2,6-Disubstituted tetrahydropyrans by tandem cross-metathesis/ iodocyclisation

Article abstract of DOI:10.1002/ejoc.200700902

A new approach to 2,6-disubstituted tetrahydropyrans by a tandem cross-metathesis/iodocyclisation reaction has been developed. The stereochemical outcome of the cyclisation reactions has been studied for different substrates. This sequence has allowed the

Full text of DOI:10.1002/ejoc.200700902

FULL PAPER
DOI: 10.1002/ejoc.200700902
2,6-Disubstituted Tetrahydropyrans by Tandem Cross-Metathesis/
Iodocyclisation
Marie-Aude Hiebel,[a] Béatrice Pelotier,[a] Peter Goekjian,[a] and Olivier Piva*[a]
Keywords: Metathesis / Cyclization / Tandem reactions / Tetrahydropyrans
A new approach to 2,6-disubstituted tetrahydropyrans by a
tandem cross-metathesis/iodocyclisation reaction has been
developed. The stereochemical outcome of the cyclisation re-
actions has been studied for different substrates. This se-
quence has allowed the preparation of a series of cis- and
trans-2,6-disubstituted analogues of the tetrahydropyran
subunit of bistramide A.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
The tetrahydropyran subunit is present in numerous nat-
ural products and many strategies have been developed over
the years to build this heterocycle.[1] The most widely used
methods in natural product synthesis are the hetero-Diels–
Alder cyclisation,[2] the Prins and related cyclisation reac-
tions,[3] intramolecular oxo-Michael additions[4] and ring-
closing metathesis.[5,6] Other strategies include the cycli-
sation of non-activated hydroxy alkenes promoted by an
electrophilic species. Thus, the tetrahydropyran core struc-
ture of different synthetic targets can be obtained by the
oxypalladation of allylic acetates[7] or terminal alkenes,[8]
but also by alkene activation with selenonium[9] or iodo-
nium ions.[10]
Bistramide A is a marine metabolite containing substi-
tuted tetrahydropyran and spiroketal subunits linked by a
γ-amino acid (Figure 1). This molecule was initially isolated
in 1988 from the marine ascidian Lissoclinum bistratum[11]
and four other members of the bistramide family (bistram-
ides B, C, D and K) have been identified to date.[12] Bistra-
mides exhibit significant biological properties, in particular,
antiproliferative,[13] neurotoxic[14] and cytotoxic[12] activi-
ties. More specifically, the potent antiproliferative profile of
bistramide A was initially attributed to a highly selective
activation of protein kinase C-δ.[15] Recent studies have
called into question this mode of action and instead re-
ported actin to be the primary cellular receptor of bistram-
ide A.[16] Since the first total synthesis of bistramide A by
Kozmin and co-workers, which provided the full structural
assignment of this complex molecule,[5] two other syntheses
have been achieved.[17,18]
Figure 1. Strategic route to 2,6-disubstituted tetrahydropyran ana-
logues of the north part of bistramide A.
We are interested in the synthesis of analogues of the
north part of bistramide A (the tetrahydropyran subunit)
as part of a research program devoted to the discovery of
new modulators of protein kinases in order to investigate
the potential role of this subunit in actin- and kinase-medi-
ated effects. In connection with our work on tandem pro-
cesses involving metathesis reactions,[19] we envisaged a ra-
pid access to various 2,6-disubstituted tetrahydropyranyl es-
ter analogues by a cross-metathesis of a common hydroxy
alkene precursor followed by iodocyclisation to form the
tetrahydropyran ring (Figure 1). These two reactions have
previously been closely associated with the synthesis of
bis(tetrahydrofuran) acetogenin derivatives[20] (THF frag-
ments obtained by iodocyclisation and assembled after fur-
ther functionalisation by a cross-metathesis reaction) and
with the synthesis of spiroketal-containing bioactive com-
pounds such as attenol A[21] (iodoetherification used as a
protection method for a 1,5-alkenol subunit before a sili-
[a] ICBMS, Institut de Chimie et Biochimie Moléculaires et Supra-
moléculaires, CNRS, UMR5246, Université de Lyon,
43 boulevard du 11 novembre 1918, 69622 Villeurbanne, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 713–720
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
713

M.-A. Hiebel, B. Pelotier, P. Goekjian, O. Piva
FULL PAPER
con-tether-aided coupling metathesis step). However, nei- Table 1. Cross-metathesis of β-hydroxy esters 3 or 4 with various
olefins.
ther of these approaches was reported to involve a tandem
process of these two reactions. Herein, we wish to report
our results based on this strategy.
Results and Discussion
First, we performed cross-metathesis reactions on a com-
mon δ- or ε-unsaturated alcohol precursor easily prepared
in two steps. Next, we optimised the electrophile-mediated
cyclisation step by testing different activating agents and
the resulting cycloadducts were submitted to hydrogenolysis
in order to determine the regio- and stereochemical out-
come of the haloetherification step. Finally, the cross-me-
tathesis and iodocyclisation reactions were combined in a
tandem process to rapidly access the target 2,6-disubsti-
tuted tetrahydropyranyl ester analogues.
Cross-Metathesis Reactions
The initial attempt at the cross-metathesis reaction was
performed on unsaturated β-keto ester 2, prepared by γ-
alkylation of methyl acetoacetate with 4-bromobut-1-ene
(Scheme 1). The next step involved the reduction of the
[a] This reaction was performed on β-keto ester 2. [b] Approximate
ketone to the alcohol and, considering that the presence
ratio determined by 1H and 13C NMR signal intensity. [c] Exact
of a free hydroxy group has been shown to favour cross-
1
value determined by H NMR signal integration.
metathesis reactions,[22] we performed cross-metathesis re-
actions on β-hydroxy esters 3 and 4, prepared by selective
reduction of 1 and 2 with sodium borohydride.
Cyclisation Reactions
Optimisation of Conditions
Different activating agents for the cyclisation of butyl-
substituted hydroxy alkene 8 were examined in order to find
suitable conditions for the haloetherification step (Table 2,
entries 1–3). N-Bromo- and N-iodosuccinimide (1.5 equiv.)
in acetone/water (10:1) gave, respectively, traces or a low
yield (37%, method A) of cyclised products. In both cases,
the starting material was primarily recovered. The cyclis-
ation promoted by iodine (3 equiv.) in the presence of so-
dium hydrogen carbonate (3.2 equiv.) occurred to give a
good yield of 78% (entry 2). Finally, the best conditions
were found by using bis(sym-collidine)iodine(I) hexafluoro-
phosphate as the iodonium ion source[23] which gave a
higher 93% yield of cycloadducts (entry 3).
Scheme 1. Synthesis of β-hydroxy esters 3 and 4. Reagents and con-
ditions: (a) NaH, BuLi, alkyl bromide, THF; (b) NaBH4, MeOH,
room temp.
