Studies towards the synthesis of secoiridoids

Article abstract of DOI:10.1016/j.tet.2015.07.067

A new approach to secoiridoids, based on the synthesis of the key functionalized intermediates 4 and 5, is presented. These compounds were tested in formal [3+3] cycloadditions. Acyl-chloride 15 was transformed into enol α,β-unsaturated ester 16, which was involved in a N-heterocyclic carbene rearrangement to give an advanced precursor 17 in the total synthesis of secoiridoids.

Full text of DOI:10.1016/j.tet.2015.07.067

Accepted Manuscript
Studies towards the synthesis of secoiridoids
Shaoping Wu, Yongmin Zhang, Jyoti Agarwal, Emilie Mathieu, Serge Thorimbert, Luc
Dechoux
PII:
S0040-4020(15)01144-8
10.1016/j.tet.2015.07.067
TET 27012
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 June 2015
Revised Date: 24 July 2015
Accepted Date: 25 July 2015
Please cite this article as: Wu S, Zhang Y, Agarwal J, Mathieu E, Thorimbert S, Dechoux L, Studies
towards the synthesis of secoiridoids, Tetrahedron (2015), doi: 10.1016/j.tet.2015.07.067.
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ACCEPTED MANUSCRIPT
Studies towards the synthesis of secoiridoids
a,b,c
a,b,c
a,b
a,b
a,b,
Shaoping Wu , Yongmin Zhang , Jyoti Agarwal , Emilie Mathieu , Serge Thorimbert *, Luc
a,b,
Dechoux
*
a
Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 place Jussieu, F-75005
Paris, France
b
CNRS, UMR8232, IPCM, F-75005 Paris, France
Biomedicine Key Laboratory of Shaanxi Province, Northwest University, No. 229 Taibai North Road, Xi’an, Shaanxi
c
7
*
10069, PR China
Corresponding author. Tel.: + 33 1 44 27 30 84; e-mail address: serge.thorimbert@upmc.fr; luc.dechoux@upmc.fr
Graphical Abstract
CO Me
O
O
2
CO Me
2
H
6a
O
O
O
O
OH
OH
O
O
OAc
HO
OH
7a
OH
OH
CO Me
2
O
D-(-)-Mannitol
5
4
O
O
CO Et
2
CO Et
H
2
6
b
O
O
O
17
Abstract: A new approach to secoiridoids, based on the synthesis of the key functionalized
intermediates 4 and 5, is presented. These compounds were tested in formal [3+3]
cycloadditions. Acyl-chloride 15 was transformed into enol α,β-unsaturated ester 16 which
was involved in a N-Heterocyclic Carbene rearrangement to give an advanced precursor 17 in
the total synthesis of secoiridoids
Keywords: Secoiridoids / Gentiopicroside / Organocatalysis / [3+3] Cycloadditions / N-
Heterocyclic-Carbenes.
1
. Introduction
[
1]
The iridoid monoterpenes represent a large family of cyclopentanopyran natural products.
They usually occur as glucoside derivatives. Among them loganin is the biosynthetic
precursor of secologanin, a secoiridoid playing an important role in the biosynthesis of indole
[
2]
alkaloids. Moreover secologanin is also a key intermediate in the biosynthesis of
1

ACCEPTED MANUSCRIPT
[
3]
secoiridoids, such as sweroside, swertiamarin and gentiopicroside. The synthesis of this
[
4]
class of bioactive natural products continues to be an active area of research. Among these
[
5]
compounds, no total synthesis of gentiopicroside has been realized to date, and so, is still a
challenge for organic chemists.
O
O
O
O
O
O
CO Me
CHO CO Me
2
2
H
OH
HO
O
O
OGlc
O
O
O
H
OGlc
OGlc
OGlc
OGlc
Loganin
Secologanin
Sweroside
Swertiamarin
Gentiopicroside
Figure 1. Chemical structures of Loganin and selected secoiridoids.
The main strategies to the access to the 3,4-dihydropyran ring systems of iridoids or
secoiridoids are depicted in Scheme 1. G. Büchi’s group presented the first synthesis of an
iridoid glucoside (loganin) in 1970, the first step of the synthesis was a photochemical [2+2]
cycloaddition between 2-formylmalonaldehydic acid methyl ester and a cyclopentene
derivative followed by a rearrangment leading to loganin aglycone via an acetalization of the
[
6]
transient formed
δ
-di-aldehyde.
Similarly, Grée synthesized (-)-verbenalol and (-)-
epiverbenalol by ozonolysis of a diquinane intermediate, which led to the formation of the
[7]
[8]
[9]
iridoids. The same strategy was also used by Liao to synthesize (+/-)-forsythide. Chang
[
10]
synthesized secologanoside aglycone and Trost prepared loganine aglycone, respectively.
In fact, R. T. Brown was the first chemist who developed this strategy (oxidation and further
[
11]
acetalization of
δ
-di-aldehyde intermediates to form 3, 4-dihydropyran rings).
A second
strategy adopted by Tietze relied on an hetero [4+2] cycloaddition reaction as a key step for
[
12]
the convergent synthesis of the (±)-sweroside aglycone O-Et.
The intramolecular formal [4+2] enamine-enal cycloaddition, first described by
[
13]
Schreiber,
that iridoid systems could be obtained by domino enamine Michael addition-acetalisation.
has been used for the entry into the iridoid carbon skeleton. He demonstrated
[
14]
MacMillan
took advantage of this strategy in the total synthesis of brasolide and
littoralisone using catalytic amount of proline as organocatalyst. Using the same formal [4+2]
enamine-enal cycloaddition, similar iridoid scaffolds (without the ester function) were
[
15]
[16]
synthesized by C. Garcia’s group and J. E. Hofferberth , respectively. More recently D.
W. Lupton used N-heterocyclic carbenes to catalyze rearrangement of -unsaturated enol-
esters allowing the access to dihydropyranones possessing the monoterpene skeleton of the
α, β
[
17]
iridoid’s family.
2

