Alkylation studies of a polyhydroxylated-cyano-piperidine scaffold

Article abstract of DOI:10.3998/ark.5550190.0015.403

Hexahydro-3-phenyl-6,7,8-trihydroxy-3R-[3α,5β,6β,7α, 8β,8aβ]-5H-oxazolo[3,2-a]pyridine-5- carbonitrile is endowed with two non equivalent reactive sites: an α-amino nitrile at the C-5 position and an α-amino ether at the C-8a position. Herein, alkylation

Full text of DOI:10.3998/ark.5550190.0015.403

General Papers
ARKIVOC 2014 (iv) 24-37
Alkylation studies of a polyhydroxylated-cyano-piperidine scaffold
Alicia M. Dilmaç,a Tony Tite,a Andriamihamina Tsimilaza,a Pascale Lemoine,b
Sabrina Boutefnouchet,a Sylvie Michela and Marie-Christine Lallemand a*
a Laboratoire de Pharmacognosie, UMR CNRS 8638 Université Paris Descartes, Sorbonne
Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 4, Avenue de l'Observatoire,
75006 Paris, France
bLaboratoire de Cristallographie et RMN Biologiques UMR CNRS 8015 Université Paris
Descartes, Sorbonne Paris Cité Faculté des Sciences Pharmaceutiques et Biologiques, 4, Avenue
de l'Observatoire, 75006 Paris, France
E-mail: marie-christine.lallemand@parisdescartes.fr
DOI:http://dx.doi.org/10.3998/ark.5550190.0015.403
Abstract
Hexahydro-3-phenyl-6,7,8-trihydroxy-3R-[3
carbonitrile is endowed with two non equivalent reactive sites: an
position and an -amino ether at the C-8a position. Herein, alkylation at the C-5 position was
α,5β
,6β
,7
α,8
β
,8aβ
]-5H-oxazolo[3,2-a]pyridine-5-
α-amino nitrile at the C-5
α
studied. The scope and limitations of these reactions have been investigated.
Keywords: Trihydroxy-cyano piperidine scaffold, alkylation studies, scope and limitations
Introduction
Polyhydroxylated piperidine and indolizidine alkaloids, called iminosugars, are important targets
in organic synthesis due to their potential value as glycosidase inhibitors.1-4 These compounds
have been designed as therapeutic solutions in several diseases5-10 (type II diabetes, viral and
bacterial infections, lysosomal storage disorders, tumor metastasis). They have also been found
in a number of natural11-16 or synthetic17-24 heterocyclic compounds, such as castanospermine and
N-butyl-deoxynojirimycin (N-butyl-DNJ) respectively (Figure 1).
Figure 1
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Chemists have been inspired by the numerous pharmacological activities of iminosugars, but
unfortunately some of them are also toxic to human cells. Nevertheless, there is still a need for
an easy access to alkaloid analogs and for the development of more potent, selective and less
toxic drug candidates. In this context, we decided to consider the chiral building block 1 (Figure
1) as starting material.25 As a part of our ongoing research program on the reactivity of
compound 1, we already reported a rapid access to substituted six- or seven- membered ring
iminosugars via ring-expansion reactions26 and a new asymmetric synthesis of (2S,3R,4R,5S)-
trihydroxypipecolic acid.27 In order to prepare indolizidine analogs such as castanospermine
derivatives, we have extended, herein, our research on the alkylation study at the C-5 position of
the building block 1 (Scheme 1). Compound 1 possesses two non-equivalent reactive sites on the
polyhydroxylated piperidine ring system: an
ether at the C-8a position.
α-amino nitrile at the C-5 position and an α-amino
Scheme 1
Results and Discussion
In this paper, we focus on the methylation reactions at the C-5 position. The scope and
limitations of this alkylation are discussed. Our purpose is to compare the reactivity of our
building block 1 with regard to the CN(R,S) synthon created by Husson’s group (Scheme 2),
under the same experimental conditions.28 Following the literature data,29 we studied the
methylation of 1 with iodomethane at
– 78 °C in THF in presence of lithium diisopropylamine.
First attempts were carried out on compound 1 without success. Therefore, it was decided to use
the protected form, which was obtained by benzylation of the hydroxyl functions (Scheme 2).26
In contrast with the CN(R,S) synthon, the treatment of 2 with LDA in the presence of
iodomethane gave two different products: the desired C5-alkylated compound 3 and an
α-
cyanoenamine 4, in 10% and 30% yield, respectively. The major compound 4 was obtained
through the elimination of the adjacent benzyloxy group. A careful analysis of 4 by 1H- and 13C-
NMR allowed the characterization of its structure. The typical NMR signals at
at
= 112.5 ppm, observed in the 1H and 13C NMR spectra respectively, were attributed to the C-
6 position.
