Electrocyclic processes in aromatic biosynthesis: A biomimetic study of pseudorubrenoic acid A

Article abstract of DOI:10.1016/S0040-4020(02)00320-4

The possible involvement of 6π electrocyclic ring closures, mediated by electrocyclase enzymes, of polyunsaturated acyclic polyketide intermediates in the biosynthesis of certain o-dialkyl-substituted benzenoid natural products is discussed. The feasibili

Full text of DOI:10.1016/S0040-4020(02)00320-4

TETRAHEDRON
Pergamon
Tetrahedron 58 ,2002) 3793±3800
Electrocyclic processes in aromatic biosynthesis: a biomimetic
study of pseudorubrenoic acid A
Rodney W. Rickardsp and Danielle Skropeta
Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia
Received 24 September 2001; revised 13 February 2002; accepted 14 March2002
AbstractÐThe possible involvement of 6p electrocyclic ring closures, mediated by electrocyclase enzymes, of polyunsaturated acyclic
polyketide intermediates in the biosynthesis of certain o-dialkyl-substituted benzenoid natural products is discussed. The feasibility of the
process is illustrated by the electrocyclic ring closure of 7E,9Z,11E,13Z-1-t-butyldimethylsilyloxy-hexadeca-7,9,11,13-tetraene ,12a) to th e
cyclohexadiene 13 followed by dehydrogenation to the analogue 14 of the o-dialkyl-substituted aromatic metabolite pseudorubrenoic acid A
,1). q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
aromatic systems involving 6p electrocyclisation of
polyunsaturated acyclic precursors to dihydroaromatic
intermediates, followed by dehydrogenation. The retrobio-
synthetic analysis is illustrated ,Scheme 1) for the formation
of pseudorubrenoic acid A ,1) from the hexadeca-7,9,11,13-
tetraenoic acid ,3) via the cyclohexadiene intermediate 2.
The acyclic precursors themselves could arise by well-
known processes, either from fatty acids by enzymic
desaturation, or from enzyme-bound oxygenated polyketide
intermediates by reduction of carbonyl groups and subse-
quent elimination processes. In the present case, the acid 3
must necessarily have the 9Z ole®nic con®guration to permit
electrocyclisation of the 7,9,11-triene component, and it is
notable that this con®guration is that found in the common
D9-unsaturated C16 fatty acid palmitoleic acid. The
existence in Nature of electrocyclase enzymes capable of
catalysing electrocyclic reactions would complement the
two enzymes already reported to catalyse pericyclic
reactions, chorismate mutase9 and Diels±Alderase.10
Aromatic natural products usually contain diagnostic struc-
tural features that re¯ect their biosynthetic formation by one
of several major well established biosynthetic routes.1 A
small group of o-dialkyl-substituted benzenoid microbial
products, however, are exceptions. These include the
pseudorubrenoic acids ,e.g. pseudorubrenoic acid A, 1),
antimicrobial antibiotics produced by the soil bacterium
Pseudomonas ¯uorescens,2 the rubrenoic acids A±C from
the marine bacterium Alteromonas rubra,3 demetric acid
from Streptomyces
umbrosus,4 serpentene
from
Streptomyces sp. TuÈ-3851,5 and the amino-terminal acyl
moieties of the PDGF-binding inhibitor RP-1776 from
Streptomyces sp. KY11784,6 the farnesyl-protein
transferase inhibitors pepticinnamins A±F from
Streptomyces sp. OH-46527 and the tachykinin antagonist
WS9326A produced by S. violaceusniger.8 Their even-
numbered C12, C14, C16, C18 and C20 carbon skeletons
indicate that these structures are all acetate-derived. They
are distinguished from most aromatic polyketides, however,
by the absence of oxygen functionality on or adjacent to the
aromatic ring, indicative of normal polyketide ring closure.
Structural analysis suggests that these metabolites may be
formed by a hitherto unrecognised biosynthetic route to
Although Diels±Alder reactions have been proposed as
key steps in the biosynthesis of a number of natural
products,11 electrocyclic reactions12 have seldom been
invoked in biosynthetic pathways, and never in aromatic
biosynthesis. To our knowledge, the biosynthetic
Scheme 1. Retrobiosynthetic analysis of pseudorubrenoic acid A ,1).
Keywords: biosynthesis; biomimetic synthesis; electrocyclase; electrocyclic reactions; pseudorubrenoic acid.
Corresponding author. Tel.: 161-2-6125-3507; fax: 161-2-6125-8114; e-mail: rickards@rsc.anu.edu.au
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,02)00320-4

3794
R. W. Rickards, D. Skropeta / Tetrahedron 58 -2002) 3793±3800
involvement of electrocyclic reactions has been suggested
only in relation to vitamin D chemistry,13 the polycyclic
endiandric acids14 and the eudesmane sesquiterpene ,1)-
occidentalol15 from plants, the polypropionate-derived
9,10-deoxytridachione16 produced by a marine mollusc,
and a small number of pheromones isolated from a brown
alga.17
arise by Bergman cyclisation18 of an enediyne precursor,
and in principle sucha process could also account for the
related o-dialkyl-substituted aromatic structures cited
above. Effective Bergman cyclisation, however, would
require the enediynes to be constrained in medium ring
systems,19 and the present structures show no evidence of
suchprecursors.
Despite their lack of diagnostic oxygen functionality,
however, biosynthesis of such o-dialkyl-substituted
benzenoid metabolites from polyketide intermediates by
aldol cyclisation processes cannot be entirely excluded.
