A divergent enantioselective synthesis of 9-J1-phytoprostane and 9-A1-phytoprostane methyl ester

Article abstract of DOI:10.1002/ejoc.201301703

The first syntheses of 9-J₁-phytoprostane and 9-A ₁-phytoprostane methyl ester were achieved enantioselectively using a divergent approach from a common intermediate sulfone 4. The divergence was accomplished using a sigmatropic rearrangement (swap protocol) to give sulfone 5 in 47% overall yield. The two upper side-chains, with a stereodefined E double bond, were installed using consolidated Julia-Lythgoe olefination reactions of sulfones 4 and 5, with the same enantiopure α-protected aldehyde 6. Copyright

Full text of DOI:10.1002/ejoc.201301703

FULL PAPER
DOI: 10.1002/ejoc.201301703
A Divergent Enantioselective Synthesis of 9-J1-Phytoprostane and
9-A1-Phytoprostane Methyl Ester
Alessio Porta,*[a] Francesco Chiesa,[a] Marco Quaroni,[a] Marco Persico,[b]
Remigio Moratti,[b] Giuseppe Zanoni,[a] and Giovanni Vidari[a]
Keywords: Total synthesis / Asymmetric synthesis / Olefination / Natural products / Phytoprostanes
The first syntheses of 9-J1-phytoprostane and 9-A1-phytopro-
stane methyl ester were achieved enantioselectively using a
divergent approach from a common intermediate sulfone 4.
The divergence was accomplished using a sigmatropic re-
arrangement (swap protocol) to give sulfone 5 in 47% overall
yield. The two upper side-chains, with a stereodefined E
double bond, were installed using consolidated
Julia–Lythgoe olefination reactions of sulfones 4 and 5, with
the same enantiopure α-protected aldehyde 6.
tanes is the absence of control of the absolute stereochemis-
try of the stereogenic centres of the cyclopentane ring and
the allylic hydroxy group. There are seven classes of phyto-
prostanes, which, in analogy to the prostaglandin no-
menclature system, have been named PPA1, PPB1, PPD1,
PPE1, PPF1, PPJ1, and PPL1, with the latter being the re-
gioisomer of PPB1.[2a] (Figure 1).
Introduction
Phytoprostanes (PhytoPs) are prostaglandin-like com-
pounds produced in plants by nonenzymatic free-radical
peroxidation of membrane-bound α-linolenic acid.[1] The
main differences between most PhytoPs chiefly and the
prostaglandins are in the lengths and the thermodynami-
cally less stable cis stereochemical relationship of the two
It should be pointed out that the compounds of each of
side-chains on the five-membered ring. Another important the classes of phytoprostanes have two possible regioiso-
feature of the nonenzymatic pathway to natural phytopros- mers, i.e., the 9 and 16 regioisomers, each of which com-
Figure 1. Representative phytoprostanes of the A1, B1, D1, E1, F1, J1, and L1 classes.
prises several stereoisomers due to the stereocentres of the
[a] Department of Chemistry, University of Pavia,
Viale Taramelli 10, 27100 Pavia, Italy
E-mail: aporta@unipv.it
prostanoid ring. Accordingly to the more recent proposed
phytoprostane nomenclature system, our synthetic targets
were 9-J1-PhytoP (1) and 9-A1-PhytoP (2),[2a,2b] which
correspond to PPA1-II and PPJ1-II, respectively, in an older
nomenclature system.[2c] Phytoprostane 9-J1-PhytoP (1) has
been detected in tobacco cell cultures after an induced oxi-
http://b2chem.unipv.it
[b] Foundation IRCCS San Matteo,
Viale Golgi 19, 27100 Pavia, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301703.
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A. Porta et al.
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dative stress, and also, in very low quantities, in tomato However, no synthesis of 9-J1-PhytoP or 9-A1-PhytoP has
plants infected with the necrotrophic fungus Botrytis ci- been reported in the literature to date.
nerea.[3] The isolation and characterization of 9-J1-PhytoP,
has also been claimed, but in fact, the reported spectro-
scopic data correspond to the respective dehydration prod-
Results and Discussion
uct. On the other hand, 9-A1-PhytoP (2) is too elusive to
have been isolated and characterized.[2a,4] A few biological
In this paper, we describe the first enantioselective diver-
activities have been attributed to cyclopentenone 9-J1-phy- gent synthesis of cyclopentenone phytoprostane 1 and the
toprostane (1) both in plants and in humans. For example, methyl ester of 2, starting from a common chiral building
In plants, 9-J1-PhytoP significantly activated the mitogen- block, namely the enantiopure hydroxymethyl γ-lactone
activated protein kinase in cell suspension of tomato cul- (–)-(3aS,4S,6aR)-3, which is available on a multigram
tures, and induced a high expression of the orthologous scale.[7] According to our retrosynthetic strategy
gene in tobacco. Moreover, 1 induced glutathione-S-trans- (Scheme 1), the upper side-chains (α side-chains) of phyto-
ferase 1 expression in Arabidopsis; this enzyme plays a key prostanes 1 and 2, with a stereodefined E double bond,
role in the detoxification of reactive electrophiles, thus trig- were installed by consolidated Julia–Lythgoe olefination re-
gering an adaptive response in plants and partially pre- actions of sulfones 4 and 5, respectively, with enantiopure
venting cell death.[5] In humans, J1-phytoprostanes show α-protected aldehyde 6.
significant anti-inflammatory activity in HEK 293 cells and
The S absolute stereochemistry of the alcohol in the α
RAW 264.7 macrophages, through the down-regulation of side-chain precursor 6 was secured by a regio- and stereo-
the NF-κB signalling pathway and the inhibition of nitric controlled nucleophilic oxirane ring-opening of (S)-glycidyl
oxide synthesis, respectively. In addition, 9-J1-PhytoP shows benzyl ether 8 by hept-6-ynoic acid TIPS ester 7. Sulfone 5
antitumor activity by inducing the apoptosis of leukaemia converged to sulfone 4 via cyclopentenyl aryl selenoether
Jukart T cells.[6] Considering that J1-phytoprostanes have intermediate 9 using our swap protocol.[8] The ethyl group
been detected in edible oils,[6] it is of paramount importance of the ω side-chain of 1 and the methyl ester of 2 was ob-
to clarify their physiological activity, as has been done for tained from the reduction of tosylhydrazone 10 with
prostanoids and isoprostanes in animals.[1c] This is espe- (Ph3P)2CuBH4 to give the corresponding hydrocarbon.[9]
cially true for the elusive 9-A1-phytoprostane, whose bio- Retrosynthetically, simple functional group manipulations
logical activity is unknown. A detailed evaluation of the indicated that lactone 3 was the ideal precursor.
biological activities of 9-J1-PhytoP and 9-A1-PhytoP has
been prevented so far by the poor availability of the pure the methyl ester of 2 thus began with the preparation
compounds. of enantiopure O-TBS-protected α-hydroxyaldehyde
The enantioselective synthesis of phytoprostanes 1 and
6
Thus, the chemical synthesis of 9-J1-PhytoP and 9-A1- (Scheme 2). In the event, nucleophilic addition of the alkyn-
PhytoP is not only a highly challenging goal, but it is the ide anion of hept-6-ynoic acid TIPS ester 7 to commercially
only way to prepare enough material for biological studies. available enantiopure (S)-glycidyl benzyl ether 8 under
Scheme 1. Retrosynthesis of 9-J1- and 9-A1-phytoprostanes; Ts = 4-tolylsulfonyl, EE = ethoxyethyl, TBDPS = tert-butyldiphenylsilyl,
TIPS = triisopropylsilyl, Ar = 2-nitrophenyl.
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Synthesis of Phytoprostane Methyl Esters
Scheme 2. Synthesis of α side-chain precursor 6. Reagents and conditions: a) 7, BuLi, –78 °C, 1 h, then BF3·Et2O, 10 min. then 8, –78 °C,
2 h; b) i. K2CO3, THF/H2O (1:1), room temp., 4 d; ii. CAL-B lipase, MTBE/MeOH (9:1), room temp., 30 h, 70%; c) TBSCl, imidazole,
CH2Cl2, room temp., 36 h, quant.; d) Pd/C (10%), H2, EtOAc/MeOH (9:1), room temp., 7 d, 86%; e) DMP, CH2Cl2, room temp., 1 h,
75%. DMP = Dess–Martin periodinane, MTBE = methyl tert-butyl ether, CAL-B = Candida antarctica lipase B, TBSCl = tert-butyldi-
methylsilyl chloride.
Yamaguchi conditions[10] (BuLi, –78 °C, followed by
Having established an efficient route to key intermediate
BF3·Et2O, and then epoxide 8) gave alcohol 11 as a single 6, we then turned our attention to the enantioselective syn-
regioisomer, which was used in the next step without purifi- thesis of the two phytoprostane cores 4 and 5, and this was
cation.
achieved by the reaction sequences shown in Scheme 3.
