Survey of synthetic approaches to natural (peyssonenynes) and unnatural acetoxyenediynes

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FULL PAPER

DOI: 10.1002/ejoc.201200246

Survey of Synthetic Approaches to Natural (Peyssonenynes) and Unnatural

Acetoxyenediynes

[a]

Patricia García-Domínguez, Rosana Alvarez,* and Ángel R. de Lera*

Dedicated to Professor Patxi Palacios on the occassion of his 60th birthday

Keywords: Natural products / Total synthesis / Synthetic methods / Cross-coupling

Four convergent synthetic approaches to acetoxyenediynes

have been explored to gain access to peyssonenynes A and

B, which are natural products isolated from the red alga

Peyssonelia caulifera. After optimization of the routes with a

palmitic acid based model system, the synthesis of the

peyssonenynes was completed by using, as the key steps,

Cadiot–Chodkiewicz cross-coupling reaction. Because bulky

amide bases stereoselectively provided the (E)- and (Z)-acet-

oxyenynes from the precursor ynones, the cross-coupling

routes to obtaining the acetoxyenediynes by using these

stereochemically homogeneous intermediates are compar-

able to the alternatives in which enolacetate formation of the

acetoxyenediyne motif takes place at a late stage in the syn-

thesis.

1) Ni/Cu co-catalyzed cross-coupling of terminal alkynes,

) Sonogashira cross-coupling, 3) the addition of a diynyl

2

anion to a Weinreb amide, and 4) the previously reported

Introduction

drogenation of an ω-3-polyunsaturated fatty acid, was un-

Peyssonenynes A and B (1a; Scheme 1) are oxylipin metab- precedented at the time of the discovery of 1a. The diyne

[

2]

olites that were isolated in 2004 from the Fijian red marine moiety is also quite uncommon among the structurally

alga Peyssonelia caulifera.^[The structures were proposed diverse oxylipins, as is the monoacyl glycerol functionality

1]

[

3]

to correspond to the Z and E isomers [(Z)-1a and (E)-1a] in red algae. All of these structural features make peys-

at the enol acetate double bond. The acetoxyenediyne mo- sonenynes particularly appealing from chemical and bioge-

[

4]

tif, which presumably is generated biosynthetically by dehy- netic perspectives.

Scheme 1. Original structures proposed for the peyssonenynes A and B [(Z) and (E)-1a, the sn-1- or sn-3-glycerol acetoxyenediyne fatty

acid], and the corrected structure of the latter [(Z)-2a, the sn-2 glycerol Z-acetoxyenediyne fatty acid].

[

a] Departamento de Química Orgánica, Facultade de Química,

Of additional interest is the finding that peyssonenynes

Universidade de Vigo,

1

a exhibit DNA methyl transferase 1 (DNMT1) inhibitory

3

6310 Vigo, Spain

[

1]

Fax: +34-986-818622

activity. DNMT1 is a member of the DNA methyl trans-

E-mail: rar@uvigo.es

[5]

ferase protein family, which in mammals is responsible for

qolera@uvigo.es

the methylation of the cytosine residues at their C-5 posi-

tions, primarily in the CpG dinucleotides and only occa-

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201200246.

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P. García-Domínguez, R. Alvarez, Á. R. de Lera

FULL PAPER

sionally at non-CG sites. The methylation of DNA, the compounds for biological evaluation as well as to pave the

most widely studied epigenetic modification, is involved in way for the synthesis of analogues. In this full account of

the control of gene expression, the regulation of genomic/ the synthetic work (for the first synthetic approach see

[

11]

parental imprinting, the stabilization of X chromosome in- ref. ) we report on the preparation of natural and unnatu-

activation, and the maintenance of the genome integrity. ral acetoxyenediynes, represented by the peyssonenynes and

This process is also implicated in the development of the their analogues derived from palmitic acid, respectively. The

immune system and in cellular reprogramming, as well as in latter compound was used as a model system to optimize

brain function and behavior.^[Aberrant patterns of DNA the synthetic approaches. The advantages and limitations of

methylation are associated with several neurological disor- the routes studied will be discussed.

ders and autoimmune diseases and are also involved in can-

6]

cer initiation and progression.^[Cancer cells often show ge-

7]

nome-wide hypomethylation and site-specific hypermethyl- Results and Discussion

ation of DNA promoter regions (in particular, of tumor

It was clear at the outset that the most challenging task

suppressor genes), which are normally unmethylated.

in synthesizing the target structures was the stereoselective

DNMT inhibitors might reactivate the silenced tumor sup-

construction of the (E)- and (Z)-enol acetates conjugated to

pressors or several DNA repair genes and therefore are

the diyne functionality. In principle, two general convergent

novel and promising anticancer drugs^[that in combination

strategies for obtaining this arrangement were explored and

with other therapies could lead to the growth inhibition of

these involved C –C (with variants labeled as A and B)

8]

sp

tumor cells or alteration of their sensitivity to other anti-

cancer therapies.

or C_s_p₂–C_s_p(labeled as C and D) bond-formation processes.

In the first-generation approach (route A in Scheme 2, see

also Scheme 1) the C –C bond was constructed by a Ca-

[

9]

The interest of our group in the development of new epi-

genetic modulators inspired by the structures of natural

sp

[

14]

diot–Chodkiewicz cross-coupling reaction

between

[

10]

products prompted us to synthesize the four possible ste-

reoisomers (geometric isomers and enantiomers at the glyc-

erol moiety) of the proposed structure following the ap-

iodoalkyne 4 and propargylic alcohol 3a. We also explored

the stereoselective formation of the acetoxyenynes 5 prior

to the Cadiot–Chodkiewicz Cu-catalyzed cross-coupling re-

action (route B). It was envisaged that the alternative C_s_p₂

C_s_pbond formation could be achieved by Sonogashira

[

11]

proach indicated in Scheme 1 (see route A in Scheme 2).

–

The four stereoisomers proved to be roughly equipotent

when tested in radioactive DNMT1 enzymatic assays and

showed similar biological activities in the cell cycle, cell dif-

ferentiation, and apoptosis of K562 human leukemia cells.

Neither the enol acetate geometry nor the configuration of

the glycerol stereocenter appears to play an important role

in the activity of these compounds.^[

11]

Moreover, after noticing spectroscopic inconsistencies

between the synthetic and natural products, we developed

unambiguous methods for the determination of the geome-

tries of the synthetic acetoxyenynes and acetoxyenediynes.

3

Both the value of J_H_–_Ccalculated by using EXSIDE (exci-

tation-sculptured indirect detection experiment)^[and the

value of the chemical shift of the C-6 carbon of the alkyne

attached to the enol acetate unit are useful fingerprints of

the acetoxyenediyne geometrical isomers.^[The spectro-

scopic data of the natural peyssonenynes isolated by Ger-

wick and co-workers^[from Peyssonelia caulifera led us to

propose that the natural compounds are not geometric iso-

mers at the enol acetate unit, but regioisomers of the (Z)-

enol acetate at the glycerol moiety [i.e., the sn-1,3 (Z)-1a

12]

13]

1]

and sn-2 (Z)-2a positional isomers]. The finding that both

isomers interconvert rapidly in solution^[

11a]

(and possibly

on the timescale of the biological tests) lends further sup-

port to the observed lack of enantiomeric discrimination by

the DNMT1 enzyme.

Given the unprecedented acetoxyenediyne functionality,

which has only been found thus far in these natural prod-

ucts, and the biological relevance of these compounds as

inhibitors of the epigenetic enzyme DNMT1, we have car-

ried out in-depth synthetic studies into complementary

Scheme 2. Retrosynthetic analysis of the acetoxyenediynes and pro-

posed precursors for synthesis by routes A, B, C, and D based on

strategies to gain access to sufficient amounts of the target the two key disconnections shown.

2

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Syntheses of Natural and Unnatural Acetoxyenediynes

cross-coupling between diyne 7 and the preformed α-chlor- (LDA) alone or in the presence of the cationic solvating

oenol acetates (8; route C) or by the addition of the diynyl agent 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

anion derived from 7 to a Weinreb amide (6; route D). This (DMPU) afforded a mixture of the E/Z enol acetates 11b

synthetic survey benefits from the use of intermediates that with moderate and opposite diastereoselectivities in good

are common to some of the routes.

yields (entries 1 and 2). Also, an opposite stereochemical

Moreover, to streamline these alternative pathways and outcome was obtained with the bulkier lithium bis(dimeth-

compare their efficacy, the skipped diene chain of the peys- ylphenylsilyl)amide (11b: 72:28 Z/E ratio) and lithium bis-

sonenynes (system a)^[

11]

was replaced with a saturated (trimethylsilyl)amide (11b: 7:93 Z/E ratio) in almost quanti-

model system (system b), which was conveniently derived tative yields (entries 3 and 4). Lithium 2,2,6,6-tetrameth-

from palmitic acid. Protected glycerols were used in any of ylpiperidide (LTMP) also gave excellent E stereoselectivity

the enantiomeric forms.

(entry 5), which could be improved in the presence of LiBr,

but at the cost of a lower yield (entry 6). The addition of

DMPU as co-solvent had a detrimental effect in this case

(entry 7). The results are consistent with those previously

reported for the formation of enol acetates starting from

C –C Bond-Formation Strategies

sp

[

18]

Route A Ϫ Cadiot–Chodkiewicz Cross-Coupling of an

Iodoalkyne and a Propargylic Alcohol

ketones with nonbulky substituents and can be rational-

ized by using the transition-state model proposed by Ire-

[

19]

land et al.

The geometries of the chromatographically

Route A in Scheme 2, in which the C –C_s_pbond-forma-

tion step proceeds by a Cadiot–Chodkiewicz cross-coupling

sp

separated double-bond isomers were assigned on the basis

of NOE experiments.

[

14]

reaction

a has already been successfully executed (see Scheme 2).

The enol acetates were generated at a late stage in the se- Table 1. Formation of enol acetate by deprotonation of propargylic

between iodoalkyne 4 and propargylic alcohol

[

11]

3

quence, albeit with poor (2:1) E/Z diastereoselectivity.

2

ketone 10b with lithium amide bases and trapping with Ac O.

Entry

LiNR

LDA

LDA/DMPU

2

Z/E

11b [%]

Route B Ϫ Cadiot–Chodkiewicz Cross-Coupling of

Iodoalkynes and Acetoxyenynes

1

2

3

4

5

6

7

20:80

73:27

72:28

7:93

9:91

Ͻ1:Ͼ99

46:54

84

86

99

98

99

37

86

The implementation of route B required the stereoselec-

tive synthesis of the acetoxyenyne 11b from propargylic

ketone 10b. Treatment of 10b, which was prepared in two

(Me PhSi) NLi

2

LHMDS

LTMP

LTMP/LiBr

LTMP/DMPU

[

11]

steps from palmitic acid (9b; Scheme 3),

3

with Ac O,

2

[

15]

Et N, and DMAP under a variety of conditions provided

enol acetate 11b in quantitative yields but disappointingly

as 50:50 isomeric mixtures. Treatment of the unsaturated

After removing the silyl-protecting group with TBAF, the

ketone 10b with Ac O in EtOAc containing a catalytic resulting acetoxyenynes 5b were treated with iodoalkyne

2

amount of perchloric acid^[led to improved Z/E selectivity (R)-4

16]

[11a]

under the modified reaction conditions for the Ca-

[

14]

(

27:73 after 24 h at 0.001 m concentration) but the yield was diot–Chodkiewicz cross-coupling reaction

developed by

(CuI/CuCl, piperidine). In contrast to

shorten the reaction time and led to higher E selectivity the successful coupling of the same iodoalkyne (R)-4 and

26:74 after 4 h, 53%; 11:89 after 24 h, 84%) but some de- propargylic alcohol 3a (Scheme 1),^[¹¹^a^]only enaminone 13b

[

20]

low (43%). Higher concentrations of HClO (0.01 m) helped Alami and Ferri

4

(

gradation of the starting material and products was noted. was obtained starting from 5b and (R)-4 (Scheme 4). This

The use of lithium amides for the generation of the enol derivative is likely formed by 1,4-addition of the secondary

acetates of 10b provided better results, as shown in amine to the propargylic ketone resulting from the piper-

[

17]

Table 1.

enol acetates 11b were generally obtained in good yields merization.

and with high selectivities. Trapping with Ac O, the enol- As an alternative to the Cadiot–Chodkiewicz reaction for

ates generated by using common lithium diisopropylamide the synthesis of unsymmetrical 1,3-diynes, we turned our

Under conditions of kinetic control (–78 °C), idine-mediated transacylation of the enol acetate and tauto-

[

21]

2

Scheme 3. Reagents and conditions: (a) EDCI, DMAP, HN(OMe)Me, HCl, CH

c) Et N, DMAP, Ac O, CH Cl , 25 °C, 72 h (99%, 50:50 Z/E); (d) HClO , Ac O, EtOAc, 25 °C, 24 h (84%, 11:89 Z/E); (e) LiNR

to 0 °C, then Ac O, see Table 1; (f) nBu NF, THF, 25 °C, 0.5 h [63%, (Z)-5b; 69%, (E)-5b].

2 2

Cl , 25 °C (95%); (b) n-BuLi, THF, –10 to 25 °C (92%);

(

3

2

4

2

, –78

2

4

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Scheme 4. Reagents and conditions: (a) CuCl, piperidine, 0 °C; (b) NiCl

2

6H

2

O, CuI, TMEDA, THF, air, 25 °C [(E,R)-12b, 40%; (Z,R)-

1

2b, 29%]; (c) CAN (3 mol-%), CH CN/H O, 70 °C (74% for a 30:70 mixture of Z/E isomers).

3

2

attention to the recently reported Ni/Cu co-catalyzed oxi-

The lithium amides that offered the best Z/E selectivities

[

22]

dative cross-coupling reaction of different alkynes.

methodology employs

TMEDA) as a ligand and oxygen or air as oxidant and Although the Z/E selectivities showed the same trends as in

This in the case of the model system were selected for the genera-

tetramethylethylenediamine tion of the enolates in the more unsaturated substrate 10a.

(

requires the use of an excess of one of the two terminal the model system 10b, the yields of 11a were lower [with

alkynes to maximize cross- versus homocoupling. Given the (Me PhSi) NLi, 88% yield in a 79:21 Z/E ratio; with

2

mild reaction conditions and the absence of an interfering LHMDS, 78% yield in a Ͻ1:Ͼ99 Z/E ratio]. Moreover, sep-

nucleophile in the reaction media, we adapted this method aration of the isomers by flash chromatography was cum-

to the construction of the acetoxyenediyne motif. The reac- bersome and the determination of the Z/E ratio by integra-

1

tion of (Z)- or (E)-enol acetate 5b with excess (5 equiv.) of tion of the corresponding signals in the H NMR spectrum

the glycerol ester-containing alkyne (R)-14^[

11a]

promoted by was complicated by the presence of additional vinylic and

NiCl ·6H O and CuI in THF/TMEDA in air led to the de- allylic proton resonances. Given these shortcomings we de-

2

sired compounds (Z,R)-12b and (E,R)-12b in 29 and 40% cided to deprotect the silyl group in the Z/E mixtures and

yields, respectively. Lastly, ketal deprotection with catalytic separate the terminal alkynes 5a. To our surprise, the depro-

[

23]

amounts of cerium(IV) ammonium nitrate (CAN)

pro- tection of 11a in the presence of TBAF led to decomposi-

vided the analogues 1b.

tion, probably due to the incompatibility of the skipped

The extension of this approach to the peyssonenyne nat- diene moiety with the basic fluoride anion.^[²⁶^]Because

ural products (series a) required the preparation of proparg- TMS-substituted alkynes can be deprotected under milder

ylic ketone 10a (Scheme 5). This compound was obtained basic conditions than the more robust TIPS-alkynes, pro-

by the addition of (triisopropylsilyl)acetylene to Weinreb pargylic ketone 16a was prepared by following the same

amide 6a, which in turn was prepared by semihydrogen- sequence (Scheme 5). In this case, small amounts of the ter-

ation of the unstable 1,4-diyne 15a (itself prepared from the minal alkynone 18a, which arises from the removal of the

corresponding alkyne and propargylic bromide precur- silyl group under the basic conditions used in this step, were

sors^[) to the skipped 1,4-diene

11]

[24]

using the P2-Ni cata- also obtained together with 16a. Enol acetates 17a with Z

lyst,^[as described in our first-generation synthesis of the and E geometries were generated by using the previously

25]

[

11]

peyssonenynes.

optimized protocols (LDA/DMPU, which gave a 70:30 Z/E

4

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Syntheses of Natural and Unnatural Acetoxyenediynes

Scheme 5. Reagents and conditions: (a) Ni(OAc)

THF, –40 to 25 °C (10a, 94%; 16a, 84%); (c) LiNR

tBuOH/H O, 25 °C (61–62%).

2

·4H

2

O, NaBH

, THF, Ac

4

, ethylenediamine, EtOH, 1 atm H

2

(82% combined yield); (b) nBuLi,

3

, MeOH, 0 °C (66%); (e) K CO ,

2

O, –78 to 0 °C (see text); (d) K

2

CO

3

2

ratio in 80% yield; and LHMDS, which afforded a Ͻ1:Ͼ99 alkyne, but led instead to the dimethyl ketal 19a.^[³¹^]This

Z/E ratio in 81% yield, followed by an Ac O trap). With product most likely originates from cleavage of the enol

2

the same limitations as indicated above, we decided to de- acetate followed by double conjugate addition of methanol

protect the TMS group at this stage and separate both ter- to the unsaturated ketone. This reactivity parallels the be-

minal acetoxyenynes. However, treatment of 17a with po- havior observed for the model system 5b in the presence of

tassium carbonate in methanol did not afford the terminal piperidine (see above, Scheme 4).

Scheme 6. Reagents and conditions: (a) NiCl

Scheme; (S)-20a, 20%]; (b) CAN (3 mol-%) CH

2

·6H

3

2

O, CuI, TMEDA, THF, air, 25 °C [(E,R)-12a, 29%; (Z,R)-12a, 28%; (S)-20b, see

O, 70 °C (86% of a 33:67 mixture of Z/E isomers).

CN/H

2

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P. García-Domínguez, R. Alvarez, Á. R. de Lera

FULL PAPER

To circumvent the incompatibility of the acetoxyenyne is the synthesis of α-chloroenol esters with the desired ge-

moiety with nucleophiles, potassium carbonate in a tBuOH/ ometry because only a method for the preparation of the Z

[32]

[33]

H O mixture was used instead for TMS release, and this isomers has been reported.

2

modification afforded the desired products 5a in moderate

yields (61–62%) together with recovered starting material. construction step, and commercially available decanal 21

A model system was considered to optimize this bond

TM

After HPLC separation (Sunfire

5 μm, 4.6ϫ250 mm, was chosen as the starting material. The synthesis of the

9

9:1 hexane/tert-butyl methyl ether, 1 mL/min or Waters (Z)-α-chloroenol ester (Z)-24 is shown in Scheme 7. The

TM

Spherisorb

5 μm, 10ϫ250 mm, 99:1 hexane/tert-butyl preparation of this type of substrate usually requires two or

methyl ether, 1.5 mL/min) each acetoxyenyne isomer was three steps and involves the formation of trihalomethylcarb-

coupled to excess (R)-14 by using the Ni/Cu co-catalyzed inol and the derived trihalomethylcarbinol esters as inter-

[

34]

cross-coupling procedure to afford 12a (29 and 28% for E mediates. Among the methods described for the synthesis

and Z isomers, respectively, see Scheme 6). Homocoupled of trihalomethylcarbinols, the base-promoted addition of

products derived from the acetoxyenynes were also isolated. the chloroform anion to aldehydes or ketones is the most

Lastly, efficient CAN-mediated cleavage of the isopropylid- commonly reported. The use of common bases such as

[

37]

ene ketal of 12a provided peyssonenynes (1a) as described tBuOK or NaH in DMF,

previously, and therefore this approach provides a formal as DBU or DBN,

or cyclic amidine bases such

failed to provide the decanal-derived

[

11]

[38]

total synthesis of the natural products. Relative to the first- trichloromethylcarbinol 22 or led to trichloromethylcarb-

generation route A, strategy B is more convergent, more inol ester 23, albeit in low yields. A more efficient method

[

39]

stereoselective, and saves two steps. However, approach B is is that reported by Corey et al. involving the room-tem-

limited by the moderate yield of the key coupling step.

perature decarboxylation of a 1:1 mixture of trichloroacetic

To complement route A and further document the appli- acid and sodium trichloroacetate in dimethylformamide to

cation of the reaction to give functionalized systems, the generate the highly nucleophilic trichloromethyl anion. Re-

Ni/Cu co-catalyzed cross-coupling reaction of alkyne 14 action with decanal gave trichloromethylcarbinol 22 in ex-

was also performed with propargylic alcohols 3a^[and 3b cellent yield, and this was efficiently acetylated to 23 by

11]

(

Scheme 6). In the case of the model system, the yield of treatment with Ac O in pyridine.

