Asymmetric synthesis of 3-oxa-15-deoxy-16-(m-tolyl)-17,18,19,20- tetranorisocarbacyclin and its neuroprotective analogue 15-deoxy-16-(m-tolyl)- 17,18,19,20-tetranorisocarbacyclin based on the conjugate addition-azoalkene- asymmetric olefination strategy

Article abstract of DOI:10.1002/chem.200600728

A fully stereocontrolled synthesis of 3-oxa-15-deoxy-16-(m-tolyl)17,18,19, 20-tetranorisocarbacyclin (3-oxa-15-deoxy-TIC, 7b) and a formal one of 15-deoxy-16-(w-tolyl)-17,18,19,20-tetranorisocarbacyclin (15- deoxy-TIC, 7a) are described. 15Deoxy-TIC is sp

Full text of DOI:10.1002/chem.200600728

DOI: 10.1002/chem.200600728
Asymmetric Synthesis of 3-Oxa-15-deoxy-16-(m-tolyl)-17,18,19,20-
tetranorisocarbacyclin andIts Neuroprotective Analogue 15-Deoxy-16-( m-
tolyl)-17,18,19,20-tetranorisocarbacyclin Based on the Conjugate Addition–
Azoalkene–Asymmetric Olefination Strategy
Marc van de Sande and Hans-Joachim Gais*[a]
Abstract: A fully stereocontrolled syn-
thesis of 3-oxa-15-deoxy-16-(m-tolyl)-
17,18,19,20-tetranorisocarbacyclin (3-
oxa-15-deoxy-TIC, 7b) and a formal
are the readily available bicyclic azoal-
kene 14 and the alkenylcopper deriva-
tive 15. The stereoselective conjugate
addition of 15 to 14 gave hydrazone 13,
which was stereoselectively converted
to the bicyclic ketone 11. The key steps
for the construction of the a side chain
of 7a and 7b and the regioselective in-
troduction of the endocyclic D6,6a
double bond are: 1) a highly selective
asymmetric olefination of ketone 11
with the chiral Horner–Wadsworth–
Emmons reagent 28 and 2) a regiose-
lective deconjugation of the a,b-unsa-
turated ester (E)-10 with the chiral lith-
ium amide 29, which gave the b,g-unsa-
turated ester anti-9 with high selectivi-
ty. The homoallylic alcohol 8 served at
a late stage as the joint intermediate in
the syntheses of 7a and 7b. While an
etherification of 8 furnished, after hy-
drolysis and deprotection, 3-oxa-15-
deoxy-TIC, its alkylation afforded alco-
hol 37, the known precursor for the
synthesis of 15-deoxy-TIC.
one
of
15-deoxy-16-(m-tolyl)-
17,18,19,20-tetranorisocarbacyclin (15-
deoxy-TIC, 7a) are described. 15-
Deoxy-TIC is specific for the neuronal
prostacyclin receptor (IP2) and exhibits
neuroprotective activities, and the new
3-oxa-15-deoxy-TIC is expected to be
metabolically more stable than 15-
deoxy-TIC. The syntheses of 7a and 7b
are based on the convergent conjugate
addition–azoalkene–asymmetric olefi-
nation strategy. Key building blocks
Keywords: asymmetric synthesis ·
isocarbacyclins · medicinal chemis-
try
·
olefination
·
prostacyclin
receptor
Introduction
bacyclin (15-deoxy-TIC, 7a),[25,26] has significantly aided in-
vestigations of the neuronal functions of 1. They revealed a
widespread expression of two different prostacyclin recep-
tors in the brain: the IP1 receptor, also found in the periph-
eral system, and the IP2 receptor, apparently expressed only
in the neuronal system.[27–41] While isocarbacyclin (5a) ex-
hibits similar binding affinities for both IP1 and IP2 subtypes,
iloprost (3a) is specific for the IP1 receptor and (15R)-TIC
(6a) for the IP2 receptor.[28] Recently, it was found that 15-
deoxy-TIC (7a) has an even higher affinity and specificity
for the IP2 receptor than (15R)-TIC (6a).[25,31] In agreement
with the binding studies, iloprost (3a) is a very potent vaso-
dilator and inhibitor of blood platelet aggregation, while iso-
carbacyclins 6a and 7a exhibit only very weak inhibitory ef-
fects on platelet aggregation.[32] Most interestingly, the IP2-
specific (15R)-TIC (6a) and 15-deoxy-TIC (7a), the methyl
esters of which are able to cross the blood–brain barrier, but
not iloprost (3a) show, besides an inhibition of oxygen-in-
duced apoptosis of neuronal cells, a neuroprotective effect
on transient ischemia and an improvement of learning as
Evidence has been provided which suggests that prostacyclin
(1)[1–3] is not only an important hemostasis regulator but also
that it plays an important role in the central nervous
system.[4–6] Studies of prostacyclin are severely hampered,
however, by its short chemical and metabolic half-lifes. The
synthesis of a number of chemically stable prostacyclin ago-
nists, including carbacyclin (2a),[7–13] (16S)-iloprost (3a),[12–15]
cicaprost (4a),[12,13,16,17] isocarbacyclin (5a),[12,13,18–23] (15R)-
16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin ((15R)-TIC,
6a),[24] and 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocar-
[a] Dipl.-Chem. M. van de Sande, Prof. Dr. H.-J. Gais
Institut für Organische Chemie
Rheinisch-Westfälischen Technischen Hochschule (RWTH) Aachen
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49)241-809-2665
E-mail: Gais@RWTH-Aachen.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
well as memory impairments in a rat model of Alzheimerꢁs
disease.[31,34,36] The difference in the prevention of neuronal
cell death by (15R)-TIC (6a) and 15-deoxy-TIC (7a) is well
correlated with the difference in their binding potency for
the IP2 receptor.[32] Thus, there is hope that the design and
synthesis of new w-side-chain-modified isocarbacyclin deriv-
atives as specific targets for the IP2 receptor will contribute
to the elucidation of the neuronal functions of prostacyclin.
The IP2 receptor could, perhaps, be a novel target for the
development of prostacyclin-derived agents for the treat-
ment of neurodegenerative diseases and brain disorders,[42–51]
a topic that will gain increasing importance in the future be-
cause of the aging world population.[52]
As carbacyclin (2a), iloprost (3a), and isocarbacyclin (5a)
are rapidly metabolized by b-oxidation of the a side
chain,[53–55] (15R)-TIC (6a) and 15-deoxy-TIC (7a) are ex-
pected to also suffer such a metabolization. However, the
metabolic degradation of the a side chain of carbacyclins
and isocarbacyclins can be prevented by the introduction of
an oxygen atom at the b-position, as shown by the examples
of 3-oxa-iloprost (3b),[15,56,57] cicaprost (4a),[16,17,56,58] 3-oxa-
carbacyclin (2b),[59–62] 3-oxa-isocarbacyclin (5b),[62,63] and iso-
cicaprost (4b).[17] Thus, the new 3-oxa derivatives 3-oxa-
(15R)-TIC (6b) and 3-oxa-15-deoxy-TIC (7b) would be in-
teresting synthetic targets, as they are expected to have a
much higher metabolic stability than 6a and 7a, respective-
ly. Because of the IP2-specific drug-like action of 6a and 7a
and the current strong interest in the discovery of new neu-
roprotective drugs, it would be desirable to develop a new
route to isocarbacyclins that would enable a fully stereocon-
trolled synthesis of both isocarbacyclin and 3-oxa-isocarba-
cyclin derivatives carrying the various w side chains. Al-
though imaginative and yielding, the known syntheses of
isocarbacyclins do not allow all of these criteria to be
met.[12,13,18–26] The most challenging aspects of the synthesis
of isocarbacyclins are, besides the control of the absolute
configuration, the construction of the bicyclic ring system,
the regioselective introduction of the D6,6a double bond, and
the variability in regard to the w side chain, the structure of
which is crucial for biological activity.
We have recently developed a new general strategy for
the fully stereocontrolled synthesis of carbacyclins and 3-
oxa-carbacyclins including 2a, 3a, 2b, and 3b.[11,15] This
strategy features the establishment of the complete w side
chain through a conjugate addition of the corresponding
chiral alkenylcopper building block to a chiral bicyclic azoal-
kene building block, and uses an asymmetric olefination as
the key step for the construction of the a side chain. Herein,
we describe the fully stereocontrolled synthesis of both the
known 15-deoxy-TIC (7a) and the new 3-oxa-15-deoxy-TIC
(7b) based on the conjugate addition–azoalkene–asymmet-
ric olefination strategy. We thus show that this strategy is
also well suited for the asymmetric synthesis of isocarbacy-
clin (5a), 3-oxa-isocarbacyclin (5b), and their derivatives.
The 15-deoxy-TICs 7a and 7b were selected as primary tar-
gets because of their higher potency and expected higher
metabolic stability than 6a, respectively.
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1785

H.-J. Gais and M. van de Sande
Results andDiscussion
tion with a corresponding homoenolate could perhaps be
more difficult to achieve.[64]
Retrosynthesis: The retrosynthetic analysis of 7a and 7b
called for a stereoselective conjugate addition of the C13–
C20 alkenylcopper derivative 15 to the C6–C12 bicyclic
azoalkene 14 with the formation of hydrazone 13 and its
chemo- and stereoselective conversion to ketone 11
(Scheme 1).
Synthesis of the C6–C12 andC13–C20 builidng blocks
:
Azoalkene 14 of 98% enantiomeric excess (ee) was synthe-
sized in four steps by starting from the achiral bicyclic
ketone 16 (Scheme 2) in 40% overall yield as described pre-
viously.[11,15,65] It was planned to synthesize the C13–C20 al-
kenylcopper building block 15
through an iodine–lithium–
copper exchange of the alkenyl
iodide 21 (Scheme 3). The re-
quired alkyne 20 was obtained
from aldehyde 19 following two
different routes. The palladium-
catalyzed addition of the aryl
iodide 17 to allyl alcohol 18 af-
forded aldehyde 19 in 80%
yield.[66] The conversion of alde-
hyde 19 into alkyne 20 was ac-
complished through the reac-
tion with lithiated trimethylsilyl
diazomethane,[67] which furnish-
ed the alkyne in 84% yield.
The alternative and less ex-
pensive route to 20 started with
the treatment of aldehyde 19
with Cl3CCO2H/Cl3CCO2Na in
DMF,[68] which gave trichloro-
carbinol rac-22. The tosylation
of crude rac-22 with TsCl in the
presence of DABCO afforded
tosylate rac-23. Finally, elimina-
tion of the crude trichloro tosy-
late rac-23 upon treatment with
an excess of MeLi[67] afforded
alkyne 20 in 79% overall yield
based on aldehyde 19.
Scheme 1. Retrosynthetic analysis of 15-deoxy-TIC and 3-oxa-15-deoxy-TIC based on the conjugate addition–
azoalkene–asymmetric olefination strategy. Ts=p-toluenesulfonyl (tosyl).
