Synthesis of naturally occurring cyclohexene rings using stereodirected intramolecular diels-alder reactions through asymmetric 1,3-dioxane tethering

Article abstract of DOI:10.1002/ejoc.201001678

The utility of the readily available asymmetric 1,3-dioxane template in intramolecular Diels-Alder reactions is reported. The 1,3,9-decatrienoates substrates gave predominantly the endo-boat products, with minor amounts of the exo-boat isomer. Various substitutions (14 examples) were introduced and the results gave an indication of the scope and also a few limitations of the method. In particular, the approach was applicable to (E,Z)-diene substrates, for which good yields and selectivities were obtained. By applying suitable substrates, we describe the successful synthesis of valuable intermediates for the total synthesis of the diterpene harringtonolide (1) and the pyrrocidine polyketides (2), affording the appropriate stereochemistry of the natural product within the highly functionalized cyclohexene ring system. This is the first time that an asymmetric synthetic approach toward both compound series has been reported.

Full text of DOI:10.1002/ejoc.201001678

FULL PAPER
DOI: 10.1002/ejoc.201001678
Synthesis of Naturally Occurring Cyclohexene Rings Using Stereodirected
Intramolecular Diels–Alder Reactions Through Asymmetric 1,3-Dioxane
Tethering
Hajer Abdelkafi,[a] Laurent Evanno,[a] Alexandre Deville,[a] Lionel Dubost,[a]
Angèle Chiaroni,[b] and Bastien Nay*[a]
Keywords: Intramolecular Diels–Alder reaction / Diastereoselectivity / Template synthesis / Natural products /
Total synthesis
The utility of the readily available asymmetric 1,3-dioxane
template in intramolecular Diels–Alder reactions is reported.
The 1,3,9-decatrienoates substrates gave predominantly the
endo-boat products, with minor amounts of the exo-boat iso-
mer. Various substitutions (14 examples) were introduced
and the results gave an indication of the scope and also a
few limitations of the method. In particular, the approach was
applicable to (E,Z)-diene substrates, for which good yields
and selectivities were obtained. By applying suitable sub-
strates, we describe the successful synthesis of valuable in-
termediates for the total synthesis of the diterpene harring-
tonolide (1) and the pyrrocidine polyketides (2), affording the
appropriate stereochemistry of the natural product within the
highly functionalized cyclohexene ring system. This is the
first time that an asymmetric synthetic approach toward both
compound series has been reported.
directed IMDA reactions for the asymmetric synthesis of
the cyclohexane ring system contained within these com-
pounds.
Introduction
In the course of our work on the total synthesis of natu-
ral products with chiral cyclohexane moieties, we studied
the stereodirected intramolecular Diels–Alder reaction
(IMDA).[1,2] This reaction has been used for decades but,
depending on the natural target requirements, it is some-
times difficult to bring about because of unfavorable steric
or electronic effects, low selectivity, or incompatibilities be-
tween fragile substrates and harsh reaction conditions. Nev-
ertheless, many elegant achievements have been reported on
the synthesis of complex natural products,[3] which have
been extensively reviewed by others.[4] These works were
possible only after careful analysis of substrate reactivity,
with regard to the targeted structural features. Recently, we
have been particularly interested in methodologies aimed at
synthesizing two unrelated compounds: the diterpene har-
ringtonolide (1)[5] and a number of polyketides in the pyrro-
cidine series (2)[6] and related compounds (hirsutellone B;
3)[7] (Figure 1). We are now reporting our efforts on stereo-
To this end, template 1,3,9-decatrienoates precursors
were designed on the basis of a chiral 1,3-dioxane tether.
We assumed that stereocontrol of the IMDA reaction
would be provided by some preferred conformation of the
transition state, which would be guided by well-documented
stereoelectronic effects.[2] It has been shown that positioning
an internal carbonyl group on the dienophile strongly fa-
vors endo-boat transitions states in the case of 1,3,9-decatri-
enes, leading to cis-fused bicyclic systems, and that substitu-
ents on the decatrienoate tether can lead to important ster-
eoselective preferences.[8] A chiral 1,3-dioxane tether was
expected to make the decatrienoate system more rigid and
to increase the possibility of efficient stereocontrol. More-
over, this particularly stable template would be useful in the
case of less reactive substrates, especially Z-dienes, for
which harsh thermal IMDA conditions are often required.
Seeking the ideal 1,3-dioxane system, we found that com-
mon sugars could be well-suited starting materials; such
compounds have a high density of stereocenters that are
predisposed for transfer of asymmetry onto novel sp3 cen-
ters and late functional group interconversions. In particu-
lar, d-glucose is a precursor of (1ЈR)-(–)-2,4-O-ethylidene-
d-erythrose (4),[9] which is a C4-building block with a po-
tentially useful dual reactivity for selective functionalization
(encompassing both a free nucleophilic hydroxyl group and
an electrophilic aldehyde; Figure 2). This promising sub-
strate was thus considered for our synthetic purpose.
[a] Molécules de Communication et Adaptation des Micro-
organismes (UMR 7245 CNRS-MNHN), Muséum National
d’Histoire Naturelle,
57 rue Cuvier (CP 54), 75005 Paris, France
Fax: +33-1-40793135
E-mail: bnay@mnhn.fr
[b] Institut de Chimie des Substances Naturelles CNRS,
Bâtiment 27, Avenue de la Terrasse, 91198 Gif-sur-Yvette
Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001678.
Eur. J. Org. Chem. 2011, 2789–2800
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2789

B. Nay et al.
FULL PAPER
Figure 1. Natural products with an asymmetric cyclohexane ring that could arise from IMDA reaction and structural requirements for
IMDA substrates.
the reaction outcome, but steric effects resulting from
methyl substituents on both the diene and dienophile,
proved to be much more important. We now report in detail
the scope and limitations of this method.
Results and Discussion
Figure 2. The dual functionality of (1ЈR)-(–)-2,4-O-ethylidene-d-
Synthesis of IMDA substrates: All 1,3,9-decatriene sub-
erythrose (4) toward IMDA substrates.
strates were built from (1ЈR)-(–)-2,4-O-ethylidene-d-ery-
throse (4), which was synthesized in two steps from d-glu-
Previously, the diastereoselectivity of the Diels–Alder re- cose (Scheme 1).[9] The diene part was assembled from the
action has only once been controlled with this type of chiral aldehyde function on the 1,3-dioxane ring. A Horner–Wad-
building block; in that case, the reaction was performed in sworth–Emmons reaction was used first to install the E
an intermolecular manner in the total synthesis of forsko- double bond within the α,β-unsaturated esters 5 and 6,
lin.[10,11] To the best of our knowledge, the chiral 1,3-diox- which were obtained after hydroxy tert-butyldimethylsilyl
ane template was not used again until we reported a few (TBS) ether protection. The α,β-unsaturated aldehydes 7
years ago our first attempts to apply it to IMDA reac- and 8 were formed by a reduction–oxidation sequence (di-
tions.[12] Very recently, this template was again applied by isobutylaluminum hydride (DIBAL-H) then MnO2) from
others to intermolecular Diels–Alder reactions with diaza- the esters. Wittig olefination allowed a collection of dienes
dienophiles.[13] In all cases, the diastereomeric ratio resulted 11–16 to be generated by divergent functionalization. De-
from important secondary orbital interactions depending protection of the hydroxyl group and esterification with
on the dienophile, but the selectivity was also strongly influ- various dienophiles (fumarate, maleate, acrylate and substi-
enced by steric interactions related to the substitution tuted derivatives) finally gave the IMDA substrates
pattern. In our case, because the substrates contained an (Scheme 2). Especially, the methylated (E,Z)-diene 16 and
internal carbonyl within the 1,3,9-decatriene system, the the (E,E)-triene 15 are remarkable intermediates for the
endo mode was always preferred under thermal conditions, synthesis of natural compounds 1 and 2, respectively. The
operating through boat transition states. The presence of a synthetic utility of the method was exemplified by a reac-
terminal ester on the dienophile (e.g., fumarate) improved tion sequence performed on a 30 g scale to generate (E,Z)-
2790
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2789–2800

Synthesis of Naturally Occurring Cyclohexene Rings
diene 16 as a synthetic intermediate that can be used for the ric factors associated with the presence of methyl substitu-
synthesis of diterpene 1. Depending on the diastereomeric ents to be compared. The tricarboxylate 20 and the mesa-
selectivity of the IMDA reaction, dienes 14 and 15 could conate 21 were synthesized by applying the Wittig reaction
also be interesting intermediates in the synthesis of pyrroci- between tert-butyl triphenylphosphoranylidene-acetate and
dines (2) with cis AB ring fusion, or hirsutellones (3) with either diethyl oxomalonate or methyl pyruvate,[14] respec-
trans AB ring fusion (Figure 1). The other dienes 11–13 will tively, before deprotection under acid (trifluoroacetic acid
be used to assess the influence of substituents on the reac- (TFA)) catalysis. All dienophiles were coupled to the dienes
tivity of the dienes.
by esterification of the residual hydroxyl group of 11–16,
under variable conditions depending on the nature of the
acylating reagent (Scheme 2).
Exploring the conditions of the Diels–Alder reactions:
Starting from the readily accessible Diels–Alder substrate
24, we found that heating of a 0.1 m solution of the com-
pound to reflux in toluene at atmospheric pressure for 18 h,
in the presence of sub-stoichiometric amounts of 2,6-di-
tert-butyl-4-hydroxytoluene (BHT; 0.2 equiv.), afforded
both stereoisomers 38a and 38b in 85 and 13% yield (87:13
ratio), respectively (Table 1, entry 1).[15] Heating of the same
reaction mixture at 200 °C for only 1.5 h in a sealed tube
gave 38a and 38b in 96% combined yield (86:14) (Table 1,
entry 2). In N,N-dimethylformamide (DMF) (Table 1, entry
3) at reflux, the cycloadducts were obtained in 80% yield
in a 83:17 ratio after only 1 h, whereas degradation was
observed in dimethylsulfoxide (DMSO) at 200 °C (Table 1,
entry 4), giving only 40% of 38a. Cycloaddition also oc-
curred when the reaction was catalyzed by a Lewis acid (Et2-
AlCl) in dichloromethane at –30 °C (Table 1, entry 5). Un-
der the latter conditions, however, degradation of the start-
ing material led to a low yield of cycloadduct 38a (33%),
although complete selectivity seemed to occur in this case.
Following these preliminary experiments, the use of toluene
at elevated temperature, in the presence of a polymerization
inhibitor (BHT), were established as the conditions of
Scheme 1. Divergent synthesis of the diene substrates. Reagents and
conditions: (a) triethylphosphonoacetate, NaH, THF, 0 °C (74%);
(b) triethylphosphonopropionate, BuLi, LiBr, MeCN, 0 °C (48%);
(c) TBSCl, imidazole, DMAP, CH2Cl2, reflux (5: 86%; 6: 90%); (d)
DIBAL-H, CH2Cl2, –78 °C (9: 89%; 10: 70%, two steps); (e)
MnO2, CH2Cl2, reflux (7: 92%; 8: 78%, two steps); (f) MePPh3PBr,
NaHMDS, THF, –78 °C; (g) TBAF, THF, 0 °C (11: 70%; 12: 67%;
13: 85%; 16: 84%, two steps; 14: 90%; 15: 58%, three steps); (h)
NaH, THF, then MeI, 0 °C; (i) EtPPh3PBr, NaHMDS, THF,
–78 °C.
Table 1. Optimization of the conditions for the IMDA reaction of
substrate 24 toward the cycloadducts 38a (endo-boat product) and
38b (exo-boat product).
Entry Conditions
T [°C]
t
a
b
Ratio
[h] [%] [%] a/b
1
2
3
4
5
toluene, BHT
(0.2 equiv.)
toluene, BHT
(0.2 equiv.)[a]
DMF, BHT
(0.2 equiv.)
DMSO, BHT
(0.2 equiv.)[a]
CH2Cl2, Et2AlCl
(1 equiv.)
110
200
153
200
18 85
1.5 83
13
13
14
0
87:13
86:14
Scheme 2. The acylating dienophile reagents and the synthesis of
the IMDA substrate series. Reagents and conditions: (a) for 17 and
23: DCC, DMAP, CH2Cl2; (b) for 20 and 21: MsCl, NEt3, CH2Cl2;
(c) for 18, 19, 22: NEt3/CH2Cl2. For compound correspondence,
see Table 2.
1
1
66
40
83:17
100:0[b]
100:0[b]
–
15 33
0
30Ǟr.t.
Various acylating reagents (17–23) were used to intro-
duce the dienophiles (Scheme 2). This allowed the electronic
[a] Reaction was performed in a sealed tube. [b] Significant degra-
effect of internal versus terminal carboxylates, and the ste- dation was observed.
Eur. J. Org. Chem. 2011, 2789–2800
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2791

