Toward a synthesis of hirsutellone B by the concept of double cyclization

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Toward a Synthesis of Hirsutellone B by the Concept of Double

Cyclization

Keith P. Reber, S. David Tilley, Cheryl A. Carson, and Erik J. Sorensen*

Frick Chemistry Laboratory, Department of Chemistry, Princeton University, Princeton, New Jersey, 08544, United States

*

S Supporting Information

ABSTRACT: This account describes a strategy for directly forming three of the six rings found in the polyketide natural product

hirsutellone B via a novel cyclization cascade. The key step in our approach comprises two transformations: a large-ring-forming,

nucleophilic capture of a transient acylketene and an intramolecular Diels−Alder reaction, both of which occur in tandem

through thermolyses of appropriately functionalized, polyunsaturated dioxinones. These thermally induced “double cyclization”

cascades generate three new bonds, four contiguous stereocenters, and a signiﬁcant fraction of the polycyclic architecture of

hirsutellone B. The advanced macrolactam and macrolactone intermediates that were synthesized by this process possess key

features of the hirsutellone framework, including the stereochemically dense decahydroﬂuorene core and the strained para-

cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon−carbon bond

formation were undermined by competitive O-alkylation reactions. This account also documents how we adapted to this

undesired outcome through an evaluation of several distinct strategies for synthesis, as well as our eventual achievement of a

formal total synthesis of hirsutellone B.

INTRODUCTION

promising antitubercular activity, and they have emerged as

compelling targets for research eﬀorts in organic synthesis.

■

6

−11

Hirsutellone B (1) is one of ﬁve structurally related natural

As of this writing, three total syntheses of hirsutellone B (1)

have been described. The ﬁrst synthesis of this natural product

^p^r^o^d^u^c^t^sⁱ^s^o^l^a^t^e^d^f^r^o^m^t^h^eⁱⁿ^s^e^c^t^p^a^t^h^o^g^eⁿⁱ^c^f^uⁿ^g^u^s^Hⁱ^r^s^u^t^e^l^l^a1

nivea BCC 2594 in 2005 by Isaka and co-workers (Figure 1).

12

was reported by Nicolaou in 2009, and their group later

developed a second bioinspired route to access hirsutellones A,

The stereochemically complex decahydroﬂuorene core (i.e., the

fused 6−5−6 ring system) and 13-membered para-cyclophane

ether that distinguish these natural products are also found in

13

B, and C. The Nicolaou approach oﬀers an incisive, direct

construction of the tricyclic decahydroﬂuorene framework of 1

from a polyunsaturated acyclic precursor and a late-stage

2

3

the related GKK1032s (2), pyrrocidines (3), and pyrrospir-

4

ones (4). This intriguing polycyclic architectural motif is thus

Ramberg−Bac

̈

klund ring contraction to form the strained para-

the hallmark of an expansive group of biologically active

polyketide natural products.

The isotope incorporation studies of Oikawa demonstrated

that the impressive molecular structure of GKK1032A (2)

originates from one molecule of tyrosine, nine molecules of

acetic acid, and ﬁve molecules of L-methionine. On the basis of

these observations, they reasoned that four of its six rings arise

by a remarkable tetracyclization of the polyunsaturated

cyclophane ether. The third total synthesis of hirsutellone B

14

was achieved in 2011 by Uchiro and features an intra-

molecular Ullmann reaction to annulate the para-cyclophane

onto a functionalized decahydroﬂuorene core.

2

5

Our laboratory was intrigued by the possibility of directly

forming much of the structure of hirsutellone B from a

trisubstituted cyclohexane by capitalizing on the intrinsic

15

reactivity of acylketene 7 (Figure 1). In the course of this

double cyclization” event, three new rings would arise by an

nonaketide 5 (Figure 1). In relation to GKK1032A (2), the

2

“

hirsutellones possess four fewer methyl groups as well as the

opposite conﬁguration at the C-13 stereocenter. Presumably, an

analogous tetracyclization of the monomethylated, tyrosine

nonaketide 6 aﬀords the related structure of hirsutellone B (1),

although this seemingly plausible biogenetic connection

remains unproven.

internal nucleophilic capture of a transient acylketene and a

concomitant intramolecular Diels−Alder (IMDA) reaction.

Herein, we provide the full account of our development of this

concept for synthesis as well as our investigations of several

distinct strategies for addressing the challenging para-cyclo-

phane ether substructural element of hirsutellone B. We also

Isaka and co-workers also reported that the hirsutellones

inhibit Mycobacterium tuberculosis H Ra with minimum

3

7

inhibitory concentration values in the range of 0.78−3.125

Received: August 15, 2013

Published: September 13, 2013

1

μg/mL. The hirsutellones thus oﬀer a new chemotype with

©

2013 American Chemical Society

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Figure 1. (i) Structures of hirsutellone B and related natural products and (ii) concepts for evolving these polycyclic architectures from

polyunsaturated precursors.

describe the preparation of an advanced intermediate that

intercepts Nicolaou’s pioneering route to hirsutellone B,

constituting a formal total synthesis of this natural product.

would induce a cycloreversion, expelling acetone to give

15

transient acylketene 7. This reactive intermediate could then

be trapped intramolecularly by the pendent amine to form the

macrocyclic β-keto amide 9. However, the thermal fragmenta-

tion of the dioxinone heterocycle in 8 would also generate an

α,β-unsaturated ketone, which, in the presence of the

conjugated triene, could undergo an intramolecular Diels−

Alder reaction to complete the decahydroﬂuorene framework

(9 → 10). We were willing to accept the risk associated with

this concept for synthesis because of its potential to deal

directly with the complex cyclic connectivity of hirsutellone B.

We also anticipated that the setup costs for synthesizing the

required trisubstituted cyclohexane 8 would not be excessively

high.

RESULTS AND DISCUSSION

■

We envisioned that much of the complexity of the hirsutellone

framework could be generated in a single step through a

tandem reaction sequence, as shown in Scheme 1. Inspired by

Boeckman’s elegant tetronolide synthesis, we hoped to make

use of an intramolecular acylketene capture/IMDA cascade,

which, to the best of our knowledge, was unprecedented in the

chemical literature. Thus, thermolysis of vinyldioxinone 8

16

Scheme 1. Acylketene Trapping/IMDA Cascade To Access

the Hirsutellone Framework (DMB = 2,4-Dimethoxybenzyl;

If we could generate compound 10 by a thermolysis of

dioxinone 8, we believed that the γ-lactam ring could be formed

P = TBDPS = t-BuPh Si)

2

via a transannular alkylation (S i) reaction to give 11,

N

completing the full carbon skeleton of the natural product. At

this stage, a ﬁnal C−H oxidation would install the hemiaminal

functionality, and subsequent cleavage of the nitrogen

protecting group would provide rapid access to hirsutellone B.

Having formulated an attractive strategy for contending with

the polycyclic structure of hirsutellone B, we turned our

attention to the synthesis of key intermediate 8 (Figure 2). Our

approach focused on three strategic bond disconnections,

7

ultimately leading to α-hydroxy aldehyde 16. This trisub-

Figure 2. Strategic bond disconnections for the synthesis of key

intermediate 8.

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stituted cyclohexane intermediate would then serve as a central

scaﬀold onto which the remaining three fragments could be

appended. We proposed that the desired aryl ether bond could

be formed via a palladium-catalyzed Tsuji−Trost reaction with

Having accessed phenol 14, our next objective was to

investigate formation of the key aryl ether linkage via a

palladium-catalyzed Tsuji−Trost reaction. Our initial eﬀorts

toward the decahydroﬂuorene core of the hirsutellones led us

1

7

phenol 14. Our design also makes use of the Wittig reaction

to form two key carbon−carbon bonds, utilizing phosphonium

to develop a synthesis of enantioenriched allylic alcohol 12,

which is the product of a Wittig reaction between α-hydroxy

aldehyde 16 and phosphorane 15 (see Figure 2). Although we

originally converted secondary alcohol 12 to the corresponding

allylic carbonate, all attempts to engage this substrate in a

Tsuji−Trost reaction with the sodium phenolate of 14 were

unsuccessful. Similarly, no reaction was observed using the

corresponding allylic acetate or triﬂuoroacetate esters, despite

our eﬀorts to screen many diﬀerent palladium sources and

ligands. In an attempt to enhance the reactivity of the substrate,

we next explored preparation of the related allylic phosphate

1

8

19

salt 13 and the known phosphorane 15. In both cases, the

use of a stabilized or semistabilized phosphorus ylide would

20

establish the desired trans oleﬁn geometry.

We began our synthesis of phenol coupling partner 14 by

21

protecting known tyrosinol derivative 17 as the correspond-

ing bis-TBDPS (t-BuPh Si) ether, as shown in Scheme 2. When

2

Scheme 2. Synthesis of Phenol Coupling Partner 14

24

(

Scheme 3). Thus, deprotonation of alcohol 12 at low

temperature with methyllithium followed by the addition of

diethyl chlorophosphate cleanly gave allylic phosphate 20 in

8

2% yield. When this substrate was treated with the sodium

phenolate of 14 in the presence of 10 mol % of Pd(PPh ) as

3

4

catalyst, we were pleased to observe the rapid formation of 21,

which contained the desired aryl ether linkage. Despite two

potential sites of nucleophilic attack on the intermediate

palladium π-allyl complex, only the regioisomer that maintains

conjugation of the oleﬁn with the dioxinone ring was observed.

Furthermore, this reaction proceeds with overall retention of

conﬁguration, as is well-documented for the Tsuji−Trost

this compound was treated with tetrabutylammonium ﬂuoride

at 0 °C, selective deprotection of the phenolic silyl ether

occurred to give free phenol 18 in 81% yield over the two steps.

Subsequent removal of the Boc group proceeded cleanly with

triﬂuoroacetic acid to form ammonium salt 19. On the basis of

the precedent from Pfaltz and Suzuki’s synthesis of macrocidin

25

reaction.

With the key aryl ether in place, we turned our attention to

the construction of the triene side chain. Acid-induced

desilylation of 21 gave primary alcohol 22 in 82% yield.

However, oxidation of this alcohol to the corresponding

aldehyde in the presence of the secondary benzylic amine

proved to be diﬃcult. After screening several diﬀerent oxidation

2

A, we anticipated that transannular alkylation to form the γ-

lactam ring (i.e., 10 → 11) would only be possible if the

macrolactam were protected as a tertiary amide. Therefore, we

decided to utilize the 2,4-dimethoxybenzyl (DMB) protecting

group, which could be readily cleaved at a late stage in the

2

6

methods (e.g., Dess−Martin periodinane, PCC, MnO ,

2

27

28

Swern ), we found that the Ley oxidation gave the best

results, producing amino aldehyde 23 in 62% yield. Subsequent

Wittig oleﬁnation with the phosphorus ylide derived from 13

proceeded smoothly to give triene 8 in 76% yield as a 7:1

mixture of inseparable E/Z isomers.

23

synthesis under acidic conditions. We found that this group

was easily installed via reductive amination of 19 with 2,4-

dimethoxybenzaldehyde and sodium triacetoxyborohydride to

give the desired DMB-protected coupling partner 14 in 77%

yield over the two steps.

With key intermediate 8 in hand, we were in a position to

test the feasibility of the tandem ketene trapping/IMDA

Scheme 3. Synthesis of Key Triene Intermediate 8 and Execution of the Cyclization Cascade To Form 10 (TPAP =

Tetrapropylammonium Perruthenate; KHMDS = Potassium Bis(trimethylsilyl)amide)

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sequence portrayed in Scheme 1. Our initial attempts to bring

about this transformation in reﬂuxing toluene or xylenes were

unsuccessful. Despite our best eﬀorts to run the reaction under

scrupulously anhydrous conditions (azeotropic drying of the

starting material, ﬂame-dried glassware, and freshly distilled

solvent), we were only able to obtain products derived from

trapping of the putative acylketene intermediate with

adventitious water. However, when a 0.3 mM solution of 8

was heated in reﬂuxing benzene under Dean−Stark con-

Since our eﬀorts to form the γ-lactam ring via an

intramolecular nucleophilic displacement were unsuccessful,

we decided to explore an intramolecular Knoevenagel

condensation as an alternative way to make the carbon−carbon

bond (Scheme 5). Importantly, we anticipated that conjugate

Scheme 5. Attempted Synthesis of 28 via an Intramolecular

Knoevenagel Condensation

2

9

ditions for 14 h, we were pleased to observe formation of the

desired macrocycle 10 as a single diastereomer in 39−50% yield

(

Scheme 3). We suggest that the reactive acylketene 7 may well

be a ﬂeeting intermediate on the path leading from compound

to polycycle 10. Although the precise ordering of the new

8

bond constructions is unclear, the production of compound 10

from unsaturated dioxinone 8 is consistent with an endo-

selective IMDA reaction to form the decahydroﬂuorene core

and an intramolecular trapping of the acylketene intermediate

by the pendent secondary amine to form the macrolactam ring.

Notably, this cascade process rapidly generates much of the

complex topology of hirsutellone B: three new rings, including

a strained cyclophane, three new bonds, and four contiguous

stereocenters are formed in a single laboratory operation.

Having realized our key tandem reaction sequence, we

eagerly turned our attention to the transannular carbon−carbon

bond formation that would form the γ-lactam ring and

complete the carbon framework of hirsutellone B. Desilylation

of 10 proceeded smoothly with tetrabutylammonium triphenyl-

diﬂuorosilicate (TBAT), giving primary alcohol 24 in 98% yield

reduction of the expected condensation product 28 would lead

to the same γ-lactam 11 targeted in our previous alkylation

strategy. To this end, alcohol 24 was oxidized to the

corresponding aldehyde 27 in good yield using Dess−Martin

(

Scheme 4). At this point, all that remained was to activate the

26

periodinane (DMP). However, the intramolecular condensa-

tion product 28 was not observed under basic or acidic

cyclization conditions, and we were unable to obtain any

evidence for carbon−carbon bond formation. In fact, the only

reaction that occurred under basic conditions was slow

epimerization at the α-position of aldehyde 27. An attempted

intramolecular Claisen condensation using the corresponding

methyl ester was similarly unsuccessful, leading only to

recovered starting material.

Scheme 4. Unexpected Formation of Acylketene

Hemiaminal Ether 26

On the basis of these unsuccessful attempts at carbon−

carbon bond formation, we believe that there are several factors

that could make this type of transannular reaction quite

challenging. First, the preferred conformations of macrocyclic

rings are diﬃcult to predict, and it is possible that the reactive

30

centers are too far apart to enable facile ring closure. In

addition, restricted rotation about the amide C−N bond may

further bias the conformation of the macrocycle, preventing

correct alignment for nucleophilic attack of the enolate at

carbon rather than at oxygen. Finally, and perhaps most

signiﬁcantly, there is a considerable diﬀerence in strain between

the starting 14-membered cyclophane and the 13-membered

cyclophane present in the natural product. Therefore, the

desired transannular ring closure may be disfavored due to the

buildup of strain in the transition state leading to carbon−

carbon bond formation.

In light of the unexpected diﬃculty of transannular carbon−

carbon bond formation, we chose to modify our strategy. More

speciﬁcally, we reasoned that targeting a macrolactone instead

of a macrolactam could impart more conformational ﬂexibility

for the desired alkylation reaction. Moreover, the carbonyl

oxygen of the ester group should be less nucleophilic than that

of an amide, disfavoring the undesired O-alkylation product.

Finally, examination of hand-held molecular models suggested

that a more favorable trajectory for transannular C-alkylation

primary alcohol and induce the desired S i reaction upon

N

treatment with a suitable base. In the event, treatment of

alcohol 24 with methanesulfonyl chloride in the presence of

triethylamine gave the corresponding primary mesylate 25,

which proved to be somewhat unstable. To our surprise, when

2

5 was treated with the amidine base DBU, the desired product

11 was not formed; instead, we were only able to isolate the

isomeric O-alkylated compound 26, which features an unusual

acylketene hemiaminal ether. Indeed, we were never able to

isolate the desired C-alkylated product 11, despite extensive

experimentation with diﬀerent leaving groups, bases, and Lewis

acid additives.

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might be achieved using a substrate with the alternative

conﬁguration at the carbon bearing the side chain with the

leaving group.

With these points in mind, we devised a new approach to

hirsutellone B, as shown in Scheme 6. Thus, thermolysis of

tosylate ester as a protecting group that could also serve as a

leaving group for γ-lactone formation after the macro-

lactonization step. Thus, the known enantioenriched diol

31

34 was monoprotected with p-toluenesulfonyl chloride to

give the desired primary tosylate 35 in 75% yield. Under the

basic conditions of the Tsuji−Trost reaction, we found that

intramolecular nucleophilic displacement of tosylate to give the

corresponding epoxide was a signiﬁcant side reaction. There-

fore, the secondary alcohol of 35 was protected as the

corresponding TBS ether to give 36 in 98% yield. Finally,

hydrogenolysis of the benzyl ether proceeded smoothly to give

the desired phenol 37 in high yield.

Scheme 6. Revised Strategy to Hirsutellone B Featuring a

Macrolactone Intermediate

We were pleased to ﬁnd that the Tsuji−Trost reaction of

allylic phosphate 20 and the sodium phenolate derived from 37

proceeded under our standard coupling conditions to give 38 in

6

5% yield (Scheme 8). Notably, intermolecular phenolate

displacement of tosylate was not observed, likely due to the

steric bulk of the nearby TBS group and the rapid rate of aryl

ether bond formation. Simultaneous deprotection of both TBS

groups could be accomplished under mild conditions using

excess triethylamine trihydroﬂuoride to give diol 39 in 88%

yield. At this point, we hoped to achieve a chemoselective

oxidation of the primary alcohol in the presence of the free

secondary alcohol. We found that this could be achieved using

1

0 mol % of TEMPO and stoichiometric iodobenzene

32

diacetate to give aldehyde 40 in 95% yield without any

detectable ketone byproduct or undesired epimerization at the

α-position of the aldehyde.

Having obtained aldehyde 40, we turned our attention to

installation of the triene. In our previous routes, the triene had

been introduced using a Wittig reaction with the ylide derived

from phosphonium salt 13. However, this reaction had several

disadvantages. First, the triene product was typically formed as

a 7:1 mixture of E/Z isomers that were inseparable by silica gel

chromatography. In addition, some material was always lost due

to competitive nucleophilic opening of the dioxinone ring by

excess ylide. Moreover, α-hydroxy tosylate 40 was unstable

under basic conditions, and the corresponding epoxide was

formed as a signiﬁcant byproduct. To overcome these

diﬃculties, we decided to use an alternative two-step procedure

dioxinone 29 would initiate a similar tandem acylketene

capture/IMDA sequence to give macrolactone 30. At this

stage, it was our hope that transannular γ-lactone formation

could be achieved through intramolecular nucleophilic displace-

ment to form 31, completing the carbon framework of

hirsutellone B. Another attractive feature of this strategy is

the straightforward endgame which would not require a late-

stage C−H functionalization. Thus, nucleophilic opening of γ-

lactone 31 with ammonia would form primary amide 32.

Finally, oxidation of the resulting secondary alcohol would give

ketone 33, which would yield hirsutellone B (1) directly via

intramolecular hemiaminal formation. With our new strategy

established, we turned our attention to the synthesis of the

required triene substrate 29.

8

to introduce the triene, as reported by Liu. Thus, Takai

33

oleﬁnation of aldehyde 40 gave exclusively (E)-vinyl iodide

1 in 74% yield, avoiding the mixture of oleﬁn isomers obtained

4

34

in the Wittig reaction. A subsequent Stille coupling of 41 with

35

known dienyl stannane 42 proceeded under mild conditions

at room temperature to give the desired triene 29 in 85% yield.

Having secured our key intermediate, the stage was set for

the tandem intramolecular acylketene capture/IMDA reaction.

Interestingly, we found that this macrolactonization was much

more sensitive to concentration than our previous acylketene-

trapping cascade. As with any macrocyclization, dilute

conditions are necessary to disfavor competing intermolecular

oligomerization reactions. Typically, we had been able to

achieve good yields of our intramolecular acylketene-trapping

products at a concentration of 0.3 mM. However, when the

cyclization of compound 29 was attempted at this concen-

tration, the desired macrolactone 30 was obtained only in low

yield; to our surprise, the major product was the 28-membered

dimer 43. The formation of 43 suggests that the acylketene

derived from 29 may be relatively long-lived; that is, trapping of

this intermediate by the pendent secondary alcohol is slow. We

attribute this phenomenon to the reduced nucleophilicity of the

secondary alcohol due to the inductive eﬀect of the nearby

Our ﬁrst goal was preparing the new phenol coupling partner

7, as shown in Scheme 7. For this route, we selected a primary

3

Scheme 7. Synthesis of Enantioenriched Phenol Coupling

Partner 37

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Scheme 8. Synthesis of Key Triene Intermediate 29 and Its Unexpected Dimerization

tosylate group. Indeed, it has been experimentally observed that

the rate of alcohol addition to acylketenes correlates with the

relative nucleophilicity of the attacking species.

Fortunately, we were able to minimize the formation of 43

by running the reaction at a lower concentration of 0.1 mM;

this aﬀorded a single diastereomer of the desired macrolactone

in toluene, we were surprised to isolate the relatively unstable

acylketene acetal 45. As was observed in our previous

macrolactam route, compound 45 is the product of undesired

O-alkylation of the ester carbonyl group.

36

Similarly, when the alkylation reaction was run in the

presence of chelating Lewis acids, acylketene acetal 45 was still

the only isolable product. Indeed, controlling the selectivity of

C- versus O-alkylation is a general problem in the reaction of

electrophiles with enolates derived from 1,3-dicarbonyl

30 in 50% yield, as shown in Scheme 9. At this stage, we began

Scheme 9. Attempted γ-Lactone Synthesis and Formation of

Acylketene Acetal 45

3

7

compounds. For intermolecular alkylation reactions, C-

alkylation can often be favored by choosing an appropriate

solvent, counterion, or leaving group. However, the corre-

sponding intramolecular alkylation reactions are often con-

trolled by stereoelectronic eﬀects and strongly favor O-

38

alkylation regardless of the reaction conditions.

One of the few reliable methods to favor C-alkylation of 1,3-

39

dicarbonyl compounds involves the use of thallium enolates.

This methodology was pioneered by Taylor, who postulated

that the general insolubility of thallium enolates accounted for

the observed selectivity. Although thallium enolates of β-keto

esters are typically generated using thallium(I) ethoxide, we

found that tosylate 30 decomposed under these conditions.

However, the combination of thallium(I) carbonate and DBU

cleanly converted 30 to a new compound, which was identiﬁed

as 46 (Scheme 10). Notably, compound 46 is the geometrical

isomer of acylketene acetal 45, the product obtained upon

exposure of 44 to DBU alone (see Scheme 9). The origin of

this remarkable switch in stereoselectivity is unclear. One

possibility is that the thallium salt forms a strong chelate with

the 1,3-dicarbonyl that enforces a speciﬁc geometry for the

alkylation step. Notably, the thallium(I) cation is a soft

screening conditions to induce γ-lactone formation via a

transannular S i reaction (see 30 → 31, Scheme 6).

N

Unfortunately, treatment of 30 with a wide variety of bases

resulted either in no reaction or slow decomposition of the

starting material. Closer examination of a hand-held model

suggested that a more favorable trajectory for alkylation might

be achieved if the two carbonyl groups were held in a syn

orientation. Thus, several chelating Lewis acids were also

screened in combination with either triethylamine or DBU as a

base. However, none of the desired γ-lactone product 31 was

observed under any of these conditions.

39

electrophile and known to be highly enophilic; therefore,

coordination with the nearby vinyl group could lead to the

formation of a π-complex that inﬂuences the observed enolate

geometry.

Interestingly, acylketene acetal 46 was unstable in solution

and slowly isomerized to its geometrical isomer 45 at a rate of

1

approximately 1% per hour, as determined by H NMR. As

In an eﬀort to enhance the reactivity of the substrate, we

decided to convert the primary tosylate into a diﬀerent leaving

group. We found that the Finkelstein reaction of 30 with

sodium iodide in acetone was relatively slow and required

heating to 45 °C to give primary iodide 44 in 54% yield.

However, when this compound was treated with DBU at 45 °C

mentioned previously, 45 is a somewhat sensitive compound,

complicating isolation and puriﬁcation. We found that upon

exposure to silica gel, acylketene acetals 45 and 46 were

converted to macrolactone 49 in quantitative yield. We propose

that 45 is protonated by the mildly acidic silica gel to give a

resonance-stabilized oxocarbenium ion 47 that could be

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Scheme 10. Formation of Acylketene Acetal 46 and Its

Subsequent Ring Expansion to 49

Scheme 11. Proposed Carroll Rearrangement for the Formal

Synthesis of Hirsutellone B (LiHMDS = Lithium

Bis(trimethylsilyl)amide)

trapped by adventitious water to give 48. This intermediate

could then open to give macrolactone 49; presumably, this

transformation is driven by release of strain upon ring

expansion to the larger 15-membered cyclophane.

penultimate intermediate in Nicolaou’s total synthesis of

12

hirsutellone B.

The synthesis of the phenol coupling partner required for

44

this route began with TBS-protected 4-bromophenol 56,

Despite extensive experimentation, we were never able to

observe formation of the desired γ-lactone 31. Having obtained

the same undesired O-alkylation product in both of our

which was converted to the corresponding Grignard reagent 57

under standard conditions (Scheme 12). After titration, a

transannular S i substrates, we decided to abandon this

Scheme 12. Synthesis of Phenol Coupling Partner 60

N

particular strategy toward hirsutellone B. It is likely that the

conformation of the macrocycle does not allow the two reactive

centers to come close enough for carbon−carbon bond

formation to occur. Undoubtedly, this conformational

restriction is due to the strained nature of the cyclophane

ring, which remains the most challenging feature of this natural

product.