Three such processes can be distinguished, but each is
accompanied by reactivity questions. In the case of pseudo-
rubrenoic acid A ,1), for example, the enzyme-bound trione
intermediate A could undergo aldol cyclisation and
aromatisation to afford the aromatic acid A ,Scheme 2).
Subsequent conversion to pseudorubrenoic acid A ,1),
however, would require the dif®cult reductive removal of
the phenolic hydroxyl group. If this oxygen function is
removed prior to cyclisation to give the minimally
oxygenated enzyme-bound dione intermediate B, then the
aldol cyclisation to the aromatic acid B becomes dis-
favoured bothelectronically and stereoelectronically.
Partial reduction to the enzyme-bound hydroxy-dione inter-
mediate C might avoid the disadvantages inherent in inter-
mediates A and B, the aldol cyclisation product now
yielding the same aromatic acid B by dehydration. The
apparent ease of this sequence raises the question as to
why so few aromatic metabolites corresponding to such a
pathway are observed in Nature, compared to those formed
from trione intermediates of the type A without subsequent
removal of the phenolic hydroxyl group. It may be that
methylene activation by two ¯anking ketonic groups, as in
the trione A, is necessary for the enzymic aldol cyclisation.
In all three cases, conversion of the residual aryl ketone of
acid A or B to the styrene functionality of pseudorubrenoic
acid A ,1) by reduction and elimination would be
enzymically straightforward.
In order to illustrate the feasibility of electrocyclic processes
in the biosynthesis of such aromatic natural products, and to
provide access to possible biosynthetic intermediates, we
describe here the synthesis of an analogue of the putative
hexadeca-7,9,11,13-tetraenoic acid precursor ,3) of pseudo-
rubrenoic acid A ,1) and its biomimetic conversion into the
corresponding analogue of the natural acid itself.
2. Results and discussion
2.1. Retrosynthetic analysis
The natural electrocyclisation substrate in the case of
pseudorubrenoic acid A ,1) would probably be an
enzyme-bound tetraenoic acid ,e.g. 3) or a related polyene.
For increased stability and ease of handling we have
focussed on the preparation and electrocyclisation of the
silyl-protected tetraenol analogue 12a rather than the
carboxylic acid itself ,Scheme 3). Apart from the necessary
9Z-con®guration noted above, the tetraenoic acid 3 and
hence its analogue 12a require the 13Z-con®guration to
yield the ultimate Z-styrene. The 7- and 11-con®gurations
cannot be de®ned in the proposed biosynthetic pathway
since their stereochemistry is lost in the natural product 1,
but in conjunction with the electrocyclisation mechanism
they will control the stereochemistry of the intermediate
cyclohexadiene. We chose E-con®gurations for these latter
ole®ns, to optimise orbital overlap in a thermal electro-
cyclisation designed to yield a cis-dihydrobenzene product.
The retrosynthetic analysis employed ,Scheme 3) for the
required conjugated 7E,9Z,11E,13Z-tetraene 12a comprises
four key features: ,1) the crucial Z-alkene at C-9 of the
Ritzau and co-workers5 suggested that serpentene might
Scheme 2. Hypothetical aldol-based biosynthetic routes to pseudorubrenoic acid ,1).

R. W. Rickards, D. Skropeta / Tetrahedron 58 -2002) 3793±3800
3795
Scheme 3. Retrosynthetic analysis of the tetraene 12a.
Scheme 4. Synthesis of the tetraenes 12a±d. Reagents and conditions: ,a) 1.0 equiv. LDA, 08C, 40 min, then add 5, 2.0 equiv. HMPA, THF, 08C, 1.5 h; 75%.
,b) 1.2 equiv. m-CPBA, 1.6 equiv. NaHCO3, CH2Cl2, 2788C, 5 h; 63%. ,c) Piperidine, xylene, 508C, 22 h; 55%. ,d) 7 equiv. CrCl2, 2 equiv. CHI3, THF, room
temperature, 18 h; 90%. ,e) 0.06 equiv. Pd[Ph3]4, 0.06 equiv. CuI, 0.06 equiv. TEBACl, MeCN±50% aq. NaOH ,1:1), 0±408C, 18 h; 82%. ,f) Zn,Cu/Ag),
MeOH±H20 ,1:1), room temperature, 20 h; 84%.

3796
R. W. Rickards, D. Skropeta / Tetrahedron 58 -2002) 3793±3800
tetraene is introduced in the last step of the synthesis by a
selective, stereospeci®c reduction of the conjugated alkyne
11a; ,2) the C16-trienyne skeleton is constructed by Pd-
catalysed cross-coupling between the sp and sp2 carbon
centres of the components 8a and 10a; ,3) the E-alkene at
C-3 of the alkynyl coupling component 8a is introduced via
sulfoxide pyrolysis, the Z-alkene at C-5 being derived from
the appropriate starting material; and ,4) the E-alkene at C-1
of the alkenyl coupling component 10a is generated by a
Takai reaction.
of the procedure described by Roser et al.28 for Si±C bond
29
cleavage in silyl alkynes withthat of Rossi et al.
for the
Pd-catalysed coupling of aryl halides with free alkynes,
however, and performing the cross-coupling under phase
transfer conditions in acetonitrile±50% aqueous sodium
hydroxide, the trienyne stereoisomers 11a±d could be
obtained in high yield ,82%). The stereochemical composi-
tion of the resulting trienyne could not be quantitatively
assessed since the stereoisomers 11a±d were inseparable
1
by HPLC. It was clear from H spectroscopy, however,
that the coupled product contained a dominant species,
assigned as the 7E,11E,13Z-isomer 11a in view of the
composition of the starting materials. This conclusion was
con®rmed by cleavage of the silyl ether ,in 86% yield) from
a portion of the trienyne mixture 11a±d. In contrast to the
parent ethers, the resulting free trienynol stereoisomers were
separable by HPLC, and the major product was clearly
de®ned by 1H NMR spectroscopy as the expected
This ¯exible strategy provides both an ef®cient route to the
tetraene 12a and also access to the other C-7 and C-11
alkene stereoisomers 12b±d which are capable of under-
going electrocyclisation. Thus the sulfoxide pyrolysis used
in the preparation of intermediate 8a gives rise to a mixture
of E- and Z-isomers of the newly formed double bond, and
the E-alkene of intermediate 10a can easily be replaced with
a Z-alkene by employing a Wittig instead of a Takai
reaction.
