Stereoselective synthesis of a cis-1,2-dialkylcyclopentane building block and its application in isoprostane synthesis (5-ent-F2c-IsoP)

Article abstract of DOI:10.1002/ejoc.200800010

The all-cis substituted cyclopentane 3a, an analogue of the Corey lactone, has been prepared from a readily available nortricyclanone derivative by a five-step sequence in an overall yield of 34%. This chiral building block has been applied in total syntheses of two diastereomeric isoprostanes belonging to the 5-F₂ family: ent-5-F_2c-IsoP (ent-1) and 5-epient-5-F_2c-IsoP (ent-2). Key features of the syntheses are the introduction of the two unsaturated alkyl side chains through an E-selective Horner-Wadsworth-Emmons reaction with the base-sensitive syn-aldehyde 10, along with a Z-selective Wittig olefination. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800010

FULL PAPER
DOI: 10.1002/ejoc.200800010
Stereoselective Synthesis of a cis-1,2-Dialkylcyclopentane Building Block and
Its Application in Isoprostane Synthesis (5-ent-F2c-IsoP)
Petteri Elsner,[a] Peter Jetter,[a] Kerstin Brödner,[a] and Günter Helmchen*[a]
Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday
Keywords: Natural products / Stereoselective synthesis / Wittig reaction / Total synthesis / Protecting groups
The all-cis substituted cyclopentane 3a, an analogue of the
Corey lactone, has been prepared from a readily available
nortricyclanone derivative by a five-step sequence in an
overall yield of 34%. This chiral building block has been ap-
plied in total syntheses of two diastereomeric isoprostanes
belonging to the 5-F2 family: ent-5-F2c-IsoP (ent-1) and 5-epi-
ent-5-F2c-IsoP (ent-2). Key features of the syntheses are the
introduction of the two unsaturated alkyl side chains through
an E-selective Horner–Wadsworth–Emmons reaction with
the base-sensitive syn-aldehyde 10, along with a Z-selective
Wittig olefination.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Isoprostanes (IsoPs) are a family of eicosanoids discov-
ered in the early 1990s by Morrow et al.[1,2] These prosta-
glandin-like compounds are formed in vivo by free radical-
initiated peroxidation of phospholipid-bound arachidonic
acid. This process is independent of the cyclooxygenase en-
zyme system and can occur either by an endoperoxide
mechanism or by a dioxetane/endoperoxide mechanism.[3]
The key structural difference between isoprostanes and
prostaglandins is the cis arrangement of the two carbon side
chains on the five-membered ring in isoprostanes. Formulas
of representative examples are collected in Figure 1. F2-,
D2-, and E2-IsoPs are directly formed, while A2- and J2-
IsoPs are presumably derived from E- and D-IsoPs by dehy-
dration.[4]
Figure 1. Important classes of isoprostanes.
The all-cis isomers of the 5-F2 series constitute the most
abundant IsoPs discovered in human urine.[5] Given the all-
cis configuration of the cyclopentane moiety, four stereoiso-
mers are possible: 5-F2c-IsoP (1) and its enantiomer ent-
5-F2c-IsoP (ent-1), as well as 5-epi-5-F2c-IsoP (2) and its
enantiomer 5-epi-ent-5-F2c-IsoP (ent-2) (Figure 2).[6]
Thanks to the chemical stability of F2-IsoPs, the quanti-
fication of these compounds constitutes a reliable method
for assessing the status of oxidative stress in vivo.[7] This
provides an important tool for the exploration of the role
Figure 2. Stereoisomeric isoprostanes of the 5-F2-IsoP series.
[a] Organisch-Chemisches Institut der Ruprecht-Karls-Universität
Heidelberg,
of oxidative stress in the pathogenesis of a variety of human
diseases such as Alzheimer’s disease,[8] arteriosclerosis,[9]
and several lung diseases, such as asthma.[10] Besides their
ability to act as biomarkers of oxidative stress, isoprostanes
have also been shown to possess numerous biological activi-
Im Neuenheimer Feld 270, 69120 Heidelberg
Fax: +49-6221-544205
E-mail: g.helmchen@oci.uni-heidelberg.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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ties. Most of the knowledge available is based on the bio- ous isoprostanes.[3a,21] A highly stereoselective radical cycli-
logical actions of 15-F2t-IsoP, which is a potent vasocon- zation to provide the all-cis Corey lactone analogue 3b was
strictor.[11]
devised by Mulzer and co-workers in 2001.[12d] Recently, the
Many efforts towards the total synthesis of isoprostanes Diels–Alder-based preparation of a precursor of lactone 3
have been made in order to supply necessary amounts for with the CH2OH group replaced by a vinyl group was re-
their in vivo detection and identification, as well as for ex- ported.[22]
amination of their biological properties. The dominant key
Apart from isoprostane synthesis, all-cis lactones 3 are
strategy in isoprostane synthesis is the stereocontrolled con- also of interest for accessing highly substituted cyclopenta-
struction of a functionalized cyclopentane core into which noids with biological significance. Their synthesis should be
the two alkyl side chains are introduced through olefination highly diastereoselective and provide both pure enantio-
reactions.[12–18] Versatile building blocks should be the mers. In this paper we describe a short synthesis of all-cis
monoprotected bicyclic lactones 3 (Scheme 1), all-cis ana- lactone 3a starting from the tricyclic carboxylic acid 4
logues of the well known Corey lactone, which has been (Scheme 1). Enantiomerically pure 4 is readily available in
applied successfully in the synthesis of numerous naturally large quantities (up to 50 g) from cheap starting materials,
occurring prostaglandins.[19] We have now developed a as shown previously by this group.[23] The all-cis lactone 3a
route allowing access to compounds of type 3 from the was used in total syntheses of two isoprostanes of the 5-F2
readily available nortricyclanone (4, see below).
series. As syntheses of isoprostanes 1 and 2 (see Figure 2)
have been reported by Rokach et al.,[24] we decided to pre-
pare the enantiomers ent-1 and ent-2 in order to complete
the characterization of all all-cis isomers of the 5-F2 series,
which would be desirable for biological evaluation.
Results and Discussion
Scheme 1. Lactones of type 3 as key intermediates for syntheses of
isoprostanes.
Preparation of the all-cis Lactone 3
In the first phase of the synthesis, carboxylic acid 4 was
Several syntheses of all-cis isoprostanes involve mono- transformed into the bicyclic lactone 8 by route A or
protected lactones of type 3 as key intermediates. An early route B (Scheme 2).
racemic approach based on a radical addition-acyl mi-
Treatment of the carboxylic acid 4 with aqueous concen-
gration sequence of a bicyclic monoselenoacetal was re- trated HCl at 120 °C proceeded with high selectivity to give
ported by Renaud et al.[20] Most of the stereoselective syn- the exo-chloronorbornane derivative 5 in a pure form and
theses are based on a biomimetic free-radical-induced cycli- in 82% yield after recrystallization. Although racemization
zation as a key step to construct the bicyclic lactone moiety. is unlikely in this step, the enantiomeric purity of 5 was
Rokach’s and Rossi’s groups were the first to implement this determined and found to be Ͼ99% ee.[25] Baeyer–Villiger
strategy in the synthesis of all-cis isoprostanes, although, oxidation of ketone 5 with peracetic acid generated in situ
unfortunately, mixtures of diastereomeric bicyclic lactones at 60 °C gave the lactone 6 with perfect regioselectivity
were obtained in all cases. Nevertheless, bicyclic lactones (Scheme 2, route A). This compound was obtained pure in
isolated from these mixtures were used for syntheses of vari- 88% yield after removal of acetic acid by azeotropic distil-
Scheme 2. Synthesis of the bicyclic lactone 8.
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Building Block for Isoprostane Synthesis
lation with toluene and recrystallization. Lactone 6 dis- alcohols gave low yields.[27] Finally, bicyclic lactone 8 was
played a characteristic 1H NMR signal for C-1 at δ = 5.05– transformed into its p-methoxybenzyl (PMB) ether 9 in
5.08 ppm. Reactions with other peracids such as performic 87% yield by treatment with p-methoxybenzyl trichloro-
acid, mCPBA/NaHCO3, and mCPBA/pTSA proceeded acetimidate in the presence of a catalytic amount of tri-
with low selectivities of 2:1 to 4:1 for secondary vs. primary phenylmethyl tetrafluoroborate.[28] Conversion of the lac-
carbon migration. Chemoselective reduction of carboxylic tone 9 into the targeted all-cis lactone 3 by lactone hydroly-
acid 6 via a mixed anhydride, prepared in situ by treatment sis/nucleophilic displacement was achieved in 82% isolated
with ethyl chloroformate, gave the corresponding alcohol, yield by treatment with lithium hydroxide/hydrogen perox-
which underwent intramolecular transesterification to af- ide in a THF/water mixture as described previously in a
ford bicyclic lactone
chromatography. Among a number of reducing agents in-
8
in 66% yield after column synthesis of the Corey lactone.[26,29]
The five-step sequence starting from carboxylic acid 4
vestigated, zinc borohydride gave the highest chemoselectiv- furnished lactone 3a in an excellent overall yield of 34%.
ity. This reducing agent was previously applied by Corey The presumed configuration was validated by nOe experi-
and co-workers in a synthesis of the Corey lactone.[26]
ments. The proton 3a-H displayed nOes of 5.8% and 5.1%
Reductions of mixed anhydrides derived from cyanuryl to protons 6a-H and 4-H, respectively; this confirms the cis
chloride (2,4,6-trichloro-1,3,5-triazine) and trifluoroacetic relationship of these protons (Figure 3).
acid, as well as the acid chloride of 6, were less effective in
combination with zinc borohydride and sodium borohyd-
ride. Attempts to reduce the carboxylic acid 6 directly with
borane/THF, borane/dimethyl sulfide, or borane generated
in situ from sodium borohydride and iodine also resulted in
lower yields. Lactone 8 was prone to decomposition during
column chromatography on silica gel, though the use of
dried silica gel reproducibly gave the yields stated above.
Figure 3. Nuclear Overhauser effects observed for lactone 3a.
In an alternative route to the bicyclic lactone 8
(Scheme 2, route B) the order of reduction and rearrange-
ment was reversed. Route B began with the chemoselective
reduction of carboxylic acid 5 via the mixed anhydride,
again formed with ethyl chloroformate. With zinc borohyd-
Total Syntheses of the Isoprostanes ent-1 and ent-2
ride (0.25 equiv.) as reducing agent, the carbonyl group of
With the chiral building block 3a to hand, the syntheses
the anhydride moiety was reduced in preference to the keto of isoprostanes ent-1 and ent-2 were elaborated by the strat-
group. The alcohol 7 was obtained in 85% yield after col- egy displayed in Scheme 4. Stereoselective Wittig ole-
umn chromatography. Transformation of 7 into the lactone finations were the key steps.
8 by Baeyer–Villiger oxidation under the conditions de-
For the introduction of the α-side chain, a Horner–
scribed above gave an isolated yield of only 63%; the unde- Wadsworth–Emmons (HWE) olefination was planned.
sired regioisomer could not be detected. In general, both From previous work by Weinges et al. and others[20,21,30] it
pathways are suitable to provide lactone 8 in multigram was clear that a key problem would be epimerization of
quantities.
the aldehyde 10 formed from 3a by oxidation (Scheme 5).