ACCEPTED MANUSCRIPT
CO Me
2
H
H
CO Me
THPO
2
[2+2]
δ
-dialdehydes
HO
O
acetalization
O
OH
OH
Loganin aglycone (Büchi G.)
CO Me
2
O
H
H
Ozonolysis
H
CO Me
2
δ
-dialdehydes
HO
O
acetalization
H
OH
Forsythide aglycone (Liao C. C.)
-)-Epiverbenalol aglycone (Grée R.)
Secologanoside aglycone (Chang N. C.)
Elenolide (Brown R. T.)
(
Loganin aglycone (Trost B.M.)
Cl C
3
O
O
O
O
S
HDA
[
4+2] cycloaddition
S
O
PhS
O
OEt
OEt
Sweroside aglycone (Tietze L. F.)
TBSO
O
H
H
L-Proline
Enamine-enal
formal [4+2]
cycloaddition
O
O
O
OAc
Brasoside aglycone (MacMillan W. C.)
CO Me
2
H
CO Me
2
Formal
NH-Carbene
[
3+3]
O
cycloaddition
O
O
H
OGlc
Deoxyloganin (Lupton D. W.)
Scheme 1. Different strategies towards synthesis of iridoid or secoiridoid aglycones.
Few [3+3] cycloadditions have been described but only between activated
β
-diketones
with unsaturated aldehydes under
organocatalysis (with proline derivatives). In contrast non-activated -diketones or
ketoesters reacted with unsaturated aldehydes to give cyclopentanones
[
18]
[19]
(
coumarin derivatives)
or unsaturated β-ketoesters
β
β-
[
20]
and
[
21]
cyclohexenones,
respectively. To the best of our knowledge no formal direct [3+3]
3

ACCEPTED MANUSCRIPT
cycloaddition between two aldehydes (R = H) was explored in order to get 3,4-dihydropyran
3
scaffolds (Scheme 2).
E
E
E
[
3+3]
E
[
3+3]
R3
R1
R2
R
1
R3
R3
R1
R1
R2
R3
cycloaddition
cycloaddition
O
O
O
O
R2
R
2
OH
O
OH
O
-
-
-
-
Jorgensen (β-diketones)
Rovis (β-ketoesters)
Rueping (coumarine)
This study, R = H, E = ester
3
Gong (unsaturated β-ketoesters)
Scheme 2. [3+3] cycloaddition strategies.
At the origin of our study towards the total synthesis of gentiopicroside, we envisaged
such original approaches based on an organocatalyzed intermolecular [3+3] cycloaddition
between aldehyde B and enol ester C or an intramolecular [3+3] cycloaddition version from
precursor D. We thought that either an intermolecular [3+3] cycloaddition or an
intramolecular [3+3] cycloaddition relying on a domino enamine Michael addition
acetalisation (using secondary amines as catalyst) would operate. These approaches were
unfortunately inoperative. Nevertheless we wish to present here our study related to these two
approaches (pathways I and II, scheme 3) and in the mean time the efficient synthesis of the
α,β-unsaturated ester 4 (A) and α,β-unsaturated aldehyde 5 (B) which could be easily
prepared in few steps from D-(-)-manitol and methylcrotonate. These compounds could be
useful synthons in diverse cycloaddition processes and were finally used in the third
retrosynthetic strategy (pathway III). This one is based on a N-heterocyclic carbene catalyzed
rearrangement of
α,β-unsaturated enol-esters E (Scheme 3) which gave an advanced
intermediate H toward the synthesis of gentiopicroside.
4

ACCEPTED MANUSCRIPT
O
O
O
CO Et
CO Et
2
2
Intermolecular
O
[3+3] CA
O
O
pathway I
pathway II
C
O
F
OR
B
O
O
O
O
O
O
O
OH
OH
HO
O
O
O
OH
Intramolecular
[3+3] CA
PO
PO
OH OH
CO Me
2
O
CO Me
2
OR
G
O
CO Me
D
2
A
pathway III
O
O
O
CO Et
CO Et
2
2
NHC Cat.
O
O cycloaddition
O
O
O
H
E
Scheme 3. Retrosynthetic analysis of gentiopicroside.
2
. Results and Discussion
The Michael acceptor 5 was synthesized starting from D-(-)-manitol. Protection in standard
[
22]
conditions led to diacetonide 1. After an oxidative cleavage, addition of methyl crotonate
enolate onto the aldehyde 2 was performed. The alcohol function in 3 was mesylated and
eliminated to obtain the
However, slow change in the diastereomeric ratio from 3:2 to 8:2 was observed in favor of E
isomer over some days even at 0 . Finally the ester function of the mixture of both
diastereoisomers was reduced to alcohol using DIBAL-H then oxidized to afford aldehyde
α,β-unsaturated ester 4 with a 3:2 E:Z ratio (established by NOESY).
ꢀ
[
23]
[24]
[25]
[26]
5
.
Oxidation using PCC,
MnO2
or Dess-Martin conditions
gave the desired
aldehyde 5 in less then 20% yield whereas Parikh-Doering conditions gave the desired
[
23]
aldehyde 5 in 81% yields over two steps. The Michael acceptor 5 was thus obtained on a
gram scale (> 5g) stereoselectively as the thermodynamically more stable E isomer in 34%
overall yield from D-(-)-manitol (Scheme 4).
5

