General Access to Concave-Substituted cis-Dioxabicyclo[3.3.0]octanones: Enantioselective Total Syntheses of Macfarlandin C and Dendrillolide A

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General Access to Concave-Substituted cis-

Dioxabicyclo[3.3.0]octanones: Enantioselective Total Syntheses of

Macfarlandin C and Dendrillolide A

́

Tyler K. Allred, Andre P. Dieskau, Peng Zhao, Gregory L. Lackner, and Larry E. Overman*

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Supporting Information

ACCESS

ABSTRACT: The evolution of a strategy to access the family of

rearranged spongian diterpenoids harboring a concave-substituted

cis-2,8-dioxabicyclo[3.3.0]octan-3-one fragment is described. The

approach involves late-stage fragment coupling of a tertiary-carbon

radical and an electron-deﬁcient double bond to form vicinal

quaternary and tertiary stereocenters with high ﬁdelity. A

stereoselective Mukaiyama hydration is the key step in the

subsequent elaboration of the cis-2,8-dioxabicyclo[3.3.0]octan-3-

one moiety. This strategy was utilized in enantioselective total

syntheses of (−)-macfarlandin C and (+)-dendrillolide A. An

eﬃcient construction of enantiopure tetramethyloctahydronaph-

thalenes was developed during the construction of (−)-macfarlandin C.

Treatment of cells with these structures results in irreversible

INTRODUCTION

■

fragmentation of the Golgi apparatus with the residual

components remaining localized in the pericentriolar region

of the cell.^10,11Investigations revealed that both the bridged

and fused dioxabicyclooctanone subunits convert to pyrrole

products in the presence of primary amines, most likely via 1,4-

dialdehyde intermediates that arise from fragmentation of

these oxabicyclic agents. This degradation pathway is

postulated to be signiﬁcant in eliciting the Golgi phenotype

of these natural products.¹⁰⁻¹²

Formation of the σ-bond that joins the two chiral fragments

in a stereocontrolled fashion is a principal challenge in the

chemical synthesis of the rearranged spongian diterpenoids

depicted in Figure 1. In members having the bulky hydro-

carbon fragment on the concave face of the cis-2,8-

dioxabicyclo[3.3.0]octan-3-one, such as macfarlandin C (3)

and dendrillolide A (4), the diﬃculty of this bond construction

is ampliﬁed. The extent of steric congestion in these structures,

which is not readily apparent in two-dimensional drawings, is

obvious in the X-ray model of macfarlandin C (3) (Figure 1).²

The central C-8/C-14 σ-bond of 3 is abnormally long at 1.577

Å, in stark contrast to cheloviolene A whose corresponding

bond is quite standard (1.546 Å).^4a,6b,13

A cis-2,8-dioxabicyclo[3.3.0]octan-3-one (1) is a common

structural motif in a diverse group of diterpenoids.¹This

structure can be decorated in multitude ways, such as being

incorporated into a polycyclic framework or appended to a

complex lipophilic substituent. The second subset contains

several marine-derived diterpenoids that are characterized by a

cis-2,8-dioxabicyclo[3.3.0]octan-3-one appended at C-6 to a

quaternary carbon of a 14-carbon bicyclic fragment (Figure 1).

The hydrocarbon substituent can be attached to either the

convex or concave face of the cis-2,8-dioxabicyclo[3.3.0]octan-

3-one, with the latter being more common. Macfarlandin C

(3)²and dendrillolide A (4)³exemplify this latter group. The

linkage that joins the two fragments is freely rotatable, making

identiﬁcation of the relative conﬁgurations of these natural

products challenging. X-ray crystallographic analysis and

chemical synthesis have proven to be the only methods of

establishing the relative and absolute conﬁgurations of this

group of diterpenoids.¹⁻⁸For many of these natural products,

stereochemical assignments are based solely on their presumed

biosynthetic relationship to the spongian diterpenoid skeleton

(2).⁹

The Golgi-altering activity of macfarlandin E, a rearranged

spongian diterpenoid harboring a 2,7-dioxabicyclo[3.2.1]-

octan-3-one, was the original impetus for our interest in this

class of natural products.¹⁰The unique mode of action elicited

by macfarlandin E could be recapitulated with simpliﬁed 2,7-

dioxabicyclo[3.21]octan-3-one or cis-2,8-dioxabicyclo[3.3.0]-

octan-3-one congeners.^10,11

Received: September 22, 2020

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A

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outlined in Scheme 1 and its use to accomplish enantiose-

lective total syntheses of macfarlandin C (3) and dendrillolide

A (4) are the subject of this report.⁷

RESULTS AND DISCUSSION

■

Exploratory Investigations in Model Systems to

Develop a Synthesis of cis-2,8-Dioxabicyclo[3.3.0]-

octan-3-ones Harboring an Endo C-6 Substituent. Initial

Attempts. Our studies began with butyrolactone 14, which is

readily available from the union of tertiary-radical precursor 12

and 5-methoxybutenolide (13) (Scheme 2).^6bWe anticipated

Scheme 2

Figure 1. The cis-2,8-dioxabicyclo[3.3.0]octan-3-one ring system,

three rearranged-spongian diterpenoids harboring this fragment, and

the spongian skeleton, which is the presumed biosynthetic precursor

of these diterpenoids. An ORTEP ball-and-stick representation of the

X-ray model of (−)-macfarlandin C showing the unusually long

(1.577 Å) C-8/C-14 σ-bond linking the two chiral fragments.

that the carboxymethyl side chain could be installed cis to the

bulky methylcyclohexyl substituent by diastereoselective

hydrogenation of a 3-alkylidene fragment. To access such an

intermediate, lactone 14 was deprotonated with LHMDS and

the resulting enolate allowed to react with methyl (or ethyl)

glyoxylate at −78 °C in THF to provide epimeric aldol

adducts, which were directly dehydrated to provide alkylidene

products 17 or 18 as mixtures of E and Z stereoisomers. The

aldol step proceeded in variable yields with methyl glyoxylate,

likely reﬂecting the purity of this reagent. Fortunately,

changing to ethyl glyoxylate resulted in the aldol step being

more eﬃcient and reproducible.

The reduction of alkylidene butyrolactones 17 and 18 under

a variety of conditions was examined (Scheme 3). Several

heterogeneous catalysts were explored with the anticipation

that the Re face of the double bond would approach the metal

surface in order to minimize steric interactions with the 1-

methylcyclohexyl substituent. However, under both the

homogeneous and heterogeneous hydrogenation conditions

From the outset, our synthetic strategy was to forge the

challenging C-8/C-14 σ-bond by the coupling of tertiary

radicals 6 or 7, which embody the octahydronaphthalene and

cis-methyleneperhydroazulene fragments of macfarlandin C

and dendrillolide A, with an enantiopure 5-alkoxybutenolide 8

(Scheme 1). This approach would exploit the high eﬃciency

and typical high diastereoselectivity of tertiary radical/alkene

fragment couplings¹⁴and our earlier success in employing this

step to prepare cheloviolenes A (5) and B.⁶In these previous

syntheses, elaborating coupling product 9 to the targeted

diterpenoids was fairly straightforward as the remaining two

carbons could be installed stereoselectively by the direct

alkylation of the lithium enolate of 9 with an iodoacetic acid

ester to yield intermediate 11.⁶To synthesize the related

diterpenoids in this series that display the bulky hydrocarbons

substituent on the more-hindered concave face, 9 would need

to be elaborated to a butyrolactone intermediate such as 10.

The successful development of the divergent synthetic strategy

Scheme 1

B

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Discovery of the α-Hydroxy Blocking Group Strategy and

Successful Synthesis of cis-2,8-Dioxabicyclo[3.3.0]octan-3-

one 36 Having a C-6 Tertiary Substituent on the Concave

Face. The approach that was ﬁnally successful resulted from a

study whose objective was to position the vicinal alkyl

substituents of a butyrolactone intermediate cis, by ﬁrst

forming a lactone enolate from alkylidene precursor 18, and

quenching this enolate with a halogen electrophile, which was

expected to react from the enolate face opposite the 1-

methylcyclohexyl substituent (Scheme 5). To our surprise,

Scheme 3

Scheme 5

that we examined, the undesired all-trans products 19 or 20

were formed preferentially (see the Supporting Information for

details). The use of nucleophilic metal-hydride reagents

allowed for facile reduction of the electron-deﬁcient double

bond. Within this reaction manifold, we explored a variety of

proton sources with the hope of inﬂuencing facial selectivity

for protonation of the in situ-generated lactone enolate.

However, all conditions examined proved to be either

unselective or returned the all-trans products selectively. Partial

epimerization of the desired (less stable) hydrogenation

product 19 (20) under some of the reduction conditions

was observed.^6b,15We also explored brieﬂy the potential of

directed hydrogenation by employing lactol 23, but the

conditions examined resulted in no reaction or decomposition

of the starting material.

when iodine was employed in the trapping step and the

reaction was quenched by adding water at −20 °C, α-hydroxy

lactone 32 was isolated as the major product in variable yields.

That this product had the desired cis orientation of the alkyl

substituents at C-3 and C-4 was conﬁrmed by X-ray

crystallographic analysis. Alcohol 32 might result from

ionization of the expected iodination product 30 upon

warming in aqueous THF to form α-acyloxy carbenium ion

31, which is trapped from the face opposite the 1-

methylcyclohexyl substituent to form alcohol 32; however,

alternate pathways proceeding by radical intermediates cannot

be excluded.^19,20Unfortunately, this synthesis of alcohol 32

was capricious, with the reduction byproduct 20 being formed

in signiﬁcant and variable yields.

Another approach that we examined attempted to capitalize

on the recent advances in transition metal catalyzed cross-

electrophile coupling (Scheme 4).¹⁶In this study, radical

Scheme 4

In order to develop a more reliable route to alcohol 32, we

examined the possibility of obtaining this product by

Mukaiyama hydration of alkylidene lactone 18.²¹It seemed

likely that hydrogen-atom addition to 18 would occur at the

less substituted alkylidene carbon,^21dand considerable

precedent existed that C−O bond-formation would take

place from the sterically more accessible face of the radical

intermediate.²²Using standard conditions ﬁrst reported by

Mukaiyama,^21b18 was transformed with high regio- and

stereoselectivity to α-hydroxylactone 32 (Scheme 6). Although

the yield was modest (65%), this reaction was suﬃciently

reproducible to allow us to proceed ahead to see whether 32

would be a viable precursor to the desired endo-substituted cis-

2,8-dioxabicyclo[3.3.0]octan-3-one product.

With a reliable method of establishing the cis relationship

between the carboxymethyl and 1-methylcyclohexyl substitu-

ents in hand, we explored ways to transform alcohol 32 into

the elusive concave-substituted cis-2,8-dioxabicyclo[3.3.0]-

octan-3-one 36. Reaction of alcohol 32 with a variety of

hydride reducing agents led to inconsistent results,^6bwith

signiﬁcant amounts of the starting alcohol being recovered

unchanged. This issue was circumvented by ﬁrst protecting the

alcohol as its trimethylsilyl ether. Reduction of this

intermediate with excess DIBALH at −78 to −20 °C followed

coupling product 14 was ﬁrst transformed to dihydrofuran 26

by sequential reaction with diisobutylaluminum hydride

(DIBALH) and triﬂuoroacetic anhydride and base. Exposure

of this intermediate to NBS and bromoacetic acid aﬀorded

bromoacetal 27 with high diastereoselectivity. With this

intermediate in hand, a wide variety of Ni-catalyzed cross-

coupling conditions were explored with no success.¹⁷The

desired butyrolactone product 28 was only observed in trace

amounts, with either ester hydrolysis and/or reductive

debromination of the ester side chain being the products

1

detected by H NMR analysis. Presumably, the steric bulk of

the 1-methylcyclohexyl substituent limits the ability of the

nickel catalyst to eﬀectively engage the secondary bromide. In

addition to the approaches outlined in Schemes 3 and 4,

several other strategies were examined without success and

have been described elsewhere.¹⁸

C

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Scheme 6

Scheme 7

Scheme 8

by oxidation of the resulting mixture of lactols with pyridinium

chlorochromate (PCC) aﬀorded cis-dioxabicyclooctanone 33

in high yield.

Exposure of this intermediate to dilute HCl at room

temperature (rt) cleaved the silyl ether and methoxy groups

giving diol 34. This product was then allowed to react with

excess acetic anhydride and pyridine in the presence of DMAP

to yield a mixture of the corresponding diacetate and its

elimination product 35. During chromatographic puriﬁcation

of this product mixture on silica gel, the diacetate was observed

to partially convert into the elimination product 35. In

subsequent experiments, this crude product was adsorbed on

silica gel at rt, and after standing for 16 h, chromatography on

silica gel gave bicyclic butenolide 35 in nearly quantitative

yield. Conjugate-silane reduction using an N-heterocyclic

carbene copper complex, as described by Buchwald and co-

workers, aﬀorded cis-2,8-bicyclo[3.3.0]octan-3-one 36 in 66%

yield.²³

Developing the Enantioselective Total Synthesis of

(−)-Macfarlandin C. Initial Syntheses of the Octahydro-

naphthalene Fragment of Macfarlandin C. With a successful

strategy to access the concave-substituted cis-2,8-bicyclo-

[3.3.0]octan-3-one fragment available, we turned our attention

to the total synthesis of (−)-macfarlandin C (3). Octahy-

dronaphthalene alcohol 38 was envisaged as the precursor of

tertiary radical 6 in the fragment-coupling step depicted in

Scheme 1.²⁴The axial alcohol epimer 38 was initially targeted

because of its anticipated formation from (E)-ethylidenecyclo-

hexane acetal 37 by the intramolecular carbonyl-ene

cyclization depicted in Scheme 7. Carbonyl-ene cyclizations

of this type have long been used to form octahydronaphthalene

products, and the cyclization of a related methylidene analogue

of 37 had been reported.^25,26

Our initial exploration of this route was carried out in the

racemic series and is summarized in Scheme 8. The approach

commenced with a copper-catalyzed conjugate addition of

MeMgBr to 3-methylcyclohexenone (39) followed by reaction

of the in situ-generated enolate with aldehyde 40 to give aldol

adduct 41 as a mixture of stereoisomers. This crude material

was dehydrated to aﬀord alkenes 42 and 43 as an inseparable

mixture. Hydrogenation of this mixture followed by Wittig

oleﬁnation delivered the desired cyclization precursor rac-37

with high E stereoselectivity. Exposure of this intermediate to

catalytic amounts of p-toluenesulfonic acid in wet CH₂Cl₂

resulted in hydrolysis of the ketal and subsequent intra-

molecular carbonyl-ene cyclization to give octahydronaphtha-

lene rac-38 as the sole detected product. We were pleased to

ﬁnd that alcohol rac-38 could be converted into tertiary-

homoallylic oxalate derivative 45 without the formation of

diene elimination byproducts.

As the projected fragment-coupling step would require the

union of enantioenriched fragments, we turned to develop an

enantioselective synthesis of alcohol 38. We were attracted

initially to the possibility that enantioselective hydrogenation

of enone 42 might allow the route we had already developed to

be employed.²⁷However, this approach was rendered

impractical by our inability to produce useful amounts of

pure enone 42 from the mixture of aldol products.

We turned to develop an alternate synthesis in which the

neopentylic stereocenter of the cyclohexanone intermediate

would be formed by a stereoselective S_N2′ displacement

reaction (Scheme 9). Particularly appealing was the synthesis

of enantiopure α-substituted cyclohexanones by anti-S_N2′

displacement of allylic phosphate intermediates developed by

Knochel and co-workers, which had been shown to be useful

for preparing enantioenriched 2-alkyl-3,3-dimethylcyclohexa-

nones.²⁸The sequence began with (S)-2-iodocyclohexenol 48,

whose synthesis by Corey−Bakshi−Shibata reduction had

been described earlier in the enantiomeric series.,^28b29After

converting alcohol 48 to the corresponding allylic phosphate,

reaction of 49 with an excess of the organocuprate generated in

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Scheme 9

Scheme 10

aqueous cesium hydroxide provided oxalate salt 53, ﬁnally

positioning us to explore the critical fragment-coupling step.

Fragment Coupling Is Undermined by Cyclization of an

Alkoxyacyl Intermediate and Synthesis of the Epimeric

Octahydronaphthalene Tertiary Alcohol. Following fragment

coupling procedures developed in our earlier studies,⁶cesium

oxalate 53 was irradiated with blue LEDs in the presence of 1

mol % of the iridium photocatalyst Ir[dF(CF₃)ppy]₂(dtbbpy)-

PF₆and 1 equiv of (S)-5-methoxybutenolide (S)-13 (Scheme

11). However, no trace of the desired coupling product was

Scheme 11

situ from Grignard reagent 50 and CuCN produced vinyl

iodide 51 with complete stereospeciﬁcity,²⁸as conﬁrmed by

enantioselective HPLC analysis. Transformation of 51 to

ketone (S)-44 was accomplished without loss of enantiopurity

by Knochel’s procedure.²⁸Wittig oleﬁnation of (S)-44, as

carried out in the racemic series, gave ethylidene product 37,

which was transformed to oxalate diester 45 in high yield.

However, the enantiomeric purity of 45 was quite low, and

epimerization of the labile α-stereocenter during the Wittig

oleﬁnation was identiﬁed as the culprit of this erosion of

enantiopurity. A wide variety of Wittig reaction conditions

were then explored in attempts to suppress epimerization,

including salt- and base-free conditions.³⁰Unfortunately,

substantial racemization was observed under all the conditions

surveyed.

The high eﬃciency and high enantiomeric purity of the

synthesis of vinyl iodide 51 led us to explore alternative

methods of converting this intermediate to the (E)-ethylidene

cyclization precursor (S)-37. We reasoned that installation of a

vinyl unit followed by stereocontrolled 1,4-reduction of the

resultant diene would be a viable way to access this

intermediate (Scheme 10). The required 1,3-diene 52 was

readily prepared in high yield by Negishi vinylation.³¹The

most direct method to access (S)-37 from diene 52 would be a

selective 1,4-delivery of hydrogen. Regio- and stereocontrolled

hydrogenations of this type have been known for some time

and are aﬀected by use of chromium η⁶-arene tricarbonyl

complexes.³²In the event, hydrogenation of 52 in the presence

of 20 mol % of (η⁶-naphthalene)chromium tricarbonyl at high

pressures of hydrogen occurred in nearly quantitative yield to

give (E)-ethylidene product (S)-37. Advancing this material

over two steps furnished methyl oxalate 45 of high

enantiomeric purity (>97% ee). Saponiﬁcation of 45 with

observed; the only product obtained was the tricyclic

butyrolactone 54. This tricyclic lactone would be the result

of 5-exo-cyclization of the intermediate alkoxycarbonyl radical

56, produced from oxalate radical 55 in the initial rapid

decarboxylation event. Although 5-exo cyclizations of alkox-

yacyl radicals are well known,³³⁻³⁵we had hoped that bond

formation at the β,β-disubstituted alkene center would have

been retarded. As moderating the rate of this intramolecular

process appeared impossible, another precursor of octahy-

dronaphthalene tertiary radical 6 depicted in Scheme 1 would

be required.

To preclude cyclization of an alkoxycarbonyl radical

intermediate, we turned to develop a synthesis of the epimeric

octahydronaphthalene tertiary alcohol, which would tether an

oxalate fragment in a pseudo-equatorial orientation. Using the

same sequence that we had employed to prepare tertiary

alcohol 38, the related octahydronaphthalene secondary

alcohol 62 was prepared in four steps and 57% overall yield

from allylic phosphate 49 and Grignard reagent 58 (Scheme

12).

Oxidation of 62 with Dess−Martin periodinane³⁶gave β,γ-

unsaturated ketone 63, a labile oil that was prone to

E

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Scheme 12

Scheme 13

autoxidation. To no surprise, reaction of this ketone with MeLi

or MeMgBr aﬀorded predominantly the undesired axial tertiary

alcohol 38. In order to reverse the selectivity, we employed

Yamamoto’s bulky bis[2,6-bis(1,1-dimethylethyl)-4-

methylphenolato]methylaluminum (MAD), which is thought

to coordinate with the carbonyl oxygen and favor nucleophilic

addition from the axial vector.³⁷In the event, addition of

MeMgBr to a solution of MAD (6 equiv) and ketone 63 in

toluene at −78 °C delivered equatorial tertiary alcohol 64 in

63% yield (70% corrected for recovered 63) and superb 20:1

facial selectivity. Alkoxyacylation of 64 with methyl chloroox-

alate and selective saponiﬁcation of the resulting diester with

aqueous CsOH provided cesium oxalate 65 in high yield.

