Total synthesis of the anti-inflammatory lipid mediator Resolvin E2

Article abstract of DOI:10.1016/j.tetlet.2012.01.136

The total synthesis of Resolvin E2, an endogenous lipid mediator of the resolution of inflammation derived from eicosapentaenoic acid, has been achieved. The chiral hydroxy-groups at C5 and C18 were generated in a simple, efficient, and environmentally friendly manner via an asymmetric Noyori transfer hydrogenation in water using sodium formate as a reducing agent. Pd ⁰/Cu^I Sonogashira couplings of the three key fragments and Zn(Cu/Ag) reduction completed the synthesis of Resolvin E2.

Full text of DOI:10.1016/j.tetlet.2012.01.136

Tetrahedron Letters 53 (2012) 1912–1915
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of the anti-inflammatory lipid mediator Resolvin E2
⇑
Ana R. Rodriguez, Bernd W. Spur
Department of Cell Biology, University of Medicine and Dentistry of New Jersey, SOM, Stratford, NJ 08084, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of Resolvin E2, an endogenous lipid mediator of the resolution of inflammation
derived from eicosapentaenoic acid, has been achieved. The chiral hydroxy-groups at C5 and C18 were
generated in a simple, efficient, and environmentally friendly manner via an asymmetric Noyori transfer
hydrogenation in water using sodium formate as a reducing agent. Pd /Cu Sonogashira couplings of the
three key fragments and Zn(Cu/Ag) reduction completed the synthesis of Resolvin E2.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 22 November 2011
Revised 26 January 2012
Accepted 31 January 2012
Available online 9 February 2012
0
I
Keywords:
Resolvin E2
Total synthesis
Inflammation resolution
Asymmetric transfer hydrogenation in
water
Sonogashira coupling
Inflammation plays a key role in asthma, arthritis, atherosclero-
sis, and Alzheimer’s disease among others.1 The beneficial effects
water; we investigated this protocol to generate both chiral centers
of RvE2 in a simple, efficient, and environmentally friendly
–4
2
6–29
of
x
-3 fatty acids (fish oil) in these diseases could be addressed in
manner.
The C1–C7 fragment 2 was prepared in five steps as outlined in
part by shifting the formation of pro-inflammatory leukotrienes
derived from arachidonic acid to the less inflammatory leukotri-
enes derived from eicosapentaenoic acid.5 Recently, Serhan et al.
have identified in vivo a series of lipid mediators of the resolution
of inflammation derived from eicosapentaenoic acid (Resolvins E1
and E2) and from docosahexaenoic acid (Resolvins D1, D2, D3, D4,
2
3,30
Scheme 1. Reduction of the ketone 5,
2
in H O/ethyl acetate in
the presence of a catalytic amount of the phase transfer catalyst
hexadecyl trimethyl ammonium bromide (CTABr) using the Noyori
RuCl[(S,S)-TsDPEN](p-cymene) precatalyst (0.035 equiv) with so-
dium formate as a reducing agent, produced the chiral intermedi-
ate 6 with >93% ee as determined by chiral HPLC [Chiracel OD,
6
,7
D5, D6, Neuroprotectin D1 and Maresin).
These endogenous
Resolvins are potent anti-inflammatory lipid mediators.8
–16
hexane/i-PrOH 90:10, 0.6 mL/min, 210 nm, t
= 8.5 min (R-isomer)
TMS desilylation of 6 with
3
OH gave cleanly the terminal acety-
R
3
1,32
The growing interest to study the pharmacological properties of
the Resolvins combined with the limited availability from natural
sources requires their preparation by total syntheses.17–25
Two independent syntheses of Resolvin E2 by Inoue et al. and
Kobayashi et al. have been recently reported. Inoue utilized a cyc-
lobutene lactone approach for the chiral hydroxy-groups whereas
Kobayashi generated the chiral centers by Sharpless kinetic
and t
R
= 9.6 min (S-isomer, 6)].
CO /Na SO in CH
1.2 equiv K
2
3
2
4
33
lene 7. Under these conditions no ester cleavage was observed.
