Synthetic studies on furanosteroids: Construction of the viridin core structure via diels-alder/ retro- diels-alder and vinylogous mukaiyama aldol-type reaction

Article

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Synthetic Studies on Furanosteroids: Construction of the Viridin Core

Structure via Diels−Alder/retro-Diels−Alder and Vinylogous

Mukaiyama Aldol-Type Reaction

Evans O. Onyango and Peter A. Jacobi*

Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States

S

* Supporting Information

ABSTRACT: The synthesis of the viridin class of furanosteroids core skeleton from the readily available 2,3-dihydro-4-

hydroxyinden-1-one (6) is described. Our strategy was broken down into three parts: (1) Synthesis of functionalized alkyne

oxazoles of type 5; (2) intramolecular Diels−Alder/retro-Diels−Alder reaction of 5 followed by tautomerization and elaboration

of R to give silylated furanonaphthols 4 bearing an aldehyde side chain; and (3) annulation of ring A by intramolecular

vinylogous Mukaiyama aldol-type cyclization. Two major challenges were faced in the last step: (i) furanonaphthol derivatives

bearing a β-hydroxyaldehyde functionality (R₁= OH) suﬀered from dehydration to the E-enal, which is geometrically incapable

of cyclization, and (ii) the functionality at C17 had a strong inﬂuence on the conversion of 4 to 3, as exempliﬁed by the failure of

the free ketone (X = O) or its derivatives (X = H, OH; X = H, OAc) to cyclize. In the end, success was realized with the

analogous C17-norketone (X = H, H).

studies in which amines and thiols rapidly open the furan

ring.^15,16Other congeners have a similar mechanism of action

due to the identical furan ring system. However, the

development of furanosteroids into pharmaceutical drugs has

been slow due to toxicity, instability, and selectivity issues.¹⁶⁻¹⁸

These challenges were recently featured in Chemical and

Engineering News¹⁹under the title: “PI3K at the Clinical

Crossroads.” There are ongoing intense eﬀorts to derivatize

these molecules by medicinal and biological chemists, aimed at

ﬁnding more potent, less toxic, and more stable ana-

logues.^{12,13,15,20−22}There is therefore a need to develop more

eﬃcient synthetic routes to these targets to meet the above

demands.

Although the furanosteroids are relatively small in size, the

synthetic assembly of the strained pentacyclic structure has

been particularly challenging. In the case of wortmannin,

Shibasaki has accomplished two racemic and one formal

enantioselective syntheses.²³⁻²⁵Only one total synthesis of

viridin in racemic form has been achieved, by the Sorensen

group.²⁶There are also several incomplete syntheses targeting

either the core or some select rings.²⁷⁻²⁹Five years ago,^30,31

and more recently,³²our group completed the synthesis of the

A,B,C,E-ring core of viridin and wortmannin. The skeleton

contained many of the key structural features found in 1 and 2,

but lacked the D ring and also the C2- and C3- functional

INTRODUCTION

■

The furanosteroids are a special class of natural products that

feature a furan ring fused to the steroid nucleus at C-4 and C-6,

thus making the pentacyclic core highly strained (Figure 1). In

1945, viridin (1a), the parent member of this group, was

isolated from the fungus Gliocladium virens.¹The structure of

1a was determined 24 years later through chemical degradation,

spectroscopic, and X-ray studies.²To date several other

members of the viridin family have been isolated from various

fungal species and characterized.³⁻⁶These fungal metabolites

have attracted attention for many years because of their potent

anti-inﬂammatory and antibiotic properties.^4,7However, it is

their selective inhibition of certain intracellular pathways that

has attracted the most attention.⁸For example, wortmannin

(2a) is a potent and irreversible inhibitor of phosphatidylino-

sitol-3-kinase (PI3−K) at nanomolar concentrations (IC₅₀

=

4.2 nM), and more recently it has been shown to inhibit Polo-

like kinase 1 and 3 at IC₅₀= 24−49 nM.⁹It also inhibits other

PI3-related kinases at higher concentrations.^10,11

Mechanistically, PI3-kinase is proposed to interact with 2a

through covalent bonding of Lys-802, found in the ATP-

binding site, to the C20-position of wortmannin, leading to

opening of the furan ring and formation of an enamine that is

stable at physiological pH.^12,13The opening of the furan ring,

rendered highly electrophilic by virtue of being ﬂanked by the

C3- and C7- carbonyls, relieves ring strain. This mechanism has

been supported by an X-ray structure¹⁴showing wortmannin

bound to the PI3-kinase, and further validated by in vitro

Received: June 19, 2012

Published: July 31, 2012

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Figure 1. Furanosteroid class of PI3-kinase inhibitors.

groups. We therefore planned a synthetic scheme that

incorporates ring D early in the synthesis, with the hope of

functionalizing ring A at the very end of the synthetic sequence.

In the retrosynthetic analysis delineated in Scheme 1, the

skeleton 3 is considered to be a precursor to demethoxyviridin

with PPh₃provided the most practical access to the aldehyde

13, in a yield of 93%. Aldehyde 13 was then reacted with

carbon tetrabromide and triphenylphosphine in the presence of

zinc dust to give the dibromo oleﬁn 14 in a yield of 90%.³⁸

Ketalization of the ketone with ethylene glycol gave the

dioxolane 15 in a yield of 95%. Lithiation of the dibromo oleﬁn

followed by in situ capture of the resulting lithium acetylide

with chlorotrimethylsilane furnished the alkyne triﬂate 16 in a

yield of 89% (Scheme 2).

Scheme 1. Synthetic Analysis of Viridin Skeleton 3

Scheme 2. Synthesis of Alkyne Triﬂate 16

(1b) and other congeners. It was expected that on treatment

with an appropriate Lewis acid catalyst furanoaldehyde

intermediate 4 would undergo a diastereoselective vinylogous

Mukaiyama aldol-type reaction to aﬀord 3. A key consideration

in our retrosynthetic approach was that 4 could be assembled

by intramolecular Diels−Alder/retro-Diels−Alder reaction of

alkyne oxazole precursors of general structure 5. It was further

envisioned that a palladium-catalyzed C−C bond formation

between an oxazole derivative and alkyne triﬂate 7, itself

derived from ortho-functionalization of the known starting

material 6, would give alkyne oxazole 5.

RESULTS AND DISCUSSION

■

The implementation of this strategy began with the multigram

synthesis of hydroxyindanone 6 from the inexpensive

dihydrocumarin 8 through a literature procedure.³³In

preparation for a Claisen rearrangement, allylic ether precursor

9 was synthesized in a yield of 94% via Tsuji−Trost allylation³⁴

of 6 with the known allylic carbonate 10.³⁵Gratifyingly,

thermal Claisen rearrangement in N,N-diethylaniline furnished

only the ortho-allyl phenol 11 in a yield of 91%.³⁶Triﬂation of

the phenol under conditions which suppress the enol triﬂation

of the ketone furnished the triﬂate 12 in a yield of 88%.³⁷

Ozonolysis of the double bond followed by reductive workup

With the attachment of the alkyne side chain nearly

complete, attention was turned to the oxazole side chain.

Several C−C bond forming reactions were explored, but in the

end Stille cross-coupling proved to be the most promising in

terms of reproducibility and scalability. Vinyl arene 17 was thus

formed in a yield of 91% by simply heating the triﬂate 16 and

commercially available tributyl(vinyl)stannane to 90 °C in

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DMF in the presence of PdCl₂(MeCN)₂and DPEPhos

(Scheme 3). Although substrate 16 was sterically hindered,

was achieved at 170 °C and the much anticipated Diels−Alder

reaction, followed by retro-Diels−Alder reaction of the transient

adduct 24, furnished dienone 25. Tautomerization of 25 with

Et₃N in the presence of TBSOTf then gave the phenolic TBS

derivative 26 in a yield of 80%.

Scheme 3. Synthesis of Alkyne-Oxazole 22

The synthesis of the aldehyde side chain was initiated by

LiAlH₄reduction of ester 26 to the corresponding alcohol,

followed by Dess−Martin oxidation of the crude alcohol to the

aldehyde 27 in an overall yield of 87%. With 27 in hand, the

ultimate goal was to perform its enantioselective allylation to a

homoallylic alcohol.⁴⁶However, for the purpose of obtaining

material for testing, the ﬁnal ring closing reaction, racemic

homoallylic alcohol 28, was prepared in 96% yield by treatment

of 27 with allylmagnesium bromide. We had planned to protect

the alcohol functionality in 28 either as its PMB or Bn ether for

the purpose of chelation control, prior to oxidative cleavage of

the double bond. Unfortunately, though, all attempts to install

these protecting groups under basic, acidic, or neutral

conditions led to degradation of the starting material to

unidentiﬁed polar products. We thus continued with the

unprotected alcohol 28. In this case, OsO₄/NaIO₄mediated

oxidative cleavage of the oleﬁn was selective and gave the β-

hydroxyaldehyde 29, in which ketal deprotection to the ketone

occurred during silica gel puriﬁcation (yield 41%, Scheme 5).

no special additives were required.³⁹⁻⁴¹In fact, their inclusion

decreased the rate of this reaction. However, we did observe a

strong dependency on the rate of the Stille reaction on remote

functionality in the molecule. For example, this reaction failed

when the dioxolane ring was replaced with an OTBS or OPMB

group, or when the TMS group was replaced with CO₂Me.

Furthermore, an initial attempt to cleave the double bond in 17

Scheme 5. Synthesis of β-Hydroxyaldehyde 29

42

using OsO₄/NaIO₄gave only modest yields and was not

amenable to scale up. Instead, a scalable synthesis of the

aldehyde 18 was achieved in a yield of 83% by careful

ozonolysis under conditions in which Red 23 (0.1% Sudan III

solution) was added as an internal indicator, allowing for

selective cleavage of the oleﬁn in the presence of the alkyne.⁴³

Lithiation of the known TIPS oxazole 19⁴⁴with tert-BuLi,

followed by electrophilic capture of the resulting lithium

oxazole with the aldeyhde 18, then led to the expected

secondary alcohol 20 as an inconsequential mixture of

diastereomers (73%).⁴⁵The alcohol was then oxidized to the

corresponding ketone 21 employing the Dess−Martin period-

inane procedure, followed by TBAF induced desilylation of

both the TMS and TIPS protecting groups to give the terminal

alkyne 22.

The synthesis of β-hydroxyaldehyde 29 set the stage for the

ﬁnal ring closing reaction. Successful cyclization of this

aldehyde was expected to provide demethoxyviridiol (1d,

Scheme 6). The free hydroxyl, in principle, could chelate Lewis

Next, palladium-catalyzed ethoxycarbonylation³¹converted

the terminal alkyne 22 to the ynoate 23 in a yield of 78% and

set the stage for a bis-heteroannulation reaction (Scheme 4).

Thus, upon heating 23 in o-dichlorobenzene, thermal activation

Scheme 6. Unsuccessful Attempt at Cyclization

Scheme 4. Diels−Alder/retro-Diels−Alder Reaction

acids as reported by Reetz,⁴⁷resulting in a diastereoselective

aldol reaction. With the report by Reetz as a precedent, 29 was

submitted to various Mukaiyama aldol reaction conditions.

However, 29 turned out to be relatively stable to TiCl₄and

other Lewis acids (BF₃.OEt₂, TMSOTf, and lanthanide

triﬂates⁴⁸⁻⁵⁰) at temperatures between −78 and −30 °C.

Quenching the reaction at low temperatures essentially gave

back the starting material. In a separate experiment, when a

reaction conducted at −78 °C was allowed to warm to room

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Scheme 7. Attempts at Avoiding Dehydration of 29

Scheme 8. Synthesis and Hydrogenation of 35

temperature, TLC analysis showed dehydration to the

thermodynamically stable E-enal 30 (see insert in Scheme 6),

which occurred slowly at approx. −30 °C and rapidly at higher

temperatures. No desilylation was observed. Also, treatment of

29 with TBAF or HF·Py complex gave intractable mixtures.

Two conclusions were drawn at this point: (i) substrate 29 is

inert to Lewis acids and bases at low temperatures, and (ii)

higher temperatures favor dehydration, wherein the resultant E-

α,β-unsaturated aldehyde 30 is incapable of cyclization.⁵¹We

then unsuccessfully attempted to protect the alcohol function-

ality in 29 either as its Bn or PMB derivative as in 31 (Scheme

7). We also sought to stem the competitive elimination of the

hydroxyl group by oxidizing it to the ketone 32 prior to

treatment with TiCl₄. However, in this case equilibration

favored the strongly hydrogen bonded Z-keto−enol tautomer

33, which was also conﬁgurationally incapable of cyclization.

Examples from the literature show that for such dicarbonyl

systems, the keto−enol form is favored over the keto-aldehyde

tautomer.^52,53Nevertheless we still treated the product from

the Dess−Martin oxidation with TiCl₄, with the hope that any

32 in equilibrium with 33 would undergo cyclization. However,

no cyclization product was observed from those attempts.

Cyclization of 32 could have potentially given demethoxyviridin

(1b) directly.

hydroxyaldehyde were put on hold. Instead, the synthesis of

an analogous aldehyde lacking the β-hydroxyl group was

pursued. Two strategies for achieving this goal were developed.

In the ﬁrst method (Scheme 8), Horner−Wadsworth−

Emmons reaction of the aldehyde 27 with methyl diethyl

phosphonoacetate (34) extended the chain to the E-α,β-

unsaturated ester 35 in a yield of 74%.⁵⁴Next, catalytic

hydrogenation of the α,β-unsaturated ester 35 with 5% Pd/C

left the furan ring intact and gave the saturated ester 36 in a

yield of 79% for reactions run on a small scale. However, in

larger scale reactions (>50 mg), hydrogenation gave signiﬁcant

amounts of side products 37−39 in addition to 36. This

diﬃculty was circumvented by careful adjustment of the

reaction conditions (H₂, freshly distilled EtOAc, −10 °C, and

portion wise addition of “fresh”⁵⁵5% Pd/C over 1 h), which

provided a 3:1 mixture of 36 and 37 in a yield of (69%), with

formation of only small amounts (10%) of 38 and a trace of 39.

Hydrogenation under ionic conditions (PdCl₂, Et₃SiH/

BF₃·OEt₂)⁵⁶gave similar results. The loss of the ketal

protecting group in 35 was not without precedent. Palladium

on carbon is known to be acidic enough to induce the cleavage

of labile groups, and in our case, older batches of this catalyst

led to instant deketalization and subsequent hydrogenolytic

cleavage of the free ketone.^57,58Fortunately, the mixture could

be separated by column chromatography, with 38 and 39

eluting together from the ﬁrst fractions, followed by an

inseparable mixture of 36 and 37. Further puriﬁcation by

Since it was apparent that the desired cyclization reaction of

29 was being forestalled by competitive elimination of the

hydroxyl group, our attempts at cyclization of a β-

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successive recrystallization from hexanes separated 38 from 39,

while the ketone 37 was separated from 36 by enol-silylation

(Et₃N/TBSOTf) to 40 (Scheme 8).

achieved in TBAF without subsequent cyclization indicated that

electronic rather than steric factors were probably at play.

In order to explore this possibility, we developed a second

route to synthesizing 42 in a more eﬃcient way (Scheme 11).

The ketal 36 and enol silyl ether 40 were prone to hydrolysis

1

and, following H NMR characterization, were immediately

used in the next step. The originally intended monoreduction

of the ester moiety of 36 to the aldehyde 41 in one step using

DIBAL failed (vide infra). However, LiAlH₄reduction of 36 to

the corresponding alcohol, followed by Swern oxidation

furnished the aldehyde 41 in a yield of 83% (Scheme 9).

