Lewis acid catalyzed enlargement of cyclic β-alkoxyenals and one-pot synthesis of polyfunctional enoxysilanes derived from aucubin with trimethylsilyldiazomethane

Article abstract of DOI:10.1002/chem.201203968

Pyrane to oxepane in one step: Highly regio- and stereoselective homologations dependent on the nature of carbonyl function and catalysts have been observed during the formation of enoxysilanes (see scheme). Trimethylsilyl trifluoromethanesulfonate (TMSOT

Full text of DOI:10.1002/chem.201203968

DOI: 10.1002/chem.201203968
Lewis Acid Catalyzed Enlargement of Cyclic b-Alkoxyenals and One-Pot
Synthesis of Polyfunctional EnoxyACTHNUTRGNEUGNsilanes Derived from Aucubin with
Trimethylsilyldiazomethane
Christelle Lemus, Marko Poleschak, Sophie Gailly, Marine Desage-El Murr,
Michel Koch, and Brigitte Deguin*[a]
In memory of Professor FranÅois Tillequin
Aldehyde and ketone homologations, such as the Tiffe-
neau–Demjanov–Tchoubar rearrangement with diazo-
ACHTUNGTRENNUNGmethane are well studied reactions and lead to various prod-
ucts depending on the nature of substrates and reaction con-
ditions.[1] Employment of trimethylsilyldiazomethane
(TMSDM)[2] instead of CH2N2 makes the reactions safer
and allows us to capitalize on the rearrangement of the re-
sulting b-silylcarbonyl compounds.[3] These reactions require
nonprotic anhydrous conditions to avoid protolysis of the
targeted enoxysilanes. Efforts to find methodologies to con-
vert aldehydes and ketones into homologated enoxysilanes
of type 6 and 8 by using TMSDM or TMSC(Li)N2, in one-
step protocols, have been presented (Scheme 1).[4] In the
case of aldehydes reacting with TMSDM, the product distri-
bution 6 versus 8 depends on the relative rates of alkyl, aryl,
and alkenyl group migration 2!3 versus hydride migration
2!5 and epoxide formation 2!4 (Scheme 1). However, the
reactions between TMSDM and cyclic aldehydes have been
poorly studied. When enones were reacted, 1,4-addition of
TMSDM and subsequent trimethylsilylcyclopropanation
were observed.[5]
Scheme 1. Expected reactions of TMSDM with aldehydes RCHO and
RCDO.
In this work, we disclose an unusual reaction of TMSDM
with b-alkoxyenals. When cyclic b-alkoxyenals are employed
(Scheme 2), ring enlargement might compete with the classi-
cal aldehyde homologations (Scheme 1) and with suitable
Lewis acids may become the major process. This procedure
has been applied to carbaldehydes derived from aucubin
and it opens a new avenue for the one-pot conversion of
these scaffolds into complicated polyfunctional enoxysilanes
and their exploitation in semi-synthesis. To our knowledge
this methodology represents the first ring expansion from b-
alkoxyenals by using TMSDM in one step.
[a] Dr. C. Lemus, Dr. M. Poleschak, S. Gailly, Dr. M. Desage-El Murr,
Prof. M. Koch, Prof. B. Deguin
Laboratoire de Pharmacognosie de lꢀUniversitꢁ Paris - Descartes
Sorbonne Paris Citꢁ, U.M.R./C.N.R.S. n88638
Facultꢁ des Sciences Pharmaceutiques et Biologiques
4, Avenue de lꢀObservatoire, 75006 Paris (France)
Fax: (+33)1-40-46-96-58
Scheme 2. Proposed mechanism for the ring expansion of b-oxyenal 1 f
into 9.
We explored the reaction of TMSDM with benzaldehydes
1a–c, cyclohexanecarbaldehyde (1d), furfural (1e), and 3,4-
dihydro-2H-pyran-3-carbaldehyde (1 f; Table 1) to establish
E-mail: brigitte.deguin@parisdescartes.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203968.
