A new approach to the synthesis of polyunsaturated deuterated isoprostanes: Total synthesis of d4-5-epi-8,12-iso-iPF3α-VI and d4-8,12-iso-iPF3α-VI

Article abstract of DOI:10.1016/j.bmcl.2009.09.099

The total and stereospecific synthesis of d₄-5-epi-8,12-iso-iPF_3α-VI 55 and d₄-8,12-iso-iPF_3α-VI 64, EPA-derived all-syn-isoprostanes (iPs), has been accomplished. Because of issues related to volatility and yie

Full text of DOI:10.1016/j.bmcl.2009.09.099

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6755–6758
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A new approach to the synthesis of polyunsaturated deuterated
isoprostanes: Total synthesis of d4-5-epi-8,12-iso-iPF3 -VI and
a
d4-8,12-iso-iPF3 -VI
a
Chih-Tsung Chang a, Pranav Patel a, Vivek Gore a, Wen-Liang Song b, John A. Lawson b, William S. Powell c,
Garret A. FitzGerald b, Joshua Rokach a,
*
a Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 W. University Blvd., Melbourne, FL 32901, USA
b Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
c Meakins-Christie Laboratories, Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, QC, Canada H2X 2P2
a r t i c l e i n f o
a b s t r a c t
Article history:
The total and stereospecific synthesis of d4-5-epi-8,12-iso-iPF3 -VI 55 and d4-8,12-iso-iPF3 -VI 64, EPA-
a
a
Received 26 August 2009
Revised 24 September 2009
Accepted 25 September 2009
Available online 29 September 2009
derived all-syn-isoprostanes (iPs), has been accomplished. Because of issues related to volatility and yield
with some of the primary deuterated synthons an improved synthesis is presented. These two deuterated
analogs were used to discover and quantify the presence of the corresponding endogenous isoprostanes
in human urine. These assays may serve as a valuable index of oxidative stress in population with omega-
3 fatty acid enriched diets containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and
may also be useful as an index of the severity of inflammatory diseases such as atherosclerosis and Alz-
heimer’s disease.
Keywords:
Eicosapentaenoic acid
EPA
Ó 2009 Elsevier Ltd. All rights reserved.
Docosahexaenoic acid
DHA
Arachidonic acid
AA
Isoprostane
iP
Deuterated isoprostanes
Isoprostanes (iPs) are natural products of non-enzymatic free
radical peroxidation of polyunsaturated fatty acids (PUFAs) such
as arachidonic acid (AA) and eicosapentaenoic acid (EPA).1,2 Iso-
prostanes are isomeric with prostaglandins (PGs), which are
natural products generated by the action of enzymes. The mecha-
nisms of formation of isoprostanes have been discussed in some
detail.3–5 Several syntheses of iPs have been reported.3,6 These
compounds have been widely used as markers of oxidative stress
in various diseases. We and others have shown that the measure-
ment of iPs in urine can be used as an index of the severity of
inflammatory diseases such as Alzheimer’s disease (AD) and
atherosclerosis.2,7
synthesized these two all-syn Group VI isoprostanes and identified
their occurrence in human urine.13 The reason for choosing Group
VI isoprostanes derived from EPA stems from our experience that
the presence of a hydroxyl group in the 5-position of these iPs causes
them to be resistant to b-oxidation,8 facilitating their detection in
urine. For example, we have shown that iPF3 -VI is highly resistant
a
to b-oxidation and we have been able to detect appreciable amounts
of this substance in human urine.8 Recent studies from our labora-
tory suggest that 5-epi-8,12-iso-iPF3 -VI 24 and 8,12-iso-iPF3 -VI
a
a
25 are considerably more abundant in urine than iPF3 -VI and may
a
therefore serve as excellent markers for oxidative stress involving
degenerative diseases of the brain, which contains high levels of
Isoprostanes generated from EPA have received less attention
than AA-derived isoprostanes.8,9 However, the AA-derived iPs we
and others have measured so far as an index of oxidative stress10–12
may not be appropriate for individuals in which the major PUFAs
in the phospholipids are EPA and DHA. A more appropriate index in
these cases might be the measurement of EPA- and/or DHA-derived
iPs, for example, 24 and 25 (Scheme 2A). For these reasons we have
DHA, as well as in individuals who consume large amounts of x3-
PUFA. To provide the deuterium-labeled standards required for the
quantitation of these major EPA-derived iPs in biological fluids14
we are reporting here the total synthesis of deuterated analogs of
24 and 25, namely d4-5-epi-8,12-iso-iPF3 -VI 55 and d4-8,12-iso-
a
iPF3 -VI 64 (Scheme 4).
a
Site of deuteration: We have previously developed methods to
introduce four deuterium atoms into the lower side chains of iPs,
as this would avoid the loss of deuterium as a result of b-oxidation.