Successful Fragment Coupling and Total Synthesis of

(−)-Macfarlandin C. With the epimeric tertiary oxalate 65 in

hand, we examined its participation in the pivotal fragment-

coupling step with (R)-chlorobutenolide 66 (Scheme 13). This

coupling partner was chosen for its higher reactivity with

nucleophilic tertiary radicals.⁶

workers.³⁸Under these conditions, competitive hydration of

the more electron-rich trisubstituted alkene was relatively

minor and only observed under forcing conditions. Tertiary

alcohol 71 was then derivatized as its trimethylsilyl silyl ether

prior to attempting cyclization to form the cis-2,8-dioxabicyclo-

[3.3.0]octan-3-one ring system.

At this stage, we encountered an unexpected hurdle. When

lactone ester 72 was exposed to excess DIBALH followed by

oxidation with PCC, the desired cis-2,8-dioxabicyclo[3.3.0]-

octan-3-one was not formed (Scheme 14). The presence of an

Scheme 14

To our delight, irradiation of oxalate 65 with 34 W blue

(465 nm) LEDs in the presence of 1 mol % of the iridium

photocatalyst and 1 equiv of chlorobutenolide 66 gave as the

major products the coupled lactone 67 and its chloro analogue

68. In situ reductive dechlorination of 68 could be achieved by

addition of tributylamine and continued irradiation. Using this

procedure, lactone 67 was isolated in 74% yield and >20:1

diastereoselectivity from oxalate salt 65.

Lactone 67 was elaborated by the aldol-dehydration

sequence optimized in the model system to access vinylogous

α-alkoxyacyl esters 70. Treatment of these electron-deﬁcient

alkenes under Mukaiyama hydration conditions provided

tertiary alcohol 71 with high regio- and stereoselectivity. A

small screen of manganese catalysts and silane reductants

showed that optimal yields of alcohol 71 were achieved with

the more active catalytic system reported by Shenvi and co-

aldehyde signal in the ¹H NMR spectrum and a six-membered

lactone carbonyl peak at 1720 cm⁻¹in the IR spectra indicated

that the major product was valerolactone 73. Presumably, a

Lewis acidic aluminum species facilitated skeletal rearrange-

ment prior to the oxidation step. We brieﬂy considered if it was

possible to induce a rearrangement of 73 into its cis 2,8-

dioxabicyclo[3.3.0]octan-3-one analogue and screened several

potential Lewis and Brønsted acid catalysts to no avail.

These setbacks forced us to explore other reducing agents in

the hope of restoring the desired reduction/cyclization

sequence (Scheme 15). Surprisingly, both silyl ether 72 and

tertiary alcohol 71 were stable to a variety of reducing agents.³⁹

Finally we found that exposing alcohol 71 to 5 equiv of LiAlH₄

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Scheme 15

Scheme 16

in Et₂O at 0 °C followed by oxidation of the resulting products

with PCC gave rise to a mixture of the desired cis-2,8-

dioxabicyclo[3.3.0]octan-3-one 74 and recovered 71. Increas-

ing the amount of LiAlH₄to 15 equiv, prior to oxidation with

PCC resulted in complete and, more importantly, consistent

conversion to cis-dioxabicyclooctanone 74.

With a reliable method of constructing 74 in hand, we were

poised to complete the total synthesis of (−)-macfarlandin C.

The menthol auxiliary was removed by exposing 74 to dilute

HCl at 35 °C for several days. Increasing the temperature

above 35 °C in order to accelerate the conversion to the

corresponding diol resulted in extensive decomposition. The

crude diol 75 was then peracetylated by reaction with excess

acetic anhydride in the presence of DMAP. An intermediate

Somewhat to our surprise, one of the ﬁnal steps in the

synthesis of dendrillolide A required modiﬁcation. Speciﬁcally,

removal of the menthol fragment from acetal 81 necessitated

more forcing conditions as the dilute HCl conditions used in

the macfarlandin C series resulted in little reaction of acetal 81.

Eventually, it was found that in a solution containing equal

volumes of TFA/H₂O/acetone at 30 °C, the desired hydrolysis

was slowly yet eﬃciently realized. It is of interest that identical

treatment of macfarlandin C precursor 74 results in its

complete decomposition. The two ﬁnal steps proceeded

without complications to provide (+)-dendrillolide A (4),

[α]²_D²+ 64 (c = 1.0, CHCl₃) of ca. 90% purity in 34% yield over

the three-step sequence. The spectroscopic properties of

synthetic dendrillolide A and optical rotation agreed with

those reported for the natural isolate.^3,41

1

diacetate could be observed in H NMR spectra of reaction

aliquots; however, in this case, extended exposure of the crude

products to silica gel resulted in decomposition. This issue

could be circumvented if the peracetylation step was

accomplished in the presence of Et₃N, which promotes acetate

elimination in situ aﬀording exclusively butenolide 76. Without

puriﬁcation, this product was reduced to deliver (−)-macfar-

landin C (3), [α]²_D¹− 28 (c = 0.4, CHCl₃), in 38% yield over

the three steps. Spectroscopic properties of synthetic

(−)-macfarlandin C were fully consistent with those reported

for the natural isolate, as was its optical rotation.²

Generalization of the Alcohol-Blocking Route En-

ables the Total Synthesis of (+)-Dendrillolide A. In order

to probe the generality of our approach to concave-substituted

cis-2,8-dioxabicyclo[3.3.0]octan-3-ones, we turned to access

(+)-dendrillolide A by a related sequence (Scheme 16). The

synthesis began with tricyclic lactone 77, which we had

prepared previously from (+)-fenchone.⁶This lactone was

advanced through the aldol-dehydration sequence without

issue. However, under Mukaiyama hydration conditions, both

exocyclic double bonds of intermediate 78 reacted at

comparable rates aﬀording a 3−4:1 mixture of diol 79 and

alcohol 80.⁴⁰Fortunately, this selectivity issue proved

irrelevant because carrying these products individually or as a

mixture through the reduction−oxidation sequence delivered

bicyclic lactone 81 exclusively. We postulate that the

destabilizing syn-pentane interaction between the C-17 and

C-18 methyl groups facilitates elimination of the C-18 acetate

intermediate under the mildly acidic conditions of the PCC

oxidation.

CONCLUSIONS

■

The ﬁrst synthesis of cis-2,8-dioxabicyclo[3.3.0]octan-3-ones

that display a bulky C-6 hydrocarbon substituent on the

sterically congested concave face has been developed. The

general route is exempliﬁed by enantioselective total syntheses

of the rearranged spongian diterpenoids (−)-macfarlandin C

(3) and (+)-dendrillolide A (4), with the synthesis of 4

rigorously establishing the absolute conﬁguration of natural

(+)-dendrillolide A.⁹The ancillary investigations discussed in

this account provide insight into the evolution of the ultimately

successful synthetic strategies.

Our approach to these marine natural products builds on

our prior studies in the area⁶and now allows for divergent

access to either convex- or concave-substituted cis-2,8-

dioxabicyclo[3.3.0]octan-3-one products. The newly devel-

oped sequence relies on a highly regio- and diastereoselective

Mukaiyama hydration reaction that orient vicinal carbon side

G

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4.37−4.34 (m, 0.66H, major), 3.84 (s, 2H, major), 3.75 (s, 1H,

minor), 3.50 (s, 1H, minor), 3.49 (s, 2H, major), 3.48−3.47 (m,

0.33H, minor), 3.26 (d, J = 4.3 Hz, 0.66H, major), 3.06 (dd, J = 6.5,

3.2 Hz, 0.66H, major), 2.91−2.89 (m, 0.33H, minor), 2.38−2.33 (m,

0.66H, major), 2.11−2.07 (m, 0.33H, minor), 1.60−1.16 (m, 10H,

major and minor), 0.90 (s, 2H, major), 0.81 (s, 1H, minor); ¹³C{¹H}

NMR (125 MHz, CDCl₃, mixture of diastereomers) δ (Major) 174.8,

172.9, 106.0, 70.6, 57.3, 53.2, 52.3, 45.9, 35.6, 35.4, 34.5, 26.0, 21.4,

21.3, 20.3, (Minor) 176.2, 172.8, 105.4, 70.8, 56.9, 52.6, 52.1, 45.5,

34.9, 34.6, 34.0, 25.9, 21.45, 21.38, 19.5; IR (thin ﬁlm) 2929, 2854,

1777, 1747, 1446, 1124, 964 cm⁻¹; HRMS (CI-TOF) m/z: (M + H)⁺

calcd for [C₁₅H₂₅O₆] 301.1651; found 301.1658.

chains cis on a butyrolactone precursor of the cis-

dioxabicyclooctanone fragment. In both syntheses, the hydro-

carbon and lactone fragments were united by an eﬃcient

stereoselective fragment coupling between a tertiary alcohol-

derived tertiary radical and an electron-deﬁcient alkene

resulting in the formation of a new quaternary and tertiary

carbon stereocenter.¹⁴In the total synthesis of macfarlandin C,

we developed a nine-step enantioselective route to the

octahydronaphthalene fragment, which relied on a key

carbonyl-ene cyclization to fashion the decalin framework.

We anticipate that aspects of these studies will prove useful in

future synthetic endeavors in this and related areas.

Preparation of Alcohol 16. A ﬂame-dried 250 mL round-bottom

ﬂask was charged with lactone 14 (1.37 g, 6.44 mmol) and THF (64

mL, 0.1 M). The solution was cooled to −78 °C, and a solution of

LHMDS (7.3 mL, 7.3 mmol, 1.15 equiv, 1 M in THF) was added

dropwise. The reaction was maintained at −78 °C for 1 h. During the

enolate formation, ethyl glyoxylate (50 wt % in toluene) was distilled

over P₂O₅under argon (10−15 min at 110 °C then over 10 min

warmed to 140 °C and over 10 min warmed to 200 °C); the yellow

distillate was used immediately. Freshly distilled ethyl glyoxylate (6.4

mL, 32 mmol, 5 equiv) was added, and the reaction mixture was

maintained at −78 °C for 1.5 h and then subsequently quenched by

the addition of H₂O (50 mL) and allowed to warm to rt. The layers

were separated, and the aqueous layer was extracted with EtOAc (3 x

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

(40 mL) and dried over MgSO₄. The organic layer was ﬁltered and

concentrated to an orange oil. The residue was puriﬁed by ﬂash

column chromatography (SiO₂, 20:1 → 4:1 Hex/EtOAc) to aﬀord

alcohol 16 (1.64 g, 5.22 mmol, 81%) as a colorless oil and as a ∼7:3

mixture of alcohol epimers. R_f= 0.3 (4:1 Hex/EtOAc, visualized with

EXPERIMENTAL SECTION

■

Unless stated otherwise, reactions were conducted in oven-dried

glassware under an atmosphere of argon. Tetrahydrofuran (THF),

1,2-dimethoxyethane (DME), dimethylformamide (DMF), toluene,

dichloromethane (CH₂Cl₂), and methanol (MeOH) were dried by

passage through activated alumina. Commercial solutions of ethyl

glyoxylate were distilled over P₂O₅immediately prior to use. All other

commercial reagents were used as received unless otherwise noted.

Reaction temperatures were controlled using a temperature

modulator, and unless stated otherwise, reactions were performed at

room temperature (rt, approximately 23 °C). Thin-layer chromatog-

raphy (TLC) was conducted with silica gel 60 F254 pre-coated plates,

(0.25 mm) and visualized by exposure to UV light (254 nm) or

staining with p-anisaldehyde, ceric ammonium molybdate (CAM), or

KMnO₄. Silica gel 60 (particle size, 0.040−0.063 mm) was used for

ﬂash column chromatography. ¹H NMR spectra were recorded at 500

or 600 MHz and are reported relative to deuterated solvent signals.

1

KMnO₄); H NMR (600 MHz, CDCl₃) δ 5.23 (d, J = 1.2 Hz, 0.3H,

1

minor), 5.17 (d, J = 3.0 Hz, 0.7H, major), 4.66 (dd, J = 3.0, 8.9, 0.3H,

minor), 4.39−4.25 (m, 2.4H, major and minor), 4.18−4.10 (m, 0.3H,

minor), 3.52 (s, 0.9H, minor), 3.51 (s, 2.1H, major), 3.48−3.44 (m,

0.3H, minor), 3.25 (d, J = 4.1 Hz, 0.7H, major), 3.08 (dd, J = 3.0, 6.5

Hz, 0.7H, major), 3.07 (app t, J = 3.4 Hz, 0.3H, minor), 2.40 (dd, J =

3.1, 6.2 Hz, 0.7H, major), 2.15−2.11 (m, 0.3H, minor), 1.64−1.51

(m, 3H), 1.50−1.41 (m, 2H), 1.38−1.21 (m, 5H), 1.35 (t, J = 7.0 Hz,

2.1H, major), 1.31 (t, J = 7.1 Hz, 0.9H, minor), 0.93 (s, 2.1H, major),

0.84 (s, 0.9H, minor); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ (Major)

174.6, 172.4, 105.9, 70.5, 62.6, 57.2, 45.8, 35.6, 35.4, 34.4, 31.6, 25.9,

21.4, 21.3, 20.3, 14.0, (Minor) 176.1, 172.3, 105.3, 70.7, 62.0, 56.8,

45.4, 34.9, 34.6, 33.9, 29.7, 25.9, 21.37, 21.33, 19.5, 14.0; IR (thin

ﬁlm) 3475, 2927, 2852, 1773, 1737, 1446, 1371, 1263, 1220, 1184,

1121 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

[C₁₆H₂₆O₆Na]⁺337.1627; found 337.1614.

Data for H NMR spectra are reported as follows: chemical shift (δ

ppm), multiplicity, coupling constant (Hz), and integration. ¹³C

NMR spectra were recorded at 125 or 150 MHz. IR spectra were

recorded on a ThermoFisher Nicolet iS5 FT-IR spectrometer with an

iD7 ATR accessory and are reported in terms of frequency of

absorption (cm⁻¹). High-resolution mass spectra were obtained from

the UC Irvine Mass Spectrometry Facility with a Micromass LCT

spectrometer. The instrument utilized for crystallographic data

collection was a three-circle, sealed-tube, Mo radiation, Bruker

SMART APEX II CCD-based system. Optical rotation readings

were obtained using JASCO P-1010 polarimeter. Kessil KSH150B

LED Grow Light 150, Blue (34 W blue LED lamps) were purchased

from http://www.amazon.com. Enantiomeric excess for compounds

45, 48, 51, and 59 was determined by HPLC analysis using an Agilent

1100 series analytical HPLC. Abbreviations commonly used are as

follows: IPA (isopropyl alcohol), Hex (hexanes), DMAP (4-

dimethylaminopyridine), EtOAc (ethyl acetate), rt (room temper-

ature); for others, see the JOC Standard Abbreviations and Acronyms

(http://pubs.acs.org/paragonplus/submission/joceah/joceah_

abbreviations.pdf).

Preparation of Alkenes 17. A scintillation vial containing a stir

bar was charged with alcohol 15 (486 mg, 1.62 mmol), DMAP (20

mg, 0.16 mmol), and 1,2-dichloromethane (11 mL) under argon.

After sequential addition of pyridine (520 μL, 6.48 mmol) and

triﬂuoroacetic anhydride (460 μL, 3.24 mmol), the reaction mixture

was maintained at rt for 45 min when complete consumption of the

starting material was observed by TLC analysis. After this time, DBU

(1.45 mL, 9.72 mmol) was added by a syringe, and the reaction

mixture was stirred at rt for 1 h. The reaction mixture was then

quenched by the addition of saturated aqueous NH₄Cl solution (6

mL), and the layers were separated. The aqueous layer was extracted

with Et₂O (3 x 15 mL), and the combined organic layers were washed

with brine (2 x 30 mL), dried over MgSO₄, ﬁltered through cotton,

and concentrated under reduced pressure. The residue obtained was

puriﬁed by ﬂash column chromatography (SiO₂, 4:1 Hex/EtOAc) to

provide alkenes 17 (415 mg, 1.47 mmol, 91%) as a colorless oil and as

a 1.5:1 mixture of alkene isomers: R_f= 0.68 and 0.50 (3:1 Hex/

Preparation of Alcohol 15. A solution of lactone 14 (500 mg,

2.36 mmol)⁶in THF (12 mL) was cooled to −78 °C, and a solution

of LHMDS (2.8 mL, 2.8 mmol, 1.2 equiv, 1 M in THF) was added

dropwise. The resulting yellow solution was maintained at −78 °C for

15 min, after which a solution of freshly prepared and distilled methyl

glyoxylate (30 mL, 24.0 mmol, 0.81 M in THF) was added.⁴²The

reaction mixture was maintained at −78 °C for 1 h and was

subsequently quenched by the addition of saturated aqueous NH₄Cl

solution (7 mL). The layers were separated, and the aqueous layer

was extracted with Et₂O (3 x 15 mL). The combined organic layers

were washed with brine (2 x 30 mL), dried over MgSO₄, ﬁltered

through cotton, and concentrated under reduced pressure. The

residue obtained was puriﬁed by ﬂash column chromatography (SiO₂,

3:1 → 1.5:1 Hex/EtOAc) to obtain alcohol 15 (492 mg, 1.64 mmol,

69%) as a colorless oil and as an inseparable 2:1 mixture of

diastereomers. R_f= 0.36 (3:1 Hex/EtOAc, visualized with KMnO₄);

¹H NMR (500 MHz, CDCl₃) δ 5.22 (br s, 0.33H, minor), 5.16 (d, J =

3.1 Hz, 0.66H, major), 4.67 (dd, J = 9.4, 3.1 Hz, 0.33H, minor),

1

EtOAc); H NMR (500 MHz, CDCl₃, mixture of alkene isomers) δ

6.90 (s, 0.6H, major), 6.28 (s, 0.4H, minor), 5.39 (s, 0.6H, major),

5.27 (s, 0.4H, minor), 3.83 (s, 1.2H, minor), 3.78 (s, 1.8H, major),

3.49−3.46 (m, 0.6H), 3.48 (s, 1.2H, minor), 3.47 (s, 1.8H, major),

2.70 (s, 0.4H, minor), 1.64−1.04 (m, 10H, major and minor), 0.93 (s,

1.8H, major), 0.86 (s, 1.2H, minor); ¹³C{¹H} NMR (125 MHz,

H

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CDCl₃, mixture of diastereomers) δ (Major) 170.5, 165.7, 141.7,

127.6, 105.1, 56.6, 55.9, 52.2, 38.1, 35.1, 34.3, 25.9, 21.7, 21.6, 19.8

(Minor) 167.3, 165.6, 133.5, 130.2, 104.2, 56.6, 55.6, 52.6, 35.8, 35.3,

34.6, 26.0, 21.50, 21.4, 20.5; IR (thin ﬁlm) 2931, 2858, 1774, 1731,

1214, 938, 911 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

[C₁₅H₂₂O₅Na]⁺305.1365; found 305.1362.

was dried over MgSO₄, ﬁltered, and concentrated to a colorless oil,

which was used without further puriﬁcation.

A 10 mL ﬂask was charged with the crude lactol dissolved in THF

(2.4 mL, 0.2 M) and cooled to 0 °C. DMAP (6 mg, 0.047 mmol, 10

mol %) was added followed by Et₃N (0.26 mL, 1.88 mmol, 4 equiv)

and TFAA (0.13 mL, 0.94 mmol, 2 equiv). The mixture was then

warmed to 65 °C for 1 h. The reaction mixture was cooled to rt and

quenched with the addition of sat. aq. NH₄Cl (20 mL). The mixture

was then extracted with Et₂O (2 x 10 mL), and the organic layer were

washed with brine (20 mL). The organic layers were then dried over

MgSO₄, ﬁltered, and concentrated to a yellow oil. The crude residue

was puriﬁed by ﬂash column chromatography (SiO₂neutralized with

1% Et₃N in Hex, 1:0 → 20:1 → 10:1 Hex/EtOAc) to aﬀord

dihydrofuran 26 (64 mg, 67% over two steps) as a colorless oil. R_f=

0.88 (4:1 Hex/EtOAc, visualized with KMnO₄); ¹H NMR (500 MHz,

CDCl₃) δ 6.36 (dd, J = 1.8, 2.5 Hz, 1H), 5.15 (d, J = 2.5 Hz, 1H),

4.97 (t, J = 2.8 Hz, 1H), 3.46 (s, 3H), 2.61−2.55 (m, 1H), 1.60−1.20

(m, 10 H), 0.80 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 143.8,

107.6, 101.0, 59.5, 55.5, 35.6, 35.4, 34.3, 26.4, 21.7, 21.6, 20.4; IR

(thin ﬁlm) 2923, 2851, 1619, 1445, 1379, 1218, 1140, 1105, 1053,

1034, 961, 928, 902 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd

for [C₁₂H₂₀O₂Na]⁺197.1542; found 197.1550.