Transesterification of TIPS ester 11, in the presence of
Enantiopure hydroxymethyl lactone 3[7] was converted
the free C-9 hydroxy group, was accomplished in a biocata- into sulfide 15 in 88% yield with PhSSPh in the presence
lytic approach using Candida antarctica lipase B (CAL-B) of nBu3P and pyridine at room temp. Tosylhydrazone 10
in the presence of MeOH at room temp. The corresponding was then obtained in three steps in 63% overall yield. DI-
methyl ester (i.e., 12) was thus obtained in a satisfactory BAL-H reduction of 15 at –78 °C gave the corresponding
70% isolated yield over three steps. Subsequently, alcohol lactol, which was then treated with tosylhydrazine in dry
12 was protected as its TBS ether 13, and then the triple THF at room temp., followed by protection of the allylic
bond was fully reduced [Pd on carbon (10%), H2 (1 atm), alcohol with TBDPSCl in the presence of imidazole in
EtOAc/MeOH, 9:1] with concomitant benzyl ether cleavage, CH2Cl2 at room temp. After some experiments, the crucial
to give saturated primary alcohol 14 in 86% overall yield. reduction of 10 to give ethyl derivative 16 was achieved with
Dess–Martin periodinane oxidation[11] of alcohol 14 (Ph3P)2CuBH4 in refluxing dry CHCl3 for 3 h;[9] compound
smoothly delivered aldehyde 6, [α]2D0 = –22.1 (c = 1.55, 16 was thus obtained in 55% isolated yield, [α]D20 = 39.1 (c
CH2Cl2), in 75% isolated yield.
= 0.35, CH2Cl2). Subsequently, sulfone 4, a key building
Scheme 3. Synthesis of key sulfones 4 and 5. Reagents and conditions: a) PhSSPh, THF, 0 °C to room temp. 88%; b) i. DIBAL-H,
CH2Cl2, –78 °C, 1 h, 95%; ii. TsNHNH2, THF, room temp., 18 h, 99%; iii. TBDPSCl, CH2Cl2, imidazole, room temp., 2 d, 70%;
c) (Ph3P)2CuBH4, CHCl3, 70 °C, 3 h, 55%; d) H2O2 (50% v/v solution), (NH4)MoO4 (cat.), room temp., 2 d, 50%; e) i. TBAF (1 m in
THF), THF, room temp., 2 d, 70%; ii. 2-nitrophenyl selenocyanate, nBu3P, THF, room temp., 1 h, 90%; f) i. H2O2 (35% v/v solution),
pyridine, 0 °C to 4 °C, 18 h, 60%; ii. Ethyl vinyl ether, CH2Cl2, PPTS, room temp., 4 h, 87%; PPTS = pyridinium p-toluenesulfonate, Ts
= p-tolylsulfonyl, TBDPSCl = tert-butyldiphenylsilyl chloride, TBAF = tetrabutylammonium fluoride, DIBAL-H = diisobutylaluminium
hydride.
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Scheme 4. Finale of the total synthesis of phytoprostanes 1 and 21. Reagents and conditions: a) i. TBAF (1 m in THF), THF, room temp.,
5 d, 70%; ii. Ethyl vinyl ether, CH2Cl2, PPTS, room temp., 4 h, 80%; b) i. 17, BuLi (2.5 m in hexane), THF, –78 °C, 40 min, then 6 in
THF, –78 °C, 4 h; ii. Na2HPO4, MeOH, –40 °C, then Na (20% Hg), –40 °C to –20 °C, 2 h, 61%; c) i. PPTS, EtOH/CH2Cl2 (3:1), room
temp., 4 h, 91%; ii. DMP, CH2Cl2, room temp., 1.5 h, 95%; d) i. HF (48% aq. v/v), MeCN, room temp., 4 h, 93%; ii. CAL-B, H2O,
MTBE, room temp., 1 d, 90%; e) NH4F, MeOH, room temp., 4 h, 65%.
block for the synthesis of phytoprostane 1 and the divergent O-TBS ether was detached using NH4F in MeOH instead
synthesis of phytoprostane 2 was easily prepared by chemo- of aq. HF, in order to prevent a biomimetic dehydration[2a,4]
selective oxidation of 16 with H2O2 in the presence of a (Scheme 4) of the corresponding free alcohol. Under these
catalytic amount of (NH4)2MoO4 in methanol at room conditions, the elusive 9-A1-PhytoP (2) was obtained as its
temp.[12] A divergent route to 2 from sulfone 4 was ac- methyl ester (i.e., 21) in 65% isolated yield, [α]D20 = 67.5 (c
complished after cleavage of the TBDPS group, using our = 0.12, CH2Cl2). The extreme instability of the 9-A1-phyto-
“swap” strategy,[8] via 2-nitrophenyl selenyl ether 9, which prostane structure is reflected in both the yield of the cru-
was prepared in 90% yield using 2-nitrophenyl selenocyan- cial Dess–Martin oxidation (31%) en route to 20, and the
ate in the presence of nBu3P in THF at room temp. Hydro- extensive decomposition of 9-A1-PhytoP methyl ester 21
gen peroxide [H2O2 (30%), pyridine, THF, 7 °C] smoothly that was observed during an attempted hydrolysis under ex-
triggered the [2,3]-sigmatropic rearrangement of the corre- tremely mild CAL-B mediated conditions.[15]
sponding secondary allylic selenoxide 9a to give the desired
alcohol (i.e., 5a) in 60% isolated yield. This alcohol was
subsequently protected as its ethoxyethyl ether 5 (ethyl vinyl
Conclusions
In summary, the first enantioselective divergent synthesis
of the elusive cyclopentenone 9-J1-phytoprostane 1 and of
9-A1-phytoprostane methyl ester 21 has been accomplished
starting from the common chiral building block 3, which is
available in multigram amounts in enantiopure form. Fur-
ther studies aiming for the total synthesis of the other two
regioisomeric A1 and J1 cyclopentenone phytoprostanes,
16-J1-PhytoP and 16-A1-PhytoP, are in progress in our labo-
ratory, and the results will be reported in due course.
ether, CH2Cl2, pyridinium p-toluenesulfonate, 87% yield).
With the two key sulfones 4 and 5 in hand, the synthesis
was expected to proceed readily to give target phytopros-
tanes 1 and 21, respectively (Scheme 4), using the same ole-
fination strategy for both compounds to introduce the un-
saturated side-chains. In the event, simple functional group
manipulation in 4 gave EE-protected sulfone 17, which was
condensed with aldehyde 6 under our modified Julia–
Lythgoe olefination conditions[13] to give olefin 18 as a sin-
gle E stereoisomer (13C NMR spectroscopy) in 61% iso-
lated yield over two steps. Removal of the labile EE protect-
ing group [abs. EtOH/CH2Cl2 (3:1), pyridinium p-toluene-
sulfonate, room temp., 91% yield], followed by Dess–
Martin periodinane oxidation, gave the corresponding en-
one (i.e., 19) in 95% isolated yield. Finally, two consecutive
deprotection steps, namely O-TBS ether cleavage with aq.
HF, and methyl ester hydrolysis under our “buffer-free”
conditions,[14] delivered the expected 9-J1-PhytoP (1), [α]2D0
= –170.4 (c = 0.55, CH2Cl2), in 84% yield over two steps.
Following the same synthetic sequence used for the trans-
formation of 4 into enone 19, sulfone 5 gave the expected
Experimental Section
General Information: THF was distilled from sodium with benzo-
phenone ketyl radical as indicator. CHCl3 and CH2Cl2 were dis-
tilled from CaH2. All moisture-sensitive reactions were carried out
under O2-free Ar using oven-dried glassware and a vacuum line.
Flash column chromatography was carried out using Merck SiO2
60 (230–400 mesh), and TLC was carried out using commercially
available Merck F254 precoated sheets. Visualization of reaction
components was achieved under UV light at a wavelength of
254 nm, or by staining by exposure to vanillin (0.5% solution in
1
H2SO4/EtOH) followed by gentle heating. H and 13C NMR spec-
enone (i.e., 20; see Supporting Information), from which the tra were recorded with a Bruker Avance 300 instrument. Chemical
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Synthesis of Phytoprostane Methyl Esters
shifts are given in ppm, and are referenced using the residual sig-
nals of the solvent as internal standard (1H: CHCl3, δ = 7.26 ppm;
[D5]acetone, δ = 2.05 ppm. 13C: CDCl3, δ = 77.0 ppm). IR spectra
were recorded with a Perkin–Elmer Paragon 100 PC spectrometer.
Mass spectra were recorded with a Thermo LTQ-XL mass spec-
trometer (H-ESI) or a Finnigan MAT-90 mass spectrometer. Melt-
ing points were determined using an OptiMelt MPA100 device
from Stanford Research Systems.
H), 7.3 (m, 11 H), 6.25 (dd, J = 2.77, 5.8 Hz, 1 H), 5.66 (dd, J =
1.4, 5.7 Hz, 1 H), 4.5 (dd, J = 2.5, 5.3 Hz, 1 H), 3.36 (dd, J = 4.4,
12.2 Hz, 1 H), 3.02 (t, J = 11.4 Hz, 1 H), 2.73 (m, 1 H), 1.78 (m,
4 H), 1.08 (s, 9 H), 0.96 (t J = 7.3 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 139.3 (d), 137.3 (s), 136.2 (d), 136.1 (d),
135.5 (d), 134.7 (d), 134.2 (d), 133.8 (s), 129.7 (d), 129.4 (d), 128.9
(d), 127.6 (d), 127.4 (d), 125.7 (d), 49.4 (d), 45.4 (d), 37.2 (t), 27.0
(s), 19.3 (d), 18.5 (t), 12.8 (d) ppm. MS (ESI): m/z (%) = 479 (100)
[M + Na]+. HRMS: calcd. for C31H36OS 456.2487; found 456.2496.