The results of the cross-metathesis reactions between un-
saturated β-keto ester 2 or unsaturated β-hydroxy esters 3
and 4 and various olefins are reported in Table 1. The reac-
tions were performed by using the second-generation
Grubbs reagent as the catalyst (2 mol-%) and 5 equivalents
of olefin in refluxing dichloromethane. The functionalised
products 5–12 were isolated in good to high yields (61–
83%), the E isomer being the major product in all cases,
Cyclisation of All Substrates
Next, the unsubstituted hydroxy alkene 4 and the re-
reflecting the reversibility of the process. The cross-metathe- maining cross-metathesis products 5 and 9–12 were cyclised
sis product of unsaturated β-keto ester 2 with 1-hexene was with bis(sym-collidine)iodine(I) hexafluorophosphate as the
obtained in good yield (78%, entry 3) and the same reaction iodonium ion source (Table 2, method C). In some cases,
with unsaturated β-hydroxy ester 4 (entry 4) delivered in the cyclisation was also tested with iodine and sodium hy-
slightly better yield the corresponding butyl-substituted drogen carbonate (method B) to compare the efficiency of
product 8 (82%). When the chain length of the olefin was the two methods. In general, better yields of cyclised prod-
increased (R = C4H9 or R = C8H17, entries 4 and 5), we ucts were obtained with bis(sym-collidine)iodine(I) hexaflu-
observed similar yields of products, but a quite different orophosphate (75–99%). However, the iodocyclisation of
E/Z selectivity: the E/Z ratio dropped from 9:1 with 1-hex- phenyl-substituted hydroxy alkene 11 was more complete
ene to 1.2:1 with 1-decene.
with iodine (67 vs. 49%, entries 9 and 10).
714
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 713–720

Tetrahydropyrans by Tandem Cross-Metathesis/Iodocyclisation
Table 2. Iodoetherification and hydrogenolysis of compounds 4, 5 and 8–12.
Entry
n
SM (E/Z)
Method[a]
Combined yield
(%)[b]
Combined yield
(%)[c]
c/d
c[d]
cis/trans
d
dr[e]
1
2
3
4
5
6
7
8
1
1
1
0
1
1
1
1
1
1
1
8 (9:1)
8 (9:1)
8 (9:1)
5 (9:1)
4
A
B
C
C
B
C
C
C
C
B
C
37
78
93
75
76
99
87
93
49
67
55
77
94
85
84
–
3.5:1
4:1
4:1
9:1
1:0[f]
1:0[f]
1.8:1
1:0
0:1
–
67:33
63:37
68:32
70:30
67:33[g]
73:27[g]
75:25
100:0
–
≈50:50
≈50:50
≈50:50
cis only
–
–
4
–
9 (1.2:1)
10 (9:1)
11 (Ͼ19:1)
11 (Ͼ19:1)
12 (5.7:1)
87
42
92
–
64:36
–
9
10
11
76:24[h]
–
–
–
–
–
–
[a] Conditions: A) NIS (1.5 equiv.), acetone/H2O (1:0.1); B) I2 (3 equiv.), NaHCO3 (3.2 equiv.), CH3CN; C) bis(collidine)I·PF6 (1.2 equiv.),
CH2Cl2. [b] Yield of iodoetherification. [c] Yield of hydrogenolysis. [d] The cis and trans isomers of tetrahydropyrans c were isolated. [e]
Diastereomeric ratio of the isolated mixture of cis- and trans-oxepanes d were determined by NMR spectroscopy. [f] These values refer
to the 4a/4b ratio. [g] These values refer to the cis/trans ratio of 4a. [h] The cis and trans isomers were isolated.
Hydrogenolysis of the Iodocycloadducts: Regio- and
Stereochemical Outcome of the Cyclisation Reactions
data.[10,24,25] For the tetrahydropyran compounds, the rela-
tive chemical shifts are: δ H2-trans (4.30–4.20 ppm) Ͼ δ H2-
cis (3.80–3.70 ppm) Ͼ δ H1-trans (3.75–3.70 ppm) Ͼ δ H1-
The stereochemical outcome of iodine-mediated intra- cis (3.30–3.20 ppm).
molecular cyclisations has been studied for a diverse range
Except for compound 10, the relative ratio of c and d
of substituted substrates.[10,24] In our case, the regio- and obtained after deiodination can be correlated to the relative
stereoselectivities of ring closure is essentially governed by ratio of cycloadducts a and b. In agreement with Baldwin’s
the E/Z ratio and the nature of the substitution of the olefin rules,[26] the iodocyclisation of compound 5 (n = 0) led with
as there is no substitution between the alcohol and the ole- high regioselectivity to tetrahydrofuran 5a in preference to
fin functions. In order to determine the structures and rela- tetrahydropyran 5b (5-exo-trig favoured over 6-endo-trig
tive ratios of the cyclised products, the isolated mixtures ring closure, Scheme 2). In the case of compounds 4, 8–10
of the iodinated cycloadducts (a and b) were submitted to and 12 (n = 1), the regioselective formation of the corre-
hydrogenolysis over Pd/C under 10 bars of hydrogen to re- sponding tetrahydropyrans (6-exo adduct) was also fav-
duce the carbon–iodine bonds. The hydrogenolysis reac- oured over oxepane (7-endo adduct) formation. A 4:1 mix-
tions proceeded in high yields (77–94%, Table 2) except ture of tetrahydropyran 8a and oxepane 8b was obtained
with the mixture of bromo-substituted compounds 10a and from butyl-substituted hydroxy alkene 8 whatever the
10b: cis-10c was the only isomer recovered and this in a low method of cyclisation used. In contrast, the only cycload-
yield of 42% (entry 8). The competitive hydrogenolysis of duct obtained from the phenyl-substituted olefin 11 was the
the C–Br bond along with the C–I bond may explain the oxepane (endo cyclisation) but in a low yield of 49% (for
low yield in this case. The dehalogenated products were sep- 55% conversion, entry 9). As the iodocyclisation occurs un-
arated by flash chromatography and in the case of six-mem- der kinetic control,[27] this could be explained by a higher
bered ring derivatives, the cis and trans isomers could be stabilisation of a partial positive charge next to the phenyl
isolated. Only the cis- and trans-oxepanes 11d could also be group in the transition state and hence a lower energy bar-
separated. The structures of the cycloadducts (ring size and rier for the endo attack of the alcohol function on this site.
cis or trans relationship of the tetrahydrofuran and tetra- Interestingly, no oxepane adduct was observed when the
hydropyran derivatives) were determined by HMBC, HSQC olefin was terminal (entries 5 and 6, tetrahydropyran 4a
and NOESY experiments and by comparison of the NMR only). Unlike compound 11, the endo attack is not observed
spectra and the relative chemical shifts of the protons next as a partial positive charge on the terminal site of the olefin
to the ring oxygen atom (H1 and H2) with the literature would not be stabilised. The exclusive formation of the exo
Eur. J. Org. Chem. 2008, 713–720
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
715

M.-A. Hiebel, B. Pelotier, P. Goekjian, O. Piva
FULL PAPER
Scheme 2. Different modes of iodine-promoted cyclisation of compounds 4–12.
cycloadduct from terminal hydroxy alkenes has been re- ε-unsaturated alcohol 4, the sequence was first tested with
ported with similar substrates[21,24a] and for the synthesis of only 2 equivalents (instead of 5 equivalents) of 1-hexene for
oxepanes[25] (7-exo vs. 8-endo) and oxocanes[28] (8-exo vs. 9- the cross-metathesis reaction in order to use a minimum of
endo).
the relatively expensive bis(sym-collidine)iodine(I) hexaflu-
It is also worth noting that the E/Z ratio of the starting orophosphate in the second iodocyclisation step (Table 3,
hydroxy alkene has more effect on the regioselectivity of the entry 1). The resulting yield of the cyclised products by this
cyclisation (path A or path B, Scheme 2) than on the rela- sequential process was only 48% as against 76% after the
tive cis/trans relationship of the resulting major cycload- two separate steps. In order to improve the yield, we next
duct, which remains constant (around 7:3 in favour of the focused on iodine which, as a cheaper activating agent, can
cis isomer) whatever the geometry (E/Z ratio) of the start- be used in large excess. As in preliminary experiments, the
ing substrate. This selectivity was also observed with similar cross-metathesis step was then performed with 5 equivalents
substrates by other groups.[21,29] In the case of these unsatu- of olefin and after the disappearance of 4, iodine (4 equiv.)