Preparation of Bromoester 27. A ﬂame-dried 10 mL ﬂask was

charged with dihydrofuran 26 (55 mg, 0.28 mmol) in CH₂Cl₂(3 mL,

0.1 M) and cooled to 0 °C. Bromoacetic acid (58 mg, 0.42 mmol, 1.5

equiv) was added followed by NBS (58 mg, 0.32 mmol, 1.2 equiv).

The mixture was stirred at 0 °C for 1 h. TLC analysis indicated that

the starting material had been consumed. The reaction was quenched

with sat. aq. NaHCO₃(10 mL) and extracted with CH₂Cl₂(2 x 10

mL). The combined organic layer was then washed with sat. aq.

Na₂S₂O₃(10 mL), dried over MgSO₄, ﬁltered, and concentrated. The

crude residue was puriﬁed by ﬂash column chromatography (SiO₂,

1:0 → 9:1 Hex/EtOAc) to aﬀord bromoester 27 (83 mg, 72%) as a

colorless oil as a 7:1 mixture of partially separable diastereomers. R_f=

0.55 (9:1 Hex/EtOAc, visualized with KMnO₄); ¹H NMR (600 MHz,

CDCl₃) δ 6.44 (d, J = 2.1 Hz, 1H), 5.04 (d, J = 4.2 Hz, 1H), 4.04 (dd,

J = 2.1, 4.4 Hz, 1H), 3.84 (s, 2H), 3.47 (s, 3H), 2.60 (t, J = 4.2 Hz,

1H), 1.61−1.25 (m, 10H), 0.95 (s, 3H); ¹³C{¹H} NMR (150 MHz,

CDCl₃) δ 165.6, 108.2, 104.3, 62.9, 56.5, 46.7, 36.4, 36.1, 34.7, 26.0,

25.4, 21.5, 21.4, 21.3; IR (thin ﬁlm) 2925, 2850, 1756, 1446, 1395,

1268, 1097, 1030, 951, 901, 877 cm⁻¹; HRMS (ESI-TOF) m/z: (M +

Na)⁺calcd for [C₁₄H₂₂O₄Br₂Na]⁺434.9782, 436.9763, 438.9745

(1:2:1); found 434.9784, 436.9751, 438.9742 (1:2:1).

Preparation of Alcohol 32. A 25 mL round-bottom ﬂask

containing a stir bar was charged with alkene 18 (281 mg, 0.95 mmol)

and toluene (9 mL, 0.1 M) under argon. The solution was cooled to

−78 °C, and a solution of ^L-selectride (1.4 mL, 1.4 mmol, 1 M in

THF) was added dropwise. The resulting solution was maintained at

−78 °C for 1 h, after which a solution of iodine (1.2 g, 4.75 mmol) in

toluene (5 mL) was added. The reaction mixture was allowed to

warm to −20 °C and then quenched by the addition of H₂O (5 mL).

This mixture was stirred at rt for 30 min. The aqueous layer was

extracted with EtOAc (3 x 15 mL), and the combined organic layers

were washed with sat. aq. Na₂S₂O₃(2 x 30 mL) and then brine (2 x

30 mL), dried over MgSO₄, ﬁltered through cotton, and concentrated

under reduced pressure. The residue obtained was puriﬁed by ﬂash

column chromatography (SiO₂, 10:1 → 4:1 Hex/EtOAc) to provide

tertiary alcohol 32 (220 mg, 0.70 mmol, 74%) as a colorless solid.

Preparation of Alcohol 32 by Mukaiyama Hydration. A 25

mL round-bottom ﬂask was charged with alkenes 18 (169 mg, 0.57

mmol) and i-PrOH (6 mL, 0.1 M). The mixture was sparged with O₂

for 5 min. Then, Mn(acac)₂(23.5 mg, 0.092 mmol, 15 mol %) and

PhSiH₃(0.28 mL, 2.26 mmol, 4 equiv) were added. The mixture was

gently warmed with a heat gun until the reaction turned yellow and

started to bubble. The reaction was then allowed to cool to rt and

stirred at rt for 24 h. The reaction was then concentrated under

reduced pressure, and the residue was puriﬁed by ﬂash column

chromatography (SiO₂, 10:1 → 4:1 Hex/EtOAc) to aﬀord alcohol 32

(116 mg, 65%) as a colorless oil, which solidiﬁes over time. X-ray

quality crystals were obtained from slow evaporation of CH₂Cl₂. R_f=

Preparation of Alkenes 18. A 100 mL round-bottom ﬂask was

charged with alcohol 16 (1.63 g, 5.2 mmol), DMAP (63 mg, 0.52

mmol, 10 mol %), and CH₂Cl₂(25 mL, 0.2 M). After sequential

addition of pyridine (1.67 mL, 20.8 mmol, 4 equiv) and triﬂuoroacetic

anhydride (1.4 mL, 10 mmol, 2 equiv), the reaction mixture was

maintained at 40 °C for 1 h when complete consumption of the

starting material was observed by TLC analysis. The reaction was

cooled to rt, and DBU (4.6 mL, 31 mmol, 6 equiv) was added via a

syringe. The mixture was stirred at rt for 1 h and then quenched by

the addition of H₂O (20 mL). The layers were separated, and the

aqueous layer was washed with CH₂Cl₂(2 x 20 mL). The combined

organic layers were then washed with brine (30 mL), dried over

MgSO₄, ﬁltered, and concentrated under reduced pressure to a brown

oil. This residue was puriﬁed by ﬂash column chromatography (SiO₂,

20:1 → 10:1 Hex/EtOAc) to aﬀord (E)-18 (865 mg, 2.91 mmol,

56%) and (Z)-18 (459 mg, 1.56 mmol, 30%) as colorless oils. R_f=

0.60 and 0.45 (4:1 Hex/EtOAc), respectively; (E)-18: ¹H NMR (600

MHz, CDCl₃) δ 6.90 (d, J = 1.6 Hz, 1H), 5.39 (s, 1H), 4.31−4.19 (m,

2H), 3.51 (d, J = 1.6 Hz, 1H), 3.48 (s, 3H), 1.66−1.59 (m, 1H),

1.56−1.50 (m, 2H), 1.49−1.35 (m, 3H), 1.32 (t, J = 7.1 Hz, 3H),

1.29−1.18 (m, 3H), 1.15−1.06 (m, 1H), 0.94 (s, 3H); ¹³C{¹H} NMR

(150 MHz, CDCl₃) δ 170.4, 165.2, 141.2, 127.9, 104.9, 61.2, 56.47,

55.7, 38.0, 35.0, 34.2, 25.8, 21.6, 21.5, 19.6, 14.1; IR (thin ﬁlm) 2927,

2851, 1776, 1724, 1465, 1446, 1372, 1353, 1255, 1206, 1113, 1065,

1024, 999, 929, 786, 673; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd

for [C₁₆H₂₄NaO₅]⁺319.1521; found 319.1533; (Z)-18: ¹H NMR

(600 MHz, CDCl₃) δ 6.27 (d, J = 1.6 Hz, 1H), 5.27 (s, 1H), 4.31 (q, J

= 7.2 Hz, 2H), 3.48 (s, 3H), 2.69 (s, 1H), 1.60−1.37 (m, 8H), 1.34 (t,

J = 7.2 Hz, 3H), 1.31−1.22 (m, 2H), 0.87 (s, 3H); ¹³C{¹H} NMR

(150 MHz, CDCl₃) δ 167.1, 165.1, 133.0, 130.6, 104.1, 61.7, 56.5,

55.5, 35.7, 35.2, 34.6, 25.9, 21.44, 21.40, 20.5, 14.0; IR (thin ﬁlm)

2927, 2851, 1772, 1732, 1465, 1446, 1367, 1328, 1219, 1176, 1090,

1025, 942, 674 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

[C₁₆H₂₄NaO₅]⁺319.1521; found 319.1533.

Preparation of Lactol 23. A 10 mL round-bottom ﬂask was

charged with alkene (Z)-18 (160 mg, 0.54 mmol) in THF (3 mL,

0.18 M) and cooled to 0 °C. Then concentrated HCl (3 mL) was

added dropwise. The reaction was allowed to warm to rt and stirred

for 24 h. The reaction was then cooled to 0 °C and diluted with H₂O

(10 mL). The mixture was extracted with CH₂Cl₂(3 x 10 mL), and

the combined organic layers were then dried over MgSO₄, ﬁltered,

and concentrated to an orange oil. The crude residue was puriﬁed by

ﬂash column chromatography (SiO₂, 5:1 Hex/EtOAc) to aﬀord 23

(132 mg, 87%) as a yellow oil. R_f= 0.32 (5:1 Hex/EtOAc); ¹H NMR

(600 MHz, CDCl₃) δ 6.93 (d, J = 1.6 Hz, 1H), 5.95 (s, 1H), 4.31−

4.20 (m, 2H), 3.54 (d, J = 1.6 Hz, 1H), 1.64−1.59 (m, 1H), 1.55−

1.50 (m, 2H), 1.49−1.35 (m, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.29−

1.19 (m, 3H), 1.15−1.06 (m, 1H), 0.94 (s, 3H); ¹³C{¹H} NMR (150

MHz, CDCl₃) δ 170.4, 165.4, 141.1, 128.6, 98.4, 61.3, 56.3, 38.1, 35.0,

34.2, 25.9, 21.6, 21.5, 19.7, 14.1; IR (thin ﬁlm) 3402, 2927, 2858,

1774, 1724, 1446, 1372, 1253, 1206, 1107, 1025, 940; HRMS (ESI-

TOF) m/z: (M + Na)⁺calcd for [C₁₅H₂₂O₅Na]⁺305.1365; found

305.1371.

Preparation of Dihydrofuran 26. A ﬂame-dried 10 mL round-

bottom ﬂask was charged with lactone 14 (100 mg, 0.47 mmol) and

CH₂Cl₂(4.7 mL, 0.1 M). The solution was cooled to −78 °C, and

DIBAL (0.52 mL, 0.52 mmol, 1.1 equiv, 1 M in hexanes) was added

dropwise. The reaction was then stirred at −78 °C for 1 h, quenched

by the addition of acetone (1 mL), and stirred for 5 min. A saturated

aqueous solution of Rochelle’s salt (2 mL) was added, and the

reaction mixture was allowed to warm to rt and stirred for 40 min.

This mixture was then extracted with Et₂O (2 x 10 mL), and the

organic extracts were washed with brine (20 mL). The organic layer

I

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1

0.3 (9:1 Hex/EtOAc, visualized with KMnO₄); H NMR (600 MHz,

CDCl₃) δ 5.31 (d, J = 7.3 Hz, 1H), 4.68 (s, 1H), 4.26−4.16 (m, 2H),

3.57 (s, 3H), 2.98 (d, J = 15.1 Hz, 1H), 2.68 (d, J = 15.0 Hz, 1H),

2.48 (d, J = 7.4 Hz, 1H), 1.70−1.64 (m, 1H), 1.63−1.57 (m, 1H),

1.55−1.48 (m, 2H), 1.48−1.38 (m, 5H), 1.32−1.24 (m, 1H), 1.28 (t,

J = 7.1 Hz, 3H), 1.09 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ

175.1, 170.5, 104.4, 77.0, 61.7, 58.2, 57.5, 39.2, 38.2, 36.3, 34.4, 25.8,

22.3, 21.4, 21.3, 14.0; IR (thin ﬁlm) 3448, 2930, 2854, 1782, 1735,

1448, 1392, 1373, 1298, 1216, 1175, 1135, 1044, 922 cm⁻¹; HRMS

(ESI-TOF) m/z: (M + Na)⁺calcd for [C₁₆H₂₇O₆]⁺315.1808; found

315.1811.

over MgSO₄, ﬁltered, and concentrated to aﬀord lactol 34 as a

colorless oil.

A 10 mL round-bottom ﬂask was charged with the crude lactol 34,

DMAP (1.5 mg, 0.012 mmol, 35 mol %), and CH₂Cl₂(2 mL, 0.01

M). Then, freshly distilled pyridine (60 μL, 0.75 mmol, 20 equiv) was

added followed by Ac₂O (50 μL, 0.53 mmol, 15 equiv). The reaction

mixture was then stirred at rt for 24 h. The reaction was quenched by

the addition of H₂O (10 mL) and extracted with CH₂Cl₂(3 x 5 mL).

The combined organic layers were dried over MgSO₄and ﬁltered.

SiO₂(2 g) was added to the ﬁltrate, and the mixture was concentrated

to give a colorless solid, which was allowed to sit at rt under vacuum

for 16 h. The material was then puriﬁed by column chromatography

(SiO₂, 4:1 Hex/EtOAc) to aﬀord butenolide 35 (10 mg, >95%) as a

colorless oil. R_f= 0.26 (4:1 Hex/EtOAc, visualized with KMnO₄); ¹H

NMR (600 MHz, CDCl₃) δ 6.48 (d, J = 3.9 Hz, 1H), 6.16 (s, 1H),

5.97 (d, J = 2.1 Hz, 1H), 3.25−3.21 (m, 1H), 2.13 (s, 3H), 1.54−1.48

(m, 4H), 1.47−1.35 (m, 3H), 1.34−1.27 (m, 3H), 1.01 (s, 3H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 171.0, 169.3, 167.5, 115.4,

104.1, 100.5, 53.7, 36.2, 36.1, 34.3, 25.9, 21.5, 21.3, 21.2, 20.7; IR

(thin ﬁlm) 2925, 2851, 1790, 1749, 1660, 1446, 1368, 1215, 1164,

1133, 1043, 987, 973, 944, 863 cm⁻¹; HRMS (ESI-TOF) m/z: (M +

Na)⁺calcd for [C₁₅H₂₀NaO₅]⁺303.1208; found 303.1214.

Preparation of TMS-Protected Alcohol S1. A 10 mL round-

bottom ﬂask was charged with alcohol 32 (113 mg, 0.358 mmol) and

CH₂Cl₂(3 mL, 0.1 M). Imidazole (148 mg, 2.17 mmol, 6 equiv) was

added followed by freshly distilled TMSCl (0.14 mL, 1.1 mmol, 3

equiv). The reaction was then stirred at rt for 3 h, at which time TLC

analysis indicated consumption of the starting material. The reaction

was quenched by the addition of H₂O (5 mL). The layers were

separated, and the aqueous layer was extracted with CH₂Cl₂(3 x 5

mL). The organic layers were then dried over MgSO₄, ﬁltered, and

concentrated to aﬀord lactone S1 (127 mg, 92%) as a pale yellow oil

that was used without further puriﬁcation. R_f= 0.66 (4:1 Hex/EtOAc,

1

visualized with KMnO₄); H NMR (600 MHz, C₆D₆) δ 5.32 (d, J =

Preparation of Dioxabicyclo[3.3.0]octan-3-one 36. A 5 mL

round-bottom ﬂask was charged with (iPr)CuCl (2.3 mg, 0.0047

mmol, 15 mol %), NaOtBu (0.05 mL, 0.1 M in toluene, 15 mol %),

and toluene (0.5 mL). PMHS (7 μL, 0.1 mmol, 4 equiv) was added as

a solution in toluene (0.1 mL). The reaction mixture was then stirred

for 5 min. Then, a solution of butenolide 35 (8.1 mg, 0.029 mmol)

and t-BuOH (11 μL, 0.12 mmol, 4 equiv) in toluene (0.5 mL) was

added to the reaction. The mixture was then stirred at rt for 16 h. The

reaction was quenched by the addition of H₂O (5 mL) and allowed to

stir for 5 min. The mixture was then extracted with EtOAc (3 x 5

mL). The organic layers were dried over MgSO₄, ﬁltered, and

concentrated to a colorless solid. This material was puriﬁed by ﬂash

column chromatography (SiO₂, 4:1 hexanes/EtOAc) to aﬀord lactone

36 (5.3 mg, 66%) as a colorless solid. R_f= 0.36 (4:1 hexanes/EtOAc,

visualized with KMnO₄); ¹H NMR (600 MHz, CDCl₃) δ 6.41 (d, J =

7.1 Hz, 1H), 6.04 (d, J = 4.0 Hz, 1H), 3.07 (dddd, J = 4.4, 6.4, 9.2,

10.2 Hz, 1H), 2.72 (dd, J = 10.2, 17.5 Hz, 1H), 2.55 (dd, J = 9.1, 17.6

Hz, 1H), 2.57−2.53 (m, 1H), 2.09 (s, 3H), 1.56−1.51 (m, 2H),

1.51−1.43 (m, 3H), 1.37−1.31 (m, 3H), 1.29−1.21 (m, 2H), 1.03 (s,

3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 175.5, 169.9, 105.1, 96.7,

54.1, 41.3, 38.0, 37.4, 34.0, 29.7, 25.8, 22.7, 21.7, 21.3, 21.2; IR (thin

ﬁlm) 2925, 2851, 1795, 1749, 1376, 1228, 1163, 1016, 984, 939, 865

cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for [C₁₅H₂₂O₅Na]⁺

305.1365; found 305.1375.

Preparation of Alkenes 42 and 43. A ﬂame-dried 250 mL

round-bottom ﬂask was charged with CuBr·DMS (180 mg, 0.87

mmol, 10 mol %) and suspended in Et₂O (54 mL, 0.16 M). MeMgBr

(3.3 mL, 11 mmol, 1.2 equiv, 3.31 M in Et₂O) was added to the

suspension, and the mixture was stirred for 15 min at rt then cooled to

0 °C. 3-Methylcyclohexenone (39) (1.02 mL, 9 mmol) was added

dropwise at 0 °C and stirring was continued for 30 min until TLC

showed full consumption of the starting material. The reaction was

then cooled to −78 °C, and a solution of aldehyde 40 (1.93 g, 14.8

mmol, 1.65 equiv)⁴³in Et₂O (15 mL) was added slowly. The reaction

was allowed to warm to rt overnight. Then, sat. aqueous NH₄Cl (70

mL) was added, the phases were separated, and the aqueous phase

was extracted with Et₂O (3 x 50 mL). The combined organic extracts

were washed with brine (15 mL), dried over Na₂SO₄, and

concentrated. The crude aldol product 41 was obtained as a yellowish

oil, which was directly used in the subsequent step.

7.7 Hz, 1H), 3.93 (dq, J = 7.1, 11.0 Hz, 1H), 3.79 (dq, J = 7.1, 11.0

Hz, 1H), 3.13 (s, 3H), 3.10 (d, J = 16.4 Hz, 1H), 2.93 (d, J = 16.4 Hz,

1H), 2.58 (d, J = 7.7 Hz, 1H), 1.67−1.58 (m, 1H), 1.55−1.43 (m,

3H), 1.43−1.30 (m, 4H), 1.30−1.25 (m, 1H), 1.24−1.14 (m, 1H),

0.93 (s, 3H), 0.91 (t, J = 7.1 Hz, 3H), 0.33 (s, 9H); ¹³C{¹H} NMR

(150 MHz, C₆D₆) δ 174.3, 169.0, 104.2, 79.7, 61.5, 60.4, 56.6, 42.9,

38.0, 36.5, 34.3, 25.9, 21.8, 21.6, 21.4, 13.6, 1.6; IR (thin ﬁlm) 2925,

2850, 1780, 1739, 1373, 1339, 1248, 1132, 954, 844 cm⁻¹; HRMS

(ESI-TOF) m/z: (M + Na)⁺calcd for [C₁₉H₃₄NaO₆Si]⁺409.2022;

found 409.2013.

Preparation of Dioxabicyclo[3.3.0]octan-3-one 33. A 10 mL

round-bottom ﬂask was charged with lactone S1 (19 mg, 0.05 mmol)

and Et₂O (1.5 mL, 0.03 M). The mixture was cooled to −78 °C, and

DIBAL (0.25 mL, 0.25 mmol, 5 equiv, 1 M in hexanes) was added.

The reaction was then stirred at −78 °C for 2 h and then allowed to

warm passively over an hour to −20 °C. The reaction was stirred at

−20 °C for 30 min and then quenched by the addition of a saturated

aqueous solution of Rochelle’s salt (2 mL) and saturated aqueous

NaHCO₃(2 mL). The mixture was then vigorously stirred for 30 min.

The reaction mixture was then extracted with Et₂O (3 x 10 mL). The

organic extracts were then dried over MgSO₄, ﬁltered, and

concentrated to aﬀord the crude lactols as a colorless oil.

