A short asymmetric synthesis of octahydroindole derivatives by application of catalytic C(sp3)-H amination reaction

Article abstract of DOI:10.1002/ejoc.201301174

The stereoselective synthesis of octahydroindole derivatives is reported according to 3-4-step sequences. The strategy relies on our previously developed catalytic asymmetric C(sp³)-H amination reaction. Its application to cyclic enol triflates affords allylic amines in good yields and stereoselectivity. The C-H functionalization step, then, is followed by a Heck coupling reaction, a Mitsunobu reaction and a final intramolecular cycloaddition reaction thereby leading to the isolation of the expected heterocyclic compounds with an overall yield of up to 69 %. In addition, the chirality introduced in the intermolecular C(sp³)-H amination reaction allows controlling the configuration of the three other stereocenters created in the intramolecular cycloaddition reaction. A second sequence starts from benzocyclobutene and affords fused benzo-octahydroindole derivatives over three steps. The short stereoselective synthesis of octahydroindole derivatives is reported. Catalytic asymmetric C(sp³)-H amination reactions and stereoselective intramolecular cycloaddition reactions are the key steps of the strategy that affords an efficient versatile access to molecular diversity. Copyright

Full text of DOI:10.1002/ejoc.201301174

FULL PAPER
DOI: 10.1002/ejoc.201301174
A Short Asymmetric Synthesis of Octahydroindole Derivatives by Application
of Catalytic C(sp3)–H Amination Reaction
Marie Mazurais,[a] Camille Lescot,[a] Pascal Retailleau,[a] and Philippe Dauban*[a]
Keywords: Synthetic methods / Medicinal chemistry / Nitrogen heterocycles / Amination / Diastereoselectivity /
Cycloaddition
The stereoselective synthesis of octahydroindole derivatives
is reported according to 3–4-step sequences. The strategy re-
lies on our previously developed catalytic asymmetric
C(sp3)–H amination reaction. Its application to cyclic enol tri-
flates affords allylic amines in good yields and stereoselec-
tivity. The C–H functionalization step, then, is followed by a
Heck coupling reaction, a Mitsunobu reaction and a final
intramolecular cycloaddition reaction thereby leading to the
isolation of the expected heterocyclic compounds with an
overall yield of up to 69%. In addition, the chirality intro-
duced in the intermolecular C(sp3)–H amination reaction al-
lows controlling the configuration of the three other
stereocenters created in the intramolecular cycloaddition re-
action. A second sequence starts from benzocyclobutene and
affords fused benzo-octahydroindole derivatives over three
steps.
lycorine, pancracine, and mesembrine that belong to the
families of Amaryllidaceae and Sceletium alkaloids,[7] as
well as aeruginosins of marine origin (Figure 1).[8] The mo-
tif is also present in the angiotensin-converting-enzyme
(ACE) inhibitor Perindorpil® that has been approved for
the treatment of hypertension.[9] These compounds illus-
trate the capacity to access new bioactive compounds by
derivatization of polyhydroindole scaffolds.
Introduction
Classical medicinal chemistry mainly relies on the cou-
pling and functionalization of aromatic compounds, as mir-
rored by the structure of the 33 new molecular entities ap-
proved by the US Food and Drug Administration in 2012.[1]
Recent trends in medicinal chemistry, however, encourage
medicinal chemists to “escape from flatland”[2] and explore
a new chemical space with the preparation of complex satu-
rated molecules. In addition to providing new molecular
scaffolds with improved chances of patentability, it has been
recently proposed that molecular topology has a long ne-
glected influence on the pharmacokinetics of bioactive
compounds. Reducing the aromatic character of a molecule
as well as the introduction of chiral centers are likely to
improve these properties.[3] The search for efficient stereose-
lective methodology giving a rapid access to a collection of
natural product-like molecules, thus, should offer invaluable
opportunities as emphasized in the reviews on diversity-ori-
ented synthesis.[4]
Indole is one of the most investigated privileged scaf-
folds.[5] It has been the purpose of many methodological
developments because of its ubiquity in nature and medici-
nal chemistry.[6] The saturated hydroindole analogs are no
less important and are receiving increasing attention. These
heterocycles are found in several natural products such as
[a] Institut de Chimie des Substances Naturelles, UPR 2301
CNRS, Centre de Recherche de Gif-sur-Yvette,
Avenue de la Terrasse, Bât. 27, 91198 Gif-sur-Yvette Cedex,
France
Figure 1. Naturally occurring polyhydroindole derivatives.
E-mail: philippe.dauban@cnrs.fr
http://www.icsn.cnrs-gif.fr/spip.php?article667
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301174.
The growing importance of perhydroindole analogs has
driven the design of stereoselective methods for their prepa-
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A Short Asymmetric Synthesis of Octahydroindole Derivatives
ration. These rely, for example, on catalytic hydrogenation proved by carrying out the reaction in the presence of
of indolic substrates,[10] stereospecific reactions from tyr- 3 equiv. of triflates 3. This allowed isolating compounds 4
osine derivatives,[11] cycloaddition,[12] or palladium-cata- and 5 in 84% and 92% yields, respectively. Moreover, we
lyzed allylic alkylation.[13] It was with the aim to develop have found that C–H aminated product 5 could be obtained
an alternative rapid access to the octahydroindole scaffold with a higher diatereomeric ratio of Ͼ 20:1 after recrystalli-
that we have envisaged the application of catalytic C–H zation in diisopropyl ether. Seven-membered product 6 was
functionalization reactions. This new class of transforma- isolated with a low yield of 18% and a dr of 2:1, which were
tion has received considerable attention in the last dec- not optimized.[22]
ade.[14] Several natural product and drug syntheses,[15] such
as, the recent application of C(sp3)–H alkenylation reaction
to the preparation of hexahydroindoles,[15h] highlight the
opportunities offered by the selective functionalization of
C(sp3)–H bonds. We therefore wish to report that the appli-
cation of catalytic intermolecular C(sp3)–H amination pro-
vides an efficient stereoselective route to chiral octahydro-
indole scaffolds. Short sequences involving Heck couplings,
Mitsunobu reactions and intramolecular [4+2] cycload-
dition reactions, then, lead to the sequential introduction
of structural elements that could be further derivatized to
create libraries for biological screening. In addition, the chi-
rality introduced in the C–H functionalization step gen-
erally allows control of the configuration of the other
stereogenic centers in the final octahydroindole products.
Results and Discussion
Scheme 1. Catalytic stereoselective C–H amination reaction of
vinyl triflates 3.
Catalytic C(sp3)–H and C(sp2)–H amination has been ex-
tensively investigated in the last decade.[16] The most spec-
Aminated triflates 4 and 5 were then engaged in a Heck
tacular results, to date, have been obtained with the applica- coupling reaction with various alkenes. Optimization of the
tion of oxidative conditions for the formation of metall- reaction conditions were carried out with six-membered de-
anitrenes and their subsequent insertion into different rivative 5 in the presence of methyl acrylate as the coupling
C(sp3)–H bonds. Several metal complexes have been shown partner. The screening of either the solvent or the catalyst
to catalyze efficiently the overall process with dinuclear rho- led us to find that use of Pd(dppf)Cl2 in dimethylformamide
dium(II) species remaining the catalyst of choice to this (DMF) affords the best conversion, the corresponding
end.[17–19] In this domain, our group has demonstrated that product 7a being isolated in 90% yield after 12 h of reaction
highly stereo- and chemoselective C(sp3)–H amination can (Scheme 2).[23] These conditions allowed us to introduce ef-
be performed in very good yields by using a chiral nitrene ficiently various alkenes with different electron-withdrawing
generated from the combination of the (S)-sulfonimidamide groups such as an ester, a ketone, a nitrile or a sulfone.
1 and the chiral rhodium(II) complex Rh2(S-nta)4 2.[20] The However, the introduction of a styrenyl unit required the
reaction particularly applies to benzylic and allylic methyl- use of Pd(PPh3)2Cl2.[24] This was also necessary in the case
ene sites as well as to the tertiary C(sp3)–H bonds of simple of the five-membered derivative 4 that was converted into
alkanes. The scope has recently been extended to more the corresponding product 8 with a lower yield of 42%.
functionalized substrates such as terpenes and enol carbon-
With dienes 7 and 8 in hand, we then investigated the
ates.[20d] The rapid stereoselective access to perhydroindole introduction of an alkenyl side chain with the aim to per-
derivatives, as a first application of this method, capitalizes form the subsequent intramolecular Diels–Alder cycload-
on these results.
dition reaction. Surprisingly, the alkylation of the sulfon-
The first route relies on vinyl triflates which have been imidamides with simple allyl halides did not afford the ex-
previously shown to be relevant substrates for this reaction pected tertiary derivatives thereby confirming the non-clas-
in a single example.[20d] Catalytic asymmetric C–H amin- sical behavior of the terminal nitrogen of these functional
ation reaction of cyclic triflates 3, that were prepared from groups. We thus took inspiration from a previous study of
corresponding ketones under standard conditions,[21] leads Fensterbank, Lacôte, and Malacria that describes the func-
to the expected products with various results according to tionalization of primary sulfonimidamides through a Mit-
the ring size (Scheme 1). The reaction with cyclopentenyl sunobu reaction.[25] Application of the reported conditions
derivative 3a used as the limiting agent gave the best dia- with allyl alcohol, however, led to the corresponding prod-
stereomeric ratio of 17:1, whereas the highest yield was ob- uct always being contaminated by traces of diisopropyl azo-
tained starting from cyclohexenyl analog 3b. It should be dicarboxylate (DIAD). Accordingly, replacement of the lat-
mentioned that, in both cases, the conversion could be im- ter by its tert-butyl analog combined with the use of PPh3
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67

M. Mazurais, C. Lescot, P. Retailleau, P. Dauban
FULL PAPER
The intramolecular Diels–Alder reaction,[26] pleasingly,
has been found to proceed smoothly in toluene heated to
reflux for 12h (Scheme 4). The corresponding cycloadduct
11a is isolated from compound 9a as a single stereoisomer
after flash chromatography on SiO2. The product is sup-
Scheme 2. Heck coupling reactions with aminated vinyl triflates 4
and 5.
allowed ready access to tertiary allyl sulfonimidamides after
an acidic treatment, with yields generally in the 62–83%
range (Scheme 3). These conditions also revealed appropri-
ate for the allylation of the five-membered analog 8 as well
as for the introduction of a methallyl, a propargyl, and a
but-3-en-1-yl side chain on compound 7a. Unexpectedly,
the application of these conditions did not allow the intro-
duction of a but-2-en-1-yl and a but-3-yn-1-yl side chain.
Scheme 4. Intramolecular Diels–Alder reaction.
Scheme 3. Mitsunobu reaction for introduction of unsaturated side chains.
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A Short Asymmetric Synthesis of Octahydroindole Derivatives
posed to arise from an exo-transition state.[27,28] Applica-
tion of the reaction conditions to 9b–9f has then allowed
isolating the expected tricyclic compounds 11b–11f with
yields in the 54–79% range.[28] However, while the more
substituted methallyl substrate 9g did not undergo cycliza-
tion, propargyl analog 9h gave a diene that spontaneously
aromatized to afford benzofused product 11h in 62% yield.
It was also possible to form efficiently higher or lower
analogs of octahydroindole derivatives starting from,
respectively, but-2-en-1-yl substrate 9i and cyclopentenyl
motif 10. However, in the latter case, corresponding
cycloadduct 12 has been isolated with a diastereomeric ratio
of 7:1. Such erosion of diastereoselectivity appears to result
from the epimerization of the stereocenter prior to the
cycloaddition reaction because heating resulting cycload-
duct 12 in toluene for several hours does not change the dr.
More interestingly, during attempts to introduce an acryloyl
side chain final onto compound 7a prior to the intramolec-
ular cycloaddition, we were very pleased to observe the
Scheme 5. Formation of compound 13 from 7a.
clean one-pot formation of cycloadduct 13 at room tem- H amination of benzylic substrates. We had previously dem-
perature. This was isolated as a diastereoisomerically pure onstrated that indane and tetrahydronaphthalene can be ef-
crystalline solid in 77% yield, and the X-ray crystal struc- ficiently converted under these conditions to the corre-
ture leads us to secure the formerly supposed absolute sponding benzylic amines with excellent yields and dia-
stereochemistry of the octahydroindole derivatives stereoselectivities.[20] Application of the reaction to benzo-
(Scheme 5).
cyclobutene was envisaged because the latter is a useful pre-
These results obtained for the stereoselective formation cursor to perform intramolecular [4+2] cycloaddition reac-
of octahydroindole analogues prompted us to design a sec- tions.[29,30] However, contrary to the sequence designed
ond straightforward strategy based on the catalytic C(sp3)– from vinyl triflates, we recognized that the stereochemical
Scheme 6. Synthesis of perhydroindole derivatives from benzocyclobutene.
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69

M. Mazurais, C. Lescot, P. Retailleau, P. Dauban
FULL PAPER
information introduced in the C(sp3)–H amination step Work is now in progress to produce chemical libraries of
should be lost after the thermally-induced benzocyclobut- nitrogen-containing molecules by application of the cata-
ene ring opening. Nevertheless, it was conjectured that the lytic selective C(sp3)–H amination reaction.[33]
remaining stereochemistry on the sulfur center could secure
good diastereocontrol in the cycloaddition reaction.
Catalytic C(sp3)–H amination reaction of benzocyclobut-
ene was found to proceed efficiently on a millimolar scale
to afford expected aminated product 14 with a yield of 82%
and a dr of 16:1, thereby confirming that secondary benz-
ylic positions are highly reactive towards nitrene insertion
(Scheme 6). The precursors of the intramolecular [4+2]
cycloaddition reaction, then, were directly obtained
through application of the previous condition reactions re-
ported in Scheme 3 for the Mitsunobu reaction, or by sim-
ple acylation in the case of 15a. Various alkenyl side chains
likely to react with the in situ generated ortho-quinodi-
methane, were thus introduced leading to compounds 15a–
15e with yields ranging from 47 to 82%. The last step of
the strategy, finally, occurred with complete conversion in
octane heated to reflux except, not surprisingly, in the case
of vinylacetyl derivative 15a. The 5,6-bicyclic products and
the 6,6 analogs were isolated in yields of up to 96%, and as
cis isomers, as corroborated by the coupling constant of
approximately 8 Hz for the benzylic proton in the 1H NMR
spectra.[30a,30b] Pleasingly, the substitution on the alkene
unit was tolerated as 15c could be converted into corre-
sponding cycloadduct 16c, contrary to the case of com-
pound 9g. However, the results in terms of diastereoselec-
tivity proved to be below our expectations, as the chirality
transfer did not proceed efficiently. Screening of the condi-
tions in the case of compound 16e revealed that the best dr
of 3:1, obtained by running the reaction in octane, was
slightly lower (around 2:1) in other solvents such as toluene.