2

20b was higher with an excess of the propargylic alcohol 3b

Compound 23 was subjected to the conditions used for

(36 vs. 27%), but this version is impractical in the case of the chromous chloride induced synthesis of (Z)-α-haloenol

the peyssonenynes because the skipped diene moiety is esters [and (Z)-β-haloenol ethers] from trichloromethyl-

more valuable. Therefore the use of excess (S)-14 (the S carbinol esters developed by Falck and co-workers^[and

enantiomer was used for this study) allowed the skeleton of this produced (Z)-24 stereoselectively in good yield (88%).

33]

these compounds to be built, but the yields were lower for

Given the scarcity of data on the reactivity of (Z)-α-chlo-

both the model system and the peyssonenynes, which con- roenol esters^[³³^]and the lack of precedents for their use in

firms the limitations of the Ni/Cu co-catalyzed cross-cou- cross-coupling reactions, we adopted the conditions de-

[

22]

pling of alkynes in a complex setting.

scribed for the Sonogashira cross-coupling of the structur-

ally related 4,6-dichloro-2-pyrones or 6-chloro-2-pyrones

[

40]

with terminal alkynes.

^Csp2^–^Csp Bond-Formation Strategies

The results of the treatment of α-chloroenol ester (Z)-24

with (triisopropylsilyl)acetylene as a model alkyne are

shown in Table 2. Initial screening conditions employed bis-

Route C Ϫ Sonogashira Cross-Coupling of an Alkyne and

an α-Chloroenol Acetate

(

triphenylphosphane)dichloropalladium as catalyst, a 4:1

Route C in this strategy is based on a Sonogashira cou- THF/Et N mixture as solvent, and co-catalytic amounts of

3

pling reaction between the α-chloroenol ester 8 and diyne 7 CuI in a 1:2 ratio relative to Pd. The reaction mixture was

(see Scheme 2). The main limitation found in this approach stirred at room temperature overnight and the coupled

Scheme 7. Reagents and conditions: (a) Cl

3

CCO

2

H/Cl

3

CCO

2

Na (1:1), DMF, 25 °C, 14 h (86%); (b) Ac

2

O, pyridine, 25 °C, 24 h (94%);

(

c) i. DBN, CHCl , 25 °C; ii. Ac O (31%); (d) CrCl

3

2

, THF, reflux, 72 h (88%); (e) see Table 2.

6

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Syntheses of Natural and Unnatural Acetoxyenediynes

product (E)-25 was obtained in 20% yield. An increase in coupling reaction and the lack of a procedure for the syn-

the Pd/Cu ratio from 1:2 to 1:4 resulted in only a slight thesis of the (E)-α-chloroenol esters, which are the precur-

increase in yield (entries 1 and 2). Changes in both the tem- sors of the isomers present in the natural products (1a, 2a),

perature (70 °C) and the solvent (DMF or toluene) were led us to abandon this route to the peyssonenynes.

detrimental (entries 3–5), and an increase in the amount of

Route D Ϫ Formation of Diynones by the Addition of

palladium and copper to 5 and 15% (a 1:3 Pd/Cu ratio),

Diynyl Anion to Weinreb Amides

respectively, in toluene with only 3 equiv. of base led to low

conversions to (E)-25 (entry 6). The use of tetrakis(triphen-

ylphosphane)palladium as the catalyst led to a slight im-

provement in yield (entry 7) but this was insufficient for

Route D was explored with a focus on the condensation

of Weinreb amide 6 with the diynyl anion derived from 7.

A two-step sequence was initially proposed for the prepara-

tion of 7, namely the cross-coupling of alkynes using either

synthetic applications. The low yields obtained in the cross-

the Cadiot–Chodkiewicz conditions or the Ni/Cu co-cata-

lyzed reaction followed by deprotection of the terminal al-

kyne (Scheme 8). Cross-coupling of iodoalkyne (R)-4 with

Table 2. Conditions for the Sonogashira cross-coupling of α-chloro-

[

20]

excess (triisopropylsilyl)acetylene

led to (R)-26 in good

enol acetate (Z)-24 and TIPS-ethyne (2 equiv.).

yields. The alternative Ni/Cu co-catalyzed coupling of al-

kyne (R)-14 and excess (triisopropylsilyl)acetylene also pro-

vided (R)-26, but in this case disappointing yields were ob-

tained.

Entry Pd catalyst

amount)

mol-%]

Cu

Solvent

T

(E)-25

(

[

mol-%]

[°C] Yield [%]

1

2

3

4

[PdCl

2)

[PdCl

2)

[PdCl

2)

[PdCl

2)

2

(PPh

3

)

2

]

4

8

THF/Et

(4:1)

THF/Et

(4:1)

THF/Et

(4:1)

DMF/Et

(4:1)

toluene/

3

Et N

(4:1)

toluene

3

N

25

70

25

20

22

14

4

Deprotection of the silyl group of (R)-26 with TBAF af-

forded two new compounds in moderate yields. These com-

(

®

pounds were separated by HPLC (Waters Spherisorb 5 μm

silica gel, 10ϫ250 mm, 90:10 hexane/EtOAc, 3 mL/min)

and identified as the diastereomeric hepta-2,4-dien-6-

ynoates (R)-27 (Scheme 8). These new structures probably

result from the reaction of the fluoride anion at the α- and

β-(propargylic) positions of the formal glycerol-derived

hepta-4,6-diynoate through the mediation of yne-allenes

and the corresponding ketene enolate intermediates fol-

lowed by protonation. Interestingly, the cyclohexylidenegly-

cerol-derived octa-5,7-diynoate (a related homologue not

shown) afforded the terminal diyne in 67% yield under the

(

3

N

(

5

6

[PdCl

2)

[PdCl

5)

[Pd(PPh

2)

2

(PPh

3

)

2

]

8

25

13

5

(

2

(PPh

)

15

(3 equiv.

(

Et N)

3

7

3

)

4

]

8

THF/Et

(4:1)

3

N

25

28

(

Scheme 8. Reagents and conditions: (a) NiCl

2

·6H

2

O, CuI, TMEDA, THF, air, 25 °C (32%); (b) CuCl, piperidine, 0 °C [(R)-26, 66%; (R)-

, MeOH, 0 °C (20%); (e) K CO , tBuOH/H O, 25 °C (63%); (f) nBuLi or tBuLi or

2

8, 81%]; (c) TBAF, THF, 25 °C (39%); (d) K

CO

3

2

3

2

LHMDS, THF, –40 to 25 °C.

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P. García-Domínguez, R. Alvarez, Á. R. de Lera

FULL PAPER

same reaction conditions. This result indicates that both the formation of the glycerol ester and use instead the cor-

acidic positions must be adjacent to induce the isomeriza- responding alcohol as the precursor. Commercially avail-

tion of the butyne to the butadiene unit.

able 5-pentyn-1-ol (31) was protected as the tert-butyldi-

[

43]

An alternative procedure for the deprotection of (R)-26 phenylsilyl ether 32, which was iodinated to 33 and then

by using HF·Py, in which the fluoride is involved in the subjected to Cadiot–Chodkiewicz coupling with (trimethyl-

formation of pyridinium poly(hydrogen fluoride) com- silyl)acetylene to give the corresponding diyne 34 in excel-

[

41]

plexes,

failed to provide the terminal alkyne and the lent yield (Scheme 9). Orthogonal deprotection of the tri-

starting material was fully recovered. The Cadiot–Chodkie- methylsilyl group with potassium carbonate in methanol

wicz cross-coupling between the iodoalkyne (S)-4 and (tri- provided the desired terminal diyne 35. The addition to 6b

methylsilyl)acetylene (with a more labile silyl protecting of the diynyl anion generated by in situ treatment of 35

group) furnished diyne (R)-28 in good yield (Scheme 8). As with nBuLi at –40 °C afforded diynone 36b. The enol acet-

in route B, the trimethylsilyl group was removed with potas- ates were prepared under the standard conditions with

sium carbonate in tBuOH/H O (in this case the use of Et N, DMAP, and Ac O with poor E/Z stereoselectivities,

2

3

2

methanol also induced transesterification with the glycerol as observed in route B. However, we decided to optimize

ester to give the hepta-4,6-diynoate 29^[).

42]

the remaining steps of the synthesis with the mixture of

The addition of the diynyl anion of (R)-7, generated in the two isomers. Deprotection of the silyl ether with TBAF

situ, to Weinreb amide 6b was attempted by using three afforded alcohol 38b, which was converted into the corre-

different organolithium bases under the conditions that had sponding carboxylic acid 40b after a consecutive Swern and

[

44]

proven successful in the preparation of the propargylic Lindgren

two-step oxidation protocol. HPLC separa-

ketones 10b, 10a, and 16a (see Schemes 3 and 5). However, tions were successful after each of the steps in this sequence

these experiments failed to afford the desired product, even (tert-butyldiphenylsilyl ether 37b, alcohol 38b, and carbox-

on using 2 equiv. of base at –40 °C. In all cases the Weinreb ylic acid 40b intermediates) affording the corresponding E

amide 6b was fully recovered. The failure of this approach and Z isomers, which were fully characterized. Final esteri-

was probably due to the competing deprotonation of the α- fication of 40b with (R)-isopropylidene glycerol (R)-41 in

enolizable position and, despite the fact that 2 equiv. of the presence of DCC and DMAP as coupling agents led to

base were used, only the starting materials were recovered. the desired compounds (S)-12b in moderate yields. As in

In an effort to avoid the incompatibility of functional route B, the final ketal CAN-catalyzed deprotection to (S)-

groups with the reaction conditions, we opted to postpone 1b was accomplished in a straightforward manner.

Scheme 9. Reagents and conditions: (a) TBDPSCl, DMAP, Et

c) CuCl, piperidine, 0 °C (100%); (d) K CO , MeOH, 0 °C (95%); (e) nBuLi, THF, –40 to 25 °C (74%); (f) Et

5 °C, 44 h (93%, 41:59 Z/E); (g) TBAF, THF, 25 °C (50%); (h) DMSO, (COCl) , Et N, CH Cl , –60 to 25 °C; (i) NaClO

butene, NaH PO , tBuOH/H O (69%, over two steps); (j) (R)-41, DCC, DMAP, CH Cl , 25 °C, 8 h (58%); (k) CAN (3 mol-%), CH

O, 70 °C (74% of a 30:70 mixture of Z/E isomers).

3

N, CH

2

Cl

2

, 0 to 25 °C (86%); (b) NIS, AgNO

3

, acetone, 25 °C, 12 h (60%);

N, DMAP, Ac O, CH Cl

, 2-methyl-2-

CN/

(

2

3

2

,

2

3

2

4

2

3

H

2

8

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Syntheses of Natural and Unnatural Acetoxyenediynes

Scheme 10. Reagents and conditions: (a) nBuLi, THF, –40 to 25 °C (92%); (b) LiNR

2

, –78 to 0 °C, then Ac

NLi; 13:87 Z/E, 82% using LHMDS]; (c) TBAF, THF, 25 °C (46–59%); (d) DMSO, (COCl) , Et

, 2-methyl-2-butene, NaH PO , tBuOH/H O (74–78% combined); (f) DCC, DMAP, CH Cl , 25 °C (46% of a 13:87 mixture

CN/H O, 70 °C (86% of a 33:67 mixture of Z/E isomers).

2

O [67:33 Z/E, 50% using

(

Me

e) NaClO

2

PhSi)

2

3

N, CH Cl , –60 to 25 °C;

2

4

2

of Z/E isomers); (g) CAN (3 mol-%) CH

3

2

Route D was subsequently extended to the synthesis of routes with a model system derived from palmitic acid. The

the natural products. Addition of the diynyl anion of com- number of steps in the three new synthetic schemes has

pound 35 to Weinreb amide 6a afforded the corresponding been reduced relative to the previously reported first-gener-

diynone 36a in an improved yield compared with the model ation approach to these natural products. This initial ap-

system (Scheme 10). The poor E/Z selectivity obtained in proach was based on a Cadiot–Chodkiewicz cross-coupling

the formation of the enol acetate with Et N, DMAP, and and late-stage construction of the enol acetate, a step that

3

Ac O in the model diynone forced us to modify this meth- was limited by low stereoselectivity. We found that the for-

2

odology and generate the enolates with lithium amide bases mation of the acetoxyenynes is highly stereoselective with

followed by trapping with acetic anhydride. As in route B particular lithium amide bases. The skeleton of the peys-

with ynones 10a and 16a, (Me PhSi) NLi and LHMDS sonenynes was completed by using the isolated isomers of

2

were chosen to obtain the (Z)- or (E)-acetoxyenediynes as this component in the Ni/Cu co-catalyzed cross-coupling of

major isomers, respectively (Scheme 10). Surprisingly, both terminal alkynes. Despite the fact that the terminal func-

the yields and the E/Z selectivities obtained in this case tionalization of one alkyne is avoided compared with in the

were lower than those achieved by route B.^[

45]

Cadiot–Chodkiewicz cross-coupling reaction, the yields ob-

Although the two isomeric alcohols 38a, obtained by de- tained in the construction of these complex molecules were

protection of the silyl ethers 37a with TBAF, were separated moderate, which makes further optimization of the process

by HPLC and characterized, the synthetic sequence was desirable. Moreover, although the (Z)-α-chlorovinylacetate

continued with the mixture of isomers obtained with each was obtained with complete stereoselectivity, the subse-

lithium amide base. As in the model system, consecutive quent Sonogashira cross-coupling gave only low yields. Fi-

Swern and Lindgren oxidations afforded the carboxylic ac- nally, the addition of diynyl anions to Weinreb amides to

ids 40a, which were separated by HPLC. The final DCC- generate the diynones directly is highly efficient, but the se-

induced coupling of the mixture of isomers of acid 40a with quence is limited by the low stereoselectivity of the genera-

the glycerol isopropylidene ketal (R)-41 provided peys- tion of the (Z)-acetoxyenediyne.

sonenyne precursors (S)-12a in moderate yields, thus com-

The methodological survey reported herein is expected

pleting a third formal approach to these natural prod- to guide ensuing synthetic efforts to prepare new analogues

[

11]

ucts.

endowed with the acetoxyenediyne functionality that show

greater stability and contain more drug-like structural

features than the natural products. The acetoxyenediynes

are considered as prodrugs that release the highly reactive

Conclusions

Complementary stereoselective and convergent synthetic Michael acceptor diynone, which can undergo conjugate

approaches to the natural products peyssonenynes have additions with reactive thiols (much like those observed in

been developed following optimization of the different this study with the formation of secondary products 13b

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P. García-Domínguez, R. Alvarez, Á. R. de Lera

FULL PAPER

and 19a). The peyssonenynes are, in this respect, one of the 3 H, NCH

3

), 2.39 (t, J = 7.6 Hz, 2 H, 2-H), 1.68–1.52 (m, 2 H, 3-

H), 1.37–1.18 (m, 24 H, 12 CH

2

), 0.86 (t, J = 6.8 Hz, 3 H,

“

chemical weapons” natural products that are disguised as

1

3

[47]

CH ) ppm. C NMR (100.62 MHz, CDCl ): δ = 174.4 (s, C-1),

3

a less-reactive precursor.

60.7 (q, OMe), 31.7 (t), 31.5 (t), 29.4 (t, 5ϫ), 29.2 (t, 3ϫ), 29.1 (t),

9.1 (t), 26.8 (q, NCH ), 24.3 (t), 22.4 (t), 13.8 (q, C-16) ppm. IR

2

3

–

1

(

NaCl): ν˜ = 2925 (s, C–H), 2855 (m, C–H), 1674 (m, C=O) cm .

Experimental Section

+

MS (FAB ): m/z (%) = 300 (100) [M + 1] . HRMS (FAB ): calcd.

for C18

H38NO

2

[M + 1]⁺300.2903; found 300.2910.

General Procedures: Solvents (acetone, CHCl

3

, EtOAc, and EtOH)

were dried according to published methods and distilled before use.

1

-(Triisopropylsilyl)octadec-1-yn-3-one (10b): nBuLi (14.20 mL,

.57 m in THF, 22.28 mmol) was added dropwise to a stirred solu-

TM

THF, CH

solvent purification system. Et

dried by distillation with CaH . All other reagents were commercial

2

Cl

2

, DMF, and MeOH were dried by using a Puresolv

3

N, piperidine, and pyridine were

tion of (triisopropylsilyl)acetylene (6.09 g, 33.41 mmol, 7.4 mL) in

THF (0.2 mmol/mL) at –40 °C and the solution was stirred for 1 h.

Subsequently, a solution of N-methoxy-N-methylhexadecanamide

2

compounds of the highest purity available. All the reactions were

carried out under argon, and those not involving aqueous reagents

were carried out in oven-dried glassware. All solvents and anhy-

drous solutions were transferred through syringes and cannulae

previously dried in an oven for at least 12 h and stored in a desicca-

(

6b; 3.33 g, 11.14 mmol) in THF (0.84 mmol) was added dropwise

at –10 °C and the reaction was further stirred for 1 h at –10 °C and

for 1 h at room temperature. A saturated aqueous solution of

NH

The combined organic layers were washed with brine, dried with

Na SO , and the solvent was evaporated. The residue was purified

by flash chromatography (reversed-phase, 10:90 CH Cl /acetoni-

trile) to afford 4.31 g (92%) of the title product as a colorless oil.

4 2

Cl was added and the mixture was extracted with Et O (3ϫ).

2

tor with KOH. For reactions at low temperature, ice/water or CO /

acetone systems were used. Analytical TLC was performed on alu-

minium plates with Merck Kieselgel 60F254 and visualized by UV

irradiation (254 nm) or by staining with an ethanolic solution of

phosphomolybdic acid or an ethanolic solution of anisaldehyde.

Flash column chromatography was carried out on Merck Kieselgel

2

4

2

1

H NMR (400.13 MHz, CDCl

H), 1.74–1.63 (m, 2 H, 3-H), 1.36–1.18 (m, 24 H, 12 CH

.03 (m, 21 H, iPr Si), 0.88 (t, J = 6.8 Hz, 3 H, CH ) ppm.

NMR (100.62 MHz, CDCl ): δ = 188.1 (s), 104.4 (s, C-2), 95.4 (s),

5.8 (t), 32.1 (t), 29.8 (t, 6ϫ), 29.6 (t), 29.5 (t, 2ϫ), 29.1 (t), 24.4

t), 22.8 (t), 18.6 (q, 6ϫ, iPr Si), 14.2 (q), 11.1 (d, 3ϫ, iPr Si) ppm.

MS (EI): m/z (%) = 421 (0.2) [M + 1] , 420 (0.6) [M] , 378 (19),

3

): δ = 2.54 (t, J = 7.4 Hz, 2 H, 2-

2

), 1.17–

60 (230–400 mesh) under pressure. UV/Vis spectra were recorded

13

1

3

C

with a Cary 100 Bio spectrophotometer in MeOH. IR spectra were

recorded with a JASCO IR 4200 spectrophotometer from a thin

film deposited onto NaCl glass. Mass spectra were recorded with

a Hewlett–Packard HP59970 spectrometer operating at 70 eV by

electron ionization and with an APEX III FT-ICR MS spectrome-

ter (Bruker Daltonics, Billerica, MA) equipped with a 7T actively

shielded magnet. Ions were generated by using an Apollo API elec-

trospray ionization (ESI) source with a voltage of between 1800

and 2200 V (to optimize ionization efficiency) applied to the needle

and a counter voltage of 450 V applied to the capillary. Samples

were prepared by adding a spray solution of 70:29.9:0.1 (v/v/v)

3

4

(

3

+

377 (100), 167 (15). IR (NaCl): ν˜ = 2925 (s, C–H), 2855 (m, C–H),

–1

1

681 (m, C=O), 1460 (m) cm . UV (MeOH): λmax = 234 nm.