The regioselective establishment of the D6,6a double bond
and the construction of the a side chains of 7a and 7b
should be accomplished by an asymmetric Horner–Wads-
worth–Emmons (HWE) olefination of ketone 11 with a
chiral HWE reagent, leading to the E-configured a,b-unsa-
turated ester 10. Because of the highly stereoselective olefi-
nation of similar bicyclic ketones carrying, however, differ-
ent w side chains, we were confident of achieving a similarly
efficient transformation of ketone 11.[11,15,17,60–62] The next
crucial stereochemical step would be the regioselective de-
conjugation of ester 10 with the formation of the b,g-unsatu-
rated ester 9. We had previously realized the regioselective
deconjugation of structurally analogous esters by using a
chiral lithium amide.[17,21] Alcohol 8 was planned to serve at
a late stage as a joint intermediate in the synthesis of 7a
and 7b. The etherification and alkylation of the allyl alcohol
8 should give 15-deoxy-TICs 7a and 7b, respectively. While
the etherification of 8 should pose no problems, its alkyla-
Scheme 2. Asymmetric synthesis of azoalkene 14.[11,15,65]
The alkenyl iodide 21 was stereoselectively synthesized
through the hydrozirconation of alkyne 20 with
Cp2Zr(H)Cl[69,70] and treatment of the corresponding alke-
nylzirconium derivative with an excess of iodine.[69,70] There-
by, the E-configured alkenyl iodide 21 was obtained in 76%
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Synthesis of Tetranorisocarbacyclin Derivatives
FULL PAPER
days afforded a mixture of the
two diastereomeric esters (E)-
10 and (Z)-10 in a ratio of 96:4
(Scheme 5). Separation of the
esters by preparative HPLC
gave (E)-10 with ꢀ99% diaste-
reomeric excess (de) in 79%
yield and (Z)-10 with ꢀ99% de
in 2% yield. The excess of 28
was recovered almost quantita-
tively.
Scheme 3. Synthesis of the alkenyl iodide 21. a) PdACHTRE(UGN OAc)2, NaHCO3, Bu4NCl, DMF, 308C; b) (CH3)3SiCHN2,
nBuLi, THF, À788C to RT; c) Cp2Zr(H)Cl, CH2Cl2, RT; d) I2, CH2Cl2, RT; e) Cl3CCO2H/Cl3CCO2Na, DMF,
A highly regioselective de-
conjugation of the unsaturated
RT; f) TsCl, NEt3, DABCO, CH2Cl2, RT; g) MeLi, THF, À788C to RT. Cp=cyclopentadienyl; DABCO=1,4-
diazabicycloACHTREUNG[2.2.2]octane.
yield. 1H NMR spectroscopic analysis showed the iodoal-
kene to be free of the corresponding Z isomer.[71]
Alkenylcopper–azoalkene conjugate addition: The stereose-
lective conjugate addition of the alkenylcopper derivative 15
to the azoalkene 14 is a key step in the synthesis of 7a and
7b. Treatment of iodoalkene 21 with nBuLi afforded the al-
kenyllithium derivative 24, which was converted to the alke-
nylcopper derivative 15 upon treatment with one equivalent
of CuI and 2.6 equivalents of Bu3P (Scheme 4). We had pre-
viously shown that alkenyl- and arylcopper reagents readily
react with azoalkene 14 in the presence of the phosphane by
a 1,4-addition.[11,15,65] Accordingly, reaction of azoalkene 14
with two equivalents of 15 cleanly afforded the diastereo-
merically pure hydrazone 13 in 79% yield. Quenching of
the reaction mixture with 2.9 equivalents of Bu3SnCl ena-
bled the isolation of stannane 25 in 54% yield based on
iodide 21. Thus, because of the quantitative conversion of
stannane 25 to the alkenyllithium derivative 24 upon treat-
ment with tBuLi in THF at À788C, the excess of iodide 21
used in the synthesis of 13 can be recycled.
The chemoselective cleavage of hydrazone 13 was accom-
plished by its treatment with 1.05 equivalents of (PhSeO)2O
in the presence of seven equivalents of cyclohexene, which
serves as a radical scavenger.[11,15,72] Because of the instabili-
ty of the thus-formed ketone 12, it was not further purified
but stereoselectively reduced with NaBH4, which afforded
the diastereomerically pure alcohol 26 in 61% overall yield
based on hydrazone 13. The deprotection of acetal 26 with
TsOH in acetone/water gave ketone 27 in 94% yield. The
subsequent protection of the hydroxy group of 27 furnished
the silyl ether 11 in 93% yield.
Scheme 4. Conjugate addition of the alkenylcopper compound 15 to
azoalkene 14. a) 21 (2 equiv), nBuLi (2 equiv), THF, À788C, 3 h; b) CuI
(2 equiv), Bu3P (5.2 equiv), THF, À788C, 10 min; c) 14 (1 equiv), THF,
À788C, 45 min; d) Bu3SnCl (2.9 equiv); e) tBuLi, THF, À788C;
f) aqueous NH4Cl; g) cyclohexene (7.4 equiv), (PhSeO)2O, THF, RT;
h) NaBH4, EtOH, 08C; i) H2O, TsOH, acetone, RT; j) tBuMe2SiCl, imi-
dazole, DMF, RT.
Regioselective introduction of the D6,6a double bond: It was
planned to regioselectively establish the D6,6a double bond
and O–C5 moiety of 7b as well as the D6,6a double bond and
C4,C5 moiety of 7a through an asymmetric HWE reaction
of ketone 11 with a chiral phosphonoacetate,[11,15,17,60–62] fol-
lowed by a regioselective deconjugation of the correspond-
ing a,b-unsaturated ester.[17,62]
ester (E)-10 was achieved through deprotonation with the
chiral lithium amide 29[11,15,65] in THF at À1058C, followed
by a regioselective protonation of the lithium enolates anti-
30 and syn-30 at the a-position. Thereby, a mixture of the
two isomeric esters anti-9 and syn-9 was obtained in a ratio
of 99:1 in 89% yield. Separation of the esters by preparative
HPLC afforded pure anti-9 in 82% yield and pure syn-9 in
1% yield.
The reaction of ketone 11 with ten equivalents of the
chiral phosponate 28[11,15,17,60–62] in THF at À628C for seven
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H.-J. Gais and M. van de Sande
ene group. Evidence has been provided, however, suggesting
that an achiral lithium amide would also cause a regioselec-
tive deprotonation of ester (E)-10.[62] The high selectivity of
the formation of the lithium enolate anti-30 in the deproto-
nation of (E)-10 with 29 is perhaps not a reflection of the
chirality of the base, but due to its prior coordination to the
carbonyl group followed by an intramolecular deprotonation
at the syn position.[73] Finally, the reduction of ester anti-9
with DIBAL-H afforded the homoallylic alcohol 8 in 88%
yield.
Synthesis of 3-oxa-15-deoxy-TIC (7b): The synthesis of 7b
from alcohol 8 was completed by its etherification with tert-
butyl 2-bromoacetate in the presence of aqueous
NaOH,[11,15–17,62] followed by deprotection of the correspond-
ing silyl ether, which gave ester 31 in 89% yield (Scheme 6).
The hydrolysis of ester 31 with aqueous NaOH in MeOH
followed by careful acidification with NaH2PO4 to pH 4 fur-
nished 3-oxa-15-deoxy-TIC (7b) in 98% yield.
Formal synthesis of 15-deoxy-TIC (7a): The homoallylic al-
cohol 8 was designed to function as the late-stage intermedi-
ate in the synthesis of both 7a and 7b. Thus, an alkylation
of 8 en route to 7a was required. Tosylate 32 was prepared
from alcohol 8 in 90% yield (Scheme 7). The alkylation of
tosylate 32 with the functionalized copper reagent 33,[74]
which was prepared from the corresponding organozinc
iodide,[75,76] with formation of ester 34 could not be accom-
plished. Treatment of 32 with 33 led to an almost quantita-
tive recovery of 32. Thus, an alternative route involving al-
kylation of 32 with the copper reagent 35c was envisioned.
The alkylcopper derivative 35c required for the alkylation
of 32 was prepared from iodide 35a[77] via the alkyllithium
derivative 35b.[78] The treatment of tosylate 32 with four
equivalents of the alkylcopper reagent 35c[79] afforded the
ether 36 in 82% yield. The selective deprotection of the
THP ether 36 was achieved through treatment with an
excess of freshly prepared MgBr2 in Et2O,[80,81] which gave
alcohol 37 in 64% yield after preparative HPLC.
As a two-step oxidation of alcohol 37 to 15-deoxy-TIC
(7a) via the corresponding aldehyde had recently been de-
scribed,[26] its preparation represents a formal asymmetric
synthesis of 7a. In our previously described asymmetric syn-
thesis of iloprost (3a) and isocarbacyclin (5a) from alcohols
38 and 39, respectively, (Scheme 8) we had already success-
Scheme 5. Regioselective establishment of the D6,6a double bond and
a side chain of 7a and 7b. a) THF, À628C, 7 d, HPLC; b) THF, À1058C;
c) aq. NaHCO3, HPLC; d) DIBAL-H, THF, 08C to RT. DIBAL-H=dii-
sobutylaluminum hydride.
Because of the highly enan-
tioselective deprotonation of
the prochiral bicyclic ketone 16
with the chiral base 29, which is
the first step of the synthesis of
azoalkene 14 (see Scheme 2),
we also applied this base for
the selective deprotonation of
Scheme 6. Completion of the synthesis of 3-oxa-15-deoxy-TIC (7b). a) BrCH2CO2tBu, aq NaOH, Bu4NHSO4,
ester (E)-10 at the 6a-methyl- CH2Cl2; b) Bu4NF, THF; c) NaOH, MeOH, NaH2PO4, pH 4.
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Synthesis of Tetranorisocarbacyclin Derivatives
FULL PAPER
kene (Figure 1), it is to be ex-
pected that this strategy will
allow for the synthesis of a
broad range of w-side-chain-
modified isocarbacyclins, which
will be required for the further
investigation of the neuronal-
specific IP2 receptor and the de-
velopment of a prostacyclin-de-
rived neuroprotective agent.
Experimental Section
General methods: All reactions were
carried out under an argon atmos-
phere in absolute or dry solvents with
syringe and Schlenk techniques in
oven-dried glassware. THF, Et2O, and
n-pentane were distilled under argon
from lead/sodium in the presence of
benzophenone. CH2Cl2 was distilled
from CaH2. Dry DMF was obtained
from commercial sources and stored
over molecular sieves. CuI from com-
Scheme 7. Formal synthesis of 15-deoxy-TIC (7a). a) TsCl, NEt3, DABCO, CH2Cl2, RT; b) Zn (1 equiv), dibro-
moethane (0.036 equiv), ClSiMe3 (0.036 equiv); 33 (0.97 equiv), THF; CuCN (0.80 equiv), LiCl (1.7 equiv),
THF; 32; c) tBuLi (2 equiv), Et2O, n-pentane, À788C, 1 h; d) CuI (1 equiv), Bu3P (2.6 equiv), Et2O, À78 to
À408C; e) 32 (0.25 equiv), Et2O, À40 to 08C, 2 h; f) MgBr2, Et2O. THP=tetrahydropyranyl.
Figure 1. Alkenyl- and arylcopper derivatives used in conjugate addition
to the bicyclic azoalkene.
mercial sources was dried by heating to 2008C in high vacuo for 10 min
prior to use. Bulk solvents for chromatography and extraction were distil-
led prior to use. Reagents were obtained from commercial sources and
used without further purification unless otherwise stated. nBuLi and
tBuLi were standardized by titration with diphenylacetic acid. Molecular
sieves (4 Š) were activated prior to use by heating at 2008C for 4 h in
vacuo (0.01 mbar). Bis[(R)-1-phenylethyl]ammonium chloride[82] with
ꢀ99% ee and (1S,2R)-2-(2-phenylpropan-2-yl)cyclohexyl-2-(dimethoxy-
phosphoryl) acetate[62] with ꢀ98% ee were prepared according to the lit-
erature. TLC was performed on Merck precoated plates (silica gel 60
Scheme 8. Application of the two-step oxidation of primary alcohols to
carboxylic acids in the synthesis of iloprost and isocarbacyclin.