(E)-NЈ-(2-{(1R,2S,5R)-2-[(tert-Butyldiphenylsilyl)oxy]-5-[(phenyl-
thio)methyl]cyclopent-3-en-1-yl}ethylidene)-4-methylbenzenesulf- tert-Butyl({(1S,4R,5R)-5-ethyl-4-[(phenylsulfonyl)methyl]cyclopent-
onohydrazide (10): A stirred solution of sulfide 15 (260 mg,
1.057 mmol) in CH2Cl2 (10 mL) was cooled to –78 °C, and
DIBAL-H (1 m in hexane; 1.3 mL, 1.2 equiv.) was added dropwise.
Stirring was continued for an additional 1 h, and then a saturated
solution of NH4Cl (10 mL) was added at –78 °C. The mixture was
gradually warmed to room temp., then it was diluted with CH2Cl2
(30 mL), and acidified with concentrated HCl. The aqueous layer
was extracted with CH2Cl2 (3ϫ 25 mL), and the combined organic
phases were washed with H2O and brine, and dried with MgSO4.
The volatiles were evaporated in vacuo to give the desired lactol
2-en-1-yl}oxy)diphenylsilane (4): Sulfide 16 (40 mg, 0.085 mmol)
was dissolved in MeOH (8 mL), and the resulting solution was co-
oled to 0 °C. Solid (NH4)2MoO4 (6 mg) and H2O2 (50%; 180 μL,
96 equiv.) were added. The temperature was allowed to reach room
temp., and stirring was continued for 3 h. Further H2O2 (50 %;
70 μL) and (NH4)2MoO4 (4 mg) were added, and the resulting yel-
low slurry was stirred for an additional 14 h. The reaction was
quenched by adding solid Na2SO3. The mixture was stirred for
40 min at room temp., then the MeOH was removed by evaporation
in vacuo, and the residue was partitioned between a saturated solu-
(256 mg, 98%), a 9:1 mixture of diastereomeric hemiacetals, as a tion of NH4Cl (6 mL) and CH2Cl2 (10 mL). The aqueous phase
white solid, m.p. 107–110 °C. Spectroscopic data are in agreement
was extracted with CH2Cl2 (3ϫ 25 mL), and the combined organic
layers were washed with brine, and dried with Na2SO4. The residue
obtained from evaporation of the volatiles was purified on silica
gel (8 g; n-hexane/EtOAc, 9:1) to give sulfone 4 (21 mg, 50%) as a
pale yellow viscous oil. [α]2D0 = +39.5 (c = 0.4, CH2Cl2). IR (neat):
with the literature.[13]
TsNHNH2 (284 mg, 1.3 mmol, 1.2 equiv.) was added portionwise
to a stirred solution of the sulfide lactol (276 mg, 1.1 mmol) in dry
THF (11 mL) at room temperature. Stirring was continued for 18 h,
and then the volatiles were removed under reduced pressure. Imid-
azole (6 equiv., 332 mg) and TBDPS chloride (2.5 equiv., 0.53 mL)
were added to a stirred solution of the crude hydrazone (0.34 g,
0.815 mmol) in dry CH2Cl2 (8 mL) under an Ar atmosphere. After
40 h, H2O (15 mL) was added, and the layers were separated. The
aqueous phase was then extracted with CH2Cl2 (3ϫ 10 mL). The
combined organic phases were washed with brine, dried with
MgSO4, filtered, and concentrated under reduced pressure. The re-
sulting residue was purified by flash chromatography on silica gel.
Elution with n-hexane/Et2O (7:3) gave silyl ether 10 (361 mg, 70%)
ν = 3070, 2931, 2857, 1447, 1428, 1306, 1147, 1112, 1075, 1040,
˜
1
1021, 865, 822 cm–1. H NMR (300 MHz, CDCl3): δ = 7.98 (m, 2
H), 7.62 (m, 7 H), 7.45 (m, 6 H), 6.20 (dd, J = 2.83, 5.80 Hz, 1 H),
5.6 (dd, J = 2.02, 5.61 Hz, 1 H), 4.46 (dd, J = 2.52, 5.09 Hz, 1 H),
3.4 (m, 2 H), 2.92 (m, 1 H), 1.9 (m, 1 H), 1.65 (m, 1 H), 1.45 (m,
1 H), 1.12 (s, 9 H), 0.85 (t, J = 7.34 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 140.0 (s), 138.1 (d), 136.0 (d), 135.9 (d),
134.6 (d), 134.2 (s), 133.5 (d), 133.4 (s), 129.7 (d), 129.2 (d), 127.8
(d), 127.5 (d), 127.4 (d), 76.3 (d), 59.5 (t), 49.2 (t), 40.0 (d), 26.9
(q), 19.2 (s), 18.5 (t), 12.1 (d) ppm. MS (ESI): m/z (%) = 489 (100)
[M + H]+. HRMS: calcd. for C31H36O3S 488.2385; found 488.2376.
as a colourless oil. IR (neat): ν = 3204.1, 3061, 2929, 2857, 1587,
˜
1480, 1471, 1428, 1360, 1320, 1186, 1166, 1111, 1055, 885, 814,
({[(1R,4S,5R)-4-(1-Ethoxyethoxy)-5-ethylcyclopent-2-en-1-yl]-
1
739 cm–1. H NMR (300 MHz. CDCl3): δ = 7.88–7.19 (m, 21 H), methyl}sulfonyl)benzene (17): TBAF (418 μL, 0.12 mmol, 4 equiv.)
6.90 (s, 1 H), 6.11 (dd, J = 5.8, 2.6 Hz, 1 H), 5.68 (d, J = 5.8 Hz,
1 H), 4.51 (dd, J = 5.6, 2.3 Hz, 1 H), 3.13 (dd, J = 12.2, 5.2 Hz, 1
was added to a solution of 4 (60 mg, 0.1203 mmol) in dry THF
(1.2 mL) under Ar. The reaction mixture was stirred at room temp.
H), 2.93–2.24 (m, 8 H), 1.03 (d, J = 13.1 Hz, 9 H) ppm. 13C NMR until complete conversion was reached. The reaction was quenched
(75 MHz, CDCl3): δ = 151.8 (d), 149.7 (s), 144.1 (s), 138.5 (d),
with saturated aq. NH4Cl (2 mL), and the mixture was diluted with
137.7 (s), 136.8 (s), 136.0 (d), 135.9 (d), 135.8 (d), 135.2 (s), 134.0 Et2O (2 mL). The layers were separated, and the aqueous layer was
(s), 133.8 (s), 133.6 (d), 133.3 (s), 130.0 (s), 129.8 (d), 129.7 (s),
129.6 (d), 129.5 (s), 129.0 (d), 128.9 (d), 128.8 (d), 128.0 (d), 127.8
(d), 127.5 (d), 126.2 (d), 125.8 (d), 77.1 (d), 45.2 (d), 45.0 (d), 44.4
(d), 43.8 (d), 36.4 (t), 36.2 (t), 28.5 (t), 27.0 (q), 23.4 (t), 21.6 (q),
extracted with Et2O (3ϫ 5 mL). The combined organic layers were
washed with brine, dried with Na2SO4, filtered, and concentrated
under vacuum. The residue was purified by column chromatog-
raphy on silica gel (n-hexane/EtOAc, 6:4) to give the free alcohol
19.2 (s), 19.1 (s) ppm. MS (ESI): m/z (%) = 662 (100) [M + Na]+, (22.4 mg, 70%). [α]2D0 = –50.0 (c = 0.5, CH Cl ). IR (neat): ν =
˜
2
2
639 (20). HRMS: calcd. for C38H42N2O3S2 638.2637; found 3435, 3073, 2933, 2864, 1451, 1426, 1316, 1147, 1045, 1030, 1022,
1
638.2629.
870 cm–1. H NMR (300 MHz, CDCl3): δ = 7.93 (m, 2 H), 7.6 (m,
3 H), 6.33 (dd, J = 2.12, 5.79 Hz, 1 H), 6.00 (dd, J = 2.66, 5.45 Hz,
1 H), 3.30 (m, 1 H), 3.10 (m, 2 H), 2.04 (m, 1 H), 1.54 (m, 2 H),
1.36 (m, 1 H), 0.97 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 139.9 (s), 139.4 (d), 133.8 (d), 133.7 (d), 129.3 (d), 127.9 (d), 74.8
(d), 59.5 (t), 47.8 (d), 40.0 (d), 18.2 (t), 12.3 (d) ppm. MS (ESI):
m/z (%) = 289 (100) [M + Na]+. HRMS: calcd. for C14H18O3S
266.0977; found 266.0983.
tert-Butyl({(1S,4R,5R)-5-ethyl-4-[(phenylthio)methyl]cyclopent-2-
en-1-yl}oxy)diphenylsilane (16): (PPh3)2CuBH4 (285 mg,
0.474 mmol, 1.1 equiv.) was added to a stirred solution of hydraz-
one 10 (282 mg, 0.43 mmol) in dry CHCl3 (4 mL). The reaction
mixture was heated at reflux for 3 h, and then it was filtered
through short Celite pad. The filtrate was concentrated under re-
duced pressure, and the residue was purified by flash chromatog-
raphy on silica gel. Elution with n-hexane/Et2O (97:3) gave 16
(112 mg, 55%) as a colourless oil. [α]2D0 = +39.1 (c = 3.5, CH2Cl2).