HRMS (EI): calcd. for C27H52OSi 420.3787; found 420.3795.

(E)- and (Z)-1-(Triisopropylsilyl)octadec-3-en-1-yn-3-yl Acetate

(11b). General Procedure for Enol Formation and Subsequent Trapp-

ing with Acetic Anhydride

3

CH OH/water/formic acid to a solution of the sample at a v/v ratio

Method A: n-Butyllithium (0.11 mL, 1.56 m in THF, 0.18 mmol)

was added dropwise to a cooled (0 °C) stirred solution of diisopro-

pylamine (34 μL, 24 mg, 0.24 mmol) in THF (0.5 mmol/mL) and

the solution was stirred for 30 min. After cooling to –78 °C, a solu-

tion of 1-(triisopropylsilyl)octadec-1-yn-3-one (10b; 0.05 g,

of 1 to 5% to give the best signal-to-noise ratio. HRMS were re-

corded a VG Autospec spectrometer. ¹H NMR spectra were re-

corded in CDCl

Bruker AMX-400 spectrometer at 400 MHz with the residual pro-

tic solvent as the internal reference [CDCl , δ = 7.26 ppm; (CD

CO, δ = 2.05 ppm; C , δ = 7.16 ppm]; chemical shifts (δ) are

3 6 6

, C D , or acetone at ambient temperature with a

3

H

3 2

) -

0.12 mmol) and DMPU (72 μL, 76 mg, 0.59 mmol) in THF

H

6

D

6

H

(

0.06 mmol/mL) was added and the resulting solution was stirred

given in parts per million (ppm), and coupling constants (J) are

for 2 h. Subsequently, acetic anhydride (56 μL, 0.06 g, 0.59 mmol)

was added dropwise and the reaction was stirred for a further 1 h

1

given in Hz. The H NMR spectra are reported as follows: δ (multi-

plicity, coupling constant J, number of protons, assignment). The

at –78 °C. A saturated aqueous solution of NaHCO

and the mixture was extracted with Et O (3ϫ). The combined or-

ganic layers were washed with brine (2ϫ), dried (Na SO ), and

3

was added

1

3

C NMR spectra were recorded in CDCl

temperature on the same spectrometer at 100 MHz with the central

peak of CDCl (δ = 77.16 ppm), C (δ = 128.06 ppm), or

CD CO (δ = 29.84 ppm) as the internal reference. The

3 6 6

and C D at ambient

2

4

3

C

6

D

6

C

the solvent was evaporated. The residue was purified by column

chromatography (silica gel, 98:2 hexane/EtOAc) to afford 48 mg

(

3

)

2

C

DEPT135 pulse sequence was used to aid the assignment of signals

(

86%) of a colorless oil that was identified as the title product as

in the ¹³C NMR spectra.

a 27:73 mixture of E/Z isomers of acetoxyenyne 11b.

Route B

1

(

E)-1-(Triisopropylsilyl)octadec-3-en-1-yn-3-yl Acetate [(E)-11b]: H

N-Methoxy-N-methylhexadecanamide (6b): N,O-Dimethylhydroxyl-

amine hydrochloride (1.71 g, 17.55 mmol), EDCI (3.36 g,

NMR (400.13 MHz, CDCl

3

): δ = 5.67 (t, J = 8.0 Hz, 1 H, 4-H),

CH ), 1.55–1.35 (m, 2

), 1.14–0.95 (m, 21 H, iPr Si),

) ppm. ¹C NMR (100.62 MHz,

), 130.6 (s, C-3), 129.5 (d, C-4), 98.7

(s, C-1 or C-2), 96.8 (s, C-1 or C-2), 32.1 (t), 29.8 (t, 6ϫ), 29.6 (t),

29.5 (t), 29.3 (t), 29.0 (t), 28.3 (t), 22.8 (t), 20.9 (q, CO CH ), 18.7

(q, 6ϫ, iPr Si), 14.2 (q, C-18), 11.3 (d, 3ϫ, iPr Si) ppm. IR (NaCl):

ν˜ = 2926 (s, C–H), 2857 (m, C–H), 1769 (m, C=O), 1463 (m), 1205

2.36–2.21 (m, 2 H, 5-H), 2.13 (s, 3 H, CO

H, 7-H), 1.35–1.16 (m, 22 H, 11 CH

0.88 (t, J = 6.8 Hz, 3 H, CH

CDCl ): δ = 168.8 (s, CO CH

2

3

17.55 mmol), and DMAP (2.14 g, 17.55 mmol) were added to a

2

3

solution of palmitic acid (3.0 g, 11.79 mmol) in CH Cl (5 mL) and

2

3

the reaction was stirred overnight at room temperature. A saturated

aqueous solution of NaCl was added and the mixture was extracted

with EtOAc (3ϫ). The combined organic layers were washed with

3

2

3

2

3

an aqueous solution of HCl (5%) and brine, dried with Na

2

SO

4

,

3

and the solvent was evaporated to afford 3.33 g (95%) of the title

–

1

+

compound as a white solid; m.p. 62–64 °C (hexane/diethyl ether).

(m) cm . UV (MeOH): λmax = 235 nm. MS (FAB ): m/z (%) = 463

1

H NMR (400.13 MHz, CDCl

3

): δ = 3.66 (s, 3 H, OCH

3

), 3.16 (s,

(24)

[M

+

10

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Syntheses of Natural and Unnatural Acetoxyenediynes

+

1

(

4

] , 462 (6) [M] , 461 (8) [M – 1] , 421 (12), 419 (22), 377 (12), 174 0.59 mmol), and acetic anhydride (56 μL, 0.06 g, 0.59 mmol) in

+

Si [M + 1]⁺

14), 173 (100). HRMS (FAB ): calcd. for C29

63.3971; found 463.3963.

H

55

O

2

THF (2.5 mL) at –78 °C afforded, after purification by column

chromatography (silica gel, 98:2 hexane/EtOAc), 48 mg (86%) of a

colorless oil that was identified as the title product as a 54:46 mix-

ture of E/Z isomers.

1

(

Z)-1-(Triisopropylsilyl)octadec-3-en-1-yn-3-yl Acetate [(Z)-11b]: H

NMR (400.13 MHz, CDCl

.17 (s, 3 H, CO CH

H, 12 CH ), 1.14–0.96 (m, 21 H, iPr

CH ) ppm.

CO CH

s, C-1 or C-2), 32.1 (t), 29.8 (t, 6ϫ), 29.7 (t), 29.5 (t), 29.4 (t), 28.6

t), 26.3 (t), 22.8 (t), 20.7 (q, CO CH ), 18.7 (q, 6ϫ, iPr Si), 14.2

q, C-18), 11.3 (d, 3ϫ, iPr Si) ppm. IR (NaCl): ν˜ = 2926 (s, C–

3

): δ = 5.70 (t, J = 7.6 Hz, 1 H, 4-H),

3

), 2.08–1.96 (m, 2 H, 5-H), 1.42–1.15 (m, 24 Method F: Using a modification of the general procedure described

2

3

Si), 0.88 (t, J = 6.8 Hz, 3 H,

above for the synthesis of enol acetates, the reaction of 1-(triiso-

13

3

C NMR (100.62 MHz, CDCl

), 129.9 (s, C-3), 129.1 (d, C-4), 101.0 (s, C-1 or C-2), 91.1

3

): δ = 168.1 (s, propylsilyl)octadec-1-yn-3-one (0.05 g, 0.12 mmol), 1,1,3,3-tet-

2

3

ramethyl-1,3-diphenyldisilazane (69 μL, 68 mg, 0.24 mmol), n-but-

yllithium (0.14 mL, 1.26 m in THF, 0.18 mmol), and acetic anhy-

dride (56 μL, 0.06 g, 0.59 mmol) in THF (2.5 mL) at –78 °C af-

forded, after purification by column chromatography (silica gel,

98:2 hexane/EtOAc), 55 mg (100%) of a colorless oil that was iden-

tified as the title product as a 28:72 E/Z mixture of isomers.

(

2

3

–

1

H), 2859 (m, C–H), 1770 (m, C=O), 1463 (m), 1193 (m) cm . UV

+

(

MeOH): λmax = 234 nm. MS (FAB ): m/z (%) = 463 (27) [M +

+

1

] , 462 (7) [M] , 461 (10) [M – 1] , 421 (14), 419 (23), 377 (12),

Method G: Using a modification of the general procedure described

above for the synthesis of enol acetates, the reaction of 1-(triiso-

propylsilyl)octadec-1-yn-3-one (10b; 0.05 g, 0.12 mmol), hexa-

methyldisilazane (50 μL, 38.4 mg, 0.24 mmol), n-butyllithium

(0.14 mL, 1.26 m in THF, 0.18 mmol), and acetic anhydride (56 μL,

0.06 g, 0.59 mmol) in THF (2.5 mL) at –78 °C afforded after purifi-

cation by column chromatography (silica gel, 98:2 hexane/EtOAc)

54.1 mg (98%) of a colorless oil that was identified as the title prod-

uct as a 93:7 mixture of E/Z isomers.

+

55 2

74 (16), 173 (100). HRMS (FAB ): calcd. for C29H O Si [M +

+

]

463.3971; found 463.3971.

Method B: Using a modification of the general procedure described

above for the synthesis of enol acetates, the reaction of 1-(triiso-

propylsilyl)octadec-1-yn-3-one (10b; 0.07 g, 0.17 mmol), diisoprop-

ylamine (47 μL, 34 mg, 0.33 mmol), n-butyllithium (0.19 mL,

.32 m in THF, 0.25 mmol), and acetic anhydride (79 μL, 85 mg,

.83 mmol) in THF at –78 °C afforded, after purification by col-

1

0

umn chromatography (silica gel, 98:2 hexane/EtOAc), 65 mg (84%)

of a colorless oil that was identified as the title product as an 80:20

mixture of E/Z isomers of the acetoxyenyne 11b. Separation by

HPLC [Spherisorb 5 μm, 10ϫ250 mm, 95.5:0.5 hexane/EtOAc,

Method H: Et

.05 mmol), and acetic anhydride (60 μL, 64 mg, 0.63 mmol) were

added to a stirred solution of 1-(triisopropylsilyl)octadec-1-yn-3-

one (10b; 44 mg, 0.10 mmol) in CH Cl (2.6 mL) at 0 °C and the

reaction mixture was stirred for 72 h at room temperature. A satu-

rated aqueous solution of NH Cl was added and the mixture was

extracted with CH Cl (3ϫ). The combined organic layers were

dried (Na SO ) and the solvent was evaporated. The residue was

3

N (73 μL, 53 mg, 0.52 mmol), DMAP (6.4 mg,

0

2

1

mL/min, t

R R R

= 9.8 min; t [(Z)-11b] = 7.9 min; t [(E)-11b) =

0.9 min] allowed the isolation of both isomers together with small

4

amounts of a byproduct, characterized as propargylic acetate SI-1

see the Supporting Information).

2

(

2

4

Method C: Using a modification of the general procedure described

above for the synthesis of enol acetates, the reaction of 1-(triiso-

propylsilyl)octadec-1-yn-3-one (10b; 0.05 g, 0.12 mmol), 2,2,6,6-

tetramethylpiperidine (41 μL, 34 mg, 0.24 mmol), n-butyllithium

purified by column chromatography (silica gel, 98:2 hexane/EtOAc)

to afford 48.4 mg (quantitative) of a colorless oil that was identified

as the title product as a 50:50 mixture of E/Z isomers.

Method I: A 0.01 m solution of HClO

acetic anhydride (61 mL) was added to 1-(triisopropylsilyl)octadec-

-yn-3-one (10b; 0.85 g, 2.01 mmol). After stirring for 24 h, the

mixture was washed with a saturated aqueous solution of

NaHCO , dried (Na SO ), and the solvent was removed under vac-

4

in EtOAc containing 10%

(0.14 mL, 1.26 m in THF, 0.18 mmol), and acetic anhydride (56 μL,

0.06 g, 0.59 mmol) in THF (2.5 mL) at –78 °C afforded, after puri-

1

fication by column chromatography (silica gel, 98:2 hexane/

EtOAc), 51.9 mg (100%) of a colorless oil that was identified as

the title product as a 91:9 mixture of E/Z isomers of the acetoxy-

enyne 11b.

3

2

4

uum. The residue was purified by column chromatography (silica

gel, 98:2 hexane/EtOAc) to afford 0.79 g (84%) of a colorless oil

that was identified as the title product as an 89:11 mixture of E/Z

isomers.

Method D: n-Butyllithium (0.14 mL, 1.26 m in THF, 0.18 mmol)

was added dropwise to a cooled (0 °C) stirred solution of 2,2,6,6-

tetramethylpiperidine (41 μL, 34 mg, 0.24 mmol) and lithium

bromide (16 mg, 0.18 mmol) in THF (0.5 mmol/mL) and the solu-

tion was stirred for 30 min. After cooling to –78 °C, a solution of

(

Z)-Octadec-3-en-1-yn-3-yl Acetate [(Z)-5b]. General Procedure for

the Deprotection of (Triisopropylsilyl)alkynes: nBu NF (0.12 mL,

m in THF, 0.12 mmol) was added to a stirred solution of (Z)-

-(triisopropylsilyl)octadec-3-en-1-yn-3-yl acetate [(Z)-11b; 0.05 g,

.11 mmol] in THF (3 mL) and the reaction was stirred for 45 min

4

1

0

1-(triisopropylsilyl)octadec-1-yn-3-one (10b; 0.05 g, 0.12 mmol) in

THF (0.06 mmol/mL) was added and the resulting solution was

stirred for 2 h. Subsequently, acetic anhydride (56 μL, 0.06 g,

at 25 °C. A saturated aqueous solution of NaHCO

the mixture was extracted with Et O (3ϫ). The combined organic

layers were washed with brine, dried with Na SO , and the solvent

3

was added and

0

.59 mmol) was added dropwise and the reaction mixture was

stirred for a further 1 h at –78 °C. A saturated aqueous solution of

NaHCO was added and the mixture was extracted with Et

3ϫ). The combined organic layers were washed with brine (2ϫ),

dried (Na SO ), and the solvent was evaporated. The residue was

2

4

3

2

O

was evaporated. The residue was purified by column chromatog-

(

raphy (silica gel, 95:5 hexane/EtOAc) to afford 0.02 g (63%) of the

2

4

1

title compound as a white solid. H NMR (400.13 MHz, CDCl

3

):

purified by column chromatography (silica gel, 98:2 hexane/EtOAc)

to afford 20.4 mg (37%) of a colorless oil that was identified as the

title product 11b as the E isomer.

δ = 5.75 (t, J = 7.6 Hz, 1 H, 4-H), 2.96 (s, 1 H, 1-H), 2.19 (s, 3 H,

CO CH ), 2.10–1.97 (m, 2 H, 5-H), 1.40–1.18 (m, 24 H, 12 CH ),

.88 (t, J = 6.8 Hz, 1 H, CH ) ppm. C NMR (100.62 MHz,

CDCl ): δ = 168.4 (s, CO CH ), 130.6 (d), 129.1 (s), 78.3 (s), 77.0

(d), 32.1 (t), 29.8 (t, 5ϫ), 29.7 (t), 29.5 (t, 2ϫ), 29.3 (t), 28.5 (t),

26.2 (t), 22.8 (t), 20.7 (q, CO CH ), 14.3 (q, C-18) ppm. IR (NaCl):

ν˜ = 2924 (s, C–H), 2854 (m, C–H), 1768 (s, C=O), 1462 (w), 1370

2

3

2

13

0

3

Method E: Using a modification of the general procedure described

above for the synthesis of enol acetates, the reaction of 1-(triiso-

propylsilyl)octadec-1-yn-3-one (10b; 0.05 g, 0.12 mmol), 2,2,6,6-

tetramethylpiperidine (41 μL, 34 mg, 0.24 mmol), n-butyllithium

3

2

3

2

3

–

1

+

(0.14 mL, 1.26 m in THF, 0.18 mmol), DMPU (72 μL, 76 mg, (w), 1200 (s) cm . UV (MeOH): λmax = 220 nm.MS (FAB ): m/z

Eur. J. Org. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 11

Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:26

Pages: 22

P. García-Domínguez, R. Alvarez, Á. R. de Lera

%) = 307 (100) [M + 1] , 306 (4) [M] , 305 (7) [M – 1] . HRMS above, the reaction of (Z)-octadec-3-en-1-yn-3-yl acetate [(Z)-5b;

FULL PAPER

+

(

+

FAB ): calcd. for C20

H

35

O

2

307.2637 [M + 1] ; found 307.2641.

37 mg, 0.12 mmol], (2ЈR)-2,3-O-isopropylidene-2,3-dihydroxy-

propyl pent-4-ynoate [(R)-14; 0.13 g, 0.60 mmol], CuI (5 mol-%),

and NiCl ·6H O (5 mol-%) in THF (1 mL) and TMEDA (4.0 μL)

2 2

at room temperature under air afforded, after purification by col-

umn chromatography (silica gel, 85:15 hexane/EtOAc), 18.2 mg

(

E)-Octadec-3-en-1-yn-3-yl Acetate [(E)-5b]: Following the general

procedure for the deprotection of (triisopropylsilyl)alkynes de-

scribed above, the reaction of (E)-1-(triisopropylsilyl)octadec-3-en-

1-yn-3-yl acetate [(E)-11b; 0.1 g, 0.22 mmol] with nBu

4

NF

(

29%) of the title compound as a colorless oil.

(

0.24 mL, 1 m in THF, 0.24 mmol) in THF (6 mL) afforded, after

purification by column chromatography (silica gel, 95:5 hexane/

EtOAc), 46 mg (69%) of the title product as a white solid. H NMR

(

5Z,8Z)-N-Methoxy-N-methylundeca-5,8-dienamide (6a): Prepara-

N-Methoxy-N-methylhex-5-ynamide

2.24 g, 14.46 mmol) and 1-bromo-2-yne (1.5 mL, 2.13 g,

4.46 mmol) were added to a stirred suspension of Cs CO (5.66 g,

2 3

7.36 mmol), NaI (2.60 g, 17.36 mmol), and CuCl (1.72 g,

7.36 mmol) in DMF (29 mL), were added and the reaction mix-

1

[11]

tion of compound 15a:

(

1

ture was vigorously stirred at 25 °C for 3 h. After the addition of

a saturated aqueous solution of NH Cl the mixture was extracted

with EtOAc (3ϫ). The combined organic layers were washed with

water (4ϫ), dried (Na SO ), and the solvent was evaporated to af-

ford a residue that was used in the next step without further purifi-

cation.

(

400.13 MHz, C

H, 1-H), 2.29–2.15 (m, 2 H, 5-H), 1.62 (s, 3 H, CO

.16 (m, 24 H, 12 CH ), 0.92 (t, J = 6.8 Hz, CH ) ppm. H NMR

400.13 MHz, CDCl ): δ = 5.75 (t, J = 8.0 Hz, 1 H, 4-H), 3.23 (s,

H, 1-H), 2.34–2.22 (m, 2 H, 5-H), 2.15 (s, 3 H, CO CH ), 1.47–

.38 (m, 2 H, CH ), 1.36–1.17 (m, 22 H, 11 CH ), 0.88 (t, J =

.8 Hz, 3 H) ppm. ¹³C NMR (100.62 MHz, C

): δ = 168.0 (s,

CH ), 130.5 (d), 130.4 (s), 82.3 (d), 76.8 (s), 32.4 (t), 30.2 (t,

ϫ), 30.1 (t), 30.0 (t), 29.9 (t), 29.8 (t), 29.4 (t), 29.2 (t), 28.2 (t),

6

D

6

): δ = 5.62 (t, J = 8.0 Hz, 1 H, 4-H), 2.75 (s, 1

2

CH ), 1.39–

3

1

(

1

6

CO

2

(

8

2

3

2

3

2

4

6

D

6

2

3

2

4

13

3.2 (t), 20.2 (q, CO

): δ = 169.0 (s, CO

2.2 (d), 76.2 (s), 32.1 (t), 29.8 (t, 5ϫ), 29.7 (t), 29.5 (t, 2ϫ), 29.2

CH ), 14.3 (q, C-18) ppm.

