Studies for the total synthesis of amphidinolide P

Article

pubs.acs.org/joc

Studies for the Total Synthesis of Amphidinolide P^†

David R. Williams,* Brian J. Myers, Liang Mi, and Randall J. Binder

Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States

S

* Supporting Information

ABSTRACT: A convergent, enantiocontrolled total synthesis of the

15-membered macrolide, amphidinolide P, is described. The

synthesis utilizes three nonracemic components for an eﬃcient

assembly of the macrolactone in 12 steps via the longest linear

pathway. Key developments include studies of the Hosomi−Sakurai

reaction for the formation of the C₆−C₇bond, a “ligandless”

palladium-mediated Stille cross-coupling of the vinylic stannane 4

and the alkenyl bromide 5 to produce a highly functionalized dienol,

and a thermally induced, intramolecular lactonization via the late-

stage formation of an intermediate α-acylketene.

INTRODUCTION

■

The amphidinolides are a structurally diverse family of

approximately 40 representative substances that have been

isolated from dinoﬂagellates of the genus Amphidinium sp.¹

Naturally occurring metabolites are produced by symbiotic

dinoﬂagellates that live within the digestive tract of the

Okinawan ﬂatworm Amphiscolops sp. Additional examples of

the family have also been produced by cultured, free-living

dinoﬂagellates.²Many amphidinolides display potent antineo-

plastic activity against a variety of cancer cell lines and produce

IC₅₀values in the low micromolar range. In fact, caribenolide I³

and amphidinolide N,⁴two closely related macrolide structures,

exhibit subpicomolar activity against murine lymphoma L1210

and human epidermoid carcinoma KB. The exceedingly small

quantities of isolated amphidinolides present a serious

challenge for studies of structure determination, and for the

assignments of relative and absolute stereochemistry. Because

of the high biological activity and limited availability, these

novel structures have been important targets for total

synthesis.⁵A number of studies have also documented the

development of new methodology in the course of these

investigations.⁶

Kobayashi and co-workers reported the isolation and

structure determination of amphidinolides O (1) and P (2)

in 1995.⁷In 2000, we described a synthetic strategy that

resulted in the ﬁrst total synthesis of amphidinolide P (2).⁸

Subsequently, Chakraborty and co-workers completed a formal

synthesis of 2 by the preparation of key intermediates, which

correlated with our prior eﬀort.⁹More recently, Trost has

described the development of a ruthenium-catalyzed alkene−

alkyne coupling strategy for the total synthesis of 2.¹⁰Herein,

we report, in full detail, our studies leading to the total synthesis

of 2, and we conﬁrm the absolute conﬁguration of natural

amphidinolide P as the (+)-enantiomer.

RESULTS AND DISCUSSION

■

Our retrosynthetic analysis of 2, as shown in Scheme 1,

developed several postulates that were important elements for

the success of the overall strategy. These primary consid-

erations involved (a) macrolactonization via the internal

capture of the acyl ketene intermediate 3 by the C₁₄allylic

alcohol, (b) cross-coupling of the E-alkenylstannane 4 with the

functionalized bromide 5, and (c) nucleophilic addition to the

β,γ-unsaturated aldehyde of 6 with appropriate oxidations at C-

3. The later transformations were cause for concern in our

initial analysis because commonly used reaction conditions

could jeopardize the integrity of the (R)-C₄stereochemistry as

incorporated from the nonracemic allylsilane 8 via the

Hosomi−Sakurai reaction with chiral aldehyde 9.

From the outset, our synthetic planning investigated a

convergent pathway that promised to minimize the number of

operations of signiﬁcant potential for epimerization of the C₄

stereochemistry subsequent to the assembly of the carbon

skeleton. On this basis, our eﬀorts sought to circumvent the

multistep sequence of enolate addition and oxidation chemistry

suggested for the conversion of alcohol 7 into the ketoester 5

(Scheme 1). This premise led us to construct an elaborated

nonracemic C₁−C₆component. We began these studies with

Received: February 6, 2013

A

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

was recycled through the alkylation step on multigram scale

without additional eﬀorts on our part to optimize conditions for

the deprotonation. Protections of 12 as the corresponding

tetrahydropyranyl (THP) ether and the tert-butyldiphenylsilyl

(TBDPS) ether provided quantities of 13 and 14 that were

allocated for further explorations.

Scheme 1. Retrosynthetic Analysis of Amphidinolide P (2)

The cleavage of the TBS ether of 13 followed by Swern

oxidation¹³aﬀorded the nonracemic aldehyde 15, and the

successful transformation of 15 into the terminal alkyne 17 was

accomplished by application of the Corey−Fuchs protocol.¹⁴

Our studies planned to utilize the alkyne 17 for direct

conversion into an allylic silane or stannane, which could eﬀect

an eﬃcient S_E′ reaction with the chiral aldehyde 9 of Scheme 1.

Unfortunately, our attempts to achieve a regioselective cuprate

addition to the internal (C₅) carbon of the alkyne moiety

failed,^15,16and additional eﬀorts to functionalize C₅of 17 using

hydroiodation techniques¹⁷or a hydrostannylation¹⁸also gave

poor results. In both cases, starting 17 was consumed.

However, hydroiodation led to cleavage of the THP ether,

and hydrostannylation proceeded to give a mixture of

regioisomeric stannanes. We were able to overcome these

diﬃculties as illustrated in Scheme 3, starting with the chiral

Scheme 3. Formation of the C₁−C₆Allylsilane Component

the commercially available methyl (S)-(+)-3-hydroxy-2-meth-

ylpropionate (99% ee) via formation of the tert-butyldime-

thylsilyl (TBS) ether, followed by reduction, oxidation, and

conversion to the known 1,3-dithiane 11 as summarized in

Scheme 2.¹¹The nonracemic, primary alcohol 12 (Scheme 2)

was obtained in 60% yield by the deprotonation of dithiane 11

with tert-butyllithium in THF and HMPA followed by the

addition of ethylene oxide.¹²A convenient puriﬁcation of 12

was achieved by ﬂash silica gel chromatography, which also led

to the recovery of substantial amounts (20%) of recovered

dithiane 11. Thus, for these initial eﬀorts, the starting dithiane

Scheme 2. Preparation of Nonracemic Alkyne 17

aldehydes 15 and 16. Our concerns regarding C₄epimerization

in the course of the Swern oxidation¹³of the precursor primary

alcohols were initially addressed by carefully conducting these

oxidations at low temperatures (−78 °C) with subsequent

warming to −50 °C for dropwise addition of freshly distilled

triethylamine (2.2 equiv). The crude aldehyde 15 was evaluated

by submitting a sample for DIBAL−H reduction at −78 °C.

Proton NMR data of the recovered alcohol indicated a 1:1

mixture of OTHP diastereomers, which was identical to the

starting alcohol. In the case of aldehyde 16, DIBAL−H

reduction was followed by the preparation of the corresponding

Mosher esters. Once again, NMR analysis indicated that the

extent of C₄epimerization was less than 5%. Subsequently, we

employed the Swern oxidation in scale-up reactions and used

the Dess−Martin periodinane oxidation¹⁹at ambient temper-

ature with similar outcomes. This evidence alleviated our

concerns regarding problems for C₄epimerization in the

B

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

production of the corresponding methyl ketones. Thus, we

pressed ahead with the conversion to ketones 18 and 19, which

allowed for kinetic, low-temperature deprotonation resulting in

the formation of the stable vinyl triﬂates 20 and 21 as a reactive

species for installation of the desired allylic silane or stannane.

In fact, the cross-coupling reactions of alkenyl triﬂates with

various organometallic species are well precedented.²⁰How-

ever, initial attempts for a palladium-catalyzed coupling of the

triﬂate 20 with an organocopper reagent, derived from tri-n-

butylstannylmethyl iodide,^21,22led to approximately equal

amounts of the previously prepared alkyne 17 (42%) and the

allene 22 (44%) (Scheme 4). These products presumably arise

via a facile β-hydride elimination of the vinyl palladium(II)

intermediate, which is formed upon oxidative insertion.

Scheme 5. Synthesis of the C₃−C₁₁Component 35

Scheme 4. Facile β-Hydride Eliminations of Triﬂate 20

HMPA (4 equiv) and cuprous iodide. The application

advantageously avoids side reactions that eﬀect a reductive

elimination, producing an allylic alcohol from 27 as well as

base-induced isomerization of the desired product 29 to the

corresponding conjugated dienol. The electrophilic replace-

ment of the trimethylsilyl substituent to yield the correspond-

ing vinylic iodide from silane 29 was attempted under various

conditions, but the apparent instability of the alkenyliodide

product complicated our puriﬁcation eﬀorts. The conversion of

29 to the alkenylbromide 30 proceeded uneventfully with the

low temperature addition of bromine followed by elimination

upon treatment with sodium methoxide.²⁷Our successful

preparation of the nonracemic α,β-epoxyaldehyde 9 was

concluded by ﬂuoride-induced deprotection and an eﬃcient

Dess−Martin oxidation.¹⁹However, the isolated yield (75%) of

the aldehyde 9 was somewhat reduced because of the volatility

of this material at reduced pressures.

Investigations for C₆−C₇bond formation using aldehyde 9

initially examined the Hosomi−Sakurai reaction²⁸of chiral

allylsilane 31. The preparation of silane 31 followed a similar

procedure as described by Forsyth and co-workers for the

corresponding benzyl ether.²⁹In this manner, the para-

methoxybenzyl ether of methyl (2S)-3-hydroxy-2-methylpropi-

onate (99% ee) was reacted with 3 equiv of trimethylsilylme-

thylmagnesium chloride in the presence of anhydrous CeCl₃(3

equiv) to generally aﬀord yields of 31 ranging from 50−60%.

Preliminary model studies of reactions of the allylic silane 31

used aldehyde 32, which was readily obtained by Parikh−

Doering oxidation (SO₃·pyr) of the alcohol derived from TBAF

deprotection of 29. Using BF₃·OEt₂at −78 °C, the Hosomi−

Sakurai reaction of 31 provided for the facile formation of the

C₆−C₇bond and resulted in a mixture (2:1) of diastereomeric

alcohols. The homoallylic alcohol 33 of Scheme 6 was puriﬁed

and was identiﬁed as the major product (34% yield) by use of

the Mosher ester analysis. On the basis of this positive

outcome, we sought to extend these studies of the nonracemic

aldehyde 32 for the Lewis acid-catalyzed Hosomi−Sakurai

reaction of the fully elaborated (C₁−C₆) silane component 24

(from Scheme 3). Unfortunately, all attempts for the S_E′

This side reaction was avoided by the use of Ni(acac)₂as

previously described by Kumada and co-workers for cross-

coupling reactions of trimethylsilylmethylmagnesium chlor-

ide.²³To our delight, the initial experiments produced

allylsilanes 23 (56% yield) and 24 (53% yield) as conﬁrmed

by ¹H NMR data indicating the presence of the terminal alkene

with characteristic hydrogen singlets at δ 4.88 and δδ 4.84 as

well as the incorporation of the anticipated trimethylsilyl and

methylene signals. A subsequent report has detailed the scope,

limitations and ligand eﬀects of nickel-catalyzed cross-couplings

of vinylic triﬂates and Grignard reagents.²⁴This study

concluded that Ni(acac)₂does not generally support cross-

coupling reactions of alkyl (sp³) Grignard reagents with vinyl

triﬂates, which may suggest unique behavior for trimethylsi-

lylmethylmagnesium chloride in our examples.

Construction of the C₁−C₁₁Segment of Amphidino-

lide P. Our plan for a convergent, enantiocontrolled synthesis

of amphidinolide P (2) relied on two crucial carbon−carbon

bond forming reactions. These processes undertake a bidirec-

tional extension of the carbon skeleton utilizing the central α,β-

epoxyaldehyde 9 (Scheme 1). First, we envisioned a stereo-

selective S_E′ reaction, which would aﬀord a homoallylic alcohol

via formation of the C₆−C₇bond. A subsequent operation

would then introduce the conjugated diene of 2 by sp²−sp²

coupling for C₁₁−C₁₂bonding. To this end, Scheme 5

illustrates an eﬃcient preparation of the required aldehyde 9

(91% ee), starting with the known epoxyalcohol 26, which was

obtained by Sharpless asymmetric epoxidation of the

corresponding allylic alcohol 25.²⁵The straightforward

conversion to the epoxy iodide 27 led to a direct nucleophilic

displacement resulting from a copper-catalyzed coupling with

the Grignard reagent 28 to provide alkenylsilane 29 in excellent

yield. This technique was previously described by Nicolaou and

co-workers²⁶and involves the addition of the vinylic Grignard

species into a THF solution of iodide 27 containing anhydrous

C

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Destruction of starting 24 was rapid, whereas secondary

decomposition of aldehyde 32 proceeded at a slower pace.

These observations renewed some prior concerns about the

inherent compatibility of the homoallylic dithiane moiety of

silane 24, as well as the stability of the epoxy aldehydes 9 and

32 in our planned condensation event. We rationalized that the

destruction of silane 24 was due to the proximity of the

thioketal functionality, which provided for facile solvolysis to

yield a stabilized, nonclassical cyclopropylcarbinyl carbocation.

Further rearrangements of this cation and the loss of the

trimethylsilyl substituent would be anticipated. In fact, the

decomposition of silane 24 gave numerous byproducts that

lacked the TMS group. The instability of 24 may also

contribute to the slow protodesilation of 32, which was

identiﬁed as the major degradation pathway for the aldehyde.

This negative outcome led us to examine the Sakurai process

for the reaction of 9 with the allylic silane 31 (Scheme 5).

Careful control of the reaction temperature led to a 65% yield

of the desired homoallylic diastereomers 35 and 36 (dr 4:1).

The puriﬁcation by ﬂash chromatography aﬀorded 35 (51%) as

the major product resulting from a Felkin−Anh addition to the

α,β-epoxy-aldehyde. In addition, quantities of the puriﬁed

minor adduct 36 (13% yield) were also obtained. This

facilitated a full characterization of both isomers, and pertinent

Scheme 6. Hosomi−Sakurai Studies of Allyl Silanes 31 and

24

allylation of aldehyde 32 with 24 did not result in any

signiﬁcant formation of the desired alcohol 34. In these

experiments, we observed substantial decomposition.

Table 1. Mosher Ester Analysis of Alcohols 35 and 36

assignable hydrogens of C7 (S)-isomer

chemical shifts in δ S-MTPA 37b

chemical shifts in δ R-MTPA 37a

shift diﬀerence Δδ^SR(δS − δR)

35

(ppm)

C₇−H

C₆−H

C₁₈−H

C₁₉−H

C₈−H

C₉−H

C₁₀−H

5.36

2.43

1.08

4.86

2.97

3.17

2.63

5.31

2.52

1.12

4.98

2.85

3.06

2.57

−0.09

−0.04

−0.12

+0.12

+0.11

+0.06

assignable hydrogens of C7(R)-isomer

chemical shifts in δ S-MTPA 38a

chemical shifts in δ R-MTPA 38b

shift diﬀerence Δδ^SR(δS − δR)

36

(ppm)

C₇−H

C₆−H

C₁₈−H

C₁₉−H

C₈−H

C₉−H

C₁₀−H

5.18

2.50

5.05

2.44

+0.06

+0.04

1.07

1.03

4.97

4.89

+0.08

obscured

3.01

obscured

3.11

obscured

−0.10

−0.05

2.57

2.62

D

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

data from the Mosher ester analysis³⁰is compiled in Table 1.

The Mosher NMR-based technique allowed for the assign-

ments of conﬁguration of the stereogenic C-7 carbinols by

conversion of the puriﬁed alcohols 35 and 36 into individual

diastereomeric α-methoxy-α-triﬂuoromethyl phenylacetic acid

(MTPA) esters. Thus, the preparation of S-MTPA and R-

MTPA esters from 35 gave the pair of Mosher esters 37a and

37b, and likewise, alcohol 36 led to the Mosher esters 38a and

38b. Our ¹H NMR analysis of the R-MTPA ester 37a, resulting

from the (S)-C₇alcohol 35, shows signals for C₆H, C₁₈H and

C₁₉H hydrogens, which are downﬁeld relative to the

corresponding chemical shifts of the (S)-Mosher ester 37b.

On the other hand, the chemical shifts of hydrogens at C₈, C₉

and C₁₀of 37a are shielded compared to the signals of 37b.

Conversely, the pair of (R)- and (S)-MTPA esters 38a and 38b,

which are derived from the minor product 36, showed the

opposite trend of shielding eﬀects as measured by the shift

diﬀerence Δδ^SR(δ(S-MTPA ester) − δ(R-MTPA ester).³¹

Thus, our detailed analysis of the data correlates with Mosher’s

original conclusions. In this fashion, the C-7 stereochemistry of

the chiral secondary alcohols 35 and 36 was assigned, and the

major product, 7(S)-alcohol 35, was utilized for further studies.

Because of the inability to perform the desired Sakurai

reaction with silane 24, we chose to functionalize the C₁−C₁₁

component using the enolate condensations as documented in

our original retrosynthetic analysis (Scheme 1). This required

our reassessment of potential problems arising from base-

induced conjugation of the C₅-alkene, deprotonation at C₄, and

epimerization of C₄stereochemistry. These studies are

examined in Scheme 7 by protection of 35 as the C₇TBS

acetate by treatment with lithium diisopropylamide (LDA) at

−78 °C.³²The resulting β-hydroxy esters (dr 2:1) were then

directly oxidized using the buﬀered Dess−Martin protocol to

provide the desired β-keto ester 42 in 65% overall yield for the

two steps following ﬂash chromatography. As in the case of

1

aldehyde 41, our H NMR characterization of 42 showed no

evidence of C-4 epimerization or CC double bond

conjugation.