Scheme 11. Synthesis of the Enyne 46 via Sonogashira

Reaction

Scheme 9. Synthesis of Aldehyde 41

In this second method, PdCl₂(PPh₃)₂/CuI catalyzed Sonoga-

shira cross-coupling of the terminal alkyne 22 with the known

(Z)-ethyl 3-iodoacrylate (45) furnished the Z-enyne 46 in a

yield of 65%.⁵⁹

Diels−Alder/retro-Diels−Alder reaction of 46 then gave a

mixture of dienone 47 and the quinone methide oxidation

product 48 (E,Z mixtures, Scheme 12). Thermolysis of 46 was

With the aldehyde 41 in hand, we turned our attention to its

cyclization. The expectation was that Lewis acids would in

addition to initiating the ring closure, hydrolyze the dioxolane

ring to the ketone. However, when 41 was reacted with typical

Lewis acids (TiCl₄, BF₃·OEt₂) at room temperature, only

deketalization occurred to furnish the ketone 42 in a yield of

82% (Scheme 10). The ester 40 was also converted to the

Scheme 12. Diels-Alder Reaction of Enyne 46

Scheme 10. Attempted Cyclization of 42

a relatively slow reaction, requiring heating to 185 °C for 8 h.

Partial isomerization of the double bond occurs during this

1

transformation, as evidenced by the large H NMR coupling

constant observed for 47-E (J = 12.8 Hz), consistent with a

trans vicinal relationship. Separation of 47 from 48 was not

necessary, and the entire mixture was instead hydrogenated

under mild conditions (5% Pd/C, H₂, EtOAc, −10 °C) to the

saturated ester dienone 49 in a yield of 65% from 46. The

dienone 49 was very unstable and prone to aromatization with

subsequent oxidation to the corresponding p-quinol. Therefore,

aldehyde 42 in a similar fashion. Following puriﬁcation, 42 was

also submitted to various ring closing reaction conditions.

However, only starting material was recovered from these

reactions.

1

it was only characterized by H NMR and then converted to

The observed lack of reactivity of 42 toward cyclization was

surprising, in view of the fact that an analogous aldehyde only

lacking ring D, employed in model studies, underwent smooth

cyclization when reacted with two equivalents of TiCl₄at room

temperature.³¹The possibility that the bulky TBS was more

stable toward Lewis acids in this case prompted us to synthesize

the analogous phenolic TES derivative, but that too was inert to

the reaction conditions. Exposure of 42 to TBAF at 0 °C

released the TBS to aﬀord the unstable phenol 44 that also

failed to cyclize (Scheme 10). When allowed to warm to room

temperature in the presence of TBAF, 44 eventually degraded

into an intractable mixture. Treatment of 44 with Lewis acids

also gave a complex mixture. The fact that desilylation was

the more stable TBS-phenol derivative 50 in a yield of 81%. In

addition to reducing the number of steps required to arrive at

50, another advantage of this approach was that the dioxolane

ring is not lost during hydrogenation. This observation was not

surprising, since studies in our laboratory had by this time

shown that the ketal protecting group is relatively stable in

intermediates in which the B ring has not been aromatized, as

in 49. In intermediates of type 36 (Scheme 9), hydrolysis of the

ketal group is favored because of resonance stabilization of the

intermediate cation by the lone pair of electrons of the phenol

TBS ether.

Upon treatment of 50 with DIBAL-H at −78 °C, the ester

moiety was partially reduced to the corresponding aldehyde

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(Scheme 13). However, coordination between DIBAL-H and

the oxygen atom of the dioxolane ring also led to its cleavage

Scheme 14. Synthesis of the Common Alkyne 59

Scheme 13. Synthesis and Attempted Cyclization of 51

with subsequent reduction of the free ketone to the unstable

alcohol 51, in a yield of 60%. In contrast, exposure of 50 to

LiAlH₄, which lacks a free coordination site, permitted

chemoselective reduction of the ester to the alcohol without

causing deketalization. Swern oxidation of the alcohol then

furnished the aldehyde 41 in a yield of 78%.

Upon the basis of TLC analysis, both alcohol 51 and its

acetate derivative 51a appeared to cyclize upon treatment with

TiCl₄, but the anticipated products underwent rapid decom-

position. This observation led us to suspect that the C17

ketone might be inductively deactivating the furanonaphthol

ring toward the Mukaiyama aldol reaction. To test this

hypothesis, the C17 norketone 52 was synthesized by DIBAL

reduction of its ester precursor 38, earlier obtained as a side

product by the route outlined in Scheme 8. We were pleased to

observe the cyclization of 52 at room temperature under TiCl₄

catalysis, to give syn-53 (=3) and anti-53 in combined yield of

72% (Table 1). The syn relationship between the OH and Me

groups was conﬁrmed by X-ray analysis.⁶⁰

group were employed because of lower cost and ease of

operation.⁶²Thus, after palladium on carbon mediated

hydrogenolytic cleavage of the ketone moiety of 6 in near

quantitative yield, the resultant dihydroindenol 54 was

subjected to Tsuji−Trost allylation, Claisen rearrangement,

and triﬂation to give 55 in an overall yield of 70% from 54.

Next, dibromo oleﬁn 56 was obtained in an overall yield of 65%

upon ozonolysis of 55 followed by Corey−Fuchs alkenylation.

Lithiation of 56, followed by trapping of the lithium acetylide

with chlorotrimethylsilane, then furnished 91% of the TMS

alkyne 57, that was employed in a robust Stille cross-coupling

with tributyl(vinyl)tin to furnish the vinyl arene 58 in 90%

yield. After chemoselective ozonolytic cleavage of the oleﬁn, the

resultant aldehyde was trapped with lithiated oxazole 19 to

aﬀord an alcohol that was oxidized to the corresponding ketone

under Swern conditions. Removal of both silyl protecting

groups with K₂CO₃in MeOH (which was much cleaner and

higher yielding than TBAF) then produced the terminal alkyne

59, a common intermediate for both routes.

Table 1. Cyclization Studies of 42 and its Derivatives

Once the terminal alkyne 59 was in hand, palladium

catalyzed carboethoxylation gave the ynoate 60 in a yield of

88% (Scheme 15). Subjecting 60 to the Diels−Alder/retro-

Diels−Alder/tautomerization sequence furnished the phenol

TBS derivative 61 in a combined yield of 65% for two steps.

The ester moiety of 61 was then converted in two steps to the

corresponding aldehyde that was subsequently extended to the

α,β-unsaturated ester 62 using standard Horner−Wadsworth−

entry

X

conditions

result

a

1

2

3

4

5

41

42

51

51a

52

TiCl₄, −78 °C or rt

TiCl₄, −78 °C

TiCl₄, −78 °C or rt

TiCl₄, rt

No reaction

Scheme 15. Synthesis of Aldehyde 52 via Carboethoxylation

Decomposition

72% of 53

a

Only hydrolysis of the ketal protecting group is observed.

The C17 norketone 52 was then synthesized in more

eﬃcient fashion beginning with the known 2,3-dihydro-1H-

inden-4-ol (54, Scheme 14).⁶¹All steps leading from 54 to 52

were analogous to those employed in the conversion of 6 to 42

(cf. Schemes 2−13). However, alternative reagents whose

utility had been precluded by the presence of the labile ketal

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Emmons reaction conditions. Finally, catalytic hydrogenation

of the double bond in 62 with H₂/Pd−C, followed by DIBAL

reduction of the ester, gave the aldehyde 52 in a yield of 67%.

Finally, we also developed an improved route to the target

aldehyde 52 employing a Sonogashira reaction (Scheme 16).

53 with the desired syn-53 dominating in a ratio of 5:1, due to a

more a favorable Burgi−Dunitz trajectory angle (Scheme 17,

best seen with models). Colorless needle crystals of syn-53 were

obtained after recrystallization from methylene chloride. A side-

1

by-side comparison of the H NMR spectra of 53 to that of a

closely related alcohol previously synthesized in our group,³¹

and to demethoxyviridin itself, showed a strong correlation

between diagnostic protons. In particular the chemical shifts

Scheme 16. Synthesis of 52 via Sonogashira Reaction

1

observed for H₁(4.12 ppm) and H₁₁(8.14 ppm) in the H

NMR spectra of syn-53 is nearly identical to those observed in

the spectra of advanced viridin intermediates.³¹In addition to

the X-ray analysis,⁶⁰NOE studies conﬁrmed the syn relation-

ship between the OH and the methyl group.

CONCLUSIONS

■

We have synthesized the aldehyde 42 and its C17-norketone

analogue 52 through two separate routes. The shorter of the

two routes involved 16 steps and is preferred. The C17 ketone

had a strong electronic eﬀect on the cyclization reaction leading

to ring A, as exempliﬁed by the fact that only 52 underwent

cyclization to 53 under mild conditions. Other substrates in

Table 1 did not aﬀord the cyclized product. Functionalization

of rings A and D via benzylic oxidation of C3 and C17 is

currently under investigation. We are also screening for

conditions that would allow for cyclization of β-hydroxyalde-

hydes of type 29 and subsequent enantioselective synthesis of

viridin.

Thus, the terminal alkyne 59 underwent clean cross-coupling

with the Z-iodoacrylate 45, aﬀording enyne 63 in a yield of

78%. Thermolyis of 63 at 185 °C then induced the Diels−

Alder/retro-Diels−Alder reaction to yield a mixture of 64 and

65. As before, this mixture was hydrogenated over palladium on

carbon and then converted to the target aldehyde 52 by a two-

step sequence involving silylation with TBSOTf followed by

DIBAL reduction (55% yield).

EXPERIMENTAL SECTION

■

The general experimental methods are provided in the

Supporting Information.

With two secure synthetic routes to the furanoaldehyde 52

established, we set out to optimize the conditions for the ring

closing reaction forming ring A. Cyclization at low temperature

was desirable because it would lay a foundation for the

cyclization of aldehydes bearing the sensitive β-hydroxy

functionality. Although several attempts were made, 52 did

not undergo cyclization at low temperatures with TiCl₄.

Starting material was recovered at −78 °C and at 0 °C only

slow decomposition occurred. It was eventually determined

that stirring a rigorously degassed CH₂Cl₂solution of aldehyde

52 with 4 equivalents of TiCl₄at room temperature were the

best conditions for this transformation. The reaction proceeded

largely under kinetic control, aﬀording 72% of syn-53 and anti-

4-((E)-Pent-3-en-yloxy)-2,3-dihydroinden-1-one (9).

To a solution of hydroxyindanone 6 (11 g, 74.24 mmol) and

allyl carbonate 10 (11.77 g, 81.67 mmol) in CH₂Cl₂(150 mL)

was added Pd(PPh₃)₄(857.89 mg, 0.74 mmol). The mixture

was then reﬂuxed for 3 h, cooled to room temperature and the

solvent removed under reduced pressure. Puriﬁcation by

column chromatography (SiO₂, 30:1 hexanes/EtOAc) gave

15.1 g (94%) of the desired product as a yellow solid. Mp:

1

42.0−44.0 °C. R_f= 0.75 (3:1 hexanes/EtOAc). H NMR (500

MHz, CDCl₃) δ 7.33 (1H, d, J = 7.0 Hz), 7.29 (1H, d, J = 7.0

Hz), 7.05 (1H, d, J = 8.0), 5.77−5.70 (1H, m), 5.58−5.52 (1H,

m), 5.50−4.80 (1H, m), 3.06−3.02 (2H, m), 2.69−2.65 (2H,

m), 1.69 (3H, d, J = 6.3 Hz), 1.45 (3H, d, J = 6.3 Hz). ¹³C

Scheme 17. Kinetic Control via the Most Favorable Burgi−Dunitz Trajectory Angle

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NMR (75 MHz, CDCl₃) δ 207.5, 155.8, 145.1, 138.8, 132.0,

128.7, 127.8, 118.2, 115.4, 75.0, 36.4, 22.9, 21.9, 17.9. FT-IR

(CDCl₃cm⁻¹) 3243.9, 2928.6, 1680.8, 1427.8, 1283.6. HRMS

(EI) calcd for C₁₄H₁₆O₂216.1150, found 216.1147.

630. HRMS (EI) calcd for C₁₃H₁₁O₅F₃S 336.0279, found

336.0275.

5-(4,4-Dibromobut-3-en-2-yl)-2,3−1-oxo-1H-inden-4-

yl Triﬂuoromethanesulfonate (14). To a solution of the

aldehyde 13 (3.77 g, 11.21 mmol) in CH₂Cl₂(100 mL) at 0 °C

was added, carbon tetrabromide (7.44 g, 22.42 mmol),

triphenylphosphine (5.88 g, 22.42 mmol), and zinc dust

(1.47 g, 22.42 mmol). The mixture was warmed to room

temperature and stirred for 30 min. The mixture was then

ﬁltered through a thin ﬁlm of silica gel, the cake washed twice

with CH₂Cl₂, silica gel (30 g) was added to the ﬁltrate and the

solvent was removed under reduced pressure. The residue was

puriﬁed by dry pack column chromatography (SiO₂, 20:1

hexanes/EtOAc) to give 4.98 g (90%) of the dibromooleﬁn 14

as a yellow solid. Recrystallization from hexanes gave pale

yellow needle crystals. Mp: 74−76 °C. R_f= 0.70 (5:1 hexanes/

2,3-Dihydro-4-hydroxy-5-((E)-pent-3-en-2-yl)inden-1-

one (11). A solution of 9 (10 g, 46.24 mmol) in Et₂NPh (50

mL) was heated at 180 °C for 6 h. The dark brown mixture was

then cooled to room temperature, diluted with 50 mL of ice

water and then stirred at room temperature for several minutes.

The two layers were separated and the aqueous layer was

extracted with EtOAc. The combined organic extracts were

washed with dil. HCl, rinsed with brine, dried over MgSO₄and

concentrated under reduced pressure. Puriﬁcation by column

chromatography (SiO₂, 20:1 to 5:1 hexanes/EtOAc) gave 9.1 g

(91%) of 11 as a brown solid. Recrystallization from EtOAc

gave white round crystals; Mp: 112−114 °C. R_f= 0.35 (2:1

hexanes/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 7.35 (1H, d, J

= 7.5 Hz), 7.18 (1H, d, J = 8.0 Hz), 5.78−5.98 (2H, m), 5.69

(1H, s), 3.05 (2H, t, J = 6.0 Hz), 2.71 (2H, t, J = 5.7 Hz), 1.74

(3H, d, J = 7.2 Hz), 1.41 (3H, d, J = 7.2 Hz). ¹³C NMR (75

MHz, CDCl₃) δ 151.7, 142.7, 134.4, 128.0, 126.1, 116.1, 37.8,

37.7, 36.7, 22.4, 19.5, 18.1. FT-IR (CDCl₃cm⁻¹) 3481, 2974,

2922, 1712, 1602.2, 1482, 1440, 1202, 969, 770. HRMS (EI)

calcd for C₁₄H₁₆O₂216.1150, found 216.1147.

1

EtOAc). H NMR (300 MHz, CDCl₃) δ 7.77 (1H, d, J = 7.8

Hz), 7.42 (1H, d, J = 8.1 Hz), 6.59 (1H, d, J = 8.7 Hz), 4.20

(1H, q, J = 7.2 Hz), 3.34−3.18 (2H, m), 2.78−2.71 (2H, m),

1.44 (3H, d, J = 8.7 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 204.4,

148.1, 144.1, 140.3, 128.8, 124.5, 120.9, 116.7, 91.9, 37.5, 36.3,

23.7, 21.3. FT-IR (CDCl₃, cm⁻¹) 1723, 1408, 1216, 1133, 817.

HRMS (EI) calcd for C₁₄H₁₁Br₂F₃O₄S 489.8697, found

489.8692.

2,3-Dihydro-1-oxo-5-((E)-pent-3-en-2-yl)-1H-inden-4-

yl Triﬂuoromethanesulfonate (12). To a solution of 11 (9

g, 41.61 mmol) in CH₂Cl₂(50 mL) at 0 °C was added pyridine

(6.70 mL, 83.22 mmol) followed by Tf₂O (8.4 mL, 49.93

mmol) dropwise over 20 min and the mixture was then stirred

for an additional 10 min. The resulting purple reaction was

diluted with Et₂O and then quenched with dil. HCl. The

aqueous layer was extracted twice with CH₂Cl₂, the combined

organic extracts washed with NaHCO₃, rinsed with brine, dried

over MgSO₄and then concentrated under reduced pressure.