rated β-hydroxy ester substrates, the main factor that gov- and sodium hydrogen carbonate (4.3 equiv.) were added to
erns the exo-type cyclisation step is therefore the position the reaction mixture. Although the cyclisation step usually
of the activated olefin, either in the favoured pseudo-equa- gave slightly lower yields with iodine, the overall tandem
torial or the disfavoured pseudo-axial position, whatever process gave comparatively higher yields than with bis(sym-
the double bond configuration (cf. Scheme 2), whereas the collidine)iodine(I) hexafluorophosphate. Thus, the results
E or Z stereochemistry and the stabilisation of the activated obtained by tandem cross-metathesis and iodine-promoted
double bond (nature of the R group) have an impact on the iodocyclisation (35–66% of cyclised products) were closer
type of cyclisation.
to those obtained after two separate steps. Moreover, this
In the case of compound 12, the hydrogenolysis reaction
of the cycloadducts could not be carried out because of
the benzyl ester. An attempt at dehalogenation by radical
chemistry (Bu3SnH, AIBN) gave 70% yield of tin-contami-
nated products. Finally, an elimination reaction promoted
by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) performed di-
rectly on the cycloadducts allowed us to isolate compound
13 in 70% yield (Scheme 3). The cis-tetrahydropyranyl
structure of this major cycloadduct was easily determined
by NMR spectroscopy.
Table 3. Tandem cross-metathesis/iodoetherification reactions.
Scheme 3. Synthesis of analogue 13.
[a] Isolated mixture of iodinated tetrahydropyrans and oxepanes
after the tandem process (in parentheses, yield calculated from two
separate steps). [b] Yield calculated from the reaction carried out
Tandem Cross-Metathesis/Iodoetherification Reactions
Finally, the possibility of a tandem cross-metathesis/
iodoetherification process was also studied. Starting from by using bis(collidine)I·PF6 for the cyclisation step.
716 Eur. J. Org. Chem. 2008, 713–720
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Tetrahydropyrans by Tandem Cross-Metathesis/Iodocyclisation
Methyl 9-(tert-Butyldiphenylsilyloxy)-3-hydroxynon-6-enoate (6):
Purification with EtOAc/hexanes, 5:95. Grey oil (61%), E/Z =
60:40. E isomer: 1H NMR (300 MHz, CDCl3): δ = 1.04 (s, 9 H,
3ϫCH3), 1.56–2.55 (m, 7 H), 2.76–2.84 (m, 1 H), 3.64–3.70 (m, 2
H), 3.70 (s, 3 H, OCH3), 3.98–4.07 (m, 1 H, CHOH), 5.40–5.53
(m, 2 H, CH=CH), 7.35–7.42 (m, 5 H), 7.65–7.68 (m, 5 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 19.4, 27.1 (3 C), 28.9, 36.3, 36.5,
41.4, 51.9, 63.9, 68.1, 127.6 (2 C), 127.8 (3 C), 127.9, 129.8, 131.1,
131.7, 134.2, 135.8 (4 C), 173.4 ppm.
sequential process eliminates the need for an intermediate
purification step, which is non-negligible in library synthesis
as it is time- and solvent-consuming.
Conclusions
In conclusion, we have developed a new approach to 2,6-
disubstituted tetrahydropyrans that involves a cross-me-
tathesis and an iodocyclisation reaction. Both cis and trans
isomers could be obtained and isolated. We have also
shown that the competitive formation of 6-exo- and 7-endo-
type cycloadducts can be modulated by the geometry (E/Z
ratio) of the substrate and the substitution on the reacting
double bond. Finally, we have demonstrated that the target
cycloadducts could be obtained more rapidly by a tandem
Methyl 3-Oxododec-7-enoate (7): Purification with ethyl acetate/pe-
troleum ether, 15:95. Red oil (78%), E/Z = Ͼ95:5. 1H NMR
(300 MHz, CDCl3): δ = 0.84–0.88 (m, 3 H, CH3), 1.269–1.35 (m,
4 H), 1.63 (quint, J = 7.4 Hz, 2 H, CO-CH2-CH2), 1.92–2.04 (m,
4 H, CH2-CH=CH-CH2), 2.50 (t, J = 7.4 Hz, 2 H, CH2-CO), 3.42
(s, 2 H, CH2-COOMe), 3.71 (s, 3 H, O-CH3), 5.25–5.44 (m, 2 H,
CH=CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 22.5, 22.5,
23.5, 32.0, 32.5, 42.5, 49.3, 52.6, 129.1, 132.0, 168.0, 203.0 ppm. IR
(film): νmax = 2956, 2928, 2873, 2857, 1750, 1719, 1654, 1631, 1449,
˜
cross-metathesis/iodine-promoted cyclisation process. This 1438, 1407, 1320, 1260, 1150, 1090, 1015, 968, 801 cm–1.
methodology has allowed us to prepare a series of cis- and
trans-2,6-disubstituted tetrahydropyran analogues of the
north part of bistramide A, which will be tested against
protein kinase C-δ.
Methyl 3-Hydroxydodec-7-enoate (8): Purification with EtOAc/hex-
anes, 10:90. Brown oil (82%), E/Z = 90:10. E isomer: 1H NMR
(300 MHz, CDCl3): δ = 0.87 (t, J = 6.8 Hz, 3 H, CH3), 1.24–1.55
(m, 8 H), 1.91–2.03 (m, 4 H), 2.39 (dd, JAB = 16.4, J = 8.7 Hz, 1 H,
CHAHBCO2Me), 2.50 (dd, JAB = 16.4, J = 3.4 Hz, 1 H, CHAHB-
CO2Me), 2.89 (br. s, 1 H, OH), 3.69 (s, 3 H, OCH3), 4.00 (m, 1 H,
CHOH), 5.28–5.45 (m, 2 H, CH=CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.3, 22.5, 25.7, 32.1, 32.5, 32.6, 36.2, 41.4, 52.0, 68.2,
Experimental Section
129.9, 131.3, 173.8 ppm. IR (film): νmax = 3700 (–3100), 2956, 2928,
˜
General: 1H and 13C NMR spectra were recorded with a Bruker
AM 300 MHz NMR spectrometer which provided all the necessary
data for the full assignment of each compound. Chemicals shifts
are reported in ppm. High-resolution mass spectrometry (HRMS)
analyses were conducted by using a ThermoFinigan-MAT 95 XL
instrument. IR spectra were measured with a Perkin-Elmer Spec-
trum One FT-IR spectrometer. Melting points were measured with
a B-540 Büchi apparatus. TLC analyses were performed on plates
(layer thickness 0.25mm) and were visualised with UV light, phos-
phomolybdic acid or p-anisaldehyde solution. Column chromatog-
raphy was performed on silica gel (40–63 µm) by using ethyl acetate
(EtOAc) and hexanes as eluents. When appropriate, solvents and
reagents were dried by distillation over the appropriate drying
agents prior to use. Diethyl ether and tetrahydrofuran were distilled
from Na/benzophenone and used fresh. Dichloromethane was dis-
tilled from CaH2.
1739, 1438, 1261, 1174, 1089, 969 cm–1. MS (ESI): m/z = 229 (54)
[MH]+, 251 (69) [M + Na]+, 313 (56), 355.2 (54), 362.3 (87), 478.9
(93) [2M + Na]+, 541 (100).