δ = 5.29 ppm and
δ
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Scheme 2
As shown above, the
β
-elimination that took place was an obvious limitation for the access to
the desired C-5-alkylated derivatives. This prompted us to change the protecting group for the β-
hydroxyl function at the C-6 position to butane 2,3-bisacetal. This bisacetal was previously
applied to various sugars30-32 or shikimic derivatives33-36 and in spite of the creation of two new
stereogenic centers, the protection of vicinal diequatorial diols is described as being
stereoselective.10-37 Thus, the protection of hydroxyl functions of 1 with 2,2,3,3-
tetramethoxybutane, through stirring for a week in the presence of trimethylorthoformate and
catalytic camphorsulfonic acid, has been performed. A 1:2 mixture (NMR determination) of the
6,7-butane-bisacetal 5 and its regioisomer 6 (Scheme 3) were obtained.
Ph
Ph
Ph
TMB
trimethyl
orthoformate
O
O
O
O
NC
RO
N
NC
HO
N
NC
O
N
+
CSA, reflux
1 week
OH
OR
OMe
MeO
O
OH
O
1
MeO
6 R = H
OMe
MOMCl
DIPEA
Reflux, 3 hours
5
7
R = H
R = MOM
8
R = MOM
Scheme 3
Interestingly, an unexpected mixture of diastereoisomers on the butane 2,3-bisacetal
protection for compounds 5 and 6, is formed. After crystallizing the diastereoisomers 6 in diethyl
ether solution, this observation was confirmed by an X-Ray study. The stereochemistry of the
protecting group is represented in Figure 2.
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Figure 2
Structural features of interest of 6a and 6b, which crystallizes in the non-centrosymmetric
P21 21 21 space group, are collected in Table 1.
Table 1. Lengths (Å), angles and torsion (°) of interest for complex 6a and 6b
6a
6b
C7 O
C8 O
C2’ O
C3’ O
C2’ C3’
1.433(3)
1.437(4)
1.431(4)
1.436(4)
1.541(5)
1.440(3).
1.441(4)
1.424(4)
1.448(4)
1.546(5)
C7 O C2’
C7 C8 O
C3’ O C8
C2’ C3’ O
C3’ C2’ O
115.7(3)
110.9(2)
115.3(2)
111.1(3)
110.7(2)
111.9(2)
107.8(2)
113.1(3)
111.1(3)
110.5(3)
C7 - O - C2’ – C
C8 - O - C3’ – C
C7 - O - C2’ - O
C8 - O - C3’ - O
151.1(3)
151.0(3)
86.5(3)
87.4(3)
177.8(3)
175.4(3)
60.1(3)
62.2(4)
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The protecting group of 6a favors a twist boat conformation while a chair conformation is
1
preferred for 6b (Figure 2). H NMR studies indicated that after one week of reaction,
compounds 6 were present in a mixture 80/20 with prevalence for the twist boat conformation of
6a. After two weeks of reaction, compounds 6 were still a mixture 80/20, but now with
prevalence for the chair conformation of 6b. This result suggests a kinetic and a thermodynamic
form, with an equilibration to the more stable derivative under the acidic experimental
conditions. To the best of our knowledge, no report exists for the characterization of the twist
boat conformation with this stereochemistry, for the butane 2,3-bisacetal protection of vicinal
diequatorial diols.
To pursue our work on the alkylation, the protection of compounds 5 and 6 on their free
hydroxyl function was achieved by reacting with methoxymethyl chloride (MOMCl) in the
presence of Hünig’s base (Scheme 3). The structures of 7 and 8 were unambiguously deduced
from their spectral data. Indeed, in the HMBC spectrum of compound 7 the cross peaks,
observed between the triplet signal at
δ = 3.77 of H-8 proton and carbon signals at δ = 91.7 and δ
= 95.9, were attributed to C-8a and MOM methylene C-1’ positions (Figure 3). Based on the
HMBC correlation between H-6 and MOM methylene carbon (Figure 3), the structure of 8 was
in full agreement with the proposed skeleton.