2

CH

3

), 14.4 (q, C-18) ppm. C NMR

100.62 MHz, CDCl

3

2

CH ), 130.9 (d), 129.4 (s),

3

A solution of sodium borohydride (0.09 g, 2.31 mmol) in ethanol

(

32 mL) was added to a suspension of nickel acetate tetrahydrate

0.58 g, 2.31 mmol) in ethanol (32 mL) under H and the reaction

(

t), 28.9 (t), 27.9 (t), 22.8 (t), 20.9 (q, CO

2

3

IR (NaCl): ν˜ = 3307 (w, –CϵC–H), 2925 (s, C–H), 2854 (m, C–

2

was vigorously stirred for 30 min. Then ethylenediamine (0.31 mL,

0.28 g, 4.63 mmol) and a solution of the residue obtained above in

ethanol (32 mL) were added. After stirring for 4 h, the mixture was

filtered through a small pad of silica gel and the solvent was evapo-

rated. The residue was purified by column chromatography (silica

gel, 80:20 hexane/EtOAc) to afford 2.69 g (82% over the two steps)

H), 1766 (m, C=O), 1564 (m), 1458 (m), 1370 (m), 1208 (m), 1107

–1

+

(

m) cm . UV (MeOH): λmax = 220, 309 nm. HRMS (ESI ): calcd.

+

for C20

H

34

O

2

Na [M + Na] 329.24510; found 329.24480.

E)-1-(Piperidin-1-yl)octadec-1-en-3-one [(E)-13b]: A solution of

E)-octadec-3-en-1-yn-3-yl acetate [(E)-5b; 5.4 mg, 0.15 mmol) in

(

piperidine was stirred at 25 °C for 30 min. A saturated aqueous

solution of NH Cl was added and the mixture was extracted with

CH Cl (3ϫ). The combined organic layers were washed with brine,

dried (Na SO ), and the solvent was evaporated. The residue was

1

of the title compound as a yellow oil. H NMR (400.13 MHz,

4

CDCl

NCH

H), 2.15–1.94 (m, 4 H, 4-H, 10-H), 1.73–1.63 (m, 2 H, 3-H), 0.93

3

): δ = 5.40–5.21 (m, 4 H), 3.64 (s, 3 H, OCH

3

), 3.14 (s, 3 H,

2

3

), 2.74 (t, J = 6.0 Hz, 2 H, 7-H), 2.40 (t, J = 7.5 Hz, 2 H, 2-

2

4

purified by column chromatography (silica gel, 70:30 hexane/

EtOAc) to afford 45.8 mg (89%) of (E)-1-(piperidin-1-yl)octadec-

13

(

t, J = 7.5 Hz, 3 H, CH

δ = 174.6 (s, C-1), 131.9 (d), 129.2 (d), 129.0 (d), 127.2 (d), 61.2 (q,

OCH ), 32.2 (q, NCH ), 31.3 (t), 26.8 (t), 25.6 (t), 24.5 (t), 20.6 (t),

4.3 (q, C-11) ppm. IR (NaCl): ν˜ = 3008 (m, –C=C–H), 2963 (m,

C–H), 2936 (m, C–H), 1669 (s, C=O), 1461 (m), 1414 (m), 1385

3 3

) ppm. C NMR (100.62 MHz, CDCl ):

1

-en-3-one [(E)-13b] as a yellow solid; m.p. 49–51 °C (hexane/

O). H NMR (400.13 MHz, CDCl ): δ = 7.47 (d, J = 12.8 Hz,

2 3

3

1

Et

H, 1-H), 5.12 (d, J = 12.8 Hz, 1 H, 2-H), 3.31–3.13 (m, 4 H, 2Ј-

H, 6Ј-H), 2.29 (t, J = 7.7 Hz, 2 H, 4-H), 1.65–1.54 (m, 8 H, 5-H,

1

–1

+

(

1

m), 1178 (w), 1107 (w), 997 (m) cm . MS (EI ): m/z (%) = 226

1) [M + H] , 225 (3) [M] , 165 (40), 164 (51), 147 (29), 121 (24),

19 (16), 107 (14), 105 (22), 103 (90), 97 (27), 95 (51), 93 (37), 91

3

2

Ј-H, 4Ј-H, 5Ј-H), 1.32–1.18 (m, 26 H, 13 CH

2

), 0.86 (t, J = 6.8 Hz,

): δ = 198.9 (s, C-

+

H, CH

3

) ppm. ¹³C NMR (100.62 MHz, CDCl

3

), 151.3 (d, C-1), 94.6 (d, C-2), 41.9 (t, 2ϫ), 32.0 (t), 29.8 (t, 11ϫ),

9.7 (t), 29.5 (t), 26.2 (t), 24.2 (t), 22.8 (t), 14.2 (q, C-18) ppm. IR

+

(

37), 81 (100), 79 (80). HRMS (EI ): calcd. for C13H23NO

2

225.1729; found 225.1728.

(

1

NaCl): ν˜ = 2952 (s, C–H), 2849 (m, C–H), 1651 (m, CO), 1551 (s),

–1

458 (m), 1378 (m) cm . UV (MeOH): λmax = 311 nm. MS (EI): (7Z,10Z)-1-(Triisopropylsilyl)trideca-7,10-dien-1-yn-3-one (10a) Ϫ

+

m/z (%) = 349 (2) [M] , 153 (56), 138 (100). HRMS (EI): calcd. for

C

General Procedure for the Synthesis of Propargylic Ketones. Ad-

dition of Alkynyllithium Compounds to Weinreb Amides: nBuLi

H

43ON [M]⁺349.3345; found 349.3350.

2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl

23

(

2.42 mL, 1.45 m in THF, 3.51 mmol) was added dropwise to a co-

oled (–40 °C) stirred solution of (triisopropylsilyl)acetylene

0.90 mL, 0.74 g, 4.05 mmol) in THF (0.2 mmol/mL) and the re-

(

(8E)-8-Acetoxy-

tricosa-8-ene-4,6-diynoate [(E,R)-12b] Ϫ General Procedure for the

Oxidative Ni/Cu Co-catalyzed Cross-Coupling of Terminal Alkynes:

(

sulting solution was stirred for 1 h. Subsequently, the solution was

warmed to –10 °C and a solution of (5Z,8Z)-N-methoxy-N-meth-

ylundeca-5,8-dienamide (6a; 0.61 g, 2.70 mmol) in THF

A suspension of CuI (5 mol-%) and NiCl

1 mL) and TMEDA (4.53 μL) was stirred for 2 min at room tem-

perature. (E)-Octadec-3-en-1-yn-3-yl acetate [(E)-5b; 46 mg,

.15 mmol] and (2ЈR)-2,3-O-isopropylidene-2,3-dihydroxypropyl

2 2

·6H O (5 mol-%) in THF

(

0.84 mmol/mL) was added dropwise and the reaction mixture was

further stirred for 1 h at –10 °C and then for 1 h at room tempera-

ture. A saturated aqueous solution of NH Cl was added and the

mixture was extracted with Et O (3ϫ). The combined organic lay-

ers were washed with brine, dried (Na SO ), and the solvent was

evaporated. The residue was purified by column chromatography

silica gel, 97:3 hexane/EtOAc) to afford 0.88 g (94%) of (7Z,10Z)-

-(triisopropylsilyl)trideca-7,10-dien-1-yn-3-one (10a) as a colorless

0

pent-4-ynoate [(R)-14; 0.16 g, 0.75 mmol] were subsequently added

and the reaction mixture was stirred at room temperature for 24 h

under air. After completion of the reaction the solvent was evapo-

rated and the residue was purified by column chromatography (sil-

ica gel, 85:15 hexane/EtOAc) to afford 31 mg (40%) of the title

compound as a colorless oil.

4

2

4

(

1

(2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl

(8Z)-8-Acetoxy-

3

oil. H NMR (400.13 MHz, CDCl ): δ = 5.43–5.21 (m, 4 H, 7-H,

tricosa-8-ene-4,6-diynoate [(Z,R)-12b]: Following the general pro-

8-H, 10-H, 11-H), 2.74 (t, J = 6.8 Hz, 2 H, 9-H), 2.56 (t, J = 7.4 Hz,

cedure for the synthesis of unsymmetrical 1,3-diynes described

2 H, 4-H), 2.14–1.97 (m, 4 H, 6-H, 12-H), 1.80–1.69 (m, 2 H, 5-

12

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:26

Pages: 22

Syntheses of Natural and Unnatural Acetoxyenediynes

H), 1.17–1.02 (m, 21 H, iPr

3

Si), 0.95 (t, J = 7.5 Hz, 3 H, CH

C NMR (100.62 MHz, CDCl ): δ = 187.6 (s, C-3), 132.1 (d),

29.5 (d), 128.6 (d), 127.1 (d), 104.3 (s), 95.4 (s), 45.1 (t), 26.4 (t),

5.6 (t), 24.1 (t), 20.6 (t), 18.6 (q, 6ϫ, iPr Si), 14.3 (q), 11.1 (d, 3ϫ,

Si) ppm. IR (NaCl): ν˜ = 3008 (w, –C=C–H), 2948 (s, C–H),

3

) ppm.

(3E,7Z,10Z)- and (3Z,7Z,10Z)-1-(Trimethylsilyl)trideca-3,7,10-

trien-1-yn-3-yl Acetate (17a): Following the general procedure for

the synthesis of enol acetates (Method A) described above, the reac-

tion of (7Z,10Z)-1-(trimethylsilyl)trideca-7,10-dien-1-yn-3-one

(16a; 0.28 g, 1.07 mmol), bis(trimethylsilyl)amide (0.33 mL, 0.26 g,

13

3

1

2

3

iPr

3

2

868 (s, C–H), 2145 (w, –CϵC–), 1678 (s, C=O), 1461 (m), 1213 1.60 mmol), n-butyllithium (0.84 mL, 1.52 m in THF, 1.28 mmol),

–1

(w), 1110 (w), 1066 (w), 1000 (w) cm . UV (MeOH): λmax

=

and acetic anhydride (0.51 mL, 0.54 g, 5.34 mmol) in THF (21 mL)

at –78 °C afforded, after purification by column chromatography

(silica gel, 97:3 hexane/EtOAc), 0.26 g (100%) of a yellow oil that

was identified as the title product as a Ͼ99:1 mixture of E/Z iso-

mers.

+

2

3

35 nm. HRMS (ESI ): calcd. for C22

69.25841; found 369.25799.

H38OSiNa [M + Na]

(7Z,10Z)-1-(Trimethylsilyl)trideca-7,10-dien-1-yn-3-one (16a): Fol-

lowing the general procedure described above for the synthesis of

propargylic ketones, the reaction of (5Z,8Z)-N-methoxy-N-meth-

ylundeca-5,8-dienamide (6a; 0.84 g, 3.74 mmol), trimethyl-

silylacetylene (0.74 mL, 0.51 g, 5.23 mmol), and n-butyllithium

(3E,7Z,10Z)- and (3Z,7Z,10Z)-1-(Trimethylsilyl)trideca-3,7,10-

trien-1-yn-3-yl Acetate (17a): Following the general procedure for

the synthesis of enol acetates (Method G) described above, the re-

action of (7Z,10Z)-1-(trimethylsilyl)trideca-7,10-dien-1-yn-3-one

(16a; 0.11 g, 0.43 mmol), diisopropylamine (92 μL, 66 mg,

0.65 mmol), n-butyllithium (0.35 mL, 1.50 m in THF, 0.52 mmol),

(2.9 mL, 1.52 m in THF, 4.48 mmol) in THF at –40 °C afforded

after purification by column chromatography (silica gel, 97:3 hex-

ane/EtOAc) 0.83 g (84%) of the title compound as a colorless oil.

1

6 6

H NMR (400.13 MHz, C D ): δ = 5.45–5.29 (m, 3 H), 5.29–5.15 DMPU (0.26 mL, 0.28 g, 2.17 mmol), and acetic anhydride

(

4

(

m, 1 H), 2.72 (t, J = 6.6 Hz, 2 H, 9-H), 2.31 (t, J = 7.3 Hz, 2 H, (0.20 mL, 0.22 g, 2.17 mmol) in THF (8.5 mL) at –78 °C afforded,

-H), 2.07–1.95 (m, 2 H, 6-H), 1.94–1.85 (m, 2 H, 12-H), 1.66–1.53 after purification by column chromatography (silica gel, 97:3 hex-

m, 2 H, 5-H), 0.91 (t, J = 7.6 Hz, 3 H, 13-H), 0.05 (s, 9 H, ane/EtOAc), 105 mg (80%) of a yellow oil that was identified as

Me ): δ = 186.3 (s, C-3), the title product as a 30:70 mixture of E/Z isomers.

Si) ppm. ¹³C NMR (100.62 MHz, C

32.1 (d), 129.5 (d), 129.0 (d), 127.6 (d), 103.2 (s), 95.9 (s), 44.8 (t),

3

6 6

D

1

2

(

7Z,10Z)-1,1-Dimethoxytrideca-7,10-dien-3-one (19a): Potassium

6.5 (t), 25.9 (t), 23.9 (t), 20.9 (t), 14.5 (q), –0.9 (q, 3ϫ, Me Si) ppm.

3

carbonate (0.10 g, 0.76 mmol) was added to a cooled (0 °C) stirred

solution of (3E,7Z,10Z)- and (3Z,7Z,10Z)-1-(trimethylsilyl)tri-

deca-3,7,10-trien-1-yn-3-yl acetate (16a; 0.19 g, 0.63 mmol) in

MeOH (2.5 mL). After stirring for 15 min the reaction mixture was

passed through a pad of Celite and the solvent was removed under

vacuum. The residue was purified by column chromatography (sil-

ica gel, 85:15 hexane/EtOAc) to provide 0.11 g (66%) of a colorless

IR (NaCl): ν˜ = 3010 (m, –C=C–H), 2963 (m, C–H), 2933 (m, C–

H), 2874 (w, C–H), 2149 (w, –CϵC–), 1679 (s, C=O), 1252 (m),

1

–

1

+

109 (m) cm . UV (MeOH): λmax = 226 nm. HRMS (ESI ): calcd.

+

for C16

7Z,10Z)-Trideca-7,10-dien-1-yn-3-one (18a): This compound was

formed upon reaction of 6a with the lithium anion derived from

H26OSiNa [M + Na] 285.16451; found 285.16478.

(

1

trimethylsilylacetylene (Scheme 5). H NMR (400.13 MHz, C

δ = 5.48–5.29 (m, 3 H), 5.26–5.11 (m, 1 H), 2.71 (t, J = 6.8 Hz, 2

H, 9-H), 2.37 (s, 1 H, 1-H), 2.19 (t, J = 7.3 Hz, 2 H, 4-H), 2.04– 5.6 Hz, 1 H, 1-H), 3.11 (s, 6 H, 2 OCH

1

5

C

(

6

D

6

):

oil that was identified as the title product. H NMR (400.13 MHz,

C

6

D

6

): δ = 5.47–5.24 (m, 4 H, 7-H, 8-H, 10-H, 11-H), 4.81 (t, J =

), 2.76 (t, J = 6.1 Hz, 2 H,

.95 (m, 2 H, 6-H), 1.90–1.80 (m, 2 H, 12-H), 1.56–1.46 (m, 2 H, 9-H), 2.48 (d, J = 5.6 Hz, 2 H, 2-H), 2.14–1.89 (m, 6 H, 4-H, 6-H,

-H), 0.91 (t, J = 7.5 Hz, CH 12-H), 1.62–1.49 (m, 2 H, 5-H), 0.91 (t, J = 7.5 Hz, 3 H, CH ) ppm.

) ppm. ¹³C NMR (100.62 MHz,

): δ = 186.1 (s), 132.1 (d), 129.6 (d), 128.9 (d), 127.5 (d), 81.9 ): δ = 206.1 (s), 132.0 (d), 129.5 (d),

s), 77.7 (d), 44.8 (t), 26.4 (t), 25.9 (t), 23.7 (t), 20.9 (t), 14.5 129.2 (d), 127.7 (d), 102.1 (d), 53.5 (q, 2ϫ), 46.7 (t), 43.1 (t), 26.7

3

1

3

6

D

6

6 6

C NMR (100.62 MHz, C D

q) ppm. IR (NaCl): ν˜ = 3268 (m, –CϵC–H), 3010 (m, –C=C–H),

(t), 25.9 (t), 23.5 (t), 20.9 (t), 14.5 (q) ppm. IR (NaCl): ν˜ = 2961 (s,

2

963 (m, C–H), 2933 (m, C–H), 2873 (w, C–H), 2093 (s, –CϵC–), C–H), 2934 (s, C–H), 2877 (w, C–H), 2093 (w, –CϵC–), 1713 (s,

–1

1684 (s, C=O), 1105 (m) cm .

C=O), 1452 (w), 1407 (w), 1368 (m), 1193 (m), 1120 (s), 1056 (s),

–

1

+

9

70 (m) cm . UV (MeOH): λmax = 232 nm. HRMS (ESI ): calcd.

(3E,7Z,10Z)- and (3Z,7Z,10Z)-1-(Triisopropylsilyl)trideca-3,7,10-

for C15

26 3

H O

Na [M + Na]⁺277.17742; found 277.17745.

trien-1-yn-3-yl Acetate (11a): Following the general procedure for

the synthesis of enol acetates (Method G) described above, the re-

(3E,7Z,10Z)- and (3Z,7Z,10Z)-Trideca-3,7,10-trien-1-yn-3-yl Acet-

action of (7Z,10Z)-1-(triisopropylsilyl)trideca-7,10-dien-1-yn-3-one ate (5a). General Procedure for the Deprotection of Trimethylsilyl-

(

0

10a; 0.05 g, 0.16 mmol), bis(trimethylsilyl)amide (65 μL, 51 mg,

.31 mmol), n-butyllithium (0.15 mL, 1.6 m in THF, 0.23 mmol),

alkynes. Method A: Potassium carbonate (0.07 g, 0.51 mmol) was

added to a stirred solution of a 30:70 mixture of (3E,7Z,10Z)- and

(3Z,7Z,10Z)-1-(trimethylsilyl)trideca-3,7,10-trien-1-yn-3-yl acetate

and acetic anhydride (74 μL, 0.08 g, 0.78 mmol) in THF (3.2 mL)

at –78 °C afforded, after purification by column chromatography

2

(17a; 78 mg, 0.26 mmol) in tBuOH/H O (1.3 mL, 1:1, v/v) at 25 °C.

(silica gel, 98:2 hexane/EtOAc), 47 mg (78%) of a yellow oil that

After stirring for 24 h the tert-butanol was evaporated under vac-

was identified as the title product as a Ͼ99:1 mixture of E/Z iso-

uum. The reaction mixture was diluted with water and the mixture

mers.

was extracted with Et

washed with brine, dried with Na

moved. The residue was purified by column chromatography (silica

gel, 97:3 hexane/EtOAc) to afford 36.5 mg (61%) of a colorless oil

that was identified as the title product as a 30:70 mixture of E/Z

2

O (3ϫ). The combined organic layers were

SO , and the solvent was re-

2

4

(3E,7Z,10Z)- and (3Z,7Z,10Z)-1-(Triisopropylsilyl)trideca-3,7,10-

trien-1-yn-3-yl Acetate (11a): Following the general procedure for

the synthesis of enol acetates (Method F) described above, the reac-

tion of (7Z,10Z)-1-(triisopropylsilyl)trideca-7,10-dien-1-yn-3-one

TM

isomers. These were separated by HPLC [Sunfire

5 μm,

(E)

(Z) = 172.5 min; alternatively: Waters Spheri-

sorb 5 μm silica gel, 10ϫ250 mm, 99:1 hexane/tert-butyl methyl

ether, 1.5 mL/min, t (E) = 37 min and t (Z) = 32.5 min].

