Synthesis of deuterated 5(Z),11(Z)-eicosadienoic acid as a biomarker for trophic transfer

Article abstract of DOI:10.1016/j.tetlet.2010.12.027

The poly-methylene interrupted fatty acid 5(Z),11(Z)-eicosadienoic acid and its tetradeuterated analogue were prepared via a convergent synthetic sequence.

Full text of DOI:10.1016/j.tetlet.2010.12.027

Tetrahedron Letters 52 (2011) 787–788
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Tetrahedron Letters
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Synthesis of deuterated 5(Z),11(Z)-eicosadienoic acid as a biomarker
for trophic transfer
Siliva Albu a, Ed Sverko b, Michael T. Arts b, Alfredo Capretta a,
⇑
a Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada L8S 4M1
b Water Science and Technology Directorate, National Water Research Institute, Environment Canada, 867 Lakeshore Road, PO Box 5050, Burlington, Ontario, Canada L7R 4A6
a r t i c l e i n f o
a b s t r a c t
Article history:
The poly-methylene interrupted fatty acid 5(Z),11(Z)-eicosadienoic acid and its tetradeuterated analogue
were prepared via a convergent synthetic sequence.
Received 28 October 2010
Revised 2 December 2010
Accepted 6 December 2010
Available online 17 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Fatty acids (FAs) are recognized as important tools in ecology,1
toxicology2 and conservation biology.3 While they have been uti-
lized previously as trophic markers,4–6 their use is hampered by
the fact that they exhibit species-specific bioconversion rates and
also because many FAs are ubiquitous and abundant in aquatic
food webs. In contrast, poly-methylene interrupted fatty acids7
(PMI-FAs) possess an unusual methylene substitution pattern
and, as such, occur much less frequently in nature. In the marine
environment, it is thought that PMI-FAs are synthesized de novo
primarily in bivalves and carnivorous gastropods8–10 and further
accumulate, to varying extents (depending on diet), in marine
mammals.9
Our interest in PMI-FAs stems from their potential as biomark-
ers for zebra (Dreissena polymorpha) and quagga (D. bugensis)
mussels (termed dreissenids). Since their introduction in the Lau-
rentian Great Lakes, their adaptability, rapid life cycle, and high
reproductive potential have ensured their continued invasion suc-
cess11,12 and has resulted in extensive ecosystem impact and dam-
age.13,14 New methods designed to enable researchers to better
track the passage of dreissenid-derived carbon to both native and
introduced consumers at different trophic levels through the food
web are required in an effort to understand the extent to which
dreissenids alter the function and stability of aquatic ecosystems.
The PMI-FA 5(Z),11(Z)-eicosadienoic acid (1) was identified as a
useful biomarker for these studies and the present paper describes
the synthesis of a deuterated analogue applicable for analytical
studies using isotopic dilution.15
kyne reduction using Lindlar’s catalyst. Furthermore, the route
offers the opportunity to introduce deuterium at either alkene or
both as desired.
Initial development of the synthesis focused on preparation of
the non-deuterated fatty acid. The route to the C7–C20 fragment
appears in Scheme 1 (R = H). While 4-bromo-1-butanol (3) is com-
mercially available, a convenient synthesis has been described pre-
viously wherein tetrahydrofuran (2) is treated with HBr.16 The
resulting bromo-alcohol was then protected as its THP ether (4)17
before coupling with 1-decyne (5) in THF at À78 °C to give 6. Het-
erogeneous hydrogenation of the alkyne to the alkene (7) is carried
out in the presence of Lindlar’s catalyst. Inspection of the 1H NMR
(at 700 MHz) allowed for resolution of the alkenic protons and
revealed only a single isomer. Furthermore, coupling of the alkenic
protons to each other with a J = 6.9 Hz was consistent with the
desired cis geometry. Removal of the THP protecting group affords
the free alcohol 8 that was subsequently tosylated (to give 9).
Finally, treatment with NaI in acetone provides 10, the required
C7–C20 synthon.
Synthesis of the C1–C6 synthon along with its coupling to the
C7–C20 fragment appears in Scheme 2 (R = H). Commercially avail-
able 5-hexyn-1-ol (11) was protected as its THP ether (12)18 before
coupling to iodo-alkene 10 to yield alkene-alkyne 13. It should be
noted that attempts to couple 12 with the tosylate 9 failed prompt-
ing the use of the iodo compound 10. Reduction to the bisalkene
(14) once again took advantage of the H2/Lindlar’s catalyst system
with cis geometry at the newly formed C5@C6 alkene confirmed
via 1H NMR. Deprotection of the THP ether 14 to the alcohol 15
is followed by oxidation using pyridinium dichromate in DMF to
yield the desired 5(Z),11(Z)-eicosadienoic acid (1: R = H).
Despite having been isolated from a variety of natural sources,
the synthesis of 5(Z),11(Z)-eicosadienoic acid (1) has not been de-
scribed in the literature. The synthetic route developed appears in
Schemes 1 and 2. The approach was designed so as to insure cis ste-
reochemistry at C5@C6 and C11@C12 by taking advantage of an al-
Having established the viability of the synthetic route, attention
was turned to the preparation of the deuterated analogue
(Schemes 1 and 2 where R = D). Use of D2 gas in place of H2 in
the hydrogenations of 6 to 7 and 13 to 14 allowed for the incorpo-
ration of deuterium into the newly generated cis alkenes. [2H4]-
⇑
Corresponding author. Tel.: +1 905 525 9140x27318; fax: +1 905 522 2509.
E-mail address: capretta@mcmaster.ca (A. Capretta).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.027