Ph
Ph
O
O
O
O
NC
O
N
O
NC
O
N
8a
6
8
O
O
1'
OMe
MeO
O
MeO
OMe
7
8
Figure 3
Initial attempts towards the stereoselective alkylation at the C-5 position of compounds 7
1
(mixture 50/50 of 7a and 7b confirmed by H NMR), under classic conditions (LDA at – 78
°C), were unsuccessful and only starting material was recovered. In contrast, when HMPA was
added to the reaction and the temperature was gradually raised up to - 15 °C, lactams 9 were
obtained in 60% yield as confirmed by NMR and MS spectroscopy (δ 162.7 (CO); MS [M + H]+
424) and represented in Scheme 4. According to the literature,38 the lactam formation can be
explained by in situ addition of oxygen from the solvent to an extremely oxygen sensitive anion.
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Ph
Ph
O
O
NC
O
N
O
O
N
LDA, MeI
THF + HMPA
OMOM
OMOM
MeO
MeO
O
O
OMe
OMe
7
9 yield = 60%
Scheme 4
This result showed that the anion formation occurred and that the 6,7-butane-bisacetal
protection prevented the -elimination. However, the alkylation reaction probably failed because
β
of steric hindrance. In order to confirm this last hypothesis, we investigated the alkylation study
on the less hindered 7,8-butane-bisacetals 8 (Scheme 5). Alkylation of 8 with iodomethane
(LDA, THF,
– 78 °C) led to the formation of the unexpected β-methylated-α-cyanoenamines 10
(Scheme 5). These compounds were isolated in 77% yield after flash chromatography.
Ph
Ph
O
O
O
O
NC
N
NC
N
LDA, MeI
MOMO
THF, -78°C
OMe
OMe
O
O
MeO
MeO
10 yield = 77%
8
Scheme 5
These results suggested that the alkylation at
α-aminonitrile position was strongly dependant
on the adjacent substituent. In the presence of a leaving group, the enamine formation is favored,
whereas the presence of a sterically bulky group leads to the lactam derivative. Finally, we chose
to use the non protected compounds 6 as a starting material, as seen in Scheme 6.
Scheme 6
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Under similar conditions, compounds 6 are transformed into the corresponding alkylated
compound 11a and the lactams 12 in equivalent yield, based on recovered starting material.
Encouraged by this result, we decided to investigate the reactivity of the two diastereisomers
separately. In this context, we first studied reactivity of compound 6a. The alkylation reaction,
following the same procedure, led to a mixture of 11a and 12a in 60% and 40% yield
respectively. We then turned our attention to the second diasteroisomer 6b. Reaction of 6b
furnished the lactam 12b in quantitative yield. This result showed in our case the substrate-
dependent reactivity concerning the butane 2,3-bisacetal protection group. The above
observations led us to consider this method as a new and alternative access to alkylated or lactam
compound, with increased yields.
Conclusions
In conclusion, we have demonstrated that compound 6a is a useful building block for alkylation
reaction and that its diastereoisomer 6b allowed a selective access to the lactam scaffold.
Considering the high potential of so-called “azasugars” for drug discovery, we want to extend
this methodology to a new approach for the synthesis of indolizidine scaffold, through alkylation
with suitable side chains and subsequent cyclization on the nitrogen after elimination of the
chiral appendage. Efforts in this direction are currently being pursued in our laboratory.
Experimental Section
General. All reactions were carried out in dried glassware under an argon atmosphere. All
solvents were purchased with an analytical grade from SDS. Acetone and chloroform were dried
over molecular sieves. Reactions were monitored using thin-layer chromatography (TLC) carried
out on 0.25mm E. Merk silica gel plates (60F-254) using UV light as visualizing agent and
sulfuric vanillin heated as developing agent. Flash chromatography was performed with silica gel
CHROMATOGEL 60 (particle size 20-45 µm or 35-70 µm) supplied by SDS. Yield refers to
1
chromatography and spectroscopically pure compounds, unless otherwise noted. H NMR
spectra were recorded on a BRUCKER AC 300 MHz spectrometer or a BRUCKER AVANCE
400 MHz spectrometer. Chemical shifts are reported in ppm and coupling constants (J) in Hz.
13C NMR spectra were recorded on a BRUCKER AC 300 spectrometer at 75 MHz. The
assignments are based upon 1D and 2D spectra recorded using the following pulse sequences
from the Bruker standard pulse program library: DEPT, COSY, HSQC, HMBC and NOESY.
Mass spectra were measured with a ZQ 2000 Waters mass spectrometer (ESI). High resolution
mass spectra were obtained on a Q-ToF1 ESI mass spectrometer (Waters). Infra-red spectra were
recorded with a PerkinElmer spectrum 65 FT-IR spectrometer and wavelengths (ν) are given in
cm-1. Specific rotations were measured using a PerkinElmer model 341 polarimeter in a
chloroform solution at 20 °C.
