Rhodium catalysed conjugate addition of a chiral alkenyltrifluoroborate salt: The enantioselective synthesis of hermitamides A and B

DOI: 10.1039/b812897a

Source and publish data:

Organic and Biomolecular Chemistry p. 4340 - 4347 (2008)

Update date:2022-08-03

Topics:

Authors:

Frost, Christopher G.

Penrose, Stephen D.

Gleave, Robert

Read Full Text PDF DownLoad Join now for total 90,000,000 free articles

Article abstract of DOI:10.1039/b812897a

The concise enantioselective synthesis of hermitamides A and B is presented utilising a rhodium catalysed conjugate addition reaction to introduce the side chain and chiral information in a single step via an alkenyltrifluoroborate salt.

Full text of DOI:10.1039/b812897a

View Article Online / Journal Homepage / Table of Contents for this issue

PAPER

www.rsc.org/obc | Organic & Biomolecular Chemistry

Rhodium catalysed conjugate addition of a chiral alkenyltriﬂuoroborate salt:

the enantioselective synthesis of hermitamides A and B

Christopher G. Frost,*^aStephen D. Penrose^aand Robert Gleave^b

Received 25th July 2008, Accepted 12th September 2008

First published as an Advance Article on the web 18th October 2008

DOI: 10.1039/b812897a

The concise enantioselective synthesis of hermitamides A and B is presented utilising a rhodium

catalysed conjugate addition reaction to introduce the side chain and chiral information in a single step

via an alkenyltriﬂuoroborate salt.

Introduction

Marine natural products from Lyngbya mujuscula cyanobacteria

have provided a diverse set of natural products including lyngbic

acid and the malyngamide family, a range of nitrogen containing

lipopeptides derived from amino acid metabolism (Fig. 1).¹

The amide portion of the malyngamide family contains varied

functionality such as amino acids, lactone, amide, alkaloid or

pyrrole affording a number of further subclasses including the

hermitamide and isomalyngamide series.²It is important to note

that the 7-methoxytetradec-4-enoic acid unit is usually present

in these materials and the (7S)-stereoisomer (lyngbic acid) has

been the focus of most synthetic interest.³Apart from lyngbic

acid, a small range of malyngamide natural products have been

prepared, including the synthesis of serinol-derived malyngamides

by Chen et al.⁴and the enantioselective synthesis of malyngamide

U by Li et al.⁵The illustrated malyngamide X contains the ﬁrst

isolated (7R)-lyngbic acid side chain and is also connected to a

novel tripeptide backbone.⁶The total synthesis of malyngamide

X has recently been reported by Isobe et al.⁷The synthesis

of hermitamides A and B as racemic mixtures was reported

by Virolleaud et al. in 2006.⁸The group employ a ruthenium

Fig. 1 Natural products from L. mujuscula cyanobacteria.

catalysed cross-metathesis reaction in the key step to install the

alkene fragment. In this paper a concise, enantioselective synthesis

of the hermitamide natural product family is presented that

utilises a unique rhodium catalysed conjugate addition of a chiral

organometallic donor to an acrylamide acceptor to assemble the

required functionalised carbon chain in a single step.

The concept involves the retrosynthesis of hermitamide A (1)

and B (2) to synthons that could be accessed via catalytic conjugate

addition methodology. The transition-metal catalysed conjugate

addition of organometallics to activated alkenes is an important

tool for organic synthesis.⁹For the addition of aryl and alkenyl

groups, the elegant rhodium-catalysed addition of organoboron

reagents to a,b-unsaturated carbonyl acceptors, pioneered by

Hayashi and Miyaura offers signiﬁcant advantages in terms of

accessibility of reagents, efﬁciency and operational simplicity.¹⁰

As illustrated in Fig. 2, a simple disconnection of hermitamide A

^aDepartment of Chemistry, University of Bath, Claverton Down, Bath,

BA2 7AY, UK. E-mail: c.g.frost@bath.ac.uk; Fax: +44 (0)1225 386231;

Tel: +44 (0)1225 386142

^bGastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmith-

Kline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19

5AW, UK

Fig. 2 Synthetic strategy.