In developing a new route toward hirsutellone B, we wished

to retain the intramolecular acylketene trapping/IMDA cascade

to simultaneously construct the tricyclic core and the

cyclophane ring. However, instead of using a polar S_Ni

mechanism to form the transannular carbon−carbon bond,

we sought to explore pericyclic and radical reactivity. To this

end, we targeted macrolactone 50 as a potentially attractive

substrate, as shown in Scheme 11. One possibility for ring

contraction of 50 is the Carroll rearrangement, which

4

5

solution of 57 was added to known allylic bromide 58 to form

the coupled product 59. Upon workup, the crude product was

treated with lithium hydroxide to chemoselectively cleave the

phenolic TBS group, giving the desired phenol 60 in 77% yield

over the three steps.

40

transforms allyl β-keto esters into γ,δ-unsaturated ketones.

This reaction would proceed through enol tautomer 51, which

undergoes a [3,3]-sigmatropic rearrangement to give β-keto

acid 52. Under the thermal reaction conditions, 52 would

spontaneously decarboxylate to give ring-contracted ketone 53.

Alternatively, macrolactone 50 might be directly converted to

The Tsuji−Trost reaction of allylic phosphate 20 and the

sodium phenolate derived from 60 proceeded under our

standard coupling conditions to give aryl ether 61 (Scheme 13).

After chemoselective desilylation of the primary TBS group,

alcohol 62 was isolated in 60% yield over the two steps.

Oxidation of 62 with DMP cleanly gave aldehyde 63 in 90%

yield, and subsequent Takai oleﬁnation proceeded in 86% yield

to give exclusively (E)-vinyl iodide 64. At this stage, we found

that the TBDPS protecting group could be conveniently

removed using TBAT to give allylic alcohol 65 in good yield.

5

3 under more mild conditions using a metal-catalyzed

decarboxylative allylation, constituting a formal Carroll

rearrangement.

could be achieved using LiHMDS and Mander’s reagent to

give β-keto ester 54. Finally, chemoselective oxidative cleavage

of the exocyclic alkene would give ketone 55, intercepting the

4

1,42

Next, diastereoselective acylation of 53

43

9

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Scheme 13. Synthesis of Macrolactone 50

Next, vinyl iodide 65 was coupled with dienyl stannane 42 as

before to give triene 66 as a single geometrical isomer in 87%

yield. With cascade precursor 66 in hand, we were again in a

position to test our tandem intramolecular acylketene trapping/

IMDA cascade. Thus, we were pleased to observe that heating a

dilute solution of 66 in reﬂuxing benzene gave the desired

macrolactone 50 in 46% yield as a single diastereomer.

Unfortunately, all attempts to induce Carroll rearrangement

of 50 under thermal conditions were unsuccessful. At the

elevated temperatures required for rearrangement (175 °C in

Scheme 14. Construction of Polycycle 67 via a Radical

Cyclization Reaction

1,2-dichlorobenzene or 200 °C in 1,2,4-trichlorobenzene),

macrolactone 50 likely underwent the retro-acylketene

15

trapping, leading to decomposition products. Eﬀorts to

induce a more mild transition-metal-catalyzed decarboxylative

41

42

allylation using a range of palladium and ruthenium

catalysts were similarly unsuccessful.

Having investigated pericyclic and transition-metal-catalyzed

processes to achieve the ring contraction of macrolactone 50,

we next explored a radical reaction to form the key transannular

carbon−carbon bond. For this strategy, we decided to use

manganese(III) acetate which readily oxidizes enolizable β-

that the synthesis of the decahydroﬂuorene core precede the

macrocyclization step; otherwise, the presence of the trans-

alkene required for the Diels−Alder reaction would introduce

even more strain into the 13-membered cyclophane. Therefore,

our initial target was decahydroﬂuorene 70, which features a

functionalized dioxinone.

46,47

ketoesters to give carbon-centered radicals.

However,

treatment of 50 with manganese(III) acetate and copper(II)

acetate in acetic acid did not result in the desired transannular

bond formation; instead, the only observable product was

cyclized compound 67 (Scheme 14). We rationalize the

formation of this byproduct in the following way. First,

hydrogen atom abstraction from 50 by the action of Mn(OAc)₃

gives the stabilized radical 68. However, instead of reacting with

the exocyclic alkene, this radical engages the proximal vinyl

group in an alternative 6-endo-trig cyclization to form secondary

Strategically, we envisioned that 70 could be elaborated to a

compound such as 71, setting the stage for a pivotal palladium-

catalyzed macrocyclization reaction to give the elusive cyclo-

34,48

phane 72. We found the intramolecular Stille coupling

to

be especially appealing since the reaction would proceed

through a larger 14-membered palladacycle intermediate. In

this way, ring contraction to the more highly strained 13-

membered paracyclophane accompanies the irreversible reduc-

tive elimination step. Another attractive feature of this route is

the straightforward endgame; thus, thermolysis of dioxinone 72

would again expel acetone in a retro-hetero-Diels−Alder

reaction to give reactive acylketene 73. If this reaction were

conducted in the presence of ammonia, nucleophilic capture of

the reactive acylketene would occur to form the same primary

radical 69. Reaction of this intermediate with Cu(OAc) then

2

generates an organocopper species which, in turn, undergoes β-

hydride elimination to deliver 67. Although the radical

cyclization did not form the desired carbon−carbon bond, we

note that this reactivity could prove useful for the synthesis of

the tetracyclic framework of the related pyrrospirone (4)

4

natural products.

1

2

At this stage, we began to investigate an alternative strategy

for the synthesis of hirsutellone B that would not require a late-

stage ring contraction. In particular, we were attracted to the

possibility of directly forming the 13-membered cyclophane

using a palladium-catalyzed coupling reaction (Scheme 15).

After examining hand-held molecular models, it seemed critical

amide 33 that appears in Nicolaou’s route. Finally,

spontaneous hemiaminal formation would complete the total

synthesis of hirsutellone B in a single cascade reaction

sequence.

Our ﬁrst goal in pursuing this new route was to gain access to

the substituted dioxinone fragment, as shown in Scheme 16.

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Scheme 15. Approach to Macrocyclic Ketone 72 Using a

Palladium-Catalyzed Coupling Reaction

aqueous sodium carbonate under biphasic conditions gave the

desired ylide 79 in 24% yield over the three steps.

Having secured functionalized dioxinone ylide 79, we

returned to the tandem dihydroxylation/Wittig sequence

from our original synthesis of the decahydroﬂuorene core of

7

the hirsutellones. Thus, diastereoselective dihydroxylation of

50

enol ether 80 (Scheme 17) under Upjohn conditions gave α-

Scheme 17. Synthesis of Allylic Phosphate 82

hydroxyaldehyde 16, which was subsequently treated with

dioxinone ylide 79 following an aqueous workup. This

sequence gave the expected Wittig product as a 3:1 mixture

of separable alcohol epimers, favoring the desired allylic alcohol

8

1. As before, deprotonation of 81 with methyllithium followed

Scheme 16. Synthesis of Dioxinone Ylide 79

by the addition of diethyl chlorophosphate gave allylic

phosphate 82 in 77% yield.

51

Next, treatment of 82 with the sodium phenolate of 83

under our standard Tsuji−Trost conditions produced aryl ether

4 (Scheme 18). Subsequent chemoselective cleavage of the

8

TBS silyl ether of 84 using acetic acid gave primary alcohol 85

in 50% yield over the two steps. Next, oxidation of primary

alcohol 85 with DMP aﬀorded aldehyde 86 in 97% yield.

Proceeding as in our previous route, Takai oleﬁnation of

aldehyde 86 gave exclusively (E)-vinyl iodide 87 in 94% yield.

The Stille coupling of vinyl iodide 87 and dienyl stannane 42

occurred under our usual conditions to give the desired triene

8

8 in 88% yield.

At this stage, we were ready to test whether we could achieve

the intramolecular Diels−Alder reaction while retaining the

dioxinone group. In the event, we were pleased to observe that

the IMDA reaction occurred, albeit slowly, when a solution of

8

8 was heated to 75 °C in benzene. It is interesting to note that

70 was obtained as an inseparable 3:1 mixture of endo/exo

isomers, whereas all of our tandem acylketene trapping/IMDA

reactions occurred with complete diastereoselectivity. This

observation provides some evidence that acylketene formation

precedes the Diels−Alder reaction in the tandem sequences.

Continuing on toward the precursor for the Stille reaction,

deprotection of the TBDPS silyl ether of 70 using TBAT

proceeded smoothly to give the corresponding benzylic alcohol.

Conveniently, the endo/exo diastereomers were separable by

chromatography at this stage, and the major product 89 was

isolated in 70% yield.

Our synthesis began with tert-butyl acetoacetate 74, which was

alkylated with methyl bromoacetate to give diester 75. This

crude material was then cyclized under acidic conditions in a

mixture of acetone and acetic anhydride to aﬀord substituted

dioxinone 76 in 63% yield over the two steps. When 76 was

brominated under Wohl−Ziegler conditions, primary bro-

mide 77 was formed as the major product along with a small

amount of the isomeric α-bromo ester. Next, treatment of this

mixture with triphenylphosphine led to formation of

phosphonium salt 78, and subsequent deprotonation with

At this stage, we needed to activate the benzylic alcohol as

the corresponding halide as a prelude to forming the required

stannane (Scheme 19). Although we were able to transform 89

into the corresponding benzylic bromide using the Appel

49

52

reaction, this intermediate was unstable to chromatography.

Therefore, we decided to form the less reactive chloride by

9

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Scheme 18. Synthesis of Decahydroﬂuorene 89 via an IMDA Reaction

Scheme 19. Synthesis of Key Intermediate 71 and Attempted

Intramolecular Stille Coupling

we could consistently achieve yields in the 50% range, although

this required the addition of several aliquots of the stannyl-

lithium reagent. Interestingly, the reaction of 90 with the less

toxic reagent tributylstannyllithium led to complete decom-

position of the starting material.

Having secured benzylic stannane 91, we next focused on

synthesizing the acid chloride in order to test the intra-

molecular Stille reaction. Hydrolysis of the methyl ester of 91

using lithium hydroxide in aqueous THF proceeded slowly at

room temperature to give carboxylic acid 92 in 79% yield.

Notably, the substituted dioxinone heterocycle survives the

action of excess aqueous lithium hydroxide, whereas the

corresponding unsubstituted dioxinones are highly susceptible

to ring openings under basic conditions. An exceptionally mild

method for converting carboxylic acids to acid chlorides under

neutral conditions utilizes chloroenamine 93, also known as the

54

Ghosez reagent. We were pleased to observe that the reaction

of carboxylic acid 92 with 93 proceeded almost instantaneously

at room temperature to give the desired acid chloride 71 in

essentially quantitative yield. The identity of 71 was conﬁrmed

when an aliquot was quenched with methanol, producing

methyl ester 91; alternatively, the formation of 71 could be

1

monitored by H NMR. Since the only byproduct of this

reaction is an innocuous amide, the crude solution of 71 in

chloroform was used directly without puriﬁcation. Conven-

iently, Stille’s original coupling protocol also used chloroform

as the reaction solvent along with 94 as the palladium

48

precatalyst. In order to minimize possible decarbonylation,

we ran all reactions under an atmosphere of carbon monoxide.

Unfortunately, we were unable to observe formation of the

desired cyclophane 72 when acid chloride 71 was exposed to

these reaction conditions. No reaction occurred at room

temperature, and only decomposition of 71 was observed upon

heating.

Notably, we found that acid chloride 71 was a competent

substrate for an intermolecular Stille coupling with phenyltri-

methylstannane under the conditions shown in Scheme 19.

Unfortunately, we were never able to isolate the desired

cyclophane 72 that would arise from an intramolecular Stille

coupling, despite screening a wide variety of palladium catalysts,

ligands, and solvents. One possible explanation is that the

transfer of benzyl groups in the transmetalation step of the

Stille reaction is often extremely slow. Indeed, benzyl groups

treating 89 with methanesulfonyl chloride, which gave the

isolable compound 90 in 86% yield.

The conversion of benzylic chloride 90 to the corresponding

stannane proved to be a challenging transformation. Ultimately,

we were able to synthesize 91 via nucleophilic displacement of

chloride with trimethylstannyllithium. After screening several

conditions, this reagent was most conveniently prepared in situ

53

from the reaction of hexamethylditin and methyllithium.

Nevertheless, the displacement reaction itself suﬀered from low

yields and reproducibility issues. We found that conducting the

reaction at −40 °C was critical; at higher temperatures, the

strongly nucleophilic stannyllithium reacts with the methyl

ester or opens the dioxinone. Using our optimized conditions,

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are only slightly more reactive than alkyl groups, which are

Scheme 21. Formal Synthesis of Hirsutellone B

typically used as “inert” dummy ligands in the stannane

3

4

component.

Having developed an eﬃcient route to compounds featuring

a substituted dioxinone, we decide to pursue a formal total

synthesis of hirsutellone B. We returned to triene 88 and found

that heating this compound to 160 °C in a biphasic mixture of

m-xylene and water gave decahydroﬂuorene 96 in 72% yield as

a single diastereomer (Scheme 20). Presumably, the acylketene

Scheme 20. Synthesis of Diol 97

alcohols (both primary and secondary) as the nucleophile to

form 14-membered macrolactams and macrolactones, respec-

tively. Notably, the IMDA reaction is highly diastereoselective,

establishing the correct conﬁguration at four contiguous

stereocenters along the decahydroﬂuorene core. Although we

were unable to achieve the necessary ring contraction to form

the complete carbon framework of hirsutellone B, our attempts

at transannular carbon−carbon bond formation did produce a

series of unexpected cyclization products with interesting

structures. This surprising reactivity demonstrates how the

subtle interplay of stereoelectronic eﬀects, conformation, and

proximity can still be diﬃcult to predict, especially in complex

molecular settings.

is trapped by water to give an intermediate β-keto acid 95 that

undergoes in situ decarboxylation to form 96. Interestingly,

thermolysis of substituted dioxinone 88 required a much higher

temperature than was needed for any of the unsubstituted

dioxinone substrates. For example, when 88 was heated to 120

EXPERIMENTAL SECTION

■

All reactions were carried out in oven or ﬂame-dried glassware (unless

water was present in the reaction mixture) with magnetic stirring

under a positive pressure of argon unless otherwise indicated.

Reactions were monitored by thin layer chromatography (TLC)

carried out on 0.25 mm Merck silica gel plates (60 F254) containing a

ﬂuorescent indicator (254 nm). TLC plates were visualized under a

UV lamp before treatment with the indicated stain and development

with heat. Flash column chromatography was performed using

Silicycle SiliaFlash P60 silica gel (60 Å pore size, 40−63 μm particle

size, 230−400 mesh) and ACS reagent grade solvents. Preparative

TLC was performed using Analtech silica gel GF glass-backed

UNIPLATES (250, 500, 1000, or 2000 μm thickness). All Grignard

and alkyllithium reagents were titrated with salicylaldehyde phenyl-

°

C in a mixture of toluene/water for 3 h, Diels−Alder adduct

7

0 was again isolated as an inseparable 3:1 mixture of endo/exo

isomers. In contrast, 96 was formed as a single diastereomer

under the conditions shown in Scheme 20. These observations

suggest that proceeding through the acylketene intermediate is

critical in order to achieve high levels of diastereoselectivity in

the IMDA reaction.

At this stage, exhaustive reduction of 96 with diisobutyl-

aluminum hydride gave diol 97, which was formed as an

inconsequential 1:1 mixture of diastereomers. The primary

alcohol could then be selectively protected as the correspond-

ing TBDPS ether in 72% yield to give secondary alcohol 98

5

hydrazone before use. Anhydrous methanol, 1,2-dichloroethane, and

acetone were purchased and used without further puriﬁcation.

Tetrahydrofuran (THF), dichloromethane (CH Cl ), toluene, diethyl

(

Scheme 21). Next, oxidation of 98 with DMP proceeded

smoothly in 97% yield to provide ketone 99. Finally, removal of

both silyl ether protecting groups could be achieved with

buﬀered TBAF to give diol 100 in 97% yield. This constitutes a

formal total synthesis since Nicolaou has previously shown that

2

ether, benzene, acetonitrile (CH CN), dimethyl sulfoxide (DMSO),

3

triethylamine (NEt ), and pyridine were dried by passing previously

3

degassed solvents through activated alumina columns. High-resolution

mass spectral (HRMS) data were obtained on an electrospray

ionization LC/MS equipped with a time-of-ﬂight mass analyzer.

tert-Butyl (S)-(1-((tert-Butyldiphenylsilyl)oxy)-3-(4-hydroxy-

12

1

00 can be converted to hirsutellone B in a 10-step sequence.

21

CONCLUSION

phenyl)propan-2-yl)carbamate (18). To a solution of 17 (223

■

mg, 0.83 mmol, 1.00 equiv) in 6 mL of CH Cl was added imidazole

In summary, we have described the evolution of a strategy for a

total synthesis of hirsutellone B featuring a novel “double

cyclization” cascade. This key transformation takes advantage of

the intrinsic reactivity of an acylketene to trigger macro-

cyclization and IMDA events that rapidly construct both the

decahydroﬂuorene core and the strained para-cyclophane ring

in a single step. We have demonstrated that the intramolecular

acylketene trapping can be achieved using either amines or

2

(382 mg, 5.62 mmol, 6.75 equiv) followed by the dropwise addition of

neat tert-butyldiphenylchlorosilane (487 μL, 1.87 mmol, 2.25 equiv).

After 30 min at room temperature, TLC (10:1 hexanes/EtOAc, UV/

ninhydrin) showed complete consumption of the starting material and

formation of the product of R = 0.33. The reaction was quenched with

f

water, the layers were separated, and the aqueous phase was extracted

with one additional portion of CH Cl . The combined organics were

2

dried over anhydrous Na SO , and the solvent was removed under

2

4

9

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reduced pressure to give 598 mg of the crude bis-TBDPS-protected

tyrosinol as a colorless oil.

A solution of this crude product in 11 mL of THF was cooled to 0

with EtOAc. The layers were separated, and the aqueous phase was

extracted with two additional portions of EtOAc. The combined

organics were dried over anhydrous Na SO , the solvent was removed

2

4

°

C in an ice bath, and a 1.0 M solution of TBAF in THF (804 μL, 0.80

under reduced pressure, and the residue was puriﬁed by column

chromatography (3:1 hexanes/EtOAc → 2:1 hexanes/EtOAc) to give

20 as a colorless oil (1.13 g, 82%): [α]_D²⁰= −18.8 (c 2.66, CH Cl );

mmol, 1.00 equiv) was added dropwise. The resulting light yellow

solution was stirred at 0 °C for 30 min, at which point TLC (3:1

hexanes/EtOAc, ninhydrin) showed complete consumption of the

starting material (R = 0.70) and formation of the product (R = 0.37).

2

IR (neat) ν 2951, 2928, 2857, 1732, 1659, 1597, 1391, 1271, 1034,

−

1 1

986, 837 cm ; H NMR (500 MHz, CDCl ) δ 0.04 (3H, s), 0.05 (3H,

f

3

The reaction was quenched with saturated NH Cl and diluted with

s), 0.83 (1H, m), 0.89 (9H, s), 1.01 (1H, q, J = 12.09 Hz), 1.23−1.37

(8H, m), 1.47−1.68 (4H, m), 1.72 (6H, s), 3.58 (1H, d, J = 10.24 Hz),

3.84 (1H, dd, J = 4.73 Hz, 10.23 Hz), 4.10 (4H, m), 5.18 (1H, m),

5.32 (1H, s), 6.12 (1H, d, J = 15.58 Hz), 6.48 (1H, dd, J = 5.06 Hz,

4

water and EtOAc. The layers were separated, and the organic phase

was washed with brine before drying over anhydrous Na SO . The

2

4

solvent was removed under reduced pressure, and the residual oil was

15.59 Hz); ¹³C NMR (125 MHz, CDCl ) δ −5.5, −5.4, 16.2 (d, J

=

puriﬁed by column chromatography (3:1 hexanes/EtOAc) to aﬀord 18

3

C−P

as a colorless, viscous oil (340 mg, 81% over two steps): [α]_D²⁰

=

6.96 Hz), 18.3, 22.6, 25.0, 25.06, 25.09, 25.9, 32.2, 34.5, 38.9, 39.8,

+

18.7 (c 1.04, CH Cl ); IR (neat) ν 3050, 2870, 2857, 1617, 1542,

42.6 (d, J_C₋_P= 6.02 Hz), 63.87 (d, J_C₋_P= 5.80 Hz), 63.89 (d, J_C₋_P=

2

−1 1

1

522, 1438, 1294, 1237, 1148, 1022, 847 cm ; H NMR (500 MHz,

5.80 Hz), 64.2, 77.7 (d, J_C₋_P= 6.24 Hz), 95.2, 106.6, 123.0, 138.9 (d,

J_C₋_P= 1.95 Hz), 161.8, 162.3; HRMS (ESI+) calcd for

CDCl ) δ 1.10 (9H, s), 1.43 (9H, s), 2.81 (2H, m), 3.56 (1H, dd, J =

3

+

3.08 Hz, 10.16 Hz), 3.61 (1H, m), 3.84 (1H, m), 4.87 (1H, d, J = 8.96

C H NaO PSi ([M + Na] ) 583.2832, found 583.2807.

27

49

8

Hz), 6.24 (1H, br s), 6.68 (2H, d, J = 8.08 Hz), 6.97 (2H, d, J = 7.89

Aryl Ether 21. A 0.015 M stock solution of tetrakis(triphenyl-

13

Hz), 7.38−7.63 (10H, m); C NMR (125 MHz, CDCl ) δ 19.4, 27.0,

phosphine)palladium(0) was prepared by dissolving 52.5 mg of the

solid catalyst in 3.0 mL of THF. A 0.125 M solution of phenolate was

prepared by adding a solution of phenol 14 (223 mg, 0.40 mmol, 1.05

equiv) in 3.21 mL of THF to 16 mg of 60% sodium hydride dispersion

in mineral oil. Vigorous bubbling was observed, and a colorless

phenolate solution was obtained after 10 min. To a ﬂask containing

neat allylic phosphate 20 (214 mg, 0.38 mmol, 1.00 equiv) was added

a portion of the bright yellow catalyst solution (2.54 mL, 38.2 μmol,

0.10 equiv) followed by dropwise addition of the phenolate solution.

After each drop, the reaction mixture turned dark orange before

returning to light yellow after several seconds. After 5 min, TLC (1:1

hexanes/EtOAc, UV/anisaldehyde) showed complete consumption of

3

2

1

8.5, 36.9, 53.5, 64.0, 79.6, 115.3, 127.8, 129.7, 129.8, 130.4, 133.2,

35.60, 135.63, 154.6, 155.7; HRMS (ESI+) calcd for C H NO Si

30

40

4

+

(

[M + H] ) 506.2727, found 506.2730.

(

S)-4-(3-((tert-Butyldiphenylsilyl)oxy)-2-((3,4-dimethyl-

benzyl)amino)propyl)phenol (14). A solution of 18 (1.35 g, 2.67

mmol, 1.00 equiv) in 35 mL of dry CH Cl was cooled to 0 °C in an

2

ice bath, and neat triﬂuoroacetic acid (17.5 mL, 236 mmol, 89 equiv)

was added dropwise. After 15 min, TLC (100% EtOAc, UV/

ninhydrin) showed complete consumption of the starting material

and formation of the product of R = 0.70. The solvent was removed

f

under reduced pressure, and the residue was dried under high vacuum

to give crude TFA salt 19 as a white amorphous solid (1.20 g, 87%).

To a portion of this crude material (150 mg, 0.29 mmol, 1.00 equiv)

and 2,4-dimethoxybenzaldehyde (46 mg, 0.27 mmol, 0.95 equiv) in 2.5

mL of 1,2-dichloroethane were added triethylamine (80.4 μL, 0.58

mmol, 2.00 equiv) and solid sodium triacetoxyborohydride (128 mg,

the phosphate and formation of the product of R = 0.54. The solvent

f

was removed under reduced pressure, and the residue was puriﬁed by

column chromatography (10:1 hexanes/EtOAc → 3:1 hexanes/EtOAc

→ 1:1 hexanes/EtOAc) to give aryl ether 21 as a colorless oil (236 mg,

64%): [α]_D²⁰= −9.6 (c 1.11, CH Cl ); IR (neat) ν 2928, 2856, 1730,

2

0

.61 mmol, 2.10 equiv). The resulting cloudy reaction mixture was

1655, 1612, 1590, 1508, 1463, 1390, 1375, 1258, 1235, 1208, 1113

−

1 1

stirred at room temperature for 15 h at which point TLC (2:1 EtOAc/

cm ; H NMR (500 MHz, CDCl ) δ −0.06 (3H, s), −0.04 (3H, s),

3

hexanes, UV/KMnO ) showed clean conversion to the product of R =

0.86 (9H, s), 0.89 (1H, m), 0.91 (3H, d, J = 6.31 Hz), 0.97 (1H, m),

1.04 (9H, s), 1.43 (1H, m), 1.47 (1H, m), 1.59 (1H, m), 1.62 (1H, m),

1.64 (1H, m), 1.67 (1H, m), 1.71 (3H, s), 1.72 (3H, s), 1.74 (1H, m),

2.67 (1H, dd, J = 6.57 Hz, 1.83 Hz), 2.74 (1H, dd, J = 6.18 Hz, 13.85

Hz), 2.88 (1H, m), 3.48 (2H, m), 3.56 (1H, m), 3.62 (3H, s), 3.65

(3H, m), 3.81 (3H, s), 4.97 (1H, m), 5.24 (1H, s), 6.02 (1H, d, J =

15.67 Hz), 6.38 (2H, m), 6.56 (1H, dd, J = 4.01 Hz, 15.72 Hz), 6.68

4

f

0

.31. The reaction mixture was diluted with CH Cl and quenched

2 2

with pH 7 phosphate buﬀer. The layers were separated, and the

aqueous phase was extracted with one additional portion of CH Cl .