1
7E,11E,13Z-isomer. Furthermore, the H NMR spectrum
of this major trienynol matched that of the dominant species
seen in the parent trienyne ether mixture 11a±d.
2.2. Synthesis
The selective, stereospeci®c partial reduction of an alkyne,
centrally located in a conjugated system, to a Z-alkene is not
trivial.30 The partial reduction of the trienynes 11a±d was
achieved using the Cu/Ag-activated zinc metal described by
Boland et al.31 which works best for the partial reduction of
alkynes in highly unsaturated substrates. In contrast to
Lindlar's catalyst,30 which gave a mixture of unreacted,
dihydro and perhydro material, use of this activated zinc
resulted in the selective reduction of the trienynes 11a±d
to the tetraenes 12a±d in high yield ,84%), with no over-
reduced product detectable by analytical HPLC. A quanti-
tative assessment of the stereoisomer ratio could not be
made, as the tetraenes 12a±d were again inseparable by
HPLC. It was evident from 1H and 13C NMR spectroscopy,
however, that the tetraene mixture contained primarily one
species, presumably the 7E,9Z,11E,13Z-isomer 12a in
accord with the expected reduction of the dominant
7E,11E,13Z-trienyne 11a.
The synthesis of the silyloxytetraenes 12a±d is presented
in Scheme 4. Following the procedure of Nicolaou
et al.,20 lithium diisopropylamide-mediated alkylation of
1-trimethylsilyl-3-phenylthioprop-1-yne20 ,4) with Z-1-
bromopent-2-ene21 ,5) gave the sul®de 6 ,75% yield),
which was subjected to mild oxidation with m-chloro-
perbenzoic acid and solid sodium hydrogen carbonate in
dichloromethane to afford the sulfoxides 7 ,63% yield) as
a mixture of diastereomers ,7:322). No epoxidation of the
double bond was observed.
Thermolysis of the diastereomeric mixture of sulfoxides 7 in
the presence of piperidine23 effected the syn-elimination of
benzenesulfenic acid to furnisha mixture of the 3 E- and
3Z-alkenes 8a,b ,3:2,22 55% yield), as desired. Thermolysis
in the absence of an acid scavenger resulted in extensive Z-
to E-isomerisation of the product.23 The dienynes 8a and 8b
were inseparable by ¯ash chromatography, and were
employed in the next synthetic step as the stereoisomeric
mixture.
The presence of minor tetraene stereoisomers 12b±d con-
taminating the major isomer 12a at this stage was not
considered a problem. Tetraene 12a, withteh optimum
triene arrangement for achieving orbital overlap, was
expected to undergo 6p electrocyclisation at the lowest
temperature, leaving the other stereoisomers unreacted
and separable from the cyclohexadiene product 13.
The C16-skeleton of the 7E,11E,13Z-trienyne 11a ,and its
stereoisomers 11b±d) was assembled by a Pd-catalysed
cross-coupling reaction similar to that described by
Nicolaou et al.24 The predominantly E-vinyl iodide 10a,b
,9:122) required for the coupling was prepared ,90% yield)
by Takai methylenation25 of 7-t-butyldimethylsilyloxy-
heptanal ,9) with iodoform and chromous chloride, adopting
the solvent modi®cation ,tetrahydrofuran±dioxane 1:6)
suggested by Evans et al.26 Use of the original reaction
conditions described by Takai et al.25 led to a lower yield
,48%) of the iodide 10a and poorer stereoselectivity
,10a±10bˆ6:122).
2.3. Biomimetic electrocyclisation
The tetraene mixture 12a±d was heated in toluene at 1508C,
conditions typical for 6p electrocyclisation of an E,Z,E-
triene12,32 ,Scheme 5). HPLC puri®cation of the complex
reaction product gave an 11% yield of the cyclohexadiene
13. A strong cross-peak in the NOESY spectrum between
the methine protons 5-H and 6-H on the cyclohexadiene ring
veri®ed that the 5,6-substituents were cis-oriented. This
stereochemistry accords with Woodward and Hoffmann's
prediction for the thermal 6p electrocyclisation of an
E,Z,E-triene,33 and con®rms that the observed product is
derived from the major tetraene stereoisomer 12a.
Attempts to couple the dienyne stereoisomers 8a,b ,3:2),
after desilylation, withteh vinyl iodide stereoisomers
10a,b ,9:1) under standard Sonogashira conditions27 with
catalytic
palladium and cuprous iodide in benzene containing
amounts
of
tetrakis,triphenylphosphine)-
n-propylamine were unsuccessful. By combining elements

R. W. Rickards, D. Skropeta / Tetrahedron 58 -2002) 3793±3800
3797
Scheme 5. Electrocyclisation of the tetraene 12a. Reagents and conditions: ,a) sealed tube, toluene, 1508C, 18 h; 11%. ,b) MnO2, xylene, 1208C, 18 h; 100%.