The preparation of an O-protected derivative of lactone Weinges et al. obtained the best results upon protection of
8 turned out to be more difficult than anticipated 5-OH with a benzyl group. Mulzer et al.,[31] as well as Rok-
(Scheme 3). Due to the sensitivity of the lactone moiety ach et al.[32] and Rossi et al.,[21] showed that a 5-O-silyl-pro-
towards base and nucleophiles, effecting either intermo- tected alcohol of type 3 can be oxidized to the correspond-
lecular nucleophilic substitution or C–O cleavage, respec- ing aldehyde without significant epimerization. Addition-
tively, many standard protocols for the protection of ally, Renaud et al. reported that 5-O-silyl-protected alde-
hydes of type 10 do not undergo unwanted side reactions
during HWE olefination as had been observed for p-phen-
ylbenzoyl-protected aldehydes of type 10.[20] After consider-
able experimentation with 3a, we obtained good results
with Dess–Martin periodinane as oxidant. Attempted puri-
fication of 10 caused epimerization to a considerable degree,
but the crude aldehyde 10 was sufficiently pure for the sub-
sequent olefination with β-keto phosphonate 11. In the
event, a mild HWE olefination protocol devised by Masa-
mune and Roush was used.[33] With ethyldiisopropylamine
as base and lithium chloride as additive, the enone 12 was
obtained in 86% overall yield with a high preference (dr =
16:1) for the desired all-cis enone 12. Within the limits of
Scheme 3. Synthesis of key intermediate 3a.
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detection (NMR), only the E isomer was formed.
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Scheme 4. General strategy for the syntheses of isoprostanes ent-1 and ent-2.
Figure 4. Nuclear Overhauser effects observed for enone 12.
enone 12 with BINAL-H[37] was accompanied by reduction
of the lactone CO, and transfer hydrogenation[38] proceeded
with predominant reduction of the double bond.[39]
Finally, good chemoselectivity was obtained with a
Luche reduction (Scheme 6). A mixture of the dia-
stereomeric allylic alcohols 13a and 13b was formed, and
Scheme 5. Preparation of enone 12.
The cis relationship of the substituents on the cyclopen- these were separated by preparative HPLC to give alcohols
tane ring of enone 12 was confirmed by nOe experiments 13a and 13b in 50 and 35% yields, respectively.
(Figure 4).
The relative configuration of C-5 was assigned by Mosh-
For the next step the reduction of enone 12 to the allylic er’s method (Scheme 7).[40] Alcohol 13a was esterified with
alcohols 13a and 13b was investigated. It was hoped that it (S)-O-methylmandelic acid [(+)-14] and (R)-O-methylman-
would be possible to generate both diastereomers selectively delic acid [(–)-14] to give the esters 15a and 15b, respec-
1
using reagent control. However, the Itsuno–Corey pro- tively. Analysis of H NMR spectra allowed an unambigu-
cedure with B-methyl-oxazaborolidine catalyst[34] or with B- ous assignment of the configuration at C-5 (Figure 5).
methoxy-oxazaborolidine catalyst[35] generated in situ with
In a first attempt to prepare the target compounds, the
H3B·THF or H3B·SMe2 as reducing agents did not succeed. OH group in alcohol 13a was protected as a tert-butyldime-
Treatment with catecholborane as stoichiometric reduct- thylsilyl (TBS) ether (Scheme 8). The ω-side chain was com-
ant[36] suffered from low levels of conversion, reduction of pleted by reduction of 16a with DIBAL-H to the lactol
Scheme 6. Preparation of the diastereomeric alcohols 13a and 13b.
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Building Block for Isoprostane Synthesis
Scheme 7. Esterification of alcohol 13a with (S)- and (R)-O-methylmandelic acid.
Figure 5. Assignment of the relative configuration at the stereogenic center C-5.
stage and subsequent Wittig olefination; it was important 20a in very low yield or resulted in decomposition (DDQ,
to mix the pre-cooled lactol with the cold (–45 °C) Wittig cerium ammonium nitrate, CeCl3/NaI,[41] ZrCl4,[42]
reagent derived from phosphonium salt 17. The Z olefin CF3COOH, 1  HCl or Me2S/MgBr2·OEt2[43]).
18a was obtained in 69% isolated yield. Unfortunately, all
It could be argued that steric crowding within 18a might
attempts to remove the PMB group either furnished the diol be responsible for this failure, so it was decided to carry out
Scheme 8. First attempt to synthesize compounds 20.
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Scheme 9. Completion of the synthesis of isoprostanes ent-1 and ent-2.
the deprotection at the stage of the less bulky lactones 16a
and 16b. Indeed, treatment of these with DDQ in a CH2Cl2/
phosphate buffer gave clean formation of alcohols 19a and
19b in 93–94% yields (Scheme 9). Introduction of the ω-
side chain was then accomplished by reduction/Wittig ole-
fination as described above. The Z olefins 20a and 20b were
obtained in 47–60% isolated yields.
The total synthesis was completed as follows. The silyl
groups was removed by treatment with nBu4NF, and the
resultant esters, 21a or 21b (see Exp. Section and Support-
ing Information), were saponified with KOH/methanol.
The isoprostanes ent-1 and ent-2 were obtained in 65 and
77% yields, respectively. The 13C NMR chemical shifts of
ent-1 recorded in [D6]acetone are listed in the Supporting
Information; data are in good agreement with those of Rok-
ach et al.[24] For the assignment of all resonances of ent-1
and ent-2, NMR spectra were recorded in [D6]DMSO in
order to avoid overlapping resonances.
Experimental Section
General Remarks: Melting and boiling points are uncorrected.
NMR spectra were recorded on a Bruker Avance DRX 300
(300.13 MHz and 75.47 MHz for 1H and 13C, respectively) or a
Bruker Avance DRX 500 (500.13 MHz and 125.75 MHz for 1H
and 13C, respectively) spectrometer. The assignments of the reso-
nances are based on 1H,1H COSY, HMQC, and HMBC experi-
ments. Chemical shifts are reported in δ units relative to CHCl3 (δH
1
= 7.24), acetone (δH = 2.04), or DMSO (δH = 2.49) for H NMR
spectra and relative to the central CDCl3, [D6]acetone, or [D6]-
DMSO resonance for 13C NMR spectra. The following abbrevi-
ations were used throughout: s = singlet, d = doublet, t = triplet,
q = quartet, quin = quintet, dd = doublet of doublets, td = triplet
of doublets, m = multiplet, mc = centered, symmetric multiplet.
Optical rotations were measured on a Perkin–Elmer 341 polarime-
ter. Mass spectra were recorded on a JOEL JMS 700 (FAB) or a
ZAB 2F (EI) instrument. Analytical thin-layer chromatography
was performed on precoated TLC plates (Polygram Sil G/UV254
,
Macherey–Nagel); bromocresole green or molybdatophosphoric
acid solutions were used for visualization. For column chromatog-
raphy Macherey–Nagel silica gel grade 60 (0.032–0.062 mm) was
used. For chromatography of sensitive compounds, silica gel was
dried by heating for ca. 24 h at 200 °C under vacuum (0.01 mbar).
Preparative HPLC was carried out with a LATEK silica gel column
(250ϫ21 mm, 5µ). Reagents were purchased from Aldrich or
Fluka. Ethyl chloroformate was distilled prior to use and stored at
5 °C over molecular sieves (4 Å). Zinc borohydride was prepared
as described in the literature[44] and stored under argon at –30 °C.
p-Methoxybenzyl trichloroacetimidate was prepared as described
in the literature[45] and stored under argon at 5 °C. Ketophosphon-
ate 11[46] and Dess–Martin periodinane[47] were prepared as de-
scribed in the literature. THF was distilled from sodium/benzophe-
none ketyl, and dichloromethane was distilled from calcium hy-
dride under argon. Reactions in dry solvents were carried out under
argon with use of standard Schlenk techniques.
Conclusions
A short and efficient stereoselective synthesis of the all-
cis substituted cyclopentane building block 3a has been de-
veloped. This compound is a versatile starting compound
for the synthesis of cyclopentanoid natural products. As ex-
amples, total syntheses of two diastereomeric isoprostanes
belonging to the 5-F2 family – ent-5-F2c-IsoP (ent-1) and 5-
epi-ent-5-F2c-IsoP (ent-2) – have been carried out. Key steps
of the syntheses were the introduction of the two unsatu-
rated alkyl side chains through an E-selective Horner–
Wadsworth–Emmons reaction with the base-sensitive syn-
aldehyde 10 and a Z-selective Wittig olefination. The syn-
theses each required 12 isolated linear steps and each gave
an overall yield, from carboxylic acid 4, of 4%.
(–)-2-Chloro-5-oxobicyclo[2.2.1]heptane-7-carboxylic Acid (5):
mixture of the tricyclic acid (+)-4 (1.00 g, 6.60 mmol) and concen-
trated hydrochloric acid (15 mL) was heated at reflux at 120 °C for
A
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Building Block for Isoprostane Synthesis
2 h in a 50 mL three-necked flask fitted with a reflux condenser
and a thermometer. After the mixture had cooled to room temp.,
water (15 mL) was added, and the mixture was extracted with ethyl
acetate (5ϫ50 mL). The combined organic phases were washed
with brine, dried (Na2SO4), and concentrated under reduced pres-
sure. The solid residue was recrystallized from ethyl acetate/petro-
leum ether to yield chlorocarboxylic acid (–)-5 (1.01 g, 82%) as
colorless rod-like crystals. Rf = 0.16 (petroleum ether/ethyl acetate/
acetic acid, 65:35:0.5). M.p. 134–136 °C. [α]2D0 = –27.0 (c = 3.0,
NMR (300.13 MHz, CDCl3): δ = 1.77 (dd, J = 2.3, J = 18.8 Hz,
1 H, 3-HA), 2.12–2.37 (m, 4 H, 3-HB, 6-H, and OH), 2.55 (d, J =
4.0 Hz, 1 H, 1-H), 2.73–2.83 (m, 2 H, 4-H and 7-H), 3.63–3.69 (mc,
2 H, 1Ј-H), 4.08 (dd, J = 3.4, J = 7.0 Hz, 1 H, 5-H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ = 36.79 (t, C-6), 38.49 (t, C-3), 46.02 (d,
C-4 or C-7), 47.88 (d, C-4 or C-7), 51.14 (d, C-1), 59.05 (d, C-5),
60.02 (t, C-1Ј), 214.94 (s, C-2) ppm. HRMS (EI+): [M]+
(C8H11O237Cl): calcd. 176.0418; found 176.0403; [M]+
(C8H11O235Cl): calcd. 174.0447; found 174.0446. C8H11ClO2
(174.63): calcd. C 55.02, H 6.35, Cl 20.30; found C 54.95, H 6.32,
1
EtOH). H NMR (300.13 MHz, CDCl3): δ = 1.89 (dd, J = 2.5, J
= 18.6 Hz, 1 H, 6-HA), 2.16 (dt, J = 3.8, J = 15.1 Hz, 1 H, 3-HA), Cl 19.65.
