 118.8, 118.0, 117.0, 116.2,

116.1, 115.9, 112.1, 77.0, 73.8, 53.3, 48.8, 47.7, 43.8; HRMS (FAB)

1

1633, 1513, 1454, 1262, 1204, 1163, 1139, 1021, 736, 697 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 7.46−7.30 (m, 21H), 6.91−6.88 (m, 2H),

6.82−6.79 (m, 2H), 6.50 (d, J = 2.5 Hz, 1H), 6.44−6.40 (m, 2H), 6.09

(d, J = 15.5 Hz, 1H), 5.86 (ddt, J = 17.5, 10.5, 6.0 Hz, 1H), 5.35−5.23

(m, 3H), 5.14−5.07 (m, 8H), 4.63 (dd, J = 13.0, 5.5 Hz, 1H), 4.59

(dd, J = 13.0, 5.5 Hz, 1H), 3.78 (dd, J = 5.0, 1.5 Hz, 1H), 3.65 (dd, J =

5.0, 2.5 Hz, 1H), 3.55 (br s, 1H), 3.45 (s, 3H), 3.17−3.09 (m, 3H),

2.85 (dd, J = 4.5, 1.5 Hz, 1H), 2.48 (d, J = 5.5 Hz, 1H); ¹³C NMR

(125 MHz, CDCl₃) δ 173.5, 169.3, 165.8, 149.0, 148.5, 148.3, 148.2,

142.5, 139.8, 137.3, 137.2, 137.1, 137.0, 134.1, 131.4, 129.0, 128.5

(3C), 127.9 (2C), 127.8, 127.4 (2C), 127.3 (2C), 127.2, 122.5, 120.8,

118.9, 117.0, 116.6, 115.3, 115.2, 114.8, 107.5, 73.3, 72.1, 71.6, 71.4,

71.3 (2C), 66.0, 53.4, 52.2, 48.1, 47.3, 42.8, 39.9, 37.0; HRMS (FAB)

+

calcd for C₂₈H₂₇O₁₂[M + H]⁺555.1503, found 555.1512.

Yunnaneic Acid D (3). Carboxylic acid S9 (0.035 g, 0.063 mmol,

1.0 equiv) was suspended in CH₂Cl₂/H₂O (2:1, 1.5 mL), and HCl

(4.0 M in dioxane, 0.5 mL) was added at 25 °C. The mixture was

stirred at 25 °C for 2 h and then poured into brine (5 mL) and

extracted with EtOAc (3 × 5 mL). The combined organic layers were

then dried (MgSO₄), ﬁltered, and concentrated. Subsequent

coevaporation with toluene (2 × 2 mL) removed any residual 1,4-

dioxane, aﬀording yunnaneic acid D (3) (0.030 g, 88% yield) as a

white powder. [Note: this compound appeared to isomerize readily in

the presence of trace acid, and thus, removal of trace EtOAc from the

crude product by prolonged drying could not be performed without

compromising the purity of the sample.] 3: IR (ﬁlm) ν_max3328, 2529,

2919, 2849, 1710, 1626, 1521, 1446, 1255, 1175, 1115, 1076, 978, 812

+

calcd for C₅₉H₅₄O₁₂[M]⁺954.3615, found 954.3622.

38b: R_f= 0.41 (CH₂Cl₂:Et₂O, 9:1); [α]²_D²= −64.7 (c = 0.80,

CHCl₃); IR (ﬁlm) ν_max3474, 3062, 3024, 2936, 1780, 1754, 1718,

1

1633, 1513, 1454, 1262, 1204, 1163, 1139, 1021, 736, 697 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 7.46−7.29 (m, 21H), 6.92−6.89 (m, 2H),

6.83−6.79 (m, 2H), 6.50 (d, J = 2.0 Hz, 1H), 6.44−6.38 (m, 2H), 6.07

(d, J = 16.0 Hz, 1H), 5.88 (ddt, J = 12.5, 8.0, 5.5 Hz, 1H), 5.34−5.24

(m, 3H), 5.14−5.10 (m, 8H), 4.67−4.59 (m, 2H), 3.78 (dd, J = 4.5,

1.5 Hz, 1H), 3.63 (br s, 1H), 3.56 (br s, 1H), 3.48 (s, 3H), 3.21−3.07

(m, 3H), 2.84 (dd, J = 4.5, 1.5 Hz, 1H), 2.51 (d, J = 5.0 Hz, 1H); ¹³C

NMR (125 MHz, CDCl₃) δ 173.5, 169.3, 165.7, 149.0, 148.5, 148.3,

148.1, 142.4, 139.8, 137.3, 137.1 137.0, 134.1, 131.4, 129.0, 128.5

(5C), 127.9 (3C), 127.8, 127.4, 127.3 (3C), 127.2, 122.5, 120.7, 118.9,

117.1, 116.6, 115.4, 115.2, 114.8, 107.5, 73.4, 72.1, 71.6, 71.4, 71.3,

66.0, 52.2, 48.1, 47.2, 42.7, 39.8, 37.0.

1

cm⁻¹; H NMR (500 MHz, acetone-d₆) δ 7.39 (d, J = 16.0 Hz, 1H),

6.90−6.84 (m, 2H), 6.76−6.72 (m, 3H), 6.64 (dd, J = 8.0, 2.0 Hz,

1H), 6.57−6.53 (m, 1H), 6.22 (d, J = 16.0 Hz, 1H), 5.21 (dd, J = 8.5,

3.5 Hz, 1H), 4.01 (d, J = 1.5 Hz, 1H), 3.87 (br s, 1H), 3.55 (br s, 1H),

3.28 (d, J = 6.0 Hz, 1H), 3.12 (dd, J = 14.5, 3.5 Hz, 1H), 2.99 (dd, J =

14.5, 8.5 Hz, 1H), 2.88 (d, J = 2.0 Hz, 1H); ¹³C NMR (125 MHz,

acetone-d₆) δ 207.8, 175.5, 171.0, 166.5, 145.8, 145.6, 143.3, 141.9,

136.8, 136.3, 129.1, 121.7, 119.9, 117.9, 117.3, 116.1 (2C), 115.5, 74.1,

72.4, 51.1, 50.1, 48.8, 47.0, 37.4; HRMS (FAB) calcd for

C₂₇H₂₄O₁₂Na⁺[M + Na]⁺563.1166; HRMS data could not be

obtained because of facile side-chain cleavage, but a molecular ion peak

at m/z 563.11 was observed via LRMS (FAB). All of the spectroscopic

data for this compound matched those reported by Tanaka and co-

workers¹(see Table S1 in the Supporting Information), noting that

some isomerization of the characterization sample was observed

during the time when the ¹³C NMR spectrum was taken.