The above cyclopentenol (22.4 mg, 0.084 mmol) was dissolved in
CH2Cl2/ethyl vinyl ether (7:1; 1 mL), and PPTS (cat.) was added.
The resulting mixture was stirred for 4 h, then excess solid
NaHCO3 was added, followed by a saturated solution of NaHCO3
IR (neat): ν = 3071, 2932, 2862, 1450, 1422, 1301, 1148, 1110, 1060,
˜
1
1022, 874, 830 cm–1. H NMR (300 MHz, CDCl3): δ = 7.67 (m, 4
Eur. J. Org. Chem. 2014, 2111–2119
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2115

A. Porta et al.
FULL PAPER
(5 mL). The layers were separated, and the aqueous phase was ex-
tracted with CH2Cl2 (3ϫ 15 mL). The combined organic phases
were washed with brine, dried with Na2SO4, filtered, and concen-
trated under reduced pressure. The resulting residue was purified
by flash chromatography on silica gel. Elution with n-hexane/
Cyclopentenol 5a (33.6 mg, 0.084 mmol) was dissolved in CH2Cl2/
ethyl vinyl ether (7:1; 1.5 mL), and PPTS (cat.) was added. The
resulting mixture was stirred for 4 h, then excess solid NaHCO3
was added, followed by a saturated solution of NaHCO3 (5 mL).
The layers were separated, and the aqueous phase was extracted
EtOAc (8:2) gave acetal 17 (22.6 mg, 80%, 1:1 mixture of anomers) with CH2Cl2 (3 ϫ 15 mL). The combined organic phases were
as a colourless oil. IR (neat): ν = 2972, 1446, 1306, 1386, 1306,
washed with brine, dried with Na2SO4, filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel. Elution with n-hexane/EtOAc (8:2)
˜
1147, 1086, 997, 863, 691 cm–1. 1H NMR (300 MHz, CD3COCD3):
δ = 7.98 (m, 2 H), 7.71 (m, 3 H), 6.24 (m, 1 H), 6.11 (m, 1 H), 4.72
(m, 1 H), 4.35 (dm 1 H), 3.50 (m, 3 H), 3.01 (m, 2 H), 2.10 (m, 1 gave acetal 5 (33.8 mg, 87%, 1:1 mixture of anomers) as a colour-
H), 1.50 (m, 2 H), 1.18 (m, 6 H), 0.89 (m, 3 H) ppm. 13C NMR less oil. IR (neat): ν = 2973, 1450, 1310, 1389, 1309, 1150, 1087,
˜
(75 MHz, CD3COCD3): δ = 141.3 (s), 140.3 (d), 139.3 (d), 134.4
(d), 133.7 (d), 130.2 (d), 128.7 (d), 101.0 (d), 98.7 (d), 81.8 (d), 77.4
(d), 61.2 (t), 60.0 (t), 49.4 (d), 41.5 (d), 21.2 (d), 20.6 (d), 18.9 (t),
15.6 (d), 12.5 (d) ppm. MS (ESI): m/z (%) = 339 (100) [M + H]+.
HRMS: calcd. for C18H26O4S 338.1552; found 338.1562.
999, 861, 692 cm–1. 1H NMR (300 MHz, CD3COCD3): δ = 7.90
(m, 2 H), 7.70 (m, 3 H), 6.00 (m, 1 H), 5.8 (m, 1 H), 4.75 (m, 1
H), 4.45 (m, 1 H), 3.30 (m, 3 H), 2.70 (m, 1 H), 2.50 (m, 1 H), 1.65
(m, 1 H), 1.27 (m, 3 H), 1.18 (m, 3 H), 1.06 (m, 1 H), 0.85 (t, J =
7.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CD3COCD3): δ = 141.3
(s), 140.3 (d), 139.3 (d), 134.4 (d), 133.7 (d), 130.2 (d), 128.7 (d),
101.0 (d), 98.7 (d), 81.8 (d), 77.4 (d), 61.2 (t), 60.0 (t), 49.4 (d), 41.5
(d), 21.2 (d), 20.6 (d), 18.9 (t), 15.8 (d), 12.5 (q) ppm. MS (ESI):
m/z (%) = 339 (100) [M + H]+. HRMS: calcd. for C18H26O4S
338.1552; found 338.1561.
{(1R,4R,5R)-5-Ethyl-4-[(phenylsulfonyl)methyl]cyclopent-2-en-1-
yl}(2-nitrophenyl)selane (9): Solid, freshly sublimed (o-nitrophenyl)-
selenocyanate (136.8 mg, 0.6 mmol, 1.5 equiv.) was added to the
cyclopentenol prepared from 4 (see above; 106.6 mg, 0.4 mmol) in
dry THF (5 mL) under an argon atmosphere, and then nBu3P
(0.158 mL, 0.64 mmol, 1.6 equiv.) was added dropwise by cannula
at room temperature. Stirring was continued for an additional 1 h.
The reaction mixture was then diluted with EtOAc, and the organic
layer was separated and washed with a saturated solution of
NaHCO3 and then with brine. The combined organic phases were
dried with MgSO4, filtered, and concentrated in vacuo. The oily,
brown-orange residue was purified on silica gel. Elution with hex-
anes/EtOAc (8:2) gave selenide 9 (151 mg, 90%) as a brown-yellow
Triisopropylsilyl Hept-6-ynoate (7): Imidazole (621 mg, 9.13 mmol,
1.3 equiv.) and then TIPSCl (1.6 mL, 7.37 mmol, 1.05 equiv.) were
added to a solution of hept-6-ynoic acid (886 mg, 7.02 mmol) in
dry CH2Cl2 (14 mL). The reaction mixture was stirred for 3 h at
room temperature, then it was quenched with water (5 mL). The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (3ϫ 15 mL). The combined organic phases were washed
with brine, dried with Na2SO4, filtered, and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography on silica gel. Elution with n-hexane/MTBE (98:2)
oil. IR (neat): ν = 3063, 2964, 2932, 2876, 2255, 1710, 1654, 1590,
˜
1566, 1510, 1448, 1332, 1305, 1148, 1086, 1037, 911, 852, 783, 732,
688 cm–1 1H NMR (300 MHz, CDCl3): δ = 8.3 (dd, J = 1.18,
.
gave ester 7 (1.87 g, 99%) as a colourless oil. IR (neat): ν = 3313,
˜
2946, 2869, 1718, 1465, 1213 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 2.39 (t, J = 7.3 Hz, 2 H), 2.24 (td, J = 7.0, 2.6 Hz, 2 H), 1.96
(t, J = 2.7 Hz, 1 H), 1.77 (dd, J = 8.4, 7.3 Hz, 2 H), 1.62–1.57 (m,
2 H), 1.30 (td, J = 7.9, 6.1 Hz, 3 H), 1.09 (d, J = 7.3 Hz, 19 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 173.5 (s), 83.9 (s), 68.5 (d),
35.3 (t), 27.8 (t), 24.2 (t), 18.2 (t), 17.8 (q), 11.9 (d) ppm. MS (ESI):
m/z (%) = 305 (100) [M + Na]+. HRMS: calcd. for C16H30O2Si
282.2015; found 282.2020.
8.25 Hz, 1 H), 7.9 (m, 2 H), 7.6 (m, 5 H), 7.3 (t, J = 7.14 Hz, 1 H),
6.0 (m, 2 H), 4.2 (m, 1 H), 3.4 (m, 1 H), 3.35 (dd, J = 4.52,
13.84 Hz, 1 H), 3.15 (dd, J = 10.0, 13.81 Hz, 1 H), 2.35 (m, 1 H),
1.5 (m, 2 H), 0.97 (t, J = 7.27 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 174.3 (s), 139.2 (s), 135.4 (d), 133.8 (d), 133.6 (s), 133.3
(d), 131.6 (d), 130.0 (d), 129.4 (d), 128.0 (d), 126.3 (d), 125.7 (d),
56.5 (t), 49.3 (d), 48.8 (d), 40.6 (d), 21.6 (t), 12.3 (q) ppm. MS
(ESI): m/z (%) = 452 (100) [M + H]+. HRMS: calcd. for
C20H21O4SSe 451.0357; found 451.0361.