2.28 (dd, J = 7.2, J = 14.9 Hz, 1 H, 3-HB), 2.47 (dd, J = 4.9, J =
(–)-(4aR,5R,7R,7aR)-5-Chloro-7-hydroxy-hexahydrocyclopenta[c]-
18.5 Hz, 1 H, 6-HB), 2.87 (d, J = 4.7 Hz, 1 H, 4-H), 3.06 (d, J =
4.5 Hz, 1 H, 1-H), 3.44 (br. s, 1 H, 7-H), 4.10 (dd, J = 3.0, J =
7.2 Hz, 1 H, 2-H), 10.80 (br. s, 1 H, COOH) ppm. 13C NMR
(75.47 MHz, CDCl3): δ = 36.2, 39.0 (2ϫt, C-3 and C-6), 48.3, 49.5,
51.4 (3ϫd, C-1, C-4, and C-7), 58.1 (d, C-2), 177.2 (s, C-8), 211.3
(s, C-5) ppm. C8H9ClO3 (188.60): calcd. C 50.94, H 4.81, Cl 18.80;
found C 50.99, H 4.82, Cl 18.62.
pyran-3(1H)-one (8): A cold (0 °C) solution of (–)-6 (5.0 g,
24.4 mmol) in anhydrous THF (100 mL) was treated dropwise with
ethyl chloroformate (2.3 mL, 24.4 mmol). At the same temperature,
an ice-cold solution of anhydrous triethylamine (3.4 mL,
24.4 mmol) in anhydrous THF (40 mL) was added dropwise. A
white precipitate formed, and the mixture was stirred for another
30 min. The precipitate was filtered off and washed twice with an-
hydrous THF. The red-brown filtrate was cooled to 0 °C, and a
solution of zinc borohydride in DME (17.0 mL, 0.5 ) was added
dropwise. The solution was further stirred at 0 °C for 3 h and was
then diluted with dichloromethane. The mixture was treated with
saturated sodium bitartrate solution until evolution of hydrogen
ceased, which caused precipitation of a white solid. The residue
was filtered off and washed thoroughly with dichloromethane. Dry-
ing of the filtrate (Na2SO4) and evaporation of the solvent afforded
crude (–)-8 as a brownish oil. Flash chromatography (dried silica
gel, petroleum ether/ethyl acetate, 1:1) yielded pure alcohol (–)-8
(3.06 g, 66%) as a yellowish oil. Rf = 0.19 (petroleum ether/ethyl
(–)-6-Chloro-3-oxo-2-oxabicyclo[3.2.1]octane-8-carboxylic Acid (6):
A solution of chlorocarboxylic acid (–)-5 (4.00 g, 21.20 mmol) and
anhydrous sodium acetate (1.74 g, 21.20 mmol) in glacial acetic
acid (40 mL) was stirred at room temperature in a 100 mL three-
necked flask fitted with a reflux condenser, a reaction thermometer,
and a dropping funnel, and hydrogen peroxide (50 wt.-%, 8 mL)
was added dropwise. The reaction mixture was then warmed to
60 °C for 6 h. Ethyl acetate (40 mL) was then added, and the mix-
ture was washed with NaHSO3 solution (10%, 20 mL) in order to
remove peroxides. The aqueous phase was saturated with sodium
chloride and extracted with ethyl acetate (5ϫ100 mL). The organic
phases were combined, washed with brine (50 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was dried by
double addition and evaporation of toluene. The resultant crude
product (4.80 g) was crystallized from ethyl acetate/petroleum ether
to give pure (–)-6 (3.80 g, 88%) as needles. Rf = 0.11 (petroleum
acetate, 1:1). [α]2D0
= –55.6 (c =
1.0, CHCl3). 1H NMR
(500.13 MHz, CDCl3): δ = 1.67 (br. s, 1 H, OH), 2.13 (ddd, J =
5.0, J = 8.3, J = 13.3 Hz, 1 H, 6-HA), 2.24 (ddd, J = 4.6, J = 5.0,
J = 13.5 Hz, 1 H, 6-HB), 2.52 (dd, J = 7.6, J = 14.9 Hz, 1 H, 4-
HA), 2.66–2.72 (m, 1 H, 4a-H), 2.74–2.81 (m, 1 H, 7a-H), 2.79 (dd,
J = 6.6, J = 14.9 Hz, 1 H, 4-HB), 4.10 (dt, J = 5.8, J = 7.9 Hz, 1
H, 5-H), 4.31 (dd, J = 5.5, J = 11.9 Hz, 1 H, 1-HA), 4.47 (dd, J =
7.3, J = 11.9 Hz, 1 H, 1-HB), 4.60 (dt, J = 4.6, J = 6.4 Hz, 1 H, 7-
H) ppm. 13C NMR (125.75 MHz, CDCl3): δ = 32.97 (t, C-4), 39.93
(d, C-7a), 44.79 (d, C-4a), 45.51 (t, C-6), 61.36 (d, C-5), 66.01 (t,
C-1), 71.83 (d, C-7), 172.30 (s, C-3) ppm. C8H11ClO3 (190.63):
calcd. C 50.41, H 5.82, Cl 18.60; found C 50.60, H 5.90, Cl 18.40.
ether/ethyl acetate/acetic acid, 65:35:0.5). M.p. 156–158 °C. [α]2D0
=
1
–103.9 (c = 3.0, EtOH). H NMR (300.13 MHz, [D6]acetone): δ =
2.47 (dd, J = 5.2, J = 16.8 Hz, 1 H, 7-HA), 2.62 (dt, J = 1.1, J =
19.2 Hz, 1 H, 4-HA), 2.82–2.95 (m, 2 H, 5-H and 7-HB), 3.18 (dd,
J = 6.4, J = 19.2 Hz, 1 H, 4-HB), 3.42–3.45 (m, 1 H, 8-H), 4.66
(dd, J = 2.3, J = 7.5 Hz, 1 H, 6-H), 5.05–5.08 (m, 1 H, 1-H) ppm.
13C NMR (75.47 MHz, [D6]acetone): δ = 36.23 (t, C-4), 46.31 (d,
C-5), 46.88 (d, C-7), 47.92 (t, C-8), 62.97 (t, C-6), 80.94 (t, C-1),
168.80 (s, C-3), 171.82 (COOH) ppm. C8H9ClO4 (204.61): calcd. C
46.96, H 4.43, Cl 17.33; found C 46.67, H 4.50, Cl 17.08.
Preparation of Alcohol (–)-8 from Ketone (–)-7: Ketone (–)-7 (2.15 g,
12.30 mmol) was dissolved in a solution of anhydrous sodium ace-
tate (1.00 g, 12.30 mmol) in glacial acetic acid (55 mL) in a 100 mL
three-necked flask fitted with a reflux condenser and a reaction
thermometer. The reaction mixture was stirred at room tempera-
ture, and hydrogen peroxide (50 wt.-%, 4.80 mL) was added drop-
wise. After complete addition, the mixture was warmed to 60 °C
for 3 h and was then diluted with ethyl acetate and washed with
NaHSO3 solution (10%, 20 mL) in order to remove peroxides. The
aqueous phase was reextracted with ethyl acetate (4ϫ50 mL). The
combined organic layers were dried (Na2SO4) and concentrated in
vacuo. The residue was dried by double addition and evaporation
of toluene. The resultant crude (–)-8 was subjected to flash
chromatography (dried silica gel, petroleum ether/ethyl acetate, 1:1)
to give pure alcohol (–)-8 (1.49 g, 63%) as a colorless oil. For ana-
lytical data see previous procedure.
(–)-5-Chloro-7-(hydroxymethyl)bicyclo[2.2.1]heptan-2-one (7):
A
cold (0 °C) solution of (–)-5 (2.0 g, 10.6 mmol) in dry THF (43 mL)
was treated dropwise with ethyl chloroformate (1.0 mL, 10.6 mmol)
and subsequently with an ice-cold solution of dry triethylamine
(1.5 mL, 10.6 mmol) in dry THF (21.5 mL). A white precipitate
formed, and the mixture was stirred for another 30 min. The pre-
cipitate was filtered off and washed twice with a small amount of
anhydrous THF. The filtrate was cooled to 0 °C and was treated
dropwise with a solution of zinc borohydride (5.3 mL, 0.5  in
DME) and further stirred at 0 °C for 30 min. Dichloromethane was
then added, together with saturated sodium bitartrate solution un-
til evolution of hydrogen ceased, which caused precipitation of a
white solid. This was filtered off and washed thoroughly with
dichloromethane. Drying (Na2SO4) of the organic fraction and
evaporation of the solvent afforded crude (–)-7 as a colorless oil.
Flash chromatography (silica gel, petroleum ether/ethyl acetate, 8:2)
yielded pure (–)-7 (1.57 g, 85%) as a colorless oil. Rf = 0.31 (petro-
leum ether/ethyl acetate, 1:1). [α]2D0 = –21.3 (c = 1.0, CHCl3). 1H
(–)-(4aR,5R,7R,7aR)-5-Chloro-7-[(4-methoxybenzyl)oxy]-hexa-
hydrocyclopenta[c]pyran-3(1H)-one (9): A solution of the alcohol
(–)-8 (0.60 g, 3.14 mmol) in dry THF (50 mL) was treated success-
ively at room temperature with p-methoxybenzyl trichloroacetimid-
Eur. J. Org. Chem. 2008, 2551–2563
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2557

P. Elsner, P. Jetter, K. Brödner, G. Helmchen
FULL PAPER
ate (2.60 g, 9.43 mmol) and triphenylcarbonium tetrafluoroborate
(104 mg, 315 µmol). The pale yellow solution was stirred overnight
at room temperature and then diluted with THF (20 mL), and the
resultant mixture was treated with saturated NaHCO3 solution.
The organic solvent was evaporated under reduced pressure, and
the remaining aqueous phase was extracted with dichloromethane
(3ϫ50 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. Flash chromatography of the residue (dried
silica gel, petroleum ether/ethyl acetate, 75:25) yielded pure (–)-9
(0.86 g, 87%) as a yellowish oil. Rf = 0.56 (petroleum ether/ethyl
acetate, 1:1). [α]2D0 = –28.7 (c = 1.8, EtOH). 1H NMR (300.13 MHz,
CDCl3): δ = 2.01 (ddd, J = 4.9, J = 7.8, J = 13.0 Hz, 1 H, 6-HA),
Freshly fused LiCl (237 mg, 5.58 mmol) was suspended in dry ace-
tonitrile (51 mL) in a Schlenk tube, and phosphonate 11 (1.64 g,
5.58 mmol) and iPr2NEt (0.97 mL, 5.58 mmol) were then added at
room temperature. After the mixture had been stirred for 15 min,
a solution of aldehyde 10 in dry acetonitrile (20 mL) was added by
syringe and the resulting solution was stirred for 1.5 h at room
temperature. The reaction mixture was treated with saturated
NaHCO3 solution (25 mL) and with water (25 mL). The aqueous
phase was extracted with ethyl acetate (3ϫ25 mL) and the com-
bined organic layers were dried with MgSO4. Evaporation of the
solvent afforded an oily residue that was subjected to flash column
chromatography (silica gel, petroleum ether/ethyl acetate, 1:1) to
2.34–2.45 (m, 2 H, 4-HA and 6-HB), 2.66 (mc, 1 H, 4a-H), 2.76– yield enone (+)-12 (1.73 g, 81%) and 4Ј-epi-12 (0.11 g, 5%) as col-
2.86 (m, 2 H, 4-HB and 7a-H), 3.79 (s, 3 H, OCH3), 4.04 (dd, J = orless oils. Rf(12) = 0.21 (petroleum ether/ethyl acetate, 1:1), Rf(4Ј-
5.7, J = 13.5 Hz, 1 H, 5-H), 4.21–4.27 (m, 2 H, 1-HA and 7-H), epi-12) = 0.24 (petroleum ether/ethyl acetate, 1:1). [α]2D0 = +7.6 (c
1
4.32 (d, J = 11.5 Hz, 1 H, 1Ј-HA), 4.38 (dd, J = 9.4, J = 12.0 Hz,
= 1.15, CHCl3). H NMR (500.13 MHz, CDCl3): δ = 1.42 [s, 9 H,
1 H, 1-HB), 4.50 (d, J = 11.5 Hz, 1 H, 1Ј-HB), 6.87 (d, J = 8.6 Hz, OC(CH3)3], 1.77 (ddd, J = 3.7, J = 6.7, J = 15.7 Hz, 1 H, 6Ј-HA),
2 H, Ar-H), 7.19 (d, J = 8.6 Hz, 2 H, Ar-H) ppm. 13C NMR
1.87 (quin, J = 7.4 Hz, 2 H, 3-H), 2.24 (t, J = 7.4 Hz, 2 H, 4-H),
(75.47 MHz, CDCl3): δ = 32.89 (t, C-4), 39.48 (d, C-7a), 41.38 (t, 2.47–2.53 (m, 2 H, 3Ј-HA and 6Ј-HB), 2.57 (t, J = 7.4 Hz, 2 H, 2-
C-6), 44.45 (d, C-4a), 55.28 (q, OCH3), 61.39 (d, C-5), 65.89 (t, C- H), 2.69–2.77 (m, 2 H, 3Ј-HB and 4Ј-H), 3.12–3.19 (m, 1 H, 3Јa-
1), 71.54 (t, C-1Ј), 77.87 (d, C-7), 113.92 (d, Ar-CH), 129.09 (d,
H), 3.77 (s, 3 H, OCH3), 3.99 (t, J = 3.4 Hz, 1 H, 5Ј-H), 4.19 (d, J
= 11.4 Hz, 1 H, 1ЈЈ-HA), 4.55 (d, J = 11.4 Hz, 1 H, 1ЈЈ-HB), 5.11
Ar-CH), 129.63 (s, Ar-C), 159.37 (s, Ar-C), 172.02 (s, C-3) ppm.