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General procedure for the synthesis of 6,7,8-tribenzyloxy-5-methyl-3-phenylhexahydo-2H-
oxazolo[3,2-a]pyridine-5-carbonitrile (3) and 7,8-bisbenzyloxy-3-phenyl-3,7,8,8a-
tetrahydro-2H-oxazolo[3,2-a]pyridine-5-carbonitrile (4). To a solution of 2 (100 mg, 0.18
mmol) in dry THF (0.4 mL) under argon (– 78 °C), was added dropwise a solution of LDA 1.6
M in dry THF (0.32 mL, 0.72 mmol, 4 eq). After one hour at – 78 °C iodomethane (0.08 mL,
1.52 mmol, 8 eq.) was added and the reaction stirred at this temperature for 3 h. Then the
temperature was raised up gradually to 0 °C. The reaction was quenched with NH4Cl (sat) then
extracted with ethyl acetate (3 x 40 mL) . The combined organic layers was dried over anhydrous
Na2SO4, filtered and concentrated to dryness. After purification by chromatography on silica gel
using as eluent a mixture of cyclohexane/ether 9/1, 10 mg of 3 (10%) and 24 mg of 4 (30%) were
afforded as yellow oils.
1
Data for 3. Rf: 0.41 (cyclohexane/ether 8/2), IR ν cm-1: 2229 (CN), H NMR (400 MHz,
CDCl3): δ 1.13 (s, 3H, CH3), 3.35 (d, 1H, J = 9 Hz), 3.75 (dd, 1H, OH, J = 8 Hz, J = 9 Hz), 3.86
(t, 1H, J = 9 Hz), 3.89 (dd, 1H, J = 4.5 Hz, J = 8.5 Hz), 4.10 (dd, 1H, J = 4.5 Hz, J = 8.5 Hz),
4.37 (t, 1H, J = 8.5 Hz), 4.40 (d, 1H, J = 8 Hz), 4.59 (d, 1H, J = 11.5 Hz), 4.78 (d, 1H, J = 11.1
Hz), 4.80 (d, 1H, J = 11.5 Hz), 4.96 (d, 1H, J = 11.1 Hz), 4.99 (d, 1H, J = 11.5 Hz), 5.03 (d, 1H,
J = 11.5 Hz), 7.15-7.50 (m, 20 H, H-aro). 13C NMR (75 MHz, CDCl3): δ 24.2 (CH3), 59.9, 61.3,
74.0, 76.1, 76.3 (3 x CH2-Ph), 76.4, 81.4, 83.3, 84.3, 94.0, 117.3 (CN), 126.9, 127.5, 127.8,
128.0, 128.2, 128.7 (CArH), 137.5, 138.1, 138.5, 143.5 (CAr). MS (IC, NH3) : m/z [M + H]+ 561.
HRMS (IC, NH3) m/z: calcd. for C36H36N2O4Na [M+Na]+: 583.2573; found 583.2513.
Data for 4. Rf: 0.5 (cyclohexane/ether 8/2), IR ν cm-1: 2361 (CN), 1H NMR (400 MHz, CDCl3):
δ 3.84 (dd, 1H, J = 7.5 Hz, J = 8.5 Hz), 4.20 (dd, 1H, J = 1.5 Hz, J = 9 Hz), 4.35 (dd, 1H, J = 6
Hz, J = 9 Hz), 4.38 (ddd, 1H, J = 1 Hz, J = 3 Hz, J = 7.5 Hz), 4.6-4.7 (d, 2H, J = 11.5 Hz), 4.72
(dd, 1H, J = 1.5 Hz, J = 6 Hz), 4.87 (d, 1H, J = 8.5 Hz), 4.9-5.1 (d, 2H, J = 11.5 Hz), 5.29 (d, 1H,
13
J = 3 Hz), 7.20-7.50 (m, 15 H, H-aro). C NMR (75 MHz, CDCl3): δ 60.9, 72.3, 74.1, 74.9
(2XCH2Ph), 77.0, 78.1, 91.1, 112.5, 113.7 (CN), 127.3, 127.8, 128.1, 128.3, 128.5, 128.6 (CArH),
137.9, 138.2, 140.7 (CAr). MS (IC, NH3): m/z [M + H]+ 439. HRMS (IC, CH4) m/z: calcd. for
C28H26N2O3 [M+H]+: 439.2022; found 439.1995.