This journal is The Royal Society of Chemistry 2008

4340 | Org. Biomol. Chem., 2008, 6, 4340–4347

View Article Online

or B reveals an alkenylboron donor and an acrylamide acceptor

(3 or 4). The chiral alkenylboron fragment required for the key

conjugate addition was envisioned to arise from the (E)-selective

hydroboration of alkyne 5. Access to enantioenriched 5 will be

addressed using the elegant hydrolytic kinetic resolution strategy

developed by Jacobsen to provide enantiopure epoxide 6, followed

by a regioselective ring opening with a suitable metal acetylide

and subsequent methylation.¹¹

Results and discussion

The racemic epoxide 6 required for the hydrolytic kinetic reso-

lution step was prepared in high yield by the m-CPBA epoxida-

tion of 1-nonene 7. As monosubstituted aliphatic epoxides are

excellent substrates for the hydrolytic kinetic resolution process,

the standard experimental procedure was followed.¹²Thus, the

chiral cobalt-salen ligand complex was formed by stirring the

commercial cobalt(II) complex 8 in air with acetic acid for

one hour. The dark brown solid remaining after removal of

solvent was resuspended in neat epoxide (rac)-6 and cooled to

0 ^◦C. Finally water was added dropwise and the solution stirred for

72 h at ambient temperature. The crude reaction mixture was then

distilled to afford the chiral epoxide (S)-6 as a colourless oil in 43%

yield. The enantioselectivity was conﬁrmed as being greater than

96% e.e. by comparison with the literature optical rotation as well

as chiral HPLC analysis of the product from ring opening with

2-naphthalene thiol.¹³Addition of lithium acetylide complexed

with ethylene diamine led to the isolation of the homopropargylic

alcohol 9 in 92% yield. The alcohol was methylated in 98% yield

by treatment with sodium hydride and then methyl iodide to set

the stage for the key hydroboration-conjugate addition sequence

(Scheme 1).

Scheme 1 Hydrolytic kinetic resolution strategy.

were also unsuccessful (Table 1)._.All NMR traces contained a

complex mixture of products with no observed peak in the ¹¹B

decoupled NMR spectra. It is plausible that the methoxy group

could undergo elimination under the reaction conditions to give an

enyne side product previously observed on treatment with strong

bases.¹⁵

With a view to developing a mild protocol for preparing

an isolatable chiral alkenylboron species, a route of trapping

an organometallic species with pinacolborane was considered.

Knochel has shown previously that pinacolborane can be used as

an improved hydroboration reagent, which affords air and mois-

ture stable boronic esters with good yields and selectivity.¹⁶One

potential route to the sensitive alkenylpinacol boronic ester entails

the trapping of the appropriate alkenylzirconium species with

pinacolborane. This is an attractive method as the alkenylzirco-

nium intermediate can be formed in-situ by reaction of a terminal

A method for the tandem rhodium catalysed hydroboration-

conjugate addition has been reported by Hayashi et al.¹⁴However,

this method was not transferable to the alkyne substrate 5. A

range of conditions were screened with no product being isolated.

Further attempts at hydroboration with catecholborane (to pre-

pare 10) or BHBr₂.SMe₂followed by hydrolysis (to prepare 11)

Table 1 Attempts at hydroboration

Entry

Borane source

Temperature/^◦C

Time

% Conv.^a

1^b

2^b

3^b

4^b

5^b

6^c

Catecholborane (Neat)

Catecholborane (0.5 M in THF)

BHBr₂·SMe₂

48 h

3 h

72 h

24 h

20 min

3 h

<5%

100 microwave

^aConversion by H NMR. ^bTypical reaction conditions: terminal alkyne (0.5 mmol), catecholborane source (2 eq.), temp ^◦C. ^cReaction conditions:

alkyne (1.0 mmol), BHBr₂·SMe₂1 M in CH₂Cl₂(1.05 eq.) 0 ^◦C, 3 h, followed by diethyl ether/H₂O (10/1), 0 ^◦C, 30 min.