HRMS (EI+): [M]+ (C16H19O437Cl): calcd. 312.0942; found (t, J = 6.7 Hz, 1 H, 6Јa-H), 6.12 (d, J = 16.1 Hz, 1 H, 6-H), 6.84
312.0964; [M]+ (C16H19O435Cl): calcd. 310.0972; found 310.0991.
(d, J = 8.7 Hz, 2 H, Ar-H), 6.94 (dd, J = 7.7, J = 16.4 Hz, 1 H, 7-
H), 7.17 (d, J = 8.7 Hz, 2 H, Ar-H) ppm. 13C NMR (125.75 MHz,
CDCl3): δ = 19.37 (t, C-3), 28.10 [q, OC(CH3)3], 31.08 (t, C-3Ј),
34.56 (t, C-4), 37.25 (t, C-6Ј), 38.97 (t, C-2), 41.48 (d, C-3Јa), 49.74
(d, C-4Ј), 55.23 (q, OCH3), 70.38 (t, C-1ЈЈ), 80.30 [s, OC(CH3)3],
81.07 (d, C-5Ј), 84.11 (d, C-6Јa), 113.82 (d, Ar-CH), 129.43 and
129.54 (d and s, Ar-CH and Ar-C), 132.87 (d, C-6), 142.14 (d, C-
7), 159.28 (s, Ar-C), 172.49 (s, C-1), 176.97 (s, C-2Ј), 199.27 (s, C-
5) ppm. C26H34O7 (458.55): calcd. C 68.10, H 7.47; found C 68.07,
H 7.54.
(–)-(3aR,4R,5R,6aS)-4-(Hydroxymethyl)-5-[(4-methoxybenzyl)oxy]-
hexahydro-2H-cyclopenta[b]furan-2-one (3a): A solution of (–)-9
(1.00 g, 3.22 mmol) in THF (11 mL) was treated dropwise at room
temperature with hydrogen peroxide (50 wt.-%; 3.70 mL) and with
lithium hydroxide (1  in water, 3.22 mL). After 24 h (TLC moni-
toring), peroxides were destroyed by addition of NaHSO3 solution
(10%), and the organic solvent was removed under reduced pres-
sure. The remaining aqueous phase was saturated with sodium
chloride and extracted with ethyl acetate (5ϫ30 mL), and the or-
ganic layer was dried (Na2SO4) and concentrated in vacuo to give
crude (–)-3a as a yellowish oil. Flash chromatography (silica gel,
petroleum ether/ethyl acetate, 1:1, to ethyl acetate) yielded pure lac-
tone (–)-3a (0.77 g, 82%) as a colorless oil. Rf = 0.06 (petroleum
ether/ethyl acetate, 1:1). [α]2D0 = –52.0 (c = 1.1, EtOH). 1H NMR
tert-Butyl (6E)-5-Hydroxy-7-{(3aR,4S,5R,6aS)-5-[(4-methoxyben-
zyl)oxy]-2-oxo-hexahydro-2H-cyclopenta[b]furan-4-yl}hept-6-enoate
(13): A solution of enone (+)-12 (1.73 g, 3.77 mmol) in dry meth-
anol (17 mL) in a Schlenk tube was treated with CeCl3·7 H2O
(1.41 g, 3.77 mmol), and the resulting slurry was stirred until all
(300.13 MHz, CDCl3): δ = 1.71 (ddd, J = 3.8, J = 6.6, J = 15.6 Hz, the solid was dissolved (approx. 15 min). After the solution had
1 H, 6-HA), 2.08–2.17 (mc, 1 H, 4-H), 2.45–2.55 (m, 2 H, 3-HA and
6-HB), 2.83 (dd, J = 4.6, J = 18.5 Hz, 1 H, 3-HB), 3.05–3.16 (mc,
been cooled to 0 °C, NaBH4 (143 mg, 3.77 mmol) was added in
small portions. After 1.5 h the reaction mixture was treated with
1 H, 3a-H), 3.77 (s, 3 H, OCH3), 3.79–3.93 (m, 2 H, 1ЈЈ-H), 4.03 water and saturated with sodium chloride. The aqueous phase was
(t, J = 3.7 Hz, 1 H, 5-H), 4.15 (d, J = 11.5 Hz, 1 H, 1Ј-HA), 4.56
(d, J = 11.5 Hz, 1 H, 1Ј-HB), 5.10 (t, J = 7.2 Hz, 1 H, 6a-H), 6.85
(d, J = 8.7 Hz, 2 H, Ar-H), 7.18 (d, J = 8.7 Hz, 2 H, Ar-H) ppm.
extracted with ethyl acetate (5ϫ20 mL) and the combined organic
layers were dried with Na2SO4. The solvent was evaporated under
reduced pressure and the residue was subjected to flash chromatog-
13C NMR (75.47 MHz, CDCl3): δ = 30.31 (t, C-3), 36.83 (t, C-6), raphy (silica gel, petroleum ether/ethyl acetate, 1:1) to yield a mix-
38.72 (d, C-3a), 48.94 (d, C-4), 55.25 (q, OCH3), 59.82 (t, C-1ЈЈ),
70.13 (t, C-1Ј), 79.48 (d, C-5), 84.52 (d, C-6a), 113.83 (d, Ar-CH),
ture of diastereomeric alcohols 13a and 13b (1.53 g, 88%) as a col-
orless oil. Separation of the diastereomers was accomplished by
129.36 (d, Ar-CH), 129.85 (s, Ar-C), 159.24 (s, Ar-C), 177.75 (s, C- preparative HPLC (column: LATEK 250ϫ21 mm, 5 µ silica gel,
2) ppm. C16H20O5 (292.33): calcd. C 65.74, H 6.90; found C 65.64,
H 6.90.
solvent: petroleum ether/ethyl acetate, 1:1; flow: 20 mLmin–1, UV
detection at 254 nm) to afford pure alcohol (–)-13a (878 mg, 50%)
and pure alcohol (–)-13b (616 mg, 35%).
(+)-tert-Butyl (6E)-7-{(3aR,4S,5R,6aS)-5-[(4-Methoxybenzyl)oxy]-
2-oxo-hexahydro-2H-cyclopenta[b]furan-4-yl}-5-oxohept-6-enoate
(12): A solution of lactone (–)-3a (1.36 g, 4.65 mmol) and Dess–
Analytical Data for (–)-13a: Rf = 0.13 (petroleum ether/ethyl ace-
1
tate, 1:1). [α]2D0 = –10.7 (c = 1.07, CHCl3). H NMR (500.13 MHz,
Martin periodinane (2.37 g, 5.58 mmol) in dry dichloromethane CDCl3): δ = 1.41 [s, 9 H, OC(CH3)3], 1.43–1.66 (m, 4 H, 3-H and
(51 mL) was stirred at room temperature for 1.5 h. Diethyl ether
(50 mL) was then added, and the resulting white suspension was
poured into a solution of Na2S2O3 (0.25 ) in a saturated NaHCO3
solution (40 mL). The mixture was stirred until dissolution of the
solid material, and then the layers were separated. The organic
layer was extracted with saturated NaHCO3 solution (40 mL) and
water (40 mL), dried (MgSO4), and concentrated under reduced
pressure to give the crude aldehyde 10 as an oily residue.
4-H), 1.72–1.77 (m, 2 H, 6Ј-HA and OH), 2.21 (td, J = 2.7, J =
7.1 Hz, 2 H, 2-H), 2.41–2.47 (m, 2 H, 3Ј-HA and 6Ј-HB), 2.59 (td,
J = 3.9, J = 8.3 Hz, 1 H, 4Ј-H), 2.74 (dd, J = 4.7, J = 18.3 Hz,
1 H, 3Ј-HB), 2.99–3.06 (mc, 1 H, 3Јa-H), 3.76 (s, 3 H, OCH3), 3.89
(t, J = 3.4 Hz, 1 H, 5Ј-H), 4.06 (q, J = 6.9 Hz, 1 H, 5-H), 4.17 (d,
J = 11.3 Hz, 1 H, 1ЈЈ-HA), 4.52 (d, J = 11.7 Hz, 1 H, 1ЈЈ-HB), 5.05
(t, J = 6.9 Hz, 1 H, 6Јa-H), 5.56 (dd, J = 6.9, J = 15.7 Hz, 1 H, 6-
H), 5.84 (dd, J = 8.3, J = 15.7 Hz, 1 H, 7-H), 6.83 (d, J = 8.3 Hz,
2558
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2551–2563

Building Block for Isoprostane Synthesis
2 H, Ar-H), 7.17 (d, J = 8.3 Hz, 2 H, Ar-H) ppm. 13C NMR
CH), 128.74 (d, C-7), 129.21 (d, Ar-CH), 129.37 (d, Ar-CH), 129.88
(125.75 MHz, CDCl3): δ = 20.80 (t, C-3), 28.07 [q, OC(CH3)3], (s, Ar-C), 131.24 (d, C-6), 136.29 (s, Ar-C), 159.13 (s, Ar-C), 169.93
30.95 (t, C-3Ј), 35.12 (t, C-2), 36.46 (t, C-4), 37.10 (t, C-6Ј), 41.68 (s, C-1Ј), 172.37 (s, C-1), 177.41 (s, C-2ЈЈ) ppm. HRMS (FAB+):
(d, C-3Јa), 49.51 (d, C-4Ј), 55.20 (q, OCH3), 70.31 (t, C-1ЈЈ), 72.27
[M + K]+ (C35H44O9K): calcd. 647.2622; found 647.2573; [M –
(d, C-5), 80.20 [s, OC(CH3)3], 81.60 (d, C-5Ј), 84.30 (d, C-6Јa), H]+ (C35H43O9): calcd. 607.2907; found 607.2870.