(R)-1-(Allyloxy)-3-(3,4-dihydroxyphenyl)-1-oxopropan-2-yl

(E)-3-(8-(3,4-Dihydroxyphenyl)-7a-methoxy-2,7-dioxo-

2,3,3a,6,7,7a-hexahydro-3,6-methanobenzofuran-4-yl)acrylate

(S10). The debenzylation procedure described above for the synthesis

of S9 was applied to ketone 36b (0.045 g, 0.031 mmol, 1.0 equiv) to

give a crude brown oil. This crude product was puriﬁed by ﬂash

column chromatography (silica gel, hexanes:EtOAc, 2:3→3:7) to give

tetraphenol S10 (0.022 g, 79% yield) as a yellow oil. S10: R_f= 0.59

(CH₂Cl₂:MeOH, 9:1); [α]²_D²= −44.5 (c = 0.55, MeOH); IR (ﬁlm)

ν_max3382, 2945, 2916, 1853, 1739, 1711, 1625, 1599, 1523, 1444,

1365, 1282, 1191 cm⁻¹; ¹H NMR (400 MHz, acetone-d₆) δ 7.48 (d, J

= 16.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.77−6.72 (m, 2H), 6.69−

6.62 (m, 3H), 6.50−6.42 (m, 2H), 5.91 (ddt, J = 17.2, 10.4, 5.2 Hz,

1H), 5.36−5.19 (m, 3H), 4.66 (dd, J = 5.2, 2.0 Hz, 1H), 4.65 (dd, J

=5.2, 2.0 Hz, 1H), 4.62 (dd, J = 5.2, 0.8 Hz, 1H), 3.82 (br s, 1H), 3.73

(dd, J = 6.8, 2.8 Hz, 1H), 3.64 (s, 3H), 3.33 (dd, J = 5.2, 0.8 Hz, 1H),

3.12 (dd, J = 14.4, 4.8 Hz, 1H), 3.03 (dd, J = 14.4, 8.4 Hz, 1H); ¹³C

NMR (125 MHz, acetone-d₆) δ 195.4, 173.0, 169.0, 165.5, 145.0,

144.6, 144.1, 141.8, 137.5, 135.1, 132.1, 131.0, 128.3, 127.6, 120.7,

119.2, 118.4, 117.5, 116.4, 115.2, 115.1, 115.0, 99.7, 73.6, 65.2, 56.5,

52.7, 47.4, 44.7, 42.9, 36.5; HRMS (FAB) calcd for C₃₁H₂₉O₁₂⁺[M +

H]⁺593.1659, found 593.1686.

Compound 36b (as a Single Diastereomer).³⁸To a stirred

suspension of pulverized and activated 4 Å molecular sieves (0.035 g,

0.5 g/mmol of alcohol) and NMO (0.017 g, 0.15 mmol, 2.0 equiv) in

CH₂Cl₂(1.0 mL) at 25 °C was added endo-alcohol 38b (0.070 g, 0.073

mmol, 1.0 equiv) as a solution in CH₂Cl₂(0.5 mL). The resulting

slurry was stirred at 25 °C for 10 min and then cooled to 0 °C, and

TPAP (1 mg, 0.003 mmol, 0.05 equiv) was added in a single portion.

The resulting black slurry was stirred at 0 °C for 1 h. Upon

completion, the reaction mixture was ﬁltered through a plug of silica

gel (eluted with hexanes:EtOAc, 7:3) and concentrated to give 36b

(0.045 g, 67% yield) as a pale-yellow oil.

Carboxylic Acid S9.³⁹exo-Alcohol 37b (0.107 g, 0.112 mmol, 1.0

equiv) was dissolved in benzene (1.0 mL). The solution was

concentrated to remove any trace/adventitious H₂O, and the

concentrate was dissolved in CH₂Cl₂(2.0 mL) at 25 °C. The

resultant solution was cooled to −78 °C, and BCl₃(0.9 mL, 1.0 M in

CH₂Cl₂, 8.0 equiv) was added in a single portion. The resulting yellow

solution was then stirred at −78 °C for 5 min, after which time pH 7

phosphate buﬀer (0.18 M, 1.0 mL) was added, and the ﬂask was

immediately immersed in a warm water bath to melt the ice that

formed upon addition of the buﬀer solution. This mixture was then

diluted with EtOAc (10 mL) and washed with brine (10 mL). The

aqueous layer was then re-extracted with EtOAc (2 × 10 mL), and the

combined organic layers were dried (MgSO₄), ﬁltered, and

concentrated. The resultant crude pale-brown oil was then dissolved

in THF (2.0 mL), and the mixture was degassed by bubbling argon

through the solution for 10 min. To this mixture were sequentially

added Meldrum’s acid (24 mg, 0.168 mmol, 1.5 equiv) and Pd(PPh₃)₄

(6 mg, 0.006 mmol, 0.05 equiv) at 25 °C. The resultant yellow

solution was then stirred at 25 °C for 15 min and concentrated

directly. Puriﬁcation of the resultant crude residue by preparative TLC

(CH₂Cl₂:MeOH, 4:1 doped with 1% AcOH) gave deprotected

compound S9 (0.062 g, 55% yield over two steps) as a white solid.

Yunnaneic Acid C (2). To a degassed solution of tetraphenol S10

(22 mg, 0.037 mmol, 1.0 equiv) in THF (1.0 mL) at 25 °C were

sequentially added Meldrum’s acid (8 mg, 0.056 mmol, 1.5 equiv) and

Pd(PPh₃)₄(4 mg, 0.004 mmol, 0.1 equiv). The resultant yellow

solution was stirred at 25 °C for 15 min and then concentrated

directly. The so-obtained residue was puriﬁed by preparative TLC

(CH₂Cl₂:MeOH, 4:1 doped with 1% AcOH) to give a translucent

colorless wax. This newly synthesized material was suspended in

CH₂Cl₂/H₂O (2:1, 0.75 mL), and TFA (0.5 mL) was added at 25 °C.