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 4340–4347 | 4341

View Article Online

alkyne with chloridobis(h -cyclopentadienyl)hydridozirconium

chloride and a suitable base.²⁰There are a number of reported ex-

amples in which pinacolboronate reagents are used successfully in

rhodium-catalysed conjugate addition processes.²¹Using a range

of established conditions the addition of chiral alkenylpinacol

boronic ester 13 to phenylethylacrylamide 3 in the presence of

various rhodium sources gave no conversion to hermitamide A

(Table 2, entries 1–4). The addition of a range of bases such as

Na₂CO₃, LiOH and NaF and triethylamine in order to form the

more reactive boronate species gave no discernible improvement in

the reaction (Table 2, entries 5–10). A further attempt at activating

the alkenylboron derivative by treatment with methyl lithium

prior to reaction gave a trace of product formation, although the

predominant species by NMR were still the pinacolboronic ester

and acrylamide starting materials (Table 2, entry 11).²²

It was clear that a more reactive and stable boronate species

would need to be employed. Removal of the diol protecting

group in boronic esters is difﬁcult with methods generally

involving oxidative cleavage of the diol or harsh hydrolytic

protocols.²³In general all deprotection reactions suffer from

incomplete conversions or problems in separating the desired

boronic acid from a large excess of transesteriﬁcation partner.²⁴

In contrast there is signiﬁcant literature precedent for the con-

version of pinacolboronic esters to the corresponding potassium

triﬂuoro(organo)borate salts and these are commonly air-stable,

crystalline solids.²⁵Subjecting the chiral alkenylpinacol boronic

ester 5 to potassium hydrogen diﬂuoride resulted in a modest

yield of the chiral alkenyltriﬂuoroborate salt 14 as shown in

Scheme 3. The precipitated salts were washed successively with

chilled or room temperature acetone, rather than hot solvent as

previously described. Upon chilling in a freezer for three days

multigram quantities of product could be collected as a crystalline

solid and stored until required. NMR studies showed a single

component by multinuclear analysis and no pinacol was observed

after recrystallisation. For completeness we attempted to prepare

the corresponding alkenylboronic acid 11 using the hydrolysis

(Schwartz Reagent) 12.¹⁷Early studies of this type of reaction

were undertaken by Srebnik et al and high yields of product were

noted with a useful range of substrates.¹⁸Wang et al determined

that with bulky silyl protected propargylic ethers an undesirable

Zr–O bond could form leading to problems with catalyst turnover

and resulting in more of the undesired (Z)-isomer.¹⁹This could

be rectiﬁed by heating the reaction mixture to 60 ^◦C, and

adding an amine base such as DMAP or triethylamine to remove

this interaction giving the (E)-zirconiate species. Trapping this

compound with pinacolborane provides optimum yields and

excellent selectivity for the (E)-pinacolboronate isomer. Following

this protocol, alkyne 5 was treated with 0.1 equivalents of Schwartz

reagent and 0.1 equivalents of anhydrous triethylamine in neat

pinacolborane and heated to 60 ^◦C for 16 h. The reaction ﬂask

was covered to reduce exposure to light as the Schwartz reagent is

sensitive to decomposition (Scheme 2). The reaction occurred with

complete conversion to the chiral alkenylpinacol boronic ester 13.

After puriﬁcation by stirring with hexane to precipitate excess

pinacol and ﬁltering through a short silica column eluting with

hexanes, a 91% yield of 13 with high (E) : (Z)-selectivity was

obtained. Using this route the reaction was reproducible on a

multigram scale.

Scheme 2 Synthesis of chiral alkenylboron derivative.

With the desired alkenylboron species in hand, rhodium-

catalysed conjugate additions could now be investigated. Both

phenylethylamine and tryptamine acrylamide (3 and 4) were

prepared by direct reaction of the appropriate amine with acryloyl

Table 2 Rhodium catalysed conjugate addition of pinacolboronate

Entry^a

[Rh]

Ligand

Base

% Conversion^b

[Rh(acac)(eth)₂]

[Rh(cod)₂][BF₄]

[Rh(nbd)₂][BF₄]

[Rh(cod)Cl]₂

[Rh(cod)OH]₂

Rh(cod)OH]₂

cod 10 mol%

—

cod 10 mol%

Na₂CO₃1 eq.

NaOH 1 eq.

LiOH 1 eq.

NaF 1 eq.

TEA

Na₂CO₃1 eq.

MeLi

11^c

^aTypical reaction conditions: N-phenylethyl acrylamide (0.25 mmol), (S,E)-2-(4-methoxyundec-1-enyl)-pinacolboronic ester (2 eq.), followed by rhodium

catalyst (5 mol%), ligand, dioxane/H₂O (10/1), 80 ^◦C, 16 h. ^bConversion by¹H NMR spectroscopy. ^cMeLi (2 eq.) added to boronic ester at 0 ^◦C prior

to reaction.

4342 | Org. Biomol. Chem., 2008, 6, 4340–4347

This journal is

The Royal Society of Chemistry 2008

View Article Online

Scheme 3 Synthesis of potassium triﬂuoroborate salt.

protocol reported by Yuen et al.²⁶Thus, the chiral alkenyltriﬂuo-

roborate salt 14 was treated with a solution of lithium hydroxide

in acetonitrile. Following the reported procedure afforded an

intractable white gum that darkened on standing. The material

could not be successfully puriﬁed and was unsuitable for further

transformations.

Scheme 5 Competition between b-hydride elimination and hydrolysis.

entries 2–4). Other rhodium complexes using achiral bidentate

phosphine ligands such as dppb, and dppf led to a lower conversion

to product, suggesting that diene ligands are superior to phosphine

based systems for this particular reaction (Table 3, entries 5–

7). Using 1.5 equivalents of triﬂuoroalkenylborate salt 14 with

optimal ligand catalyst permutation [Rh(cod)OH]₂with 10 mol%

cod afforded a 60 : 40 mixture of hermitamide A (1) to b-hydride

elimination product 15. The only effective method of suppressing

formation of 15 was by using at least four equivalents of the

chiral triﬂuoroalkenylborate salt (Table 3, entry 10). Under these

conditions hermitamide A (1) was isolated in 81% yield after

column chromatography.

With a successful approach to hermitamide A (1) demonstrated,

we turned our attention to the synthesis of hermitamide B

(2). The same chiral triﬂuoroalkenylborate salt 14 is employed,

the synthesis necessitates only a variation in acceptor to the

tryptamine acrylamide derivative 4. Using the original conditions

for synthesis of hermitamide A; 2 mol% rhodium catalyst, 10 mol%

cod, dioxane : water 10 : 1 gave a low conversion to product with

a number of unidentiﬁed side-products that could not be success-

fully removed by column chromatography. Upon changing the

conditions to use a higher catalyst loading, 5 mol% rhodium and

four equivalents of triﬂuoroalkenylborate salt 14, hermitamide B

(2) was isolated in 36% yield after column chromatography. The

spectral data and optical rotation of synthetic hermitamide B (2)

were identical with those of the natural product (Scheme 6).²

In conclusion, a unique approach to the hermitamide nat-

ural product family has been successfully developed using a

rhodium catalysed conjugate addition of a chiral potassium

triﬂuoroalkenylborate donor to introduce the side chain and

It has been reported that potassium triﬂuoro(organo)borate

salts offer practical advantages in terms of reactivity and

stability for rhodium catalysed conjugate addition reactions.²⁷

Pleasingly, the reaction of phenylethylacrylamide 3 with two

equivalents of chiral alkenyltriﬂuoroborate salt 14 in the presence

of [Rh(cod)(OH)₂] and 10 mol% cyclooctadiene as the ligand

resulted in complete conversion to two new products (Scheme 4).