B. Nay et al.
FULL PAPER
choice for this study. By controlling the tolerance of the
reaction to steric and electronic factors, the scope and
limitations of this method were then investigated.
found (86:14 ratio). The dienophile thus always gave com-
plete facial selectivity, whereas the diene part adopted two
possible conformations relative to the dioxane ring. The
major endo-boat transition state 24a, with the CH-eclipsed
diene, followed the endo rule with respect to the internal
ester. Consequently, the trans,cis-fused 6-6-6 tricyclic system
(38a) was the main product formed in this reaction. The
exo-boat conformation 24b afforded the minor trans,trans-
isomer 38b. This selectivity is consistent with previous re-
ports,[8e,8f] which have often invoked endo-boat transition
states to explain the observed selectivities. In our case, the
observed results were also strongly influenced by con-
straints in the chiral dioxane tether, which tended to lower
the entropy loss during the reaction.
Selectivity in the IMDA reaction of the 1,3-dioxane teth-
ered substrates: With one exception (Table 2, entry 4), all
the reactions that were worked up yielded only two of the
four possible stereoisomers. When substrate 24 (Table 2, en-
try 1) was considered, four stereoisomers of the cycload-
ducts 38a–d could indeed be found; these arose from combi-
nations of endo/exo and boat/chair transition state con-
formers (see scheme in Table 2 and Figure 3).
Influence of substituents on the IMDA reaction: The
endo/exo selectivity between boat transition states a and b
ranged from nearly 50:50 to 96:4 (Table 2). We have shown
with fumarate 24 (Table 2, entry 1) that the good stereose-
lectivity of the cycloaddition (86:14 ratio) followed the
endo-rule with respect to the internal ester. However, sec-
ondary orbital interactions between the diene and the ter-
minal ester in the exo transition state 24b could be responsi-
ble for the formation of a significant amount of 38b. In-
deed, the use of an acrylate (25) instead of a fumarate led
Figure 3. Four possible transition states to explain the selectivity
of the IMDA reaction of 1,3-dioxane tethered substrates.
The stereoisomers 24c and 24d, arising from the chair to an improved endo/exo ratio of 92:8 in favor of the isomer
transition states, were not observed, and only the products 39a (Table 2, entry 2). However, maleate 26 gave a slightly
stemming from the boat transition states 24a and 24b were lower 80:20 ratio of compound 40a and 40b (Table 2, entry
Table 2. Chemical diversity and reactivity of the Diels–Alder substrates.
Entry
IMDA
Cycloadducts R1
R2
R3
R4
E
Z
T
t
a [%]
b [%]
d [%] Ratio a/b
substrate
a–d
[°C]
[h]
1
2
3
4
5
6
7
8
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
–
42
43
44
45
46
47
–
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
CO2Et
H
H
H
CH3
CO2Et
H
H
200
200
1.5
1
2
83
81
74[a]
17
–
45
70
94
72
44
66
–
13
7
0
0
0
11
–
0
0
0
0
0
0
–
–
0
86:14
92:8
CO2Me 200
H
CH3
CO2Et 200
18[a]
–
80:20[a]
[b]
220
200
144
150
4.5
48
2.5
1
72
110
72
1.3
3
–
[c]
–
–
49
22
4
11
24
21
–
48:52
76:24
96:4
CO2Me CH3
200
200
200
220
220
CO2Et
CO2Et
H
CO2Et
H
H
H
H
H
9
CH2OMe
H
H
H
CH=CH2
CH=CH2
H
87:13
65:35
76:24
10
11
12
13
14
CH3
CH3
CH3
H
[c]
CO2Me 220
H
H
–
–
[c,d]
48
49
CO2Et
CO2Et
200
200
38
70
–
6
H
CH3
92:8
[a] Inseparable cycloadducts (94% global yield after purification). Specific yields and ratio were determined by NMR analysis. Both
diastereoisomers were separated by chromatography after catalytic hydrogenation, and stereochemical assignments were then determined
by 2D NMR spectroscopic analysis. [b] For this reaction, it was difficult to isolate all the products from the complex reaction mixture
(with significant degradation being observed). The presence of other stereoisomers (i.e., b and c) cannot therefore be excluded. [c] Entries
5 and 13: significant degradation was observed; Entry 12: complete degradation was observed. [d] Comparable results were obtained at
110 °C with longer reaction times.
2792
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2789–2800

Synthesis of Naturally Occurring Cyclohexene Rings
3), which we explained by unfavorable steric interactions strate 33, Table 2, entry 10) led to 44 and 24% yield of
between the maleate dienophile and the diene. Interestingly, cycloadducts 46a and 46b (ca. 2:1 selectivity), respectively.
when methacrylate 27 (Table 2, entry 4) was used, despite a Although the latter reaction was performed at higher tem-
long reaction time (144 h), it was possible to isolate 11% of perature (220 °C) and for a longer reaction time (72 h), the
the endo-chair cycloadduct 41d beside the usual endo-boat result was particularly interesting considering the harsh
derivative 41a, which was obtained in 17% yield (Figure 4). conditions used and the usually poor reactivity of (E,Z)-
The chair transition state 27d would indeed be the confor- dienes in the Diels–Alder reaction.[16]
mation with minimized steric interactions. The alternative
Synthetic utility of the 1,3-dioxane-templated Diels–Alder
stereoisomers were not detected, although their formation reactions: With such encouraging results and with the aim
could not be excluded because significant degradation was of synthesizing biologically important natural products
observed during the reaction. Moreover, this was the only (Figure 1), especially the diterpene harringtonolide (1) and
experimental result of our work that contradicted the gene- polyketides such as pyrrocidine A (2), we applied our stere-
ral boat stereoselectivity depicted in Figure 3. The results odirected IMDA reaction to substrates 34–37.
unambiguously revealed the strong steric effects associated
Harringtonolide (1) is a diterpene isolated from the Chi-
with the use of a methacrylate-type dienophile with this nese yew tree Cephalotaxus harringtonia.[5] It belongs to a
kind of IMDA substrates.
small family of molecules all bearing a cage-shaped archi-
tecture and possesses a high biological value (phytotoxic,
cytotoxic or antiviral properties). To build the highly func-
tionalized cycle D of harringtonolide 1, with the appropri-
ate relative stereochemistry of every substituent (cycle D
holds the entire stereochemistry of 1), the use of fumarate
ester 34 bearing an (E,Z)-diene was planned (Scheme 3).
The Z geometry was important to introduce the methyl
group on the α-side of the cycle. Preliminary experiments
with fumarates (e.g., Table 2, entry 1) and with the (E,Z)-
dienyl acrylate 33 (Table 2, entry 10) had indeed shown that
the desired stereochemistry can be reached. Encouragingly,
Figure 4. The outcome of the reaction with substrate 27 and steric
interactions in the transition states explaining the unusual forma-
tion of cycloadduct 41d.
The use of dimethylacrylate ester 28 (Table 2, entry 5) with substrate 34 (Table 2, entry 11), the reaction worked
was even more discouraging because no cycloaddition prod- successfully, giving the expected endo-boat 47a and exo-
uct was detected in the reaction mixture and only degrada- boat 47b cycloadducts in 66 and 21% yields, respectively,
tion occurred after long reaction times at 200 °C (150 h). thus significantly increasing the diastereofacial selectivity
Nevertheless, tricarboxylate 29 (Table 2, entry 6) reacted
quickly, giving 45 and 49% of the isolated cycloadducts 42a
and 42b, respectively, after only 4.5 h at 200 °C. The selec-
tivity in this reaction was, however, almost nonexistent,
with a 48:52 ratio of both isomers being obtained; this con-
trasted with the results obtained in our previous experi-
ments with fumarate 24 and maleate 26. Finally, when mes-
aconate ester 30 (Table 2, entry 7) was used, we were ple-
ased to achieve good selectivity and good yields in the
IMDA reaction, giving 70 and 22% yield of stereoisomers
43a and 43b, respectively (ratio 76:24), and showing that
the presence of β-substituents on the dienophile was not
detrimental to the reaction.
We then turned our efforts towards the use of variously
substituted dienes. The IMDA reactions in these cases were
much more convincing, and allowed us to consider a
number of promising applications. First, the presence of a
methyl substituent as R3 of the diene facing the fumarate
on substrate 31 (Table 2, entry 8), compared to 24, gave an
excellent yield of the cycloadducts 44a (94%) after 2.5 h at
200 °C, accompanied by the formation of only 4% of its
stereoisomer 44b, corresponding to a diastereofacial selec-
tivity of 96:4. The presence of a terminal alkyl group (meth-
oxymethyl) in the R1 position of the diene (substrate 32,
Scheme 3. The 1,3-dioxane IMDA reaction applied to (E,Z)-dienyl
fumarate 34, as a key step in the synthesis of harringtonolide 1.
Table 2, entry 9) also gave good yield and selectivity of cy-
Reagents and conditions: (a) BHT (0.2 equiv.), toluene, 220 °C (se-
aled tube), 110 h; (b) l-Selectride, THF, –78 °C; (c) TFA/H2O (1:1),
cloadducts 45a and 45b; a methyl group on the terminal R2
position of the diene facing an acrylate dienophile (sub- 80 °C.
Eur. J. Org. Chem. 2011, 2789–2800
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2793