ACCEPTED MANUSCRIPT
OH
2,2-dimethoxypropane (2.4 eq.),
OH
4 2
NaIO -SiO (2.4 eq.),
DCM, 1 h, r.t.
OH
O
SnCl
2
(cat.), DME, reflux
O
O
HO
OH
O
53%
82%
O
OH
O
CHO
OH
OH
1
2
MsCl (1.1 eq.),
Et N (5 eq.), DCM,
3
4h, 0 °C to r.t.
1) DIBAL-H (2.2 eq.),
DCM, 15 min, -78°C
2) SO Py, Et N, DMSO
O
Methylcrotonate (2 eq.),
LDA (2.2 eq.), HMPA (2,2 eq.),
THF, -78 °C to -20°C
O
O
O
O
3
3
OH
O
99%
99%
81% (over 2 steps)
CO Me
CO Me
2
2
O
3
4
5
Scheme 4. Synthesis of the Michael acceptor 5.
In order to investigate the best conditions for the formal intermolecular [3+3]
cycloaddition, reactions between aldehyde 5 and methylacetoacetate 6a or the aldehyde-ester
6
b as partners were tested using four different secondary amines derived from proline as
catalyst (L-proline, (S)-prolinol, (S)-t-butylester proline, (S)-diaryl prolinol trimethylsilyl
[
27]
ether) (Scheme 5).
With methylacetoacetate 6a (R =Me) as Michael donor, the combination of benzoic acid
1
and diaryl prolinol trimethylsilyl ether 8 as catalyst allowed, after acetylation of the transient
hemi-acetal, the formation of dihydropyran 7a.
1
) cat.8 (10 mol%), PhCO H,
DCM, 3 days, r.t.
) Ac O (3 eq.), DMAP (10 mol%),
2
Et N (1.4 eq.), DCM, 2 h, r.t.
3
2
O
O
R2
O
O
R2
2
H
+
R1
Ph
Ph
OTMS
O
O
N
H
O
6
a R =Me, R =CO Me
1 2 2
7
a
40%
OAc
8
5
6b R =H, R =CO Et
1 2 2
7b NR
Scheme 5. Formal [3+3] cycloaddition with β-ketoester.
This [3+3] cycloaddition worked moderately and the product 7a was isolated as a mixture
of two diastereoisomers in 40% yield. The observed high stereoselectivity (d.r. > 90/10) in
[
28]
favor of syn product could be explained by a cooperative effect between a Felkin control
[
27]
and the chiral (R)-organocatalyst. The relative configuration of the double bond was not
unambiguously determined on each isomer. We observed the migration of the vinylic double
bond, which could be explained by the protonation of the intermediate enamine at the delta
carbon (Scheme 6).
6

ACCEPTED MANUSCRIPT
O
O
CO Me
O
O
2
CO Me
O
O
2
H
CO Me
H
2
H
1
,4-addition
H+
H O
Acetylation
on iminium
2
5
+ 6a
7a
OH
N
OH
OH
O
H
H
Ph
Ph
OTMS
N+
Ph
Ph
OTMS
Scheme 6. Proposed mechanism for the vinyl migration.
In spite of the moderate yield obtained in the model reaction with crotonaldehyde 6a, we
explored the reaction with the aldehyde-ester 6b. Unfortunately, no traces of 3,4-
dihydropyran compound (F, pathway I, Scheme 3) could be detected in the crude reaction
mixture. At this stage we concluded that the organocatalyzed reaction, for the formal [3+3]
cycloaddition between the two aldehydes 5 and 6b did not work. The normal course of the
reaction, that is the formation of the unsaturated iminium from enal 5, is overwhelmed by the
formation of Z-enamines from the condensation of aldehyde 6b and proline derivatives.
Indeed, we observed, the rapid formation of stable Z-enamines arising from the condensation
between aldehyde 6b and the various catalysts.
At this stage we sought to test the feasibility of an intramolecular cycloaddition (Scheme 3,
[
29]
pathway II). Deprotection of acetal 4 was realized in the presence of copper chloride. The
primary alcohol function of 9 reacted with formyl-Meldrum acid 10 to give the expected ester
1
1 which was unambiguously detected as a mixture of two diastereoisomers as major
products in the crude. All attempts to purify 11 were unsuccessful. Treatment of the crude in
[
30]
acidic media (NH OAc, TsOH)
or with proline gave complex reaction mixtures. In the
4
presence of catalytic amount of MeONa in THF, the Z-isomer of 11 gave the γ-lactone 13
arising from intramolecular transesterification and left the E-isomer 11 unreacted (Scheme 7).
OH
O
O
NaOMe
or proline
or TsOH
O
O
O
O
O
O
HO
HO
O
O
1
0
CuCl2 2H O (3.0 eq.)
2
HO
HO
CHO
6
4%
Benzene, reflux, 2 h
O
CO Me
CO Me
CO Me
2
2
2
O
9
11
12
4
NaOMe (0.1 eq.),
THF, 10 h, r.t.
O
O
CHO
O
O
1
3
Scheme 7. Intramolecular approach towards synthesis of bicyclic lactone.
7