Upon puriﬁcation by column chromatography, hermitamide A

(1) was isolated as a colourless oil in 75% yield. The spectral

data and optical rotation of synthetic hermitamide A were in

agreement with those of the natural product.²The minor product

from the reaction was isolated in 15% yield and identiﬁed by H

NMR and 2D correlation experiments as the diene 15. This side-

product results from a b-hydride elimination of the a-rhodium

carbonyl intermediate formed at the carbometalation step and is

in competition with the favoured hydrolysis pathway (Scheme 5).²⁸

The b-hydride elimination of the a-rhodium carbonyl interme-

diates arising from the conjugate addition of aryl boronic acids

has been investigated in detail by Zou et al.²⁹The systematic study

revealed a number of factors that affected the product distribution

including; the supporting ligand on rhodium, the ratio of aryl

boronic acid to a,b-unsaturated carbonyl and the pH value of

the aqueous phase. We examined other catalyst-ligand systems

and reaction conditions in an attempt to eliminate the b-hydride

elimination pathway and improve the yield of conjugate addition

product. Using other neutral catalysts such as [Rh(acac)(C₂H₄)₂]

and [Rh(nbd)Cl]₂gave no improvement in selectivity (Table 3,

Scheme 4 Rhodium catalysed conjugate addition of chiral organotriﬂuoroborate salt.

The Royal Society of Chemistry 2008 Org. Biomol. Chem., 2008, 6, 4340–4347 | 4343

This journal is

View Article Online

Table 3 Reaction optimisation

Entry^a

[Rh]

Ligand

Base

% Conv 1^b,c

[Rh(acac)(eth)₂]

[Rh(cod)₂][BF₄]

[Rh(nbd)Cl]₂

cod 10 mol%

—

[Rh(nbd)₂][BF₄]

[Rh(cod)OH]₂

Rh(cod)OH]₂

—

83 (72%)

91 (81%)

cod 10 mol%

dppb 5 mol%

dppf 5 mol%

cod 10 mol%

NaF 1 eq.

LiOH 1 eq.

—

10^d

^aTypical reaction conditions: N-phenylethyl acrylamide 3 (0.25 mmol), 14 (2 eq.), followed by rhodium catalyst (2 mol%), ligand, dioxane/H₂O (10/1),

80 ^◦C, 16 h. ^bConversion by¹H NMR spectroscopy. ^cIsolated yields in parentheses. ^dUsing four equivalents of 14.

Scheme 6 Synthesis of hermitamide B by rhodium catalysed conjugate addition.

chiral information in a single step. The application of chiral

organometallic donors in rhodium catalysed conjugate addition

offers opportunities for chemists to consider new synthetic strate-

gies and access unique intermediates. This research is ongoing

in our laboratory and further applications of chiral organoboron

donors in catalytic conjugate addition reactions will be reported

in due course.

(2H, q, J 7.2 Hz, CH₂); 0.87 (3H, t, J 6.8 Hz, CH₂). d_C(75.5 MHz;

CDCl₃); 138.7, 165.5, 130.8, 128.6, 128.5, 126.4, 126.1, 40.6, 35.4.

All data in correspondence with literature values.³⁰

N-[2-(1H-Indol-3-yl)-ethyl]-acrylamide (4)

Tryptamine (2.40 g, 15 mmol) was charged to a 100 mL round

bottomed ﬂask and dissolved in anhydrous dichloromethane

(40 mL). The resulting solution was cooled to 0 ^◦C (ice/water). To

the cooled ﬂask anhydrous triethylamine (1.62 g, 16 mmol) was

added followed by dropwise addition of acryloyl chloride (1.44 g,

16 mmol in 5 mL dichloromethane) with _◦vigorous stirring. The

mixture was stirred for a further 3 h at 4 C. Upon warming to

room temperature reaction was quenched with 1 M HCl solution

(50 mL) and the organic phase extracted, washed with 1 M NaOH

(50 mL) then brine (50 mL), dried (NaSO₄) and concentrated to

give orange oils. The crude mixture was eluted through a short

pad of silica gel (2 : 1 Petrol : EtOAc) to give the title product as a

Experimental

N-Phenethyl-acrylamide (3)

Phenethylamine (2.42 g, 20 mmol) was charged to a 50 mL round

bottomed ﬂask and dissolved in anhydrous di_◦chloromethane

(25 mL). The resulting solution was cooled to 0 C (ice/water).