The cyclohexadiene 13 was then dehydrogenated over
manganese dioxide to afford the aromatic silyl ether 14 in
quantitative yield ,Scheme 5). Conversion of the silyl ether
14 into the natural product pseudorubrenoic acid A ,1)
would require only desilylation followed by oxidation of
the resulting primary alcohol to a carboxylic acid, but was
precluded by lack of material. This minor adjustment of
oxygen functionality is immaterial to the consideration of
the biosynthesis of the pseudorubrenoic acids.
distilled solvents under anhydrous conditions. All reactions
involving conjugated polyenes or polyenynes were
protected from light. All reactions were monitored by
TLC using Merck aluminium sheets coated with Merck
Silica Gel 60 F254 and visualised using either UV light
,254 or 366 nm) or a vanillin staining reagent.38 The phrase
`work-up' refers to separation of an organic phase, washing
withsaturated aq. NaHCO , brine and then water, drying
3
,MgSO4), ®ltration and evaporation of the solvent under
reduced pressure. Except for ,7E,11E,13Z)-hexadeca-
7,11,13-trien-9-yn-1-ol and the cyclohexadiene 13 ,both
puri®ed by RP-HPLC), and the aromatic silyl ether 14
,obtained pure upon work-up), all compounds were puri®ed
by ¯ash chromatography as described by Still et al.39 using
Merck Silica Gel 60 ,particle size 40±63 m). Unless speci-
®ed otherwise, the yields refer to chromatographically and
spectroscopically ,1H NMR) homogenous material. NMR
spectra were recorded for acid-free CDCl3 solutions on a
Varian Gemini-300 instrument at 300 MHz for 1H and
75.43 MHz for 13C. The solvent 1H and 13C signals,
7.27 ppm for residual CHCl3 and 77.0 ppm for CDCl3,
were used as internal references. Signal assignments are
based on direct spectrum analysis, selective proton
decoupling, H,H-COSY and APT data. EIMS and HREIMS
were recorded at 70 eV on VG AutoSpec or ZAB2-SEQ
Mass Spectrometers. UV spectra were recorded on a
Hewlett±Packard 8450A Spectrophotometer. Micro-
analyses were performed by the Australian National
University Microanalytical Service on a Carlo Erba EA
1106 CHN-O analyser.
3. Conclusion
The successful 6p electrocyclic ring closure of the
7E,9Z,11E,13Z-tetraene 12a to the 5,6-cis-dialkylcyclo-
hexadiene 13, followed by dehydrogenation to the analogue
14 of pseudorubrenoic acid A ,1), illustrates the feasibility
of the proposal that the pseudorubrenoic acids and related
o-dialkyl-substituted aromatic metabolites arise via bio-
logical 6p electrocyclisations of acyclic polyene precursors
suchas the enzyme-bound acid 3. Given the submerged
growthconditions of the Pseudomonas, Alteromonas and
Streptomyces microoganisms known to produce such
metabolites in culture, the biosynthetic electrocyclisations
are unlikely to be photochemically promoted. In the present
in vitro model, the cyclisation was effected thermally at a
temperature well beyond that accessible in vivo. An
enzyme, here termed an `electrocyclase', would be needed
to lower the activation energy of the process in vivo. In this
connection, we note the dramatic acceleration of peri-
cyclisation of a substrate analogue achieved by a puri®ed
Diels±Alderase, operating at ambient temperature in an
aqueous medium,10 compared to the thermal cyclisation of
the same substrate in an organic solvent at 1608C.34 The
electrocyclase would constrain the triene moiety of the
substrate into the less preferred s-cis conformation required
for cyclisation, and could catalyse the cyclisation by elec-
tron transfer, a common process in biology. Whereas there
are no reports to date of hole-catalysed 6p electrocyclisa-
tion, reversible one-electron electrochemical reduction to
the radical anion has been reported to promote ef®cient
6p electrocyclisation.35 The application of such electron
transfer catalysis to the biomimetic synthesis of the pseudo-
rubrenoic acids and related o-dialkyl-substituted aromatic
metabolites is currently being explored in our laboratories.
4.1.1. )E)- and )Z)-8-t-Butyldimethylsilyloxy-1-iodooct-
1-enes )10a,b). 7-t-Butyldimethylsilyloxyheptanal ,9)
,125 mg, 511 mmol) and CHI3 ,394 mg, 1.00 mmol) in
dioxane ,9 mL) were added to ¯ame-dried, anhydrous
CrCl2 ,377 mg, 3.60 mmol) in THF ,1.5 mL) and the result-
ing mixture stirred at room temperature. After 18 h, the
reaction mixture was poured into water and extracted with
Et2O. The residue obtained upon work-up was chromato-
graphed ,5% CH2Cl2 in hexane) to afford the vinyl iodide
stereoisomers 10a,b ,9:122) as a colourless oil ,170 mg,
90%) with 1H NMR data identical to that reported by
Makabe et al.40
4.1.2. )Z)-3-Phenylthio-1-trimethylsilyloct-5-en-1-yne )6).
3-Phenylthio-1-trimethylsilylprop-1-yne
,4)
,3.15 g,
14.3 mmol) in THF ,10 mL) was added to a stirred solution
of diisopropylamine ,2.00 mL, 14.3 mmol) and n-BuLi
,10.2 mL, 14.3 mmol, 1.4 M) in THF ,20 mL) at 08C.