Methyl 3-Hydroxyhexadec-7-enoate (9): Purification with EtOAc/
hexanes, 10:90. Orange oil (76%), E/Z = 55:45. E isomer: 1H NMR
(300 MHz, CDCl3): δ = 0.87 (t, J = 7.0 Hz, 3 H, CH3), 1.25–1.60
(m, 16 H), 1.93–2.20 (m, 4 H), 2.43 (dd, JAB = 16.5, J = 8.6 Hz, 1
H, CHAHBCO2Me), 2.51 (dd, JAB = 16.5, J = 3.4 Hz, 1 H,
CHAHBCO2Me), 2.89 (br. s, 1 H, OH), 3.70 (s, 3 H, OCH3), 3.95–
4.07 (m, 1 H, CHOH), 5.34–5.44 (m, 2 H, CH=CH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.4, 23.0, 25.4, 29.5, 29.8, 28.9, 29.9,
32.2, 32.7, 32.9, 36.3, 41.4, 52.1, 68.2, 129.9, 131.3, 173.8 ppm. IR
(film): ν
= 3680 (–3200), 2925, 2851, 1739, 1456, 1438, 1262,
˜
max
1172, 1078, 966 cm–1. MS (ESI): m/z = 284 [M]+·, 129 (64), 116
(90), 103 (80), 96 (72), 81 (83), 71 (52), 69 (60), 55 (100), 43 (83),
41 (75).
General Procedure for Cross-Metathesis Reactions (Table 1, en-
tries 1–7): Methyl 3-hydroxyhept-6-enoate (3) (1 mmol) or methyl
3-hydroxyoct-7-enoate (4) (1 mmol) and olefin (5 mmol) were di-
luted in dichloromethane (10 mL). The solution was degassed with
nitrogen and the 2nd-generation Grubbs catalyst (2 mol-%) was
added. The mixture was heated under reflux until reaction comple-
tion (4–12 h). After evaporation of the solvent, the residue was
purified by flash chromatography to yield the (E)-olefin as the
major isomer (5–12).
Methyl 11-Bromo-3-hydroxyundec-7-enoate (10): Purification with
EtOAc/hexanes, 20:80. Colourless oil (83%), E/Z = 90:10. E iso-
mer: 1H NMR (300 MHz, CDCl3): δ = 1.40–1.54 (m, 4 H), 1.89
(quint, J = 6.8 Hz, 2 H), 2.00 (q, J = 6.4 Hz, 2 H), 2.07–2.20 (m,
2 H), 2.40 (dd, JAB = 16.4, J = 8.9 Hz, 1 H, CHAHBCO2Me), 2.50
(dd, JAB = 16.4, J = 3.4 Hz, 1 H, CHAHBCO2Me), 2.91 (br. s, 1
H, OH), 3.39 (t, J = 6.7 Hz, 2 H, CH2Br), 3.70 (s, 3 H, OCH3),
3.98–4.10 (m, 1 H, CHOH), 5.29–5.51 (m, 2 H, CH=CH) ppm. 13
NMR (75 MHz, CDCl3): δ = 25.6, 31.1, 32.6, 32.7, 33.7, 36.2, 41.4,
C
52.1, 68.2, 128.8, 131.9, 173.8 ppm. IR (film): νmax = 3692 (–3071),
˜
Methyl 3-Hydroxyundec-6-enoate (5): Purification with EtOAc/hex-
anes, 10:90. Brown oil (70%), E/Z = 90:10. E isomer: 1H NMR
(300 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H, CH3), 1.28–1.33
3005, 2934, 2852, 1733, 1438, 1261, 1201, 1168, 1086 cm–1. MS
(ESI): m/z = 293 (96) [MH]+, 295 (67), 315 (95) [MNa]+, 317 (100),
326 (62).
(m, 4 H), 1.40–1.65 (m, 2 H), 1.94–2.23 (m, 4 H), 2.41 (dd, JAB
=
16.4, J = 8.9 Hz, 1 H, CHAHBCO2Me), 2.51 (dd, JAB = 16.4, J =
Methyl 3-Hydroxy-8-phenyloct-7-enoate (11): Purification with
3.4 Hz, 1 H, CHAHBCO2Me), 2.86 (br. s, 1 H, OH), 3.71 (s, 3 H, EtOAc/hexanes, 20:80. Grey oil (75%), E/Z = Ͼ95:5. E isomer: 1H
OCH3), 3.98–4.07 (m,
1
H, CHOH), 5.33–5.48 (m,
2
H,
NMR (300 MHz, CDCl3): δ = 1.42–1.63 (m, 4 H, CH2CH2OH),
2.17 (q, J = 6.8 Hz, 2 H, CH2CH=), 2.35 (dd, JAB = 16.4, J =
8.9 Hz, 1 H, CHAHBCO2Me), 2.47 (dd, JAB = 16.4, J = 3.4 Hz, 1
CH=CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 22.5, 28.9,
32.0, 32.5, 36.6, 41.4, 52.0, 67.8, 129.4, 131.6, 173.6 ppm.
Eur. J. Org. Chem. 2008, 713–720
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
717

M.-A. Hiebel, B. Pelotier, P. Goekjian, O. Piva
FULL PAPER
H, CHAHBCO2Me), 3.64 (s, 3 H, OCH3), 3.86–4.05 (m, 1 H,
CHOH), 6.13 (dt, J = 15.8, 6.8 Hz, 1 H,=CHCH2), 6.32 (d, J =
15.8 Hz, 1 H, PhCH=), 7.12–7.28 (m, 5 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 25.5, 33.1, 36.3, 41.4, 52.1, 68.2, 126.3 (2
C), 127.2, 128.8 (2 C), 130.6, 130.7, 133.5, 173.8 ppm. IR (film):
and purified by flash chromatography (EtOAc/hexanes) to give
compounds c and/or d.
Methyl 2-(6-Iodomethyltetrahydropyran-2-yl)ethanoate (4a): Purifi-
1
cation with EtOAc/hexanes, 2:98. cis isomer: yellow oil. H NMR
(300 MHz, CDCl3): δ = 1.10–1.15 (m, 2 H), 1.48–1.62 (m, 2 H),
1.80–1.87 (m, 2 H), 2.41 (dd, JAB = 14.9, J = 5.5 Hz, 1 H,
ν
= 3700 (–3100), 2962, 2856, 1732, 1438, 1414, 1261, 1092,
˜
max
1070, 1044, 1019 cm–1. HRMS (EI): calcd. for C15H20O3 [M]+
CHAHBCO2Me), 2.56 (dd, JAB
= 14.9, J = 7.9 Hz, 1 H,
248.1412; found 248.1417.
CHAHBCO2Me), 3.13 (d, J = 6.2 Hz, 2 H, CH2I), 3.35–3.40 (m, 1
H, OCHCH2I), 3.69 (s, 3 H, OCH3), 3.76–3.84 (m, 1 H, OCHCH2-
CO2Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 9.7, 23.4, 31.0,
31.2, 41.6, 52.1, 75.2, 77.6, 172.0 ppm. IR (film): ν˜max = 2938, 2861,
Benzyl 8-Hydroxy-9-(methoxycarbonyl)non-3-enoate (12): Purifica-
tion with EtOAc/hexanes, 20:80. Orange oil (69%), E/Z = 85:15.