It should be nevertheless mentioned that optically pure
heterocycles are accessible through this sequence as we have
been able to separate the two diastereoisomers of com-
pound 16b by column chromatography over SiO2.
Experimental Section
General Remarks: Melting points were measured in capillary tubes
and recorded with a Büchi B-540 melting point apparatus. Infrared
spectra were recorded with a Perkin–Elmer Spectrum BX FT-IR
spectrometer. Optical rotations were determined with a JASCO P-
1010 polarimeter. Proton (1H) and carbon (13C) NMR spectra were
recorded with Bruker spectrometers: Avance 300 NMR (300 MHz).
Chemical shifts (δ) are reported in parts per million (ppm) relative
to tetramethylsilane (TMS) as internal standard. NMR spectro-
scopic experiments were carried out in deuteriochloroform
(CDCl3). The following abbreviations are used for the proton spec-
tra multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, m: mul-
tiplet. Coupling constants (J) are reported in Hertz (Hz). Mass
spectra were obtained with an LCT (Micromass) instrument by
using electrospray ionization and Time of Flight analyzer (ESI-
MS) for high-resolution mass spectra (HRMS). Thin-layer
chromatography was performed on silica gel 60 plates with a fluor-
escent indicator and visualized under a UVP Mineralight UVGL-
58 lamp (254 nm) and with a solution of ninhydrin in ethanol.
Flash chromatography was performed with silica gel 60 (40–63 μm,
230–400 mesh ASTM) at medium pressure (200 mbar). All solvents
were distilled and stored over 4 Å molecular sieves before use. All
reagents were obtained from commercial suppliers unless otherwise
stated. Organic extracts were, in general, dried with magnesium
sulfate (MgSO4).
Typical C–H Amination Procedure (4–6): In an oven-dried tube
were introduced activated 4 Å molecular sieves (100 mg), Rh2[(S)-
nta]4
2 (7.70 mg, 0.006 mmol) and (–)-N-(p-tolylsulfonyl)-p-
toluenesulfonimidamide (–)-(S)-1 (78.0 mg, 0.240 mmol). The tube
was capped with a rubber septum and purged with argon. Anhy-
drous and degassed 1,1,2,2-tetrachloroethane (0.75 mL) and meth-
anol (0.25 mL) were added under argon, and the mixture was
stirred for 5 min before addition of the substrate (0.200 mmol). The
tube was cooled to –78 °C, and bis(tert-butylcarbonyloxy)iodo-
benzene (115 mg, 0.280 mmol) was added. The mixture was stored
in the freezer (–35 °C) for 3 days. After dilution with dichlorometh-
ane (3 mL), the molecular sieves were removed by filtration and
the filtrate was evaporated to dryness under reduced pressure. The
oily residue was purified by flash chromatography on silica gel,
affording the following C–H amination products.
Conclusions
In conclusion, the catalytic intermolecular C(sp3)–H
amination of cycloalken-1-yl triflates as well as of benzo-
cyclobutene affords chiral amines, which are versatile build-
ing blocks for the stereoselective formation of natural-prod-
uct-like compounds. The octahydroindole derivatives are
produced in only 3 to 4 steps with overall yields of up to
Compound 4: Prepared following the typical amination procedure
from cyclopenten-1-yl trifluoromethanesulfonate 3a. Correspond-
ing amination product was obtained (dichloromethane/ethyl acet-
ate, 20:1) as an orange solid in 62% yield (67.0 mg) and 17:1 dr
(1H NMR evaluation), m.p. 79–80 °C. 1H NMR (300 MHz,
69% and excellent diastereomeric ratios generally CDCl3, 25 °C): diastereoisomer A 17/diastereoisomer B 1 δ = 1.75–
Ͼ 20:1.[31,32] These privileged heterocyclic scaffolds should
be further derivatized following either cleavage of the
1.88 (m, 1 H), 2.20–2.31 (m, 1 H), 2.44–2.50 (m, 1 H), 2.42 (s, 3
H), 2.44 (s, 3 H), 2.57–2.69 (m, 1 H), 4.33–4.44 (m, 1 H), 5.26–5.30
(m, 1 H), 5.53–5.55 (m, 1 H), 5.84–5.88 (m, 1 H), 6.33–6.36 (d, J
double bond, reduction of the ester, keto, or cyano groups,
= 9.1, 1 H, NH), 6.40–6.46 (d, J = 9.1, 1 H NH), 7.24–7.34 (m, 4
or deprotection of the amine.[20] It should be also emphas-
H), 7.80–7.87 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
ized that the use of the enantiomeric matched pair of rea-
diastereoisomer A 17/diastereoisomer B 1 δ = 21.5 (CH3), 21.6
gents, i.e. sulfonimidamide (R)-1 with rhodium complex
(CH3), 29.0 (CH2), 29.7 (CH2), 30.9 (CH2), 55.6 (CH), 116.3 (Cq),
Rh2(R-nta)4, gives access to the other enantiomer of allylic
117.0 (CH), 126.7 (2ϫ CH), 127.7 (2ϫ CH), 129.3 (2ϫ CH), 130.0
(2ϫ CH), 135.6 (Cq), 140.2 (Cq), 143.1 (Cq), 145.1 (Cq), 152.4
amines.[20] The chirality transfer observed during the intra-
molecular cycloaddition reaction gives an opportunity to
(Cq) ppm. IR: ν = 3235, 1667, 1596, 1424, 1299, 1264, 1250, 1204,
˜
isolate the enantiomers of these heterocyclic structures. 1139, 1080, 1090, 1016, 1000, 922, 813, 760, 658 cm–1. HRMS
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A Short Asymmetric Synthesis of Octahydroindole Derivatives
(ESI): calcd. for C20H20F3N2O6S3 [M – H]– 537.0436; found
537.0458.
(2ϫ CH), 134.6 (CH), 136.1 (CH), 136.2 (Cq), 137.7 (Cq), 138.2
(Cq), 140.3 (Cq), 142.8 (Cq), 144.7 (Cq), 146.4 (CH) 146.5 (CH),
167.4 (Cq) ppm. IR: ν = 2945, 1715, 1631, 1433, 1303, 1284, 1248,
˜
Compound 5: Prepared following the typical amination procedure
from cyclohexen-1-yl trifluoromethanesulfonate 3b. Corresponding
amination product was obtained (heptane/ethyl acetate, 70:30) as a
white solid in 70% yield (77.5 mg) and 5:1 dr (1H NMR evalu-
1124, 1106, 1090, 1062, 1035, 1016, 977, 930, 813, 752, 702,
658 cm–1. HRMS (ESI): calcd. for C24H29N2O5S2 [M + H]+
589.1518; found 589.1539.
1
ation), m.p. 114–115 °C. H NMR (300 MHz, CDCl3, 25 °C): dia-
Compound 7b: To a solution of Pd(dppf)Cl2 (9.20 mg, 13.0 μmol)
stereoisomer A 5/diastereoisomer B 1 δ = 1.35–1.49 (m, 1 H), 1.60–
in dry DMF (0.5 mL) under argon, were introduced a solution of
1.81 (m, 3 H), 2.21–2.33 (m, 2 H), 2.40 (s, 3 H), 2.42 (s, 3 H), 3.94– C–H amination product of cyclohexen-1-yl trifluoromethanesulf-
4.04 (m, 1 H), 5.30–5.35 (m, 1 H), 5.63–5.67 (m, 1 H), 6.01 (d, J
= 8.9 Hz, 1 H), 7.24–7.34 (m, 4 H), 7.74–7.86 (m, 4 H) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): diastereoisomer A 5/diastereoiso-
mer B 1 δ = 19.4, 21.57, 21.63, 27.1, 28.1, 48.7, 118.8, 120.6, 126.7,
126.8, 127.6, 127.7, 129.3, 129.4, 130.0, 130.1, 135.7, 140.2, 143.2,
onate 5 (100 mg, 0.181 mmol) in dry DMF (1.5 mL), tert-butyl ac-
rylate (58.0 μL, 0.398 mmol) and triethylamine (86.0 μL,
0.634 mmol). The reaction mixture was stirred at room temperature
for 12 h. Dichloromethane was added (2 mL) and the organic layer
was washed with a saturated solution of ammonium chloride
145.2, 152.0 ppm. IR: ν = 3208, 2925, 1686, 1597, 1417, 1303, 1210, (2 mL), water (2 mL) and brine (2 mL). After concentration under
˜
1143, 1109, 1061, 1017, 897, 815 cm–1. HRMS (ESI): calcd. for reduced pressure, the residue was purified by flash chromatography
C21H24F3N2O6S3 [M + H]+ 553.0749; found 553.0757. Compound
5 can be recrystallized from diisopropyl oxide affording white need-
les with Ͼ 20:1 dr. [α]2D0 = +93.5 (c = 1.04, CHCl3).
(petroleum ether/ethyl acetate, 70:30) to afford a colorless gum in
85% yield (81 mg). 1H NMR (300 MHz, CDCl3, 25 °C): dia-
stereoisomer A 9/diastereoisomer B 1 δ = 1.36–1.46 (m, 1 H), 1.48
(s, 9 H), 1.49–1.54 (m, 10 H), 1.62–1.75 (m, 2 H), 2.01–2.10 (m, 2
H), 2.41 (s, 3 H), 2.43 (s, 3 H), 3.88–4.01 (m, 1 H), 5.56–5.50 (m,
1 H), 5.75–5.80 (d, J = 15.8 Hz, 1 H), 5.86–5.92 (m, 1 H), 6.19–
6.21 (d, J = 8.8 Hz, NH), 6.97–7.02 (d, J = 15.8 Hz, 1 H), 7.08–
7.13 (d, J = 15.8 Hz, 1 H), 7.17–7.26 (m, 4 H), 7.73–7.79 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): diastereoisomer A 9/
diastereoisomer B 1 δ = 19.5 (CH2), 21.55 (CH3), 21.62 (CH3), 23.6
(CH2), 23.8 (CH2), 28.2 (3ϫ CH3), 29.2 (CH2), 29.7 (CH2), 50.0
(CH), 80.5 (Cq), 120.2 (CH), 126.8 (2ϫ CH), 127.8 (2ϫ CH),
129.3 (2ϫ CH), 129.9 (2ϫ CH), 134.5 (CH), 136.2 (Cq), 138.2
(Cq), 140.3 (Cq), 143.0 (Cq), 144.92 (Cq), 144.93 (CH), 166.2
Compound 6: Prepared following the typical amination procedure
from cyclohepten-1-yl trifluoromethanesulfonate 3c (0.600 mmol,
3 equiv.). Corresponding amination product was obtained (di-
chloromethane/ethyl acetate, 20:1) as an orange oil in 18% yield
1
(20.0 mg) and 2:1 dr (1H NMR evaluation). H NMR (300 MHz,
CDCl3, 25 °C): diastereoisomer A 2/diastereoisomer B 1 δ = 1.45–
1.78 (m, 6 H), 2.34 (s, 3 H), 2.35 (s, 3 H), 2.37–2.44 (m, 2 H), 3.32–
3.44 (m, 1 H), 3.86–3.98 (m, 1 H), 5.31–5.33 (d, J = 4.7 Hz,
1 H), 5.66–5.70 (d, J = 4.7 Hz, 1 H), 6.21–6.26 (d, J = 8.3 Hz, 1
H NH), 6.30–6.32 (d, J = 8.3 Hz, 1 H, NH), 7.14–7.26 (m, 4 H),
7.69–7.80 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): dia-
stereoisomer A 2/diastereoisomer B 1 δ = 21.5 (CH3), 21.6 (CH3),
24.1 (CH2), 24.2 (CH2), 5.0 (CH2), 25.1 (CH2), 30.7 (CH2), 32.6
(CH2), 32.8 (CH2), 33.8 (CH2), 50.2 (CH), 50.4 (CH), 123.8 (Cq),
125.0 (CH), 126.7 (2ϫ CH), 126.7 (2ϫ CH), 127.6 (2ϫ CH),
127.6 (2ϫ CH), 129.3 (2ϫ CH), 129.3 (2ϫ CH), 129.9 (2ϫ CH),
135.6 (Cq), 140.2 (Cq), 143.1 (Cq), 145.1 (Cq), 153.2 (Cq) ppm.
(Cq) ppm. IR: ν = 3587, 2255, 1750, 1640, 1392, 1039, 919 cm–1.
˜
HRMS (ESI): calcd. for C27H33N2O5S2 [M – H]– 529.1831; found
529.1828.
Compound 7c: To a solution of Pd(dppf)Cl2 (9.20 mg, 12.6 μmol)
in dry DMF (0.5 mL) under argon, were introduced a solution of
C–H amination product of cyclohexen-1-yl trifluoromethanesul-
IR: ν = 2927, 1597, 1413, 1303, 1246, 1206, 1107, 1089, 1017, 988, fonate 5 (100 mg, 0.181 mmol) in dry DMF (1.5 mL), but-3-en-2-
˜
869, 813 cm–1. HRMS (ESI): calcd. for C22H26F3N2O6S3 [M + one (34.0 μL, 0.398 mmol) and triethylamine (86.0 μL,
H]+ 567.0905; found 567.0904.