To the cooled ﬂask was added anhydrous triethylamine (2.12 g,

21 mmol) followed by dropwise addition of acryloyl chloride

(1.90 g, 21 mmol in 5 mL dichloromethane) with vigorous stirring.

The mixture was stirred for a further 3 h at 4 ^◦C. Upon warming to

room temperature reaction was quenched with 1 M HCl solution

(30 mL) and the organic phase extracted, washed with 1 M NaOH

(30 mL) then brine (30 mL), dried (NaSO₄) and concentrated to

give orange oils. The crude mixture was eluted through a short pad

of silica gel (6 : 1 Petrol : EtOAc) gave the title product as a light

yellow oil (Yield 2.06 g, 64%); R_f(petrol : ethyl acetate, 1 : 1) 0.1;

-1

n_max(neat)/cm ; 3439 3309 (N–H), 3022,1667 (C O), 1628, 976,

911 (C CH₂); d_H(300 MHz; CDCl₃), 8.20 (1H, br s, NH indole);

7.61 (1H, d, J 7.9 Hz, CH indole); 7.38 (1H, d, J 7.9 Hz, CH

indole); 7.22 (1H, t, J 7.9 Hz, CH indole); 7.13 (1H, t, J 7.9 Hz,

CH indole); 7.03 (1H, s, CH indole); 6.25 (1H, dd, J 17.0, 1.5 Hz,

CHCH₂); 6.0 (1H, dd, J 17.0, 10.0 Hz, CHCH₂); 5.68 (1H, br s,

NH); 5.60 (1H, dd, J 10.0, 1.5 Hz, CHCH₂); 3.69 (2H, q, J 6.8,

CH₂); 3.02 (2H, t, J 6.8 Hz, CH₂); d_C(75.5 MHz; CDCl₃); 165.5,

136.4, 130.9, 127.3, 126.2, 122.2, 122.0, 119.5, 118.6, 112.8, 111.2,

39.7, 25.2; HRMS (ESI^-) calcd for C₁₃H₁₄N₂O₁[M + H⁺] m/z

yellow oil (Yield 3.26 g, 93%); R_f(petrol : ethyl acetate, 3 : 1) 0.15;

-1

n_max(neat)/cm ; 3279 (N–H), 3028,1657 (C O), 1625, 985, 958

(C CH₂); d_H(300 MHz; CDCl₃), 7.22–7.10 (5H, m, Ph); 6.16 (1H,

dd, J 17.0, 1.5 Hz, CHCH₂); 6.0 (1H, dd, J 17.0, 10.0 Hz, CHCH₂);

5.52 (1H, br s, NH); 5.52 (1H, dd, J 10.2, 1.1 Hz, CHCH₂); 3.49

4344 | Org. Biomol. Chem., 2008, 6, 4340–4347

This journal is

The Royal Society of Chemistry 2008

View Article Online

213.1028 found: m/z 213.1036. All data in correspondence with

at 4 ^◦C. Upon warming to room temperature silica was added

(0.50 g) and the mixture was concentrated. Elution by column

chromatography (40 : 1–20 : 1 gradient petrol: diethyl ether) gave

the title product as a white solid (Yield 0.206 g,_◦34%); R_f(petrol :

(c = 1.50, CHCl₃); n_max(KBr)/cm^-1; 3426 (O–H), 2927 (C–H); 2856

(C–S–Ar); d_H(300 MHz; CDCl₃), 7.86–7.70 (4H, m, naphthalene);

7.54–7.41 (3H, m, naphthalene); 3.78–3.66 (1H, m, CHOH); 3.26

(1H, dd, J 14.0, 3.9 Hz, CHS); 2.94 (1H, dd, J 14.0, 8.7 Hz,

CHS); 2.34 (1H, br s, OH); 1.63–1.39 (3H, m, CH₂), 1.39–1.17

(9H, m, CH₂); 0.87 (3H, t, J 6.8 Hz, CH₃); d_C(75.5 MHz; CDCl₃);

134.1, 133.15, 132.4, 128.6, 128.1, 127.8, 127.6, 127.1, 126.6, 125.9,

69.4, 42.1, 36.1, 31.7, 29.5, 29.1, 25.6, 22.6, 14.0; HRMS (ESI⁺)

calcd for C₁₉H₂₆O₁S₁Na₁[M + Na⁺] m/z 325.1602 found: m/z

325.1594; Daicel Chiralcel OD-H, hexane/propan-2-ol (99.9 :

0.01), 1 mL min^-1, t_R= 37.95 (S) and 53.3 (R) (96% e.e.).

literature values.³¹

2-Heptyloxirane (rac-6)

ethyl acetate, 40 : 1) 0.10; mp (hexane) 65–67 C; [a]²⁰= -27^◦

1-Nonene 7 (25.0 g, 0.20 mol) was charged to a 500 mL 3-

necked round bottomed ﬂask equipped with nitrogen inlet and

pressure equalising dropping funnel, and dissolved in anhydrous

dichloromethane (150 mL). The resulting solution was cooled to

0 ^◦C (ice/water). The dropping funnel was charged with a ﬁltered

solution of 75% meta-chloroperoxybenzoic acid (62.0 g, 0.35 mol)

in dichlorometha_◦ne (200 mL). The solution was added dropwise

over 45 min at 4 C. The mixture was stirred for a further 3 h at

^◦C and 1 h at room temperature. The reaction was quenched

with 10% potassium thiosulfate (300 mL) and extracted with

saturated sodium bicarbonate solution (2 ¥ 250 mL) and brine

(250 mL), dried (MgSO₄) and concentrated to give crude product.