2

The combined organics were dried over anhydrous Na SO , and the

2

4

solvent was removed under reduced pressure to give a yellow oil. The

crude product was then puriﬁed by column chromatography (1:1

hexanes/EtOAc → 100% EtOAc) to give phenol 14 as a white foam

(2H, d, J = 8.50 Hz), 6.97 (2H, d, J = 8.45 Hz), 7.00 (1H, m), 7.33

142 mg, 77% over two steps): [α]_D²⁰= −6.3 (c 1.45, CH Cl ); IR

13

(

1

(4H, m), 7.36 (2H, m), 7.62 (4H, m); C NMR (125 MHz, CDCl ) δ

2

3

neat) ν 3071, 2999, 2931, 2857, 1614, 1589, 1508, 1463, 1428, 1289,

−5.43, −5.41, 18.4, 19.3, 22.7, 25.1, 25.2, 25.8, 26.0, 26.9, 32.3, 34.9,

36.9, 39.1, 40.3, 43.1, 46.6, 55.1, 55.4, 59.6, 65.1, 65.6, 77.2, 94.7, 98.4,

103.5, 106.5, 115.0, 121.0, 122.8, 127.68, 127.71, 129.64, 129.67,

130.3, 131.8, 133.63, 133.68, 135.64, 135.65, 140.8, 156.7, 158.6,

160.0, 161.9, 162.5; HRMS (ESI+) calcd for C H NO Si ([M +

−

1 1

260, 1208, 1157, 1137, 1112, 1037, 823, 702 cm ; H NMR (500

MHz, CDCl ) δ 1.05 (9H, s), 2.66 (1H, dd, J = 7.11 Hz, 13.86 Hz),

3

2

.76 (1H, dd, J = 6.43 Hz, 13.87 Hz), 2.88 (1H, q, J = 6.29 Hz), 3.57

(

1H, m), 3.59 (3H, s), 3.67 (1H, d, J = 13.46 Hz), 3.68 (1H, m), 3.71

57

80

8

2

+

(

=

1H, d, J = 13.23 Hz), 3.80 (3H, s), 6.37−6.39 (2H, m), 6.65 (2H, d, J

H] ) 962.5422, found 962.5431.

8.28 Hz), 6.90 (2H, d, J = 8.29 Hz), 6.98 (1H, d, J = 7.77 Hz), 7.33−

Primary Alcohol 22. To a solution of aryl ether 21 (416 mg, 0.43

mmol, 1.00 equiv) in 40 mL of 1:1 THF/water was added glacial acetic

acid (17.32 mL, 303 mmol, 700 equiv), and the reaction mixture was

stirred at room temperature for 14 h. After this time, TLC (100%

EtOAc, UV/anisaldehyde) showed complete conversion to the

7

(

.38 (4H, m), 7.40−7.44 (2H, m), 7.61 (2H, d, J = 7.53 Hz), 7.64

2H, d, J = 7.53 Hz); ¹³C NMR (125 MHz, CDCl ) δ 19.3, 26.9, 36.6,

3

4

1

6.6, 55.1, 55.5, 59.4, 65.5, 98.5, 103.6, 115.3, 127.74, 127.77, 129.71,

29.74, 130.3, 130.7, 133.44, 133.49, 135.62, 135.65, 154.4, 158.6,

60.3 [Note: one fully substituted carbon from the tyrosine ring was

product of R = 0.47. The reaction mixture was diluted with water

f

+

not observed]; HRMS (ESI+) calcd for C H NO Si ([M + H] )

and EtOAc and quenched by the dropwise addition of saturated

aqueous K CO solution. The layers were separated, and the aqueous

34

42

4

556.2883, found 556.2874.

2

3

Allylic Phosphate 20. A solution of 12 (1.04 g, 2.46 mmol, 1.00

phase was extracted with two additional portions of EtOAc. The

combined organics were dried over anhydrous Na SO , the solvent

was removed under reduced pressure, and the residue was puriﬁed by

equiv) in 25 mL of THF was cooled to −78 °C, and a 1.6 M solution

of methyllithium in ether (1.69 mL, 2.70 mmol, 1.10 equiv) was added

dropwise to give a dark yellow solution. After 5 min, neat diethyl

chlorophosphate (530 μL, 3.69 mmol, 1.50 equiv) was added, and the

ﬂask was transferred to an ice bath. After 10 min, TLC (1:1 hexanes/

EtOAc, UV/anisaldehyde) showed complete consumption of the

starting material (R = 0.66) and formation of the product of R = 0.36.

2

4

column chromatography (1:1 hexanes/EtOAc → 100% EtOAc) to

2

0

give primary alcohol 22 as a colorless oil (302 mg, 82%): [α]_D

=

−12.6 (c 1.64, CH Cl ); IR (neat) ν 2928, 2858, 1724, 1654, 1612,

2

−1 1

1590, 1508, 1463, 1390, 1375, 1289, 1236, 1208, 1112 cm ; H NMR

(500 MHz, CDCl ) δ 0.91 (1H, m), 0.92 (3H, d, J = 6.53 Hz), 0.98

f

3

The reaction was quenched with pH 7 phosphate buﬀer and diluted

(1H, m), 1.03 (9H, s), 1.42 (1H, m), 1.47 (1H, m), 1.60 (1H, m), 1.68

9

595

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

Featured Article

(

1H, m), 1.69 (1H, m), 1.70 (3H, s), 1.71 (3H, s), 1.72 (1H, m), 1.78

1H, m), 2.66 (1H, dd, J = 6.65 Hz, 13.87 Hz), 2.74 (1H, dd, J = 6.45

6.07 (1H, dd, J = 10.63 Hz, 15.05 Hz), 6.25 (1H, dt, J = 10.37 Hz,

16.92 Hz), 6.38 (2H, m), 6.54 (1H, dd, J = 4.05 Hz, 15.61 Hz), 6.66

(2H, d, J = 8.52 Hz), 6.94 (2H, d, J = 8.45 Hz), 6.98 (1H, d, J = 8.73

Hz), 7.34 (4H, m), 7.40 (2H, m), 7.61 (4H, m); ¹³C NMR (125 MHz,

Hz, 13.89 Hz), 2.85 (1H, m), 3.53 (2H, m), 3.62 (3H, s), 3.64 (4H,

m), 3.81 (3H, s), 4.97 (1H, m), 5.26 (1H, s), 6.06 (1H, dd, J = 1.41

Hz, 15.68 Hz), 6.38 (2H, m), 6.60 (1H, dd, J = 4.49 Hz, 15.67 Hz),

CDCl ) δ 19.3, 22.5, 24.8, 25.1, 25.2, 26.9, 32.0, 34.6, 36.7, 42.0, 43.2,

3

6

.70 (2H, d, J = 8.57 Hz), 6.96 (2H, d, J = 8.64 Hz), 6.98 (1H, m),

46.5, 47.3, 55.1, 55.5, 59.5, 65.4, 77.6, 94.7, 98.4, 103.6, 106.5, 115.3,

117.0, 120.5, 122.7, 127.70, 127.74, 129.67, 129.69, 130.2, 130.5,

131.7, 132.0, 132.7, 132.9, 133.55, 133.59, 135.63, 135.65, 136.9,

138.3, 140.9, 156.7, 158.6, 160.1, 161.9, 162.5; HRMS (ESI+) calcd for

13

7

.34 (4H, m), 7.40 (2H, m), 7.60 (4H, m); C NMR (125 MHz,

CDCl ) δ 19.3, 22.6, 25.1, 25.2, 26.9, 27.1, 32.3, 34.8, 36.9, 38.9, 40.5,

3

4

1

3.5, 46.6, 55.1, 55.5, 59.5, 65.6, 65.9, 79.0, 95.0, 98.5, 103.5, 106.6,

15.1, 120.9, 123.4, 127.69, 127.72, 129.65, 129.68, 130.4, 132.3,

33.60, 133.66, 135.65, 135.66, 139.3, 156.3, 158.6, 160.0, 161.8,

+

C H NO Si ([M + H] ) 896.4922, found 896.4920.

56

70

7

Macrolactam 10. A two-neck 500 mL ﬂask equipped with a

+

62.3; HRMS (ESI+) calcd for C H NO Si ([M + H] ) 848.4558,

magnetic stirring bar, Dean−Stark trap, and a reﬂux condenser was

ﬂame-dried under high vacuum and cooled to room temperature

under argon. A solution of triene 8 (93.8 mg, 0.11 mmol, 1.00 equiv)

in 350 mL of freshly distilled benzene (sodium/benzophenone) was

added, and the reaction mixture was heated to reﬂux in a 105 °C oil

bath overnight. After cooling to room temperature, TLC (2:1

hexanes/EtOAc, UV/anisaldehyde) showed complete consumption

51

66

8

found 848.4547.

Aldehyde 23. To a solution of alcohol 22 (187 mg, 0.22 mmol,

.00 equiv) and NMO (30.9 mg, 0.26 mmol, 1.20 equiv) in 6.0 mL of

1

anhydrous CH Cl was added 500 mg of 4 Å molecular sieves. A 0.05

M solution of TPAP was prepared by dissolving 17.6 mg of the solid

catalyst in 1.0 mL of CH Cl . A portion of the TPAP solution (352 μL,

2

0

.18 μmol, 0.08 equiv) was added to the reaction mixture, and the dark

of the starting material and formation of the product of R = 0.63. The

f

black solution was stirred at room temperature for 1.5 h. After this

time, TLC (100% EtOAc, UV/anisaldehyde) showed complete

conversion of the starting material (R = 0.55) to the product of R_f

=

solvent was removed under reduced pressure, and the residue was

puriﬁed by column chromatography (3:1 hexanes/EtOAc → 2:1

hexanes/EtOAc → 1:1 hexanes/EtOAc) to give macrolactam 10 (34.1

mg, 39%) as a colorless oil. NMR showed that this compound exists as

f

0.68. The reaction was ﬁltered through a plug of Celite/Florisil, the

solvent was removed under reduced pressure, and the residue was

puriﬁed by column chromatography (3:1 hexanes/EtOAc → 1:1 →

a 3:1 mixture of enol/keto tautomers in CDCl solution but almost

3

2

0

exclusively as the enol tautomer in C D solution: [α] = +17.7 (c

6 6 D

1

[

1

00% EtOAc) to give aldehyde 23 as a white foam (116 mg, 62%):

1.10, CH Cl ); IR (neat) ν 2923, 2854, 1613, 1588, 1505, 1462, 1427,

2 2

α]_D²⁰= −12.0 (c 1.40, CH Cl ); IR (neat) ν 2928, 2856, 1724, 1656,

1343, 1287, 1257, 1207, 1187, 1156, 1111, 1037, 1005, 963, 822, 738,

2

−1 1

611, 1590, 1508, 1462, 1391, 1375, 1273, 1233, 1208, 1112, 1038

702, 504 cm ; H NMR (500 MHz, C D ) δ 0.86 (1H,m), 0.90 (3H,

6 6

−1 1

cm ; H NMR (500 MHz, CDCl ) δ 0.89 (1H, m), 0.94 (1H, m),

0

1

d, J = 7.03 Hz), 0.96 (1H, m), 0.97 (1H, m), 1.17 (9H, s), 1.25 (1H,

m), 1.29 (1H, m), 1.67 (1H, m), 1.74 (1H, m), 1.85 (1H, m), 2.06

(1H, m), 2.39 (1H, m), 2.52 (1H, m), 2.59 (1H, d, J = 11.98 Hz), 2.71

(1H, dd, J = 12.0 Hz, 6.8 Hz), 2.81 (1H, d, J = 12.69 Hz), 2.93 (1H,

m), 3.20 (3H, s), 3.34 (3H, s), 3.43 (1H, m), 3.59 (1H, m), 3.84 (1H,

s), 3.86 (1H, m), 4.49 (1H, d, J = 15.87 Hz), 4.82 (1H, m), 5.05 (2H,

m), 5.28 (1H, d, J = 16.10 Hz), 5.62 (1H, m), 6.03 (1H, d, J = 9.96

Hz), 6.10 (1H, m), 6.25 (1H, dd, J = 8.48 Hz, 2.30 Hz), 6.39 (1H, d, J

= 2.26 Hz), 6.56 (1H, dd, J = 8.34 Hz, 1.92 Hz), 6.71 (1H, dd, J = 8.34

Hz, 1.92 Hz), 6.79 (1H, dd, J = 8.29 Hz, 2.34 Hz), 6.88 (1H, dd, J =

8.22 Hz, 2.41 Hz), 7.22 (6H, m), 7.51 (1H, d, J = 8.40 Hz), 7.59 (2H,

m), 7.64 (2H, m), 15.18 (1H, s); ¹³C NMR (125 MHz, C D ) δ 19.4,

3

.95 (3H, d, J = 6.49 Hz), 1.02 (9H, s), 1.39 (1H, m), 1.48 (1H, m),

.75 (1H, m), 1.77 (1H, m), 1.84 (1H, m), 2.07 (1H, m), 2.47 (1H,

m), 2.65 (1H, dd, J = 6.77 Hz, 13.96 Hz), 2.73 (1H, dd, J = 6.48 Hz,

3.93 Hz), 2.85 (1H, m), 3.54 (1H, dd, J = 5.30 Hz, 10.12 Hz), 3.59

1

(

3H, s), 3.62 (2H, m), 3.69 (1H, d, J = 13.19 Hz), 3.80 (3H, s), 4.91

(

1H, m), 5.28 (1H, s), 6.07 (1H, dd, J = 1.38 Hz, 15.67 Hz), 6.38 (2H,

m), 6.55 (1H, dd, J = 4.79 Hz, 15.67 Hz), 6.65 (2H, d, J = 8.60 Hz),

6

7

.94 (2H, d, J = 8.56 Hz), 6.97 (1H, d, J = 8.64 Hz), 7.34 (4H, m),

.41 (2H, m), 7.61 (4H, m), 9.52 (1H, d, J = 3.00 Hz); ¹³C NMR (125

MHz, CDCl ) δ 19.3, 22.4, 25.1, 25.2, 25.4, 26.9, 31.7, 34.0, 34.5, 36.9,

3

4

1

8

1.5, 46.6, 51.3, 55.1, 55.5, 59.4, 65.6, 78.2, 95.3, 98.4, 103.5, 106.6,

15.2, 120.9, 124.0, 127.69, 127.72, 129.65, 129.69, 130.4, 132.3,

33.59, 133.65, 135.65, 135.65, 138.3, 155.9, 158.6, 160.0, 161.7,

6

22.8, 27.1, 29.6, 33.4, 36.1, 37.0, 38.7, 39.1, 42.9, 44.8, 46.8, 47.4, 50.4,

54.6, 54.9, 56.4, 64.7, 65.1, 82.8, 87.6, 98.6, 104.2, 115.6, 118.8, 120.0,

120.7, 128.3, 128.4, 128.5, 129.3, 129.5, 130.0, 130.1, 130.7, 130.8,

132.9, 133.59, 133.63, 136.06, 136.08, 139.1, 157.4, 159.5, 160.2,

+

62.1, 203.5; HRMS (ESI+) calcd for C H NO Si ([M + H] )

51

64

8

46.4401, found 846.4397.

Triene 8. A suspension of phosphonium salt 13 (449 mg, 1.10

mmol, 8.00 equiv) in 3.5 mL of dry THF was cooled to −78 °C, and a

.5 M solution of KHMDS in toluene (1.92 mL, 9.60 mmol, 7.00

+

174.9, 175.1; HRMS (ESI+) calcd for C H NO Si ([M + H] )

53

64

6

838.4503, found 838.4506.

0

Macrolactam Alcohol 24. To a solution of macrolactam 10 (34.1

mg, 40.7 μmol, 1.00 equiv) in 3 mL of THF was added solid

tetrabutylammonium triphenyldiﬂuorosilicate (TBAT, 132 mg, 0.24

mmol, 6.00 equiv), and the reaction mixture was stirred at room

temperature. After 6 h, TLC (1:1 hexanes/EtOAc, UV/anisaldehyde)

showed complete consumption of the starting material and formation

equiv) was added dropwise. The resulting dark red ylide solution was

warmed to 0 °C for 30 min before the dropwise addition of a solution

of aldehyde 23 (116 mg, 0.14 mmol, 1.00 equiv) in 3.0 mL of dry

THF. After 30 min at 0 °C, TLC (1:1 hexanes/EtOAc, UV/

anisaldehyde) showed complete consumption of the aldehyde and

formation of the product of R = 0.49. The reaction was quenched with

of the product of R = 0.45. The reaction mixture was diluted with

f

pH 7 phosphate buﬀer and diluted with EtOAc. The layers were

separated, and the aqueous phase was extracted with one additional

portion of EtOAc. The combined organic phases were dried over

EtOAc and quenched with pH 7 phosphate buﬀer. The layers were

separated, and the organic phase was dried over anhydrous Na SO .

2

4

The solvent was removed under reduced pressure, and the residue was

puriﬁed by column chromatography (3:1 hexanes/EtOAc → 1:1

hexanes/EtOAc) to give primary alcohol 24 as a colorless oil (24 mg,

98%). NMR showed that this compound exists as a 6:1 mixture of

anhydrous Na SO₄before removal of the solvent under reduced

2

pressure. The residue was puriﬁed by column chromatography to give

1

triene 8 as a colorless oil (93.8 mg, 76%). H NMR showed that the

triene was formed as an 7:1 mixture of E/Z isomers: IR (neat) ν 2928,

enol/keto tautomers in C D₆solution: [α]_D²⁰= +24.7 (c 0.97,

6

2

857, 1726, 1654, 1612, 1590, 1507, 1463, 1390, 1375, 1267, 1233,

CH Cl ); IR (neat) ν 3496, 2922, 2853, 1616, 1589, 1506, 1463, 1291,

1258, 1237, 1208, 1182, 1157, 1121, 1038 cm ; H NMR (500 MHz,

2

−1

1

−1 1

1207, 1156, 1112, 1008 cm ; H NMR (500 MHz, CDCl ) δ 0.89

3

(

1H, m), 0.90 (3H, d, J = 6.46 Hz), 0.96 (1H, m), 1.03 (9H, s), 1.38

1H, m), 1.48 (1H, m), 1.76 (1H, m), 1.78 (1H, m), 1.82 (1H, m),

C D ) δ 0.88 (1H, m), 0.91 (3H, d, J = 6.60 Hz), 0.93 (1H, m), 1.01

6

(1H, td, J = 12.4 Hz, 3.9 Hz), 1.21 (1H, m), 1.27 (1H, m), 1.70 (1H,

m), 1.85 (1H, ddd, J = 13.1 Hz, 8.0 Hz, 2.7 Hz), 1.92 (1H, m), 2.05

(1H, m), 2.06 (1H, ddd, J = 11.7 Hz, 9.1 Hz, 4.5 Hz), 2.28 (1H, m),

2.33 (1H, m), 2.38 (1H, m), 2.57 (1H, dd, J = 12.0 Hz, 6.7 Hz), 2.89

(1H, m), 3.28 (3H, s), 3.29 (3H, s), 3.37 (1H, m), 3.65 (1H, m), 3.45

(1H, m), 3.93 (1H, s), 4.31 (1H, d, J = 15.9 Hz), 4.83 (1H, t, J = 3.6

Hz), 5.06 (2H, m), 5.30 (1H, d, J = 15.8 Hz), 5.58 (1H, m), 6.01 (1H,

2

.08 (1H, m), 2.25 (1H, m), 2.72 (2H, m), 2.88 (1H, m), 3.56 (1H,

dd, J = 5.25 Hz, 10.30 Hz), 3.61 (3H, s), 3.63−3.67 (2H, m), 3.70

1H, d, J = 13.26 Hz), 3.80 (3H, s), 4.90 (1H, m), 4.99 (1H, d, J =

(

1

9

0.29 Hz), 5.05 (1H, d, J = 16.93 Hz), 5.22 (1H, s), 5.43 (1H, dd, J =

.30 Hz, 15.17 Hz), 5.63 (1H, dd, J = 10.59 Hz, 15.19 Hz), 5.75 (1H,

dd, J = 10.71 Hz, 14.80 Hz), 6.01 (1H, dd, J = 1.46 Hz, 15.64 Hz),

9

596

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

Featured Article

d, J = 10.0 Hz), 6.12 (1H, m), 6.15 (1H, dd, J = 8.3 Hz, 2.5 Hz), 6.41

tosylate byproduct (72.4 mg, 11%): [α] ²⁰= −1.9 (c 1.03, CH Cl );

D

2

(

=

8

1H, d, J = 2.4 Hz), 6.53 (1H, dd, J = 8.3 Hz, 2.2 Hz), 6.63 (1H, dd, J

8.3 Hz, 2.2 Hz), 6.80 (1H, dd, J = 8.3 Hz, 2.5 Hz), 6.87 (1H, dd, J =

.2 Hz, 2.6 Hz), 7.51 (1H, d, J = 8.4 Hz), 15.10 (1H, s); C NMR

IR (neat) ν 3523, 3034, 2922, 1611, 1511, 1454, 1358, 1241, 1189,

−1 1

1175, 1096, 978 cm ; H NMR (500 MHz, CDCl ) δ 2.02 (1H, d, J =

3

13

4.66 Hz), 2.46 (3H, s), 2.72 (2H, m), 3.93 (1H, dd, J = 5.97 Hz, 9.06

Hz), 4.03 (2H, m), 5.04 (2H, s), 6.89 (2H, d, J = 8.05 Hz), 7.06 (2H,

(

125 MHz, C D ) δ 22.8, 29.6, 33.4, 35.4, 37.0, 37.7, 38.4, 42.9, 44.8,

6

1

3

4

1

6.7, 47.3, 50.5, 54.87, 54.89, 56.4, 63.6, 65.5, 82.9, 87.6, 99.2, 104.6,

15.7, 118.8, 119.7, 123.1, 128.1, 129.4, 129.9, 130.5, 130.7, 132.5,

d, J = 8.02 Hz), 7.32−7.43 (7H, m), 7.79 (2H, d, J = 7.84 Hz); C

NMR (125 MHz, CDCl ) δ 21.8, 38.5, 70.1, 70.5, 72.7, 115.1, 127.5,

3

39.1, 157.4, 159.5, 160.6, 175.3, 176.2; HRMS (ESI+) calcd for

128.1, 128.7, 128.8, 130.0, 130.4, 132.6, 137.0, 145.2, 157.8; HRMS

+

C H NO ([M + H] ) 600.3325, found 600.3314.

(ESI+) calcd for C H O S ([M + H] ) 413.1423, found 413.1430.

37

46

6

23 25

5

Acylketene Hemiaminal Ether 26. A solution of primary alcohol

(R)-3-(4-(Benzyloxy)phenyl)-2-((tert-butyldimethylsilyl)oxy)-

2

°

4 (4.5 mg, 7.50 μmol, 1.0 equiv) in 1 mL of CH Cl was cooled to 0

propyl 4-Methylbenzenesulfonate (36). A solution of 35 (238

2

C, and triethylamine (10 μL, 71.7 μmol, 9.6 equiv) was added

mg, 0.58 mmol, 1.00 equiv) in 4 mL of CH Cl was cooled to −78 °C,

2 2

followed by neat methanesulfonyl chloride (6.0 μL, 77.5 μmol, 10.3

equiv). The reaction mixture was stirred at 0 °C for 30 min before the

addition of neat DBU (10 μL, 66.9 μmol, 8.9 equiv). The cooling bath

was removed, and the reaction mixture was stirred at room

temperature for 15 min before the addition of water and EtOAc.

The layers were separated, and the organic phase was washed with

water and brine before drying over anhydrous Na SO . The solvent

and neat 2,6-lutidine (100 μL, 0.87 mol, 1.50 equiv) was added

followed by the dropwise addition of neat TBSOTf (159 μL, 0.69

mmol, 1.20 equiv). After 1.5 h at −78 °C, TLC (2:1 hexanes/EtOAc,

UV/anisaldehyde) showed complete consumption of the starting

material and formation of the product of R

diluted with CH Cl and quenched with water at −78 °C, at which

= 0.68. The reaction was

f

2

point a bright yellow color appeared. After warming to room

temperature, the organic layer was isolated, and the aqueous phase

2

4

was removed under reduced pressure, and the residue was puriﬁed by

preparative TLC (eluting with 100% EtOAc) to give 26 as a colorless

oil (1.2 mg, 28%): [α]_D²⁰= −16.0 (c 0.10, CH Cl ); IR (neat) ν 2919,

was extracted with one additional portion of CH

Cl . The combined

2

organics were dried over anhydrous Na SO before removal of the

2

4

2

1

850, 1729, 1612, 1536, 1508, 1456, 1292, 1240, 1209, 1173, 1158,

solvent under reduced pressure and puriﬁcation of the residue by

column chromatography (3:1 hexanes/EtOAc) to give 36 as a

−1 1

114, 1032 cm ; H NMR (500 MHz, CDCl ) δ 0.88 (1H, m), 0.93

3

20

(

1H, m), 0.95 (3H, d, J = 6.6 Hz), 1.07 (1H, qd, J = 12.5 Hz, 4.1 Hz),

colorless oil (298 mg, 98%): [α]

D

= +4.3 (c 2.05, CH Cl ); IR (neat)

2 2

1.40 (1H, m), 1.42 (1H, m), 1.56 (1H, m), 1.80 (1H, m), 1.83 (1H,

ν 2952, 2928, 2856, 1612, 1511, 1471, 1454, 1362, 1244, 1190, 1176,

−1 1

m), 1.99 (1H, m), 2.04 (1H, m), 2.06 (1H, m), 2.66 (1H, d, J = 14.1

Hz), 2.85 (1H, dd, J = 11.7 Hz, 7.0 Hz), 2.91 (1H, dd, J = 14.1 Hz, 4.7

Hz), 2.96 (1H, m), 3.76 (1H, s), 3.81 (3H, s), 3.82 (1H, m), 3.85 (3H,

s), 3.99 (1H, d, J = 14.8 Hz), 4.24 (1H, d, J = 14.9 Hz), 4.26 (1H, m),

1118, 1097, 983, 834, 813, 777 cm ; H NMR (500 MHz, CDCl ) δ

3

−0.26 (3H, s), −0.10 (3H, s), 0.78 (9H, s), 2.45 (3H, s), 2.58 (1H, dd,

J = 7.10 Hz, 13.73 Hz), 2.73 (1H, dd, J = 5.23 Hz, 13.74 Hz), 3.85

(2H, d, J = 5.25 Hz), 3.95 (1H, quintet, J = 5.59 Hz), 5.04 (2H, s),

6.85 (2H, d, J = 7.78 Hz), 7.00 (2H, d, J = 7.90 Hz), 7.33 (3H, m),

7.38 (2H, t, J = 7.31 Hz), 7.43 (2H, d, J = 7.57 Hz), 7.77 (2H, d, J =

4

.38 (1H, d, J = 8.9 Hz), 4.78 (1H, d, J = 17.0 Hz), 4.86 (1H, m), 4.87

1H, m), 5.41 (1H, dt, J = 9.8 Hz, 3.4 Hz), 5.66 (1H, ddd, J = 17.6 Hz,

.8 Hz, 8.4 Hz), 5.90 (1H, d, J = 9.8 Hz), 6.43 (1H, dd, J = 8.3 Hz, 2.3

Hz), 6.47 (1H, d, J = 2.2 Hz), 6.80 (1H, dd, J = 8.3 Hz, 2.6 Hz), 6.91

(

9

7.68 Hz); ¹³C NMR (125 MHz, CDCl

39.8, 70.0, 71.3, 72.5, 114.8, 127.5, 128.0, 128.1, 128.7, 129.6, 129.9,

) δ −5.2, −4.9, 18.0, 21.8, 25.8,

3

(

1H, dd, J = 8.6 Hz, 2.5 Hz), 6.94 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.06

1H, d, J = 8.0 Hz), 7.16 (1H, dd, J = 8.6 Hz, 2.0 Hz); C NMR (125

130.8, 132.9, 137.1, 144.9, 157.5; HRMS (ESI+) calcd for

13

+

C

H

39

O

5

SSi ([M + H] ) 527.2287, found 527.2290.