Puriﬁcation by column chromatography (SiO₂, 20:1 hexanes/

EtOAc) gave 12.76 g (88%) of the triﬂate 12 as a yellow oil. R_f

5-(4,4-Dibromobut-3-en-2-yl)-2′,3′-dihydrospiro(1,3-

dioxolane-1-oxo-1H-inden-4-yl) Triﬂuoromethanesulfo-

nate (15). A solution of 14 (3.5 g, 7.11 mmol), ethylene glycol

(1.17 mL, 21.33 mmol) and pyridinium p-tosylate (893.3 mg,

3.56 mmol) in benzene (50 mL) was placed in 100 mL round-

bottom ﬂask. A Dean−Stark trap equipped with a condenser

was ﬁtted and the reaction mixture reﬂuxed for 24 h. The

reaction mixture was cooled and then washed vigorously with

saturated NaHCO₃, rinsed with brine, dried over MgSO₄and

concentrated under reduced pressure to give 4.8 g of brown

crude material. Trituration from hexanes gave 3.62 g (95%) of

the pure desired ketal as a pale yellow oil. R_f= 0.75 (5:1

hexanes/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 7.37 (1H, d, J

= 7.8 Hz), 7.27 (1H, d, J = 8.1 Hz), 6.57 (1H, d, J = 8.7 Hz),

4.21−4.10 (5H, m), 3.11−3.06 (2H, m), 2.36−2.30 (2H, m),

1.40 (3H, d, J = 6.9 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 144.7,

142.4, 141.2, 138.2, 137.5, 128.2, 123.8, 120.9, 116.7, 90.8, 65.6,

37.2, 37.1, 26.6, 21.0. FT-IR (CDCl₃, cm⁻¹) 2966, 2883, 1408,

1320, 1138, 1014, 908, 820. HRMS (EI) calcd for

C₁₆H₁₅Br₂F₃O₅S 533.8959, found 533.8959.

1

= 0.82 (3:1 hexanes/EtOAc). H NMR (300 MHz, CDCl₃) δ

7.32 (1H, d, J = 7.8 Hz), 7.25 (1H, d, J = 8.1 Hz), 5.59−5.5.7

(2H, m), 3.86−3.81 (1H, m), 3.08−3.03 (2H, m), 2.34−2.30

(2H, m), 1.69−1.68 (2H, m), 1.35 (2H, d, J = 7.2 Hz), ¹³C

NMR (75 MHz,CDCl₃) δ 204.7, 147.8, 147.2, 143.6, 138.5,

133.3, 129.3, 126.1, 124.2, 120.9, 116.7, 36.3, 35.6, 23.6, 21.2,

18.1. FT-IR (CDCl₃, cm⁻¹) 3274, 2953, 1686, 1695, 1435,

1286, 1200, 1066, 970. HRMS (EI) calcd for C₁₅H₁₅O₄F₃S

348.0643, found 348.0636.

2,3-Dihydro-1-oxo-5-(1-formylethyl)-1H-inden-4-yl

Triﬂuoromethanesulfonate (13). To stirred solution of the

oleﬁn 12 (4.24 g, 12.17 mmol) in CH₂Cl₂(120 mL) was

bubbled ozone at −78 °C until a pale blue solution resulted and

persisted (approximately 20 min). Excess ozone was removed

by a nitrogen stream, triphenylphosphine (7.98 g, 30.43 mmol)

was added, and the mixture warmed to rt and stirred overnight.

Silica gel was added to the mixture and the solvent removed

under reduced pressure. Dry pack silica gel column

chromatography (10:1 to 3:1 hexanes/EtOAc) gave 3.78 g

(93%) of the aldehyde 13 as an oﬀ white solid. R_f= 0.55 (3:1

hexanes/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 9.72 (1H, s),

7.83 (1H, d, J = 8.1 Hz), 7.31 (1H, d, J = 8.1 Hz), 4.18 (1H, q, J

= 7.2 Hz), 3.30 (2H, t, J = 6.3 Hz), 2.83 (2H, t, J = 6.5 Hz),

1.36 (3H, d, J = 6.9 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 204.3,

198.4, 148.0, 138.9, 129.9, 124.5, 120.8, 116.6, 46.5, 36.2, 23.6,

15.1. FT-IR (CDCl₃, cm⁻¹) 1725, 1615, 1411, 1215, 1051, 815,

5′-[4-(Trimethylsilyl)but-3-yn-2-yl]-2′,3′-dihydrospiro-

[1,3-dioxolane-2,1′-indene]-4′-yl Triﬂuoromethanesul-

fonate (16). To a solution of compound 15 (2 g, 3.73

mmol) in THF (60 mL) at −78 °C was added n-BuLi (2.50 M

solution in hexanes, 3.28 mL, 8.21 mmol) dropwise over 30

min under a nitrogen atmosphere. After 30 min, TMSCl (1.05

mL, 8.21 mmol) was added and the mixture stirred for an

additional 30 min and then quenched with H₂O. The resulting

white suspension was warmed to room temperature, extracted

with ethyl acetate, washed with brine, dried over MgSO₄and

concentrated in vacuo. Puriﬁcation by column chromatography

(SiO₂, 10:1 hexanes/EtOAc) gave 1.48 g (88%) of 16 as a clear

1

oil. R_f= 0.55 (5:1 hexanes/EtOAc). H NMR (300 MHz,

CDCl₃) δ 7.65 (1H, d, J = 7.8 Hz), 7.38 (1H, d, J = 9.3 Hz),

4.22−4.06 (5H, m), 3.06 (2H, t, J = 7.5 Hz), 2.34 (2H, t, J =

7.2 Hz), 1.45 (3H, d, J = 6.9 Hz), 0.16 (9H, s). ¹³C NMR (75

MHz, CDCl₃) δ 144.8, 142.1, 137.9, 137.0, 129.4, 123.8, 116.7,

108.0, 86.8, 65.6, 37.3, 27.2, 26.5, 23.8, 0.2. FT-IR (CDCl₃,

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cm⁻¹) 2960, 2174, 1408, 1216, 1144, 1017, 911, 845. HRMS

(EI) calcd for C₁₉H₂₃F₃O₅SSi 448.0988, found 448.0994.

5-(4-(Trimethylsilyl)but-3-yn-2-yl-2′,3′-dihydrospiro-

[1,3-dioxolane-2,1′-inden]-4′-yl)-4-vinylinden-1-one

(17). A solution of the triﬂate 16 (2.5 g, 5.57 mmol),

PdCl₂(MeCN)₂(72.38 mg, 0.279 mmol) and DPEPhos

(299.98 mg, 0.557 mmol) in DMF (50 mL) was sparged

with nitrogen for 10 min. Tributyl(vinyl)tin (1.95 mL, 6.68

mmol) was added and the mixture heated at 100 °C for 54 h,

cooled to room temperature, diluted with 50 mL of water,

extracted with ethyl acetate, washed with brine and ﬁnally dried

over MgSO₄. Puriﬁcation by column chromatography (SiO₂,

30:1 to 10:1 hexanes/EtOAc) gave 1.68 g (91%) of 17 as a pale

133.0, 128.3, 128.0, 124.3, 123.7, 116.9, 110.5, 85.7, 65.9, 65.3,

37.1, 29.9, 27.9, 24.9, 18.5, 11.1, 0.3. FT-IR (CDCl₃, cm⁻¹)

3425, 2947, 2868, 2167, 1465, 1319, 1250, 1040, 914, 843, 734.

HRMS (ESI) calcd for C₃₁H₄₈NO₄Si₂[M + H]⁺554.3122,

found 554.3126.

4-((Triisopropyl)oxazol-5-yl)(hydroxy)methyl)-

trimethylsilyl)but-3-yn-2-yl-2′,3′-dihydrospiro[1,3-diox-

olane-2,1′-inden]-4′-yl)-4-methanone (21). The alcohol

20 (700 mg, 1.26 mmol) in CH₂Cl₂(50 mL) was treated with

Dess−Martin periodinane (806 mg, 1.90 mmol) at 0 °C and

stirred for 4 h. The mixture was quenched with 20 mL of

NaHCO₃−Na₂SO₃(1:1) and then extracted with CH₂Cl₂. The

combined organic extracts were washed with brine, dried over

MgSO₄and concentrated under reduced pressure. Puriﬁcation

by column chromatography (SiO₂, 4:1 hexanes/EtOAc) gave

640 mg (92%) of 21 as a pale yellow waxy solid. R_f= 0.60 (3:1

hexanes/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 7.6 (1H, d, J

= 7.8 Hz), 7.49 (1H, s), 7.48 (1H, d, J = 7.8 Hz), 4.21−4.18

(2H, m), 4.11−4.06 (2H, m), 3.78 (1H, q, J = 6.9 Hz), 2.76−

2.67 (2H, m), 2.24 (2H, t, J = 6.9 Hz), 1.53−1.39 (3H, m),

1.42 (3H, d, J = 6.9 Hz), 1.13 (18H, d, J = 7.5 Hz), 0.13 (9H,

s). ¹³C NMR (125 MHz, CDCl₃) δ 175.0, 151.9, 142.7, 141.4,

136.9, 134.2, 127.3, 125.5, 116.6, 109.1, 86.5, 65.6, 65.5, 37.3,

30.2, 27.4, 25.1, 18.5, 11.1, 0.3. FT-IR (CDCl₃, cm⁻¹) δ 2947,

2869, 1665, 1548, 1249, 1114, 879, 842. HRMS (ESI) calcd for

C₃₁H₄₅NO₄Si₂[M + H]⁺552.2965, found 552.2966.

1

yellow oil. R_f= 0.45 (5:1 hexanes/EtOAc). H NMR (300

MHz, CDCl₃) δ 7.52 (1H, d, J = 7.8 Hz), 7.27 (1H, d, J = 9.6

Hz), 6.79 (1H, dd, J = 11.7, 17.7 Hz), 5.54 (1H, d, J = 11.7

Hz), 5.39 (1H, d, J = 17.7 Hz), 4.22−4.03 (5H, m), 2.96−2.91

(2H, m), 2.27 (2H, t, J = 6.9 Hz), 1.40 (3H, d, J = 7.2 Hz), 0.15

(9H, s). ¹³C NMR (125 MHz, CDCl₃) δ 142.4, 142.1, 140.9,

133.1, 126.6, 122.3, 120.5, 110.3, 85.8, 65.5, 65.4, 37.4, 29.7,

29.0, 27.1, 23.9, 17.8, 13.8, 0.4. FT-IR (CDCl₃cm⁻¹) 2960,

2174, 1409, 1317, 1216, 1144, 1017, 911, 844. HRMS (EI)

calcd for C₂₀H₂₆O₂Si 326.1702, found 326.1711.

5′-[4-(Trimethylsilyl)but-3-yn-2-yl]-2′,3′-dihydrospiro-

[1,3-dioxolane-2,1′-indene]-4′-carbaldehyde (18). The

vinyl arene 17 (1.7 g, 5.21 mmol) in CH₂Cl₂(100 mL) was

cooled to −78 °C and then exposed to a stream of ozone. Red

23 (0.1% solution of Sudan III in MeOH, 2 mL) was used as an

internal indicator. Triphenylphosphine (3.4 g, 13.03 mmol) was

added when the pink color had faded. The resulting mixture

was allowed to warm to rt and stirred for an additional 6 h. The

solvent was removed under reduced pressure and the residue

puriﬁed by column chromatography (SiO₂, hexanes/EtOAc

100:1 to 50:1 to 20:1) to give 1.5 g (87%) of the aldehyde 18 as

a white solid. Mp: 93−95 °C. R_f= 0.50 (3:1 hexanes/EtOAc).

¹H NMR (300 MHz, CDCl₃) δ 10.57 (1H, s), 7.71 (1H, d, J =

8.1 Hz), 7.56 (1H, d, J = 8.1 Hz), 4.74, (1H, q, J = 6.9 Hz),

4.22−4.11 (2H, m), 4.11−4.07 (2H, m), 3.29 (2H, t, J = 6.9

Hz), 2.34 (2H, t, J = 7.2 Hz), 1.50 (3H, d, J = 6.9 Hz), 0.16

(9H, s). ¹³C NMR (125 MHz, CDCl₃) δ 191.5, 147.6, 142.4,

127.0, 128.8, 128.6, 128.3, 116.3, 109.4, 87.1, 65.5, 37.2, 29.2,

28.4, 25.1, −0.3. FT-IR (CDCl₃cm⁻¹) 2928, 2238, 1690, 843.

HRMS (EI) calcd for C₁₉H₂₄O₃Si 328.1495, found 328.1492.

5′-[4-(Trimethylsilyl)but-3-yn-2-yl]-2′,3′-dihydrospiro-

[1,3-dioxolane-2,1′-indene]-4′-yl({2-[tris(propan-2-yl)-

silyl]-1,3-oxazol-5-yl})methanol (20). tert-BuLi (1.6 M in

pentane, 5.32 mL, 8.52 mmol) was added to TIPS oxazole 19

(1.92 g, 8.52 mmol) at −78 °C in THF (50 mL). In a separate

ﬂask, the aldehyde 18 (1.4 g, 4.26 mmol) was dissolved in THF

(50 mL) and cooled to −78 °C. After 10 min, the anion of the

TIPS oxazole was added via cannula to the aldehyde. The

mixture was stirred for an additional 20 min, quenched with

saturated aqueous NaHCO₃, diluted with water, extracted with

EtOAc and washed with brine. The organic layer was dried over

MgSO₄and concentrated under reduced pressure. Puriﬁcation

by column chromatography (SiO₂, 5:1 hexanes/EtOAc) gave

1.72 g (73%) of 20 as a white waxy solid. Major diastereomer:

(5-(But-3-yn-2-yl)-2,3-dihydrospiro[1,3-dioxolane-

2,1′-inden]-4′-yl)(oxazol-5-yl)methanone (22). The start-

ing material 21 (520 mg, 0.94 mmol) in THF (40 mL) was

treated with TBAF (1 M in THF, 0.47 mL, 0.47 mmol; use of

more than 0.5 equivalents of TBAF leads to extensive

decomposition) at 0 °C and stirred for 30 min. The mixture

was then quenched with water. The two layers were separated

and the aqueous layer extracted with Et₂O, the combined

organic extracts washed with brine, dried over MgSO₄and

concentrated under reduced pressure. Puriﬁcation by column

chromatography (SiO₂, 3:1 hexanes/EtOAc) gave 245 mg

(81%) of 22 as a yellow waxy oil. R_f= 0.25 (1:1 hexanes/

1

EtOAc). H NMR (300 MHz, CDCl₃) δ 8.10 (1H, s), 7.60

(1H, d, J = 8.1 Hz), 7.59 (1H, s), 7.49 (1H, d, J = 7.2 Hz),

4.20−4.05 (4H, m), 3.75 (1H, q, J = 6.9 Hz), 2.83−2.68 (2H,

m), 2.26 (2H, t, J = 6.9 Hz), 2.16 (1H, s), 1.44 (3H, t, J = 7.2

Hz). ¹³C NMR (125 MHz, CDCl₃) δ 184.4, 154.6, 142.5,

141.9, 141.5, 136.4, 127.3, 125.9, 116.5, 86.6, 70.6, 65.6, 37.3,

29.1, 27.5, 24.7, 24.1, 18.5, 11.2. FT-IR (CDCl₃, cm⁻¹) 2359,

1665, 1560, 1317, 1127, 1041, 638. HRMS (ESI) calcd for

C₁₉H₁₈NO₄[M + H]⁺324.1236, found 324.1230.