Over time, the initially colorless mixture became increasingly yellow,

with the mixture being stirred at 25 °C for a total of 16 h. Upon

completion, the reaction contents were poured into brine (5 mL) and

S9: R_f= 0.07 (CH₂Cl₂:MeOH, 4:1 doped with 1% AcOH); [α]_D²²

=

−40.9 (c = 1.0, MeOH); IR (ﬁlm) ν_max3233, 2962, 2925, 2361, 1773,

1

1702, 1528, 1599, 1401, 1268, 1206, 1024, 930, 668 cm⁻¹; H NMR

(400 MHz, DMSO-d₆) δ 7.25 (d, J = 15.6 Hz, 1H), 6.64 (d, J = 1.6 Hz,

1H), 6.61−6.57 (m, 2H), 6.53 (d, J = 6.4 Hz), 6.47 (dd, J = 7.6, 1.6

Hz, 1H), 6.33 (d, J = 2.0 Hz, 1H), 6.23 (dd, J = 8.0, 2.0 Hz, 1H), 6.18

(d, J = 16.0 Hz, 1H), 4.85 (dd, J = 10.4, 2.4 Hz, 1H), 4.18 (d, J = 4.0

101

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extracted with EtOAc (3 × 5 mL). The combined organic layers were

then dried (MgSO₄), ﬁltered, and concentrated to give yunnaneic acid

C (2) (10 mg, 50% over two steps) as a yellow solid. 2: IR (ﬁlm) ν_max

3282, 2919, 1705, 1687, 1633, 1521, 1442, 1260, 1191, 1148 cm⁻¹; ¹H

NMR (500 MHz, acetone-d₆) δ 7.47 (d, J = 16.0 Hz, 1H), 6.84−6.83

(m, 2H), 6.76−6.60 (m, 5H), 6.43 (d, J = 15.5 Hz, 1H), 5.23 (dd, J =

9.0, 4.0 Hz, 1H), 4.34 (br s, 1H), 3.79 (app t, J = 3.0 Hz, 1H), 3.74

(dd, J = 6.5, 2.5 Hz, 1H), 3.32−3.25 (m, 1H), 3.14 (dd, J = 14.5, 4.0

Hz, 1H), 3.01 (dd, J = 14.5, 9.0 Hz, 1H); ¹³C NMR (125 MHz,

acetone-d₆) δ 174.6, 171.3, 166.4, 146.0, 145.8, 145.4, 144.9, 139.4,

136.2, 129.0, 121.5, 120.1, 120.0, 117.4, 116.2, 116.1, 115.9, 74.3, 66.1,

56.9, 54.9, 45.7, 37.4; HRMS data could not be obtained because of

instability of the diketone. All of the spectroscopic data for this

compound matched those reported by Tanaka and co-workers¹(see

Table S2 in the Supporting Information).

Hz, 1H), 6.54 (d, J = 6.4 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 6.43 (dd, J

= 8.4, 2.0 Hz, 1H), 6.18 (d, J = 16.0 Hz, 1H), 4.34 (d, J = 4.8 Hz, 1H),

4.15 (d, J = 3.6 Hz, 1H), 3.97 (app t, J = 4.8 Hz, 1H), 3.86 (s, 3H),

3.84 (s, 3H), 3.82 (s, 3H), 3.44−3.40 (m, 1H), 3.29 (br s, 1H), 2.75

(d, J = 4.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 177.7, 167.1,

148.8, 148.2, 141.3, 138.5, 134.7, 133.3, 119.6, 117.5, 111.2, 111.0,

82.2, 73.7, 55.9 (2C), 51.9, 46.7, 44.4, 44.2, 39.3; HRMS (FAB) calcd

+

for C₂₁H₂₂O₇[M]⁺386.1366, found 386.1370.

39: R_f= 0.44 (hexanes:EtOAc, 3:7); IR (ﬁlm) ν_max2956, 2838,

1784, 1715, 1635, 1516, 1437, 1314, 1254, 1188, 1026, 912, 734 cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ 7.29 (d, J = 16.0 Hz, 1H), 6.74 (d, J =

8.4 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 6.41 (dd, J = 8.4, 2.0 Hz, 1H),

6.37 (d, J = 6.4 Hz, 1H), 6.01 (d, J = 15.6 Hz, 1H), 4.29 (d, J = 3.6 Hz,

1H), 3.86 (s, 3H), 3.83 (s, 6H), 3.62 (d, J = 4.4 Hz, 1H), 3.49 (app

quintet, J = 3.2 Hz, 1H), 3.39 (br s, 1H), 2.91 (dd, J = 4.4, 2.0 Hz,

1H); ¹³C NMR (125 MHz, CDCl₃) δ 173.1, 166.8, 148.9, 148.4,

140.8, 136.4, 133.1, 132.5, 119.7, 117.7, 111.2, 111.0, 106.6, 74.2, 55.9

(3C), 51.9, 47.1, 44.3, 43.6; HRMS (FAB) calcd for C₄₂H₄₀O₁₄⁺[M]⁺

768.2418, found 768.2448.

Quinoxaline Derivative (S11).¹The following was performed on

a diastereomeric mixture. Yunnaneic acid C (2) and its diastereomer

(∼1:1, 0.027 g total, 0.049 mmol, 1.0 equiv) were dissolved in EtOH/

AcOH (4:1, 1.6 mL). The light-brown solution was degassed via the

freeze−pump−thaw method (liquid N₂; repeated twice). 1,2-Phenyl-

enediamine (0.011 g, 0.10 mmol, 2.0 equiv) was then added. The

resulting brown solution was stirred at 60 °C for 19 h. Upon

completion, the mixture was cooled to 25 °C and concentrated

directly. The resulting red-orange oil was taken up in EtOAc/1 M HCl

(1:1, 10 mL). The layers were separated, and the organic layer was

washed with 1 M HCl (2 × 5 mL). The organic layer was then dried

(MgSO₄), ﬁltered, and concentrated to give the crude quinoxaline as a

brown solid (1:1 d.r.). This material was separated by reversed-phase

semipreparative HPLC (C18, 5 μ, 250 mm × 9.6 mm, H₂O/MeCN,

95%→65% for 40 min, 65% for 20 min, UV detector at 280 nm, t_R

(undesired) = 44.9 min, t_R(desired) = 46.8 min) to aﬀord pure

quinoxaline S11 (0.0025 g, 19% yield). S11: [α]²_D²= +103.4 (c = 0.05,

MeOH); IR (ﬁlm) ν_max2922, 2851, 1707, 1625, 1521, 1445, 1260,

Rufescenolide (41). To a solution of 40 (0.012 g, 0.031 mmol, 1.0

equiv) in CH₂Cl₂(1.0 mL) at 0 °C was added BBr₃(1.0 M in CH₂Cl₂,

0.19 mL, 0.19 mmol, 6.0 equiv) in a single portion. The resultant dark-

yellow solution was then stirred at 0 °C for 10 min. Upon completion,

saturated aqueous NaHCO₃(1.0 mL) was added, and the mixture was

poured into water (5 mL) and then extracted with EtOAc (2 × 5 mL).