(S)-Methyl 10-(Benzyloxy)-9-hydroxydec-6-ynoate (12): nBuLi
(0.49 mL, 1.24 mmol, 2 equiv.) was added dropwise to a solution
of 7 (0.33 g, 1.23 mmol, 2 equiv.) in dry THF (6 mL) under Ar at
–78 °C. After 1 h, BF3·Et2O (0.155 mL, 1.24 mmol, 2 equiv.) was
added, and after 10 min, 8 (0.101 g, 0.62 mmol) in dry THF (2 mL)
was added. The reaction was monitored by TLC (hexane/EtOAc,
8:2), and after 2 h at –78 °C was quenched with saturated aq.
NH4Cl (10 mL) and CH2Cl2 (15 mL). The aqueous layer was ex-
tracted with CH2Cl2 (4ϫ 7 mL), and the combined organic layers
were dried with Na2SO4, filtered, and concentrated under vacuum.
The residue was filtered through short pad of silica gel (hexane/
EtOAc, 9:1) to give compound 11 (0.495 g, 90%) as a pale yellow
oil, which was used immediately in the next step.
({[(1S,2S,5S)-2-(1-Ethoxyethoxy)-5-ethylcyclopent-3-en-1-
yl]methyl}sulfonyl)benzene (5): Pyridine (126 mg, 1.568 mmol,
4 equiv.) was added by syringe to a stirred solution of selenide 9
(164 mg, 0.392 mmol) in THF (10 mL) at room temperature. The
mixture was cooled to 0 °C, and hydrogen peroxide (30 % v/v;
532 μL, 15.7 mmol, 14 equiv.) was added dropwise. Stirring was
continued at +7 °C for an additional 18 h. The reaction was then
quenched with water and diluted with EtOAc. The aqueous phase
was extracted with EtOAc, and the combined organic layers were
washed with a saturated solution of NaHCO3 and with brine, dried
with MgSO4, and filtered, and the solvents were evaporated in
vacuo. The residue was purified by flash column chromatography
(silica gel, n-hexane/EtOAc, 7:3) to give pure cyclopentenol 5a
H2O (2 mL) and K2CO3 (0.14 g, 1.01 mmol, 1.01 equiv.) were
added to a magnetically stirred solution of 11 (0.45 g, 1.0 mmol) in
THF (2 mL) at room temp. After 16 h of stirring at room temp.,
the reaction was quenched with saturated aq. NaHSO4 (2 mL),
H2O (2 mL), and CH2Cl2 (10 mL). The aqueous layer was ex-
tracted with CH2Cl2 (4ϫ 6 mL), and the combined organic layers
were washed with brine, dried with Na2SO4, filtered, and concen-
trated under vacuum.
(54 mg, 60%). IR (neat): ν = 3504, 3060, 2964, 2929, 2876, 1448,
˜
1304, 1146, 1085, 742, 689 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.95 (m, 2 H), 7.75 (m, 1 H), 7.65 (m, 2 H), 6.00 (m, 1 H), 5.8 (m,
1 H), 4.77 (m, 1 H), 3.30 (m, 3 H), 3.20 (s 1 H), 2.70 (m, 1 H),
2.45 (m, 1 H), 1.50 (m, 2 H), 1.05 (m, 1 H), 0.85 (m, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 139.9 (s), 136.9 (d), 134.7 (d),
134.2 (d), 130.2 (d), 128.8 (d), 81.7 (d), 57.6 (t), 49.3 (d), 46.4 (d),
24.9 (t), 12.5 (q) ppm. MS (ESI): m/z (%) = 267 (100) [M + H]+.
HRMS: calcd. for C14H18O3S 266.0977; found 266.0981.
The crude acid was dissolved in HPLC-grade MTBE (4 mL), and
HPLC-grade MeOH (0.50 mL) was added. Solid-supported CAL-
2116
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Synthesis of Phytoprostane Methyl Esters
B (80 mg) was added to the stirred solution, and the resulting sus-
pension was gently stirred at 35 °C for 18 h. The enzyme was re-
moved by filtration through a sintered glass funnel, and the solid
was carefully washed with MeCN/MTBE (1:1, 4ϫ 2 mL). The fil-
trates were combined, and the solvents were evaporated under vac-
uum (CAUTION: without heating). The residue was purified by
silica gel column chromatography (n-hexane/EtOAc, 7:3) to give
CH2Cl2 (4 mL). The reaction was complete after 2 h, and was
quenched with H2O (8 mL), MTBE (9 mL), saturated aq. NaHCO3
(5 mL), and saturated aq. Na2S2O3 (5 mL). The aqueous layer was
extracted with MTBE/n-hexane, 9:1. The combined organic layers
were dried with Na2SO4, filtered, and concentrated under vacuum.
The residue was filtered through silica gel (hexane/EtOAc, 9:1) to
give compound 6 (85 mg, 75%) as a colourless oil, which was used
in the next step without further purification. [α]2D0 = –22.12 (c =
pure ester 12 (213 mg, 70%). [α]2D0 = +9.45 (c = 0.85, CH2Cl2). IR
1
(neat): ν = 3462, 2931, 1736, 1454, 1208, 1118, 739, 699 cm–1. H
1.55, CH Cl ). IR (neat): ν = 2930, 2857, 1739, 1464, 1437, 1362,
˜
˜
2
2
NMR (300 MHz, CDCl3): δ = 7.37–7.28 (m, 5 H), 4.58 (s, 2 H), 1253, 1170, 1118, 1006, 838, 779, 666 cm–1. 1H NMR (300 MHz,
3.93 (dd, J = 3.4, 3.2 Hz, 1 H), 3.67 (s, 3 H), 3.60 (dd, J = 9.5,
4.0 Hz, 1 H), 3.50 (dd, J = 9.5, 6.6 Hz, 1 H), 2.61 (d, J = 3.8 Hz,
1 H), 2.42 (dt, J = 6.1, 2.5 Hz, 2 H), 2.33 (t, J = 7.4 Hz, 2 H), 2.18
(tt, J = 6.9, 2.4 Hz, 2 H), 1.72 (dt, J = 15.2, 7.5 Hz, 2 H), 1.51
(quint, J = 7.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
173.8 (s), 137.9 (s), 128.3 (d), 127.6 (d), 81.9 (s), 76.0 (s), 73.3 (t),
72.9 (t), 69.1 (d), 51.4 (q), 33.4 (t), 28.2 (t), 24.0 (t), 23.8 (t), 18.3
(t) ppm. MS (ESI): m/z (%) = 305 (100) [M + H]+. HRMS: calcd.
for C18H24O4 304.1675; found 304.1679.
CDCl3): δ = 9.4 (d, J = 1.6 Hz, 1 H), 3.9 (m, 1 H), 3.6 (s, 3 H), 2.3
(t, J = 7.5 Hz, 2 H), 1.6 (m, 5 H), 1.3 (s, 9 H), 0.9 (m, 10 H), 0.1
(m, 6 H) ppm. MS (ESI): m/z (%) = 331 (100) [M + H]+.
Methyl (9S,E)-9-[(tert-Butyldimethylsilyl)oxy]-11-[(1S,4S,5R)-4-(1-
ethoxyethoxy)-5-ethylcyclopent-2-en-1-yl]undec-10-enoate (18):
Sulfone 17 (22.5 mg, 0.067 mmol) was dissolved in dry THF
(1.2 mL), and the solution was cooled to –78 °C. The solution was
stirred for 10 min, and then nBuLi (2.5 m in hexane; 0.030 mL,
1.11 equiv.) was added dropwise. The mixture was stirred for
45 min at the same temperature, then the deep orange solution was
slowly added by cannula to a solution of aldehyde 6 (25.3 mg,
0.077 mmol, 1.16 equiv.) in dry THF (0.4 mL). The solution was
stirred at the same temperature for an additional 2 h, then a satu-
rated solution of NH4Cl (5 mL) was added at –78 °C, and the tem-
perature was allowed to reach room temp. The two layers were
separated, and the aqueous phase was extracted with CH2Cl2 (3ϫ
5 mL). The combined organic phases were washed with brine, dried
with Na2SO4, and evaporated under reduced pressure. The crude
product was filtered through a short pad of silica gel using n-hex-
ane/EtOAc (8:2) as eluent. The crude hydroxysulfone was immedi-
ately used in the next step.