◦

The epoxide was distilled under high vacuum (55 C, 5 mmHg)

(S)-Undec-1-yn-4-ol (9)

to give the title product as a colourless oil (Yield 25.6 g, 90%); R_f

(petrol : ethyl acetate, 20 : 1) 0.6; n_max(neat)/cm^-1; 2958, 2930, 2858

(C–H), 916, 838 (C–O epoxide); d_H(300 MHz; CDCl₃), 2.90–2.80

(1H, m, CHOCH₂); 2.68 (1H, dd, J 4.9, 4.1 Hz, CHOCH₂); 2.4

(1H, dd, J 4.9, 3.0 Hz, CHOCH₂); 1.60–1.19 (12H, m, CH₂); 0.83

(3H, t, J 6.6 Hz, CH₃); d_C(75.5 MHz; CDCl₃); 52.1, 46.8, 32.3,

31.6, 29.2, 29.0, 25.8, 22.4, 13.8. All data in correspondence with

literature values.³²

Lithium acetylide EDA complex (8.38 g, 91 mmol) was charged

to a 250 mL round bottomed ﬂask and suspended in anhydrous

dimethysulfoxide (45 mL). The resulting reaction mixture was

immersed in a room temperature water bath. To the brown-

black suspension was added (S)-2-heptyloxirane ((S)-6) (4.98 g,

35.0 mmol) in one portion with vigorous stirring. The mixture was

stirred for a further_◦2 h at 23 ^◦C. Upon completion the suspension

was poured into 4 C water (150 mL) and stirred for 30 min to

quench excess acetylide. This was then ﬁltered through a pad of

(S)-(-)-Heptyloxirane ((S)-6)

Celite^ꢀwashing with diethyl ether (3 ¥ 100 mL). The combined

(S,S)-N,N¢-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanedia-

minocobalt(II) 8 (0.30 g, 0.50 mmol) was charged to a 25 mL round

bottomed ﬂask. Dichloromethane (2 mL) and acetic acid (300 mL)

were added and the red solution stirred in air for 30 min. The

resulting brown solution was concentrated in vacuo to give a brown

residue. The active catalyst was dissolved in neat 2-heptyloxirane

(rac-6) (14.2 g, 100 mmol) with anhydrous THF (2 mL) and the

ﬂask cooled to 0 ^◦C (ice/water). Water (1.0 mL, 55 mmol, 0.55 eq.)

was added dropwise. The mixture was capped with a greased glass

stopper and stirred for 48 h at 23 ^◦C. After this time the reaction

ﬂask was attached to a short path distillation head and the volatiles

distilled under high vacuum (55 ^◦C, 5 mmHg). The recovered

epoxide was passed through a short silica pad to removed residual

water and THF to give the title product as a colourless oil (Yield

6.12 g, 43%, 86% theoretical maximum); R_f(petrol : ethyl acetate,

washings were then extracted with water (2 ¥ 100 mL), brine (2 ¥

150 mL), dried (NaSO₄) and concentrated. Final traces of DMSO

and water were removed through a short silica pad to give the title

product as a golden yellow oil (yield 5.420 g, 92%); R_f(petrol :

ethyl acetate, 9 : 1) 0.2; [a]²⁰= -23.0^◦(c = 1.23, CHCl₃); n_max

-1

∫

(KBr)/cm ; 3401 (O–H), 3300 (C–H alkyne); 2120 (C C); d_H

(300 MHz; CDCl₃), 3.69 (1H, quint, J = 5.5, CHOH); 2.33–2.30

(2H, m, CHOCH₂); 1.99 (1H, t, J 2.6 Hz, CH₂CCH); 1.58–1.64

(12H, m, CH₂); 0.81 (3H, t, J 6.6 Hz, CH₃); d_C(75.5 MHz; CDCl₃);

80.9, 70.6, 69.8, 36.1, 31.7, 29.4, 29.1, 27.2, 25.5 (2C), 22.5, 14.0;

HRMS (ESI⁺) calcd for C₁₁H₁₉O₁Na₁[M + Na⁺] m/z 190.2577

found: m/z 190.2583. All data in correspondence with literature

values.