29

MHz, CDCl ) δ 22.7, 29.2, 33.1, 36.6, 37.6, 38.2, 42.0, 43.1, 43.3, 46.6,

(R)-2-((tert-Butyldimethylsilyl)oxy)-3-(4-hydroxyphenyl)-

3

4

1

9.2, 50.4, 55.52, 55.46, 56.2, 58.6, 71.3, 79.6, 81.6, 98.6, 104.1, 114.7,

16.0, 117.1, 119.0, 126.3, 127.8, 129.7, 130.0, 130.3, 131.1, 139.1,

58.3, 159.8, 160.8, 163.1, 192.5; HRMS (ESI+) calcd for C H NO

5

propyl 4-Methylbenzenesulfonate (37). To a ﬂask containing

solid 10% palladium on carbon (150 mg, 0.14 mmol, 0.25 equiv) was

added a solution of protected diol 36 (298 mg, 0.57 mmol, 1.00 equiv)

in 10 mL of anhydrous methanol and 5 mL of EtOAc. The ﬂask was

evacuated, put under an atmosphere of hydrogen gas (balloon), and

allowed to stir at room temperature. After 3 h, TLC (2:1 hexanes/

EtOAc, UV/anisaldehyde) showed complete consumption of the

37

44

+

([M + H] ) 582.3219, found 582.3215.

Aldehyde 27. To a solution of macrolactam alcohol 24 (3.0 mg,

5

.0 μmol, 1.00 equiv) in 500 μL of CH Cl was added solid Dess−

2

Martin periodinane (2.75 mg, 6.50 μmol, 1.30 equiv). After 15 min at

room temperature, TLC (1:1 hexanes/EtOAc, UV/anisaldehyde)

starting material and formation of the product of R = 0.46. The crude

f

showed complete conversion to the product of R = 0.62. The reaction

reaction mixture was ﬁltered through Celite topped with a thin layer of

silica gel to remove the solids, and the pad was washed with additional

EtOAc. The solvent was evaporated under reduced pressure, and the

residue was puriﬁed by column chromatography (3:1 hexanes/EtOAc)

f

was diluted with CH Cl₂and quenched with saturated aqueous

2

sodium thiosulfate solution and saturated aqueous NaHCO solution.

3

The layers were separated, and the aqueous phase was extracted with

one additional portion of CH Cl . The combined organics were dried

2

0

to aﬀord phenol 37 as a colorless oil (242 mg, 98%): [α]

1.41, CH Cl ); IR (neat) ν 3480, 2953, 2929, 2857, 1614, 1598, 1516,

1472, 1359, 1258, 1189, 1175, 1118, 983, 835, 778 cm ; H NMR

(500 MHz, CDCl

= +0.59 (c

2

D

over anhydrous Na SO before removal of the solvent under reduced

2

4

−1 1

pressure to give essentially pure aldehyde 27 (2.5 mg, 84%) which was

used without further puriﬁcation.

) δ −0.25 (3H, s), −0.10 (3H, s), 0.78 (9H, s), 2.45

3

(

S)-4-(3-((tert-Butyldiphenylsilyl)oxy)-2-((3,4-dimethyl-

(3H, s), 2.57 (1H, dd, J = 7.11 Hz, 13.79 Hz), 2.72 (1H, dd, J = 5.32

Hz, 13.79 Hz), 3.84 (2H, d, J = 5.35 Hz), 3.94 (1H, td, J = 5.39 Hz,

10.80 Hz), 4.75 (2H, s), 6.71 (2H, d, J = 8.48 Hz), 6.96 (2H, d, J =

benzyl)amino)propyl)phenol (35). To a solution of enantioen-

31

riched diol 34 (400 mg, 1.55 mmol, 1.00 equiv) in 8 mL of CH Cl₂

2

1

3

were added dibutyltin oxide (7.71 mg, 31 μmol, 0.02 equiv), p-

toluenesulfonyl chloride (295 mg, 1.55 mmol, 1.00 equiv), and neat

triethylamine (216 μL, 1.55 mmol, 1.00 equiv). Over the course of 30

min, the reaction mixture turned cloudy and the dibutyltin oxide

dissolved. After 4 h at room temperature, TLC (2:1 hexanes/EtOAc,

8.45 Hz), 7.34 (2H, d, J = 8.03 Hz), 7.77 (2H, d, J = 8.28 Hz); C

NMR (125 MHz, CDCl ) δ −5.2, −4.9, 18.0, 21.8, 25.8, 39.7, 71.3,

3

72.5, 115.2, 128.0, 129.4, 129.9, 130.9, 132.8, 145.0, 154.2; HRMS

+

(ESI+) calcd for C H O SSi ([M + H] ) 437.1818, found 437.1813.

22

33

5

Aryl Ether 38. To a solution of phenol 37 (345 mg, 0.46 mmol,

1.10 equiv) in 6 mL of THF was added solid 60% sodium hydride

dispersion in mineral oil (18 mg, 0.0.46 mmol, 1.10 equiv). Vigorous

bubbling was observed, and the resulting colorless phenolate solution

was used immediately. A 15 mM solution of Pd(PPh ) was also

UV/anisaldehyde) showed formation of the primary tosylate at R =

f

0

.26 and the secondary tosylate byproduct of R = 0.19. The reaction

f

mixture was quenched with water and diluted with CH Cl . The layers

2

were separated, and the aqueous phase was extracted with two

3

4

additional portions of CH Cl . The combined organics were dried over

prepared by dissolving 47.8 mg of the solid catalyst in 2.75 mL of

THF. The palladium catalyst solution was then added to a ﬂask

containing neat allylic phosphate 20 (232 mg, 0.41 mmol, 1.00 equiv),

and the phenolate solution was added dropwise. The reaction

remained yellow throughout the addition and only turned light orange

2

anhydrous Na SO , the solvent was removed under reduced pressure,

2

4

and the residue was puriﬁed by column chromatography (3:1 hexanes/

EtOAc → 2:1 hexanes/EtOAc) to give primary tosylate 35 as a

colorless oil (476 mg, 75%) along with the corresponding secondary

9

597

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

Featured Article

after the addition was complete. Over 5 min, the color gradually faded

to yellow again. After this time, TLC (3:1 hexanes/EtOAc, UV/

anisaldehyde) showed complete consumption of the starting

(1H, d, J = 2.93 Hz); ¹³C NMR (125 MHz, CDCl ) δ 21.8, 22.3,

3

25.13, 25.14, 25.4, 31.7, 34.0, 34.5, 38.4, 41.5, 51.2, 70.5, 72.7, 78.1,

95.4, 106.7, 115.6, 124.1, 128.1, 129.5, 130.1, 130.6, 132.6, 138.0,

145.3, 156.6, 161.8, 162.0, 203.6; HRMS (ESI+) calcd for C H O S

phosphate and formation of the product of R = 0.47. The solvent

f

33 41

9

+

was removed under reduced pressure, and the residue was puriﬁed by

column chromatography (10:1 hexanes/EtOAc → 4:1) to give 38 as a

pale yellow oil (227 mg, 65%): [α]_D²⁰= −13.3 (c 0.74, CH Cl ); IR

([M + H] ) 613.2471, found 613.2444.

Vinyl Iodide 41. To a ﬂame-dried 50 mL ﬂask under argon

equipped with a magnetic stirring bar was added solid chromium(II)

chloride (774 mg, 6.30 mmol, 8.00 equiv) in the glovebox. The ﬂask

was sealed with a septum, removed from the glovebox, and put under a

balloon of argon. Fifteen milliliters of anhydrous THF was added, and

the resulting suspension was cooled to 0 °C. A solution of aldehyde 40

(483 mg, 0.79 mmol, 1.00 equiv) and iodoform (620 mg, 1.57 mmol,

2.00 equiv) in 15 mL of THF was then added dropwise. After addition

was complete, the reaction mixture was allowed to warm slowly to

room temperature. After 1.5 h, TLC (1:1 hexanes/EtOAc, UV/

anisaldehyde) showed complete consumption of the starting material

2

(

1

neat) ν 2950, 2927, 2856, 1726, 1655, 1596, 1509, 1471, 1462, 1390,

366, 1237, 1206, 1189, 1176, 1117, 1097, 972, 834, 812, 776 cm ;

−1

1

H NMR (500 MHz, CDCl ) δ −0.35 (3H, s), −0.14 (3H, s), −0.04

3

(

3H, s), −0.03 (3H, s), 0.76 (9H, s), 0.85 (9H, s), 0.86 (1H, m), 0.90

3H, d, J = 6.66 Hz), 0.97 (1H, m), 1.43 (1H, m), 1.46 (1H, m), 1.61

1H, m), 1.64 (3H, m), 1.71 (3H, s), 1.72 (3H, s), 1.74 (1H, m), 2.45

3H, s), 2.52 (1H, dd, J = 7.65 Hz, 13.73 Hz), 2.75 (1H, dd, J = 4.31

(

Hz, 13.61 Hz), 3.48 (2H, m), 3.86 (2H, m), 3.93 (1H, m), 5.00 (1H,

m), 5.21 (1H, s), 5.97 (1H, d, J = 15.68 Hz), 6.53 (1H, dd, J = 3.50

Hz, 15.74 Hz), 6.72 (2H, d, J = 7.65 Hz), 6.99 (2H, d, J = 7.79 Hz),

and formation of the product of R = 0.44. The reaction was quenched

f

13

7

.34 (2H, d, J = 7.71 Hz), 7.78 (2H, d, J = 7.68 Hz); C NMR (125

with water and diluted with ether. The organic phase was isolated, and

the aqueous phase was extracted with two additional portions of ether.

MHz, CDCl ) δ −5.4, −5.36, −5.3, −4.9, 18.0, 18.4, 21.8, 22.7, 25.1,

3

2

7

1

5.2, 25.72, 25.74, 26.0, 32.4, 35.0, 39.1, 39.8, 40.2, 42.9, 65.0, 71.4,

2.6, 76.9, 94.7, 106.5, 115.0, 122.9, 128.1, 129.93, 129.95, 130.9,

The combined organics were washed with saturated aqueous Na

S O

2 2 3

solution and brine before drying over anhydrous Na SO . The solvent

2

4

32.9, 140.4, 145.0, 157.1, 161.9, 162.5; HRMS (ESI+) calcd for

was removed under reduced pressure, and the residue was puriﬁed by

column chromatography (10:1 hexanes/EtOAc → 3:1 → 2:1 → 1:1)

+

C H O SSi ([M + H] ) 843.4357, found 843.4365.

45

71

9

2

0

Diol 39. To a solution of 38 (227 mg, 0.27 mmol, 1.00 equiv) in 10

to give vinyl iodide 41 as a white foam (431 mg, 74%): [α]

(c 0.75, CH Cl ); IR (neat) ν 3487, 2922, 1718, 1654, 1596, 1508,

1454, 1391, 1362, 1271, 1233, 1204, 1189, 1175, 1097, 1020, 971

D

= −80.9

mL of dry THF was added neat triethylamine trihydroﬂuoride (951

μL, 0.27 mmol, 22 equiv), and the reaction mixture was stirred at

room temperature for 36 h. After this time, TLC (100% EtOAc, UV/

anisaldehyde) showed complete consumption of the starting material

2

−

1 1

cm ; H NMR (500 MHz, CDCl ) δ 0.86 (1H, m), 0.89 (3H, d, J =

3

6.33 Hz), 0.91 (1H, m), 1.41 (1H, m), 1.44 (1H, m), 1.46 (1H, m),

1.63 (1H, m), 1.70 (1H, m), 1.71 (6H, s), 1.77 (1H, m), 2.25 (1H, m),

2.46 (3H, s), 2.69 (1H, dd, J = 7.37 Hz, 13.86 Hz), 2.76 (1H, dd, J =

5.23 Hz, 13.83 Hz), 3.95 (1H, dd, J = 5.54 Hz, 9.41 Hz), 4.05 (2H, m),

4.89 (1H, m), 5.25 (1H, s), 5.51 (1H, d, J = 14.34 Hz), 6.03 (1H, d, J

= 15.62 Hz), 6.22 (1H, dd, J = 10.06 Hz, 14.29 Hz), 6.53 (1H, dd, J =

3.61 Hz, 15.62 Hz), 6.75 (2H, d, J = 8.00 Hz), 7.05 (2H, d, J = 7.94

and formation of the product of R = 0.57. The reaction was quenched

f

with water and diluted with EtOAc. The layers were separated, and the

organic phase was washed with an additional portion of water before

drying over anhydrous Na SO . The solvent was removed under

2

4

reduced pressure, and the residue was puriﬁed by column

chromatography (3:1 hexanes/EtOAc → 1:1 hexanes/EtOAc →

00% EtOAc) to give diol 39 as a colorless oil (146 mg, 88%): [α]_D²⁰

13

1

Hz), 7.36 (2H, d, J = 7.86 Hz), 7.81 (2H, d, J = 7.80 Hz); C NMR

=

−24.7 (c 0.55, CH Cl ); IR (neat) ν 3434, 2923, 1709, 1654, 1595,

(125 MHz, CDCl ) δ 21.8, 22.4, 24.8, 25.1, 25.2, 31.8, 34.4, 38.5, 41.1,

46.5, 47.1, 70.5, 72.6, 76.5, 77.7, 95.0, 106.5, 115.5, 123.0, 128.1, 129.3,

3

2

1

9

510, 1453, 1392, 1375, 1276, 1235, 1205, 1189, 1176, 1097, 1021,

76 cm ; H NMR (500 MHz, CDCl ) δ 0.89 (1H, m), 0.91 (3H, d, J

−1 1

130.0, 130.6, 132.6, 139.7, 145.2, 149.2, 157.4, 161.9, 162.3; HRMS

3

+

=

6.37 Hz), 0.95 (1H, m), 1.42 (1H, m), 1.45 (1H, m), 1.60 (1H, m),

(ESI+) calcd for C34

H42IO

8

S ([M + H] ) 737.1645, found 737.1628.

1

2

1

.68 (1H, m), 1.69 (1H, m), 1.70 (1H, m), 1.71 (6H, s), 1.77 (1H, m),

.07 (1H, d, J = 3.75 Hz), 2.46 (3H, s), 2.68 (1H, dd, J = 7.48 Hz,

3.86 Hz), 2.74 (1H, dd, J = 5.05 Hz, 13.90 Hz), 3.52 (1H, m), 3.64

Triene 29. A 0.01 M solution of dichlorobis(acetonitrile)palladium-

(II) was prepared by dissolving 15.2 mg of the solid catalyst in 5 mL of

DMF under argon. To a solution of vinyl iodide 41 (431 mg, 0.59

mmol, 1.00 equiv) in 3 mL of DMF was added a 0.25 M solution of

stannane 42 in DMF (4.68 mL, 1.17 mmol, 2.00 equiv). The

palladium catalyst solution was then added dropwise, and the reaction

mixture immediately turned dark brown/black. After stirring at room

temperature for 2 h, the reaction was diluted with water and ether. The

layers were separated, and the organic phase was washed with two

(

1H, m), 3.93 (1H, dd, J = 5.82 Hz, 9.43 Hz), 4.04 (2H, m), 5.02 (1H,

m), 5.26 (1H, s), 6.05 (1H, d, J = 15.71 Hz), 6.59 (1H, dd, J = 4.06

Hz, 15.57 Hz), 6.78 (2H, d, J = 7.78 Hz), 7.06 (2H, d, J = 7.84 Hz),

13

7.36 (2H, d, J = 7.74 Hz), 7.79 (2H, d, J = 7.58 Hz); C NMR (125

MHz, CDCl ) δ 21.8, 22.6, 25.13, 25.16, 26.9, 32.3, 34.7, 38.4, 38.8,

3

4

1

0.5, 43.5, 65.9, 70.5, 72.7, 78.8, 95.1, 106.6, 115.6, 123.4, 128.1, 129.4,

30.1, 130.6, 132.6, 139.1, 145.3, 157.0, 161.9, 162.2; HRMS (ESI+)

additional portions of water before drying over anhydrous Na SO .

2 4

+

calcd for C H O S ([M + H] ) 615.2628, found 615.2621.

TLC (1:1 hexanes/EtOAc, UV/anisaldehyde) showed the triene of R_f

= 0.51, which was essentially copolar with the starting vinyl iodide.

The solvent was removed under reduced pressure, and the residue was

puriﬁed by column chromatography (10:1 hexanes/EtOAc → 3:1 →

2:1 → 1:1) to aﬀord triene 29 as a pale yellow oil (331 mg, 85%):

[α]_D²⁰= −18.6 (c 1.10, CH Cl ); IR (neat) ν 3449, 2924, 1719, 1654,

33

43

9

Aldehyde 40. To a solution of diol 39 (509 mg, 0.83 mmol, 1.00

equiv) in 20 mL of CH Cl were added iodobenzene diacetate (280

2

mg, 0.87 mmol, 1.05 equiv) and TEMPO (12.9 mg, 82.7 μmol, 0.10

equiv). After 12 h at room temperature, TLC (1:1 hexanes/EtOAc,

UV/anisaldehyde) showed complete consumption of the starting

material and clean formation of the product of R = 0.26. The solvent

was removed under reduced pressure, and the residue was puriﬁed by

column chromatography (3:1 hexanes/EtOAc → 2:1 hexanes/EtOAc

2

1596, 1509, 1455, 1391, 1374, 1273, 1234, 1205, 1189, 1176, 1097,

f

−1 1

1020, 976, 904, 835 cm ; H NMR (500 MHz, CDCl ) δ 0.88 (1H,

3

m), 0.90 (3H, d, J = 6.40 Hz), 0.91 (1H, m), 1.37 (1H, m), 1.45 (1H,

m), 1.51 (1H, m), 1.65 (1H, m), 1.69 (1H, m), 1.695 (3H, s), 1.701

(3H, s), 1.78 (1H, m), 2.23 (1H, m), 2.45 (3H, s), 2.68 (1H, dd, J =

7.47 Hz, 14.10 Hz), 2.74 (1H, dd, J = 5.40 Hz, 13.96 Hz), 3.94 (1H,

dd, J = 5.98 Hz, 9.62 Hz), 4.02 (1H, br s), 4.05 (1H, dd, J = 3.48 Hz,

9.59 Hz), 4.91 (1H, m), 5.02 (1H, d, J = 10.03 Hz), 5.10 (1H, d, J =

16.88 Hz), 5.24 (1H, s), 5.42 (1H, dd, J = 9.39 Hz, 15.13 Hz), 5.62

(1H, dd, J = 10.62 Hz, 15.16 Hz), 5.75 (1H, dd, J = 10.71 Hz, 14.93

Hz), 6.00 (1H, d, J = 15.65 Hz), 6.06 (1H, m), 6.27 (1H, ddd, J =

10.41 Hz, 10.41 Hz, 16.98 Hz), 6.52 (1H, dd, J = 3.99 Hz, 15.63 Hz),

6.74 (2H, d, J = 8.53 Hz), 7.03 (2H, d, J = 8.52 Hz), 7.35 (2H, d, J =

→

1:1 hexanes/EtOAc) to aﬀord aldehyde 40 as a colorless oil (483

20

mg, 95%): [α]_D= −24.5 (c 0.57, CH Cl ); IR (neat) ν 3430, 2924,

1

2

720, 1655, 1596, 1509, 1454, 1392, 1361, 1275, 1234, 1205, 1189,

−1

1

176, 1097, 1019, 976 cm ; H NMR (500 MHz, CDCl ) δ 0.88

3

(

3

1H, m), 0.92 (1H, m), 0.96 (3H, d, J = 6.46 Hz), 1.40 (1H, ddd, J =

.07 Hz, 12.86 Hz, 16.44 Hz), 1.48 (1H, m), 1.71 (6H, s), 1.75 (1H,

m), 1.79 (1H, m), 1.86 (1H, m), 2.07 (1H, m), 2.46 (3H, s), 2.49 (1H,

m), 2.67 (1H, dd, J = 7.45 Hz, 13.95 Hz), 2.72 (1H, dd, J = 5.44 Hz,

1

3.95 Hz), 3.93 (1H, dd, J = 5.84 Hz, 9.51 Hz), 4.02 (2H, m), 4.94

1H, m), 5.28 (1H, s), 6.05 (1H, dd, J = 1.27 Hz, 15.68 Hz), 6.54 (1H,

dd, J = 4.70 Hz, 15.67 Hz), 6.73 (2H, d, J = 8.56 Hz), 7.04 (2H, d, J =

.55 Hz), 7.36 (2H, d, J = 8.13 Hz), 7.79 (2H, d, J = 8.26 Hz), 9.53

(

8.14 Hz), 7.80 (2H, d, J = 8.23 Hz); ¹³C NMR (125 MHz, CDCl ) δ

3

8

21.8, 22.5, 24.8, 25.1, 25.2, 31.9, 34.6, 38.5, 42.0, 43.4, 47.2, 70.5, 72.7,

9

598

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

Featured Article

7

1

7.8, 94.8, 106.5, 115.7, 117.0, 122.8, 128.1, 129.0, 130.1, 130.4,

31.77, 131.82, 132.6, 133.0, 137.0, 138.2, 140.5, 145.2, 157.5, 161.9,

step: [α] ²⁰= +54.3 (c 0.30, CH Cl ); IR (neat) ν 2924, 1762, 1712,

1610, 1510, 1454, 1232, 1151, 1097, 1022, 954, 587, 562 cm ; H

D

2

−1 1

+

62.4; HRMS (ESI+) calcd for C H O S ([M + H] ) 663.2992,

NMR (500 MHz, CDCl ) δ 0.91 (1H, m), 0.92 (1H, m), 0.96 (3H, d,

38

47

8

3

found 663.2980.

J = 6.6 Hz), 1.09 (1H, qd, J = 12.4 Hz, 4.3 Hz), 1.42 (1H, m), 1.44

(1H, m), 1.61 (1H, m), 1.66 (1H, td, J = 11.5 Hz, 4.7 Hz), 1.85 (1H,

m), 1.99 (1H, m), 2.12 (1H, m), 2.14 (1H, m), 2.65 (1H, dd, J = 13.2

Hz, 10.9 Hz), 2.84 (1H, d, J = 15.8 Hz), 2.94 (1H, m), 2.96 (1H, d, J =

15.7 Hz), 3.05 (1H, dd, J = 11.5 Hz, 6.4 Hz), 3.22 (1H, dd, J = 13.2

Hz, 5.5 Hz), 3.35−3.36 (2H, m), 4.88 (1H, m), 4.93 (1H, d, J = 10.4

Hz), 4.94 (1H, m), 4.95 (1H, d, J = 17.1 Hz), 5.31 (1H, m), 5.35 (1H,

m), 5.90 (1H, d, J = 9.8 Hz), 6.84 (1H, dd, J = 8.4 Hz, 2.5 Hz), 6.90

(1H, dd, J = 8.7 Hz, 2.5 Hz), 6.95 (1H, dd, J = 8.4 Hz, 2.3 Hz), 6.97

Macrolactone 30 and Dimer 43. An oven-dried two-neck 2 L

ﬂask was equipped with a glass stopper, a Dean−Stark trap with a

reﬂux condenser, and a magnetic stirring bar. The apparatus was

evacuated and put under an atmosphere of argon before the addition

of 1.5 L of freshly distilled benzene (sodium/benzophenone). A

solution of triene 29 (100 mg, 0.15 mmol, 1.00 equiv) in 5 mL of

benzene was added, and the reaction mixture was heated to reﬂux in a

preheated 110 °C oil bath. Three 25 mL aliquots of benzene were

drained through the side arm of the Dean−Stark trap, and the reaction

mixture was heated at reﬂux for 12 h. After cooling to room

temperature, TLC (2:1 hexanes/EtOAc, UV/anisaldehyde) showed

complete consumption of the starting material and formation of

(1H, dd, J = 8.7 Hz, 2.3 Hz); ¹³C NMR (125 MHz, CDCl ) δ 7.9,

3

22.6, 29.3, 33.1, 36.6, 38.1, 40.8, 42.4, 42.7, 46.0, 46.7, 49.5, 52.1, 56.1,

72.1, 82.0, 117.1, 119.5, 120.1, 128.11, 128.12, 128.8, 130.0, 132.5,

136.5, 157.4, 164.4, 198.7; HRMS (ESI+) calcd for C H IO ([M +

28

34

4

+

macrolactone 30 as a spot of R = 0.52 along with a small amount of

H] ) 561.1502, found 561.1489.

f

dimer 43 of R = 0.54. The solvent was removed under reduced

pressure, and the residue was puriﬁed by preparative TLC (1500 μm

Acylketene Acetal 45. To a solution of primary iodide 44 (5.6

mg, 10 μmol, 1.00 equiv) in 500 μL of toluene was added neat DBU

(25 μL, 167 μmol, 16.7 equiv), and the reaction mixture was heated to

45 °C for 3 h. After this time, TLC (1:1 hexanes/EtOAc, UV/

anisaldehyde) showed complete consumption of the starting material

f

plate, loaded in CH Cl , eluted in 9:1 toluene/EtOAc, silica washed

2

with EtOAc) to give macrolactone 30 as a white foam (46 mg, 50%)

along with dimer 43 (10 mg) as a colorless oil.