After 40 min, ,Z)-1-bromopent-2-ene ,5) ,2.13 g,
14.3 mmol) and hexamethylphosphoramide ,4.97 mL,
28.6 mmol) in THF ,10 mL) were introduced and the stir-
ring continued at 08C. After 1.5 h, the resulting solution was
warmed to room temperature, poured into water and
4. Experimental
4.1. General
3-Phenylthio-1-trimethylsilylprop-1-yne20,36 ,4), ,Z)-1-
bromopent-2-ene21 ,5) and 7-t-butyldimethylsilyloxy-
heptanal37 ,9) were prepared as described in the literature.
Unless speci®ed otherwise, all reactions were performed
under an inert atmosphere of argon with dry, freshly
extracted withEt O. The residue obtained upon work-up
2
was chromatographed ,100% pentane) to afford sul®de 6

3798
R. W. Rickards, D. Skropeta / Tetrahedron 58 -2002) 3793±3800
as a colourless oil ,3.10 g, 75%) ,Found: C, 70.8; H, 8.1.
C17H24SSi requires C, 70.8; H, 8.4%); dH 0.11 ,s, 9H,
SiMe3), 0.97 ,t, Jˆ7.5 Hz, 3H, Me), 2.04 ,quin, Jˆ7.2 Hz,
2H, 7-H), 2.49 ,t, Jˆ6.9 Hz, 2H, 4-H), 3.80 ,t, Jˆ7.0 Hz,
1H, 3-H), 5.51 ,m, 2H, 5-H and 6-H), 7.24±7.40 ,m, 3H, m-
and p-ArH), 7.50±7.62 ,m, 2H, o-ArH); dC 20.10 ,q,
SiMe3), 14.2 ,q, C8), 20.8 ,t, C7), 32.7 ,t, C4), 39.6 ,d,
C3), 89.1 ,s, C1), 105.1 ,s, C2), 124.3 ,d, ArC), 127.9 ,d,
ArC), 128.7 ,d, ArC), 133.2 ,s, ArC1), 133.6 ,d, C5), 134.6
,d, C6) ,the last two assignments may be reversed); m/z 288
,M1, 22%), 273 ,[M2Me]1, 3), 219 ,[M2C5H9]1, 100),
205 ,3), 191 ,26), 151 ,31), 129 ,37), 109 ,ArS1, 30), 97
,Me3SiCC1, 20), 83 ,26), 73 ,Me3Si1, 81).
sulfoxides 7 ,179 mg, 588 mmol), piperidine ,58.2 mL,
588 mmol) and toluene ,2 mL) were stirred at 508C. After
22 h, the reaction mixture was cooled, poured into saturated
aq. NaHCO3, the organic phase separated and the aqueous
phase extracted with Et2O. The organic phases were
combined, worked-up and chromatographed ,100% hexane)
to afford the dienyne stereoisomers 8a,b ,3:222) as a colour-
less oil ,57.4 mg, 55%) ,Found: M1, 178.1176. C11H18Si
requires 178.1178); dH 0.21 and 0.22 ,eachs, 18H, SiMe
3
of 8a/b), 1.01 and 1.02 ,eacht, Jˆ7.5 Hz, 6H, Me of 8a/b),
2.19 ,br quin, Jˆ7.6 Hz, 4H, 7-H of 8a/b), 5.47 ,br d,
Jˆ10.8 Hz, 1H, 3-H of 8b), 5.56 ,dt, Jˆ10.8, 7.8 Hz, 1H,
6-H of 8a), 5.59 ,d, Jˆ15.4 Hz, 1H, 3-H of 8a), 5.69 ,br dt,
Jˆ10.7, 7.8 Hz, 1H, 6-H of 8b), 5.99 ,br t, Jˆ11.1 Hz, 1H,
5-H of 8a), 6.52 ,br t, Jˆ11.2 Hz, 1H, 5-H of 8b), 6.72 ,dt,
Jˆ11.2, 0.9 Hz, 1H, 4-H of 8b), 6.95 ,ddd, Jˆ15.5, 11.5,
1.2 Hz, 1H, 4-H of 8a); dC 20.1 and 0.0 ,q, SiMe3 of 8a/b),
14.1 ,q, Me of 8a/b), 21.4 ,t, C7 of 8a/b), 96.8, 101.4, 102.2,
104.8 ,s, C1/C2 of 8a/b), 108.6, 110.5, 125.1, 127.1, 136.1,
137.5, 138.0, 138.1 ,unassigned doublets for C3-6 of 8a/b);
m/z 178 ,M1, 55%), 163 ,[M2Me]1, 100), 145 ,25), 135
,42), 89 ,80), 83 ,25), 75 ,25), 73 ,Me3Si1, 52).
4.1.3.