0.634 mmol). The reaction mixture was stirred at room temperature
for 12 h. Dichloromethane was added (2 mL) and the organic layer
was washed with a saturated solution of ammonium chloride
(2 mL), water (2 mL) and brine (2 mL). After concentration under
reduced pressure, the residue was purified by flash chromatography
(petroleum ether/ethyl acetate, 50:50) affording a yellow oil in 89%
yield (76.0 mg). [α]2D0 = +218.3 (c = 1.03, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.35–1.48 (m, 1 H), 1.50–1.61 (m, 1
H), 1.67–1.77 (m, 2 H), 2.08–2.17 (m, 2 H), 2.32 (s, 3 H), 2.43 (s,
3 H), 2.46 (s, 3 H), 3.91–4.03 (m, 1 H), 6.02–6.05 (d, J = 8.8 Hz, 1
H NH), 6.06–6.09 (m, 1 H), 6.10–6.16 (d, J = 16.4 Hz, 1 H), 7.05–
7.10 (d, J = 16.2 Hz, 1 H), 7.25–7.37 (m, 4 H), 7.81–7.87 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 19.6 (CH2), 21.5
(CH3), 21.6 (CH3), 23.5 (CH2), 27.2 (CH3), 29.1 (CH2), 50.1 (CH),
126.7 (2ϫ CH), 127.0 (CH), 127.8 (2ϫ CH), 129.2 (2ϫ CH), 129.9
(2ϫ CH), 136.0 (Cq), 136.5 (CH), 138.3 (Cq), 140.3 (Cq), 142.9
Compound 7a: To a solution of Pd(dppf)Cl2 (32.3 mg, 44.0 μmol)
in dry DMF (15 mL) under argon, were introduced C–H amination
product of cyclohexen-1-yl trifluoromethanesulfonate 5 (347 mg,
0.630 mmol) in dry DMF (6 mL), methyl acrylate (125 μL,
1.38 mmol) and triethylamine (296 μL, 2.20 mmol). The reaction
mixture was stirred at room temperature for 12 h. Dichloromethane
was added (30 mL) and the solution was washed with a saturated
solution of ammonium chloride (1ϫ 30 mL), water (1ϫ 30 mL)
and brine (1ϫ 30 mL). After drying, filtration and concentration
under reduced pressure, the residue was purified by flash
chromatography (petroleum ether/ethyl acetate, 70:30 to 65:35) to
afford a white solid in 90% yield (276 mg), m.p. 63–64 °C. 1H
NMR (300 MHz, CDCl3, 25 °C): diastereoisomer A 8/diastereoiso-
mer B 1 δ = 1.35–1.53 (m, 2 H), 1.56–1.76 (m, 2 H), 1.98–2.06 (m,
2 H), 2.38 (s, 3 H), 2.40 (s, 3 H), 3.70 (s, 3 H), 3.73 (s, 3 H), 3.86–
3.99 (m, 1 H), 5.62–5.65 (m, 1 H), 5.76–5.82 (d, J = 15.8 Hz, 1
H), 5.78–5.83 (d, J = 15.8 Hz, 1 H), 5.87–5.92 (m, 1 H), 6.40–6.43
(d, J = 8.6 Hz, 1 H NH), 7.03–7.09 (d, J = 15.7 Hz, 1 H), 7.14–
(Cq), 144.9 (Cq), 145.1 (CH), 198.8 (Cq) ppm. IR: ν = 2320, 1737,
˜
1375, 1039, 919 cm–1. HRMS (ESI): calcd. for C24H27N2O4S2 [M –
H]– 471.1412; found 471.1413.
7.29 (m, 5 H), 7.76–7.87 (m, 4 H) ppm. 13C NMR (75 MHz, Compound 7d: To a solution of Pd(dppf)Cl2 (9.20 mg, 13.0 μmol)
CDCl3, 25 °C): diastereoisomer A 8/diastereoisomer B 1 δ = 19.2 in dry DMF (0.5 mL) under argon, were introduced a solution of
(CH2), 19.6 (CH2), 21.5 (CH3), 21.6 (CH3), 23.4 (CH2), 23.5 C–H amination product 5 (100 mg, 0.181 mmol) in dry DMF
(CH2) 28.9 (CH2), 30.0 (CH2), 49.9 (CH), 50.0 (CH), 51.7 (CH3), (1.5 mL), acrylonitrile (26.0 μL, 0.396 mmol) and triethylamine
117.4 (CH), 126.8 (2ϫ CH), 127.7 (2ϫ CH), 129.2 (2ϫ CH), 129.8 (86.0 μL, 0.634 mmol). The reaction mixture was stirred at 75 °C
Eur. J. Org. Chem. 2014, 66–79
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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71

M. Mazurais, C. Lescot, P. Retailleau, P. Dauban
FULL PAPER
for 1 h. Dichloromethane was added (2 mL) and the organic layer
was washed with a saturated solution of ammonium chloride
(2 mL), water (2 mL), and brine (2 mL). After concentration under
reduced pressure, the residue was purified by flash chromatography
4.04 (m, 1 H), 5.11–5.15 (m, 1 H), 5.73–5.78 (m, 1 H), 6.02–6.05
(d, J = 8.5 Hz, 1 H NH), 6.20–6.22 (d, J = 8.5 Hz, 1 H), 6.34–
6.40 (d, J = 16.1 Hz, 1 H), 6.51–6.56 (d, J = 16.1 Hz, 1 H), 6.69–
6.75 (d, J = 16.1 Hz, 1 H), 7.22–7.27 (m, 2 H), 7.31–7.36 (m, 4 H),
7.40–7.44 (m, 2 H), 7.83–7.89 (m, 5 H) ppm. 13C NMR (75 MHz,
(dichloromethane/ethyl acetate, 95:5 to 90:10) affording a colorless
1
gum in 80% yield (66.0 mg). H NMR (300 MHz, CDCl3, 25 °C): CDCl3, 25 °C): diastereoisomer A 10/diastereoisomer B 1 δ = 19.2
diastereoisomer A 6/diastereoisomer B 1 δ = 1.38–1.57 (m, 2 H),
1.63–1.81 (m, 2 H), 1.97–2.05 (m, 2 H), 2.43 (s, 3 H), 2.44 (s, 3
(CH2), 19.5 (CH2), 21.5 (CH3), 21.6 (CH3), 23.9 (CH2), 29.4
(CH2), 50.1 (CH), 126.4 (2ϫ CH), 126.7 (2ϫ CH), 127.6 (CH),
H), 2.46 (s, 3 H), 3.93–4.01 (m, 1 H), 5.23–5.26 (d, J = 16.4 Hz, 1 127.8 (2ϫ CH), 128.1 (CH), 128.3 (CH), 128.6 (2ϫ CH), 129.2
H), 5.31–5.34 (d, J = 16.4 Hz, 1 H), 5.66–5.69 (m, 1 H), 5.98–6.00
(m, 1 H), 6.04–6.05 (d, J = 8.6 Hz, 1 H, NH), 6.60–6.63 (d, J =
16.4 Hz, 1 H), 6.93–6.97 (d, J = 16.4 Hz, 1 H), 7.26–7.36 (m, 4
H), 7.83–7.87 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
diastereoisomer A 6/diastereoisomer B 1 δ = 19.4 (CH2), 21. 6
(CH3), 21.7 (CH3), 22.8 (CH2), 28.5 (CH2), 28.8 (CH2), 49.9 (CH),
94.4 (CH), 96.1 (CH), 118.1 (CN), 126.7 (2ϫ CH), 127.8 (2ϫ
CH), 129.3 (2ϫ CH), 129.9 (2ϫ CH), 136.0 (Cq), 137.0 (CH),
137.2 (Cq), 140.3 (Cq), 143.0 (Cq), 145.0 (Cq), 151.9 (CH) ppm.
(2ϫ CH), 129.8 (2ϫ CH), 130.8 (CH), 136.4 (Cq), 137.1 (Cq),
139.6 (Cq), 140.5 (Cq), 142.8 (Cq), 144.7 (Cq) ppm. IR: ν = 2927,
˜
1709, 1597, 1494, 1448, 1302, 1256, 1152, 1100, 1091, 1064, 1017,
965, 814, 751, 694, 658 cm–1. HRMS (ESI): calcd. for
C28H29N2O3S2 [M – H]– 505.1620; found 505.1650.
Compound 8: To a solution of Pd(PPh3)2Cl2 (8.35 mg, 11.9 μmol)
in dry DMF (1 mL) under argon, were introduced a solution of C–
H amination product of 4 (44.0 mg, 79.6 μmol) in dry DMF
(0.7 mL), methyl acrylate (16.3 μL, 0.175 mmol) and triethylamine
(39.2 μL, 0.279 mmol). The reaction mixture was stirred at 75 °C
for 3 h. Dichloromethane was added (2 mL) and the organic layer
was washed with a saturated solution of ammonium chloride
(2 mL), water (2 mL) and brine (2 mL). After concentration under
reduced pressure, the residue was purified by flash chromatography
(petroleum ether/ethyl acetate, 70:30) affording a colorless gum in
IR: ν = 2928, 2217, 1735, 1598, 1374, 1302, 1244, 1150, 1090, 1016,
˜
968, 926, 813, 753, 703 cm–1. HRMS (ESI): calcd. for
C23H26N3O3S2 [M + H]+ 456.1416; found 456.1415.
Compound 7e: To a solution of Pd(PPh3)2Cl2 (17.5 mg, 25.3 μmol)
in dry DMF (1 mL) under argon, were introduced a solution of C–
H amination product 5 (200 mg, 0.362 mmol) in dry DMF (3 mL),
(vinylsulfonyl)benzene (135 mg, 0.796 mmol) and triethylamine
(171 μL, 1.27 mmol). The reaction mixture was stirred at 75 °C for
2 h. Dichloromethane was added (4 mL) and the organic layer was
washed with a saturated solution of ammonium chloride (4 mL),
water (4 mL) and brine (1ϫ 4 mL). After concentration under re-
duced pressure, the residue was purified by flash chromatography
(petroleum ether/ethyl acetate, 80:20 to 60:40) affording a yellow
37% yield (14.0 mg). [α]2D0 = +147.2 (c = 1.02, CHCl3). H NMR
1
(300 MHz, CDCl3, 25 °C): δ = 1.53–1.64 (m, 1 H), 2.05–2.15 (m, 1
H), 2.17–2.26 (m, 1 H), 2.33 (s, 3 H), 2.37 (s, 3 H), 2.38–2.51 (m,
1 H), 3.69 (s, 3 H), 4.29–4.40 (m, 1 H), 5.72–5.77 (d, J = 15.8 Hz,
1 H), 5.85–5.88 (m, 1 H), 5.91–5.94 (d, J = 9.0 Hz, 1 H NH), 7.15–
7.26 (m, 4 H), 7.29–7.34 (d, J = 15.8 Hz, 1 H), 7.72–7.78 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 21.5 (CH3), 21.6
(CH3), 29.2 (CH2), 31.0 (CH2), 51.7 (CH), 59.5 (CH), 121.1 (CH),
126.7 (2ϫ CH), 127.8 (2ϫ CH), 129.2 (2ϫ CH), 129.9 (2ϫ CH),
135.8 (Cq), 136.7 (CH), 139.3 (CH), 140.3 (Cq), 142.9 (Cq), 143.7
1
solid in 63% yield (130 mg), m.p. 71–72 °C. H NMR (300 MHz,
CDCl3, 25 °C): diastereoisomer A 5/diastereoisomer B 1 δ = 1.38–
1.45 (m, 1 H), 1.46–1.54 (m, 1 H), 1.66–1.73 (m, 2 H), 1.97–2.03
(m, 2 H), 2.43 (s, 3 H), 2.44 (s, 3 H), 3.91–4.00 (m, 1 H), 5.65–5.68
(m, 1 H), 5.88–5.90 (m, 1 H), 5.92–5.93 (d, J = 8.8 Hz, 1 H,
NH), 6.08–6.10 (m, 1 H), 6.24–6.26 (d, J = 8.8 Hz, 1 H NH), 6.31–
6.34 (d, J = 15.3 Hz, 1 H), 7.20–7.23 (d, J = 15.3 Hz, 1 H), 7.26–
7.33 (m, 4 H), 7.53–7.58 (m, 2 H), 7.62–7.65 (t, J = 7.2 Hz, 1 H),
7.79–7.87 (m, 4 H), 7.89–7.94 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): diastereoisomer A 5/diastereoisomer B 1 δ = 19.4
(CH2), 19.8 (CH2), 21.57 (CH3), 21.62 (CH3), 23.6 (CH2), 24.8
(CH2), 28.8 (CH2), 29.1 (CH2), 50.0 (CH), 50.1 (CH), 126.7 (2ϫ
CH), 127.2 (2ϫ CH), 127.4 (2ϫ CH), 127.6 (2ϫ CH), 127.8 (2ϫ
CH), 129.2 (CH), 129.3 (2ϫ CH), 129.4 (2ϫ CH), 129.8 (2ϫ
CH), 129.9 (2ϫ CH), 133.4 (CH), 135.8 (Cq), 136.3 (Cq), 138.1
(CH), 140.1 (Cq), 140.2 (Cq), 142.9 (Cq), 144.0 (CH), 144.8
(Cq), 144.9 (Cq), 167.1 (Cq) ppm. IR: ν = 2254, 1717, 1709, 1449,
˜
1388, 1305, 1201, 1163, 1124, 1050, 908 cm–1. HRMS (ESI): calcd.
for C23H30N3O5S2 [M + NH4]+ 492.1627; found 492.1610.
Typical Mitsunobu Procedure (for 9a–10): Secondary sulfonimid-
amide 7 or 8 (0.150 mmol) was dissolved in tetrahydrofuran
(0.7 mL) at room temperature, under an argon atmosphere. Tri-
phenylphosphine (0.225 mmol), the alcohol (0.300 mmol) and di-
tert-butyl azodicarboxylate (0.210 mmol) were then added at room
temperature and the reaction mixture was stirred overnight. A 4 m
solution of hydrochloric acid in dioxane (0.6 mL) was then added
and the mixture was stirred for 1 h at room temperature. The sol-
vents were removed under reduced pressure and the resulting resi-
due was dissolved in CH2Cl2 (2 mL). The organic phase was
washed successively with a solution of HCl 4 m (2 mL), and HCl
1 m (2 mL), before being dried with MgSO4, filtered and concen-
trated under reduced pressure. The crude product was purified by
column chromatography on silica gel.