Macrolactone 30: [α]_D²⁰= +83.5 (c 0.70, CH Cl ); IR (neat) ν

and formation of the product of R = 0.07. After cooling to room

2

f

2

1

0

916, 1759, 1714, 1610, 1508, 1454, 1365, 1237, 1190, 1177, 1148,

temperature, the mixture was diluted with EtOAc, and the organic

phase was washed twice with water and once with brine before drying

over anhydrous Na SO . The solvent was removed under reduced

−1 1

097, 1067, 1035, 985, 928, 815 cm ; H NMR (500 MHz, CDCl ) δ

3

.91 (1H, m), 0.92 (1H, m), 0.95 (3H, d, J = 6.5 Hz), 1.09 (1H, qd, J

2

4

=

12.7 Hz, 4.1 Hz), 1.42 (1H, m), 1.44 (1H, m), 1.61 (1H, m), 1.65

pressure, and the residue was puriﬁed by preparative TLC (500 μm

(

1H, m), 1.84 (1H, m), 1.99 (1H, m), 2.10 (1H, m), 2.13 (1H, m),

plate, loaded in CH Cl , eluted with 3:1 EtOAc/hexanes, silica washed

2

.46 (3H, s), 2.69 (1H, m), 2.74 (1H, d, J = 15.7 Hz), 2.88 (1H, d, J =

5.7 Hz), 2.94 (2H, m), 3.01 (1H, dd, J = 11.4 Hz, 6.5 Hz), 4.15 (2H,

with EtOAc) to give acylketene acetal 45. Although suﬃcient material

was obtained for characterization, the product is very susceptible to

hydrolysis and decomposes over time in chloroform, upon storage, and

during puriﬁcation eﬀorts: [α]_D²⁰= +110 (c 0.24, CH Cl ); IR (neat)

1

m), 4.86 (1H, m), 4.93 (1H, d, J = 17.5 Hz), 4.94 (1H, d, J = 8.4 Hz),

5

6

.14 (1H, m), 5.29 (1H, m), 5.34 (1H, m), 5.90 (1H, d, J = 9.8 Hz),

.81 (1H, m), 6.88 (1H, m), 6.89 (1H, m), 6.91 (1H, m), 7.36 (2H, d,

2

ν 2925, 1610, 1562, 1422, 1364, 1225, 1190, 1143, 1097, 1063, 1035,

13

−1 1

J = 7.9 Hz), 7.80 (2H, d, J = 8.2 Hz); C NMR (125 MHz, CDCl ) δ

928, 833 cm ; H NMR (500 MHz, CDCl ) δ 0.85 (1H, m), 0.91

3

1.8, 22.6, 29.2, 33.1, 35.9, 36.5, 38.0, 42.3, 42.7, 45.8, 46.6, 49.5, 52.1,

6.0, 70.0, 70.5, 81.9, 117.0, 119.5, 120.0, 128.0, 128.09, 128.10, 128.8,

(1H, m), 0.95 (3H, d, J = 6.6 Hz), 1.07 (1H, qd, J = 12.6 Hz, 4.2 Hz),

1.39 (1H, m), 1.44 (1H, m), 1.58 (1H, m), 1.71 (1H, td, J = 11.5 Hz,

6.0 Hz), 1.83 (1H, m), 1.99 (1H, m), 2.01 (1H, m), 2.12 (1H, m),

2.87 (1H, d, J = 13.9 Hz), 2.91 (1H, dd, J = 11.6 Hz, 6.6 Hz), 3.01

(1H, m), 3.38 (1H, dd, J = 13.8 Hz, 9.0 Hz), 4.31−4.34 (2H, m), 4.36

(1H, s), 4.81 (1H, d, J = 17.0 Hz), 4.86 (1H, d, J = 10.1 Hz), 4.96 (1H,

t, J = 5.3 Hz), 5.11 (1H, m), 5.41 (1H, dt, J = 9.8 Hz, 3.5 Hz), 5.48

(1H, ddd, J = 17.6 Hz, 9.8 Hz, 8.5 Hz), 5.89 (1H, d, J = 9.8 Hz), 6.71

(1H, dd, J = 8.2 Hz, 2.5 Hz), 6.92 (1H, dd, J = 8.2 Hz, 1.8 Hz), 7.00

29.0, 130.0, 132.5, 132.6, 136.4, 145.2, 157.3, 164.4, 198.6; HRMS

+

3

5

41

7

2

0

Dimer 43: [α]_D= +67.2 (c 1.19, CH Cl ); IR (neat) ν 2920,

2

−1 1

3

1

3

(1H, dd, J = 8.6 Hz, 2.4 Hz), 7.05 (1H, dd, J = 8.6 Hz, 1.8 Hz); C

dd, J = 14.2 Hz, 5.2 Hz), 2.47 (6H, s), 2.50 (2H, dd, J = 14.3 Hz, 7.6

Hz), 3.22 (2H, d, J = 14.1 Hz), 3.32 (2H, m), 3.41 (2H, m), 3.44 (2H,

d, J = 14.2 Hz), 3.57 (2H, dd, J = 10.9 Hz, 4.4 Hz), 3.67 (2H, dd, J =

NMR (125 MHz, CDCl ) δ 22.7, 29.1, 32.9, 36.3, 38.2, 40.6, 43.3,

44.5, 45.7, 48.4, 51.7, 55.8, 72.5, 77.4, 79.3, 82.8, 115.6, 118.7, 119.8,

3

126.3, 128.0, 128.3, 129.1, 133.5, 138.0, 159.3, 166.4, 195.4; HRMS

+

10.9 Hz, 3.2 Hz), 4.56 (2H, m), 5.07 (2H, d, J = 11.0 Hz), 5.08 (2H, d,

(ESI+) calcd for C H O ([M + H] ) 433.2379, found 433.2377.

28

33

4

J = 15.9 Hz), 4.65 (2H, dd, J = 6.5 Hz, 3.8 Hz), 5.47 (2H, dt, J = 9.7

Hz, 3.2 Hz), 5.60 (2H, dt, J = 17.7 Hz, 9.2 Hz), 5.98 (2H, d, J = 9.8

Hz), 6.61 (4H, d, J = 8.5 Hz), 6.77 (4H, d, J = 8.5 Hz), 7.37 (4H, d, J

Acylketene Acetal 46 and Ring-Expanded Macrolactone 49.

To a solution of macrolactone tosylate 30 (8.0 mg, 13.2 μmol, 1.00

equiv) in 1 mL of THF was added thallium(I) carbonate (15 mg, 32

μmol, 2.42 equiv). After stirring at room temperature for 20 min, neat

DBU (25 μL, 167 μmol, 12.7 equiv) was added, and the reaction was

stirred for an additional 10 min at room temperature. After this time,

TLC (1:1 hexanes/EtOAc, UV/anisaldehyde) showed complete

=

8.1 Hz), 7.78 (4H, d, J = 8.2 Hz); ¹³C NMR (125 MHz, CDCl ) δ

3

2

5

1

1.8, 22.5, 30.7, 32.8, 34.7, 36.1, 38.0, 43.0, 44.1, 45.3, 49.1, 49.8, 51.9,

6.5, 68.4, 72.9, 77.9, 116.0, 117.0, 127.6, 128.1, 128.8, 129.0, 130.0,

30.4, 132.8, 137.0, 145.0, 156.4, 165.7, 202.1; HRMS (ESI+) calcd for

+

C H O S ([M + H] ) 1209.5068, found 1209.5092.

conversion of the starting material to the product of R = 0.24. The

70

81 14

2

f

Primary Iodide 44. To a solution of macrolactone tosylate 30

11.1 mg, 18.4 μmol, 1.00 equiv) in 500 μL of anhydrous acetone was

added sodium iodide (207 mg, 1.38 mmol, 75 equiv). The ﬂask was

tightly sealed with a yellow Teﬂon cap, and the reaction mixture was

heated to 40 °C in an oil bath for 12 h. After this time, TLC (2:1

hexanes/EtOAc, UV/anisaldehyde) showed complete consumption of

reaction was diluted with ether, and water was added. The layers were

separated, and the organic phase was washed with pH 7 phosphate

buﬀer before drying over anhydrous Na SO . The solvent was

removed under reduced pressure, and the residue was dried under high

vacuum to give acylketene acetal 46, which was immediately submitted

(

2

4

for NMR analysis. In CDCl solution, 46 slowly isomerized to 45 at

3

the starting material and formation of the iodide of R = 0.65. The

the rate of 1% per hour; this isomerization was accelerated upon

f

reaction was diluted with water and EtOAc, the layers were separated,

and the organic phase was washed with one additional portion of water

before drying over anhydrous Na SO . The solvent was removed

under reduced pressure, and the residue was puriﬁed by preparative

TLC (500 μm plate, sample loaded in EtOAc, plate eluted in 3:1

hexanes/EtOAc, silica washed with EtOAc) to give primary iodide 44

as a colorless oil (5.6 mg, 54%) that was used immediately in the next

exposure to silica, eventually leading to the ring-expanded macro-

lactone 49.

1

Acylketene Acetal 46: H NMR (500 MHz, CDCl ) δ 0.94 (1H,

2

4

3

m), 0.96 (3H, d, J = 6.62 Hz), 1.00 (1H, m), 1.11 (1H, qd, J = 12.39

Hz, 4.21 Hz), 1.41 (1H, ddd, J = 16.08 Hz, 10.53 Hz, 3.81 Hz), 1.46

(1H, m), 1.68 (1H, ddd, J = 13.35 Hz, 5.98 Hz, 2.90 Hz), 1.81 (1H,

m), 1.95 (1H, dt, J = 11.5 Hz, 4.5 Hz), 2.00 (1H, m), 2.05 (1H, m),

9

599

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

Featured Article

2

.07 (1H, m), 2.69 (1H, dd, J = 14.32 Hz, 1.75 Hz), 2.84 (1H, m),

.93 (1H, dd, J = 11.03 Hz, 7.76 Hz), 3.13 (1H, dd, J = 14.30 Hz, 3.31

raphy (9:1 hexanes/EtOAc, → 2:1 → 1:1) to aﬀord phenol 60 as a

colorless oil (1.90 g, 77% over three steps): IR (neat) ν 3339, 3071,

2930, 2892, 2857, 1613, 1597, 1512, 1472, 1428, 1226, 1112, 824, 741,

Hz), 4.24 (1H, dd, J = 8.33 Hz, 6.70 Hz), 4.34 (1H, dd, J = 8.71 Hz,

−1 1

1

4

.03 Hz), 4.51 (1H, s), 4.71 (1H, m), 4.83 (1H, m), 4.85 (1H, m),

.99 (1H, m), 5.46 (1H, dt, J = 10 Hz, 3 Hz), 5.53 (1H, ddd, J = 16.82

702 cm ; H NMR (500 MHz, CDCl ) δ 1.05 (9H, s), 3.29 (2H, s),

3

4.07 (2H, s), 4.58 (1H, s), 4.85 (1H, s), 5.21 (1H, d, J = 1.49 Hz), 6.71

(2H, d, J = 8.49 Hz), 7.00 (2H, d, J = 8.46 Hz), 7.35 (4H, m), 7.41

Hz, 10.10 Hz, 8.82 Hz), 5.93 (1H, d, J = 9.68 Hz), 6.82 (1H, dd, J =

8.25 Hz, 2.55 Hz), 6.85 (1H, dd, J = 8.29 Hz, 2.57 Hz), 7.03 (1H, dd, J

(2H, m), 7.64 (4H, d, J = 6.62 Hz); ¹³C NMR (125 MHz, CDCl ) δ

3

13

=

8.23 Hz, 2.10 Hz), 7.08 (1H, dd, J = 8.31 Hz, 2.14 Hz); C NMR

19.3, 26.8, 38.7, 65.9, 110.7, 115.1, 127.7, 129.6, 130.0, 131.4, 133.6,

+

(

125 MHz, CDCl ) δ 22.7, 29.5, 33.3, 36.6, 38.2, 39.0, 41.9, 42.5, 45.7,

135.5, 147.8, 153.8; HRMS (ESI+) calcd for C H O Si ([M + H] )

3

26 31

2

4

1

8.2, 49.6, 56.2, 70.3, 78.0, 80.6, 84.6, 114.9, 115.6, 119.9, 123.7, 128.8,

403.2093, found 403.2080.

29.6, 129.7, 134.3, 138.8, 159.6, 167.7, 198.7; HRMS (ESI+) calcd for

Primary Alcohol 62. A 15 mM solution of Pd(PPh₃)₄was

prepared under argon by dissolving 43 mg of the solid catalyst in 2.50

mL of THF. To a 0.125 M solution of phenol 60 (3.30 mL, 0.41

mmol, 1.10 equiv) in dry THF was added solid 60% sodium hydride

dispersion in mineral oil (16.5 mg, 0.41 mmol, 1.10 equiv); vigorous

bubbling was observed, and the resulting phenolate solution was used

immediately. The bright yellow catalyst solution was added to a ﬂask

containing neat allylic phosphate 20 (210 mg, 0.38 mmol, 1.00 equiv)

followed by the dropwise addition of the phenolate solution. After

each drop, the solution would turn dark orange before fading to yellow

again over the course of several seconds. After addition was complete,

TLC (3:1 hexanes/EtOAc, UV/anisaldehyde) showed complete

consumption of the starting phosphate and formation of the desired

product of R = 0.60 along with the elimination byproduct of R = 0.54

+

C H O ([M + H] ) 433.2379, found 433.2375.

28

33

4

20

Ring-Expanded Macrolactone 49: [α]_D= +19.5 (c 0.70,

CH Cl ); IR (neat) ν 3456, 2916, 2849, 1749, 1711, 1612, 1583, 1508,

2

1

456, 1406, 1377, 1335, 1296, 1237, 1176, 1158, 1114, 1063, 1037,

014, 964, 927, 805 cm ; H NMR (500 MHz, CDCl ) δ 0.88 (1H, q,

−1 1

3

J = 11.2 Hz), 0.94 (1H, m), 0.95 (3H, d, J = 6.5 Hz), 1.06 (1H, qd, J =

2.7 Hz, 4.2 Hz), 1.40 (1H, m), 1.43 (1H, m), 1.56 (1H, m), 1.75

1H, m), 1.82 (1H, m), 2.00 (1H, m), 2.05 (1H, m), 2.08 (1H, m),

.63 (1H, dd, J = 13.1 Hz, 9.3 Hz), 2.93 (1H, d, J = 16.6 Hz), 2.99

1H, d, J = 16.6 Hz), 3.02 (1H, m), 3.04 (1H, m), 3.19 (1H, dd, J =

3.1 Hz, 4.1 Hz), 3.94 (1H, d, J = 11.0 Hz), 4.07 (1H, m), 4.21 (1H,

1

(

2

(

1

dd, J = 11.0 Hz, 8.1 Hz), 4.91 (1H, t, J = 5.1 Hz), 4.97 (1H, d, J = 17.0

Hz), 4.99 (1H, d, J = 9.9 Hz), 5.37 (1H, m), 5.41 (1H, m), 5.93 (1H,

d, J = 9.7 Hz), 6.73 (1H, dd, J = 8.3 Hz, 2.7 Hz), 6.80 (1H, dd, J = 8.4

Hz, 2.5 Hz), 7.01 (1H, dd, J = 8.2 Hz, 2.1 Hz), 7.04 (1H, dd, J = 8.5

f

and unreacted phenol at R = 0.46. The solvent was removed under

f

reduced pressure, and the residue was puriﬁed by column

chromatography (9:1 hexanes/EtOAc → 4:1) to give a mixture of

aryl ether 61 and the elimination byproduct that was used directly in

the next step (248 mg total).

Hz, 2.1 Hz); ¹³C NMR (125 MHz, CDCl ) δ 22.6, 29.1, 32.9, 36.3,

3

1

4

8.0, 42.5, 43.3, 43.6, 45.2, 47.6, 48.6, 51.1, 56.1, 68.7, 69.7, 79.8,

15.5, 117.1, 117.7, 128.3, 128.38, 128.44, 130.3, 130.7, 136.3, 157.4,

65.2, 201.0; HRMS (ESI+) calcd for C H O ([M + H] )

51.2484, found 451.2480.

-(2-(((tert-Butyldiphenylsilyl)oxy)methyl)allyl)phenol (60).

+

To a solution of mixed 61 (248 mg, 0.31 mmol, 1.00 equiv) in 16

28

35

5

mL of 1:1 THF/H O was added glacial acetic acid (15 mL, 262 mmol,

2

4

845 equiv). After 12 h at room temperature, TLC (1:1 hexanes/

To a two-neck 250 mL ﬂask equipped with a magnetic stirring bar,

a rubber septum, and a reﬂux condenser were added magnesium

turnings (2.37 g, 97.5 mmol, 7.00 equiv). The entire apparatus was

ﬂame-dried under high vacuum and cooled to room temperature

under argon. Approximately 8 mL of THF was added to the

magnesium turnings followed by 100 μL of 1,2-dibromoethane;

bubbling was observed, and the solution turned gray. A solution of aryl

EtOAc, UV/anisaldehyde) showed complete conversion to the

product of R = 0.49. The acid was neutralized with saturated aqueous

f

K CO solution, and the reaction mixture was diluted with water and

2

3

EtOAc. The layers were separated, and the aqueous phase was

extracted with three additional portions of EtOAc. The combined

organics were dried over anhydrous Na SO , the solvent was removed

2

4

under reduced pressure, and the residue was puriﬁed by column

chromatography (10:1 hexanes/EtOAc → 3:1 → 2:1 → 1:1) to give

primary alcohol 62 as a white foam (157 mg, 60% over two steps):

[α]_D²⁰= −15.1 (c 2.80, CH Cl ); IR (neat) ν 3482, 2927, 2857, 1717,

44

bromide 56 (4.00 g, 13.9 mmol, 1.00 equiv) in 50 mL of THF was

added slowly, and the reaction was initiated with a heat gun. The ﬂask

was then transferred to a preheated 100 °C oil bath, and the reaction

was heated to reﬂux for 2 h. After cooling to room temperature, the

dark gray/black solution of Grignard reagent 57 was titrated with

2

1654, 1592, 1507, 1472, 1428, 1390, 1375, 1273, 1234, 1205, 1174,

−1 1

1111, 1020, 971, 939, 903, 823, 742, 703 cm ; H NMR (500 MHz,

55

salicylaldehyde phenylhydrazone, giving a ﬁnal concentration of 0.14

CDCl ) δ 0.92 (1H, m), 0.93 (3H, d, J = 6.51 Hz), 0.97 (1H, m), 1.03

3

M.

(9H, s), 1.43 (1H, m), 1.46 (1H, m), 1.59 (1H, m), 1.68 (1H, m), 1.69

(1H, m), 1.70 (3H, s), 1.71 (4H, m), 1.76 (1H, m), 3.29 (2H, s), 3.52

(1H, d, J = 11.04 Hz), 3.66 (1H, d, J = 11.02 Hz), 4.07 (2H, s), 4.84

(1H, s), 4.99 (1H, m), 5.22 (1H, s), 5.26 (1H, s), 6.07 (1H, d, J =

15.69 Hz), 6.61 (1H, dd, J = 4.44 Hz, 15.66 Hz), 6.74 (2H, d, J = 8.54

Hz), 7.03 (2H, d, J = 8.46 Hz), 7.35 (4H, m), 7.41 (2H, m), 7.63 (4H,

To an oven-dried ﬂask under argon equipped with a magnetic

45

stirring bar was added a solution of allylic bromide 58 (2.39 g, 6.13

mmol, 1.00 equiv) in 50 mL of THF. The 0.14 M solution of Grignard

reagent 57 (52 mL, 7.28 mmol, 1.19 equiv) was transferred to the ﬂask

via cannula, and the homogeneous gray/black reaction mixture was left

to stir at room temperature overnight. After this time, TLC (10:1

hexanes/EtOAc, UV/anisaldehyde) showed complete consumption of

the allylic bromide (R = 0.59) and formation of the coupled product

of R = 0.73. The reaction was quenched with saturated aqueous

NH Cl solution and diluted with ether. The layers were separated, and

m); ¹³C NMR (125 MHz, CDCl ) δ 19.3, 22.6, 25.1 25.2, 26.9, 27.1,

3

32.3, 34.8, 38.7, 38.9, 40.5, 43.5, 65.9, 66.0, 79.1, 95.0, 106.6, 110.9,

115.3, 123.5, 127.7, 129.7, 130.1, 132.3, 133.6, 135.6, 139.2, 147.7,

156.4, 161.8, 162.3; HRMS (ESI+) calcd for C H NaO Si ([M +

f

43 54

6

+

Na] ) 717.3587, found 717.3591.

4

the organic phase was dried over anhydrous Na SO . The solvent was

Aldehyde 63. To a solution of primary alcohol 62 (157 mg, 0.23

2

4

removed under reduced pressure, and the mixture containing crude 59

was used directly in the next step without further puriﬁcation.

Solid lithium hydroxide monohydrate (692 mg, 16.5 mmol, 2.69

equiv) was added in a single portion to a solution of crude 59 (3.74 g)

in 100 mL of THF and 50 mL of water; the reaction mixture

immediately turned yellow and eventually became purple. After stirring

at room temperature for 30 min, TLC (10:1 hexanes/EtOAc, UV/

anisaldehyde) showed complete conversion to the deprotected

mmol, 1.00 equiv) in 5 mL of CH Cl was added solid Dess−Martin

2

periodinane (115 mg, 0.27 mmol, 1.20 equiv). The reaction mixture

immediately turned slightly yellow and was stirred at room

temperature for 30 min. After this time, TLC (1:1 hexanes/EtOAc,

UV/anisaldehyde) showed complete conversion to the product of R =

f

0.67. The reaction was diluted with water and CH Cl and quenched

2

with saturated aqueous sodium thiosulfate solution and saturated

aqueous NaHCO₃solution. The layers were separated, and the

aqueous phase was extracted with one additional portion of CH Cl .

product of R = 0.16. The reaction was quenched with pH 7

f

2

phosphate buﬀer (discharging the purple color to yellow) and diluted

with EtOAc. The layers were separated, and the organic phase was

dried over anhydrous Na SO before the solvent was removed under

The combined organics were dried over anhydrous Na SO before

2 4

removal of the solvent under reduced pressure and puriﬁcation of the

residue by column chromatography (3:1 hexanes/EtOAc → 1:1) to

2

4

2

0

reduced pressure. The residue was puriﬁed by column chromatog-

aﬀord aldehyde 63 as a colorless oil (141 mg, 90%): [α]_D= −11.2 (c

9

600

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

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1

0

1

.24, CH Cl ); IR (neat) ν 2932, 1724, 1653, 1596, 1507, 1457, 1428,

= 1.72 Hz, 15.61 Hz), 6.24 (1H, dd, J = 9.99 Hz, 14.34 Hz), 6.54 (1H,

dd, J = 3.87 Hz, 15.61 Hz), 6.76 (2H, d, J = 8.60 Hz), 7.09 (2H, d, J =

2

−1 1

390, 1273, 1235, 1112, 1019 cm ; H NMR (500 MHz, CDCl ) δ

3

8.56 Hz); ¹³C NMR (125 MHz, CDCl ) δ 22.4, 24.7, 25.1, 25.2, 31.8,

.90 (1H, m), 0.95 (1H, m), 0.96 (3H, d, J = 6.51 Hz), 1.03 (9H, s),

.42 (1H, ddd, J = 3.89 Hz, 13.72 Hz, 16.53 Hz), 1.49 (1H, m), 1.70

3

34.5, 39.1, 41.2, 46.5, 47.1, 65.4, 76.5, 77.7, 94.9, 106.5, 111.4, 115.3,

123.0, 130.1, 131.8, 140.0, 148.5, 149.3, 157.0, 161.9, 162.4; HRMS

(

3H, s), 1.71 (3H, s), 1.76 (1H, m), 1.78 (1H, m), 1.85 (1H, m), 2.08

1H, m), 2.49 (1H, m), 3.27 (2H, s), 4.06 (2H, s), 4.82 (1H, s), 4.92

1H, m), 5.21 (1H, d, J = 1.38 Hz), 5.27 (1H, s), 6.06 (1H, dd, J =

+

(ESI+) calcd for C H IO ([M + H] ) 579.1607, found 579.1596.

28

36

5

Triene 66. A 0.01 M solution of dichlorobis(acetonitrile)palladium-

(II) was prepared by dissolving 13 mg of the solid catalyst in 5 mL of

dry DMF. To a separate ﬂask containing neat vinyl iodide 65 (78.5 mg,

0.14 mmol, 1.00 equiv) was added a 0.25 M solution of stannane 42 in

DMF (679 μL, 0.17 mmol, 1.25 equiv) followed by a portion of the

palladium catalyst solution (1.36 mL, 13.6 μmol, 0.10 equiv). The

reaction mixture immediately turned dark brown/black, and was

stirred at room temperature for 1.5 h. After this time, the reaction was

diluted with ether and water and poured into a separatory funnel. The

layers were separated, and the organic phase was washed with two

additional portions of water before drying over anhydrous Na SO .