General procedure for the synthesis of 5-hydroxy-7,8-dimethoxy-7,8-dimethyl-3-phenyl-
octahydro-1,6,9-trioxa-3a-aza-cyclopenta[a]naphthalene-4-carbonitrile (5)
and
9-hydroxy-6,7-dimethoxy-6,7-dimethyl-3-phenyl-octahydro-1,5,8-trioxa-3a-aza-
β]naphthalene-4-carbonitrile (6). To a solution of trihydroxy derivative in dry
cyclopenta[
MeOH (2 mL), were added successively tetramethoxybutane (500 mg, 2.8 mmol, 2.5 eq.),
trimethylorthoformate (0.5 mL), and camphorsulfonic acid (0.1 mmol, 0.1 eq.). The solution was
refluxed for 1 week, then neutralized with NaHCO3 (220 mg). After extraction with CH2Cl2 (5 x
30 mL), the combined organic layers were washed with a saturated solution of NaHCO3, then
dried over Na2SO4 and evaporated to dryness. After purification by flash chromatography on
silica gel using as eluent a mixture of cyclohexane/ether 1/1, compound 5 was isolated as a
colorless oil (65 mg, 15%) and compound 6 as a white crystals (135 mg, 30%).
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Data for 5. Mp: 264 °C, Rf: 0.35 (cyclohexane/ether 1/1.5), IR ν cm-1: 3456 (OH), 2229 (CN),
1H NMR (400 MHz, CDCl3): δ 1.42, 1.44 (2 s, 6H, 2 CH3), 2.59 (d, 1H, OH, J = 3 Hz), 3.37,
3.41 (2 s, 6H, 2 OCH3), 3.80-3.90 (m, 1H), 3.88 (t, 1H, J = 8 Hz), 3.98 (d, 1H, J = 5.5 Hz), 4.05
(t, 1H, J = 8 Hz), 4.17 (dd, 1H, J = 8Hz, J = 10.5 Hz), 4.27 (d, 1H, J = 8 Hz), 4.28 (d, 1H, J =
10.5 Hz), 4.39 (t, 1H, J = 8 Hz), 7.30-7.40 (m, 5 H, C6H5). 13C NMR (75 MHz, CDCl3): δ 18.9
(2 CH3), 48.4 (OCH3), 48.5 (OCH3), 50.0, 62.7, 70.0, 72.5, 72.8, 74.9, 90.6, 101.8, 102.1 (Civ),
113.7 (CN), 127.8, 129.1, 129.2 (CArH), 135.9 (CAr). MS (IC, NH3): m/z [M + H]+ 391. HRMS
(IC, NH3) m/z: calcd. for C20H26N2O6Na [M+Na]+: 413.1689; found 413.1692
Data for 6. Rf: 0.25 (cyclohexane/ether 1/1.5), IR ν cm-1: 3450 (OH), 2229 (CN). 1H NMR (400
MHz, CDCl3): δ 1.41, 1.44 (2 s, 6H, 2 CH3), 2.57 (d, 1H, OH, J = 2.5 Hz), 3.41, 3.45 (2s, 6H, 2
OCH3), 3.69 (t, 1H, J = 9 Hz), 3.84 (dd, 1H, J = 9 Hz, J = 5 Hz), 4.0-4.10 (m, 1H), 4.27 (d, 1H, J
13
= 7.5 Hz), 4.33 (dd, 1H, J = 11 Hz, J = 5Hz), 4.30-4.40 (m, 2H), 7.30-7.40 (m, 5H, C6H5). C
NMR (75 MHz, CDCl3): δ 18.7, 18.8 (2 CH3), 47.8 (OCH3), 48.3 (OCH3), 48.9, 62.7, 69.8,
72.9, 73.5, 74.3, 91.6, 101.7, 102.0 (Civ), 113.9 (CN), 127.8, 129.0, 129.1 (CArH), 135.7 (CAr).
MS (IC, NH3): m/z [M + H]+ 391.
Crystallographic data for 6a. C20 H26 N2 O6, orthorhombic, P21 21 21, colorless, a =
6.9853(5) Å, b= 10.5499(6) Å, c = 26.538(2) Å, V= 1955.7(2) Å3, T = 293(2)K, Z = 4, Final R
(I > 2 σ(I)): R1 = 0.0463, wR2 = 0.0986, GOF = 1.070. Structural information for 6a has been
deposited with CCDC as 845878.
Crystallographic data for 6b. C20 H26 N2 O6, orthorhombic, P21 21 21, colorless, a =
6.6354(1) Å, b= 12.4162(2)(6) Å, c = 24.790(2)Å, V = 2042.4(2) Å3, T = 293(2)K, Z = 4, Final
R (I > 2 σ(I)): R1 = 0.0441, wR2 = 0.0834, GOF = 1.154. Structural information for 6b has been
deposited with CCDC as 845879.
