Tur-Lcrras
Vol. 35.No. 7. pp. 10674070.
1994
Elsevim
ScimceLul
Priitcdin Gmt Bitin
cnl40-4039~s6.olko.oa
First Total Synthesis of a Barnacle Hatching
Hydroxy-eicosa-S(Z),9(E),ll(Z),14(Z),17(Z)-pentaenoic
Tony
K.
M. Shing,*a
a Department
K. H. Gibson,b Jonathan
R.
Wiley,c
Factor
8(R ) acid
C. Ian F. Watt=
of Chemistry,
The Chinese University of Hong Kong, Shatin, Hong
Kong
b Chemistry Department II, ICI pharmaceutical
Division, Alderley Park,
Macclesfeld, Cheshire SKI0 4TG. U.K.
C Department of Chemistry, University of Manchester, Manchester Ml3 9PL, U.K.
Abstract-The
fast total synthesis of a barnacle hatching factor (BHF) establishes its constitution and
absolute stereochemistry as B(R)-Hydroxy-eicosa-S(Z),Q(f)),l
1(2),14(i!).17(2)-pentaenoic
acid
1.
Recently, an eicosanoid monohydroxy fatty acid was isolated from the homogenates of Balanus
balanoides and Eliminus tnodestus in minute quantities (lOSg g) and shown to induce the hatching of
barnacle&
(IQ
cu. 5.0 x 10-S M).3 The structure of the barnacle hatching factor (BHF) was suggested
to be S(R)-Hydroxyeicosa-5(2),9(E),
biogenetic
consideration4
11(Z), 14(2),17(Z)-pentaenoic
acid 1 [I(R)-HEPE]
and of an analysis of its mass fragmentation
pattem.te2
on the basis of
Other spectroscopic
studies are not possible because of the scarcity of the material which therefore watrauts a total synthesis.
Only the 8(R)-enantiomer
statftsh.4 Commercially
hatching.5
of 8-hydroxy-eicosatetraenoic
acid was active in inducing oocyte maturation in
available 8(S)-HEPE has been shown to be biologially inactive towards barnacle
The limited availability
of I(S)-HEPE in microgram quantities and the prohibitive cost render
investigation of its chemistry impractical.
Here we report, starting from Dmannitol
and pmpargyl alcohol,
the first total and stereoselective synthesii of 1, which displayed a mass spectrum in accord with that of the
BHF and, most importantly, exhibited bioactivity towards barnacle hatching (KS ca. 2.4 x lo-6 ~),3
thereby enabling the assignment of the constitution and absolute configuration
1067
1 to the BHF.
analysis of 1 shows that dissection of the strategic 11-allcene gives the upper haIf
Retrosynthetic
aldehyde
2 and the bottom half phosphonium
reaction to yield the target molecule.
salt 3 which can bc assembled
The construction
(c 1.0, CHCl3)P
Selective
metbanolysis
+ 9.00 (c 1.3. CHCl3).
cataIyst
followed
Stereoselective
by deacetonation
in four steps, with the lithium salt
afforded the benzoate 6 as a viscous oil, [CC]D~ + 10.10
of the tetrahydropyranyl
ether in 6 gave the corresponding
primary alcohol which then was subjected to an oxidation-esterification
7, [a]#
Wittig
of 2 is illustrated in Scheme 1. Oxirane opening
teaction6 of the known diepoxide 4.7 readily accessible from Dmannitol
of the allcyne 58 followed by in situ benxoylation
via a Z-selective
hydrogenation
gave the ene-diol
sequence to form the methyl ester
of the triple bond in 7 with Liidlar’s
8. [a]~~~
+ 51.2O (c 6.5, CHC13).lo
Glycol
cleavage oxidation** of the diol moiety in 8 with sodium metaperiodate followed by Wittig reaction with
formylmethylenetriphenylphosphorane
CHCl3).12
The stereochemistry
in CH2C12 furnished
the Z,Bdienal
of the two double bonds in 2 was indicated
2, [IX]+
- 108.20 (c 0.9.
from the 1NMR spectrum
(J5,e = 10.2 Hz and 59.10 = 15.6 Hz).
.. ... ,$.q
u,ubiv
:‘;;I4
I
Scheme 1 ReamIs
i. Hm(CH2)3CH2oTHp
5. n-BSi, ~/DImlJ,
iii, (COCth, DMSO. BtgN, (78%); iv, NaCQ.
2-methYl-Z-butene. t-BuOWHzO (94%); v, MeOH, HCI (93%): vi Hi. L~IKIWS
catalyst
0 %J (79%
vii.
80%
and condXcms:
ii. TsoH.
aquas
WA.
MeOH, A (74%);
0 ‘C
(84%);
viii
On the other hand, the synthesis
reaction of I-bromo-pent-Zyne
catalysed
phase
hydrogenation
transfer
spectrum
(33.4
phosphonium
conditions14
gave the skipped
salt 3 in the conventional
~.ZCWIK.
(97%); ix, Pb+CHCHO,
salt is depicted
available
diyne
The alcohol
(gg%):
CHzC12 (85%).
in Scheme 2. Coupling
but-3-yn-l-01
10 under copper (l)
11 in 73% yield.
of the dieue moiety in 12 was evident
= 10.9 Hz).
phco~.
N&I$Q+
with a catalyst modifier ethylenediaminele
The Z&geometry
= 10.6 Hz and J6,7
0k
of the phosphonium
913 with the commercially
of 11 over nickel boridels
diene 1217 in 79% yield.
NdO4, MeOHMfl.
& w
Stereoselective
afforded the Z,Zfrom the 1NMR
12 was then transformed
into the
way.