F
254, layer thickness 0.2 mm), and chromatography was performed with
fully applied such a two-step oxidation by using DMSO/
Merck silica gel 60 (0.040–0.063 mm) in the flash mode with a nitrogen
pressure of 0.2 bar. Preparative HPLC was carried out with a Dynamax
SD-1 pump by using Varian 320 UV/Vis and Knauer refractive index
(RI) detectors on Kromasil Si-100 and Chiralpak AD columns. GC analy-
ses were run on Varian 3800, Chrompack CP-9000, and Carlo Erba Mega
NEt3/pyr·SO3 and Ag2O.[15,19,21]
Conclusion
instruments. H and 13C NMR spectra were recorded on a Varian Mercu-
1
ry 300, or a Varian Inova 400 instrument. Chemical shifts are reported
relative to TMS( d=0.00 ppm) as internal standard. The following abbre-
viations are used to designate the multiplicity of the peaks in 1H NMR
spectra: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, b=
broad, and combinations thereof. Peaks in the 13C NMR spectra are de-
noted as “u” for carbons with zero or two attached protons or as “d” for
carbons with one or three attached protons, as determined from the at-
tached proton test (APT) pulse sequence. Assignments in the 1H NMR
spectra were made by gradient multiple quantum (GMQ) COSY and het-
We have developed a fully stereocontrolled convergent syn-
thesis of 3-oxa-15-deoxy-TIC and a formal one of 15-deoxy-
TIC based on a conjugate addition–azoalkene–asymmetric
olefination strategy. The key step of these syntheses is the
conjugate addition of the alkenylcopper derivative 15 to the
azoalkene 14. Because of the successful conjugate addition
of several alkenyl- and arylcopper derivatives to the azoal-
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H.-J. Gais and M. van de Sande
eronuclear correlation spectroscopy (HETCOR) experiments and those
in the 13C NMR spectra were made by (DEPT) experiments. IR spectra
were recorded on a Perkin–Elmer PE 1759 FT instrument. Only peaks of
n˜ ꢀ800 cmÀ1 are listed, vs=very strong, s=strong, m=medium, w=
weak. LRMS were recorded on a Finnigan SSQ 7000 instrument by using
either electron-impact ionization (EI, 70 eV) or chemical ionization (CI,
CH4, or isobutane). Only peaks of m/zꢀ80 and an intensity of 5%,
except decisive ones, are listed. HRMSwere recorded on a Varian MAT
95 mass spectrometer. Optical rotations were measured with a Perkin–
Elmer model 241 polarimeter at approximately 228C. Specific rotations
are in gradmLdmÀ1 gÀ1, and c is in grams per 100 mL. Elemental analyses
were performed by the Institut für Organische Chemie Microanalytical
Laboratory.
the complete consumption of the alcohol. Then water (80 mL) and Et2O
(200 mL) were added and the mixture was stirred for 30 min. The organic
phase was washed with 5m HCl (50 mL), and the combined aqueous
phases were extracted with Et2O (3”100 mL). The combined organic
phases were washed successively with 2.5m HCl (100 mL) and water
(100 mL) and were then dried (MgSO4). Concentration in vacuo gave the
crude tosylate rac-23, which was used without purification in the next
step. Purification of a small amount of the crude tosylate by chromatog-
raphy (n-hexane/EtOAc 8:1) gave tosylate rac-23 as a colorless oil. Rf =
0.43 (n-hexane/EtOAc 7:1); 1H NMR (400 MHz, CDCl3): d=2.16–2.28
(m, 1H), 2.32 (s, 3H; CH3), 2.44 (s, 3H; CH3), 2.44–2.53 (m, 1H), 2.68–
2.77 (m, 1H), 2.79–2.88 (m, 1H), 5.12 (dd, J=2.5, 8.8 Hz, 1H; CHOTs),
6.96 (d, J=7.5 Hz, H), 6.97 (s, 1H), 7.02 (d, J=7.5 Hz, 1H), 7.18 (t, J=
7.5 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.86 ppm (d, J=8.2 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=21.3 (d), 21.6 (d), 31.7 (u), 33.7 (u), 88.3
(d), 98.6 (u), 125.2 (d), 126.9 (d), 127.7 (d), 128.3 (d), 129.0 (d), 129.5 (d),
133.8 (u), 138.0 (u), 139.7 (u), 144.9 ppm (u); IR (neat): n˜ =3065 (w),
2941 (m), 2864 (w), 2257 (w), 1589 (m), 1491 (w), 1453 (w), 1371 (s),
1177 (vs), 1096 (m), 1028 (m), 936 (s), 910 (s), 851 (s), 812 cmÀ1 (m); MS
(EI, 70 eV): m/z (%): 424 (4), 422 (11), 420 (11) [M+], 247 (8), 176 (17),
141 (25), 139 (65), 131 (17), 119 (15), 118 (100), 105 (26); elemental anal-
ysis calcd (%) for C18H19Cl3O3S(421.77): C 51.26, H 4.54; found: C 51.33,
H 4.58; HRMS(EI, 70 eV) calcd for C 18H19Cl3O3S [M]+: 420.012051;
found: 420.012028.
3-m-Tolylpropanal (19): Allyl alcohol 18 (24 mL, 351 mmol) was added
to a suspension of NaHCO3 (49.7 g, 592 mmol) and Bu4NCl (70.9 g,
255 mmol) in DMF (200 mL). After the mixture had been stirred at
room temperature for 10 min, PdACHTRE(UNG OAc)2 (681 mg, 3.03 mmol) was added.
Then a solution of the iodide 17 (30 mL, 234 mmol) in DMF was added
dropwise at 308C over a period of 45 min to the orange suspension,
which turned black during the addition. According to GC analysis, iodide
17 was consumed after 18 h. The mixture was left to cool to room tem-
perature and the excess of 18 was removed in vacuo. Water (100 mL) and
n-pentane (100 mL) were added and the mixture was stirred for 30 min.
After this time, the mixture was filtered through Celite and the aqueous
phase was extracted with n-pentane (3”100 mL). The combined organic
phases were washed with water (100 mL) and dried (MgSO4). Concentra-
tion in vacuo and purification by chromatography (n-hexane/EtOAc 6:1)
afforded aldehyde 19 (27.7 g, 80%) as a colorless oil. Rf =0.57 (n-hexane/
1-(But-3-ynyl)-3-methylbenzene (20):
From tosylate rac-23: MeLi (500 mL, 1.6m in hexanes, 800 mmol) was
added dropwise at À788C to a stirred solution of the crude tosylate rac-
23 in THF (200 mL). After the mixture had been stirred at À788C for
1 h, it was warmed to room temperature and saturated aqueous NH4Cl
(50 mL) was added. Then water (60 mL) and Et2O (100 mL) were added
and the aqueous phase was extracted with Et2O (3”100 mL). The com-
bined organic phases were dried (MgSO4) and concentrated in vacuo. Pu-
rification by chromatography (n-hexane) gave alkyne 20 (21.3 g,
148 mmol) as a colorless liquid.
1
EtOAc 4:1); H NMR (300 MHz, CDCl3): d=2.31 (s, 3H; CH3), 2.71 (dt,
J=1.4, 7.5 Hz, 2H; CH2CHO), 2.89 (t, J=7.5 Hz, 2H; CH2CH2CHO),
6.93–7.02 (m, 3H), 7.16 (t, J=7.8 Hz, 1H), 9.76 ppm (t, J=1.4 Hz, 1H;
CHO); 13C NMR (75 MHz, CDCl3): d=21.3 (d), 28.0 (u), 45.2 (u), 125.0
(d), 126.8 (d), 128.2 (d), 128.8 (d), 137.9 (u), 140.0 (u), 201.2 ppm (d); IR
(neat): n˜ =3103 (w), 3022 (m), 2922 (m), 2862 (m), 2823 (m), 2722 (m),
1724 (vs), 1608 (m), 1590 (w), 1489 (m), 1450 (w), 1408 (w), 1387 (w),
1356 (w), 1277 (w), 1172 (w), 1095 (w), 1056 (w), 907 (w), 884 (w),
848 cmÀ1 (w); MS(EI, 70 eV): m/z (%): 148 (100) [M]+, 120 (13), 119
(22), 117 (15), 115 (15), 106 (66), 105 (98), 103 (18), 92 (55), 91 (60);
HRMS(EI, 70 eV): m/z: calcd for C10H12O: 148.088815 [M]+; found:
148.088846.
From aldehyde 19: nBuLi (24 mL, 1.6m in hexanes, 38 mmol) was added
at À788C to a solution of (CH3)3SiCHN2 (20 mL, 2.0m in hexanes,
40 mmol) in THF (40 mL). After the mixture had been stirred for
20 min, a solution of aldehyde 19 (4.85 g, 32.7 mmol) in THF (15 mL)
was added. After stirring for 1 h at À788C, the mixture was left to warm
to room temperature and saturated aqueous NH4Cl (40 mL) was added.
The aqueous phase was extracted with Et2O (5”40 mL) and the com-
bined organic phases were dried (MgSO4) and concentrated in vacuo. Pu-
rification by chromatography (n-hexane) gave alkyne 20 (3.96 g, 84%) as
a colorless liquid. Rf =0.65 (n-hexane/EtOAc 2:1); 1H NMR (400 MHz,
1,1,1-Trichloro-4-m-tolylbutan-2-ol
(rac-22):
Cl3CCO2Na
(61.2 g,
331 mmol) was added in portions at 08C to
a
stirred solution of
Cl3CCO2H (54.2 g, 331 mmol) and aldehyde 19 (25 g, 169 mmol) in DMF
(180 mL). After the mixture had been stirred for 1 h, it was left to warm
to room temperature and stirring was continued for 3 h. GC analysis
showed the consumption of the aldehyde. Then water (250 mL) was
added and the aqueous phase was extracted with n-pentane (4”80 mL).
The combined organic phases were dried (MgSO4), and the solvent was
removed in vacuo. The resulting crude alcohol was used for the next step
without further purification. Purification of a small amount of the crude
alcohol by chromatography (n-hexane/EtOAc 8:1) gave alcohol rac-22 as
a colorless solid. Rf =0.35 (n-hexane/EtOAc 7:1); 1H NMR (400 MHz,
CDCl3): d=1.91–2.01 (m, 1H), 2.31–2.41 (m, 1H), 2.33 (s, 3H; CH3),
2.67–2.77 (m, 1H), 2.91–2.99 (m, 1H), 3.04–3.09 (m, 1H; OH), 3.97 (ddd,
J=1.9, 5.7, 10.0 Hz, 1H; CHOH), 7.00–7.06 (m, 3H), 7.19 ppm (t, J=
7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=21.3 (d), 31.8 (u), 32.94
(u), 81.9 (d), 104.0 (u), 125.2 (d), 126.8 (d), 128.2 (d), 129.1 (d), 137.9 (u),
140.4 ppm (u); IR (neat): n˜ =3447 (m, br), 3021 (m), 2967 (m), 2927 (m),
2863 (m), 2250 (w), 1712 (w), 1608 (m), 1488 (w), 1452 (m), 1384 (w),
1265 (w, br), 1161 (w), 1086 (m), 1008 (w), 909 cmÀ1 (s); MS(EI, 70 eV):
m/z (%): 270 (3), 268 (10), 266 (10) [M]+, 195 (16), 131 (10), 119 (10),
106 (13), 105 (100), 91 (6); elemental analysis calcd (%) for C11H13Cl3O
(267.58): C 49.38, H 4.90; found: C 49.45, H 4.93; HRMS(EI, 70 eV):
m/z: calcd for C11H13Cl3O: 266.003199 [M]+; found: 266.003204.