E isomer: 1H NMR (300 MHz, CDCl3): δ = 1.37–1.59 (m, 4 H,
CH2CH2OH), 2.04–2.07 (m, 2 H, CH2CH=), 2.39 (dd, JAB = 16.4, 1739, 1435, 1371, 1343, 1287, 1255, 1200, 1176, 1129, 1087, 1051,
J = 8.9 Hz, 1 H, CHAHBCO2Me), 2.49 (dd, JAB = 16.4, J = 3.4 Hz,
H, CHAHBCO2Me), 3.07 (dd, 3.4, 1.1 Hz, H,
1015 cm–1. HRMS (EI): calcd. for C9H15IO3 [M]+ 298.0066; found:
298.0066. trans isomer: yellow oil. H NMR (300 MHz, CDCl3): δ
1
1
J
=
2
=CHCH2CO), Z isomer (d, J = 5.6 Hz, 2 H, =CHCH2CO), 3.71 = 1.23–1.41 (m, 2 H), 1.56–1.79 (m, 4 H), 2.43 (dd, JAB = 14.7, J
(s, 3 H, OCH3), 3.95–4.03 (m, 1 H, CHOH), 5.12 (s, 2 H, OCH2- = 5.6 Hz, 1 H, CHAHBCO2Me), 2.68 (dd, JAB = 14.7, J = 8.5 Hz,
Ph), 5.53–5.59 (m, 2 H, CH=CH), 7.34–7.36 (m, 5 H) ppm. 13C 1 H, CHAHBCO2Me), 3.26 (dd, JAB = 10.2, J = 6.4 Hz, 1 H,
NMR (75 MHz, CDCl3): δ = 25.3, 32.5, 36.2, 38.3, 41.4, 52.1, 66.7, CHAHBI), 3.31 (dd, JAB = 10.2, J = 7.0 Hz, 1 H, CHAHBI), 3.71
68.1, 122.2, 128.5 (3 C), 128.9 (2 C), 133.4, 134.7, 172.3, 173.8 ppm.
(s, 3 H, OCH3), 3.83–3.91 (m, 1 H, OCHCH2I), 4.19–4.27 (m, 1
IR (film): νmax = 3703 (–3137), 3033, 2940, 2863, 1731, 1498, 1451,
H, OCHCH2CO2Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 8.3,
˜
1438, 1377, 1262, 1161, 974 cm–1. MS (ESI): m/z = 321 (100)
18.3, 29.0, 29.6, 39.2, 52.1, 68.9, 72.0, 171.9 ppm. IR (film): ν
˜
max
[MH]+, 343 (65) [MNa]+.
= 2938, 2861, 1739, 1435, 1371, 1343, 1287, 1256, 1200, 1176, 1129,
1088, 1051, 1043, 1015 cm–1. HRMS (ESI): calcd. for C9H15IO3Na
[MNa] requires 320.9964; found 320.9961.
General Procedures for Iodoetherification
Method A (with NIS): N-Iodosuccinimide (1.5 mmol) was added to
a solution of unsaturated alcohol (1 mmol) in acetone (50 mL) and
water (5 mL) at 0 °C and the mixture was warmed to room tem-
perature and stirred in the dark for 24 h. The solvents were evapo-
rated and the residue partitioned between dichloromethane
(20 mL) and an aqueous solution of sodium thiosulfate (5%,
20 mL). After extraction with dichloromethane, the organic phase
was washed with brine, dried with MgSO4 and concentrated. The
crude residue was purified by flash chromatography to give the
iodinated cyclised products.
Methyl 2-(5-Pentyltetrahydrofuran-2-yl)ethanoate (5c): Purification
with EtOAc/hexanes, 5:95. Colourless oil. Mixture of isomers
(70:30): 1H NMR (300 MHz, CDCl3): δ = 0.87 (t, J = 6.8 Hz, 3 H,
CH3), 1.28–1.64 (m, 11 H), 1.90–1.92 (m, 1 H), 2.42 (dd, JAB
=
15.1, J = 6.4 Hz, 1 H, CHAHBCO2Me), 2.62 (dd, JAB = 15.1, J =
6.8 Hz, 1 H, CHAHBCO2Me) [minor isomer: 2.63 (dd, JAB = 15.1,
J = 6.6 Hz, 1 H, CHAHBCO2Me)], 3.67 (s, 3 H, OCH3) [minor
isomer: 3.82 (quint, J = 6.2 Hz, 1 H, OCH)], 3.94 (quint, J =
6.2 Hz, 1 H, OCH) [minor isomer: 4.23 (quint, J = 6.6 Hz, 1 H,
OCH)], 4.35 (quint, J = 6.6 Hz, 1 H, OCH) ppm. 13C NMR
(75 MHz, CDCl3): [major isomer] δ = 14.3, 22.9, 26.0, 31.3, 32.1,
Method B (with I2): Iodine (3 mmol) was added in one portion to
a solution of unsaturated alcohol (1 mmol) and sodium hydrogen
carbonate (3.16 mmol) in acetonitrile (25 mL) at room temp. The
mixture was stirred in the dark for 24 h before quenching with an
aqueous saturated solution of sodium thiosulfate (20 mL). The ace-
tonitrile was removed under reduced pressure and the residue parti-
tioned between ethyl acetate (20 mL) and water (20 mL). The aque-
ous phase was further extracted with ethyl acetate and the com-
bined organic extracts dried with MgSO4, filtered and concen-
trated. The crude residue was purified by flash chromatography to
give the iodinated cyclised products.
32.2, 36.1, 41.0, 51.8, 74.9, 79.4, 172.0 ppm. IR (film): νmax = 2956,
˜
2923, 2851, 1731, 1632, 1454, 1434, 1264, 1091, 1018 cm–1. HRMS
(EI): calcd. for C12H22O3 [M]+ requires 214.1569; found 214.1569.
Methyl 2-(6-Butyltetrahydropyran-2-yl)ethanoate (5d): Purification
with EtOAc/hexanes, 5:95. Yellow oil. cis isomer: 1H NMR
(300 MHz, CDCl3): δ = 0.88 (t, J = 6.0 Hz, 3 H, CH3), 1.08–1.64
(m, 11 H), 1.80–1.85 (m, 1 H), 2.39 (dd, JAB = 14.7, J = 5.7 Hz, 1
H, CHAHBCO2Me), 2.54 (dd, JAB = 14.7, J = 7.9 Hz, 1 H,
CHAHBCO2Me), 3.24–3.31 (m, 1 H, OCHCH2), 3.68 (s, 3 H,
OCH3), 3.69–3.78 (m, 1 H, OCHCH2CO2Me) ppm.
Method C [with bis(collidine)I·PF6]: A solution of unsaturated
alcohol (1 mmol) in dichloromethane (5 mL) was added over 1 h at
room temp. to a solution of bis(sym-collidine)iodine(I) hexafluoro-
phosphate (1.22 mmol) in dichloromethane (15 mL). The resulting
mixture was stirred for an additional 1 h and silica gel (2 g) was
added. The solvent was evaporated under reduced pressure and the
resulting residue purified by chromatography (EtOAc/hexanes) to
give the iodinated cyclised products.