(Cq) ppm. IR: ν = 3211, 2927, 1596, 1495, 1447, 1302, 1253, 1145,
˜
1105, 1062, 1016, 972, 928, 836, 812 cm–1. HRMS (ESI): calcd. for
C28H34N3O5S3 [M + NH4]+ 588.1661; found 588.1631.
Compound 7f: To a solution of Pd(PPh3)2Cl2 (5.00 mg, 7.21 μmol)
in dry DMF (1 mL) under argon, were introduced a solution of C–
H amination product 5 (57.0 mg, 0.103 mmol) in dry DMF (2 mL), Compound 9a: Prepared following the typical Mitsunobu procedure
styrene (25.3 μL, 0.227 mmol) and triethylamine (49.3 μL,
0.361 mmol). The reaction mixture was stirred at 75 °C for 12 h.
Dichloromethane was added (10 mL) and the organic layer was
washed with a saturated solution of ammonium chloride (10 mL),
water (10 mL) and brine (10 mL). After concentration under re-
duced pressure, the residue was purified by flash chromatography
(petroleum ether/ethyl acetate, 70:30) to afford a colorless gum in
20% yield (11.0 mg). 1H NMR (300 MHz, CDCl3, 25 °C): dia-
stereoisomer A 10/diastereoisomer B 1 δ = 1.38–1.46 (m, 1 H), 1.64–
from 7a and allylic alcohol. Corresponding product 9a was ob-
tained (petroleum ether/ethyl acetate, 70:30) as a colorless gum in
83% yield (66 mg), m.p. 63–65 °C. 1H NMR (300 MHz, CDCl3,
25 °C): diastereoisomer A 12/diastereoisomer B 1 δ = 1.51–1.74 (m,
3 H), 1.90–2.00 (m, 1 H), 2.11–2.17 (m, 1 H), 2.17–2.25 (m, 1 H),
2.39 (s, 3 H), 2.45 (s, 3 H), 3.75 (s, 3 H), 3.76 (s, 3 H), 3.79–3.84
(m, 1 H), 3.87–3.97 (m, 1 H), 4.74–4.84 (m, 1 H), 5.07–5.13 (m, 1
H), 5.16–5.25 (m, 1 H), 5.37–5.42 (m, 1 H), 5.53–5.59 (m, 1 H),
5.72–5.87 (m, 1 H), 5.80–5.85 (d, J = 15.9 Hz, 1 H), 6.01–6.04 (m,
1.77 (m, 3 H), 2.22–2.27 (m, 2 H), 2.43 (s, 3 H), 2.46 (s, 3 H), 3.94– 1 H), 7.08–7.13 (d, J = 15.9 Hz, 1 H), 7.22–7.35 (m, 4 H), 7.77–
72
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Eur. J. Org. Chem. 2014, 66–79

A Short Asymmetric Synthesis of Octahydroindole Derivatives
7.83 (m, 2 H), 7.85–7.90 (m, 2 H) ppm. 13C NMR (75 MHz, 25 °C): diastereoisomer A 4/diastereoisomer B 1 δ = 1.56–1.74 (m,
CDCl3, 25 °C): diastereoisomer A 12/diastereoisomer B 1 δ = 21.3
2 H), 1.95–2.03 (m, 2 H), 2.07–2.14 (m, 1 H), 2.17–2.29 (m, 1 H),
(CH2), 21.5 (CH3), 21.6 (CH3), 23.6 (CH2), 27.6 (CH2), 47.4 (CH2), 2.41 (s, 3 H), 2.44 (s, 3 H), 2.46 (s, 3 H), 3.10–3.17 (m, 1 H), 3.26–
51.7 (CH3), 56.7 (CH), 117.2 (CH), 117.9 (CH2), 126.7 (2ϫ CH), 3.35 (m, 1 H), 3.46–3.54 (m, 1 H), 3.77–3.83 (dd, J = 16.4, 6.1 Hz,
127.3 (2ϫ CH), 129.2 (2ϫ CH), 129.9 (2ϫ CH), 134.9 (CH), 136.1
1 H), 3.90–3.96 (dd, J = 16.4, 6.1 Hz, 1 H), 4.34–4.46 (m, 1 H),
(CH), 137.2 (Cq), 139.3 (Cq), 141.0 (Cq), 142.6 (Cq), 144.6 (Cq),
4.73–4.87 (m, 1 H), 5.07–5.14 (m, 1 H), 5.14–5.33 (m, 2 H), 5.62–
146.1 (CH), 167.5 (Cq) ppm. IR: ν = 2947, 1712, 1597, 1435, 1362, 5.66 (m, 1 H), 5.71–5.83 (m, 1 H), 6.50–6.54 (d, J = 16.5 Hz,
˜
1303, 1247, 1153, 1101, 1062, 1014, 813, 749, 703, 656 cm–1. HRMS
(ESI): calcd. for C27H33N2O5S2 [M + H]+ 529.1857; found
529.1831.
1 H), 6.83–6.86 (d, J = 16.5 Hz, 1 H), 7.23–7.35 (m, 4 H), 7.77–
7.90 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): dia-
stereoisomer A 4/diastereoisomer B 1 δ = 21.1 (CH2), 21.48
(CH3), 21.53 (CH3), 21.6 (CH3), 22.9 (CH2), 25.1 (CH2), 27.2
(CH2), 27.4 (CH2), 47.6 (CH2), 47.7 (CH2), 56.2 (CH), 56.5
(CH), 94.1 (CH), 95.6 (CH), 118.1 (CH2), 118.2 (CH2), 118.3
(CN), 126.6 (2ϫ CH), 127.4 (2ϫ CH), 129.2 (2ϫ CH), 130.0 (2ϫ
CH), 134.56 (CH), 134.64 (CH), 137.5 (CH), 138.0 (CH), 138.5
(Cq), 139.5 (Cq), 140.9 (Cq), 142.8 (Cq), 144.8 (Cq), 150.1 (CH),
Compound 9b: Prepared following the typical Mitsunobu procedure
from 7b and allylic alcohol. Corresponding product 9b was ob-
tained (dichloromethane 100%) as a white solid in 83% yield
1
(71 mg), m.p. 79–80 °C. H NMR (300 MHz, CDCl3, 25 °C): dia-
stereoisomer A 6/diastereoisomer B 1 δ = 1.49 (s, 9 H), 1.61–1.67
(m, 2 H), 1.88–1.97 (m, 1 H), 2.00–2.09 (m, 1 H), 2.10–2.15 (m, 1
H), 2.16–2.28 (m, 1 H), 2.39 (s, 3 H), 2.42 (s, 3 H), 2.44 (s, 3 H),
3.73–3.79 (dd, J = 16.9, 6.2 Hz, 1 H), 3.89–3.95 (dd, J = 16.9,
5.6 Hz, 1 H), 4.01–4.10 (m, 1 H), 4.26–4.37 (m, 1 H), 4.73–4.82
(m, 1 H), 5.08–5.11 (dd, J = 10.4 Hz, 1.2 Hz, 1 H), 5.18–5.24 (dd,
J = 17.0 Hz, 1.2 Hz, 1 H), 5.33–5.38 (m, 1 H), 5.45–5.49 (m, 1 H),
5.72–5.78 (d, J = 15.8 Hz, 1 H), 5.72–5.87 (m, 1 H), 6.96–7.02 (d,
J = 15.8 Hz, 1 H), 7.22–7.33 (m, 4 H), 7.76–7.89 (m, 4 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): diastereoisomer A 6/dia-
stereoisomer B 1 δ = 21.3 (CH2), 21.5 (CH3), 21.6 (CH3), 23.7
(CH2), 26.4 (CH2), 26.8 (CH2), 27.7 (CH2), 28.1 (3ϫ CH3), 38.2
(CH), 42.4 (CH), 45.5 (CH), 47.3 (CH2), 53.0 (CH2), 56.8 (CH),
59.8 (CH), 80.5 (Cq), 117.8 (CH2), 118.5 (CH), 119.5 (CH), 126.6
(2ϫ CH), 126.7 (2ϫ CH), 127.3 (2ϫ CH), 127.5 (2ϫ CH), 129.1
(2ϫ CH), 129.7 (2ϫ CH), 129.9 (2ϫ CH), 135.0 (CH), 135.1
(CH), 136.5 (Cq), 139.5 (Cq), 141.0 (Cq), 142.6 (Cq), 144.6 (Cq),
151.7 (CH) ppm. IR: ν = 3480, 2953, 2292, 1761, 1374, 1198, 1153,
˜
1094, 815, 754, 658 cm–1. HRMS (ESI): calcd. for C26H33N4O3S2
[M + NH4]+ 513.1994; found 513.2011.
Compound 9e: Prepared following the typical Mitsunobu procedure
from 7e and allylic alcohol. Corresponding product 9e was ob-
tained (petroleum ether/ethyl acetate, 70:30) as a colorless gum in
30% yield (28 mg). 1H NMR (300 MHz, CDCl3, 25 °C): dia-
stereoisomer A 6/diastereoisomer B 1 δ = 1.49–1.73 (m, 2 H), 180–
1.97 (m, 3 H), 2.11–2.23 (m, 1 H), 2.31 (s, 3 H), 2.37 (s, 3 H), 2.39
(s, 3 H), 2.90–2.97 (m, 1 H), 3.03–3.12 (m, 1 H), 3.67–3.73 (dd, J
= 16.9, 6.2 Hz, 1 H), 3.82–3.87 (dd, J = 16.9, 5.6 Hz, 1 H), 4.18–
4.30 (m, 1 H), 4.66–4.77 (m, 1 H), 5.00–5.04 (m, 1 H), 5.09–5.15
(m, 1 H), 5.40–5.45 (m, 1 H), 5.60–5.65 (m, 1 H), 5.65–5.78 (m, 1
H), 6.16–6.21 (d, J = 15.0 Hz, 1 H), 7.00–7.05 (d, J = 15.0 Hz, 1
H), 7.19–7.29 (m, 4 H), 7.42–7.51 (m, 2 H), 7.51–7.59 (m, 1 H),
7.67–7.75 (m, 2 H), 7.76–7.86 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): diastereoisomer A 6/diastereoisomer B 1 δ = 21.1
(CH2), 21.5 (CH3), 21.6 (CH3), 23.7 (CH2), 27.4 (CH2), 29.7
(CH2), 47.49 (CH2), 47.53 (CH2), 56.7 (CH), 118.0 (CH2), 126.6
(2ϫ CH), 126.8 (CH), 127.3 (2ϫ CH), 127.6 (2ϫ CH), 129.2 (2ϫ
CH), 129.3 (2ϫ CH), 130.0 (2ϫ CH), 133.4 (CH), 134.7 (CH),
136.4 (Cq), 137.6 (Cq), 138.8 (CH), 140.6 (Cq), 140.9 (Cq), 142.7
144.8 (CH), 166.4 (Cq) ppm. IR: ν = 2937, 1724, 1368, 1315, 1249,
˜
1165, 1064, 1015, 845, 813, 734, 702, 657 cm–1. HRMS (ESI): calcd.
for C30H42N3O5S2 [M + NH4]+ 588.2566; found 588.2596.
Compound 9c: Prepared following the typical Mitsunobu procedure
from 7c and allylic alcohol. Corresponding product 9c was ob-
tained (petroleum ether/ethyl acetate, 70:30) as a colorless gum in
62% yield (48 mg). 1H NMR (300 MHz, CDCl3, 25 °C): dia-
stereoisomer A 5/diastereoisomer B 1 δ = 1.59–1.71 (m, 2 H), 1.84–
2.03 (m, 1 H), 2.05–2.10 (m, 1 H), 2.11–2.14 (m, 1 H), 2.20–2.24
(m, 1 H), 2.29 (s, 3 H), 2.40 (s, 3 H), 2.43 (s, 3 H), 2.45 (s, 3 H),
3.08–3.25 (m, 2 H), 3.31–3.39 (m, 1 H), 3.79–3.85 (dd, J = 16.7,
6.2 Hz, 1 H), 3.94–3.99 (dd, J = 16.7, 6.2 Hz, 1 H), 4.76–4.86 (m,
1 H), 5.07–5.11 (d, J = 9.9 Hz, 1 H), 5.16–5.22 (d, J = 17.1 Hz, 1
H), 5.40–5.44 (m, 1 H), 5.70–5.75 (m, 1 H), 5.75–5.85 (m, 1 H),
6.08–6.13 (d, J = 15.9 Hz, 1 H), 6.21–6.26 (m, 2 H), 6.95–7.00 (d,
J = 15.9 Hz, 1 H), 7.08–7.14 (d, J = 15.9 Hz, 1 H), 7.12–7.27 (m,
4 H), 7.67–7.83 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
diastereoisomer A 5/diastereoisomer B 1 δ = 21.3 (CH2), 21.5
(CH3), 21.6 (CH3), 23.7 (CH2), 27.67 (CH2), 27.75 (CH3), 28.4
(CH3), 45.6 (CH2), 47.5 (CH2), 56.7 (CH), 59.6 (CH), 117.0
(CH2), 118.0 (CH2), 126.3 (CH), 126.6 (2ϫ CH), 126.7 (2ϫ
CH), 127.4 (2ϫ CH), 127.5 (2ϫ CH), 129.2 (2ϫ CH), 129.7 (2ϫ
CH), 130.0 (2ϫ CH), 134.8 (CH), 136.5 (Cq), 137.1 (CH), 139.5
(Cq), 140.9 (Cq), 142.6 (Cq), 144.6 (CH), 144.7 (Cq), 198.7
(Cq), 143.4 (CH), 144.8 (Cq) ppm. IR: ν = 3578, 2981, 2254, 1727,
˜
1441, 1380, 1209, 1039, 917, 750 cm–1. HRMS (ESI): calcd. for
C31H35N2O5S3 [M + H]+ 611.1708; found 611.1708.