General procedure for the synthesis of 6,7-dimethoxy-9-methoxymethoxy-6,7-dimethyl-3-
phenyl-octahydro-1,5,8-trioxa-3a-aza-cyclopenta[a]naphthalene-4-carbonitrile (7) and
7,8-dimethoxy-5-methoxymethoxy-7,8-dimethyl-3-phenyl-octahydro-1,6,9-trioxa-3a-aza-
cyclopenta[a]naphthalene-4-carbonitrile (8). To a solution of 5 (50 mg, 0.13 mmol) or of 6
(65 mg, 0.15 mmol) in dry CHCl3 (1 mL), was added at 0 °C methoxymethyl chloride (26 µL,
2.5 eq., 0.32 mmol) and N-N-diisopropylamine (68 µL, 3 eq., 0.4 mmol). The resulting mixture
was refluxed for 3 h, then let to cool down to rt. The solution was quenched with water and
extracted with dichloromethane (5 x 30 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered and evaporated to dryness. After purification by chromatography on
silica gel using as eluent a mixture of cyclohexane/ether 1/0.5) the compound 7 was recovered as
a colorless oil (7.5 mg, 77%).
1
Data for 7. Rf : 0.60 (cyclohexane/ether 1/1.5), H NMR (400 MHz, CDCl3): δ 1.34, 1.40 (2 s,
6H, 2 CH3), 3.40, 3.42, 3.52 (3s, 9H, 3 OCH3), 3.77 (t, 1H, J = 8 Hz), 3.83 (t, 1H, J = 8 Hz), 3.96
(d, 1H, J = 5.5 Hz), 3.99 (t, 1H, J = 8 Hz), 4.28 (d, 1H, J = 8 Hz), 4.30-4.40 (m, 2H, H-8), 4.46
(t, 1H, J = 10 Hz), 4.85-5.00 (2d, 2H, OCH2O, J = 6.5 Hz), 7.20-7.50 (m, 5H, C6H5). 13C NMR
(75 MHz, CDCl3): δ 18.7, 19.0 (2 CH3), 48.2, 48.8, 55.4 (3XOCH3), 62.5, 70.1, 72.3, 74.3, 75.4,
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91.7, 95.9 (OCH2O), 101.5, 101.8 (Civ), 113.9 (CN), 127.7 129.0, 129.2 (CArH), 135.9 (CAr). MS
(IC, NH3): m/z [M + H]+ 435. HRMS (IC, NH3) m/z: calcd. for C22H30N2O7Na [M+Na]+:
457.1951; found 457.1903.
Data for 8. Rf: 0.40 (cyclohexane/ether 1/1), IR ν cm-1: 2229 (CN). 1H NMR (400 MHz, CDCl3):
δ 1.42, 1.43 (2s, 6H, 2 CH3), 3.37, 3.40, 3.41 (3s, 9H, 3 OCH3), 3.81 (dd, 1H, J = 5.5 Hz, J = 10
Hz), 3.86 (t, 1H, J = 8 Hz), 4.00 (d, 1H, J = 5.5 Hz), 4.05 (t, 1H, J = 8 Hz), 4.19 (dd, 1H, J = 8
Hz, J = 10 Hz), 4.24 (d, 1H, J = 8Hz), 4.37 (t, 1H, J = 10 Hz), 4.38 (t, 1H, J = 8 Hz), 4.70, 4.79
(2d, 2H, OCH2O, J = 7 Hz), 7.20-7.50 (m, 5H, C6H5). 13C NMR (75 MHz, CDCl3): δ 18.8, 19.0
(2 CH3), 48.1 (OCH3), 48.3 (OCH3), 49.6, 56.2, 62.8, 71.8, 72.6, 74.6, 74.9, 90.2, 96.8 (OCH2O),
101.4, 101.7 (Civ), 113.6 (CN), 127.8, 129.1, 129.2 (CArH), 136.0 (CAr). MS (IC, NH3): m/z [M +
Na]+ 457. HRMS (IC, NH3) m/z: calcd. for C22H30N2O7Na [M+Na]+: 457.1951; found 457.1929.