Ethyl 4-{4′-[(1,3-Oxazol-5-yl)carbonyl]-2′,3′-

dihydrospiro[1,3-dioxolane-2,1′-indene]-5′-yl}pent-2-

ynoate (23). The terminal alkyne 22 (240 mg, 0.74 mmol) in

DMF (30 mL) was treated with Pd(OAc)₂(PPh₃)₂(55.6 mg,

0.074 mmol) at rt. The ﬂask was evacuated and backﬁlled with

CO/O₂(1:1) in a balloon. 2.17 mL of EtOH (approx 50

mmol) was added via syringe and the mixture stirred at rt for

65 h and then quenched with sat. aq. NH₄Cl. The cloudy

suspension was ﬁltered through short pad of Celite. The two

layers were separated and the aqueous layer extracted with

EtOAc. The combined organic extracts were washed twice with

water and then rinsed with brine. After drying over MgSO₄the

extracts were concentrated under reduced pressure. Puriﬁcation

by column chromatography (SiO₂, 3:1 hexanes/EtOAc) gave

228 mg (78%) of 23 as a yellow sticky oil. R_f= 0.20 (1:1

hexanes/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 8.10 (1H, s),

1

R_f= 0.25 (3:1 hexanes/EtOAc). H NMR (300 MHz, CDCl₃)

δ 7.56 (1H, d, J = 8.1 Hz), 7.36, (1H, d, J = 8.1 Hz), 6.91 (1H,

s), 6.37 (1H, brs), 4.21−4.04 (5H, m), 3.06−2.96 (1H, m),

2.82−2.74 (1H, m), 2.27−2.18 (2H, m), 1.43 (3H, d, J = 7.2

Hz), 1.39−1.23 (3H, m), 1.08 (18H, d, J = 7.2 Hz), 0.12 (9H,

s). ¹³C NMR (125 MHz, CDCl₃) δ 154.2, 143.6, 143.1, 141.4,

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7.62 (1H, s), 7.56 (1H, d, J = 8.1 Hz), 7.51 (1H, d, J = 8.1 Hz),

4.22−4.06 (6H, m), 3.91 (1H, q, J = 6.9 Hz), 2.77−2.67 (2H,

m), 2.26 (2H, t, J = 7.2 Hz), 1.50 (3H, d, J = 6.9 Hz), 1.27 (3H,

t, J = 7.2 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 184.1, 154.7,

153.7, 150.1, 142.4, 141.7, 140.6, 136.5, 133.5, 127.4, 126.2,

116.3, 89.9, 74.9, 65.6, 62.2, 37.3, 29.2, 27.6, 23.7, 14.2. FT-IR

(CDCl₃, cm⁻¹) 2980, 2237, 1710, 1666, 1561, 1469, 1253,

1127, 1037. HRMS (ESI) calcd for C₂₂H₂₂NO₆[M + H]⁺

396.1447, found 396.1442.

and the solvent evaporated under reduced pressure to aﬀord

120 mg of the crude alcohol that was used without further

puriﬁcation. The crude alcohol (120 mg, 0.27 mmol) in 30 mL

of CH₂Cl₂was treated with Dess−Martin periodinane (127 mg,

0.3 mmol) at 0 °C and stirred for 2 h. The mixture was then

quenched with 10 mL of NaHCO₃−Na₂SO₃(1:1), diluted with

more CH₂Cl₂and stirred vigorously at room temperature for

10 min. The two layers were separated and the aqueous layer

extracted with CH₂Cl₂. The combined organic extracts were

dried over MgSO₄and concentrated under reduced pressure.

Puriﬁcation by column chromatography (SiO₂, 4:1 hexanes/

EtOAc) gave 103 mg (87%) of the aldehyde 27 as a pale yellow

Ethyl-4,9-drospiro[1,3-dioxolane-2,1′-inden]-4′-yl-4-

methyl-9-oxonaphtho[2,3-b]furan-3-carboxylate (25). A

solution of the alkyne oxazole 23 (200 mg, 0.51 mmol) in 10

mL of dry 1,2-dichlorobenzene was stirred for 4 h at 170 °C

under a nitrogen atmosphere. After cooling to rt, the solution

was passed through a short plug of silica gel using hexanes to

elute 1,2-dichlorobenzene. The product was then eluted from

the silica gel with hexanes/ethyl acetate (5:1) to give 148 mg

(80%) of the dienone 25 as a pale yellow oil. R_f= 0.35 (1:1

hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.25 (1H, s),

7.59 (1H, d, J = 8.0 Hz), 7.48 (1H, d, J = 8.0 Hz), 4.56 (1H, q, J

= 7.0 Hz), 4.42 (2H, q, J = 7.2 Hz), 4.21−4.08 (4H, m), 3.65−

3.42 (2H, m), 2.35 (2H, t, J = 7.5 Hz), 1.62 (3H, d, J = 7.0 Hz),

1.41 (3H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 174.9,

162.4, 152.5, 149.7, 146.7, 142.1, 138.8, 128.5, 127.5, 118.8,

116.6, 65.5, 65.4, 61.2, 37.2, 34.6, 30.5, 25.5, 14.5. FT-IR

(CDCl₃, cm⁻¹) 2977, 1722, 1668, 1302, 1125, 1035. HRMS

(ESI) calcd for C₂₁H₂₁O₆[M + H]⁺369.1338, found 369.1335.

Ethyl 16′-[(tert-butyldimethylsilyl)oxy]-10′- methyl-

14′-oxaspiro[1,3-dioxolane-2,5′- tetracyclo-

[7.7.0.0^2,6.0^11,15]hexadecane]- 1′,6′,8′,10′,12′,15′-hex-

aene-12′-carboxylate (26). To a solution of 25 (130 mg,

0.35 mmol) in THF (20 mL) at ice bath temperature was

added Et₃N (146 μL, 1.05 mmol) followed by TBSOTf (160

μL, 0.7 mmol). The mixture was gradually warmed to rt and

stirred for an additional 30 min and then quenched with sat. aq.

NaHCO₃. The two layers were separated and aqueous layer was

extracted twice with Et₂O. The combined organic extracts were

washed with brine, dried over MgSO₄, and concentrated under

reduced pressure. Puriﬁcation by column chromatography

(SiO₂, 20:1 hexanes/EtOAc) gave 135 mg (80%) of 26 as a

1

solid. R_f= 0.55 (3:1 hexanes/EtOAc). H NMR (500 MHz,

CDCl₃) δ 10.17 (1H, s), 8.32 (1H, s), 8.15 (1H, d, J = 9.0 Hz),

7.44 (1H, d, J = 9.0 Hz), 4.26−4.24 (2H, m), 4.16−4.11 (2H,

m), 3.76 (2H, t, J = 7.5 Hz), 3.20 (3H, s), 2,27 (2H, t, J = 6.9

Hz), 0.99 (9H, s), 0.30 (6H, s). ¹³C NMR (125 MHz, CDCl₃)

δ 183.9, 159.8, 144.8, 140.0, 138.4, 133.4, 126.2, 125.0, 123.7,

122.2, 120.0, 117.7, 65.6, 37.1, 31.7, 26.5, 19.4, 18.0, −2.5. FT-

IR (CDCl₃cm⁻¹) 1691, 1158, 832. HRMS (ESI) calcd for

C₂₅H₃₁O₅Si [M + H]⁺439.1941, found 439.1932.

1-{16′-[(tert-butyldimethylsilyl)oxy]-10′-methyl-14′-

oxaspiro[1,3-dioxolane-2,5′-tetracyclo[7.7.0.0^2,6.0^11,15]-

hexadecane]- 1′,6′,8′,10′,12′,15′-hexaen-12′-yl}but-3-

en-1-ol (28). A solution of the aldehyde 27 (50 mg, 0 11

mmol) in 5 mL of THF at ice bath temperature was treated

with allylmagnesium bromide (1.0 M in Et₂O, 0.57 mL, 0.57

mmol). The mixture was warmed to room temperature and

stirred for 2 h, quenched with NaHCO₃and extracted with

Et₂O. The combined organic layers were washed with brine,

dried over MgSO₄, and concentrated in vacuo. Puriﬁcation by

column chromatography (SiO₂, 3:1 hexanes/EtAOc) gave 51

mg (96%) of the product 28 as a pale yellow oil. R_f= 0.50 (3:1

hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.02 (1H, d, J

= 9 Hz), 7.68 (1H, s), 7.40 (1H, d, J = 9 Hz), 5.97−5.94 (1H,

m), 5.30−5.22 (3H, m), 4.28−4.23 (2H, m), 4.17−4.13 (2H,

m), 3.67, (2H, t, J = 7 Hz), 2.91 (3H, s), 2.86−2.83 (1H, m),

2.66−2.62 (1H, m), 2.38 (2H, dt, J = 7.5 Hz, J = 6 Hz), 2.12

(1H, s), 1.06 (9H, s), 0.96 (9H, s), 0.35 (6H, s). ¹³C NMR

(125 MHz, CDCl₃) δ 143.6, 140.0, 137.2, 134.5, 132.6, 127.2,

124.6, 124.3, 119.1, 66.7, 65.5, 42.3, 37.1, 31.8, 26.6, 19.4, 16.2,

−2.4. FT-IR (CDCl₃, cm⁻¹) 3446, 2929, 1623, 1462, 1372,

1315, 1130, 1039, 833, 733. HRMS (EI) calcd for C₂₈H₃₆O₅Si

480.2332, found 480.2341.

1

yellow oil. R_f= 0.75 (3:1 hexanes/EtOAc). H NMR (300

MHz, CDCl₃). δ 8.31 (1H, s), 8.11 (1H, d, J = 9.0 Hz), 7.14

(1H, d, J = 9.0 Hz), 4.40 (2H, q, J = 6.9 Hz), 4.26−4.24 (2H,

m), 4.16−4.11 (2H, m), 3.67 (2H, t, J = 6.6 Hz), 3.10 (3H, s),

2.40 (2H, t, J = 6.6 Hz), 1.42 (3H, t, J = 7.2 Hz), 0.97 (9H, s),

0.35 (6H, s). ¹³C NMR (75 MHz, CDCl₃) δ 163.7, 153.6,

144.2, 139.9, 137.9, 135.2, 133.1, 124.9, 123.2, 121.4, 119.6,

117.8, 116.2, 65.6, 61.1, 37.2, 31.7, 26.5, 25.9, 19.4, 16.8, 14.6,

−2.3. FT-IR (CDCl₃, cm⁻¹) 2930, 1728, 1465, 1373, 1253,

1142, 832. HRMS (ESI) calcd for C₂₇H₃₅O₆Si [M + H]⁺

483.2203, found 483.2203.

16′-[(tert-Butyldimethylsilyl)oxy]-10′-methyl-14′-

oxaspiro[1,3-dioxolane-2,5′-tetracyclo[7.7.0.0^2,6.0^11,15]-

hexadecane]- 1′,6′,8′,10′,12′,15′-hexaene-12′-carbalde-

hyde (27). LiAlH₄(4 M in Et₂O, 32.5 μL, 0.13 mmol) was

added dropwise to a solution of the ester 26 (130 mg, 0.27

mmol) in 10 mL of anhydrous THF at 0 °C. After addition was

complete, the reaction mixture was stirred for 30 min, and then

slowly quenched with 2.5 mL of MeOH and 5 mL of Rochelle’s

salt. The gelatinous mixture was diluted with Et₂O and then

stirred at room temperature for 20 min followed by ﬁltration

through a Celite pad and the cake washed with Et₂O. The

ﬁltrate was washed with brine, dried over anhydrous MgSO₄,

3-{16-[(tert-Butyldimethylsilyl)oxy]-10-methyl-5- oxo-

14-oxatetracyclo[7.7.0.0^{2 , 6}. 0^{1 1 , 1 5}]hexadeca-

1,6,8,10,12,15-hexaen-12-yl}-3-hydroxypropanal (29).

To a solution of the oleﬁn 28 (25 mg, 0.05 mmol) in

dioxane-water (4 mL; 3:1) was added OsO₄(4% weight in

H₂O, 35 μL, 0.005 mmol), and NaIO₄(43 mg, 0.2 mmol). The

mixture was stirred at rt for 1 h and then diluted with CH₂Cl₂

(2 mL) and H₂O (1 mL). The two layers were separated and

the aqueous layer was extracted twice with CH₂Cl₂. The

combined organic extracts were washed with brine, dried over

MgSO₄and then concentrated in vacuo to give a brown oil.

Puriﬁcation by preparative thin layer chromatography (1:1

hexanes/EtOAc) gave 9 mg (41%) of 29 as a pale yellow oil. R_f

1

= 0.35 (2:1 hexanes/EtOAc) H NMR (500 MHz, CDCl₃) δ

9.99 (1H, s), 8.05 (1H, d, J = 8.5 Hz), 7.78 (1H, s), 7.67 (1H,

d, J = 9.0 Hz), 5.82 (1H, d, J = 8 Hz), 3.82−3.80 (2H, t, J = 6.5

Hz), 3.18−3.16 (1H, m), 3.06−2.91 (1H, m), 2.92 (3H, s),

2.77−2.75 (2H, m), 0.98 (9H, s), 0.42 (6H, s). ¹³C NMR (125

MHz, CDCl₃) δ 201.4, 157.1, 144.8, 133.7, 129.1, 124.8, 119.5,

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117.8, 63.9, 62.5, 51.1, 36.4, 29.7, 26.5, 16.2, 14.0, −2.2. FT-IR

(CDCl₃, cm⁻¹) 3419, 2930, 1731, 1620, 1374, 1254, 1171, 830.

HRMS (ESI) calcd for C₂₅H₃₁O₅Si [M + H]⁺439.1941, found

439.1933.

methyl-14-oxatetracyclo[7.7.0.0^2,6.0^11,15]hexadeca-

1,6,8,10,15-pentaen-12-yl}propanoate (39). To a solution

of the unsaturated ester 35 (120 mg, 0.242 mmol) in 6 mL of

ethyl acetate at −10 °C was added 5% Pd on carbon (50.68 mg,

0.024 mmol) portionwise over 1 h. The reaction mixture was

stirred for 1.5 h under a balloon of H₂at −10 °C and then

ﬁltered through a Celite pad. The ﬁltrate was concentrated in

vacuo to give a yellow residue. Puriﬁcation by column

chromatography (SiO₂, 10:1 hexanes/EtAOc) gave 80 mg

(69%) 3:1 mixture of 36 and 37 a yellow solid. R_f= 0.50 (5:1

hexanes/EtOAc) and 12 mg mixture of the C17-norketone 38

and dihydrofuran 39 as a yellow solid. Recrystallization of the

mixture of 38 and 39 from hexanes gave 8 mg (8%) of 38 as

pale yellow needle crystals. Mp: 140−142 °C, and 2 mg (1%)

(2E)-3-{16-[(tert-Butyldimethylsilyl)oxy]-10-methyl-5-

oxo-14-oxatetracyclo[7.7.0.0^2,6.0^11,15]hexadeca-

1,6,8,10,12,15-hexaen-12-yl}prop-2-enal (30). A solution

of the aldehyde 29 (5.0 mg, 0.01 mmol) in 2 mL of dry

degassed CH₂Cl₂at rt under atmosphere of N₂was slowly

added TiCl₄(1.0 M in CH₂Cl₂, 20 μL, 0.020 mmol) The

resulting dark purple reaction was stirred for 45 min and then

quenched via the dropwise addition of NaHCO₃. The solution

was diluted with CH₂Cl₂and then washed with H₂O. The

aqueous portion was extracted three times with CH₂Cl₂. The

combined organic extracts were washed with brine, dried over

MgSO₄and concentrated in vacuo. Puriﬁcation by preparative

thin layer chromatography (3:1 hexanes/EtOAc) gave 1.5 mg

(35%) of the enal 30 as a pale yellow oil. ¹H NMR (500 MHz,

CDCl₃) δ 9.80 (1H, d, J = 7.5 Hz), 8.09 (1H, d, J = 9.0 Hz),

8.05 (1H, s), 7.98 (1H, d, J = 16.0 Hz), 7.73 (1H, d, J = 8.5

Hz), 7.68 (1H, d, J = 9.0 Hz), 6.66 (1H, dd, J = 16.0, 7.5 Hz),

3.85−3.83 (2H, m), 2.97 (3H, s), 2.80−2.78 (2H, m), 1.00

(9H, s), 0.44 (6H, s). ¹³C NMR (125 MHz, CDCl₃) δ 193.5,

145.8, 144.2, 142.7, 140.8, 138.4, 131.1, 129.9, 124.5, 124.0,

122.8, 122.7, 121.9, 119.7, 119.343.8, 36.0, 33.2, 29.9, 26.6,

25.4, 19.4, 19.0, 16.1, −2.5. FT-IR (CDCl₃, cm⁻¹) 2359, 1682,

1669, 1360, 1120, 833. HRMS (EI) calcd for C₂₅H₂₈O₄Si

420.1757, found 420.1761.