Protection of 7 with TBSCl in DMF produced the silyl ether 8 in
quantitative yield. Hydrostannylation of 8 with excess tributyltin
hydride at 130 °C in the presence of a catalytic amount of AIBN
produced the trans-vinyl tin compound 9 in a 74% yield. Excess
of tributyltin hydride was removed in high vacuo. The key interme-
diate 2 was obtained from 9 by reaction with iodine in ether at
0 °C. On large scale the removal of tributyltin iodide by flash chro-
matography became a problem due to its similar solubility and
1
9,21
resolution.
In this communication, we wish to report a short total synthesis
of Resolvin E2 [RvE2; (5S,6E,8Z,11Z,14Z,16E,18R)-5,18-dihydroxy-
6
,8,11,14,16-eicosapentaenoic acid; (1)]. As shown in Figure 1,
RvE2 was prepared from the readily available key intermediates
, 3, and 4. We have successfully employed a similar strategy for
3
4
35
chromatographic behavior with 2. Corey
and Harrowven
2
reported effective procedures to remove organotin halides from
reaction mixtures. A combination of both methods, stirring the
2
5
the synthesis of RvD6. Intrigued by recent reports that the asym-
metric Noyori transfer hydrogenation could be carried out in
reaction mixture with K
ple filtration, produced a tin-free hexane solution of 2. Neither
CO nor silica gel alone was capable to remove the tin impurities.
2 3
CO /silica gel in hexane followed by sim-
K
2
3
⇑
Corresponding author. Tel.: +1 856 566 7016; fax: +1 856 566 6195.
E-mail address: spurbw@umdnj.edu (B.W. Spur).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.136

A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 1912–1915
1913
Figure 1. Retrosynthetic approach to RvE2.
Scheme 1. Reagents and conditions: (a) RuCl[(S,S)-TsDPEN](p-cymene), CTABr, HCOONa, H
°C to rt, 99%; (d) (Bu) SnH, AIBN, 130 °C, 74%; (e) I , ether, 0 °C, 90%.
2
O, EtOAc, rt, 65%; (b) K
2
CO
3
, Na
2
SO
4
, CH
3
OH, rt, 85%; (c) TBSCl, imidazole, DMF,
0
3
2
Scheme 2. Reagents and conditions: (a) RuCl[(R,R)-TsDPEN](p-cymene), CTABr, HCOONa, H
AgNO , CH OH, H O, NaCN, 0 °C; (d) (Bu) SnH, AIBN, 130 °C, 84%; (e) I , ether, 0 °C, 89%.
2
O, EtOAc, rt; (b) TBSCl, imidazole, DMF, 0 °C to rt, 84% (two-steps, a and b); (c)
3
3
2
3
2
Scheme 3. Reagents and conditions: (a) Pd(PPh , benzene, rt, 58%; (b) AgNO
3
)
4
, CuI, n-PrNH
2
3 3 2 3 3
, CH OH, H O, NaCN, 0 °C; (c) MeCOCl, CH OH, 0 °C to rt.; (d) Zn(Cu/Ag), CH OH,
+
H
2
O, 50 °C; (e) 1 N LiOH, H O, CH OH, 0 °C, then H (NaH PO saturated), 79%.
2
3
2 4

1
914
A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 1912–1915
7. Serhan, C. N.; Petasis, N. A. Chem. Rev. 2011, 111, 5922–5943.
The chiral key intermediate 3 was obtained from 1-(trimethyl-
silyl)-1-pentyn-3-one (10)36 via a transfer hydrogenation with the
Noyori RuCl[(R,R)-TsDPEN](p-cymene) precatalyst (0.035 equiv) as
8.
de Souza, P. M.; Newson, J.; Gilroy, D. W. Chem. Biol. 2006, 13, 1121–1122.
Tjonahen, E.; Oh, S. F.; Siegelman, J.; Elangovan, S.; Percarpio, K. B.; Hong, S.;
Arita, M.; Serhan, C. N. Chem. Biol. 2006, 13, 1193–1202.