Methyl (S)-10-(Benzyloxy)-9-[(tert-butyldimethylsilyl)oxy]dec-6-
ynoate (13): Imidazole (272 mg, 4 mmol, 2 equiv.) and TBSCl
(361 mg, 2.4 mmol, 1.2 equiv.) were added to a solution of 12
(0.608 g, 2 mmol) in dry CH2Cl2 (6 mL) under Ar. The reaction
was complete after 2 h, and it was quenched with H2O (10 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ 10 mL), and
the combined organic layers were dried on MgSO4, filtered, and
concentrated under vacuum. The residue was purified by
chromatography on silica gel column (n-hexane/EtOAc, 95:5) to
give compound 13 (0.827 g, 99%) as a slightly yellow oil. [α]2D0
+2.96 (c = 2.2, CH Cl ). IR (neat): ν = 2929, 2857, 1741, 1436,
=
˜
2
2
1362, 1255, 1123, 1006, 837, 778, 736 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.37–7.28 (m, 5 H), 4.58 (s, 2 H), 3.93 (dd, J = 3.4,
3.2 Hz, 1 H), 3.67 (s, 3 H), 3.60 (dd, J = 9.5, 4.0 Hz, 1 H), 3.50
(dd, J = 9.5, 6.6 Hz, 1 H), 2.61 (d, J = 3.8 Hz, 1 H), 2.42 (dt, J =
6.1, 2.5 Hz, 2 H), 2.33 (t, J = 7.4 Hz, 2 H), 2.18 (tt, J = 6.9, 2.4 Hz,
2 H), 1.72 (dt, J = 15.2, 7.5 Hz, 2 H), 1.51 (quint, J = 7.5 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.9 (s), 1384 (s), 128.5
(d), 127.5 (d), 127.4 (d), 81.0 (s), 77.3 (s), 73.8 (t), 73.3 (t), 70.8 (d),
51.4 (q), 33.6 (t), 28.3 (t), 25.8 (q), 25.0 (t), 24.1 (t), 18.5 (t), 18.1
(s), –4.6 (q), 4.8 (q) ppm. MS (ESI): m/z (%) = 441 (100)
[M + Na]+. HRMS: calcd. for C24H38O4Si 418.2539; found
418.2546.
Crude hydroxysulfone (20 mg, 0.03 mmol) was dissolved in dry
MeOH (2 mL) under an argon atmosphere. Na2HPO4 (190 mg)
was added , and the slurry was cooled to –40 °C. The mixture was
stirred vigorously for 10 min, then sodium amalgam (20 % Na;
60 mg) was slowly added portionwise in such a way as to keep the
temperature below –40 °C. At the end of the addition, the tempera-
ture was allowed to reach –20 °C, and stirring was continued for
an additional 1.5 h. The mixture was warmed to room temp. and
filtered through filter paper. Evaporation of volatiles in vacuo un-
der 40 °C gave a residue, which was partitioned between CH2Cl2
(5 mL) and a saturated aqueous solution of NaHCO3. The two
phases were separated, and the aqueous layer was reextracted with
CH2Cl2 (3ϫ 3 mL). The combined organic phases were washed
with brine, dried with Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash chromatography on sil-
ica gel (10 g). Elution with n-hexane/EtOAc (94:6) gave compound
Methyl (S)-9-[(tert-Butyldimethylsilyl)oxy]-10-hydroxydecanoate
(14): Palladium on charcoal (10% Pd w/w; 80 mg) was added to a
solution of 13 (0.766 mg, 1.88 mmol) in EtOAc/MeOH (9:1;
19 mL). The suspension was stirred at room temp. under a hydro-
gen atmosphere for 7 d. The suspension was filtered, and the sol-
vent was removed from the filtrate under vacuum. The residue was
purified by silica gel column chromatography (n-hexane/EtOAc,
95:5) to give compound 14 (0.537 g, 86 %) as a colourless oil.
18 as a colourless oil (13.7 mg, 61%). IR (neat): ν = 2929, 2360,
˜
1736, 1466, 1273, 1123, 1074, 992, 836, 775, 668 cm–1. 1H NMR
[300 MHz, (CD3)2CO]: δ = 6.05 (dddd, J = 14.2, 5.8, 2.3, 1.2 Hz,
1 H), 5.91 (ddd, J = 17.0, 5.8, 2.9 Hz, 1 H), 5.50–5.37 (m, 2 H),
4.76 (qd, J = 5.9, 5.3 Hz, 1 H), 4.47 (dd, J = 6.2, 2.3 Hz, 0.5 H),
4.33 (dd, J = 6.2, 2.4 Hz, 0.5 H), 4.15–4.08 (m, 1 H), 3.69–3.40 (m,
5 H), 3.17–3.08 (m, 1 H), 2.81–2.77 (m, 1 H), 2.30 (t, J = 7.4 Hz,
2 H), 2.10–1.97 (m, 2 H), 1.64–0.86 (m, 35 H), 0.12–0.09 (m, 6 H)
ppm. 13C NMR [75 MHz, (CD3)2CO]: δ = 174.8 (s), 148.0 (s), 141.3
(d), 141.1 (d), 140.3 (d), 136.2 (d), 136.1 (d), 134.1 (d), 133.6 (d),
133.3 (d), 133.0 (d), 132.8 (d), 132.6 (d), 101.8 (d), 99.4 (d), 83.1
(d), 79.4 (d), 74.9 (d), 74.9 (d), 61.7 (t), 60.5 (t), 52.2 (q), 52.1 (q),
[α]2D0 = +7.19 (c = 1.2, CH Cl ). IR (neat): ν = 3468, 2930, 2857,
˜
2
2
1
1742, 1464, 1362, 1255, 1116, 837, 776 cm–1. H NMR (300 MHz,
CDCl3): δ = 3.73–3.39 (m, 6 H), 2.29 (t, J = 7.5 Hz, 2 H), 1.97 (t,
J = 6.0 Hz, 1 H), 1.63–1.56 (m, 2 H), 1.48–1.44 (m, 2 H), 1.29–
1.23 (m, 8 H), 0.92 (s, 9 H), 0.07 (m, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 174.2 (s), 72.8 (d), 66.2 (t), 51.4 (q), 34.0
(t), 33.9 (t), 29.5 (t), 29.1 (t), 29.0 (t), 25.8 (q), 25.2 (t), 24.8 (t),
18.0 (s), –4.5 (q), –4.6 (q) ppm. MS (ESI): m/z (%) = 333 (100) [M
+ H]+. HRMS: calcd. for C17H36O4Si 332.2383; found 332.2379.
Methyl (S)-9-[(tert-Butyldimethylsilyl)oxy]-10-oxodecanoate (6): 51.9 (d), 50.3 (d), 50.3 (d), 40.1 (t), 35.1 (t), 27.1 (t), 26.9 (t), 26.7
Dess–Martin periodinane (DMP; 0.158 g, 0.37 mmol, 1.1 equiv.)
(q), 26.4 (t), 22.0 (q), 21.4 (q), 20.7 (t), 20.6 (t), 19.5 (s), 16.5 (q),
was added to a solution of alcohol 14 (0.113 g, 0.34 mmol) in dry
13.8 (q), –3.2 (q), –3.8 (q) ppm. MS (ESI): m/z (%) = 534 (20) [M
Eur. J. Org. Chem. 2014, 2111–2119
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2117

A. Porta et al.
FULL PAPER
+ Na – H2O]+, 515 (80) [M + Na – H2O]+. HRMS: calcd. for
C29H54O5Si 510.3741; found 510.3746.
3 H), 1.96 (dt, J = 4.9, 2.5 Hz, 1 H), 1.68–1.25 (m, 14 H), 1.00 (t,
J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CD3CN): δ = 211.4
(s), 174.6 (s), 166.2 (d), 138.4 (d), 132.9 (d), 127.7 (d), 72.2 (d), 51.7
(d), 51.6 (q), 48.0 (d), 38.0 (t), 34.3 (t), 29.8 (t), 29.7 (t), 29.5 (t),
25.9 (t), 25.4 (t), 20.3 (t), 12.6 (q) ppm. MS (ESI): m/z (%) = 355
(100) [M + Na]+. HRMS: calcd. for C19H30O4 332.2144; found
332.2133.
Methyl (S,E)-9-[(tert-Butyldimethylsilyl)oxy]-11-[(1R,5R)-5-ethyl-4-
oxocyclopent-2-en-1-yl]undec-10-enoate (19): PPTS (cat.) was added
to a stirred solution of acetal 18 (30 mg, 0.059 mmol) in EtOH/
CH2Cl2 (3:1; 2 mL), and the resulting mixture was stirred for 4 h.
An excess of solid NaHCO3 was added, and the resulting mixture
was filtered and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel. Elution with n-
hexane/EtOAc (90:10) gave the desired alcohol (18.8 mg, 90%) as
The methyl ester prepared as described above (11.1 mg,
0.034 mmol) was dissolved in HPLC-grade MTBE (0.4 mL), and
HPLC-grade H2O (0.043 mL, 2.4 mmol, 70 equiv.) was added. So-
lid-supported CAL-B (2 mg) was added to the resulting stirred
solution, and the suspension was gently stirred at room tempera-
ture for 18 h. The enzyme was removed by filtration through a sin-
tered glass funnel, and the solid was carefully washed with MeCN/
MTBE (1:1; 4ϫ 2 mL). The filtrates were combined, and the sol-
vents were evaporated under vacuum (CAUTION: without heat-
ing). The residue was purified by silica gel column chromatography
(hexane/EtOAc, 1:1, with 0.5% AcOH) to give pure acid 1 (6.7 mg,
90%) as a pale yellow oil. [α]2D0 = –129.1 (c = 0.11, EtOAc). IR
a colourless oil. [α]2D0 = –77.0 (c = 1.16, CH Cl ). IR (neat): ν =
˜
2
2
3502, 2931, 1713, 1472, 1358, 1360, 1254, 1077, 986, 840, 776 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.08–5.98 (m, 2 H), 5.43 (t, J =
5.8 Hz, 2 H), 4.52–4.49 (m, 1 H), 4.04 (q, J = 5.9 Hz, 1 H), 3.68
(s, 3 H), 3.21–3.10 (m, 1 H), 2.31 (t, J = 7.5 Hz, 2 H), 1.99 (quint,
J = 7.0 Hz, 1 H), 1.65–1.22 (m, 18 H), 1.02 (t, J = 7.3 Hz, 3 H),
0.94–0.91 (m, 11 H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 174.3 (s), 139.6 (d), 135.2 (d), 133.3 (d),
131.6 (d), 76.5 (d), 73.4 (d), 51.4 (d), 49.3 (q), 48.7 (d), 38.5 (t),
34.1 (t), 29.7 (t), 29.3 (t), 29.2 (t), 29.1 (t), 25.9 (q), 25.2 (t), 24.9
(t), 19.0 (t), 18.2 (t), 12.7 (q), –4.3 (q), –4.8 (q) ppm. MS (ESI): m/z
(%) = 421 (100) [M – H2O]+, 515 (80) [M + Na – H2O]+. HRMS:
calcd. for C25H46O4Si 438.3165; found 438.3151.