Procedure for the synthesis of 6,7-dimethoxy-9-methoxymethoxy-6,7-dimethyl-3-phenyl-
octahydro-1,5,8-trioxa-3a-aza-cyclopenta[a]naphthalene-4-one (9). To a solution of 7 (13
mg, 0.03 mmol) in dry THF (100 µL) under argon and at – 78 °C, was added dropwise a solution
of LDA 2.5 M in dry THF (110 µL, 0.12 mmol, 4 eq) and HMPA (26 µL, 0.15 mmol, 5 eq).
After 20 min at – 78 °C iodomethane (15 µL, 0.24 mmol, 8 eq.) was added and the reaction was
stirred at this temperature for 3 h 30. Then the temperature was raised up gradually to – 15 °C for
2 h. The reaction was quenched with NH4Cl (sat) then extracted with CH2Cl2. The organic layer
was dried over anhydrous Na2SO4, filtered and concentrated to dryness. After purification by
chromatography on silica gel using as eluent a mixture of cyclohexane/ether 1/0.3, compound 9
was afforded as a yellow oil (8 mg, 60 %).
1
Data for 9. Rf : 0.5 (CH2Cl2/MeOH 9/1). H NMR (400 MHz, CDCl3) : δ 1.31, 1.49 (2s, 6H, 2
CH3), 3.20-3.60 (m, 9H, 3 OCH3), 4.05 (t, 1H, J = 8.5 Hz), 4.10-4.20 (m, 3H), 4.40-4.50 (m,
1H), 4.77 (d, 1H, J = 7.5 Hz), 4.86 (t, 1H, J = 8Hz), 4.94, 5.01 (2d, 2H, OCH2O, J = 7 Hz), 7.20-
7.60 (m, 5H, C6H5). 13C NMR (75 MHz, CDCl3): δ 17.5, 18.6 (2 CH3), 47.8, 48.2, 55.6
(3XOCH3), 58.1, 70.6, 72.7, 74.7, 74.8, 89.8, 96.1 (O-CH2-O), 99.6, 101.8 (Civ), 126.8 128.0,
128.9 (CArH), 139.9 (CAr), 162.7 (CO). MS (IC, NH3): m/z [M + H]+ 424.
General procedure for the alkylation reaction of 7,8-dimethoxy-5,7,8-trimethyl-1,3-phenyl-
2,3,7,8,9a,9b-hexahydro-5aH-1,6,9-trioxa-3a-aza- cyclopenta[a]naphthalene-4-carbonitrile
(10), of (2R, 3R, 4aR, 5S, 6R, 8R, 10aR, 10bS)-5-hydroxy-2,3-dimethoxy-2,3,6-trimethyl-8-
phenyloctahydro-2H-[1,4]dioxino[2,3−c]oxazolo[3,2-a]pyridine-6-carbonitrile (11a), of
(2R, 3R, 4aR, 5S, 8R, 10aR, 10bS)-5-hydroxy-2,3-dimethoxy-2,3-dimethyl-8-
phenylhexahydro-2H-[1,4]dioxino[2,3−c]oxazolo[3,2-a]pyridin-6(3H)-one (12a)
and of (2R, 3R, 4aR, 5S, 8R, 10aR, 10bS)-5-hydroxy-2,3-dimethoxy-2,3-dimethyl-8-
phenylhexahydro-2H-[1,4]dioxino[2,3−c]oxazolo[3,2-a]pyridin-6(3H)-one (12b). To
a
solution of 8, 6, 6a or 6b (0.025 mmol) in dry THF (40 µL) under argon (– 78 °C), was added
dropwise a solution of LDA 2.5 M in dry THF (0.1 mmol, 4 eq). After 15 min. at – 78 °C,
iodomethane (0.35 mmol, 14 eq.) was added and the reaction was stirred at this temperature for 3
h. The reaction was quenched with NH4Cl (sat) then extracted with CH2Cl2 (3 x 30 mL). The
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ARKIVOC 2014 (iv) 24-37
combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to
dryness. Purification by chromatography on silica gel was then performed using as eluent a
mixture of cyclohexane/ether, 9/1.
1
Data for 10. Rf : 0.5 (cyclohexane/ether 1/1), IR ν cm-1: 2223 (CN). H NMR (400 MHz,
CDCl3): δ 1.11-1.30 (3 s, 6H, 2 CH3), 1.62 (s, 3H, CH3), 2.90-3.20 (3 s, 6 H, 2 OCH3), 3.90-4.00
(m, 1H), 4.10 (dd, 1H, J = 6Hz, J = 8Hz), 4.17 (t, 1H, J = 9Hz), 4.49 (t, 1H, J = 6 Hz, J = 6.5
13
Hz), 4.56 (d, 1H, J = 10 Hz), 4.69 (d, 1H, J = 9 Hz), 7.10-7.30 (m, 5H, C6H5). C NMR (75
MHz, CDCl3): δ 14.1 (CH3), 19.0 (2 CH3), 47.8 (2 OCH3), 62.3, 69.6, 70.5, 74.6, 89.0, 102.1
(Civ), 111.0, 112.9, 114.1 (CN), 128-129 (CArH), 140.4 (CAr). MS (IC, NH3): m/z [M + Na]+ 409.