The combined organic layers were washed with brine (5 mL), dried

(MgSO₄), ﬁltered, and concentrated. Puriﬁcation of the resultant

colorless oil by preparative thin-layer chromatography (hexanes:E-

tOAc, 3:7) aﬀorded rufescenolide (41) (0.006 g, 55% yield) as an

amorphous white solid. 41: R_f= 0.56 (EtOAc); IR (ﬁlm) ν_max3354,

1

1766, 1696, 1630, 1518, 1438, 1271, 1172, 1116, 1074, 986 cm⁻¹; H

NMR (400 MHz, CD₃OD) δ 7.45 (d, J = 16.0 Hz, 1H), 6.64 (d, J =

8.0 Hz, 1H), 6.52 (d, J = 6.5 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 6.34

(dd, J = 8.4, 2.4 Hz, 1H), 6.27 (d, J = 16.0 Hz, 1H), 4.24 (d, J = 5.2

Hz, 1H), 4.11 (app t, J = 4.5 Hz, 1H), 4.01 (d, J = 3.6 Hz, 1H), 3.77 (s,

3H), 3.35 (m, 1H), 3.15 (br s), 2.66 (d, J = 4.5 Hz, 1H); ¹³C NMR

(125 MHz, CD₃OD) δ 179.4, 167.9, 144.7, 143.9, 142.1, 140.0, 133.9,

133.2, 118.8, 116.1, 114.7, 114.6, 82.7, 73.5, 50.8, 46.3, 44.2 (2C),

38.8; ¹³C NMR (175 MHz, CDCl₃containing ca. 5% CD₃OD) δ

178.3, 167.6, 144.0, 143.3, 141.8, 139.2, 134.0, 133.1, 119.5, 116.9,

114.7, 114.4, 82.4, 73.5, 51.9, 46.4, 44.4, 44.2, 39.1; HRMS (FAB)

1

1020, 799 cm⁻¹; H NMR (400 MHz, acetone-d₆) δ 8.04−7.99 (m,

2H), 7.79−7.75 (m, 2H), 7.53 (d, J = 16.0 Hz, 1H), 7.23 (d, J = 5.2 H,

1H), 6.88 (d, J = 2.0 Hz, 1H), 6.83−6.75 (m, 3H), 6.70−6.65 (m,

2H), 6.52 (d, J = 16.0 Hz, 1H), 5.24 (dd, J = 8.4, 4.0 Hz, 1H), 4.93

(app t, J = 2.0 Hz, 1H), 4.35 (dd, J = 6.4, 2.0 Hz, 1H), 3.63 (dd, J =

6.0, 1.2 Hz, 1H), 3.19 (dd, J = 6.0, 2.4 Hz, 1H), 3.14 (dd, J = 14.3, 4.0

Hz, 1H), 3.05 (dd, J = 14.4, 8.4 Hz, 1H); ¹³C NMR (125 MHz,

acetone-d₆) δ 173.5, 170.8, 166.4, 157.8, 155.2, 145.9, 145.6, 145.1,

144.7 (2C), 141.7 (2C), 141.6, 141.3, 134.8, 130.0, 129.7 (3C), 128.9,

121.6, 120.0, 118.2, 117.3, 116.2, 115.9, 115.4, 74.0, 52.0, 51.5, 48.4,

46.7, 37.4; HRMS (FAB) calcd for C₃₃H₂₇N₂O₁₀[M + H]⁺611.1666,

found 611.1648. All of the spectroscopic data for this compound

matched those reported by Tanaka and co-workers¹(see Table S3 in

the Supporting Information).

+

calcd for C₁₉H₁₉O₇[M + H]⁺359.1131, found 359.1125. All of the

spectroscopic data for this material matched those reported by David

and co-workers²⁶(see Table S4 in the Supporting Information).

C₂-Symmetric Dimer 61.^4bTo a solution of dimethyl ketal 60

(0.075 g, 0.16 mmol, 1.0 equiv) in CH₂Cl₂(1.5 mL) at 0 °C was

added BF₃·OEt₂(0.09 mL, 0.65 mmol, 4.0 equiv) in a single portion.

The resulting pale-orange solution was stirred at 0 °C for 30 min.

Upon completion, saturated aqueous NaHCO₃(0.5 mL) was added,

and the mixture was warmed to 25 °C. The mixture was then poured

into H₂O (10 mL) and extracted with EtOAc (3 × 10 mL). The

combined organic layers were washed with brine (10 mL), dried

(MgSO₄), ﬁltered, and concentrated. The resultant crude pale-brown

oil was puriﬁed by ﬂash column chromatography (silica gel,

hexanes:EtOAc, 1:1→3:7) to give 61 (0.025 g, 36% yield) as a

colorless waxy solid that could be crystallized from CH₂Cl₂/n-hexane

(colorless prisms). 61: R_f= 0.47 (hexanes:EtOAc, 3:7); IR (ﬁlm) ν_max

2961, 1720, 1631, 1516, 1436, 1265, 1236, 1169, 1132, 1028, 841

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J = 16.0 Hz, 2H), 6.75

(d, J = 8.8 Hz, 2H), 6.67−6.64 (m, 4H), 6.26 (d, J = 6.4 Hz, 2H), 6.03

(d, J = 15.6 Hz, 2H), 3.85 (s, 6H), 3.84 (s, 6H), 3.83 (s, 6H), 3.74 (s,

6H), 3.69 (d, J = 3.2 Hz, 2H), 3.62 (br d, J = 6.0 Hz, 2H), 3.43 (app q,

J = 4.4, 2.0 Hz, 2H), 3.37 (s, 6H), 3.05 (dd, J = 6.8, 1.2 Hz, 2H), 2.58

(dd, J = 6.8, 2.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 173.0,

167.7, 148.8, 147.9, 142.2, 140.0, 136.7, 136.3, 119.3, 116.7, 111.1,

111.0, 100.2, 70.2, 55.9 (2C), 52.3, 51.7, 49.3, 48.9, 44.7, 39.9, 39.2;

(E)-Methyl 3-(8-(3,4-Dimethoxyphenyl)-7-hydroxy-2-oxo-

2,3,3a,6,7,7a-hexahydro-3,6-methanobenzofuran-4-yl)acrylate

(40).²⁸Hydroxyketal 31 (0.075 g, 0.18 mmol, 1.0 equiv) was added to

CH₂Cl₂(9.0 mL), and the mixture was stirred at 25 °C until complete

dissolution was achieved (typically 20 min). To this solution was then

added Et₃SiH (0.57 mL, 3.60 mmol, 20.0 equiv). After 5 min of

stirring at 25 °C, TMSOTf (0.10 mL, 0.54 mmol, 3.0 equiv) was

added, and the resulting yellow mixture was stirred at 25 °C for 2.5 h.