)Z)-3-Phenylsul®nyl-1-trimethylsilyloct-5-en-1-
ynes )7). The sul®de 6 ,229 mg, 794 mmol), m-chloro-
perbenzoic acid ,166 mg, 962 mmol) and NaHCO3
,108 mg, 1.28 mmol) in CH2Cl2 ,4 mL) were stirred at
2788C. After 5 h, the reaction mixture was warmed to
room temperature, ®ltered, the ®ltrate diluted with saturated
aq. NaHCO3, the organic phase separated and the aqueous
phase extracted with Et2O. The organic phases were
combined, worked-up and chromatographed ,9% EtOAc
in hexane) to afford sulfoxide 7 as a mixture of dia-
stereomers ,154 mg, 63% yield; diastereomer A±dia-
stereomer B 3:722). Re-chromatography of the material
using 7% EtOAc in hexane as eluent afforded ®rst dia-
stereomer A of sulfoxide 7 as a colourless oil ,30.0 mg,
12%) ,Found: MH1, 305.1393. C17H25OSSi requires
305.1395); dH 0.14 ,s, 9H, SiMe3), 0.95 ,t, Jˆ7.5 Hz, 3H,
Me), 2.04 ,quind, Jˆ7.4, 1.5 Hz, 2H, 7-H), 2.13 ,br ddd,
Jˆ14.0, 9.6, 7.4 Hz, 1H, 4-Ha), 2.80 ,br ddd, Jˆ14.0, 7.5,
5.3 Hz, 1H, 4-Hb), 3.55 ,dd, Jˆ9.6, 5.3 Hz, 1H, 3-H), 5.37
,br dt, Jˆ10.8, 7.2 Hz, 1H, 5-H), 5.57 ,br dt, Jˆ10.8,
7.4 Hz, 1H, 6-H), 7.45±7.55 ,m, 3H, m- and p-ArH),
7.65±7.72 ,m, 2H, o-ArH); dC 20.3 ,SiMe3), 14.2 ,q,
Me), 20.7 ,t, C7), 25.1 ,t, C4), 57.6 ,d, C3), 98.3 ,s, C1),
103.2 ,s, C2), 123.0, 125.4, 128.4, 131.3, 135.7 ,unassigned
doublets for C5, C6 and 4ArC, some signals overlapping),
143.0 ,s, ArC1); m/z 305 ,[MH]1, 1%), 304 ,M1, 1), 289
,[M2Me]1, 1), 288 ,[M2O]1, 1), 275 ,[M2Et]1, 1), 219
,[M2O±C5H9]1, 5), 179 ,[M2ArSO]1, 26), 125 ,ArSO1,
32), 109 ,ArS1, 25), 97 ,Me3SiCC1, 19), 77 ,Ar1, 30), 73
,Me3Si1, 100). This was followed by diastereomer B of
sulfoxide 7, also a colourless oil ,53.5 mg, 22%) ,Found:
MH1, 305.1371. C17H25OSSi requires 305.1395); dH 0.10
,s, 9H, SiMe3), 0.98 ,t, Jˆ7.5 Hz, 3H, Me), 2.13 ,quind,
Jˆ7.5, 3.0 Hz, 2H, 7-H), 2.72 ,br t, Jˆ6.8 Hz, 2H, 4-H),
3.43 ,dd, Jˆ7.4, 5.3 Hz, 1H, 3-H), 5.50 ,br dt, Jˆ10.8,
7.0 Hz, 1H, 5-H), 5.55±5.70 ,br dt, Jˆ10.8, 6.7 Hz, 1H,
6-H), 7.45±7.57 ,m, 3H, m- and p-ArH), 7.72±7.78 ,m,
2H, o-ArH); dC 20.4 ,SiMe3), 14.2 ,q, Me), 20.9 ,t, C7),
27.0 ,t, C4), 60.8 ,d, C3), 94.6 ,s, C1), 96.6 ,s, C2), 122.4,
122.5, 125.6, 125.7, 128.5, 131.6, 135.9, ,unassigned
doublets for C5, C6 and 5ArC), 137.0 ,s, ArC1); m/z 305
,[MH]1, ,1%), 304 ,M1, ,1), 289 ,[M2Me]1, 1), 288
,[M2O]1, 2), 275 ,[M2Et]1, 0.4), 219 ,[M2O±C5H9]1,
15), 179 ,[M2ArSO]1, 29), 163 ,21), 126 ,ArSOH1, 13),
125 ,ArSO1, 9), 109 ,ArS1, 16), 97 ,Me3SiCC1, 16), 77
,Ar1, 11), 73 ,Me3Si1, 100).
4.1.5. )7E,11E,13Z)-, )7E,11Z,13Z)-, )7Z,11E,13Z)- and
)7Z,11Z,13Z)-1-t-Butyldimethylsilyloxyhexadeca-7,11,
13-trien-9-ynes )11a±d). Deaerated 50% aq. NaOH ,1 mL)
was added dropwise to the following reagents in deaerated
acetonitrile ,1 mL) at 08C; the dienynes 8a,b ,3:2; 229 mg,
1.30 mmol), the vinyl iodides 10a,b ,9:1; 233 mg,
630 mmol), triethylbenzylammonium chloride ,8.80 mg,
38.4 mmol), Pd,PPh3)4 ,44.4 mg, 38.4 mmol) and CuI
,7.30 mg, 38.4 mmol), and the resulting mixture stirred at
408C. After 18 h, the organic material was extracted into
CH2Cl2, worked-up and chromatographed ,10% CH2Cl2 in
hexane) to afford the trienyne stereoisomers 11a±d as a
yellow oil ,180 mg, 82% yield) ,Found: C, 76.3; H, 10.8.
C22H38OSi requires C, 76.2; H, 11.1%) ,Found: M1,
346.2697. C22H38OSi requires 346.2692); dH 0.05 ,s, 6H,
SiMe2), 0.90 ,s, 9H, t-Bu), 1.02 ,m, 3H, Me), 1.20±1.60
,m, 8H, 2-H to 5-H), 2.19±2.41 ,m, 4H, 6-H and 15-H),
3.61 ,t, Jˆ7.5 Hz, 2H, 1-H), 5.41±6.92 ,m, 6H, 7-H, 8-H
and 11-H to 14-H); m/z 346 ,M1, 18%), 331 ,[M2Me]1, 1),
289 ,[M2t-Bu]1, 20), 215 ,[M2OTBDMS]1, 28), 157
,25), 145 ,31), 143 ,31), 131 ,27), 129 ,28), 119 ,32), 117
,33), 115 ,29), 105 ,23), 91 ,33), 88 ,26), 77 ,28), 75
,HOvSiMe2, 100).