A 10 mL round-bottom ﬂask was charged with the crude lactols

and CH₂Cl₂(1.5 mL, 0.03 M). PCC (22 mg, 0.10 mmol, 2 equiv) was

added, and the reaction mixture was stirred at rt for 16 h. Celite (2 g)

was added to the reaction mixture followed by dilution with 10 mL of

4:1 hexane/EtOAc. The mixture was then ﬁltered through a SiO₂plug

with 4:1 hexanes/EtOAc (30 mL). The ﬁltrate was concentrated to

aﬀord dioxabicyclo[3.3.0]octanone 33 (16 mg, 91% over two steps)

as a colorless oil: R_f= 0.35 (9:1 hexanes/EtOAc, visualized with

KMnO₄). This material was taken on without further puriﬁcation as

the TMS-protecting group was quite labile. A small sample was

puriﬁed by ﬂash column chromatography for characterization

1

purposes. H NMR (600 MHz, C₆D₆) δ 5.71 (s, 1H), 4.55 (d, J =

6.4 Hz, 1H), 3.16 (s, 3H), 2.63 (d, J = 17.4 Hz, 1H), 2.43 (d, J = 6.3

Hz, 1H), 2.28 (d, J = 17.4 Hz, 1H), 1.53−1.03 (m, 10H), 0.70 (s,

3H), 0.01 (s, 9H); ¹³C{¹H} NMR (150 MHz, C₆D₆) δ 174.2, 106.8,

105.0, 85.3, 55.4, 39.0, 37.4, 37.0, 34.2, 25.9, 21.6, 21.3, 1.2; IR (thin

ﬁlm) 2924, 2850, 1803, 1254, 1162, 1129, 1111, 1054, 1031, 946,

913, 844 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

[C₁₇H₃₀NaO₅Si]⁺365.1760; found 365.1761.

Preparation of Dioxabicyclo[3.3.0]oct-4-en-3-one 35. A 10

mL round-bottom ﬂask was charged with lactone 33 (12 mg, 0.035

mmol) and THF (1 mL, 0.03 M). Aqueous HCl (1 mL, 4 M aqueous,

110 equiv) was added, and the reaction mixture was stirred at rt for 48

h. The reaction was then diluted with H₂O (10 mL) and extracted

with EtOAc (3 x 5 mL). The combined organic layers were then dried

To a solution of crude alcohol 41 in CH₂Cl₂(90 mL, 0.1 M),

DMAP (5.5 g, 45 mmol, 5 equiv) and MsCl (1.75 mL, 22.5 mmol, 2.5

equiv) were added. The reaction was then heated at reﬂux overnight.

The mixture was then concentrated under reduced pressure (ca. 20

mL volume) and ﬂushed through a SiO₂plug with EtOAc (150 mL).

The solvent was removed, and the crude mesylates were taken up in

THF (70 mL, 0.13 M) followed by the dropwise addition of DBU

(4.71 mL, 31.5 mmol, 3.5 equiv). The mixture was maintained at rt

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overnight, after which time it was concentrated to 10% of its original

volume. Et₂O (100 mL) was added, and the organic phase was

washed with water (25 mL) and brine (25 mL). After drying over

Na₂SO₄and removal of all volatiles, the crude product was puriﬁed by

ﬂash column chromatography (SiO₂, 10:1 → 4:1 Hex/EtOAc). The

desired compound was obtained as a colorless oil and as a 2:1 mixture

extracted with CH₂Cl₂(3 x 50 mL). The combined organic extracts

were washed with brine (50 mL), dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. The crude product was puriﬁed

by ﬂash column chromatography (SiO₂, 15:1 → 10:1 Hex/EtOAc) to

yield alcohol 38 as a yellowish oil (358 mg, 1.73 mmol, 85%). R_f=

0.35 (hexanes/EtOAc, 10:1); ¹H NMR (600 MHz, CDCl₃) δ 5.44 (br

s, 1H), 2.09−2.04 (m, 3H), 1.77−1.70 (m, 2H), 1.63 (s, 1H), 1.53

(td, J = 13.4, 4.3 Hz, 1H), 1.47 (br d, J = 12.9 Hz, 1H), 1.43−1.38 (m,

1H), 1.28−1.22 (m, 1H), 1.21 (s, 3H), 1.18−1.15 (m, 1H), 1.00 (d, J

= 6.5 Hz, 3H), 0.90 (s, 3H), 0.88 (s, 3H); ¹³C{¹H} NMR (125 MHz,

CDCl₃) δ 141.9, 119.0, 72.5, 49.2, 47.9, 40.7, 31.9, 31.3, 27.6, 27.5,

26.7, 26.5, 23.1, 10.7; IR (thin ﬁlm) 2925, 2866, 1454, 1380, 1363,

1271, 1246, 999, 948, 909, 724 cm⁻¹; HRMS (ESI-TOF) m/z: (M +

H)⁺calcd for [C₁₄H₂₅O]⁺209.1905; found 209.1907; Optical

1

of 42:43 (1.3 g, 5.5 mmol, 61% over three steps); Diagnostic H

NMR (600 MHz, CDCl₃) δ 5.93 (dd, J = 9.8, 15.5 Hz, 0.3H), 5.59 (t,

J = 7.1 Hz, 0.7H), 5.39 (d, J = 15.5 Hz, 0.3H), 3.97−3.90 (m, 4H),

2.75 (d, J = 9.8 Hz, 0.3H), 2.57 (d, J = 7.4 Hz, 1.4H), 2.43 (t, J = 6.7

Hz, 1.4H), 2.37 (dt, J = 5.7, 13.6 Hz, 0.3H), 2.29−2.22 (m, 0.3H),

1.94−1.82 (m, 2H), 1.70−1.62 (m, 2H), 1.47 (s, 0.9), 1.29 (s, 2.1H),

1.08 (s, 4.2H), 0.96 (s, 0.9), 0.83 (s, 0.9H) ppm.

Preparation of rac-Ketone 44. The mixture of alkene isomers

42 and 43 (1.3 g, 5.5 mmol, 1 equiv) was dissolved in EtOAc (55 mL,

0.1 M), and Pd(OH)₂(309 mg, 0.44 mmol, 0.08 equiv, 20 wt %) and

NaHCO₃(462 mg, 5.5 mmol, 1 equiv) were added in one portion.

The reaction vessel was evacuated and backﬁlled with a hydrogen

balloon (three times). With the balloon attached, the reaction was

stirred under a hydrogen atmosphere overnight after which time TLC

showed full consumption of the starting materials. The solids were

removed by ﬁltration over Celite and washing the solids with EtOAc

(100 mL). The ﬁltrate was then concentrated under reduced pressure

to aﬀord ketone 44 (1.22 g, 5.1 mmol, 93%) as a colorless oil. R_f=

0.36 (4:1 Hex/EtOAc, visualized with KMnO₄); ¹H NMR (600 MHz,

CDCl₃) δ 3.97−3.90 (m, 4H), 2.35−2.32 (m, 1H), 2.28−2.23 (m,

1H), 2.12 (app. d, J = 11.2 Hz, 1H), 1.91−1.87 (m, 1H), 1.84−1.80

(m, 1H), 1.77−1.65 (m, 2H), 1.64−1.59 (m, 2H), 1.47−1.38 (m,

2H), 1.32 (s, 3H), 1.05 (s, 3H), 0.79 (s, 3H); ¹³C{¹H} NMR (125

MHz, CDCl₃) δ 213.6, 110.1, 64.7, 64.6, 61.1, 41.2, 39.8, 39.0, 37.8,

29.5, 23.8, 23.3, 22.5, 18.9; IR (thin ﬁlm) 2962, 2874, 1708, 1459,

1370, 1259, 1222, 1058, 868 cm⁻¹; HRMS (CI-TOF) m/z: (M + H)⁺

calcd for [C₁₂H₂₅O₃]⁺241.1804; found 241.1798.

Preparation of rac-Alkene 37. A suspension of EtPPh₃Br (1.53

g, 4.13 mmol, 8.25 equiv) and KOt-Bu (421 mg, 3.75 mmol, 7.5

equiv) in THF (6.5 mL) was stirred for 30 min at rt. The reaction was

then cooled to 0 °C, and a solution of ketone 44 (121 mg, 0.5 mmol,

1 equiv) in THF (5 mL) was added dropwise. The reaction was

allowed to warm to rt overnight and was then heated to 60 °C for 5 h.

The reaction was quenched with sat. aqueous NH₄Cl (20 mL), the

phases were separated, and the aqueous phase was extracted with

EtOAc (2 x 50 mL). The combined organic extracts were washed with

brine (10 mL), dried over Na₂SO₄, and concentrated. The crude

product was dissolved in acetone (3 mL) followed by the addition of

Merriﬁeld resin (253 mg, 4.38 Cl/g) and NaI (150 mg, 1 mmol, 2

equiv). The suspension was stirred at rt overnight, after which time

the mixture was ﬁltered over Celite and the solids were washed with

THF (15 mL), CH₂Cl₂(15 mL), H₂O (15 mL), acetone (15 mL),

and MeOH (15 mL). This washing cycle was repeated three times.

The biphasic mixture was concentrated under reduced pressure

followed by the addition of Et₂O (50 mL). The organic phase was

washed with water (10 mL) then brine (10 mL) and dried over

MgSO₄, ﬁltered, and concentrated. The crude residue was puriﬁed by

ﬂash column chromatography (SiO₂, 30:1 Hex/Et₂O) to aﬀord alkene

37 as a colorless oil (116 mg, 0.46 mmol, 92%). R_f= 0.46 (10:1 Hex/

EtOAc, visualized with KMnO₄); ¹H NMR (600 MHz, CDCl₃) δ 5.07

(q, J = 6.7 Hz, 1H), 3.95−3.90 (m, 4H), 2.25 (dt, J = 14.1, 3.5 Hz,

1H), 1.78−1.74 (m, 1H), 1.60 (d, J = 6.6 Hz, 3H), 1.55−1.50 (m,

5H), 1.45−1.39 (m, 2H), 1.35−1.34 (m, 1H), 1.32 (s, 3H), 1.20−

1.18 (m, 1H), 0.88 (s, 3H), 0.86 (s, 3H); ¹³C{¹H} NMR (125 MHz,

CDCl₃) δ 139.2, 117.7, 110.6, 64.7, 64.7, 55.9, 37.9, 35.8, 34.9, 28.3,

27.9, 24.0, 23.9, 23.0, 21.1, 12.8; IR (thin ﬁlm) 2953, 2926, 2864,

1449, 1376, 1238, 1220, 1063, 864, 825 cm⁻¹; HRMS (CI-TOF) m/

z: (M + H)⁺calcd for [C₁₆H₂₉O₂]⁺253.2168; found 253.2161.

Preparation of Alcohol 38. In a 100 mL round-bottom ﬂask,

ketal 37 (594 mg, 2.03 mmol, 1 equiv) was dissolved in dry CH₂Cl₂

(83 mL, 0.025 M). para-Toluenesulfonic acid monohydrate (77 mg,

0.41 mmol, 20 mol %) was added, and the reaction was maintained at

rt for 3 h. After TLC showed complete consumption of the starting

material, water (20 mL) was added and the aqueous phase was

25

25.0

25

Rotation [α]²_D⁵− 78.6, [α]

− 83.2, [α]

− 95.0, [α]

−

577

546

435

25

405

163.8, [α] − 200.1 (c = 1.24, CHCl₃).

Preparation of Oxalate 45. Tertiary alcohol 38 (81 mg, 0.38

mmol) and DMAP (4.6 mg, 0.038 mmol, 10 mol %) were dissolved in

CH₂Cl₂(4 mL, 0.1 M) in a scintillation vial under argon. After the

addition of Et₃N (64 μL, 0.46 mmol, 1.2 equiv) and methyl

chlorooxacetate (42 μL, 0.46 mmol, 1.2 equiv), the vial was sealed

with a Teﬂon-coated cap and was placed in an aluminum block

preheated to 40 °C. The homogeneous mixture was maintained at this

temperature for 2 h. After this time, the vial was removed from the

block and allowed to cool to rt. Additional portions of Et₃N (64 μL,

0.46 mmol, 1.2 equiv) and methyl chlorooxacetate (42 μL, 0.46

mmol, 1.2 equiv) were added, and the vial was capped, placed in the

aluminum heating block at 40 °C, and maintained at this temperature

for a further 3 h. The vial was then allowed to cool to rt, and the

reaction mixture was quenched with saturated aqueous NH₄Cl

solution (2 mL). The biphasic mixture was transferred to a separatory

funnel and diluted with H₂O (10 mL). The aqueous layer was

extracted with CH₂Cl₂(3 x 20 mL), and the combined organic layers

were washed with brine (2 x 30 mL), dried over Na₂SO₄, ﬁltered

through cotton, and concentrated under reduced pressure. The

residue obtained was puriﬁed by ﬂash column chromatography (SiO₂,

20:1 Hex/EtOAc) to provide methyl oxalate ester 45 (105 mg, 0.35

mmol, 92%) as a colorless oil. R_f= 0.45 (9:1 Hex/EtOAc, visualized

with KMnO₄); ¹H NMR (500 MHz, CDCl₃) δ 5.45 (s, 1H), 3.83 (s,

3H), 2.85 (br d, J = 15.0 Hz, 1H), 2.07−2.00 (m, 2H), 2.00−1.96 (m,

1H), 1.69−1.64 (m, 1H), 1.63−1.55 (m, 1H), 1.60 (s, 3H), 1.50 (td,

J = 14.4, 3.7 Hz, 1H), 1.38−1.31 (m, 1H), 1.20−1.14 (m, 2H), 1.12

(d, J = 6.6 Hz, 3H), 0.91 (s, 3H), 0.82 (s, 3H); ¹³C{¹H} NMR (125

MHz, CDCl₃) δ 159.2, 157.2, 138.5, 119.2, 88.7, 53.2, 48.4, 48.0, 35.2,

33.7, 31.5, 28.2, 25.8, 24.7, 24.3, 23.0, 10.9; IR (thin ﬁlm) 2951, 2919,

1766, 1739, 1452, 1331, 1208, 1164, 1100, 873 cm⁻¹; HRMS (ESI-

TOF) m/z: (M + Na)⁺calcd for [C₁₇H₂₆O₄Na]⁺317.1729; found

25

317.1736; Optical Rotation [α]²_D⁵− 12.9, [α] − 13.3, [α] − 14.9,

577

546

25

[α] − 20.3, [α] − 29.3 (c = 1.15, CHCl₃); Analysis by HPLC

435

405

conﬁrmed that the compound was obtained in 98% ee: AD column,

1% IPA/n-hexane, 0.5 mL/min. t_R: 9.7 min (major), 10.9 min

(minor).

Preparation of Dioxolane 51. A solution of 2-(2-bromoethyl)-2-

methyl-1,3-dioxolane (6.00 g, 30.9 mmol, 3 equiv)⁴⁴and 1,2-

dibromoethane (0.6 mL) in THF (20 mL) was added to a suspension

of Mg turnings (2.25 g, 92.8 mmol, 9 equiv) in THF (45 mL, 0.5 M

overall). The mixture was brieﬂy warmed with a heat gun for 10 s and

was then stirred for 2 h at rt. The resulting black suspension of 50 was

transferred via cannula to a round-bottom ﬂask containing a stir bar

under argon. The mixture was cooled to −78 °C, and a homogeneous

solution of CuCN (2.77 g, 30.9 mmol, 3 equiv) and LiCl (2.62 g,

61.85 mmol, 6 equiv) in THF (31 mL) was added via a syringe. After

stirring vigorously for 15 min at −78 °C, a solution of phosphate 49

(4.00 g, 10.3 mmol) in THF (20 mL) was added. The suspension was

stirred for 30 min at −78 °C and then was allowed to warm to 0 °C

while stirring for an additional 30 min. Saturated aqueous NH₄Cl

solution (150 mL) was added, and the biphasic mixture was

transferred to a separatory funnel. The aqueous layer was extracted

with Et₂O (3 x 200 mL), and the combined organic layers were

washed with brine (2 x 300 mL), dried over MgSO₄, ﬁltered, and

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concentrated. The residue obtained was puriﬁed by ﬂash column

chromatography (SiO₂, 15:1 Hex/EtOAc) to provide vinyl iodide 51

(3.49 g, 9.97 mmol, 97%) as a colorless oil. Spectral data acquired for

the compound matched those previously reported.^28bOptical

pressure was released, and the reaction mixture was transferred to a

round-bottom ﬂask and concentrated under reduced pressure. The

crude residue was puriﬁed by ﬂash column chromatography (SiO₂,

50:1 → 20:1 Hex/EtOAc) provided exocyclic alkene (S)-37 (496 mg,

1.97 mmol, 98%) as a colorless oil. Spectral data acquired for the

27

Rotation [α]²_D⁷− 58.5, [α]

− 61.8, [α]

− 70.7, [α]

−

577

546

435

27

405

123.2, [α]

− 152.6 (c = 0.58, CH₂Cl₂). Analysis by HPLC

compound matched those reported above. Optical Rotation [α]_D²⁵

+

25

conﬁrmed that the compound was present in 99% ee: AD column,

215 nm, 0.5% IPA/n-hexane, 0.15 mL/min. t_R: 36.528 min (major),

39.080 min (minor).

24.7, [α] + 24.9, [α] + 27.7, [α] + 45.3, [α] + 56.1 (c =

577 546 435 405

1.04, CHCl₃).

Preparation of Cesium Oxalate 53. A 1 dram vial containing a

stir bar was charged with methyl oxalate ester 45 (101 mg, 0.340

mmol) and THF (340 μL, 1.0 M). To this colorless solution was

added dropwise aqueous 1 N CsOH (340 μL, 0.340 mmol, 1 equiv)

with vigorous stirring. The progress of the reaction was monitored by

TLC during addition of the aqueous CsOH solution. After complete

addition of the aqueous CsOH solution, the reaction mixture was

transferred to a round-bottom ﬂask and was concentrated under

reduced pressure at 50 °C to yield cesium oxalate salt 53 (133 mg,

0.322 mmol, 95%) as a colorless powder. The oxalate was dried under

Preparation of (S)-Ketone 44. A 100 mL round-bottom ﬂask

was charged with vinyl iodide 51 (1.50 g, 4.28 mmol) and Et₂O (14

mL, 0.3 M) under Ar. The reaction mixture was cooled to −78 °C,

and a solution of t-BuLi (6.0 mL, 9.00 mmol, 2.1 equiv, 1.5 M in

pentane) was added slowly. The homogeneous solution was

maintained at this temperature for 45 min, after which B(OMe)₃

(1.2 mL, 10.71 mmol, 2.5 equiv) was added in one portion. The

reaction mixture was then allowed to warm to rt and was maintained

at this temperature for 3 h. After this time, THF (15 mL), NaBO₃·

4H₂O (6.59 g, 42.85 mmol, 10 equiv), and H₂O (15 mL) were added

sequentially. The heterogeneous mixture was stirred at rt for 24 h,

after which it was diluted with H₂O (40 mL) and extracted with Et₂O

(3 x 50 mL). The combined organic layers were washed with brine (2

x 100 mL) and dried over MgSO₄. The suspension was ﬁltered

through cotton to remove the drying agent, and the ﬁltrate was

concentrated under reduced pressure. The residue obtained was

puriﬁed by ﬂash column chromatography (SiO₂, 9:1 → 6:1 Hex/

EtOAc) to provide (S)-ketone 44 (830 mg, 3.45 mmol, 80%) as a

colorless oil: R_f= 0.36 (3:1 Hex/EtOAc, visualized with KMnO₄).

Spectral data for (S)-44 matched that of the racemic material reported

1

vacuum for 18 h before use. H NMR (600 MHz, DMSO-d₆) δ 5.27

(br s, 1H), 2.74−2.69 (m, 1H), 1.95−1.86 (m, 2H), 1.85−1.78 (m,

1H), 1.56−1.47 (m, 2H), 1.41 (s, 3H), 1.34 (dt, J = 13.8, 3.6 Hz,

1H), 1.29−1.23 (m, 1H), 1.22−1.14 (m, 1H), 1.31−1.08 (m, 1H),

0.98 (d, J = 6.9 Hz, 3H), 0.85 (s, 3H), 0.75 (s, 3H); ¹³C{¹H} NMR

(150 MHz, DMSO-d₆) δ 168.0, 163.7, 139.5, 117.3, 81.6, 47.7, 47.3,

34.8, 34.2, 31.1, 28.5, 24.84, 24.76, 23.4, 22.4, 10.8; HRMS (ESI-

TOF) m/z: (M − Cs)⁻calcd for [C₁₆H₂₃O₄]⁻279.1596; found

279.1588.