Although this is much less of an issue with Group VI iPs, as
* Corresponding author.
E-mail address: jrokach@fit.edu (J. Rokach).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.099

6756
C.-T. Chang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6755–6758
CO2H
CO2H
CO2H
O2
CO2H
22
1
2
AA
EPA
3
DHA
OH
OH
CO2H
COOH
Group I
Group II
O2
CO2H
23
O
O
8
14
OH
OH
OH
OH
OH
OH
OH
OH
COOH
CO2H
9
15
CO2H
16
OH
OH
OH
OH
OH
CO2H
CO2H
Group III
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
4
OH
OH
10
CO2H
CO2H
CO2H
Group IV
Group V
Group VI
OH
OH
11
OH
OH
OH
OH
5
17
CO2H
CO2H
CO2H
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
6
12
18
OH
HO
CO2H
CO2H
CO2H
CO2H
HO
OH
13
OH
Group VI
OH
OH
7
19
13
CO2H
Group VII
Group VIII
OH
OH
OH
OH
20
21
CO2H
OH
Scheme 1. iPs and nPs derived from AA, EPA, and DHA by free radical peroxidation.
cause of the presence of the
elected to introduce four deuterium atoms in positions 19 and 20
of these molecules.
x3-double bond in 24 and 25, we
OH
OH
HO
HO
HO
HO
CO2H
CO2H
Synthesis: The most difficult step in our prior synthesis of tetra-
deutero iPF4 -VI was the isolation of deuterated propanol 32
a
(Scheme 3).15 The continuation of the synthesis to obtain derivative
38 was impractical at that point because of the dwindling yields due
to the multistep synthesis. We elected at that time to redesign the
synthesis by extending the isoprostane synthon by three additional
carbons and reacting it with deuterated synthon 35.15 This was
hardly a fruitful alternative since the isoprostane synthon requires
a multistep synthesis, making the synthesis completely linear rather
than convergent, which was our original intention.
8,12-iso-iPF3α−VI 25
5-epi-8,12-iso-iPF3α−VI 24
Scheme 2. Structures of the major EPA-derived iPs 5-epi-8,12-iso-iPF3 -VI and
a
8,12-iso-iPF3 -VI.
a
discussed above, there is an additional advantage in avoiding the
addition of deuterium to the upper side chain due to the risk of
scrambling in the synthetic oxo precursors of this side chain. Be-
D
D
D
D
D
D
I
OTs
D
D
a
c
e
d
a)
b
D
D
D
D
TsO
Ph3P
Ph3P
HO
D
THPO
THPO
D
D
D
D
D
32
D
35
D
30
31
33
34
b)
D
D
D
D
D
D
I
Ph3P
g
D
D
D
D
D
f
CHO
h
TBDMSO
HO
TsO
TBDMSO
d
D
D
D
D
D
D
D
38
37
36
39
35
D
D
I
OTs
Ph3P
e
Ph3P
D
D
D
D
41
40
Scheme 3. Synthesis of deuterated side chain. Reagents and conditions: (a) Wilkinson’s catalyst, benzene, D2, 97%; (b) Me2AlCl, CH2Cl2, À25 °C to rt, 8 h; (c) TsCl, pyridine,
CH2Cl2, 0 °C to rt, 6 h, 75% (two steps); (d) PPh3, CH3CN, 70 °C, 96%; (e) NaI, CH3CN, rt, 97%; (b) (f) KHMDS, THF, À90 °C to rt, 85%; (g) 1 N HCl, THF, rt; (h) TsCl, pyridine, CH2Cl2,
rt, 6 h, 80% (two steps).