ꢁ
CDCl3): d=1.94 (t, J=2.7 Hz, 1H; C CH), 2.31 (s, 3H; CH3), 2.44 (dt,
ꢁ
ꢁ
J=2.7, 7.6 Hz, 2H; CH CCH2), 2.78 (t, J=7.6 Hz, 2H; CH CCH2CH2),
6.99–7.01 (m, 3H), 7.17 ppm (t, J=7.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=20.5 (u), 21.3 (d), 34.7 (u), 68.7 (d), 83.7 (u), 125.2 (d), 126.9
(d), 128.1 (d), 129.0 (d), 137.7 (u), 140.1 ppm (u); IR (neat): n˜ =3297
(vs), 3022 (s), 2924 (vs), 2862 (s), 2117 (m), 1609 (s), 1590 (m), 1488 (s),
1451 (s), 1431 (m), 1378 (w), 1339 (w), 1251 (m, br), 1172 (w), 1093 (w),
1040 (w), 880 (m), 844 cmÀ1 (m); MS(EI, 70 eV): m/z (%): 144 (41)
[M]+, 129 (54), 106 (11), 105 (100), 103 (12); elemental analysis calcd
(%) for C11H12 (144.21): C 91.61, H 8.39; found: C 91.41, H 8.48; HRMS
(EI, 70 eV): m/z: calcd for C11H12 [M]+: 144.093004; found: 144.092963.
(E)-1-(4-Iodobut-3-enyl)-3-methylbenzene (21): Alkyne 20 (1.14 g,
7.91 mmol) was added at room temperature to a stirred suspension of
Cp2Zr(H)Cl (2.03 g, 7.88 mmol) in CH2Cl2 (20 mL). After the suspension
had been stirred for 10 min, a clear solution was formed and a solution of
iodine (2.07 g, 8.16 mmol) in CH2Cl2 (50 mL) was added. Then the mix-
ture was stirred for 15 min and saturated aqueous NaHSO3 (20 mL) was
added. The mixture was filtered through Celite and the organic phase
was washed with saturated aqueous NaCl (10 mL). The aqueous phase
was extracted with Et2O (3”30 mL). The combined organic phases were
dried (MgSO4) and concentrated in vacuo. Purification by chromatogra-
1,1,1-Trichloro-4-m-tolylbutan-2-yl 4-methylbenzenesulfonate (rac-23):
TsCl (57.9 g, 304 mmol) was added at room temperature to a stirred solu-
tion of the crude alcohol rac-22, NEt3 (23 mL, 304 mmol), and DABCO
(7.62 g, 67.9 mmol) in CH2Cl2 (200 mL). After 2.5 h, GC analysis showed
phy (n-hexane) afforded alkene 21 as
a colorless oil. Rf =0.62 (n-
hexane); 1H NMR (400 MHz, C6D6): d=1.87–1.94 (m, 2H; CH2CH=
CHI), 2.13 (s, 3H; CH3), 2.28 (t, J=7.8 Hz, 2H; CH2CH2CH=CHI), 5.64
1790
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1784 – 1795

Synthesis of Tetranorisocarbacyclin Derivatives
FULL PAPER
(dt, J=1.5, 14.6 Hz, 1H; CH=CHI), 6.29 (dt, J=7.1, 14.6 Hz, 2H; CH=
CHI), 6.74 (s, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H),
7.08 ppm (t, J=7.6 Hz, 1H); 13C NMR (100 MHz, C6D6): d=21.3 (d),
34.7 (u), 37.8 (u), 75.4 (d), 125.5 (d), 126.9 (d,), 128.3 (d), 129.2 (d), 137.7
(u), 140.8 (u), 145.5 ppm (d); IR (neat): n˜ =3415 (w), 3045 (s), 3016 (s),
2921 (vs), 2854 (s), 1935 (w), 1860 (w, br), 1677 (w), 1606 (s), 1487 (s),
1450 (s), 1378 (w), 1339 (w), 1277 (w), 1238 (m), 1205 (s), 1136 (m), 1092
(m), 1041 (m), 940 (vs), 879 (m), 834 cmÀ1 (w); MS(CI, isobutane): m/z
(%): 329 (5) [M+57]+, 273 (6) [M+1]+, 147 (12), 146 (12), 145 (100), 105
(6); elemental analysis calcd (%) for C11H13I (272.13): C 48.55, H 4.82;
found: C 48.69, H 4.84.
264 (11), 263 (20), 262 (6), 261 (9), 211 (5), 177 (6), 145 (11), 143 (5), 120
(9), 119 (8), 116 (5), 105 (12); HRMS(EI, 70 eV): m/z: calcd for
C23H40Sn: 379.144706 [MÀC4H9]+; found: 379.144708.
(3a’S,4’R,6a’R)-5,5-Dimethyl-4’-[(E)-4-m-tolylbut-1-enyl]tetrahydro-1’H-
spiroACTHERNGU([1,3]-dioxane-2,2’-pentalen)-5’ACHTRE(UGN 3’H)-one (12): (PhSeO)2O (2.86 mg,
2.79 mmol) was added in portions to a stirred solution of hydrazone 13
(1.43 g, 2.67 mmol) and cyclohexene (2 mL, 19.7 mmol) in THF (10 mL).
After the mixture had been stirred for 45 min at room temperature, satu-
rated aqueous NaHCO3 (2 mL) and n-pentane (10 mL) were added. The
aqueous phase was extracted with Et2O (3”10 mL). The combined or-
ganic phases were dried (MgSO4) and the volatiles were removed in
vacuo. The crude ketone 12 was not purified but directly used for the
next step.
(E)-N’-{(3a’S,4’R,6a’R)-5,5-Dimethyl-4’-[(E)-4-m-tolylbut-1-enyl]dihydro-
1’H-spiroACHTREUNG([1,3]dioxane-2,2’-pentalene)-5’-(3’H,6’H,6a’H)ylidene}-4-meth-
ylbenzenesulfonohydrazide (13) and (E)-tributyl(4-m-tolylbut-1-enyl)-
stannane (25): nBuLi (0.48 mL, 1.6m in hexanes, 0.768 mmol) was added
at À788C under argon to a solution of iodide 21 (209 mg, 0.768 mmol) in
THF (3 mL). After the yellow solution of 24 had been stirred for 3 h, a
precooled solution (À788C) of CuI (146 mg, 0.768 mmol) and Bu3P
(0.50 mL, 1.997 mmol) in THF (3 mL) was added by a double-ended
needle. The solution of 15 was stirred for 10 min, and a precooled solu-
tion (À788C) of azoalkene 14 (150 mg, 0.384 mmol) in THF (4 mL) was
added by a double-ended needle. Then the mixture was stirred for 45 min
at À788C and Bu3SnCl (0.30 mL, 1.106 mmol) was added. After the mix-
ture had been stirred for 45 min, H2O (2 mL) was added and the mixture
was left to reach ambient temperature. Then, saturated aqueous NH4Cl
(3 mL) was added and the organic phase was washed with saturated
aqueous NH4Cl (3”5 mL). Subsequently, the combined aqueous phases
were extracted with Et2O (5”10 mL), and the combined organic phases
were dried (MgSO4) and concentrated in vacuo. Purification by chroma-
tography (n-hexane/Et2O 1:1) afforded hydrazone 13 (162 mg, 79%) as a
colorless solid and a mixture of 25 and Bu3P. Chromatography (n-hexane/
EtOAc 20:1) gave stannane 25 (182 mg, 0.418 mmol) as a colorless oil.
(3a’S,4’R,5’R,6a’R)-5,5-Dimethyl-4’-[(E)-4-m-tolylbut-1-enyl]hexahydro-
1’H-spiro
A
(26):
NaBH4
(420 mg,
11.1 mmol) was added in portions at 08C to a solution of the crude
ketone 12 in EtOH (10 mL). After the mixture had been stirred for
90 min at 08C, saturated aqueous NH4Cl (5 mL), saturated aqueous NaCl
(10 mL), and Et2O (10 mL) were added. The aqueous phase was extract-
ed with Et2O (3”10 mL), and the combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by chromatography (n-
hexane/Et2O 2:1) afforded alcohol 26 (606 mg, 61% based on hydrazone
13) as a colorless oil. [a]D =+21.5 (c=0.99 in THF); Rf =0.44 (n-hexane/
Et2O 1:1); 1H NMR (300 MHz, CDCl3): d=0.94 (s, 3H; C
(s, 3H; C(CH3)2), 1.33–1.46 (m, 1H), 1.73–1.82 (m, 3H; OH), 1.99–2.26
(m, 5H), 2.27–2.46 (m, 3H), 2.32 (s, 3H; CH3), 2.57–2.74 (m, 2H; CH=
CHCH2CH2), 3.45 (s, 2H; C(CH2O)2), 3.47 (s, 2H; C(CH2O)2), 3.54–3.64
ACHTRE(UNG CH3)2), 0.97
AHCTREUNG
A
ACHTREUNG
(m, 1H; CHOH), 5.20 (dd, J=8.0, 15.2 Hz, 1H; CH=CHCH2), 5.52 (dt,
J=6.7, 15.2 Hz, 1H; CH=CHCH2), 6.92–7.02 (m, 3H), 7.16 ppm (t, J=
7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=21.4 (d), 22.5 (d), 22.6 (d),
30.0 (u), 34.4 (u), 35.3 (d), 35.7 (u), 37.8 (u), 40.4 (u), 40.9 (u), 43.8 (d),
58.3 (d), 72.0 (u), 72.0 (u), 77.9 (d), 110.2 (u), 125.6 (d), 126.5 (d), 128.1
(d), 129.3 (d), 131.6 (d), 132.2 (d), 137.7 (u), 141.7 ppm (u); IR (neat):
n˜ =3421 (m, br), 2950 (vs), 2860 (s), 2243 (w), 1608 (m), 1468 (m), 1395
(w), 1327 (m), 1257 (m), 1219 (m), 1177 (w), 1114 (s), 1041 (m), 1015
(m), 968 (m), 908 (m), 875 cmÀ1 (w); MS(EI, 70 eV): m/z (%): 371 (6),
370 (22) [M]+, 353 (19), 352 (70), 297 (17), 267 (9), 266 (30), 265 (33),
255 (7), 251 (9), 238 (7), 237 (5), 224 (14), 209 (9), 208 (31), 185 (6), 183
(13), 181 (23), 179 (12), 169 (7), 168 (13), 167 (22), 161 (24), 157 (11), 155
(6), 154 (12), 151 (6), 147 (6), 145 (13), 144 (11), 143 (10), 141 (8), 135
(11), 133 (14), 131 (22), 129 (16), 128 (47), 122 (9), 121 (7), 119 (33), 118
(11), 117 (6), 107 (7), 106 26), 105 (100), 96 (5), 94 (13), 93 (6), 91 (19),
83 (10), 82 (6), 81 (11); HRMS(EI, 70 eV): m/z: calcd for C24H34O3:
370.250795 [M]+; found: 370.250789.