1

of dihydrodrofuran 39 as yellow oil. Compound 38: H NMR

(300 MHz, CDCl₃) δ 7.90 (1H, d, J = 9.0 Hz), 7.39 (1H, s),

7.34 (1H, d, J = 8.7 Hz), 3.71 (3H, s), 3.65 (2H, t, J = 7.5 Hz),

3.26 (2H, t, J = 8.1 Hz), 3.02 (2H, t, J = 7.5 Hz), 2.89 (3H, s),

2.76 (2H, t, J = 7.5 Hz), 2.17 (2H, q, J = 7.5 Hz), 0.96 (H, s),

0.34 (6H, s). ¹³C NMR (125 MHz, CDCl₃) δ 173.4, 142.6,

140.0, 138.2, 130.5, 126.9, 123.5, 122.3, 121.8, 119.9, 118.8,

52.0, 36.0, 34.4, 33.2, 26.6, 25.4, 21.9, 19.4, 15.2, −2.5. FT-IR

(CDCl₃, cm⁻¹) HRMS (ESI) calcd for C₂₆H₃₅O₄Si [M + H]⁺

439.2305, found 439.2300.

Compound 39: ¹H NMR (300 MHz, CDCl₃) δ 7.67 (1H, d,

J = 8.4 Hz), 7.24 (1H, d, J = 8.4 Hz), 6.98 (1H, s), 4.42−4.35

(2H, m), 3.65 (3H, s), 3.55 (2H, t, J = 7.5 Hz), 2.99 (2H, t, J =

8.7 Hz), 2.54 (3H, s), 2.39−2.27 (2H, m), 2.09 (2H, t, J = 7.5

Hz), 1.92−1.89 (2H, m), 0.96 (9H, s), 0.28 (6H, s). ¹³C NMR

(125 MHz, CDCl₃) δ 174.0, 145.3, 141.4, 137.9, 130.7, 129.8,

127.2, 125.8, 122.9, 122.6, 120.9, 75.3, 51.8, 41.2, 35.8, 33.1,

31.2, 30.5, 29.9, 26.3, 19.5, 15.8, −2.6. FT-IR (CDCl₃, cm⁻¹)

2953, 1739, 1256, 837. HRMS (ESI) calcd for C₂₆H₃₇O₄Si [M

+ H]⁺441.2461, found 441.2455.

Methyl (2E)-3-{16′-[(tert- butyldimethylsilyl)oxy]-10′-

methyl-14′-oxaspiro[1,3-dioxolane-2,5′-tetracyclo-

[7.7.0.0^2,6.0^11,15]hexadecane]-1′,6′,8′,10′,12′,15′-hexaen-

12′-yl}prop-2-enoate (35). To a stirred solution of n-BuLi

(1.6 M in hexanes, 1.05 mL, 1.71 mmol) in THF (15 mL) was

added the phosphonate reagent 34 (418.5 μL, 2.28 mmol) at

ice bath temperature. The mixture was then warmed to room

temperature. After 15 min, a solution of the aldehyde 27 (250

mg, 0.57 mmol) in THF (15 mL) was added at 0 °C. The

resulting mixture was stirred at 0 °C for 1 h, quenched with

NaHCO₃, and extracted with EtOAc. The organic extracts were

dried over MgSO₄, concentrated under reduced pressure and

puriﬁed by column chromatography (SiO₂, hexanes/EtOAc;

10:1) to give 209 mg (74%) of 35 as a yellow solid. M.p: 192−

3-{16′-[(tert-Butyldimethylsilyl)oxy]-10′-methyl-14′-

oxaspiro[1,3-dioxolane-2,5′-tetracyclo[7.7.0.0^2,6.0^11,15]-

hexadecane]-1′,6′,8′,10′,12′,15′-hexaen-12′-yl}propanal

(41). To a solution of a 3:1 mixture of the ketal 36 and ketone

37 (80 mg) in CH₂Cl₂(5 mL) at ice bath was added Et₃N

(31.2 μL, 0.132 mmol) followed by TBSOTf (20 μL, 0 09

mmol). The mixture was stirred at ice bath temperature for 30

min and then quenched with sat. aq. NaHCO₃. The two layers

were separated and the aqueous layer extracted twice with

CH₂Cl₂. The combined organic extracts were washed with

brine, dried over MgSO₄, and concentrated in vacuo to give a

brown oil. Puriﬁcation by column chromatography (SiO₂, 20:1

hexanes/EtOAc) gave 48 mg of the ketal 36 as a yellow solid.

Mp = 174−177 °C, and gave 20 mg of silyl enol ether 40 as a

1

194 °C. R_f=0.75 (5:1 hexanes:EtOAc). H NMR (300 MHz,

CDCl₃) δ 8.13 (1H, d, J = 15.6 Hz), 8.02 (1H, d, J = 8.7 Hz),

7.86 (1H, s), 7.41 (1H, d, J = 9.0 Hz), 6.32 (1H, d, J = 15.9

Hz), 4.29−4.11 (4H, m), 3.85 (3H, s), 3.67 (1H, t, J = 6.9 Hz),

2.89 (3H, s), 2.38 (2H, t, J = 6.9 Hz), 2,27 (2H, t, J = 7.2 Hz),

0.97 (9H, s), 0.36 (6H, s). ¹³C NMR (75 MHz, CDCl₃) δ

167.2, 144.8, 143.8, 140.1, 137.6, 136.3, 135.3, 132.5, 126.4,

125.8, 124.3, 123.1, 119.8, 119.5, 117.8, 65.6, 52.0, 37.1, 31.8,

30.5, 26.5, 19.4, 16.1, −2.3. FT-IR (CDCl₃cm-¹) 2952, 1719,

1633, 1370, 1312, 1169, 1038, 832. HRMS (EI) calcd for

C₂₈H₃₄O₆Si 494.2125, found 494.2131.

1

yellow oil. Compound 36: R_f= 0.25 (5:1 hexanes/EtOAc). H

NMR (500 MHz, CDCl₃) δ 8.00 (1H, d, J = 9 Hz), 7.43 (1H,

s), 7.39 (1H, d, J = 9.0 Hz), 4.28−4.25 (2H, m), 4.15−4.12

(2H, m), 3.71 (3H, s), 3.67 (2H, t, J = 6.5 Hz), 3.27 (2H, t, J =

8.0 Hz), 2.88 (3H, s), 2.77 (2H, t, J = 8.4 Hz), 2.38 (2H, 6.5

Hz), 0.96 ((H, s), 0.34 (6H, s). HRMS (EI) calcd for

C₂₈H₃₆O₆Si: 496.2279, found 496.2281. Compound 40: R_f=

Methyl 3-{16′-[(tert-Butyldimethylsilyl)oxy]-10′-meth-

yl-14′-oxaspiro[1,3-dioxolane-2,5′-tetracyclo-

[7.7.0.0^2,6.0^11,15]hexadecane]-1′,6′,8′,10′,12′,15′-hexaen-

12′-yl}propanoate (36), Methyl 3-{16-[(tert-

Butyldimethylsilyl)oxy]-10-methyl-14-oxatetracyclo-

[7.7.0.0^2,6.0^11,15]hexadeca-1,6,8,10,12,15-hexaen-12-yl}-

propanoate (37), Methyl 3-{16-[(tert-Butyldimethylsilyl)-

oxy]-10-methyl-14-oxatetracyclo[7.7.0.0.^2,6.0^11,15]-

hexadeca-1,6,8,10,12,15-hexaen-12-yl}propanoate (38)

and Methyl 3-{16-[(tert-Butyldimethylsilyl)oxy]-10-

1

0.65 (5:1 hexanes/EtOAc). H NMR (500 MHz, CDCl₃) δ

8.07 (1H, d, J = 9.0 Hz), 7.57 (1H, d, J = 8.5 Hz), 5.56 (1H, t, J

= 4.5 Hz), 3.95 (2H, d, J = 1.5 Hz), 3.78 (3H, s), 3.28 (2H, t, J

= 8.0 Hz), 2.92−2.91 (2H, m), 2.92 (3H, s), 2.78−2.76 (2H, t,

J = 7.0 Hz), 1.07 (9H, s), 0.97 (9H, s), 0.43 (6H, s), 0.29 (6H,

s). HRMS (EI) calcd for C₃₂H₄₆O₅Si₂566.2884, found

566.2878. A solution of the ester 36 (24 mg, 0.048 mmol) in

6 mL of dry THF was cooled to 0 °C. LiAlH₄(4 M in Et₂O, 6

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μL, 0.024 mmol) was added dropwise. The mixture was stirred

for 30 min and then slowly quenched with 0.5 mL of MeOH

followed by 1 mL of Rochelle’s salt. The mixture was diluted

with Et₂O, warmed to room temperature and stirred vigorously

for 30 min. The precipitate was ﬁltered through a Celite pad

and the ﬁltrate was washed with brine, dried over anhydrous

MgSO₄, and the solvent evaporated in vacuo to aﬀord the

corresponding alcohol (22 mg). This alcohol was used in the

next step without further puriﬁcation. Oxalyl chloride (9 μL,

0.11 mmol) in 0.5 mL of CH₂Cl₂was cooled to −78 °C.

DMSO (12 μL, 0.21 mmol) in 0.5 mL of CH₂Cl₂was added via

syringe and the mixture stirred for 5 min. The crude alcohol

above (22 mg, 0.048 mmol) in 0.5 mL of CH₂Cl₂was added via

syringe followed by Et₃N (34 μL, 0.24 mmol). The mixture was

allowed to warm to room temperature and then quenched with

water. The two layers were separated and aqueous layer

extracted with CH₂Cl₂. The combined organic extracts were

washed with water twice, rinsed with brine, dried over MgSO₄

and concentrated under reduced pressure. Puriﬁcation by

column chromatography (SiO₂, 4:1 hexanes/EtOAc) gave 18.6

mg (83%) of 41 as a pale yellow oil. R_f=0.65 (2:1 hexanes/

EtOAc) ¹H NMR (500 MHz, CDCl₃) δ 9.90 (1H, s), 8.00 (1H,

d, J = 8.5 Hz), 7.41 (1H, s), 7.40 (1H, d, J = 9.5 Hz), 4.28−4.25

(2H, m), 4.15−4.12 (2H, m), 3.67 (2H, t, J = 7 Hz), 3.27 (2H,

t, J = 7 Hz), 2.95−2.91 (2H, m), 2.88 (3H, s), 2.38 (2H, t, J =

6.5 Hz), 0.96 (9H, s), 0.35 (6H, s). ¹³C NMR (125 MHz,

CDCl₃) δ 201.3, 143.1, 140.1, 137.1, 132.0, 128.0, 124.1, 119.9,

119.0, 110.0, 65.5, 43.7, 37.1, 31.8, 29.9, 26.5, 19.4, 18.9, 15.3,

−2.2. FT-IR (CDCl₃, cm⁻¹) 2928, 2359, 1716, 1372, 832.

HRMS (ESI) calcd for C₂₇H₃₅O₅Si [M + H]⁺467.2254, found

467.2259.

170 mg (65%) of 46 as a sticky yellow oil. R_f= 0.25 (1:1

hexanes/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.10 (1H, s),

7.70 (1H, d, J = 8.0 Hz), 7.63 (1H, s), 7.51 (1H, d, J = 8.0 Hz),

6.06−6.01 (2H, m), 4.22−4.16 (4H, m), 4.12−4.09 (2H, m),

3.98 (1H, q, J = 7.5 Hz), 2.83 (1H, m), 2.73−2.67 (1H, m),

2.27 (2H, t, J = 7.0 Hz), 1.51 (3H, d, J = 7.0 Hz), 1.28 (3H, t, J

= 7.5 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 184.4, 164.8, 142.4,

141.9, 141.5, 133.4, 128.8, 127.7, 126.0, 123.0, 116.5, 104.7,

79.7, 65.6, 65.5, 60.6, 37.3, 30.6, 27.5, 24.7, 14.5, 14.4. FT-IR

(CDCl₃, cm⁻¹) 2979, 1720, 1666, 1184, 1042. HRMS (ESI)

calcd for C₂₄H₂₄NO₆[M + H]⁺422.1604, found 422.1608.

Ethyl 3-{16′-[(tert-Butyldimethylsilyl)oxy]-10′-methyl-

14′-oxaspiro[1,3-dioxolane-2,5′-tetracyclo-

[7.7.0.0^2,6.0^11,15]hexadecane]-1′,6′,8′,10′,12′,15′-hexaen-

12′-yl}propanoate (50). A solution of the enyne oxazole 46

(100 mg, 0.24 mmol) in 10 mL of dry 1,2-dichlorobenzene was

stirred for 8 h in a 30 mL round-bottom ﬂask at 180 °C under a

nitrogen atmosphere. After cooling to rt, the solution was

passed through a plug of silica gel using hexanes to elute the

1,2-dichlorobenzene. The product was then eluted from the

silica gel with hexanes/EtOAc (4:1) to give 70 mg of 47 and 48

as a yellow solid, R_f= 0.45 (1:1 hexanes/EtOAc). To a solution

of the mixture of 47 and 48 (70 mg) in EtOAc (10 mL) at −10

°C was added approximately 10% of 5% Palladium on carbon.

The ﬂask was evacuated and then backﬁlled by attaching a

balloon full of H₂. The mixture was vigorously stirred for 1 h at

−10 °C and then ﬁltered through a Celite pad. The product

and starting material have very close R_f, but the stronger

ﬂuorescence of the product makes it easy to monitor the

reaction. The ﬁltrate was concentrated in vacuo to give 65 mg

(68%) of the dienone saturated ester 49 as a pale yellow oil. R_f

1

3-{16-[(tert-Butyldimethylsilyl)oxy]-10-methyl-5-oxo-

14-oxatetracyclo[7.7.0.0^{2 , 6}.0^{1 1 , 1 5}]hexadeca-

1,6,8,10,12,15-hexaen-12-yl}propanal (42). To a solution

of the aldehyde 41 (10.0 mg, 0.02 mmol) in 4 mL of dry

CH₂Cl₂at rt under N₂was slowly added TiCl₄(1.0 M in

CH₂Cl₂, 40 μL, 0.04 mmol). The resulting dark purple reaction

was stirred for 45 min and then quenched with NaHCO₃,

extracted with CH₂Cl₂, dried over MgSO₄and concentrated

under reduced pressure. Puriﬁcation by preparative thin layer

chromatography (SiO₂, 3:1 hexanes/EtOAc) gave 7.6 mg

= 0.40 (1:1 hexanes/EtOAc). H NMR (300 MHz, CDCl₃) δ

7.58 (1H, d, J = 7.8 Hz), 7.52 (1H, s), 7.46 (1H, d, J = 7.8 Hz),

4.26−4.09 (5H, m), 3.58 (2H, q, J = 6.6 Hz), 2.91 (2H, t, J =

7.2 Hz), 2.68 (2H, t, J = 7.5 Hz), 2.34 (2H, t, J = 6.9 Hz), 1.55

(3H, d, J = 9 Hz), 1.26 (3H, t, J = 7.8 Hz). A solution of

dienone 49 (65 mg, 0.17 mmol) in CH₂Cl₂(10 mL) at ice bath

temperature was treated with Et₃N (71 μL, 0.51 mmol)

followed by TBSOTf (58 μL, 0.34 mmol). The mixture was

stirred at ice bath temperature for 30 min and then quenched

with sat. aq. NaHCO₃. The two layers were separated and the

aqueous layer extracted with CH₂Cl₂. The combined organic

extracts were washed with brine, dried over MgSO₄and

concentrated under reduced pressure. Puriﬁcation by column

chromatography (SiO₂, 10:1 hexanes/EtOAc) gave 70 mg

(81%) of the desired product (50) as a yellow oil. R_f= 0.75

(3:1 hexanes/EtOAc) ¹H NMR (500 MHz, CDCl₃) δ 8.0 (1H,

d, J = 8.5 Hz), 7.43 (1H, s), 7.39 (1H, d, J = 9.0 Hz), 4.28−4.25

(2H, m), 4.56 (2H, q, J = 7.5 Hz), 4.42−4.22 (2H, m), 4.21−

4.08 (4H, m), 3.67 (2H, t, J = 7.0 Hz), 3.26 (2H, t, J = 7.0 Hz),

2.88 (3H, s), 2.76 (2H, t, J = 7.5 Hz), 2.38 (2H, t, J = 6.5 Hz),

1.26 (3H, t, J = 7.0 Hz), 0.95 (9H, s), 0.35 (6H, s). ¹³C NMR

(125 MHz, CDCl₃) δ 172.9, 143.0, 140.0, 137.1, 132.0, 128.1,

124.1, 122.7, 120.1, 119.1, 118.0, 65.5, 60.9, 37.1, 34.6, 31.8,

26.6, 21.9, 19.4, 15.2, 14.5, −2.4. FT-IR (CDCl₃cm⁻¹) 2929,

1735, 1163, 833. HRMS (ESI) calcd for C₂₉H₃₉O₆Si [M + H]⁺

511.2516, found 511.2523.