C.-T. Chang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6755–6758
6757
48
CO CH
2
OTBDMS
OTBDMS
CO CH
3
HO
O
N
N
TESO
O
a)
N
N
TESO
TESO
O
O
S
3
OH
2
N
N
OHC
S
i-k
N
l
N
O
m
n
O
49
O
O
O
O
45
47
46
OTBDMS
TESO
TESO
OTBDMS
OTBDMS
TESO
CO CH
2
3
TESO
q
CO CH
p
2
3
CO CH
2
3
o
CHO
D
D
I
OH
D
OTES
OH
50
51
HO
TESO
HO
Ph3P
52
D
41
OTBDMS
CO CH
TESO
CO H
2
2
3
r-s
D
D
D
D
HO
TESO
D
D
D
D
55
54
d4-5-epi-8,12-iso-iPF3α -VI
b)
v
TESO
O
TESO
O
CHO
TESO
TESO
OTES
CO2CH3
w
u
t
CO2CH3
O
O
O
O
P
CO2CH3
O
O
O
O
56
MeO
60
57
58
59
OMe
O
O
D
OTBDMS
CO CH
OH
OTBDMS
CO CH
TESO
OH
HO
HO
TESO
TESO
CO H
2
2
3
CO CH
2
3
2
3
n-p
q-s
D
D
x
D
CHO
O
TESO
D
D
O
I
61
64
O
O
62
Ph3P
63
d4-8,12-iso-iPF3α -VI
D
D
41
Scheme 4. Stereospecific synthesis of d4-5-epi-8,12-iso-iPF3 -VI 55 and d4-8,12-iso-iPF3 -VI 64. Reagents and conditions: (a) (i) TESCl, Et3N, DMAP, CH2Cl2, rt, 20 h, 98%; (j)
a
a
Wilkinson’s catalyst, catechol borane, THF, 0 °C to rt, overnight, 91%;16 (k) PT-SH, Ph3P, DIAD, THF, 0 °C to rt, 4.5 h, 97%; (l) m-CPBA, NaHCO3, CH2Cl2, rt, overnight, 96%; (m)
KHMDS, 48, DME, À60 °C to rt, 8 h, 52% (E:Z = 63:37), separated by silica gel chromatography; (n) NaBH4, ethylether/MeOH (2:1), rt, 35 min, 70%; (o) TESCl, Et3N, DMAP,
CH2Cl2, 20 h, 95%; (p) DMSO, (COCl)2, Et3N, CH2Cl2, À70 °C to À20 °C, 1.5 h; (q) LiHMDS, 41, THF, À78 °C to rt, 2 h, (two steps 73%); (r) TBAF, THF, rt, overnight; (s) LiOH, iPrOH/
H2O (1:1), rt, 4 h 93% (two steps); (b) (t) DMSO, (COCl)2, Et3N, CH2Cl2, À70 °C to À20 °C, 1.5 h; (u) LiHMDS, 48, THF, À78 °C to rt, 2 h, (59, 8.4%, 60, 73%) (80% after I2
treatment); (v) I2, CH2Cl2, rt, 15 h, 87%; (w) EtOH, LiAlH4, (S)-Binal-H, THF, À100 °C, 45 min, 92%; (x) TBDMSCl, Et3N, DMAP, CH2Cl2, rt, overnight, 85%.
OH
OH
OH
HO
OH
HO
HO
HO
HO
HO
COOH
Acyl-CoA
COOH
2,4-Dienoyl-CoA
COOH
Enoyl-CoA
COOH
24
HO
β-oxidation
Dehydrogenase HO
65
Isomerase
reductase
66
68
67
7-epi-10,14-iso-nPF4α-VI
Scheme 5. b-Oxidation of neuroprostane to EPA-derived isoprostane.
In the present study we circumvented the volatility issue in two
ways. We used a non-volatile tosylate intermediate and a very effi-
cient procedure to convert a tosylate phosphonium salt into an io-
dide derivative, as the use of the phosphonium tosylate by itself
results in low yields in a Wittig reaction. Transformation of tosyl-
ate salts 34 and 40 to iodides 35 and 41, respectively, proceeds in
quantitative yields. We were surprised to note that the literature
does not contain examples of such transformations. This can be a
useful general procedure to deal with deuterium labeled small
molecules.