Three drops of pyridine were then added, after which the mixture

became colorless and gas evolution was observed. The mixture was

poured into 1.0 M HCl (35 mL) and extracted with EtOAc (2 × 35

mL). The combined organic layers were then washed with brine (35

mL), dried (MgSO₄), ﬁltered, and concentrated to give a waxy, white

solid. Puriﬁcation of this crude residue by ﬂash column chromatog-

raphy (silica gel, CH₂Cl₂:Et₂O, 2:3) gave protected rufescenolide 40

(0.037 g, 54% yield) alongside the separable (2E,2′E)-dimethyl 3,3′-

((6aR,7aR,13aR,14aR)-15,16-bis(3,4-dimethoxyphenyl)-2,9-dioxo-

2,3,3a,6,6a,9,10,10a,13,13a-decahydro-3,6:10,13-dimethanodifuro[3,2-

d:3′,2′-k]dibenzo[b,e][1,4]dioxine-4,11-diyl)diacrylate (39) (0.017 g,

25% yield).

+

HRMS (FAB) calcd for C₄₆H₅₂O₁₆[M]⁺860.3255, found 860.3265.

40: R_f= 0.28 (hexanes:EtOAc, 3:7); IR (ﬁlm) ν_max3474, 2952,

(1R,2R,3S,4R)-Methyl 3-(3,4-Dimethoxyphenyl)-8-hydroxy-

6-((E)-3-methoxy-3-oxoprop-1-en-1-yl)-7-oxobicyclo[2.2.2]oct-

5-ene-2-carboxylate (62). To a solution of carboxylic acid 32 (0.116

1

2914, 1774, 1717, 1625, 1515, 1430, 1252, 1160, 1027, 983 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 16.0 Hz, 1H), 6.75 (d, J = 8.4

102

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The Journal of Organic Chemistry

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g, 0.29 mmol, 1.0 equiv) in THF/MeOH (9:1, 3.0 mL) at −78 °C was

added TMSCHN₂(2.0 M in Et₂O, 0.18 mL, 0.36 mmol, 1.2 equiv).

The resultant yellow solution was then stirred at −78 °C for 15 min,

after which AcOH was added dropwise until all bubbling ceased. The

resulting pale-yellow solution was then diluted with EtOAc (15 mL)

and washed with saturated aqueous NaHCO₃(15 mL). The aqueous

layer was then extracted with EtOAc (2 × 15 mL), and the combined

organic layers were dried (MgSO₄), ﬁltered, and concentrated. The

resultant crude white foam product was puriﬁed by ﬂash column

chromatography (silica gel, hexanes:EtOAc, 2:3) to give ester 62

(0.033 g, 28% yield) as a colorless oil. 62: R_f= 0.39 (hexanes:EtOAc,

3:7); IR (ﬁlm) ν_max3458, 3069, 2999, 2954, 2841, 1740, 1631, 1518,

NMR (500 MHz, CDCl₃) δ 7.41 (d, J = 16.0 Hz, 1H), 7.33 (d, J =

16.0 Hz, 1H), 6.78−6.73 (m, 3H), 6.69−6.61 (m, 4H), 6.46 (d, J = 6.0

Hz, 1H), 6.16 (d, J = 15.5 Hz, 1H), 6.07 (d, J = 16.0 Hz, 1H), 4.43 (d,

J = 3.5 Hz, 1H), 3.87−3.82 (m, 15H), 3.78 (s, 3H), 3.78 (s, 3H), 3.74

(s, 3H), 3.69 (s, 3H), 3.61 (d, J = 7.0 Hz, 1H), 3.28 (app t, J = 5.0 Hz,

1H), 2.90 (dd, J = 6.5, 2.5 Hz, 1H), 2.74 (dd, J = 6.0, 1.5 Hz, 1H), 2.45

(dd, J = 7.5, 2.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 206.1, 172.6

(2C), 167.6, 166.6, 149.1, 148.9, 148.5, 148.0, 141.1, 140.8, 139.2,

138.8, 136.2 (2C), 134.9, 119.4, 119.2, 119.0, 117.5, 111.4, 111.3 (4C),

107.7, 101.7, 86.3, 56.0 (2C), 55.9 (2C), 52.7, 52.1, 52.0, 51.8, 50.6,

50.0, 49.4, 48.1, 44.0, 43.3, 42.2, 40.5; HRMS (FAB) calcd for

+

C₄₄H₄₇O₁₆[M + H]⁺831.2864, found 831.2842.

1

1464, 1437, 1314, 1256, 1196, 1174, 1087, 1026, 735 cm⁻¹; H NMR

S13: R_f= 0.35 (hexanes:EtOAc, 3:7); IR (ﬁlm) ν_max3461, 3062,

3009, 2951, 2834, 1724, 1632, 1518, 1436, 1313, 1258, 1198, 1028

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.61 (d, J = 15.5 Hz, 1H), 7.37

(d, J = 15.5 Hz, 1H), 6.80−6.75 (m, 4H), 6.71−6.68 (m, 2H), 6.46 (d,

J = 6.5 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 6.25 (d, J = 16.0 Hz, 1H),

6.03 (d, J = 16.0 Hz, 1H), 4.36 (d, J = 3.0 Hz, 1H), 4.00 (d, J = 8.0 Hz,

1H), 3.91 (br s, 1H), 3.88−3.85 (m, 15H), 3.80 (s, 3H), 3.72 (s, 6H),

3.63 (d, J = 7.0 Hz, 1H), 3.49−3.47 (m, 2H), 3.13 (app t, J = 5.0 Hz,

1H), 2.65 (dd, J = 7.5, 2.0 Hz, 1H), 2.54 (dd, J = 7.0, 2.0 Hz, 1H); ¹³C

NMR (125 MHz, CDCl₃) δ 203.7, 172.5, 171.4, 167.2, 166.7, 149.1,

149.0, 148.5, 148.1, 143.2, 141.1, 140.8, 139.4, 136.1, 135.7, 134.6,

130.8, 120.0, 119.0, 118.9, 118.1, 111.5, 111.4 (2C), 111.1, 108.0,

101.1, 86.8, 55.9 (4C), 54.6, 52.2, 52.1, 51.8, 51.7, 49.1, 49.0, 44.5, 43.3

(500 MHz, CDCl₃) δ 7.37 (d, J = 16.0 Hz, 1H), 6.77 (d, J = 8.5 Hz,

1H), 6.70 (d, J = 6.0 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 6.61 (dd, J =