1

.45 Hz, 15.68 Hz), 6.55 (1H, dd, J = 4.77 Hz, 15.66 Hz), 6.69 (2H, d,

J = 8.63 Hz), 7.01 (2H, d, J = 8.61 Hz), 7.35 (4H, m), 7.41 (2H, m),

.63 (4H, m), 9.53 (1H, d, J = 3.00 Hz); ¹³C NMR (125 MHz,

CDCl ) δ 19.3, 22.3, 25.1, 25.5, 26.9, 31.7, 34.0, 34.5, 38.7, 41.6, 51.3,

7

3

6

1

6.0, 78.3, 95.4, 106.6, 110.9, 115.3, 124.1, 127.7, 129.7, 130.1, 132.3,

33.6, 135.6, 138.2, 147.7, 16.1, 161.7, 162.1, 203.6; HRMS (ESI+)

+

calcd for C H O Si ([M + H] ) 693.3611, found 693.3588.

43

53

6

Vinyl Iodide 64. To a ﬂame-dried 25 mL round-bottom ﬂask

equipped with a magnetic stirring bar was added solid chromium(II)

chloride (200 mg, 1.63 mmol, 8.00 equiv) in the glovebox. The ﬂask

was tightly sealed with a septum, removed from the glovebox, and put

under a balloon of argon. Then 3.50 mL of freshly distilled THF

2

4

TLC (2:1 hexanes/EtOAc, UV/anisaldehyde) showed the product of

R_f= 0.28, which was essentially copolar with the starting vinyl iodide.

The solvent was removed under reduced pressure, and the residue was

puriﬁed by column chromatography (10:1 hexanes/EtOAc → 4:1 →

(

sodium/benzophenone) was added, and the resulting green slurry

was cooled to 0 °C. To a separate ﬂask containing neat aldehyde 63

141 mg, 0.20 mmol, 1.00 equiv) was added solid iodoform (160 mg,

.41 mol, 2.00 equiv). This mixture was dissolved in 3 mL of THF and

(

0

3

:1 → 2:1 → 1:1) to aﬀord triene 66 as a yellow oil (59.5 mg, 87%):

20

[

α]_D= −31.0 (c 0.57, CH Cl ); IR (neat) ν 3436, 2923, 2866, 1717,

2

added slowly to the chromium suspension; the vial was rinsed with

two additional 2.0 mL portions of THF, which were also added to the

reaction mixture. The cooling bath was removed, and after 1.5 h, TLC

1

654, 1594, 1507, 1455, 1391, 1375, 1271, 1232, 1204, 1175, 1111,

−1

1

060, 1020, 1008, 974, 902 cm ; H NMR (500 MHz, CDCl ) δ 0.87

3

(1H, m), 0.89 (1H, m), 0.90 (3H, d, J = 6.49 Hz), 1.36 (1H, m), 1.45

(1H, m), 1.50 (1H, m), 1.64 (1H, m), 1.67 (1H, m), 1.69 (3H, s), 1.70

(3H, s), 1.77 (1H, m), 2.24 (1H, ddd, J = 3.52 Hz, 12.41 Hz, 12.77

(

3:1 hexanes/EtOAc, UV/anisaldehyde) showed clean formation of

the product of R = 0.51. The reaction was quenched with water and

f

diluted with ether. The layers were separated, and the aqueous phase

was extracted with two additional portions of ether. The combined

organics were washed with saturated aqueous sodium Na S O

3

solution (yellow color discharged) and brine before drying over

anhydrous Na SO . The solvent was removed under reduced pressure,

and the residue was puriﬁed by column chromatography (9:1 hexanes/

EtOAc → 4:1 → 3:1) to aﬀord vinyl iodide 64 as a white foam (144

mg, 86%): [α]_D²⁰= −29.5 (c 1.04, CH Cl ); IR (neat) ν 2928, 2856,

1

Hz), 3.34 (2H, s), 4.03 (2H, s), 4.87 (1H, s), 4.91 (1H, m), 5.03 (1H,

d, J = 10.27 Hz), 5.10 (1H, s), 5.11 (1H, d, J = 16.68 Hz), 5.24 (1H,

s), 5.41 (1H, dd, J = 9.40 Hz, 15.17 Hz), 5.62 (1H, dd, J = 10.60 Hz,

2

1

5.19 Hz), 5.78 (1H, dd, J = 10.71 Hz, 15.02 Hz), 6.02 (1H, dd, J =

.74 Hz, 15.72 Hz), 6.07 (1H, dd, J = 11.02 Hz, 15.33 Hz), 6.27 (1H,

2

4

dt, J = 10.45 Hz, 17.04 Hz), 6.54 (1H, dd, J = 3.95 Hz, 15.62 Hz), 6.75

13

(2H, d, J = 8.57 Hz), 7.06 (2H, d, J = 8.54 Hz);

C NMR (125 MHz,

2

CDCl ) δ 22.5, 24.8, 25.1, 25.2, 31.9, 34.7, 39.1, 42.0, 43.4, 47.3, 65.4,

3

728, 1655, 1596, 1507, 1428, 1390, 1375, 1269, 1233, 1204, 1174,

−1

1

77.9, 94.7, 106.5, 111.2, 115.5, 116.8, 122.8, 129.9, 131.5, 131.81,

111, 1020, 951, 902 cm ; H NMR (500 MHz, CDCl ) δ 0.88 (1H,

3

1

31.83, 133.0, 137.1, 138.3, 140.8, 148.6, 157.1, 161.9, 162.5; HRMS

m), 0.90 (1H, m), 0.91 (3H, d, J = 6.44 Hz), 1.05 (9H, s), 1.40 (1H,

m), 1.45 (1H, m), 1.49 (1H, m), 1.64 (1H, m), 1.69 (1H, m), 1.70

+

(ESI+) calcd for C H O ([M + H] ) 505.2954, found 505.2931.

32 41 5

Macrolactone 50. Benzene (400 mL) was freshly distilled from

(

6H, s), 1.75 (1H, m), 2.25 (1H, ddd, J = 3.55 Hz, 10.54 Hz, 10.63

sodium/benzophenone directly into a ﬂame-dried two-neck 500 mL

ﬂask equipped with a magnetic stirring bar and a 24/40 glass stopper.

A solution of triene 66 (46.2 mg, 91.5 μmol, 1.00 equiv) in 5 mL of

dry benzene was added, a ﬂame-dried Dean−Stark trap/reﬂux

condenser was attached, and the ﬂask was heated to reﬂux in a

preheated 110 °C oil bath. Benzene (3 × 10 mL) was drained from the

Dean−Stark side arm, and the reaction was heated at reﬂux for 22 h.

After this time, TLC (4:1 hexanes/EtOAc, UV/anisaldehyde) showed

Hz), 3.29 (2H, s), 4.07 (1H, d, J = 14.06 Hz), 4.11 (1H, d, J = 14.11

Hz), 4.84 (1H, s), 4.89 (1H, m), 5.23 (2H, m), 5.52 (1H, d, J = 14.35

Hz), 6.04 (1H, dd, J = 1.59 Hz, 15.61 Hz), 6.23 (1H, dd, J = 9.96 Hz,

14.34 Hz), 6.53 (1H, dd, J = 3.88 Hz, 15.61 Hz), 6.71 (2H, d, J = 8.56

Hz), 7.02 (2H, d, J = 8.52 Hz), 7.36 (4H, m), 7.41 (2H, m), 7.65 (4H,

_m₎_;₁3C NMR (125 MHz, CDCl ) δ 19.4, 22.4, 24.7, 25.1, 25.2, 26.9,

3

1

1.8, 34.5, 38.7, 41.2, 46.5, 47.0, 66.1, 76.5, 77.5, 94.9, 106.5, 110.9,

15.1, 123.0, 127.7, 129.7, 130.1, 132.0, 133.6, 135.6, 140.1, 147.8,

49.3, 156.7, 161.9, 162.4; HRMS (ESI+) calcd for C H INaO Si

^c^o^m^p^l^e^t^e^c^oⁿ^s^u^m^p^tⁱ^oⁿ^o^f^t^h^e^t^rⁱ^eⁿ^e^aⁿ^d^f^o^r^m^a^tⁱ^oⁿ^o^f^t^h^e^p^r^o^d^u^c^t^o^f^Rf

= 0.53. After cooling to room temperature, the solvent was removed

4

53

5

+

(

[M + Na] ) 839.2605, found 839.2594.

under reduced pressure, and the residue was puriﬁed by column

chromatography (10:1 hexanes/EtOAc → 4:1) to give the macro-

Primary Alcohol 65. To a solution of vinyl iodide 64 (129 mg,

.16 mmol, 1.00 equiv) in 5 mL of THF was added solid TBAT (340

0

20

^l^a^c^t^oⁿ^e⁵⁰^a^s^a^w^hⁱ^t^e^f^o^a^m⁽¹⁸^.⁸^m^g^,⁴⁶^%⁾^:^[^α^]D = +125.0 (c 0.77,

mg, 0.63 mmol, 4.00 equiv). The ﬂask was then wrapped in aluminum

foil to protect the reaction mixture from light. After 7 h at room

temperature, TLC (3:1 hexanes/EtOAc, UV/anisaldehyde) showed

CH Cl ); IR (neat) ν 2947, 2915, 2851, 1748, 1715, 1647, 1610, 1507,

2

−1 1

1

456, 1402, 1326, 1238, 1173, 1153, 1000, 922 cm ; H NMR (500

MHz, CDCl ) δ 0.89 (1H, q, J = 11.4 Hz), 0.92 (1H, m), 0.95 (3H, d,

complete conversion to the product of R = 0.15. The reaction was

3

f

J = 6.57 Hz), 1.01 (1H, qd, J = 12.44 Hz, 4.02 Hz), 1.39 (1H, m), 1.41

quenched with pH 7 phosphate buﬀer and diluted with EtOAc. The

layers were separated, and the organic phase was washed with water

before drying over anhydrous Na SO . The solvent was removed

under reduced pressure, and the residue was puriﬁed by column

chromatography (3:1 hexanes/EtOAc → 2:1 → 1:1) to give primary

alcohol 65 as a colorless oil (79 mg, 86%): [α]_D²⁰= −42.3 (c 0.77,

CH Cl ); IR (neat) ν 3520, 1720, 1654, 1594, 1507, 1391, 1375, 1275,

(1H, m), 1.54 (1H, m), 1.76 (1H, td, J = 11.2 Hz, 5.6 Hz), 1.79 (1H,

m), 1.97 (1H, m), 2.03 (1H, m), 2.05 (1H, m), 2.89 (1H, d, J = 16.63

Hz), 2.94 (1H, d, J = 16.70 Hz), 3.01 (2H, m), 3.32 (1H, d, J = 14.24

Hz), 3.54 (1H, d, J = 14.23 Hz), 4.23 (1H, d, J = 11.34 Hz), 4.61 (1H,

d, J = 11.27 Hz), 4.92 (1H, m), 4.97 (1H, d, J = 16.9 Hz), 4.98 (1H, d,

J = 8.9 Hz), 5.11 (1H, s), 5.24 (1H, s), 5.37 (1H, m), 5.42 (1H, m),

5.92 (1H, d, J = 9.77 Hz), 6.74 (1H, dd, J = 8.64 Hz, 2.60 Hz), 6.79

2

4

2

−1 1

1

233, 1204, 1174, 1021, 952, 905 cm ; H NMR (500 MHz, CDCl )

3

1

3

δ 0.87 (1H, m), 0.88 (1H, m), 0.89 (3H, d, J = 6.53 Hz), 1.40 (1H,

(1H, dd, J = 8.87 Hz, 2.54 Hz), 7.01 (1H, m), 7.03 (1H, m); C NMR

(125 MHz, CDCl ) δ 22.6, 29.1, 32.9, 36.3, 38.0, 42.6, 43.1, 43.4, 45.3,

m), 1.45 (1H, m), 1.49 (1H, m), 1.64 (1H, m), 1.705 (3H, s), 1.709

3

(

3H, s), 1.71 (1H, m), 1.77 (1H, m), 2.27 (1H, ddd, J = 3.58 Hz, 10.36

Hz, 10.39 Hz), 3.35 (2H, s), 4.04 (2H, d, J = 3.42 Hz), 4.90 (2H, s),

.11 (1H, s), 5.25 (1H, s), 5.54 (1H, d, J = 14.35 Hz), 6.05 (1H, dd, J

47.4, 48.7, 51.0, 56.1, 68.5, 79.5, 115.6, 117.0, 117.9, 118.9, 128.3,

128.4, 129.4, 130.6, 131.3, 136.4, 143.0, 156.8, 165.1, 201.0; HRMS

+

5

(ESI+) calcd for C H NaO ([M + Na] ) 469.2355, found 469.2349.

29

34

4

9

601

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

Featured Article

Macrolactone 67. To a solution of macrolactone 50 (2.0 mg, 4.5

μmol, 1.00 equiv) in 500 μL of acetic acid was added solid

manganese(III) acetate dihydrate (3.1 mg, 11.6 μmol, 2.60 equiv)

and copper(II) acetate (0.8 mg, 4.40 μmol, 0.98 equiv). The vial was

then purged with argon and heated to 45 °C in an oil bath for 5 h.

After cooling to room temperature, the mixture was diluted with ether

ﬂask equipped with a reﬂux condenser and a magnetic stirring bar was

ﬂame-dried under high vacuum and cooled to room temperature

under argon. A solution of dioxinone ester 76 (18.52 g, 86.5 mmol,

1.00 equiv) in 1050 mL of CCl₄was added followed by solid

recrystallized NBS (16.17 g, 90.8 mmol, 1.05 equiv) and benzoyl

peroxide (978 mg, 3.30 mmol, 0.035 equiv). The reaction mixture was

then heated to reﬂux for 5 h before cooling to room temperature. TLC

(2:1 hexanes/EtOAc, UV/anisaldehyde) showed almost complete

consumption of the starting material and formation of the desired

product of R = 0.45 and the isomeric α-bromo ester byproduct at R =

0.37. The solvent was removed under reduced pressure, and the

residue was absorbed onto silica gel for puriﬁcation by column

chromatography (3:1 hexanes/EtOAc → 2:1 → 1:1) to give slightly

impure 77 as a colorless oil (8.48 g, 33%) that was used directly in the

next step.

and washed sequentially with saturated aqueous NaHCO , water, and

3

brine. The organic phase was dried over anhydrous MgSO , the

4

solvent was removed under reduced pressure, and the residue was

puriﬁed by preparative TLC (eluted in 30% EtOAc in hexanes) to give

f

20

a small amount (<1 mg) of macrolactone 67: [α]_D= −6.2 (c 0.10,

CH Cl ); IR (neat) ν 2917, 2849, 1746, 1723, 1644, 1507, 1456, 1378,

2

−1 1

1

352, 1313, 1235, 1175, 1107 cm ; H NMR (500 MHz, CDCl ) δ

3

0.87 (1H, m), 0.94 (1H, m), 0.96 (3H, d, J = 6.6 Hz), 1.07 (1H, qd, J

=

12.5 Hz, 4.1 Hz), 1.40 (1H, m), 1.42 (1H, m), 1.57 (1H, m), 1.67

(

1H, td, J = 11.8 Hz, 6.0 Hz), 1.81 (1H, m), 2.00 (1H, m), 2.13 (1H,

To a solution of 77 (8.48 g, 28.9 mmol, 1.00 equiv) in 60 mL of

toluene was added a solution of triphenylphosphine (8.35 g, 31.8

mmol, 1.10 equiv) in 20 mL of toluene. A white precipitate formed

immediately, and the reaction was left to stir at room temperature for

12 h. After this time, the solid was collected by vacuum ﬁltration and

washed with cold toluene to give crude phosphonium salt 78 that was

used directly in the next step.

m), 2.20 (1H, t, J = 11.5 Hz), 2.68 (1H, m), 2.82 (1H, m), 3.34 (1H,

d, J = 14.3 Hz), 3.41 (1H, dd, J = 11.0 Hz, 8.4 Hz), 3.59 (1H, d, J =

1

4.4 Hz), 3.74 (1H, d, J = 11.8 Hz), 4.39 (1H, d, J = 11.2 Hz), 4.53

1H, d, J = 11.3 Hz), 4.95 (1H, t, J = 5.3 Hz), 5.13 (1H, s), 5.25 (1H,

s), 5.47 (1H, d, J = 3.3 Hz), 5.87 (1H, d, J = 9.8 Hz), 5.94 (1H, dd, J =

(

9

8

3

1

4

.7 Hz, 2.5 Hz), 6.77 (1H, dd, J = 8.3 Hz, 2.6 Hz), 6.95 (1H, dd, J =

.4 Hz, 2.6 Hz), 7.02 (1H, dd, J = 8.3 Hz, 2.0 Hz), 7.06 (1H, dd, J =

To a solution of phosphonium salt 78 in 60 mL of CH Cl was

2 2

.5 Hz, 1.9 Hz); ¹³C NMR (125 MHz, CDCl ) δ 22.6, 29.1, 32.4, 32.8,

added a solution of sodium carbonate (6.00 g, 56.6 mmol, 1.96 equiv)

in 150 mL of water. The resulting biphasic reaction mixture was then

stirred vigorously at room temperature for 1 h. After this time, the

layers were separated, and the aqueous phase was extracted with one

3

6.2, 38.0, 42.7, 43.5, 47.5, 48.2, 49.0, 52.7, 55.7, 69.0, 81.2, 117.5,

18.6, 119.2, 122.7, 128.6, 129.6, 129.9, 130.6, 131.9, 136.7, 142.9,

+

57.4, 168.2, 203.7; HRMS (ESI+) calcd for C H O ([M + H] )

29

33

4

45.2379, found 445.2381.

Methyl 2-(2,2,6-Trimethyl-4-oxo-4H-1,3-dioxin-5-yl)acetate

76). A solution of tert-butyl acetoacetate 74 (20 mL, 121 mmol

.00 equiv) in 900 mL of THF was cooled to 0 °C, and 60% NaH

additional portion of CH

2

Cl

. The solvent was removed under reduced

4

2

before the combined organics were dried

over anhydrous Na SO

2

(

1

pressure, and the residue was puriﬁed by column chromatography on

neutral alumina (100% EtOAc) to give ylide 79 as a yellow

microcrystalline solid (9.84 g, 24% over three steps): IR (neat) ν

3056, 2994, 2949, 1719, 1665, 1625, 1526, 1437, 1387, 1198, 1150,

dispersion in mineral oil (4.82 g, 121 mmol, 1.00 equiv) was added in

ﬁve portions over the course of 40 min. After the last addition, the

cooling bath was removed, and the reaction mixture was stirred at

room temperature for 1 h to give a pale yellow solution. The reaction

mixture was again cooled to 0 °C, and neat methyl bromoacetate

−

1 1

1118, 752, 721, 694, 542, 521 cm ; H NMR (500 MHz, CDCl ) δ

3

2

1.09 (6H, s), 3.14 (1H, d, J

= 17.1 Hz), 3.42 (2H, s), 3.66 (3H, s),

7.49−7.53 (6H, m), 7.59−7.63 (9H, m); C NMR (125 MHz,

H−P

13

1

(

11.42 mL, 121 mmol, 1.00 equiv) was added. The cooling bath was

CDCl ) δ 24.7, 31.2, 40.1 (d, J

= 122 Hz), 51.7, 102.7, 110.0,

3

C−P

1

3

4

removed, and the reaction was left to stir at room temperature for 14

h. After this time, TLC (3:1 hexanes/EtOAc, UV/anisaldehyde)

showed clean formation of the product of R = 0.36. The reaction was

127.1 (d, J

3 Hz), 133.1 (d, J

= 91.5 Hz), 129.0 (d, J

= 12 Hz), 132.6 (d, J

=

C−P

2

= 10 Hz), 163 (d, J

= 3 Hz), 169.4, 173.9;

C−P

+

HRMS (ESI+) calcd for C H O P ([M + H] ) 475.1674, found

f

28 28 5

quenched with pH 7 phosphate buﬀer and diluted with EtOAc. The

layers were separated, and the aqueous phase was extracted with two

additional portions of EtOAc before the combined organics were dried

over anhydrous Na SO . The solvent was removed under reduced

475.1666.

7

Allylic Alcohol 81. A solution of enol ether 80 (3.11 g, 10.4

mmol, 1.00 equiv) in 60 mL of acetone and 6 mL of water was cooled

to 0 °C, and solid NMO (1.28 g, 10.9 mmol, 1.05 equiv) was added

2

4

pressure to give crude diester 75 that was used directly in the next step

followed by a 4% aqueous solution of OsO (663 μL, 0.10 mmol, 0.01

4

without further puriﬁcation.

A solution of crude diester 75 in 20 mL of acetone was cooled to 0

equiv). After stirring at 0 °C for 5 h, TLC showed almost complete

conversion of the starting material to α-hydroxyaldehyde 16. The

°C, and neat acetic anhydride (38.6 mL, 409 mmol, 3.00 equiv) was

reaction was quenched with saturated aqueous Na S O solution and

2 2 3

added followed by the dropwise addition of 18 M sulfuric acid (7.68

mL). After addition of the acid was complete, the cooling bath was

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

After 10 h, TLC (2:1 hexanes/EtOAc, UV/anisaldehyde) showed

complete consumption of the starting material and formation of the

diluted with EtOAc. The layers were separated, and the aqueous phase

was extracted with two additional portions of EtOAc. The combined

organics were washed with saturated aqueous Na

S O and brine

2 2 3

before drying over anhydrous Na SO . The solvent was removed

2

4

under reduced pressure to give crude α-hydroxy aldehyde 16 that was

used directly in the next step.

To a solution of the crude α-hydroxy aldehyde 16 in 60 mL of

product of R = 0.20. The reaction mixture was cooled in an ice bath

f

and quenched by the slow addition of cold water to decompose the

excess acetic anhydride. The reaction was diluted with CH Cl , the

CH Cl was added solid dioxinone ylide 79 (4.94 g, 10.4 mmol, 1.00

2

2 2

layers were separated, and the aqueous phase was extracted with two

additional portions of CH Cl before the combined organics were

equiv), and the reaction was stirred at room temperature for 12 h.

After this time, TLC (2:1 hexanes/EtOAc, UV/anisaldehyde) showed

2

dried over anhydrous Na SO . The solvent was removed under

formation of the desired product of R

hydroxy aldehyde, α-hydroxy ketone, and their dimers at R

When the mobile phase was changed to 9:1 toluene/acetone, the

major allylic alcohol diastereomer 81 appeared at R = 0.42 and the

minor diastereomer appeared at R = 0.37. The solvent was removed

f

= 0.33 along with the mixed α-

2

4

reduced pressure, and the residue was puriﬁed by column

chromatography (3:1 hexanes/EtOAc) to give dioxinone ester 76 as

a tan amorphous solid (16.3 g, 63% over two steps): IR (neat) ν 2999,

f

= 0.62.

f

2

953, 1714, 1648, 1436, 1400, 1379, 1360, 1333, 1272, 1241, 1197,

f

−1 1

1151, 1058, 1000, 973, 921, 832, 786, 758 cm ; H NMR (500 MHz,

under reduced pressure, and the residue was puriﬁed by column

13

CDCl ) δ 1.71 (6H, s), 1.98 (3H, s), 3.33 (2H, s), 3.70 (3H, s);

C

chromatography (19:1 toluene/acetone) to give 81 as a colorless oil

3

20

D

NMR (125 MHz, CDCl ) δ 17.7, 25.0, 30.4, 52.2, 99.8, 105.6, 162.1,

(2.73 g, 59%): [α]

= +10.5 (c 0.74, CH Cl ); IR (neat) ν 3469,

2 2

3

+

1

65.7, 171.5; HRMS (ESI+) calcd for C H O ([M + H] )

2950, 2927, 2856, 1742, 1722, 1650, 1601, 1461, 1390, 1376, 1338,

10 15 5

−1 1

2

15.0919, found 215.0914.

Methyl 2-(2,2-dimethyl-4-oxo-6-((triphenyl-λ -phosphanyl-

idene)methyl)-4H-1,3-dioxin-5-yl)acetate (79). A two-neck 2 L

1253, 1202, 1149, 1118, 1093, 1004, 836 cm ; H NMR (500 MHz,

CDCl ) δ 0.086 (3H, s), 0.091 (3H, s), 0.75 (1H, q, J = 12.8 Hz), 0.87

5

3

(1H, m), 0.88 (3H, d, J = 6.5 Hz), 0.90 (9H, s), 1.16 (1H, qd, J = 13.0

9

602

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

Featured Article

Hz, 3.7 Hz), 1.37−1.43 (2H, m), 1.50−1.57 (3H, m), 1.73 (1H, m),

43.4, 52.2, 65.17, 65.23, 77.5, 100.4, 105.7, 115.1, 119.7, 127.8, 129.8,

133.6, 133.7, 135.6, 141.9, 157.5, 158.9, 162.9, 171.2; HRMS (ESI+)

1

.745 (3H, s), 1.748 (3H, s), 3.46 (2H, s), 3.53 (1H, dd, J = 10.4 Hz,

.2 Hz), 3.60 (1H, dd, J = 10.5 Hz, 2.5 Hz), 3.69 (3H, s), 3.83 (1H, d,

+

7

calcd for C H NaO Si ([M + Na] ) 863.4350, found 863.4343.