Scheme 3 describes the synthesis of the deuterated side chain,
which was subsequently connected to the 5-membered all-syn iso-
prostane ring. Using commercial propargyl alcohol as our starting
material, the alcohol was protected using THP. The acetylene deriv-
ative 30 (Scheme 3) was then treated with Wilkinson’s catalyst in
the presence of deuterium gas to generate the deuterated interme-
diate 31, which on further treatment with dimethyl aluminum
chloride generated the low-boiling volatile three-carbon alcohol
32. Attempts to isolate this alcohol resulted in very low recovery.
The crude 32, which was used without purification or workup in
the next step, was treated with TsCl to generate tosylate 33. After
workup and purification, 33 was treated with triphenyl phosphine
in the presence of CH3CN to generate the phosphonium salt 34,
which was purified by column chromatography. We attempted to
react 34 with aldehyde 36 and obtained a low yield of the desired
product 37 (22–38%). By changing the tosylate to an iodide using
sodium iodide, we obtained the iodo phosphonium salt 35.17 This
was then used in a Wittig reaction with aldehyde 36 to obtain
the desired product in 85% isolated yield. A cursory look at the lit-
erature reveals that tosylate salts, when used in Wittig reactions,
afford low yields of the desired products. It is worth mentioning
that an attempt to prepare the tetradeutero propyl iodide from

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C.-T. Chang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6755–6758
5. Yin, H.; Havrilla, C. M.; Gao, L.; Morrow, J. D.; Porter, N. A. J. Biol. Chem. 2003,
278, 16720.
6. (a) Pudukulathan, Z.; Manna, S.; Hwang, S. W.; Khanapure, S. P.; Lawson, J. A.;
FitzGerald, G. A.; Rokach, J. J. Am. Chem. Soc. 1998, 120, 11953; (b) Jacobo, S. H.;
Chang, C. T.; Lee, G. J.; Lawson, J. A.; Powell, W. S.; Pratico, D.; FitzGerald, G. A.;
Rokach, J. J. Org. Chem. 2006, 71, 1370; (c) Taber, D. F.; Herr, R. J.; Gleave, D. M. J.
Org. Chem. 1997, 62, 194; (d) Taber, D. F.; Xu, M.; Hartnett, J. C. J. Am. Chem. Soc.
2002, 124, 13121; (e) Larock, R. C.; Lee, N. H. J. Am. Chem. Soc. 1991, 113, 7815;
(f) Zanoni, G.; Fabio, A.; Meriggi, A.; Vidari, G. Tetrahedron: Asymmetry 2001, 12,
1779; (g) Schrader, T. O.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 10998; (h)
Quan, L. G.; Cha, J. K. J. Am. Chem. Soc. 2002, 124, 12424; (i) Rodriguez, A. R.;
Spur, B. W. Tetrahedron Lett. 2002, 43, 4575; (j) Mulzer, J.; Czybowski, M.; Bats,
J. W. Tetrahedron Lett. 2001, 42, 2961.
7. Montine, T. J.; Neely, D. M.; Quinn, J. F.; Beal, F. M.; Markesbery, W. R.; Roberts,
L. J., II; Morrow, J. D. Free Radical Biol. Med. 2002, 33, 620.
8. Lawson, J. A.; Kim, S.; Powell, W. S.; FitzGerald, G. A.; Rokach, J. J. Lipid Res.
2006, 47, 2515.
9. Gao, L.; Yin, H.; Milne, G. L.; Porter, N. A.; Morrow, J. D. J. Biol. Chem. 2006, 281,
14092.
Figure 1. High Performance Liquid Chromatography: The UHPLC was performed
using an Accela solvent delivery system (Thermo, Waltham, MA) and a column of
Hypersil GOLD C18 (2) (200 mm  2.1 mm; 1.9
lm particle size column; Thermo).
The mobile phase consisted of water (solvent A) and acetonitrile:methanol (95:5,
10. Kadiiska, M. B.; Gladen, B. C.; Baird, D. D.; Germolec, D.; Graham, L. B.; Parker,
C. E.; Nyska, A.; Wachsman, J. T.; Ames, B. N.; Basu, S.; Brot, N.; FitzGerald, G. A.;
Floyd, R. A.; George, M.; Heinecke, J. W.; Hatch, G. E.; Hensley, K.; Lawson, J. A.;
Marnett, L. J.; Morrow, J. D.; Murray, D. M.; Plastaras, J.; Roberts, L. J., II; Rokach,
J.; Shigenaga, M. K.; Sohal, R. S.; Sun, J.; Tice, R. R.; VanThiel, D. H.; Wellner, D.;
Walter, P. B.; Tomer, K. B.; Mason, R. P.; Barrett, J. C. Free Radical Biol. Med. 2005,
38, 698.