113.68 (d, Ar-CH), 126.92 (d, C-7), 129.35 (d, Ar-CH), 129.94 (s,
(–)-tert-Butyl (5R,6E)-7-{(3aR,4S,5R,6aS)-5-[(4-Methoxybenzyl)-
Ar-C), 136.55 (d, C-6), 159.10 (s, Ar-C), 172.95 (s, C-1), 177.55 (s,
C-2Ј) ppm. C26H36O7 (460.56): calcd. C 67.80, H 7.88; found C
67.58, H 7.71.
oxy]-2-oxo-hexahydro-2H-cyclopenta[b]furan-4-yl}-5-{[(2R)-2-meth-
oxy-2-phenylacetyl]oxy}hept-6-enoate (15b): Compound 15b was
prepared from alcohol (–)-13a (12.5 mg, 27.0 µmol) as described
above for ester 15a. Flash chromatography (silica gel, petroleum
ether/ethyl acetate, 6:4) and preparative HPLC (solvent: petroleum
ether/ethyl acetate, 1:1; flow: 20 mLmin–1, UV detection at 254 nm)
Analytical Data for (–)-13b: Rf = 0.07 (petroleum ether/ethyl ace-
1
tate, 1:1). [α]2D0 = –20.7 (c = 1.27, CHCl3). H NMR (300.13 MHz,
CDCl3): δ = 1.42 [s, 9 H, OC(CH3)3], 1.47–1.67 (m, 4 H, 3-H and
4-H), 1.71–1.79 (m, 2 H, 6Ј-HA and OH), 2.22 (t, J = 7.0 Hz, 2 H, afforded ester (–)-15b (14.4 mg, 88%) as a colorless oil. Rf = 0.20
2-H), 2.41–2.51 (m, 2 H, 3Ј-HA and 6Ј-HB), 2.59 (td, J = 3.7, J = (petroleum ether/ethyl acetate, 1:1). [α]2D0 = –46.1 (c = 1.70, CHCl3).
8.1 Hz, 1 H, 4Ј-H), 2.78 (dd, J = 4.0, J = 18.4 Hz, 1 H, 3Ј-HB),
2.99–3.10 (mc, 1 H, 3Јa-H), 3.77 (s, 3 H, OCH3), 3.89 (t, J = 3.3 Hz,
1 H, 5Ј-H), 4.07 (q, J = 7.0 Hz, 1 H, 5-H), 4.18 (d, J = 11.4 Hz, 1
H, 1ЈЈ-HA), 4.51 (d, J = 11.4 Hz, 1 H, 1ЈЈ-HB), 5.06 (t, J = 7.0 Hz,
1H NMR (300.13 MHz, CDCl3): δ = 1.41 [s, 9 H, OC(CH3)3], 1.49–
1.70 (m, 5 H, 3-H, 4-H and 6ЈЈ-HA), 2.15–2.25 (m, 3 H, 2-H and
3ЈЈ-HA), 2.36–2.45 (m, 3 H, 3ЈЈ-HB, 4ЈЈ-H and 6ЈЈ-HB), 2.82–2.93
(mc, 1 H, 3aЈЈ-H), 3.36 (s, 3 H, OCH3), 3.74–3.78 (m, 1 H, 5ЈЈ-H),
1 H, 6Јa-H), 5.57 (dd, J = 6.8, J = 15.6 Hz, 1 H, 6-H), 5.83 (dd, J 3.77 (s, 3 H, OCH3), 4.12 (d, J = 11.5 Hz, 1 H, 1ЈЈЈ-HA), 4.44 (d,
= 7.9, J = 15.6 Hz, 1 H, 7-H), 6.83 (d, J = 8.8 Hz, 2 H, Ar-H), 7.17
J = 11.5 Hz, 1 H, 1ЈЈЈ-HB), 4.73 (s, 1 H, 2Ј-H), 4.99 (t, J = 7.0 Hz,
1 H, 6aЈЈ-H), 5.24–5.29 (mc, 1 H, 5-H), 5.36 (dd, J = 5.8, J =
(d, J = 8.5 Hz, 2 H, Ar-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ
= 20.81 (t, C-3), 28.11 [q, OC(CH3)3], 31.06 (t, C-3Ј), 35.15 (t, C- 15.5 Hz, 1 H, 6-H), 5.57 (dd, J = 7.7, J = 15.5 Hz, 1 H, 7-H), 6.85
2), 36.53 (t, C-4), 37.14 (t, C-6Ј), 41.54 (d, C-3Јa), 49.54 (d, C-4Ј),
55.22 (q, OCH3), 70.39 (t, C-1ЈЈ), 72.32 (d, C-5), 80.22 [s, OC-
(d, J = 8.7 Hz, 2 H, Ar-H), 7.13 (d, J = 8.7 Hz, 2 H, Ar-H), 7.25–
7.29 (m, 3 H, Ar-H), 7.35–7.38 (m, 2 H, Ar-H) ppm. 13C NMR
(CH3)3], 81.79 (d, C-5Ј), 84.29 (d, C-6Јa), 113.73 (d, Ar-CH), (75.47 MHz, CDCl3): δ = 20.53 (t, C-3), 28.08 [q, OC(CH3)3], 30.69
126.88 (d, C-7), 129.33 (d, Ar-CH), 129.97 (s, Ar-C), 136.65 (d, C-
6), 159.15 (s, Ar-C), 172.98 (s, C-1), 177.58 (s, C-2Ј) ppm. C26H36O7
(460.56): calcd. C 67.80, H 7.88; found C 67.68, H 8.05.
(t, C-3ЈЈ), 33.60 (t, C-4), 34.89 (t, C-2), 37.15 (t, C-6ЈЈ), 41.45 (d,
C-3ЈЈa), 49.61 (d, C-4ЈЈ), 55.21 (q, OCH3), 57.21 (q, OCH3), 70.19
(t, C-1ЈЈЈ), 74.21 (d, C-5), 80.24 [s, OC(CH3)3], 81.28 (d, C-5ЈЈ),
82.54 (d, C-2Ј), 84.08 (d, C-6ЈЈa), 113.68 (d, Ar-CH), 127.09 (d, Ar-
CH), 128.30 (d, C-7), 128.65 (d, Ar-CH), 128.84 (d, Ar-CH), 129.37
(d, Ar-CH), 129.90 (s, Ar-C), 130.84 (d, C-6), 136.13 (s, Ar-C),
159.10 (s, Ar-C), 169.81 (s, C-1Ј), 172.95 (s, C-1), 177.55 (s, C-
2ЈЈ) ppm. HRMS (FAB+): [M + K]+ (C35H44O9K): calcd.
647.2622; found 647.2591; [M – H]+ (C35H43O9): calcd. 607.2907;
found 607.2848.
(+)-tert-Butyl (5R,6E)-7-{(3aR,4S,5R,6aS)-5-[(4-Methoxybenzyl)-
oxy]-2-oxo-hexahydro-2H-cyclopenta[b]furan-4-yl}-5-{[(2S)-2-
methoxy-2-phenylacetyl]oxy}hept-6-enoate (15a): DCC (9.0 mg,
43.0 µmol) was added to a cold (0 °C) solution of alcohol (–)-13a
(16.6 mg, 36.0 µmol), (S)-O-methylmandelic acid ((+)-14, 18.0 mg,
108.0 µmol), and DMAP (1.0 mg, 8.2 µmol) in dry dichlorometh-
ane (1 mL). The solution was allowed to warm to room tempera-
ture and was stirred overnight. Dichloromethane was then added,
and the mixture was filtered through a short pad of Celite in order
to remove the solids. The filtrate was washed with aqueous HCl
(0.5 ) and brine, dried with MgSO4, and concentrated in vacuo.
The residue was subjected to flash chromatography (silica gel, pe-
troleum ether/ethyl acetate, 6:4) to yield (+)-15a (19.1 mg, 86%) as
a colorless oil that contained traces of N,N-dicyclohexylurea. The
compound was purified by preparative HPLC (solvent: petroleum
ether/ethyl acetate, 1:1; flow: 20 mL min–1, UV detection at
(–)-tert-Butyl (5R,6E)-5-{[tert-Butyl(dimethyl)silyl]oxy}-7-
{(3aR,4S,5R,6aS)-5-[(4-methoxybenzyl)oxy]-2-oxo-hexahydro-2H-
cyclopenta[b]furan-4-yl}hept-6-enoate (16a): A solution of alcohol
(–)-13a (93.9 mg, 0.2 mmol), imidazole (27.3 mg, 0.4 mmol), and
TBSCl (46.1 mg, 0.3 mmol) in dry dichloromethane (1 mL) was
stirred at room temperature overnight. Saturated NaHCO3 solution
(2 mL) was then added, and the aqueous phase was extracted with
ethyl acetate (4ϫ10 mL). The combined organic layers were dried
with Na2SO4 and the solvent was evaporated under reduced pres-
sure. Flash chromatography (silica gel, petroleum ether/ethyl ace-
tate, 78:22) afforded pure (–)-16a (108.0 mg, 91%) as a colorless
oil. Rf = 0.64 (petroleum ether/ethyl acetate, 1:1). [α]2D0 = –18.2 (c
= 1.03, CHCl3). 1H NMR (300.13 MHz, CDCl3): δ = –0.05 (s, 3
H, SiCH3), 0.00 (s, 3 H, SiCH3), 0.83 [s, 9 H, SiC(CH3)3], 1.41 [s,
254 nm). Rf = 0.22 (petroleum ether/ethyl acetate, 1:1). [α]2D0
=
+19.7 (c = 1.06, CHCl3). 1H NMR (300.13 MHz, CDCl3): δ =
1.24–1.36 (m, 2 H, 3-H), 1.39 [s, 9 H, OC(CH3)3], 1.46–1.60 (m, 2
H, 4-H), 1.70 (ddd, J = 3.7, J = 6.7, J = 15.5 Hz, 1 H, 6ЈЈ-HA),
2.02 (t, J = 7.4 Hz, 2 H, 2-H), 2.32–2.46 (m, 2 H, 3ЈЈ-HA and 6ЈЈ-
HB), 2.54 (td, J = 3.5, J = 8.0 Hz, 1 H, 4ЈЈ-H), 2.64 (dd, J = 4.6, 9 H, OC(CH3)3], 1.43–1.63 (m, 4 H, 3-H and 4-H), 1.71 (ddd, J =
J = 18.6 Hz, 1 H, 3ЈЈ-HB), 2.95–3.06 (mc, 1 H, 3aЈЈ-H), 3.36 (s, 3 3.5, J = 6.6, J = 15.5 Hz, 1 H, 6Ј-HA), 2.17 (t, J = 7.3 Hz, 2 H, 2-
H, OCH3), 3.76 (s, 3 H, OCH3), 3.87 (t, J = 3.5 Hz, 1 H, 5ЈЈ-H), H), 2.38–2.48 (m, 2 H, 3Ј-HA and 6Ј-HB), 2.56 (td, J = 3.7, J =
4.16 (d, J = 11.5 Hz, 1 H, 1ЈЈЈ-HA), 4.50 (d, J = 11.5 Hz, 1 H, 1ЈЈЈ- 8.2 Hz, 1 H, 4Ј-H), 2.79 (dd, J = 4.6, J = 18.4 Hz, 1 H, 3Ј-HB),
HB), 4.70 (s, 1 H, 2Ј-H), 5.05 (t, J = 7.0 Hz, 1 H, 6aЈЈ-H), 5.22 (q,
J = 6.5 Hz, 1 H, 5-H), 5.50 (dd, J = 6.5, J = 15.6 Hz, 1 H, 6-H),
5.85 (dd, J = 7.9, J = 15.6 Hz, 1 H, 7-H), 6.84 (d, J = 8.7 Hz, 2 H,
2.98–3.09 (mc, 1 H, 3Јa-H), 3.76 (s, 3 H, OCH3), 3.86 (t, J = 3.8 Hz,
1 H, 5Ј-H), 4.06 (q, J = 6.1 Hz, 1 H, 5-H), 4.16 (d, J = 11.3 Hz, 1
H, 1ЈЈ-HA), 4.51 (d, J = 11.3 Hz, 1 H, 1ЈЈ-HB), 5.06 (t, J = 7.1 Hz,
Ar-H), 7.17 (d, J = 8.7 Hz, 2 H, Ar-H), 7.27–7.32 (m, 3 H, Ar-H), 1 H, 6Јa-H), 5.50 (dd, J = 6.3, J = 15.7 Hz, 1 H, 6-H), 5.76 (dd, J
7.37–7.41 (m, 2 H, Ar-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 7.7, J = 15.5 Hz, 1 H, 7-H), 6.82 (d, J = 8.7 Hz, 2 H, Ar-H),
= 20.30 (t, C-3), 28.06 [q, OC(CH3)3], 30.87 (t, C-3ЈЈ), 33.41 (t, C-
4), 34.79 (t, C-2), 37.20 (t, C-6ЈЈ), 41.59 (d, C-3ЈЈa), 49.55 (d, C-
4ЈЈ), 55.21 (q, OCH3), 57.30 (q, OCH3), 70.31 (t, C-1ЈЈЈ), 74.66 (d,
7.16 (d, J = 8.7 Hz, 2 H, Ar-H) ppm. 13C NMR (125.76 MHz,
CDCl3): δ = –4.77 (q, SiCH3), –4.30 (q, SiCH3), 18.15 [s, SiC-
(CH3)3], 20.95 (t, C-3), 25.82 [q, SiC(CH3)3], 28.09 [q, OC(CH3)3],
C-5), 80.14 [s, OC(CH3)3], 81.33 (d, C-5ЈЈ), 82.68 (d, C-2Ј), 84.19 30.90 (t, C-3Ј), 35.45 (t, C-2), 37.13 (t, C-6Ј), 37.52 (t, C-4), 41.70
(d, C-6ЈЈa), 113.73 (d, Ar-CH), 127.11 (d, Ar-CH), 128.59 (d, Ar- (d, C-3Јa), 49.72 (d, C-4Ј), 55.19 (q, OCH3), 70.34 (t, C-1ЈЈ), 73.02
Eur. J. Org. Chem. 2008, 2551–2563
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2559

P. Elsner, P. Jetter, K. Brödner, G. Helmchen
FULL PAPER
(d, C-5), 79.95 [s, OC(CH3)3], 81.89 (d, C-5Ј), 84.35 (d, C-6Јa), sion was stirred for 4 h at room temperature (TLC monitoring).