Methyl 2-(6-Butyltetrahydropyran-2-yl)ethanoate (8c): Purification
with EtOAc/hexanes, 2:98. cis isomer: yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 0.87 (t, J = 6.6 Hz, 3 H, CH3), 1.12–1.64
(m, 13 H), 1.78–1.85 (m, 1 H), 2.39 (dd, JAB = 14.7, J = 5.5 Hz, 1
H, CHAHBCO2Me), 2.54 (dd, JAB = 14.7, J = 7.9 Hz, 1 H,
CHAHBCO2Me), 3.23–3.30 (m, 1 H, OCHCH2), 3.67 (s, 3 H,
OCH3), 3.70–3.78 (m, 1 H, OCHCH2CO2Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.3, 22.9, 23.8, 25.5, 31.6, 31.6, 32.1, 36.6,
General Procedure for the Iodoetherification/Hydrogenolysis of
41.9, 51.8, 74.7, 78.4, 172.3 ppm. IR (film): ν
= 2934, 2857,
˜
max
Compounds 4, 5 and 8–12 (Table 3, entries 1–10): Compounds 4, 5 1744, 1457, 1438, 1369, 1344, 1287, 1254, 1196, 1075 cm–1. HRMS
and 8–12 were cyclised by iodoetherification following method A,
B or C. Pd/C (10%, w/w) and sodium hydrogen carbonate
(0.86 mmol) were added to the isolated mixture of iodinated prod-
ucts a and/or b (0.75 mmol) in methanol (6 mL). The mixture was
hydrogenated under pressure (10 atm) for 24 h at room tempera-
ture. The catalyst was filtered through Celite and washed with di-
ethyl ether. The filtrate was concentrated under reduced pressure
(ESI): calcd. for C13H25O3 [M]+ 228.1725; found 228.1727. trans
1
isomer: colourless oil. H NMR (300 MHz, CDCl3): δ = 0.88 (t, J
= 6.6 Hz, 3 H, CH3), 1.23–1.37 (m, 10 H), 1.54–1.77 (m, 4 H), 2.40
(dd, JAB = 14.5, J = 5.5 Hz, 1 H, CHAHBCO2Me), 2.66 (dd, JAB
= 14.5, J = 8.7 Hz, 1 H, CHAHBCO2Me), 3.67 (s, 3 H, OCH3),
3.68–3.75 (m, 1 H, OCHCH2), 4.15–4.24 (m, 1 H, OCHCH2-
CO2Me) ppm.13C NMR (75 MHz, CDCl3): δ = 14.4, 18.8, 23.0,
718
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 713–720

Tetrahydropyrans by Tandem Cross-Metathesis/Iodocyclisation
25.7, 30.0, 30.2, 32.1, 33.3, 39.5, 51.9, 68.2, 71.9, 172.3 ppm. IR 172.3 ppm. IR (film): ν
= 2934, 2860, 1739, 1435, 1373, 1346,
˜
max
(film): νmax = 2933, 2863, 1744, 1457, 1436, 1377, 1358, 1287, 1259,
1286, 1257, 1199, 1741, 1088, 1040 cm–1. HRMS (ESI): calcd. for
˜
1207, 1165, 1091, 1045 cm–1. HRMS (EI): calcd. for C13H25O3 C12H21O3Br [M]+ 315.0572; found 315.0571.
[M]+ 228.1725; found 228.1726.
Methyl 2-(7-Phenyloxepan-2-yl)ethanoate (11d): Purification with
EtOAc/hexanes, 2:98. Less polar isomer: colourless oil. 1H NMR
(300 MHz, CDCl3): δ = 1.57–1.89 (m, 7 H), 2.02–2.15 (m, 1 H),
2.46 (dd, JAB = 15.2, J = 4.9 Hz, 1 H, CHAHBCO2Me), 2.64 (dd,
JAB = 15.2, J = 8.9 Hz, 1 H, CHAHBCO2Me), 3.62 (s, 3 H, OCH3),
4.16–4.23 (m, 1 H, OCHCH2CO2Me), 4.62 (dd, J = 8.3, 3.9 Hz, 1
H, OCHPh), 7.30–7.31 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 25.1, 25.4, 36.0, 38.2, 42.3, 51.7, 76.7, 81.7, 125.9,
Methyl 2-(7-Butyloxepan-2-yl)ethanoate (8d): Purification with
EtOAc/hexanes, 2:98. Colourless oil. Mixture of cis and trans iso-
mers (dr = 50:50). H NMR (300 MHz, CDCl3): δ = 0.87 (t, J =
1
7.0 Hz, 3 H, CH3), 1.25–1.67 (m, 12 H), 1.90–2.17 (m, 2 H), 2.43
(dd, JAB = 15.1, J = 6.4 Hz, 1 H, CHAHBCO2Me), 2.62 (dd, JAB
= 15.1, J = 7.8 Hz, 1 H, CHAHBCO2Me) [other isomer: 2.63 (dd,
JAB = 15.1, J = 7.8 Hz, 1 H, CHAHBCO2Me)], 3.68 (s, 3 H, OCH3),
3.82 (quint, J = 6.8 Hz, 1 H, OCH) [other isomer: 3.92 (quint, J =
6.6 Hz, 1 H, OCH)], 4.22 (quint, J = 6.8 Hz, 1 H, OCH) [other
isomer: 4.35 (quint, J = 6.6 Hz, 1 H, OCH)] ppm. 13C NMR
(75 MHz, CDCl3): [cis and trans isomers] δ = 14.3, 22.9, 23.1, 26.1,
28.6, 31.1, 31.3, 32.0, 32.2, 36.1, 41.1, 43.3, 51.9, 74.9, 75.4 79.5,
126.9 (2 C), 128.2 (2 C), 144.4, 172.3 ppm. IR (film): ν
= 3066,
˜
max
3027, 2927, 2860, 1738, 1634, 1445, 1434, 1260, 1196, 1106,
1021 cm–1. HRMS (ESI): calcd. for C15H20O3 [M]+ 248.1412;
found 248.1410. More polar isomer: colourless oil. 1H NMR
(300 MHz, CDCl3): δ = 1.51–2.07 (m, 8 H), 2.40 (dd, JAB = 14.5,
J = 5.6 Hz, 1 H, CHAHBCO2Me), 2.58 (dd, JAB = 14.5, J = 7.9 Hz,
1 H, CHAHBCO2Me), 3.45 (s, 3 H, OCH3), 4.26–4.33 (m, 1 H,
OCHCH2CO2Me), 4.69 (dd, J = 11.0, 2.5 Hz, 1 H, OCHPh), 7.28–
7.38 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 27.1, 28.4,
36.2, 37.1, 41.8, 51.7, 73.0, 76.6, 126.4 (2 C), 127.3, 128.4 (2 C),
80.2, 172.1 ppm. IR (film): ν
= 2956, 2931, 2863, 1743, 1460,
˜
max
1435, 1380, 1196, 1161, 1070 cm–1.
Methyl 2-(6-Octyltetrahydropyran-2-yl)ethanoate (9c): Purification
with EtOAc/hexanes, 2:98. cis isomer: colourless oil. 1H NMR
(300 MHz, CDCl3): δ = 0.87 (t, J = 6.4 Hz, 3 H, CH3), 1.12–1.64
(m, 21 H), 1.64–1.85 (m, 1 H), 2.38 (dd, JAB = 14.8, J = 5.5 Hz, 1
H, CHAHBCO2Me), 2.54 (dd, JAB = 14.8, J = 7.9 Hz, 1 H,
CHAHBCO2Me), 3.23–3.30 (m, 1 H, OCHCH2), 3.69 (s, 3 H,
OCH3), 3.71–3.78 (m, 1 H, OCHCH2CO2Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.4, 23.0, 23.8, 25.9, 29.7, 29.9 (3 C), 31.6,
144.3, 172.1 ppm. IR (film): ν
= 2930, 2857, 1739, 1437, 1290,
˜
max
1200, 1151, 1102, 1026 cm–1. HRMS (EI): calcd. for C15H20O3
[M]+ 248.1412; found 248.1412 (,).