11. Kadiiska, M. B.; Gladen, B. C.; Baird, D. D.; Graham, L. B.; Parker, C. E.; Ames, B.
N.; Basu, S.; FitzGerald, G. A.; Lawson, J. A.; Marnett, L. J.; Morrow, J. D.; Murray,
D. M.; Plastaras, J.; Roberts, L. J., II; Rokach, J.; Shigenaga, M. K.; Sun, J.; Walter,
P. B.; Tomer, K. B.; Barrett, J. C.; Mason, R. P. Free Radical Biol. Med. 2005, 38,
711.
solvent B), both with 0.005% acetic acid adjusted to pH 5.7 with ammonium
hydroxide. The flow rate was 350
solvent gradient programs.
ll/min. The separations involved various linear
32 resulted in very low yield of the iodo derivative, probably due to
volatility problems. As shown in Scheme 3, phosphonium salt 41
was prepared in good yield by a similar sequence (Panel B). Scheme
4 describes the stereospecific synthesis of d4-5-epi-8,12-iso-iPF3
-
a
VI 55 and d4-8,12-iso-iPF3 -VI 64.18 For reasons of clarity we have
a
included the first few structures, which we have previously dis-
closed.15 Step u, Scheme 4B afforded in addition to the desired
product 60, 8–9% of the cis derivative 59. The isomerization proce-
dure works well also on the crude mixture and no special purifica-
tion and isolation of 59 is necessary. The transformation of bis-TES
56 to a TES aldehyde 57 was accomplished in high yields using
Spur’s procedure.19
Metabolism: The iPs 24 and 25 (Scheme 2) can be formed by the
direct autooxidation of EPA as shown in Scheme 1. Alternatively,
these iPs can be formed as a result of b-oxidation of DHA-derived
neuroprostanes (nPs) as shown in Scheme 5, which we have previ-
ously demonstrated in the case of isomers of 65.8 Furthermore we
and others have shown the DHA-derived nPs could not be detected
in urine, a fact we interpreted as being due to b-oxidation.8,9 Since
iPs such as 24 and 25 are resistant to b-oxidation we were readily
able to measure them in urine. Hence the measurement of 24 and
25, which we have accomplished in human and murine urine,14 is
an indication of the in vivo formation of either or both EPA-derived
iPs and DHA-derived nPs that have been converted to the corre-
sponding C20 derivatives by endogenous b-oxidation. Figure 1 shows
LC/MS/MS chromatogram of tetradeutero isoprostones 55 and 64.
12. Praticò, D.; Rokach, J.; Lawson, J.; FitzGerald, G. A. Chem. Phys. Lipids 2004, 128,
165.
13. Chang, C. T.; Patel, P.; Kang, N.; Lawson, J. A.; Song, W. L.; Powell, W. S.;
FitzGerald, G. A.; Rokach, J. Bioorg. Med. Chem. Lett. 2008, 18, 5523.
14. Song, W. L.; Paschos, G.; Fries, S.; Reilly, M. P.; Rokach, J.; Chang, C. T.; Patel, P.;
Lawson, J. A.; FitzGerald, G. A. J. Biol. Chem. 2009, 284, 23636.
15. Kim, S.; Lawson, J. A.; Praticò, D.; FitzGerald, G. A.; Rokach, J. Tetrahedron Lett.
2002, 43, 2801.
16. Patel, P.; Chang, C. T.; Kang, N.; Lee, G. J.; Powell, W. S.; Rokach, J. Tetrahedron
Lett. 2007, 48, 5289.
17. Experimental procedure for Scheme 3a: Step a: To the solution of acetylene 30
(4 g, 28.54 mmol) in 70 mL benzene was added 1 g of Wilkinson’s catalyst
(25 wt %) at room temperature. The mixture was purged with argon gas. The
deuterium gas was passed in the flask until deuterium gas absorption stopped.