788
S. Albu et al. / Tetrahedron Letters 52 (2011) 787–788
(a)
(b)
Br
Br
O
O
O
OH
4
3
2
(c)
(CH2)7CH3
5
R
7: R' = O-THP
8: R' = OH
9: R' = O-Ts
10: R' = I
(e)
(f)
(g)
(d)
R
CH3(CH2)7
O
O
R'
(CH2)7CH3
6
Scheme 1. Synthesis of the C7–C20 synthon. Reagents and conditions: (a) HBr, H2SO4 (90%); (b) DHP, p-TsOH, DCM (72%); (c) (i) 5, n-BuLi, THF, À78 °C; (ii) dropwise addition
of 4 then heat (85%); (d) 1 atm H2, Lindlar’s catalyst (72%); (e) p-TsOH, MeOH (68%); (f) p-TsCl, DCM, pyridine (73%); (g) NaI, acetone (71%).
R
R
(a)
10
(b)
(CH2)4-OH
11
O
(CH2)4-O
(CH2)4-O
(CH2)7CH3
O
12
13
(c)
R
R
5
R
R
CO2H
(e)
6
R
R''
14: R'' = O-THP
15: R'' = OH
(d)
11
12
R
R
R
1: 5(Z),11(Z)-eicosadienoic acid (R = H or D)
Scheme 2. Synthesis of the C1–C6 synthon and coupling to the C7–C20 fragment. Reagents and conditions: (a) DHP, p-TsOH, DCM (92%); (b) (i) 12, n-BuLi, HMPA, THF,
À78 °C; (ii) dropwise addition of 10 then heat (65%); (c) 1 atm H2, Lindlar’s catalyst (62%); (d) p-TsOH, MeOH (92%); (e) PDC, DMF (45%).
6. Desvilettes, C.; Bourdier, G.; Amblard, C.; Barth, B. Freshwater Biol. 1997, 38,
629–637.
ized by 1H NMR, 13C NMR and HRMS.19 Furthermore, gas chro-
7. Mezek, T.; Arts, M. T.; Sverko, E.; Fisk, A. T. Verh. Int. Ver. Limnol. 2009, 30, 903–
5(Z), 11(Z)-Eicosadienoic acid (1: R = D) was completely character-
matographic analysis of the deuterated PMI-FA with an authentic
standard revealed that both samples had similar retention times.20
In conclusion, 5(Z),11(Z)-eicosadienoic acid and its tetradeuter-
ated analogue were prepared via a convergent 12-step synthesis.
The nature of the route is such that other PMI-FAs can be prepared
in this fashion. Work describing the use of the deuterated standard
as a biomarker for trophic transfer will be described elsewhere.
906.
8. Saito, H. J. Chromatogr., A 2007, 1163, 247–259.
9. Budge, S. M.; Springer, A. M.; Iverson, S. J.; Sheffield, G. Mar. Ecol. Prog. Ser. 2007,
336, 305–309.
10. Budge, S. M.; Iverson, S. J.; Koopman, H. N. Mar. Mamm. Sci. 2006, 22, 759–801.
11. Schloesser, D. W.; Metcalfe-Smith, J. L.; Kovalak, W. P.; Longton, G. D.; Smithee,
R. D. Am. Midl. Nat. 2009, 155, 307–320.
12. Zanatta, D. T.; Mackie, G. L.; Metcalfe-Smith, J. L.; Woolnough, D. A. J. Great
Lakes Res. 2002, 28, 479–489.
13. Connelly, N.; O’Neill, C.; Knuth, B.; Brown, T. Environ. Manage. 2007, 40,
105–112.