B. Nay et al.
FULL PAPER
(ca. 3:1 ratio) compared with that obtained with substrate At the same time, the recyclable dioxolane 52 was isolated,
33. Although the reaction required 110 h at 220 °C to reach the α-isomer of which gave crystals that were suitable for
completion, the result was very good considering that this X-ray analysis.
step was intrinsic to our retrosynthetic plan for the asym-
The pyrrocidines A (2) and B are polycyclic polyketides
metric total synthesis of this diterpene family of com- with antibiotic properties that are isolated from the fungus
pounds. The reaction was performed on a multigram scale Cylindrocarpon sp.[6] These compounds are cytotoxic
with high reproducibility. Moreover, we showed that this against leukemia HL-60 cells and share the same carbocy-
methodology would afford the correct absolute stereochem- clic skeleton as hirsutellones (e.g., 3),[7] but differ in the
istry of the natural product.[17] Preliminary studies showed methylation pattern and the stereochemistry. According to
that the use of a maleate dienophile (35) instead of a fumar- the diastereofacial selectivity discussed above, we antici-
ate (entry 12) only resulted in complete degradation.
pated that using a fumarate and a vinylogous (E,E)-diene
An important achievement was the obtainment of crys- such as 36 or 37 would result in the correct relative stereo-
tals of compound 47b and of the lactol derivative 50 from chemistry of the cycloadduct. However, substrate 36 only
47a, that were suitable for X-ray crystallography (Fig- afforded the endo-boat product 48a in 38% yield after 1.3 h
ure 5).[18] The X-ray structures confirmed the NMR struc- at 200 °C, with significant degradation of the starting mate-
ture determinations and showed that the complete stereo- rial (Table 2, entry 13). Encouragingly, with the methylated
chemistry of the natural product 1 was correctly estab- analogue substrate 37, it was pleasing to observe that high
lished. Furthermore, opening of the dioxane ring in acidic diastereofacial selectivity occurred (92:8) in favor of the ex-
medium proved successful. No isomerization product (both pected cycloadduct 49a, which was isolated in 70% yield
carboxylic groups could be epimerized) was detected during after 3 h heating at 200 °C (Table 2, entry 14). Accordingly,
this reaction, giving the reorganized diol 51 in 67% yield. 49a bears the cycle A of pyrrocidines, and the high stereose-
Figure 5. ORTEP drawings from X-ray crystallography of 47b, 50 and α-52.
2794
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2789–2800

Synthesis of Naturally Occurring Cyclohexene Rings
lectivity of the cycloaddition would be applicable to the to- Alder reaction proved to be highly efficient in these pro-
tal synthesis of ent-pyrrocidine ent-2 (Scheme 4).[19] It is jects. Moreover, it is the first time that an asymmetric syn-
noteworthy that the exo-boat isomer (49b) holds a trans- thetic approach toward both compound series has been re-
ring fusion, with the relative stereochemistry of hir- ported.
sutellones (3) and GKK1032 compounds.[20] The latter nat-
ural products have been synthetically approached using the
Diels–Alder reaction of 1,3,8-nonatrienes, for which the
IMDA reaction is known to proceed in the exo mode, to
Experimental Section
usually afford the trans-fused ring system.[21] To the best of
General Methods: Toluene was distilled in the presence of sodium/
benzophenone just before use. All reactions were performed under
argon. The products were isolated by flash silica gel column
chromatography (Geduran silica gel Si 60; 40–63 μm). Thin layer
our knowledge, this is the first time that a successful ap-
proach toward the cis-fused cyclohexene ring of pyrrocid-
ines has been reported.
chromatography (TLC) was conducted with Merck silica gel 60
F254 aluminum sheets (ref. 1.05554.0001). 1H NMR spectra were
recorded with a Bruker AC300 (300 MHz) or a Bruker Avance 400
spectrometer (400 MHz). 13C NMR spectra were recorded with a
Bruker AC300 spectrometer (75 MHz). High resolution mass spec-
tra (HRMS) were measured with an Applied Biosystem QSTAR
Pulsar-i spectrometer, using electrospray ionization. Infrared spec-
tra were recorded with a Shimatzu 8400S FTIR spectrometer. Spe-
cific rotations were recorded with a Perkin–Elmer 341 polarimeter.
Melting points were measured with a Büchi Melting Point B-545
apparatus. In the following sections, atom numbering follows that
depicted for compounds 47a and 51 in Scheme 3. More synthetic
procedures concerning the Diels–Alder substrates (compounds 5–
37), copies of 1H and 13C NMR spectra, and crystallographic data
are provided in the Supporting Information.
Ethyl (–)-(3R,4aS,4bR,8R,8aR,10aR)-3-Methyl-9-oxo-1,4a,4b,7,8,
8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8-carboxylate (38a)
Scheme 4. The IMDA reaction of vinylogous (E,E)-dienyl fumarate
and
Ethyl
(–)-(3R,4aS,4bS,8R,8aR,10aR)-3-Methyl-9-oxo-
37, as a key step in the total synthesis of ent-pyrrocidines A (2) and
B. Reagents and conditions: (a) BHT (0.2 equiv.), toluene, 200 °C
(sealed tube), 3 h.
1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8-carb-
oxylate (38b): A solution of triene 24 (52 mg, 0.169 mmol) in anhy-
drous toluene (1.7 mL) was heated at 200 °C in a sealed tube in the
presence of BHT (7.5 mg, 0.034 mmol) for 1.5 h. The mixture was
concentrated under reduced pressure and purified by flash
chromatography (cyclohexane/ethyl acetate, 9:1) providing isomer
38a (44 mg, 84%) as a colorless oil and isomer 38b (7 mg, 13%) as
a white solid.
Conclusions
During this work, we have demonstrated the utility and
efficiency of the readily available asymmetric 1,3-dioxane
template in intramolecular Diels–Alder reactions. All reac-
tions yielded significant amounts of products resulting from
endo-boat transition states. We studied the effect of various
substitutions on the 1,3,9-decatrienoate systems, and
showed that the only limiting situation was associated with
the presence of alkyl and dialkyl substitutions on the α and
β positions of the acrylate dienophile (Table 2, entries 4 and
5). Even an (E,Z)-diene gave good yields and selectivities
(performed on a multigram scale from 34), although
harsher reaction conditions were required (Table 2, entries
Isomer 38a: [α]2D5 = –38.5 (c = 0.4, MeOH). H NMR (300 MHz,
1
CDCl3): δ = 5.78 (m, 2 H, 5-H and 6-H), 4.74 (q, J = 5.1 Hz, 1 H,
3-H), 4.34 (dd, J = 10.6, 5.2 Hz, 1 H, 1-H), 4.19 (m, 3 H, 10a-H
and CH2CH3), 3.62 (m, 1 H, 8a-H), 3.57 (ЈtЈ, J = 10.3 Hz, 1 H, 1-
H), 3.32 (m, 1 H, 8-H), 3.21 (ЈtЈ, J = 9.3 Hz, 1 H, 4a-H), 2.99 (m,
1 H, 4b-H), 2.56 (m, 1 H, 7-H), 2.47 (m, 1 H, 7-H), 1.38 (d, J =
5.1 Hz, 3 H, 3-Me), 1.26 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 172.9, 171.8, 126.2, 125.6, 99.9, 80.2,
68.0, 67.4, 61.1, 37.9, 37.2, 34.4, 22.8, 20.2, 14.1 ppm. IR (KBr): ν
˜
= 2992, 2926, 2866, 1758, 1725, 1196, 1043 cm–1. HRMS (ESI+):
m/z [M + H+] calcd. for C15H21O6 297.1338; found 297.1338.
1
10 and 11). This is a remarkable achievement because Isomer 38b: M.p. 146 °C. [α]2D5 = –6.1 (c = 0.5, CHCl3). H NMR
(300 MHz, CDCl3): δ = 5.97 (m, 1 H, 5-H), 5.77 (m, 1 H, 6-H),
4.78 (q, J = 5.1 Hz, 1 H, 3-H), 4.33 (dd, J = 9.9, 4.6 Hz, 1 H, 1-
H), 4.23 (m, 3 H, 10a-H and CH2CH3), 3.84 (dd, J = 10.0, 9.9 Hz,
1 H, 4a-H), 3.69 (ЈtЈ, J = 9.9 Hz, 1 H, 1-H), 3.10 (ЈtЈ, J = 11.4 Hz,
1 H, 8a-H), 2.85 (m, 2 H, 8-H and 4b-H), 2.57 (m, 1 H, 7-H), 2.28
(m, 1 H, 7-H), 1.39 (d, J = 5.1 Hz, 3 H, 3-Me), 1.29 (t, J = 7.2 Hz,
3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.3, 172.1,
126.1, 123.2, 100.6, 75.5, 69.8, 68.3, 60.9, 40.8, 40.5, 35.2, 29.3,
(E,Z)-dienes are often unsuitable substrates for Diels–Alder
reactions and sometimes undergo undesirable side reactions
such as [1,5]-sigmatropic rearrangements.[22] The results
also showed that the 1,3-dioxane tether was resistant to
harsh reaction conditions, such as high temperatures, over
relatively long periods, but was easily removed in acidic me-
dium. Finally, the methodology was applied to the synthesis
of valuable intermediates that are suitable for the total syn-
thesis of diterpene harringtonolide (1) from 34, and of the
20.2, 14.1 ppm. IR (KBr): ν = 2991, 2941, 2874, 1768, 1736, 1189,
˜
1038 cm–1. HRMS (ESI+): m/z [M + H+] calcd. for C15H21O6
pyrrocidine polyketides (e.g., 2) from 37. The key Diels– 297.1338; found 297.1347.
Eur. J. Org. Chem. 2011, 2789–2800
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2795