(

10a; 0.05 g, 0.16 mmol), 1,1,3,3-dimethyl-1,3-diphenyldisilazane

90 μL, 89 mg, 0.31 mmol), n-butyllithium (0.15 mL, 1.6 m in THF,

4.6ϫ250 mm, 99:1 hexane/tert-butyl methyl ether, 1 mL/min, t

R

=

20.4 min and t

R

0.23 mmol), and acetic anhydride (74 μL, 0.08 g, 0.78 mmol) in

®

THF (3.2 mL) at –78 °C afforded, after purification by column

chromatography (silica gel, 98:2 hexane/EtOAc), 52.3 mg (88%) of

a yellow oil that was identified as the title product as a 21:79 mix-

ture of E/Z isomers.

R

Following the general procedure for the deprotection of (trimethyl-

silyl)alkynes described above, the reaction of a Ͼ99:1 mixture of

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

13

Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:26

Pages: 22

P. García-Domínguez, R. Alvarez, Á. R. de Lera

FULL PAPER

(

3E,7Z,10Z)- and (3Z,7Z,10Z)-1-(trimethylsilyl)trideca-3,7,10-

trien-1-yn-3-yl acetate (17a; 0.05 g, 0.16 mmol) and potassium

carbonate (0.03 g, 0.20 mmol) in tBuOH/H O (1.0 mL, 1:1 v/v) at

5 °C afforded, after purification by column chromatography (silica

thesis of unsymmetrical 1,3-diynes described above, the reaction of

(2ЈS)-2,3-O-isopropylidene-2,3-dihydroxypropyl pent-4-ynoate

[(S)-14; 0.71 g, 3.33 mmol], octadec-1-yn-3-ol (3b; 0.13,

0.66 mmol), CuI (5 mol-%), and NiCl ·6H O (5 mol-%) in THF

2

gel, 97:3 hexane/EtOAc), 24 mg (62%) of the E isomer of 12a as a

colorless oil.

(4.7 mL) and TMEDA (21.0 μL) at room temperature and under

air afforded, after purification by column chromatography (silica

gel, 80:20 hexane/EtOAc), 73 mg (27%) of the title compound as a

white solid.

3Z,7Z,10Z)-Trideca-3,7,10-trien-1-yn-3-yl Acetate [(Z)-5a]: 1_H

NMR (400.13 MHz, CDCl ): δ = 5.76 (t, J = 7.4 Hz, 1 H, 4-H),

.46–5.24 (m, 4 H, 7-H, 8-H, 10-H, 11-H), 2.97 (s, 1 H, 1-H), 2.77

t, J = 7.1 Hz, 2 H, 9-H), 2.19 [s, 3 H, OC(O)CH ], 2.17–2.01 (m,

(

3

5

(2ЈS)-2,3-O-Isopropylidene-2,3-dihydroxypropyl 8-Hydroxytricosa-

4,6-diynoate [(S)-20b]: Following the general procedure for the syn-

thesis of unsymmetrical 1,3-diynes described above, the reaction of

(

6

3

1

3

H, 5-H, 6-H, 12-H), 0.97 (t, J = 7.5 Hz, 3 H, CH

3

) ppm.

C

NMR (100.62 MHz, CDCl

3

): δ = 168.3 (s), 132.2 (d), 129.7 (d),

(2ЈS)-2,3-O-isopropylidene-2,3-dihydroxypropyl

pent-4-ynoate

1

2

3

29.6 (d), 129.3 (s), 128.2 (d), 127.1 (d), 78.2 (s), 77.2 (d), 26.2 (t), [(S)-14; 32 mg, 0.15 mmol], octadec-1-yn-3-ol (3b; 0.2 g,

6.1 (t), 25.7 (t), 20.7 (t), 20.7 (q), 14.4 (q) ppm. IR (NaCl): ν˜ = 0.75 mmol), CuI (5 mol-%), and NiCl ·6H O (5 mol-%) in THF

289 (w, –CϵC–H), 3010 (w, –C=C–H), 2962 (w, C–H), 2930 (w, (1 mL) and TMEDA (5 μL) at room temperature and under air

2

–1

C–H), 2866 (w, C–H), 1769 (s, C=O), 1200 (s) cm . UV (MeOH):

afforded, after purification by column chromatography (silica gel,

80:20 hexane/EtOAc), 26 mg (36%) of the title compound as a

white solid.

+

20 2

H O

Na [M + Na]⁺

λmax = 219 nm. HRMS (ESI ): calcd. for C15

255.13555; found 255.13564.

3E,7Z,10Z)-Trideca-3,7,10-trien-1-yn-3-yl Acetate [(E)-5a]: ¹H (2ЈS)-2,3-O-Isopropylidene-2,3-dihydroxypropyl (12Z,15Z)-8-Hy-

(

NMR (400.13 MHz, CDCl

.46–5.23 (m, 4 H, 7-H, 8-H, 10-H, 11-H), 3.25 (s, 1 H, 1-H), 2.77

t, J = 6.4 Hz, 2 H, 9-H), 2.39–2.31 (m, 2 H, 5-H), 2.25–2.17 (m,

H, 6-H), 2.15 [s, 3 H, OC(O)CH

t, J = 7.5 Hz, 3 H, CH

) ppm. ¹³C NMR (100.62 MHz, CDCl

δ = 168.9 (s), 132.2 (d), 129.9 (d), 129.8 (s), 129.6 (d), 128.3 (d),

27.1 (d), 82.4 (s), 76.0 (d), 28.0 (t), 26.6 (t), 25.7 (t), 20.9 (q), 20.7 at room temperature and under air afforded, after purification by

3

): δ = 5.76 (t, J = 7.8 Hz, 1 H, 4-H),

droxyoctadeca-12,15-dien-4,6-diynoate [(S)-20a]: Following the ge-

neral procedure for the synthesis of unsymmetrical 1,3-diynes de-

scribed above, the reaction of (2ЈS)-2,3-O-isopropylidene-2,3-dihy-

5

(

2

(

], 2.11–2.01 (m, 2 H, 12-H), 0.97 droxypropyl pent-4-ynoate [(S)-14; 0.23 g, 1.06 mmol], (7Z,10Z)-

):

trideca-7,10-dien-1-yn-3-ol (3a; 41 mg, 0.21 mmol), CuI (5 mol-%),

and NiCl ·6H O (5 mol-%) in THF (1.5 mL) and TMEDA (7 μL)

3

2

1

+

(

t), 14.4 (q) ppm. HRMS (ESI ): calcd. for C15

H

20

O

2

Na [M +

Na] 255.13555; found 255.13553. H NMR (400 MHz, C ): δ

5.62 (t, J = 7.9 Hz, 1 H, 4-H), 5.51–5.26 (m, 4 H, 7-H, 8-H, 10-

H, 11-H), 2.81–2.65 (m, 3 H, 9-H, 1-H), 2.32–2.19 (m, 2 H, 5-H),

.09–1.93 (m, 4 H, 6-H, 12-H), 1.61 [s, 3 H, OC(O)CH ], 0.91 (t, J

7.5 Hz, 3 H, 13-H) ppm. ¹³C NMR (100.62 MHz, C

): δ =

67.9 (s), 132.1 (d), 130.8 (s), 129.7 (d), 128.6 (d), 128.4 (d), 127.5

d), 82.5 (s), 76.7 (d), 28.2 (t), 26.8 (t), 25.9 (t), 20.9 (t), 20.1 (q),

4.5 (q) ppm. IR (NaCl): ν˜ = 3289 (w, –CϵC–H), 3013 (w, –C=C–

H), 2963 (w, C–H), 2934 (w, C–H), 2871 (w, C–H), 2012 (w, –CϵC–

column chromatography (silica gel, 80:20 hexane/EtOAc), 17 mg

(20%) of the title compound as a colorless oil.

+

1

6

D

6

=

Route C

1,1,1-Trichloroundecan-2-ol (22): Trichloroacetic acid (0.16 g,

2

=

1

(

3

0.96 mmol) and sodium trichloroacetate (0.18 g, 0.96 mmol) were

6 6

D

added to a stirred solution of decanal (21; 0.12 mL, 0.10 g,

.64 mmol) in DMF (1 mL) keeping the temperature at 23 °C with

0

a water bath. The mixture was stirred for 1 h, diluted with diethyl

ether/hexane (9:1, v/v), and washed with a saturated aqueous solu-

1

tion of NaHCO

ers were dried (Na

3

(3ϫ) and NaCl (1ϫ). The combined organic lay-

SO ) and the solvent was evaporated. The resi-

–

1

)

, 1763 (s, C=O), 1370 (m), 1205 (s), 1113 (s) cm . UV (MeOH):

2

4

λmax = 223 nm.

due was purified by column chromatography (silica gel, 97:3 hex-

(

2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl

(8E,12Z,15Z)-8-

ane/EtOAc) to give 0.152 g (86%) of 1,1,1-trichloroundecan-2-ol as

1

Acetoxyoctadeca-8,12,15-trien-4,6-diynoate [(E,R)-12a]: Following a colorless oil. H NMR (400.13 MHz, CDCl ): δ = 4.00 (app. ddd,

3

the general procedure for the synthesis of unsymmetrical 1,3-diynes

J = 9.4, 5.6, 1.9 Hz, 1 H, 2-H), 2.66 (m, 1 H, 3-H ), 2.10–1.99 (m,

A

described above, the reaction of (3E,7Z,10Z)-trideca-3,7,10-trien-

1 H, 3-H ), 1.71–1.57 (m, 2 H, 4-H), 1.51–1.19 (m, 12 H, 6 CH ),

B

2

1

3

1

-yn-3-yl acetate [(E)-5a; 36 mg, 0.16 mmol], (2ЈR)-2,3-O-isoprop-

ylidene-2,3-dihydroxypropyl pent-4-ynoate [(R)-14; 0.16 g,

.78 mmol], CuI (5 mol-%), and NiCl ·6H

1 mL) and TMEDA (5 μL, 3.6 mg, 0.03 mmol) at room tempera-

0.88 (t, J = 6.9 Hz, 3 H, CH ) ppm. C NMR (100.62 MHz,

3

CDCl ): δ = 104.5 (s), 83.0 (d), 32.0 (t), 31.6 (t), 29.6 (t, 2ϫ), 29.4

3

0

2

O (5 mol-%) in THF (t, 2ϫ), 26.2 (t), 22.8 (t), 14.2 (q) ppm. IR (NaCl): ν = 3600–3200

˜

–

1

(

(br., O–H), 2926 (s, C–H), 2856 (m, C–H), 1462 (m), 812 (m) cm .

MS (EI ): m/z (%) = 157 (36) [M – CCl ] , 149 (13), 124 (26), 122

+

ture and under air afforded, after purification by column

chromatography (silica gel, 85:15 hexane/EtOAc), 20 mg (29%) of

the title compound as a colorless oil.

3

(43), 114 (13), 112 (22), 111 (13), 97 (82), 95 (11), 84 (11), 83 (100),

+

82 (13), 81 (18), 71 (19), 70 (16), 69 (75), 67 (18). HRMS (EI ):

+

calcd. for C10

H

21O [M – CCl

3

]

157.1595; found 157.1595.

(2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl

(8Z,12Z,15Z)-8-

Acetoxyoctadeca-8,12,15-trien-4,6-diynoate [(Z,R)-12a]: Following

the general procedure for the synthesis of unsymmetrical 1,3-diynes

described above, the reaction of (3Z,7Z,10Z)-trideca-3,7,10-trien-

1,1,1-Trichloroundecan-2-yl Acetate (23) Ϫ Method A: Acetic anhy-

dride (0.85 mL, 0.92 g, 9.01 mmol) was added to a solution of

1,1,1-trichloroundecan-2-ol (22; 0.50 g, 1.80 mmol) in pyridine

(6 mL) and the mixture was stirred at 25 °C for 14 h. When the

1

-yn-3-yl acetate [(Z)-5a; 20.3 mg, 0.09 mmol], (2ЈR)-2,3-O-iso-

propylidene-2,3-dihydroxypropyl pent-4-ynoate [(R)-14; 93 mg,

.44 mmol], CuI (5 mol-%), and NiCl ·6H

1 mL) and TMEDA (2.6 μL) at room temperature and under air

afforded, after purification by column chromatography (silica gel,

reaction was completed it was diluted with Et O and washed with

2

0

2

O (5 mol-%) in THF a saturated aqueous solution of CuSO₄(2ϫ). The combined or-

(

ganic layers were dried (Na SO ) and the solvent was evaporated

2

4

to obtain 0.53 g (94%) of a colorless oil that was identified as 1,1,1-

trichloroundecan-2-yl acetate (23) and was used in the next step

without further purification.

8

5:15 hexane/EtOAc), 11 mg (28%) of the title compound as a col-

[

11]

orless oil.

(2ЈS)-2,3-O-Isopropylidene-2,3-dihydroxypropyl 8-Hydroxytricosa-

Method B: DBN (0.24 mL, 0.24 g, 1.92 mmol) was added dropwise

4,6-diynoate [(S)-20b]: Following the general procedure for the syn-

to a solution of decanal (22; 0.36 mL, 0.30 g, 1.92 mmol) in CHCl

3

14

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:26

Pages: 22

Syntheses of Natural and Unnatural Acetoxyenediynes

0.31 mL, 0.46 g, 3.84 mmol) and the reaction mixture was stirred

(

3

NMR (100.62 MHz, CDCl ): δ = 168.8 (s), 130.5 (s), 129.6 (d),

for 3 h. Acetic anhydride (0.20 mL, 0.22 g, 2.11 mmol) was slowly

added at 0 °C and the reaction was stirred for a further 2 h. The

reaction mixture was diluted with AcOEt and washed with a 0.5 n

aqueous solution of HCl (3ϫ) and a saturated aqueous solution of

98.6 (s), 96.8 (s), 32.0 (t), 29.7 (t), 29.6 (t), 29.4 (t), 29.3 (t), 29.0

(t), 28.3 (t), 22.8 (t), 20.9 (q), 18.7 (q, 6ϫ), 14.3 (q), 11.3 (d,

+

3ϫ) ppm. HRMS (ESI ): calcd. for C24

H

45

O

2

Si [M + H]

393.31833; found 393.31809.

2 3 2 4

Na CO (3ϫ). The combined organic layers were dried (Na SO )

and the solvent was evaporated. The residue was purified by col-

umn chromatography (silica gel, 97:3 hexane/EtOAc) to afford

Route D

(2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl 7-(Triisopropylsilyl)-

hepta-4,6-diynoate [(R)-26]. Method A: Following the general pro-

cedure for the synthesis of unsymmetrical 1,3-diynes described

above, the reaction of (2ЈR)-2,3-O-isopropylidene-2,3-dihydroxy-

propyl pent-4-ynoate [(R)-14; 0.5 g, 2.36 mmol], (triisopropylsilyl)-

acetylene (2.62 mL, 2.15 g, 11.79 mmol), CuI (5 mol-%), and

0

.19 g (31%) of 1,1,1-trichloroundecan-2-yl acetate (23) as a color-

1

less oil. H NMR (400.13 MHz, CDCl

3

): δ = 5.49 (app. d, J =

0.2 Hz, 1 H, 2Ј-H), 2.22–2.02 (m, 4 H, CO CH , 3Ј-H ), 1.91–

.72 (m, 1 H, 3Ј-H ), 1.41–1.11 (m, 14 H, 7 CH ), 0.88 (t, J =

₎_p_p_m_.1 C NMR (100.62 MHz, CDCl

.8 Hz, 3 H, CH ): δ =

69.7 (s), 100.3 (s), 80.9 (d), 31.9 (t), 30.5 (t), 29.5 (t), 29.4 (t), 29.3

1

6

1

2

3

A

B

2

3

NiCl

2 2

·6H O (5 mol-%) in THF (10 mL) and TMEDA (71 μL) at

room temperature and under air afforded, after purification by col-

(t), 29.2 (t), 25.6 (t), 22.7 (t), 20.7 (q), 14.2 (q) ppm. IR (NaCl): ν˜

umn chromatography (silica gel, 80:10:10 hexane/CH

2 2

Cl /EtOAc),

=

2927 (s, C–H), 2857 (m, C–H), 1762 (s, C=O), 1462 (w), 1371

–1

+

0.28 g (32%) of the title compound as a colorless oil.

(

m), 1215 (s) cm . MS (FAB ): m/z (%) = 317 (47) [M + 1] , 316

+

5) [M] , 315 (22), 302 (18), 300 (15), 296 (24), 295 (100), 294 (19), Method B. General Procedure for the Cadiot–Chodkiewicz Cross-

2

93 (25), 283 (45), 281 (71), 185 (28), 184 (70), 155 (71), 154 (29).

Coupling Reaction: Copper chloride (3 mg, 0.03 mmol) was added

to a stirred solution of (2ЈR)-2,3-O-isopropylidene-2,3-dihydroxy-

propyl 5-iodopent-4-ynoate [(R)-4; 0.1 g, 0.3 mmol] and (triiso-

propylsilyl)acetylene (0.16 mL, 0.14 g, 0.74 mmol) in degassed pi-

peridine (0.5 mL) at 0 °C. After stirring for 2 h, a saturated aque-

+

HRMS (FAB ): calcd. for C13

17.0840.

3 2

H24Cl O [M + 1] 317.0842; found

3

(Z)-1-Chloroundec-1-enyl Acetate [(Z)-24]: A solution of 1,1,1-tri-

chloroundecan-2-yl acetate (23; 0.07 g, 0.22 mmol) in THF (1 mL)

was added to a stirred suspension of chromium(II) chloride

ous solution of NH

with CH Cl (3ϫ). The combined organic layers were dried with

Na SO and the solvent was removed under vacuum. The residue

4

Cl was added and the mixture was extracted

2

(81.3 mg, 0.66 mmol) in THF (1 mL) at 25 °C and the resulting

2

4

mixture was heated at reflux for 72 h. The reaction was cooled to

room temperature, quenched with a 5% aqueous solution of HCl,

was purified by column chromatography (silica gel, 85:15 hexane/

EtOAc) to provide 76 mg (66%) of a colorless oil that was iden-

and diluted with Et

layer was extracted with Et

were washed with brine (3ϫ), dried (Na

evaporated. The residue was purified by column chromatography

silica gel, 97:3 hexane/EtOAc) to afford 47.6 mg (88%) of a color-

less oil that was identified as (Z)-1-chloroundec-1-enyl acetate [(Z)-

2

O. The layers were separated and the aqueous

O (2ϫ). The combined organic layers

SO ), and the solvent was

1

tified as the title compound. H NMR (400.13 MHz, CDCl

4

3

): δ =

),

), 4.05 (dd, J = 8.5, 6.5 Hz,

), 3.72 (dd, J = 8.5, 6.0 Hz, 1 H, 3Ј-H ), 2.60–2.55 (m,

H, 2-H, 3-H), 1.39 (s, 3 H), 1.33 (s, 3 H), 1.06–1.01 (m, 21 H,

2

.34–4.24 (m, 1 H, 2Ј-H), 4.16 (dd, J = 11.5, 4.7 Hz, 1 H, 1Ј-H

.09 (dd, J = 11.5, 5.9 Hz, 1 H, 1Ј-H

H, 3Ј-H

A

2

4

B

1

A

B

(

4

1

3

1

3 3

iPr Si) ppm. C NMR (100.62 MHz, CDCl ): δ = 171.2 (s, C-1),

2

4]. H NMR (400.13 MHz, C

Ј-H), 2.10–1.97 (m, 2 H, 3Ј-H), 1.54 (s, 3 H, CO

), 0.91 (t, J = 7.0 Hz, 3 H, CH ) ppm. C NMR

): δ = 167.1 (s), 134.9 (s), 118.6 (d), 32.3 (t),

6

D

6

): δ = 5.20 (t, J = 7.4 Hz, 1 H,

1

09.9 (s, C-1ЈЈ), 89.7 (s), 81.1 (s), 76.1 (s), 73.5 (d, C-2Ј), 66.7 (s),

66.3 (t), 65.1 (t), 32.7 (t), 26.7 (q), 25.4 (q), 18.6 [q, 6ϫ, SiCH(CH

], 15.2 (t), 11.3 [d, 3ϫ, SiCH(CH ] ppm. IR (NaCl): ν˜ = 2946 (s,

C–H), 2870 (s, C–H), 2225 (w, –CϵC–), 2103 (w, –CϵC–), 1744 (s,

2

CH ), 1.35–1.11

3

1

3

)

(

m, 14 H, 7 CH

100.62 MHz, C

2

3

2

3 2

)

6

D

6

3

1

0.0 (t), 29.8 (t, 2ϫ), 29.4 (t), 28.8 (t), 27.7 (t), 23.1 (t), 19.8 (q),

4.4 (q) ppm. IR (NaCl): ν˜ = 2926 (s, C–H), 2856 (m, C–H), 1788

–

1

C=O), 1461 (m), 1374 (m), 1219 (s), 1168 (s), 1062 (m) cm .