9.
outlined in Scheme 2. The asymmetric reduction was carried out in
10. Bannenberg, G.; Serhan, C. N. Biochim. Biophys. Acta 2010, 1801, 1260–1273.
11. Xu, Z. Z.; Zhang, L.; Liu, T.; Park, J. Y.; Berta, T.; Yang, R.; Serhan, C. N.; Ji, R. R.
Nat. Med. 2010, 16, 592–597.
2
H O, as described above for 6, producing the chiral intermediate 11
in a fast reaction with >93.7% ee as determined by chiral HPLC
12. Spite, M.; Norling, L. V.; Summers, L.; Yang, R.; Cooper, D.; Petasis, N. A.; Flower,
R. J.; Perretti, M.; Serhan, C. N. Nature 2009, 461, 1287–1291.
[
Chiracel OF, hexane/i-PrOH 99.7:0.3, 1.5 mL/min, 210 nm,
= 9.7 min (S-isomer) and t = 11.2 min (R-isomer, 11)]. The same
13. Serhan, C. N.; Chiang, N.; Van Dyke, T. E. Nat. Rev. Immunol. 2008, 8, 349–361.
14. Serhan, C. N.; Lu, Y.; Hong, S.; Yang, R. Methods Enzymol. 2007, 432, 275–317.
15. Yacoubian, S.; Serhan, C. N. Nat. Clin. Pract. Rheumatol. 2007, 3, 570–579.
t
R
R
reduction could be carried out in i-PrOH but the active Noyori cat-
alyst had to be used, in addition to carefully controlled conditions
16. Serhan, C. N.; Savill, J. Nat. Immunol. 2005, 6, 1191–1197.
17. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717–8720.
and longer reaction times, to obtain a higher ee.36 Protection of 11
1
1
8. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2005, 46, 3623–3627.
9. Ogawa, S.; Urabe, D.; Yokokura, Y.; Arai, H.; Arita, M.; Inoue, M. Org. Lett. 2009,
11, 3602–3605.
with TBSCl in DMF at 0 °C to rt produced the silyl ether derivatives
1
2 in an 84% combined yield (two-steps). TMS desilylation using
followed by NaCN work-up gave 13.3
7,38
Hydrostannylation
20. Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2009, 50, 6079–6082.
21. Kosaki, Y.; Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2010, 51, 1856–1859.
22. Sasaki, K.; Urabe, D.; Arai, H.; Arita, M.; Inoue, M. Chem. Asian J. 2011, 6, 534–
543.
AgNO
3
of 13 with excess tributyltin hydride at 130 °C in the presence of a
catalytic amount of AIBN produced the trans-vinyl tin compound
1
4 in an 84% yield. The tin-iodine exchange was accomplished by
treating 14 with an ether solution of iodine at 0 °C. Work-up with
sat. Na followed by flash chromatography gave the key inter-
mediate 3.
23. Allard, M.; Barnes, K.; Chen, X.; Cheung, Y.-Y.; Duffy, B.; Heap, C.; Inthavongsay,
J.; Johnson, M.; Krishnamoorthy, R.; Manley, C.; Steffke, S.; Varughese, D.;
Wang, R.; Wang, Y.; Schwartz, C. E. Tetrahedron Lett. 2011, 52, 2623–2626.
2 2
S O
3
24. Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2011, 52, 3001–3004.
25. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2012, 53, 86–89.
2
2
6. Wu, X.; Wang, C.; Xiao, J. Platinum Metals Rev. 2010, 54, 3–19.
7. Wu, X.; Li, X.; Zanotti-Gerosa, A.; Pettman, A.; Liu, J.; Mills, A. J.; Xiao, J. Chem.
Eur. J. 2008, 14, 2209–2222.
We have recently described the synthesis of the C8–C15 frag-
ment 4 in two-steps by CuI catalyzed coupling of cis-1,4-dibro-
mo-2-butene with excess trimethylsilyl acetylene followed by
28. Li, X.; Wu, X.; Chen, W.; Hancock, F. E.; King, F.; Xiao, J. Org. Lett. 2004, 6, 3321–
catalyzed monodesilylation.25
3324.
AgNO
3
2
3
9. Wu, X.; Li, X.; King, F.; Xiao, J. Angew. Chem., Int. Ed. 2005, 44, 3407–3411.
0. Nicolaou, K. C.; Zipkin, R. E.; Dolle, R. E.; Harris, B. D. J. Am. Chem. Soc. 1984, 106,
3548–3551.