Benzyl cis-(E)-3-[6-(Methoxycarbonylmethyl)tetrahydropyran-2-yl]-
propenoate (13): 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.18 mmol)
was added to a solution of benzyl cis-3-iodo-3-[6-(methoxycarbon-
ylmethyl)tetrahydropyran-2-yl]propanoate (12a) (0.18 mmol) in
dichloromethane (5 mL) at room temp. The mixture was stirred for
24 h before quenching with an aqueous saturated solution of so-
dium thiosulfate (5 mL). The aqueous phase was extracted with
dichloromethane (3ϫ5 mL) and the combined organic extracts
dried with MgSO4, filtered and concentrated. The crude residue
was purified by flash chromatography to give 12 as a colourless oil
(40 mg, 0.13 mmol, 70%). 1H NMR (300 MHz, CDCl3): δ = 1.19–
1.32 (m, 2 H), 1.62–1.72 (m, 3 H), 1.87–1.91 (m, 1 H), 2.42 (dd,
JAB = 15.2, J = 5.5 Hz, 1 H, CHAHBCO2Me), 2.57 (dd, JAB = 15.2,
J = 7.5 Hz, 1 H, CHAHBCO2Me), 3.68 (s, 3 H, OCH3), 3.81–3.89
(m, 1 H), 4.00–4.06 (m, 1 H), 5.14 (d, JAB = 12.4 Hz, 1 H,
CHAHBPh), 5.19 (d, JAB = 12.4 Hz, 1 H, CHAHBPh), 6.04 (dd, J
= 15.7, 1.7 Hz, 1 H, COCH=), 6.91 (dd, J = 15.7, 3.8 Hz, 1 H,
COCH=CH), 7.30–7.36 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 23.6, 30.9, 30.9, 41.6, 52.0, 66.5, 74.6, 76.4, 119.9,
31.7, 32.2, 36.7, 42.0, 51.9, 74.8, 78.5, 172.4 ppm. IR (film): ν
˜
max
= 2929, 2856, 1745, 1457, 1437, 1371, 1344, 1287, 1251, 1198, 1177,
1089, 1073 cm–1. HRMS (ESI): calcd. for C17H32O3 [M]+ 284.2351;
1
found 284.2355. trans isomer: colourless oil. H NMR (300 MHz,
CDCl3): δ = 0.87 (t, J = 5.5 Hz, 3 H, CH3), 1.25–1.34 (m, 17 H),
1.58–1.71 (m, 5 H), 2.40 (dd, JAB = 14.5, J = 5.6 Hz, 1 H,
CHAHBCO2Me), 2.66 (dd, JAB
= 14.5, J = 8.7 Hz, 1 H,
CHAHBCO2Me), 3.68 (s, 3 H, OCH3), 3.68–3.70 (m, 1 H,
OCHCH2), 4.15–4.21 (m, 1 H, OCHCH2CO2Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.4, 18.8, 23.0, 26.0, 29.7, 30.0 (3 C), 30.1,
30.2, 32.2, 33.4, 39.6, 51.9, 68.2, 71.9, 172.3 ppm. IR (film): ν
˜
max
= 2928, 2855, 1744, 1460, 1437, 1289, 1259, 1204, 1170, 1092,
1045 cm–1. HRMS (EI): calcd. for C17H32O3 [M]+ 284.2351; found
284.2350.
Methyl 2-(7-Octyloxepan-2-yl)ethanoate (9d): Purification with
EtOAc/hexanes, 2:98. Colourless oil. Mixture of cis and trans iso-
1
mers (dr = 64:36). H NMR (300 MHz, CDCl3): δ = 0.87 (t, J =
128.5, 128.5, 128.8, 136.3, 148.7, 166.8, 171.9 ppm. IR (film): ν
˜
7.0 Hz, 3 H, CH3), 1.25–1.67 (m, 20 H), 1.90–2.17 (m, 2 H), 2.43
(dd, JAB = 15.1, J = 6.4 Hz, 1 H, CHAHBCO2Me), 2.62–2.63 (dd,
JAB = 15.1, J = 7.8 Hz, 1 H, CHAHBCO2Me) [minor isomer: 2.63
(dd, JAB = 15.1, J = 7.8 Hz, 1 H, CHAHBCO2Me)], 3.68 (s, 3 H,
OCH3) [minor isomer: 3.82 (quint, J = 6.6 Hz, 1 H, OCH)], 3.92
(quint, J = 6.4 Hz, 1 H, OCH) [minor isomer: 4.22 (quint, J =
6.6 Hz, 1 H, OCH)], 4.35 (quint, J = 6.4 Hz, 1 H, OCH) ppm. 13C
NMR (75 MHz, CDCl3) [cis and trans isomers]: δ = 14.4, 23.0,
26.4, 29.6, 29.7, 29.9 (2 C), 30.1, 31.1, 32.1, 32.2, 36.2, 36.4, 41.1,
max
= 3034, 2942, 2861, 1722, 1660, 1498, 1456, 1438, 1377, 1296, 1269,
1199, 1167, 1114, 1080, 1022 cm–1. HRMS (ESI): calcd. for
C18H22O5 [M]+ 341.1365; found 341.1368.
General Procedure for Tandem Cross-Metathesis/Iodoetherification:
Methyl 3-hydroxyoct-7-enoate (4) (0.5 mmol) and olefin (2.5 mmol)
were diluted in dichloromethane (5 mL). The solution was degassed
with nitrogen and the second-generation Grubbs catalyst (2 mol-
%) was added. The mixture was heated under reflux until reaction
completion (4–12 h) and then cooled to room temperature. The re-
action mixture was diluted with dichloromethane (10 mL) and io-
43.3, 51.9, 75.0, 79.5, 172.2 ppm. IR (film): ν
= 2927, 2856,
˜
max
1743, 1462, 1437, 1377, 1278, 1257, 1196, 1172, 1068 cm–1.
Methyl 2-[6-(3-Bromopropyl)tetrahydropyran-2-yl]ethanoate (10c): dine (2 mmol) and sodium hydrogen carbonate (2.15 mmol) were
Purification with EtOAc/hexanes, 2:98. Pale yellow oil. cis isomer: added in one portion. The mixture was stirred in the dark for 24 h
1H NMR (300 MHz, CDCl3): δ = 1.14–1.87 (m, 12 H), 2.39 (dd, before quenching with an aqueous saturated solution of sodium
JAB = 14.9, J = 5.5 Hz, 1 H, CHAHBCO2Me), 2.52 (dd, JAB = 14.9, thiosulfate (20 mL). The aqueous phase was separated and ex-
J = 8.1 Hz, 1 H, CHAHBCO2Me), 3.25–3.32 (m, 1 H, OCHCH2), tracted with dichloromethane (3ϫ10 mL). The organic phases
3.39 (t, J = 6.8 Hz, 2 H, CH2Br), 3.68 (s, 3 H, OCH3), 3.70–3.79
(m, 1 H, OCHCH2CO2Me) ppm. 13C NMR (75 MHz, CDCl3): δ
= 23.8, 24.6, 31.6, 31.6, 33.0, 34.3, 35.7, 41.9, 51.9, 74.8, 78.1,
were dried with MgSO4, filtered and concentrated. The crude resi-
due was purified by flash chromatography to give the iodocycload-
ducts.
Eur. J. Org. Chem. 2008, 713–720
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
719

M.-A. Hiebel, B. Pelotier, P. Goekjian, O. Piva
FULL PAPER
[15] G. Griffiths, B. Garrone, E. Deacon, P. Owen, J. Pongracz, G.
Mead, A. Bradwell, D. Watters, J. Lord, Biochem. Biophys. Res.
Commun. 1996, 222, 802–808.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and spectroscopic data for
compounds 1–4, 1H and 13C NMR spectra of cycloadducts 4a, 5d,
8c, 9c, 10c, 11d and 13.