Compound 9f: Prepared following the typical Mitsunobu procedure
from 7f and allylic alcohol. Corresponding product 9f was obtained
(petroleum ether/ethyl acetate, 80:20) as a colorless gum in 62%
yield (51 mg). 1H NMR (300 MHz, CDCl3, 25 °C): diastereoisomer
A 5/diastereoisomer B 1 δ = 1.58–1.67 (m, 2 H), 1.90–2.02 (m, 1
H), 2.14–2.24 (m, 2 H), 2.28–2.33 (m, 1 H), 2.40 (s, 3 H), 2.46 (s,
3 H), 3.83–3.88 (dd, J = 16.7, 6.2 Hz, 1 H), 3.95–4.01 (dd, J = 16.7,
6.2 Hz, 1 H), 4.09–4.20 (dd, J = 16.7, 6.2 Hz, 1 H), 4.62–7.71 (m,
1 H), 4.73–4.83 (m, 1 H), 5.06–5.14 (m, 1 H), 5.17–5.26 (m, 1 H),
5.34–5.39 (m, 1 H), 5.47–5.51 (m, 1 H), 5.76–5.92 (m, 1 H), 6.48–
6.53 (d, J = 16.1 Hz, 1 H), 6.60–6.65 (d, J = 16.1 Hz, 1 H), 6.74–
6.79 (d, J = 16.1 Hz, 1 H), 7.22–7.42 (m, 9 H), 7.79–7.93 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): diastereoisomer A 5/
diastereoisomer B 1 δ = 21.51 (CH2), 21.53 (CH3), 21.6 (CH3), 24.0
(CH2), 28.0 (CH2), 47.1 (CH2), 53.0 (CH2), 55.3 (CH), 56.8 (CH),
117.7 (CH2), 117.8 (CH2), 126.2 (2ϫ CH), 126.4 (2ϫ CH), 126.6
(2ϫ CH), 126.7 (2ϫ CH), 127.49 (2ϫ CH), 127.55 (2ϫ CH),
127.6 (CH), 127.7 (CH), 128.4 (CH), 128.6 (2ϫ CH), 129.1 (2ϫ
CH), 129.2 (2ϫ CH), 129.7 (2ϫ CH), 129.9 (2ϫ CH), 130.7
(CH), 130.9 (CH), 135.2 (CH), 136.7 (Cq), 137.1 (Cq), 141.0 (Cq),
(Cq) ppm. IR: ν = 3405, 2891, 1726, 1672, 1366, 1245, 1150, 1089,
˜
1012, 815, 723, 650 cm–1. HRMS (ESI): calcd. for C27H33N2O4S2
[M + H]+ 513.1882; found 513.1893.
Compound 9d: Prepared following the typical Mitsunobu procedure
from 7d and allylic alcohol. Corresponding product 9d was ob-
tained (petroleum ether/ethyl acetate, 80:20) as a pasty white solid
141.1 (Cq), 142.5 (Cq), 144.4 (Cq) ppm. IR: ν = 2934, 1732, 1597,
˜
in 73% yield (54 mg), m.p. 62–63 °C. 1H NMR (300 MHz, CDCl3, 1493, 1448, 1316, 1248, 1153, 1102, 1069, 1015, 962, 910, 812, 729,
Eur. J. Org. Chem. 2014, 66–79
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
73

M. Mazurais, C. Lescot, P. Retailleau, P. Dauban
FULL PAPER
691 cm–1. HRMS (ESI): calcd. for C31H35N2O3S2 [M + H]+
547.2089; found 547.2066.
820, 656 cm–1. HRMS (ESI): calcd. for C26H34N3O5S2 [M +
NH4]+ 532.1940; found 532.1931.
Typical Diels–Alder Reaction Procedure (for 11a–12): The Mitsu-
nobu product was dissolved in toluene at room temperature under
an argon atmosphere. The resulting mixture was then stirred at
110 °C overnight. After cooling to room temperature, the solvent
was removed under reduced pressure and the resulting residue was
purified by column chromatography on silica gel.
Compound 9g: Prepared following the typical Mitsunobu procedure
from 7a and 2-methylprop-2-en-1-ol. Corresponding product 9g
was obtained (dichloromethane 100%) as a colorless gum in 50%
yield (41 mg). 1H NMR (300 MHz, CDCl3, 25 °C): diastereoisomer
A 8/diastereoisomer B 1 δ = 1.60–1.68 (m, 2 H), 1.73 (s, 3 H), 1.89–
1.99 (m, 1 H), 2.00–2.09 (m, 1 H), 2.11–2.22 (m, 1 H), 2.25–2.35
(m, 1 H), 2.40 (s, 3 H), 2.46 (s, 3 H), 2.48 (s, 3 H), 3.50–3.56 (d, J
= 16.8 Hz, 1 H), 3.76 (s, 3 H), 3.78 (s, 3 H), 3.85–3.90 (d, J =
16.8 Hz, 1 H), 4.83–4.86 (m, 1 H), 4.87–4.97 (m, 2 H), 5.07–5.11
(m, 1 H), 5.37–5.41 (m, 1 H), 5.80–5.85 (d, J = 15.9 Hz, 1 H), 6.03–
6.09 (m, 1 H), 7.02–7.08 (d, J = 15.9 Hz, 1 H), 7.22–7.38 (m, 4
H), 7.78–7.92 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
diastereoisomer A 8/diastereoisomer B 1 δ (ppm) 20.2 (CH3), 21.4
(CH2), 21.5 (CH3), 21.6 (CH3), 23.5 (CH2), 23.7 (CH2), 27.6
(CH2), 28.2 (CH2), 50.5 (CH2), 51.7 (CH3), 56.4 (CH), 57.6 (CH),
113.7 (CH2), 117.1 (CH), 126.6 (2ϫ CH), 127.2 (2ϫ CH), 127.7
(2ϫ CH), 129.2 (2ϫ CH), 129.9 (2ϫ CH), 130.0 (2ϫ CH), 135.6
(CH), 136.4 (Cq), 139.5 (Cq), 141.0 (Cq), 141.6 (Cq), 142.6 (Cq),
Compound 11a: Following the procedure for the intramolecular
Diels–Alder reaction starting from 9a (188 mg, 0.356 mmol), 11a
was obtained (petroleum ether/ethyl acetate, 80:20) as a colorless
oil in 99% yield (187 mg). [α]2D0 = +146.0 (c = 0.98, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.66–1.78 (m, 3 H), 1.99–2.09
(m, 2 H), 2.14–2.26 (m, 2 H), 2.28–2.34 (m, 1 H), 2.38–2.51 (m, 2
H), 2.40 (s, 3 H), 2.43 (s, 3 H), 3.12–3.17 (m, 1 H), 3.19–3.23 (m,
1 H), 3.27–3.32 (m, 1 H), 3.69 (s, 3 H), 4.28–4.35 (m, 1 H), 5.37–
5.42 (m, 1 H), 7.25–7.32 (m, 4 H), 7.79–7.83 (m, 2 H), 7.90–7.94
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 20.4 (CH2),
21.5 (CH3), 21.6 (CH3), 26.4 (CH2), 26.9 (CH2), 27.3 (CH2), 38.2
(CH), 41.5 (CH), 45.5 (CH), 52.1 (CH3), 53.0 (CH2), 59.8 (CH),
117.9 (CH) 126.6 (2ϫ CH), 127.5 (2ϫ CH), 129.2 (2ϫ CH), 129.8
(2ϫ CH), 135.8 (Cq), 141.0 (Cq), 141.1 (Cq), 142.5 (Cq), 144.5
144.7 (Cq), 146.2 (CH), 167.6 (Cq) ppm. IR: ν = 2947, 1713, 1631,
˜
1597, 1435, 1364, 1304, 1250, 1219, 1154, 1104, 1089, 1015, 905,
814, 656 cm–1. HRMS (ESI): calcd. for C28H38N3O5S2 [M +
NH4]+ 560.2253; found 560.2280.
(Cq), 174.8 (Cq) ppm. IR: ν = 2947, 1714, 1631, 1596, 1435, 1350,
˜
1304, 1250, 1154, 1107, 1089, 1015, 814, 656 cm–1. HRMS (ESI):
calcd. for C27H33N2O5S2 [M + H]+ 529.1831; found 529.1842.
Compound 9i: Prepared following the typical Mitsunobu procedure
from 7a and but-3-en-1-ol. Corresponding product 9i was obtained
(petroleum ether/ethyl acetate, 75:25) as a colorless oil in 71% yield
(58 mg). 1H NMR (300 MHz, CDCl3, 25 °C): diastereoisomer A
12/diastereoisomer B 1 δ = 1.54–1.69 (m, 2 H), 1.93–2.02 (m, 1 H),
2.06–2.18 (m, 2 H), 2.25–2.36 (m, 1 H), 2.36–2.53 (m, 2 H), 2.39
(s, 3 H), 2.45 (s, 3 H), 3.05–3.16 (m, 1 H), 3.22–3.34 (m, 1 H), 3.74
(s, 3 H), 3.76 (s, 3 H), 4.62–4.71 (m, 1 H), 5.00–5.02 (m, 1 H),
5.04–5.07 (m, 1 H), 5.38–5.42 (m, 1 H), 5.63–5.77 (m, 1 H), 5.79–
5.85 (d, J = 15.8 Hz, 1 H), 6.07–6.11 (m, 1 H), 6.95–7.01 (d, J =
15.8 Hz, 1 H), 7.14–7.27 (m, 4 H), 7.70–7.83 (m, 4 H) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): diastereoisomer A 12/diastereoiso-
mer B 1 δ = 21.3 (CH2), 21.5 (CH3), 21.6 (CH3), 23.6 (CH2), 27.6
(CH2), 35.7 (CH2), 35.9 (CH2), 44.7 (CH2), 51.7 (CH3), 56.1
(CH), 56.6 (CH), 117.1 (CH2), 117.2 (CH), 126.7 (2ϫ CH), 127.3
(2ϫ CH), 129.2 (2ϫ CH), 130.0 (2ϫ CH), 134.7 (CH), 136.1 (CH),
136.3 (Cq), 139.4 (Cq), 141.1 (Cq), 142.6 (Cq), 144.7 (Cq), 146.1
Compound 11b: Following the procedure for the intramolecular
Diels–Alder reaction starting from 9b (75.0 mg, 0.130 mmol), 11b
was obtained (petroleum ether/ethyl acetate, 75:25) as a colorless
oil in 70% yield (53 mg). [α]2D0 = +96.5 (c = 0.77, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.17–1.31 (m, 2 H), 1.44 (s, 9 H),
1.59–1.77 (m, 3 H), 1.95–2.02 (m, 1 H), 2.19–2.26 (m, 3 H), 2.38–
2.47 (m, 1 H), 2.40 (s, 3 H), 2.43 (s, 3 H), 3.10–3.23 (m, 3 H), 4.27–
4.37 (m, 1 H), 5.33–5.40 (m, 1 H), 7.20–7.35 (m, 4 H), 7.75–7.85
(m, 2 H), 7.87–7.96 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 20.4 (CH2), 21.50 (CH3), 21.54 (CH3), 26.4 (CH2), 26.8
(CH2), 27.3 (CH2), 28.1 (3ϫ CH3), 38.2 (CH), 42.4 (CH), 45.5
(CH), 53.1 (CH2), 59.8 (CH), 80.7 (Cq), 118.5 (CH), 126.6 (2ϫ
CH), 127.5 (2ϫ CH), 129.1 (2ϫ CH), 129.7 (2ϫ CH), 135.8 (Cq),
140.6 (Cq), 141.2 (Cq), 142.4 (Cq), 144.5 (Cq), 173.8 (Cq) ppm.
IR: ν = 2932, 1723, 1368, 1303, 1249, 1152, 1028, 1015, 813, 753,
˜
657 cm–1. HRMS (ESI): calcd. for C30H39N2O5S2 [M + H]+
571.2300; found 571.2330.
(CH), 167.5 (Cq) ppm. IR: ν = 2947, 1717, 1631, 1435, 1303, 1249,
˜
1153, 1102, 1088, 1085, 1015, 911, 813, 728, 655 cm–1. HRMS
(ESI): calcd. for C28H35N2O5S2 [M + H]+ 543.1987; found
543.1996.
Compound 11c: Following the procedure for the intramolecular
Diels–Alder reaction starting from 9c (23.0 mg, 37.7 μmol), 11c was
obtained (petroleum ether/ethyl acetate, 70:30) as a colorless oil in
59% yield (14.0 mg). [α]2D0 = +36.7 (c = 0.54, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.51–1.61 (m, 1 H), 1.70–1.87 (m, 3
H), 1.88–1.98 (m, 2 H), 2.17–2.27 (m, 2 H), 2.32 (s, 3 H), 2.37–2.45
(m, 2 H), 2.40 (s, 3 H), 2.43 (s, 3 H), 2.68–2.73 (dd, J = 17.1,
4.8 Hz, 1 H), 3.09–3.16 (m, 1 H), 3.32–3.39 (m, 1 H), 4.46–4.54 (m,
1 H), 6.58–6.62 (m, 1 H), 7.23–7.34 (m, 4 H), 7.78–7.84 (m, 2 H),
7.85–7.90 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
18.3 (CH2), 21.5 (CH3), 21.6 (CH3), 25.8 (CH3), 27.1 (CH2), 30.1
(CH2), 33.4 (CH2), 36.0 (CH), 49.5 (CH), 52.8 (CH2), 58.5 (CH),
71.8 (CH), 126.6 (2ϫ CH), 127.5 (2ϫ CH), 129.2 (2ϫ CH), 129.9
(2ϫ CH), 135.2 (Cq), 137.4 (Cq), 142.6 (Cq), 144.7 (Cq), 145.0
Compound 10: Prepared following the typical Mitsunobu procedure
from
8
(33 mg, 69.5 μmol) and allylic alcohol (9.45 μL,
0.139 μmol). Corresponding product 10 was obtained by prepara-
tive chromatography (dichloromethane/ethyl acetate, 80:20) as a
colorless oil in 70% yield (25 mg). 1H NMR (300 MHz, CDCl3,
25 °C): diastereoisomer A 18/diastereoisomer B 1 δ = 1.89–2.04 (m,
1 H), 2.23–2.46 (m, 3 H), 2.31 (s, 3 H), 2.36 (s, 3 H), 3.68 (s, 3 H),
3.69–3.76 (m, 2 H), 4.96–5.02 (m, 1 H), 5.02–5.10 (m, 1 H), 5.10–
5.19 (m, 1 H), 5.51–5.55 (m, 1 H), 5.62–5.75 (m, 1 H), 5.72–5.78
(d, J = 15.8 Hz, 1 H), 5.98–6.02 (m, 1 H), 7.14–7.25 (m, 4 H),
7.26–7.31 (d, J = 15.8 Hz, 1 H), 7.67–7.74 (m, 2 H), 7.76–7.83 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 21.5 (CH3),
21.6 (CH3), 27.9 (CH2), 29.5 (CH2), 47.0 (CH2), 51.7 (CH), 64.7
(CH), 117.7 (CH2), 120.9 (CH), 126.7 (2ϫ CH), 127.4 (2ϫ CH),
129.2 (2ϫ CH), 129.9 (2ϫ CH), 134.8 (CH), 135.6 (CH), 136.2
(Cq), 145.1 (CH), 199.2 (Cq) ppm. IR: ν = 2901, 1669, 1244, 1151,
˜
1082, 1025, 814, 733, 656 cm–1. HRMS (ESI): calcd. for
C27H33N2O4S2 [M + H]+ 513.1882; found 513.1918.