The skeleton of RvE2 was assembled from the key intermediates
0
I
2, 3, and 4 as outlined in Scheme 3. Pd /Cu Sonogashira coupling of
39
31. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119,
738–8739.
2. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022.
33. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.; Lee, T. H. Tetrahedron Lett.
000, 41, 823–826.
3
with 4 produced compound 15 (58%). Desilylation using AgNO
3
8
followed by NaCN work-up gave 16, that was used without further
purification in the second Sonogashira coupling with 2 to give the
diacetylene precursor of RvE2 methyl ester (17).
The synthesis was completed via deprotection of the TBS groups
of compound 17 with catalytic HCl, generated in situ from acetyl
chloride in absolute methanol at 0 °C to rt, to give 18. Zn(Cu/Ag)
3
2
3
3
4. Edelson, B. S.; Stoltz, B. M.; Corey, E. J. Tetrahedron Lett. 1999, 40, 6729–6730.
5. Harrowven, D. C.; Curran, D. P.; Kostiuk, S. L.; Wallis-Guy, I. L.; Whiting, S.;
Stenning, K. J.; Tang, B.; Packard, E.; Nanson, L. Chem. Commun. 2010, 46, 6335–
6337.
36. Krishnamurthy, V. R.; Dougherty, A.; Haller, C. A.; Chaikof, E. L. J. Org. Chem.
3 2
reduction of 18 in CH OH/H O at 50 °C (16 h) produced cleanly
2011, 76, 5433–5437.
4
0,41
RvE2 methyl ester (19).
LiOH in CH OH/H O at 0 °C followed by acidification with sat.
NaH PO in the presence of ethyl acetate gave RvE2 (1). The
and C NMR spectra and the specific rotation were in accordance
with those reported.
In summary, a concise total synthesis of RvE2 has been
achieved, making this anti-inflammatory lipid mediator from
eicosapentaenoic acid available for further biological and pharma-
cological testing. The synthesis of other Resolvins, Maresin, and
Neuroprotectin D1 will be reported in due course.
Mild alkaline hydrolysis of 19 with
37. Nicolaou, K. C.; Veale, C. A.; Webber, S. E.; Katerinopoulos, H. J. Am. Chem. Soc.
1985, 107, 7515–7518.
3
2
1
38. Yamamoto, Y. Chem. Rev. 2008, 108, 3199–3222.
2
1
4
H
3
4
9. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–4470.
0. Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. Helv. Chim. Acta 1987, 70, 1025–
1040.
3
1
9,21
4
4
1. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2001, 42, 6057–6060.
2. Satisfactory spectroscopic data were obtained for all compounds. Selected
4
2
25
43
19
physical data: Compound 6: ½
a
ꢀ
= ꢁ6.0 (c 2.1, CHCl
3
) [lit.
½
a
ꢀ
= ꢁ6.4 (c 1.4,
D
D
1
CH
2 2 3
Cl )]. H NMR (CDCl , 300 MHz): d 4.4–4.3 (m, 1H), 3.6 (s, 3H), 2.4–2.3 (t,
13
J = 7.0 Hz, 2H), 1.9 (br s, 1H), 1.8–1.6 (m, 4H), 0.2 (s, 9H); C NMR (CDCl
3
,
7
5.5 MHz): d 173.84, 106.36, 89.71, 62.40, 51.52, 36.93, 33.55, 20.55, ꢁ0.17
3C). Compound 7: 1H NMR (CDCl
(
3
, 300 MHz): d 4.4–4.3 (m, 1H), 3.6 (s, 3H),
.5–2.4 (d, J = 2.1 Hz, 1H), 2.4–2.3 (t, J = 7.0 Hz, 2H), 2.2–2.1 (br s, 1H), 1.9–1.6
, 75.5 MHz): d 173.80, 84.63, 73.09, 61.86, 51.48,
2
(
m, 4H); 13C NMR (CDCl
3
Acknowledgments
1
3
36.91, 33.55, 20.46. Compound 8: H NMR (CDCl , 300 MHz): d 4.4–4.3 (td,
J = 6.0, 2.1 Hz, 1H), 3.6 (s, 3H), 2.4–2.3 (d, J = 2.1 Hz, 1H), 2.3 (t, J = 7.2 Hz, 2H),
1.8–1.6 (m, 4H), 0.9 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3,
Financial support of this research by the DOD (AS073084P1);
the Governor’s Council on Autism, and the Office of Patent &
Licensing UMDNJ-UMDNJ Foundation is gratefully acknowledged.