20 : 1) 0.6; [a]²⁰= -8.7^◦(c = 1.15, CHCl₃); n_max(neat)/cm^-1;

(S)-4-Methoxy-undec-1-yne (5)

2958, 2930, 2858 (C–H), 916, 838 (C–O epoxide); d_H(300 MHz;

CDCl₃), 2.90–2.80 (1H, m, CHOCH₂); 2.68 (1H, dd, J 4.9, 4.1 Hz,

CHOCH₂); 2.4 (1H, dd, J 4.9, 3.0 Hz, CHOCH₂); 1.60–1.19 (12H,

m, CH₂); 0.83 (3H, t, J 6.6 Hz, CH₃); d_C(75.5 MHz; CDCl₃);

52.1, 46.8, 32.3, 31.6, 29.2, 29.0, 25.8, 22.4, 13.8. All data in

correspondence with literature values.³²

A 60% sodium hydride suspension in mineral oil (1.06 g,

44.1 mmol) was charged to a 250 mL round bottomed ﬂask and

suspended in anhydrous tetrahydrofuran (80 mL). The resulting

mixture was cooled to 0 ^◦C (ice/water) and to this was added (S)-

undec-1-yn-4-ol (9) (5.05 g, 30.0 mmol) in one portion, followed

by methyl iodide (5.12 g, 36 mmol). The mixture was allowed

to warm to room temperature over 1 h and then reﬂuxed for a

further 16 h. Upon completion the suspension was concentrated

in vacuo, and then resuspended in diethyl ether (100 mL). The

organic phase was extracted with water (2 ¥ 100 mL), brine (2 ¥

150 mL), dried (MgSO₄) and concentrated. Product was isolated

by column chromatography (40 : 1 petrol : diethyl ether) to give

the title compound as a colourless oil (yield 5.360 g, 98%); R_f

(S)-1-(Naphthalen-2-ylthio)nonan-2-ol

2-Naphthalene thiol (0.336 g, 2.1 mmol) was charged to a 25 mL

round bottomed ﬂask and dissolved in anhydrous methanol

(10 mL). The resulting solution was cooled to 0 ^◦C (ice/water). To

the cooled ﬂask, anhydrous triethylamine (0.253 g, 2.5 mmol) was

added followed by (S)-2-heptyloxirane ((S)-6) (0.280 g, 2.0 mmol)

with vigorous stirring. The mixture was stirred for a further 16 h

(petrol: ethyl acetate, 20 : 1) 0.7; [a]²⁰= -33^◦(c = 1.2, CHCl₃);

This journal is

The Royal Society of Chemistry 2008

Org. Biomol. Chem., 2008, 6, 4340–4347 | 4345

View Article Online

-1

∫

n_max(neat)/cm ; 3306 (C–H alkyne); 2857 (C C); 2830 (C–O);

d_H(300 MHz; CDCl₃), 3.37 (3H, s, OCH₃); 3.29 (1H, quint, J

5.7 Hz, CHOCH₃); 2.20–2.24 (2H, m, CHCH₂CCH); 1.97 (1H, t,

J 2.6 Hz, CHCH₂CCH); 1.66–1.49 (2H, m, CH₂); 1.48–1.19 (10H,

m, CH₂); 0.87 (3H, t, J 6.60 Hz, CH₃); d_C(75.5 MHz; CDCl₃);

81.1, 79.2, 69.7, 56.9, 33.5, 31.7, 29.2, 25.1, 23.0, 22.5, 14.0; HRMS

(ESI⁺) calcd for C₁₂H₂₂NaO [M + Na⁺] m/z 182.3025 found: m/z

182.3021. All data in correspondence with literature values.

82.9, 82.8, 56.6, 40.8, 34.5, 33.0, 30.9, 26.4, 23.7, 14.4, C–B peak

not observed; d_B(96.3 MHz; CD₃OD); -4.2; HRMS (ESI⁺) calcd

for C₁₄H₂₄B₁F₃O₁[M + H⁺] m/z 251.1794 found: m/z 251.1784.

Hermitamide A (1)

A 24 mL screw-capped vial equipped with a rubber septum was

charged with hydroxy(cyclooctadiene)rhodium(I) dimer (0.002 g,

0.004 mmol) and potassium 2-((E)-(S)-4-methoxy-undec-1-enyl)-

triﬂuoroborate (14) (0.116 g, 0.40 mmol). 1,5-Cyclooctadiene

(0.025 g, 0.040 mmol), dioxane (2 mL) and water (0.2 mL) were

added by sequentially by syringe and the vessel was purged with

argon. The red solution was stirred for 15 min before the addition

of N-phenethyl-acrylamide (3) (0.04 g, 0.20 mmol) in dioxane

(0.5 mL). The reaction was transferred to a preheated hotplate at

80 ^◦C for 24 h. Upon completion the crude reaction mixture was

taken up in diethyl ether (5 mL) and ﬁltered through a short plug

of silica (elution; diethyl ether) and the solvent removed in vacuo.