Compound 11d: Following the procedure for the intramolecular
(Cq), 139.2 (CH), 141.0 (Cq), 142.6 (Cq), 144.6 (CH), 144.7 (Cq), Diels–Alder reaction starting from 9d (26.0 mg, 52.4 μmol), 11d
167.1 (Cq) ppm. IR: ν = 2913, 1726, 1601, 1443, 1310, 1195, 1090, was obtained (petroleum ether/ethyl acetate, 75:25) as a yellow oil
˜
74
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 66–79

A Short Asymmetric Synthesis of Octahydroindole Derivatives
in 54% yield (14 mg). 1H NMR (300 MHz, CDCl3, 25 °C): dia-
stereoisomer A 5/diastereoisomer B 1 δ = 1.73–1.83 (m, 2 H), 1.91–
1.99 (m, 1 H), 2.07–2.12 (m, 1 H), 2.14–2.20 (m, 1 H), 2.21–2.29
20:1) as a colorless oil in 62% yield (37 mg). [α]2D0 = +21.5 (c =
0.99, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 1.78–1.90
(m, 1 H), 2.08–2.16 (m, 1 H), 2.39–2.49 (m, 1 H), 2.41 (s, 3 H),
1
(m, 3 H), 2.37–2.46 (m, 1 H), 2.41 (s, 3 H), 2.44 (s, 3 H), 2.52–2.59 2.45 (s, 3 H), 2.63–2.72 (m, 1 H), 2.74–2.81 (m, 1 H), 2.85–2.93
(m, 1 H), 3.13–3.20 (m, 1 H), 3.28–3.32 (m, 1 H), 3.47–3.52 (m, 1 (dd, J = 17.7, 7.1 Hz, 1 H), 3.90 (s, 3 H), 4.30–4.35 (m, 1 H), 4.74–
H), 4.23–4.31 (m, 1 H), 4.36–4.43 (m, 1 H), 5.24–5.27 (m, 1 H), 4.80 (m, 2 H), 7.25–7.30 (m, 2 H), 7.32–7.39 (m, 2 H), 7.64–7.67
5.27–5.31 (m, 1 H), 7.22–7.36 (m, 4 H), 7.74–7.96 (m, 4 H) ppm. (m, 1 H), 7.74–7.77 (m, 1 H), 7.87–7.94 (m, 4 H) ppm. 13C NMR
13C NMR (75 MHz, CDCl3, 25 °C): diastereoisomer A 5/dia-
(75 MHz, CDCl3, 25 °C): δ = 21.0 (CH2), 21.5 (CH3), 21.6 (CH3),
stereoisomer B 1 δ = 20.1 (CH2), 21.55 (CH3), 21.60 (CH3), 26.8 25.3 (CH2), 29.6 (CH2), 52.2 (CH3), 54.8 (CH2), 63.0 (CH), 120.8
(CH2), 27.3 (CH2), 27.7 (CH), 28.1 (CH), 28.7 (CH2), 28.9 (CH2)
, 37.9 (CH), 39.3 (CH), 44.8 (CH), 45.0 (CH), 52.3 (CH2), 52.4
(CH), 126.7 (2ϫ CH), 128.0 (2ϫ CH), 128.7 (CH), 129.2 (2ϫ CH),
129.9 (2ϫ CH), 130.6 (Cq), 133.9 (Cq), 134.0 (Cq), 134.7 (Cq),
(CH2), 59.4 (CH), 59.5 (CH), 114.4 (CH), 114.5 (CH), 121.5 (Cq), 141.0 (Cq), 142.4 (Cq), 142.7 (Cq), 145.1 (Cq), 166.2 (Cq) ppm.
126.6 (2ϫ CH), 127.4 (2ϫ CH), 129.3 (2ϫ CH), 129.9 (2ϫ CH), IR: ν = 2925, 1717, 1436, 1302, 1216, 1153, 1063, 1015, 814, 769,
˜
135.6 (Cq), 140.9 (Cq), 142.7 (Cq), 143.4 (Cq), 144.9 (Cq) ppm.
657 cm–1. HRMS (ESI): calcd. for C27H29N2O5S2 [M + H]+
IR: ν = 2945, 1597, 1302, 1248, 1152, 1038, 1014, 911, 813, 728, 525.1518; found 525.1527.
˜
657 cm–1. HRMS (ESI): calcd. for C26H33N4O3S2 [M + NH4]+
513.1994; found 513.1982.
Compound 11i: Following the procedure for the intramolecular
Diels–Alder reaction starting from 9i (46.0 mg, 85.0 μmol), 11i was
obtained (dichloromethane/ethyl acetate, 90:10) as a colorless oil in
62% yield (29 mg). [α]2D0 = +69.0 (c = 0.52, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.33–1.38 (m, 1 H), 1.42–1.67 (m, 6
H), 1.73–1.82 (m, 1 H), 1.95–2.01 (m, 1 H), 2.08–2.13 (m, 1 H),
Compound 11e: Following the procedure for the intramolecular
Diels–Alder reaction starting from 9e (23.0 mg, 37.7 μmol), 11e was
obtained (petroleum ether/ethyl acetate, 70:30) as a colorless oil in
78% yield (18 mg). [α]2D0 = +144.7 (c = 0.93, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 0.96–1.09 (m, 1 H), 1.69–1.80 (m, 2 2.14–2.21 (m, 1 H), 2.21–2.29 (m, 1 H), 2.39 (s, 3 H), 2.42 (s, 3 H),
H), 1.81–1.91 (m, 2 H), 1.96–2.05 (m, 1 H), 2.23–2.31 (m, 2 H), 2.81–2.89 (m, 1 H), 3.10–3.15 (m, 1 H), 3.69 (s, 3 H), 3.78–3.83 (m,
2.38–2.52 (m, 2 H), 2.40 (s, 3 H), 2.46 (s, 3 H), 2.99–3.04 (m, 1 H), 1 H), 4.46–4.53 (m, 1 H), 5.41–5.44 (m, 1 H), 7.19–7.32 (m, 4 H),
3.12–3.20 (m, 1 H), 3.85–3.92 (m, 1 H), 4.28–4.38 (m, 1 H), 5.49–
5.53 (m, 1 H), 7.22–7.34 (m, 4 H), 7.51–7.60 (m, 2 H), 7.62–7.70
(m, 1 H), 7.73–7.80 (m, 2 H), 7.83–7.93 (m, 4 H) ppm. 13C NMR
7.71–7.78 (m, 2 H), 7.81–7.87 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 20.7 (CH2), 21.2 (CH2), 21.5 (CH3), 21.6 (CH3),
27.4 (CH2), 30.0 (CH2), 30.2 (CH), 30.9 (CH2), 40.2 (CH), 41.8
(75 MHz, CDCl3, 25 °C): δ = 20.2 (CH2), 21.5 (CH3), 21.6 (CH3), (CH2), 42.4 (CH), 52.0 (CH3), 52.1 (CH), 118.2 (CH), 126.6 (2ϫ
24.6 (CH2), 27.1 (CH2), 27.2 (CH2), 36.2 (CH), 45.3 (CH), 52.5
(CH2), 59.3 (CH), 62.0 (CH), 112.3 (CH), 126.5 (2ϫ CH), 127.4
(2ϫ CH), 129.0 (2ϫ CH), 129.1 (2ϫ CH), 129.2 (2ϫ CH), 129.8
(2ϫ CH), 133.8 (CH), 135.5 (Cq), 137.5 (Cq), 141.0 (Cq), 142.6
CH), 127.3 (2ϫ CH), 129.1 (2ϫ CH), 129.8 (2ϫ CH), 136.3 (Cq),
141.1 (Cq), 141.9 (Cq), 142.5 (Cq), 144.3 (Cq), 174.9 (Cq) ppm.
IR: ν = 2948, 1730, 1597, 1436, 1315, 1303, 1251, 1197, 1152, 1102,
˜
1088, 1071, 1016, 959, 913, 813, 705, 702, 655 cm–1. HRMS (ESI):
calcd. for C28H35N2O5S2 [M + H]+ 543.1987; found 543.1981.
(Cq), 144.7 (Cq), 146.9 (Cq) ppm. IR: ν = 2927, 1596, 1445, 1299,
˜
1248, 1147, 1105, 1079, 1018, 1015, 998, 938, 807, 757, 723, 698,
656 cm–1. HRMS (ESI): calcd. for C31H35N2O5S3 [M + H]+
611.1708; found 611.1704.
Compound 12: Following the procedure for the intramolecular
Diels–Alder reaction starting from 10 (18.0 mg, 35.0 μmol), 12 was
obtained (dichloromethane/ethyl acetate, 98:2) as a colorless oil in
99% yield (18 mg). 1H NMR (300 MHz, CDCl3, 25 °C): dia-
stereoisomer A 7/diastereoisomer B 1 δ = 1.72–1.82 (m, 2 H), 2.01–
2.09 (m, 1 H), 2.21–2.37 (m, 3 H), 2.40 (s, 3 H), 2.43 (s, 3 H), 2.66–
2.72 (m, 1 H), 2.74–2.80 (m, 1 H), 2.81–2.86 (m, 1 H), 3.01–3.07
(m, 1 H), 3.59–3.64 (m, 1 H), 3.68 (s, 3 H), 4.49–4.57 (m, 1 H),
4.69–4.74 (m, 1 H), 5.40–5.43 (m, 1 H), 5.72–5.75 (m, 1 H), 7.22–
7.32 (m, 4 H), 7.74–7.76 (m, 2 H), 7.87–7.89 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): diastereoisomer A 7/diastereoiso-
mer B 1 δ = 21.5 (CH3), 21.6 (CH3), 24.0 (CH2), 24.8 (CH2), 31.9
Compound 11f: Following the general procedure for the intramo-
lecular Diels–Alder reaction starting from 9f (37.0 mg, 67.7 μmol),
11f was obtained (dichloromethane 100%) as a colorless oil in 54%
yield (20 mg). [α]2D0 = +55.9 (c = 1.08, CHCl3). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 1.31–1.38 (m, 1 H), 1.83–1.90 (m, 2 H), 2.02–
2.12 (m, 2 H), 2.12–2.18 (m, 1 H), 2.26–2.34 (m, 2 H), 2.42 (s, 3
H), 2.43 (s, 3 H), 2.45–2.48 (m, 1 H), 2.50–2.60 (m, 1 H), 3.00–3.07
(m, 1 H), 3.12–3.20 (m, 1 H), 3.67–3.74 (m, 1 H), 4.29–4.41 (m, 1
H), 5.36–5.40 (m, 1 H), 7.17–7.22 (m, 2 H), 7.23–7.26 (m, 1 H),
7.27–7.33 (m, 6 H), 7.81–7.84 (m, 2 H), 7.93–7.96 (m, 2 H) ppm. (CH2), 32.1 (CH2), 33.6 (CH), 38.7 (CH), 41.4 (CH), 46.4 (CH),
13C NMR (75 MHz, CDCl3, 25 °C): δ = 20.7 (CH2), 21.53 (CH3), 51.5 (CH2), 52.1 (CH3), 65.6 (CH), 116.3 (CH), 126.6 (2ϫ CH),
21.54 (CH3), 27.0 (CH2), 27.7 (CH2), 33.1 (CH2), 36.2 (CH), 41.4 127.3 (2ϫ CH), 129.1 (2ϫ CH), 129.8 (2ϫ CH), 136.0 (Cq), 141.1
(CH), 45.8 (CH), 53.0 (CH2), 60.0 (CH), 123.2 (CH), 126.2 (CH), (Cq), 142.2 (Cq), 142.5 (Cq), 144.4 (Cq), 174.8 (Cq) ppm. IR: ν =
˜
126.6 (2ϫ CH), 127.5 (2ϫ CH), 127.8 (2ϫ CH), 128.4 (2ϫ CH), 2953, 1732, 1597, 1436, 1315, 1250, 1152, 1053, 1015, 911, 814,
129.2 (2ϫ CH), 129.7 (2ϫ CH), 135.8 (Cq), 138.7 (Cq), 141.2 (Cq), 728, 656 cm–1. HRMS (ESI): calcd. for C26H34N3O5S2 [M +
142.5 (Cq), 144.5 (Cq), 147.0 (Cq) ppm. IR: ν = 2925, 1597, 1449,
NH4]+ 532.1940; found 532.1932.
˜
1302, 1247, 1151, 1063, 1015, 813, 757, 701, 654 cm–1. HRMS
(ESI): calcd. for C31H35N2O3S2 [M + H]+ 547.2089; found
547.2100.
Compound 13: A solution of 7a (235 mg, 0.481 mmol) in dichloro-
methane (3.4 mL) was added dropwise at 0 °C to a solution of
acryloyl chloride (47.0 μL, 0.577 mmol) in dichloromethane
(2 mL). Triethylamine (78.3 μL, 0.577 mmol) was then added and
the reaction mixture was stirred at room temperature overnight.
The solvent was removed under reduced pressure and the resulting
residue was purified by column chromatography on silica gel (pe-
troleum ether/ethyl acetate, 70:30) affording a colorless oil in 77%
yield (201 mg), m.p. 167–168 °C. [α]2D0 = +258.8 (c = 0.84, CHCl3).