75.5 MHz): d 173.80, 85.21, 72.29, 62.40, 51.42, 37.79, 33.68, 25.75 (3C), 20.62,
1
1
8.17, ꢁ4.58, ꢁ5.10. Compound 9:
3
H NMR (CDCl , 300 MHz): d 6.0 (d,
J = 19.0 Hz, 1H), 5.9 (dd, J = 19.0, 5.7 Hz, 1H), 4.1–4.0 (br q, J = 5.7 Hz, 1H), 3.6 (s,
3
0
5
9
H), 2.3 (t, J = 7.3 Hz, 2H), 1.7–1.2 (m, 16H), 1.0–0.8 (m, 15H), 0.9 (s, 9H), 0.1–
.0 (2s, 6H); 13C NMR (CDCl
, 75.5 MHz): d 173.95, 151.56, 127.15, 76.34,
1.27, 37.44, 34.14, 29.13 (3C), 27.21 (3C), 25.94 (3C), 20.89, 18.29, 13.60 (3C),
Supplementary data
3
1
.56 (3C), ꢁ4.25, ꢁ4.76. Compound 2: H NMR (CDCl
3
, 300 MHz): d 6.5–6.4 (dd,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.136.
J = 14.4, 6.0 Hz, 1H), 6.2 (dd, J = 14.4, 1.2 Hz, 1H), 4.1–4.0 (qd, J = 6.0, 1.2 Hz,
1
0
3
H), 3.6 (s, 3H), 2.3 (t, J = 7.3 Hz, 2H), 1.7–1.4 (m, 4H), 0.86 (s, 9H), 0.02 (s, 3H),
.00 (s, 3H); 13C NMR (CDCl
6.78, 33.87, 25.79 (3C), 20.27, 18.15, ꢁ4.55, ꢁ4.92. Compound 11: ½
, 75.5 MHz): d 173.73, 148.81, 75.94, 74.76, 51.42,
3
2
5
a
ꢀ
= +5.2
D
36
19
D
1
References and notes
(c 1.0, CHCl ) [lit.
½aꢀ
3 3
= +6.0 (c 2.0, CHCl )]. H NMR (CDCl , 300 MHz): d 4.3
13
3
(
t, J = 6.4 Hz, 1H), 1.8–1.6 (m, 3H), 1.0 (t, J = 7.5 Hz, 3H), 0.15 (s, 9H); C NMR
1
2
3
4
.
.
.
.
Barnes, P. J. Nat. Rev. Immunol. 2008, 8, 183–192.
Tabas, I. Nat. Rev. Immunol. 2010, 10, 36–46.
(CDCl
3
, 75.5 MHz): d 106.69, 89.44, 64.15, 30.83, 9.32, ꢁ0.13 (3C). Compound
12: 1H NMR (CDCl
, 300 MHz): d 4.3–4.2 (t, J = 6.4 Hz, 1H), 1.7–1.6 (m, 2H), 1.0–
3
13
Calder, P. C. Am. J. Clin. Nutr. 2006, 83, 1505S–1519S.
Massaro, M.; Scoditti, E.; Carluccio, M. A.; Campana, M. C.; De Caterina, R. Cell
Mol. Biol. 2010, 56, 59–82.