4686
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Chem. Eur. J. 2013, 19, 4686 – 4690

COMMUNICATION
Table 1. One-step homologation of aldehydes to enoxysilanes.
of Aucuba japonica Thunb.
(Cornaceae).[9] Through partial
syntheses,
14
permitted[10]
access to various biologically
active chiral compounds includ-
ing insect antifeedants,[11] carbo-
cyclic nucleoside analogues,[12]
aminocyclopentitol glycosidase
inhibitors,[13] several prostaglan-
dins,[14] cytotoxic cyclopente-
none glucosides series,[15] and
also polyaminoiridoids, the
structures of which can be relat-
ed to the aminoside antibiot-
ics.[16] Furthermore, 14 was used
for the syntheses of chiral rigid
g-amino acid glucosides.[17]
Entry Substrate
Catalyst
T [8C] Ratio of (Z)-6/(E)-6/8/9
Yield [%]
98[c]
1
2
3
4
5
6
benzaldehyde (1a)
TMSOTf (10%)[a] ꢀ78
(Z)-6a/(E)-6a/8a, 84:12:4[c]
p-nitrobenzaldehyde (1b)
TMSOTf (30%)[a] ꢀ30
(Z)-6b/(E)-6b/8b, 62:8:30[d] 73[d]
p-methoxybenzaldehyde (1c) TMSOTf (10%)[a] ꢀ78
(Z)-6c/(E)-6c/8c, 85:15:0[c]
99[c]
c-C6H11-CHO (1d)[e]
c-C6H11-CHO (1d)[e]
furfural (1e)
TMSOTf (30%)[b] ꢀ30
(Z)-6d/(E)-6d/8d, 24:0:76[c] 55[c]
(Z)-6d/(E)-6d/8d, 16:3:81[d] 95[d]
(Z)-6e/(E)-6e/8e, 64:36:0[d] 93[d]
AlCl3 (30%)[a]
ꢀ30
TMSOTf (10%)[a] ꢀ78
TMSOTf (10%)[a] ꢀ78
7
90[d]
[a] CH2Cl2. [b] CH3CN. Yields were evaluated by 1H NMR spectroscopic experiments in the presence of tol-
uene. [c] Yields were evaluated by 1H NMR spectroscopic experiments in the presence of dimethoxybenzene.
[d] As an internal reference. [e] Without Et3N.
In this context, we have been
the suitable conditions for one-step homologation of alde-
hydes into enoxysilanes. As shown in Table 1, trimethylsilyl
trifluoromethanesulfonate (TMSOTf) and AlCl3 were active
catalysts for these transformations at low temperature. For
the aldehydes chosen, the formation of the epoxides of type
4 was not observed, although the latter might be intermedi-
ate in the formation of enoxysilanes of type (E)-7 and (Z)-7
by the route 2!4!7 (Scheme 1).[4f]
interested in exploiting carboxaldehyde scaffolds 18–22
(Scheme 3) easily obtained in a few synthetic steps from 14.
By a parallel synthesis approach and by following described
The concurrent formation of the 2-substituted enoxysilane
of type 8 is the major process for cyclohexanecarbaldehyde
(1d),[6] whereas it was not observed for the reaction of
TMSDM with electron-rich p-methoxybenzaldehyde (1c).
This was expected as the migratory ability of the electron-
rich aryl group is significantly facilitated relative to the mi-
gratory ability of the hydride in pinacolic-type rearrange-
ments,[7] 2!3 versus 2!5. This feature is obvious also when
comparing the reaction of 1b with that of 1c (Table 1, en-
tries 2 and 3).
Surprisingly, the reaction conducted with aldehyde 1 f
gave the product of ring enlargement 9 as the major product
in 75% yield. In this case, the products of aldehyde homolo-
gation arising from homoalkylcarbinyl-rearrangement (2 f!