ACCEPTED MANUSCRIPT
In view of the unsuccessful precedent approaches (Scheme 3, pathway I and II), we
considered the unsaturated ester 4 as a possible intermediate in the synthesis of enol-ester 16
(E in Scheme 3, pathway III). This approach was inspired by Lupton’s work on similar enol-
[
17]
esters
and could be envisaged as a formal [3+3] cycloaddition if we consider the latest
steps of the mechanism (scheme 9).
The synthesis began with saponification of the ester 4 with aqueous LiOH to provide the
corresponding acid 14 as a 3:1 mixture of diastereoisomers (Scheme 8). The further
transformation into acyl-chloride 15 was difficult and standard conditions (SOCl or oxalyl-
2
chloride) were unsuccessful. Eventually the used of cyanuric chloride which has been
[
31]
described in the literature
allowed us to obtain the expected acyl-chloride 15 in moderate
[16]
yield. It was not purified and directly engaged in the esterification of the aldehyde-ester 6b
in the presence of Hünig’s base. Some degradation of the product decreased the yield to 16%
in this two steps reaction. To our delight treatment of enol-ester 16 with N-Heterocyclic-
Carbene (NHC, formed by deprotonation of the pyrrolidium salt) as catalyst, provided the
lactone 17 in 58% yield as a 3:2 mixture of two diastereoisomers (E-syn/E-anti). The E-
configurations were determined by NOESY experiments. Concerning the low syn/anti
stereoselectivity, the Felkin control which should lead to syn product seems not to be
operative (see vide infra).
(
ClCN) (0.5 eq.),
3
O
O
O
O
O
O
LiOH (4,5 eq.),
H O / THF, 12 h, r.t.
2
Et N (1 eq.),
Acetone, 3 h, r.t.
3
7
8%
CO Me
CO H
COCl
2
2
4
1
4
15
Cl-
i-Pr
N+
i-Pr
N
Hünig's base, 6b,
DCM,1 h, 0°C
O
O
O
CO Et
CO Et
2
2
(0.2 eq.)
H
i-Pr i-Pr
O
t-BuOK (0.2 eq.),
THF, 46 h, r.t.
1
6% over two steps
O
O
O
5
8%
O
16
17
Scheme 8. NHC catalyzed strategy for the synthesis of precursor 17.
Once again the migration of the vinyl moiety was observed. We speculate that the
migration of the double bond occurred after the 1,4-addition to the activated Michael
8

ACCEPTED MANUSCRIPT
[
17e]
acceptor,
The observed total E-configuration arised from the protonation of conjugated
enolate with intramolecular 1,5-proton transfer (Scheme 9).
CO Et
2
EtO C
2
O
O
O
EtO C
2
O
N
H
NHC cat.
1,4-addition
1,5-proton transfer
Cyclization
N
N
16
17
N
N
N
O
O
Scheme 9. Proposed mechanism for the vinyl migration.
Nevertheless, precursor 17 could eventually be used further in the synthesis of
secologanin, sweroside or gentiopicroside. Actually, it requires several key steps among
[
32]
others, deconjugation of the latter isomerized vinyl moiety in addition to lactonisation and
deoxygenation or elimination of the secondary hydroxyl function.
3
. Conclusion
In summary, the synthesis of synthons 4 and 5 has been achieved in excellent yield and
should be a valuable tool in the synthesis of secoiridoid derivatives. The formal [3+3]
cycloaddition between enal 5 and aldehyde 6b did not provide the expected cycloadduct even
if on a model reaction, the 3,4-dihydropyran 7a was formed. The NHC induced rearrangement
of unsaturated enol-ester 16 gave access to compound 17 that could be an advanced precursor
in the synthesis of different secoiridoids as for example the challenging gentiopicroside.
4
. Experimental Section
4
.1. General information
All reactions were performed under nitrogen atmosphere. Reagents were all analytically or
chemically pure and used without further purification unless specified. Solvents were reagent
1
13
grade and, when necessary, were purified and dried by standard methods. H NMR and C
NMR spectra were recorded on a Bruker 400 spectrometer using CDCl as solvent with its
3
residual peaks as internal standard. Chemical shifts are reported in parts per million (δ), and
signals are expressed as s (singlet), d (doublet), t (triplet), q (quartet) or m (multiplet). High
resolution mass spectral (HRMS) analyses were taken on a Bruker micrOTOF mass
9

ACCEPTED MANUSCRIPT
spectrometer using electron spray ionization. Optical rotations were determined with a
JASCO P-2000 polarimeter. TLC was performed on Silica Gel GF254 for TLC (Merk) and
spots were visualized by irradiation with UV light (254 nm) or by CAM containing Cerium
Sulfate (1.0 g) and ammonium molybdate (VI) tetrahydrate (25.0 g) in 10% H SO (500 mL)
2
4
followed by heating. Flash column chromatography was performed on column packed with
Silica Gel 60 (200-300 mesh, Merk).
4
.2. Methyl 2-((2,2-dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)but-3-enoate (3): A 1.6
M solution of n-BuLi in hexane (108 mL, 173.6 mmol, 2.3 equiv) was added to a solution of
di-iso-propylamine (27 mL, 197.5 mmol, 2.5 equiv) in anhydrous THF (300 mL) at -20 °C,
and the resulting solution stirred for 20 min at same temperature. The reaction mixture was
then cooled to -78 °C, HMPA (30.9 mL, 177.5 mmol, 2.2 equiv) was added, after stirring for
an additional 30 min, a solution of methyl crotonate (16.7 mL, 157.9 mmol, 2.0 equiv) in THF
°
(
40 mL) was added dropwise at -78 C. After stirring for 5 min, a solution of 2 (10.26 g, 78.9
mmol, 1 equiv) in THF (15 mL) was added in one portion. The mixture was allowed to reach
20 °C, then cooled again to -70 °C and quenched with aqueous NH Cl (320 mL). The
-
4
organic layers were extracted with dichloromethane (3×200 mL), dried over MgSO , filtered
4
and evaporated to obtain crude product. Flash column chromatography was performed (Ethyl
Acetate/Cyclohexane 25/75 → 35/65). Finally the product 3 was obtained in 99% yield as a
mixture of diastereoisomers. R = 0.53 (Ethyl Acetate/Cyclohexane, 1:1). Major
f
1
diastereoisomer: H NMR (400 MHz, CDCl ): δ = 5.95 (ddd, J = 17.1, 10.3, 9.1 Hz, 1 H),
3
5
3
7
2
4
.24-5.39 (m, 2 H), 3.94-4.10 (m, 4 H), 3.74 (s, 3 H), 3.38 (dd, J = 9.1, 2.3 Hz, 1 H), 1.40 (s,
1
3
H), 1.33 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = 174.1, 130.7, 121.2, 109.4, 75.6,
3
+
2.9, 67.0, 52.3, 52.0, 26.9, 25.4 ppm. HRMS (ESI): calcd. for C H NaO [M+Na]
1
1
18
5
53.1046; found 253.1038.
.3. (Z)/(E)-Methyl 2-((4S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methylene)but-3-enoate (4):
Mesyl chloride (4 mL, 51.7 mmol, 1.2 equiv) was added slowly to a solution of 3 (10.78 g,
6.9 mmol, 1.0 equiv) in anhydrous dichloromethane at 0 °C under argon atmosphere. Then
4
triethylamine (34 mL, 244 mmol, 5.0 equiv) was added dropwise to the solution and
precipitation occurred. The mixture was allowed to warm up to room temperature and stirred
for 4 h. The solution was quenched with water (100 mL) and product was extracted with
dichloromethane (3×50 mL). Combined organic layers were washed with brine, dried over
MgSO and solvent was evaporated under reduced pressure to get the product 4 (9.94 g, 99%)
4
1
E/Z ratio 3:2 (determined by H NMR) in quantitative yield after flash column
1
0