1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.32–1.46 (m, 1 H), 1.76–
Compound 11h: Prepared following the typical Mitsunobu pro-
cedure from 7a and propargylic alcohol. Corresponding product
9h, which was obtained (petroleum ether/ethyl acetate, 70:30) as a
colorless oil in 80% yield (63.0 mg), was directly engaged in the
intramolecular Diels–Alder reaction because of its low stability.
Following the general procedure starting from 9h (60.0 mg,
0.114 mmol), 11h was obtained (dichloromethane/ethyl acetate,
Eur. J. Org. Chem. 2014, 66–79
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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75

M. Mazurais, C. Lescot, P. Retailleau, P. Dauban
FULL PAPER
1.89 (m, 3 H), 2.15–2.25 (m, 1 H), 2.26–2.33 (m, 2 H), 2.39–2.43
(dd, J = 15.2, 2.5 Hz, 1 H), 3.52–3.60 (dd, J = 15.0, 4.9 Hz, 1 H),
(m, 1 H), 2.41 (s, 6 H), 2.44–2.47 (m, 1 H), 2.77–2.88 (m, 1 H), 4.85–4.96 (m, 2 H), 5.37–5.43 (m, 1 H), 5.50–5.64 (ddt, J = 17.0,
3.25–3.36 (m, 1 H), 3.66 (s, 3 H), 4.62–4.73 (m, 1 H), 5.41–5.45 (m,
10.5, 6.6 Hz, 1 H), 6.50–6.52 (d, J = 7.4 Hz, 1 H), 7.04–7.13 (m, 2
H), 7.20–7.28 (m, 3 H), 7.30–7.36 (m, 2 H), 7.85–7.92 (m, 4
1 H), 7.25–7.34 (m, 4 H), 7.87–7.95 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 19.8 (CH2), 21.5 (CH3), 21.7 (CH3), H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 21.7 (CH3), 21.8
23.6 (CH2), 23.7 (CH2), 26.2 (CH2), 40.0 (CH), 41.4 (CH), 41.7
(CH3), 35.8 (CH2), 38.3 (CH2), 44.6 (CH2), 57.6 (CH), 117.2 (CH2),
(CH), 52.1 (CH3), 59.1 (CH), 119.3 (CH), 126.7 (2ϫ CH), 128.3
123.42 (CH), 123.48 (CH), 126.9 (2ϫ CH), 127.6 (CH), 127.7 (2ϫ
(2ϫ CH), 129.3 (2ϫ CH), 129.6 (2ϫ CH), 134.2 (Cq), 140.2 (Cq), CH), 129.4 (2ϫ CH), 129.8 (CH), 130.2 (2ϫ CH), 134.9 (CH),
141.2 (Cq), 143.1 (Cq), 145.8 (Cq), 172.1 (Cq), 174.2 (Cq) ppm. 136.1 (Cq), 141.2 (Cq), 142.7 (Cq), 142.9 (Cq), 143.4 (Cq), 144.9
IR: ν = 2952, 1750, 1733, 1596, 1323, 1263, 1156, 1101, 1091, 1067, (Cq) ppm. IR: ν = 2930, 1597, 1456, 1317, 1257, 1207, 1153, 1068,
˜
˜
1016, 658 cm–1. HRMS (ESI): calcd. for C27H31N2O6S2 [M + H]+ 1015, 961, 914, 855, 813, 747, 704 cm–1. HRMS (ESI): calcd. for
543.1624; found 543.1620.
C26H29N2O3S2 [M + H]+ 481.1620; found 481.1622.
Compound 14: Prepared following the typical amination procedure
from benzocyclobutene. Corresponding amination product was ob-
tained (dichloromethane/ethyl acetate, 20:1) as a white solid in 82%
yield and 16:1 dr (1H NMR evaluation), m.p. 158–159 °C. 1H
Compound 15c: Prepared following the typical Mitsunobu pro-
cedure from 14 (100 mg, 0.234 mmol) and 3-methylbut-3-en-1-ol
(46.5 μL, 0.469 mmol). Corresponding product 15c was obtained
1
(dichloromethane) as a yellow oil in 70% yield (80 mg). H NMR
NMR (300 MHz, CDCl3, 25 °C): diastereoisomer
A
16/dia-
(300 MHz, CDCl3, 25 °C): diastereoisomer A 10/diastereoisomer B
1 δ = 1.48 (s, 3 H), 2.18–2.29 (m, 2 H), 2.38 (s, 3 H), 2.44 (s, 3 H),
2.45 (s, 3 H), 3.08–3.32 (m, 3 H), 3.51–3.60 (dd, J = 15.0, 5.1 Hz,
1 H), 4.42–4.47 (m, 1 H), 4.59–4.64 (m, 1 H), 4.70–4.72 (m,
1 H), 5.39–5.44 (m, 1 H), 5.53–5.58 (m, 1 H), 6.42–6.45 (d, J =
7.7 Hz, 1 H), 6.55–6.58 (d, J = 7.7 Hz, 1 H), 7.04–7.14 (m, 2 H),
7.20–7.28 (m, 3 H), 7.30–7.36 (m, 2 H), 7.83–7.93 (m, 4 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): diastereoisomer A 10/dia-
stereoisomer B 1 δ = 21.75 (CH3), 21.83 (CH3), 22.5 (CH3), 32.2
stereoisomer B 1 δ = 2.34 (s, 3 H), 2.38 (s, 3 H), 2.83–2.88 (dd, J =
14.7, 2.6 Hz, 1 H), 3.04–3.11 (dd, J = 14.7, 2.6 Hz, 1 H), 3.29–3.34
(dd, J = 14.6, 5.1 Hz, 1 H), 3.51–3.56 (dd, J = 14.6, 5.1 Hz,
1 H), 4.71–4.79 (m, 1 H), 6.20–6.23 (d, J = 9.4 Hz, 1 H), 6.51–6.54
(d, J = 9.4 Hz, 1 H), 6.91–6.98 (dd, J = 12.4, 7.1 Hz, 1 H), 7.10–
7.20 (m, 4 H), 7.25–7.28 (d, J = 8.4 Hz, 1 H), 7.74–7.83 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): diastereoisomer A
16/diastereoisomer B 1 δ = 21.56 (CH3), 21.64 (CH3), 39.7 (CH2),
52.5 (CH), 123.0 (CH), 123.2 (CH), 126.8 (2ϫ CH), 127.7 (CH), (CH2), 32.8 (CH2), 38.4 (CH2), 39.5 (CH2), 44.0 (CH2), 57.6
127.9 (2ϫ CH), 129.2 (2ϫ CH), 129.8 (CH), 130.0 (2ϫ CH), 135.6
(Cq), 140.4 (Cq), 142.2 (Cq), 142.9 (Cq), 144.0 (Cq), 145.0
(CH), 112.2 (CH2), 123.5 (2ϫ CH), 126.9 (2ϫ CH), 127.6 (CH),
127.7 (2ϫ CH), 129.4 (2ϫ CH), 129.8 (CH), 130.2 (2ϫ CH), 136.3
(Cq), 141.2 (Cq), 142.6 (Cq), 142.8 (Cq), 142.9 (Cq), 143.4 (Cq),
(Cq) ppm. IR: ν = 3201, 1595, 1423, 1313, 1303, 1249, 1205, 1184,
˜
1156, 1105, 1090, 1015, 997, 949, 927, 881, 813, 752, 681 cm–1. 144.9 (Cq) ppm. IR: ν = 2928, 1597, 1493, 1455, 1374, 1317, 1303,
˜
HRMS (ESI): calcd. for C22H21N2O3S2 [M – H]– 425.0994; found
425.1010.
1259, 1153, 1088, 1064, 1015, 962, 892, 812, 759, 746, 700 cm–1.
HRMS (ESI): calcd. for C27H31N2O3S2 [M + H]+ 495.1776; found
495.1775.
Compound 15a: Compound 14 (60.0 mg, 0.141 mmol) was added
at room temperature to a solution of but-3-enoyl chloride (29.3 mg,
0.280 mmol) in dichloromethane (1.5 mL). Triethylamine (22.7 μL,
0.168 mmol) was then added and the reaction mixture was stirred
at room temperature overnight. The solvent was removed under
reduced pressure and the resulting residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate, 75:25)
affording a pale yellow oil in 47% yield (33 mg). 1H NMR
(300 MHz, CDCl3, 25 °C): diastereoisomer A 17/diastereoisomer B
1 δ = 2.39 (s, 3 H), 2.42 (s, 3 H), 3.26–3.31 (m, 2 H), 3.58–3.66 (dd,
Compound 15d: Prepared following the typical Mitsunobu pro-
cedure from 14 (125 mg, 0.293 mmol) and 4-pentenol (55.8 μL,
0.545 mmol). Corresponding product 15d was obtained (dichloro-
methane) as a yellow oil in 72% yield (103 mg). [α]2D0 = +83.4 (c =
1
0.74, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 1.59–1.69
(m, 2 H), 1.82–1.92 (m, 2 H), 2.38 (s, 3 H), 2.44 (s, 3 H), 3.02–3.17
(m, 2 H), 3.20–3.28 (dd, J = 15.0, 2.5 Hz, 1 H), 3.51–3.60 (dd, J =
15.0, 5.1 Hz, 1 H), 4.80–4.83 (m, 1 H), 4.84–4.88 (m, 1 H), 5.40–
5.44 (m, 1 H), 5.48–5.62 (ddt, J = 17.6, 9.7, 6.4 Hz, 1 H), 6.48–
J = 14.4, 3.2 Hz, 1 H), 3.51–3.55 (dd, J = 13.9, 5.4 Hz, 1 H), 3.69– 6.52 (d, J = 7.3 Hz, 1 H), 7.03–7.13 (m, 2 H), 7.20–7.28 (m, 3 H),
3.76 (dd, J = 13.9, 5.4 Hz, 1 H), 4.86–4.96 (m, 1 H), 5.03–5.09 (m,
1 H), 5.69–5.81 (m, 1 H), 5.81–5.86 (m, 1 H), 6.01–6.09 (m, 1 H)
7.30–7.37 (m, 2 H), 7.83–7.92 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 21.7 (CH3), 21.8 (CH3), 30.3 (CH2), 31.0 (CH2),
, 6.96–7.01 (m, 1 H), 7.06–7.12 (m, 1 H), 7.14–7.21 (m, 1 H), 7.22– 38.4 (CH2), 44.8 (CH2), 57.6 (CH), 115.3 (CH2), 123.41 (CH),
7.34 (m, 5 H), 7.82–7.94 (m, 4 H) ppm. 13C NMR (75 MHz, 123.44 (CH), 126.9 (2ϫ CH), 127.6 (CH), 127.7 (2ϫ CH), 129.4
CDCl3, 25 °C): diastereoisomer A 17/diastereoisomer B 1 δ = 21.8
(2ϫ CH), 129.8 (CH), 130.2 (2ϫ CH), 136.2 (Cq), 137.4 (CH),
(CH3), 21.9 (CH3), 39.7 (CH2), 39.9 (CH2), 42.6 (CH2), 42.8 141.2 (Cq), 142.7 (Cq), 142.8 (Cq), 143.5 (Cq), 144.8 (Cq) ppm.
(CH2), 56.3 (CH), 119.1 (CH2), 122.7 (CH), 123.4 (CH), 126.9 IR: ν = 2931, 1597, 1457, 1318, 1258, 1153, 1068, 1015, 970, 913,
˜
(2ϫ CH), 127.8 (CH), 128.1 (2ϫ CH), 129.3 (CH), 129.6 (2ϫ CH), 812, 752, 707 cm–1. HRMS (ESI): calcd. for C27H31N2O3S2 [M +
130.0 (2ϫ CH), 130.2 (CH), 135.6 (Cq), 140.4 (Cq), 141.0 (Cq),
H]+ 495.1776; found 495.1770.
143.5 (Cq), 145.1 (Cq), 145.9 (Cq), 172.1 (Cq) ppm. IR: ν = 2932,
˜
Compound 15e: Prepared following the typical Mitsunobu pro-
cedure from 14 (217 mg, 0.469 mmol) and (2-vinylphenyl)methanol
(126 mg, 0.939 mmol). Corresponding product 15e was obtained
(dichloromethane) as a yellow oil in 79% yield (202 mg). 1H NMR
(300 MHz, CDCl3, 25 °C): diastereoisomer A 13/diastereoisomer B
1 δ = 2.38 (s, 3 H), 2.44 (s, 3 H), 2.46 (s, 3 H), 2.93–3.02 (dd, J =
15.0, 2.6 Hz, 1 H), 3.09–3.17 (dd, J = 14.9, 5.3 Hz, 1 H), 3.34–3.42
(dd, J = 14.9, 5.3 Hz, 1 H), 4.28–4.34 (d, J = 16.1 Hz, 1 H), 4.35–
1708, 1596, 1400, 1324, 1267, 1211, 1155, 1107, 1088, 1070, 1015,
927, 814, 754, 685, 658 cm–1. HRMS (ESI): calcd. for
C26H27N2O4S2 [M + H]+ 495.1412; found 495.1391.