The crude mixture was filtered through celite and florisil layers to afford the
desired deuterium product 31 in quantitative yields. Sometimes the
deuteration did not go to completion. In this case, the crude mixture was
filtered and the deuteration process repeated.Steps b and c: To the solution of
deuterium 31 (311 mg, 2.10 mmol) in CH2Cl2 (15 mL), Me2AlCl (6.29 mL,
6.29 mmol) was added dropwise at À25 °C and stirred for 30 min at À25 °C.
The reaction mixture was gradually allowed to reach room temperature and
the reaction continued for 12 h. After all the starting material was consumed
the reaction was quenched using aqueous saturated NaHCO3 solution at 0 °C.
The aqueous layer was extracted with CH2Cl2 and the organic layers combined
and dried using Na2SO4. The solvent was cautiously evaporated up to the point
where approximately 2 mL of CH2Cl2 was left inside the flask. The deuterium
compound 32 was used without further purification in the next step. To the
solution of crude alcohol 32, TsCl was added at 0 °C followed by pyridine and
stirred for 10 min. The reaction mixture was gradually allowed to reach room
temperature and the stirring continued for 12 h. The reaction was quenched by
adding water and extracted using CH2Cl2, then dried and purified by silica gel
chromatography to afford tosylate 33 in 75% combined yield.Step d: To the
solution of tosylate 33 (660 mg, 3 mmol) in 5 mL of CH3CN was added Ph3P
(3 g, 11.4 mmol) and the reaction was continued at 70 °C for 24 h. The solvent
was evaporated and the crude compound purified using silica gel column
chromatography to afford 34 in quantitative yields.Step e: To the solution of
the salt 34 (774 mg, 1.60 mmol) in 15 mL of CH3CN was added NaI (1.2 g,
8.05 mmol) at room temperature and stirred for 12 h. The solvent was
evaporated and the crude mixture purified using column chromatography to
afford the desired iodo salt 35 (683 mg) in 97% yield.
Acknowledgments
We wish to acknowledge the National Institutes of Health for
support under Grants HL-81873 (J.R.) and HL-62250 (G.A.F.). J.R.
also wishes to acknowledge the National Science Foundation for
the AMX-360 (CHE-90-13145) and Bruker 400 MHz (CHE-03-
42251) NMR instruments. G.A.F. is the McNeil Professor of Transla-
tional Medicine and Therapeutics. W.S.P. wishes to acknowledge
the Canadian Institutes of Health Research, grant number MOP-
6254, the Heart and Stroke Foundation of Quebec, and the J.R. Cos-
tello Memorial Research Fund. W.S. wishes to acknowledge the
AHA grant 09CRP2260567.
18. Spectral data of d4-5-epi-8,12-iso-iPF3 -VI 55: 1H NMR (methanol-d4, 400 MHz)
a
d 5.75 (1H, dd, J = 15.3, 10.6), 5.44–5.32 (2H, m), 5.28–5.13 (3H, m), 4.09–3.92
(3H, m), 2.72–2.64 (2H, m), 2.57–2.49 (1H, m), 2.36–2.27 (1H, m), 2.26–2.02
(4H, m), 1.77–1.68 (1H, m), 1.68–1.42 (5H, m), 0.81 (1H, s); 13C NMR
(methanol-d4, 100 MHz) d 177.59, 137.46, 132.48, 130.08, 129.60, 129.41,
128.69, 74.83, 73.09, 72.80, 52.03, 49.86, 43.49, 37.83, 35.13, 26.64, 25.10,
22.37, 13.90(m); spectral data of d4-8,12-iso-iPF3 -VI 64: 1H NMR (methanol-d4,
References and notes
a
400 MHz) d 5.72 (1H, dd, J = 15.4, 10.6), 5.47–5.132 (2H, m), 5.27–5.16 (3H, m),
4.05–3.96 (3H, m), 2.75–2.67 (2H, m), 2.56–2.52 (1H, m), 2.38–2.30 (1H, m),
2.22–1.99 (4H, m), 1.78–1.68 (1H, m), 1.63–1.36 (5H, m), 0.81 (1H, s); 13C NMR
(methanol-d4, 100 MHz) d 177.58, 137.62, 132.65, 131.11, 130.10, 129.59,
128.75, 74.97, 73.96, 72.93, 52.09, 48.63, 43.70, 37.74, 35.06, 26.81, 25.26,
22.41, 13.92 (m).
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