49

68

8

2

J = 6.3 Hz), 4.51 (1H, m), 6.39 (1H, dd, J = 15.3 Hz, 1.9 Hz), 6.59

Primary Alcohol 85. To a solution of mixed 84 (1.80 g, 2.14

mmol, 1.00 equiv) in 75 mL of THF and 75 mL of water was added

glacial acetic acid (92 mL, 1.61 mol, 751 equiv). After 12 h at room

temperature, TLC (1:1 hexanes/EtOAc, UV/anisaldehyde) showed

(

−

4

1H, dd, J = 15.3 Hz, 4.5 Hz); ¹³C NMR (125 MHz, CDCl ) δ −5.5,

3

5.4, 18.3, 22.6, 25.06, 25.13, 26.0, 27.4, 29.9, 32.5, 34.8, 39.1, 41.4,

8.1, 52.3, 68.7, 73.2, 100.1, 105.5, 118.5, 143.4, 159.4, 163.1, 171.5;

+

HRMS (ESI+) calcd for C H O Si ([M + H] ) 497.2935, found

formation of the desired product of R = 0.52 and the deprotected

26

45

7

f

4

97.2930.

f

Allylic Phosphate 82. A solution of allylic alcohol 81 (1.55 g, 3.12

mmol, 1.00 equiv) in 40 mL of THF was cooled to −78 °C, and a 1.6

M solution of methyllithium in ether (2.19 mL, 3.43 mmol, 1.10

equiv) was added dropwise. The reaction mixture immediately turned

dark red; after 10 min, neat diethyl chlorophosphate (905 μL, 3.65

mmol, 2.00 equiv) was added, and the ﬂask was transferred to a 0 °C

ice bath. After 15 min, TLC (2:1 hexanes/EtOAc, UV/anisaldehyde)

showed complete consumption of the starting material and formation

solution. The layers were separated, and the aqueous phase was

extracted with two additional portions of EtOAc before the combined

organics were dried over anhydrous Na SO . The solvent was removed

2

4

under reduced pressure, and the residue was puriﬁed by column

chromatography (9:1 hexanes/EtOAc → 4:1 → 3:1 → 2:1 → 1:1) to

give primary alcohol 85 as a colorless oil (858 mg, 50% over two

steps): [α]_D²⁰= −22.7 (c 0.76, CH Cl ); IR (neat) ν 3487, 2998,

2

of the product of R = 0.11. The reaction was quenched with pH 7

2928, 2857, 1746, 1720, 1652, 1603, 1509, 1472, 1428, 1391, 1376,

1337, 1233, 1203, 1171, 1150, 1111, 1090, 1008, 938, 824, 796, 741,

f

phosphate buﬀer and diluted with EtOAc. The layers were separated,

and the aqueous phase was extracted with two additional portions of

EtOAc before the combined organics were dried over anhydrous

Na SO . The solvent was removed under reduced pressure, and the

−1 1

703 cm ; H NMR (500 MHz, CDCl ) δ 0.92 (3H, d, J = 6.6 Hz),

3

0.93 (1H, m), 0.97 (1H, m), 1.08 (9H, s), 1.42 (1H, m), 1.47 (1H, m),

1.62 (1H, m), 1.69−1.73 (3H, m), 1.745 (3H, s), 1.750 (3H, s), 1.78

(1H, m), 3.36 (2H, s), 3.54−3.58 (1H, m), 3.60 (3H, s), 3.62−3.67

(1H, m), 4.69 (2H, s), 5.04 (1H, m), 6.29 (1H, dd, J = 15.4 Hz, 1.7

Hz), 6.63 (1H, dd, J = 15.4 Hz, 4.4 Hz), 6.83 (2H, d, J = 8.6 Hz), 7.23

2

4

residue was puriﬁed by column chromatography (3:1 hexanes/EtOAc

2:1 → 1:1) to aﬀord allylic phosphate 82 as a yellow oil (1.497 g,

7%): [α]_D²⁰= −20.5 (c 1.53, CH Cl ); IR (neat) ν 2950, 2927, 2856,

→

7

1

0

2

723, 1656, 1605, 1437, 1391, 1376, 1337, 1257, 1201, 1149, 1115,

(2H, d, J = 8.6 Hz), 7.36−7.39 (4H, m), 7.41−7.44 (2H, m), 7.67−

−

1

13

093, 1030, 984, 939, 837, 776 cm ; H NMR (500 MHz, CDCl ) δ

7.69 (4H, m); C NMR (125 MHz, CDCl ) δ 19.4, 22.6, 25.05,

3

.04 (3H, s), 0.05 (3H, s), 0.84 (1H, m), 0.88 (3H, d, J = 6.5 Hz), 0.89

25.13, 26.9, 27.1, 29.8, 32.3, 34.8, 38.9, 40.6, 43.4, 52.3, 65.1, 65.8,

79.4, 100.6, 105.7, 115.3, 120.4, 127.5, 127.8, 129.8, 133.5, 134.2,

135.6, 140.2, 157.0, 158.8, 162.8, 171.3; HRMS (ESI+) calcd for

(

9H, s), 1.01 (1H, q, J = 12.3 Hz), 1.28 (1H, m), 1.29 (3H, t, J = 6.5

Hz), 1.32 (3H, t, J = 6.5 Hz), 1.36 (1H, m), 1.53−1.58 (3H, m), 1.66−

.70 (2H, m), 1.75 (6H, s), 3.41 (2H, s), 3.57 (1H, dd, J = 10.3 Hz, 2.0

+

1

C H NaO Si ([M + Na] ) 749.3486, found 749.3487.

43

54

8

Hz), 3.69 (3H, s), 3.87 (1H, dd, J = 10.3 Hz, 4.7 Hz), 4.04−1.14 (4H,

Aldehyde 86. To a solution of primary alcohol 85 (858 mg, 1.18

m), 5.20 (1H, m), 6.35 (1H, dd, J = 15.3 Hz, 1.5 Hz), 6.50 (1H, dd, J

mmol, 1.00 equiv) in 12 mL of CH Cl was added Dess−Martin

2

1

3

=

15.3 Hz, 5.1 Hz); C NMR (125 MHz, CDCl ) δ −5.40, −5.37,

periodinane (651 mg, 1.54 mmol, 1.30 equiv). After 20 min, TLC (3:1

hexanes/EtOAc, UV/anisaldehyde) showed complete consumption of

the starting material (R = 0.11) and formation of the product of R =

3

16.2 ( J

= 5 Hz), 16.3 ( J

6.0, 29.8, 32.3, 35.5, 39.0, 39.8, 42.7 (d, J

J_C₋_P= 2.5 Hz), 64.0 ( J

01.1, 105.7, 119.8, 140.1 ( J

= 5 Hz), 18.3, 22.7, 24.9, 25.0, 25.2,

C−P

3

2

= 6 Hz), 52.3, 63.9

C−P

f

2

(

= 2.5 Hz), 64.2, 77.9 ( J

= 6 Hz),

0.26. The reaction mixture was diluted with CH Cl and quenched

C−P

2 2

3

1

= 2 Hz), 158.5, 162.7, 171.1; HRMS

with saturated aqueous Na S O solution and saturated aqueous

2 2 3

C−P

+

(

ESI+) calcd for C H NaO PSi ([M + Na] ) 655.3043, found

NaHCO solution. The layers were separated, and the aqueous phase

30

53

10

3

6

55.3041.

was extracted with one additional portion of CH Cl before the

2

51

Aryl Ether 84. To a a solution of phenol 83 (943 mg, 2.60 mmol,

combined organics were dried over anhydrous Na SO . The solvent

2 4

1

.10 equiv) in 21 mL of THF was added solid 60% sodium hydride

was removed under reduced pressure, and the residue was puriﬁed by

column chromatography (3:1 hexanes/EtOAc → 2:1 → 1:1) to aﬀord

aldehyde 86 as a yellow foam (832 mg, 97%): [α]_D²⁰= −19.1 (c 2.08,

CH Cl ); IR (neat) ν 2929, 2857, 1742, 1720, 1654, 1605, 1509, 1428,

dispersion in mineral oil (104 mg, 2.60 mmol, 1.10 equiv); gas

evolution was observed, and a colorless phenolate solution was

obtained. To a separate ﬂask containing neat allylic phosphate 82 (1.50

g, 2.36 mmol, 1.00 equiv) was added a solution of Pd(PPh ) (273 mg,

2

3

4

1391, 1377, 1337, 1230, 1203, 1150, 1111, 1090, 1008, 982, 938, 824,

−1 1

0

.24 mmol, 0.10 equiv) in 15 mL of THF. The phenolate solution was

703 cm ; H NMR (500 MHz, CDCl ) δ 0.91 (1H, m), 0.96 (3H, d, J

3

immediately added dropwise; after each drop, the reaction mixture

would turn dark orange before returning to yellow over the course of

several seconds. After addition was complete, TLC (4:1 hexanes/

EtOAc, UV/anisaldehyde) showed complete consumption of the

= 6.5 Hz), 0.97 (1H, m), 1.07 (9H, s), 1.42 (1H, m), 1.50 (1H, m),

1.75 (6H, s), 1.79−1.87 (3H, m), 2.10 (1H, m), 2.51 (1H, m), 3.37

(2H, s), 3.60 (3H, s), 4.67 (2H, s), 4.98 (1H, m), 6.29 (1H, dd, J =

15.5 Hz, 1.5 Hz), 6.58 (1H, dd, J = 15.4 Hz, 4.6 Hz), 6.78 (2H, d, J =

8.6 Hz), 7.21 (2H, d, J = 8.3 Hz), 7.37 (4H, t, J = 7.2 Hz), 7.41−7.44

(2H, m), 7.67 (4H, m), 9.54 (1H, d, J = 3.0 Hz); ¹C NMR (125

phosphate, formation of the product of R = 0.51, and formation of the

f

3

elimination byproduct of R = 0.40. The solvent was removed under

f

reduced pressure, and the residue was puriﬁed by column

chromatography (10:1 hexanes/EtOAc → 4:1 → 2:1) to give a

mixture of 84 and the elimination byproduct, which was used directly

in the next step (1.80 g). An analytical sample of 84 was obtained by

repeating the chromatographic separation on a smaller sample of the

mixture: [α]_D²⁰= −12.0 (c 0.45, CH Cl ); IR (neat) ν 3071, 2951,

MHz, CDCl ) δ 19.4, 22.4, 25.1, 25.5, 26.9, 29.8, 31.7, 34.0, 34.5, 41.6,

51.3, 52.3, 65.1, 78.5, 101.0, 105.8, 115.4, 121.1, 127.5, 127.8, 129.8,

3

133.5, 134.2, 135.6, 139.1, 156.7, 158.6, 162.8, 171.2, 203.6; HRMS

+

(ESI+) calcd for C H NaO Si ([M + Na] ) 747.3329, found

43

52

8

747.3320.

2

Vinyl Iodide 87. To a ﬂame-dried 100 mL ﬂask equipped with a

magnetic stirring bar was added solid chromium(II) chloride (1.13 g,

9.18 mmol, 8.00 equiv) in the glovebox. The ﬂask was tightly sealed

with a rubber septum, removed from the glovebox, and put under an

atmosphere of argon. Twenty-ﬁve milliliters of THF was added to give

a pale green slurry, which was cooled to 0 °C. A solution of aldehyde

86 (832 mg, 1.15 mmol, 1.00 equiv) and iodoform (903 mg, 2.29

mmol, 2.00 equiv) in 25 mL of THF was added dropwise, and the

reaction immediately turned dark red. The ﬂask was removed from the

cooling bath and stirred at room temperature for 1 h. After this time,

TLC (2:1 hexanes/EtOAc, UV/anisaldehyde) showed complete

2

928, 2856, 1742, 1724, 1653, 1604, 1509, 1472, 1462, 1428, 1391,

−

1

377, 1336, 1234, 1204, 1171, 1150, 1113, 1086, 835, 741, 703 cm ;

1

H NMR (500 MHz, CDCl ) δ −0.05 (3H, s), −0.04 (3H, s), 0.86

3

(

9H, s), 0.89 (1H, m), 0.91 (3H, d, J = 6.5 Hz), 0.99 (1H, m), 1.07

9H, s), 1.45 (1H, m), 1.49 (1H, m), 1.63−1.67 (4H, m), 1.73 (1H,

m), 1.75 (3H, s), 1.76 (3H, s), 3.33 (2H, s), 3.45−3.52 (2H, m), 3.58

(

3H, s), 4.68−4.70 (2H, m), 5.04 (1H, m), 6.23 (1H, dd, J = 15.4 Hz,

1

7

1

.7 Hz), 6.58 (1H, dd, J = 15.4 Hz, 4.2 Hz), 6.79 (2H, d, J = 8.5 Hz),

.22 (2H, d, J = 8.5 Hz), 7.36−7.39 (4H, m), 7.41−7.44 (2H, m),

1

3

.67−7.69 (4H, m); C NMR (125 MHz, CDCl ) δ −5.43, −5.42,

3

8.4, 19.4, 22.8, 25.0, 25.2, 25.6, 26.0, 26.9, 29.8, 32.4, 35.0, 39.1, 40.2,

consumption of the starting material (R = 0.38) and formation of

f

9

603

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

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the product of R = 0.49. The reaction was diluted with water and

12 h at room temperature, TLC (1:1 hexanes/EtOAc, UV/

anisaldehyde) showed complete consumption of the starting material

f

ether, and the layers were separated. The aqueous phase was extracted

with two additional portions of ether, and the combined organics were

washed with saturated aqueous Na S O solution and brine before

and formation of two products: the deprotected endo isomer 89 of R =

f

0.24 and the deprotected exo isomer of R = 0.15. The reaction was

2

3

f

drying over anhydrous Na SO . The solvent was removed under

diluted with water and EtOAc, the layers were separated, and the

organic phase was washed with water before drying over anhydrous

Na SO . The solvent was removed under reduced pressure, and the

2

4

reduced pressure, and the residue was puriﬁed by column

chromatography (9:1 hexanes/EtOAc → 3:1 → 2:1) to give vinyl

iodide 87 as an oﬀ-white foam (911 mg, 94%): [α]_D²⁰= −75.8 (c 4.88,

CH Cl ); IR (neat) ν 2927, 2856, 1742, 1720, 1653, 1604, 1509, 1460,

2

4

residue was puriﬁed by column chromatography (3:1 hexanes/EtOAc

→ 2:1 → 1:1 hexanes/EtOAc) to give the deprotected endo isomer 89

(98.8 mg, 70%) and the deprotected exo isomer (38.1 mg, 27%):

2

1

9

0

428, 1391, 1376, 1336, 1232, 1203, 1173, 1149, 1111, 1090, 1008,

−1

1

20

40, 824, 703 cm ; H NMR (500 MHz, CDCl ) δ 0.89 (1H, m),

[α]_D= −75.8 (c 1.76, CH Cl ); IR (neat) ν 3407, 2947, 2915, 2865,

3

2

.90 (3H, d, J = 6.5 Hz), 0.91 (1H, m), 1.08 (9H, s), 1.44−1.50 (3H,

1720, 1638, 1611, 1509, 1374, 1337, 1271, 1237, 1202, 1173, 1149,

1006, 940 cm ; H NMR (500 MHz, CDCl ) δ 0.83 (1H, q, J = 11.7

−

1 1

m), 1.66 (1H, m), 1.72 (1H, m), 1.74 (3H, s), 1.75 (3H, s), 1.78 (1H,

3

m), 2.29 (1H, td, J = 10.1 Hz, 6.6 Hz), 3.34 (2H, s), 3.58 (3H, s), 4.69

Hz), 0.92 (3H, d, J = 6.6 Hz), 0.98 (1H, m), 1.06 (1H, qd, J = 11.5 Hz,

2.9 Hz), 1.30 (3H, s), 1.42−1.48 (3H, m), 1.60 (3H, s), 1.77 (1H, m),

1.93 (1H, td, J = 11.3 Hz, 6.9 Hz), 2.02 (1H, m), 2.13−2.15 (2H, m),

3.19 (1H, m), 3.27 (1H, d, J = 17.1 Hz), 3.31 (1H, dd, J = 11.2 Hz, 6.5

Hz), 3.49 (1H, d, J = 17.1 Hz), 3.69 (3H, s), 4.52 (1H, dd, J = 7.0 Hz,

4.0 Hz), 4.56 (2H, d, J = 5.7 Hz), 5.04 (1H, d, J = 11.3 Hz), 5.05 (1H,

d, J = 16.1 Hz), 5.44 (1H, dt, J = 9.8 Hz, 3.5 Hz), 5.76 (1H, ddd, J =

(

2H, s), 4.95 (1H, m), 5.61 (1H, d, J = 14.3 Hz), 6.24−6.30 (2H, m),

.56 (1H, dd, J = 15.4 Hz, 3.9 Hz), 6.79 (2H, d, J = 8.5 Hz), 7.22 (2H,

d, J = 8.3 Hz), 7.36−7.39 (4H, m), 7.41−7.44 (2H, m), 7.68−7.70

4H, m); ¹³C NMR (125 MHz, CDCl ) δ 19.4, 22.4, 24.9, 25.0, 25.1,

6

(

3

2

1

6.9, 29.8, 31.8, 34.5, 41.2, 46.4, 47.0, 52.2, 65.2, 76.4, 77.8, 100.6,

05.7, 115.2, 120.0, 127.5, 127.8, 129.8, 133.6, 133.9, 135.6, 140.9,

49.4, 157.2, 158.7, 162.8, 171.2; HRMS (ESI+) calcd for

17.7 Hz, 9.6 Hz, 8.2 Hz), 5.97 (1H, d, J = 9.8 Hz), 6.74 (2H, d, J = 8.6

+

13

C H IKO Si ([M + K] ) 887.2242, found 887.2241.

Hz), 7.20 (2H, d, J = 8.5 Hz); C NMR (125 MHz, CDCl ) δ 22.5,

44

53

7

3

Triene 88. To a solution of vinyl iodide 87 (911 mg, 1.07 mmol,

.00 equiv) in 5 mL of DMF was added a solution of dichlorobis-

acetonitrile)palladium(II) (28 mg, 0.11 mmol, 0.10 equiv) in 5 mL of

DMF. Next, a 0.25 M solution of stannane 42 (8.61 mL, 2.15 mmol,

.00 equiv) in DMF was added dropwise; the reaction mixture

25.2, 25.9, 30.4, 32.8, 36.1, 38.0, 41.0, 45.4, 45.6, 49.2, 52.2, 56.5, 65.2,

79.5, 99.1, 105.5, 115.1, 117.4, 128.4, 128.8, 129.3, 133.3, 137.3, 157.8,

1

(

+

162.2, 168.5, 171.7; HRMS (ESI+) calcd for C H O ([M + H] )

32

41

7

537.2852, found 537.2852.

Benzylic Chloride 90. A 0.8 M solution of methanesulfonyl

2

immediately turned black, and stirring was continued at room

temperature for 2 h. After this time, the reaction was diluted with

ether and water. The layers were separated, and the organic phase was

washed with two additional portions of water before drying over

anhydrous Na SO . TLC (2:1 hexanes/EtOAc, UV/anisaldehyde)

chloride was prepared by dissolving 312 μL of the neat compound in 5

mL of CH

was prepared by dissolving 696 μL of the neat amine in 5 mL of

CH Cl . To a solution of benzylic alcohol 89 (33.9 mg, 63.2 μmol,

1.00 equiv) in 1.25 mL of CH Cl was added a portion of the amine

Cl . Similarly, a 0.8 M solution of diisopropylethylamine

2

4

2

showed the product of R = 0.56 which was essentially copolar with the

solution (400 μL, 0.32 mmol, 5.00 equiv) followed by a portion of the

methanesulfonyl chloride solution (400 μL, 0.32 mmol, 5.00 equiv),

and the reaction was stirred at room temperature for 10 h. After this

time, TLC (1:1 hexanes/EtOAc, UV/anisaldehyde) showed complete

consumption of the starting material and formation of the product of

f

vinyl iodide starting material. The solvent was removed under reduced

pressure, and the residue was puriﬁed by column chromatography (9:1

hexanes/EtOAc → 3:1) to give triene 88 as a yellow foam (735 mg,

8

1

8%): [α]_D²⁰= −26.3 (c 0.38, CH Cl ); IR (neat) ν 2999, 2928, 2857,

2

741, 1721, 1653, 1605, 1509, 1428, 1391, 1376, 1336, 1232, 1203,

R

f

= 0.69. The reaction was quenched with pH 7 phosphate buﬀer and

diluted with CH Cl . The layers were separated, and the aqueous

phase was extracted with one additional portion of CH Cl before the

combined organics were dried over anhydrous Na SO . The solvent

−1 1

172, 1149, 1112, 1089, 1007, 977, 824, 703 cm ; H NMR (500

2

MHz, CDCl ) δ 0.90 (3H, d, J = 6.4 Hz), 0.91−0.92 (2H, m), 1.08

2

3

(

3

9H, s), 1.38 (1H, m), 1.47 (1H, m), 1.52 (1H, m), 1.67 (1H, m), 1.71

1H, m), 1.727 (3H, s), 1.734 (3H, s), 1.79 (1H, m), 2.27 (1H, m),

.32 (2H, s), 3.57 (3H, s), 4.69 (2H, s), 4.96 (1H, m), 4.99 (1H, d, J =

0.3 Hz), 5.04 (1H, d, J = 16.7 Hz), 5.44 (1H, dd, J = 15.1 Hz, 9.3

2

4

was removed under reduced pressure, and the residue was puriﬁed by

column chromatography on neutral alumina (3:1 hexanes/EtOAc →

2:1) to aﬀord benzylic chloride 90 as a white foam (30.1 mg, 86%):

1

20

D

Hz), 5.68 (1H, dd, J = 15.2 Hz, 10.6 Hz), 5.80 (1H, dd, J = 15.2 Hz,

0.7 Hz), 6.09 (1H, dd, J = 15.1 Hz, 10.5 Hz), 6.23 (1H, dd, J = 15.3

Hz, 1.3 Hz), 6.26 (1H, m), 6.55 (1H, dd, J = 15.4 Hz, 4.0 Hz), 6.79

[α]

= +124.5 (c 0.49, CH Cl ); IR (neat) ν 2919, 2868, 1721, 1634,

2 2

1

1610, 1585, 1511, 1436, 1388, 1375, 1339, 1245, 1202, 1174, 1144,

−

1 1

1005, 932 cm ; H NMR (500 MHz, CDCl ) δ 0.82 (1H, q, J = 11.7

3

(

7

2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.3 Hz), 7.36−7.39 (4H, m),

Hz), 0.92 (3H, d, J = 6.6 Hz), 0.97 (1H, m), 1.06 (1H, m), 1.23 (3H,

s), 1.39−1.47 (3H, m), 1.60 (3H, s), 1.77 (1H, m), 1.95 (1H, m), 2.01

(1H, m), 2.12 (1H, m), 2.15 (1H, m), 3.2 (1H, m), 3.32 (1H, d, J =

17.4 Hz), 3.34 (1H, m), 3.52 (1H, d, J = 17.1 Hz), 3.70 (3H, s), 4.50

(1H, m), 4.52 (2H, s), 5.05 (2H, m), 5.45 (1H, m), 5.77 (1H, m), 5.97

13

.41−7.44 (2H, m), 7.68−7.69 (4H, m); C NMR (125 MHz,

CDCl ) δ 19.4, 22.5, 24.7, 25.05, 25.11, 26.9, 29.8, 31.9, 34.7, 42.0,

3

4

1

3.3, 47.2, 52.2, 65.2, 78.0, 100.4, 105.6, 115.4, 116.9, 119.7, 127.3,

27.8, 129.8, 131.7, 131.9, 133.0, 133.6, 133.7, 135.6, 136.9, 138.4,

41.8, 157.5, 158.9, 162.9, 171.2; HRMS (ESI+) calcd for

(1H, d, J = 9.9 Hz), 6.73 (2H, d, J = 8.2 Hz), 7.22 (2H, d, J = 8.2 Hz);

+

13

C H NaO Si ([M + Na] ) 797.3850, found 797.3836.

C NMR (125 MHz, CDCl ) δ 22.5, 25.3, 25.6, 30.4, 30.5, 32.7, 36.0,

3

48

58

7

Benzylic Alcohol 89. To a ﬂame-dried 50 mL pressure ﬂask was

38.0, 41.2, 45.4, 45.8, 46.4, 49.2, 52.2, 56.5, 79.6, 99.0, 105.5, 115.2,

117.4, 128.4, 129.3, 129.8, 130.1, 137.2, 158.2, 162.1, 168.5, 171.1;

added a solution of triene 88 (735 mg, 0.95 mmol, 1.00 equiv) in 35

mL of freshly distilled benzene (sodium/benzophenone). The ﬂask

was tightly sealed with its white Teﬂon screw cap, lowered into a

preheated 75 °C oil bath, and heated at that temperature for 72 h.

After this time, TLC (plate eluted four times in 4:1 hexanes/EtOAc,

UV/anisaldehyde) showed essentially complete consumption of the

starting triene (R = 0.64) and formation of the product of R = 0.71.

+

HRMS (ESI+) calcd for C H ClO ([M + H] ) 555.2513, found

32

40

6

555.2512.

Benzylic Stannane 91. A 0.25 M solution of trimethylstannyl-

lithium was prepared as follows: A solution of hexamethylditin (354

mg, 1.08 mmol, 1.10 equiv) in 3.31 mL of THF was cooled to −78 °C,

and a 1.6 M solution of methyllithium in ether (613 μL, 0.98 mmol,

1.00 equiv) was added dropwise. After addition was complete, the ﬂask

was transferred to an ice bath and stirred at 0 °C for 1.5 h; the

resulting colorless solution of trimethylstannyllithium was then used

directly in the next step.

A solution of benzylic chloride 90 (38.1 mg, 68.6 μmol, 1.00 equiv)

in 2.5 mL of anhydrous THF was cooled to −40 °C, and an aliquot of

the 0.25 M trimethylstannyllithium solution (300 μL, 75 μmol, 1.09

equiv) was added dropwise. The reaction mixture immediately turned

f

The solvent was removed under reduced pressure, and the residue was

puriﬁed by preparative TLC (eight 1500 μm plates, loaded in CH Cl ,

2

eluted ﬁve times in 85:15 hexanes/EtOAc, silica washed with EtOAc)

to give tricycle 70 as a white foam (407 mg, 55%). NMR showed that

this was a 3:1 mixture of inseparable endo/exo isomers, which was used

directly in the next step.