ACCEPTED MANUSCRIPT
chromatography (Ethyl Acetate/Cyclohexane, 1:5), R = 0.34 (Ethyl Acetate/Cyclohexane,
f
2
0
1
1
:3). Pure diastereoisomer E:
[
]D = + 34.4 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ): δ =
α
3
3
6
.61 (d, J = 8.4 Hz, 1 H), 6.39 (dd, J = 17.2, 11.7 Hz, 1 H), 5.37 (m, 2 H), 4.86 (m, 1 H), 4.07
(dd, J = 8.1, 6.4 Hz, 1 H), 3.71 (s, 3 H), 3.63 (dd, J = 8.1, 7.3 Hz, 1 H), 1.39 (s, 3 H), 1.33 (s,
1
3
3
6
1
1
H) ppm. C NMR (101 MHz, CDCl ): δ = 166.5, 139.3, 133.5, 128.9, 121.3, 110.0, 72.3,
3
1
9.2, 52.0, 26.5, 25.6 ppm. Diatereoisomer Z: H NMR (400 MHz, CDCl ): δ = 6.35 (dd, J =
3
7.2, 11.0 Hz, 1 H), 6.11 (d, J = 6.9 Hz, 1 H), 5.42 (d, J = 17.2 Hz, 1 H), 5.18 (d, J = 11.0 Hz,
H), 4.21-4.27 (dd, J = 8.4, 6.9 Hz, 1 H), 3.78 (s, 3 H), 3.62 (dd, J = 8.4, 6.9 Hz, 1 H), 1.35
13
(
s, 3 H) 1.41 (s, 3 H); C NMR (101 MHz, CDCl ): δ = 166.5, 139.4, 133.5, 133.3, 117.1,
3
+
1
2
4
09.6, 73.9, 69.4, 51.8, 26.5, 25.4 ppm. HRMS (ESI): calcd. for C H NaO [M+Na]
11 16 4
35.0941; found 235.0933.
.4. (E)-2-((4S)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methylene)but-3-enal (5): To a solution
of ester 4 (3.18 g, 15 mmol, 1.0 equiv) in anhydrous DCM (15 mL) at -78 °C was added
slowly DIBAL-H (1 M in hexane, 33 mL, 2.0 equiv). The solution was stirred for 15 min at -
7
8 °C. The reaction was quenched with the dropwise addition of methanol until effervescence
ceased. The reaction mixture was diluted with 5 volumes of diethyl ether and stirred
vigorously for 1 h with a saturated solution of Rochelle’s salt. The organic layers were
separated and the aqueous layer extracted once with diethyl ether. Combined organic layers
were dried over MgSO , filtered and the solvent carefully removed under reduced pressure.
4
The obtained alcohol (2.75 g, 99%) was used after flash column chromatography (Ethyl
2
0
Acetate/Cyclohexane, 1:6). R = 0.22 (Ethyl Acetate/Cyclohexane, 1:4).
[
]D = - 4.6 (c 1.0,
α
f
+
CHCl ). HRMS (ESI): calcd. for C H NaO [M+Na] 207.0997; found 207.0992.
3
10 16
3
To a stirred solution of alcohol (7.21 g, 39.2 mmol, 1.0 equiv) in anhydrous DCM/DMSO
2:1) were added Et N and sulfur trioxide pyridine complex (24.91 g, 150 mmol, 4.0 equiv) at
(
3
0
°C. The mixture was stirred for 1 h at room temperature before it was quenched with water
and extracted with Ethyl Acetate. The combined organic layers were dried with MgSO and
4
concentrated in vacuum. The aldehyde was purified by flash column chromatography (Ethyl
Acetate/Cyclohexane 1/8) and the product 5 was yielded (5.74 g, 81%). R = 0.57 (Ethyl
f
2
0
1
Acetate/Cyclohexane, 1:3).
[
]D = + 25.2 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ): δ =
α
3
3
9
.54 (s, 1 H), 6.37-6.46 (m, 2 H), 5.84 (d, J = 18.8 Hz, 1 H), 5.55 (d, J = 10.0 Hz, 1 H), 5.10
(q, J = 7.5 Hz, 1 H), 4.25 (t, J = 7.5 Hz, 1 H), 3.76 (t, J = 7.5 Hz, 1 H), 1.50 (s, 3 H), 1.44 (s, 3
1
3
H) ppm. C NMR (101 MHz, CDCl ): δ = 193.1, 150.0, 139.8, 126.4, 122.9, 110.4, 72.4,
3
1
1