Preparation of Tricyclic Butyrolactone 54. To a 1 dram vial

was added sequentially (S)-5-methoxyfuranone (13) (13 mg, 0.11

mmol, 1 equiv), cesium oxalate salt 53 (50 mg, 0.12 mmol, 1.1 equiv),

Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆(1 mg, 0.001 mmol, 1 mol %), and

DME (550 μL, 0.2 M) and H₂O (20 μL, 1.1 mmol, 10 equiv). The

yellow reaction mixture was sparged with argon for 5 min, after which

it was placed on a stir plate equipped with 2 x 34 W blue (465 nm

peak intensity, unﬁltered) LED lamps approximately 4 cm from the

lamps and stirred vigorously. The vial was irradiated for 36 h and air

was blown on the vial to prevent an increase in temperature due to the

LED lamps. After 36 h, the reaction mixture was diluted with CH₂Cl₂

(1 mL) and ﬂushed through a pipette plug of Na₂SO₄. The yellow

solution was then concentrated under reduced pressure to obtain a

crude residue that was puriﬁed by ﬂash column chromatography

(SiO₂, 30:1 Hex/EtOAc), providing lactone 54 (16 mg, 0.066 mmol,

54% based on the cesium oxalate) as a colorless oil: R_f= 0.44 (9:1

25

above. Optical Rotation [α]²_D⁵+ 11.3, [α] + 12.6, [α] + 14.9,

577

546

25

[α] + 47.5, [α] + 75.6 (c = 1.00, CHCl₃).

435

405

Wittig oleﬁnation of enantioenriched (S)-44 under the conditions

reported for the formation of rac-37 followed by subsequent

conversion to oxalate 45 provides 45 in signiﬁcantly diminished

enantiopurity as determined by enantioselective HPLC analysis.

Preparation of Diene 52. A solution of vinylmagnesium bromide

(4.6 mL, 2.9 mmol, 2 equiv, 0.62 M in THF) was added to a solution

of ZnCl₂(8.6 mL, 4.3 mmol, 3 equiv, 0.5 M in THF) at −78 °C. The

suspension was then allowed to warm to rt while stirring for 1.5 h.

After this time, a solution of iodide 51 (500 mg, 1.43 mmol) and

Pd(PPh₃)₄(165 mg, 0.143 mmol, 10 mol %) in THF (3.3 mL) and

DMF (3.3 mL) was added slowly. The reaction mixture was stirred at

rt for 36 h, and saturated aqueous NH₄Cl solution (10 mL) and Et₂O

(50 mL) were added. The organic layer was separated, washed with

brine (2 x 40 mL), dried over MgSO₄, ﬁltered through cotton, and

concentrated under reduced pressure. The residue obtained was

puriﬁed by ﬂash column chromatography (SiO₂, 30:1 → 20:1 Hex/

EtOAc) to provide diene 52 (333 mg, 1.33 mmol, 93%) as a colorless

1

Hex/EtOAc); H NMR (500 MHz, CDCl₃) δ 2.13−2.02 (m, 1H),

1.95−1.87 (m, 3H), 1.71 (q, J = 7.1 Hz, 1H), 1.63−1.57 (m, 2H),

1.52−1.43 (m, 2H), 1.34 (dd, J = 12.2, 5.0 Hz, 1H), 1.28 (s, 3H),

1.18−1.08 (m, 2H), 0.91−0.88 (m, 9H); ¹³C{¹H} NMR (125 MHz,

CDCl₃) δ 180.2, 83.6, 53.8, 50.5, 50.4, 41.8, 36.5, 34.1, 32.2, 29.3,

21.9, 21.6, 20.3, 18.7, 10.4; IR (thin ﬁlm) 2932, 1754, 1136 cm⁻¹;

1

oil: R_f= 0.49 (9:1 Hex/EtOAc, visualized with KMnO₄); H NMR

(500 MHz, CDCl₃) δ 6.23 (dd, J = 17.8, 11.0 Hz, 1H), 5.61 (t, J = 3.8

Hz, 1H), 5.05 (d, J = 17.8 Hz, 1H), 4.89 (d, J = 11.0 Hz, 1H), 3.95−

3.86 (m, 4H), 2.15−2.10 (m, 2H), 1.90−1.86 (m, 1H), 1.79−1.65

(m, 2H), 1.64−1.52 (m, 2H), 1.41−1.32 (m, 1H), 1.28 (s, 3H),

1.18−1.12 (m, 1H), 0.99 (s, 3H), 0.84 (s, 3H); ¹³C{¹H} NMR (150

MHz, DMSO-d₆) δ 140.05, 140.04, 127.3, 109.9, 109.1, 63.94, 63.92,

42.3, 32.0, 30.0, 28.4, 26.7, 26.3, 23.5, 23.0; IR (thin ﬁlm) 3088, 2953,

2872, 1375, 1060 cm⁻¹; HRMS (ESI-TOF) m/z: (M + H)⁺calcd for

HRMS (CI-TOF) m/z: (M + NH₄)⁺calcd for [C₁₅H₂₈NO₂]⁺

25

254.2120; found 254.2111; Optical Rotation [α]²_D⁵− 3.4, [α]

−

577

25

3.2, [α] − 3.9, [α] − 4.8, [α] − 3.3 (c = 1.29, CHCl₃).

546

435

405

Preparation of Dioxolane 59. A solution of 2-(2-bromoethyl)-

1,3-dioxolane (6.96 g, 38.7 mmol, 3 equiv) and 1,2-dibromoethane

(0.7 mL, 8 mmol, 0.65 equiv) in THF (25 mL) was added to a

suspension of Mg turnings (2.82 g, 116 mmol, 9 equiv) in THF (55

mL). The mixture was brieﬂy warmed with the heat gun for 10 s and

was then stirred for 2 h at rt. The resulting black suspension of

Grignard reagent 58 was then transferred via cannula to a round-

bottom ﬂask containing a stir bar under argon. The mixture was

cooled to −78 °C, and a homogeneous solution of CuCN (3.46 g,

38.7 mmol, 3 equiv) and LiCl (3.28 g, 77.3 mmol, 6 equiv) in THF

(40 mL) was added via a syringe. After stirring vigorously for 15 min

at −78 °C, a solution of phosphate 49 (5.00 g, 12.8 mmol) in THF

(25 mL) was added. The resulting suspension was stirred for 30 min

at −78 °C and then was allowed to warm to 0 °C while stirring for an

additional 30 min. Saturated aqueous NH₄Cl solution (150 mL) was

added, and the biphasic mixture was transferred to a separatory

funnel. The aqueous layer was extracted with Et₂O (3 x 200 mL), and

the combined organic layers were washed with brine (2 x 300 mL),

[C₁₆H₂₇O₂]⁺251.2011; found 251.1920; Optical Rotation [α]²_D⁵

−

25

72.0, [α] − 75.4, [α] − 85.5, [α] − 146.5, [α] − 177.8 (c =

577

546

435

405

1.14, CHCl₃).

Preparation of (S)-Alkene 37. In a glove box under a N₂

atmosphere, a stainless steel Parr bomb containing a stir bar was

charged with (η⁶-naphthalene)chromium tricarbonyl (106 mg, 0.40

mmol, 20 mol %), diene 52 (500 mg, 2.00 mmol), and acetone (20

mL, degassed in a Schlenk tube by three freeze−pump−thaw cycles

prior to bringing into the glove box, 0.1 M). The Parr bomb was

sealed, removed from the glove box, and quickly purged with H₂gas

three times before being pressurized to 75 atm (∼1100 psi) H₂. The

apparatus was then placed in a sand bath preheated to 55 °C and was

maintained at this temperature while stirring for 18 h. The H₂

L

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Article

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

puriﬁed by ﬂash column chromatography (SiO₂, 20:1 Hex/EtOAc) to

aﬀord vinyl iodide 59 (4.03 g, 11.9 mmol, 93%) as a colorless oil.

Spectral data acquired for the compound matched those previously

column chromatography (SiO₂, 9:1 Hex/EtOAc) to aﬀord alcohol 62

(2.23 g, 11.5 mmol, 69%) as a colorless oil, which solidiﬁed upon

storage at −20 °C: R_f= 0.40 (9:1 Hex/EtOAc); ¹H NMR (600 MHz,

CDCl₃) δ 5.38 (br s, 1H), 3.82−3.72 (m, 1H), 2.28−2.24 (m, 1H),

2.05−2.02 (m, 2H), 1.92 (dq, J = 13.7, 3.2 Hz, 1H), 1.69−1.65 (m,

1H), 1.60 (tdd, J = 2.4, 4.5, 13.6 Hz, 1H), 1.53−1.50 (m, 1H), 1.41−

1.34 (m, 2H), 1.32 (qd, J = 4.0, 12.9 Hz, 1H), 1.17 (dt, J = 4.7, 13.0

Hz, 1H), 1.06 (d, J = 6.9 Hz, 3H), 0.90 (s, 3H), 0.86 (s, 3H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 140.0, 119.6, 72.4, 49.1, 43.7,

33.9, 32.7, 31.4, 27.8, 27.0, 24.4, 23.0, 14.3; IR (thin ﬁlm) 2911, 2867,

2360, 2340, 1452, 1382, 1363, 1186, 1093, 969, 940, 714 cm⁻¹;

HRMS (CI-TOF) m/z: (M⁺) calcd for [C₁₃H₂₂O]⁺194.1671; found

reported for the enantiomer.^28b[α]_D²⁵− 59.2, [α] − 62.6, [α]

−

25

577

546

25

435

25

405

70.5, [α] − 126.5, [α] − 156 (c = 1.02, CHCl₃). Analysis of a

comparable sample ([α]²_D⁷− 58.5) by HPLC conﬁrmed that the

enantiomeric purity of this sample was 99% ee: AD column, 215 nm,

0.5% IPA/n-hexane, 0.15 mL/min. t_R: 36.5 min (major), 39.0 min

(minor).

Preparation of Diene 60. A solution of vinylmagnesium bromide

(22.5 mL, 22.5 mmol, 2 equiv, 1 M in THF) was added to a solution

of ZnCl₂(48 mL, 34 mmol, 3 equiv, 0.7 M in THF) and THF (19

mL) at −78 °C. The suspension was then allowed to warm over 1.5 h

to rt while stirring. A solution of iodide 59 (3.78 g, 11.2 mmol) and

Pd(PPh₃)₄(1.30 g, 1.12 mmol, 10 mol %) in THF (25 mL) and DMF

(25 mL) was added slowly. The reaction mixture was allowed to stir

at rt for 36 h, after which saturated aqueous NH₄Cl solution (100

mL) was added. The mixture was extracted with Et₂O (3 x 150 mL),

and the organic layer was separated, washed with brine (2 x 200 mL),

dried over MgSO₄, ﬁltered, and concentrated under reduced pressure.

The residue was puriﬁed by ﬂash column chromatography (SiO₂, 30:1

→ 15:1 Hex/EtOAc) to provide diene 60 (2.54 g, 10.7 mmol, 95%)

22

194.1672; Optical Rotation [α]²_D^2.5− 84.8, [α] − 89.2, [α]

−

577

546

22

435

22

405

101, [α] − 174, [α] − 208 (c = 1.1, CHCl₃).

Preparation of Ketone 63. A round-bottom ﬂask was charged

with alcohol 62 (808 mg, 4.16 mmol) and CH₂Cl₂(40 mL, 0.1 M)

under argon. The solution was cooled to 0 °C, and Dess−Martin

periodinane (DMP, 2.11 g, 4.99 mmol, 1.2 equiv) was added in one

portion. The reaction mixture was then allowed to warm to rt and was

maintained at this temperature for 2 h. TLC analysis indicated that

the starting material was still present, so an additional portion of DMP

(0.35 g, 0.82 mmol, 0.2 equiv) was added. The reaction was stirred for

an additional 2 h, after which TLC analysis indicated that the starting

material was consumed. The reaction mixture was then diluted with

Et₂O (40 mL), and the solution was ﬂushed through a pad of Celite.

The pad of Celite was washed with Et₂O (300 mL), and the ﬁltrate

was concentrated under reduced pressure. The oily solid residue was

suspended in 9:1 Hex/EtOAc (20 mL) and ﬂushed through a small

plug of silica gel. The plug of silica gel was eluted with 9:1 Hex/

EtOAc (300 mL), and the ﬁltrate was concentrated to aﬀord ketone

63 (777 mg, 4.04 mmol, >95%) as a colorless oil. β,γ-Unsaturated

ketone 63 was prone to double bond isomerization during storage and

was used immediately in the next step: R_f= 0.48 (9:1 Hex/EtOAc).

¹H NMR (600 MHz, CDCl₃) δ 5.41 (br s, 1H), 3.04−3.00 (m, 1H),

2.48 (ddd, J = 3.5, 5.1, 14.5 Hz, 1H), 2.41 (dddd, J = 1.0, 6.2, 12.3,

14.6 Hz, 1H), 2.11−2.04 (m, 2H), 2.04−1.98 (m, 2H), 1.48−1.42

(m, 1H), 1.41−1.36 (m, 1H), 1.23 (dt, J = 5.1, 13.1 Hz, 1H), 1.16 (d,

J = 6.6 Hz, 3H), 1.00 (s, 3H), 0.92 (s, 3H); ¹³C{¹H} NMR (125

MHz, CDCl₃) δ 210.9, 139.0, 118.5, 52.2, 48.0, 41.1, 32.9, 31.8, 28.1,

27.7, 26.5, 23.1, 10.5; IR (thin ﬁlm) 2953, 2869, 1717, 1673, 1453,

1365, 1337, 1174, 953, 849 cm⁻¹; HRMS (EI-TOF) m/z: (M⁺) calcd

1

as a colorless oil: R_f= 0.61 (9:1 Hex/EtOAc); H NMR (500 MHz,

CDCl₃) δ 6.29 (dd, J = 17.7, 10.8 Hz, 1H), 5.64−5.61 (m, 1H), 5.06

(d, J = 17.7 Hz, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.75 (t, J = 4.8 Hz,

1H), 3.98−3.91 (m, 2H), 3.84−3.79 (m, 2H), 2.15−2.10 (m, 2H),

1.96−1.92 (m, 1H), 1.76−1.69 (m, 2H), 1.66−1.57 (m, 2H), 1.42−

1.34 (m, 1H), 1.18−1.12 (m, 1H), 1.00 (s, 3H), 0.85 (s, 3H);

¹³C{¹H} NMR (125 MHz, CDCl₃) δ 140.5, 140.2, 127.9, 109.8,

105.1, 64.95, 64.92, 43.0, 34.7, 32.5, 20.5, 28.8, 27.0, 26.8, 23.7; IR

(thin ﬁlm) 2954, 2870, 1647, 1406, 1139, 1034, 893 cm⁻¹; HRMS

(ESI-TOF) m/z: (M + NH₄)⁺calcd for [C₁₅H₂₈NO₂]⁺254.2120;

22

found 254.2129; Optical Rotation [α]²_D²− 87.4, [α] − 93.7, [α]

577

546

22

− 105, [α] − 183, [α] − 219 (c = 1.02, CHCl₃).

435

405

Preparation of Ethylidene 61. In a glove box under a N₂

atmosphere, a stainless steel Parr bomb containing a stir bar was

charged with (η⁶-naphthalene)chromium tricarbonyl (560 mg, 2.1

mmol, 13 mol %), diene 60 (3.94 g, 16.7 mmol), and acetone (170

mL, 0.1 M, degassed in a Schlenk tube by three freeze−pump−thaw

cycles prior to bringing into the glove box). The Parr bomb was

sealed, removed from the glove box, and quickly purged with H₂gas

three times before being pressurized to 75 atm (∼1100 psi) H₂. The

apparatus was then placed in a sand bath preheated to 55 °C and was

maintained at this temperature while stirring for 60 h. The H₂

pressure was released, and the reaction mixture was transferred to a

round-bottom ﬂask and concentrated. The crude residue was puriﬁed

by ﬂash column chromatography (SiO₂, 50:1 Hex/EtOAc) to aﬀord

(E)-ethylidene acetal 61 (3.97 g, 16.6 mmol, >95%) as a colorless oil:

R_f= 0.67 (9:1 Hex/EtOAc); ¹H NMR (600 MHz, CDCl₃) δ 5.08 (q,

J = 6.4 Hz, 1H), 4.82 (t, J = 4.4 Hz, 1H), 3.98−3.95 (m, 2H), 3.87−

3.82 (m, 2H), 2.28−2.25 (m, 1H), 1.76−1.71 (m, 1H), 1.59 (dd, J =

6.7, 1.0 Hz, 3H), 1.56−1.34 (m, 8H), 1.19−1.14 (m, 1H), 0.87 (s,

3H), 0.85 (s, 3H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 138.9, 118.0,

105.2, 65.0, 64.9, 55.7, 35.6, 34.8, 32.8, 28.2, 28.0, 23.8, 22.9, 21.2,

12.8; IR (thin ﬁlm) 2951, 2926, 2460, 1408, 1382, 1364, 1140, 1037,

955, 891, 907, 824 cm⁻¹; HRMS (CI-TOF) m/z: (M⁺) calcd for

for [C₁₃H₂₀O]⁺192.1514; found 192.1519; Optical Rotation [α]²_D²

−

22

139, [α] − 148, [α] − 171, [α] − 333, [α] − 72.8 (c = 1.05,

577

546

435

405

CHCl₃).

Preparation Alcohol 64. A round-bottom ﬂask was charged with

2,6-di-tert-butyl-4-methylphenol (5.34 g, 24.2 mmol, 6 equiv) and

toluene (40 mL) under argon. A solution of AlMe₃(6.1 mL, 12 mmol,

3 equiv, 2 M in toluene) was added slowly via a syringe at rt, and

vigorous gas evolution was observed. The homogeneous light yellow

solution was maintained at rt for 1 h, after which it was cooled to −78

°C. Ketone 63 (777 mg, 4.04 mmol) was added slowly as a solution in

toluene (16 mL), and the resulting solution was maintained at −78

°C for 10 min. A solution of MeMgBr (4.0 mL, 12 mmol, 3 equiv, 3.0

M in Et₂O) was added slowly, and the solution was maintained at −78

°C for 1.5 h. The reaction mixture was then allowed to slowly warm

to −20 °C overnight (16 h). After this time, the solution was then

allowed to warm to 0 °C over 20 min. The reaction mixture was then

quenched with saturated aqueous NH₄Cl solution (40 mL), and the

layers were separated. The aqueous layer was extracted with Et₂O (3 x

50 mL), and the combined organic layers were washed with brine (2 x

40 mL), dried over MgSO₄, ﬁltered, and concentrated under reduced

pressure. The residue was puriﬁed by ﬂash column chromatography

(SiO₂, 9:1 Hex/EtOAc) to aﬀord alcohol 64 (532 mg, 2.55 mmol,

63%) as a colorless solid: R_f= 0.30 (9:1 Hex/EtOAc) and recovered

ketone 63 (64.3 mg, 0.33 mmol, 8%). ¹H NMR (500 MHz, CDCl₃) δ

5.35 (br s, 1H), 2.07−1.98 (m, 3H), 1.84 (dt, J = 3.7, 12.8 Hz, 1H),

1.76 (dq, J = 4.4, 13.3 Hz, 1H), 1.61−1.53 (m, 2H), 1.45−1.35 (br s,

1H), 1.35−1.29 (m, 1H), 1.20−1.15 (m, 1H), 1.11 (qd, J = 4.0, 13.1

Hz, 1H), 1.04 (d, J = 6.9 Hz, 3H), 0.96 (s, 3H), 0.91 (s, 3H), 0.83 (s,

3H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 140.9, 117.8, 74.5, 48.9,

[C₁₅H₂₆O₂]⁺238.1933; found 238.1942; Optical Rotation [α]²_D³

+

23

32.8, [α] + 33.3, [α] + 38.2, [α] + 60.8, [α] + 74.5 (c =

577

546

435

405

0.96, CHCl₃).