1

(82%) of the ketone 42 as a pale yellow oil. H NMR (500

MHz, CDCl₃) δ 9.91 (1H, s), 8.04 (1H, d, J = 5.5 Hz), 7.67

(1H, d, J = 5.7 Hz), 7.5 (1H, s), 3.84−3.82 (2H, m), 3.30 (2H,

t, J = 4.5 Hz), 2.95 (2H, d, J = 4.5 Hz), 2.92 (3H, s), 2.78−2.76

(2H, m), 0.97 (9H, s), 0.42 (6H, s). ¹³C NMR (125 MHz,

CDCl₃) δ 207.4, 200.9, 157.2, 144.2, 136.7, 136.0, 133.7, 133.4,

130.4, 125.8, 124.6, 122.5, 120.3, 119.6, 117.6, 43.7, 36.5, 30.6,

29.8, 26.5, 22.9, 21.5, 18.8, 15.3, −2.2. FT-IR (CDCl₃, cm⁻¹)

HRMS (ESI) calcd for C₂₅H₃₀O₄Si [M + H]⁺423.1992, found

423.1986.

Bis(ethyl (2Z)-6-{4′-[(1,3-oxazol-5-yl)carbonyl]-2′,3′-

dihydrospiro[1,3-dioxolane-2,1′-indene]-5′-yl}hept-2-

en-4-ynoate) (46). A mixture of the terminal alkyne 22 (200

mg, 0.62 mmol) and iodoacrylate 45 (168 mg, 0.74 mmol) in

THF (20 mL) was treated with PdCl₂(PPh₃)₂(21 mg, 0.03

mmol) and CuI (5.7 mg, 0.03 mmol) under N₂. Et₃N (432 μL,

3.1 mmol) was added via syringe and the mixture stirred at rt

for 3 h then quenched with sat. aq. NH₄Cl. The two layers were

separated and the aqueous layer extracted with EtOAc. The

combined organic extracts were washed with brine, dried over

MgSO₄, and concentrated under reduced pressure. Puriﬁcation

by column chromatography (SiO₂, 2:1 hexanes/EtOAc) gave

3-{16-[(tert-Butyldimethylsilyl)oxy]-5-hydroxy-10-

methyl-14-oxatetracyclo[7.7.0.0^2,6.0^11,15]hexadeca-

1,6,8,10,12,15-hexaen-12-yl}propanal (51). A solution of

the ester 50 (6.5 mg, 0.013 mmol) in 2.5 mL of dry CH₂Cl₂

was cooled to −78 °C. DIBAL-H (1 M in toluene, 14 μL, 0.014

mmol) was added dropwise. After the addition was complete,

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the reaction mixture was stirred for 30 min, and then slowly

quenched with 0.5 mL of MeOH followed by 1 mL of

Rochelle’s salt and the mixture warmed and stirred at room

temperature for 30 min. The precipitate was ﬁltered through a

Celite pad and ﬁltrate washed with brine, dried over anhydrous

MgSO₄, and the solvent was removed under reduced pressure

to aﬀord 3.3 mg (60%) of the aldehyde 51 as a yellow oil. R_f=

MHz, CDCl₃) δ 7.69 (1H, d, J = 8.1 Hz), 7.50 (1H, d, J = 8.0

Hz), 7.40 (1H, s), 4.70 (1H, t, J = 2.8 Hz), 3.67−3.38 (2H, m),

3.02−2.81 (4H, m), 2.12 (2H, t, J = 8.5 Hz), 1.45 (3H, s). ¹³

C

NMR (125 MHz, CDCl₃) δ 175.0, 148.2, 147.0, 146.4, 145.6,

143.5, 129.0, 128.1, 125.1, 122.6, 80.6, 71.4, 44.1, 35.1 34.6,

32.7, 32.3, 32.1, 25.4, 25.1, 16.5, 13.9. FT-IR (CDCl₃, cm⁻¹)

3421, 2953, 1660, 1030, 732.

1

0.25 (3:1 hexanes/EtOAc). H NMR (300 MHz, CDCl₃) δ

2,3-Dihydro-1-oxo-5-((E)-pent-3-en-2-yl)-1H-inden-4-

yl Triﬂuoromethanesulfonate (55). To a solution of 2,3-

dihydro-1H-inden-4-ol (54)⁶¹(6 g, 44.72 mmol) and allyl

carbonate 10 (7.74 g, 53.66 mmol) in CH₂Cl₂(150 mL) was

added Pd(PPh₃)₄(516.5 mg, 0.45 mmol). The mixture was

then reﬂuxed for 3 h, cooled to room temperature and the

solvent removed under reduced pressure. Puriﬁcation by

column chromatography (SiO₂, 100:1 hexanes/EtOAc) gave

8.68 g (96%) of 4-[(3E)-pent-3-en-2-yloxy]-2,3-dihydro-1H-

9.90 (1H, s), 8.00 (1H, d, J = 9.0 Hz), 7.50 (1H, d, J = 8.7 Hz),

7.40 (1H, s), 5.37 (1H, t, J = 5.7 Hz), 3.80 (2H, t, J = 8.4 Hz),

3.27 (2H, t, J = 7.2 Hz), 2.92 (2H, t, J = 6.6 Hz), 2.88 (3H, s),

2.63−2.54 (2H, m), 2.06−1.97 (2H, m), 0.95 (9H, s), 0.34

(3H, s). ¹³C NMR (125 MHz, CDCl₃) δ 201.4, 142.6, 142.4,

138.4, 134.5, 131.7, 123.1, 119.2, 63.9, 43.8, 43.5, 37.4, 33.3,

29.9, 26.5, 22.9, 19.0, 15.2, 14.4, −2.1. FT-IR (CDCl₃, cm⁻¹)

3420, 2927, 1725, 1624, 1461, 1388, 1258, 834. HRMS (ESI)

calcd for C₂₅H₃₃O₄Si [M + H]⁺425.2148, found 425.2155.

3-{16-[(tert-butyldimethylsilyl)oxy]-10-methyl-14-

oxatetracyclo[7.7.0.0^2,6.0^11,15]hexadeca-1,6,8,10,12,15-

hexaen-12-yl}propanal (52). A solution of the ester 38 (200

mg, 0.5 mmol) in 50 mL of dry CH₂Cl₂was cooled to −78 °C.

DIBAL-H (1 M in toluene, 600 μL, 0.6 mmol) was added

dropwise. The reaction mixture was stirred for 30 min, and then

slowly quenched with 5 mL of MeOH followed by 10 mL of

Rochelle’s salt and warmed and stirred at room temperature for

30 min. The precipitate was ﬁltered through a Celite pad and

the ﬁltrate washed with brine, dried over anhydrous MgSO₄,

and the solvent was evaporated in vacuo to aﬀord 170 mg

(81%) of the aldehyde 52 as white solid. Recrystallization from

1

indene as a colorless oil. R_f= 0.75 (10:1 hexanes/EtOAc). H

NMR (300 MHz, CDCl₃) δ 7.06 (1H, t, J = 7.2 Hz), 6.83 (1H,

d, J = 7.2 Hz), 6.69 (1H, d, J = 8.1 Hz), 5.74−5.65 (1H, m),

5.59−5.51 (1H, m), 4.79−4.71 (1H, m), 2.93−2.85 (4H, m),

2.05 (2H, q, J = 7.5 Hz), 1.68 (2H, d, J = 6.3 Hz), 1.40 (2H, d, J

= 6.3 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 155.0, 146.5, 133.2,

133.0, 127.5, 127.0, 117.1, 111.5, 74.7, 33.6. 30.0, 25.3, 22.0,

18.0. FT-IR (CDCl₃, cm⁻¹) 2953, 1587, 1474, 1259, 1051, 964,

764. HRMS (EI) calcd for C₁₄H₁₈O 202.1358, found 202.1367.

The solution of 4-[(3E)-pent-3-en-2-yloxy]-2,3-dihydro-1H-

indene (8 g, 39.55 mmol) obtained above in Et₂NPh (50

mL) was heated at 180 °C for 15 h. The dark brown mixture

was then cooled to room temperature, diluted with 50 mL of

ice water, and then stirred at room temperature for several

minutes. The two layers were separated and the aqueous layer

extracted with EtOAc. The combined organic extracts were

washed with brine, dried over MgSO₄and concentrated under

reduced pressure. Puriﬁcation by column chromatography

(SiO₂, 30:1 to 10:1 hexanes/EtOAc) gave 7.36 g (92%) of

2,3-dihydro-5-((E)-pent-3-en-2-yl)-1H-inden-4-ol as a pale

1

hexanes gave colorless needle crystals. Mp: 175−176 °C. H

NMR (300 MHz, CDCl₃) δ 9.89 (1H, s), 7.90 (1H, d, J = 8.7

Hz), 7.36 (1H, d, J = 9 Hz), 3.66 (2H, t, J = 7.2 Hz), 3.26 (2H,

t, J = 7.2 Hz), 3.03 (2H, t, J = 7.5 Hz), 2.93 (2H, t, J = 7.8 Hz),

2.88 (3H, s), 2.16 (2H, t, J = 8.2 Hz), 0.97 (9H, s), 0.35 (6H,

s), ¹³C NMR (125 MHz, CDCl₃) δ 201.4, 142.6, 140.1, 138.2,

130.5, 122.7, 121.9, 119.8, 118.7, 43.7, 36.1, 33.3, 26.7, 26.6,

25.6, 19.0, 15.2, −2.4. FT-IR (CDCl₃, cm⁻¹) 2926, 1721, 1361,

1254, 1110, 845, 788. HRMS (ESI) calcd for C₂₅H₃₃O₃Si [M +

H]⁺409.2199, found 409.2208.

1

yellow oil. R_f=0.35 (5:1 hexanes/EtOAc). H NMR (300

MHz, CDCl₃) δ 6.94 (1H, d, J = 7.8 Hz), 6.79 (1H, d, J = 7.5

Hz), 5.74−5.67 (2H, m), 5.16 (1H, s), 3.61−3.57 (1H, m),

2.90 (2H, t, J = 8.1 Hz), 2.84 (2H, t, J = 7.2 Hz), 2.09 (2H, t, J

= 7.8 Hz), 1.74 (3H, d, J = 7.2 Hz), 1.38 (3H, d, J = 7.2 Hz).

¹³C NMR (125 Hz, CDCl₃) δ 150.5, 144.8, 135.9, 135.4, 130.6,

128.3, 126.4, 125.5, 124.5, 116.9, 37.3, 33.2, 29.1, 25.5, 19.9,

18.2. FT-IR (CDCl₃, cm⁻¹) 3418, 2960, 1446, 1196, 998, 809.

HRMS (EI) calcd for C₁₄H₁₈O 202.1349, found 202.1358. To a

solution of 2,3-dihydro-5-((E)-pent-3-en-2-yl)-1H-inden-4-ol

(7 g, 34.6 mmol) in CH₂Cl₂(50 mL) at 0 °C was added

pyridine (5.57 mL, 69.2 mmol) followed by dropwise addition

of Tf₂O (6.99 mL, 41.52 mmol). The reaction was then stirred

for an additional 10 min. The resulting dark green residue was

diluted with Et₂O and then quenched with dil. HCl. The

aqueous layer was extracted with CH₂Cl₂, the combined

organic extracts washed with NaHCO₃, rinsed with brine, dried

over MgSO₄and then concentrated under reduced pressure.

Puriﬁcation by column chromatography (SiO₂, 80:1 hexanes/

EtOAc) gave 11.33 g (98%) of the triﬂate 55 as a colorless oil.

1 8 - H y d r o x y - 1 - m e t h y l - 1 3 - o x a p e n t a c y c l o -

[10.6.1.0^2,10.0^5,9.0^15,19]nonadeca-2,4,9,12(19),14-pen-

taen-11-one (53) (=3). A solution of the aldehyde 52 (100

mg, 0.24 mmol) in 25 mL of dry CH₂Cl₂at room temperature

was added TiCl₄(1 M in CH₂Cl₂, 960 μL, 0.96 mmol)

dropwise. The reaction mixture was stirred for 30 min, and then

slowly quenched with 1 mL of H₂O. The two layers were

separated and aqueous layer extracted with CH₂Cl₂. The

combined organic extracts were washed with brine, dried over

MgSO₄, and concentrated under reduced pressure. Puriﬁcation

by column chromatography (SiO₂, 2:1 hexanes/EtOAc) gave

43 mg (60%) of syn-53 as a yellow solid and 12 mg (12%) of

anti-53 as a purple oil. Recrystallization of syn-53 from CH₂Cl₂

gave colorless needle crystals. Mp: 208−210 °C. Syn-53: R_f=

1

0.35 (2:1 hexanes/EtOAc). H NMR (500 MHz, CDCl₃) δ

8.14 (1H, d, J = 8 Hz), 7.40 (1H, s), 7.39 (1H, d, J = 9.5 Hz),

4.12 (1H, dd, J = 11.5 Hz, 5.5 Hz), 3.64−3.52 (2H, m), 3.50−

3.45 (2H, m), 2.95−2.89 (4H, m), 2.80−2.73 (2H, m), 2.28

(2H, dd, J = 14, 3 Hz), 2.19−2.05 (3H, m), 2.00 (1H, d, J = 5.5

Hz). ¹³C NMR (125 MHz, CDCl₃) δ 175.0, 148.5, 147.7,

146.2, 144.9, 144.1, 142.8, 129.8, 127.9, 126.5, 120.6, 73.1, 41.4,

35.2, 32.1, 29.8, 26.3, 25.4, 17.3. FT-IR (CDCl₃, cm⁻¹) 3417,

2952, 1659, 1429, 1027, 731. HRMS (ESI) calcd for C₁₉H₁₉O₃

1

R_f= 0.8 (10:1 hexanes/EtOAc). H NMR (500 MHz, CDCl₃)

δ 7.20 (1H, d, J = 6.5 Hz), 7.13 (1H, d, J = 7.5 Hz), 5.60−5.48

(2H, m), 3.84−3.81 (1H, m), 3.06 (2H, t, J = 7.5 Hz), 2.95

(2H, t, J = 7.5 Hz), 2.16−10 (2H, m), 1.68 (3H, d, J = 7.2 Hz),

1.35 (3H, d, J = 7.2 Hz). ¹³C NMR (125 MHz, CDCl₃) δ

146.0, 143.3, 137.2, 134.7, 127.5, 124.9, 120.1, 117.6, 34.9, 33.3,

31.2, 25.7, 22.9, 18.1. FT-IR (CDCl₃, cm⁻¹) 2966, 1407, 1212,

1

[M + H]⁺295.1334, found 295.1333. Anti-53: H NMR (300

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1144, 970, 852, 825, 643. HRMS (EI) calcd forC₁₅H₁₇O₃F₃S

334.0851, found 334.0843.

24.1, 0.3. FT-IR (CDCl₃, cm⁻¹) 2961, 2174, 1408, 1214, 1143,

972, 846, 643. HRMS (EI) calcd for C₁₇H₂₁F₃O₃SSi 390.0933,

found 390.0930.

5-(4,4-Dibromobut-3-en-2-yl)-2,3-dihydro-1H-inden-

4-yl Triﬂuoromethanesulfonate (56). To a solution of the

triﬂate 55 (10 g, 29.91 mmol) in CH₂Cl₂(200 mL) was

bubbled ozone at −78 °C until a blue solution resulted and

persisted (approximately 30 min). Excess ozone was removed

by a nitrogen stream, triphenylphosphine (19.61 g, 74.77

mmol) was added, the mixture warmed to rt and stirred

overnight. Silica gel was added to the mixture and the solvent

removed under reduced pressure. Dry pack silica gel column

chromatography puriﬁcation (100% hexanes to 100:1 hexanes/

EtOAc) gave 7.71 g (80%) of the corresponding aldehyde as

(3-(2,3-Dihydro-4-vinyl-1H-inden-5-yl)but-1-ynyl)-

trimethylsilane (58). A solution of the triﬂate 57 (3 g, 7.68

mmol), PdCl₂(MeCN)₂(98.58 mg, 0.38 mmol), and DPEPhos

(409.98 mg, 0.76 mmol) in DMF (50 mL) was sparged with

nitrogen for 10 min. Tributyl(vinyl)tin (2.92 mL, 9.98 mmol)

was added and the mixture heated at 110 °C for 66 h, cooled to

room temperature, diluted with 50 mL of water, extracted with

ethyl acetate, washed with brine and ﬁnally dried over MgSO₄.