ACCEPTED MANUSCRIPT
+
6
3
4
9.0, 26.6, 25.6 ppm. HRMS (ESI): calcd. for C H NaO [2M+Na] 387.1778; found
10 14 3
87.1777.
.5. (3E)-Methyl
2-acetoxy-4-((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-ethylidene-6-
methyl-3,4-dihydro-2H-pyran-5-carboxylate (7a): To a solution of aldehyde 5 (200 mg, 1.1
mmol, 1.0 equiv) in DCM (2 mL), R- (+)-α,α-diphenyl-2-pyrrolidine methanol trimethylsilyl
ether (32.5 mg, 0.11 mmol, 0.1 equiv) and benzoic acid (13 mg, 0.11 mmol, 0.1 equiv) were
added. After 5 min stirring, methylacetoacetate (0.12 mL, 1.1 mmol, 1.0 equiv) was also
added to the reaction mixture. After 40 h, DCM (2 mL), acetic anhydride (0.33 mL, 3.3 mmol,
3
equiv), triethylamine (0.21 mL, 1.54 mmol, 1.4 equiv) and 4-dimethylaminopyridine (13
mg, 0.11 mmol, 0.1 equiv) were added and stirred for 10 h at room temperature. The reaction
mixture was quenched with water (20 mL), extracted with DCM (3×10 mL), combined
organic layers were dried over MgSO and solvent was evaporated under reduced pressure.
4
Purification by flash column chromatography (Ethyl acetate/Cyclohexane 15:85) gave the
product 7a with traces of impurities in 40% yield. R = 0.31 (Ethyl Acetate/Cyclohexane, 1:5).
f
2
0
1
[
α
]D = - 19.4 (c 1.0, CHCl
). H NMR (400 MHz, CDCl ): δ = 6.69 (d, J = 1.8 Hz, 1 H), 5.86-
3 3
5
.75 (m, 1 H), 4.11 (q, J = 6.2 Hz, 1 H), 3.98-3.88 (m, 2 H), 3.72 (s, 3 H), 3.71-3.68 (m, 1 H),
2
.23 (s, 3 H), 2.19 (s, 3 H), 1.81-1.75 (m, 3 H), 1.37-1.34 (m, 3 H), 1.31-1.28 (m, 3 H) ppm.
1
3
C NMR (101 MHz, CDCl ): δ = 169.3, 168.2, 162.7, 130.2, 123.0, 109.5, 103.4, 90.6, 79.2,
3
6
7.2, 51.5, 36.9, 26.4, 25.7, 21.2, 20.0, 13.8 ppm. HRMS (ESI): calcd. for C H NaO
7
1
7
24
+
[
M+Na] 363.1420; found 363.1426.
4
.6. (E)-(4S)-4, 5-Dihydroxy-2-vinyl-pent-2-enoic acid methyl ester (9): To a stirred
solution of 4 (7.546 g, 35.55 mmol, 1.0 equiv) in anhydrous CH CN was added CuCl ·2H O
3
2
2
(18.18 g, 106.65 mmol, 3.0 equiv) at 0 °C. The mixture was allowed to warm up to room
temperature and stirred for 3 h. The reaction mixture was quenched with water (100 mL) and
extracted with dichloromethane (3×150 mL). The combined organic extracts were washed
with brine and dried over MgSO and concentrated under vacuum. The desired product 9 was
4
obtained (3.893 g, 64%) after flash column chromatography (Ethyl Acetate/Cyclohexane 3/2).
2
0
1
R = 0.25 (Ethyl Acetate/Cyclohexane, 1:1).
f
[
α
]D = - 14.3 (c 1.0, H O). H NMR (400 MHz,
2
CDCl ): δ = 6.63-6.51 (m, J = 8.7 Hz, 1 H), 6.44 (dd, J = 17.6, 11.5 Hz, 1 H), 5.56 (dd, J =
3
1
7.6, 1.6 Hz, 1 H), 5.41 (dd, J = 11.5, 1.6 Hz, 1 H), 4.65 (dt, J = 8.6, 7.3, 3.5 Hz, 1 H), 3.75
13
(
s, 3 H), 3.65 (dd, J = 11.5, 3.5 Hz, 1 H), 3.56 (dd, J = 11.5, 7.3 Hz, 1 H) ppm. C NMR (101
MHz, CDCl ): δ = 167.5, 139.7, 132.8, 128.8, 121.4, 69.1, 65.6, 52.3 ppm. HRMS (ESI):
3
+
calcd. for C H LiO [M+Li] 179.0890; found 179.0883.
8
10
4
1
2