3 f!6 f) are minor (Scheme 2),[8] whereas products of type 8
obtained by a hydride migration pathway were not ob-
served. The proposed mechanism for the formation of 9 is
described in Scheme 2. Activation of b-oxyenal 1 f with
TMSOTf catalyst generates intermediate 10, which possess a
strong cationic character on the b-carbon center. The 1,4-ad-
dition of TMSDM is favored leading to adduct 11. A fast
1,2-shift of the electron-rich alkoxy group produces ion-pair
12, which eliminates an equivalent of TMSOTf to form 9.
Our research program involves the discovery of new me-
dicinal chemical leads from plant secondary metabolites. By
using abundant natural compounds, we deliberately created
new chiral scaffolds or building blocks for the synthesis of
chemical libraries to screen their biological activities.
Among them, a natural iridoid glycoside, aucubin (14), is
particularly suitable to be used as a starting material as it is
easily extracted in large amounts from the fresh aerial parts
Scheme 3. Syntheses of aucubin-derived carbaldehydes 18–22.
procedures,[15b,18] we have prepared the (6S)-perpivalolyl-
AHCTUNGTREGaNNUN ucubin (15), the (6R)-perpivalolylepiaucubin (16), and the
6,10-dideoxyaucubin (17). Epimeric iridoids 15 and 16 were
converted to cyclopenta[c]furan heterosidic aldehydes 18
and 19, respectively.[18b] Vilsmeier reaction allowed the intro-
duction of a carbonyl group at C-4 of 15–17 producing the
cyclopentano[c]pyran heterosidic aldehydes 20–22.[14,15b]
Firstly, we used aldehydes 20–22, for the one-pot conver-
sion into polyfunctional enoxysilanes by applying our ring-
enlargement reaction (Table 2). This allowed the formation
of the expected enoxysilanes 23 (52%) and 25 (12%) pro-
duced by hydrolysis of enoxysilane 24.[19] When the experi-
ment was performed with molecular sieves (Table 2,
entry 2), 23 was formed exclusively (98%). The structure of
Chem. Eur. J. 2013, 19, 4686 – 4690
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4687

B. Deguin et al.
1
Whereas for 26 and 28, the H NMR spectra disclose a cor-
3
relation between the ethylenic proton H-3 (doublet, J (H-3/
H-5)=1.5 Hz) with C-1 and the reciprocal correlation H-1/
C-3. The coupling constants between vicinal H-3/H-4 (Jcis
=
7.5 Hz) of 23 and 27 are larger than the corresponding cou-
pling constants of the H-11/H-12 (Jcis =6.5 Hz) of 26 and 28.
Ethylenic protons H-3, H-4, and H-5 of (Z)-6 f, (E)-6 f, and
9 show similar values.
Since a large number of classical procedures using TMSCl
and organic bases have failed to form enoxysilane 29 from
ketone 30, this single-step procedure has been very useful to
transform the iridoids derivatives 18–19 to enoxysilanes 29
and 31. In contrast to the ring expansion of cyclic b-alkoxy-
A
a
lithiated form
[4f]
TMSC(Li)N2
33.
To determine the mechanistic pathway for the formation
of enoxysilanes by the reaction of TMSDM with aldehydes
1 (Scheme 1), we employed the deuterated benzaldehyde
(PhDCO=[D]1a). The same conditions as for the reaction
of TMSDM with 1a resulted in a mixture of 84:16 of (Z)-
[D]6a and (E)-[D]6a, accompanied with less than 1% of
[D]8a (Table 1, entry 1). The proportion of 8a/[D]8a (4%/
!1%) is consistent with a rate-determining step involving
hydride/deuteride migrations and it might be characterized
as a primary kinetic isotopic effect (kH/kD @2; Scheme 4).
Table 2. Lewis acid catalyzed formation of enoxysilanes and enones 23–
32 from aucubin-derived carbaldehydes 18–22.