HRMS (IC, NH3) m/z: calcd. for C21H26N2O5Na [M+Na]+: 409.1739; found 409.1745.
Data for 11a. Rf 0.4 (cyclohexane/ether, 1:1), [α]D = -109 (c 0.58, MeOH); IR (film) cm-1: 3484
1
(OH). H NMR (CDCl3)
δ 1.20 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.44 (s, 3H, CH3), 3.38 (s, 3H,
OCH3), 3.41 (s, 3H, OCH3), 3.88 (dd, 1H, J = 4.7; 8.6 Hz), 4.13 (dd, J = 4.7; 8.6 Hz, 1H), 4.21-
4.30 (m, 3H), 4.36 (t, J = 8.6 Hz, 1H), 7.22-7.38 (m, 5H arom). 13C NMR (CDCl3):
19.1
δ
(2XCH3), 23.6 (CH3), 48.4 (OCH3), 48.5 (OCH3), 60.1, 61.5, 71.9, 73.0, 76.1, 76.6, 92.0, 101.8,
102.2, 117.3 (CN), 127.1, 128.0, 129.0 (CH arom), 143.2 (CIV arom). HRMS (ESI): calcd for
C21H29N2O6 [M+H]+: 405.2026; found 405.2026. calcd. for C20H27NO6Na [M-HCN+Na]+:
400.1736; found 401.1737.
Data for 12a. Rf 0.6 (dichloromethane/methanol, 9:1), [α]D = -26 (c 1.01, MeOH); IR (film) cm-
1: 3390 (OH), 1668 (CO); 1H NMR (CDCl3)
δ 1.45 (s, 3H, CH3), 1.47 (s, 3H, CH3), 3.40 (s, 6H,
OCH3), 3.91 (d, J = 8.2 Hz, 1H), 4.20 (d, J = 9.7 Hz, 1H), 4.27-4.35 (m, 1H), 4.36 -4.69 (m, 2H),
13
4.79 (d, J = 6.7 Hz, 1H), 4.88 (d, J = 6.5 Hz, 1H), 7.20-7.50 (m, 5H arom). C NMR (CDCl3):
δ
18.8 (CH3), 19.0 (CH3), 48.7 (OCH3), 48.8 (OCH3), 58.7, 70.8, 71.0, 72.7, 75.2, 89.3, 101.6,
101.7, 127.0-128.4-128.9 (CH arom), 139.9 (CIV arom). 166.0 (CO), MS (ES+, MeOH): m/z
[M+Na]+ 402; [2M+Na]+ 780. HRMS (ES) : calcd. for C19H25NO7Na [M+Na]+: 402.1529; found
402.1526.
Data for 12b. Rf 0.62 (dichloromethane/methanol, 9:1); IR (film) cm-1: 3390 (OH), 1670 (CO);
1H NMR (CDCl3)
δ
1.38 (s, 3H, CH3), 1.40 (s, 3H, CH3), 3.41 (s, 6H, OCH3), 4.05 (m, 2H), 4.18
(t, J = 8.1 Hz, 1H), 4.27-4.35 (m, 1H), 4.39 -4.49 (m, 2H), 4.95-4.97 (m, 2H), 7.20-7.50 (m, 5H
13
arom). C NMR (CDCl3):
δ 17.6 (CH3), 17.8.0 (CH3), 48.4 (OCH3), 48.6 (OCH3), 58.7, 68.5,
68.9, 70.5, 75.1, 87.7, 99.4, 99.06, 126.7-128.3-131.0 (CH arom), 139.9 (CIV arom). 166.2 (CO).
MS (ES+, MeOH): m/z [M+Na]+ 402; [2M+Na]+ 780. HRMS HRMS (ES): calcd. for
C19H25NO7Na [M+Na]+: 402.1529; found 402.1526.
Acknowledgements
Financial supports of this work by Université Paris Descartes, Sorbonne Paris Cité (grant to
Alicia M. Dilmaç) is gratefully acknowledged. We thank Drs. Xavier Cachet, Andy Gum and
François-Hugues Porée for proofreading of our manuscript.
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