CuI, t-BuJUI. DMF (73%); ii, H2, Ni(OAc)2, N&H,, F&H,
fkb~
2 ReoSents and COnditiOM: i, kfls.
HzN(CHdzNH2 (79%): iii. MsC1,Et3N. Et20 (87%6); iv, Nd, ace(88%); v, pph3, Ma,
A (98%).
1069
With the upper and lower half of the target molecule readily at hand, we set to complete the
synthesis of 1 (Scheme 3). Thus the phosphonium salt 3 was deprotonated (n-BuLi, THF, -78 Oc) and
the aldehyde 2 added followed by 1,3dimethy1-3,4,5,6-tet.rahydro-2(1H)-pyrimidinone (DMPU). HPIC
analysis of the mixture isolated by flash chromatography showed that the Z : E ratio of the newly formed
1I-alkene was 12 : 1. Fractionation by preparative HPLC then gave the pentacne 13 as a clear oil, [a]#
- 75.7O (c 2.7. CHC13). Saponification of the two ester groups in 13 foilowed by acidification with formic
acid furnished the target molecule 8(R)-HEPE 1 as a colourless oil, [a]#
+ 33.4O (c 2.1, CHC13). with
86% e.e.t* Since derivatisedI9 1 showed a mass fragmentation pattern similar with that of the BHF and
exhibited bioactivity towards barnacle hatching (IC50 cu. 2.4 x 10-e M).~O the structure and
stereochemistry of the BHF is confirmed as 8(R)-Hydroxy-eicosa-5(Z),9(E),ll(Z),14(2),17(Z)pcntaenoic acid 1.
13
Sebcme 3 Reagents and conditions: i, n-BuLi. THF, -78 OC. then 2. DMPU. -78 to -25 OC (87%);
ii, K2C@,
M&H.
H@ (85%).
In conclusion, we have developed a convergent and enantioselective synthesis of 1 using
tafftmannitol as the source of chirality and using Wittig reactions and catalytic hydrogenation of alkynes to
introduce stereoselectively the five double bonds. The convergent strategy employed allows facile
syntheses of acetylenic analogues and geometric isomers. Research in this direction is in progress.
Acknowledgment.
We thank the S.E.R.C. for financial support and Dr. D. L. Holland for discussion
and performing the bioassay.
References
and notes
(1) Hill, E. M.; Holland, D. L.; Gibson, K. H.; Clayton, E.; Oldfield. A. Proc. Royal Sot. Lam! B,
1988,234,
455.
(3)
Hill, E. M.; Holland, D. L.; Gibson, K. H.; Clayton, E.; Oldfield. A. Proc. Royal Sot. L,und B,
1989,235, 407.
IC~o is defined as the concentration of the material to cause a 50% hatch.
(4)
Mcijer, A. R.; Brash, A. R.; Bryant, R. W.; Ng, K.; Maclouf, J.; Sprecher, H. J. Biol. Chem,
(51
(6)
Hill, E. M.; Holland, D. L. Proc. Royul Sot. Lund. B, 1992,247, 41.
Le Merrer. Y.; Gravier-Pelletier, C; Micas-Languin. D.; Mcstrc. F.; Durcault, A.; Depexay, J. C. .I.
(7)
Org. Chem, 1989.54. 2409.
Le Merrer, Y.; Dureault, A.; Greek, C.; Micas-Languin. D.; Gravier-Pelletier, C; Depexay, J. C.
Heterocycles, 1987.25, 541.
(2)
1986,262,
17040.
1070
(8)
Beaction of the commtxciaUy available hex-5yn-l-01
(9)
All new compounds
with 2,3-dihydropyran
(CH2Cl2, Tk0I-I) gave
5 in 98% yield.
gave aatisfactoty spectral and HMRS or analytical data
(10) Reversed phase HPLC analysis showed that 8 was > 95% one isomer.
(11) For a recent teview, see Shing, T. K. M. Cowtprehensivc Orgcudc Sywhcsis. eds. Trost, B. M. and
Fleming,
I., Pergamon
Press, Oxford, 1991, vol. 7, p. 703.
(12) There was no indication of the undesited ZZ
isomer by TLC and tNMB spectml analysis.
(13) Bromide 9 was ptepated from propargyl alcohol in four steps, see: Kajiwara, T.; Odake. Y.;
Hatanaha,
A. Agr. Biol. Gem.,
(14) ‘l&se conditions
1975.39,
1617.
wets used previously for the substitution
of ally1 halides with terminal alkynes, see:
Jeffery, T. Tetrahedron L-en.. 1989,225.
(15) Brown, H. C.; Brown, C. A. J. Am Chem. Sot.. 1963.85,
1005.
(16) Brown, C. A.; Ahuja, V. J. Chem. Sm., Chem Contmun., 1973,553.
hydrogenation
was signilkmtly
Stereoselectivity
for the
poorer without the ethylenediamlue.
(17) GC analysis showed that 12 was > 95% one isomer.
(18) 1 was derivatised with ethereal diazomethane
into the corresponding
methyl ester whose e.e. was
determined by the Mosher’s protocol.21 The aldehyde 2 is believed to undergo a little racemization.
(19) 1 was txeated with ethemsl diazomethanc
followed by silylation with bis-trimethylslly-
tfifluoroacetamide.
(20) The bioassay was carried out by Dr. D. L. Holland at the Mark
Bridge, Anglesey,
Science Laboratories,
Menai
U.K. The IC5u (5.0 x 10-4 M) of the natural material is higher than that of the
synthetic I(R)-HEPE
1. The likely explanation
of this discrepancy
is the error in the determination
of
the molar@ of the test solution of the natural material since only small quantities (10-g g) of the BHF
was isolated from crushed barnacles.
(21) Dale, J. A.; Dull, D. L.; Mosher. H. S. J. Org. Chew
1%9,34.
(Received in China 20 March 1993; accepted 29 November 19%)
2543.