Puriﬁcation by column chromatography (100% hexanes to

100:1 to 30:1 hexanes/EtOAc) gave 1.86 g (85%) of 58 as a

pale yellow oil. R_f= 0.55 (5:1 hexanes/EtOAc). ¹H NMR (500

MHz, CDCl₃) δ 7.41 (1H, d, J = 7.5 Hz), 7.16 (1H, d, J = 7.5

Hz), 6.83 (1H, dd, J = 11.0, 17.5 Hz), 5.53 (1H, d, J = 11.0

Hz), 5.37 (1H, d, J = 17.5 Hz), 4.06 (1H, q, J = 7.0 Hz), 2.94−

2.90 (4H, m), 2.08−2.02 (2H, m), 1.42 (3H, d, J = 8.0 Hz),

0.18 (9H, s). ¹³C NMR (125 MHz, CDCl₃) δ 143.2, 142.8,

138.8, 134.0, 133.1, 125.5, 123.7, 119.8, 110.8, 85.5, 33.5, 33.2,

29.6, 25.8, 24.2, 0.4. FT-IR (CDCl₃, cm⁻¹) 2956, 2168, 1464,

1317, 1249, 842. HRMS (EI) calcd for C₁₈H₂₄Si 268.1647,

found 268.1638.

1

colorless oil. R_f= 0.50 (10:1 hexanes/EtOAc) H NMR (300

MHz, CDCl₃) δ 9.67 (1H, s), 7.24 (1H, d, J = 7.5 Hz), 6.96

(1H, d, J = 7.5 Hz), 4.03 (1H, q, J = 7.2 Hz), 3.08 (2H, t, J =

7.2 Hz), 2.98 (2H, t, J = 7.5 Hz), 2.17 (2H, t, J = 7.8 Hz),1.36

(3H, d, J = 6.9 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 199.7,

148.2, 138.3, 129.2, 128.3, 125.3, 120.0, 117.5, 46.1, 33.4, 31.1,

25.6, 15.2. FT-IR (CDCl₃, cm⁻¹) 2961, 1730, 1407, 1214, 1143,

970, 849, 642. HRMS (EI) calcd for C₁₃H₁₃O₄F₃S 322.0487,

found 322.0486. To a solution of the aldehyde obtained above

(7 g, 21.72 mmol) in CH₂Cl₂(150 mL) at 0 °C was added,

carbon tetrabromide (14.41 g, 43.44 mmol), triphenylphos-

phine (11.39 g, 43.44 mmol), and zinc dust (2.84 g, 43.44

mmol). The mixture was warmed to room temperature and

stirred until TLC analysis showed all the starting material

consumed (about 30 min). The mixture was ﬁltered through a

thin ﬁlm of silica gel, and the cake washed twice with CH₂Cl₂.

The solvent was removed under reduced pressure and the

residue taken up in hexanes where upon most of the

triphenylphosphine oxide precipitated at the bottom of the

ﬂask. The solvent was decanted and concentrated under

reduced pressure to give an orange residue. The residue was

puriﬁed by silica gel column chromatography (SiO₂, 100:1

hexanes/EtOAc) to give 9.24 g (89%) of the dibromooleﬁn 56

as a yellow oil. R_f= 0.70 (5:1 hexanes/EtOAc). ¹H NMR (300

MHz, CDCl₃) δ 7.23 (1H, d, J = 7.8 Hz), 7.12 (1H, d, J = 7.8

Hz), 6.56 (1H, d, J = 9.0 Hz), 4.10 (1H, q, J = 6.9 Hz), 3.07

(2H, t, J = 8.1 Hz), 2.95(2H, t, J = 7.5 Hz), 2.19−2.06 (2H, m),

1.39 (3H, d, J = 7.2 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 147.0,

141.7, 137.9, 134.4, 127.0, 125.1, 121.0, 116.7, 90.2, 36.9, 33.3,

31.2, 25.6, 21.4. FT-IR (CDCl₃, cm⁻¹). 1723, 1408, 1216, 1133,

817. HRMS (EI) calcd for C₁₄H₁₃O₃F₃S Br₂475.8905, found

475.8895.

2,3-Dihydro-5-(4-(trimethylsilyl)but-3-yn-2-yl)-1H-

inden-4-yl triﬂuoromethanesulfonate (57). To a solution

of the dibromooleﬁn 56 (9 g, 18.82 mmol) in THF (200 mL)

at −78 °C was added n-BuLi (1.6 M solution in hexanes, 25.88

mL, 41.40 mmol) dropwise under a nitrogen atmosphere. After

30 min, TMSCl (5.25 mL, 41.40 mmol) was added and the

mixture stirred for an additional 30 min and then quenched

with dil. HCl. The resulting white suspension was warmed to

room temperature, extracted with ethyl acetate, washed with

brine, dried over MgSO₄and concentrated in vacuo. Puriﬁcation

by column chromatography (SiO₂, 100:1 to 50:1 hexanes/

EtOAc) gave 6.69 g (91%) of the TMS alkyne 57 as a clear oil.

R_f= 0.55 (10:1 hexanes/EtOAc). ¹H NMR (300 MHz, CDCl₃)

δ 7.50 (1H, d, J = 7.8 Hz), 7.23 (1H, d, 7.8 Hz), 4.09 (1H, q, J

= 7.2 Hz), 3.04 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 7.5 Hz),

2.13 (2H, q, J = 7.5 Hz), 1.45 (3H, d, J = 6.9 Hz), 0.16 (9H, s).

¹³C NMR (125 MHz, CDCl₃) δ 147.2, 142.5, 137.4, 134.0,

128.1, 125.0, 120.1, 117.6, 108 6. 86.4, 33.3, 31.4, 27.1, 25.7,

(5-(but-3-yn-2-yl)-2,3-dihydro-1H-inden-4-yl)(oxazol-

5-yl)methanone (59). A solution of the vinyl arene 58 (1.7 g,

6.33 mmol) in CH₂Cl₂(100 mL) containing a drop of Red 23

(0.1% solution of Sudan III in MeOH) was cooled to −78 °C

and then exposed to a stream of ozone. Triphenylphosphine

(4.15 g, 15.83 mmol) was added when the pink color had

faded. The resulting mixture was allowed to warm to rt and

stirred overnight. The solvent was evaporated in vacuo and the

residue puriﬁed by column chromatography (SiO₂, 200:1 to

100:1 to 50:1 hexanes/EtOAc) to give 1.23 g (72%) of the

corresponding aldehyde as a clear oil. R_f= 0.50 (3:1 hexanes/

1

EtOAc). H NMR (300 MHz, CDCl₃) δ 10.54 (1H, s), 7.56

(1H, d, J = 7.8 Hz), 7.42 (1H, d, J = 7.8 Hz), 4.75 (1H, q, J =

6.9 Hz), 3.25 (2H, t, J = 7.8 Hz), 2.90 (2H, t, J = 7.5 Hz), 2.13

(2H, t, J = 7.8 Hz), 1.49 (3H, d, J = 6.9 Hz), 0.17 (9H, s). ¹³

C

NMR (125 MHz, CDCl₃) δ 192.5, 148.7, 144.8, 143.5, 130.1,

128.6, 127.2, 110.0, 86.6, 32.3, 32.1, 29.0, 25.5, 25.2, 0.3. FT-IR

(CDCl₃, cm⁻¹) 2958, 2168, 1690, 1249, 843. HRMS (EI) calcd

for C₁₇H₂₂Si O 270.1440, found 270.1437. tert-BuLi (1.7 M in

pentane, 2.86 mL, 4.48 mmol) was added to TIPS oxazole 19

(1 g, 4.48 mmol) at −78 °C in THF (40 mL). In a separate

ﬂask, the aldehyde above (1.2 g, 4.44 mmol) was dissolved in

THF (40 mL) and cooled to −78 °C. After 5 min, the anion of

the TIPS oxazole 19 was added via cannula to the aldehyde.

The mixture was stirred for an additional 20 min, quenched

with saturated aqueous NaHCO₃, diluted with water and

extracted with EtOAc. The organic layer was dried over MgSO₄

and concentrated in vacuo to give 1.6 g of the alcohol pure

enough to be used in the next reaction. Oxalyl chloride (610.4

μL, 7.11 mmol) in 30 mL of CH₂Cl₂was cooled to −78 °C.

DMSO (1.01 mL, 14.21 mmol) in 5 mL of CH₂Cl₂was added

via syringe and the mixture stirred for 5 min. The crude alcohol

above (1.6 g, 3.23 mmol) in 30 mL of CH₂Cl₂was added via

syringe followed by Et₃N (9.9 mL, 71.10 mmol). The mixture

was allowed to warm to room temperature and quenched with

1 N HCl. The two layers were separated and the aqueous layer

extracted with CH₂Cl₂. The combined organic extracts were

washed with brine, dried over MgSO₄and concentrated under

reduced pressure. Puriﬁcation by column chromatography

(SiO₂, 5:1 hexanes/EtOAc) gave 1.4 g (90%) of the

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corresponding 4 (2,3-dihydro-5-(4-(trimethylsilyl)but-3-yn-2-

yl)-1H-inden-4-yl)(2-(triisopropylsilyl)oxazol-5-yl)methanone

as a pale yellow waxy oil. R_f= 0.40 (5:1 hexanes/EtOAc) H

The product was then eluted from the silica gel with 30%

EtOAc/hexanes to give 392 mg (71%) of ethyl 10-methyl-16-

oxo-14-oxatetracyclo[7.7.0.0^2,6.0^11,15]hexadeca-1,6,8,11(15),12-

pentaene-12-carboxylate as a yellow solid. Mp: 128−130 °C. R_f

1

NMR (300 MHz, CDCl₃) δ 7.6 (1H, s), 7.49 (2H, d, J = 8 Hz),

7.33 (1H, d, J = 8 Hz), 3.77 (1H, q, J = 7.0 Hz), 2.90 (2H, t, J =

7.0 Hz), 2.67−2.64 (2H, m), 2.03 (2H, t, J = 7.0 Hz), 1.49−

1.43 (3H, m), 1.39 (3H, d, J = 6.9 Hz), 1.13 (18H, d, J = 7.5

Hz), 0.13 (9H, s) ¹³C NMR (125 MHz, CDCl₃) δ 174.7, 152.1,

143.6, 141.5, 138.9, 136.5, 133.8, 126.6, 126.0, 109.7, 86.1, 32.5,

31.9, 30.0, 25.8,25.3 11.2, 11.1, 0.3. FT-IR (CDCl₃, cm⁻¹).

2957, 1668, 1250. HRMS (ESI) calcd for C₂₉H₄₄NO₂Si₂[M +

H]⁺494.2911, found 494.2906. The solution of 4 (2,3-dihydro-

5-(4-(trimethylsilyl)but-3-yn-2-yl)-1H-inden-4-yl)(2-

(triisopropylsilyl)oxazol-5-yl)methanone (1.4 g, 2.83 mmol) in

MeOH (40 mL) was treated with K₂CO₃(1.56 g, 11.32 mmol)

at ice bath temperature. The mixture was warmed up to room

temperature and stirred for 4 h. The mixture was then

quenched with water, the two layers separated and the aqueous

layer extracted with Et₂O. The combined organic extracts were

washed with brine, dried over MgSO₄and concentrated under

reduced pressure. Puriﬁcation by column chromatography

(SiO₂, 5:1 to 2:1 hexanes/EtOAc) gave 608 mg (80%) of 59

1

= 0.35 (1:1 hexanes/EtOAc). H NMR (500 MHz, CDCl₃) δ

8.24 (1H, s), 7.45 (1H, d, J = 7.8 Hz), 7.35 (1H, d, J = 7.8. Hz),

4.53 (1H, q, J = 7.2 Hz), 4.42 (2H, q, J = 7.2 Hz), 3.65−3.44

(2H, m), 2.93 (2H, t, J = 7.5 Hz), 2.13 (2H, t, J = 7.5 Hz), 1.62

(3H, d, J = 7.2 Hz), 1.41 (3H, t, J = 6.9 Hz). ¹³C NMR (75

MHz, CDCl₃) δ 175.2, 162.4, 152.3, 148.7, 146.9, 145.8, 144.6,

138.6, 128.6, 128.1, 127.3, 118.8, 116.6, 61.1, 34.6, 34.2, 32.0,

25.7, 25.3, 14.5. FT-IR (CDCl₃, cm⁻¹) 2977, 1722, 1668, 1302,

1125, 1035. HRMS (ESI) calcd for C₁₉H₁₉O₄[M + H]⁺

311.1283, found 311.1285. To a solution of the dienone (350

mg, 1.13 mmol) in CH₂Cl₂(30 mL) at ice bath temperature

was added Et₃N (478 μL, 3.39 mmol) followed by TBSOTf

(519 μL, 2.26 mmol). The mixture was stirred for 30 min and

then quenched with sat. aq. NaHCO₃. The two layers were

separated and the aqueous layer extracted twice with CH₂Cl₂.

The combined organic extracts were washed with brine, dried

over MgSO₄, and concentrated under reduced pressure.

Puriﬁcation by column chromatography (20:1 hexanes/

EtOAc) gave 441 mg (92%) of the TBS phenol derivative as

a yellow solid. Mp: 146−148 °C. R_f= 0.75 (5:1 hexanes/

EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 8.29 (1H, s), 8.0 (1H,

d, J = 8.7 Hz), 7.39 (1H, d, J = 8.7 Hz), 4.42 (2H, q, J = 7.2

Hz), 3.65 (2H, t, J = 7.5 Hz), 3.09 (3H, s), 3.03 (2H, t, J = 7.5

Hz), 2.16 (2H, t, J = 7.5 Hz), 1.42 (3H, t, J = 7.2 Hz), 0.98

(9H, s), 0.33 (6H, s). ¹³C NMR (125 MHz, CDCl₃) δ 163.7,

153.6, 144.2, 139.9, 137.9, 135.2, 133.1, 124.9, 123.2, 121.4,

119.6, 117.8, 116.2, 65.6, 61.1, 37.2, 31.7, 26.5, 25.9, 19.4, 16.8,

14.6, −2.3. FT-IR (CDCl₃, cm⁻¹) 2930, 1728, 1465, 1373,

1253, 1142, 832. HRMS (ESI) calcd for C₂₅H₃₃O₄Si [M + H]⁺

425.2148, found 425.2147.

1

as a pale yellow waxy oil. R_f= 0.25 (2:1 hexanes/EtOAc). H

NMR (300 MHz, CDCl₃) δ 8.09 (1H, s), 7.56 (1H, s), 7.47

(1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 7.8 Hz), 3.72 (1H, q, J =

7.2 Hz), 2.91 (2H, t, J = 7.5 Hz), 2.80−2.60 (2H, m), 2.14 (1H,

s), 2.04 (2H, t, J = 7.5 Hz), 1.44 (3H, d, J = 7.2 Hz). ¹³C NMR

(125 MHz, CDCl₃) δ 185.2, 154.6, 150.4, 144.0, 141.8, 141.9,

138.6, 136.0, 133.0, 127.5, 126.4, 126.1, 87.1, 70.4, 32.8, 31.9,

28.7, 25.8, 24.9. FT-IR (CDCl₃, cm⁻¹) 3289, 2934, 1666, 1560,

1469, 1335, 1125, 848. HRMS (ESI) calcd for C₁₇H₁₆NO₂[M

+ H]⁺266.1181, found 266.1183.

Ethyl 4-{4-[(1,3-Oxazol-5-yl)carbonyl]-2,3-dihydro-1H-

inden-5-yl}pent-2-ynoate (60). The terminal alkyne 59 (600

mg, 2.26 mmol) in DMF (40 mL) was treated with

Pd(OAc)₂(PPh₃)₂(84.65 mg, 0.011 mmol) at rt. The ﬂask

was evacuated and backﬁlled with CO/O₂(1:1) in a balloon.