Preparation of Alcohol 62. A round-bottom ﬂask was charged

with ethylidene acetal 61 (3.97 g, 16.6 mmol), acetone (150 mL, 0.1

M), and H₂O (57 mL, 220 equiv). To the mixture was added pyridine

p-toluenesulfonate (PPTS, 1.26 g, 5.01 mmol, 30 mol %), and the

ﬂask was placed in a sand bath pre-heated to 70 °C. The reaction was

stirred at this temperature for 20 h, after which it was allowed to cool

to rt. The mixture was diluted with H₂O (100 mL) and extracted with

Et₂O (3 x 100 mL). The combined organic layers were washed with

brine (2 x 100 mL), dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure. The crude residue was puriﬁed by ﬂash

M

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48.5, 42.8, 34.0, 31.4, 28.4, 26.0, 23.0, 20.2, 10.6; IR (thin ﬁlm) 3307,

2947, 2922, 2845, 1454, 1374, 1126, 1001, 948 cm⁻¹; HRMS Several

attempts to acquire HRMS data for alcohol 64 using ESI-TOF and

CI-TOF ionization techniques were unsuccessful; Optical Rotation

¹H NMR (600 MHz, CDCl₃) δ 5.68 (d, J = 1.3 Hz, 1H), 5.33 (dd, J =

2.2, 3.5 Hz, 1H), 3.52 (dt, J = 4.1, 10.5 Hz, 1H), 2.72 (dd, J = 9.8,

18.3 Hz, 1H), 2.49 (ddd, J = 1.3, 3.3, 10.1 Hz, 1H), 2.36 (dd, J = 3.5,

18.2 Hz, 1H), 2.18−2.12 (m, 1H), 2.11−2.05 (m, 2H), 2.05−2.00

(m, 2H), 1.73−1.60 (m, 3H), 1.51−1.45 (m, 1H), 1.42 (dt, J = 3.1,

12.6 Hz, 1H), 1.40−1.33 (m, 2H), 1.28 (dt, J = 3.8, 8.9 Hz, 1H),

1.24−1.14 (m, 3H), 1.05−0.97 (m, 1H), 0.96 (d, J = 7.0 Hz, 3H),

0.94 (d, J = 6.8 Hz, 3H), 0.92−0.81 (m, 2H), 0.91 (s, 3H), 0.88 (d, J

= 7.1 Hz, 3H), 0.84 (s, 3H), 0.79 (d, J = 6.9 Hz, 3H), 0.66 (s, 3H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 177.1, 140.6, 118.3, 101.0, 76.7,

49.1, 48.8, 47.9, 43.3, 39.7, 39.2, 34.3, 33.3, 32.4, 31.4, 31.3, 29.7,

28.0, 26.3, 25.4, 24.5, 23.1, 22.9, 22.3, 20.9, 17.3, 15.6, 11.1; IR (thin

ﬁlm) 2952, 2920, 2867, 1788, 1455, 1384, 1168, 1091, 1015, 970, 945

cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for [C₂₈H₄₆O₃₂N_2.3a]⁺

22

[α]²_D²− 88.5, [α] − 91.6, [α] − 109, [α] − 181, [α] − 212

577

546

435

405

(c = 0.04, CHCl₃).

Preparation of Methyl Oxalate S2. A round-bottom ﬂask was

charged with alcohol 64 (558 mg, 2.67 mmol), DMAP (33 mg, 0.27

mmol, 10 mol %), and CH₂Cl₂(14 mL, 0.2 M) under argon. After

sequential addition of Et₃N (0.75 mL, 5.4 mmol, 2 equiv) and methyl

chlorooxacetate (0.49 mL, 5.3 mmol, 2 equiv), the reaction was

maintained at rt for 5 h, after which time TLC analysis indicated

complete conversion. The reaction mixture was diluted with saturated

aqueous NH₄Cl solution (20 mL), and the layers were separated. The

aqueous layer was extracted with CH₂Cl₂(3 x 20 mL), and the

combined organic layers were washed with brine (2 x 20 mL), dried

over MgSO₄, ﬁltered, and concentrated under reduced pressure. The

crude residue was puriﬁed by ﬂash column chromatography (SiO₂,

30:1 Hex/EtOAc) to aﬀord methyl oxalate ester S2 (773 mg, 2.62

453.3345; found 453.3342; Optical Rotation [α]²_D^2.2+ 27.4, [α]₅₇₇

+

22

546

22

435

22

405

28.3, [α] + 29.0, [α] + 39.9, [α] + 46.5 (c = 0.75, CHCl₃).

Preparation of Alcohols 69. A ﬂame-dried 100 mL round-

bottom ﬂask was charged with lactone 67 (712 mg, 1.65 mmol) and

toluene (17 mL, 0.1 M). The solution was cooled to −78 °C, and a

solution of LHMDS (2.5 mL, 2.5 mmol, 1.5 equiv, 1 M in THF) was

added dropwise. The reaction was maintained at −78 °C for 1 h.

During the enolate formation, ethyl glyoxylate (50 wt % in toluene)

was distilled over P₂O₅under argon (10−15 min at 110 °C, over 10

min warmed to 140 °C, and then warmed to 200 °C); the obtained

yellow distillate was used immediately. The freshly distilled ethyl

glyoxylate (1.6 mL, 8.2 mmol, 5 equiv) was added dropwise to the

cold enolate solution. The reaction mixture was maintained at −78 °C

for 2 h and then quenched by the addition of H₂O (20 mL) and

allowed to warm to rt. The layers were separated, and the aqueous

layer was extracted with EtOAc (3 x 20 mL). The combined organic

layers were washed with brine (40 mL) and dried over MgSO₄. After

ﬁltration, concentration of the ﬁltrate gave a yellow oil, which was

puriﬁed immediately by ﬂash column chromatography (SiO₂, 20:1 →

9:1 Hex/EtOAc) to aﬀord alcohols 69 (678 mg, 77%) as a colorless

oil and an inseparable ∼4:1 mixture of alcohol epimers. R_f= 0.3 (9:1

1

mmol, >95%) as a colorless oil: R_f= 0.57 (9:1 Hex/EtOAc); H

NMR (500 MHz, CDCl₃) δ 5.43 (s, 1H), 3.86 (s, 3H), 2.65−2.55 (m,

2H), 2.03−1.98 (m, 2H), 1.89 (td, J = 13.2, 4.0 Hz, 1H), 1.83−1.77

(m, 1H), 1.64−1.57 (m, 1H), 1.33 (s, 3H), 1.32−1.28 (m, 1H),

1.23−1.16 (m, 1H), 1.16−1.07 (m, 1H), 1.05 (d, J = 7.1 Hz, 3H),

0.90 (s, 3H), 0.82 (s, 3H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ

159.2, 156.8, 139.3, 119.7, 91.2, 53.4, 48.2, 46.1, 36.7, 34.0, 31.4, 28.4,

25.7, 25.4, 23.0, 17.3, 10.9; IR (thin ﬁlm) 2951, 2919, 1772, 1741,

1200, 1168 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

[C₁₇H₂₆O₄Na]⁺317.1729; found 317.1732; Optical Rotation [α]²_D²

−

22

103, [α] − 101, [α] − 108, [α] − 187, [α] − 222 (c = 0.22,

577

546

435

405

CHCl₃).

Preparation of Cesium Oxalate 65. A round-bottom ﬂask was

charged with methyl oxalate ester S2 (379 mg, 1.29 mmol) and THF

(2.6 mL). A solution of CsOH (1.29 mL, 1.29 mmol, 1 M in H₂O)

was added slowly. The reaction was then stirred at rt for 1 h, after

which TLC analysis indicated that the starting material had been

consumed. The reaction was then carefully concentrated under

reduced pressure at 50 °C. The residue was then dried under vacuum

overnight to produce cesium oxalate salt 65 (525 mg, 1.27 mmol,

1

Hex/EtOAc, visualized with KMnO₄); H NMR (600 MHz, CDCl₃)

δ 5.67 (m, 0.2H, minor), 5.66 (d, J = 2.6 Hz, 0.8H, major), 5.37−5.34

(m, 0.8H, major), 5.34−5.31 (m, 0.2H, minor), 4.66 (dd, J = 3.7, 9.7

Hz, 0.2H, minor), 4.40−4.30 (m, 1.6H, major), 4.30−4.25 (m, 0.2H,

minor), 4.24 (dd, J = 3.2, 4.4 Hz, 0.8H, major), 4.14−4.05 (m, 0.2H,

minor), 3.52 (dt, J = 4.0, 10.8 Hz, 1H), 3.27 (d, J = 9.7 Hz, 0.2H,

minor), 3.23 (d, J = 4.7 Hz, 0.8H, major), 3.08 (dd, J = 3.0, 6.0 Hz,

0.8H, major), 2.84 (app t, J = 3.3 Hz, 0.2H, minor), 2.64 (dd, J = 2.6,

6.0 Hz, 0.8H, major), 2.39 (app d, J = 2.8 Hz, 0.2H, minor), 2.24−

2.15 (m, 1H), 2.10−2.00 (m, 4H), 1.75−1.70 (m, 1H), 1.69−1.60

(m, 3H), 1.53−1.46 (m, 2H), 1.41−1.31 (m, 3.6H), 1.34 (t, J = 7.1

Hz, 2.4H, major), 1.31−1.12 (m, 4.4H), 1.29 (t, J = 7.2 Hz, 0.6H,

minor), 0.99 (d, J = 6.7 Hz, 3H), 0.95−0.90 (m, 6H), 0.87 (d, J = 7.1

Hz, 3H), 0.85 (s, 2.4H, major), 0.83 (s, 0.6H, minor), 0.73 (s, 2.4H,

major), 0.55 (s, 0.6H, minor); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ

(only major listed) 175.0, 172.5, 140.3, 118.6, 103.3, 100.2, 77.5, 71.2,

62.5, 51.2, 49.1, 47.9, 46.3, 43.2, 40.0, 39.5, 34.4, 33.3, 32.6, 31.5,

31.4, 28.0, 26.4, 25.0, 24.5, 23.0, 22.4, 21.0, 17.3, 15.5, 14.2, 11.3; IR

(thin ﬁlm) 3500, 2952, 2920, 2868, 1775, 1738, 1662, 1454, 1382,

1369, 1320, 1297, 1266, 1239, 1180, 1114, 1097, 945, 732 cm⁻¹;

HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for [C₃₂H₅₂NaO₆]⁺

555.3661; found 555.3676.

Preparation of Alkenes (E)-70 and (Z)-70. A 50 mL round-

bottom ﬂask containing a stir bar was charged with the mixture of

alcohol epimers 69 (678 mg, 1.27 mmol), DMAP (19 mg, 0.15 mmol,

∼10 mol %), and CH₂Cl₂(13 mL, 0.1 M) under argon. After

sequential addition of pyridine (0.42 mL, 5.2 mmol, 4 equiv) and

triﬂuoroacetic anhydride (0.36 mL, 2.6 mmol, 2 equiv), the reaction

mixture was maintained at 40 °C for 1.5 h at which time complete

consumption of the starting material was observed by TLC analysis.

After this time, DBU (1.1 mL, 7.7 mmol, 6 equiv) was added by a

syringe and the reaction mixture was stirred at rt for 16 h. The

reaction mixture was then quenched by the addition of H₂O (10 mL),

and the layers were separated. The aqueous layer was extracted with

CH₂Cl₂(3 x 20 mL), and the combined organic layers were washed

1

99%) as a colorless powder. H NMR (500 MHz, DMSO-d₆) δ 5.36

(br s, 1 H), 2.56−2.52 (m, 1H), 2.41−2.35 (m, 1H), 2.00−1.93 (m,

1H), 1.84 (td, J = 3.5, 13.6 Hz, 1H), 1.75−1.69 (m, 1H), 1.61−1.55

(m, 1H), 1.33−1.26 (m, 1H), 1.18−1.14 (m, 1H), 1.12 (s, 3H), 1.05

(qd, J = 3.8, 13.7 Hz, 1H), 0.93 (d, J = 7.0 Hz, 3H), 0.88 (s, 3H), 0.80

(s, 3H); ¹³C{¹H} NMR (125 MHz, DMSO-d₆) δ 167.5, 163.4, 139.8,

118.0, 83.7, 47.6, 45.3, 36.4, 33.6, 30.9, 28.1, 25.3, 24.8, 22.4, 17.5,

10.5; IR (thin ﬁlm) 2943, 2907, 2866, 2843, 1705, 1689, 1644, 1605,

1381, 1221, 1089, 898, 780, 764, 749 cm⁻¹; HRMS (ESI-TOF) m/z:

(M − Cs)⁻calcd for C₁₆H₂₃O₄279.1596; found 279.1602.

Preparation of Lactone 67. Cesium oxalate 65 (414 mg, 1.00

mmol), chlorobutenolide 66 (274 mg, 1.00 mmol, 1 equiv),⁶

[Ir(dF(CF₃)ppy)₂(dtbpy)]PF₆(22.8 mg, 0.02 mmol, 2 mol %),

H₂O (0.18 mL, 10 mmol, 10), and THF (2 mL, 0.5 M) were divided

equally into four 2 dram vials. The vials were then sparged with argon

for 15 min. The vials were then placed on a stir plate equipped with

two 34 W blue (465 nm peak intensity, unﬁltered) LEDs and a

cardboard box (to block light pollution from entering the lab) with

double-sided tape inside to hold the vials. The vials were placed in a

square pattern approximately 4 cm from the lamps and stirred

vigorously. The samples were irradiated by the lamps for 20 h inside

the closed box, allowing the temperature of the reaction to rise to 60

°C and the air inside the box to 40−45 °C because of the heat given

oﬀ from the LEDS. Then, n-Bu₃N (0.30 mL, 1.3 mmol, 5 equiv) was

added to each vial and irradiation was continued for another 6 h. The

reactions were then poured into a separatory funnel and diluted with

H₂O (15 mL) and extracted with Et₂O (3 x 10 mL). The organic

layers were then dried over MgSO₄, ﬁltered, and concentrated to an

orange oil. The residue was then puriﬁed by ﬂash column

chromatography (SiO₂, 30:1 → 20:1 Hex/EtOAc) to aﬀord lactone

67 (320 mg, 74%) as a colorless solid. R_f= 0.45 (9:1 Hex/EtOAc);

N

https://dx.doi.org/10.1021/acs.joc.0c02273

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

with 1 M HCl (10 mL), dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure. The orange residue was puriﬁed by ﬂash

column chromatography (SiO₂, 1:0 → 30:1 → 20:1 Hex/EtOAc) to

provide (E)-70 (375 mg, 0.73 mmol, 57%) as a colorless foam: R_f=

0.65 (4:1 hexanes/EtOAc, visualized with KMnO₄) and (Z)-70 (206

mg, 0.40 mmol, 32%) as a colorless oil: R_f= 0.40 (4:1 hexanes/

EtOAc). (E)-70: ¹H NMR (600 MHz, CDCl₃) δ 6.84 (d, J = 1.7 Hz,

1H), 5.79 (s, 1H), 5.34 (bs, 1H), 4.27−4.19 (m, 2H), 3.82 (d, J = 1.6

Hz, 1H), 3.51 (dt, J = 4.2, 10.7 Hz, 1H), 2.28−2.24 (m, 1H), 2.06−

2.01 (m, 3H), 1.94−1.89 (m, 1H), 1.67−1.58 (m, 4H), 1.50−1.47

(m, 1H), 1.40−1.28 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H), 1.22−1.13 (m,

4H), 1.03 (d, J = 7.0 Hz, 3H), 1.01−0.95 (m, 1H), 0.93 (d, J = 6.6

Hz, 3H), 0.88 (s, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.80 (s, 3H), 0.72 (d,

J = 6.9 Hz, 3H), 0.67 (s, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ

170.6, 165.4, 143.2, 140.4, 127.0, 118.6, 100.1, 77.1, 61.1, 51.8, 49.2,

47.5, 43.7, 43.6, 39.8, 34.3, 33.7, 33.4, 31.4, 31.3, 28.0, 26.2, 25.3,

24.2, 23.2, 22.9, 22.3, 20.8, 16.0, 15.6, 14.2, 11.4; IR (thin ﬁlm) 2952,

2920, 2850, 1777, 1727, 1455, 1370, 1254, 1209, 1111, 1026, 918

distilled TMSCl (0.05 mL, 0.4 mmol, 3 equiv). The reaction mixture

was then stirred at rt for 16 h. TLC indicated consumption of the

starting material. The reaction was then diluted with H₂O (10 mL)

and extracted with CH₂Cl₂(3 x 5 mL). The organic layers were then

dried over MgSO₄, ﬁltered, and concentrated to an orange oil. The

crude residue was puriﬁed by ﬂushing through a neutralized SiO₂plug

(neutralized before use with 2% Et₃N in hexanes, ﬂushed with 50 mL

of 9:1 Hex/EtOAc) and concentrated to aﬀord lactone 72 (69.6 mg,

88%) as a colorless oil. R_f= 0.5 (9:1 Hex/EtOAc, visualized with

1

KMnO₄); H NMR (600 MHz, C₆D₆) δ 6.05 (d, J = 8.1 Hz, 1H),

5.37−5.34 (m, 1H), 3.96 (dq, J = 7.1, 10.8 Hz, 1H), 3.83 (dq, J = 7.1,

10.8 Hz, 1H), 3.65 (dt, J = 4.1, 10.6 Hz, 1H), 3.19 (d, J = 16.4 Hz,

1H), 3.05 (d, J = 16.4 Hz, 1H), 2.93 (d, J = 8.1 Hz, 1H), 2.67−2.59

(m, 1H), 2.45 (dp, J = 2.6, 6.8 Hz, 1H), 2.15−2.09 (m, 1H), 2.05−

1.92 (m, 2H), 1.74−1.59 (m, 2H), 1.53−1.28 (m, 7H), 1.26−1.18

(m, 2H), 1.17 (d, J = 6.6 Hz, 3H), 1.14−1.09 (m, 1H), 1.03 (s, 3H),

1.01 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 7.1 Hz, 3H), 0.94 (s, 3H), 0.92

(t, J = 7.1 Hz, 3H), 0.89−0.86 (m, 1H), 0.84 (s, 3H), 0.82−0.76 (m,

1H), 0.74 (d, J = 6.5 Hz, 3H), 0.39 (s, 9H); ¹³C{¹H} NMR (150

MHz, C₆D₆) δ 174.3, 169.2, 140.7, 118.2, 98.8, 79.9, 77.6, 60.4, 58.6,

49.8, 47.9, 44.9, 43.3, 40.0, 39.9, 35.2, 33.9, 32.7, 31.0, 30.9, 27.5,

26.6, 25.7, 25.3, 23.1, 21.9, 20.8, 16.0, 15.7, 13.7, 11.8, 1.5; IR (thin

ﬁlm) 2952, 2921, 2868, 1780, 1740, 1455, 1371, 1341, 1249, 1151,

1128, 1107, 947, 862, 844 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺

calcd for [C₃₅H₆₀O₆SiNa]⁺627.4057; found 627.4061; Optical

cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for [C₃₂H₅₀NaO₅]⁺

537.3556; found 537.3576; Optical Rotation [α]²_D¹+ 0.7, [α] + 0.4,

21

577

21

546

21

435

21

405

[α] − 0.8, [α] − 12.8, [α] − 20.9 (c = 1.0, CHCl₃). (Z)-70:

¹H NMR (600 MHz, CDCl₃) δ 6.28 (d, J = 1.6 Hz, 1H), 5.72 (s, 1H),

5.35 (bs, 1H), 4.33−4.22 (m, 2H), 3.55 (dt, J = 4.2, 10.7 Hz, 1H),

2.87 (d, J = 1.3 Hz, 1H), 2.21 (q, J = 6.6 Hz, 1H), 2.09−1.98 (m,

4H), 1.69−1.57 (m, 4H), 1.51−1.46 (m, 1H), 1.40−1.26 (m, 4H),

1.31 (t, J = 7.1 Hz, 3H), 1.26−1.10 (m, 4H), 1.03−0.97 (m, 1H),

0.95 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.89 (s, 3H), 0.85

(d, J = 7.1 Hz, 3H), 0.82 (s, 3H), 0.81 (s, 3H), 0.76 (d, J = 6.9 Hz,

3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.3, 165.3, 140.3, 134.9,

129.7, 118.8, 98.6, 76.7, 61.5, 54.8, 49.1, 47.8, 43.3, 41.2, 39.7, 34.3,

33.42, 33.39, 31.41, 31.39, 28.0, 26.2, 25.4, 24.3, 23.2, 22.9, 22.3, 20.9,

16.6, 15.7, 13.9, 11.2; IR (thin ﬁlm) 2954, 2922, 2867, 1775, 1733,

1667, 1455, 1367, 1325, 1241, 1180, 1087, 1029, 933 cm⁻¹; HRMS

(ESI-TOF) m/z: (M + Na)⁺calcd for [C₃₂H₅₀NaO₅]⁺537.3556;

23

22

23

405

Rotation [α]²_D³+ 6.1, [α] + 6.8, [α] + 7.1, [α] + 7.9, [α]

577

546

435

+ 10.0 (c = 1.5, CHCl₃).

Preparation of Valerolactone 73. In a 10 mL ﬂame-dried

round-bottom ﬂask, a solution of lactone 72 (50 mg, 0.082 mmol) in

Et₂O (2.8 mL, 0.03 M) was cooled to −78 °C. DIBAL (0.41 mL, 0.41

mmol, 5 equiv) was added, and the mixture was stirred at −78 °C for

2 h. The reaction mixture was then warmed to −20 °C slowly over an

hour and then stirred at this temperature for 30 min. The reaction was

then quenched with sat. aqueous Rochelle’s salt (2 mL) and 1 M

NaOH (0.41 mL). The mixture was then stirred for 20 min at rt then

diluted with H₂O (10 mL). The mixture was extracted with Et₂O (3 x

10 mL), and the organic layer were dried over MgSO₄, ﬁltered, and

concentrated to a colorless oil. This material was used immediately in

the next step.