Preparation of Nonracemic C₁₂−C₁₇Segment of

Amphidinolide P. The synthesis of the C₁₂−C₁₇segment of

amphidinolide P was designed to incorporate the asymmetry of

the C₁₄and C₁₅stereocenters by utilizing a Stille cross coupling

reaction of the C₁₁alkenylbromide of 42 and the nonracemic

(E)-organostannane 4 (Scheme 1). The nonracemic stannane 4

was prepared in eight steps from the optically active epoxide 43

as diagrammed in Scheme 8. The synthesis of the

Scheme 8. Preparation of the C₁₂−C₁₇Stannane Component

4

Scheme 7. Formation of β-Keto Ester 42

enantioenriched epoxide 44 was accomplished via the

asymmetric Sharpless epoxidation of cis-2-butenol³³followed

by in situ protection of the primary alcohol as the p-

methoxytrityl (MMTr) ether.³⁴Thus, large quantities of

nonracemic 44 were available in a one-pot operation, and the

product was readily puriﬁed by ﬂash silica gel chromatography

(80% yield). The deprotection of a puriﬁed sample of 44 using

DDQ in wet CH₂Cl₂allowed for the Mosher ester

derivatization and analysis of the Sharpless epoxyalcohol as

its corresponding (R)- and (S)-MTPA esters.³⁰The integration

of ¹H NMR signals of the MTPA esters indicated 83% ee (91:9

er) for the asymmetric oxidation. A Lewis acid-promoted,

regioselective opening of epoxide 44 was undertaken via the

copper(I)-mediated addition of freshly prepared isopropenyl-

magnesium bromide. In the event, the 1,2-diol derivative 45

was obtained in 84% yield as the sole product arising from

nucleophilic attack at the less hindered carbon of the starting

oxirane. The role of the unusual MMTr protecting group is 2-

fold in this reaction scheme. First, it provides the steric bulk

necessary to direct nucleophilic opening to the β-carbon of 44

(labeled as C15 of alcohol 45). Second, the MMTr ether is

readily cleaved under pH 7 conditions with DDQ in wet

CH₂Cl₂. This feature permitted the formation of the secondary

TBS ether 46, followed by the removal of the MMTr ether,

without eﬀecting O-migration of the silyl (TBS) group.

silyl ether 39, and DDQ oxidation to provide the C₃primary

alcohol 40 in excellent yield. A buﬀered oxidation with Dess−

Martin periodinane¹⁹gave the sensitive aldehyde 41, which was

generated immediately prior to its use in subsequent reactions

1

and was puriﬁed by ﬂash silica gel chromatography. Our H

NMR analysis showed no evidence for migration of the β,γ-

alkene into conjugation, and NMR spectra of 41 did not

indicate the presence of diastereomers resulting from

epimerization at C-4. With this crucial information in hand, a

solution of aldehyde 41 was added into an excess of the lithium

enolate generated from a kinetic deprotonation of methyl

E

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Migration of the TBS substituent to the less hindered primary

alcohol was generally observed under the standard basic or

acidic conditions employed to remove other protecting groups,

and this behavior presented diﬃculties for the chromatographic

puriﬁcation of the desired alcohol. Small samples of the

Grignard addition product 45 were submitted for the Mosher

ester analysis protocol, and these results also conﬁrmed the

83% ee (91:9 er) of the asymmetric Sharpless epoxidation.

The use of p-anisyldiphenylcarbinyl as a protecting group is

not common, and it is notable that ether cleavage is

accomplished with a buﬀer at pH 7 using excess DDQ (5

equiv). After 18 h at ambient temperature, the primary alcohol

47 (Scheme 7) was reproducibly obtained in 73% yield along

with small quantities (2−4%) of the corresponding unprotected

diol and recovered starting material 46. We could not observe

the complete consumption of 46 by forcing these reactions to

completion with longer reaction times or elevated temperatures

without causing TBS ether migration and/or increasing the

production of the undesired 1,2-diol. Support for an acid-

catalyzed hydrolysis comes from the appearance of the bright

red color of the reaction medium, which is indicative of the

formation of the p-anisyldiphenylcarbinyl cation as well as the

isolation of the p-methoxytrityl alcohol product. It is known

that the hydration of DDQ provides an organic acid, which may

promote the mild hydrolysis.³⁵However, we could not

duplicate these mild hydrolytic conditions for the removal of

MMTr using aqueous acetic acid or by the addition of various

phenols in wet CH₂Cl₂. Furthermore, the deprotection of 46

was achieved with ceric ammonium nitrate in a biphasic mixture

of water and CH₂Cl₂leading to an 83% yield of the alcohol 47.

Although there is no clear evidence of oxidative electron

transfer in these processes, the latter reagent became the

method of choice for scale-up reactions to provide 47 for Swern

oxidation¹³to give quantities of aldehyde 48.

Scheme 9. Macrocyclization Considerations via the Stille

Reaction

protodestannylated product of 4. The addition of copper(I)

salts facilitated the protodestannylation at lower temperatures.

Our further studies showed that ligandless palladium conditions

using Pd(OAc)₂in toluene provided the expected diene at

room temperature, whereas the addition of triphenylphosphine

or other phosphines and polar solvents (DMF, NMP, THF)

aﬀorded little or none of the desired cross coupling.³⁷

Furthermore, the use of triphenylarsine in these reactions

resulted in none of the desired product even after prolonged

reaction times or elevated temperatures.³⁸Our optimization of

this Stille reaction, using Pd₂dba₃·CHCl₃in methylene

chloride³⁹at room temperature overnight, resulted in the

isolation of diene 54 in 81% yield (Scheme 10) along with

small amounts (5−8%) of diastereomers arising from minor

enantiomers of the starting chiral epoxides 26 and 44. The

subsequent macrolactonization of puriﬁed 54 was undertaken

via a broadly applicable transesteriﬁcation protocol for β-

ketoesters as originally described by Bader and co-workers.⁴⁰

The mechanism of this reaction has been studied and suggests a

concerted elimination of alcohol, which is consistent with a

unimolecular process. Formation of an intermediate acylketene

is followed by nucleophilic addition.⁴¹In the event, the β-keto

ester 54 was heated at 110 °C in reﬂuxing toluene, and

macrolactone 55 was produced as a single diastereoisomer in

72% yield (Scheme 10).

Subsequently, our application of the Corey−Fuchs reaction¹⁴

was utilized for conversion to give the terminal alkyne 49

(Scheme 8). Hydrostannylation³⁶of 49 was successful using tri-

n-butylstannane in the presence of a catalytic amount of

PdCl₂(PPh₃)₂, and the crude E-alkenylstannane 50 was

characterized by the large coupling constant (J = 19.1 Hz)

observed for vinylic hydrogen signals at δ 6.02 (d, 1H) and δ

5.85 (dd, 1H) in the ¹H NMR spectrum. Immediate treatment

of 50 with tetra-n-butylammonium ﬂuoride resulted in pure

samples of nonracemic stannane 4, which was isolated in 64%

yield from the starting alkyne 49.

Formation of the C₁₁−C₁₂Bond and Completion of

the Total Synthesis. We recognized two possible pathways in

our considerations for joining components 4 and 42 toward the

completion of the synthesis of amphidinolide P. One route

would join the C-14 alcohol 4 to 42 via transesteriﬁcation to

produce intermediate 51 for a subsequent intramolecular Stille

macrocyclization (Scheme 9). This transformation was

envisioned to be problematic because of competing oppor-

tunities leading to the formation of a π-allylpalladium species

from the allylic ester 51. Furthermore, the formation of a π-

allylpalladium intermediate from product 52 could proceed to

yield the stable tetraene 53 via a facile β-hydride elimination.

On the basis of our risk analysis, we ﬁrst elected to explore

formation of the C₁₁−C₁₂bond of amphidinolide P followed by

macrolactonization. Using stannane 4 and the previously

prepared alkenyl bromide 42, we found that Pd(PPh₃)₄in

DMF at 110 °C provided 10−20% yields of the Stille cross-

coupling product 54 along with varying amounts of the

Final conversion to the natural product required depro-

tection of the C₇TBS silyl ether and intramolecular hemiketal

formation. This was cleanly accomplished in one step upon

treatment of 55 with tetra-n-butyl ammonium ﬂuoride in THF

at 22 °C. Cleavage of the silyl ether led to spontaneous ring

closure to yield a single hemiketal diastereomer, which proved

to be synthetic (+)-amphidinolide P (2). The synthetic material

F

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

natural product. Concerns regarding this transformation

involved the presence of the C₁₅alcohol and related derivatives,

and is based on the proclivity for side reactions via the

formation of π-allyl palladium species leading to β-hydride

elimination. We have successfully demonstrated mild ligandless

conditions for a Pd(0)-catalyzed Stille cross-coupling reaction,

which successfully led to the desired, highly functionalized

dienol. Finally, macrocyclization of the 15-membered lactone is

achieved by an intramolecular transesteriﬁcation via the

formation and capture of an intermediate α-acylketene.

Scheme 10. Completion of the Total Synthesis of

Amphidinolide P

EXPERIMENTAL SECTION

■

General Methods. Flash chromatography was performed using

silica gel 60 (230−400 mesh size). Preparative thin layer

chromatography was performed on either 0.25 or 0.5 mm thick silica

gel plates precoated with 60 F-254 on a 20 × 20 cm glass plate.

Analytical thin layer chromatography (TLC) was performed on glass-

backed 0.25 mm thick silica gel plates precoated with 60 F-254. Spots

were visualized under UV light and/or with staining with ethanolic p-

anisaldehyde or ceric ammonium molybdate. All silica products were

commercially obtained. Optical rotations were obtained on a

polarimeter at 589 nm (sodium D line) using a 10 cm path length

and a 1.0 mL volume. Concentration (c) is reported in g per 100 mL

of the solvent speciﬁed. Infrared (FT-IR) spectra are reported in

wavenumbers (cm⁻¹).

was isolated as a white powder following ﬂash silica gel

chromatography: R_f0.65 (15% EtOAc in hexanes); [α]_D²³

+30.0° (c 0.26, MeOH) ([α]²_D⁵lit. +31° (c 0.098, MeOH)).⁷

The optical rotation data is a correction of our previous

studies,^8bwhich had led us to conclude that our route had

erroneously produced (−)-amphidinolide P. In fact, we

prepared three samples of synthetic 2 and can report that our

speciﬁc rotations, at slightly diﬀerent concentrations, ranged

from [α]²_D³+27.5 (c 0.40, MeOH) to [α]²_D³+30.0° (c 0.26,

MeOH). In all other respects, our synthetic sample is identical

with the detailed spectroscopic data as reported for the natural

product (Supporting Information contains comparison tables of

Proton and carbon nuclear magnetic resonance (¹H NMR, ¹³C

NMR) spectra were measured on 400 and 500 MHz spectrometers.

Proton NMR spectra were recorded in CDCl₃or C₆D₆solutions and

are reported in parts per million (ppm) downﬁeld (δ) from

tetramethlysilane using residual chloroform (δ 7.26) or benzene (δ

7.20) as an internal reference. Proton NMR data are reported in the

following form: δ (multiplicity, coupling constants, number of

protons). Carbon NMR spectra were recorded in CDCl₃or C₆D₆

solutions and are reported in parts per million (ppm) downﬁeld (δ)

from tetramethlysilane (TMS) using residual chloroform (CHCl₃, δ

77.0) or benzene (δ 128.0) as an internal standard. Mass spectral data

(MS, HRMS) were recorded on a magnetic sector mass spectrometer

by use of chemical ionization (CI), electron impact (EI), or fast atom

bombardment (FAB).

All reagents and solvents were commercial grade and were used as

received unless noted otherwise. Diethyl ether (Et₂O) and

tetrahydrofuran (THF) were distilled under N₂from sodium

benzophenone ketyl immediately before use. Acetonitrile (CH₃CN),

benzene, N,N-diisopropylamine, N,N-diisopropylethylamine, methyl-

ene chloride (CH₂Cl₂), pyridine, toluene, and triethylamine (Et₃N)

were distilled from calcium hydride. Dimethylsulfoxide (DMSO), 1,3-

dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), and hex-

amethylphosphoramide (HMPA) were distilled under argon from

calcium hydride and stored over 4 Å molecular sieves under argon.

Dimethylformamide (DMF) was distilled from anhydrous MgSO₄and

stored under an atmosphere of argon. 2-Methoxyethyl ether (diglyme)

and ethylene glycol dimethyl ether (DME) were distilled from lithium

aluminum hydride and were stored under an atmosphere of argon.

Acetyl chloride and oxalyl chloride were distilled from calcium hydride.

Boron triﬂuoride diethyl etherate (BF₃·OEt₂) was freshly distilled from

calcium hydride and Et₂O under an atmosphere of argon. Hexanes and

ethyl acetate (EtOAc) were distilled prior to use in chromatography. 1-

Lithiopropyne was prepared from n-butyllithium (n-BuLi) and

propyne gas on a calibrated Schlenk line; it was stored and handled

in a glovebox under N₂. Copper(I) bromide-dimethyl sulﬁde

(CuBr·DMS) was prepared from Cu₂Br₂.²¹

1

proton and carbon NMR data and H and ¹³C NMR spectra).

Thus, our synthesis eﬀort has corrected our communication

report and has shown that the absolute conﬁguration of our

synthetic (+)-amphidinolide P (2) is the same as the natural

metabolite.

CONCLUSION

■

In summary, we have described an eﬃcient, enantiocontrolled

pathway to (+)-amphidinolide P in 12 steps (longest linear

route) from readily available starting materials. Our studies

have developed a pathway for the synthesis of functionalized,

nonracemic allylsilanes incorporating the intact C₁−C₆segment

of the natural product. Advantageously, this strategy is designed

to directly incorporate the labile C₄asymmetry of amphidino-

lide P from a chiral pool precursor. However, our studies of the

subsequent Hosomi−Sakurai reaction failed because of the

instability of these allylic silanes. We have concluded that

allylsilanes that display homoallylic ketal and thioketal

functionality are problematic and may result in facile formation

of nonclassical cyclopropylcarbinyl cations, leading to further

decomposition under the Lewis conditions of the reaction. This

diﬃculty is circumvented by the stepwise assembly of the C₁−

C₆region of the natural product. The process has utilized the

Hosomi−Sakurai reaction of chiral silane 31 for Felkin−Anh

addition with aldehyde 9. A careful Mosher ester analysis of 35

and 36 provided the basis of the C₇stereochemical assignment.

Further oxidations and a condensation using an acetate aldol

procedure avoided epimerization of the labile C₄chirality.

These studies have also examined the sp²−sp²cross coupling

process required to assemble the functionalized diene of the

All reactions were conducted in ﬂame or oven-dried glassware under

an atmosphere of argon unless otherwise noted. All nonvolatile

samples were pumped to constant weight at ambient temperature

(0.2−0.1 mmHg) following the removal of solvents in vacuo.

2-{2-[(1R)-2-(tert-Butyldimethylsilanyloxy)-1-methylethyl]-

[1,3]dithian-2-yl}ethanol (12). n-Butyllithium (8.1 mL 2.5 M in

hexanes) was added to a solution of dithiane 11¹¹(4.58 g, 15.7 mmol)

G

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

in THF (75 mL) at ambient temperature. The reaction stirred 5 min

and was cooled to −78 °C. Condensed ethylene oxide (2.3 mL, 47

mmol) was cannulated into the reaction mixture, and the reaction was

warmed to ambient temperature over 3.5 h. Saturated aqueous NH₄Cl

(10 mL) was added, and the mixture was transferred to a separatory

funnel using Et₂O (50 mL) and water (10 mL). The aqueous layer was

separated and washed with Et₂O (3 × 20 mL). The combined organic

layers were washed with brine (50 mL), dried over MgSO₄, ﬁltered,

and concentrated in vacuo. Puriﬁcation by ﬂash column chromatog-

raphy (200 g SiO₂), using a gradient elution (hexanes to 25% EtOAc

in hexanes) provided 3.00 g (60%) of 12 as a clear colorless oil: R_f0.11

(20% EtOAc in hexanes); [α]²_D⁶+12.9 (c 0.850, CHCl₃); IR (neat)

diastereomers and are not readily assignable); MS (CI, NH₃) m/z

(relative intensity) 306 (14), 247 (25), 181 (22), 142 (85), 100 (40),

85 (100); HRMS m/z calcd for C₁₄H₂₆O₃S₂(M⁺) 306.1323, found

306.1312.

Dimethylsulfoxide (0.77 mL, 10.9 mmol) was added to a −78 °C

solution of oxalyl chloride (0.47 mL, 5.44 mmol) and CH₂Cl₂(18

mL). The reaction stirred 10 min, and a solution of the primary

alcohol (1.51 g, 4.94 mmol) and CH₂Cl₂(5 mL) was added dropwise

via cannula. The reaction stirred 30 min, and Et₃N (3.4 mL, 24.7

mmol) was added dropwise. The reaction was stirred 15 min at −78

°C, warmed to room temperature, diluted with hexanes (50 mL), and

quenched with H₂O (5 mL). The aqueous layer was extracted with

hexanes (3 × 15 mL). The combined organic layers were washed with

brine (75 mL), dried over MgSO₄, ﬁltered, and concentrated in vacuo.

Aldehyde 15 was obtained in 98% yield as a 1:1 mixture of

tetrahydropyran diastereomers, which was used in subsequent

reactions without further puriﬁcation. Characteristic data for aldehyde

15: R_f0.33 (20% EtOAc in hexanes); IR (neat) 2942, 2672, 1715,

1

3395, 2955, 2857, 1422, 1254, 1044, 837, 777 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 4.10 (dd, J = 10.2, 3.76 Hz, 1H), 3.87 (m, 2H), 3.56

(dd, J = 10.2, 8.1 Hz, 1H), 2.91 (m, 2H), 2.81 (m, 2H), 2.65 (s, OH),

2.34 (m, 1H), 2.26 (m, 2H), 2.08−1.84 (m, 2H), 1.17 (d, J = 6.7 Hz,

3H), 0.90 (s, 9H), 0.07 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 64.9,

59.7, 55.8, 42.1, 38.0, 26.0, 25.9, 25.8, 25.0, 18.3, 12.98, −5.3; MS (CI,

NH₃) m/z (relative intensity) 336 (8), 291 (13), 279 (73), 261 (79),

249 (45), 231 (63), 191 (57), 187 (72), 175 (51), 165 (68), 149 (75),

105 (63), 89 (72), 75 (100), 73 (84); HRMS m/z calcd for

C₁₅H₃₂O₂SiS₂(M⁺) 336.1613, found 336.1607. Anal. Calcd for

C₁₅H₃₂S₂: C, 53.52; H, 9.58; S, 19.05. Found: C, 53.83; H, 9.46; S,

19.38.

1

1441, 1352, 1123, 1061, 1032, 905, 870 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 9.56 (m, 1H), 4.59 (m, 1H), 3.99 (m, 1H), 3.86 (m, 1H),

3.64 (m, 1H), 3.51 (m, 1H), 2.87 (m, 3H), 2.80 (m, 1H), 2.41 (m,

1H), 2.28 (m, 1H), 1.98 (m, 2H), 1.72−1.67 (m, 2H), 1.53 (m, 4H),

1.29 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H).

2-[2-(Tetrahydropyran-2-yloxy)ethyl]-2-(1-methylprop-2-

ynyl)-[1,3]-dithiane (17). Carbon tetrabromide (2.16 g, 6.5 mmol)

was added to a solution of triphenylphosphine (3.41 g, 13 mmol)

dissolved in CH₂Cl₂(10 mL) at 0 °C. The yellow reaction was stirred

10 min and was cooled to −78 °C. Anhydrous granular Na₂SO₄was

added to a solution of aldehyde 15 (∼2.64 mmol) and CH₂Cl₂(6

mL). The mixture stirred 15 min and was added via cannula to the

solution containing carbon tetrabromide and triphenylphosphine using

CH₂Cl₂(3 × 1 mL). The reaction stirred 15 min at −78 °C, was

warmed to room temperature, and diluted with CH₂Cl₂(10 mL) and

H₂O (15 mL). The organic layer was separated and washed with brine

(20 mL), dried over MgSO₄, ﬁltered, and concentrated in vacuo. The

residue was puriﬁed by ﬂash column chromatography (250 g SiO₂,

10% EtOAc in hexanes), which provided 645 mg (54% over 2 steps

from alcohol 12) of a 1:1 mixture of tetrahydropyranyl diastereomers

2-[(1R)-3,3-dibromo-1-methylallyl]-2-[(tetrahydropyran-2-yloxy)-

ethyl]-[1,3]-dithiane as a colorless oil: R_f0.38 (20% EtOAc in

hexanes); IR (neat) 3023, 2944 2733, 2658, 1736, 1638, 1439, 1371,

1103, 909, 787 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.67 (d, J = 9.6

Hz, 1H), 4.60 (m, 1H), 3.96 (m, 1H), 3.87 (m, 1H), 3.52 (m, 1H),

3.52 (m, 1H), 3.04 (m, 1H), 2.82 (m, 4H), 2.29 (m, 2H), 1.66−2.01

(m, 4H), 1.55 (m, 4H), 1.20 (d, J = 6.9, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 139.5, 99.1 (2), 88.8 (2), 64.4, 64.3, 62.4, 62.3, 55.1, 45.2,

35.6, 30.7, 26.0, 35.4, 24.8, 19.6, 19.5, 14.1 (2); MS (CI, NH₃) m/z

(relative intensity) 460 (5), 377 (33), 359 (18), 247 (73), 147 (95),

146 (60), 145 (100), 85 (92); HRMS m/z calcd for C₁₅H₂₄Br₂O₂S₂

(M⁺) 459.9565, found 459.9560.