The crude residue was puriﬁed by ﬂash column chromatography

on silica gel (petrol : ethyl acetate 4 : 1) to give the title compound

as a light yellow oil (yield 0.052 g, 72%); R_f(petrol : ethyl acetate,

2-((E)-(S)-4-Methoxy-undec-1-enyl)-4,4,5,5-tetramethyl-

[1,3,2]dioxaborolane (13)

(S)-4-Methoxy-undec-1-yne (5) (4.56 g, 25.0 mmol) and 4,4,5,5-

tetramethyl-1,3,2-dioxaborolane (3.36 g, 26.3 mmol) were charged

to a 25 mL Schlenk tube under a positive pressure of

dry argon. To the resulting solution was added sequen-

tially bis(cyclopentadienyl)zirconium(IV) chloride hydride (0.65 g,

2.50 mmol) followed by triethylamine (0.25 g, 2.50 mmol) the

mixture was capped then heated at 60 ^◦C for 16 h protected from

light. Upon completion hexane (5 mL) was added and mixture

stirred for 10 min. The material was isolated through a short silica

pad (elution: hexanes) to give the title product as a colourless

oil (yield 7.06 g, 91%); R_f(petrol: diethyl ether, 20 : 1) 0.3;

4 : 1) 0.2; [a]²⁰= -9.1^◦(c = 1.05, CHCl₃); lit = -9.3^◦(CHCl₃);

-1

_max(KBr)/cm ; 3302 (N–H), 1675 (C C), 1658 (C C), 1527 (C O

[a]²⁰= -8.9^◦(c = 0.95, CHCl₃); n_max(neat)/cm^-1; 1714 (C–O),

amide) 1134, 1093; d_H(500 MHz; C₆D₆), 7.24 (2H, t, J 7.3 Hz, Ph);

7.16 (1H, t, J 7.3 Hz Ph); 7.10 (2H, d, J 7.3 Hz Ph); 5.68 (1H, dt, J

15.0, 7.3 Hz CH alkene); 5.51 (1H, dt, J 15.0, 7.0 Hz CH alkene);

5.37 (1H, br s, NH); 3.42 (2H, dd, J 13.0, 6.6, NHCH₂CH₂);

3.21 (3H, s, OCH₃); 3.19–3.15 (1H, m); 2.94 (2H, dd, J 13.0, 6.8,

Hz, NHCH₂CH₂); 2.68 (2H, t, J 7.0 Hz, CH₂); 2.20–2.11 (2H, m);

1.63–1.53 (2H, m); 1.52–1.33 (12H, m); 1.01 (3H, t, J 7.0 Hz, CH₃);

d_C(125.8 MHz; CDCl₃); 169.7, 139.44, 133.16, 128.9, 128.5, 126.3,

123.1, 79.7, 55.4, 40.7, 35.8, 35.3, 33.3, 32.0, 30.1, 29.6, 28.5, 25.6,

25.4, 23.2, 22.9, 14.1; HRMS (ESI⁺) calcd for C₂₃H₃₈N₁O₂[M +

H⁺] m/z 360.2903 found: m/z 360.2897. All data in accordance

with literature values.²

1675 (C C), 1620 (C C), 1358 (B–O); d_H(300 MHz; CDCl₃),

6.57 (1H, dt, J 17.0, 7.0 Hz CH alkene); 5.42 (1H, dt, J 17.0,

1.3 Hz CH alkene); 3.26 (3H, s, OCH₃); 3.18 (1H, quint, J 5.6 Hz,

CHOCH₃); 2.56–2.19 (2H, m, CHCH₂CHCH); 1.33–1.26 (2H,

m, CH₂); 1.04–1.25 (22H, m, CH₂, CH₃); 0.88 (3H, t, J 6.6 Hz,

CH₃); d_C(75.5 MHz; CDCl₃); 151.0, 83.4, 80.5, 56.8, 40.3, 34.0,

32.2, 30.1, 29.7, 25.7, 25.17, 25.15, 24.9, 23.0, 14.5. C–B peak not

observed; d_B(96.3 MHz; CDCl₃); 31.1; HRMS (ESI⁺) calcd for

C₁₈H₃₅B₁NaO₃[M + Na⁺] m/z 333.2577 found: m/z 333.2589.

Potassium 2-((E)-(S)-4-methoxy-undec-1-enyl)-triﬂuoroborate

(14)

(S,2E,4E)-7-methoxy-N-phenethyltetradeca-2,4-dienamide (15)

2-((E)-(S)-4-Methoxy-undec-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]-

dioxaborolane (5) (1.55 g, 5.0 mmol) in acetonitrile (10 mL), was

charged to a 25 mL round bottom ﬂask under an atmosphere of

nitrogen. The ﬂask was cooled to 0 ^◦C (ice/salt) and to the resulting

solution was added sequentially potassium hydrogen diﬂuoride

(1.56 g, 20 mmol) followed by water (4 mL). The mixture was

capped, warmed to room temperature and stirred for 3 h until

a heavy white precipitate formed. Upon completion the reaction

mixture was concentrated in vacuo and thoroughly dried under

high vacuum (0.01 mmHg). The solids were then washed with

A 24 mL screw-capped vial equipped with a rubber septum was

charged with hydroxy(cyclooctadiene)rhodium(I) dimer (0.002 g,

0.004 mmol) and potassium 2-((E)-(S)-4-methoxy-undec-1-enyl)-

triﬂuoroborate (14) (0.116 g, 0.40 mmol). 1,5-cyclooctadiene