B. Nay et al.
FULL PAPER
(–)-(3R,4aS,4bR,8aS,10aR)-3-Methyl-9-oxo-1,4a,4b,7,8,8a,9,10a-oc- Hydrogenation Product of Isomer 40b: White solid; m.p. 153 °C;
tahydro-2,4,10-trioxaphenanthrene (39a) and (+)-(3R,4aS,4bS,8a-
[α]2D5 = +59 (c = 1.1, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
S,10aR)-3-Methyl-9-oxo-1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-tri- 4.74 (q, J = 5.1 Hz, 1 H, 3-H), 4.30 (dd, J = 10.3, 4.8 Hz, 1 H, 1-
oxaphenanthrene (39b):
A
solution of substrate 25 (46 mg,
H), 4.10 (ЈdtЈ, J = 10.3, 4.8 Hz, 1 H, 10a-H), 3.80 (ЈtЈ, J = 10.3 Hz,
1 H, 4a-H), 3.71 (s, 3 H, CO2Me), 3.64 (ЈtЈ, J = 10.3 Hz, 1 H, 1-
H), 3.17 (m, 1 H, 8-H), 3.07 (m, 1 H, 4b-H), 2.48 (dd, J = 11.5,
3.6 Hz, 1 H, 8a-H), 2.17 (m, 1 H, 7-H), 2.03 (m, 1 H, 5-H), 1.78
(m, 1 H, 6-H), 1.62 (m, 1 H, 7-H), 1.39 (m, 1 H, 6-H), 1.35 (d, J
= 5.1 Hz, 3 H, 3-Me), 1.29 (m, 1 H, 5-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 173.5, 172.2, 100.2, 75.7, 68.5, 68.3, 51.8, 44.4, 39.0,
0.205 mmol) in anhydrous toluene (2 mL) was heated in a sealed
tube at 200 °C in the presence of BHT (8 mg, 0.041 mmol) for 1 h.
The mixture was concentrated under reduced pressure and purified
by flash chromatography (cyclohexane/ethyl acetate, 9:1), providing
41 mg of a 93:7 mixture of diastereoisomers 39a and 39b, respec-
tively (NMR ratio). These isomers were separated by HPLC (SiO2–
C18 column, elution with water/acetonitrile/trifluoroacetic acid
70:30:0.005).
32.4, 28.7, 26.1, 22.3, 20.3 ppm. IR (KBr): ν = 2996, 2955, 2875,
˜
1767, 1735, 1233, 1193, 1152, 1132, 1072, 961 cm–1. HRMS (ESI+):
m/z [M + H+] calcd. for C14H21O6 285.1338; found 285.1339.
Isomer 39a: White solid; m.p. 96–97 °C; [α]2D5 = –26.5 (c = 0.7,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 5.86 (m, 1 H, 6-H), 5.75
(m, 1 H, 5-H), 4.74 (q, J = 5.1 Hz, 1 H, 3-H), 4.29 (dd, J = 10.7,
5.2 Hz, 1 H, 1-H), 4.13 (m, 1 H, 10a-H), 3.56 (ЈtЈ, J = 10.2 Hz, 1
H, 1-H), 3.27 (ЈtЈ, J = 9.2 Hz, 1 H, 4a-H), 3.05 (m, 1 H, 8a-H),
2.80 (m, 1 H, 4b-H), 2.26 (m, 1 H, 7-H), 2.12 (m, 1 H, 8-H), 2.02
(m, 1 H, 7-H), 1.78 (m, 1 H, 8-H), 1.38 (d, J = 5.1 Hz, 3 H, 3-
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.5, 128.3, 125.5,
(–)-(3R,4aS,4bR,8aS,10aR)-3,8a-Dimethyl-9-oxo-1,4a,4b,7,8,
8a,9,10a-octahydro-2,4,10-trioxaphenanthrene (41a) and (+)-
(3R,4aS,4bS,8aR,10aR)-3,8a-Dimethyl-9-oxo-1,4a,4b,7,8,8a,9,10a-
octahydro-2,4,10-trioxaphenanthrene (41d): A solution of substrate
27 (122 mg, 0.514 mmol) in anhydrous toluene (5 mL) was heated
in a sealed tube at 220 °C in the presence of BHT (23 mg,
0.103 mmol) for 6 d. The mixture was concentrated under reduced
pressure and purified by flash chromatography (cyclohexane/
dichloromethane, 5:1) to provide isomer 41a (21 mg, 17%) and iso-
mer 41d (13 mg, 11%) as colorless solids.
99.9, 79.8, 68.6, 68.1, 36.6, 36.3, 22.4, 21.6, 20.3 ppm. IR (KBr): ν
˜
= 3031, 2880, 1763, 1191, 1032 cm–1. HRMS (ESI+): m/z [M + H+]
calcd. for C12H17O4 225.1127; found 225.1126.
1
Isomer 41a: M.p. 105 °C; [α]2D5 = –86 (c = 1.02, CHCl3). H NMR
Isomer 39b: Colorless resin; [α]2D5 = +44 (c = 0.2, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 5.95 (m, 1 H, 6-H), 5.78 (m, 1 H, 5-H),
4.79 (q, J = 5.1 Hz, 1 H, 3-H), 4.32 (dd, J = 7.5, 4.6 Hz, 1 H, 1-
H), 4.18 (m, 1 H, 10a-H), 3.84 (ЈtЈ, J = 10.2 Hz, 1 H, 4a-H), 3.69
(ЈtЈ, J = 10.1 Hz, 1 H, 1-H), 2.83 (m, 1 H, 4b-H), 2.69 (m, 1 H, 8a-
H), 2.25 (m, 2 H, 7-H and 8-H), 1.68 (m, 2 H, 7-H and 8-H), 1.40
(d, J = 5.1 Hz, 3 H, 3-Me) ppm. 13C NMR (75 MHz, CDCl3): δ =
173.5, 128.1, 123.2, 100.6, 75.8, 70.0, 68.4, 39.2, 36.3, 25.0, 22.6,
(400 MHz, CDCl3): δ = 5.88 (m, 1 H, 6-H), 5.80 (m, 1 H, 5-H),
4.76 (q, J = 5.1 Hz, 1 H, 3-H), 4.22 (dd, J = 10.6, 5.0 Hz, 1 H, 1-
H), 4.10 (m, 1 H, 10a-H), 3.55 (ЈtЈ, J = 10.4 Hz, 1 H, 1-H), 3.43
(dd, J = 9.3, 1.8 Hz, 1 H, 4a-H), 2.34 (m, 1 H, 4b-H), 2.14 (m, 2
H, 7-H), 1.83 (m, 2 H, 8-H), 1.38 (d, J = 5.1 Hz, 3 H, 3-Me), 1.36
(s, 3 H, 8a-Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.2,
127.5, 123.9, 99.9, 78.4, 71.5, 68.0, 43.8, 41.9, 30.7, 23.4, 21.3,
20.3 ppm. IR (film on NaCl): ν = 3036, 2993, 2928, 2874, 1735,
˜
20.2 ppm. IR (film on NaCl): ν = 2933, 2872, 1763, 1222, 1159,
˜
1466, 1411, 1377, 1273, 1234, 1199, 1145, 1091, 1041 cm–1. HRMS
(ESI+): m/z [M + H+] calcd. for C13H19O4 239.1277; found
239.1289.
1151, 1085, 1072, 1030 cm–1. HRMS (ESI+): m/z [M + H+] calcu-
lated for C12H17O4 225.1127; found 225.1120.
Hydrogenation Product of Methyl (+)-(3R,4aS,4bR,8S,8aR,10aR)-
3-Methyl-9-oxo-1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-trioxaphen-
anthrene-8-carboxylate (40a) and of Methyl (+)-(3R,4aS,4bS,8S,8a-
R,10aR)-3-Methyl-9-oxo-1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-tri-
oxaphenanthrene-8-carboxylate (40b): A solution of substrate 26
(53 mg, 0.198 mmol) in anhydrous toluene (2 mL) was heated in a
sealed tube at 200 °C in the presence of BHT (8 mg, 0.036 mmol)
for 2 h. The mixture was concentrated and purified by flash
chromatography (cyclohexane/ethyl acetate, 8:2), providing 50 mg
of a 8:2 mixture (NMR ratio) of the two cycloadducts 40a and 40b
(94% yield). For structural determination purposes, both com-
pounds were separated after hydrogenation in the presence of Pd/
C in methanol under a balloon of hydrogen. Purification was then
performed by silica gel flash chromatography (cyclohexane/ethyl
acetate, 9:1).
Isomer 41d: M.p. 83 °C. [α]2D5 = +24.1 (c = 0.78, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 6.04 (m, 1 H, 6-H), 5.82 (m, 1 H, 5-H),
4.82 (q, J = 5.0 Hz, 1 H, 3-H), 4.19 (dd, J = 9.9, 5.0 Hz, 1 H, 1-
H), 4.11 (dd, J = 9.8, 5.0 Hz, 1 H, 10a-H), 3.95 (dd, J = 9.4, 4.3 Hz,
1 H, 4a-H), 3.58 (ЈtЈ, J = 9.6 Hz, 1 H, 1-H), 2.62 (m, 1 H, 4b-H),
2.32 (m, 1 H, 8-H), 2.04 (m, 2 H, 7-H), 1.45 (s, 4 H, 8-H and 8a-
Me), 1.39 (d, J = 5.0 Hz, 3 H, 3-Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 175.1, 131.1, 123.8, 100.0, 74.5, 68.8, 68.1, 43.5, 42.8,
33.8, 29.0, 22.6, 20.3 ppm. IR (film on NaCl): ν = 2982, 2940, 2874,
˜
1732, 1473, 1381, 1230, 1184, 1149, 1122, 1091, 1068, 1057,
1038 cm–1. HRMS (ESI+): m/z [M + Na+] calcd. for C13H18NaO4
261.1097; found 261.1104.
Diethyl (–)-(3R,4aS,4bR,8aR,10aR)-3-Methyl-9-oxo-1,4a,4b,7,8,8a,
9,10a-octahydro-2,4,10-trioxaphenanthrene-8,8-dicarboxylate (42a)
and Diethyl (+)-(3R,4aS,4bS,8aR,10aR)-3-Methyl-9-oxo-1,4a,4b,
7,8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8,8-dicarboxylate
(42b): A solution of substrate 29 (50 mg, 0.136 mmol) in anhydrous
toluene (1.3 mL) was heated in a sealed tube at 200 °C in the pres-
ence of BHT (6 mg, 0.027 mmol) for 4.5 h. The mixture was con-
centrated under reduced pressure and purified by flash chromatog-
raphy (cyclohexane/ethyl acetate, 11:1) to provide isomer 42a
(23 mg, 45%) and isomer 42b (24 mg, 49%) as colorless resins.
Hydrogenation Product of Isomer 40a: White solid; m.p. 92 °C;
[α]2D5 = +82 (c = 1, CHCl3). 1H NMR (300 MHz, CD3OD): δ =
4.78 (q, J = 5.0 Hz, 1 H, 3-H), 4.35 (m, 1 H, 10a-H), 4.22 (dd, J
= 10.1, 4.9 Hz, 1 H, 1-H), 3.76 (dd, J = 7.5, 4.9 Hz, 1 H, 8a-H),
3.65 (s, 3 H, CO2Me), 3.62 (ЈtЈ, J = 10.1 Hz, 1 H, 1-H), 3.27 (dd,
J = 9.7, 5.0 Hz, 1 H, 4a-H), 2.59 (ЈdtЈ, J = 12.5, 4.6 Hz, 1 H, 8-
H), 2.18 (m, 1 H, 4b-H), 2.05 (m, 2 H, 5-H and 7-H), 1.79 (m, 1
H, 6-H), 1.57 (m, 1 H, 7-H), 1.30 (m, 4 H, 6-H and 3-Me), 0.97
(m, 1 H, 5-H) ppm. 13C NMR (75 MHz, CD3OD): δ = 175.3,
Isomer 42a: [α]2D5 = –52 (c = 0.13, CHCl3). 1H NMR (300 MHz,
174.2, 101.3, 83.9, 70.4, 69.1, 52.3, 42.6, 40.6, 38.8, 32.6, 25.2, 24.4, CDCl3): δ = 5.77 (m, 2 H, 5-H and 6-H), 4.72 (q, J = 5.0 Hz, 1 H,
20.5 ppm. IR (KBr): ν = 2955, 2865, 1755, 1730, 1240, 1225, 1200,
3-H), 4.24 (m, 7 H, two CH2CH3, 1-H, 4a-H and 10a-H), 3.56 (ЈtЈ,
J = 9.8 Hz, 1 H, 1-H), 3.20 (m, 2 H, 4b-H and 8a-H), 2.95 (dd, J
= 18.1, 4.6 Hz, 1 H, 7-H), 2.75 (d, J = 18.1 Hz, 1 H, 7-H), 1.38 (d,
˜
1130, 1060, 920 cm–1. HRMS (ESI+): m/z [M + H+] calcd. for
C14H21O6 285.1338; found 285.1327.
2796
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2789–2800