The alkenyl dibromide prepared above (0.579 g, 1.26 mmol) was

diluted with THF (6.3 mL) and cooled to −78 °C. n-Butyllithium

(1.11 mL, 2.5 M in hexanes) was added dropwise. The yellow reaction

stirred 15 min and was quenched with saturated aqueous NH₄Cl. The

mixture was diluted with Et₂O (10 mL) and H₂O (5 mL). The organic

layer was washed with H₂O (2 × 10 mL) and brine (15 mL), dried

over MgSO₄, ﬁltered and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography (15 g SiO₂, 10% EtOAc in

hexanes), which provided 229 mg (62%) of a 1:1 mixture of

tetrahydropyranyl diastereomers of 17 as a white solid: mp 89.0−91.5

°C; R_f0.34 (20% EtOAc in hexanes); [α]²_D⁵+18.8 (c 1.67, CHCl₃); IR

(neat) 3306, 3001, 2945, 2875, 1121, 1074, 1028, 746 cm⁻¹; ¹H NMR

(400 MHz, CDCl₃) δ 4.61 (m, 1H), 4.01 (m, 1H), 3.89 (m, 1H), 3.69

(m, 1H), 3.51 (m, 1H), 3.20 (m, 1H), 2.85 (m, 4H), 2.47 (m, 1H),

2.30 (m, 1H), 2.23 (d, J = 2.6, 1H), 1.94 (m, 2H), 1.81 (m, 1H). 1.71

(m, 1H), 1.54 (m, 4H), 1.44 (d, J = 7.0, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 99.0, 98.9, 84.7, 77.2, 71.7, 64.2, 64.1, 62.4, 62.3, 54.9, 54.8,

35.8, 34.8, 30.7, 30.6, 26.1, 26.0, 25.4, 24.5, 19.6, 19.5, 16.9, 14.2

(Some carbon signals are coincident (overlapping) for these THP

diastereomers and are not readily assignable); MS (CI, NH₃) m/z

2-{2-[(1R)-2-(tert-Butyldimethylsilanyloxy)-1-methylethyl]-

[1,3]dithian-2-yl}-1-(tetrahydropyran-2-yloxy)ethane (13). Al-

cohol 12 (3.12 g, 9.3 mmol) was stirred at room temperature with

dihydropyran (0.45 mL, 4.97 mmol) and PPTS (104 mg, 0.41 mmol)

in CH₂Cl₂(21 mL) for 2 d. The reaction was quenched with saturated

aqueous NaHCO₃and diluted with CH₂Cl₂(20 mL) and H₂O (20

mL). The aqueous layer was extracted with CH₂Cl₂(4 × 40 mL). The

combined organic layers were dried over MgSO₄, ﬁltered, and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (325 g SiO₂, 5% EtOAc in hexanes), which provided

3.51 g (90%) of a 1:1 mixture of tetrahydropyran diastereomers 13 as a

colorless oil: R_f0.64 (20% EtOAc in hexanes); [α]²_D²+25.7 (c 1.50,

CHCl₃); IR (neat) 2955, 2932, 2859, 1470, 1258, 1134, 1076, 1028,

839, 760 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.59 (m, 1H), 4.14 (m,

0.5H), 4.12 (m, 0.5H), 3.96 (m, 1H), 3.88 (m, 1H), 3.63 (m, 1H),

3.53 (m, 2H), 2.92 (m, 2H), 2.76 (m, 2H), 2.32 (m, 2H), 2.10 (m,

1H), 1.90 (m, 3H), 1.71 (m, 1H), 1.54 (m, 4H), 1.18 (d, J = 6.8 Hz,

3H), 0.90 (s, 9H), 0.06 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 99.2,

99.1, 64.9 (2), 65.5, 62.5, 62.4, 55.6, 42.4 (2), 35.4, 30.7 (2), 25.9 (3),

25.8, 25.7, 25.4, 25.1 (2), 19.7 (2), 18.3 (2), 12.6 (2), −5.3 (2) (Some

carbon signals are coincident (overlapping) for these THP

diastereomers and are not readily assignable); MS (CI, NH₃) m/z

(relative intensity) 420 (2), 363 (4), 261 (32), 145 (81), 119 (24), 85

(100); HRMS m/z calcd for C₂₀H₄₀O₃SiS₂(M⁺) 420.2188, found

420.2207.

(2R)-2-{2-[2-(Tetrahydropyran-2-yloxy)ethyl]-[1,3]dithian-2-

yl}propionaldehyde (15). Tetrabutylammonium ﬂuoride (TBAF)

(15 mL, 1.0 M in THF, 14.9 mmol) was added to a solution of 13

(1.25 g, 2.98 mmol) and THF (5 mL). The reaction stirred 1 h at

room temperature and was diluted with Et₂O (25 mL) and H₂O (25

mL). The organic layer was washed with H₂O (2 × 20 mL) and brine

(25 mL). The aqueous layer was extracted with Et₂O (2 × 15 mL).

The combined organic layers were dried over MgSO₄, ﬁltered, and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (45 g SiO₂, 30% EtOAc in hexanes), which provided

0.91 g of (2R)-2-{2-[2-(tetrahydropyran-2-yloxy)ethyl]-[1,3]dithian-2-

yl}propan-1-ol as a 1:1 mixture of tetrahydropyran diastereomers

(99%) as a colorless oil: R_f0.12 (20% EtOAc in hexanes); IR (neat)

3420, 2938, 2878, 2735, 2660, 1736, 1466, 139, 1422, 1088, 1032, 905,

1

870, 810, 752 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 4.59 (m, 1H),

3.96 (m, 2H), 3.86 (m, 1H), 3.65 (m, 2H), 3.51 (m, 1H), 2.86 (m,

2H), 2.78 (m, 2H), 2.78 (m, 2H), 2.52 (m, 1H), 2.37 (m, 1H), 2.26

(m, 2H), 1.95 (m, 2H), 1.71 (m, 2H), 1.55 (m, 4H), 1.16 (d, J = 7 Hz,

3H); ¹³C NMR (100 MHz, CDCl₃) δ 99.2, 99.1, 65.1, 64.4 (2), 62.5,

62.4, 55.4, 41.9, 35.2, 30.7, 25.9 (2), 25.4, 24.9, 19.7, 19.6, 13.1, 13.0

(Some carbon signals are coincident (overlapping) for these THP

H

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(relative intensity) 300 (16), 247 (100), 171 (20), 147 (88), 85 (58);

HRMS m/z calcd for C₁₅H₂₄O₂S₂(M⁺) 300.1218, found 300.1218.

(3R)-3-{-2-[2-(Tetrahydropyran-2-yloxy)ethyl]-[1,3]dithian-2-

yl}butan-2-one (18). Aldehyde 15 (4.94 mmol) was diluted in THF

(25 mL) and was cooled to −78 °C. Methylmagnesium bromide (3.8

mL, 3 M in Et₂O) was added dropwise. After stirring 10 min, the

reaction was warmed to 0 °C. After another 10 min, saturated aqueous

NH₄Cl was added. The mixture was transferred to a separatory funnel

using Et₂O (20 mL) and H₂O (10 mL). The organic layer was washed

with H₂O (2 × 25 mL) and brine (30 mL), dried over MgSO₄, ﬁltered,

and concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (40 g SiO₂, 15% EtOAc in hexanes), which provided

1.33 g of a 1:1:1:1 mixture of diastereomeric alcohols as a colorless oil:

R_f0.34 (20% EtOAc in hexanes); [α]²_D³−5.87 (c 1.50, CHCl₃); IR

(neat) 3489, 2940, 1452, 1422, 1352, 1273, 1119, 1059, 1032, 907, 812

2-[2-(Tetrahydropyran-2-yloxy)ethyl]-2-(1-methylpropa-1,2-

dienyl)-[1,3]-dithiane (22). Tri-n-butylstannylmethyl iodide²²(0.82

g, 1.89 mmol) was dissolved in benzene (9 mL) and HMPA (0.66

mL). Zinc−copper couple (490 mg) was added, and the reaction was

heated to 75 °C for 2 h and then reﬂuxed for 30 min. Proton NMR

and TLC indicated than none of the starting stannane remained. The

reaction was cooled to ambient temperature, and triﬂate 20 (85 mg,

0.19 mmol), LiCl (32 mg, 0.76 mmol) and Pd(PPh₃)₄(8.7 mg, 7.6

mmol) were added. The reaction stirred 14 h at ambient temperature

and was heated to 57 °C for 4 h. After cooling to ambient temperature,

saturated aqueous NH₄Cl was added (5 mL). The reaction was ﬁltered

through a pad of silica to remove the zinc salts using Et₂O. The ﬁltrate

was transferred to a separatory funnel using Et₂O. The organic layer

was washed with H₂O (10 mL) and brine (15 mL). The combined

organic layers were dried over Na₂SO₄, ﬁltered, and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromatography (20 g

SiO₂, 10% EtOAc in hexanes), which provided 25 mg (44%) of allene

22 and 24 mg (42%) of alkyne 17 a colorless oil. Alkyne 17 was fully

characterized as previously described. Data for 22: R_f0.54 (20%

EtOAc in hexanes); IR (neat) 2944, 2926, 1952, 1439, 1352, 1262,

1136, 1121, 1061, 1032, 907, 847 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)

δ 4.85 (q, J = 2.9 Hz, 2H), 4.58 (m, 1H), 3.86 (m, 2H), 3.67 (m, 2H),

2.91 (m, 2H), 2.70 (ddd, J = 14.3, 6.3, 3.2 Hz, 2H), 2.27 (t, J = 7.3,

2H), 1.99 (m, 1H), 1.93 (m, 1H), 1.83 (t, J = 3.0, 3H), 1.79 (m, 1H),

1.69 (m, 1H), 1.53 (m, 3H), 1.30 (m, 1H); ¹³C NMR (100 MHz,

CDCl₃) δ 208.6, 102.0, 99.0, 76.3, 63.5, 62.2, 53.0, 38.6, 30.6, 27.3,

25.4, 25.2, 19.5, 16.3; MS (CI, NH₃) m/z (relative intensity) 300 (57),

247 (13), 198 (74), 172 (62), 156 (60), 151 (53), 138 (69), 112 (44),

85 (100); HRMS m/z calcd for C₁₅H₂₄O₂S₂(M⁺) 300.1218, found

300.1223.

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 4.68 (m, 1H), 4.58 (m, 1H),

3.81−3.92 (m, 2H), 3.47−3.57 (m, 2H), 2.92−3.02 (m, 2H) 2.64−

2.72 (m, 2H), 2.52−2.61 (m, 1H), 2.41 (br s, 1H−OH), 2.33−2.41

(m, 1H), 2.04 (m, 1H), 1.75−1.90 (m, 3H), 1.69 (m, 1H), 1.49−1.58

(m, 4H), 1.15 (d, J = 6.4 Hz, 3H), 1.12 (d, J = 7.1 Hz, 1.5H), 1.11 (d, J

= 7.1 Hz, 1.5H); ¹³C NMR (100 MHz, CDCl₃) δ 99.1, 99.0, 66.6, 64.4

(2), 62.4, 62.3, 57.1, 45.7, 35.7, 30.6, 25.9, 25.9, 25.8, 25.3, 25.1, 22.0,

22.0, 19.6, 19.5, 6.8 (2); MS (CI, CH₄) m/z (relative intensity) 320

(14), 247 (21), 192 (9), 147 (30), 85 (100); HRMS m/z calcd for

C₁₅H₂₈O₃S₂(M⁺) 320.1480, found 320.1483.

Dess−Martin periodinane¹⁹(0.8 g, 1.88 mmol) was added to a

solution of the diastereomeric alcohols (0.50 g, 1.56 mmol), pyridine

(0.76 mL, 9.39 mmol), and CH₂Cl₂(8 mL). The reaction stirred 8 h at

ambient temperature and was quenched by dilution with Et₂O (20

mL) and H₂O (10 mL). The organic layer was washed with saturated

aqueous NaHCO₃(2 × 10 mL) and brine (10 mL), dried over

Na₂SO₄, ﬁltered, and concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography (15 g SiO₂, 10% EtOAc in hexanes),

which provided 460 mg (92%) of a 1:1 mixture of tetrahydropyranyl

isomers of 18 as a white solid: mp 57−59 °C, R_f0.33 (30% EtOAc in

hexanes); [α]²_D⁴+40.1 (c 2.08, CHCl₃); IR (neat) 2938, 1711, 1424,

2-[2-(Tetrahydropyran-2-yloxy)ethyl]-2-[(1R)-1-methyl-2-

(trimethylsilanylmethyl)allyl]-[1,3]-dithiane (23). Trimethylsilyl-

methylmagnesium chloride (2.7 mL, 1 M in Et₂O) was added to a

solution of vinyl triﬂate 20 (150 mg, 0.334 mmol), Ni(acac)₂(2.0 mg,

6.7 mmol), and THF (2 mL). The reaction stirred 24 h, and additional

Grignard reagent was added (2 mL, 1 M in Et₂O). After 24 h the

reaction was quenched by the addition of saturated aqueous NH₄Cl.

The mixture was diluted with Et₂O, and the organic layer was washed

with saturated aqueous NH₄Cl (10 mL), H₂O (10 mL), and brine (15

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

and concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (12 g SiO₂, 10% EtOAc in hexanes), which provided

97 mg (56%) of 23 as a colorless oil: R_f0.49 (20% EtOAc in hexanes);

[α]²_D⁵+35.2 (c 0.815, CHCl₃); IR (neat) 3081, 2944, 1626, 1452, 1422,

1

1352, 1032, 934, 754 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 4.58 (m,

1H), 4.00 (m, 1H), 3.86 (m, 1H), 3.65 (m, 1H), 3.49 (m, 1H), 3.40

(q, J = 7.1 Hz, 1H), 2.86 (m, 1H), 2.84−2.65 (m, 3H), 2.42 (m, 1H),

2.28 (s, 3H), 2.22 (m, 1H), 2.02−1.62 (m, 5H), 1.52 (m, 3H), 1.27 (d,

J = 7.1 Hz, 1.5 Hz), 1.26 (d, J = 7.1 Hz, 1.5 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 209.2, 99.0, 98.9, 64.3, 62.4, 62.3, 52.8, 52.1, 34.9, 31.5, 30.7,

26.4, 26.1, 26.0, 25.4, 24.5, 19.6, 19.5, 13.3 (Some carbon signals are

coincident (overlapping) for these THP diastereomers and are not

readily assignable); MS (CI, NH₃) m/z (relative intensity) 318 (20),

275 (44), 247 (17), 189 (17), 147 (49), 85 (100); HRMS m/z calcd

for C₁₅H₂₆O₃S₂(M⁺) 318.1323, found 318.1327.

1

1248, 1123, 1030, 855 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 4.88 (s,

1H), 4.84 (s, 1H), 4.60 (m, 1H), 3.85−4.00 (m, 2H), 3.63 (m, 1H),

3.51 (m, 1H), 2.94 (m, 2H), 2.73 (m, 2H), 2.58 (m, 1H), 2.40 (m,

2H), 1.97 (m, 1H), 1.80−1.90 (m, 2H), 1.76 (d, 4.0 Hz, 2H), 1.71 (m,

1H), 1.53 (m, 4H), 1.29 (d, J = 7.0 Hz, 1.5H), 1.28 (d, J = 7.0 Hz,

1.5H), 0.04 (s, 9H); MS (CI, CH₄) m/z (relative intensity) 388 (1),

287 (3), 247 (52), 163 (13), 147 (79), 145(100), 85 (80), 73 (66);

HRMS m/z calcd for C₁₉H₃₆O₂S₂Si (M⁺) 388.1926, found 388.1910.

2-{2-[(1R)-2-(tert-Butyldimethylsilanyloxy)-1-methylethyl]-

[1,3]dithian-2-yl}-1-(tert-butyldiphenylsilanyloxy)ethane (14).

Alcohol 12 (2.79 g, 8.31 mmol), tert-butyldiphenylsilyl chloride (2.2

mL, 8.31 mmol), dimethylaminopyridine (DMAP) (∼50 mg), and

imidazole (2.1 g, 31 mmol) were stirred in CH₂Cl₂(15 mL) at

ambient temperature 24 h. The reaction mixture was diluted with

CH₂Cl₂(20 mL) and extracted with saturated aqueous NH₄Cl (3 × 20

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

and concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (160 g SiO₂, 3% Et₂O in hexanes), which provided

4.63 g (97%) of 14 as a thick oil: R_f0.62 (20% EtOAc in hexanes);

[α]²_D⁴+8.93 (c 2.89, CHCl₃); IR (neat) 3071, 3050, 2955, 2859, 1589,

1472, 1427, 1254, 1113, 1067, 835, 777, 739, 702 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 7.69 (m, 4H), 7.40 (m, 6H), 4.06 (dd, J = 9.9, 3.5 Hz,

1H), 3.87 (t, J = 7.5 Hz, 2H), 3.49 (dd, J = 9.8, 8.7 Hz, 1H), 2.65 (m,

4H), 2.31 (m, 1H), 2.24 (m, 1H), 2.00 (m, 1H), 1.86 (m, 1H), 1.80

(m, 1H), 1.08 (d, J = 6.7 Hz, 3H), 1.05 (s, 9H), 0.88 (s, 9H), 0.04 (s,

3H), 0.03 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 135.6, 133.9,

Triﬂuoromethanesulfonic acid (1R)-1-(1-{2-[2-(tetrahydro-

pyran-2-yloxy)ethyl]-[1,3]-dithian-2-yl}ethyl)vinyl ester (20).

Lithium diisopropylamine (LDA) (1.2 mL, 0.5 M in THF) was

added to a −78 °C solution of ketone 18 (150 mg) and THF (2.0

mL). The reaction stirred 50 min, and a solution of N-(5-chloro-2-

pyridyl)triﬂimide⁴²and THF (0.5 mL) was added via cannula. The

reaction warmed to −20 °C over 2 h and then was stirred for an

additional 2 h. The reaction was concentrated via rotary evaporator.