22

found 537.3576; Optical Rotation [α]²_D²+ 27.3, [α] + 28.4, [α]

+

577

546

22

22.2

30.9, [α] + 52.4, [α] + 64.2 (c = 1.0, CHCl₃).

435

405

Preparation of Tertiary Alcohol 71. A 50 mL round-bottom

ﬂask was charged with alkenes 70 (103 mg, 0.20 mmol) and

Mn(dpm)₃(12 mg, 0.02 mmol, 10 mol %) dissolved in 1:1 CH₂Cl₂/

iPrOH (20 mL, 0.01 M) at 0 °C. The system was then sparged with

oxygen for 10 min. Then, Ph(O-iPr)SiH₂(0.07 mL, 0.39 mmol, ∼2

equiv) in CH₂Cl₂(0.5 mL) was added via a syringe pump over 1 h

while sparging continued. The reaction was then allowed to slowly

warm to rt overnight (16 h). The reaction mixture was then quenched

with saturated Na₂S₂O₃(10 mL) and stirred for 10 min. The reaction

mixture was then diluted with H₂O (30 mL) and extracted with

EtOAc (3 x 20 mL). The organic layers were then dried over MgSO₄,

ﬁltered, and concentrated to a brown oil. The residue was then

puriﬁed by ﬂash column chromatography (SiO₂, 1:0 → 9:1 → 4:1

Hex/EtOAc) to aﬀord alcohol 71 (71.5 mg, 67%) as a colorless oil: R_f

= 0.3 (9:1 Hex/EtOAc, visualized with KMnO₄); ¹H NMR (600

MHz, CDCl₃) δ 5.78 (d, J = 5.4 Hz, 1H), 5.33 (broad s, 1H), 4.79 (s,

1H), 4.26−4.13 (m, 2H), 3.61 (dt, J = 3.4, 10.4 Hz, 1H), 2.89 (d, J =

15.4 Hz, 1H), 2.78 (d, J = 15.4 Hz, 1H), 2.69 (d, J = 5.2 Hz, 1H),

2.36−2.29 (m, 1H), 2.22−2.10 (m, 2H), 2.06−1.98 (m, 2H), 1.70−

1.62 (m, 3H), 1.61−1.56 (m, 2H), 1.53−1.49 (m, 1H), 1.45−1.31

(m, 4H), 1.28 (t, J = 7.1 Hz, 3H), 1.25−1.20 (m, 2H), 1.20−1.14 (m,

1H), 1.03−0.98 (m, 1H), 0.97−0.92 (m, 6H), 0.91 (s, 3H), 0.89 (s,

3H), 0.88 (d, J = 6.7 Hz, 3H), 0.83 (s, 3H), 0.79 (d, J = 6.7 Hz, 3H);

¹³C{¹H} NMR (125 MHz, CDCl₃) δ 175.3, 170.9, 140.3, 118.9, 99.6,

78.3, 76.8, 61.5, 56.7, 49.4, 47.8, 44.8, 39.9, 39.5, 39.0, 34.7, 34.2,

33.3, 31.5, 31.3, 28.0, 26.2, 25.3, 24.7, 23.0, 22.9, 22.3, 21.0, 16.7,

15.7, 14.0, 11.6; IR (thin ﬁlm) 3457, 2950, 2920, 2867, 1778, 1734,

1453, 1370, 1333, 1201, 1153, 1137, 1035, 919, 733 cm⁻¹; HRMS

(ESI-TOF) m/z: (M + Na)⁺calcd for [C₃₂H₅₂NaO₆]⁺555.3661;

A 10 mL round-bottom ﬂask was charged with the crude lactols

dissolved in CH₂Cl₂(2.8 mL, 0.03 M), PCC (35.4 mg, 0.164 mmol, 2

equiv) was added, and the mixture was stirred at rt for 16 h. Celite

(0.5 g) was added to the reaction, and it was diluted with 4:1 Hex/

EtOAc (10 mL). The mixture was then ﬁltered through a neutralized

SiO₂plug (neutralized with 2% Et₃N in hexanes, ﬂushed with 30 mL

of 4:1 Hex/EtOAc). The ﬁltrate was concentrated to aﬀord lactone

73 (26.4 mg, 57%) as a light brown foam. R_f= 0.45 (4:1 Hex/EtOAc,

visualized with KMnO₄); ¹H NMR (600 MHz, C₆D₆) δ 10.01 (dd, J =

1.5, 3.0 Hz, 1H), 5.38 (d, J = 8.0 Hz, 1H), 5.33−5.29 (m, 1H), 3.52

(dt, J = 4.1, 10.7 Hz, 1H), 2.76 (dd, J = 1.5, 15.6 Hz, 1H), 2.73 (d, J =

8.0 Hz, 1H), 2.5−2.44 (m, 1H), 2.35 (dp, J = 2.5, 7.0 Hz, 1H), 2.29

(dd, J = 3.0, 15.6 Hz, 1H), 2.05−1.93 (m, 3H), 1.51−1.22 (m, 11H),

1.18−1.09 (m, 3H), 1.07 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 6.9 Hz,

3H), 0.94 (d, J = 6.9 Hz, 3H), 0.93 (s, 3H), 0.91 (s, 3H), 0.85 (s,

3H), 0.81 (d, J = 6.6 Hz, 3H), 0.30 (s, 9H); ¹³C{¹H} NMR (150

MHz, C₆D₆) δ 198.6, 174.3, 140.5, 118.4, 98.4, 80.1, 77.9, 57.3, 49.8,

49.6, 47.8, 44.9, 40.0, 39.7, 35.0, 33.8, 32.8, 31.1, 31.0, 27.6, 26.5,

25.8, 25.0, 23.2, 22.9, 21.9, 20.7, 16.0, 15.4, 11.8, 1.3; IR (thin ﬁlm)

2953, 2919, 2850, 1777, 1722, 1632, 1455, 1251, 1125, 942 cm⁻¹;

HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for [C₃₃H₅₆O₅SiNa]⁺

23

583.3795; found 583.3779; Optical Rotation [α]²_D³+ 45.6, [α]

+

577

23

47.6, [α] + 53.8, [α] + 86.1, [α] + 101 (c = 1.0, CHCl₃).

546

435

405

Preparation of Dioxabicyclo[3.3.0]octan-3-one 74. A 10 mL

round-bottom ﬂask was charged with lactone 71 (14.2 mg, 0.0266

mmol), which was dissolved in Et₂O (5 mL, 0.005 M) and cooled to 0

°C. Solid LiAlH₄(16 mg, 0.43 mmol, 15 equiv) was added in one

portion. The mixture was then allowed to stir at 0 °C for 30 min and

then quenched by the Fieser method (0.02 mL of H₂O, then 0.02 mL

of 15% aqueous NaOH, then 0.06 mL of H₂O). The mixture was then

warmed to rt and stirred for 1 h or until the residual gray color of

22

found 555.3665; Optical Rotation [α]²_D²+ 37.9, [α] + 39.5, [α]

+

577

546

22

44.4, [α] + 68.2, [α] + 79.5 (c = 1.0, CHCl₃).

435

405

Preparation of Silyl Ether 72. A round-bottom ﬂask was charged

with 71 alcohol (69.4 mg, 0.13 mmol) and CH₂Cl₂(1.5 mL, ∼0.1 M).

Imidazole (55 mg, 0.80 mmol, 6 equiv) was added followed by freshly

O

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LiAlH₄had been fully converted to colorless solids. Then, MgSO₄was

added and the mixture was ﬁltered. The ﬁltered solids were washed

with Et₂O (30 mL), and the ﬁltrate was concentrated to aﬀord a

mixture of lactol epimers as a colorless foam, which was carried on

without further puriﬁcation.

CDCl₃) δ 6.53 (d, J = 7.3 Hz, 1H), 6.04 (d, J = 4.1 Hz, 1H), 5.31 (br.

t, J = 3.7 Hz, 1H), 3.06−3.00 (m, 1H), 2.81 (app t, J = 6.8 Hz, 1H),

2.74 (dd, J = 10.4, 17.4 Hz, 1H), 2.55 (dd, J = 8.9, 17.4 Hz, 1H), 2.09

(s, 3H), 2.05−1.98 (m, 2H), 1.89 (bq, J = 7.0 Hz, 1H), 1.76−1.69

(m, 1H), 1.66−1.57 (m, 2H), 1.43−1.37 (m, 1H), 1.36−1.31 (m,

1H), 1.25−1.19 (m, 1H), 1.15 (dt, J = 4.8, 12.8 Hz, 1H), 1.00 (d, J =

6.8 Hz, 3H), 0.87 (s, 3H), 0.84 (s, 3H), 0.82 (s, 3H); ¹³C{¹H} NMR

(150 MHz, CDCl₃) δ 175.4, 169.7, 140.3, 118.4, 104.8, 96.1, 51.7,

49.0, 44.4, 42.1, 39.7, 35.5, 32.6, 31.2, 30.2, 27.6, 26.8, 25.2, 23.0,

21.2, 18.9, 11.6; IR (thin ﬁlm) 2921, 2851, 1799, 1750, 1455, 1375,

1225, 999 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

A 10 mL round-bottom ﬂask was charged with the crude lactols

and dissolved in CH₂Cl₂(5 mL, 0.005 M) at rt. PCC (12 mg, 0.056

mmol, 2.1 equiv) was then added to the reaction, and the mixture was

stirred at rt overnight (∼16 h). Celite (100 mg) was then added to

the reaction, and the mixture was concentrated. The solids were then

suspended in 4:1 hexanes/EtOAc (10 mL) and ﬁltered through a

SiO₂plug, which was washed with 4:1 hexanes/EtOAc (30 mL). The

ﬁltrate was then concentrated to aﬀord lactone 74 (9.4 mg, 72%) as a

colorless oil, which was used without further puriﬁcation: R_f= 0.3

(9:1 Hex/EtOAc, visualized with KMnO₄); ¹H NMR (600 MHz,

CDCl₃) 5.61 (s, 1H), 5.46 (d, J = 5.8 Hz, 1H), 5.33−5.28 (m, 1H),

3.54 (dt, J = 3.9, 10.5 Hz, 1H), 3.09 (d, J = 17.5 Hz, 1H), 2.55 (d, J =

17.5 Hz, 1H), 2.55 (d, J = 5.9 Hz, 1H), 2.20−2.11 (m, 2H), 2.10−

2.05 (m, 1H), 2.05−1.98 (m, 2H), 1.74−1.69 (m, 1H), 1.68−1.65

(m, 1H), 1.65−1.62 (m, 2H), 1.62−1.60 (m, 1H), 1.43 (s, 1H),

1.40−1.32 (m, 3H), 1.29−1.24 (m, 3H), 1.23−1.20 (m, 1H), 1.20−

1.18 (m, 1H), 1.18−1.13 (m, 1H), 1.03−0.98 (m, 1H), 0.96 (d, J =

6.7 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 7.2 Hz, 3H), 0.89

(s, 3H), 0.88 (s, 3H), 0.84 (s, 3H), 0.82 (d, J = 6.9 Hz, 3H); ¹³C{¹H}

NMR (150 MHz, CDCl₃) δ 174.7, 140.4, 118.3, 108.8, 100.0, 83.6,

76.2, 58.4, 49.4, 47.9, 44.5, 40.0, 39.7, 38.6, 35.3, 34.4, 32.7, 31.4,

31.2, 27.7, 26.8, 25.7, 25.2, 23.2, 23.0, 22.3, 21.0, 18.0, 15.8, 11.6; IR

(thin ﬁlm) 3403, 2921, 2867, 1792, 1455, 1383, 1219, 1163, 1104,

1035, 924, 772 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

[C₂₂H₃₂O₅Na]⁺399.2148; found 399.2159; Optical Rotation [α]²_D¹

−

21

577

21

546

21

435

21

405

27.7, [α] − 29.5, [α] − 43.1, [α] − 112, [α] − 125 (c = 0.4,

CHCl₃); [α]_D− 29.1 (c = 0.75, CHC1₃) is reported for the natural

isolate.^2a

Preparation of Alcohol S3. A ﬂame-dried 100 mL round-bottom

ﬂask was charged with lactone 77 (882 mg, 2.04 mmol)⁶and toluene

(20 mL, 0.1 M). The solution was cooled to −78 °C, and a solution of

LiHMDS (3.1 mL, 3.1 mmol, 1.55 equiv, 1 M in THF) was added

dropwise. The reaction was maintained at −78 °C for 1 h. During the

enolate formation, ethyl glyoxylate (50 wt % in toluene, ∼5.04 M)

was distilled over P₂O₅under argon (10−15 min at 110 °C, then

warmed over 10 min to 140 °C, then warmed to 200 °C). The

obtained yellow distillate was used immediately. The freshly distilled

ethyl glyoxylate (2.0 mL, 10 mmol, 5 equiv) was added. The reaction

mixture was maintained at −78 °C for 2 h and then quenched by the

addition of H₂O (20 mL) and allowed to warm to rt. The layers were

separated, and the aqueous layer was extracted with EtOAc (3 x 50

mL). The combined organic layers were then washed with brine (50

mL) and dried over MgSO₄. The organic layer were ﬁltered and

concentrated to a dark yellow oil, which was puriﬁed immediately.⁴⁵

The residue was puriﬁed by column chromatography (SiO₂, 20:1 →

9:1 Hex/EtOAc) to aﬀord alcohol S3 (931 mg, 85%) as a colorless oil

and an inseparable 4:1 mixture of diastereomers. R_f= 0.3 (9:1 Hex/

[C₃₀H₄₈O₅Na]⁺511.3399; found 511.3399; Optical Rotation [α]²_D³

+

23

23.7, [α] + 24.4, [α] + 24.4, [α] + 34.3, [α] + 39.7 (c = 0.6,

577

546

435

405

CHCl₃).

Preparation of (−)-Macfarlandin C (3). Aqueous HCl (4 M, 1.5

mL, 0.06 M overall) was added to a solution of acetal 74 (9.1 mg,

0.019 mmol) in THF (1.5 mL). The reaction was then warmed to 35

°C and stirred at this temperature for 5 days. The reaction was then

cooled to rt and diluted with H₂O (5 mL) and extracted with EtOAc

(3 x 5 mL). The combined organic extracts were dried over MgSO₄

and ﬁltered. The ﬁltrate was concentrated to aﬀord the intermediate

lactol alcohol 75 as a pale yellow oil, which was carried on without

further puriﬁcation.

The crude lactol alcohol 75 was dissolved in CH₂Cl₂(3 mL, 0.06

M) and DMAP (2.2 mg, 0.019 mmol, 1 equiv) and Et₃N (0.06 mL,

0.4 mmol, 20 equiv) were added, followed by Ac₂O (0.03 mL, 0.3

mmol, 20 equiv). The reaction was then stirred at rt overnight (∼16

h) and then quenched by the addition of H₂O (5 mL) and saturated

aq. NaHCO₃(5 mL). The mixture was then extracted with CH₂Cl₂(3

x 5 mL), and the combined organic extracts were dried over MgSO₄.

Filtration and concentration of the ﬁltrate gave a yellowish solid. This

residue was taken up in 4:1 hexanes/EtOAc (5 mL) and ﬂushed

through a SiO₂plug (neutralized with 10 mL of 5% Et₃N in hexanes)

with 25 mL of 4:1 hexanes/EtOAc. The ﬁltrate was then concentrated

to aﬀord butenolide 76 as a pale yellow oil, which was used

immediately without further puriﬁcation.⁴⁶

A ﬂame-dried 10 mL ﬂask was charged with (IPr)CuCl (2.2 mg,

0.0046 mmol, 25 mol %) and toluene (0.5 mL). To this solution,

NaOt-Bu (2.3 μL, 2 M in THF, 0.0046 mmol, 25 mol %) was added

followed by PMHS (3.3 μL, 0.056 mmol, 3 equiv). The resulting

yellow solution was stirred at rt for 5 min. Then, crude butenolide 76

and t-BuOH (3.5 μL, 0.037 mmol, 2 equiv) as a solution in toluene

(1.5 mL, 0.01 M ﬁnal concentration) were added to the reaction. The

mixture was then stirred at rt overnight (∼16 h). The reaction was

then quenched with H₂O (5 mL) and vigorously stirred for 5 min.

The mixture was then diluted with brine (5 mL) and poured into a

separatory funnel. The mixture was extracted with EtOAc (3 x 10

mL). The organic layers were then dried over MgSO₄, ﬁltered, and

concentrated to a green oil. The residue was then puriﬁed by

preparative TLC (SiO₂, 4:1 Hex/EtOAc) to aﬀord (−)-macfarlandin

C (3) (2.7 mg, 38% over three steps) as a colorless solid:⁴⁷R_f= 0.29

(4:1 Hex/EtOAc, visualized with KMnO₄); ¹H NMR (600 MHz,

1

EtOAc, visualized with KMnO₄); H NMR (600 MHz, CDCl₃) δ:

5.51−5.50 (m, 0.2H, minor), 5.49 (d, J = 2.2 Hz, 0.8H, major), 4.83

(d, J = 1.7 Hz, 0.8H, major), 4.81 (d, J = 1.6 Hz, 0.2H, minor), 4.69−

4.66 (m, 0.8H, major), 4.65 (dd, J = 3.8, 9.6 Hz, 0.2H, minor), 4.61−

4.58 (m, 0.2H, minor), 4.40−4.30 (m, 1.8H, major and minor), 4.32

(dd, J = 2.7, 4.3 Hz, 0.8H, major), 4.13 (dq, J = 7.1, 10.8 Hz, 0.2H,

minor), 3.56 (dt, J = 4.3, 10.7 Hz, 0.2H, minor), 3.53 (dt, J = 4.1, 10.6

Hz, 0.8H, major), 3.30 (d, J = 9.5 Hz, 0.2H, minor), 3.23 (d, J = 4.5

Hz, 0.8H, major), 3.10 (dd, J = 2.6, 5.2 Hz, 0.8H, major), 2.86 (app t,

J = 3.2 Hz, 0.2H, minor), 2.64 (d, J = 9.0 Hz, 0.8H, major), 2.51 (dd,

J = 2.2, 5.2 Hz, 0.8H, major), 2.39−2.33 (m, 1H, major and minor),

2.30 (m, 0.2H, minor), 2.22 (dp, J = 2.5, 7.0 Hz, 0.8H, major), 2.17

(dp, J = 2.2, 6.9 Hz, 0.2H, minor), 2.13−2.07 (m, 1H, major and

minor), 1.93 (q, J = 9.4 Hz, 1H), 1.83 (t, J = 12.9 Hz, 1H), 1.79−1.70

(m, 3H), 1.68−1.57 (m, 4H), 1.43−1.32 (m, 2.4H, major and minor),

1.35 (t, J = 7.1 Hz, 2.4H, major), 1.30 (t, J = 7.2 Hz, 0.6H, minor),

1.29−1.24 (m, 2.6H, major and minor), 1.03−0.98 (m, 1H), 0.97 (s,

3H), 0.95 (s, 3H), 0.94 (d, J = 3.6 Hz, 0.6H, minor), 0.93 (d, J = 6.5

Hz, 2.4H, major), 0.91 (s, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.77 (d, J =

6.8 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ (Major) 175.1,

172.4, 153.4, 114.8, 102.0, 77.5, 71.7, 62.6, 55.1, 55.0, 54.2, 48.0, 47.8,

47.4, 39.9, 37.8, 37.2, 37.0, 36.2, 34.4, 34.3, 31.5, 28.6, 26.2, 25.7,

25.0, 22.9, 22.4, 21.5, 21.0, 15.4, 14.1, (Minor, not all peaks visible)

176.4, 172.6, 153.3, 114.7, 102.3, 78.3, 71.0, 62.0, 54.9, 52.1, 47.63,

47.61, 47.5, 40.2, 37.7, 37.3, 37.1, 34.2, 31.6, 28.61, 26.1, 24.8, 22.6,

22.3, 21.1, 15.1, 14.0; IR (thin ﬁlm) 3502, 2950, 2921, 2868, 1775,

1738, 1454, 1386, 1367, 1264, 1240, 1178, 1112, 1093, 1022, 959,

933, 909, 731 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

[C₃₂H₅₂O₆Na]⁺555.3661; found 555.3679.