Entry Substrate Lewis acid[a]
T [8C]/t [h] Product (yield [%])[c]
1
2
3
4
5
6
7
8
9
20
20
20
21
22
18
18
18
19
TMSOTf (10%)
ꢀ40/4
23 (52)/25 (12)
23 (98)
23 (31)
TMSOTf (10%)[b] ꢀ40/2
AlCl3 (30%)
ꢀ40/2
TMSOTf (10%)[b] ꢀ40/2
26 (60)
TMSOTf (10%)[b] ꢀ40/2
28 (56)/27 (44)
29 (21)/30 (68)
29 (11)/30 (66)
29 (100)
TMSOTf (10%)
ꢀ78/44
TMSOTf (10%)[b] ꢀ10/3
AlCl3 (30%)[b]
AlCl3 (30%)[b]
ꢀ40/2
ꢀ40/2
31 (98)/32 (12)
[a] Solvent CH2Cl2. [b] Molecular sieves 4 ꢃ. [c] Yields are given after
chromatography over silica gel.
1
23 was deduced from NOEꢀs by H NMR spectroscopy. The
NOESY correlations between H-1 and H-8’, H-5a and H-8a
showed that the configurations of C-5a, C-8a, and C-1 did
not change during the rearrangement and NOEꢀs between
H-4 and H-5’ defined the configuration of the enoxysilane
moiety of 23.
Scheme 4. Ratios of enoxysilanes derived from the reaction of RCDO
with TMSDM.
The (Z)-enoxysilane 26 which conserved the cyclopenta-
no[c]pyran skeleton was obtained from the (6S)-aldehyde 21
in 60% isolated yield (Table 2, entry 4). For the reaction of
iridoid derivative 22, the cyclopentene part of the aglycon is
responsible for the lower regioselectivity and provides two
enoxysilanes, 27 (65%) and 28 (35%; entry 5). Thus the re-
gioselectivity of the formation of enoxysilanes 26–28 de-
pends on stereoelectronic factors induced by the cyclopenta-
no[c]pyran skeleton and the nature of substituent on C-6
and its configuration.
The observation that product ratios (Z)-6a/(E)-6a (84:12)
and (Z)-[D]6a/(E)-[D]6a (84:16) are nearly the same, is in
agreement with the reaction pathway by the rearrangement
3!6, for which no kinetic isotopic effect is expected. Impor-
tantly, the absence of the isotopomeric compounds (E)-
[D]7a and (Z)-[D]7a demonstrates that the route through
1!2!4!7 is not followed. The above observation is also
in agreement with the reaction of TMSDM with deuterated
cyclohexanecarbaldehyde (c-C6H11-CDO=([D]1d)) and 1d
(Table 1, entry 5). Under the same conditions (AlCl3/
CH2Cl2, ꢀ308C), the reaction of nondeuterated aldehyde 1d
forms a 16:3:81 mixture of (Z)-6d/(E)-6d/8d and its deuter-
ated isotopomer [D]1d gives a 38:!1:31:31 mixture of (Z)-
[D]6d/(E)-[D]6d/(Z)-[D]8d/(E)-[D]8d (Scheme 3). These
To distinguish the structure of enoxysilane isomers 9, 23,
27, 6 f, 26, and 28, NMR spectroscopic studies were per-
formed. Significant differences in chemical shifts, coupling
constants, and HMBC correlations were observed. Enoxysi-
lane 9 and major constituents 23 and 27 were nonambigu-
ously established by HMBC correlations. Notably, the corre-
lations exist between the doublet of ethylenic proton H-3
(3J
ACHTUNGTRENNUNG(H-3/H-4)=7.5 Hz) and C-1 and between H-1 and C-3.