Puriﬁcation by ﬂash column chromatography (25 g SiO₂, using 10%

EtOAc in hexanes) provided 155 mg (73%) of triﬂate 20 as a 1:1

mixture of tetrahydropyranyl diastereomers as a colorless oil: R_f0.31

(20% EtOAc in hexanes); [α]²_D⁶+31.6 (c 0.995, CHCl₃); IR (neat)

1

2942, 2876, 1738, 1657, 1416, 1248, 1125, 1032, 934 cm⁻¹; H NMR

(400 MHz, CDCl₃) δ 5.33 (dt, J = 4.1, 1.3 Hz, 1H), 5.18 (d, J = 3.9

Hz, 1H), 4.60 (m, 1H), 4.02 (m, 1H), 3.88 (m, 1H), 3.67 (m, 1H),

3.51 (m, 1H), 3.16 (m, 1H), 2.82 (m, 4H), 2.24 (m, 2H), 1.94 (m,

2H), 1.80 (m, 1H), 1.72 (m, 1H), 1.50−1.59 (m, 4H), 1.41 (dd, J =

7.3, 1.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 156.7, 107.0, 99.3,

99.2, 64.4, 62.5, 62.4, 45.9, 34.8, 30.6, 26.4, 26.3,25.4, 24.3, 19.6, 15.0;

MS (CI, NH₃) m/z (relative intensity) 367 (10), 317 (82), 233 (81),

215 (77), 163 (95), 147 (74), 145 (100), 133 (68), 85 (97); HRMS

m/z calcd for C₁₁H₁₆F₃O₃S₃(M⁺− C₅H₉O₂) 349.0214, found

349.0224.

I

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

133.8, 129.6, 127.6, 64.8, 60.9, 55.0, 42.5, 38.0, 26.9, 25.9, 25.8, 25.6,

25.1, 19.1, 18.2, 12.4, −5.3; MS (CI, CH₄) m/z (relative intensity) 574

(3), 517 (62), 445 (42), 401 (60), 385 (64), 355 (40), 313 (47), 261

(63), 181 (80), 115 (100), 91 (77), 89 (96), 73 (84); HRMS m/z

calcd for C₃₁H₅₀O₂S₂Si₂(M⁺) 574.2791, found 574.2781.

z (relative intensity) 417 (2), 373 (40), 343 (5), 295 (13), 199 (100),

169 (22), 119 (36); HRMS m/z calcd for C₂₂H₂₉O₂S₂Si (M⁺− C₄H₉)

417.1378, found 417.1381.

Dimethylsulfoxide (0.39 mL, 5.51 mmol) was added dropwise to a

solution of oxalyl chloride (0.14 mL, 1.65 mmol) and CH₂Cl₂(6 mL)

at −78 °C. After 15 min, a solution of the secondary alcohols, as

prepared above, (654 mg, 1.38 mmol) and CH₂Cl₂(1 mL) was added.

The reaction stirred 30 min at −78 °C, and Et₃N (0.77 mL, 5.51

mmol) was added dropwise. The reaction was stirred 30 min at −78

°C, warmed to ambient temperature, and diluted with hexanes (30

mL) and H₂O (8 mL). The organic layer was washed with saturated

aqueous NH₄Cl (2 × 10 mL), H₂O (10 mL), and brine (15 mL);

dried over Na₂SO₄; ﬁltered; and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (40 g SiO₂, 8% EtOAc

in hexanes), which provided 512 mg (78%) of ketone 19 as a waxy

white solid: mp 70.5−76 °C; R_f0.27 (20% EtOAc in hexanes); [α]_D²³

+18.7 (c 2.07, CHCl₃); IR (neat) 3071, 2957, 2932, 2857, 1713, 1460,

(2R)-2-{2-[2-(tert-Butyldiphenylsilanyloxy)ethyl]-[1,3]-

dithian-2-yl}propionaldehyde (16). A mixture of the silyl ether 14,

acetic acid (8 mL), THF (5 mL), and H₂O (5 mL) was heated to 42

°C for 22 h. The reaction was cooled to ambient temperature and

diluted with Et₂O (20 mL). The organic layer was washed with NaOH

(2 × 10 mL), saturated aqueous NaHCO₃(2 × 10 mL), and brine (20

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

and concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (28 g SiO₂, 20% EtOAc in hexanes), which provided

589 mg (75%) of the primary alcohol, resulting from selective cleavage

of the TBS silyl ether, as a thick oil: R_f0.20 (20% EtOAc in hexanes);

IR (neat) 3407, 3071, 2930, 2888, 2857, 1589, 1472, 1427, 1103, 1030,

1

909, 824, 739, 704 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.69 (m,

1

1427, 1352, 1107, 1072, 824, 741, 704 cm⁻¹; H NMR (500 MHz,

4H), 7.41 (m, 6H), 3.89 (m, 2H), 3.86 (A of ABX, J_AB= 11.6 Hz, J_AX

=

CDCl₃) δ 7.69 (m, 4H), 7.40 (m, 6H), 3.94 (t, J = 7.4 Hz, 2H), 3.31

(q, J = 7.1 Hz, 1H), 2.85 (m, 1H), 2.66−2.77 (m, 2H), 2.62 (m, 1H),

2.40 (m, 1H), 2.25 (s, 3H), 2.19 (m, 1H), 1.89 (m, 1H), 1.82 (m, 1H),

1.20 (d, J = 7.1 Hz, 3H), 1.05 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ

209.1, 135.6, 133.8 (2), 129.6, 128.3, 127.6, 60.8, 52.3, 52.1, 37.6, 31.5,

26.9, 26.2, 26.0, 24.4, 19.1, 13.1; MS (CI, NH₄) m/z (relative

intensity) 415 (38), 343 (90), 309 (14), 199 (100), 146 (40), 135

(50), 106 (26); HRMS m/z calcd for C₂₂H₂₇O₂S₂Si (M⁺− C₄H₉)

415.1221, found 415.1222.

5.6 Hz, 1H), 3.66 (B of ABX, J_AB= 11.6 Hz, J_BX= 5.1 Hz, 1H), 2.77

(m, 2H), 2.65 (m, 2H), 2.32 (m, 1H), 2.21 (m, 1H), 2.13 (m, 1H),

1.68 (m, 3H), 1.06 (d, J = 7.0 Hz, 3H), 1.06 (s 9H); ¹³C NMR (100

MHz, CDCl₃) δ 135.6, 133.7, 129.6, 127.7, 65.2, 60.8, 60.4, 55.2, 41.8,

37.9, 26.9, 25.8, 24.9, 19.1, 12.8; MS (CI, CH₄) m/z (relative

intensity) 460 (1), 443 (1), 403 (36), 385 (23), 373 (35), 343 (39),

325 (58), 295 (51), 273 (30), 211 (69), 199 (100), 197 (63), 135

(78), 77 (51); HRMS m/z calcd for C₂₅H₃₆O₂S₂Si (M⁺) 460.1926,

found 460.1942.

Triﬂuoromethanesulfonic acid (1R)-1-(1-{2-[2-(tert-

butyldiphenylsilanyloxy)ethyl]-[1,3]-dithian-2-yl}ethyl)vinyl

ester (21). Sodium bis(trimethylsilyl)amide (NaHMDS) (0.16 mL,

1.0 M in THF) was added to a −78 °C solution of ketone 19 (25 mg)

and THF (0.5 mL). The reaction stirred 50 min, and DMPU (26 mL,

0.21 mmol) was added. After an additional 40 min at −78 °C, a

solution of N-phenyltriﬂuoromethanesulfonimide (94 mg, 0.264

mmol) and THF (0.5 mL) was added via cannula. The reaction was

stirred 1 h at −78 °C, warmed to ambient temperature, stirred 1 h, and

concentrated via rotary evaporator. Puriﬁcation by ﬂash column

chromatography (4 g SiO₂, using 5% EtOAc in hexanes) provided 16

mg (56%) of triﬂate 21 as a colorless oil: R_f0.53 (20% EtOAc in

hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.68 (m, 4H), 7.41 (m, 6H),

5.26 (d, J = 4.0 Hz, 1H), 5.05 (d, J = 4.0 Hz, 1H), 3.93 (dt, J = 7.5, 1.9

Hz, 2H), 3.07 (q, J = 7.0 Hz, 1H), 2.75 (m, 1H), 2.70−2.63 (m, 3H),

2.18 (m 3H), 1.85 (m, 2H), 1.33 (d, J = 7.3 Hz, 3H), 1.05 (s, 9H).

Triﬂate 21 was not characterized further but was directly used for

production of 24.

2-[2-(tert-Butyldiphenylsilanyloxy)ethyl]-2-[(1R)-1-methyl-2-

(trimethylsilanylmethyl)allyl]-[1,3]-dithiane (24). Trimethylsilyl-

methylmagnesium chloride (0.83 mL, 1 M in Et₂O) was added to a

solution of vinyl triﬂate 21 (45 mg, 0.083 mmol), Ni(acac)₂(∼2.0

mg), and THF (2 mL). The reaction stirred 16 h, and the reaction was

quenched by the addition of pH 7 aqueous buﬀer. The mixture was

diluted with Et₂O. The aqueous layer was extracted with Et₂O (2 × 10

mL). The combined organic layers were dried over Na₂SO₄, ﬁltered,

and concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (5 g Et₃N washed SiO₂, hexanes), which provided 24

mg (53%) of 24 as a colorless oil: R_f0.70 (20% EtOAc in hexanes); IR

(neat) 3092, 2945, 1425, 1030, 855 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 7.70 (m, 4H), 7.40 (m, 6H), 4.80 (s, 1H), 4.78 (s, 1H), 3.86

(m, 2H), 2.53−2.75 (m, 4H), 2.28−2.44 (m, 2H), 1.87 (m, 1H), 1.78

(m, 1H), 1.71 (m, 1H), 1.56 (s, 2H), 1.19 (d, J = 7.3 Hz, 3H), 1.05 (s,

9H), 0.00 (s, 9H); HRMS m/z calcd for C₃₀H₄₆OS₂Si₂(M⁺) 542.2529,

found 542.2531.

Dimethylsulfoxide (0.12 mL, 1.74 mmol) was added dropwise to a

solution of oxalyl chloride (0.45 mL, 0.52 mmol) and CH₂Cl₂(2 mL)

at −78 °C. After 15 min, a solution of the primary alcohol, prepared as

described above, (200 mg, 0.434 mmol) and CH₂Cl₂(1 mL) was

added. The reaction stirred 30 min at −78 °C, and Et₃N (0.24 mL,

1.74 mmol) was added dropwise. The reaction was stirred 30 min at

−78 °C, warmed to ambient temperature, and diluted with hexanes

(10 mL) and H₂O (2 mL). The organic layer was washed with

saturated aqueous NH₄Cl (2 × 5 mL), H₂O (2 mL), and brine (10

mL); dried over Na₂SO₄; ﬁltered; and concentrated in vacuo to

provide 191 mg (96%) of aldehyde 16 as a colorless oil, which was of

suﬃcient purity for further use. Spectroscopic characterization data for

16: R_f0.50 (20% EtOAc in hexanes); IR (neat) 3069, 2955, 2932,

1

2859, 1717, 1466, 1427, 1389, 1109, 1078, 739, 704, 617 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 9.89 (d, J = 2.7 Hz, 1H), 7.69 (m, 4H),

7.42 (m, 6H), 3.89 (m, 2H), 2.76 (m, 3H), 2.67 (m, 2H), 2.35 (m,

1H), 2.21 (m, 1H), 1.89 (m, 2H), 1.14 (d, J = 7.3 Hz, 3H), 1.05 (s,

9H); ¹³C NMR (100 MHz, CDCl₃) δ 202.0, 135.6, 133.5, 129.7,

127.7, 60.6, 51.8, 51.4, 38.1, 26.8, 26.0, 25.4, 24.5, 19.1, 9.8; MS (CI,

CH₄) m/z (relative intensity) 401 (85), 343 (24), 311 (17), 239 (45),

225 (40), 211 (57), 199 (100), 183 (71), 135 (80), 77 (50); HRMS

m/z calcd for C₂₁H₂₅O₂S₂Si (M⁺− C₄H₉) 401.1065, found 401.1071.

(3R)-3-{2-[2-(tert-Butyldiphenylsilanyloxy)ethyl]-[1,3]-

dithian-2-yl}butan-2-one (19). Aldehyde 16 (188 mg, 0.410 mmol)

was diluted in THF (2.8 mL) and was cooled to −78 °C.

Methylmagnesium bromide (0.57 mL, 3 M in Et₂O) was added

dropwise. After stirring 30 min, the reaction was warmed to ambient

temperature and saturated aqueous NH₄Cl was added. The mixture

was transferred to a separatory funnel using Et₂O (10 mL) and H₂O

(3 mL). The organic layer was washed with H₂O (2 × 3 mL) and

brine (3 mL), dried over MgSO₄, ﬁltered, and concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatography (8 g SiO₂,

20% EtOAc in hexanes), which provided 166 mg (85%) of a 1:1

mixture of alcohol diastereomers as a colorless oil: R_f0.43 (20%

EtOAc in hexanes); [α]²_D⁴−4.46 (c 1.12, CHCl₃); IR (neat) 3464,

3071, 2928, 2857, 1589, 1460, 1427, 1271, 1109, 1069, 999, 689 cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ 7.70 (m, 4H), 7.42 (m, 6H), 4.61 (qd,

(2S,3S)-4-(tert-Butyldiphenylsilanyloxy)-2,3-epoxy-1-iodo-

butane (27). Triphenylphosphine (2.62 g, 10.0 mmol) and imidazole

(1.36 g, 20.0 mmol) were dissolved in CH₂Cl₂(25 mL) at 0 °C. Iodine

(2.54 g, 10.0 mmol) was added, and the resulting mixture stirred 30

min. Alcohol 26 ([α]²_D⁴−13.0 (c 2.86, CHCl₃), 91% ee by Mosher

Ester analysis)³⁰(1.7 g, 5.0 mmol) was added, and the resulting

mixture stirred 1 h. Aqueous sodium sulﬁte (10%, 20 mL) was added,

and the organic layer was separated. The aqueous layer was extracted

J = 6.5, 1.2 Hz, 1H), 3.81 (m, 2H), 2.88 (m, 1H), 2.66 (m, 2H), 2.52

(m, 2H), 2.35 (m, 1H), 1.99 (m, 2H), 1.80 (m, 2H), 1.70 (q, J = 7 Hz,

1H), 1.08 (d, J = 6.4 Hz, 3H), 1.05 (s, 9H), 1.03 (d, J = 7.0 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃) δ 135.6, 133.7, 129.7, 127.7, 66.7, 61.0,

45.6, 38.3, 26.8, 25.8 (2), 25.7, 25.2, 21.7, 19.1, 6.7; MS (CI, NH₃) m/

J

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

with CH₂Cl₂, and the combined organic layers were dried over

MgSO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation by ﬂash

column chromatography (80g SiO₂), using a gradient elution (hexanes

to 5% EtOAc in hexanes) provided 2.1 g (91%) of 27 as a colorless oil:

R_f0.44 (5% EtOAc in hexanes); [α]²_D³+1.74 (c 1.95, CHCl₃); IR

J_BX= 5.6 Hz, 1H), 1.05 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ

135.6, 133.3, 129.8, 128.4, 127.7, 118.9, 63.6, 58.3, 54.0, 43.8, 26.8,

19.2; MS (CI, CH₄) m/z (relative intensity) 373 (14), 293 (39), 263

(78), 253 (47), 241 (77), 225 (84), 199 (100), 183 (80), 163 (86),

139 (88), 115 (47), 91 (78); HRMS m/z calcd for C₁₈H₁₈BrO₂Si (M⁺

− C₄H₉) 373.0259, found 373.0260. Anal. Calcd for C₂₂H₂₇BrO₂Si: C,

61.25; H, 6.31; Br 18.52. Found: C, 61.48; H, 6.31; Br 18.33.

(2R,3S)-5-Bromo-2,3-epoxy-hex-5-enal (9). Tetra-n-butylam-

monium ﬂuoride (0.83 mL, 1 M in THF) was added into a ﬂask

containing the silyl ether 30 (300 mg, 0.7 mmol), and the reaction

stirred 1 h. The mixture was placed directly on a column of silica gel,

and puriﬁcation by ﬂash chromatography using a solvent gradient

elution (40% Et₂O in hexanes to 90% Et₂O in hexanes) provided 125

mg (93%) of the expected alcohol as a clear yellow oil: R_f0.20 (20%

EtOAc in hexanes); [α]²_D³+14.0 (c 1.0, CHCl₃); IR (neat) 3404, 2998,

2920, 1632, 1415, 1150, 1010, 897 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 5.73 (d, J = 1.1 Hz, 1H), 5.55 (d, J = 1.1 Hz, 1H), 3.96 (A of

ABX, J_AB= 12.7 Hz, J_AX= 4.1 Hz, 1H), 3.69 (B of ABX, J_AB= 12.7 Hz,

1

(neat) 3071, 2959, 2930, 2859, 1472, 1427, 1113, 741, 702 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 7.68 (m, 4H), 7.42 (m, 6H), 3.81 (A of

ABX, J_AB= 12.0 Hz, J_AX= 4.3 Hz, 1H), 3.77 (B of ABX, J_AB= 12.0 Hz,

J_BX= 3.4 Hz, 1H), 3.25 (A of ABX, J_AB= 9.7 Hz, J_AX= 6.4 Hz, 1H),

3.05 (B of ABX, J_AB= 9.7 Hz, J_BX= 5.8 Hz, 1H), 3.18 (ddd, J = 6.4,

5.8, 2.0 Hz, 1H), 3.02 (ddd, J = 4.3, 3.4, 2.0 Hz, 1H), 1.06 (s, 9H); ¹³C

NMR (100 MHz, CDCl₃) δ 135.6, 135.5, 129.8, 127.8, 63.0, 62.0, 55.7,

26.7, 19.2, 4.1; MS (CI, CH₄) m/z (relative intensity) 395 (50), 365

(80), 309 (100), 267 (40), 199 (70), 181 (50), 128 (92), 91 (65);

HRMS m/z calcd for C₁₆H₁₆IO₂Si (M⁺− C₄H₉) 394.9964, found

394.9979. Anal. Calcd for C₂₀H₂₅IO₂Si: C, 53.10; H, 5.57. Found: C,

53.04; H, 5.58.

(4S,5S)-6-(tert-Butyldiphenylsilanyloxy)-4,5-epoxy-2-trime-

thylsilylhex-1-ene (29). 1,2-Dibromoethane (0.45 mL, 5.0 mmol)

was added to magnesium turnings (1.7 g, 72 mmol) in THF (20 mL).