HRMS (ESI ): calcd. for C22

found 415.22705.

+

36 4

H O

SiNa [M + Na]⁺415.22751;

–

1

(s, C=O), 1462 (w), 1370 (w), 1215 (w), 1193 (w), 1100 (w) cm .

+

HRMS (ESI ): calcd. for C13

found 269.12773.

2

H23ClO Na [M + Na] 269.12788;

(2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl

(2E,4Z)-

and

(

2E,4E)-Hepta-2,4-dien-6-ynoate (27): Following the general pro-

(

E)-1-(Triisopropylsilyl)tridec-3-en-1-yn-3-yl Acetate [(E)-25]. Gene-

cedure for the deprotection of (triisopropylsilyl)alkynes described

above, the reaction of (2ЈR)-2,3-O-isopropylidene-2,3-dihydroxy-

propyl 7-(triisopropylsilyl)hepta-4,6-diynoate [(R)-26; 0.1 g,

ral Procedure for the Sonogashira Cross-Coupling Reaction: A solu-

tion of (Z)-1-chloroundec-1-enyl acetate [(Z)-24; 0.05 g, 0.20 mmol]

and (triisopropylsilyl)acetylene (0.09 mL, 74 mg, 0.40 mmol) in

THF (2.2 mL) and CuI (3.1 mg, 0.02 mmol) were sequentially

added to a stirred solution of [PdCl

THF (1 mL) and the mixture was degassed at –78 °C three times.

Then Et N (0.75 mL) was added and the mixture was stirred at

room temperature for 24 h. After completion of the reaction it was

poured into a saturated aqueous solution of NH Cl and the mix-

ture was extracted with CH Cl (3ϫ). The combined organic layers

were dried (Na SO ) and the solvent was evaporated. The residue

0

4

.25 mmol] with nBu NF (0.28 mL, 1 m in THF, 0.28 mmol) in

THF (6.4 mL) afforded, after purification by column chromatog-

raphy (silica gel, 80:20 hexane/EtOAc), 23.4 mg (39%) of the title

compound as a 2:1 mixture of 4Z/4E isomers. The isomers were

separated by HPLC (Spherisorb 5 μm, 10ϫ250 mm, 90:10 hexane/

2 3 2

(PPh ) ] (4.7 mg, 4.0 μmol) in

3

EtOAc, 3 mL/min) to afford 2.8 mg (5%) of the 2E,4E isomer (t

19.2 min) and 5.6 mg (9%) of the (2Z,4E) isomer (t = 21.6 min)

of 27.

R

4

=

R

2

4

was purified by column chromatography (silica gel, 100% acetoni-

(2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl (2E,4Z)-Hepta-2,4-

dien-6-ynoate [(2E,4Z,2ЈR)-27]: H NMR [400.13 MHz, (CD ) -

3 2

CO]: δ = 7.76 (dd, J = 15.4, 11.5 Hz, 1 H, 3-H), 6.79 (t, J = 11.1 Hz,

1 H, 4-H), 6.20 (d, J = 15.5 Hz, 1 H, 2-H), 5.94 (dd, J = 10.6,

1

trile) to afford 22 mg of pure (E)-1-(triisopropylsilyl)tridec-3-en-1-

1

yn-3-yl acetate [(E)-25] as a colorless oil. H NMR (400.13 MHz,

CDCl

H), 2.13 (s, 3 H, CO

2 H, 6 CH ), 1.15–1.00 (m, 21 H, iPr

H, CH ) ppm. IR (NaCl): ν˜ = 2926 (s, C–H), 2865 (m, C–H), 2151

w, –CϵC–), 1768 (m, C=O), 1464 (w), 1367 (w), 1209 (m), 1107 1.30 (s, 3 H, CH

3

): δ = 5.68 (t, J = 8.0 Hz, 1 H, 4-H), 2.34–2.21 (m, 2 H, 5-

2

CH

3

), 1.49–1.36 (m, 2 H, 6-H), 1.36–1.20 (m, 2.2 Hz, 1 H, 5-H), 4.42–4.29 (m, 1 H, 2Ј-H), 4.26–4.15 (m, 2 H, 1Ј-

Si), 0.88 (t, J = 6.9 Hz, 3 H), 4.13 (d, J = 2.2 Hz, 1 H, 7-H), 4.09 (dd, J = 8.4, 6.6 Hz, 1 H,

3Ј-H ), 3.78 (dd, J = 8.4, 6.1 Hz, 1 H, 3Ј-H ), 1.36 (s, 3 H, CH ),

) ppm. C NMR [100.62 MHz, (CD CO]: δ =

166.6 (s, C-1), 140.8 (d), 139.4 (d), 125.2 (d), 117.1 (d), 110.0 (s, C-

1

2

3

A

B

3

1

3

(

3

3 2

)

–1

13

m), 883 (w) cm . UV (MeOH): λmax = 225, 244, 289 nm.

C

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

15

Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:26

Pages: 22

H, 3Ј-H

P. García-Domínguez, R. Alvarez, Á. R. de Lera

FULL PAPER

1ЈЈ), 88.9 (d), 80.4 (s), 74.5 (d, C-2Ј), 66.8 (t), 65.4 (t), 27.1 (q), 25.7

B

), 2.11–2.05 (m, 2 H, 2-H), 2.02–1.95 (m, 2 H, 3-H), 1.53

(

q) ppm. IR (NaCl): ν˜ = 3263 (w, –CϵC–H), 2986 (w, C–H), 2937 (t, J = 1.0 Hz, 1 H, 7-H), 1.34 (s, 3 H, CH

3

), 1.23 (s, 3 H,

1

3

(w, C–H), 1717 (s, C=O), 1628 (w), 1376 (w), 1305 (w), 1264 (s), CH ) ppm. C NMR (100.62 MHz, C D ): δ = 170.6 (s, C-1),

3

6

–1

1

λ

2

221 (m), 1167 (s), 1105 (m), 1055 (m), 998 (m) cm . UV (MeOH):

109.7 (s, C-1ЈЈ), 76.5 (s), 73.8 (d, C-2Ј), 68.6 (s), 66.3 (t), 66.1 (s),

65.9 (d), 65.1 (t), 32.4 (t), 26.9 (q), 25.6 (q), 14.9 (t) ppm. IR

(NaCl): ν˜ = 3265 (m, CϵC–H), 2988 (m, C–H), 2938 (w, C–H),

+

16 4

H O

Na [M + Na]⁺

max = 283 nm. HRMS (ESI ): calcd. for C13

59.09408; found 259.09395.

2

889 (w, C–H), 2228 (w, –CϵC–), 1740 (s, C=O), 1372 (m), 1212

(

2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl (2E,4E)-Hepta-2,4-

–

1

(

m), 1165 (s), 1055 (m), 839 (m) cm . UV (MeOH): λmax = 214,

1

dien-6-ynoate [(2E,4E,2ЈR)-27]: H NMR [400.13 MHz, (CD

CO]: δ = 7.35 (ddd, J = 15.3, 11.3, 0.7 Hz, 1 H, 3-H), 6.87 (dd, J

15.6, 11.3 Hz, 1 H, 4-H), 6.20 (ddt, J = 15.6, 2.4, 0.7 Hz, 1 H,

-H), 6.13 (d, J = 15.3 Hz, 1 H, 2-H), 4.34 (ddd, J = 12.2, 6.0,

.7 Hz, 1 H, 2Ј-H), 4.21 (dd, J = 11.5, 4.7 Hz, 1 H, 1Ј-H ), 4.16

), 4.09 (dd, J = 8.5, 6.5 Hz, 1 H,

), 3.88 (d, J = 2.4 Hz, 1 H, 7-H), 3.77 (dd, J = 8.5, 6.0 Hz, 1

), 1.35 (s, 3 H, CH ), 1.30 (s, 3 H, CH

) ppm. ¹³C NMR

100.62 MHz, (CD CO): δ = 166.4 (s, C-1), 143.9 (d), 141.3 (d),

3 2

) -

+

2

24, 237, 250 nm. HRMS (ESI ): calcd. for C13

H

17

O

4

[M + H]

37.11214; found 237.11121.

=

5

4

1

0

-(tert-Butyldiphenylsilyloxy)-4-pentyne (32): DMAP (8 mg,

A

.06 mmol), Et N (0.25 mL, 0.18 g, 1.82 mmol), and tert-butylchlo-

3

(dd, J = 11.5, 5.8 Hz, 1 H, 1Ј-H

B

rodiphenylsilane (0.38 mL, 0.40 g, 1.47 mmol) were added to a co-

oled (0 °C) stirred solution of pent-4-yn-1-ol (31; 0.1 g, 1.19 mmol)

3

Ј-H

A

H, 3Ј-H

(

1

2

(

B

3

in CH

the mixture was cooled to 0 °C, a saturated aqueous solution of

NaHCO was added, and the mixture was extracted with Et

3ϫ). The combined organic layers were washed with brine, dried,

2 2

Cl (4.3 mL). After stirring for 24 h at room temperature

3 2

)

24.3 (d), 119.4 (d), 110.0 (s, C-1ЈЈ), 85.4 (d), 82.8 (s), 74.5 (d, C-

Ј), 66.9 (t), 65.5 (t), 27.0 (q), 25.7 (q) ppm. IR (NaCl): ν˜ = 3267

w, –CϵC–H), 2985 (w, C–H), 2927 (w, C–H), 1715 (s, C=O), 1627

3

2

O

(

and the solvent was evaporated. The residue was purified by col-

umn chromatography (silica gel, 75:25 hexane/EtOAc) to afford

0

m), 1377 (m), 1322 (m), 1231 (s), 1177 (m), 1136 (s), 1053 (m), 995

–

1

+

m) cm . UV (MeOH): λmax = 279 nm. HRMS (ESI ): calcd. for

1

.33 g (86%) of the title product as a colorless oil. H NMR

+

C

13

H

16

O

4

Na [M + Na] 259.09408; found 259.09399.

(

3

400.13 MHz, CDCl ): δ = 7.69–7.63 (m, 4 H, ArH), 7.46–7.34 (m,

6

2

1

4

6

3

H, ArH), 3.74 (t, J = 6.0 Hz, 2 H, 1-H), 2.34 (td, J = 7.2, 2.6 Hz,

H, 3-H), 1.91 (t, J = 2.7 Hz, 1 H, 5-H), 1.81–1.72 (m, 2 H, 2-H),

.04 (s, 9 H) ppm. C NMR (100.62 MHz, CDCl ): δ = 135.7 (d,

3

(

2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl 7-(Trimethylsilyl)-

hepta-4,6-diynoate [(R)-28]: Following the general procedure for the

Cadiot–Chodkiewicz cross-coupling reaction described above, the

reaction of (2ЈR)-2,3-O-isopropylidene-2,3-dihydroxypropyl 5-

iodopent-4-ynoate [(R)-4; 0.96 g, 2.84 mmol], (trimethylsilyl)acetyl-

ene (1.0 mL, 0.70 g, 7.1 mmol), and copper chloride (28 mg,

1

3

ϫ), 133.9 (s, 2ϫ), 129.7 (d, 2ϫ), 127.8 (d, 4ϫ), 84.3 (s), 68.5 (d),

2.4 (t), 31.6 (t), 27.0 (q), 19.4 (s), 15.1 (t) ppm. IR (NaCl): ν˜ =

304 (w, CϵC–H), 3069 (w), 2953 (w, C–H), 2934 (w, C–H), 2860

–

1

+

(

w), 1468 (w), 1428 (w), 1107 (s), 981 (w) cm . HRMS (ESI ):

0

.28 mmol) in degassed piperidine (2.3 mL) at 0 °C afforded, after

calcd. for C21

H

26OSiNa [M + Na]⁺345.16451; found 345.16450.

purification by column chromatography (silica gel, 85:15 hexane/

EtOAc), 0.71 g (81%) of the title compound as a colorless oil. H

1

1-(tert-Butyldiphenylsilyloxy)-5-iodopent-4-yne (33): NIS (0.11 g,

NMR (400.13 MHz, CDCl

3

): δ = 4.29–4.19 (m, 1 H, 1Ј-H

dd, J = 11.4, 4.7 Hz, 1 H, 1Ј-H ), 4.08–3.98 (m, 2 H, 2Ј-H, 3Ј-

), 3.67 (dd, J = 8.5, 6.0 Hz, 1 H, 3Ј-H ), 2.55–2.49 (m, 4 H, 2-

), 1.28 (s, 3 H, CH ), 0.10 (s, 9 H,

Si) ppm. ¹³C NMR (100.62 MHz, CDCl

): δ = 171.0 (s, C-1),

09.7 (s, C-1ЈЈ), 88.1 (s), 83.9 (s), 77.3 (s), 73.4 (d, C-2Ј), 66.2 (t),

5.0 (t), 32.6 (t), 26.6 (q, CH ), 25.3 (q, CH ), 15.1 (t), –0.4 (q,

ϫ) ppm. IR (NaCl): ν˜ = 2985 (w, C–H), 2959 (w, C–H), 2896 (w,

A

), 4.11

0.48 mmol) and AgNO (0.07 g, 0.40 mmol) were added to a stirred

3

(

H

B

solution of 1-(tert-butyldiphenylsilyloxy)-4-pentyne (32; 0.13 g,

.40 mmol) in acetone (1 mL) and the reaction mixture was stirred

A

B

0

H, 3-H), 1.35 (s, 3 H, CH

Me

1

6

3

overnight at room temperature. The solvent was evaporated and

the residue was purified by column chromatography (90:10 hexane/

3

CH

2

1

Cl

2

) to afford 0.11 g (60%) of the title compound as a yellow

oil. H NMR (400.13 MHz, CDCl ): δ = 7.71 (dd, J = 7.5, 1.6 Hz,

H), 7.50–7.40 (m, 6 H), 3.77 (t, J = 5.9 Hz, 2 H, 1-H), 2.57 (t, J

7.1 Hz, 2 H, 3-H), 1.84–1.75 (m, 2 H, 2-H), 1.09 (s, 9 H) ppm.

3

4

C–H), 2228 (w, –CϵC–), 2109 (w, –CϵC–), 1742 (s, C=O), 1371

(

UV (MeOH): λmax = 225, 238, 251, 266 nm. HRMS (ESI ): calcd.

for C16

=

–

1

m), 1252 (s), 1211 (m), 1182 (m), 1160 (m), 1056 (w), 846 (s) cm .

13

3

C NMR (100.62 MHz, CDCl ): δ = 135.7 (d, 4ϫ), 133.8 (s, 2ϫ),

+

1

2

9

4

29.7 (d, 2ϫ), 127.8 (d, 4ϫ), 94.4 (s), 62.2 (t), 31.4 (t), 27.0 (q),

9.4 (s), 17.5 (t), –7.0 (s, C-5) ppm. IR (NaCl): ν˜ = 3062 (w, C–H),

936 (m, C–H), 2861 (m), 1467 (w), 1430 (w), 1105 (s), 997 (w),

53 (w) cm . HRMS (ESI ): calcd. for C21

49.07921; found 449.07845.

Si [M + H]⁺309.15166; found 309.15087.

25 4

H O

Methyl Hepta-4,6-diynoate (29): Following the procedure for the

deprotection of (trimethylsilyl)alkynes described above, the reaction

of (2ЈR)-2,3-O-isopropylidene-2,3-dihydroxypropyl 7-(trimethyl-

silyl)hepta-4,6-diynoate [(R)-28; 0.14 g, 0.45 mmol], potassium

carbonate (0.08 g, 0.54 mmol) in MeOH (1.8 mL) at 0 °C afforded,

after purification by column chromatography (silica gel, 90:10 hex-

–

1

+

H26IOSi [M + H]

1-(tert-Butyldiphenylsilyloxy)-7-(trimethylsilyl)hepta-4,6-diyne (34):

Following the general procedure for the Cadiot–Chodkiewicz cross-

coupling reaction described above, the reaction of 1(-tert-butyldi-

phenyloxy)-5-iodopent-4-yne (33; 3.83 g, 8.56 mmol), (trimethyl-

silyl)acetylene (3 mL, 2.10 g, 21.38 mmol), and copper chloride

ane/EtOAc), 12 mg (20%) of the title compound as a colorless oil.

1

H NMR (400.13 MHz, CDCl

3 3

): δ = 3.71 (s, 3 H, OCH ), 2.65–

2

.49 (m, 4 H, 2-H, 3-H), 1.98 (s, 1 H, 7-H) ppm.

(

85 mg, 0.86 mmol) in degassed piperidine (6.7 mL) at 0 °C af-

(2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl Hepta-4,6-diynoate

forded, after purification by column chromatography (silica gel,

[

(R)-7]: Following the procedure for deprotection of (trimethylsilyl)- 98:2 hexane/EtOAc), 3.62 g (100%) of the title compound as a col-

1

alkynes described above, the reaction of (2ЈR)-2,3-O-isopropylid-

ene-2,3-dihydroxypropyl 7-(trimethylsilyl)hepta-4,6-diynoate [(R)-

2

6 6

orless oil. H NMR (400.13 MHz, C D ): δ = 7.75–7.63 (m, 4 H),

7.31–7.18 (m, 6 H), 3.52 (t, J = 5.9 Hz, 2 H, 1-H), 2.13 (t, J =

7.0 Hz, 2 H, 3-H), 1.49–1.39 (m, 2 H, 2-H), 1.10 (s, 9 H, SitBu),

8; 0.16 g, 0.52 mmol] and potassium carbonate (0.09 g,

1

3

0

.62 mmol) in tBuOH/H O (2 mL, 1:1, v/v) at 25 °C afforded, after

2

0.09 (s, 9 H, SiMe

(d, 4ϫ), 134.0 (s, 2ϫ), 130.0 (d, 2ϫ), 128.1 (d, 4ϫ), 90.0 (s), 83.1

EtOAc), 77 mg (63%) of the title compound as a colorless oil. H (s), 80.0 (s), 67.0 (s), 62.2 (t), 31.2 (t), 27.1 [q, C(CH ], 19.4 [s,

NMR (400.13 MHz, C ): δ = 4.03–3.78 (m, 3 H, 1Ј-H, 2Ј-H), C(CH ], 15.9 (t), –0.2 [q, 3ϫ, Si(CH ] ppm. IR (NaCl): ν˜ = 3066

.64 (dd, J = 8.4, 6.3 Hz, 1 H, 3Ј-H ), 3.40 (dd, J = 8.4, 5.9 Hz, 1 (w, Ar–H), 2954 (m, C–H), 2861 (w, C–H), 2223 (w, –CϵC–), 2107

3 6 6

) ppm. C NMR (100.62 MHz, C D ): δ = 136.0

purification by column chromatography (silica gel, 80:20 hexane/

1

3 3

)

6

D

6

3

)

3

3 3

)

3

1

A

6

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:26

Pages: 22

Syntheses of Natural and Unnatural Acetoxyenediynes

w, –CϵC–), 1427 (w), 1251 (w), 1110 (m), 844 (s), 772 (s) cm .

–

1

(

H, 10-H), 1.62 [s, 3 H, OC(O)CH

3

], 1.48–1.39 (m, 2 H, 2-H), 1.36–

), 1.12 (s, 9 H,

+

UV (MeOH): λmax = 219 nm. HRMS (ESI ): calcd. for C26

[

H35OSi

2

1.20 (m, 18 H, 9 CH

SitBu), 0.92 (t,

100.62 MHz, C

1

7

3

2

), 1.20–1.14 (m, 6 H, 3 CH

6.8 Hz, H, CH ) ppm.

): δ = 167.3 (s), 136.0 (d, 4ϫ), 134.0 (s, 2ϫ),

31.5 (d), 130.3 (d), 130.0 (d, 2ϫ), 128.2 (d, 4ϫ), 85.9 (s), 75.0 (s),

0.30 (s), 65.9 (s), 62.2 (t), 32.4 (t), 31.1 (t), 30.2 (t, 4ϫ), 30.1 (t),

0.0 (t), 29.9 (t), 29. 8 (t), 29.5 (t), 28.7 (t), 27.1 [q, 3ϫ, C(CH ],

6.7 (t), 23.2 (t), 19.9 (q), 19.4 [s, C(CH ], 16.2 (t), 14.4 (q) ppm.