EtOH (6.6 mL, 50 mmol) was added via syringe and the

mixture stirred at rt for 64 h. After quenching with sat. aq.

NH₄Cl, the two layers were separated and the aqueous layer

extracted with EtOAc. The combined organic extracts were

washed twice with water and then rinsed with brine. After

drying over MgSO₄the extracts were concentrated under

reduced pressure. Puriﬁcation by column chromatography

(SiO₂, 3:1 hexanes/EtOAc) gave 671 mg (88%) of the ester

60 as a pale yellow sticky oil. R_f= 0.20 (1:1 hexanes/EtOAc)

¹H NMR (300 MHz, CDCl₃) δ 8.09 (1H, s), 7.59 (1H, s), 7.42

(1H, d, J = 7.8 Hz), 7.37 (1H, d, J = 7.8 Hz), 4.17 (2H, q, J =

7.8 Hz), 3.87 (1H, q, J = 7.2 Hz), 2.92 (2H, t, J = 7.2 Hz), 2.69

(2H, q, J = 7.5 Hz), 2.07 (2H, t, J = 7.5 Hz), 1.50 (3H, d, J =

7.2 Hz), 1.27 (3H, t, J = 7.5 Hz). ¹³C NMR (125 MHz, CDCl₃)

δ 185.2, 155.6, 150.1, 142.0, 139, 138.2, 132.5, 125.8, 125.2,

90.3, 74.2, 62.2, 32.5, 32.1, 28.5, 24.2, 23.9,14.2. FT-IR (CDCl₃,

cm⁻¹) 2980, 2237, 1710, 1666, 1561, 1469, 1253, 1127, 1037.

HRMS (ESI) calcd for C₂₀H₂₀NO₄[M + H]⁺338.1392 found,

338.1399.

Methyl (2E)-3-{16-[(tert-Butyldimethylsilyl)oxy]-10-

methyl-14-oxatetracyclo[7.7.0.0^2,6.0^11,15]hexadeca-

1,6,8,10,12,15-hexaen-12-yl}prop-2-enoate (62). DIBAL

(1 M in toluene, 1.13 mL, 1.13 mmol) was added dropwise to a

solution of the ester 61 (400 mg, 0.94 mol) in 10 mL of

anhydrous CH₂Cl₂at −78 °C. After the addition was complete,

the reaction mixture was stirred for 30 min, and then slowly

quenched with 2.5 mL of MeOH and 5 mL of Rochelle’s salt.

The gelatinous mixture was stirred at room temperature for 30

min. The precipitate was ﬁltered through a Celite pad and the

cake washed with EtOAc. The ﬁltrate was washed with brine,

dried over MgSO₄, and the solvent evaporated in vacuo to

aﬀord 359 mg of the alcohol which was used without further

puriﬁcation. Oxalyl chloride (177.5 μL, 2.07 mmol) in 20 mL of

CH₂Cl₂was cooled to −78 °C. DMSO (323 μL, 4.14 mmol) in

3 mL of CH₂Cl₂was added via syringe and the mixture stirred

for 5 min The crude alcohol (359 mg, 0.94 mmol) in 20 mL of

CH₂Cl₂was added and the mixture stirred for 15 min. Et₃N

(1.3 mL, 9.4 mmol) was added and the mixture was allowed to

warm to room temperature and quenched with dil. HCl. The

two layers were separated and the aqueous layer extracted with

CH₂Cl₂. The combined organic extracts were washed with

brine, dried over MgSO₄and concentrated under reduced

pressure. Puriﬁcation by column chromatography (10:1

hexanes/EtOAc) gave 322 mg (90%) of the furanoaldehyde

as a pale yellow solid. Mp: 156−158 °C. R_f= 0.75 (3:1

Ethyl 16-[(tert-Butyldimethylsilyl)oxy]-10-methyl-14-

oxatetracyclo[7.7.0.0^2,6.0^11,15]hexadeca-1,6,8,10,12,15-

hexaene-12-carboxylate (61). A solution of the alkyne

oxazole 60 (600 mg, 1.78 mmol) in 20 mL of dry 1,2-

dichlorobenzene was stirred for 6 h at 170 °C under a nitrogen

atmosphere. After cooling to rt, the mixture was passed through

a plug of silica gel using hexanes to elute 1,2-dichlorobenzene.

1

hexanes/EtOAc). H NMR (300 MHz, CDCl₃) δ 10.13 (1H,

s), 8.29 (1H, s), 8.10 (1H, d, J = 9.0 Hz), 7.42 (1H, d, J = 8.7

Hz), 3.65 (2H, t, J = 7.2 Hz), 3.15 (3H, s), 3.04 (2H, t, J = 7.5

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Hz), 2,17 (2H, t, J = 7.5 Hz), 0.98 (9H, s), 0.34 (6H, s). ¹³C

NMR (125 MHz, CDCl₃) δ 183.9, 159.8, 144.8, 140.0, 138.4,

133.4, 126.2, 125.0, 123.7, 122.2, 120.0, 117.7, 65.6, 37.1, 31.7,

26.5, 19.4, 18.0, −2.5. FT-IR (CDCl₃, cm⁻¹) 2928, 1690, 1153,

1390, 1370, 1252, 1160, 833. HRMS (ESI) calcd for

C₂₃H₂₉O₃Si [M + H]⁺381.1886, found 381.1880. To a stirred

solution of n-BuLi (1.6 M in hexanes, 1.48 mL, 2.37 mmol) in

THF (15 mL) was added the phosphonate reagent 34 (664 mg,

3.16 mmol) at ice bath temperature; the mixture was then

warmed to room temperature. After 15 min, a solution of the

aldehyde above (300 mg, 0.79 mmol) in THF (15 mL) was

added at 0 °C. The resulting mixture was stirred at 0 °C for 1 h,

quenched with NaHCO₃(5 mL) and extracted with EtOAc.

The organic extracts were dried over MgSO₄and concentrated

in vacuo. Puriﬁcation by column chromatography (SiO₂, 10:1

hexanes/EtOAc) gave 238 mg (69%) of the unsaturated ester

62 as a yellow solid. Mp: 168−170 °C. R_f= 0.5 (10:1 hexanes/

128.5, 127.2, 126.6, 123.2, 105.3, 79.5, 60.6, 32.5, 31.9, 30.4,

25.8, 24.7, 14.5. FT-IR (CDCl₃, cm⁻¹) 2979, 1720, 1666, 1184,

1042. HRMS (ESI) calcd for C₂₂H₂₁NO₄[M + H]⁺364.1549

found 364.1555.

3-{16-[(tert-butyldimethylsilyl)oxy]-10-methyl-14-

oxatetracyclo[7.7.0.0^2,6.0^11,15]hexadeca- 1,6,8,10,12,15-

hexaen-12-yl}propanal (52). A solution of the enyne oxazole

63 (100 mg, 0.28 mmol) in 10 mL of dry 1,2-dichlorobenzene

was stirred for 10 h in a 30 mL round-bottom ﬂask at 180 °C

under a nitrogen atmosphere. After cooling to room temper-

ature, the mixture was passed through a plug of silica gel using

100% hexanes to elute 1,2-dichlorobenzene. The product was

then eluted from the silica gel with 5:1 (hexanes/EtOAc) to

give 65 mg of 64 and 65 as a yellow solid. R_f= 0.45 (1:1

hexanes/EtOAc). To a solution of the mixture of 64 and 65 (65

mg) in EtOAc (5 mL) at −10 °C was added approximately 40

mg (10%) of 5% Pd/C. The ﬂask was evacuated and then

backﬁlled by attaching a balloon full of H₂. The mixture was

vigorously stirred for 1 h at −10 °C and then ﬁltered through a

Celite pad. The ﬁltrate was concentrated in vacuo to give 60 mg

of the corresponding ethyl 3-{10-methyl-16-oxo-14-

oxatetracyclo[7.7.0.0^2,6.0^11,15]hexadeca-1,6,8,11(15)-12-pen-

taen-12-yl}propanoate, as pale yellow oil. R_f= 0.40 (1:1

hexanes/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 7.52 (1H, s),

7.46 (1H, d, J = 7.8 Hz), 7.30 (1H, d, J = 7.8 Hz), 4.18 (2H, q, J

= 6.8 Hz), 3.58 (2H, q, J = 6.8 Hz), 2.92 (2H, t, J = 7.2 Hz),

2.68 (2H, t, J = 7.5 Hz), 2.34 (2H, t, J = 6.9 Hz), 1.54 (3H, d, J

= 9 Hz), 1.26 (3H, t, J = 7.8 Hz). A solution of the dienone

above (60 mg, 0.18 mmol) in CH₂Cl₂(5 mL) at ice bath

temperature was treated with Et₃N (75 μL, 0.54 mmol)

followed by TBSOTf (83 μL, 0.36 mmol). The mixture was

stirred at ice bath temperature for 30 min and then quenched

with sat. aq. NaHCO₃.The two layers were separated and the

aqueous layer extracted with CH₂Cl₂. The combined organic

extracts were washed with brine, dried over MgSO₄and

concentrated under reduced pressure. Puriﬁcation by column

chromatography (SiO₂, 10:1 hexanes/EtOAc) gave 71 mg

(86%) of the desired product as a yellow oil. R_f= 0.75 (4:1

hexanes/EtOAc). ¹H NMR (300 MHz, CDCl₃): ¹H NMR (300

MHz, CDCl₃) δ 7.90 (1H, d, J = 8.7 Hz), 7.39 (1H, s), 7.34

(1H, d, J = 8.7 Hz), 4.18 (2H, q, J = 7.5 Hz), 3.65 (2H, t, J =

7.2 Hz), 3.25 (2H, t, J = 8.4 Hz), 3.02 (2H, t, J = 7.5 Hz), 2.89

(3H, s), 2.76 (2H, t, J = 7.2 Hz), 2.15 (2H, q, J = 7.2 Hz), 1.26

(3H, t, J = 7.0 Hz), 0.95 (9H, s), 0.35 (6H, s). A solution of the

ester above (70 mg, 0.15 mmol) in 8 mL of dry CH₂Cl₂was

cooled to −78 °C. DIBAL-H (1 M in toluene, 165 μL, 0.165

mmol) was added dropwise. The reaction mixture was stirred

for 30 min and then slowly quenched with 1 mL of MeOH

followed by 2 mL of Rochelle’s salt and warmed and stirred at

room temperature for 30 min. The precipitate was ﬁltered

through a Celite pad and the ﬁltrate was washed with brine,

dried over anhydrous MgSO₄, and the solvent evaporated in

vacuo to aﬀord 48 mg (79%) of the aldehyde 52.

1

EtOAc). H NMR (300 MHz, CDCl₃) δ 8.13 (1H, d, J = 15.6

Hz), 7.92 (1H, d, J = 9.0 Hz), 7.84 (1H, s), 7.38 (1H, d, J = 8.7

Hz), 6.32 (1H, d, J = 15.9 Hz), 3.84 (3H, s), 3.65 (2H, t, J = 7.2

Hz), 3.03 (2H, t, J = 7.8 Hz), 2.89 (3H, s), 2,27 (2H, t, J = 7.5

Hz), 0.98 (9H, s), 0.34 (6H, s). ¹³C NMR (75 MHz, CDCl₃) δ

167.3, 144.6, 140.6, 138.3, 136.6, 130.9, 122.9, 122.3, 119.5,

52.0, 36.0, 33.2, 26.5, 25.4, 19.4, 16.0, −2.5. FT-IR (CDCl₃

cm⁻¹) 2951, 1719, 1169, 832. HRMS (ESI) calcd for

C₂₆H₃₃O₄Si [M + H]⁺437.2148, found 437.2150.

Methyl 3-{16-[tert-Butyldimethylsilyl)oxy]-10-methyl-

14-oxatetracyclo methyl-14-oxatetracyclo-

[7.7.0.0.^2,6.0^11,15]hexadeca-1,6,8,10,12,15-hexaen-12-yl}-

propanoate (38) and Methyl 3-{16-[tert-

Butyldimethylsilyl)oxy]-10-methyl-14-oxatetracyclo

[7.7.0.0^2,6.0^11,15]hexadeca-1,6,8,10,15-pentaen-12-yl}-

propanoate (39). To a solution of unsaturated ester 62 (200

mg, 0.46 mmol) in 10 mL of ethyl acetate at −10 °C was added

5% Pd on carbon (96 mg, 0.046 mmol) portion wise over 1 h.

The reaction mixture was stirred for 1.5 h under a balloon of H₂

at −10 °C and then ﬁltered through a Celite pad. The ﬁltrate

was concentrated in vacuo to give a yellow residue. Puriﬁcation

by column chromatography (SiO₂, 10:1 hexanes/EtAOc) gave

160 mg mixture of 38 and 39. Recrystallization from hexanes

gave 139 mg (69%) of the furan saturated ester 38 as pale

yellow needle crystals and 20 mg (10%) of dihydrofuran 39 as a

yellow oil.

Ethyl (2Z)-6-{4-[(1,3-Oxazol-5-yl)carbonyl]-2,3-dihy-

dro-1H-inden-5-yl}hept-2-en-4-ynoate (63). A mixture of

the terminal alkyne 59 (100 mg, 0.38 mmol) and iodoacrylate

45 (103 mg, 0.46 mmol) in THF (10 mL) were treated with

PdCl₂(PPh₃)₂(14 mg, 0.02 mmol) and CuI (3.8 mg, 0.02

mmol) under N₂atmosphere; 2.17 mL of Et₃N (265 μL, 1.9

mmol) was added via syringe and the mixture stirred at rt for 3

days then quenched with sat. aq. NH₄Cl. The two layers were

separated and the aqueous layer extracted with EtOAc. The

combined organic extracts were dried over MgSO₄, washed

with brine, and concentrated under reduced pressure.

Puriﬁcation by column chromatography (SiO₂, 3:1 hexanes/

EtOAc) gave 108 mg (78%) of 63 as a brown sticky oil. R_f=

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H NMR and ¹³C NMR spectra for new compounds and a CIF

ﬁle for syn-53 (=3). This material is available free of charge via

the Internet at http://pubs.acs.org.

1

0.25 (2:1 hexanes/EtOAc). H NMR (300 MHz, CDCl₃) δ

8.09 (1H, s), 7.59 (1H, s), 7.56 (1H, d, J = 7.5 Hz), 7.38 (1H,

d, J = 8.0 Hz), 6.07−6.00 (2H, m), 4.21 (2H, q, J = 7.0 Hz),

3.96 (1H, q, J = 7.5 Hz), 2.92 (2H, t, J = 7.5 Hz), 2.77−2.73

(1H, m), 2.69−2.63 (1H, m), 2.09−2.03 (2H, m), 1.52 (3H, d,

J = 7.0 Hz), 1,27 (3H, t, J = 7.0 Hz). ¹³C NMR (125 MHz,

CDCl₃) δ 185.2, 164.9, 154.5, 144.1, 141.8, 138.6, 136.1, 133.0,

AUTHOR INFORMATION

Corresponding Author

*peter.a.jacobi@dartmouth.edu

■

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The Journal of Organic Chemistry

Article

(32) Mascall, K. C.; Jacobi, P. A. Tetrahedron Lett. 2012, 53, 1620.

(33) Kelly, T. R.; Bell, S. H.; Ohashi, N.; Armstrong-Chong, R. J. Am.

Chem. Soc. 1988, 110, 6471.

Notes

The authors declare no competing ﬁnancial interest.

(34) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815.

(35) Trost, B. M.; Malhotra, S.; Olson, D. E.; Maruniak, A.; Du Bois,

J. J. Am. Chem. Soc. 2009, 131, 4190.

(36) Bender, D. R.; Kanne, D.; Frazier, J. D.; Rapoport, H. J. Org.

Chem. 1983, 48, 2709.

ACKNOWLEDGMENTS

■

This work was supported in part by the National Science

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7427

dx.doi.org/10.1021/jo301232w | J. Org. Chem. 2012, 77, 7411−7427

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Synthetic studies on furanosteroids: Construction of the viridin core structure via diels-alder/ retro- diels-alder and vinylogous mukaiyama aldol-type reaction

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