1-Bromovinyltrimethylsilane⁴³(3.2 g, 18 mmol) in THF (5 mL) was

added dropwise while maintaining reﬂux. The reaction was heated to

reﬂux for 30 min and then cooled to ambient temperature. The

Grignard reagent was cannulated into a mixture of iodide 27 (4.10 g,

9.0 mmol), copper(I) iodide (171 mg, 0.9 mmol), HMPA (6.3 mL, 36

mmol), and THF (8.0 mL) at −25 °C. The reaction was stirred 1 h,

quenched with saturated aqueous NH₄Cl, and diluted with ether (150

mL). The organic layer was separated, and the aqueous layer was

extracted with ether. The combined organic layers were dried over

MgSO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation by ﬂash

column chromatography (80 g SiO₂), using a gradient elution

(hexanes to 5% EtOAc in hexanes) provided 3.46 g (91%) of 29 as

a clear colorless oil: R_f0.51 (5% EtOAc in hexanes); [α]²_D³−7.85 (c

1.35, CHCl₃); IR (neat) 3071, 3052, 2957, 2895, 2859, 1588, 1472,

J_BX= 2.5 Hz, 1H), 3.21 (m, 1H), 2.77 (A of ABX, J_AB= 15.3 Hz, J_AX

=

6.0 Hz, 1H), 2.65 (B of ABX, J_AB= 15.3 Hz, J_BX= 5.3 Hz, 1H), 1.90

(br s, 1H−OH); ¹³C NMR (100 MHz, CDCl₃) δ 128.1, 119.2, 61.2,

58.3, 53.7, 43.6; MS (CI, CH₄) m/z (relative intensity) 191 (1), 182

(3), 163 (50), 161 (35), 135 (10), 121 (10), 84 (100); HRMS m/z

calcd for C₆H₉BrO₂Na (M⁺+ Na) 214.9702, found 214.9734. Anal.

Calcd for C₉H₉O₂Br: C, 37.33; H, 4.70; Br, 41.39. Found: C, 37.55; H,

4.90; Br, 41.10.

Primary alcohol, prepared as described above, (1.5 g, 7.77 mmol)

was dissolved in CH₂Cl₂(28 mL). Sodium bicarbonate (6.5 g, 77.4

mmol) and Dess−Martin periodinane (6.55 g, 15.5 mmol) were

added. The reaction mixture was stirred 1.5 h and then placed directly

on a column of silica gel. Puriﬁcation by ﬂash column chromatography

using a solvent gradient elution (5% EtOAc in hexanes to 15% EtOAc

in hexanes) provided 1.1 g (75%) of aldehyde 9 as a light yellow oil: R_f

0.30 (30% EtOAc in hexanes); [α]²_D³+33.4 (c 1.0, CHCl₃); IR (neat)

1

1427, 1248, 1113, 839, 702 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

1

2999, 2917, 2836, 2733, 1730, 1632, 1415, 1146, 1018, 901 cm⁻¹; H

7.69−7.67 (m, 4H), 7.43−7.36 (m, 6H), 5.71 (ddd, J = 3.0, 1.5, 1.5

NMR (400 MHz, CDCl₃) δ 9.06 (d, J = 6.2 Hz, 1H), 5.77 (d, J = 0.8

Hz, 1H), 5.60 (d, J = 1.9 Hz, 1H), 3.49 (m, 1H), 3.28 (dd, J = 6.2, 1.6

Hz, 1H), 2.83 (A of ABX, J_AB= 15.3 Hz, J_AX= 6.1 Hz, 1H), 2.76 (B of

ABX, J_AB= 15.3 Hz, J_BX= 4.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃)

δ 197.2, 126.7, 120.1, 58.6, 54.7, 43.0; MS (CI, CH₄) m/z (relative

intensity) 161 (5), 151 (3), 135 (7), 121 (10), 88 (45), 86 (87), 84

(100), 83 (48); HRMS m/z calcd for C₆H₇BrO₂(M⁺) 189.9502,

found 189.9506.

Hz, 1H), 5.43 (d, J = 3.0 Hz, 1H) 3.80 (A of ABX, J_AB= 11.9 Hz, J_AX

=

4.4 Hz, 1H), 3.76 (B of ABX, J_AB= 11.9 Hz, J_BX= 3.6 Hz, 1H), 2.97−

2.90 (m, 2H), 2.44 (A of ABX, J_AB= 15.2 Hz, J_AX= 5.8 Hz, 1H), 2.27

(B of ABX, J_AB= 15.2 Hz, J_BX= 5.8 Hz, 1H), 1.05 (s, 9H), 0.10 (s,

9H); ¹³C NMR (100 MHz, CDCl₃) δ 147.8, 135.6, 133.3, 129.7,

127.7, 126.4, 63.9, 58.7, 55.6, 37.9, 26.7, 19.2, −1.8; MS (EI) m/z

(relative intensity) 367 (15), 293 (12), 271 (65), 241 (35), 217 (50),

195 (65), 163 (55), 135 (62), 91 (70), 73 (100); HRMS m/z calcd for

C₂₁H₂₇O₂Si₂(M⁺− C₄H₉) 367.1549, found 367.1557. Anal. Calcd for

C₂₅H₃₆O₂Si₂: C, 70.70; H, 8.54. Found: C, 70.54; H, 8.51.

(R)-4-(4′-Methoxybenzyloxy)-3-methyl-2-(trimethylsilyl-

methyl)-1-butene (31). Cerium(III) chloride heptahydrate (17.2 g,

46.2 mmol) was stirred under 2 mmHg at 150 °C for 7 h. The dried

cerium chloride was brought to ambient temperature, and anhydrous

THF (46 mL) was added. The suspension was allowed to stir at

ambient temperature for 12 h and then cooled to −78 °C. A solution

of trimethylsilylmethylmagnesium chloride (46.2 mL, 1 M in Et₂O)

was added. After stirring for 30 min, neat (S)-3-(4-methoxybenzy-

loxy)-2-methylpropionic acid methyl ester (2.75 g, 11.5 mmol) was

added dropwise over 3 min. The reaction was warmed to ambient

temperature and stirred for 4 h. The reaction was then cooled to 0 °C,

diluted with ether, and quenched by the addition of saturated aqueous

NH₄Cl. The organic layer was separated, and the aqueous layer was

extracted with ether. The combined organic layers were washed with

brine and dried over anhydrous MgSO₄, ﬁltered and concentrated in

vacuo. The residue was diluted with dichloromethane (100 mL) and

silica gel (15 g). The suspension was stirred 3 d and ﬁltered by rinsing

the silica sequentially with ether, dichloromethane, ethyl acetate. The

organic ﬁltrate was concentrated, and the residue was puriﬁed by ﬂash

column chromatography on neutralized silica using hexanes to provide

1.68 g (50%) of allyl silane 31 as a colorless oil: R_f0.44 (5% EtOAc in

hexanes); [α]]²_D³+8.15 (c 1, CHCl₃); IR (neat) 3077, 2957, 2857,

(4S,5S)-2-Bromo-6-(tert-butyldiphenylsilanyloxy)-4,5-epoxy-

hex-1-ene (30). A solution of bromine (0.49 mL, 9.5 mmol) and

CH₂Cl₂(10 mL) was added to a solution of alkene 29 (3.1 g, 7.3

mmol) and CH₂Cl₂(10 mL) at −78 °C. After 10 min, a solution of

sodium sulﬁte (0.55 g, 4.4 mmol) and methanol (10 mL) was added.

The resulting mixture stirred 10 min, and aqueous sodium sulﬁte

(10%, 10 mL) was added. The organic layer was separated, and the

aqueous layer was extracted with hexanes. The combined organic

layers were dried over MgSO₄, ﬁltered, and concentrated in vacuo. The

residue was dissolved in methanol (20 mL) and cooled to 0 °C.

Sodium methoxide (11.7 mL, 1.0 M in methanol) was added. After 2

h, water (30 mL) and hexanes (30 mL) were added. The organic layer

was separated, and the aqueous layer was extracted with hexanes. The

combined organic layers were dried over MgSO₄, ﬁltered, and

concentrated in vacuo. Puriﬁcation by ﬂash column chromatography

(65 g SiO₂), using a gradient elution (hexanes to 5% EtOAc in

hexanes) provided 2.65 g (85%) of 30 as a clear colorless oil: R_f0.49

(5% EtOAc in hexanes); [α]²_D³−3.03 (c 1.06, CHCl₃); IR (neat) 3071,

1

3050, 2930, 2855, 1632, 1472, 1427, 1111, 909 cm⁻¹; H NMR (400

1

MHz, CDCl₃) δ 7.70−7.66 (m, 4H), 7.44−7.37 (m, 6H), 5.72 (s, 1H),

5.53 (d, J = 1.9 Hz, 1H), 3.84 (A of ABX, J_AB= 11.8 Hz, J_AX= 4.5 Hz,

1H), 3.78 (B of ABX, J_AB= 11.8 Hz, J_BX= 3.4 Hz, 1H), 3.08 (ddd, J =

6.0, 6.0, 2.1 Hz, 1H), 3.01 (ddd, J = 4.5, 3.6, 2.1 Hz, 1H), 2.75 (A of

ABX, J_AB= 15.2 Hz, J_AX= 6.0 Hz, 1H), 2.58 (B of ABX, J_AB= 15.2 Hz,

1615, 1514, 1248, 1036, 853 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

7.26 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.61 (s, 1H), 4.59

(s, 1H), 4.46 (A of AB, J_AB= 11.6 Hz, 1H), 4.43 (B of AB, J_AB= 11.6

Hz, 1H), 3.81 (s, 3H), 3.49 (A of ABX, J_AB= 9.1 Hz, J_AX= 8.3 Hz,

1H), 3.20 (B of ABX, J_AB= 9.1 Hz, J_BX= 5.1 Hz, 1H), 2.24 (m, 1H),

K

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1.56 (A of AB, J_AB= 13.8 Hz, 1H), 1.51 (B of AB, J_AB= 13.8 Hz, 1H),

1.08 (d J = 6.7 Hz, 3H), 0.01 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ

159.1, 149.8, 130.8, 129.1, 113.7, 106.5, 76.7, 74.8, 72.6, 55.2, 41.0,

26.6, 17.1, −1.3; HRMS m/z calcd for C₁₇H₂₈O₂Si (M⁺− H)

291.1780, found 291.1778.

= 5.6 Hz, 2H), 2.21 (B of ABX, J_AB= 14.2 Hz, J_BX= 3.5 Hz, 1H), 2.59

(s, 1H−OH), 1.06 (d, J = 7.0 Hz, 3H), 0.11 (s, 9H).

(2R,5S,6S,7S)-9-Bromo-6,7-epoxy-1-(4-methoxybenzyloxy)-

2-methyl-3-methylene-dec-9-en-5-ol (35). Allylsilane 31 (2.02 g,

6.91 mmol) and aldehyde 9 (1.1 g, 5.76 mmol) were dissolved in

CH₂Cl₂(58 mL) and cooled to −78 °C. Boron triﬂuoride diethyl

etherate (0.85 mL, 6.91 mmol) was added, and the reaction was stirred

2 h at −78 °C. Saturated aqueous Na₂CO₃(50 mL) was then added,

and the mixture was allowed to warm to ambient temperature. The

organic layer was separated, and the aqueous layer was extracted with

CH₂Cl₂(2 × 50 mL). The combined organic layers were dried over

Na₂SO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation by ﬂash

column chromatography (200 g silica gel), using a solvent gradient

elution (5% EtOAc in hexanes to 30% EtOAc in hexanes) provided 1.2

g (51%) of alcohol 35 and 310 mg (13%) of alcohol 36 as colorless

oils. Data for 35: R_f0.25 (30% EtOAc in hexanes); [α]²_D³−6.29 (c 1.34,

CHCl₃); IR (neat) 3449, 2961, 2932, 2907, 2859, 1632, 1613, 1512,

1246, 1034, 895, 820 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.23 (d, J

= 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.74 (d, J = 1.3 Hz, 1H), 5.54

(d, J = 1.6 Hz, 1H), 4.98 (s, 2H), 4.43 (s, 2H), 3.81 (s, 3H), 3.80 (m,

1H), 3.41 (A of ABX, J_AB= 9.1 Hz, J_AX= 7.6 Hz, 1H), 3.35 (B of ABX,

J_AB= 9.1 Hz, J_BX= 6.1 Hz, 1H), 3.22 (td, J = 5.6, 2.1 Hz, 1H), 2.87

(dd, J = 4.3, 2.1 Hz, 1H), 2.72 (A of ABX, J_AB= 15.6 Hz, J_AX= 6.0 Hz,

1H), 2.66 (B of ABX, J_AB= 15.6 Hz, J_BX= 5.0 Hz, 1H), 2.58 (br s,

1H−OH), 2.52 (q, J = 6.9 Hz, 1H), 2.45 (A of ABX, J_AB= 14.3 Hz, J_AX

= 9.4 Hz, 1H), 2.24 (B of ABX, J_AB= 14.3 Hz, J_BX= 3.5 Hz, 1H), 1.06

(d, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 159.3, 148.3,

130.3, 129.3, 128.4, 118.9, 113.8, 112.7, 74.6, 72.8, 68.7, 60.5, 55.3,

53.9, 43.8, 40.1, 39.7, 17.2; MS (CI, CH₄) m/z (relative intensity) 410

(0.3), 203 (10), 137 (41), 122 (46), 121 (100), 82 (21); HRMS m/z

calcd for C₂₀H₂₇BrO₄(M⁺) 410.1093, found 410.1087. Anal. Calcd for

C₂₀H₂₇BrO₄: C, 58.40; H, 6.62; Br, 19.43. Found: C, 58.12; H, 6.59;

Br, 19.41

(2R,3S)-2,3-Epoxy-5-trimethylsilanylhexa-5-enal (32). Tetra-

n-butylammonium ﬂuoride (TBAF) (2.6 mL, 1.0 M in THF) was

added to a solution of silyl ether 29 (1.00 g, 2.35 mmol) in THF (20

mL) at 0 °C. The reaction stirred 6 h at room and was diluted with

Et₂O (10 mL) and H₂O (10 mL). The organic layer was washed with

H₂O (2 × 20 mL), saturated aqueous NH₄Cl (2 × 15 mL), and brine

(20 mL). The combined aqueous layers were extracted with Et₂O (2 ×

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

and concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (28 g SiO₂, 20% EtOAc in hexanes), which provided

0.440 g (quant.) of the desired primary alcohol as a colorless oil: R_f

0.13 (40% EtOAc in hexanes); [α]²_D⁴−29.3 (c 4.88, CHCl₃); IR (neat)

3424, 3052, 2955, 2899, 1412, 1248, 1080, 1017, 930, 841, 758, 692

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.71 (br s, 1H), 5.45 (br s, 1H),

3.93 (A of ABX, J_AB= 12.6 Hz, J_AX= 4.0 Hz, 1H), 3.65 (B of ABX, J_AB

= 12.6 Hz, J_BX= 2.4 Hz, 1H), 3.05 (td, J = 5.8, 2.3 Hz, 1H), (2.95 (m,

1H), 2.45 (A of ABX, J_AB= 15.3 Hz, J_AX= 5.9 Hz, 1H), 2.34 (B of

ABX, J_AB= 15.3 Hz, J_BX= 5.6 Hz, 1H), 1.63 (br s, 1H−OH), 0.11 (s,

9H); MS (CI, CH₄) m/z (relative intensity) 171 (4), 155 (53), 141

(36), 127 (67), 117 (42), 101 (43), 75 (100), 73 (87); HRMS m/z

calcd for C₈H₁₅O₂Si (M⁺− CH₃) 171.0841, found 171.0839.

Sulfur trioxide pyridine complex (1.12 g, 7.05 mmol) was added

into a solution of the alcohol, as prepared above, in DMSO (2 mL,

28.2 mmol), Et₃N (2 mL, 14.1 mmol), and CH₂Cl₂(15 mL). After the

reaction mixture was stirred for 17 h at ambient temperature, pentane

(50 mL) and water (10 mL) were added. The organic layer was

washed with NH₄Cl (3 × 15 mL) and H₂O (2 × 15 mL). The

combined organic layers were dried over Na₂SO₄, ﬁltered, and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (16 g SiO₂, 20% Et₂O in hexanes), which provided

300 mg (69%) of aldehyde 32 as a colorless oil: R_f0.57 (40% EtOAc in

hexanes); [α]²_D³+91.3 (c 3.14, CHCl₃); IR (neat) 3054, 2957, 2899,

2822, 2731, 1728, 1429, 1250, 934, 839, 727 692 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 9.04 (d, J = 6.2 Hz, 1H), 5.73 (d, J = 1.9 Hz, 1H),

5.50 (d, J = 1.9 Hz, 1H), 3.32 (td, J = 5.5, 1.9 Hz, 1H), 3.16 (dd, J =

6.3, 2.0 Hz, 1H), 2.47 (d, J = 5.6 Hz, 2H), 0.12 (s, 9H); ¹³C NMR

(100 MHz, CDCl₃) δ 198.1, 146.8, 127.5, 59.1, 56.1, 37.3, −1.8; MS

(CI, CH₄) m/z (relative intensity) 169 (5), 141 (17), 127 (17), 101

(16), 95 (13), 75 (62), 73 (100); HRMS m/z calcd for C₈H₁₃O₂Si

(M⁺− CH₃) 169.0685, found 169.0687. Anal. Calcd for C₉H₁₆O₂Si:

C, 58.65; H, 8.75. Found: C, 58.36; H, 8.58.

Data for the minor product, 7(R)-diastereomer 36: R_f0.13 (30%

EtOAc in hexanes); [α]²_D⁴+4.09 (c 1.20, CHCl₃); IR (neat) 3441,

1

3075, 2938, 2870, 1613, 1512, 1460, 1240, 1030, 897 cm⁻¹; H NMR

(400 MHz, CDCl₃) δ 7.21 (d, J = 6.3 Hz, 1H), 6.85 (d, J = 6.3 Hz,

1H), 5.71 (d, J = 1.2 Hz, 1H), 5.51 (d, J = 1.2 Hz, 1H), 4.97 (s, 1H),

4.96 (s, 1H), 4.41 (s, 2H), 3.78 (s, 3H), 3.75 (ddd, J = 4.5, 4.5, 3.3 Hz,

1H), 3.41 (dd, J = 6.9, 6.3 Hz, 1H), 3.33 (dd, J = 6.9, 4.5 Hz, 1H), 3.16

(ddd, J = 4.5, 4.5, 1.5 Hz, 1H), 2.89 (dd, J = 3.3, 1.5 Hz, 1H), 2.73 (dd,

J = 14.4, 4.5 Hz, 1H), 2.60 (dd, J = 14.4, 3.9 Hz, 1H), 2.45 (m, 1H),

2.32 (d, J = 4.8 Hz, 2H), 1.01 (d, J = 5.1 Hz, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 159.2, 147.7, 130.0, 129.3, 128.3, 119.0, 113.8, 112.9,

74.2, 72.7, 68.6, 61.0, 55.2, 54.1, 43.7, 40.3, 39.0, 17.4; MS (CI, CH₄)

m/z (relative intensity) 410 (3), 331 (4), 273 (9), 203 (20), 137 (55);

HRMS m/z calcd for C₂₀H₂₇BrO₄(M⁺) 410.1093, found 410.1095.

Anal. Calcd for C₂₀H₂₇BrO₄: C, 58.40; H, 6.62; Br, 19.43. Found: C,

57.81; H, 6.63; Br, 19.35.