2

M + H]⁺419.22210; found 419.22211.

J

D

6 6

=

3

13

C NMR

3

(

1-(tert-Butyldiphenyloxy)hepta-4,6-diyne (35). General Procedure

for the Deprotection of (Trimethylsilyl)alkynes. Method B: Potas-

sium carbonate (1.43 g, 10.38 mmol) was added to a cooled (0 °C)

stirred solution of 1-(tert-butyldiphenyloxy)-7-(trimethylsilyl)-

hepta-4,6-diyne (34; 3.62 g, 8.65 mmol) in MeOH (33 mL). After

stirring for 15 min the reaction mixture was passed through a pad

of Celite and the solvent was removed under vacuum. The residue

was purified by column chromatography (silica gel, 98:2 hexane/

3 3

)

3 3

)

IR (NaCl): ν˜ = 2925 (s, C–H), 2854 (m, C–H), 1769 (m, C=O),

–

1

2

6

427 (w), 1197 (m), 1110 (s) cm . UV (MeOH): λmax = 215, 239,

+

52, 266, 282 nm. HRMS (ESI ): calcd. for C41

H

59

O

3

Si [M + H]

27.42280; found 627.42333.

EtOAc) to provide 2.86 g (95%) of a colorless oil that was identified

1

as the title compound. H NMR (400.13 MHz, C

6

D

6

): δ = 7.75–

(8E)-1-(tert-Butyldiphenylsilyloxy)tricosa-8-ene-4,6-diyn-8-yl Acet-

1

6 6

7.62 (m, 4 H), 7.29–7.20 (m, 6 H), 3.51 (t, J = 5.9 Hz, 2 H, 1-H), ate [(E)-37b]: H NMR (400.13 MHz, C D ): δ = 7.78–7.66 (m, 4

2

.09 (t, J = 7.0 Hz, 2 H, 3-H), 1.48 (s, 1 H, 7-H), 1.47–1.39 (m, 2

H), 7.32–7.21 (m, 6 H), 5.69 (t, J = 8.0 Hz, 1 H, 9-H), 3.49 (t, J =

5.9 Hz, 2 H, 1-H), 2.29–2.19 (m, 2 H, 10-H), 2.14 (t, J = 7.0 Hz, 2

13

H, 2-H), 1.10 (s, 9 H, SitBu) ppm. C NMR (100.62 MHz, C

δ = 135.9 (d, 4ϫ), 134.0 (s, 2ϫ), 130.0 (d, 2ϫ), 128.1 (d, 4ϫ), 78.2

s), 69.1 (s), 65.9 (s), 65.2 (d), 62.2 (t), 31.0 (t), 27.1 [q, C(CH ],

9.4 [s, C(CH ], 15.6 (t) ppm. IR (NaCl): ν˜ = 3304 (m, –CϵC– H, CH

H), 3071 (w, Ar–H), 3048 (w, Ar–H), 2956 (m, C–H), 2931 (m, C– CH ], 136.0 (d, 4ϫ), 134.0 (s, 2ϫ), 132.0 (d), 130.7 (s), 130.0 (d,

H), 2858 (m, C–H), 2225 (w, –CϵC–), 1471 (w), 1427 (m), 1110

6 6

D ):

H, 3-H), 1.61 [s, 3 H, OC(O)CH

1.17 (m, 24 H, 12 CH ), 1.12 (s, 9 H, SitBu), 0.92 (t, J = 6.8 Hz, 3

) ppm. C NMR (100.62 MHz, C ): δ = 168.0 [s, OC(O)

3

], 1.46–1.38 (m, 2 H, 2-H), 1.37–

(

1

3

)

3

2

1

3

)

3

6 6

D

3

2ϫ), 128.2 (d, 4ϫ), 87.1 (s), 79.8 (s), 68.1 (s), 65.7 (s), 62.2 (t), 32.4

(t), 31.1 (t), 30.2 (t), 30.2 (t, 4ϫ), 30.0 (t), 29.9 (t, 2ϫ), 29.4 (t),

s), 702 (s) cm . HRMS (ESI ): calcd. for C23H

27OSi [M + H]⁺

–1

+

(

3

47.18257; found 347.18251.

29.3 (t), 28.4 (t), 27.1 [q, 3ϫ, C(CH

CH ], 19.4 [s, C(CH ], 16.2 (t), 14.4 (q) ppm. IR (NaCl): ν˜ = 2925

s, C–H), 2854 (m, C–H), 1771 (m, CO), 1428 (w), 1204 (s), 1108

3 3

) ], 23.2 (t), 20.1 [q, OC(O)

3

3 3

)

1-(tert-Butyldiphenylsilyloxy)tricosa-4,6-diyn-8-one (36b): Follow-

(

ing the general procedure for the synthesis of propargylic ketones

described above, the reaction of N-methoxy-N-methylhexadec-

anamide (6b; 0.19 g, 0.63 mmol), 1-(tert-butyldiphenylsilyloxy)-

hepta-4,6-diyne (35; 0.30 g, 0.88 mmol), and n-butyllithium

–

1

s) cm . UV (MeOH): λmax = 216, 240, 252, 266, 282 nm. HRMS

+

59 3

H O

Si [M + H]⁺627.42280; found

ESI ): calcd. for C41

27.42383.

6

(

0.49 mL, 1.54 m in THF, 0.76 mmol) in THF (5.2 mL) at –40 °C

afforded, after purification by column chromatography (silica gel,

0:8:2 hexane/CH Cl /EtOAc), 0.38 g (74%) of a yellow oil that

was identified as the title compound. H NMR (400.13 MHz,

CDCl ): δ = 7.68 (dd, J = 7.7, 1.2 Hz, 4 H, ArH), 7.49–7.36 (m, 6

H, ArH), 3.75 (t, J = 5.8 Hz, 2 H, 1-H), 2.63–2.49 (m, 4 H, 3-H,

-H), 1.88–1.75 (m, 2 H, 2-H), 1.75–1.62 (m, 2 H, 10-H), 1.36–1.21

m, 24 H, 12 CH ), 1.08 [s, 9 H, SiC(CH

) ppm. ¹³C NMR (100.62 MHz, CDCl

(8E)- and (8Z)-1-Hydroxytricosa-8-ene-4,6-diyn-8-yl Acetate (38b):

Following the general procedure for the deprotection of (triisoprop-

ylsilyl)alkynes described above, the reaction of a 59:41 mixture of

(8Z)- and (8E)-1-(tert-butyldiphenylsilyloxy)tricosa-8-ene-4,6-diyn-

8-yl acetate (37b; 0.21 g, 0.33 mmol) with nBu NF (0.36 mL, 1 m

4

in THF, 0.36 mmol) in THF (9 mL) afforded, after purification by

column chromatography (silica gel, 70:30 hexane/EtOAc), 64 mg

9

2

1

3

9

(

2

3

)], 0.90 (t, J = 6.7 Hz, 3 (50%) of the title compound. The isomers were separated by HPLC

): δ = 187.5 (s), [Spherisorb 5 μm, 10ϫ250 mm, 80:20 hexane/EtOAc, 3 mL/min,

H, CH

3

1

35.6 (d, 4ϫ), 133.6 (s, 2ϫ), 129.8 (d, 2ϫ), 127.8 (d, 4ϫ), 90.3 (s),

t

R

(E) = 21.2 min and t

8E)-1-Hydroxytricosa-8-ene-4,6-diyn-8-yl Acetate [(E)-38b]: ¹H

): δ = 5.78 (t, J = 8.0 Hz, 1 H, 9-H),

.75 (t, J = 6.1 Hz, 2 H, 1-H), 2.48 (t, J = 7.0 Hz, 2 H, 3-H), 2.31–

.21 (m, 2 H, 10-H), 2.13 [s, 3 H, OC(O)CH ], 1.85–1.74 (m, 2 H,

-H), 1.49–1.35 (m, 2 H, 11-H), 1.36–1.18 (m, 22 H, 11 CH ), 0.87

) ppm. C NMR (100.62 MHz, CDCl ):

δ = 169.0 (s), 132.3 (d), 129.7 (s), 86.2 (s), 78.9 (s), 67.1 (s), 65.2

s), 61.4 (t), 32.1 (t), 30.8 (t), 29.8 (t), 29.8 (t), 29.8 (t, 2ϫ), 29.7 (t,

8E)- and (8Z)-1-(tert-Butyldiphenylsilyloxy)tricosa-8-ene-4,6-diyn- 2ϫ), 29.6 (t), 29.5 (t), 29.2 (t), 29.0 (t), 28.1 (t), 22.8 (t), 20.9 (q),

R

(Z) = 23.8 min].

76.2 (s), 72.4 (s), 64.1 (s), 62.0 (t), 45.7 (t), 32.0 (t), 30.7 (t), 29.8

(

(t, 4ϫ), 29.8 (t), 29.8 (t), 29.7 (t), 29.6 (t), 29.5 (t), 29.4 (t), 29.1 (t),

NMR (400.13 MHz, CDCl

3

26.9 [q, 3ϫ, C(CH

3 3 3 3

) ], 24.1 (t), 22.8 (t), 19.3 [s, C(CH ) ], 16.4 (t),

4.3 (q) ppm. IR (NaCl): ν˜ = 3071 (w, C–H), 3049 (w, C–H), 2925

3

2

1

3

(s, C–H), 2854 (s, C–H), 2233 (s, –CϵC–), 2143 (w, –CϵC–), 1672

–1

2

(s, C=O), 1110 (s), 702 (s) cm . UV (MeOH): λmax = 256, 269,

1

3

(

t, J = 6.8 Hz, 3 H, CH

3

+

57 2

285 nm. HRMS (ESI ): calcd. for C39H O Si [M + 1] 585.41223;

found 585.41177.

(

8-yl Acetate (37b): Following the general procedure for the synthe-

16.2 (t), 14.3 (q) ppm. IR (NaCl): ν˜ = 3600–3200 (br., OH), 2924

sis of enol acetates described above, the reaction of 1-(tert-butyldi-

phenylsilyloxy)tricosa-4,6-diyn-8-one (36b; 0.38 g, 0.65 mmol),

(s, C–H), 2853 (m, C–H), 2233 (w, –CϵC–), 1764 (m, C=O), 1365

–

1

(w), 1204 (m), 1093 (m) cm . UV (MeOH): λmax = 215, 240, 252,

+

Et

and acetic anhydride (0.37 mL, 0.40 g, 3.89 mmol) in CH

8 mL) at 0 °C afforded, after purification by column chromatog-

3

N (0.45 mL, 0.33 g, 3.24 mmol), DMAP (0.04 g, 0.32 mmol),

266, 282 nm. HRMS (ESI ): calcd. for C25

H

41

O

3

[M + H]

2

Cl

2

389.30502; found 389.30628.

(

8Z)-1-Hydroxytricosa-8-ene-4,6-diyn-8-yl Acetate [(Z)-38b]: ¹H

raphy (silica gel, 95:5 hexane/EtOAc), 0.38 g (93%) of a colorless

oil that was identified as the title compound as a 59:41 Z/E mixture

of isomers. These were separated by HPLC [Spherisorb™ 5 μm,

3

NMR (400.13 MHz, CDCl ): δ = 5.77 (t, J = 7.7 Hz, 1 H, 9-H),

3

[

2

CH

.74 (t, J = 6.1 Hz, 2 H, 1-H), 2.46 (t, J = 7.0 Hz, 2 H, 3-H), 2.17

s, 3 H, OC(O)CH ], 2.11–1.98 (m, 2 H, 10-H), 1.88–1.70 (m, 2 H,

-H), 1.45–1.15 (m, 24 H, 12 CH ), 0.88 (t, J = 6.8 Hz, 3 H,

) ppm. C NMR (100.62 MHz, CDCl ): δ = 168.2 (s), 131.8

3

10ϫ250 mm, 98:2 hexane/EtOAc, 3 mL/min, t

R

(Z) = 12.7 min and

2

t

R

(E) = 15.6 min].

1

3

(

8Z)-1-(tert-Butyldiphenylsilyloxy)tricosa-8-ene-4,6-diyn-8-yl Acet-

(d), 129.2 (s), 85.1 (s), 74.1 (s), 69.3 (s), 65.2 (s), 61.4 (t), 32.1 (t),

30.9 (t), 29.8 (t, 5ϫ), 29.6 (t), 29.5 (t, 2ϫ), 29.3 (t), 28.5 (t), 26.5

1

ate [(Z)-37b]: H NMR (400.13 MHz, C

6

D

6

): δ = 7.77–7.65 (m, 4

H), 7.31–7.20 (m, 6 H), 5.65 (t, J = 7.7 Hz, 1 H, 9-H), 3.51 (t, J = (t), 22.8 (t), 20.7 (q), 16.2 (t), 14.3 (q) ppm. IR (NaCl): ν˜ = 3600–

.9 Hz, 2 H, 1-H), 2.14 (t, J = 7.0 Hz, 2 H, 3-H), 2.02–1.88 (m, 2 3200 (br., OH), 2924 (s, C–H), 2853 (m, C–H), 2235 (w, –CϵC–),

5

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

17

Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:26

Pages: 22

P. García-Domínguez, R. Alvarez, Á. R. de Lera

FULL PAPER

–1

1769 (m, C=O), 1371 (w), 1197 (s), 1069 (m) cm . UV (MeOH):

of isomers of 8-acetoxytricosa-8-ene-4,6-diynoic acid (40b; 45 mg,

0.11 mmol), DCC (23 mg, 0.11 mmol) and DMAP (14 mg,

0.11 mmol) in CH Cl (0.3 mL). After stirring the resulting mixture

2 2

+

λ

C

max = 215, 239, 251, 265, 281 nm. HRMS (ESI ): calcd. for

[M + H]⁺389.30502; found 389.30616.

25

H

41

O

3

at room temperature overnight, the solvent was evaporated and the

residue was purified by column chromatography (silica gel, 75:25

hexane/EtOAc) to afford 25 mg (58%) of the title compound as a

colorless oil.

(

8E)- and (8Z)-8-Acetoxytricosa-8-ene-4,6-diynoic Acid (40b). Gene-

ral Procedure for the Swern Oxidation: DMSO (68 μL, 69 mg,

.88 mmol) was added dropwise to a cooled (–60 °C) stirred solu-

tion of oxalyl chloride (45 μL, 65 mg, 0.51 mmol) in CH Cl (4 mL)

0

2

and the reaction mixture was stirred for 5 min at this temperature.

Then a solution of a 59:41 mixture of (8Z)- and (8E)-8-acetoxyte-

(12Z,15Z)-1-(tert-Butyldiphenylsilyloxy)octadeca-12,15-dien-4,6-

diyn-8-one (36a): Following the general procedure for the synthesis

of propargylic ketones described above, the reaction of (5Z,8Z)-N-

methoxy-N-methylundeca-5,8-dienamide (6a; 1.0 g, 4.44 mmol), 1-

tert-butyldiphenyloxyhepta-4,6-diyne (35; 2.16 g, 6.22 mmol), and

tracosa-8-ene-4,6-diyn-1-ol (38b; 0.14 g, 0.36 mmol) in CH

2

Cl

N (0.34 mL, 0.24 g,

.41 mmol) was added and the resulting solution was stirred for

2

(4 mL) was added. After stirring for 30 min, Et

3

2

1

0 min at –60 °C. The mixture was warmed to room temperature, n-butyllithium (3.6 mL, 1.50 m in THF, 5.33 mmol) in THF at

poured into water, and extracted with CH

2

Cl

2

(3ϫ). The combined

–40 °C afforded, after purification by column chromatography (sil-

ica gel, 98:2 hexane/EtOAc), 2.08 g (92%) of a colorless oil that was

organic layers were dried (Na SO ) and the solvent was evaporated.

2

4

1

The residue was used in the next step without further purification.

identified as the title compound. H NMR (400.13 MHz, C D ): δ

6

=

7.76–7.60 (m, 4 H, ArH), 7.32–7.19 (m, 6 H, ArH), 5.47–5.29

General Procedure for the Lindgren Oxidation: A solution of Na-

(

m, 3 H), 5.26–5.13 (m, 1 H), 3.48 (t, J = 5.8 Hz, 2 H, 1-H), 2.72

t, J = 6.8 Hz, 2 H, 14-H), 2.22 (t, J = 7.3 Hz, 2 H, 3-H), 2.10 (t,

ClO

O (2.2 mL) was added dropwise to a solution of the residue ob-

tained above (0.36 mmol) and 2-methyl-2-butene (0.17 mL, 0.11 g,

.61 mmol) in tBuOH (5.5 mL). The reaction mixture was stirred

2 2 4

(0.16 g, 1.83 mmol) and NaH PO (0.17 g, 1.40 mmol) in

H

2

J = 7.0 Hz, 2 H, 9-H), 2.05–1.95 (m, 2 H, 11-H), 1.92–1.83 (m, 2

H, 17-H), 1.59–1.49 (m, 2 H, 10-H), 1.45–1.36 (m, 2 H, 2-H), 1.10

1

3

(

1

4

2

1

s, 9 H, SitBu), 0.92 (t, J = 7.5 Hz, 3 H, CH

100.62 MHz, C ): δ = 185.8 (s), 135.9 (d, 4ϫ), 133.8 (s, 2ϫ),

32.1 (d), 130.1 (d, 2ϫ), 129.6 (d), 128.9 (d), 128.2 (d), 127.6 (d,

ϫ), 90.0 (s), 75.4 (s), 73.2 (s), 64.7 (s), 62.1 (t), 44.9 (t), 30.8 (t),

7.1 (q, 3ϫ), 26.5 (t), 25.9 (t), 23.9 (t), 20.9 (t), 19.4 (s), 16.2 (t),

4.6 (q) ppm. IR (NaCl): ν˜ = 2959 (m, C–H), 2930 (m, C–H), 2857

3

) ppm. C NMR

for 2 h at 25 °C, basified to pH 8 with a 2 m aqueous solution of

NaOH, and the tBuOH was removed under vacuum. The resulting

6

D

6

mixture was diluted with H

hexane (3ϫ). The aqueous layer was acidified to pH 3 with a 0.5 n

aqueous solution of HCl and extracted with Et O (3ϫ). The com-

bined organic layers were dried (Na SO ) and the solvent was evap-

orated. The residue was purified by column chromatography (silica

gel, 95:5 CH Cl /MeOH) to afford 102 mg (69% over the two steps)

2

O and brine and then extracted with

2

4

(

m, C–H), 2231 (s, –CϵC–), 2142 (w, –CϵC–), 1671 (s, C=O), 1427

m), 1109 (s) cm . UV (MeOH): λmax = 255, 270, 285 nm. HRMS

ESI ): calcd. for C34

11.30291.

–

1

2

+

43 2

H O

Si [M + H]⁺511.30268; found

of a white solid that was identified as the title product. The isomers

were separated by RP-HPLC [Phenomenex Luna 5 μm,

5

1

0ϫ100 mm, 70:30 acetonitrile/H

min, t (E) = 23.0 min and t (Z) = 28.0 min].