Hydrazide 13: [a]D =À24.4 (c=1.03 in THF); Rf =0.30 (n-hexane/EtOAc
2:1); 1H NMR (400 MHz, [D8]THF): d=0.88 (s, 3H; CH3CCH3), 0.90 (s,
3H; CH3CCH3), 1.55–1.61 (m, 1H), 1.73–1.78 (m, 1H), 2.08–2.61 (m,
10H), 2.29 (s, 3H; CH3), 2.35 (s, 3H; CH3), 2.91–2.94 (m, 1H; CHC=N),
3.35 (s, 2H; OCH2), 3.39 (s, 2H; OCH2), 5.29–5.44 (m, 2H; HC=CH),
6.94–6.96 (m, 2H), 6.99 (s, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.26 (d, J=
8.7 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 8.91 ppm (s, 1H; NH); 13C NMR
(100 MHz, [D8]THF): d=21.4 (d), 21.5 (d), 22.5 (d), 22.6 (d), 30.4 (u),
33.6 (u), 35.4 (u), 36.8 (u), 38.7 (u), 39.80 (d), 42.3 (u), 47.1 (d), 53.7 (d),
72.1 (u), 72.6 (u), 110.7 (u), 126.0 (d), 126.9 (d), 128.6 (d), 128.7 (d), 129.4
(d), 129.7 (d), 130.7 (d), 131.1 (d), 138.0 (u), 138.1 (u), 142.5 (u), 143.3
(u), 167.1 ppm (u); IR (KBr): n˜ =3736 (w), 3675 (m, br), 3447 (vs, br),
3238 (s), 3021 (w), 2952 (s), 2862 (m), 1638 (m), 1601 (m), 1545 (w), 1496
(w), 1463 (w), 1399 (m), 1331 (s), 1292 (m), 1216 (w), 1165 (vs), 1114 (s),
1040 (w), 1015 (w), 988 (w), 962 (w), 911 (m), 882 (w), 813 cmÀ1 (m); MS
(EI, 70 eV): m/z (%): 536 (3) [M]+, 415 (18), 382 (25), 381 (100), 378 (5),
365 (7), 296 (11), 295 (60), 280 (6), 278 (5), 262 (17), 261 (92), 237 (22),
213 (15), 189 (8), 177 (6), 174 (19), 167 (8), 156 (8), 154 (10), 147 (7), 145
(9), 143 (5), 138 (7), 133 (9), 132 (9), 131 (16), 130 (6), 129 (7), 128 (11),
119 (18), 118 (8), 117 (8), 115 (6), 107 (7), 106 (11), 105 (72), 103 (7), 95
(7), 92 (19), 91 (46), 81 (7); elemental analysis calcd (%) for
C31H40N2O4S(536.27): C 69.37, H 7.51, N 5.22; found: C 69.22, H 7.32, N
5.21.
(3aS,4R,5R,6aR)-5-Hydroxy-4-[(E)-4-m-tolylbut-1-enyl]hexahydropenta-
len-2(1H)one (27): TsOH (approximately 5 mg) was added to a solution
of alcohol 26 (600 mg, 1.62 mmol) in acetone (5 mL) and water (2 mL).
After the mixture had been stirred for 2 d at room temperature, saturat-
ed aqueous NaHCO3 (2 mL) and Et2O (20 mL) were added successively.
The aqueous phase was extracted with Et2O (3”10 mL) and the com-
bined extracts were dried (MgSO4) and concentrated in vacuo. Purifica-
tion by chromatography (n-hexane/Et2O 1:2) gave ketone 27 (433 mg,
94%) as a colorless oil. [a]D =À19.3 (c=1.06 in THF); Rf =0.41 (n-
1
hexane/Et2O 1:6); H NMR (300 MHz, C6D6): d=1.14–1.26 (m, 1H), 1.58
1
(s, 1H; OH), 1.73–2.15 (m, 8H), 2.19 (s, 3H; CH3), 2.24–2.29 (m, 2H;
CH=CHCH2CH2), 2.53–2.58 (m, 2H; CH=CHCH2), 3.50–3.58 (m, 1H;
CHOH), 5.04 (ddt, J=1.2, 8.2, 15.2 Hz, 1H; CH=CHCH2), 5.34 (dt, J=
6.7, 15.2 Hz, 1H; CH=CHCH2), 6.89–6.94 (m, 3H), 7.11–7.16 ppm (m,
1H); 13C NMR (75 MHz, C6D6): d=21.4 (d), 34.9 (d), 35.0 (u), 36.1 (u),
41.6 (u), 42.5 (u), 43.1 (d), 45.8 (u), 58.3 (d), 77.1 (d), 126.0 (d), 127.0 (d),
128.5 (d), 129.8 (d), 131.6 (d), 132.0 (d), 137.9 (u), 141.9 (u), 217.7 ppm
(u); IR (CHCl3): n˜ =3431 (s, br), 3100 (w), 3015 (s), 2924 (vs, br), 1732
(vs), 1608 (s), 1488 (w), 1451 (m), 1403 (m), 1334 (w), 1290 (w), 1247 (w),
1165 (m), 1093 (m), 970 (s), 881 cmÀ1 (w); MS(EI, 70 eV): m/z (%): 284
(11) [M]+, 266 (20), 161 (5), 145 (9), 144 (20), 143 (5), 135 (6), 131 (10),
119 (6), 118 (12), 106 (35), 105 (100), 91 (11); HRMS(EI, 70 eV): m/z:
Stannane 25: Rf =0.52 (n-hexane); H NMR (400 MHz, C6D6): d=0.79 (s,
6H; C
Me), 2.22–2.35 (m, 3H), 2.50–2.63 (m, 2H; CH=CHCH2CH2), 3.29–3.31
(m, 4H; (CH2O)2), 3.47–3.53 (m, 1H; CHOH), 5.18 (dd, J=8.4,
ACHTREUNG(CH3)2), 1.48–1.55 (m, 2H; OH), 1.81–2.18 (m, 5H), 2.19 (s, 3H;
CACHTREUNG
15.3 Hz, 1H; CH=CHCH2), 5.48 (dt, J=6.7, 15.3 Hz, 1H; CH=CHCH2),
6.90–6.93 (m, 3H), 7.13 ppm (t, J=7.4 Hz, 1H); 13C NMR (100 MHz,
C6D6): d=21.4 (d), 22.5 (d), 29.9 (u), 34.9 (u), 35.8 (d), 36.2 (u), 38.6 (u),
40.8 (u), 41.2 (u), 44.12 (d), 58.5 (d), 71.8 (u), 71.9 (u), 78.1 (d), 110.4 (u),
125.8 (d), 126.7 (d), 128.3 (d), 129.6 (d), 131.1 (d), 133.0 (d), 137.6 (u),
141.8 ppm (u); IR (CHCl3): n˜ =2924 (vs), 1600 (w), 1456 (m), 1077 (w),
988 (w), 875 cmÀ1 (w); MS(EI, 70 eV) m/z (%): 383 (17), 381 (15), 380
(20), 379 (100) [MÀ57]+, 378 (40), 377 (74), 376 (31), 375 (43), 327 (5),
323 (27), 321 (21), 320 (8), 319 (12), 269 (5), 267 (18), 266 (7), 265 (29),
+
calcd for C19H24O2 ÀC4H9: 284.177630; found: 284.177635.
Chem. Eur. J. 2007, 13, 1784 – 1795
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1791

H.-J. Gais and M. van de Sande
(3aS,4R,5R,6aR)-5-(tert-Butyldimethylsilyloxy)-4-[(E)-4-m-tolylbut-1-
enyl]hexahydropentalen-2(1H)-one (11): Imidazole (210 mg, 3.09 mmol)
and tBuMe2SiCl (200 mg, 1.33 mmol) were added to a solution of alcohol
27 (115 mg, 0.404 mmol) in DMF (6 mL). The solution was stirred at
room temperature for 16 h. Filtration of the mixture through silica gel (n-
hexane/EtOAc 4:1) afforded silyl ether 11 (150 mg, 93%) as a colorless
oil. [a]D =À17.1 (c=1.03 in THF); Rf =0.56 (n-hexane/EtOAc 4:1);
1H NMR (400 MHz, CDCl3): d=0.02 (s, 6H; SiCH3), 0.87 (s, 9H; SiC-
solution of 29. Subsequently, the mixture was cooled to À1058C and a
precooled (À788C) solution of ester (E)-10 (318 mg, 0.497 mmol) in THF
(6 mL) was slowly added. After 15 min, the solution was warmed to
À788C and stirred for 1.5 h. After this time, saturated aqueous NaHCO3
(2 mL), saturated aqueous NH4Cl (8 mL), and Et2O (10 mL) were added
successively. The organic phase was washed with H2O (3”5 mL) and the
aqueous phase was extracted with Et2O (3”20 mL). The combined or-
ganic phases were dried (MgSO4) and concentrated in vacuo. Purification
by chromatography (n-hexane/EtOAc 7:1) gave a mixture of esters anti-9
and syn-9 (287 mg, 90%) in a ratio of 99:1 as a colorless oil. Preparative
HPLC (Chiralpak AD, 250 mm”50 mm; n-hexane/isopropanol 99:1;
40 mLminÀ1; UV: 254 nm, RI) afforded anti-9 (261 mg, 82%) and syn-9
(3 mg, 1%) as colorless oils.
ACHTREUNG(CH3)3), 1.37–1.46 (m, 1H), 2.05–2.21 (m, 4H), 2.24–2.41 (m, 4H), 2.31
(s, 3H; CH3), 2.49–2.70 (m, 4H), 3.84–3.91 (m, 1H; CHOSi), 5.26 (dd,
J=8.2, 15.1 Hz, 1H; OCHCHCH=CH), 5.49 (dt, J=6.8, 15.1 Hz, 1H;
OCHCHCH=CH), 6.93–7.00 (m, 3H), 7.15 ppm (t, J=7.7 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=À4.7 (d), 18.0 (u), 21.3 (d), 25.74 (d),
34.5 (u), 35.2 (d), 35.8 (u), 42.2 (u), 42.7 (d), 42.9 (u), 45.9 (u), 57.9 (d),
78.9 (d), 125.2 (d), 126.3 (d), 127.9 (d), 129.0 (d), 131.0 (d), 131.3 (d),
137.5 (u), 141.5 (u), 219.0 ppm (u); IR (CHCl3): n˜ =3461 (w), 3016 (m),
2930 (vs), 2856 (s), 174 (vs), 1608 (m), 1466 (m), 1404 (m), 1384 (m),
1363 (m), 1252 (s), 1122 (s), 1003 (m), 969 (m), 940 (w), 898 (s), 838 cmÀ1
(s); MS(CI, CH 4): m/z (%): 399 (7) [M+1]+, 397 (8), 384 (6), 383 (21),
355 (5), 343 (7), 342 (28), 341 (100) [MÀC4H9]+, 296 (7), 295 (28), 281
(28), 268 (21), 267 (94), 249 (11), 209 (9), 131 (39), 105 (11); HRMS(EI,
70 eV): m/z: calcd for C25H38O2Si: 341.193684 [MÀC4H9]+; found:
341.193670.