Lee, T. H.; Hoover, R. L.; Williams, J. D.; Sperling, R. I.; Ravalese, J.; Spur, B. W.;
Robinson, D. R.; Corey, E. J.; Lewis, R. A.; Austen, K. F. N. Engl. J. Med. 1985, 312,
0.9 (t, J = 7.5 Hz, 3H), 0.9 (s, 9H), 0.13 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); C NMR
(CDCl
, 75.5 MHz): d 107.82, 88.39, 64.74, 31.68, 25.84 (3C), 18.30, 9.65, ꢁ0.15
(3C), ꢁ4.47, ꢁ4.90. Compound 13: H NMR (CDCl
J = 6.3, 2.1 Hz, 1H), 2.4–2.3 (d, J = 2.1 Hz, 1H), 1.8–1.6 (m, 2H), 1.0–0.9 (t,
J = 7.5 Hz, 3H), 0.9 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); 13C NMR (CDCl
, 75.5 MHz):
d 85.61, 71.84, 64.07, 31.73, 25.79 (3C), 18.23, 9.43, ꢁ4.58, ꢁ5.05. Compound 3:
3
1
3
, 300 MHz): d 4.3–4.2 (td,
5
.
.
3
1
217–1224.
1
6
Serhan, C. N.; Hong, S.; Gronert, K.; Colgan, S. P.; Devchand, P. R.; Mirick, G.;
Moussignac, R. L. J. Exp. Med. 2002, 196, 1025–1037.
H NMR (CDCl
3
, 300 MHz): d 6.5 (dd, J = 14.4, 6.0 Hz, 1H), 6.2 (dd, J = 14.4,
1.2 Hz, 1H), 4.0 (qd, J = 6.0, 1.2 Hz, 1H), 1.6–1.4 (m, 2H), 0.9 (s, 9H), 0.9–0.8 (t,

A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 1912–1915
J = 7.5 Hz, 3H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl (t, J = 7.5 Hz, 3H); 13C NMR (CDCl
, 75.5 MHz): d 149.12,
1915
3
3
, 75.5 MHz): d 173.86, 144.58, 144.34, 126.17,
126.07, 110.59, 110.39, 88.37, 88.06, 78.74, 78.61, 73.63, 71.86, 51.44, 36.33,
1
7
6.28, 75.46, 30.38, 25.83 (3C), 18.22, 9.12, ꢁ4.57, ꢁ4.88. Compound 15:
H
1
NMR (CDCl
3
, 300 MHz): d 6.0 (dd, J = 15.9, 5.4 Hz, 1H), 5.7–5.5 (m, 1H), 5.6–5.4
33.78, 29.96, 20.68, 17.86 (2C), 9.43. Compound 19:
3
H NMR (CD CN,
(
m, 2H), 4.1–4.0 (m, 1H), 3.1–2.9 (m, 4H), 1.6–1.4 (m, 2H), 0.9 (s, 9H), 0.9–0.8 (t,
300 MHz): d 6.7–6.5 (dd, J = 15.3, 11.1 Hz, 2H), 6.1–5.9 (br t, J = 10.8 Hz, 2H),
5.8–5.6 (2 dd, J = 15.3, 6.3 Hz, 2H), 5.5–5.3 (m, 4H), 4.2–4.1 (m, 1H), 4.1–4.0 (m,
1H), 3.6 (s, 3H), 3.2 (br d, J = 4.8 Hz, 1H), 3.1 (br d, J = 4.5 Hz, 1H), 3.1–2.9 (m,
4H), 2.4–2.3 (t, J = 7.5 Hz, 2H), 1.8–1.4 (m, 6H), 0.9 (t, J = 7.5 Hz, 3H); C NMR
3
(CD CN, 75.5 MHz): d 174.90, 138.55, 138.47, 130.50, 130.30, 129.40, 129.31,
1
3
J = 7.5 Hz, 3H), 0.1 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H); C NMR (CDCl
d 145.40, 126.39, 125.89, 109.11, 104.38, 87.38, 84.87, 79.08, 73.82, 30.80,
3
, 75.5 MHz):
1
13
2
5.91 (3C), 18.41, 18.25, 17.96, 9.16, 0.07 (3C), ꢁ4.45, ꢁ4.80. Compound 16:
NMR (CDCl , 300 MHz): d 6.0 (dd, J = 15.9, 5.4 Hz, 1H), 5.7–5.4 (m, 3H), 4.1–4.0
m, 1H), 3.1–2.9 (m, 4H), 2.0–1.9 (t, J = 2.7 Hz, 1H), 1.6–1.4 (m, 2H), 0.9 (s, 9H),
H
3
(
129.09, 129.04, 125.67, 125.63, 74.00, 72.27, 51.93, 37.59, 34.52, 31.21, 26.88
1
3
25
21
21
0
.9–0.8 (t, J = 7.5 Hz, 3H), 0.02 (s, 3H), 0.00 (s, 3H); C NMR (CDCl
3
, 75.5 MHz):
(2C), 21.87, 10.10. Compound 1: ½
a
ꢀ
= –3 (c 0.23, CH
3
OH) [lit.