Synthesis of Naturally Occurring Cyclohexene Rings
J = 5.1 Hz, 3 H, 3-Me), 1.23 (m, 6 H, two CH2CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 170.7, 168.8, 126.3, 124.9, 99.9, 80.0,
67.9, 67.4, 62.3, 61.9, 54.6, 40.8, 36.6, 26.4, 20.2, 13.8 ppm. IR (film
4.29 (dd, J = 10.5, 5.1 Hz, 1 H), 4.19 (m, 1 H), 4.12 (q, J = 7.1 Hz,
2 H), 3.60 (br. d, J = 10.0 Hz, 1 H), 3.54 (ЈtЈ, J = 10.0 Hz, 1 H),
3.24 (m, 2 H), 2.88 (ЈtЈ, J = 8.5 Hz, 1 H), 2.42 (m, 2 H), 1.66 (br.
s, 3 H), 1.33 (d, J = 5.0 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H) ppm.
on NaCl): ν = 2928, 1739 (br), 1273, 1238, 1188, 1161, 1103,
˜
1041 cm–1. HRMS (ESI+): m/z [M + H+] calcd. for C18H25O8 13C NMR (75 MHz, CDCl3): δ = 172.8, 171.7, 133.0, 121.1, 99.4,
369.1543; found 369.1555.
79.4, 67.9, 67.1, 60.8, 37.9, 37.6, 26.8, 22.6, 21.1, 20.3, 14.0 ppm.
IR (film on NaCl): ν = 2982, 2943, 2916, 2866, 1755, 1724, 1446,
˜
Isomer 42b: [α]2D5 = +79 (c = 0.06, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 5.91 (m, 1 H), 5.72 (m, 1 H), 4.76 (q, J = 5.0 Hz, 1
H), 4.25 (m, 6 H), 3.88 (ЈtЈ, J = 10.0 Hz, 1 H), 3.66 (ЈtЈ, J = 10.1 Hz,
1 H), 3.30 (d, J = 12.2 Hz, 1 H), 3.21 (m, 1 H), 3.09 (m, 1 H), 2.58
(m, 1 H), 1.36 (d, J = 5.1 Hz, 3 H), 1.27 (m, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 171.2, 169.3, 168.7, 125.1, 123.8, 100.5, 75.3,
69.3, 68.2, 62.2, 61.7, 54.4, 44.1, 34.5, 32.7, 20.2, 13.9, 13.8 ppm.
1411, 1276, 1203, 1165, 1141, 1114, 1068, 887, 759 cm–1. HRMS
(ESI+): m/z [M + H+] calcd. for C16H23O6 311.1489; found
311.1483.
Ethyl (+)-(3R,4aS,4bR,7S,8R,8aR,10aR)-7-Methoxymethyl-3-meth-
yl-9-oxo-1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-
8-carboxylate (45a) and Ethyl (–)-(3R,4aS,4bS,7R,8R,8aR,10aR)-7-
Methoxymethyl-3-methyl-9-oxo-1,4a,4b,7,8,8a,9,10a-octahydro-
2,4,10-trioxaphenanthrene-8-carboxylate (45b): A solution of sub-
strate 32 (200 mg, 0.588 mmol) in anhydrous toluene (6 mL) was
heated in a sealed tube at 200 °C in the presence of BHT (26 mg,
0.118 mmol) for 1 h. The mixture was concentrated under reduced
pressure and purified by flash chromatography (cyclohexane/ethyl
acetate, 9:1Ǟ4:1) to provide isomer 45a (143 mg, 72%) and isomer
45b (21 mg, 11%) as colorless resins.
Isomer 45a: [α]2D5 = +30 (c = 0.6, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 5.89 and 5.81 (2ϫm, 2 H, 5-H and 6-H), 4.73 (q, J =
5.1 Hz, 1 H, 3-H), 4.27 (dd, J = 10.7, 5.2 Hz, 1 H, 1-H), 4.17 (m,
2 H, CH2CH3), 4.14 (m, 1 H, 10a-H), 3.58 (dd, J = 10.4, 5.4 Hz,
1 H, 8a-H), 3.54 (ЈtЈ, J = 10.2 Hz, 1 H, 1-H), 3.30 (m, 4 H, 7-
CH2OMe, 4a-H and 8-H), 3.28 (s, 3 H, OMe), 2.91 (m, 2 H, 4b-H
and 7-H), 1.35 (d, J = 5.1 Hz, 3 H, 3-Me), 1.26 (t, J = 7.2 Hz, 3
H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.6, 171.0,
127.3, 126.6, 99.9, 78.8, 74.3, 69.6, 68.0, 61.3, 58.4, 42.2, 38.6, 37.2,
IR (film on NaCl): ν = 2982, 2924, 2854, 1774, 1724 (br), 1465,
˜
1388, 1257, 1188, 1149, 1072, 906 cm–1. HRMS (ESI+): m/z [M +
H+] calcd. for C18H25O8 369.1543; found 369.1560.
Methyl (–)-(3R,4aS,4bR,8R,8aR,10aR)-3,8-Dimethyl-9-oxo-1,4a,4b,
7,8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8-carboxylate
(43a) and Methyl (+)-(3R,4aS,4bS,8R,8aR,10aR)-3,8-Dimethyl-9-
oxo-1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8-
carboxylate (43b): A solution of substrate 30 (60 mg, 0.20 mmol)
in anhydrous toluene (2 mL) was heated in a sealed tube at 200 °C
in the presence of BHT (9 mg, 0.04 mmol) for 48 h. The mixture
was concentrated under reduced pressure and purified by flash
chromatography (cyclohexane/ethyl acetate, 7:1) to provide isomer
43a (42 mg, 70%) and isomer 43b (13 mg, 22%) as colorless resins.
Isomer 43a: [α]2D5 = –25 (c = 0.25, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 5.78 (m, 1 H, 5-H), 5.64 (m, 1 H, 6-H), 4.71 (q, J =
5.1 Hz, 1 H, 3-H), 4.32 (dd, J = 10.4, 5.2 Hz, 1 H, 1-H), 4.21 (m,
1 H, 10a-H), 3.69 (s, 3 H, CO2Me), 3.55 (ЈtЈ, J = 10.0 Hz, 1 H, 1-
H), 3.46 (d, J = 9.0 Hz, 1 H, 8a-H), 3.19 (dd, J = 9.4, 8.1 Hz, 1 H,
4a-H), 2.97 (m, 1 H, 4b-H), 2.53 (m, 2 H, 7-H), 1.49 (s, 3 H, 8-
Me), 1.37 (d, J = 5.1 Hz, 3 H, 3-Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 176.2, 170.4, 127.2, 125.5, 99.9, 80.3, 68.1, 67.3, 52.4,
35.4, 20.3, 14.2 ppm. IR (film on NaCl): ν = 2984, 2933, 2875,
˜
1760–1730 (br), 1142, 1078 cm–1. HRMS (ESI+): m/z [M + H+]
calcd. for C17H25O7 341.1600; found 341.1595.
Isomer 45b: [α]2D5 = –60 (c = 0.4, MeOH). 1H NMR (400 MHz,
CDCl3): δ = 6.04 and 5.72 (2ϫm, 2 H, 5-H and 6-H), 4.77 (q, J =
5.1 Hz, 1 H, 3-H), 4.22 (m, 4 H, 1-H, 10a-H and CH2CH3), 3.83
(ЈtЈ, J = 9.5 Hz, 1 H, 4a-H), 3.69 (ЈtЈ, J = 9.5 Hz, 1 H, 1-H), 3.31
(m, 2 H, 7-CH2OMe), 3.24 (s, 3 H, OMe), 3.16 (ЈtЈ, J = 12.0 Hz, 1
H, 8a-H), 2.95 (dd, J = 11.1, 7.0 Hz, 1 H, 8-H), 2.87 (m, 1 H, 7-
H), 2.79 (m, 1 H, 4b-H), 1.38 (d, J = 5.1 Hz, 3 H, 3-Me), 1.30 (t,
J = 7.2 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
172.5, 172.4, 128.0, 124.4, 100.8, 75.6, 72.8, 70.0, 68.4, 60.8, 58.7,
44.3, 41.6, 37.2, 30.0, 23.2, 20.2 ppm. IR (film on NaCl): ν = 3032,
˜
2997, 2939, 2874, 1759, 1724, 1458, 1377, 1203, 1161, 1138, 1111,
1072 cm–1. HRMS (ESI+): m/z [M + Na+] calcd. for C15H20NaO6
319.1152; found 319.1152.
Isomer 43b: [α]2D5 = +33 (c = 0.35, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 5.93 (m, 1 H, 5-H), 5.73 (m, 1 H, 6-H), 4.76 (q, J =
5.0 Hz, 1 H, 3-H), 4.32 (dd, J = 10.1, 4.6 Hz, 1 H, 1-H), 4.23 (m,
1 H, 10a-H), 3.88 (ЈtЈ, J = 10.3 Hz, 1 H, 1-H), 3.71 (s, 3 H,
CO2Me), 3.68 (ЈtЈ, J = 9.9 Hz, 1 H, 4a-H), 3.31 (d, J = 12.7 Hz, 1
H, 8a-H), 2.91 (m, 1 H, 4b-H), 2.48 (m, 1 H, 7-H), 2.10 (m, 1 H,
7-H), 1.40 (d, J = 5.1 Hz, 3 H, 3-Me), 1.35 (s, 3 H, 8-Me) ppm.
13C NMR (75 MHz, CDCl3): δ = 176.5, 171.5, 125.5, 122.6, 100.6,
76.0, 69.5, 68.3, 52.4, 43.6, 41.6, 37.8, 32.0, 20.2, 15.8 ppm. IR (film
42.5, 38.1, 37.6, 36.1, 20.3, 14.1 ppm. IR (film on NaCl): ν = 3039,
˜
2985, 2935, 2875, 1767, 1732, 1676, 1469, 1450, 1413, 1392, 1381,
1367, 1340, 1265, 1203, 1180, 1161, 1151, 1112, 1074, 1035,
981 cm–1. HRMS (ESI+): m/z [M + Na+] calcd. for C17H24O7Na
363.1420; found 363.1411.
on NaCl): ν = 2958, 2924, 2854, 1763, 1732, 1465, 1261, 1149,
˜
(–)-(3R,4aS,4bR,7R,8aR,10aR)-3,7-Dimethyl-9-oxo-1,4a,4b,7,8,
8a,9,10a-octahydro-2,4,10-trioxaphenanthrene (46a) and (–)-
(3R,4aS,4bS,7S,8aR,10aR)-3,7-Dimethyl-9-oxo-1,4a,4b,7,8,8a,
1072, 1018, 906 cm–1. HRMS (ESI+): m/z [M + Na+] calcd. for
C15H20O6 319.1152; found 319.1149.
9,10a-octahydro-2,4,10-trioxaphenanthrene (46b):
A solution of
Ethyl (–)-(3R,4aS,4bS,8R,8aR,10aR)-3,5-Dimethyl-9-oxo-1,4a,4b,7,
8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8-carboxylate (44a):
A solution of substrate 31 (330 mg, 1.06 mmol) in anhydrous tolu-
ene (10 mL) was heated in a sealed tube at 200 °C in the presence
of BHT (47 mg, 0.21 mmol) for 2.5 h. The mixture was concen-
trated under reduced pressure and purified by flash chromatog-
raphy (cyclohexane/ethyl acetate, 9:1Ǟ8:2) to provide isomer 44a
(310 mg, 94%) as a white solid and isomer 44b (14 mg, contami-
nated by 44a, 4% yield according to NMR analysis) as a colorless
resin.
substrate 33 (31 mg, 0.13 mmol) in anhydrous toluene (1.3 mL) was
heated in a sealed tube at 220 °C in the presence of BHT (7 mg,
0.033 mmol) for 3 d. The mixture was concentrated under reduced
pressure and purified by flash chromatography (cyclohexane/di-
ethyl ether, 8:1Ǟ6:1) to provide isomer 46a (13 mg, 44%) and iso-
mer 46b (7 mg, 24%) as colorless resins.
Isomer 46a: [α]2D5 = –52 (c = 0.46, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 5.66 (m, 2 H, 5-H and 6-H), 4.70 (q, J = 4.4 Hz, 1 H,
3-H), 4.28 (dd, J = 10.7, 5.2 Hz, 1 H, 1-H), 4.11 (m, 1 H, 10a-H),
3.52 (ЈtЈ, J = 10.3 Hz, 1 H, 1-H), 3.18 (ЈtЈ, J = 9.1 Hz, 1 H, 4a-H),
3.06 (m, 1 H, 8a-H), 2.76 (m, 1 H, 4b-H), 2.38 (m, 1 H, 7-H), 2.25
1
Isomer 44a: M.p. 59–60 °C; [α]2D5 = +34 (c = 1, CHCl3). H NMR
(300 MHz, CDCl3): δ = 5.43 (m, 1 H), 4.72 (q, J = 5.0 Hz, 1 H),
Eur. J. Org. Chem. 2011, 2789–2800
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2797