[16] a) A. V. Statsuk, R. Bai, J. L. Baryza, V. A. Verma, E. Hamel,
P. A. Wender, S. A. Kozmin, Nat. Chem. Biol. 2005, 1, 383–388;
b) S. A. Rizvi, V. Tereshko, A. A. Kossiakoff, S. A. Kozmin, J.
Am. Chem. Soc. 2006, 128, 3882–3883.
Acknowledgments
[17] J. T. Lowe, I. E. Wrona, J. S. Panek, Org. Lett. 2007, 9, 327–
330.
This work was supported by the European Union, FP6 Integrated
Project on Protein Kinases (No. 503467).
[18] M. T. Crimmins, A. C. DeBaillie, J. Am. Chem. Soc. 2006, 128,
4936–4937.
[19] a) M.-A. Virrolleaud, O. Piva, Eur. J. Org. Chem. 2007, 1606–
1612; b) H. Salim, O. Piva, Tetrahedron Lett. 2007, 48, 2059–
2062; c) M.-A. Virrolleaud, O. Piva, Tetrahedron Lett. 2007,
48, 1417–1420.
[20] L. Zhu, D. R. Mootoo, Org. Lett. 2003, 5, 3475–3478.
[21] P. Van de Weghe, D. Aoun, J.-G. Boiteau, J. Eustache, Org.
Lett. 2002, 4, 4105–4108.
[22] T. R. Hoye, H. Zhao, Org. Lett. 1999, 1, 1123–1125.
[23] a) Y. Brunel, G. Rousseau, J. Org. Chem. 1996, 61, 5793–5800;
b) R. D. Evans, J. W. Magee, J. H. Schauble, Synthesis 1988,
862–868.
[24] For examples, see: a) J. A. Macritchie, T. M. Peakman, A. Sil-
cock, C. L. Willis, Tetrahedron Lett. 1998, 39, 7415–7418; b) T.
Minami, A. Moriyama, M. Hanaoka, Synlett 1995, 663–665;
c) V. Bolitt, C. Mioskowski, J. Org. Chem. 1991, 56, 4238–4240;
d) M. Zarraga, M. L. Rodriguez, C. Ruiz-Perez, J. D. Martin,
Tetrahedron Lett. 1989, 30, 3725–3728; see also; e) J. D. White,
G. Wang, L. Quaranta, Org. Lett. 2003, 5, 4109–4112; f) D. W.
Knight, E. R. Staples, Tetrahedron Lett. 2002, 43, 6771–6773;
g) H. Zhang, D. Dabideen, G. Pushchinska, D. R. Mootoo, J.
Carbohydr. Chem. 2002, 21, 411–430; h) S. H. Kang, S. B. Lee,
Tetrahedron Lett. 1993, 34, 7579–7582; i) I. Marek, J.-M. Lef-
rançois, J. F. Normant, Tetrahedron Lett. 1992, 33, 1747–1748;
j) R. D. Walkup, L. Guan, S. W. Kim, Y. S. Kim, Tetrahedron
Lett. 1992, 33, 3969–3972; k) M. J. Kurth, R. L. Beard, M.
Olmstead, J. G. Macmillan, J. Am. Chem. Soc. 1989, 111, 3712–
3717; l) M. Labelle, Y. Guindon, J. Am. Chem. Soc. 1989, 111,
2204–2210; m) Y. Tamura, M. Hojo, S. Kawamura, S. Sawada,
Z. Yoshida, J. Org. Chem. 1987, 52, 4062–4072.
[1] P. A. Clarke, S. Santos, Eur. J. Org. Chem. 2006, 2045–2053.
[2] a) A. K. Ghosh, G. Gong, Org. Lett. 2007, 9, 1437–1440; b)
B. S. Lucas, V. Gopalsamuthiram, S. D. Burke, Angew. Chem.
Int. Ed. 2007, 46, 769–772; c) I. Louis, N. L. Hungerford, E. J.
Humphries, M. D. McLeod, Org. Lett. 2006, 8, 1117–1120.
[3] a) M.-A. Hiebel, B. Pelotier, O. Piva, Tetrahedron 2007, 63,
7874–7878; b) H. M. Ko, D. G. Lee, M. A. Kim, H. J. Kim, J.
Park, M. S. Lah, E. Lee, Org. Lett. 2007, 9, 141–144; c) C.-
H. A. Lee, T.-P. Loh, Tetrahedron Lett. 2006, 47, 1641–1644;
d) D. L. Aubele, S. Wan, P. E. Floreancig, Angew. Chem. Int.
Ed. 2005, 44, 3485–3488.
[4] a) R. W. Bates, P. Song, Tetrahedron 2007, 63, 4497–4499; b) S.
Chandrasekhar, S. J. Prakash, T. Shyamsunder, Tetrahedron
Lett. 2005, 46, 6651–6653.
[5] A. V. Statsuk, D. Liu, S. A. Kozmin, J. Am. Chem. Soc. 2004,
126, 9546–9547.
[6] B. Schmidt, J. Chem. Soc. Perkin Trans. 1 1999, 2627–2637.
[7] B. S. Lucas, L. M. Luther, S. D. Burke, Org. Lett. 2004, 6,
2965–2968.
[8] a) P. O. Gallagher, C. S. P. McErlean, M. F. Jacobs, D. J. Watt-
ers, W. Kitching, Tetrahedron Lett. 2002, 43, 531–535; b) J. D.
White, C. L. Kranemann, P. Kuntyong, Org. Lett. 2001, 3,
4003–4006.
[9] a) A. Fettes, E. M. Carreira, J. Org. Chem. 2003, 68, 9274–
9283; b) S. M. Kuhnert, M. E. Maier, Org. Lett. 2002, 4, 643–
646.
[10] a) D. R. Li, C. Y. Sun, C. Su, G.-Q. Lin, W.-S. Zhou, Org. Lett.
2004, 6, 4261–4264; b) S. H. Kang, S. Y. Kang, C. M. Kim, H.-
W. Choi, H.-S. Jun, B. M. Lee, C. M. Park, J. W. Jeong, Angew.
Chem. Int. Ed. 2003, 42, 4779–4782.
[11] D. Gouiffes, S. Moreau, N. Helbecque, J. L. Bernier, J. P. Hen-
ichard, Y. Barbin, D. Laurent, J. F. Verbist, Tetrahedron 1988,
44, 451–459.
[12] J. F. Biard, C. Roussakis, J. M. Kornprobst, D. Gouiffes-Bar-
bin, J. F. Verbist, P. Cotelle, M. P. Foster, C. M. Ireland, C.
Debitus, J. Nat. Prod. 1994, 57, 1336–1345.
[25] Y. Brunel, G. Rousseau, Synlett 1995, 323–324.
[26] J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734–736.
[27] P. A. Bartlett, D. P. Richardson, J. Myerson, Tetrahedron 1984,
40, 2317–2327.
[28] C. Mendes, S. Renard, M. Rofoo, M.-C. Roux, G. Rousseau,
Eur. J. Org. Chem. 2003, 463–471.
[29] S. J. Pastine, D. Sames, Org. Lett. 2005, 7, 5429–5431.
Received: September 21, 2007
Published Online: November 30, 2007
[13] D. Riou, C. Roussakis, N. Robillard, J. F. Biard, J. F. Verbist,
Biol. Cell 1993, 77, 261–264.
[14] M. P. Sauviat, J. F. Verbist, Gen. Physiol. Biophys. 1993, 12,
465–471.
720
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 713–720