8.5, 2.0 Hz, 1H), 6.11 (d, J = 15.5 Hz, 1H), 4.09 (d, J = 2.5 Hz, 1H),

3.85 (s, 3H), 3.84 (s, 3H), 3.82 (d, J = 1.5 Hz, 1H), 3.77 (s, 3H), 3.73

(s, 3H), 3.58 (dd, J = 5.5, 2.0 Hz, 1H), 3.37 (app dt, J = 6.0, 2.0 Hz,

1H), 2.94 (dd, J = 5.5, 2.5 Hz, 1H), 2.91 (br s, 1H); ¹³C NMR (125

MHz, CDCl₃) δ 207.8, 174.2, 166.9, 149.0, 148.3, 140.7, 139.5, 135.6,

135.0, 119.1, 118.4, 111.2, 111.1, 71.5, 55.9 (2C), 52.9, 51.9, 49.8, 48.9,

+

46.4, 46.1; HRMS (FAB) calcd for C₂₂H₂₄O₈[M]⁺416.1471, found

416.1484.

Hydroxyketone Homodimer 63 (Proposed Structure).^4bTo a

solution of hydroxyketone 62 (0.041 g, 0.099 mmol, 1.0 equiv) in

THF (1.0 mL) at 0 °C was added NaH (60% dispersion in mineral oil,

0.039 g, 0.99 mmol, 10.0 equiv). The resultant yellow slurry was then

warmed to 25 °C and stirred for 1 h. Upon completion, the reaction

was quenched by the addition of saturated aqueous NH₄Cl (1.0 mL),

and the mixture was poured into water (5 mL) and extracted with

EtOAc (3 × 5 mL). The combined organic layers were then washed

with brine (5 mL), dried (MgSO₄), ﬁltered, and concentrated. The

resultant crude colorless oil was puriﬁed by ﬂash column

chromatography (silica gel, hexanes:EtOAc, 3:7) to give recovered

starting material (15 mg, 37% yield) and dimeric product 63 (6 mg,

15% yield, 52% yield b.r.s.m.). 63: R_f= 0.20 (hexanes:EtOAc, 3:7); IR

(ﬁlm) ν_max3420, 2990, 2951, 2914, 2841, 1720, 1631, 1517, 1435,

1313, 1257, 1197, 1027 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.58 (d,

J = 15.0 Hz, 1H), 7.36 (d, J = 15.5 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H),

6.73−6.69 (m, 3H), 6.66 (dd, J = 8.5, 2.0 Hz, 1H), 6.61 (dd, J = 8.5,

2.0 Hz, 1H), 6.57 (d, J = 6.0 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 6.19

(d, J = 16.0 Hz, 1H), 5.93 (d, J = 16.0 Hz, 1H), 4.74 (br s, 1H), 4.14

(d, J = 4.0 Hz, 1H), 3.85 (s, 9H), 3.81 (s, 6H), 3.76 (s, 3H), 3.67 (s,

3H), 3.65 (s, 3H), 3.58 (d, J = 6.5 Hz, 1H), 3.41 (d, J = 7.5 Hz, 1H),

3.27 (br s, 1H), 3.11−3.08 (m, 2H), 2.56−2.53 (m, 2H), 2.32 (dd, J =

7.5, 2.0 Hz, 1H); ¹³C NMR δ 174.0, 172.5, 167.2, 148.9, 148.8, 148.1,

147.8, 140.9, 140.6 (2C), 140.1, 137.5, 136.5, 136.2, 135.9, 118.9,

118.1, 117.8, 111.5, 111.3, 111.2 (2C), 111.1, 106.2, 85.4, 55.9 (3C),

55.8, 52.5, 52.0, 51.8, 51.7, 49.5, 49.1, 46.4, 44.6, 43.3, 43.0, 41.7, 41.0;

+

(2C), 40.8, 40.4; HRMS calcd for C₄₄H₄₇O₁₆[M + H]⁺831.2864,

found 831.2861.

General Procedure for Heterodimer Bromination. To a

solution of the dimer (1.0 equiv) in MeCN was added NBS (4.0

equiv) at 25 °C. The clear, colorless solution was stirred at 25 °C for

14 h. Upon completion, saturated aqueous Na₂SO₃was added, and the

resulting mixture was stirred vigorously for 15 min. Upon completion,

the mixture was diluted with EtOAc and washed three times with

saturated aqueous NaHCO₃. The organic layer was dried (MgSO₄),

ﬁltered, and concentrated. The crude material was puriﬁed by

preparative TLC (silica gel, hexanes:EtOAc, 2:3) to aﬀord the

dibrominated dimer.

64: white solid, crystallized from CHCl₃/i-PrOH (colorless prisms,

0.012 g, 53%); R_f= 0.35 (hexanes:EtOAc, 2:3); IR (ﬁlm) ν_max3463,

3002, 2951, 2844, 1720, 1632, 1506, 1506, 1486, 1376, 1312, 1257,

1

1195, 1164, 1063, 1029, 913, 842, 730 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 7.63 (d, J = 15.6 Hz, 1H), 7.37 (d, J = 16.0 Hz, 1H), 7.07 (d,

J = 4.0 Hz, 2H), 6.40 (d, J = 6.0 Hz, 2H), 6.34−6.28 (m, 3H), 6.06 (d,

J = 16.0 Hz, 1H), 4.87 (s, 1H), 4.64 (d, J = 7.6 Hz, 1H), 4.48 (d, J =

3.2 Hz, 1H), 4.27 (d, J = 6.8 Hz, 1H), 3.99 (br s, 1H), 3.89 (s, 3H),

3.87 (s, 6H), 3.81 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 3.72 (s, 3H),

3.69 (s, 3H), 3.53 (br s, 1H), 3.37 (dd, J = 6.4, 1.2 Hz, 1H), 3.05−3.01

(m, 1H), 2.77 (dd, J = 7.6, 2.0 Hz, 1H), 2.66 (dd, J = 5.2, 2.4 Hz, 1H);