4.1.6. )7E,11E,13Z)-Hexadeca-7,11,13-trien-9-yn-1-ol.
The trienyne silyl ethers 11a±d ,20.6 mg, 59.0 mmol)
were stirred withTBAF ,119 mL, 119 mmol, 1.0 M) in
THF ,1 mL) at 08C for 5 min and then at room temperature
for 80 min. The reaction was diluted with Et2O, and after
addition of saturated aq. NaHCO3 worked-up in the usual
manner. Flash chromatography ,25% EtOAc in hexane)
gave the trienynol stereoisomers ,11.8 mg, 86% yield) as
a bright yellow oil. Semi-preparative RP-HPLC ,YMC
column: 30 min methanol±water gradient ,75/25±88/12),
¯owˆ4 mL/min, lˆ295 nm) afforded the major stereo-
isomer ,7E,11E,13Z)-hexadeca-7,11,13-trien-9-yn-1-ol as
a yellow oil ,Found: C, 82.9; H, 10.3. C16H24O requires:
C, 82.7; H, 10.4%) ,Found: M1, 232.1829. C16H24O
requires 232.1827); dH ,assigned from homonuclear
decoupling experiments) 1.00 ,t, Jˆ7.5 Hz, 3H, Me),
4.1.4. )3E,5Z)- and )3Z,5Z)-1-Trimethylsilylocta-3,5-
dien-1-ynes )8a,b). The diastereomeric mixture of

R. W. Rickards, D. Skropeta / Tetrahedron 58 -2002) 3793±3800
3799
1.20±1.60 ,m, 9H, 2-H to 5-H and OH), 2.13 ,qd,
J6,5<J6,7ˆ7.5 Hz, J6,8ˆ1.5 Hz, 2H, 6-H), 2.21 ,quind,
J15,14<J15,16ˆ7.5 Hz, J15,13ˆ1.5 Hz, 2H, 15-H), 3.63 ,t,
J1,2ˆ6.5 Hz, 2H, 1-H), 5.52 ,dtt, J14,13ˆ10.8 Hz,
J14,15ˆ7.7 Hz, J14,12<J14,11ˆ1.0 Hz, 1H, 14-H), 5.62 ,ddt,
J8,7ˆ15.7 Hz, J8,11ˆ2.2 Hz, J8,6ˆ1.6 Hz, 1H, 8-H), 5.68
,brdd, J11,12ˆ15.4 Hz, J11,8ˆ2.3 Hz, 1H, 11-H), 6.01 ,ttd,
J13,12<J13,14ˆ11.0 Hz, J13,15ˆ1.5 Hz, J13,11ˆ1.0 Hz, 1H,
13-H), 6.14 ,dt, J7,8ˆ15.7 Hz, J7,6ˆ7.2 Hz, 1H, 7-H), 6.86
,ddd, J12,11ˆ15.5 Hz, J12,13ˆ11.5 Hz, J12,14ˆ1.5 Hz, 1H,
12-H); dC ,assigned from HETCOR spectra) 14.7 ,Me),
22.0 ,C15), 26.1, 29.3, 29.4, and 33.2 ,C2-5), 33.7 ,C6),
63.6 ,C1), 88.4 and 101.6 ,C9 and C10), 110.4 ,C8),
111.4 ,C11), 127.9 ,C13), 137.0 ,C12), 137.2 ,C14),
145.3 ,C7); m/z 232 ,M1, 71%), 203 ,[M2Et]1, 10), 159
,[M2C4H9O]1, 27), 145 ,50), 143 ,26), 131 ,71), 130 ,30),
129 ,60), 128 ,39), 118 ,42), 117 ,100), 116 ,30), 115 ,57),
105 ,53), 103 ,29), 91 ,83), 79 ,43), 77 ,31).
,M1, 31%), 333 ,[M2Me]1, 2), 291 ,[M2t-Bu]1, 79), 235
,21), 215 ,21), 213 ,17), 173 ,34), 159 ,44), 145 ,96), 133
,76), 131 ,46), 117 ,59), 105 ,50), 91 ,97), 75 ,HOvSiMe2,
100). The cyclohexadiene 13 was not obtained when the
tetraenes 12a±d were heated under similar conditions at
1308C.
4.1.9. 1-)[Z]-But-10-enyl)-2-)600-t-butyldimethylsilyloxy-
hexyl)benzene )14). The cyclohexadiene 13 ,5.0 mg,
14.3 mmol) in xylene ,0.75 mL) was added to a suspension
41
of freshly prepared active MnO2 ,25.0 mg, 288 mmol) in
xylene ,0.75 mL) and the resulting mixture stirred at 1208C.