₈_E₎_-₈_-_A_c_e_t_o_x_y_t_r_i_c_o_s_a_-₈_-_e_n_e_-₄_,₆_-_d_i_y_n_o_i_c_A_c_i_d_[₍_E₎_-₄₀_b_]_:1H NMR

2

O with 0.1% formic acid, 3 mL/

(

8E,12Z,15Z)- and (8Z,12Z,15Z)-1-(tert-Butyldiphenylsilyloxy)-

R

octadeca-8,12,15-trien-4,6-diyn-8-yl Acetate (37a): Following the

general procedure for the synthesis of enol acetates (Method F)

described above, the reaction of (12Z,15Z)-1-(tert-butyldiphenyl-

(

500 MHz, CDCl

m, 4 H, 2-H, 3-H), 2.30–2.22 (m, 2 H, 10-H), 2.13 [s, 3 H, OC(O)-

], 1.46–1.37 (m, 2 H, 11-H), 1.36–1.19 (m, 22 H, 11 CH ), 0.88

): δ =

3

): δ = 5.79 (t, J = 8.0 Hz, 1 H, 9-H), 2.71–2.59

silyloxy)octadeca-12,15-dien-4,6-diyn-8-one

.82 mmol), 1,1,3,3-tetramethyl-1,3-diphenyldisilazane (0.36 mL,

0.35 g, 1.24 mmol), n-butyllithium (0.66 mL, 1.50 m in THF,

.99 mmol), and acetic anhydride (0.39 mL, 0.42 g, 4.12 mmol) in

(36a;

0.42 g,

0

CH

3

2

₎_p_p_m_.1 C NMR (126 MHz, CDCl

3

(t, J = 6.9 Hz, 3 H, CH

3

0

1

6

75.9 (s), 169.2 (s), 132.7 (d), 130.0 (s), 84.5 (s), 79.0 (s), 68.0 (s),

5.8 (s), 32.8 (t), 32.4 (t), 32.2 (t), 30.2 (t, 6ϫ), 29.4 (t, 2ϫ), 29.2

THF (16.5 mL) at –78 °C afforded, after purification by column

chromatography (silica gel, 97:3 hexane/EtOAc), 0.23 g (50%) of a

colorless oil that was identified as the title product as a 33:67 mix-

ture of E/Z isomers.

(t), 29.0 (t), 23.1 (t), 19.7 (q), 15.7 (t), 14.5 (q) ppm. IR (NaCl): ν˜

=

3300–3000 (br., O–H), 2924 (s, C–H), 2853 (m, C–H), 1763 (m,

–1

C=O), 1714 (m, C=O), 1204 (s), 1093 (w) cm . UV (MeOH): λmax

+

=

[

216, 239, 252, 266, 282 nm. HRMS (ESI ): calcd. for C25

39 4

H O

(

8E,12Z,15Z)- and (8Z,12Z,15Z)-1-(tert-Butyldiphenylsilyloxy)-

M + H]⁺403.28429; found 403.28444.

octadeca-8,12,15-triene-4,6-diyn-8-yl Acetate (37a): Following the

general procedure for the synthesis of enol acetates (Method G)

described above, the reaction of (12Z,15Z)-1-(tert-butyldiphenyl-

(

8Z)-8-Acetoxytricosa-8-ene-4,6-diynoic Acid [(Z)-40b]: ¹H NMR

500 MHz, CDCl ): δ = 5.79 (t, J = 7.7 Hz, 1 H, 9-H), 2.70–2.57

m, 4 H, 2-H, 3-H), 2.18 [s, 3 H, OC(O)CH

0-H), 1.39–1.18 (m, 24 H, 12 CH ), 0.87 (t, J = 7.1 Hz, 3 H,

CH

) ppm. ¹³C NMR (126 MHz, CDCl

31.9 (d), 129.2 (s), 84.2 (s), 74.1 (s), 69.5 (s), 65.2 (s), 45.7 (t), 32.0

t), 29.8 (t, 5ϫ), 29.7 (t), 29.5 (t, 2ϫ), 29.4 (t), 28.6 (t), 26.5 (t),

3

], 2.09–1.97 (m, 2 H, silyloxy)octadeca-4,6-diyn-8-one 36a (0.83 g, 1.63 mmol), hexa-

3

1

2

methyldisilazane (0.51 μL, 0.39 g, 2.44 mmol), n-butyllithium

): δ = 176.5 (s), 168.4 (s), (1.28 mL, 1.50 m in THF, 1.92 mmol) and acetic anhydride

3

1

(

(0.77 μL, 0.83 g, 8.13 mmol) in THF (32 mL) at –78 °C afforded,

after purification by column chromatography (silica gel, 97:3 hex-

2

2.8 (t), 20.6 (q), 15.0 (t), 14.3 (q) ppm. IR (NaCl): ν˜ = 3300–3000 ane/EtOAc), 0.74 g (82%) of a colorless oil that was identified as

(

br., O–H), 2924 (s, C–H), 2852 (m, C–H), 1769 (m, C=O), 1713 the title product as an 87:13 mixture of E/Z isomers.

–1

m, C=O), 1196 (s) cm . UV (MeOH): λmax = 215, 239, 252, 266,

(

4

8E,12Z,15Z)- and (8Z,12Z,15Z)-1-Hydroxyoctadeca-8,12,15-trien-

,6-diyn-8-yl Acetate (38a): Following the general procedure for the

+

38 4

H O

Na [M + Na]⁺

2

4

81 nm. HRMS (ESI ): calcd. for C25

25.26623; found 425.26679.

deprotection of (triisopropylsilyl)alkynes described above, the reac-

tion of a 33:67 mixture of (8E,12Z,15Z)- and (8Z,12Z,15Z)-1-(tert-

butyldiphenylsilyloxy)octadeca-8,12,15-trien-4,6-diyn-8-yl acetate

(2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl (8E)- and (8Z)-8-

Acetoxytricosa-8-ene-4,6-diynoate [(E,R)-12b]. General Procedure

for Ester Formation: A solution of (R)-2,3-O-isopropylidene-2,3-

4

(37a; 0.12 g, 0.22 mmol) with nBu NF (0.24 mL, 1 m in THF,

dihydroxy-1-propanol [(R)-41; 14 μL, 45 mg, 0.34 mmol] in CH

2

Cl

2

0.24 mmol) in THF (6 mL) afforded, after purification by column

chromatography (silica gel, 60:40 hexane/EtOAc), 0.04 g (59%) of

(0.3 mL) was added to a stirred solution of a 59:41 E/Z mixture

18

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:27

Pages: 22

Syntheses of Natural and Unnatural Acetoxyenediynes

the title compound. The isomers were separated by RP-HPLC

(8E,12Z,15Z)- and (8Z,12Z,15Z)-8-Acetoxyoctadeca-8,12,15-trien-

4,6-diynoic Acid (40a): Following the general procedure for the

Swern oxidation described above, the reaction of an 87:13 mixture

of isomers of (8E,12Z,15Z)- and (8Z,12Z,15Z)-1-hydroxyoctadeca-

[

Phenomenex Luna 5 μm, 10ϫ100 mm, 50:50 acetonitrile/H

with 0.1% formic acid, 3 mL/min, t (E) = 27 min and t (Z) =

1 min].

2

O

R

3

8

,12,15-triene-4,6-diyn-8-yl acetate (38a; 0.05 g, 0.16 mmol), oxalyl

chloride (20 μL, 29 mg, 0.23 mmol), DMSO (31 μL, 31 mg,

.39 mmol), and Et N (0.15 mL, 0.11 g, 1.07 mmol) in CH Cl

3.7 mL) afforded a residue that was used in the next step without

Following the general procedure for the deprotection of (triisoprop-

ylsilyl)alkynes described above, the reaction of an 87:13 mixture of

0

(

3

2

(

8E,12Z,15Z)- and (8Z,12Z,15Z)-1-(tert-butyldiphenylsilyloxy)-

octadeca-8,12,15-trien-4,6-diyn-8-yl acetate (37a; 0.39 g,

.71 mmol) with nBu NF (0.78 mL, 1 m in THF, 0.78 mmol) in

THF (20 mL) afforded, after purification by column chromatog-

further purification.

0

4

Following the general procedure for the Lindgren oxidation de-

raphy (silica gel, 60:40 hexane/EtOAc), 0.10 g (46%) of the title scribed above, the reaction of the residue obtained above

compound.

(0.13 mmol), 2-methyl-2-butene (76 μL, 0.05 g, 0.72 mmol), Na-

ClO (74 mg, 0.81 mmol), and NaH PO (0.08 g, 0.62 mmol) in a

mixture of tBuOH (2.4 mL) and H O (1 mL) afforded, after purifi-

cation by column chromatography (silica gel, 97:3 CH Cl /MeOH),

1 mg (78% over two steps) of a white solid that was identified as

the title product. The isomers were separated by RP-HPLC [Phe-

nomenex Luna 5 μm, 10ϫ100 mm, 50:50 acetonitrile/H O with

.1% formic acid, 3 mL/min, t (E) = 22 min and t (Z) = 26 min].

2

4

(

8E,12Z,15Z)-1-Hydroxyoctadeca-8,12,15-trien-4,6-diyn-8-yl Acet-

1

2

ate [(E)-38a]: H NMR (400.13 MHz, CDCl

7

3

): δ = 5.79 (t, J =

.9 Hz, 1 H, 9-H), 5.48–5.23 (m, 4 H, 12-H, 13-H, 15-H, 16-H),

.75 (t, J = 6.1 Hz, 2 H, 1-H), 2.77 (t, J = 6.4 Hz, 2 H, 14-H), 2.48

2

4

(

t, J = 7.0 Hz, 2 H, 3-H), 2.42–2.27 (m, 2 H, 10-H or 11-H), 2.24–

.17 (m, 2 H, 10-H or 11-H), 2.14 [s, 3 H, OC(O)CH ], 2.11–2.01

m, 2 H, 17-H), 1.88–1.73 (m, 2 H, 2-H), 0.97 (t, J = 7.5 Hz, 3 H,

CH ): δ = 168.9 (s), 132.2

) ppm. ¹³C NMR (100.62 MHz, CDCl

d), 131.3 (d), 130.0 (s, C-8), 129.6 (d), 128.2 (d), 127.1 (d), 86.4

s), 79.2 (s), 66.9 (s), 65.1 (s), 61.4 (t), 30.8 (t), 28.1 (t), 26.7 (t),

2

3

0

R

(

3

(

[

8E,12Z,15Z)-8-Acetoxyoctadeca-8,12,15-trien-4,6-diynoic

Acid

3

(E)-40a]: H NMR (400.13 MHz, CDCl ): δ = 5.80 (t, J = 7.9 Hz,

(

1

=

2

H, 9-H), 5.48–5.24 (m, 4 H, 12-H, 13-H, 15-H, 16-H), 2.77 (t, J

6.7 Hz, 2 H, 14-H), 2.70–2.57 (m, 4 H, 2-H, 3-H), 2.39–2.28 (m,

25.7 (t), 20.9 (q), 20.7 (t), 16.2 (t), 14.4 (q) ppm. IR (NaCl): ν˜ =

3

600–3100 (br., O–H), 3009 (w, C–H), 2930 (m, C–H), 2234 (m, –

3

H, 10-H), 2.24–2.16 (m, 2 H, 11-H), 2.14 [s, 3 H, OC(O)CH ],

–

1

CϵC–), 1761 (s, C=O), 1366 (m), 1203 (s), 1090 (m) cm . UV

1

2

.11–2.00 (m, 2 H, 17-H), 0.97 (t, J = 7.5 Hz, 3 H, CH

3

) ppm. H

+

(MeOH): λmax = 252, 267, 282 nm. HRMS (ESI ): calcd. for

NMR (400.13 MHz, C

5

1

H, 10-H, 11-H, 17-H), 1.67 [s, 3 H, OC(O)CH

3

1

6

D

6

): δ = 5.78 (t, J = 7.9 Hz, 1 H, 9-H),

[M + H]⁺315.19547; found 315.19551.

20 27 3

C H O

.60–5.47 (m, 3 H), 5.47–5.36 (m, 1 H), 2.84 (t, J = 6.7 Hz, 2 H,

4-H), 2.34 (dd, J = 14.9, 7.4 Hz, 2 H, 2-H), 2.26–1.92 (m, 8 H, 3-

], 1.03 (t, J = 7.5 Hz,

): δ = 183.6 (s),

68.0 (s), 132.1 (d), 131.4 (d), 130.8 (s), 129.7 (d), 128.7 (d), 127.6

(

8Z,12Z,15Z)-1-Hydroxyoctadeca-8,12,15-trien-4,6-diyn-8-yl Acet-

1

ate [(Z)-38a]: H NMR (400.13 MHz, CDCl

7

3

(

4

3

): δ = 5.77 (t, J =

.5 Hz, 1 H, 9-H), 5.48–5.16 (m, 4 H, 12-H, 13-H, 15-H, 16-H),

.73 (t, J = 6.1 Hz, 2 H, 1-H), 2.75 (t, J = 7.1 Hz, 2 H, 14-H), 2.45

], 2.15–2.10 (m,

H, 10-H, 11-H), 2.10–2.01 (m, 2 H, 17-H), 1.83–1.74 (m, 2 H, 2-

1

3

3 6 6

H, CH ) ppm. C NMR (100.62 MHz, C D

(

2

d), 85.3 (s), 79.6 (s), 68.6 (s), 65.9 (s), 30.2 (t), 28.3 (t), 26.8 (t),

5.9 (t), 20.9 (t), 20.1 (q), 15.5 (t), 14.5 (q) ppm. IR (NaCl): ν˜ =

t, J = 7.0 Hz, 2 H, 3-H), 2.17 [s, 3 H, OC(O)CH

3

₎_p_p_m_.1 C NMR (100.62 MHz,

3

3500–3000 (br., O–H), 3011 (m, C–H), 2924 (s, C–H), 2851 (s, C–

H), 2236 (w, –CϵC–), 1756 (s, C=O), 1715 (m, C=O), 1422 (m),

1

2

H), 0.96 (t, J = 7.5 Hz, 3 H, CH

3

CDCl

), 129.5 (d), 128.2 (d), 127.0 (d), 85.2 (s), 74.3 (s), 69.1 (s), 65.1

s), 61.4 (t), 30.8 (t), 26.5 (t), 26.1 (t), 25.6 (t), 20.7 (q), 20.6 (t),

6.2 (t), 14.4 (q) ppm. IR (NaCl): ν˜ = 3600–3100 (br., O–H), 3009

w, C–H), 2959 (m, C–H), 2235 (w, –CϵC–), 1767 (s, C=O), 1372

3

): δ = 168.2 (s), 132.2 (d), 130.7 (d), 129.7 (d), 130.0 (s, C-

–

1

365 (m), 1203 (s), 1088 (s), 1027 (m) cm . UV (MeOH): λmax =

8

(

1

+

25 4

15, 240, 252, 267, 282 nm. HRMS (ESI ): calcd. for C20H O [M

+

H] 329.17474; found 329.17469.

(

2

(

8Z,12Z,15Z)-8-Acetoxyoctadeca-8,12,15-trien-4,6-diynoic

Acid

–

1

w), 1196 (s), 1064 (m) cm . UV (MeOH): λmax = 215, 239, 252,

1

[(Z)-40a]: H NMR (400.13 MHz, C D ): δ = 5.61 (t, J = 7.4 Hz,

6 6

+

27 3

H O

[M + H]⁺

66, 282 nm. HRMS (ESI ): calcd. for C20

15.19547; found 315.19547.

1

6

H, 9-H), 5.46–5.31 (m, 3 H), 5.27–5.18 (m, 1 H), 2.71 (t, J =

.9 Hz, 2 H, 14-H), 2.10–1.87 (m, 10 H, 2-H, 3-H, 10-H, 11-H, 17-

3

(

4

8E,12Z,15Z)- and (8Z,12Z,15Z)-8-Acetoxyoctadeca-8,12,15-trien-

,6-diynoic Acid (40a): Following the general procedure for the

Swern oxidation described above, the reaction of a 33:67 mixture

of isomers of (8E,12Z,15Z)- and (8Z,12Z,15Z)-1-hydroxyoctadeca- 70.7 (s), 66.0 (s), 32.3 (t), 26.7 (t), 26.3 (t), 25.9 (t), 20.9 (t), 19.8

H), 1.57 [s, 3 H, OC(O)CH

C NMR (100.62 MHz, C D

6 6

3

], 0.92 (t, J = 7.5 Hz, 3 H, CH

): δ = 176.5 (s), 167.3 (s), 132.2 (d),

131.0 (d), 130.3 (s), 129.7 (d), 128.4 (d), 127.4 (d), 84.1 (s), 74.7 (s),

3

) ppm.

1

3

8

,12,15-trien-4,6-diyn-8-yl acetate (38a; 0.04 g, 0.13 mmol), oxalyl

chloride (16 μL, 23 mg, 0.18 mmol), DMSO (24 μL, 24 mg,

.30 mmol), and Et N (0.12 mL, 0.08 g, 0.84 mmol) in CH Cl

3 mL) afforded a residue that was used in the next step without

(q), 15.2 (t), 14.5 (q) ppm. IR (NaCl): ν˜ = 3500–3000 (br., O–H),

3010 (m, C–H), 2963 (m, C–H), 2932 (m, C–H), 2237 (w, –CϵC–

), 1766 (s, C=O), 1714 (s, C=O), 1431 (m), 1370 (m), 1198 (s), 1017

0

(

3

2

–

1

(m) cm . UV (MeOH): λmax = 215, 239, 252, 266, 282 nm. HRMS

+

24 4

H O

Na [M + Na]⁺351.15668; found

further purification.

(ESI ): calcd. for C20

51.15648.

3

Following the general procedure for the Lindgren oxidation de-

scribed above, the reaction of the residue obtained above

(2ЈR)-2,3-O-Isopropylidene-2,3-dihydroxypropyl (8E,12Z,15Z)- and

(8Z,12Z,15Z)-8-Acetoxyoctadeca-8,12,15-trien-4,6-diynoate (12a):

Following the general procedure for ester formation described

above, the reaction of an 87:13 8E/8Z mixture of isomers of

(12Z,15Z)-8-acetoxyoctadeca-8,12,15-trien-4,6-diynoic acid (40a;

29 mg, 0.09 mmol), (R)-2,3-O-isopropylidene-2,3-dihydroxy-1-

propanol [(R)-41; 33 μL, 35 mg, 0.26 mmol], DCC (19 mg,

(

0.13 mmol), 2-methyl-2-butene (59 μL, 0.04 g, 0.56 mmol), Na-

ClO (0.06 g, 0.64 mmol), and NaH PO (0.06 g, 0.49 mmol) in a

mixture of tBuOH (2 mL) and H O (1 mL) afforded, after purifica-

tion by column chromatography (silica gel, 97:3 CH Cl /MeOH),

1 mg (74% over two steps) of a white solid that was identified as

the title product. The isomers were separated by RP-HPLC [Phe-

nomenex Luna 5 μm, 10ϫ100 mm, 50:50 acetonitrile/H O with

.1% formic acid, 3 mL/min, t (E) = 22 min and t (Z) = 26 min].

2

4

2

3

2

0.09 mmol), and DMAP (11 mg, 0.09 mmol) in CH

2 2

Cl (0.5 mL)

0

R

afforded, after purification by column chromatography (silica gel,

Eur. J. Org. Chem. 0000, 0–0

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19

Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:27

Pages: 22

P. García-Domínguez, R. Alvarez, Á. R. de Lera

FULL PAPER

7

5:25 hexane/EtOAc), 18 mg (46%) of a colorless oil that was iden-

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Acknowledgments

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Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:27

Pages: 22

Syntheses of Natural and Unnatural Acetoxyenediynes

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34] Trihalomethylcarbinols are useful intermediates in organic syn-

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LHMDS and (Me

2

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2

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[15,16,46]

ucts,

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Received: March 2, 2012

Published Online: ᭿

[

18266.

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Eur. J. Org. Chem. 0000, 0–0

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Job/Unit: O20246

/KAP1

Date: 12-07-12 17:30:27

Pages: 22

P. García-Domínguez, R. Alvarez, Á. R. de Lera

FULL PAPER

Natural Product Synthesis

Four convergent synthetic approaches to

peyssonenynes have been developed after a

previous optimization with a palmitic acid

based model system.

P. García-Domínguez, R. Alvarez,*

Á. R. de Lera* ................................. 1–22

Survey of Synthetic Approaches to Natural

(

Peyssonenynes) and Unnatural Acetoxy-

enediynes

Keywords: Natural products / Total syn-

thesis / Synthetic methods / Cross-coupling

22

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Eur. J. Org. Chem. 0000, 0–0

Article Doi

Survey of synthetic approaches to natural (peyssonenynes) and unnatural acetoxyenediynes

DOI: 10.1002/ejoc.201200246

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Authors:

Article abstract of DOI:10.1002/ejoc.201200246

Full text of DOI:10.1002/ejoc.201200246

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