B. Nay et al.
FULL PAPER
(ЈdtЈ, J = 13.3, 4.2 Hz, 1 H, 8-H), 1.35 (d, J = 7.0 Hz, 3 H, 3-Me),
1.30 (m, 1 H, 8-H), 0.99 (d, J = 7.1 Hz, 3 H, 7-Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.8, 134.4, 124.9, 99.9, 80.4, 68.1, 67.9,
36.3, 35.8, 30.5, 25.9, 21.3, 20.3 ppm. HRMS (ESI+): m/z [M + H+]
calcd. for C13H19O4 239.1283; found 239.1287.
Isomer 46b: [α]2D5 = –56 (c = 0.3, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 5.77 (m, 2 H, 5-H and 6-H), 4.75 (q, J = 5.0 Hz, 1 H,
3-H), 4.19 (dd, J = 10.5, 5.0 Hz, 1 H, 1-H), 4.09 (m, 1 H, 10a-H),
3.57 (ЈtЈ, J = 10.4 Hz, 1 H, 4a-H), 3.44 (dd, J = 11.1, 9.3 Hz, 1 H,
1-H), 3.02 (ddd, J = 12.9, 7.3, 3.7 Hz, 1 H, 4b-H), 2.66 (m, 1 H,
8a-H), 2.24 (m, 2 H, 7-H and 8-H), 1.38 (m, 4 H, 8-H and 3-Me),
1.04 (d, J = 7.0 Hz, 3 H, 7-Me) ppm. 13C NMR (75 MHz, CDCl3):
δ = 172.3, 135.6, 123.1, 100.1, 77.5, 72.1, 68.0, 40.1, 36.7, 34.1,
6-H and CH=CH2), 5.05 (m, 2 H, CH=CH2), 4.75 (q, J = 5.1 Hz,
1 H, 3-H), 4.26 (dd, J = 10.6, 5.2 Hz, 1 H, 1-H), 4.17 (m, 4 H, 10a-
H and CH2CH3), 3.56 (m, 2 H, 1-H and 8a-H), 3.29 (m, 2 H, 7-H
and 4a-H), 3.02 (ЈtЈ, J = 6.5 Hz, 1 H, 8-H), 2.90 (m, 1 H, 4b-H),
1.37 (d, J = 5.0 Hz, 3 H, 3-Me), 1.26 (t, J = 7.1 Hz, 3 H,
CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.1, 170.5,
138.9, 129.0, 125.6, 116.2, 99.9, 78.5, 70.1, 67.9, 61.3, 45.2, 41.2,
38.8, 35.6, 20.3, 14.2 ppm. IR (film on NaCl): ν = 3082, 3036, 2982,
˜
2874, 1732, 1635, 1465, 1446, 1411, 1373, 1265, 1141, 1087, 1037,
918, 898 cm–1. HRMS (ESI+): m/z [M + H+] calcd. for C17H23O6
323.1489; found 323.1489.
Ethyl (+)-(3R,4aS,4bR,7S,8R,8aR,10aR)-3,5-Dimethyl-7-vinyl-9-
oxo-1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8-
carboxylate (49a): A solution of substrate 37 (100 mg, 0.3 mmol)
in anhydrous toluene (3 mL) was heated in a sealed tube at 200 °C
in the presence of BHT (13 mg, 0.06 mmol) for 3 h. The mixture
was concentrated under reduced pressure and purified by flash
chromatography (cyclohexane/ethyl acetate, 9:1Ǟ8:2) to provide
isomer 49a (70 mg, 70%) as a colorless resin and a contaminated
fraction of isomer 49b (ca. 6% according to NMR analysis).
30.5, 21.1, 20.3 ppm. IR (film on NaCl): ν = 3055, 2985, 2928,
˜
1743, 1419, 1203, 1141, 1111, 1080, 1045, 895 cm–1. HRMS (ESI+):
m/z [M + H]+ calcd. for C13H19O4 239.1283; found 239.1284.
Ethyl
(–)-(3R,4aS,4bR,7R,8R,8aR,10aR)-3,7-Dimethyl-9-oxo-
1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8-carb-
oxylate (47a) and Ethyl (+)-(3R,4aS,4bS,7S,8R,8aR,10aR)-3,7-Di-
methyl-9-oxo-1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-trioxaphenan-
Isomer 49a: [α]2D5 = +88 (c = 1, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 5.81 (m, 1 H, CH=CH2), 5.49 (m, 1 H, 6-H), 5.01 (m,
1 H, CH=CH2), 4.97 (m, 1 H, CH=CH2), 4.74 (q, J = 5.0 Hz, 1
H, 3-H), 4.26 (dd, J = 10.8, 5.1 Hz, 1 H, 1-H), 4.14 (m, 4 H, 10a-
H and CH2CH3), 3.55 (m, 2 H, 1-H and 8a-H), 3.38 (m, 2 H, 7-H
and 4a-H), 3.19 (ЈtЈ, J = 5.3 Hz, 1 H, 8-H), 2.83 (ЈtЈ, J = 9.4 Hz, 1
H, 4b-H), 1.82 (s, 3 H, 5-Me), 1.36 (d, J = 5.1 Hz, 3 H, 3-Me), 1.24
(t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 172.8, 170.7, 139.6, 134.0, 123.8, 115.4, 99.5, 78.8, 69.5, 67.9,
threne-8-carboxylate (47b):
A solution of triene 34 (5.6 g,
18.1 mmol) in anhydrous toluene (180 mL) was heated in a sealed
tube at 220 °C in the presence of BHT (800 mg, 1.81 mmol) for 5 d.
The mixture was concentrated under reduced pressure and purified
by flash chromatography (cyclohexane/ethyl acetate, 9:1Ǟ7:3) to
provide isomer 47a (3.26 g, 66%) as a colorless resin and isomer
47b (1.03 g, 21%) as a crystallizable resin.
Isomer 47a: [α]2D5 = –94 (c = 1, CH3OH). 1H NMR (300 MHz,
CDCl3): δ = 5.80 (m, 1 H, 5-H), 5.66 (m, 1 H, 6-H), 4.75 (q, J =
5.1 Hz, 1 H, 3-H), 4.33 (dd, J = 10.5, 5.3 Hz, 1 H, 1-H), 4.23 (m,
3 H, 10a-H and CH2CH3), 3.56 (dd, J = 10.5, 10.0 Hz, 1 H, 1-H),
3.43 (dd, J = 10.1, 3.4 Hz, 1 H, 8a-H), 3.29 (dd, J = 5.4, 3.4 Hz, 1
H, 8-H), 3.23 (ЈtЈ, J = 9.2 Hz, 1 H, 4a-H), 3.10 (m, 1 H, 4b-H),
2.73 (m, 1 H, 7-H), 1.39 (d, J = 5.1 Hz, 3 H, 3-Me), 1.27 (t, J =
7.2 Hz, 3 H, CH2CH3), 1.12 (d, J = 7.5 Hz, 3 H, 7-Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 172.3, 171.7, 131.3, 125.6, 99.9, 79.8,
68.0, 67.7, 60.7, 43.6, 38.3, 35.0, 28.1, 20.4, 17.9, 14.4 ppm. IR
61.1, 44.5, 41.0, 39.1, 38.8, 22.8, 20.3, 14.1 ppm. IR (KBr): ν =
˜
2978, 2939, 2920, 2870, 1735, 1635, 1446, 1411, 1373, 1265, 1234,
1184, 1165, 1134, 1118, 1091, 1045, 918, 898, 848 cm–1. HRMS
(ESI+): m/z [M + H+] calcd. for C18H25O6 337.1645; found
337.1659.
Ethyl
(–)-(3R,4aS,4bR,7R,8R,8aR,9R,10aR)-3,7-Dimethyl-9-hy-
droxy-1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8-
carboxylate (50): A solution of l-Selectride (1 m in THF, 270 μL,
0.27 mmol) was added at –78 °C to a solution of the cycloadduct
47a (76 mg, 0.25 mmol) in THF (2.7 mL). After 30 min, the reac-
tion was neutralized with a saturated solution of NH4Cl (1.5 mL)
and the mixture was extracted with diethyl ether (2ϫ 4 mL). The
organic extract was washed with brine (1.5 mL), dried with magne-
sium sulfate, filtered and concentrated to dryness. Purification by
silica gel chromatography (cyclohexane/ethyl acetate, 9:1Ǟ7:3) af-
forded compound 50 (76 mg, quantitative yield) as a colorless solid,
(KBr): ν = 2978, 2928, 2852, 1751, 1732, 1184, 1072 cm–1. HRMS
˜
(ESI+): m/z [M + Na+] calcd. for C16H22O6Na 333.1314; found
333.1311.
Isomer 47b: M.p. 72–74 °C; [α]2D5 = +79.4 (c = 1.1, CH3OH). 1H
NMR (400 MHz, CDCl3): δ = 5.90 (m, 1 H, 5-H), 5.60 (m, 1 H,
6-H), 4.78 (q, J = 5.1 Hz, 1 H, 3-H), 4.32 (dd, J = 10.3, 4.6 Hz, 1
H, 1-H), 4.23 (m, 4 H, 10a-H and CH2CH3), 3.83 (ЈtЈ, J = 10.2 Hz,
1 H, 4a-H), 3.68 (ЈtЈ, J = 10.0 Hz, 1 H, 1-H), 3.16 (ЈtЈ, J = 11.3 Hz,
1 H, 8a-H), 2.86 (m, 1 H, 4b-H), 2.53 (m, 1 H, 7-H), 2.42 (ЈtЈ, J =
10.6 Hz, 1 H, 8-H), 1.39 (d, J = 5.1 Hz, 3 H, 3-Me), 1.30 (t, J =
7.2 Hz, 3 H, CH2CH3), 1.15 (d, J = 6.9 Hz, 3 H, 7-Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 174.1, 172.0, 133.0, 121.9, 100.6, 77.4,
69.7, 68.3, 60.9, 48.6, 41.8, 35.7, 35.3, 20.2, 19.6, 14.2 ppm. IR
which was crystallized from cyclohexane; m.p. 147–148 °C; [α]2D5
=
–178 (c = 1.08, MeOH). 1H NMR (300 MHz, CDCl3): δ = 5.86
(dd, J = 10.0, 5.0 Hz, 1 H, 5-H), 5.71 (dd, J = 10.0, 4.7 Hz, 1 H,
6-H), 5.25 (s, 1 H, 9-H), 4.67 (q, J = 5.0 Hz, 1 H, 3-H), 4.13 (m, 2
H, CH2CH3), 4.00 (m, 2 H, 10a-H and 1-H), 3.43 (m, 1 H, 1-H),
3.21 (dd, J = 10.9, 8.9 Hz, 1 H, 8-H), 2.94 (dd, J = 13.3, 6.0 Hz, 1
H, 4a-H), 2.70 (m, 2 H, 7-H and 8a-H), 2.37 (dd, J = 13.3, 5.6 Hz,
1 H, 4b-H), 1.32 (d, J = 5.0 Hz, 3 H, 3-Me), 1.26 (t, J = 7.1 Hz, 3
H, CH2CH3), 1.88 (d, J = 7.1 Hz, 3 H, 7-Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 173.6, 131.9, 125.7, 100.0, 93.3, 80.8, 60.5,
(KBr): ν = 2993, 2870, 1759, 1728, 1180, 1149 cm–1. HRMS (ESI+):
˜
m/z [M + H+] calcd. for C16H23O6 311.1489; found 311.1486.
Ethyl (+)-(3R,4aS,4bR,7S,8R,8aR,10aR)-3-Methyl-7-vinyl-9-oxo-
1,4a,4b,7,8,8a,9,10a-octahydro-2,4,10-trioxaphenanthrene-8-carb-
oxylate (48a): A solution of substrate 36 (200 mg, 0.62 mmol) in
anhyrous toluene (6 mL) was heated in a sealed tube at 200 °C in
the presence of BHT (28 mg, 0.12 mmol) for 1.3 h. The mixture
was concentrated under reduced pressure and purified by flash
chromatography (cyclohexane/ethyl acetate, 9:1Ǟ8:2) to provide
isomer 48a (76 mg, 38%) as a colorless resin, which was crystallized
68.9, 60.5, 41.9, 35.6, 33.5, 32.0, 20.4, 17.0, 14.2 ppm. IR (KBr): ν
˜
= 3366, 2970, 2918, 2886, 2860, 1720, 1467, 1389, 1375, 1309, 1282,
1123, 1101, 1087, 1057, 1028, 986, 950, 905 cm–1. HRMS (ESI+):
m/z [M + Na+] calcd. for C16H24O6Na 335.1471; found 335.1468.
(1S,3aR,4R,5R,7aR,1ЈR)-1-(1Ј,2Ј-Dihydroxyethyl)-5-methyl-3-oxo-
1,3,3a,4,5,7a-hexahydroisobenzofuran-4-carboxylate Ethyl Ester
from cyclohexane; m.p. 78–79 °C; [α]2D5 = +33 (c = 2, CHCl3). H
1
NMR (300 MHz, CDCl3): δ = 5.90 (m, 1 H, 5-H), 5.79 (m, 2 H, (51): Cycloadduct 47a (3 g, 9.7 mmol) was dissolved in a solution
2798
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2789–2800