113.67 (d, Ar-CH), 125.42 (d, C-7), 129.31 (d, Ar-CH), 129.98 (s, Dichloromethane was then added, and the mixture was filtered
Ar-C), 137.14 (d, C-6), 159.08 (s, Ar-C), 172.92 (s, C-1), 177.68 (s, through a short pad of Celite. Evaporation of the solvent under
C-2Ј) ppm. C32H50O7Si (574.83): calcd. C 66.86, H 8.77; found C
67.13, H 8.69.
reduced pressure afforded crude alcohol 19a, which was purified
by flash chromatography (silica gel, petroleum ether/ethyl acetate,
7:3) to yield pure (+)-19a (60 mg, 93%) as a colorless oil. Rf = 0.39
(petroleum ether/ethyl acetate, 1:1). [α]2D0 = +9.9 (c = 1.75, CHCl3).
1H NMR (300.13 MHz, CDCl3): δ = 0.01 (s, 3 H, SiCH3), 0.03 (s,
3 H, SiCH3), 0.87 [s, 9 H, SiC(CH3)3], 1.41 [s, 9 H, OC(CH3)3],
1.45–1.69 (m, 5 H, 3-H, 4-H and OH), 1.96 (ddd, J = 3.8, J = 6.7,
J = 15.2 Hz, 1 H, 6Ј-HA), 2.17–2.22 (m, 3 H, 2-H and 6Ј-HB), 2.44–
2.60 (m, 2 H, 3Ј-HA and 4Ј-H), 2.77 (dd, J = 4.6, J = 18.6 Hz, 1
H, 3Ј-HB), 2.99–3.10 (mc, 1 H, 3Јa-H), 4.12 (q, J = 6.1 Hz, 1 H, 5-
H), 4.26 (t, J = 3.2 Hz, 1 H, 5Ј-H), 5.07 (t, J = 7.2 Hz, 1 H, 6Јa-
H), 5.59 (dd, J = 6.1, J = 15.6 Hz, 1 H, 6-H), 5.77 (dd, J = 7.7, J
= 15.6 Hz, 1 H, 7-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ =
–4.77 (q, SiCH3), –4.29 (q, SiCH3), 18.20 [s, SiC(CH3)3], 20.91 (t,
C-3), 25.85 [q, SiC(CH3)3], 28.10 [q, OC(CH3)3], 31.34 (t, C-3Ј),
35.41 (t, C-2), 37.41 (t, C-4), 41.27 (d, C-3Јa), 42.00 (t, C-6Ј), 50.07
(d, C-4Ј), 72.86 (d, C-5), 75.62 (d, C-5Ј), 80.09 [s, OC(CH3)3], 84.67
(d, C-6Јa), 124.99 (d, C-7), 137.93 (d, C-6), 172.99 (s, C-1), 177.67
(s, C-2Ј) ppm. C24H42O6Si (454.68): calcd. C 63.40, H 9.31; found
C 63.20, H 9.26.
(+)-tert-Butyl (5R,6E,8β,9β,11β,14Z)-5-{[tert-Butyl(dimethyl)silyl]-
oxy}-9-[(4-methoxybenzyl)oxy]-11-hydroxyprosta-6,14-dien-1-oate
(18a): A solution of DIBAL-H (1  in hexane, 704 µL) was added
slowly by syringe to a cooled (–78 °C) solution of (–)-16a (332 mg,
578 µmol) in dry THF (13 mL). After the mixture had been stirred
for 15 min at –78 °C, another portion of DIBAL-H (500 µL) was
added. Stirring was continued for 15 min and a last portion of DI-
BAL-H (300 µL) was added. After TLC analysis showed complete
consumption of the starting material, methanol (5 mL) and water
(1.3 mL) were added to the cold (–78 °C) mixture, and it was then
allowed to warm to room temperature. The mixture was poured
onto a mixture of MgSO4 (120 g) in diethyl ether (600 mL) and the
resultant slurry was stirred for 1 h at room temperature. The solids
were filtered off and the volatiles were evaporated under reduced
pressure to yield crude lactol.
n-Hexyltriphenylphosphonium bromide (17, 1.05 g, 2.34 mmol) in
dry THF (4 mL) was cooled to –78 °C, and KHMDS (0.5  in
toluene, 4.46 mL) was added by syringe. The resultant orange solu-
tion was allowed to warm to –45 °C over a period of 1 h and was
then added slowly by syringe to a precooled (–45 °C) solution of
the lactol in dry THF (4 mL). The temperature was raised to
–20 °C and the yellow reaction mixture was stirred overnight at this
temperature. Saturated aqueous NH4Cl was added, and the aque-
ous phase was extracted with diethyl ether (4ϫ 50 mL). Drying
over Na2SO4 and evaporation of the solvent afforded crude (+)-
18a, which was purified by flash chromatography (silica gel, petro-
leum ether/diethyl ether, 8:2) to yield pure diene (+)-18a (259 mg,
69%) as a colorless oil. Rf = 0.46 (petroleum ether/ethyl acetate,
6:4). [α]2D0 = +9.0 (c = 0.55, CHCl3). 1H NMR (300.13 MHz,
CDCl3): δ = 0.02 (s, 3 H, SiCH3), 0.04 (s, 3 H, SiCH3), 0.84–0.88
(m, 3 H, 20-H), 0.87 [s, 9 H, SiC(CH3)3], 1.24–1.34 (m, 6 H, 17-H,
18-H and 19-H), 1.41 [s, 9 H, OC(CH3)3], 1.46–1.69 (m, 4 H, 3-H
and 4-H), 1.81–2.12 (m, 6 H, 10-HA, 12-H, 13-HA, 16-H and OH),
2.14–2.26 (m, 4 H, 2-H, 10-HB and 13-HB), 2.72–2.81 (mc, 1 H, 8-
H), 3.78 (s, 3 H, OCH3), 3.89 (q, J = 5.9 Hz, 1 H, 9-H), 4.10–4.16
(m, 2 H, 5-H and 11-H), 4.35 (d, J = 11.5 Hz, 1 H, 1Ј-HA), 4.45
(d, J = 11.3 Hz, 1 H, 1Ј-HB), 5.33–5.40 (m, 2 H, 14-H and 15-H),
5.45 (dd, J = 6.3, J = 15.4 Hz, 1 H, 6-H), 5.82 (dd, J = 10.4, J =
15.4 Hz, 1 H, 7-H), 6.83 (d, J = 8.6 Hz, 2 H, Ar-H), 7.21 (d, J =
8.6 Hz, 2 H, Ar-H) ppm. 13C NMR (75.47 MHz, CDCl3): δ = –4.81
(q, SiCH3), –4.23 (q, SiCH3), 14.05 (q, C-20), 18.20 [s, SiC(CH3)3],
21.11 (t, C-3), 22.57 (t, C-18 or C-19), 24.33 (t, C-13), 25.92 [q,
(+)-tert-Butyl (5S,6E)-5-{[tert-Butyl(dimethyl)silyl]oxy}-7-
[(3aR,4S,5R,6aS)-5-hydroxy-2-oxo-hexahydro-2H-cyclopenta[b]-
furan-4-yl]hept-6-enoate (19b): Compound 19b was prepared from
alcohol (–)-16b (78 mg, 135 µmol) as described above for 19a. Flash
chromatography (silica gel, petroleum ether/ethyl acetate, 7:3) af-
forded alcohol (+)-19b (58 mg, 94%) as a colorless oil. Rf = 0.43
(petroleum ether/ethyl acetate, 1:1). [α]2D0 = +3.8 (c = 1.16, CHCl3).