(2R,5S,6S,7S)-9-Bromo-5-(tert-butyldimethylsilanoxy)-6,7-

epoxy-1-(4-methoxybenzyloxy)-2-methyl-3-methylene-dec-9-

ene (39). tert-Butyldimethylsilyl triﬂuoromethanesulfonate (1.19 mL,

5.2 mmol) was added to a solution of alcohol 35 (1.07 g, 2.6 mmol),

and N,N-diisopropylethylamine (2.27 mL, 13.0 mmol) in CH₂Cl₂

(11.6 mL). The reaction was stirred 2.5 h and diluted with CH₂Cl₂(30

mL), and saturated aqueous NH₄Cl (20 mL) was added. The aqueous

layer was extracted with CH₂Cl₂(3 × 50 mL). The combined organic

layers were dried over MgSO₄, ﬁltered, and concentrated in vacuo.

Puriﬁcation by ﬂash column chromatography (150 g SiO₂using 5%

EtOAc in hexanes) gave 0.98 g (74%) of compound 39 as a clear

colorless oil: R_f0.47 (20% EtOAc in hexanes); [α]²_D³−2.2 (c 1.5,

CHCl₃); IR (neat) 3079, 2955, 2930, 2857, 1632, 1613, 1512, 1248,

1103, 835, 777 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, J = 8.6

Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.72 (d, J = 1.6 Hz, 1H), 5.52 (d, J

= 1.6 Hz, 1H), 4.91 (s, 1H), 4.90 (s, 1H), 4.44 (A of AB, J_AB= 11.8

Hz, 1H), 4.42 (B of AB, J_AB= 11.8 Hz, 1H), 3.82 (m, 1H), 3.80 (s,

3H), 3.46 (A of ABX, J_AB= 9.1 Hz, J_AX= 7.9 Hz, 1H), 3.26 (B of ABX,

J_AB= 9.1 Hz, J_BX= 5.6 Hz, 1H), 3.15 (m, 1H), 2.81 (dd, J = 4.0, 2.0

Hz, 1H), 2.67 (A of ABX, J_AB= 15.4 Hz, J_AX= 6.6 Hz, 1H), 2.61 (B of

ABX, J_AB= 15.4 Hz, J_BX= 4.2 Hz, 1H), 2.45 (q, J = 6.7 Hz, 1H), 2.36

(2R,5S,6S,7S)-6,7-Epoxy-1-(4-methoxybenzyloxy)-2-methyl-

3-methylene-9-trimethylsilanyldec-9-en-5-ol (33). Freshly dis-

tilled boron triﬂuoride diethyl etherate (9.6 mL, 0.076 mmol) was

added to a −78 °C solution of allylsilane 31, aldehyde 32, and CH₂Cl₂.

After the reaction stirred 45 min, saturated aqueous NaHCO₃was

added. The mixture was transferred to separatory funnel using Et₂O

(10 mL). The organic layer was washed with NaHCO₃(5 mL), H₂O

(5 mL), and brine (5 mL). The combined organic layers were dried

over MgSO₄, ﬁltered, and concentrated in vacuo. The proton NMR

spectra of the crude material indicated a >2:1 mixture of C₇

diastereomeric alcohols. Puriﬁcation of the crude residue was carried

out by ﬂash column chromatography (4 g SiO₂, 10% EtOAc in

hexanes), which provided 10.4 mg (34%) of alcohol 33 as a colorless

oil. A second compound (R_f0.18 (20% EtOAc in hexanes)) was also

isolated. This minor 7R-diastereomer was not puriﬁed for further

characterization. Partial characterization data for the alcohol

1

diastereomer 33: R_f0.19 (20% EtOAc in hexanes); H NMR (400

MHz, CDCl₃) δ 7.23 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H),

5.74 (dt, J = 2.7, 1.5 Hz, 1H), 5.45 (dt, J = 2.7, 1.1 Hz, 1H), 4.98 (s,

2H), 4.43 (s, 2H), 3.80 (s, 3H), 3.74 (m, 1H), 3.42 (A of ABX, J_AB

=

9.1 Hz, J_AX= 7.3 Hz, 1H), 3.34 (B of ABX, J_AB= 9.1 Hz, J_BX= 6.4 Hz,

1H), 3.08 (td, J = 5.7, 2.2 Hz, 1H), 2.77 (dd, J = 4.6, 2.1 Hz, 1H), 2.51

(m, 1H), 2.42 (A of ABX, J_AB= 14.2 Hz, J_AX= 9.4 Hz, 1H), 2.37 (d, J

L

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(A of ABX, J_AB= 14.2 Hz, J_AX= 6.6 Hz, 1H), 2.29 (B of ABX, J_AB

=

over NaSO₄, ﬁltered, and concentrated in vacuo, which provided 188

mg (99%) of a mixture of β-hydroxy esters as a clear colorless oil: R_f

0.11 (20% EtOAc in hexanes).

14.2 Hz, J_BX= 5.5 Hz, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.87 (s, 9H), 0.04

(s, 3H), 0.02 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 159.1, 147.5,

130.7, 129.1, 128.7, 118.8, 113.8, 112.3, 74.5, 72.7, 69.5, 60.5, 55.3,

53.7, 43.9, 41.3, 39.4, 25.8, 18.1, 16.9, −4.4, −4.8; MS (CI, CH₄) m/z

(relative intensity) 467 (1), 343 (2), 228 (7), 197 (21), 135 (18), 122

(61), 121 (100); HRMS m/z calcd for C₂₆H₄₂BrO₄Si (M⁺+ 1)

525.2054, found 525.2070. Anal. Calcd for C₂₆H₄₁BrO₄Si: C, 59.42; H,

7.86; Br, 15.20. Found: C, 59.67; H, 7.90; Br, 15.26.

The mixture of alcohols (188 mg, 0.394 mmol), prepared as

described above, was dissolved in CH₂Cl₂(12.6 mL). Sodium

bicarbonate (440 mg, 5.25 mmol) and Dess−Martin periodinane

(334 mg, 0.787 mmol) were added. After stirring at room temperature

for 1 h, the mixture was placed directly on a column of silica gel (70 g).

Puriﬁcation by ﬂash column chromatography using 15% EtOAc in

hexanes provided 121 mg (65%, 2 steps) of the β-ketoester 42 as a

light yellow oil: R_f0.34 (15% EtOAc in hexanes); [α]²_D³−19.5 (c 1.42,

CHCl₃); IR (neat) 2857, 1750, 1715, 1634, 1468, 1254, 1119, 837,

(2R,5S,6S,7S)-9-Bromo-5-(tert-butyldimethylsilanoxy)-6,7-

epoxy-2-methyl-3-methylene-dec-9-en-1-ol (40). 2,3-Dichloro-

5,6-dicyano-1,4-benzoquinone (807 mg, 3.56 mmol) was added to a

solution of the PMB ether 39 (890 mg, 1.69 mmol), aqueous pH 7

buﬀer (5.9 mL), tert-butyl alcohol (5.9 mL), and CH₂Cl₂(29.6 mL).

After the red reaction stirred for 1.5 h at room temperature, it was

diluted with CH₂Cl₂(40 mL), and saturated aqueous NaHCO₃(20

mL) was added. The aqueous layer was extracted with CH₂Cl₂(3 × 50

mL). The combined organic layers were washed with saturated

NaHCO₃(25 mL), H₂O (25 mL), and brine (30 mL), dried over

Na₂SO₄, and then ﬁltered and concentrated in vacuo. Puriﬁcation of

the residual oil by ﬂash column chromatography (75 g SiO₂), using a

solvent gradient elution (10% EtOAc in hexanes to 50% EtOAc in

hexanes) gave 622 mg (95%) of primary alcohol 40 as a clear colorless

oil: R_f0.23 (20% EtOAc in hexanes); [α]²_D³+18.2 (c 1.0, CHCl₃); IR

(neat) 3451, 2955, 2930, 2857, 1632, 1472, 1254, 1107, 837, 777

1

777 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.71 (s, 1H), 5.52 (d, J =

1.7 Hz, 1H), 5.13 (s, 1H), 5.03 (s, 1H), 3.77 (m, 1H), 3.71 (s, 3H),

3.52 (A of AB, J_AB= 15.8 Hz, 1H), 3.50 (B of AB, J_AB=15.8 Hz, 1H),

3.37 (q, J = 6.9 Hz, 1H), 3.13 (m, 1H), 2.80 (dd, J = 4.8, 1.9 Hz, 1H),

2.68 (A of ABX, J_AB= 15.4 Hz, J_AX= 6.5 Hz, 1H), 2.62 (B of ABX, J_AB

= 15.4 Hz, J_BX= 4.0 Hz, 1H), 2.34 (d, J = 5.7 Hz, 2H), 1.25 (d, J = 6.9

Hz, 3H), 0.86 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 203.0, 167.7, 143.1, 128.4, 119.0, 116.2, 69.7, 60.2,

54.3, 53.3, 52.3, 46.3, 43.8, 41.1, 25.7, 18.1, 15.1, −4.4, −4.8; MS (CI,

CH₄) m/z (relative intensity) 419 (6), 417 (5), 305 (8), 269 (5), 225

(13), 101 (26), 75 (100); HRMS m/z calcd for C₂₁H₃₆BrO₅Si (M⁺+

1) 475.1533, found 475.1551. Anal. Calcd for C₂₁H₃₅O₅BrSi: C, 53.05;

H, 7.42; Br, 16.80. Found: C, 53.33; H, 7.45; Br, 16.89.

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.72 (d, J = 1.8 Hz, 1H), 5.53

(2S,3R)-2,3-Epoxy-1-[(4-methoxyphenyl)diphenylmethoxy]-

butane (44). Titanium(IV) isopropoxide (1.2 mL, 4.2 mmol) was

added to a solution of crushed, ﬂame-dried 4 Å molecular sieves (3 g),

(+)-diethyl tartrate (0.86 mL, 5.0 mmol), and CH₂Cl₂(200 mL) at

−20 °C. The reaction was stirred 10 min, and a solution of cis-but-2-

en-1-ol (6.0 g, 83 mmol) and CH₂Cl₂(5 mL) was added dropwise.

After stirring the reaction for 30 min at −20 °C, tert-butyl

hydroperoxide (33 mL, 3.77 M in toluene) was added dropwise.

The reaction was stirred for 1 h, sealed with paraﬁlm, and placed in a

−20 °C freezer. After 25 h, the reaction was placed in a −20 °C bath

under argon, and trimethylphosphite (4.9 mL, 42 mmol) was added to

the reaction over 1.6 h. The reaction stirred 15 min. Triethylamine (23

mL, 170 mmol), dimethylaminopyridine (DMAP) (0.5 g), and 4-

methoxytrityl chloride (MMTrCl) (28 g, 92 mmol) were added. The

reaction was warmed to 0 °C, stirred 6 h, and placed in a 0 °C freezer

overnight. Thin layer chromatography indicated the reaction was not

complete, and additional MMTrCl (2 g, 6.6 mmol) was then added.

After stirring 3 h at 0 °C, MeOH (10 mL) was added. The reaction

mixture was then ﬁltered through a silica (40 g) and Celite (25 g) pad

using CH₂Cl₂. The ﬁltrate was concentrated in vacuo. Hexanes (400

mL) were added to the resulting thick paste, which was transferred to a

fritted funnel. The ﬁltrate was again concentrated in vacuo. Puriﬁcation

by ﬂash column chromatography (800 g SiO₂), using a solvent

gradient elution (hexanes to 30% EtOAc in hexanes) provided 24 g

(80%) of 44 as a thick oil: R_f0.48 (40% EtOAc in hexanes); [α]_D²³

+16.0 (c 3.95, CHCl₃); IR (neat) 3032, 2928, 1607, 1501, 1447, 1250,

1179, 1034 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.47 (m, 4H), 7.21−

7.36 (m, 8H), 6.83 (m, 2H), 3.80 (s, 3H), 3.30 (A of ABX, J_AB= 9.94

Hz, J_AX= 5.37 Hz, 1H), 3.18 (m, 1H), 3.12 (B of ABX, J_AB= 9.8 Hz,

J_BX= 4.8 Hz, 1H), 3.09 (m, 1H), 1.14 (d, J = 5.6 Hz, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ 158.5, 144.4 144.2, 135.5, 130.3, 128.3, 127.8,

126.9, 113.1, 86.5, 61.9, 55.3, 55.2, 52.1, 13.4; MS (EI) m/z (relative

intensity) 360 (20), 273 (100), 213 (25), 165 (20), 135 (18), 105

(37); HRMS m/z calcd for C₂₄H₂₄O₃(M⁺) 360.1725, found 360.1734.

(2R,3R)-1-[(4-Methoxyphenyl)diphenylmethoxy]-3,4-dime-

thylpent-4-en-2-ol (45). 1,2-Dibromoethane (3 drops) was added to

a solution of 2-bromopropene (10 drops), ﬂame-dried Mg turnings

(3.1 g), and THF (30 mL). 2-Bromopropene (5.7 mL, 64.6 mmol)

and THF (60 mL) were then simultaneously added via separate

syringes maintaining a steady reﬂux. The reaction was stirred 1.5 h and

cannulated into a −78 °C slurry of CuBr·DMS (6.6 g, 32.3 mmol) and

THF (20 mL). The deep orange reaction stirred 15 min, and a

solution of epoxide 44 (7.76 g, 21.5 mmol) and THF (80 mL) was

added. After 15 min, BF₃·OEt₂(2.5 mL, 14.4 mmol) was added

dropwise. The reaction was warmed slowly to −20 °C over 2 h, at

(d, J = 1.9 Hz, 1H), 5.05 (d, J = 1.1 Hz, 1H), 4.99 (s, 1H), 3.73 (dt, J =

6.2, 5.2 Hz, 1H), 3.56 (m 2H), 3.13 (m, 1H), 2.84 (dd, J = 5.2, 2.1 Hz,

1H), 2.68 (A of ABX, J_AB= 15.4 Hz, J_AX= 6.4 Hz, 1H), 2.64 (B of

ABX, J_AB= 15.4 Hz, J_BX= 4.5 Hz, 1H), 2.40 (A of ABX, J_AB= 14.1 Hz,

J_AX= 6.3 Hz, 1H), 2.37 (m, 1H), 2.34 (B of ABX, J_AB= 14.1 Hz, J_BX

=

6.1 Hz, 1H), 1.84 (s 1H−OH), 1.06 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H),

0.07 (s, 3H), 0.05 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 146.8,

128.4, 119.0, 113.4, 70.3, 66.2, 60.6, 54.6, 43.8, 41.9, 41.8, 25.8, 18.1,

16.5, −4.4, −4.7; MS (CI, CH₄) m/z (relative intensity) 389 (1), 330

(4), 305 (40), 249 (30), 225 (60), 197 (40), 157 (50), 115 (77), 75

(100); HRMS m/z calcd for C₁₈H₃₃BrO₃SiNa (M⁺+ Na) 427.1281,

found 427.1288.

(2R,5S,6S,7S)-9-Bromo-5-(tert-butyldimethylsilanoxy)-6,7-

epoxy-2-methyl-3-methylene-dec-9-enal (41). Alcohol 40 (310

mg, 0.76 mmol) was dissolved in CH₂Cl₂(38 mL). Sodium

bicarbonate (642 mg, 7.6 mmol) and Dess−Martin periodinane

(648 mg, 1.53 mmol) were then added. The reaction mixture was

stirred for 1.5 h, and the mixture was placed directly on a column of

silica gel (100 g). Puriﬁcation by ﬂash column chromatography using

15% EtOAc in hexanes provided 277 mg (90%) of aldehyde 41 as a

colorless oil: R_f0.48 (20% EtOAc in hexanes); [α]²_D³+24.5 (c 1.0,

CHCl₃); IR (neat) 2930, 2857, 1723, 1632, 1462, 1254, 1096, 837,

1

777 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 9.48 (d, J = 1.9 Hz, 1H),

5.72 (d, J = 1.0 Hz, 1H), 5.53 (d, J = 1.6 Hz, 1H), 5.18 (s, 1H), 5.02

(s, 1H), 3.77 (q, J = 5.4 Hz, 1H), 3.13 (m, 2H), 2.81 (dd, J = 4.6, 2.2

Hz, 1H), 2.69 (A of ABX, J_AB= 15.5 Hz, J_AX= 6.9 Hz, 1H), 2.63 (B of

ABX, J_AB= 15.5 Hz, J_BX= 4.3 Hz, 1H), 2.38 (m, 2H), 1.24 (d, J = 7.0

Hz, 3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 201.2, 141.7, 128.3, 119.0, 116.4, 69.8, 60.1, 54.3,

52.6, 43.8, 41.6, 25.8, 18.1, 12.8, −4.4, −4.9; MS (CI, CH₄) m/z

(relative intensity) 401 (9), 347 (12), 305 (40), 249 (35), 225 (58),

197 (53), 155 (63), 105 (100), 75 (95) HRMS m/z calcd for

C₁₈H₃₁BrO₃Si (M⁺) 402.1226, found 402.1230.

(4R,7S,8S,9S)-11-Bromo-7-(tert-butyldimethylsilanoxy)-8,9-

epoxy-4-methyl-5-methylene-3-oxo-dodec-11-enoic acid

methyl ester (42). n-Butyllithium (0.54 mL, 2.5 M in hexanes)

was added to diisopropylamine (0.20 mL, 1.43 mmol) in THF (2.6

mL) at −78 °C. After 10 min, distilled methyl acetate (0.5 M in THF,

2.4 mL, 1.2 mmol) was added. The resulting reaction mixture was

stirred for 15 min, and aldehyde 41 (160 mg, 0.397 mmol) was then

added dropwise. After an additional 20 min at −78 °C, the reaction

was quenched by the addition of saturated aqueous NH₄Cl and was

diluted with ether. The organic layer was separated, and the aqueous

layer was extracted with ether. The combined organic layers were dried

M

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

which time it turned black. Saturated aqueous NH₄Cl (20 mL) was

added, and the mixture was transferred to a separatory funnel with

Et₂O. The organic layer was washed with H₂O (2 × 100 mL) and

brine (150 mL). The aqueous layers were extracted with Et₂O (50

mL). The combined organic layers were dried over MgSO_4,ﬁltered,

and concentrated in vacuo. Puriﬁcation by ﬂash column chromatog-

raphy (400 g SiO₂), using a solvent gradient elution (hexanes to 10%

Et₂O in hexanes) provided 7.15 g (84%) of alcohol 45 as a thick clear

colorless oil, which crystallized upon storage in a −20 °C freezer.

4.8 Hz, 2H), 2.42 (dq, J = 6.9, 6.7 Hz, 1H), 1.65 (s, 3H), 1.70 (br s,

1H−OH), 1.04 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s,

3H); ¹³C NMR (100 MHz, CDCl₃) δ 147.1, 111.7, 74.7, 64.0, 44.0,

25.8, 23.3, 21.4, 14.4, −4.5, −4.7; MS (CI, CH₄) m/z (relative

intensity) 227 (1), 213 (4), 175 (11), 159 (8), 137 (7), 115 (10), 95

(11), 87 (37), 85 (80), 83 (100); HRMS m/z calcd for C₁₃H₂₈O₂Si

(M⁺) 244.1831, found 244.1829. Anal. Calcd for C₁₃H₂₈O₂Si: C,

63.87; H, 11.55. Found: C, 63.57; H, 11.48.