¹³C NMR (100 MHz, CDCl₃) δ 204.1, 173.0, 172.0, 168.2, 167.7,

150.1, 149.7 (2C), 149.5, 144.4, 142.4, 140.1, 136.5, 134.5, 132.9,

131.6, 121.4, 119.5, 117.2, 117.0, 116.4, 116.2, 111.7, 111.4, 108.9,

101.9, 87.6, 57.3, 57.2 (4C), 55.0, 53.5, 53.3, 52.9, 52.8, 48.7, 48.5,

45.0, 44.4, 40.6, 40.0; HRMS calcd for C₄₄H₄₄Br₂O₁₆Na⁺[M + Na]⁺

1009.0894; HRMS data could not be obtained because of possible

dimer instability, but a molecular ion peak at m/z 1009.01 was

observed via LRMS (MALDI).

+

HRMS (FAB) calcd for C₄₄H₄₈O₁₆[M]⁺832.2942, found 832.2960.

Heterodimers S12 and S13. Diketone 33 (0.081 g, 0.20 mmol,

1.0 equiv) and hydroxyketone 32 (0.081 mg, 0.20 mmol, 1.0 equiv)

were dissolved in CH₂Cl₂/HFIP (1:1, 0.4 mL), and pulverized 3 Å

molecular sieves (80 mg) were added at 25 °C. The resulting yellow

mixture was then stirred at 25 °C for 14 h. Upon completion, the

sieves were removed by ﬁltration, and the ﬁltrate was concentrated.

The resultant yellow foam was dissolved in Et₂O/MeOH (10:1, 2.2

mL), and the solution was cooled to −78 °C, after which TMSCHN₂

(2.0 M in Et₂O, 0.4 mL, 0.8 mmol, 4.0 equiv) was added. After the

resultant yellow mixture was stirred at −78 °C for 30 min, AcOH was

added dropwise until bubbling ceased. The mixture was then warmed

to 25 °C, diluted with EtOAc (10 mL), and washed with water (10

mL). The organic layer was then dried (MgSO₄), ﬁltered, and

concentrated. The resultant crude yellow oil was puriﬁed by ﬂash

column chromatography (silica gel, hexanes:EtOAc, 1:1→2:3) to give

a mixture of two dimers as a colorless oil (0.042 g, 26% combined yield

over two steps, S12:S13 = 4:1). These two dimeric products were then

separated by preparative TLC (CH₂Cl₂:Et₂O, 9:1).

65: white solid, crystallized from CHCl₃/i-PrOH (colorless prisms,

1

0.007 g, 53%); R_f= 0.35 (hexanes:EtOAc, 2:3); H NMR (400 MHz,

CDCl₃) δ 7.47 (d, J = 16.0 Hz, 1H), 7.36 (d, J = 16.0 Hz, 1H), 7.06 (d,

J = 7.2 Hz, 2H), 6.54 (d, J = 6.4 Hz, 1H), 6.41−6.38 (m, 3H), 6.24 (d,

J = 15.6 Hz, 1H), 6.15 (d, J = 15.6 Hz, 1H), 4.91 (s, 1H), 4.54 (d, J =

3.6 Hz, 1H), 4.49 (dd, J = 6.8, 2.0 Hz, 1H), 4.28 (d, J = 7.2 Hz, 1H),

3.95 (br s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.81 (s, 6H), 3.77 (br s,

1H), 3.77 (s, 9H), 3.72 (s, 3H), 3.22−3.19 (m, 1H), 3.00−2.98 (m,

1H), 2.67 (dd, J = 6.8, 2.0 Hz, 1H), 2.63 (dd, J = 6.8, 2.0 Hz, 1H).

Diketone Homodimer S14. Diketone 33 (0.113 g, 0.28 mmol,

1.0 equiv) was dissolved in HFIP (0.09 mL), and the solution was

stirred at 50 °C for 16 h. Upon completion, the yellow-colored

solution was cooled to 25 °C, concentrated, and puriﬁed by

preparative TLC (CH₂Cl₂:MeOH, 93:7) to give S14 (10 mg, 5%

S12: R_f= 0.35 (hexanes:EtOAc, 3:7); IR (ﬁlm) ν_max3473, 2952,

1

2928, 2844, 1722, 1632, 1592, 1517, 1436, 1256, 1027, 734 cm⁻¹; H

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yield) as a pale-yellow foam. S14: R_f= 0.18 (hexanes:EtOAc, 3:7); IR

(ﬁlm) ν_max3385, 3059, 2999, 2953, 2933, 2844, 1804, 1718, 1635,

1518, 1464, 1438, 1313, 1257, 1242, 1145, 1027 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 7.49 (d, J = 16.0 Hz, 1H), 7.42 (d, J = 16.0 Hz, 1H),

6.78−6.75 (m, 2H), 6.73 (d, J = 8.4 Hz, 1H), 6.68 (dd, J = 8.0, 1.6 Hz,

1H), 6.53 (d, J = 6.4 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 6.44 (d, J = 6.4

Hz, 1H), 6.35 (dd, J = 8.4, 2.0 Hz, 1H), 6.17 (d, J = 16.0 Hz, 1H), 6.09

(d, J = 16.0 Hz, 1H), 5.66 (s, 1H), 4.06 (d, J = 8.0 Hz, 1H), 3.88−3.79

(m, 19H), 3.76 (br s, 1H), 3.60 (dd, J = 6.4, 1.2 Hz, 1H), 3.52 (br s,

1H), 3.47 (dd, J = 6.8, 3.2 Hz, 1H), 3.13 (br d, J = 4.0 Hz, 1H), 2.75

(dd, J = 8.0, 2.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 201.2,

172.0, 167.4, 166.7, 149.1, 148.8, 148.6, 148.1, 142.3, 140.9, 139.4,

137.6, 133.9, 133.4, 132.1, 130.9, 120.1, 119.6, 118.8, 118.5, 111.5,

111.3, 111.1, 111.0, 109.9, 105.4, 102.3, 56.0, 55.9 (2C), 54.3, 53.4,

52.1, 52.0, 48.8, 48.6, 47.0, 46.6, 44.0, 42.7, 40.0, 29.7; HRMS (FAB)

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The National Science Foundation (CHE-0619638) is thanked

for funds used to acquire an X-ray diﬀractometer. We thank

Prof. Gerard Parkin, Dr. Aaron Sattler, Dr. Wesley Sattler, Ms.