To a a solution of 70 (204 mg, 0.26 mmol, 1.00 equiv) in 8 mL of

THF was added solid TBAT (500 mg, 0.93 mmol, 3.52 equiv). After

9

604

dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

Featured Article

1

bright yellow, and this color faded over the course of 5 min. After this

time, TLC (2:1 hexanes/EtOAc, UV/anisaldehyde) showed approx-

deshielded by ∼0.5 ppm in the H NMR spectrum relative to those in

carboxylic acid 92; similarly, the corresponding methylene carbon was

deshielded by 11 ppm in the ¹³C NMR spectrum. Furthermore, a

strong HMBC signal was observed between the aforementioned

methylene protons and a carbon signal at 172 ppm, corresponding to

the acid chloride carbonyl group. The crude solution of acid chloride

71 in chloroform was used directly in the subsequent palladium-

catalyzed coupling reactions.

imately 50% conversion of the starting material (R = 0.50) to the

f

desired stannane of R = 0.63. Therefore, an additional portion of the

f

stannyllithium reagent was added (150 μL, 37.5 μmol, 0.55 equiv); the

bright yellow color reappeared, and the reaction was stirred at −40 °C

for another 10 min. At this point, TLC showed almost complete

conversion of the benzyl chloride to the stannane. The reaction was

quenched with pH 7 phosphate buﬀer and diluted with EtOAc. After

warming to room temperature, the layers were separated, and the

aqueous phase was extracted with one additional portion of EtOAc

Tricycle 96. To a 20 mL pressure tube was added a solution of

triene 88 (161 mg, 0.21 mmol, 1.00 equiv) in 5 mL of m-xylene and

1.00 mL of water. The tube was tightly sealed with its white Teﬂon

screw cap and lowered into a preheated 160 °C oil bath. After 3 h, the

reaction mixture was cooled to room temperature, and TLC (4:1

hexanes/EtOAc, UV/anisaldehyde) showed complete consumption of

the starting material (R = 0.26) and formation of the product of R =

0.44. The aqueous phase was removed with a pipet, and the organic

layer was dried over anhydrous Na SO . The solvent was removed

under reduced pressure, and the residue was puriﬁed by preparative

TLC (two 1500 μm plates, loaded in CH Cl , eluted in 95:5 hexanes/

before the combined organics were dried over anhydrous Na SO . The

2

4

solvent was removed under reduced pressure, and the residue was

puriﬁed by column chromatography on neutral alumina (4:1 hexanes/

20

^E^t^O^A^c⁾^t^o^gⁱ^v^e^s^t^aⁿⁿ^aⁿ^e⁹¹^a^s^a^w^hⁱ^t^e^f^o^a^m⁽²⁷^.⁶^m^g^,⁵⁹^%⁾^:^[^α^]D

=

f

+

115.3 (c 0.98, CH Cl ); IR (neat) ν 2947, 2914, 2868, 1724, 1635,

2 2

1504, 1435, 1387, 1375, 1338, 1268, 1240, 1205, 1152, 1007, 933, 765

2

4

−1

1

2

cm ; H NMR (500 MHz, CDCl ) δ 0.00 (9H, t, J

= 52 Hz),

3

H−Sn

0.81 (1H, q, J = 11.6 Hz), 0.91 (3H, d, J = 6.5 Hz), 0.94 (1H, m), 1.04

2

(

1H, m), 1.23 (3H, s), 1.39−1.43 (3H, m), 1.60 (3H, s), 1.75 (1H, m),

EtOAc, silica washed with EtOAc) to give tricycle 96 as a colorless oil

92.5 mg, 72%): [α]_D= +100.0 (c 0.83, CH Cl ); IR (neat) ν 2949,

927, 2856, 1740, 1714, 1610, 1587, 1509, 1428, 1371, 1241, 1169,

112, 1085, 1007, 924, 824, 741, 703 cm ; H NMR (500 MHz,

1

3

.91 (1H, m), 1.98 (1H, m), 2.11 (2H, m), 2.19 (2H, s), 3.19 (1H, m),

.33 (1H, d, J = 17.0 Hz), 3.34 (1H, m), 3.52 (1H, d, J = 17.1 Hz),

.68 (3H, s), 4.39 (1H, dd, J = 7.2 Hz, 3.6 Hz), 5.03 (1H, d, J = 14.6

20

(

2

1

2 2

−1

1

Hz), 5.04 (1H, d, J = 11.9 Hz), 5.45 (1H, dt, J = 9.6 Hz, 3.5 Hz), 5.78

1H, m), 5.96 (1H, d, J = 9.8 Hz), 6.58 (2H, d, J = 8.6 Hz), 6.80 (2H,

CDCl ) δ 0.82 (1H, q, J = 11.7 Hz), 0.90 (3H, d, J = 6.7 Hz), 0.92

3

(

1H, m), 1.04 (1H, m), 1.07 (9H, s), 1.37−1.39 (3H, m), 1.71 (1H,

1

3

d, J = 8.5 Hz); C NMR (125 MHz, CDCl ) δ −10.1, 18.9, 22.5, 25.3,

3

m), 1.96−2.06 (4H, m), 2.32 (1H, m), 2.40 (1H, dt, J = 14.6 Hz, 7.2

Hz), 2.62 (1H, dt, J = 18.4 Hz, 7.0 Hz), 2.80 (1H, dt, J = 17.7 Hz, 7.3

Hz), 3.35 (2H, m), 3.53 (3H, s), 4.62 (1H, dd, J = 7.1 Hz, 2.9 Hz),

2

7

1

6

5.7, 30.5, 30.6, 32.8, 36.1, 38.0, 41.2, 45.4, 45.5, 45.7, 49.3, 52.2, 56.6,

9.5, 98.7, 105.4, 115.3, 117.2, 127.6, 128.5, 129.3, 135.2, 137.4, 154.3,

62.3, 168.7, 171.7; HRMS (ESI+) calcd for C H O Sn ([M + H] )

85.2551, found 685.2551.

Carboxylic Acid 92. To a solution of benzylic stannane 91 (27.6

+

35

49

6

4

(

9

.67 (2H, s), 5.01 (1H, d, J = 10.9 Hz), 5.02 (1H, d, J = 15.9 Hz), 5.47

1H, d, J = 9.9 Hz), 5.60 (1H, dt, J = 17.1 Hz, 8.4 Hz), 5.97 (1H, d, J =

.9 Hz), 6.77 (2H, d, J = 7.9 Hz), 7.16 (2H, d, J = 8.0 Hz), 7.37 (4H, t,

J = 7.4 Hz), 7.42 (2H, t, J = 7.4 Hz), 7.68 (4H, d, J = 7.2 Hz);

NMR (125 MHz, CDCl ) δ 19.4, 22.6, 26.9, 27.5, 30.5, 32.7, 36.1,

7.4, 38.1, 43.5, 44.6, 45.4, 49.6, 51.1, 51.7, 56.7, 65.3, 79.1, 115.8,

16.5, 127.3, 127.7, 128.8, 129.3, 129.7, 133.3, 133.6, 135.7, 137.5,

57.2, 173.4, 209.1; HRMS (ESI+) calcd for C H NaO Si ([M +

mg, 40.4 μmol, 1.00 equiv) in 3 mL of THF and 1.5 mL of water was

added solid lithium hydroxide monohydrate (100 mg, 2.38 mmol, 59

equiv). After stirring at room temperature for 36 h, TLC (100%

EtOAc, UV/anisaldehyde) showed complete conversion of the starting

material (R = 0.90) to the product of R = 0.52. The reaction was

13

C

3

1

f

4

54

5

quenched with 1 M aqueous HCl solution and diluted with EtOAc.

The layers were separated, and the aqueous phase was extracted with

two additional portions of EtOAc before the combined organics were

dried over anhydrous Na SO . The solvent was removed under

+

Na] ) 713.3638, found 713.3645.

Diol 97. A solution of tricycle 96 (31.6 mg, 45.7 μmol, 1.00 equiv)

in 2 mL of anhydrous toluene was cooled to −78 °C, and a 1.5 M

solution of diisobutylaluminum hydride in toluene (260 μL, 0.39

mmol, 8.53 equiv) was added dropwise. After 10 min at −78 °C, the

ﬂask was transferred to an ice bath and stirred for an additional 30 min.

After this time, TLC (1:1 hexanes/EtOAc, UV/anisaldehyde) showed

complete consumption of the starting material (R = 0.74) and

formation of the product of R = 0.46. The reaction was quenched at 0

C with saturated aqueous Rochelle’s salt and diluted with EtOAc. The

resulting gelatinous suspension was ﬁltered through Celite, and the

organic phase was dried over anhydrous Na SO . The solvent was

removed under reduced pressure, and the residue was puriﬁed by

preparative TLC (500 μm plate, loaded in CH Cl , eluted in 3:2

hexanes/EtOAc, silica washed with EtOAc) to give diol 97 as a

colorless oil (25.2 mg, 83%). NMR showed that 97 was formed as a

1:1 mixture of diastereomers: IR (neat) ν 3400, 3071, 3014, 2926,

2

4

reduced pressure, and the residue was puriﬁed by preparative TLC

1000 μm plate, loaded in CH Cl , eluted in 1:3 hexanes/EtOAc, silica

(

2

washed with EtOAc) to give carboxylic acid 92 as a white foam (21.2

mg, 79%): [α]_D²⁰= +79.2 (c 2.50, CH Cl ); IR (neat) ν 2918, 2852,

2

f

1

8

5

724, 1633, 1504, 1456, 1388, 1375, 1269, 1239, 1206, 1155, 991, 935,

−1

1

2

f

06, 765 cm ; H NMR (500 MHz, CDCl ) δ 0.00 (9H, t, J

=

3

H−Sn

°

2 Hz), 0.82 (1H, q, J = 11.8 Hz), 0.92 (3H, d, J = 6.5 Hz), 0.96 (1H,

m), 1.05 (1H, m), 1.24 (3H, s), 1.40−1.42 (3H, m), 1.60 (3H, s), 1.75

(

1H, m), 1.93 (1H, m), 2.00 (1H, m), 2.12−2.14 (2H, m), 2.20 (2H,

2

4

s), 3.25 (1H, m), 3.37 (1H, d, J = 16.6 Hz), 3.41 (1H, m), 3.52 (1H, d,

J = 16.5 Hz), 4.39 (1H, dd, J = 7.3 Hz, 3.6 Hz), 5.02 (1H, d, J = 8.8

Hz), 5.03 (1H, d, J = 18.3 Hz), 5.45 (1H, dt, J = 9.6 Hz, 3.3 Hz), 5.73

2

(

8

1H, dt, J = 17.7 Hz, 9.2 Hz), 5.96 (1H, d, J = 9.9 Hz), 6.58 (2H, d, J =

_.₁_H_z₎_,₆_.₈₀₍₂_H_,_d_,_J₌₇_.₉_H_z₎_;1 C NMR (125 MHz, CDCl ) δ

3

2

1

(

857, 1610, 1587, 1509, 1428, 1375, 1298, 1240, 1169, 1112, 1082,

−

10.0, 18.9, 22.5, 25.2, 25.8, 30.6, 31.1, 32.8, 36.0, 38.0, 41.3, 45.5,

5.6, 49.3, 56.5, 79.2, 97.8, 105.9, 115.2, 117.4, 127.6, 128.4, 129.3,

−

1 1

007, 923, 824, 739, 702 cm ; H NMR (500 MHz, CDCl ) δ 0.83

4

1

3

1H, m), 0.91 (4H, m), 1.01 (1H, m), 1.08 (9H, s), 1.39−1.40 (3H,

35.2, 137.1, 154.2, 161.9, 163.6, 170.1; HRMS (ESI+) calcd for

C H O Sn ([M + H] ) 671.2395, found 671.2399.

3

+

m), 1.59−1.97 (8H, m), 2.19 (1H, m), 2.32 (0.5H, m), 2.40 (0.5H,

m), 3.07 (0.5H, m), 3.20 (0.5H, m), 3.54−3.64 (2H, m), 3.69 (0.5H, t,

J = 8.9 Hz), 3.86 (0.5H, m), 4.70−4.71 (2.5H, m), 4.78 (0.5H, dd, J =

5.8 Hz, 2.7 Hz), 5.07 (0.5H, d, J = 16.9 Hz), 5.11−5.14 (1.5H, m),

5.41 (0.5 H, dt, J = 10.1 Hz, 3.4 Hz), 5.47 (0.5H, m), 5.80 (0.5H, dt, J

= 17.8 Hz, 9.4 Hz), 5.90 (1H, m), 5.97 (0.5H, dt, J = 17.9 Hz, 9.5 Hz),

6.88 (1H, d, J = 7.9 Hz), 6.92 (1H, d, J = 8.0 Hz), 7.22 (2H, d, J = 8.0

4

47

6

Acid Chloride 71. A 0.1 M solution of chloroenamine reagent 93

was prepared by dissolving 53 μL of the neat compound in 4.0 mL of

anhydrous, degassed chloroform. To a solution of carboxylic acid 92

(

4.0 mg, 5.98 μmol, 1.00 equiv) in 500 μL of chloroform was added a

portion of the chloroenamine solution (120 μL, 12 μmol, 2.00 equiv),

and the reaction mixture was stirred at room temperature for 15 min.

After this time, a small aliquot of the reaction mixture was quenched

with methanol; TLC (2:1 hexanes/EtOAc, UV/anisaldehyde) showed

1

3

Hz), 7.36−7.39 (4H, m), 7.41−7.44 (2H, m), 7.67−7.70 (4H, m);

NMR (125 MHz, CDCl ) δ 19.4, 22.5, 26.9, 29.3, 30.3, 30.8, 31.0,

C

3

complete conversion to the corresponding methyl ester 91 of R =

32.2, 32.4, 32.9, 33.0, 36.2, 37.9, 38.0, 43.5, 44.3, 44.6, 45.1, 45.9, 46.1,

48.1, 50.4, 50.7, 55.6, 56.8, 62.9, 63.1, 65.16, 65.21, 73.1, 73.2, 80.4,

81.4, 116.3, 116.6, 116.9, 117.4, 127.39, 127.44, 127.5, 127.8, 128.0,

129.73, 129.74, 130.1, 130.2, 133.56, 133.58, 133.59, 133.60, 133.9,

f

0

.63, indicating quantitative formation of acid chloride 71. Formation

of acid chloride 71 could also be monitored by NMR. The protons of

the methylene group at the α position of the acid chloride were

9

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dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

The Journal of Organic Chemistry

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1

34.8, 135.6, 135.7, 138.2, 140.0, 154.6, 156.2; HRMS (ESI+) calcd for

Diol 100. A 1.0 M solution of buﬀered TBAF was prepared by

adding 200 μL of glacial acetic acid to 1.5 mL of a 1.0 M solution of

TBAF in THF. To a solution of ketone 99 (12 mg, 13.3 μmol, 1.00

equiv) in 1.5 mL of THF was added a portion of the buﬀered TBAF

solution (600 μL, 0.6 mmol, 45 equiv). After stirring at room

temperature for 10 h, TLC (1:1 hexanes/EtOAc, UV/anisaldehyde)

+

C H NaO Si ([M + Na] ) 687.3846, found 687.3840.

43

56

4

Secondary Alcohol 98. A 0.1 M solution of TBDPSCl was

prepared by dissolving 128 μL of the neat compound in 5 mL of

CH Cl . Similarly, a 0.1 M solution of imidazole was prepared by

dissolving 34 mg of the solid compound in 5 mL of CH Cl . To a ﬂask

containing neat mixed diol 97 (25.2 mg, 37.9 μmol, 100 equiv) was

added a portion of the imidazole solution (758 μL, 75.8 μmol, 2.00

equiv) followed by a portion of the TBDPSCl solution (758 μL, 75.8

μmol, 2.00 equiv). The reaction mixture immediately turned cloudy,

and a precipitate formed. After 25 min at room temperature, TLC (2:1

hexanes/EtOAc, UV/anisaldehyde) showed complete conversion of

the starting material to the product of R = 0.70. The reaction was

diluted with CH Cl and quenched with pH 7 phosphate buﬀer. The

layers were separated, and the aqueous phase was extracted with one

additional portion of CH Cl before the combined organics were dried

over anhydrous Na SO . The solvent was removed under reduced

2

showed complete conversion of the starting material (R

= 0.86) to the

f

product of R = 0.10. The reaction was quenched with water and

f

diluted with EtOAc. The layers were separated, and the aqueous phase

was extracted with one additional portion of EtOAc before the

combined organics were dried over anhydrous Na SO . The solvent

2

4

was removed under reduced pressure, and the residue was puriﬁed by

preparative TLC (500 μm plate, loaded in CH Cl , eluted in 4:1

2

f

EtOAc/hexanes, silica washed with acetone) to give diol 100 as a

2

20

^w^hⁱ^t^e^a^m^o^r^p^h^o^u^s^s^o^lⁱ^d⁽⁵^.⁵^m^g^,⁹⁷^%⁾^:^[^α^]D = +176.2 (c 0.55,

CH Cl ); IR (neat) ν 3349, 2946, 2902, 2866, 2843, 1703, 1612, 1513,

2

−

1 1

1

402, 1249, 1174, 1032, 1006, 918, 814, 719 cm ; H NMR (500

2

4

MHz, CDCl ) δ 0.82 (1H, q, J = 11.6 Hz), 0.91 (3H, d, J = 6.7 Hz),

pressure, and the residue was puriﬁed by preparative TLC (1000 μm

plate, loaded in CH Cl , eluted in 85:15 hexanes/EtOAc, silica washed

3

0

.94 (1H, m), 1.05 (1H, m), 1.38−1.40 (3H, m), 1.56 (2H, m), 1.74

2

(1H, m), 1.96−2.05 (4H, m), 2.36 (1H, dt, J = 17.8 Hz, 6.7 Hz), 2.47

(1H, dt, J = 18.0 Hz, 6.8 Hz), 3.27−3.41 (4H, m), 4.57 (2H, s), 4.71

(1H, dd, J = 6.7 Hz, 3.5 Hz), 4.98 (1H, d, J = 9.9 Hz), 5.00 (1H, d, J =

with EtOAc) to give secondary alcohol 98 as a colorless oil (24.8 mg,

2%). NMR showed that 98 was still a 1:1 mixture of inseparable

diastereomers: IR (neat) ν 3464, 3070, 3014, 2929, 2857, 1611, 1588,

7

−1

1

17.1 Hz), 5.45 (1H, dt, J = 9.8 Hz, 3.2 Hz), 5.55 (1H, dt, J = 17.6 Hz,

.1 Hz), 5.96 (1H, d, J = 9.9 Hz), 6.81 (2H, d, J = 8.1 Hz), 7.22 (2H,

d, J = 8.0 Hz); 22.5, 26.0, 30.3, 32.7, 36.1, 38.1, 39.4, 43.8, 44.5, 45.5,

1509, 1472, 1428, 1240, 1111, 1088, 999, 823, 702 cm ; H NMR

9

(

500 MHz, CDCl ) δ 0.84 (1H, m), 0.90 (3H, m), 0.93 (1H, m), 0.99

1H, m), 1.05 (9H, s), 1.09 (9H, s), 1.36−1.40 (3H, m), 1.53−2.02

8H, m), 2.20 (1H, m), 2.32 (1H, m), 3.06 (0.5H, m), 3.18 (0.5H, m),

3

4

1

9.5, 51.1, 56.6, 62.2, 65.2, 79.0, 115.9, 116.2, 128.7, 128.9, 129.4,

33.1, 137.5, 157.9, 211.8; HRMS (ESI+) calcd for C H O ([M +

27

37

4

3

.61−3.68 (2.5H, m), 3.85 (0.5H, m), 4.66−4.68 (2.5H, m), 4.77

+

H] ) 425.2692, found 425.2690.

(

0.5H, m), 5.03 (0.5H, d, J = 17.0 Hz), 5.06−5.10 (1.5H, m), 5.40

0.5H, ddd, J = 9.6 Hz, 4.5 Hz, 2.8 Hz), 5.47 (0.5H, ddd, J = 9.7 Hz,

ASSOCIATED CONTENT

4

(

=

.7 Hz, 2.7 Hz), 5.80 (0.5 H, ddd, J = 17.0 Hz, 10.1 Hz, 8.5 Hz), 5.90

1H, d, J = 9.4 Hz), 5.99 (0.5H, dt, J = 16.9 Hz, 9.6 Hz), 6.83 (1H, d, J

8.6 Hz), 6.90 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 8.6 Hz), 7.21 (1H,

■

*

S

Supporting Information

1

13

H NMR and C NMR spectra for all new compounds and full

13

d, J = 8.7 Hz), 7.34−7.43 (12H, m), 7.64−7.70 (8H, m); C NMR

spectral assignments for cyclophanes 10, 24, 26, 30, 43, 44, 45,

(

125 MHz, CDCl ) δ 19.3, 19.4, 22.5, 22.6, 26.91, 26.94, 28.7, 29.9,

3

4

6, 49, 50, and 67 . This material is available free of charge via

3

4

6

1

0.8, 31.0, 31.7, 32.0, 33.0, 33.1, 36.2, 36.3, 37.9, 38.1, 43.4, 43.6, 44.0,

4.3, 45.1, 45.7, 46.1, 48.0, 50.6, 50.8, 55.8, 57.0, 64.1, 64.3, 65.19,

5.24, 72.8, 73.0, 80.0, 81.1, 116.0, 116.2, 116.8, 117.1, 127.35, 127.43,

27.6, 127.7, 127.8, 127.9, 129.5, 129.6, 129.71, 129.73, 130.3, 130.5,

33.4, 133.59, 133.60, 133.62, 133.63, 134.00, 134.01, 134.10, 134.11,

the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

■

Corresponding Author

E-mail: ejs@princeton.edu.

34.4, 135.6, 135.7, 138.3, 140.4, 154.9, 156.5; HRMS (ESI+) calcd for

*

+

C H O Si ([M + H] ) 903.5204, found 903.5208.

59

75

4

2

Notes

Ketone 99. To a solution of mixed alcohol 98 (12.4 mg, 13.7 μmol,

.00 equiv) in 1 mL of CH Cl₂was added solid Dess−Martin

1

The authors declare no competing ﬁnancial interest.

2

periodinane (20 mg, 47.2 μmol, 3.44 equiv). After 30 min, TLC (4:1

hexanes/EtOAc, UV/anisaldehyde) showed complete conversion of

the starting material (R = 0.51) to the product of R = 0.56. The

ACKNOWLEDGMENTS

■

f

We gratefully acknowledge ﬁnancial support from the National

Institute of General Medical Sciences (GM065483) to E.J.S.,

the Natural Sciences and Engineering Research Council of

Canada (postdoctoral fellowship for C.A.C.), and Princeton

reaction was diluted with CH Cl₂and quenched with saturated

aqueous Na S O solution and saturated aqueous NaHCO solution.

The layers were separated, and the organic phase was dried over

anhydrous Na SO . The solvent was removed under reduced pressure,

2

3

2

4

and the residue was puriﬁed by preparative TLC (500 μm plate,

́

University. We thank Dr. Istvan Pelczer for his assistance with

loaded in CH Cl , eluted in 85:15 hexanes/EtOAc, silica washed with

NMR spectroscopy, Dr. John Eng for his help with mass

spectrometry, and Lotus Separations for compound puriﬁcation

and analysis. Finally, we also thank Rebecca Lambert for her

helpful suggestions in preparing and proofreading the manu-

script.

2

20

^a^c^e^t^oⁿ^e⁾^t^o^gⁱ^v^e^k^e^t^oⁿ^e⁹⁹^a^s^a^c^o^l^o^r^l^e^s^s^oⁱ^l⁽¹²^m^g^,⁹⁷^%⁾^:^[^α^]D

=

+

89.6 (c 1.20, CH Cl ); IR (neat) ν 3070, 2928, 2856, 1712, 1611,

2 2

1

5

0

588, 1509, 1472, 1375, 1240, 1111, 1089, 1007, 923, 823, 702, 614,

−1 1

05 cm ; H NMR (500 MHz, CDCl ) δ 0.82 (1H, q, J = 11.7 Hz),

3

.91 (3H, d, J = 6.6 Hz), 0.94 (1H, m), 1.02 (9H, s), 1.06 (9H, s), 1.07

(

1H, m), 1.37−1.41 (3H, m), 1.63 (2H, m), 1.72 (1H, m), 2.00−2.05

REFERENCES

(

4H, m), 2.41 (1H, dt, J = 17.1 Hz, 7.4 Hz), 2.50 (1H, dt, J = 17.2 Hz,

■

7

.7 Hz), 3.29 (1H, m), 3.35 (1H, dd, J = 10.9 Hz, 6.7 Hz), 3.55 (2H, t,

J = 6.1 Hz), 4.64−4.67 (3H, m), 4.94−4.98 (2H, m), 5.46 (1H, dt, J =

.7 Hz, 3.3 Hz), 5.57 (1H, ddd, J = 16.9 Hz, 10.0 Hz, 8.7 Hz), 5.97

1H, d, J = 9.7 Hz), 6.75 (2H, d, J = 8.5 Hz), 7.12 (2H, d, J = 8.2 Hz),

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9

(

7

13

.33−7.42 (12H, m), 7.60−7.62 (4H, m), 7.67−7.68 (4H, m);

C

NMR (125 MHz, CDCl ) δ 19.3, 19.4, 22.6, 26.3, 26.9, 30.6, 32.8,

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3

1

6.1, 38.1, 39.2, 43.9, 44.5, 45.4, 49.7, 51.1, 56.7, 63.2, 65.2, 79.1,

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+

calcd for C H KO Si ([M + K] ) 939.4604, found 939.4600.

59

72

4

2

9

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dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

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dx.doi.org/10.1021/jo401799f | J. Org. Chem. 2013, 78, 9584−9607

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Toward a synthesis of hirsutellone B by the concept of double cyclization

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