Ester anti-9: [a]D =À28.6 (c=1.04 in CH2Cl2); Rf =0.86 (n-hexane/
EtOAc 4:1); 1H NMR (400 MHz, C6D6): d=0.06 (s, 3H; SiCH3), 0.08 (s,
3H; SiCH3), 0.74–0.84 (m, 1H), 0.91–1.03 (m, 3H), 1.00 (s, 9H; SiC-
AHCTRE(UNG CH3)3), 1.07 (s, 3H; CACHETR(NUG CH3)2), 1.15–1.28 (m, 1H), 1.32 (s, 3H; CACHTREUNG(CH3)2),
1.36–1.44 (m, 2H), 1.49–1.53 (m, 1H), 1.94–2.01 (m, 2H), 2.05–2.17 (m,
4H), 2.18 (s, 3H; CH3), 2.27–2.43 (m, 2H; CH=CHCH2), 2.52–2.72 (m,
5H), 2.81–2.88 (m, 1H), 3.58–3.65 (m, 1H; CHOSi), 4.93 (dt, J=4.4,
10.6 Hz, 1H; CO2CH
ACHTREUNG
OCHCHCH=CH), 5.37–5.40 (m, 1H; CH=CAHCTREUNG
15.2 Hz, 1H; OCHCHCH=CH), 6.92–6.98 (m, 3H), 7.03–7.07 (m, 1H),
7.12–7.21 ppm (m, 5H); 13C NMR (100 MHz, C6D6): d=À4.3 (d), À4.3
(d), 18.3 (u), 21.4 (d), 24.8 (u), 25.3 (d), 26.1 (d), 26.1 (u), 27.2 (u), 27.9
(d), 33.8 (u), 35.3 (u), 36.4 (u), 37.2 (u), 39.9 (u), 40.1 (u), 40.5 (u), 44.1
(d), 45.7 (d), 51.0 (d), 58.0 (d), 74.4 (d), 77.9 (d), 125.1 (d), 125.6 (d),
125.7 (d), 126.7 (d), 128.3 (d), 129.4 (d), 131.3 (d), 132.4 (d), 132.6 (d),
134.4 (u), 137.6 (u), 142.0 (u), 151.6 (u), 169.5 ppm (u); IR (CHCl3): n˜ =
3937 (w), 3916 (w), 3890 (w), 3780 (w), 3725 (w), 3681 (w), 3397 (w),
3019 (w), 2929 (vs), 2856 (s), 2674 (w), 1729 (s), 1605 (w), 1496 (w), 1467
(m), 1446 (m), 1368 (w), 1301 (w), 1251 (s), 1118 (s), 1027 (m), 965 (m),
908 (w), 838 cmÀ1 (s); MS(CI, CH 4): m/z (%): 641 (7) [M+1]+, 640 (5),
639 (14), 625 (6), 584 (14), 583 (33) [MÀC4H9]+, 508 (8), 440 (5), 439
(14), 426 (5), 425 (12), 407 (5), 385 (5), 384 (23), 383 (81), 366 (5), 365
(20), 337 (5), 310 (13), 309 (34), 308 (5), 307 (10), 291 (8), 263 (5), 249
(10), 202 (17), 201 (100), 145 (8), 133 (5), 132 (10), 131 (87), 120 (8), 119
(79), 106 (5), 105 (64), 91 (10); HRMS(EI, 70 eV): m/z: calcd for
C42H60O3Si: 583.360749 [MÀC4H9]+; found: 583.360820.
(E)-[(1S,2R)-2-(2-Phenylpropan-2-yl)cyclohexyl]-2-{(3aS,4R,5R,6aS)-5-
(tert-butyldimethylsilyloxy)-4-[(E)-4-m-tolylbut-1-enyl]hexahydropenta-
len-2(1H)ylidene} acetate ((E)-10): nBuLi (4.8 mL, 1.6m in hexanes,
7.70 mmol) was added at À788C to a solution of (1S,2R)-2-(2-phenylpro-
pan-2-yl)cyclohexyl-2-(dimethoxyphosphoryl) acetate (2.99 g, 8.10 mmol)
in THF (7 mL). Subsequently, the mixture was warmed to room tempera-
ture and then cooled to À628C. The solution of 28 was slowly treated
with a precooled (À788C) solution of ketone 11 (323 mg, 0.81 mmol) in
THF (7 mL). After the mixture had been stirred for 7 d at À628C, satu-
rated aqueous NH4Cl (10 mL) was added at À628C. Then the mixture
was warmed to ambient temperature and the aqueous phase was extract-
ed with Et2O (5”15 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by chromatography (n-
hexane/EtOAc 10:1) afforded a mixture of esters (E)-10 and (Z)-10
(441 mg, 85%) in a ratio of 96:4. Preparative HPLC (Kromasil Si-100,
250 mm”30 mm; n-hexane/EtOAc 98:2; 20 mLminÀ1; UV: 254 nm, RI)
gave (E)-10 (410 mg, 79%) and (Z)-10 (10 mg, 2%) as colorless oils.
2-{(3aS,5R,6R,6aS)-5-(tert-Butyldimethylsilyloxy)-6-[(E)-4-m-tolylbut-1-
enyl]-1,3a,4,5,6,6a-hexahydropentalen-2-yl}ethanol
(8):
DIBAL-H
Ester (E)-10: [a]D =+28.6 (c=1.00 in CH2Cl2); Rf =0.86 (n-hexane/
EtOAc 4:1); 1H NMR (300 MHz, C5D5N): d=0.00 (s, 3H; SiCH3), 0.01
(1.2 mL, 1.0m in THF, 1.2 mmol) was slowly added at 08C to a stirred so-
lution of ester anti-9 (257 mg, 0.401 mmol) in THF (6 mL). After 30 min,
the mixture was left to warm to ambient temperature and stirred for 2 h.
Then the mixture was diluted with Et2O (10 mL) and successively treated
with ice (10 mg), saturated aqueous NH4Cl (3 mL), and saturated aque-
ous NaCl (10 mL). The aqueous phase was extracted with Et2O (5”
30 mL) and the combined organic phases were dried (MgSO4) and con-
centrated in vacuo. Purification by chromatography (n-hexane/EtOAc
10:1) gave alcohol 8 (150 mg, 88%) as a colorless oil. [a]D =À19.4 (c=
1.02 in THF); Rf =0.31 (n-hexane/EtOAc 4:1); 1H NMR (400 MHz,
C6D6): d=0.08 (s, 3H; SiCH3), 0.09 (s, 3H; SiCH3), 0.83–0.91 (m, 1H;
(s, 3H; SiCH3), 0.85 (s, 9H; SiC
ACHTREUNG
C
A
2.18 (s, 3H; CH3), 2.27–2.41 (m, 4H; CH=CHCH2), 2.57–2.74 (m, 2H;
CH=CHCH2CH2), 2.82–2.92 (m, 1H), 2.94–3.03 (m, 1H), 3.71 (q, J=
8.4 Hz, 1H; CHOSi), 4.88 (dt, J=4.3, 10.4 Hz, 1H; CO2CHCH2), 5.27–
5.35 (m, 2H; CO2CH=C, OCHCHCH=CH), 5.55 (dt, J=6.6, 15.3 Hz,
1H; OCHCHCH=CH), 6.95–7.03 (m, 3H), 7.09–7.19 (m, 2H), 7.26–
7.33 ppm (m, 4H); 13C NMR (75 MHz, C5D5N): d=À4.6 (d), À4.6 (d),
18.1 (u), 21.2 (d), 24.7 (u), 25.6 (d), 25.8 (d), 25.9 (u), 27.2 (u), 27.5 (d),
33.8 (u), 34.8 (u), 36.1 (u), 38.5 (d), 39.5 (u), 39.9 (u), 39.9 (u), 42.6 (u),
44.4 (d), 51.1 (d), 57.2 (d), 73.4 (d), 78.5 (d), 113.8 (d), 125.0 (d), 125.7
(d), 125.8 (d), 126.7 (d), 128.2 (d), 128.4 (d), 129.5 (d), 131.1 (d), 132.5
(d), 137.7 (u), 142.0 (u), 151.65 (u), 165.4 (u), 166.4 ppm (u); IR (CHCl3):
n˜ =3017 (w), 2932 (m), 2857 (m), 1698 (m), 1655 (w), 1605 (w), 1493 (w),
1467 (w), 1369 (w), 1252 (w), 1217 (s), 1125 (m), 1029 (m), 965 (w), 908
OH), 1.00 (s, 9H; SiCACHTRE(UNG CH3)3), 1.36–1.43 (m, 1H), 2.00–2.17 (m, 6H), 2.16
(s, 3H; CH3), 2.31–2.42 (m, 3H), 2.59–2.73 (m, 2H; CH=CHCH2CH2),
2.82–2.90 (m, 1H), 3.46–3.49 (t, J=6.6 Hz, 2H; CH2OH), 3.63–3.69 (m,
1H; CHOSi), 5.27–5.28 (m, 1H; CH=CCATHRE(UNG CH2)2), 5.34 (dd, J=8.0, 15.3 Hz,
1H; OCHCHCH=CH), 5.55 (dt, J=6.8, 15.3 Hz, 1H; OCHCHCH=CH),
6.92–6.98 (m, 3H), 7.12–7.15 ppm (m, 1H); 13C NMR (100 MHz, C6D6):
d=À4.3 (d), À4.3 (d), 18.4 (u), 21.4 (d), 26.1 (d), 34.7 (u), 35.3 (u), 36.5
(u), 40.3 (u), 40.9 (u), 43.8 (d), 45.9 (d), 58.3 (d), 60.8 (u), 78.1 (d), 125.7
(d), 126.7 (d), 128.4 (d), 129.4 (d), 130.3 (d), 131.1 (d), 132.7 (d), 137.6
(u), 138.5 (u), 142.0 ppm (u); IR (CHCl3): n˜ =3357 (m, br), 3009 (m),
2929 (s), 2875 (s), 1606 (w), 1467 (w), 1382 (w), 1253 (m), 1217 (w), 1115
(m), 1044 (w), 1006 (w), 968 (w), 908 (w), 840 cmÀ1 (m); MS(CI, CH 4):
m/z (%): 427 (15) [M+1]+, 426 (9), 425 (24), 411 (7), 409 (10), 371 (8),
370 (29), 369 (100) [MÀC4H9]+, 351 (7), 337 (6), 323 (7), 296 (18), 195
(85), 293 (9), 278 (15), 277 (73), 173 (6), 159 (9), 145 (9), 132 (7), 131
(63), 105 (23); HRMS(EI, 70 eV): m/z: calcd for C27H42O2Si: 369.224984
[MÀC4H9]+; found: 369.224932.
(w), 839 cmÀ1 (m); MS(CI, CH ): m/z (%): 641 (2) [M+1]+, 584 (5), 583
4
(9) [MÀC4H9]+, 439 (5), 426 (6), 425 (19), 423 (5), 385 (8), 384 (29), 383
(100), 365 (8), 337 (8), 310 (14), 309 (76), 292 (7), 291 (34), 201 (24), 145
(5), 131 (22), 119 (29), 105 (22); HRMS(EI, 70 eV): m/z: calcd for
C42H60O3S i [MÀC4H9]+: 583.360749; found: 583.360850.