4688
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Chem. Eur. J. 2013, 19, 4686 – 4690

Lewis Acid Catalyzed Enlargement of Cyclic b-Alkoxyenals
COMMUNICATION
methane (57 mL, 0.11 mmol) was added to a stirred mixture of aldehyde
20 (100 mg, 0.11 mmol) and molecular sieves 4 ꢃ (100 mg) in anhydrous
dichloromethane (5 mL) under an Ar atmosphere at ꢀ408C. A solution
of TMSOTf (6.2 mL, 0.011 mmol, 0.1m) diluted in dichloromethane was
carefully added dropwise. The reaction was stirred for 1.5 h. After the
complete conversion of the aldehyde, a solution of triethylamine (48 mL,
0.011 mmol, 0.1m) in dichloromethane was then added. After 1 h, the
mixture was warmed at RT and stirred for 0.5 h. Pentane (3 mL) was
added and precipitated salts were filtered after additional stirring for
0.5 h. The solvents were removed under reduced pressure. The crude
product was purified by column chromatography over silica gel (35–
70 mm, cyclohexane/EtOAc 9:1) to afford the corresponding enoxysilane
23 as a white powder (104 mg, 98%).
results also show that the deuteride migration is slower than
the hydride migration. Interestingly, the absence of the for-
mation of the enoxysilanes (Z)-[D]7d and (E)-[D]7d ex-
cludes the pathway via 1!2!4!7. The observation of a
1:1 ratio for enoxysilanes (Z)-[D]8d and (E)-[D]8d is con-
sistent with a rearrangement via [D]1d![D]5d![D]8d
that cannot be affected by a kinetic deuterium isotopic
effect (no. E vs. Z stereoselectivity).[20]
To further validate the mechanisms proposed in
Scheme 4, we examined the stereochemistry and regioselec-
tivity of the ring expansion with deuterated aldehyde [D]20.
Formation of enoxysilane [D]23 deuterated at 5’ supports
the mechanism involving the migration of the carbon–
oxygen bond (Scheme 5). The participation of the oxygen
General method for the preparation of enoxysilanes 29 and 31 (exempli-
fied for 29): a solution of trimethylsilyldiazomethane (TMSDM; 30 mL,
0.06 mmol) was added to a stirred solution of molecular sieves 4 ꢃ
(100 mg) and AlCl3 (2.3 mg, 0.017 mmol) in anhydrous dichloromethane
(5 mL) under an Ar atmosphere at ꢀ408C. A solution of 18 (50 mg,
0.06 mmol) in dichloromethane (5 mL) was then added and the reaction
was stirred for 1.5 h. After complete conversion of the aldehyde, the solu-
tion was filtered on a pad of silica and the solvent was removed under re-
duced pressure to give the crude enoxysilane as a yellow powder. The
crude product was purified by column chromatography over silica gel
(35–70 mm, cyclohexane/EtOAc 9:1) to afford the corresponding com-
pound 29 as a white powder (50 mg, 100%).
Scheme 5. Ring expansion of deuterated aldehyde [D]20.
Acknowledgements
atom in the pyran ring facilitates the activation of the car-
bonyl moiety by TMSOTf and thus favors a conjugate addi-
tion of TMSDM.
We gratefully acknowledge the Agence National de la Recherche for fi-
nancial support (ANR-09-CP2D-09–01).
Similarly, to the cyclohexylcarbaldehyde (1d), AlCl3 cata-
lyst led to higher yields than TMSOTf for the conversion of
cyclopenta[c]furan aldehydes 18 and 19 to enoxysilanes 29
and 31, respectively. Indeed, when the reaction of 18 was
catalyzed by TMSOTf in CH2Cl2 at ꢀ788C, the desired
enoxysilane 29 was obtained as a minor product (21%) next
to the corresponding methyl ketone 30 (68%). In contrast,
the reaction was quantitative in favor of 29 when AlCl3 was
used. A similar result was observed for the AlCl3-catalyzed
reaction of aldehyde 19 in CH2Cl2 at ꢀ408C leading to par-
ticularly instable enoxysilane 31 (98%).
Keywords: aldehydes · enals · homologation · Lewis acids ·
trimethylsilyldiazomethane
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Experimental Section
General method for the preparation of enoxysilanes 23, [D]23, 25, 26,
and 27 (exemplified for compound 23): A solution of trimethylsilyldiazo-
Chem. Eur. J. 2013, 19, 4686 – 4690
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Received: November 6, 2012
Published online: February 28, 2013
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Chem. Eur. J. 2013, 19, 4686 – 4690