ACCEPTED MANUSCRIPT
4
.7. 2-((4S)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methylene)but-3-enoic acid (14): LiOH (82
mg, 33.89 mmol, 4.5 equiv) was solubilized in H O (10 mL) and added dropwise to a solution
2
of 4 (1.60 g, 7.53 mmol, 1.0 equiv) in THF (20 mL). Then the reaction mixture was stirred at
room temperature for overnight. HCl (1 mol/L) was added to neutralize the reaction until pH
~3. The reaction mixture was extracted with dichloromethane (3×30 mL). The combined
organic extracts were washed with brine and dried over MgSO and concentrated under vacuo.
4
The desired product 14 was obtained (1.175 g, 78%) after flash column chromatography
2
0
(
Ethyl Acetate/Cyclohexane 1/2). R = 0.17 (Ethyl Acetate/Cyclohexane, 1:1).
[
]D = + 26.4
α
f
1
(
c 1.0, CHCl ). H NMR (400 MHz, CDCl ): δ = 10.62 (s, 1 H), 6.84 (d, J = 8.3 Hz, 1 H),
3
3
6
3
1
.50-6.38 (m, 1 H), 5.52-5.40 (m, 2 H), 4.99-4.89 (m, 1 H), 4.16 (dd, J = 8.3, 6.5 Hz, 1 H),
1
3
.79-3.67 (m, 1 H), 1.47-1.44 (m, 3 H), 1.40 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ =
3
71.6, 141.9, 132.8, 128.7, 122.0, 110.4, 72.6, 69.3, 26.7, 25.2 ppm. HRMS (ESI): calcd. for
+
C H NaO [M+Na] 221.0790; found 221.0784.
10
14
4
4
.8.
(E)-(E)-3-Ethoxy-3-oxoprop-1-en-1-yl2-(((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)methylene)but-3-enoate (16): To a stirred solution of 14 (55 mg, 0.28 mmol, 1.0 equiv) in
acetone was added cyanuric chloride (26 mg, 0.14 mmol, 0.5 equiv) and Et N (39 ꢁL, 0.28
3
mmol, 1.0 equiv) at room temperature. The mixture was stirred for 3 hours. Acetone was
removed under reduced pressure.
A magnetically stirred solution of acid chloride in DCM was cooled to 0 °C then treated
dropwise with Hünig’s base followed by intermediate. The reaction was stirred at 0 °C for 1 h.
The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane
(3×15 mL). The combined organic extracts were washed with brine and dried over MgSO4
and concentrated under vacuum. The desired product 16 was obtained (13.3 mg, 16% in two
steps) after flash column chromatography (Ethyl Acetate/Cyclohexane 1/6); R = 0.55 (Ethyl
f
2
0
1
Acetate/Cyclohexane, 1:3).
[
]D = + 15.4 (c 0.4, CHCl ). H NMR (400 MHz, CDCl ): δ =
α
3
3
8
1
3
.36 (d, J = 12.5 Hz, 1 H), 6.91-6.81 (m, 1 H), 6.45 (dd, J = 17.4, 11.5 Hz, 1 H), 5.81 (d, J =
2.5 Hz, 1 H), 5.61-5.46 (m, 2 H), 4.96 (dd, J = 8.2, 6.9 Hz, 1 H), 4.25-4.16 (m, 3 H), 3.78-
1
3
.70 (m, 1 H), 1.48 (d, J = 0.7 Hz, 3 H), 1.42-1.40 (m, 3 H), 1.33-1.24 (m, 3 H) ppm. C
NMR (101 MHz, CDCl ): δ = 166.2, 162.0, 149.6, 143.1, 131.4, 128.2, 122.6, 110.6, 106.8,
3
+
7
2.6, 69.3, 60.7, 26.8, 25.8, 14.4 ppm. HRMS (ESI): calcd. for C H NaO [M+Na]
15 20 6
3
19.1158; found 319.1152.
1
3

ACCEPTED MANUSCRIPT
4
.9. (3E)/(3Z)-Ethyl
4-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxo-3-ethylidene-3,4-
dihydro-2H-pyran-5-carboxylate (17): To a stirred solution of 16 (12 mg, 0.041 mmol, 1.0
equiv) in anhydrous THF was added catalyst (3.5 mg, 0.008 mmol, 0.2 equiv) and potassium
tert-butoxide (1 mg, 0.008 mmol, 0.2 equiv) at room temperature. The mixture was stirred for
4
6 h. The reaction mixture was then evaporated and the desired product 17 was obtained (7
mg, 58%) after flash column chromatography (Ethyl Acetate/Cyclohexane 1/6). R = 0.38
f
1
(
Ethyl Acetate/Cyclohexane, 1:3). H NMR (400 MHz, CDCl ): δ = 7.62 (d, J = 8.1 Hz, 1 H),
3
7
1
=
.24-7.10 (m, 1 H), 4.31-4.23 (m, 3 H), 4.04-4.01 (m, 1 H), 3.95-3.90 (m, 1 H), 3.72-3.67 (m,
1
3
H), 1.96-1.92 (d, J = 7.3 Hz, 3 H), 1.34-1.24 (m, 9 H) ppm. C NMR (101 MHz, CDCl ): δ
3
165.7, 162.7, 151.4, 145.2, 124.6, 111.6, 109.7, 78.7, 65.9, 61.3, 35.6, 29.8, 26.1, 15.3, 14.4
+
ppm. HRMS (ESI): calcd. for C H NaO [M+Na] 319.1152; found 319.1159.
1
5
20
6
1
13
Supporting Information (see footnote on the first page of this article): Copies of H and C
NMR spectra of all described compounds.
Acknowledgments
S. W. gratefully acknowledges China Scholarship Council (CSC) for a doctoral
scholarship. We thank the University P. et M. Curie and the European Commission for
funding of this research through a EMEA Erasmus Mundus Scholarship to J. A. The
Fédération de Recherche (FR2769) provided technical access for analysis.
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[
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(
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1
5