ACHTREUNG(1S,2R)-2-(2-Phenylpropan-2-yl)cyclohexyl-2-{(3aS,5R,6R,6aS)-5-(tert-
butyldimethylsilyloxy)-6-[(E)-4-m-tolylbut-1-enyl]-1,3a,4,5,6,6a-hexahy-
dropentalen-2-yl} acetate (anti-9): nBuLi (1.2 mL, 1.6m in hexanes,
1.98 mmol) was added at À788C to a suspension of bis[(R)-1-phenylethy-
l]ammonium chloride in THF (12 mL). Then the suspension was left to
warm to ambient temperature, which led to the formation of a clear, red
1792
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1784 – 1795

Synthesis of Tetranorisocarbacyclin Derivatives
FULL PAPER
tert-Butyl 2-(2-{(3aS,5R,6R,6aS)-5-hydroxy-6-[(E)-4-m-tolylbut-1-enyl]-
1,3a,4,5,6,6a-hexahydropentalen-2-yl}ethoxy)acetate (31): Bu4NHSO4
(67 mg, 0.12 mmol), BrCH2CO2tBu (200 mL, 1.29 mol), and aqueous
NaOH (50%, 3 mL) were added successively to a solution of alcohol 8
(96 mg, 0.23 mmol) in CH2Cl2. Then the mixture was stirred for 2.5 h at
room temperature, and BrCH2CO2tBu (200 mL, 1.29 mmol) and aqueous
NaOH (50%, 2 mL) were added. After the mixture had been stirred for
12 h, ice (10 g) was added and the aqueous phase was extracted with
CH2Cl2 (3”25 mL). The combined organic phases were dried (MgSO4)
and concentrated in vacuo. The residue was dissolved in THF (6 mL) and
Bu4NF (1.3 mL, 1.0m in THF, 1.28 mmol) was added. After the mixture
had been stirred for 16 h, Et2O (20 mL), aqueous NaCl (10 mL), and
water (10 mL) were added successively. The aqueous phase was extracted
with Et2O (5”25 mL), and the combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by chromatography (n-
hexane/EtOAc 6:1) afforded ester 31 (85 mg, 89%) as a colorless oil.
[a]D =+4.18 (c=0.98 in THF); Rf =0.21 (n-hexane/EtOAc 4:1);
(6.0 mg, 0.05 mmol) in CH2Cl2 (2 mL). After the mixture had been stirred
for 1.5 h, additional NEt3 (0.04 mL, 0.27 mmol) and TsCl (20 mg,
0.11 mmol) were added and stirring was continued for 12 h. Then water
(5 mL) was added and the organic phase was washed successively with
1m HCl (2”3 mL) and water (3 mL). The combined aqueous phases
were extracted with Et2O (3”15 mL), and the combined organic phases
were dried (MgSO4) and concentrated in vacuo. Purification by chroma-
tography (n-hexane/EtOAc 9:1) afforded tosylate 32 (92 mg, 90%) as a
colorless oil. [a]D =À9.35 (c=0.97 in THF); Rf =0.57 (n-hexane/EtOAc
4:1); 1H NMR (400 MHz, C6D6): d=0.07 (s, 3H; SiCH3), 0.08 (s, 3H;
SiCH3), 1.00 (s, 9H; SiCACTHRE(UGN CH3)3), 1.25–1.32 (m, 1H), 1.84 (s, 3H; CH3),
1.92–2.22 (m, 7H), 2.17 (s, 3H; CH3), 2.31–2.41 (m, 2H; CH=CHCH2),
2.59–2.77 (m, 3H), 3.59 (dt, J=6.9, 9.3 Hz, 1H; CHOSi), 3.99 (t, J=
6.6 Hz, 2H; CH2OSO2), 5.10–5.11 (m, 1H; CH=CACHTER(UNG CH2)2), 5.29 (dd, J=
7.9, 15.3 Hz, 1H; OCHCHCH=CH), 5.52 (dt, J=6.5, 15.3 Hz, 1H;
OCHCHCH=CH), 6.71 (d, J=8.2 Hz, 2H), 6.92–6.98 (m, 3H), 7.12–7.16
(m, 1H), 7.77 ppm (d, J=8.2 Hz, 2H); 13C NMR (100 MHz, C6D6): d=
À4.30 (d), À4.35 (d), 18.3 (u), 21.1 (d), 21.4 (d), 26.1 (d), 30.6 (u), 35.3
(u), 36.4 (u), 40.1 (u), 40.6 (u), 43.6 (d), 45.7 (d), 58.1 (d), 68.3 (u), 77.9
(d), 125.7 (d), 126.7 (d), 128.1 (d), 128.4 (d), 129.4 (d), 129.6 (d), 130.8
(d), 131.1 (d), 132.5 (d), 134.6 (u), 136.2 (u), 137.8 (u), 142.0 (u),
144.1 ppm (u); IR (CHCl3): n˜ =3378 (w, br), 2928 (vs), 2856 (s), 1601 (w),
1464 (m), 1364 (s), 1253 (m), 1179 (s), 1112 (s), 968 (s), 908 (m), 837 cmÀ1
(s); MS(CI, CH 4): m/z (%): 581 (7) [M+1]+, 580 (7) [M]+, 579 (8), 565
(7), 523 (13), 451 (6), 450 (17), 449 (56), 410 (9), 409 (28), 407 (6), 393
(8), 351 (10), 305 (8), 279 (7), 278 (22), 277 (100), 173 (5), 159 (8), 145
1H NMR (400 MHz, C6D6): d=1.34 (s, 9H; C
ACHTRE(UNG CH3)3), 1.34–1.42 (m, 2H;
OH), 1.90–1.97 (m, 1H; CHCH=CHCH2), 2.08–2.20 (m, 3H), 2.19 (s,
3H; CH3), 2.26–2.36 (m, 4H; CH=CCH2CH2O, CH=CHCH2), 2.40–2.47
(m, 1H), 2.52–2.64 (m, 2H; CH=CHCH2CH2), 2.83–2.90 (m, 1H), 3.50–
3.53 (m, 1H; CHOH), 3.55 (t, J=6.7 Hz, 2H; CH=CCH2CH2O), 3.82 (s,
2H; OCH2CO2), 5.19 (dd, J=8.5, 15.1 Hz, 1H; OCHCHCH=CH), 5.33
(d, J=1.4 Hz, 1H; CH=CACHTREU(GN CH2)2), 5.48 (dt, J=6.7, 15.1 Hz, 1H;
OCHCHCH=CH), 6.91–6.94 (m, 3H), 7.12–7.16 ppm (m, 1H); 13C NMR
(100 MHz, C6D6): d=21.4 (d), 28.0 (d), 31.8 (u), 35.0 (u), 36.2 (u), 39.8
(u), 40.4 (u), 44.6 (d), 46.1 (d), 58.9 (d), 68.8 (u), 70.1 (u), 77.3 (d), 80.5
(u), 125.8 (d), 126.7 (d), 128.3 (d), 129.6 (d), 129.9 (d), 131.4 (d), 132.7
(d), 137.6 (u), 138.5 (u), 141.8 (u), 169.3 ppm (u); IR (CHCl3): n˜ =3394
(m, br), 2925 (vs), 1747 (s), 1667 (w), 1608 (w), 1455 (m), 1393 (w), 1369
(m), 1305 (w), 1229 (m), 1132 (s), 1070 (m), 968 (w), 844 cmÀ1 (w); MS
(CI, CH4): m/z (%): 427 (2) [M+1]+, 426 (2) [M]+, 381 (6), 371 (8), 370
(7), 369 (15), 354 (24), 353 (100), 352 (18), 351 (9), 305 (6), 295 (6), 294
(6), 293 (12), 278 (18), 277 (83), 276 (7), 159 (6), 145 (9), 132 (5), 131
(48), 105 (6); HRMS(EI, 70 eV): m/z: calcd for C27H38O4: 352.203845
[MÀC4H10O]+; found: 352.203859.
(10), 131 (33); HRMS(EI, 70 eV):
m/z: calcd for C34H48O4SSi:
523.233836 [MÀC4H9]+; found: 523.233846.
2-(3-Iodopropoxy)tetrahydro-2H-pyran (35a): A small amount of pyridi-
nium p-toluenesulfonate was added to a stirred solution of 3-iodopropa-
nol (10.0 g, 53.7 mmol) and 3,4-dihydro-2H-pyran (5.2 mL, 56.5 mmol) in
CH2Cl2 (80 mL). After the mixture had been stirred for 12 h at room
temperature, saturated aqueous NaCl (30 mL) was added. The aqueous
phase was extracted with Et2O (3”30 mL) and the combined organic
phases were dried (MgSO4) and concentrated in vacuo. Purification by
chromatography (n-hexane/EtOAc 10:1) gave iodide 35a (13.5 g, 93%)
as a colorless oil. Rf 0.30 (n-hexane/EtOAc 10:1); 1H NMR (400 MHz,
CDCl3): d=1.50–1.84 (m, 6H), 2.06–2.12 (m, 2H; CH2CH2I), 3.27–3.32
(m, 2H; CH2I), 3.42–3.47 (m, 1H), 3.49–3.55 (m, 1H), 3.78–3.83 (m, 1H),
3.84–3.89 (m, 1H), 4.59–4.61 ppm (m, 1H; CHO2); 13C NMR (100 MHz,
CDCl3): d=3.4 (u), 19.4 (u), 25.4 (u), 30.5 (u), 33.5 (u), 62.1 (u), 66.7 (u),
98.7 ppm (d); IR (neat): n˜ =3852 (w), 3747 (w), 3672 (w), 3648 (w), 3625
(w), 3466 (w), 2940 (vs), 2868 (s), 2361 (m), 2335 (m), 1651 (w), 1559 (w),
1540 (w), 1506 (w), 1438 (m), 1383 (m), 1322 (w), 1279 (w), 1183 (m),
1132 (s), 1075 (s), 1031 (vs), 980 (m), 906 (w), 870 (m), 814 cmÀ1 (w); MS
(CI, CH4): m/z (%): 271 (0.6) [M+1]+, 270 (4) [M]+, 268 (6), 168 (5), 142
(9), 86 (5), 85 (100); elemental analysis calcd (%) for C8H15IO2 (270.11):
C 35.57, H 5.60; found: C 35.64, H 5.62.
2-(2-{(3aS,5R,6R,6aS)-5-Hydroxy-6-[(E)-4-m-tolylbut-1-enyl]-
1,3a,4,5,6,6a-hexahydropentalen-2-yl}ethoxy)acetic acid (7b): Aqueous
NaOH (1n, 1 mL) was added to a stirred solution of ester 31 (57 mg,
0.134 mmol) in MeOH (2.5 mL). After the mixture had been stirred for
7 h at room temperature, water (3 mL) and saturated aqueous NH4Cl
(3 mL) were successively added. The pH value was adjusted to 4 by addi-
tion of NaH2PO4 and the solution was extracted with Et2O (3”20 mL).