1H NMR (300.13 MHz, CDCl3): δ = –0.01 (s, 3 H, SiCH3), 0.02
(s, 3 H, SiCH3), 0.85 [s, 9 H, SiC(CH3)3], 1.40 [s, 9 H, OC(CH3)3],
1.44–1.69 (m, 4 H, 3-H, 4-H), 1.94 (ddd, J = 3.8, J = 6.7, J =
15.3 Hz, 1 H, 6Ј-HA), 1.99 (br. s, 1 H, OH), 2.16–2.22 (m, 3 H, 2-
H and 6Ј-HB), 2.44–2.58 (m, 2 H, 3Ј-HA and 4Ј-H), 2.78 (dd, J =
4.4, J = 18.6 Hz, 1 H, 3Ј-HB), 3.00–3.11 (mc, 1 H, 3Јa-H), 4.10 (q,
J = 6.0 Hz, 1 H, 5-H), 4.23 (t, J = 3.4 Hz, 1 H, 5Ј-H), 5.08 (t, J =
7.1 Hz, 1 H, 6Јa-H), 5.57 (dd, J = 6.6, J = 15.6 Hz, 1 H, 6-H), 5.74
(dd, J = 8.1, J = 15.6 Hz, 1 H, 7-H) ppm. 13C NMR (75.47 MHz,
CDCl3): δ = –4.76 (q, SiCH3), –4.28 (q, SiCH3), 18.18 [s, SiC-
(CH3)3], 20.86 (t, C-3), 25.83 [q, SiC(CH3)3], 28.07 [q, OC(CH3)3],
31.30 (t, C-3Ј), 35.31 (t, C-2), 37.38 (t, C-4), 41.24 (d, C-3Јa), 42.00
(t, C-6Ј), 50.03 (d, C-4Ј), 73.05 (d, C-5), 75.54 (d, C-5Ј), 80.12 [s,
OC(CH3)3], 84.77 (d, C-6Јa), 125.22 (d, C-7), 137.82 (d, C-6),
173.09 (s, C-1), 177.86 (s, C-2Ј) ppm. C24H42O6Si (454.68): calcd.
C 63.40, H 9.31; found C 63.12, H 9.19.
(–)-tert-Butyl (5R,6E,8β,9β,11β,14Z)-5-{[tert-Butyl(dimethyl)silyl]-
SiC(CH3)3], 27.37 (t, C-16), 28.10 [q, CO2C(CH3)3], 29.35 (t, C- oxy}-9,11-dihydroxyprosta-6,14-dien-1-oate (20a): A solution of DI-
17), 31.55 (t, C-18 or C-19), 35.57 (t, C-2), 37.97 (t, C-4), 39.96 (t, BAL-H in hexane (1 , 300 µL) was added slowly by syringe to a
C-10), 47.47 (d, C-12), 48.41 (d, C-8), 55.25 (q, OCH3), 70.93 (t, cold (–78 °C) solution of (+)-19a (114 mg, 251 µmol) in dry THF
C-1Ј), 72.74 (d, C-5 or C-11), 73.11 (d, C-5 or C-11), 79.89 [s, (14 mL). After the mixture had been stirred at –78 °C for 15 min,
CO2C(CH3)3], 81.44 (d, C-9), 113.69 (d, Ar-CH), 127.67 (d, C-7), another portion of DIBAL-H (300 µL) was added. Stirring was
128.38 (d, C-14 or C-15), 129.13 (d, Ar-CH), 130.50 (d, C-14 or C-
15), 130.83 (s, Ar-C), 136.07 (d, C-6), 159.07 (s, Ar-C), 173.00 (s,
C-1) ppm. C38H64O6Si (645.01): calcd. C 70.76, H 10.00; found C
70.80, H 9.93.
continued for 15 min and a last portion of DIBAL-H (60 µL) was
added (TLC monitoring). Methanol (2.3 mL) and water (0.5 mL)
were added at –78 °C, and the reaction mixture was allowed to
warm to room temperature. The mixture was poured onto a mix-
ture of MgSO4 (51 g) and diethyl ether (255 mL) and was then
stirred for 1 h at room temperature. The solids were filtered off,
and the volatiles were evaporated under reduced pressure to yield
crude lactol.
(+)-tert-Butyl (5R,6E)-5-{[tert-Butyl(dimethyl)silyl]oxy}-7-
[(3aR,4S,5R,6aS)-5-hydroxy-2-oxo-hexahydro-2H-cyclopenta[b]-
furan-4-yl]hept-6-enoate (19a): A solution of lactone (–)-16a
(82 mg, 142 µmol) in dichloromethane (2 mL) was treated at room
temperature with a KH2PO4/Na2HPO4 buffer solution (pH 7.2,
0.7 mL) and DDQ (49 mg, 213 µmol). The resultant green suspen-
A solution of hexyltriphenylphosphonium bromide (17, 677 mg,
1.50 mmol) in dry THF (6 mL) was cooled to –78 °C, and
2560
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2551–2563

Building Block for Isoprostane Synthesis
KHMDS (0.5  in toluene, 2.90 mL) was added by syringe. The
0.73, MeOH). 1H NMR (500.13 MHz, CDCl3): δ = 0.86 (t, J =
resulting orange solution was allowed to warm to –45 °C over a 6.9 Hz, 3 H, 20-H), 1.22–1.35 (m, 6 H, 17-H, 18-H, and 19-H),
period of 1 h and was then added slowly by syringe to a precooled
(–45 °C) solution of the lactol in dry THF (6 mL). The temperature
was raised to –25 °C and the yellow reaction mixture was stirred
overnight at this temperature. Saturated aqueous NH4Cl was added
and the mixture was extracted with ethyl acetate (4ϫ40 mL). Dry-
ing over Na2SO4 and evaporation of the solvent afforded crude diol
(–)-20a, which was purified by flash chromatography (silica gel,
petroleum ether/diethyl ether, 7:3) to yield the pure compound
(61.8 mg, 47%) as a colorless oil. Rf = 0.63 (petroleum ether/ethyl
acetate, 1:1). [α]2D0 = –2.8 (c = 0.90, EtOH). 1H NMR (300.13 MHz,
CDCl3): δ = 0.04 (s, 3 H, SiCH3), 0.05 (s, 3 H, SiCH3), 0.84–0.88
1.42 [s, 9 H, OC(CH3)3], 1.48–1.68 (m, 4 H, 3-H and 4-H), 1.72
(br. s, 1 H, OH), 1.84 (ddd, J = 2.0, J = 4.4, J = 14.2 Hz, 1 H, 10-
HA), 1.88–1.94 (mc, 1 H, 12-H), 1.99–2.04 (m, 3 H, 13-HA and 16-
H), 2.14 (dt, J = 6.2, J = 14.6 Hz, 1 H, 10-HB), 2.21–2.27 (m, 3 H,
2-H and 13-HB), 2.69–2.74 (mc, 1 H, 8-H), 2.91 (br. s, 1 H, OH),
2.96 (br. s, 1 H, OH), 4.08–4.12 (m, 1 H, 5-H), 4.16–4.22 (m, 2 H,
9-H and 11-H), 5.33–5.40 (m, 2 H, 14-H and 15-H), 5.51 (dd, J =
7.1, J = 15.4 Hz, 1 H, 6-H), 5.83 (dd, J = 10.5, J = 15.4 Hz, 1 H,
7-H) ppm. 13C NMR (125.76 MHz, CDCl3): δ = 14.04 (q, C-20),
20.94 (t, C-3), 22.56 (t, C-18 or C-19), 24.26 (t, C-13), 27.36 (t, C-
16), 28.10 [q, OC(CH3)3], 29.33 (t, C-17), 31.51 (t, C-18 or C-19),
(m, 3 H, 20-H), 0.87 [s, 9 H, SiC(CH3)3], 1.20–1.34 (m, 6 H, 17-H, 35.22 (t, C-2), 36.38 (t, C-4), 42.54 (t, C-10), 47.17 (d, C-12), 50.04
18-H, and 19-H), 1.41 [s, 9 H, OC(CH3)3], 1.46–1.53 (m, 2 H, 4-H), (d, C-8), 72.40 (d, C-5), 73.81 (d, C-9 or C-11), 75.57 (d, C-9 or C-
1.56–1.68 (m, 2 H, 3-H), 1.80 (ddd, J = 2.1, J = 4.8, J = 14.4 Hz, 1 11), 80.18 [s, OC(CH3)3], 128.10 (d, C-14 or C-15), 129.41 (d, C-
H, 10-HA), 1.89–2.06 (m, 6 H, 12-H, 13-HA, 16-H, and 2ϫOH),
2.11–2.33 (m, 4 H, 2-H, 10-HB, and 13-HB), 2.65–2.74 (m, 1 H, 8-
7), 131.13 (d, C-14 or C-15), 136.98 (d, C-6), 173.12 (s, C-1) ppm.
HRMS (FAB+): [M + Na]+ (C24H42O5Na): calcd. 433.2930; found
H), 4.12–4.18 (m, 2 H, 5-H and 9-H), 4.12–4.23 (m, 1 H, 11-H), 433.2955; [M – H]+ (C24H41O5): calcd. 409.2954; found 409.2955.
5.36–5.39 (m, 2 H, 14-H and 15-H), 5.52 (dd, J = 6.0, J = 15.4 Hz,
(–)-tert-Butyl (5S,6E,8β,9β,11β,14Z)-5,9,11-Trihydroxyprosta-6,14-
1 H, 6-H), 5.79 (dd, J = 10.4, J = 15.5 Hz, 1 H, 7-H) ppm. 13C
dien-1-oate (21b): A solution of diol (–)-20b (24.9 mg, 47 µmol) in
NMR (75.47 MHz, CDCl3): δ = –4.78 (q, SiCH3), –4.30 (q, SiCH3),
14.04 (q, C-20), 18.20 [s, SiC(CH3)3], 21.00 (t, C-3), 22.56 (t, C-18
or C-19), 24.47 (t, C-13), 25.87 [q, SiC(CH3)3], 27.40 (t, C-16),
28.10 [q, OC(CH3)3], 29.34 (t, C-17), 31.54 (t, C-18 or C-19), 35.50
dry THF (2 mL) was treated at room temperature with
TBAF·3 H2O (45.0 mg, 141 µmol) and stirred for 48 h. Water
(1 mL) and brine (1 mL) were added, and the aqueous phase was
extracted with ethyl acetate (4ϫ10 mL). The combined organic
(t, C-2), 37.66 (t, C-4), 42.59 (t, C-10), 47.05 (d, C-12), 50.38 (d,
layers were dried with MgSO4, and the solvent was evaporated un-
C-8), 72.79 (d, C-5 or C-9), 73.58 (d, C-11), 75.45 (d, C-5 or C-9),
der reduced pressure. Flash chromatography of the residue (silica
80.00 [s, OC(CH3)3], 126.81 (d, C-7), 128.25 (d, C-14 or C-15),
gel, dichloromethane/methanol, 10:1) yielded pure triol (–)-21b
131.14 (d, C-14 or C-15), 138.33 (d, C-6), 173.00 (s, C-1) ppm.
C30H56O5Si (524.86): calcd. C 68.65, H 10.75; found C 68.93, H
10.73.