(neat): ν = 3313, 2928, 1705, 1581, 1240, 968 cm–1 1H NMR
.
˜
(300 MHz, CD3CN): δ = 7.57 (dd, J = 5.7, 2.8 Hz, 1 H), 6.15 (dd,
J = 5.7, 1.8 Hz, 1 H), 5.56 (ddd, J = 15.4, 6.0, 0.6 Hz, 1 H), 5.39
(ddd, J = 15.4, 8.8, 1.0 Hz, 1 H), 4.00 (quint, J = 5.4 Hz, 1 H),
3.8–3.7 (m, 2 H), 2.48–1.94 (m, 9 H), 1.75–1.15 (m, 10 H), 1.04 (t,
J = 7.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CD3CN): δ = 211.4
(s), 174.9 (s), 166.2 (d), 138.4 (d), 132.9 (d), 127.8 (d), 72.2 (d), 51.6
(q), 48.0 (d), 38.0 (t), 34.0 (t), 29.9 (t), 29.7 (t), 29.5 (t), 25.8 (t),
25.4 (t), 20.3 (t), 12.6 (q) ppm. MS (ESI): m/z (%) = 309 (100) [M
+ H]+. HRMS: calcd. for C18H28O4 308.1988; found 308.1992.
DMP (23.7 mg, 0.056 mmol, 1.2 equiv.) was added to a stirred solu-
tion of the alcohol prepared as described above (20.4 mg,
0.047 mmol) in dry CH2Cl2 (1 mL). After 30 min, Et2O (6 mL) was
added, and the resulting mixture was filtered through a short pad
of silica gel, which was thoroughly washed with n-hexane/Et2O
(9:1; 70 mL). The resulting mixture was concentrated under re-
duced pressure. The residue was purified by flash chromatography
on silica gel. Elution with n-hexane/EtOAc (9:1) gave compound
19 (19.3 mg, 95%) as a colourless oil. [α]2D0 = –129.5 (c = 0.42,
Methyl (S,E)-9-[(tert-Butyldimethylsilyl)oxy]-11-[(1S,2S)-2-ethyl-5-
oxocyclopent-3-en-1-yl]undec-10-enoate (20)
Julia–Lythgoe Olefination: Following the same procedure used for
compound 18, sulfone 5 (39.4 mg, 0.117 mmol) underwent the
Julia–Lythgoe olefination reaction to give compound S1 (23.6 mg,
EtOAc). IR (neat): ν = 3734, 2929, 2856, 2360, 1741, 1712, 1587,
˜
1462, 1251, 1778, 1250, 1073, 836, 776, 668 cm–1 1H NMR
.
(300 MHz, CD3CN): δ = 7.55 (dd, J = 5.7, 2.9 Hz, 1 H), 6.13 (dd,
J = 5.7, 1.7 Hz, 1 H), 5.58 (dd, J = 15.4, 6.0 Hz, 1 H), 5.40 (dd, J
= 15.5, 8.8 Hz, 1 H), 4.17 (q, J = 6.1 Hz, 1 H), 3.74–3.73 (m, 1 H),
3.62 (s, 3 H), 2.34–2.27 (m), 1.97 (dtd, J = 4.9, 2.5, 0.5 Hz, 1 H),
1.61–1.25 (m, 14 H), 0.99 (t, J = 7.4 Hz, 3 H), 0.92–0.86 (m, 11
H), 0.07–0.00 (m, 6 H) ppm. 13C NMR (75 MHz, CD3CN): δ =
211.3 (s), 174.6 (s), 166.2 (d), 138.2 (d), 132.8 (d), 127.7 (d), 73.5
(d), 51.8 (d), 51.6 (q), 48.0 (d), 38.8 (t), 34.3 (t), 29.8 (t), 29.7 (t),
29.5 (t), 26.0 (q), 25.6 (t), 25.5 (t), 20.2 (t), 18.6 (s), 12.8 (q), –4.4
(q), –4.8 (q) ppm. MS (ESI): m/z (%) = 459 (100) [M + Na]+.
HRMS: calcd. for C25H44O4Si 436.3009; found 436.3013.
60%) as a colourless oil. IR (neat): ν = 2929, 2360, 1736, 1461,
˜
1273, 1123, 1074, 992, 836, 775, 668 cm–1. 1H NMR (300 MHz,
CD3CN): δ = 5.98 (m, 1 H), 5.77 (m, 1 H), 5.65–5.45 (m, 2 H),
4.76 (qd, J = 5.9, 5.3 Hz, 1 H), 4.47 (dd, J = 6.2, 2.3 Hz, 1 H), 4.33
(dd, J = 6.2, 2.4 Hz, 1 H), 4.15–4.08 (m, 1 H), 3.69–3.40 (m, 4 H),
3.17–3.08 (m, 1 H), 2.78–2.66 (m, 1 H), 2.30 (t, J = 7.4 Hz, 2 H),
2.10–1.97 (m, 2 H), 1.64–0.86 (m, 34 H), 0.12–0.09 (m, 6 H) ppm.
13C NMR [75 MHz, (CD3)2CO]: δ = 173.8 (s), 138.0 (s), 137.6 (d),
135.6 (d), 135.6 (d), 131.8 (d), 130.9 (d), 129.2 (d), 129.0 (d), 133.3
(d), 133.0 (d), 132.8 (d), 132.6 (d), 101.8 (d), 99.4 (d), 83.1 (d), 79.4
(d), 74.9 (d), 74.9 (d), 60.5 (t), 60.1 (t), 52.2 (q), 51.8 (q), 50.8 (d),
49.2 (d), 49.1 (d), 38.2 (t), 33.5 (t), 29.1 (t), 28.9 (t), 28.9 (q), 28.7
(t), 22.0 (q), 21.4 (q), 20.7 (t), 20.6 (t), 19.5 (s), 16.5 (q), 13.8 (q),
–5.0 (q), –5.4 (q) ppm. MS (ESI): m/z (%) = 534 (20) [M + Na]+.
HRMS: calcd. for C29H54O5Si 510.3741; found 510.3749.
(S,E)-11-[(1R,5R)-5-ethyl-4-oxocyclopent-2-en-1-yl]-9-hydroxy-
undec-10-enoic Acid (9-J1-PhytoP; 1): Aqueous HF (48 %;
0.063 mL) was added to a stirred solution of silyl ether 19 (17.1 mg,
0.0392 mmol) in HPLC-grade CH3CN (4 mL) in a PE (polyethyl-
ene) test tube. After 4 h, a phosphate buffer (pH 6.8, 5 mL) was
added. The layers were separated, and the aqueous phase was ex-
tracted with EtOAc (4ϫ 5 mL). The combined organic phases were
washed with brine, dried with MgSO4, filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel. Elution with n-hexane/EtOAc (6:4)
gave pure 9-J1-PhytoP-Me-Ester (13.9 mg, 93%) as a pale yellow
EE Deprotection: Following the same procedure used for com-
pound 18, EE-protected cyclopentenol S1 (39.4 mg, 0.077 mmol)
gave free cyclopentenol S2 (24.6 mg, 91%) as a colourless oil. IR
(neat): ν = 3502, 2931, 1713, 1472, 1358, 1360, 1254, 1077, 986,
˜
1
840, 776 cm–1. H NMR (300 MHz, CDCl3): δ = 5.98–5.96 (m, 1
H), 5.78–5.76 (m, 1 H), 5.65–5.45 (m, 2 H), 4.52–4.49 (m, 1 H),
4.04 (q, J = 5.9 Hz, 1 H), 3.68 (s, 3 H), 2.77–2.51 (m, 3 H), 2.31
(t, J = 7.5 Hz, 2 H), 1.99 (m, 1 H), 1.65–1.22 (m, 14 H), 1.00–0.65
oil. [α]2D0 = –170.4 (c = 0.55, EtOAc). IR (neat): ν = 3445, 2929,
˜
1738, 1713, 1699, 1694, 1559, 1456 cm–1
.