Dehydration to Alkenes (E)-78 and (Z)-78. A ﬂame-dried 25

mL round-bottom ﬂask was charged with alcohol S3 (270 mg, 0.507

mmol) in CH₂Cl₂(5 mL, 0.1 M). DMAP (6.2 mg, 0.051 mmol, 10

mol %), pyridine (0.17 mL, 2.1 mmol, 4 equiv), and TFAA (0.14 mL,

1.00 mmol, 2 equiv) were added in that order. The reaction mixture

was then placed in a sand bath that was preheated to 35 °C and

stirred at this temperature for 1.5 hr. The reaction was then cooled to

P

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rt, DBU (0.43 mL, 3.0 mmol, 6 equiv) was added, and the reaction

was stirred at rt for 1 h. The reaction was then quenched by the

addition of H₂O (10 mL), and the mixture was extracted with CH₂Cl₂

(3 x 10 mL). The organic layers were then dried over MgSO₄, ﬁltered,

and concentrated to an orange oil. The residue was puriﬁed by ﬂash

column chromatography (SiO₂, 1:0 → 95:5 → 9:1 Hex/EtOAc) to

aﬀord (E)-78 as a colorless foam (148 mg, 57%) R_f= 0.7 (9:1 Hex/

EtOAc) and (Z)-78 as a colorless oil (77 mg, 29%) R_f= 0.48 (9:1

Hex/EtOAc). (E)-78: ¹H NMR (600 MHz, CDCl₃) δ 6.87 (d, J = 1.5

Hz, 1H), 5.62 (s, 1H), 4.78 (d, J = 1.9 Hz, 1H), 4.49 (d, J = 1.6 Hz,

1H), 4.28−4.19 (m, 2H), 3.68 (d, J = 1.5 Hz, 1H), 3.54 (dt, J = 4.2,

10.7 Hz, 1H), 2.62 (d, J = 8.7 Hz, 1H), 2.31 (dd, J = 4.2, 12.1 Hz,

1H), 2.13−2.04 (m, 2H), 1.93 (dp, J = 2.5, 7.0 Hz, 1H), 1.80−1.69

(m, 4H), 1.69−1.58 (m, 5H), 1.51−1.45 (m, 1H), 1.43−1.33 (m,

2H), 1.31 (t, J = 7.1 Hz, 3H), 1.27−1.18 (m, 2H), 1.02−0.96 (m,1H),

0.96 (s, 3H), 0.95 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.89−0.84 (m,

1H), 0.83 (d, J = 7.1 Hz, 3H), 0.77 (s, 3H), 0.73 (d, J = 6.9 Hz, 3H);

¹³C{¹H} NMR (150 MHz, CDCl₃) δ 170.7, 165.4, 152.8, 143.1,

127.4, 114.9, 102.0, 77.1, 61.1, 54.4, 53.6, 53.5, 50.8, 47.5, 40.0, 37.7,

37.2, 36.9, 36.1, 34.3, 34.2. 31.5, 28.6, 26.2, 25.5, 25.4, 23.2, 22.4,

22.3, 20.8, 15.6, 14.1; IR (thin ﬁlm) 2953, 2923, 2868, 1777, 1724,

1455, 1371, 1253, 1208, 1092, 1026, 936 cm⁻¹; HRMS (ESI-TOF)

m/z: (M + Na)⁺calcd for [C₃₂H₅₀O₅Na]⁺537.3556; found 537.3542;

1776, 1734, 1454, 1371, 1332, 1299, 1200, 1134, 1037, 931, 849

cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for [C₃₂H₅₄O₇N₂₃a]⁺

573.3767; found 573.3751; Optical Rotation [α]²_D³+ 94.1, [α]₅₇₇

+

23

97.0, [α] + 112.5, [α] + 184.5, [α] + 220.2 (c = 1.0, CHCl₃);

546

435

405

Alcohol 80: ¹H NMR (600 MHz, CDCl₃) δ 5.63 (d, J = 7.3 Hz, 1H),

4.84 (d, J = 2.0 Hz, 1H), 4.72 (bs, 1H), 4.69 (d, J = 1.8 Hz, 1H),

4.25−4.14 (m, 2H), 3.61 (dt, J = 4.2, 10.7 Hz, 1H), 3.33 (d, J = 8.7

Hz, 1H), 3.00 (d, J = 15.0 Hz, 1H), 2.61 (d, J = 15.0 Hz, 1H), 2.57

(d, J = 7.3 Hz, 1H), 2.36 (dd, J = 5.3, 12.8 Hz, 1H), 2.19 (dp, J = 2.3,

7.0 Hz, 1H), 2.15−2.10 (m, 1H), 2.06 (q, J = 9.6 Hz, 1H), 1.97 (dt, J

= 6.6, 12.7 Hz, 1H), 1.79−1.59 (m, 8H), 1.46−1.35 (m, 3H), 1.25 (t,

J = 7.1 Hz, 3H), 1.25−1.20 (m, 3H), 1.01 (s, 3H), 0.97 (s, 3H), 0.95

(d, J = 6.5 Hz, 3H), 0.92 (s, 3H), 0.89 (d, J = 7.0 Hz, 3H), 0.87−0.83

(m, 1H), 0.81 (d, J = 6.9 Hz, 3H); ¹³C{¹H} NMR (150 MHz,

CDCl₃) δ 175.1, 170.8, 153.6, 115.0, 99.5, 77.9, 77.3, 61.7, 57.1, 53.5,

52.6, 48.1, 47.1, 40.1, 39.2, 39.0, 37.8, 37.6, 36.2, 34.3, 31.5, 29.7,

28.8, 25.8, 25.6, 25.5, 23.3, 22.9, 22.4, 20.9, 16.0, 14.0; IR (thin ﬁlm)

3447, 2951, 2922, 2868, 1781, 1734, 1455, 1371, 1336, 1219, 1138,

1031, 924 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

[C₃₂H₅₂O₆Na]⁺555.3661; found 555.3646; Optical Rotation [α]²_D¹

+

21

103, [α] + 107, [α] + 121, [α] + 200, [α] + 238 (c = 1.0,

577

546

435

405

CHCl₃).

Preparation of Dioxabicyclo[3.3.0]octan-3-one 81. A 25 mL

round-bottom ﬂask was charged with a solution of lactone 79 (27 mg,

0.049 mmol) in Et₂O (10 mL, 0.005 M) and cooled to 0 °C. Then,

LiAlH₄(28 mg, 0.72 mmol, 15 equiv) was added in three portions.

The mixture was then stirred for 10 min at 0 °C. The reaction was

then quenched by the Fieser method (0.05 mL of H₂O, then 0.05 mL

of 15% aqueous NaOH, then 0.15 mL of H₂O) and stirred for 1 h or

until the residual gray color of LiAlH₄had been fully converted to

colorless solids. Solid MgSO₄was added, and the mixture was ﬁltered.

The ﬁltered solids were washed with Et₂O (30 mL), and the

combined ﬁltrates were concentrated to aﬀord a mixture of lactols as a

colorless foam, which was carried on without further puriﬁcation.

The crude lactols were then dissolved in CH₂Cl₂(9 mL, 0.005 M),

and PCC (29 mg, 0.13 mmol, 2.7 equiv) was added. The mixture was

stirred at rt overnight (16 h). Then, Celite (100 mg) was added and

the mixture was stirred for 10 min. CH₂Cl₂was then removed from

the reaction mixture, and the residual solids were suspended in 4:1

Hex/EtOAc (10 mL) and ﬁltered through a neutralized SiO₂plug

(washed with 5% Et₃N in hexanes, 10 mL). The solids were washed

with 4:1 Hex/EtOAc (20 mL). The ﬁltrate was then concentrated to

aﬀord lactone 81 (15.5 mg, 66%) as a pale yellow oil, which was used

without further puriﬁcation: R_f= 0.32 (4:1 Hex/EtOAc, visualized

with KMnO₄); ¹H NMR (600 MHz, CDCl₃) δ 5.60 (s, 1H), 5.22 (d,

J = 4.3 Hz, 1H), 4.80 (d, J = 1.5 Hz, 1H), 4.64 (d, J = 1.6 Hz, 1H),

3.54 (dt, J = 4.0, 10.6 Hz, 1H), 3.06 (d, J = 17.7 Hz, 1H), 2.95−2.90

(m, 1H), 2.50 (d, J = 17.7 Hz, 1H), 2.41−2.35 (m, 2H), 2.22−2.14

(m, 1H), 2.09−2.03 (m, 1H), 1.84 (app t, J = 12.6 Hz, 1H), 1.78−

1.60 (m, 8H), 1.59−1.54 (m, 2H), 1.42−1.32 (m, 3H), 1.31−1.26

(m, 1H), 1.24−1.17 (m, 1H), 1.06−1.00 (m, 1H), 1.02 (s, 3H), 0.95

(s, 6H), 0.93−0.90 (m, 6H), 0.89−0.86 (m, 1H), 0.83 (d, J = 7.0 Hz,

3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 175.0, 153.1, 114.6, 108.6,

100.8, 84.0, 76.1, 61.5, 54.9, 54.2, 48.0, 47.7, 40.5, 38.1, 38.0, 37.3,

37.2, 36.1, 34.5, 34.4, 31.5, 28.2, 27.3, 25.9, 25.7, 24.0, 23.0, 22.4,

21.1, 15.5; IR (thin ﬁlm) 3441, 2950, 2922, 2867, 1798, 1455, 1376,

1219, 1180, 1088, 1061, 1031, 945, 849 cm⁻¹; HRMS (ESI-TOF) m/

z: (M + Na)⁺calcd for [C₃₀H₄₈O₅Na]⁺511.3399; found 511.3395;

21

Optical Rotation [α]²_D¹+ 56.2, [α] + 60.0, [α] + 67.3, [α]

+

577

546

435

21

405

1

104.4, [α] + 121 (c = 1.0, CHCl₃); (Z)-78: H NMR (600 MHz,

CDCl₃) δ 6.35 (d, J = 1.2 Hz, 1H), 5.54 (s, 1H), 4.83 (d, J = 1.6 Hz,

1H), 4.60 (d, J = 1.4 Hz, 1H), 4.33−4.25 (m, 2H), 3.58 (dt, J = 4.2,

10.7 Hz, 1H), 2.72 (s, 1H), 2.69 (d, J = 8.5 Hz, 1H), 2.34 (dd, J = 5.1,

12.7 Hz, 1H), 2.11−2.06 (m, 1H), 2.06−1.99 (m, 1H), 1.97−1.91

(m, 1H), 1.83−1.71 (m, 4H), 1.70−1.58 (m, 5H), 1.56−1.51 (m,

1H), 1.43−1.34 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.29−1.24 (m,

1H), 1.23−1.16 (m, 1H), 1.04−0.99 (m, 1H), 0.98 (s, 3H), 0.94 (s,

3H), 0.93 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 7.0 Hz, 3H), 0.84 (s, 3H),

0.76 (d, J = 6.9 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 167.4,

165.2, 152.3, 134.4, 130.3, 115.3, 100.6, 76.8, 61.6, 55.6, 53.9, 53.8,

49.1, 47.8, 39.9, 37.6, 37.0, 36.9, 36.2, 34.3, 34.2, 31.4, 28.6, 26.0,

25.9, 25.4, 23.2, 22.3, 22.1, 20.9, 15.7, 13.9; IR (thin ﬁlm) 2952, 2923,

2867, 1775, 1733, 1454, 1365, 1324, 1241, 1184, 1091, 1026, 976,

942, 923, 889 cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for

[C₃₀H₅₀O₅Na]⁺537.3556; found 537.3542; Optical Rotation [α]²_D²

+

22

23

69.2, [α] + 71.9, [α] + 82.4, [α] + 137, [α] + 166 (c = 1.0,

577

546

435

405

CHCl₃).

Preparation of Diol 79 and Alcohol 80. A 50 mL round-

bottom ﬂask was charged with alkene 78 (76.9 mg, 0.1493 mmol) and

Mn(dpm)₃(8.7 mg, 0.014 mmol, 10 mol %) dissolved in 1:1

CH₂Cl₂/i-PrOH (14 mL, 0.01 M). The reaction mixture was then

sparged with O₂for 10 min and then cooled to 0 °C. Then,

Ph(OiPr)SiH₂(0.11 mL, 0.61 mmol, 4 equiv) in CH₂Cl₂(1 mL) was

added via a syringe pump over 1 h. The reaction was then allowed to

slowly warm to rt overnight (16 h). The reaction was then quenched

with saturated Na₂S₂O₃(10 mL) and stirred for 30 min. The mixture

was then diluted with H₂O (20 mL) and extracted with CH₂Cl₂(3 x

15 mL). The organic layers were dried over MgSO₄, ﬁltered, and

concentrated to a brown oil. The residue was puriﬁed by ﬂash column

chromatography (SiO₂, 9:1 → 4:1 Hex/EtOAc) to aﬀord diol 79

(57.3 mg, 70%) as a colorless foam: R_f= 0.23 (4:1 Hex/EtOAc,

visualized with KMnO₄) and alcohol 80 (17.1 mg, 21%) as a colorless

oil: R_f= 0.69 (4:1 Hex/EtOAc, visualized with KMnO₄); Diol 79: ¹H

NMR (600 MHz, CDCl₃) δ 6.98 (s, 1H), 5.63 (d, J = 7.7 Hz, 1H),

4.50 (s, 1H), 4.23−4.14 (m, 2H), 3.61 (dt, J = 4.1, 10.6 Hz, 1H), 3.11

(d, J = 7.6 Hz, 1H), 2.91 (d, J = 14.9 Hz 1H), 2.87 (d, J = 11.5 Hz,

1H), 2.60 (d, J = 14.9 Hz, 1H), 2.25−2.17 (m, 1H), 2.16−2.09 (m,

2H), 1.82−1.63 (m, 6H), 1.62−1.57 (m, 1H), 1.54 (s, 3H), 1.50−

1.44 (m, 2H), 1.42−1.35 (m, 1H), 1.39 (s, 3H), 1.35−1.29 (m, 1H),

1.29−1.18 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H), 1.10 (s, 3H), 1.08−0.99

(m, 2H), 0.98−0.95 (m, 6H), 0.90 (d, J = 7.1 Hz, 3H), 0.81 (d, J =

6.9 Hz, 3H); ¹³C{¹H} NMR (150 MHz, CDCl₃) δ 175.0, 170.4, 99.4,

88.7, 78.0, 77.4, 61.7, 56.9, 55.0, 54.6, 48.4, 47.3, 44.5, 43.2, 41.2,

39.8, 38.7, 36.0, 35.6, 34.3, 31.4, 27.8, 25.9, 25.5, 24.0, 23.2, 22.4,

22.0, 21.0, 20.9, 16.0, 14.1; IR (thin ﬁlm) 3440, 2952, 2924, 2869,

21

435

Optical Rotation [α]²_D¹+ 77.5, [α] + 80.7, [α] + 89.6, [α]

+

577

546

21

143, [α] + 168 (c = 0.7, CHCl₃).

405

Preparation of (+)-Dendrillolide A (4). To a solution of acetal

81 (5.6 mg, 0.0114 mmol) in acetone (0.7 mL) and H₂O (0.7 mL) at

0 °C, TFA (0.7 mL, 0.005 M overall concentration) was added

dropwise. The reaction was stirred at this temperature for 10 min and

then warmed to 30 °C and stirred at this temperature for 3 days. The

reaction was then cooled to rt and concentrated to a brown oil under

reduced pressure. Water (5 mL) was added, and the mixture was

extracted with EtOAc (3 x 5 mL). The organic layers were dried over

MgSO₄and ﬁltered. The ﬁltrate was concentrated to a brown oil,

which was carried on without further puriﬁcation.

Q

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

The crude lactol was then dissolved in CH₂Cl₂(3 mL, 0.06 M),

and DMAP (1.4 mg, 0.0114 mmol, 1 equiv) and Et₃N (0.04 mL,

0.2856 mmol, 25 equiv) were added to the mixture followed by Ac₂O

(0.02 mL, 0.2115 mmol, ∼19 equiv). The reaction was then stirred at

rt overnight (∼16 h). The reaction was then quenched by the

addition of H₂O (5 mL) and sat. aq. NaHCO₃(5 mL). The mixture

was then extracted with CH₂Cl₂(3 x 5 mL), and the organic layer

were dried over MgSO₄. The solids were ﬁltered out, and the ﬁltrate

was concentrated to a yellow solid. The crude mixture was taken up in

4:1 hexanes/EtOAc (5 mL) and ﬂushed through a SiO₂plug

(neutralized with 10 mL of 5% Et₃N in hexanes) with 25 mL of 4:1

hexanes/EtOAc. The ﬁltrate was then concentrated to aﬀord

butenolide 82 as a pale yellow oil, which was used immediately

without further puriﬁcation.

́

Andre P. Dieskau − Department of Chemistry, University of

California, Irvine, Irvine, California 92697-2025, United

States

Peng Zhao − Department of Chemistry, University of

California, Irvine, Irvine, California 92697-2025, United

States

Gregory L. Lackner − Department of Chemistry, University of

California, Irvine, Irvine, California 92697-2025, United

States

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02273

Author Contributions

A ﬂame-dried 10 mL ﬂask was charged with (IPr)CuCl (1.4 mg,

0.0028 mmol, 25 mol %) and toluene (0.25 mL). To this solution,

NaOt-Bu (1.4 μL, 2 M in THF, 0.0028 mmol, 25 mol %) was added

followed by PMHS (2.0 μL, 16 M neat, 0.034 mmol, 3 equiv). The

resulting yellow solution was stirred at rt for 5 min. Then, crude

butenolide 82 and t-BuOH (2.1 μL, 0.023 mmol, 2 equiv) as a

solution in toluene (0.75 mL, 0.01 M ﬁnal concentration) were added

to the reaction. The mixture was then stirred at rt overnight (∼16 h).

The reaction was then quenched with H₂O (5 mL) and vigorously

stirred for 5 min. The mixture was then diluted with brine (5 mL) and

poured into a separatory funnel. The mixture was extracted with

EtOAc (3 x 10 mL). The organic extracts were dried over MgSO₄,

ﬁltered, and concentrated to a light green oil. This residue was then

puriﬁed by preparative TLC (SiO₂, 9:1 pentanes/EtOAc) to aﬀord

dendrillolide A (4) (1.5 mg, 34% over three steps) as a colorless oil:⁴⁷

R_f= 0.43 (4:1 Hex/EtOAc, visualized with KMnO₄); R_f= 0.15 (9:1

pentanes/EtOAc, visualized with KMnO₄); ¹H NMR (600 MHz,

C₆D₆) δ 6.45 (d, J = 6.3 Hz, 1H), 5.57 (d, J = 4.3 Hz, 1H), 4.71 (d, J

= 2.0 Hz, 1H), 4.42 (d, J = 2.0 Hz, 1H), 2.45 (d, J = 9.3 Hz, 1H),

2.23−2.16 (m, 3H), 2.14 (dd, J = 10.1, 17.4 Hz, 1H), 1.99−1.92 (m,

1H), 1.78 (dd, J = 9.2, 17.4 Hz, 1H), 1.66 (s, 3H), 1.61−1.52 (m,

3H), 1.45−1.36 (m, 4H), 1.21−1.13 (m, 1H), 1.09−1.02 (m, 1H),

0.96 (s, 3H), 0.92 (s, 3H), 0.51 (s, 3H); ¹³C{¹H} NMR (150 MHz,

C₆D₆) δ 174.8, 169.0, 153.8, 114.3, 105.0, 97.1, 55.7, 54.9, 54.5, 46.7,

41.9, 38.1, 37.7, 37.6, 36.0, 34.5, 28.8, 28.7, 27.1, 25.7, 24.1, 20.7; IR

(thin ﬁlm) 2951, 2925, 2856, 1797, 1751, 1454, 1374, 1224, 988

cm⁻¹; HRMS (ESI-TOF) m/z: (M + Na)⁺calcd for [C₂₂H₃₂O₅₂N₂a]⁺

The manuscript was written by contributions of all authors. All

authors have given approval to the ﬁnal version of the

manuscript.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

Financial support was provided by the National Science

Foundation (CHE-1265964 and CHE-1661612) and the

National Institute of General Medical Sciences (R01-

GM098601). We thank the ACS Organic Chemistry Division

for partial support of G.L.L. by a Graduate Fellowship and the

German Academic Exchange Service (DAAD) for postdoctoral

fellowship support of A.P.D. NMR and mass spectra were

determined at UC Irvine using instruments purchased with the

assistance of NSF and NIH shared instrumentation grants. We

are grateful to Eloisa Serrano and Yuriy Slutskyy for studies of

alternate approaches to these targets.

REFERENCES

■

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22

63.5, [α] + 69.2, [α] + 88.9, [α] + 133 (c = 1.0, CHCl₃); [α]_D²⁰

546

435

405

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ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02273.

(4) (a) Buckleton, J. S.; Cambie, R. C.; Clark, G. R. Structure of

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AUTHOR INFORMATION

■

Corresponding Author

Larry E. Overman − Department of Chemistry, University of

California, Irvine, Irvine, California 92697-2025, United

States; orcid.org/0000-0001-9462-0195;

Email: leoverma@uci.edu

Authors

Tyler K. Allred − Department of Chemistry, University of

California, Irvine, Irvine, California 92697-2025, United

States

R

https://dx.doi.org/10.1021/acs.joc.0c02273

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

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