Compound 15b: Prepared following the typical Mitsunobu pro-
cedure from 14 (304 mg, 0.713 mmol) and 3-buten-1-ol (113 μL,
1.32 mmol). Corresponding product 15b was obtained (dichloro-
methane) as a yellow oil in 82% yield (281 mg). [α]2D0 = +88.4 (c =
1
0.70, CHCl3). H NMR (300 MHz, CDCl3, 25 °C): δ = 2.26–2.35 4.41 (d, J = 16.1 Hz, 1 H), 4.52–4.57 (d, J = 16.1 Hz, 1 H), 4.58–
(m, 2 H), 2.38 (s, 3 H), 2.44 (s, 3 H), 3.07–3.27 (m, 2 H), 3.23–3.31 4.63 (d, J = 16.1 Hz, 1 H), 5.07–5.13 (dd, J = 10.9, 1.5 Hz, 1 H),
76
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 66–79

A Short Asymmetric Synthesis of Octahydroindole Derivatives
5.35–5.44 (dd, J = 17.3, 1.5 Hz, 1 H), 5.56–5.60 (m, 1 H), 5.60–
5.66 (m, 1 H), 6.13–6.18 (d, J = 7.5 Hz, 1 H), 6.48–6.59 (dd, J =
17.3, 11.0 Hz, 1 H), 6.89–7.0 (m, 2 H), 7.11–7.19 (m, 3 H), 7.21–
7.25 (m, 2 H), 7.26–7.31 (m, 1 H), 7.32–7.38 (m, 3 H), 7.87–7.93
(m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): diastereoisomer
A 13/diastereoisomer B 1 δ = 21.7 (CH3), 21.8 (CH3), 37.1 (CH2),
(Cq), 42.4 (Cq), 48.1 (CH2), 48.3 (CH2), 68.0 (CH), 68.1 (CH),
126.3 (CH), 126.6 (CH), 126.9 (2ϫ CH), 127.0 (2ϫ CH), 127.49
(CH), 127.54 (CH), 127.6 (CH), 127.8 (CH), 127.9 (2ϫ CH),
128.2 (2ϫ CH), 129.29 (2ϫ CH), 129.31 (2ϫ CH), 129.8 (2ϫ
CH), 129.82 (2ϫ CH), 130.8 (CH), 131.0 (CH), 134.8 (Cq), 135.2
(Cq), 135.4 (Cq), 137.5 (Cq), 137.9 (Cq), 142.7 (Cq), 144.5 (Cq),
37.8 (CH2), 45.7 (CH2), 57.9 (CH), 58.4 (CH), 116.8 (CH), 123.3 144.6 (Cq) ppm. IR: ν = 2927, 1597, 1494, 1456, 1316, 1254, 1153,
˜
(CH), 123.5 (CH), 126.1 (CH), 127.0 (2ϫ CH), 127.4 (CH), 127.7 1103, 1067, 1014, 989, 813, 733, 655 cm–1. HRMS (ESI): calcd. for
(CH), 127.86 (2ϫ CH), 127.91 (CH), 128.8 (CH), 129.4 (2ϫ CH), C27H31N2O3S2 [M + H]+ 495.1776; found 495.1785.
129.7 (CH), 130.3 (2ϫ CH), 133.9 (CH), 134.5 (Cq), 135.7 (Cq),
136.7 (Cq), 141.2 (Cq), 142.86 (Cq), 142.89 (Cq), 142.94 (Cq),
Compound 16d: Following the procedure for the intramolecular
Diels–Alder reaction starting from 15d (48.0 mg, 0.088 mmol) in
145.0 (Cq) ppm. IR: ν = 2925, 1596, 1491, 1455, 1318, 1259, 1207,
˜
octane, 16d was obtained (dichloromethane/ethyl acetate, 90:10) as
a pale yellow oil in 96% yield (46 mg) with two diastereoisomers
(1.6:1). 1H NMR (300 MHz, CDCl3, 25 °C): diastereoisomer A 1.6/
diastereoisomer B 1 δ = 1.33–1.41 (m, 3 H), 1.51–1.62 (m, 1 H),
1.62–2.04 (m, 3 H), 2.36 (s, 3 H), 2.37 (s, 3 H), 2.42 (s, 3 H), 2.59–
2.79 (m, 2 H), 2.80–2.97 (m, 1 H), 3.67–3.71 (d, J = 14.5 Hz,
1 H), 4.04–4.09 (d, J = 14.5 Hz, 1 H), 5.21–5.22 (d, J = 4.4 Hz, 1
H), 5.37–5.39 (d, J = 4.5 Hz, 1 H), 7.00–7.23 (m, 5 H), 7.27–7.33
(m, 2 H), 7.65–7.93 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): diastereoisomer A 1.6/diastereoisomer B 1 δ = 21.5 (CH3),
21.6 (CH3), 23.3 (CH2), 23.4 (CH2), 23.8 (CH2), 24.1 (CH2), 24.27
(CH2), 24.34 (CH2), 23.25 (CH2), 27.32 (CH2), 32.2 (CH), 32.9
(CH), 40.2 (CH2), 42.6 (CH2), 56.7 (CH), 57.1 (CH), 126.5
(CH), 126.6 (CH), 126.7 (2ϫ CH), 126.9 (2ϫ CH), 127.0 (2ϫ
CH), 127.1 (2ϫ CH), 127.6 (CH), 128.0 (CH), 128.8 (CH), 129.0
(CH), 129.1 (2ϫ CH), 129.2 (2ϫ CH), 129.9 (CH), 130.0 (2ϫ
CH), 132.9 (Cq), 130.0 (Cq), 136.8 (Cq), 137.1 (Cq), 138.1 (Cq),
141.1 (Cq), 142.3 (Cq), 142.5 (Cq), 144.2 (Cq), 144.4 (Cq) ppm.
1154, 1105, 1099, 1078, 1015, 977, 911, 838, 812, 751, 728 cm–1.
HRMS (ESI): calcd. for C31H31N2O3S2 [M + H]+ 543.1776; found
543.1741.
Compound 16b: Following the procedure for the intramolecular
Diels–Alder reaction starting from 15b (85.0 mg, 0.177 mmol) in
octane, 16b was obtained (petroleum ether/ethyl acetate, 75:25) as
a pale yellow oil in 90% yield (77 mg) with two diastereoisomers
(2:1).
Diastereoisomer A (29%): [α]2D0 = –3.9 (c = 0.62, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.66–1.81 (m, 2 H), 1.99–2.12 (m, 2
H), 2.37 (s, 3 H), 2.39 (s, 3 H), 2.56–2.67 (m, 1 H), 2.69–2.80 (m,
1 H), 2.82–2.90 (m, 1 H), 2.91–3.00 (m, 1 H), 3.54–3.63 (m, 1 H),
5.36–5.39 (d, J = 8.1 Hz, 1 H), 7.02–7.07 (m, 1 H), 7.13–7.18 (m,
2 H), 7.21–7.30 (m, 4 H), 7.69–7.72 (m, 1 H), 7.82–7.91 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 21.76 (CH3),
21.81 (CH3), 24.5 (CH2), 25.9 (CH2), 29.4 (CH2), 37.5 (CH), 48.8
(CH2), 61.2 (CH), 126.7 (CH), 126.9 (2ϫ CH), 127.2 (CH), 128.3
(2ϫ CH), 128.4 (CH), 129.4 (2ϫ CH), 130.0 (CH), 130.1 (2ϫ CH),
135.7 (Cq), 136.0 (Cq), 137.4 (Cq), 141.3 (Cq), 142.7 (Cq), 145.0
IR: ν = 2925, 1598, 1501, 1472, 1317, 1252, 1154, 1067, 1062, 1016,
˜
954, 933, 813, 746 cm–1. HRMS (ESI): calcd. for C27H31N2O3S2
[M + H]+ 495.1776; found 495.1782.
(Cq) ppm. IR: ν = 2924, 1597, 1492, 1453, 1316, 1245, 1151, 1062,
˜
Compound 16e: Following the procedure for the intramolecular
Diels–Alder reaction starting from 15e (48.0 mg, 0.088 mmol), 16e
was obtained (dichloromethane/ethyl acetate, 90:10) as a pale yel-
1014, 812, 745, 703 cm–1. HRMS (ESI): calcd. for C26H29N2O3S2
[M + H]+ 481.1620; found 481.1621.
Diastereoisomer B (61%): [α]2D0 = +94.8 (c = 1.03, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 1.48–1.56 (m, 1 H), 1.60–1.68
(m, 2 H), 1.75–1.81 (m, 1 H), 1.87–1.99 (m, 1 H), 2.04–2.14 (m, 1
H), 2.37 (s, 3 H), 2.41 (s, 3 H), 2.48–2.59 (m, 1 H), 2.62–2.75 (m,
1 H), 3.41–3.48 (m, 1 H), 4.84–4.87 (d, J = 7.9 Hz, 1 H), 6.98–7.02
(m, 1 H), 7.11–7.18 (m, 1 H), 7.18–7.23 (m, 3 H), 7.26–7.29 (m, 2
H), 7.77–7.80 (m, 3 H), 7.85–7.88 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 21.76 (CH3), 21.80 (CH3), 24.5
(CH2), 26.0 (CH2), 29.2 (CH2), 37.5 (CH), 49.1 (CH2), 61.2 (CH),
126.88 (CH), 126.92 (2ϫ CH), 127.4 (CH), 127.8 (2ϫ CH), 127.9
(CH), 129.3 (2ϫ CH), 130.0 (CH), 130.1 (2ϫ CH), 134.5 (Cq),
134.7 (Cq), 137.1 (Cq), 141.1 (Cq), 142.8 (Cq), 144.7 (Cq) ppm.
1
low oil in 96% yield (46 mg) with two diastereoisomers (2.4:1). H
NMR (300 MHz, CDCl3, 25 °C): diastereoisomer
A 2.4/dia-
stereoisomer B 1 δ = 1.91–2.04 (m, 1 H), 2.29 (s, 3 H), 2.29 (s, 3
H), 2.34–2.41 (m, 1 H), 2.35 (s, 3 H), 2.38 (s, 3 H), 2.41–2.50 (m,
2 H), 2.96–3.03 (m, 1 H), 3.39–3.46 (m, 1 H), 3.99–4.05 (d, J =
17.1 Hz, 1 H), 4.26–4.32 (d, J = 17.8 Hz, 1 H), 4.55–4.60 (d, J =
17.4 Hz, 1 H), 4.94–5.00 (d, J = 17.8 Hz, 1 H), 5.47–5.49 (d, J =
6.4 Hz, 1 H), 5.75–5.77 (d, J = 6.3 Hz, 1 H), 6.74–6.92 (m, 2 H),
7.01–7.27 (m, 10 H), 7.63–7.65 (m, 1 H), 7.71–7.80 (m, 1 H), 7.83–
7.86 (m, 2 H), 7.88–7.91 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): diastereoisomer A 2.4/diastereoisomer B 1 δ = 21.65
(CH3), 21.68 (CH3), 21.70 (CH3), 21.73 (CH3), 24.1 (CH2), 24.3
(CH2), 25.57 (CH2), 25.64 (CH2), 33.4 (CH), 34.4 (CH), 42.9
(CH2), 45.1 (CH2), 55.5 (CH), 56.4 (CH), 125.9 (CH), 126.0
(CH), 126.3 (CH), 126.4 (CH), 126.6 (CH), 126.79 (2ϫ CH),
126.83 (CH), 127.0 (2ϫ CH), 127.1 (2ϫ CH), 127.2 (2ϫ CH),
127.3 (CH), 127.38 (CH), 127.43 (CH), 127.5 (CH), 127.8 (CH),
128.0 (CH), 128.5 (CH), 128.9 (CH), 129.1 (CH), 129.3 (2ϫ
CH), 129.4 (2ϫ CH), 129.8 (2ϫ CH), 129.9 (2ϫ CH), 131.7
(Cq), 132.2 (Cq), 132.5 (Cq), 132.7 (Cq), 133.9 (Cq), 134.3
(Cq), 136.6 (Cq), 137.0 (Cq), 138.0 (Cq), 138.2 (Cq), 141.2 (Cq),
IR: ν = 2928, 1602, 1492, 1460, 1312, 1288, 1154, 1065, 1062, 1008,
˜
812, 754, 658 cm–1. HRMS (ESI): C26H29N2O3S2 [M + H]+
481.1620; found 481.1631.
Compound 16c: Following the procedure for the intramolecular
Diels–Alder reaction starting from 15c (57.0 mg, 0.115 mmol) in
octane, 16c was obtained (petroleum ether/ethyl acetate, 50:50) as
a pale yellow oil in 47% yield (27 mg) with two diastereoisomers
(1.6:1). 1H NMR (300 MHz, CDCl3, 25 °C): diastereoisomer A 1.6/
diastereoisomer B 1 δ = 0.65 (s, 3 H), 1.08 (s, 3 H), 1.52–1.70 (m,
3 H), 1.77–1.87 (m, 1 H), 2.34 (s, 3 H), 2.36 (s, 6 H), 2.50–2.75
(m, 2 H), 3.02–3.12 (m, 1 H), 3.41–3.50 (m, 1 H), 3.51–3.67 (m, 1
H), 4.46 (s, 1 H), 4.67 (s, 1 H), 6.95–7.02 (m, 1 H), 7.05–7.23 (m,
6 H), 7.61–7.73 (m, 2 H), 7.81–7.93 (m, 3 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): diastereoisomer A 1.6/diastereoisomer B
142.6 (Cq), 142.8 (Cq), 144.5 (Cq), 144.6 (Cq) ppm. IR: ν = 2900,
˜
1598, 1495, 1450, 1320, 1249, 1153, 1103, 1062, 1015, 954, 932,
900, 864, 811, 769, 743, 703, 688, 673 cm–1. HRMS (ESI): calcd.
for C31H31N2O3S2 [M + H]+ 543.1776; found 543.1802.
Supporting Information (see footnote on the first page of this arti-
1 δ = 21.7 (CH3), 21.8 (CH3), 26.0 (CH3), 26.7 (CH3), 27.0 (CH2), cle): Copies of the 1H NMR and 13C NMR spectra of all com-
27.2 (CH2), 33.9 (CH2), 34.2 (CH2), 36.4 (CH2), 37.2 (CH2), 42.3 pounds, and crystallographic data for compound 13.
Eur. J. Org. Chem. 2014, 66–79
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
77

M. Mazurais, C. Lescot, P. Retailleau, P. Dauban
FULL PAPER
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Acknowledgments
The authors thank the Institut de Chimie des Substances Natu-
relles, the LabEx CHARM3AT (CHimie des ARchitectures Molé-
culaires Multifonctionnelles et des MATériaux), the European
Union (EU) (COST Action D40, Innovative Catalysis: New Pro-
cesses and Selectivities), and the Agence Nationale de la Recherche
(ANR-08-BLAN-0013-01, grant to C. L.) for financial support.
The Ministère de l’Enseignement Supérieur et de la Recherche
(MESR) is kindly acknowledged for a fellowship to M. M.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3
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Nat. Chem. 2013, 5, 510.
Received: August 2, 2013
Published Online: October 15, 2013
Eur. J. Org. Chem. 2014, 66–79
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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