1H NMR (300 MHz, (m, 10 H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm. 13C NMR (75 MHz,
CD3CN): δ = 7.57 (dd, J = 5.7, 2.9 Hz, 1 H), 6.14 (dd, J = 5.7, CDCl3): δ = 174.3 (s), 139.6 (d), 135.2 (d), 133.3 (d), 131.6 (d), 76.5
1.8 Hz, 1 H), 5.59 (ddd, J = 15.4, 6.2, 0.6 Hz, 1 H), 5.42 (ddd, J = (d), 73.4 (d), 51.4 (d), 49.3 (q), 48.7 (d), 38.5 (t), 34.1 (t), 29.7 (t),
15.4, 8.7, 1.0 Hz, 1 H), 4.00 (quint, J = 5.6 Hz, 1 H), 3.74–3.73 (m,
29.3 (t), 29.2 (t), 29.1 (t), 25.9 (q), 25.2 (t), 24.9 (t), 19.0 (t), 18.2
1 H), 3.61 (s, 3 H), 2.75 (d, J = 4.7 Hz, 1 H), 2.30 (t, J = 7.5 Hz, (t), 12.7 (q), –4.3 (q), –4.8 (q) ppm. MS (ESI): m/z (%) = 421 (100)
2118
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2111–2119

Synthesis of Phytoprostane Methyl Esters
[M + H]+. HRMS: calcd. for C25H46O4Si 438.3165; found
438.3153.
Acknowledgments
This work was supported by Regione Lombardia (Direzione
Generale Sanità and Iniziativa Lombardia Eccellente), Fondazione
di Piacenza e Vigevano, and Ministero dell’Università e della
Ricerca (MIUR) (PRIN fund).
DMP Oxidation: DMP (28.4 mg, 0.067 mmol, 1.2 equiv.) was
added to a stirred solution of cyclopentenol ester S2 (24.5 mg,
0.056 mmol) in dry CH2Cl2 (1.5 mL). After 30 min, Et2O (6 mL)
was added, and the resulting mixture was filtered through a short
pad of silica gel, which was then thoroughly washed with n-hexane/
Et2O (9:1, 70 mL). The resulting mixture was concentrated under
reduced pressure WITHOUT HEATING! The residue was purified
by flash chromatography on silica gel. Elution with n-hexane/
EtOAc (9:1) gave compound 20 (7.2 mg, 31%) as a pale yellow oil.
[1] a) S. Parchmann, M. J. Mueller, J. Biol. Chem. 1998, 273,
32650–32655; b) M.-J. Mueller, Curr. Opin. Plant Biol. 2004, 7,
441–448; c) for a recent review, see: U. Jahn, J.-M. Galano, T.
Durand, Angew. Chem. 2008, 120, 5978–6041; Angew. Chem.
Int. Ed. 2008, 47, 5894–5955.
[2] For the recent nomenclature system, see: a) M. J. Muller, Pros-
taglandins Leukotrienes Essent. Fatty Acids 2010, 82, 71–81; b)
U. Jahn, J.-M. Galano, T. Durand, Prostaglandins Leukotrienes
Essent. Fatty Acids 2010, 82, 83–86. For the older nomencla-
ture system, see: c) M. J. Muller, J. Chem. Biol. 1998, 5, 323–
333.
[α]2D0 = 23.6 (c = 0.275, EtOAc). IR (neat): ν = 3734, 2929, 2856,
˜
2360, 1741, 1712, 1587, 1462, 1251, 1778, 1250, 1073, 836, 776,
668 cm–1. 1H NMR (300 MHz, CD3CN): δ = 7.55 (dd, J = 5.7,
2.9 Hz, 1 H), 6.13 (dd, J = 5.7, 1.7 Hz, 1 H), 5.70–5.30 (m, 2 H),
4.17 (m, 1 H), 3.62 (s, 3 H), 3.2–2.9 (m, 2 H), 2.5–1.9 (m, 10 H),
1.75–1.3 (m, 9 H), 0.95 (t, J = 7.4 Hz, 3 H), 0.92–0.86 (m, 6 H),
0.07–0.00 (m, 6 H) ppm. 13C NMR (75 MHz, CD3CN): δ = 211.3
(s), 174.6 (s), 166.2 (d), 138.2 (d), 132.8 (d), 127.7 (d), 73.5 (d), 51.8
(d), 51.6 (q), 48.0 (d), 38.8 (t), 34.3 (t), 29.8 (t), 29.7 (t), 29.5 (t),
26.0 (q), 25.6 (t), 25.5 (t), 20.2 (t), 18.6 (s), 12.8 (q), –4.4 (q), –4.8
(q) ppm. MS (ESI): m/z (%) = 437 (100) [M + H]+. HRMS: calcd.
for C25H44O4Si 436.3009; found 436.3015.
[3] I. Thoma, C. Loeffler, A. K. Sinha, M. Gupta, M. Krischke,
B. Steffan, T. Roitsch, M. J. Mueller, Plant J. 2003, 34, 363–
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62, 351–358.
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Krischke, M. J. Mueller, S. Berger, Plant Cell 2008, 20, 768–
785.
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porte, M. J. Mueller, Free Radical Res. 2007, 41, 25–37.
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Asymmetry 2001, 12, 1779–1784; b) G. Zanoni, A. Porta, A.
Meriggi, M. Franzini, G. Vidari, J. Org. Chem. 2002, 67, 6064–
6069.
[8] G. Zanoni, F. Castronovo, E. Perani, G. Vidari, J. Org. Chem.
2003, 68, 6803–6805.
[9] G. W. J. Fleet, P. J. C. Harding, M. J. Whitcombe, Tetrahedron
Lett. 1980, 21, 4031–4034.
Methyl (S,E)-11-[(1S,2S)-2-ethyl-5-oxocyclopent-3-en-1-yl]-9-hy-
droxyundec-10-enoate (9-A1-PhytoP-Me-Ester; 21): NH4F (7 m aq.;
0.057 mL, 10 equiv.) was added to a stirred solution of silyl ether
20 (6.9 mg, 0.0196 mmol) in HPLC-grade CH3OH (2 mL) in a PE
test tube. After 4 h, a phosphate buffer (pH 6.8, 3 mL) was added.
The layers were separated, and the aqueous phase was extracted
with EtOAc (4ϫ 3 mL). The combined organic phases were washed
with brine, dried with MgSO4, filtered, and concentrated under re-
duced pressure WITHOUT HEATING! The residue was purified
by flash chromatography on silica gel. Elution with n-hexane/
EtOAc (6:4) gave pure 9-A1-PhytoP-Me-Ester 21 (1.4 mg, 31%) as
[10] a) M. Yamaguchi, I. Hirao, Tetrahedron Lett. 1983, 24, 391–
394; b) H. Seike, I. Ghosh, Y. Kishi, Org. Lett. 2006, 8, 3865–
3868.
a pale yellow oil. [α]2D0 = 67.5 (c = 0.12, MeCN). IR (neat): ν =
˜
[11] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–
3448, 2930, 1739, 1715, 1700, 1693, 1555, 1453 cm–1
.
1H NMR
7287.
(400 MHz, CD3CN): δ = 7.57 (dd, J = 5.7, 2.3 Hz, 1 H), 6.10 (dd,
J = 5.7, 2.0 Hz, 1 H), 5.63 (dd, J = 15.5, 6.2 Hz, 1 H), 5.52 (dd, J
= 15.6, 7.7 Hz, 1 H), 3.98 (quint, J = 5.6 Hz, 1 H), 3.61 (s, 3 H),
2.75–2.55 (m, 3 H), 2.30 (t, J = 7.5 Hz, 2 H), 1.78–1.25 (m, 14 H),
1.00 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CD3CN): δ =
209.74 (s), 174.92 (s), 168.2 (d), 138.0 (d), 132.9 (d), 127.7 (d), 72.6
(d), 55.7 (d), 51.9 (q), 50.7 (d), 38.3 (t), 34.6 (t), 30.0 (t), 29.8 (t),
27.5 (t), 26.2 (t), 25.7 (t), 14.5 (t), 12.2 (q) ppm. MS (ESI): m/z (%)
= 355 (100) [M + Na]+. HRMS: calcd. for C19H30O4 332.2144;
found 332.2135.
[12] H. A. Earl, C. J. M. Stirling, J. Chem. Soc. Perkin Trans. 2
1987, 1273–1280.
[13] G. Zanoni, A. Porta, G. Vidari, J. Org. Chem. 2002, 67, 4346–
4351.
[14] G. Zanoni, M. Valli, L. Bendjeddou, A. Porta, P. Bruno, G.
Vidari, J. Org. Chem. 2010, 75, 8311–8314.
[15] It should be emphasized that in all the phytoprostane syntheses
reported to date, instead of the naturally occurring free acids,
the corresponding methyl esters, are prepared. See ref.[1c], and
references cited therein. See also: A. Vázquez-Romero, L.
Cárdenas, E. Blasi, X. Verdaguer, A. Riera, Org. Lett. 2009, 11,
3104–3107 and W. Perlikowska, M. Mikolajczyk, Tetrahedron:
Asymmetry 2011, 22, 1767–1771.
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic sequence for the conversion of 5 into 20. Copies of
Received: November 12, 2013
Published Online: January 29, 2014
1
the H, 13C, and DEPT NMR spectra are provided.
Eur. J. Org. Chem. 2014, 2111–2119
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2119