14. Karatayev, A. Y.; Boltovskoy, D.; Padilla, D. K.; Burlakova, L. E. J. Shellfish Res.
2009, 26, 205–213.
Acknowledgements
15. Hamon, R. E.; Parker, D. R.; Lombi, E.; Donald, L. S. In Advances in Agronomy;
Academic Press, 2008; pp 289–343.
The authors thank the Natural Sciences and Engineering
Research Council of Canada, Environment Canada, the Canadian
Foundation for Innovation and the Ontario Innovation Trust for
their financial support.
16. Nguyen, J. T.; McEwen, C. A.; Knaus, E. E. Drug Dev. Res. 2000, 51, 233–243.
17. Snider, B. B.; Lu, Q. J. Org. Chem. 1996, 61, 2839–2844.
18. Gu, H.; Xu, W. M.; Kinstle, T. H. Tetrahedron Lett. 2005, 46, 6449–6451.
19. 1H NMR (600 MHz, CDCl3): 2.36 (t, 2H, J = 7 Hz), 2.09 (t, 2H, J = 7 Hz), 2.01–1.94
(m, 6H), 1.69 (m, 2H), 1.30–1.26 (m, 16H), 0.87 (t, 3H, J = 7 Hz); 13C NMR
(120 MHz, CDCl3): 178.8, 131.2, 131.0, 129.6, 128.2, 33.3, 32.0, 29.9, 2 Â 29.6,
2 Â 29.5, 29.4, 27.2, 27.1, 27.1, 26.4, 24.7, 22.8, 14.2; ES-HRMS: Calculated for
References and notes
20H31O2D4 [MÀH]À 311.2888; observed: 311.2884.
1. Lipids in Aquatic Ecosystems; Arts, M. T., Brett, M. T., Kainz, M. J., Eds.; Springer:
New York, 2009.
C
20. The PMI-FAs were analysed by GC–MS (Agilent 6890N GC) equipped with a
2. Kainz, M. J.; Fisk, A. T. In Lipids in Aquatic Ecosystems; Arts, M. T., Brett, M. T.,
Kainz, M. J., Eds.; Springer: New York, 2009; pp 237–255.
DB-23 polar capillary column (Agilent; #122-2361; 60 m  0.25
mm id  0.15
lm film thickness), an Agilent 7683B injector, and a mass
3. Glayshev, M. I.; Arts, M. T.; Sushchik, N. N. In Lipids in Aquatic Ecosystems; Arts,
M. T., Brett, M. T., Kainz, M. J., Eds.; Springer: New York, 2009; pp 237–255.
4. Koussoroplis, A.-M.; Lemarchand, C.; Bec, A.; Desvilettes, C.; Amblard, C.;
Fournier, C.; Berny, P.; Bourdier, G. Lipids 2008, 43, 461–466.
5. Napolitano, G. In Lipids in Freshwater Ecosystems; Arts, M. T., Wainman, B. C.,
Eds.; Springer: New York, 1999; pp 21–44.
selective quadrupole detector (Agilent 5973N). Helium was used as the carrier
gas at a constant pressure (ꢀ180 kPa at 33 cm sÀ1 at 50 °C). Samples were
injected at an oven temperature of 50 °C. After 1 min, the oven temperature
was raised to 175 °C at a rate of 25 °C minÀ1, then to 235 °C at 4 °C minÀ1 and
held for 5 min. The retention times for 5(Z),11(Z)-eicosadienoic acid and [2H4]-
5(Z),11(Z)-eicosadienoic acid were 18.1 and 18.2 min, respectively.