An alternate procedure for the preparation of alcohol 47 was carried

as follows: ceric ammonium nitrate (Ce(NH₄)₂(NO₃)₆) (1.00 g, 1.82

mmol) was added to a solution of 46 (510 mg, 0.987 mmol), CH₂Cl₂

(12 mL), and H₂O (0.5 mL). The reaction stirred 2.5 h, and additional

(Ce(NH₄)₂(NO₃)₆) (0.25 g) and water (1.0 mL) were then added.

After 4 h, the reaction mixture was slowly quenched with saturated

aqueous NaHCO₃. The mixture was diluted with CH₂Cl₂, and the

organic layer was separated, washed with saturated aqueous NaHCO₃

(10 mL), H₂O (10 mL), and then brine (15 mL). It was then dried

over MgSO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation of the

residue by ﬂash column chromatography (40 g SiO₂, 10% EtOAc in

Hexanes) provided 200 mg (83%) of alcohol 47 as a clear colorless oil.

This material was identical to the sample prepared above.

1

Mosher ester analysis indicated 83% ee by H NMR integration of

selected signals. Characterization data for 45: mp 94−97 °C; R_f0.40

(20% Et₂O in hexanes); [α]²_D³−4.03 (c 1.49, CHCl₃); IR (neat) 3584,

1

3061, 2965, 2930, 1607, 1510, 1447, 1250, 1090, 1036, 702 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 7.47 (m, 4H), 7.21−7.36 (m, 8H), 6.84

(m, 2H), 4.82 (s, 1H), 4.79 (s, 1H), 3.80 (s, 3H), 3.60 (m, 1H), 3.32

(A of ABX, J_AB= 9.7 Hz, J_AX= 6.5 Hz, 1H), 3.05 (B of ABX, J_AB= 9.7

Hz, J_BX= 3.0 Hz, 1H), 2.40 (dq, J = 8.5, 6.8 Hz, 1H), 2.27 (d, J = 3.4

Hz, 1H), 1.68 (s, 3H), 0.83 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 158.5, 147.5, 144.5, 144.4, 135.6, 130.3, 128.4, 127.8, 126.9,

113.1, 86.3, 72.5, 65.5, 55.2, 44.4, 19.1, 15.6; MS (CI, CH₄) m/z

(relative intensity) 402 (8), 325 (3), 273 (100), 213 (9), 143 (8);

HRMS m/z calcd for C₂₇H₃₀O₃(M⁺) 402.2195, found 402.2197.

(2R,3R)-2-(tert-Butyldimethylsilanyloxy)-1-[(4-

methoxyphenyl)diphenylmethoxy]-3,4-dimethylpent-4-ene

(46). Alcohol 45 (3.55 g, 8.82 mmol), tert-butyldimethylsilyl chloride

(1.6 g, 11 mmol), dimethylaminopyridine (DMAP) (54 mg, 0.44

mmol), and imidazole (1.2 g, 18 mmol) were stirred in DMF (15 mL)

at ambient temperature 4 days. The reaction mixture was diluted with

hexanes (50 mL) and extracted with saturated aqueous NH₄Cl (3 × 10

mL), H₂O (10 mL), and brine (15 mL). The combined aqueous layers

were extracted with hexanes (3 × 15 mL). The combined organic

layers were dried over MgSO₄, ﬁltered, and concentrated in vacuo. The

residue was puriﬁed by ﬂash column chromatography (150 g SiO₂, 5%

EtOAc in hexanes), which provided 4.1 g (92%) of 46 as a thick oil: R_f

0.60 (20% EtOAc in hexanes); [α]²_D⁴+4.74 (c 1.02, CHCl₃); IR (neat)

3063, 2955, 2857, 1609, 1510, 1252, 1179, 1067, 1038, 833, 774, 704

(2R,3R)-2-(tert-Butyldimethylsilanyloxy)-3,4-dimethylpent-

4-enal (48). Dimethylsulfoxide (0.46 mL, 6.55 mmol) was added

dropwise to a solution of oxalyl chloride (0.29 mL, 3.3 mmol) and

CH₂Cl₂(8 mL) at −78 °C. After 20 min, a solution of alcohol 47 (400

mg, 1.6 mmol) and CH₂Cl₂(4 mL) was added. The reaction stirred 30

min at −78 °C, and Et₃N (1.8 mL, 13 mmol) was added dropwise.

The reaction was stirred 30 min at −78 °C, warmed to ambient

temperature, and diluted with pentane (30 mL) and H₂O (10 mL).

The organic layer was washed with H₂O (15 mL), saturated aqueous

NH₄Cl (3 × 15 mL), and brine (20 mL), dried over Na₂SO₄, ﬁltered,

and concentrated in vacuo. Proton NMR and TLC indicated that

alcohol 47 was cleanly converted to aldehyde 48, and this material was

used directly in the subsequent reactions without further puriﬁcation.

Data for 48: R_f0.60 (20% EtOAc in hexanes); IR (neat) 3075, 2957,

1

2932, 2897, 2859, 1736, 1462, 1256, 1080, 839, 779 cm⁻¹; H NMR

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.47 (m, 4H), 7.35 (m, 2H),

(400 MHz, CDCl₃) δ 9.53 (d, J = 2.2 Hz, 1H), 4.80 (s, 1H), 4.78 (s,

1H), 3.9 (dd, J = 5.5, 2.2 Hz, 1H), 2.59 (dq, J = 7.0, 5.5 Hz, 1H), 1.74

s (3H), 1.09 (d, J = 7.0 Hz, 3H), 0.92 (s, 9H), 0.054 (s, 3H), 0.047 (s,

3H); MS (CI, CH₄) m/z (relative intensity) 241 (3), 213 (32), 185

(100), 155 (13), 115 (9), 83 (40), 73 (45), 75 (45); HRMS m/z calcd

for C₁₃H₂₆O₂Si (M⁺) 242.1667, found 242.1671.

7.29 (m, 4H), 7.23 (m, 2H), 6.84 (m, 2H), 4.69 (s, 2H), 3.82 (s, 3H),

3.78 (m, 1H), 3.05 (d, J = 6.3 Hz, 2H), 2.57 (dq, J = 7.3, 4.0 Hz, 1H),

1.67 (s, 3H), 1.01 (d, J = 7.3 Hz, 3H), 0.87 (s, 9H), 0.04 (s, 3H),

−0.05 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 158.4, 146.8, 144.8,

136.1, 130.4, 128.5, 127.6, 112.9, 111.9, 86.3, 74.6, 65.6, 55.2, 44.1,

25.9, 21.5, 18.0, 15.4, −4.3, −5.0; MS (CI, CH₄) m/z (relative

intensity) 273 (100), 265 (50), 229 (10), 213 (30), 197 (30); HRMS

(FAB, Na) m/z calcd for C₃₃H₄₄O₃SiNa (M⁺Na⁺) 539.2958, found

539.2956. Anal. Calcd for C₃₃H₄₄O₃Si: C, 76.70; H, 8.58. Found: C,

76.98; H, 8.63.

(3R,4R)-4-(tert-Butyldimethylsilanyloxy)-2,3-dimethylhex-1-

en-5-yne (49). Triphenylphosphine (2.6 g, 9.8 mmol) was added to a

0 °C solution of CBr₄(1.6 g, 4.9 mmol), and CH₂Cl₂(15 mL). The

reaction stirred 10 min and was cooled to −78 °C. A solution of

aldehyde 48 (398 mg, 1.64 mmol) in CH₂Cl₂(5 mL) was added. After

the reaction stirred 2 h at −78 °C, it was diluted with hexanes (30 mL)

and water (5 mL). The organic layer was washed with H₂O (10 mL),

saturated aqueous NH₄Cl (15 mL), and brine (20 mL), dried over

MgSO₄, ﬁltered through a plug of silica, and concentrated in vacuo.

Puriﬁcation by ﬂash column chromatography (16 g SiO₂), using a

solvent gradient elution (hexanes to 5% EtOAc in hexanes) provided

470 mg of (3R,4R)-1,1-dibromo-3-(tert-butyldimethylsilanyloxy)-4,5-

dimethylhexa-1,5-diene (72%, 2 steps from 47) as a clear colorless oil:

R_f0.73 (20% EtOAc in hexanes); [α]²_D³−16.8 (c 1.64, CHCl₃); IR

(neat) 3075, 2957, 2930, 2859, 1649, 1616, 1462, 1375, 1254, 1074,

(2R,3R)-2-(tert-Butyldimethylsilanyloxy)-3,4-dimethylpent-

4-en-1-ol (47). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)

(1.8 g, 7.7 mmol) was added to a solution of MMTr ether 46 (1.02 g,

1.94 mmol), tert-butyl alcohol (6 mL), aqueous pH 7 buﬀer (6 mL),

and CH₂Cl₂(30 mL). The red reaction was stirred 18 h, quenched

with saturated aqueous NaHCO₃(10 mL), and transferred to a

separatory funnel using CH₂Cl₂(10 mL). The aqueous layer was

extracted with CH₂Cl₂(3 × 10 mL). The combined organic layers

were washed with saturated aqueous NaHCO₃(15 mL), H₂O (15

mL), and brine (20 mL); dried over MgSO₄; ﬁltered; and

concentrated in vacuo. The residue was taken up in hexanes (20

mL). The organic layer was washed with NaHCO₃(10 mL), H₂O (10

mL), and brine (15 mL). The combined organic layers were dried over

MgSO₄, ﬁltered, and concentrated in vacuo to provide an orange oil.

Puriﬁcation by ﬂash column chromatography (50 g SiO₂), using a

solvent gradient elution (hexanes to 10% EtOAc in hexanes) provided

373 mg (73%) of alcohol 47 as a clear colorless oil, which could be

further puriﬁed by Kugelrohr distillation (90 °C, 0.2 mmHg).

Chromatography led to the recovery of starting ether 46 (20%

yield), which was recycled. Data for 47: R_f0.55 (20% EtOAc in

hexanes); [α]²_D³+2.93 (c 2.00, CHCl₃); IR (neat) 3426, 3073, 2957,

1

839, 775 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 6.34 (d, J = 8.6 Hz,

1H), 4.79 (t, J = 1.6 Hz, 1H), 4.74 (s, 1H), 4.23 (dd, J = 8.6, 6.7 Hz,

1H), 2.3 (dq, J = 7.0, 6.7 Hz, 1H), 1.73 (s, 3H), 1.03 (d, J = 7.1 Hz,

3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 146.2, 140.9, 112.4, 88.9, 76.1, 47.0, 25.7, 20.6, 18.0, 15.2,

−4.4, −5.2; HRMS m/z calcd for C₁₄H₂₆Br₂OSi (M⁺) 398.0195, found

398.0186.

n-Butyllithium (0.35 mL, 2.5 M in hexanes) was added to a −78 °C

solution of the dibromide prepared above (150 mg, 0.377 mmol) and

THF (2.5 mL). The reaction stirred for 1.5 h while warming to −50

°C. Saturated aqueous NH₄Cl (5 mL) was added, and the mixture was

transferred to a separatory funnel using Et₂O (10 mL). The organic

layer was washed with water (5 mL) and brine (10 mL), dried over

1

2930, 2859, 1642, 1462, 1256, 1065, 812, 755 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 4.80 (s, 1H), 4.77 (s, 1H), 3.77 (m, 1H), 3.54 (d, J =

N

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

MgSO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation by ﬂash

column chromatography (8 g SiO₂, pentane) provided 65.5 mg (73%)

of the alkyne 49 as a clear colorless oil: R_f0.55 (hexanes); [α]²_D³+46.2

(c 1.8, CHCl₃); IR (neat) 3312, 3077, 2957, 2932, 2859, 1649, 1462,

1252, 1098, 837, 777, 629 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.82

(s, 1H), 4.81 (s, 1H), 4.31 (dd, J = 6.7, 2.1 Hz, 1H), 2.39 (m, 2H),

1.73 (s, 3H), 1.12 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.14 (s, 3H), 0.09

(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 146.1, 112.1, 84.4, 73.1, 66.1,

47.7, 25.7, 20.7, 18.2, 14.8, −4.5, −5.3; MS (CI, CH₄) m/z (relative

intensity) 238 (5), 223 (47), 181 (82), 169 (70), 139 (49), 113 (49),

85 (100), 75 (70); HRMS m/z calcd for C₁₄H₂₆OSi (M⁺) 238.1753,

found 238.1748.

lene-4-oxacyclopentadec-13-ene-2,4-dione (55). Methyl ester

54 (43 mg, 0.081 mmol) was dissolved in toluene (40 mL) and heated

to reﬂux (oil bath temperature, 120−130 °C) in a culture tube sealed

with a Teﬂon coated cap for 3 h. The reaction was concentrated in

vacuo and puriﬁed by ﬂash column chromatography (5% EtOAc in

hexanes) to give the macrolide 55 (23 mg, 72%) as a colorless oil: R_f

0.41 (15% EtOAc in hexanes); [α]²_D³−42.0 (c 0.27, CHCl₃); IR (neat)

1

3082, 2953, 2857, 1746, 1715, 1462, 1250, 1126, 965, 837 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 6.36 (d, J = 15.9 Hz, 1H), 5.51 (dd, J =

15.8, 9.1 Hz, 1H), 5.22 (dd, J = 15.4, 9.1 Hz, 1H), 5.20 (s, 2H), 5.11

(s, 1H), 5.08 (s, 1H), 4.78 (s, 1H), 4.75 (s, 1H), 4.00 (td, J = 5.6, 2.2

Hz, 1H), 3.51 (A of AB, J_AB= 14.1 Hz, 1H), 3.32 (B of AB, J_AB= 14.1

Hz, 1H), 3.32 (m, 1H), 2.85 (s, 1H), 2.85 (m, 1H), 2.79 (s, 1H), 2.50

(dq, J = 15.4, 6.9 Hz, 1H), 2.20 (m, 1H) 2.06 (d, J = 5.5 Hz, 2H), 1.69

(s, 3H), 1.22 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 7.1 Hz, 3H), 0.83 (s,

9H), 0.03 (s, 3H), 0.01 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

202.4, 165.1, 145.6, 143.2, 140.4, 137.3, 125.7, 121.1, 115.5, 112.7,

78.7, 68.2, 62.7, 54.6, 53.4, 46.7, 44.7, 40.1, 34.7, 25.7, 19.6, 18.2, 15.4,

14.9, −4.7, −4.9; MS (EI) m/z (relative intensity) 488 (20), 431 (67),

387 (30), 339 (25), 283 (100), 239 (60), 197 (75), 133 (40), 91 (40);

HRMS m/z calcd for C₂₈H₄₄O₅Si (M⁺) 488.2958, found 488.2950.

(+)-Amphidinolide P (2). Tetrabutylammonium ﬂuoride (1.80

mL, 0.62 M in THF) was added to the ketoester 55 (17.0 mg, 0.035

mmol). The reaction mixture was stirred for 20 h at ambient

temperature, and the mixture was placed directly on a column of silica

gel (5 g). Puriﬁcation by ﬂash column chromatography (5% EtOAc in

hexanes) gave synthetic amphidinolide P (2) (9.0 mg, 70%) as a white

solid: R_f(15% EtOAc in hexanes); [α]²_D³+30.0 (c 0.4, MeOH); IR

(1E,3R,4R)-4,5-Dimethyl-1-(tributylstannanyl)hexa-1,5-dien-

3-ol (4). Tri-n-butylstannane (0.37 mL, 1.36 mmol) was added to a

solution of alkyne 49 (290 mg, 1.21 mmol) and PdCl₂(PPh₃)₂(17.1

mg, 0.024 mmol) in THF (6.1 mL). After 15 min, the reaction was

concentrated in vacuo. Puriﬁcation by ﬂash column chromatography

(40 g, silica gel, hexanes) gave the alkenyl stannane 50 as a colorless

oil: R_f0.57 (hexanes); [α]²_D⁶+14.0 (c 0.865, CHCl₃); IR (neat) 2957,

1

2928, 2857, 1462, 1375, 1254, 1096, 1061, 835, 775 cm⁻¹; H NMR

(400 MHz, CDCl₃) δ 6.02 (d, J = 19.1 Hz, 1H), 5.85 (dd, J = 19.1, 6.3

Hz, 1H), 4.75 (s, 1H), 4.70 (s, 1H), 3.98 (apparent t, J = 6.3 Hz, 1H),

2.42 (apparent q, J = 6.8 Hz, 1H), 1.72 (s, 3H), 1.50, (m, 6H), 1.30

(m, 6H), 0.94 (d, J = 7.0 Hz, 3H), 0.89 (m, 15H), 0.88 (s, 9H), 0.03

(s, 3H), 0.00 (s, 3H).

Tetrabutylammonium ﬂuoride (5 mL, 1.0 M in THF) was added to

the vinyl stannane 50, and the mixture was stirred for 36 h. Saturated

aqueous NH₄Cl (0.4 mL) was added, and the mixture was placed

directly on a column of silica gel (40 g). Puriﬁcation by ﬂash column

chromatography using 5% EtOAc hexanes provided 325 mg of 4 (64%,

for 2 steps from alkyne 49) as a clear yellow oil: R_f0.62 (20% EtOAc

in hexanes); [α]²_D³+15.8 (c 1.39, CHCl₃); IR (neat) 3443, 2959, 2926,

1

(neat) 3488, 3081, 2930, 1713, 1643, 1439, 1188, 972, 897 cm⁻¹; H

NMR (500 MHz, C₆D₆) δ 6.24 (d, J = 16.3 Hz, 1H), 5.64 (dd, J =

16.2, 7.6 Hz, 1H), 5.34 (dd, J = 9.0, 7.8 Hz, 1H), 4.98 (br s, 1H), 4.94

(br s, 1H), 4.92 (br s, 1H), 4.86 (br s, 1H), 4.85 (br s, 1H), 4.81 (br s,

1H), 4.27 (d, J = 2.0 Hz, 1H), 3.51 (ddd, J = 11.6, 8.4, 2.6 Hz, 1H),

2.72 (d, J = 13.8 Hz, 1H), 2.66 (dd, J = 8.4, 1.8 Hz, 1H), 2.56 (dd, J =

12.8, 2.6 Hz, 1H), 2.52 (br d, J = 9.5 Hz, 1H), 2.47 (dq, J = 9.2, 7.1

Hz, 1H), 2.41 (d, J = 11.9 Hz, 1H), 2.31 (d, J = 12.1 Hz, 1H), 2.21

(dd, J = 13.6, 9.7 Hz, 1H), 2.15 (t, J = 12.6, 11.8 Hz, 1H), 1.99 (br q, J

= 6.5 Hz, 1H), 1.71 (s, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 7.0

Hz, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 172.4, 146.5, 143.7, 142.2,

133.6, 129.1, 118.2, 112.3, 110.0, 99.2, 78.5, 73.5, 62.8, 58.3, 45.2,

45.02, 45.01, 39.4, 36.3, 19.5, 16.1, 11.8; HRMS m/z calcd for

C₂₂H₃₀O₅Na (M⁺+ Na) 397.1991, found 397.1980. Our synthetic

amphidinolide P was studied by COSY-NMR experiments and by

1

2872, 2855, 1645, 1456, 1375, 1094, 990. 889 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 6.20 (d, J = 18.8 Hz, 1H), 5.92 (dd, J = 19.0, 6.4 Hz,

1H), 4.91 (s, 1H), 4.86 (s, 1H), 3.84 (m, 1H), 2.24 (dq, J = 8.9, 7.0

Hz, 1H), 1.88 (s, 1H−OH), 1.73 (s, 3H), 1.49 (m, 6H), 1.31 (m, 6H),

0.97 (d, J = 7.0 Hz, 3H), 0.89 (s, 15H); ¹³C NMR (100 MHz, CDCl₃)

δ 148.7, 147.2, 130.7, 113.0, 77.5, 47.6, 29.1, 27.2, 19.1, 15.6, 13.7, 9.5;

HRMS m/z calcd for C₂₀H₃₉OSn (M⁺− H) 415.2017, found

415.2013. Anal. Calcd for C₂₀H₄₀OSn: C, 57.85, H, 9.71. Found: C,

58.20; H, 9.77.