Synthesis of Naturally Occurring Cyclohexene Rings
Trost, I. Fleming), Pergamon, Oxford, UK, 1991, pp. 513–550.
For a sample of some well-known total syntheses featuring a
Diels–Alder reaction, see: a) For cortisone and cholesterol, see:
R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler, W. M.
McLamore, J. Am. Chem. Soc. 1952, 74, 4223–4251; b) for res-
erpine, see: R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey,
R. W. Kierstead, Tetrahedron 1958, 2, 1–57; c) for anthracy-
clines, see: A. S. Kende, Y. G. Tsay, J. E. Mills, J. Am. Chem.
Soc. 1976, 98, 1967–1969; d) for anthracyclines, see: W. W. Lee,
A. P. Martinez, T. H. Smith, D. W. Henry, J. Org. Chem. 1976,
41, 2296–2303; e) for dynemicin A: M. D. Shair, T. Y. Yoon,
K. K. Mosny, T. C. Chou, S. J. Danishevsky, J. Am. Chem. Soc.
1996, 118, 9509–9525; f) for FR182877, see: C. D. Vanderwal,
D. A. Vosburg, S. Weiler, E. J. Sorensen, J. Am. Chem. Soc.
2003, 125, 5393–5407.
a) K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. Vassilikogi-
annakis, Angew. Chem. Int. Ed. 2002, 41, 1668–1698; b) K.
Takao, R. Munakata, K. Tadano, Chem. Rev. 2005, 105, 4779–
4807; c) M. Juhl, D. Tanner, Chem. Soc. Rev. 2009, 38, 2983–
2992; d) J. Poulin, C. M. Grisé-Bard, L. Barriault, Chem. Soc.
Rev. 2009, 38, 3092–3101.
of TFA (50 mL) and H2O (50 mL) and the mixture was heated at
80 °C for 30 min. The mixture was then poured into a vigorously
stirred saturated solution of NaHCO3 and extracted with CH2Cl2
(3ϫ40 mL). The organic extract was dried with magnesium sulfate,
filtered and concentrated to dryness. Purification by silica gel
chromatography (dichloromethane/methanol, 99:1Ǟ95:5) afforded
51 (1.83 g, 67%) and acetal 52 (520 mg, 17%, 3:1 diastereomeric
mixture) as colorless resins. The α isomer 52 crystallized from cy-
clohexane.
[3]
Compound 51: [α]2D5 = –35.7 (c = 0.08, MeOH). 1H NMR
(300 MHz, CDCl3): δ = 5.9 (m, 1 H, 7-H), 5.71 (m, 1 H, 6-H), 4.42
(dd, J = 9.7, 6.3 Hz, 1 H, 1-H), 4.16 (m, 2 H, CH2CH3), 3.92 (m,
1 H, 2Ј-H), 3.80 (m, 2 H, 1Ј-H and 2Ј-H), 3.51 (m, 1 H, 7a-H),
3.23 (dd, J = 5.8, 2.1 Hz, 1 H, 4-H), 3.16 (dd, J = 7.6, 2.6 Hz, 1
H, 3a-H), 2.53 (m, 1 H, 5-H), 1.92 (br. s, 2 H, OH), 1.26 (t, J =
7.1 Hz, 3 H, CH2CH3), 1.12 (d, J = 7.5 Hz, 3 H, 5-Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 176.3, 172.0, 134.8, 121.9, 80.0, 69.6,
[4]
63.9, 60.6, 42.4, 42.1, 36.2, 27.9, 18.2, 14.2 ppm. IR (KBr): ν =
˜
3412, 3034, 2963, 2935, 2937, 2880, 1775, 1466, 1377, 1180, 1129,
1099, 1065, 1026, 1008. HRMS (ESI+): m/z [M + H+] calcd. for
C14H21O6 285.1332; found 285.1326.
[5]
[6]
[7]
[8]
J. G. Buta, J. L. Flippen, W. R. Lusby, J. Org. Chem. 1978, 43,
1002–1003.
H. He, H. Y. Yang, R. Bigelis, E. G. H. Solum, M. Greenstein,
G. T. Carter, Tetrahedron Lett. 2002, 43, 1633–1636.
Compound α-52: M.p. 96–97 °C; [α]2D5 = –68.3 (c = 1.09, MeOH).
1H NMR (300 MHz, CDCl3): δ = 5.85 (dt, J = 10.5, 2.8 Hz, 1 H,
7-H), 5.68 (m, 1 H, 6-H), 5.02 (q, J = 4.7 Hz, 1 H, CHCH3), 4.29
(dd, J = 8.9, 5.9 Hz, 1 H, 1-H), 4.10 (m, 4 H, CH3CH2, 2Ј-H and
1Ј-H), 3.94 (m, 1 H, 2Ј-H), 3.45 (m, 1 H, 7a-H), 3.20 (dd, J = 6.3,
2.7 Hz, 1 H, 4-H), 3.16 (dd, J = 7.5, 2.7 Hz, 1 H, 3a-H), 2.50 (m,
1 H, 5-H), 1.38 (d, J = 4.7 Hz, 3 H, CHCH3), 1.26 (t, J = 7.2 Hz,
3 H, CH3CH2), 1.10 (d, J = 7.5 Hz, 3 H, 5-Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 176.0, 171.9, 134.6, 122.0, 102.3, 81.7, 73.6,
M. Isaka, N. Rugseree, P. Maithip, P. Kongsaeree, S. Prabpai,
Y. Thebtaranonth, Tetrahedron 2005, 61, 5577–5583.
a) S. M. Martin, S. A. Williamson, R. P. Gist, K. M. Smith, J.
Org. Chem. 1983, 48, 5170–5180; b) T.-C. Wu, K. N. Houk,
Tetrahedron Lett. 1985, 26, 2293–2296; c) R. Zschiesche, E. L.
Grimm, H.-U. Reissig, Angew. Chem. Int. Ed. Engl. 1986, 25,
1086–1087; d) R. Zschiesche, B. Frey, E. Grimm, H.-U. Reissig,
Chem. Ber. 1990, 123, 363–374; e) D. A. Evans, D. H.
Brown Ripin, J. S. Johnson, E. A. Shaughnessy, Angew. Chem.
Int. Ed. Engl. 1997, 36, 2119–2121; f) P. Kim, M. H. Nantz,
M. J. Kurth, M. M. Olmstead, Org. Lett. 2000, 2, 1831–1834;
g) M. E. Jung, A. Huang, T. W. Johnson, Org. Lett. 2000, 2,
1835–1837; h) J. Wang, R. P. Hsung, S. K. Ghosh, Org. Lett.
2004, 6, 1939–1942; i) E. L. Pearson, L. C. H. Kwan, C. I.
Turner, G. A. Jones, A. C. Willis, M. N. Paddon-Row, M. S.
Sherburn, J. Org. Chem. 2006, 71, 6099–6109; j) H. Yanai, H.
Ogura, T. Taguchi, Org. Biomol. Chem. 2009, 7, 3657–3659; k)
E. L. Pearson, N. Kanizaj, A. C. Willis, M. N. Paddon-Row,
M. S. Sherburn, Chem. Eur. J. 2010, 16, 8280–8284.
M. Fengler-Veith, O. Schwardt, U. Kautz, B. Krämer, V. Jäger,
Org. Synth. 2002, 78; M. Fengler-Veith, O. Schwardt, U. Kautz,
B. Krämer, V. Jäger, Org. Synth., Coll. Vol. 2004, 10, 405.
a) A. Mukhopadhyay, S. M. Ali, M. Husain, S. N. Suryawan-
shi, D. S. Bhakuni, Tetrahedron Lett. 1989, 30, 1853–1856; b)
D. S. Bakhuni, Pure Appl. Chem. 1990, 62, 1389–1392.
Carbohydrate-derived Diels–Alder partners have often been
used in organic synthesis, see for instance: a) R. W. Franck,
T. V. John, J. Org. Chem. 1983, 48, 3269–3276; b) M. A. Rah-
man, B. Fraser-Reid, J. Am. Chem. Soc. 1985, 107, 5576–5578;
c) R. M. Giuliano, J. H. Buzby, N. Marcopulos, J. Org. Chem.
1990, 55, 3555–3562; d) M. J. Lilly, M. S. Sherburn, Chem.
Commun. 1997, 967–968.
68.6, 60.5, 42.3, 42.0, 36.2, 27.8, 19.9, 18.2, 14.2 ppm. IR (KBr): ν
˜
= 3036, 2990, 2976, 2933, 2910, 2877, 1767, 1728, 1418, 1373, 1335,
1242, 1179, 1151, 1130, 1117, 1088, 1036, 1022, 999, 962, 869 cm–1.
HRMS (ESI+): m/z [M + H+] calcd. for C16H23O6 311.1489; found
311.1486.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for the synthesis of molecules 5–37, X-
1
ray data for 47b, 50, α-52, and copies of H and 13C NMR spectra
for all compounds.
[9]
Acknowledgments
[10]
[11]
This work and the PhD grant for H. A. were funded by the French
Agence Nationale de la Recherche (grant number ANR-09-JCJC-
0085-01), which is gratefully acknowledged. We also thank the Cen-
tre National de la Recherche Scientifique-Institut Ecologie et Envi-
ronnement (CNRS-INEE) for financial support. The French Min-
istère de la Recherche is acknowledged for providing a PhD grant
to L. E.
[12]
[13]
[14]
[15]
L. Evanno, A. Deville, L. Dubost, A. Chiaroni, B. Bodo, B.
Nay, Tetrahedron Lett. 2007, 48, 2893–2996.
M. J. Alves, V. C. M. Duarte, H. Faustino, A. G. Fortes, Tetra-
hedron: Asymmetry 2010, 21, 1817–1820.
S. Yamazaki, H. Kumagai, T. Takada, S. Yamabe, J. Org.
[1] For the seminal publication on the Diels–Alder reaction, see:
O. Diels, K. Alder, Justus Liebigs Ann. Chem. 1928, 460, 98–
122.
[2] For leading reviews on IMDA reactions, see: a) G. Brieger, J. N.
Bennet, Chem. Rev. 1980, 80, 63–97; b) A. G. Fallis, Can. J.
Chem. 1984, 62, 183–234; c) E. Ciganek, Org. React. 1984, 32,
1–374; d) D. Craig, Chem. Soc. Rev. 1987, 16, 187–238; e) W. R.
Roush, in: Advances in cycloaddition, vol. 2 (Ed.: D. P. Curran),
JAI Press, Greenwich, 1990, pp. 91–146; f) W. Oppolzer, in:
Comprehensive Organic Synthesis, vol. 5 (Eds.: B. M. Trost, I.
Fleming), Pergamon, Oxford, UK, 1991, pp. 315–399; g) W. R.
Roush, in: Comprehensive Organic Synthesis, vol. 5 (Eds.: B. M.
Chem. 1997, 62, 2968–2974.
The stereochemistry of cycloadducts 38a and 38b was deter-
mined by NOESY experiments, which unambiguously showed
transannular H–H correlations in the lactone ring. This was
confirmed later by X-ray structure analysis of analogous deriv-
atives 47a and 47b.
For some examples of Diels–Alder reactions involving Z-
dienes, see: a) H. O. House, T. H. Cronin, J. Org. Chem. 1965,
[16]
Eur. J. Org. Chem. 2011, 2789–2800
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2799