½
a
ꢀ
= –4 (c
D
D
OH), lit.19
½aꢀ
24
D
= –2.1 (c 0.25, CH
OH)]. 1H NMR (CD
OD, 300 yMHz):
d 145.49, 126.55, 125.59, 108.91, 87.17, 81.94, 79.09, 73.71, 68.42, 30.73, 25.87
(
0.056, CH
3
3
3
1
3C), 18.23, 17.87, 16.88, 9.22, ꢁ4.49, ꢁ4.85. Compound 17: H NMR (CDCl
3
,
d 6.7–6.5 (2 ddt, J = 15.3, 11.1, 1.2 Hz, 2H), 6.1–5.9 (br t, J = 11.1 Hz, 2H), 5.7–5.6
(2 dd, J = 15.3, 6.8 Hz, 2H), 5.5–5.3 (m, 4H), 4.2–4.1 (m, 1H), 4.1–4.0 (m, 1H),
3
1
1
0
1
3
00 MHz): d 6.1–5.9 (2 dd, J = 15.9, 6.0 Hz, 2H), 5.7–5.4 (m, 4H), 4.2–4.1 (m,
H), 4.1–4.0 (m, 1H), 3.6 (s, 3H), 3.1–3.0 (m, 4H), 2.3–2.2 (t, J = 7.5 Hz, 2H), 1.7–
.5 (m, 2H), 1.6–1.4 (m, 4H), 0.87 (s, 9H), 0.86 (s, 9H), 0.9–0.8 (t, J = 7.5 Hz, 3H),
3.1–2.9 (m, 4H), 2.3 (t, J = 7.2 Hz, 2H), 1.8–1.4 (m, 6H), 0.9 (t, J = 7.5 Hz, 3H); 13
C
3
NMR (CD OD, 75.5 MHz): d 177.42, 137.71 (2C), 130.64, 130.47, 129.47,
1
3
3
.02 (s, 6H), 0.00 (s, 6H); C NMR (CDCl , 75.5 MHz): d 173.80, 145.40, 145.02,
129.41, 129.12 (2C), 126.38 (2C), 74.68, 72.90, 37.77, 34.84, 31.22, 26.99 (2C),
26.17, 126.05, 109.42, 109.02, 87.75, 87.37, 79.05, 78.85, 73.76, 72.29, 51.35,
22.19, 10.12. UV (EtOH)
k
max 232 nm. HPLC/API-ES/MS [Hypersil-ODS,
7.26, 34.03, 30.76, 25.88 (6C), 20.42, 18.22, 18.18, 17.90 (2C), 9.18, ꢁ4.44,
100 ꢂ 2.1 mm, CH OH/H
3
2
O 65+ /35 (0.1% formic acid), 0.2 mL/min,
1
ꢁ
4.47, ꢁ4.83 (2C). Compound 18: H NMR (CDCl
3
, 300 MHz): d 6.1–6.0 (2 dd,
R
t = 5.1 min] (m/z): 357.3 [M+Na] .
J = 15.9, 6.3 Hz, 2H), 5.7–5.6 (m, 2H), 5.6–5.5 (m, 2H), 4.2–4.1 (m, 1H), 4.1–4.0
m, 1H), 3.6 (s, 3H), 3.1–3.0 (m, 4H), 2.3 (t, J = 7.5 Hz, 2H), 1.8–1.4 (m, 6H), 0.9
43. Gueugnot, S.; Alami, M.; Linstrumelle, G.; Mambu, L.; Petit, Y.; Larchevêque, M.
(
Tetrahedron 1996, 52, 6635–6646.