ACCEPTED MANUSCRIPT
[
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1
6

ACCEPTED MANUSCRIPT
Supporting information
Studies towards the synthesis of secoiridoids
[
a,b,c]
[a,b,c]
[a,b]
[a,b]
a,b,*
Shaoping Wu,
Yongmin Zhang,
Jyoti Agarwal,
Emilie Mathieu , Serge Thorimbert
Luc
a,b,*
Dechoux
ꢀ
[a]
Sorbonne Universités, UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 place Jussieu, F-75005 Paris,
France
E-mail: serge.thorimbert@upmc.fr
luc.dechoux@upmc.fr
Homepage: http://www.ipcm.fr/presentation-682?lang=en
[
b]
c]
CNRS, UMR8232, IPCM, F-75005 Paris, France
[
Biomedicine Key Laboratory of Shaanxi Province, Northwest University, No. 229 Taibai North Road, Xi’an, Shaanxi 710069, PR
China
Contents
Pages
1
1
1
1
13
H NMR, C NMR of 1
2
3
13
H NMR, C NMR of 2
13
H NMR, C NMR of 3
4
13
H NMR, C NMR of 4
5
1
13
H NMR, C NMR of intermediate alcohol
6
1
13
H NMR, C NMR of 5
7
1
13
H NMR, C NMR of 7a
8
1
13
H NMR, C NMR of 9
9
1
1
1
1
13
H NMR, C NMR of 14
10
11
12
13-14
14
13
H NMR, C NMR of 16
13
H NMR, C NMR of 17
13
H NMR, C NMR of 6b
1
H NMR, NMR of 10
1
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
1
,2: 5,6-Diisopropylidene-D-mannitol (1)
1
Fig.1-1 H NMR (400MHz, 300K) spectrum of 1 in CDCl
3
1
3
Fig.1-2 C NMR (101MHz, 300K) spectrum of 1 in CDCl
3
2
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
, 3-O-Isopropylidene-D-glyceraldehyde (2)
2
1
Fig. 2-1 H NMR (400MHz, 300K) spectrum of 2 in CDCl
3
ꢀ
1
3
Fig.2-2 C NMR (101MHz, 300K) spectrum of 2 in CDCl
3
3
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
Methyl 2-((2, 2-dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)but-3-enoate (3)
1
Fig. 3-1 H NMR (400MHz, 300K) spectrum of 3 in CDCl
3
1
3
Fig. 3-2 C NMR (101MHz, 300K) spectrum of 3 in CDCl
3
4
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
Methyl 2-((2,2-dimethyl-1,3-dioxolan-4-yl)methylene)but-3-enoate（4）
1
Fig. 4-1 H NMR (400MHz, 300K) spectrum of 4 in CDCl
3
1
3
Fig. 4-2 C NMR (101MHz, 300K) spectrum of 4 in CDCl
3
5
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
-((2, 2-Dimethyl-1,3-dioxolan-4-yl)methylene)but-3-alcohol
2
1
Fig. 5-1 H NMR (400MHz, 300K) spectrum of alcohol in CDCl
3
1
3
Fig. 5-2 C NMR (101MHz, 300K) spectrum of alcohol in CDCl
3
6
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
E)-2-((2, 2-Dimethyl-1,3-dioxolan-4-yl)methylene)but-3-enal (5)
(
1
Fig.6-1 H NMR (400MHz, 300K) spectrum of 5 in CDCl
3
1
3
Fig.6-2 C NMR (101MHz, 300K) spectrum of 5 in CDCl
3
7
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ACCEPTED MANUSCRIPT
2-acetoxy-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-ethylidene-6-methyl
Methyl
-3,4-dihydro-2H-pyran-5-carboxylate (7a)
1
Fig. 7-1 H NMR (400MHz, 300K) spectrum of 7a in CDCl
3
1
3
Fig. 7-2 C (jmod) NMR (101MHz, 300K) spectrum of 7a in CDCl
3
8
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ACCEPTED MANUSCRIPT
, 5-Dihydroxy-2-vinyl-pent-2-enoic acid methyl ester (9)
4
1
Fig.8-1 H NMR (400MHz, 300K) spectrum of 9 in CDCl
3
1
3
Fig. 8-2 C NMR (101MHz, 300K) spectrum of 9 in CDCl
3
9
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ACCEPTED MANUSCRIPT
2
-((2, 2-Dimethyl-1,3-dioxolan-4-yl)methylene)but-3-enoic acid (14)
1
Fig.9-1 H NMR (400MHz, 300K) spectrum of 14 in CDCl
3
1
3
Fig.9-2 C NMR (101MHz, 300K) spectrum of 14 in CDCl
3
1
0ꢀ
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ACCEPTED MANUSCRIPT
(
E)-(E)-3-ethoxy-3-oxoprop-1-en-1-yl 2-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methylene)
but-3-enoate (16)
ꢀ
1
Fig.10-1 H NMR (400MHz, 300K) spectrum of 16 in CDCl
3
1
3
Fig. 10-2 C NMR (101MHz, 300K) spectrum of 16 in CDCl
3
1
1ꢀ
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ACCEPTED MANUSCRIPT
Ethyl 4-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxo-3-vinyl-3,4-dihydro-2H-pyran-5-carboxylate
(17)
1
Fig.11-1 H NMR (400MHz, 300K) spectrum of 17 in CDCl
3
1
3
Fig. 11-2 C NMR (101MHz, 300K) spectrum of 17 in CDCl
3
1
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ACCEPTED MANUSCRIPT
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Ethyl-3-oxopropanoate (6b)
Hydroxymethylene Meldrum’s acid (10.6 g, 62 mmol) and ethanol (4.3 mL, 93 mmol) in benzene
133 mL) were refluxed for 1h30 under argon atmosphere. The solution was cooled and distilled
(
under vacuum. Product 6b was collected at 17mbar (T= 35-50 ℃) and the desired product was
obtained (3.65 g, 49%).
1
Enol/Aldehyde ratio 1:2.6 (determined by H NMR)
Aldehyde:
1
3
H NMR (400 MHz, CDCl ): δ = 9.82 (t, J = 2.5 Hz, 1 H), 4.25 (q, J = 7.5 Hz, 2 H), 3.40 (d, J = 2.5
Hz, 2 H), 1.31 (t, J = 7.5 Hz, 3 H) ppm.
1
3
C NMR (101 MHz, CDCl
3
) δ = 194.9, 166.4, 61.3, 48.2, 13.6 ppm.
Enol:
1
H NMR (400 MHz, CDCl
3
) δ ppm 11.41 (d, J = 12.5 Hz, 1 H), 7.10 (dd, J = 7.5, 12.5 Hz, 1 H),
5
.07 (d, J = 7.5 Hz, 1 H), 4.25 (q, J = 7.5 Hz, 2 H), 1.31 (t, J = 7.5 Hz, 3 H) ppm.
1
Fig. 12-1 H NMR (400MHz, 300K) spectrum of 6b in CDCl
3
1
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