B. Nay et al.
FULL PAPER
30, 1061–1070; b) R. F. Borch, A. J. Evans, J. J. Wade, J. Am.
Chem. Soc. 1975, 97, 6282–6284; c) S. G. Pyne, M. J. Hensel,
S. R. Byrn, A. T. McKenzie, P. L. Fuchs, J. Am. Chem. Soc.
1980, 102, 5962–5964; d) R. K. Boeckman Jr, T. R. Alessi, J.
Am. Chem. Soc. 1982, 104, 3216–3217; e) S. G. Pyne, M. J.
Hensel, P. L. Fuchs, J. Am. Chem. Soc. 1982, 104, 5719–5728;
f) M. Yoshioka, H. Hakai, M. Ohno, J. Am. Chem. Soc. 1984,
106, 1133–1135; g) S. Wattanasin, F. G. Kathawala, R. K.
Boeckman Jr, J. Org. Chem. 1985, 50, 3810–3815; h) R. Mu-
nakata, T. Ueki, H. Katakai, K. Takao, K. Tadano, Org. Lett.
2001, 3, 3029–3032; i) T. J. Heckrodt, J. Mulzer, J. Am. Chem.
Soc. 2003, 125, 4680–4681; j) T. A. Dineen, W. R. Roush, Org.
Lett. 2003, 5, 4725–4728; k) T. A. Dineen, W. R. Roush, Org.
Lett. 2004, 6, 2043–2046; l) R. Munakata, H. Katakai, T. Ueki,
J. Kurosaka, K. Takao, K. Tadano, J. Am. Chem. Soc. 2004,
126, 11254–11267.
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
The absolute stereochemistry of pyrrocidines has not yet been
demonstrated.
[19]
[20]
H. Oikawa, J. Org. Chem. 2003, 68, 3552–3557.
[21] a) For a study on the total synthesis of GKK1032 compounds
involving an IMDA reaction, see: M. Asano, M. Inoue, T. Ka-
toh, Synlett 2005, 1539–1542; b) For a study on the total syn-
thesis of hirsutellones involving an IMDA reaction, see: S. D.
Tilley, K. P. Reber, E. J. Sorensen, Org. Lett. 2009, 11, 701–703.
[22] Typically, a [1,5]-sigmatropic hydrogen shift from 1,3-pentadi-
enes is expected to occur at 250–300 °C, see: a) W. R. Roth, J.
König, Justus Liebigs Ann. Chem. 1966, 699, 24–32; b) W. R.
Roth, J. König, Justus Liebigs Ann. Chem. 1966, 699, 24–32;
W. R. Roth, J. König, K. Stein, Chem. Ber. 1970, 103, 426–439.
Received: December 14, 2010
[17] L. Evanno, A. Jossang, J. Nguyen-Pouplin, D. Delaroche, M.
Seuleiman, B. Bodo, B. Nay, Planta Medica 2008, 870–872.
[18] CCDC-631622 (for 47b), -631623 (for 50), and -631621 (for α-
52) contain the supplementary crystallographic data for this
Published Online: March 11, 2011
2800
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2789–2800