,At temperatures .1308C, the xylene was oxidised to
higher-boiling tolualdehyde, whereupon isolation of the
desired product required ¯ashcrhomatograpyh.) After
18 h, the reaction mixture was ®ltered through a short pad
of Celite and the solvent evaporated under high vacuum to
afford essentially pure aromatic silyl ether 14 as a colourless
oil ,4.95 mg, 100%) ,Found: M1, 346.2694. C22H38OSi,
M1, requires 346.2692); dH 0.04 ,s, 6H, SiMe2), 0.89 ,s,
9H, t-Bu), 1.00 ,t, Jˆ7.5 Hz, 3H, Me), 1.35 ,m, 4H,
±[CH2]2±), 1.53 ,m, 4H, ±[CH2]2±), 2.16 ,quind, Jˆ7.5,
1.6 Hz, 2H, 30-H), 2.58 ,t, Jˆ7.5 Hz, 2H, 100-H), 3.59 ,t,
Jˆ6.5 Hz, 2H, 600-H), 5.70 ,dt, Jˆ11.0, 7.0 Hz, 1H, 20-H),
6.46 ,dt, Jˆ11.0, 1.7 Hz, 1H, 10-H), 7.16 ,m, 4H, ArH); dC
25.3 ,q, SiMe2), 14.3 ,q, Me), 18.4 ,s, t-Bu), 21.7 ,t), 25.7
,t), 26.0 ,q, t-Bu), 29.3 ,t), 30.6 ,t), 32.8 ,t), 33.5 ,t), 63.3 ,t,
4.1.7. )7E,9Z,11E,13Z)-, )7E,9Z,11Z,13Z)-, )7Z,9Z,
11E,13Z)- and )7Z,9Z,11Z,13Z)-1-t-Butyldimethylsilyl-
oxyhexadeca-7,9,11,13-tetraenes )12a±d). The trienynes
11a±d ,140 mg, 405 mmol) in MeOH ,2 mL) were added
to a stirred suspension of activated Zn29 ,freshly prepared
from Zn ,250 mg), Cu[OAc]2´H2O ,25.0 mg) and AgNO3
,25.0 mg)) in MeOH±water ,1:1, 10 mL) at room tempera-
ture. After 20 h, the metal was removed by ®ltration through
a short column of Celite and the ®ltrate concentrated and
extracted withpentane. The residue obtained upon work-up
was chromatographed ,100% hexane) to afford the tetraene
stereoisomers 12a±d as a yellow oil ,113 mg, 84%) ,Found:
C, 75.4; H, 11.2. C22H40OSi requires C, 75.8; H, 11.6%)
,Found: M1, 348.2844. C22H40OSi requires 348.2849); dH
0.06 ,s, 6H, SiMe2), 0.90 ,s, 9H, t-Bu), 1.02 ,t, Jˆ7.5 Hz,
3H, Me), 1.25±1.55 ,m, 8H, 2-H to 5-H), 2.13 ,q, Jˆ6.7 Hz,
2H, 6-H), 2.22 ,quind, Jˆ6.6, 1.5 Hz, 2H, 15-H), 3.60 ,t,
Jˆ6.5 Hz, 2H, 1-H), 5.42±6.72 ,m, 8H, 7-H to 14-H); m/z
349 ,[MH]1, 45%), 348 ,M1, 75), 333 ,[M2Me]1, 5), 291
,[M2t-Bu]1, 35), 213 ,35), 159 ,22), 147 ,25), 145 ,44),
133 ,36), 131 ,32), 119 ,40), 117 ,39), 115 ,22), 105 ,45), 95
,34), 93 ,25), 91 ,58), 81 ,28), 77 ,40), 75 ,HOvSiMe2,
100).
0
C600), 125.2, 126.8, 127.2, 128.8, 129.4, 134.6 ,eachd, C1 ,
C20 and C3-6), 136.3, 141.0 ,s, C1 and C2); m/z 346 ,M1,
3%), 331 ,[M2Me]1, 4), 289 ,[M2t-Bu]1, 100), 213
,[M2OTBS]1, 28), 171 ,26), 157 ,40), 145 ,63), 143
,78), 131 ,38), 117 ,59), 105 ,50), 91 ,97), 75 ,HOvSiMe2,
100).
Acknowledgements
We thank Mr A. J. Herlt for invaluable technical support,
Ms J. M. Rothschild for mass spectra, and the Australian
National University for the award of a PhD scholarship ,to
D. S.).
4.1.8. cis-5-[)Z)-But-10-enyl]-6-)600-t-butyldimethylsilyl-
oxyhexyl)cyclohexa-1,3-diene )13). The tetraene stereo-
isomers 12a±d ,80.7 mg, 231 mmol) in toluene ,15 mL)
were heated at 1508C in a sealed tube. After 18 h, the sealed
tube was cooled to 2788C, opened, the toluene evaporated
and the residue puri®ed by semi-preparative RP-HPLC
,YMC C18 column: 100% acetonitrile, ¯ow 3 mL/min, UV
detection 265 nm, Rtˆ32 min) to afford the cyclohexadiene
13 as a colourless oil ,8.9 mg, 11% yield) ,Found: M1,
348.2849. C22H40OSi requires 348.2849); dH 0.04 ,s, 6H,
SiMe2), 0.89 ,s, 9H, t-Bu), 0.96 ,t, Jˆ7.5 Hz, 3H, Me),
1.25±1.55 ,m, 8H, 100-H to 500-H), 2.06 ,quin, Jˆ7.5 Hz,
2H, 30-H), 2.46 ,m, 1H, 6-H), 3.09 ,m, 1H, 5-H), 3.59 ,t,
Jˆ6.5 Hz, 2H, 600-H), 5.37 ,dt, Jˆ11.0, 7.0 Hz, 1H, 20-H),
5.45 ,t, Jˆ10.5 Hz, 1H, 10-H), 5.58 ,m, 1H, 1-H), 5.69 ,m,
1H, 4-H), 5.86 ,m, 2H, 2-H and 3-H); dC 24.2 ,q, SiMe2),
15.7 ,q, Me), 18.4 ,s, t-Bu), 22.0 ,t, C30), 27.1 ,q, t-Bu),
26.9, 28.3, 30.7, 31.7, 33.9 ,t, C100 to C500), 36.1 ,d, C5), 38.3
,d, C6), 64.4 ,t, C600), 124.4, 125.0 ,d, C2 and C3), 126.2 ,d,
C10), 131.3 ,d, C4), 132.1 ,d, C1), 133.6 ,d, C20); m/z 348
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