(4R,7S,8S,9S,12E,14S,15R)-7-(tert-Butyldimethylsilanyloxy)-

5,11-dimethylene-8,9-epoxy-14-hydroxy-3-oxo-4,15,16-trime-

thylheptadeca-12,16-diene (54). Alkenyl bromide 42 (38 mg,

0.080 mmol), vinylic stannane 4 (31 mg, 0.080 mmol), and

tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (9.0

mg, 0.017 mmol) were combined in CH₂Cl₂(1.0 mL) under argon

atmosphere, and the mixture was stirred for 20 h at ambient

temperature. The mixture was placed directly on a silica gel column

(10 g). Puriﬁcation by ﬂash column chromatography using a solvent

gradient elution (5% EtOAc in hexanes to 30% EtOAc in hexanes)

provided 31 mg (81%) of diene 54 as a thick clear colorless oil: R_f0.40

(30% EtOAc in hexanes); [α]²_D³−25.0 (c 0.34, CHCl₃); IR (neat)

3505, 3077, 2955, 2857, 1748, 1715, 1645, 1456, 1255, 1086, 837

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.34 (d, J = 15.8 Hz, 1H), 6.34

(dd, J = 15.8, 7.3 Hz, 1H), 5.14 (s, 2H), 5.13 (s, 1H), 5.03 (s, 1H),

4.92 (s, 1H), 4.88 (s, 1H), 3.94 (ddd, J = 8.0, 8.0, 2.0 Hz, 1H), 3.73

(m, 1H), 3.72 (s, 3H), 3.53 (A of AB, J_AB= 15.8 Hz, 1H), 3.51 (B of

AB, J_AB= 15.8 Hz, 1H), 3.37 (q, J = 6.8 Hz, 1H), 3.04 (m, 1H), 2.73

(dd, J = 5.0, 2.0 Hz, 1H), 2.48 (A of ABX, J_AB= 15.4 Hz, J_AX= 6.9 Hz,

1H), 2.40 (B of ABX, J_AB= 15.4 Hz, J_BX= 4.2 Hz, 1H), 2.32 (m, 2H),

2.27 (m, 1H), 1.96 (d, J = 2.2 Hz, 1H−OH), 1.74 (s, 3H), 1.24 (d, J =

6.8 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 3H), 0.3

(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 203.1, 167.8, 146.9, 143.2,

141.4, 134.0, 130.5, 117.6, 116.1, 113.5, 74.4, 70.1, 60.5, 55.3, 53.3,

52.3, 48.2, 46.3, 41.2, 34.5, 25.8, 18.8, 18.1, 15.7, 15.1, −4.4, −4.8;

HRMS m/z calcd for C₂₉H₄₈O₆SiNa (M⁺+ Na) 543.3118, found

543.3119.

1

comparisons to the H NMR and ¹³C NMR data recorded for the

natural product. NMR spectra and these data are tabulated in

Supporting Information.

ASSOCIATED CONTENT

■

S

* Supporting Information

Tables S1 and S2 of tabulated comparisons of proton and

carbon NMR data for natural and synthetic amphidinolide P.

Proton NMR spectra of synthetic amphidinolide P (2) and

intermediate compunds 4, 9, 12−19, alcohol precursor of 15,

alcohol precursor of 16, 24, 27, 29, alcohol precursor of 30,

30−32, 35, 36, 39−42, 44−50, dibromide precursor to 49, 54

and 55 are also included. This material is available free of

charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

■

Corresponding Author

*E-mail: williamd@indiana.edu.

Notes

(5R,8S,9S,10S,13E,15S)-8-(tert-Butyldimethylsilanyloxy)-

[(1R)-1,2-dimethylallyl]-9,10-epoxy-5-methyl-6,12-dimethy-

The authors declare no competing ﬁnancial interest.

O

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(11) Ide, M.; Yasuda, M.; Nakata, M. Synlett 1998, 936−937.

ACKNOWLEDGMENTS

■

(12) For a related procedure: Williams, D. R.; Sit, S.-Y. J. Am. Chem.

Soc. 1984, 106, 2949−2954.

The authors gratefully acknowledge the National Science

Foundation (CHE1055441) and the National Institutes of

Health (GM42897) for generous support of this eﬀort.

(13) Mancuso, A. J.; Haung, S.-L.; Swern, D. J. Org. Chem. 1978, 43,

2480−2482.

(14) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769−3772.

(15) Alkyne 17 was unreactive toward cuprate reagents derived from

the transmetalation of organozinc or organolithium species prepared

from tri-n-butylstannylmethyl iodide. For preparations of these

organozinc and organolithium reagents: (a) Sato, T.; Tachibana, K.;

Kawase, A.; Hirose, T. Bull. Chem. Soc. Jpn. 1993, 66, 3825−3827.

(b) Sato, T.; Matsuoka, H.; Igarashi, T.; Minomura, M.; Murayama, E.

J. Org. Chem. 1988, 53, 1207−1212.

(16) For examples of regioselective cupration of terminal alkynes:

(a) Katagiri, T.; Fujiwara, K.; Kawai, H.; Suzuki, T. Tetrahedron Lett.

2008, 49, 3242−3247. (b) Sharma, S.; Oehlschlager, A. C. J. Org.

Chem. 1989, 54, 5064−5073.

(17) (a) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett.

1983, 24, 731−734. (b) Kawaguchi, S.; Ogawa, A. Org. Lett. 2010, 12,

1893−1895. (c) Corminboeuf, O.; Overman, L. E.; Pennington, I. D.

Org. Lett. 2003, 5, 1543−1546.

(18) For hydrostannylations of terminal alkynes: (a) Zhang, H. X.;

Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857−1867. (b) Trost,

B. M.; Ball, Z. T. Synthesis 2005, 853−887. (c) Kazmaier, U.; Schauss,

D.; Pohlman, M. Org. Lett. 1999, 1, 1017−1019.

(19) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277−

7278.

(20) Coupling vinyl triﬂates with various organometallic substrates is

well precedented. For general reviews of the use of vinyl triﬂates for

use in carbon−carbon bond reactions, see: (a) Ritter, K. Synthesis

1993, 735−762. (b) Scott, W. J. Acc. Chem. Res. 1988, 21, 47−54. For

an example using tris(trimethylsilyl)methyl aluminum for the

formation of allylsilanes, see: (c) Saulnier, M. G.; Kadow, J. F.; Tun,

M. M.; Langley, D. R.; Vyas, D. M. J. Am. Chem. Soc. 1989, 111, 8320−

8321.

(21) For preparation of a cuprate species derived from tri-n-

butylstannylmethyl iodide: McMurry, J. E.; Scott, W. J. Tetrahedron

Lett. 1980, 21, 4313−4316.

(22) For preparation of tri-n-butylstannyl methyl iodide: Seitz, D. E.;

Carroll, J. J.; Cartaya, C. P.; Lee, S.-H.; Zapata, A. Synth. Commun.

1983, 13, 129−134.

(23) (a) Hayashi, T.; Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada,

M. Synthesis 1981, 1001−1003. For the nickel catalyzed cross-

coupling with silyl enol ethers, see: (b) Hayashi, T.; Katsuro, Y.;

Kumada, M. Tetrahedron Lett. 1980, 21, 3915−3918. (c) Sengupta, S.;

Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V. J. Org. Chem. 1992,

57, 4066−4068.

(24) Basacca, C. A.; Eriksson, M. C.; Fiaschi, R. Tetrahedron Lett.

1999, 40, 3101−3104.

(25) Epoxy alcohol 26 had been previously prepared from 1,4-butyne

diol in three steps (91% ee). See: Jass, P. A. Total Synthesis of

(+)-Breynolide A, Ph.D. Thesis, Indiana University, 1994.

(26) Nicolaou, K. C.; Duggan, M. E.; Ladduwahetty, T. Tetrahedron

Lett. 1984, 25, 2069−2072.

(27) For a similar procedure: Miller, R. B.; McGarvey, G. J. Org.

Chem. 1979, 44, 4624−4633.

(28) For an overview: Biamonte, M. A. In Name Reactions for

Homologations; Li, J. J., Ed.; Wiley & Sons: Hoboken, NJ, 2009; pp

539−575.

(29) For the synthesis of the corresponding benzyl ether of 31:

(a) Mickelson, T. J.; Koviach, J. L.; Forsyth, C. J. J. Org. Chem. 1996,

61, 9617−9620. (b) Bunnelle, W. H.; Narayanan, B. A. Org. Synth.

1990, 69, 89−95. (c) Evans, D. A; Coleman, P. J.; Dias, L. C. Angew.

Chem., Int. Ed. Engl. 1997, 36, 2738−2741.

(30) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512−519.

(31) For a detailed description of this protocol: Hoye, T. R.; Jeffrey,

C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451−2458.

DEDICATION

■

^†Dedicated to the memory of Robert E. Ireland.

REFERENCES

■

(1) Ishibashi, M.; Kobayashi, J. Heterocycles 1997, 44, 543−572.

(2) For reviews: (a) Tsuda, M.; Kariya, Y.; Iwamoto, R.; Fukushi, E.;

Kawabata, J.; Kobayashi, J. Mar. Drugs 2005, 3, 1−8. (b) Kubota, T.;

Sakuma, Y.; Tsuda, M.; Kobayashi, J. Mar. Drugs 2004, 2, 83−87.

(c) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77−93.

(d) Chakraborty, T. K.; Das, S. Curr. Med. Chem.: Anti-Cancer Agents

2001, 1, 131−149. (e) Kobayashi, J. In Comprehensive Natural Products

Chemistry; Mori, K., Ed.; Elsevier: New York, 1999; Vol. 8, p 619.

(f) Ishibashi, M.; Kobayashi, J. Chem. Rev. 1993, 93, 1753−1769.

(3) A recent structure revision suggests that carbenolide I and

amphidinolide N may be identical or closely related diastereomers.

(a) Bauer, I.; Maranda, L.; Young, K. A.; Shimizu, Y.; Fairchild, C.;

Cornell, L.; MacBeth, J.; Huang, S. J. Org. Chem. 1995, 60, 1084−

1086. (b) For synthesis efforts: Seck, M.; Franck, X.; Seon-Meniel, B.;

Hocquemiller, R.; Figader

4180.

(4) (a) Takahashi, Y.; Kubota, T.; Imachi, M.; Walchi, M. R.;

Kobayashi, J. J. Antibiot. 2013, 1−3. (b) Ishibashi, M.; Yamaguchi, N.;

Sasaki, T.; Kobayashi, J. Chem. Commun. 1994, 1455−1456. (c) For

synthesis efforts: Nicolaou, K. C.; Bulger, P. G.; Brenzovich, W. E.;

Francis, T. M. Org. Biomol. Chem. 2006, 4, 2158−2183. (d) Trost, B.

M.; Rey, J. Org. Lett. 2012, 14, 5632−5635.

́

e, B. A. Tetrahedron Lett. 2006, 47, 4175−

̈

(5) Some representative examples of total syntheses of amphidino-

lides include: (a) Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am.

Chem. Soc. 2005, 127, 4297−4307. (b) Lepage, O.; Kattnig, E.;

Furstner, A. J. Am. Chem. Soc. 2004, 126, 15970−15971. (c) Trost, B.

̈

M.; Wrobleski, S. T.; Chisholm, J. D.; Harrington, P. Z.; Jung, M. J.

Am. Chem. Soc. 2005, 127, 13589−13597. (d) Ghosh, A. K.; Gong, G.

J. Am. Chem. Soc. 2004, 126, 3704−3705. (e) Williams, D. R.; Meyer,

K. G. J. Am. Chem. Soc. 2001, 123, 765−766. (f) Williams, D. R.;

Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198−11199. (g) Hara, A.;

Morimoto, R.; Iwasaki, Y.; Saitoh, T.; Ishikawa, Y.; Nishiyama, S.

Angew. Chem., Int. Ed. 2012, 51, 9877−9880. (h) Lu, L.; Zhang, W.;

Carter, R. G. J. Am. Chem. Soc. 2008, 130, 7253−7255. (i) Mahapatra,

S.; Carter, R. G. Angew. Chem., Int. Ed. 2012, 51, 7948−7951. (j) Va,

P.; Roush, W. R. Tetrahedron 2007, 63, 5768−5796. (k) Furstner, A.;

̈

́

Bouchez, L. C.; Funel, J.-A.; Liepins, V.; Poree, F.-H.; Gilmour, R.;

Laurich, D.; Beaufils, F.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46,

9265−9270.

(6) For a selection of recent methodology studies related to

amphidinolide synthesis: (a) Micalizo, G. C.; Roush, W. R. Org. Lett.

2001, 3, 1949−1952. (b) Morra, N. A.; Pagenkopf, B. L. Org. Lett.

2011, 13, 572−575. (c) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004,

6, 3865−3868. (d) Mohapatra, D. K.; Rahaman, H.; Chorghade, M. S.;

Gurjar, M. K. Synlett 2007, 567−570. (e) Roy, S.; Spilling, C. D. Org.

Lett. 2010, 12, 5326−5329. (f) Liesener, F. P.; Jannsen, U.; Kalesse, M.

Synthesis 2006, 2590−2602. (g) Petri, A. F.; Schneekloth, J. S.;

Mandal, A. K.; Crews, C. M. Org. Lett. 2007, 9, 3001−3004. (h) Deng,

L.; Ma, Z.; Zhao, G. Synlett 2008, 728−732. (i) Williams, D. R.; Fultz,

M. W. J. Am. Chem. Soc. 2005, 127, 14550−14551. (j) Ferrie,

́

L.;

Figadere, B. Org. Lett. 2010, 12, 4976−4979.

́

(7) For the isolation of amphidinolide O and P, see: Ishibashi, M.;

Takahashi, M.; Kobayashi, J. J. Org. Chem. 1995, 60, 6062−6066.

(8) (a) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945−

948. (b) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2013, 15, 2070.

(9) Chakraborty, T. K.; Das, S. Tetrahedron Lett. 2001, 42, 3387−

3390.

(10) For a full account: Trost, B. M.; Papillon, J. P. N.; Nussbaumer,

T. J. Am. Chem. Soc. 2005, 127, 17921−17937.

P

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(32) For a related procedure using the enolate of methyl acetate:

Sato, F.; Kusakabe, M.; Kato, T.; Kobaybashi, Y. J. Chem. Soc., Chem.

Commun. 1984, 1331−1332.

(33) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Sharpless, K.

B. J. Am. Chem. Soc. 1987, 109, 5765−5780.

(34) Originally, we protected the epoxy alcohol as a trityl ether.

While attempting to remove this protecting group later in the

synthesis, we produced mixtures of inseparable silyl ethers. This

prompted us to explore the more labile MMTr protecting group. See:

(a) Khorana, H. G.; Goldberg, H. I.; Rammler, D. H.; Smith, M. J. Am.

Chem. Soc. 1962, 84, 430−440. (b) Green, T. W.; Wuts, P. G. M.

Protective Groups in Organic Synthesis, 2nd ed.; John Wiley & Sons,

Inc.: New York, 1991; p 156.

(35) Tanemura, K.; Nishida, Y.; Suzuki, T.; Satsumabayashi, K.;

Horaguchi, T. J. Chem. Res., Synop. 1999, 40−41.

(36) Zhang, H. X.; Gruibe,

1857−1867.

́

F.; Balavoine, G. J. Org. Chem. 1990, 55,

(37) Subsequent to our communication of this chemistry, additional

reports have described the use of “ligandless” conditions in Pd(0)

cross-couplings: (a) Herve, A.; Rodriguez, A. L.; Fouquet, E. J. Org.

Chem. 2005, 70, 1953−1956. (b) Wiskur, S. L.; Korte, A.; Fu, G. C. J.

Am. Chem. Soc. 2004, 126, 82−83. (c) Molander, G. A.; Biulatto, B.

Org. Lett. 2002, 4, 1867−1870. (d) Kabalka, G. W.; Namboodiri, V.;

Wang, L. Chem. Commun. 2001, 775. (e) Reetz, M. T.; de Vries, J. G.

Chem. Commun. 2004, 1559−1563.

(38) We were able to couple tri-n-butylvinylstannane and bromide 42

using Pd₂dba₃and Ph₃As in THF, but these conditions did not give

any of the desired product for the coupling of 4 and 42 even under

prolonged reaction times. For an example of a related Stille cross

coupling using a vinyl bromide, see: Romo, D.; Rzasa, R. M.; Shea, H.

A.; Park, K.; Langenhan, J. M.; Sun, L.; Akhiezer, A.; Liu, J. O. J. Am.

Chem. Soc. 1998, 120, 12237−12254.

(39) (a) This catalyst system was previously used for Stille coupling

reactions of triﬂates: Baker, S. R.; Roth, G. P.; Sapino, C. Synth.

Commun. 1990, 20, 2185−2189. (b) For “ligandless” use of palladium

in various couplings, see: Beletskaya, I. P. J. Organomet. Chem. 1983,

250, 551−564. (c) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33,

314−321.

́

(40) (a) Mottet, C.; Hamelin, O.; Garavel, G.; Depres, J.-P.; Greene,

A. E. J. Org. Chem. 1999, 64, 1380−1382. (b) Bader, A. R.; Cummings,

L. O.; Vogel, H. A. J. Am. Chem. Soc. 1951, 73, 4195−4197. (c) Bader,

A. R.; Vogel, H. A. J. Am. Chem. Soc. 1952, 74, 3992−3994.

(41) (a) Cambell, D. S.; Lawrie, C. W. J. Chem. Soc., Chem. Commun.

1971, 355−356. (b) Witzeman, J. S. Tetrahedron Lett. 1990, 31, 1401−

1404.

(42) Comins, D. L.; Dehghana, A. Tetrahedron Lett. 1992, 33, 6299−

6302.

(43) Synthesis of (1-bromovinyl)trimethylsilane was carried out by

following the literature procedure. See: Boeckman, R. K.; Blum, D. M.;

Ganem, B.; Halvey, R. M. Org. Synth. 1988, Coll. Vol. 6, 1033.

Q

dx.doi.org/10.1021/jo4002382 | J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Studies for the total synthesis of amphidinolide P

DOI: 10.1021/jo4002382

Source and publish data:

Authors:

Article abstract of DOI:10.1021/jo4002382

Full text of DOI:10.1021/jo4002382

Products guided by the article

R&D Labs maybe for 1431861-05-0

Relevant to this article

Hot Product