(15.3 mg, 79%) as a colorless oil. Rf = 0.49 (dichloromethane/meth-
anol, 5:1). [α]2D0 = –2.1 (c = 1.05, EtOH). H NMR (300.13 MHz,
1
CDCl3): δ = 0.86 (t, J = 7.0 Hz, 3 H, 20-H), 1.23–1.34 (m, 6 H,
(–)-tert-Butyl (5S,6E,8β,9β,11β,14Z)-5-{[tert-Butyl(dimethyl)silyl]- 17-H, 18-H, and 19-H), 1.42 [s, 9 H, OC(CH3)3], 1.50–1.70 (m, 4
oxy}-9,11-dihydroxyprosta-6,14-dien-1-oate (20b): Compound 20b
was prepared from alcohol (+)-19b (53.6 mg, 118 µmol) as de-
scribed above for 20a. Flash chromatography (silica gel, petroleum
ether/ethyl acetate, 7:3) afforded diol (–)-20b (37.0 mg, 60%) as a
H, 3-H and 4-H), 1.84 (ddd, J = 2.0, J = 4.6, J = 14.4 Hz, 1 H,
10-HA), 1.91–2.18 (m, 5 H, 10-HB, 12-H, 13-HA, and 16-H), 2.23
(t, J = 7.0 Hz, 2 H, 2-H), 2.24–2.32 (m, 1 H, 13-HB), 2.67–2.76
(mc, 1 H, 8-H), 4.11–4.23 (m, 3 H, 5-H, 9-H, and 11-H), 5.32–5.42
(m, 2 H, 14-H and 15-H), 5.57 (dd, J = 6.1, J = 15.5 Hz, 1 H, 6-
colorless oil. Rf = 0.14 (petroleum ether/diethyl ether, 7:3). [α]2D0
=
1
–15.9 (c = 0.91, EtOH). H NMR (300.13 MHz, CDCl3): δ = 0.03 H), 5.87 (dd, J = 10.2, J = 15.5 Hz, 1 H, 7-H) ppm. 13C NMR
(s, 3 H, SiCH3), 0.05 (s, 3 H, SiCH3), 0.84–0.88 (m, 3 H, 20-H),
0.87 [s, 9 H, SiC(CH3)3], 1.21–1.35 (m, 6 H, 17-H, 18-H, and 19-
H), 1.41 [s, 9 H, OC(CH3)3], 1.45–1.67 (m, 4 H, 3-H and 4-H), 1.79
(75.47 MHz, CDCl3): δ = 14.03 (q, C-20), 20.91 (t, C-3), 22.55 (t,
C-18 or C-19), 24.35 (t, C-13), 27.39 (t, C-16), 28.10 [q, OC-
(CH3)3], 29.34 (t, C-17), 31.51 (t, C-18 or C-19), 35.15 (t, C-2),
(ddd, J = 2.1, J = 4.9, J = 14.4 Hz, 1 H, 10-HA), 1.90–2.09 (m, 5 36.48 (t, C-4), 42.58 (t, C-10), 47.15 (d, C-12), 50.22 (d, C-8), 71.83
H, 12-H, 13-HA, 16-H, and OH), 2.11–2.21 (m, 4 H, 2-H, 10-HB, (d, C-5), 73.84 (d, C-9 or C-11), 75.62 (d, C-9 or C-11), 80.26 [s,
and OH), 2.27–2.38 (m, 1 H, 13-HB), 2.66–2.74 (mc, 1 H, 8-H),
4.09–4.16 (m, 2 H, 5-H and 9-H), 4.19–4.25 (mc, 1 H, 11-H), 5.38–
5.41 (m, 2 H, 14-H and 15-H), 5.49 (dd, J = 6.9, J = 15.1 Hz, 1 H,
6-H), 5.76 (dd, J = 10.3, J = 15.2 Hz, 1 H, 7-H) ppm. 13C NMR
(75.47 MHz, CDCl3): δ = –4.77 (q, SiCH3), –4.22 (q, SiCH3), 14.04
(q, C-20), 18.20 [s, SiC(CH3)3], 21.01 (t, C-3), 22.57 (t, C-18 or C-
19), 24.45 (t, C-13), 25.87 [q, SiC(CH3)3], 27.39 (t, C-16), 28.11 [q,
OC(CH3)3], 29.35 (t, C-17), 31.55 (t, C-18 or C-19), 35.37 (t, C-2),
37.75 (t, C-4), 42.56 (t, C-10), 47.06 (d, C-12), 50.45 (d, C-8), 73.16
(d, C-5 or C-9), 73.52 (d, C-11), 75.42 (d, C-5 or C-9), 80.12 [s,
OC(CH3)3], 127.39 (d, C-7), 128.24 (d, C-14 or C-15), 131.18 (d,
C-14 or C-15), 138.24 (d, C-6), 173.16 (s, C-1) ppm. C30H56O5Si
(524.86): calcd. C 68.65, H 10.75; found C 68.56, H 10.75.
OC(CH3)3], 128.24 (d, C-7 or C-14 or C-15), 128.29 (d, C-7 or C-
14 or C-15), 131.06 (d, C-14 or C-15), 137.04 (d, C-6), 173.23 (s,
C-1) ppm. HRMS (FAB+): [M + Na]+ (C24H42O5Na): calcd.
433.2930; found 433.2919; [M – H]+ (C24H41O5): calcd. 409.2954;
found 409.2930.
(–)-(5R,6E,8β,9β,11β,14Z)-5,9,11-Trihydroxyprosta-6,14-dien-1-oic
Acid (ent-1): A solution of tert-butyl ester (–)-21a (12.5 mg,
30.4 µmol) in dry methanol (1 mL) was treated at room temp. with
powdered potassium hydroxide (53.2 mg, 900 µmol). After stirring
for 48 h, the reaction mixture was acidified (ca. pH 3) with hydro-
chloric acid (0.2 ) and was then extracted with ethyl acetate
(5ϫ10 mL). The combined organic layers were dried with MgSO4,
and volatiles were removed in vacuo. The residue was subjected to
(–)-tert-Butyl (5R,6E,8β,9β,11β,14Z)-5,9,11-Trihydroxyprosta-6,14- flash chromatography (silica gel, dichloromethane/methanol, 5:1 to
dien-1-oate (21a): A solution of diol (–)-20a (18 mg, 34 µmol) in
dry THF (2 mL) was treated at room temperature with TBAF·
3H2O (32 mg, 102 µmol) and stirred for 24 h. The solvent was re-
moved in vacuo and the residue was subjected to flash chromatog-
raphy (silica gel, ethyl acetate) to yield pure triol (–)-21a (10 mg,
71%) as a colorless oil. Rf = 0.16 (ethyl acetate). [α]2D0 = –9.4 (c =
2:1) to yield pure isoprostane (–)-ent-1 (9.8 mg, 92%) as a colorless
oil. Rf = 0.20 (CH2Cl2/methanol, 5:1). [α]2D0 = –10.7 (c = 0.83,
MeOH). 1H NMR (500.13 MHz, [D6]DMSO): δ = 0.84 (t, J =
6.9 Hz, 3 H, 20-H), 1.20–1.43 (m, 8 H, 4-H, 17-H, 18-H, and 19-
H), 1.44–1.56 (m, 3 H, 3-H and 10-HA), 1.58–1.64 (m, 1 H, 12-H),
1.93–1.99 (m, 3 H, 13-HA and 16-H), 2.03–2.16 (m, 3 H, 2-H and
Eur. J. Org. Chem. 2008, 2551–2563
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2561

P. Elsner, P. Jetter, K. Brödner, G. Helmchen
FULL PAPER
[4]
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We used the following nomenclature system for isoprostanes:
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Med. 1996, 153, 590–596.
For the synthesis of IsoPs with 5-exo-radical cyclization as the
key step, see, for example: a) B. Rondot, T. Durand, J. P. Gi-
rard, J. C. Rossi, L. Schio, S. P. Khanapure, J. Rokach, Tetrahe-
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S. Khanapure, L. Schio, J. Rokach, J. Am. Chem. Soc. 1994,
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42, 2961–2964.
13-HB), 2.22–2.27 (mc, 1 H, 10-HB), 2.37–2.42 (mc, 1 H, 8-H), 3.84–
3.91 (m, 2 H, 5-H and 9-H), 3.93–3.96 (m, 1 H, 11-H), 5.23–5.29
(m, 2 H, 6-H and 15-H), 5.33–5.38 (m, 1 H, 14-H), 5.68 (dd, J =
10.5, J = 15.4 Hz, 1 H, 7-H) ppm. 13C NMR (125.76 MHz, [D6]-
DMSO): δ = 13.91 (q, C-20), 20.99 (t, C-3), 21.97 (t, C-17 or C-18
or C-19), 23.79 (t, C-13), 26.74 (t, C-16), 28.79 (t, C-17 or C-18 or
C-19), 30.90 (t, C-17 or C-18 or C-19), 34.31 (t, C-2), 37.16 (t, C-
4), 43.07 (t, C-10), 46.85 (d, C-12), 50.38 (d, C-8), 70.19 (d, C-11),
71.26 (d, C-5 or C-9), 72.60 (d, C-5 or C-9), 128.33 (d, C-7), 129.04
(d, C-15), 129.48 (d, C-14), 136.25 (d, C-6), 175.22 (s, C-1) ppm.
HRMS (FAB+): [M – H + Na + K]+ (C20H33O5NaK): calcd.
415.1862; found 415.1866; [M + K]+ (C20H34O5K): calcd. 393.2043;
found 393.2079; [M + Na]+ (C20H34O5Na): calcd. 377.2304; found
377.2281.
[5]
[6]
[7]
(–)-(5S,6E,8β,9β,11β,14Z)-5,9,11-Trihydroxyprosta-6,14-dien-1-oic
Acid (ent-2): Isoprostane ent-2 was prepared analogously to iso-
prostane ent-1 from tert-butyl ester (–)-21b (10.5 mg, 25.6 µmol).
Flash chromatography (silica gel, dichloromethane/methanol, 5:1
to 2:1) afforded isoprostane (–)-ent-2 (8.9 mg, 98%) as a colorless
oil. Rf = 0.19 (dichloromethane/methanol, 5:1). [α]2D0 = –7.4 (c =
[8]
[9]
1
0.86, MeOH). H NMR (500.13 MHz, [D6]DMSO): δ = 0.84 (t, J
= 6.7 Hz, 3 H, 20-H), 1.22–1.29 (m, 6 H, 17-H, 18-H and 19-H),
1.34–1.38 (m, 2 H, 4-H), 1.45–1.63 (m, 4 H, 3-H, 10-HA, and 12-
H), 1.95–2.02 (m, 3 H, 13-HA and 16-H), 2.06–2.12 (m, 3 H, 2-H
and 13-HB), 2.20–2.26 (mc, 1 H, 10-HB), 2.37–2.42 (mc, 1 H, 8-H),
3.84–3.90 (m, 2 H, 5-H and 9-H), 3.93–3.96 (mc, 1 H, 11-H), 5.23–
5.31 (m, 2 H, 6-H and 15-H), 5.36–5.41 (m, 1 H, 14-H), 5.69 (dd,
J = 10.7, J = 15.4 Hz, 1 H, 7-H) ppm. 13C NMR (125.76 MHz,
[D6]DMSO): δ = 13.93 (q, C-20), 21.17 (t, C-3), 21.98 (t, C-17 or
C-18 or C-19), 23.81 (t, C-13), 26.71 (t, C-16), 28.85 (C-17 or C-
18 or C-19), 30.91 (C-17 or C-18 or C-19), 34.88 (t, C-2), 37.24 (t,
C-4), 42.98 (t, C-10), 46.91 (d, C-12), 50.53 (d, C-8), 70.19 (d, C-
11), 70.58 (d, C-5 or C-9), 72.56 (d, C-5 or C-9), 127.48 (d, C-7),
129.00 (d, C-15), 129.59 (d, C-14), 136.10 (d, C-6), 175.14 (s, C-
1) ppm. HRMS (FAB+): [M – H + 2Na]+ (C20H33O5Na2): calcd.
399.2123; found 399.2152; [M + Na]+ (C20H34O5Na): calcd.
377.2304; found 377.2272.
[10]
[11]
Supporting Information (see also the footnote on the first page of
this article): 13C NMR chemical shifts of 5-F2c-IsoP (Rokach et al.)
and 5-epi-ent-F2c-IsoP (this work) recorded in [D6]acetone. GC
data and chromatograms for compound 5. HPLC data and chro-
matograms for compounds 16a and 16b. 13C NMR spectra of com-
pounds 7, 9, 15a, 15b, 21a, 21b, ent-1, and ent-2.
[12]
Acknowledgments
This work was supported by the Fonds der Chemischen Industrie.
[13]
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Published Online: April 1, 2008
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