Yi Rong, Ms. Ava Kreider-Mueller, and Mr. Ahmed al-Harbi for

performing crystallographic analyses. We thank Dr. John

Decatur and Dr. Yasuhiro Itagaki for NMR spectroscopic and

mass spectrometric assistance, respectively. We thank Dr.

Ferenc Kontes for helpful discussions and for help with

experiments towards the synthesis of compound 28, Mr. Myles

W. Smith for assistance in obtaining NMR spectra of

+

calcd for C₄₂H₄₀O₁₆[M]⁺800.2316, found 800.2295.

́

rufescenolide, Prof. Juceni P. David (Faculdade de Farmacia

Brominated Diketone 66. Following the general bromination

procedure, Diels−Alder product 26 (0.140 g, 0.34 mmol, 1.0 equiv)

was reacted with NBS (0.073 g, 0.41 mmol, 1.2 equiv) to give the

brominated product as a pale-yellow solid (0.080 g, 48%). This

material was then carried forward and subjected to the procedure for

the acid-mediated hydrolysis of ketal lactone 25. In the event,

brominated Diels−Alder product S15 (0.071 g, 0.14 mmol) gave the

brominated diketone 66 (0.060 g, 90%) as a yellow solid. 66: R_f= 0.18

(CH₂Cl₂:MeOH, 9:1); IR (ﬁlm) ν_max3409, 2955, 2843, 1790, 1743,

1711, 1633, 1517, 1440, 1316, 1249, 1197, 1145, 1025, 981, 929 cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 15.6 Hz, 1H), 6.79 (d, J =

8.0 Hz, 1H), 6.59 (s, 1H), 6.46−6.41 (m, 2H), 6.29 (d, J = 15.6 Hz,

1H), 4.11 (br d, J = 2.0 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.84 (br s,

4H), 3.32 (br d, J = 4.8 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ

173.4, 166.8, 149.1, 148.8, 139.9, 138.2, 133.1, 131.3, 120.2, 119.6,

111.3 (2C), 56.0 (2C), 55.0, 52.1, 48.3, 44.7; HRMS data could not be

obtained because of instability of the diketone.

Universidade Federal da Bahia, Brazil) for kindly providing

NMR spectra of natural rufescenolide, and Prof. Takashi

Tanaka (Nagasaki University) for kindly providing NMR

spectra of natural yunnaneic acid D and the quinoxoline

derivative of yunnaneic acid C. Financial assistance was

provided by Columbia University, the Department of Defense

(NDSEG Fellowship to D.R.G.), Molirom (postdoctoral

fellowship to L.B.), the I. I. Rabi Scholars Program (summer

research fellowships to T.G.S.), the Research Corporation for

Science Advancement (Cottrell Scholar Award to S.A.S.),

Bristol-Myers Squibb, Eli Lilly, and Amgen. S.A.S. is a Fellow of

the Alfred P. Sloan Foundation.

ABBREVIATIONS

■

Ac = acetyl; Bn = benzyl; DIAD = diisopropylazodicarboxylate;

DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylfor-

mamide; EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodii-

mide hydrochloride; HFIP = 1,1,1,3,3,3-hexaﬂuoro-2-propanol;

NBS = N-bromosuccinimide; NMO = N-methylmorpholine-N-

oxide; Ph₃P = triphenylphosphine; TBAF = tetra-n-butylam-

monium ﬂuoride; TBS = tert-butyldimethylsilyl; Tf =

triﬂuoromethanesulfonyl; TFA = triﬂuoroacetic acid; TMS =

trimethylsilyl; TPAP = tetra-n-propylammonium perruthenate.

Brominated Diketone Homodimer 67. Diketone 66 (0.105 g,

0.22 mmol, 1.0 equiv) was dissolved in HFIP (0.055 mL). The

resulting yellow mixture was stirred at 50 °C under ambient

atmosphere for 16 h. Upon completion, the mixture was concentrated

directly, and the yellow residue was puriﬁed by preparative TLC

(CH₂Cl₂:MeOH, 92:8) to give brominated dimer 67 (0.005 g, 5%) as

a white solid. The product was crystallized from CHCl₃/i-PrOH

(colorless plates). 67: R_f= 0.47 (CH₂Cl₂:MeOH, 9:1); IR (ﬁlm) ν_max

3407, 2934, 1801, 1717, 1634, 1508, 1490, 1330, 1249, 1200, 1166,

1

1030, 847 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.50 (d, J = 16.0,

1H), 7.42 (d, J = 16.0 Hz, 1H), 7.07 (s, 1H), 7.02 (s, 1H), 6.43 (s,

1H), 6.38 (br s, 2H), 6.21 (d, J = 16.0 Hz, 1H), 6.12 (d, J = 16.0 Hz,

1H), 4.62 (d, J = 8.0 Hz, 1H), 4.18 (s, 1H), 3.98 (d, J = 4.5 Hz, 1H),

3.87 (s, 6H), 3.83 (s, 6H), 3.76 (s, 3H), 3.60 (s, 3H), 3.68−3.66 (m,

1H), 3.49 (d, J = 6.5 Hz, 1H), 3.12 (d, J = 4.5 Hz, 1H), 2.96 (d, J = 8.5

Hz, 1H); ¹³C NMR (125 MHz, acetone-d₆) δ 202.5, 171.7, 171.0,

166.6, 166.3 149.6, 149.4, 149.2 (2C), 148.8, 148.5, 143.3, 140.6,

140.0, 139.8, 136.6, 135.0, 133.4, 132.0, 130.7 (2C), 120.0, 119.5,

119.2, 116.2, 115.9, 115.8, 114.4, 113.6, 112.9, 111.5, 110.3, 105.0,

102.3, 55.6 (2C), 55.5, 55.3, 55.2, 54.0, 53.7, 51.1, 50.9, 47.1, 46.7,

46.5, 45.8, 44.4, 44.1, 41.4, 40.0; HRMS data could not be obtained

because of instability of the dimer.

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ASSOCIATED CONTENT

■

S

* Supporting Information

Copies of spectral data, comparison tables of spectroscopic data

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AUTHOR INFORMATION

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Corresponding Author

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dx.doi.org/10.1021/jo4023167 | J. Org. Chem. 2014, 79, 88−105

Article Doi

Explorations of caffeic acid derivatives: Total syntheses of rufescenolide, yunnaneic acids C and D, and studies toward yunnaneic acids A and B

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