The combined organic phases were dried (MgSO4) and concentrated in
vacuo. Removal of residual solvent and tBuOH in vacuo (10À6 mbar)
gave acid 7b (48 mg, 98%) as a colorless oil. [a]D =++4.18 (c=0.98 in
THF); 1H NMR (400 MHz, C6D6): d=1.35 (br, 1H; OH), 1.40–1.47 (m,
1H), 2.00–2.08 (m, 1H; CHCH=CHCH2), 2.12–2.26 (m, 5H), 2.20 (s, 3H;
CH3), 2.28–2.40 (m, 3H), 2.56–2.68 (m, 2H; CH=CHCH2CH2), 2.84–2.90
(m, 1H), 3.34–3.43 (m, 2H; CH=CCH2CH2O), 3.61 (dt, J=6.9, 8.8 Hz,
1H; CHOH), 3.82 (s, 2H; OCH2CO2), 5.22 (dd, J=8.2, 15.3 Hz, 1H;
tert-Butyldimethyl{(2R,3R,3aS,6aS)-5-[5-(tetrahydro-2H-pyran-2-yloxy)-
pentyl]-3-[(E)-4-m-tolylbut-1-enyl]-1,2,3,3a,4,6a-hexahydropentalen-2-
yloxy}silane (36): tBuLi (0.11 mL, 1.60m in hexanes, 0.18 mmol) was
added at À788C to a solution of iodide 35a (24 mg, 0.09 mmol) in n-pen-
tane/Et2O (1 mL, 3:2). After the resulting turbid solution of 35b had
been stirred for 5 min at À788C, a cold (À788C) solution of CuI (17 mg,
0.09 mmol) and Bu3P (0.06 mL, 0.24 mmol) in Et2O (1 mL) was added by
a syringe. Subsequently, the mixture was warmed to À408C to form a
clear yellow solution of 35c. Then a cold (À408C) solution of tosylate 32
(13 mg, 0.02 mmol) in Et2O (1 mL) was added. The solution was left to
warm to 08C within 2 h, and then saturated aqueous NH4Cl (1 mL) was
added. Subsequently, the organic phase was washed with water (2 mL)
and the combined aqueous phases were extracted with Et2O (5”3 mL).
The combined organic phases were dried (MgSO4) and concentrated in
vacuo. Preparative HPLC (Kromasil Si-100, 250 mm”30 mm; n-hexane/
EtOAc, 96:4; UV: 254 nm, RI) gave acetal 36 (10 mg, 82%) as a color-
less oil. [a]D = À11.93 (c=1.10 in THF); Rf =0.65 (n-hexane/EtOAc
6:1); 1H NMR (400 MHz, C6D6): d=0.09 (s, 3H; SiCH3), 0.10 (s, 3H;
OCHCHCH=CH), 5.27–5.30 (m, 1H; CH=CACHTRE(UNG CH2)2), 5.54 (dt, J=6.7,
15.3 Hz, 1H; OCHCHCH=CH), 6.56 (br, 1H; CO2H), 6.93–6.97 (m,
3H), 7.14–7.18 ppm (m, 1H); 13C NMR (100 MHz, C6D6): d=21.4 (d),
31.4 (u), 35.0 (u), 36.2 (u), 39.5 (u), 40.4 (u), 44.6 (d), 46.3 (d), 58.6 (d),
67.8 (u), 70.0 (u), 77.7 (d), 125.8 (d), 126.7 (d), 128.3 (d), 129.6 (d), 130.2
(d), 131.5 (d), 132.5 (d), 137.7 (u), 138.4 (u), 141.9 (u), 173.9 ppm (u); IR
(CHCl3): n˜ =3392 (m, br), 2924 (vs), 1729 (s), 1609 (m), 1455 (m), 1375
(w), 1218 (w), 1132 (m), 969 (w), 883 cmÀ1 (w). MS(CI, CH 4): m/z (%):
385 (2) [M+15]+, 370 (4) [M]+, 369 (11), 355 (6), 354 (19), 353 (77), 352
(17), 351 (8), 345 (14), 327 (7), 309 (17), 307 (10), 305 (5), 295 (17), 294
(6), 293 (18), 291 (9), 279 (19), 278 (24), 277 (100), 276 (6), 275 (10), 185
(6), 173 (6), 171 (6), 159 (11), 157 (5), 145 (22), 133 (8), 132 (8), 131 (71),
121 (5), 105 (17); HRMS(EI, 70 eV):
m/z: calcd for C23H30O4:
352.203845 [MÀH2O]+; found: 352.203947.
2-{(3aS,5R,6R,6aS)-5-(tert-Butyldimethylsilyloxy)-6-[(E)-4-m-tolylbut-1-
enyl]-1,3a,4,5,6,6a-hexahydropentalen-2-yl}ethyl 4-methylbenzenesulfo-
nate (32): TsCl (34 mg, 0.18 mmol) was added to a stirred solution of al-
cohol 8 (76 mg, 0.18 mmol), NEt3 (0.04 mL, 0.27 mmol), and DABCO
SiCH3), 1.02 (s, 9H; SiCCAHTRE(UGN CH3)3), 1.24–1.50 (m, 9H), 1.57–1.67 (m, 4H),
1.74–1.85 (m, 1H), 2.00–2.24 (m, 5H), 2.17 (s, 3H; CH3), 2.30–2.47 (m,
3H), 2.61–2.74 (m, 2H; CH=CHCH2CH2), 2.89–2.95 (m, 1H), 3.32–3.38
Chem. Eur. J. 2007, 13, 1784 – 1795
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1793

H.-J. Gais and M. van de Sande
(m, 1H), 3.40–3.45 (m, 1H), 3.68 (dt, J=7.1, 9.3 Hz, 1H; CHOSi), 3.81–
3.88 (m, 2H), 4.61 (t, J=3.4 Hz, 1H; OCHO), 5.29–5.30 (m, 1H;
CHCH=CACHTREUNG(CH2)2), 5.37 (dd, J=7.9, 15.1 Hz, 1H; OCHCHCH=CH), 5.59
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(dt, J=6.6, 15.1 Hz, 1H; OCHCHCH=CH), 6.92–6.99 (m, 3H), 7.12–
7.16 ppm (m, 1H); 13C NMR (100 MHz, C6D6): d=À4.3 (d), À4.2 (d),
18.4 (u), 19.7 (u), 21.4 (d,), 26.0 (u), 26.1 (d), 26.7 (u), 28.0 (u), 30.1 (u),
31.1 (u), 31.4 (u), 35.3 (u), 36.5 (u), 40.2 (u), 41.1 (u), 43.9 (d), 45.7 (d),
58.3 (d), 61.5 (u), 67.4 (u), 78.1 (d), 98.4 (d), 125.7 (d), 126.7 (d), 128.2
(d), 128.4 (d), 129.4 (d), 131.1 (d), 132.8 (d), 137.6 (u), 141.8 (u),
142.05 ppm (u); IR (CHCl3): n˜ =3025 (w), 2931 (vs), 2858 (s), 2361 (w),
2335 (w), 1609 (w), 1461 (m), 1358 (w), 1253 (m), 1200 (w), 1119 (s),
1078 (w), 1030 (m), 970 (w), 907 (w), 840 cmÀ1 (m); MS(EI, 70 eV): m/z
(%): 552 (2) [M+], 496 (17), 495 (48), 420 (5), 411 (15), 403 (15), 319
(16), 158 (13), 157 (5), 145 (20), 131 (26), 119 (6), 105 (37), 91 (8), 86 (5),
85 (100); HRMS(EI, 70 eV): m/z: calcd for C35H56O3Si: 495.329449
[MÀC4H9]+; found: 495.329473.
5-{(3aS,5R,6R,6aS)-5-(tert-Butyldimethylsilyloxy)-6-[(E)-4-m-tolylbut-1-
enyl]-1,3a,4,5,6,6a-hexahydropentalen-2-yl}pentan-1-ol (37): 1,2-Dibro-
moethane (0.08 mL, 0.93 mmol) was added to a stirred suspension of Mg
(25 mg, 1.03 mmol) in Et2O (1.5 mL). After a brief heating of the mixture
at reflux, it was stirred at room temperature until all of Mg was con-
sumed (2 h). A solution of acetal 36 (10 mg, 0.018 mmol) in Et2O (1 mL)
was added to the thus-formed solution of MgBr2, followed by the addi-
tion of saturated aqueous NH4Cl (2 mL). After the mixture had been stir-
red for 1.5 h, it was cooled to 08C and saturated aqueous NH4Cl (1 mL)
was added. The organic phase was washed with water (3”2 mL) and the
combined aqueous phases were extracted with Et2O (5”3 mL). The com-
bined organic phases were dried (MgSO4) and concentrated in vacuo.
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Preparative HPLC (Chiralpak AD, 250 mm”50 mm, 30 mLminÀ1
,
50 mm; n-hexane/iPrOH 97:3; UV: 254 nm, RI) gave alcohol 37 (5.4 mg,
64%) as a colorless oil. [a]D =À15.36 (c=1.10 in THF); Rf =0.16 (n-
hexane/EtOAc 6:1); 1H NMR (400 MHz, C6D6): d=0.09 (s, 3H; SiCH3),
0.11 (s, 3H; SiCH3), 0.53 (t, J=5.2 Hz, 1H; OH), 0.86 (s, 9H; SiC-
ACHTREUNG(CH3)3), 1.21–1.28 (m, 2H), 1.33–1.50 (m, 5H), 1.97–2.01 (m, 2H; CH=
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CCH2), 2.08–2.25 (m, 4H), 2.17 (s, 3H; CH3), 2.33–2.47 (m, 3H), 2.61–
2.74 (m, 2H; CH=CHCH2CH2), 2.89–2.96 (m, 1H), 3.31–3.35 (m, 2H;
CH2O), 3.69 (dt, J=7.1, 9.3 Hz, 1H; CHOSi), 5.30–5.31 (m, H; CH=C-
ACHTREUNG(CH2)2), 5.38 (dd, J=7.8, 15.2 Hz, 1H; OCHCHCH=CH), 5.60 (dt, J=
6.6, 15.2 Hz, 1H; OCHCHCH=CH), 6.92–6.99 (m, 3H), 7.12–7.16 ppm
(m, 1H); 13C NMR (100 MHz, C6D6): d=À4.2 (d), À4.3 (d), 18.4 (u),
21.4 (d), 26.0 (u), 26.1 (d), 27.9 (u), 31.4 (u), 33.0 (u), 35.3 (u), 36.5 (u),
40.2 (u), 41.1 (u), 43.9 (d), 45.7 (d), 58.3 (d), 62.5 (u), 78.1 (d), 125.7 (d),
126.7 (d), 128.3 (d), 128.4 (d), 129.4 (d), 131.1 (d), 132.8 (d), 137.6 (u),
141.8 (u), 142.0 ppm (u); IR (CHCl3): n˜ =3350 (w), 2927 (vs), 2857 (s),
1728 (w), 1605 (w), 1461 (m), 1377 (w), 1254 (m), 1217 (w), 1115 (m), 966
(w), 909 (w), 839 cmÀ1 (m); MS(EI, 70 eV): m/z (%): 413 (9), 412 (33),
411 (100) [MÀC4H9]+, 367 (5), 363 (9), 336 (5), 320 (5), 319 (19), 314 (5),
249 (5), 231 (8), 208 (6), 205 (7), 201 (9), 185 (8), 182 (8), 175 (7), 173
(6), 171 (12), 168 (5), 159 (12), 157 (14), 154 (8), 147 (10), 146 (6), 145
(45), 143 (13), 135 (11), 133 (11), 132 (10), 131 (84), 129 (8), 125 (6), 12
(5), 121 (6), 119 (21), 117 (13), 111 (8), 108 (8), 107 (7), 106 (11), 105
(98), 97 (10), 95 (14), 93 (12), 91 (24), 85 (25), 81 (12); HRMS(EI,
70 eV): m/z: calcd for C30H48O2Si: 411.271934 [MÀC4H9]+; found:
411.271953.
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Financial support of this work by the Deutsche Forschungsgemeinschaft
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thank Dr. J. Runsink for NMR spectroscopic investigations, Prof. Dr. C.
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1794
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1784 – 1795

Synthesis of Tetranorisocarbacyclin Derivatives
FULL PAPER
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Received: May 24, 2006
Published online: November 15, 2006
Chem. Eur. J. 2007, 13, 1784 – 1795
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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