Lewis acid-mediated acetal substitution reactions: Mechanism and application to asymmetric catalysis

Article abstract of DOI:10.1002/adsc.201100346

Substitution reactions of acetals with carbon nucleophiles are fundamental and conventional organic reactions. We succeeded in the preparation of an optically active acetal, which reacted with a silyl enol ether smoothly to afford the desired adducts in r

Full text of DOI:10.1002/adsc.201100346

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DOI: 10.1002/adsc.201100346
Lewis Acid-Mediated Acetal Substitution Reactions: Mechanism
and Application to Asymmetric Catalysis
Shu¯ Kobayashi,a,* Kenzo Arai,a Takeshi Yamakawa,a Yi-Jing Chen,a
Matthew M. Salter,a and Yasuhiro Yamashitaa
a
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax : (+81)-3-5684-0634; e-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Received: May 3, 2011; Published online: August 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100346.
Abstract: Substitution reactions of acetals with
carbon nucleophiles are fundamental and conven-
tional organic reactions. We succeeded in the prepa-
ration of an optically active acetal, which reacted
with a silyl enol ether smoothly to afford the de-
sired adducts in racemic forms. By comparison of
the ees of the products with the ees of the recovered
acetals, we concluded that the aldol-type reactions
proceeded not via direct displacement (SN2) or con-
tact ion pairs (intimate ion pair) (SN1) but by a free
oxocarbenium ion (SN1) mechanism. Next, a study
to achieve asymmetric catalysis of the acetal substi-
tution reactions was conducted. After many trials, it
was found that a chiral niobium complex prepared
(BF3)[2] or trimethylsilyl triflate (Me3SiOTf)[3] take
place to afford the corresponding aldol-type adducts
in high yields. These reactions are recognized as being
among the most useful carbon-carbon bond-forming
reactions, and have been applied to medicinal chemis-
try and natural product synthesis. Other substitution
reactions of acetals have also been developed.[4,5]
In the acetal substitution reactions, there are two
possible mechanisms; direct displacement (SN2) and
oxocarbenium ion (SN1) mechanisms. The SN1 mecha-
nism involves a contact ion pair (CIP) (intimate ion
pair) mechanism and a solvated or dissociated free
ion pair (FIP) mechanism (Scheme 1).[6] Denmark,[7]
Bartlett and Heathcock,[8] and Sammakia[9] studied
the mechanism of acetal substitution reactions inde-
pendently. While their model systems to investigate
the mechanism were different, another aspect is that
they often used cyclic acetals to investigate the mech-
from pentamethoxyniobium [NbACTHNUTRGNEUNG(OMe)5] and a tet-
radentate BINOL derivative could achieve high
enantioselectivities. Asymmetric aldol-type reac-
tions of acetals with silyl enol ethers proceeded
smoothly to afford the corresponding aldol-type ad-
ducts in good yields with high enantioselectivities.
Keywords: acetals; asymmetric catalysis; contact
ion pair; Lewis acids; niobium; oxocarbenium ions
Substitution reactions of acetals with carbon nucleo-
philes are powerful methods for carbon-carbon bond
formation, providing functionalized ether compounds.
In general, acetals are protecting groups of carbonyls
under neutral and basic conditions, whereas they are
decomposed (deprotected) to provide the parent car-
bonyl compounds under acidic conditions. However,
under appropriate acidic conditions, substitution reac-
tions of acetals occur. For example, aldol-type reac-
tions of acetals with silyl enol ethers in the presence
Scheme 1. Two possible mechanisms of acetal substitution
of titanium(IV) chloride (TiCl4),[1] boron trifluoride reactions.
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anism, and it might be difficult to exclude the neigh-
boring effect of the tethered oxygen atoms with Lewis
acids in an intramolecular fashion. More recently,
Davies investigated the mechanism of the nucleophil-
ic substitution of benzaldehyde acyclic simple alkyl
acetals with Me2CuLi in the presence of BF3·OEt2,
concluding that the mechanism involved both SN1 sol-
vated or dissociated FIP and CIP or SN2 pathways.[10]
While the results are critical, acetal substrates are lim-
ited to benzaldehyde acetals, where nucleophilic sub-
stitution occurs at benzylic positions.[11]
Scheme 2. Aldol-type reaction of optically active acyclic
acetal 1.
On the other hand, desymmetrization of acetal A
could provide optically active ethers. While the use of
a catalytic amount of a chiral Lewis acid is the most (Table 1). It was confirmed that racemization of 1 oc-
efficient, to the best of our knowledge no successful curred under the current reaction conditions even
examples of chiral Lewis acid-catalyzed substitution when the reaction time was very short (Table 1, en-
reactions of acyclic acetals have been reported. We tries 1–4). The ee of the acetal decreased to 83% after
thought that this was related to the mechanism. If the 10 min and 16% after 80 min. On the other hand, it
mechanism is SN2 or involves the SN1 CIP, a standard was shown that the desired substitution reaction with
method of desymmetrization using a chiral Lewis acid 2 proceeded at the same time, and the product 3 was
may be possible. On the other hand, if the mechanism obtained in 16% yield after 10 min and in 83% yield
involves the SN1 solvated or dissociated FIP, control after 80 min. In both cases, the product was complete-
of the newly created stereogenic centers might be dif- ly racemic. These results indicate that the desired re-
ficult because solvated or dissociated free chiral oxo- action proceeded faster than the racemization of 1,
carbenium ion/counter anion pairs must be controlled, and the enantioselectivity (0% ee) of the product sug-
and successful examples of such a process are rare.[12] gested the SN1 mechanism of the reaction via nucleo-
We focused on substituion reactions of acyclic philic addition to the solvated or dissociated free oxo-
simple alkyl acetals. We thought that simple alkyl ace- carbenium ion intermediate.
tals were more appropriate for investigating the
Next, the effect of solvents and other Lewis acids in
mechanism of acetal substitution reactions, because the current reaction system was investigated
effects of alkyl groups (sometimes with chiral moiet- (Table 2). Typical Lewis acids such as RuCl3, FeCl3,
ies) could be minimized. We assumed that the Lewis TiCl4, AlCl3, and SnCl4 were evaluated in the aldol-
acid-mediated reaction of enantiomerically pure chiral type reaction of 1 with 2. In all cases except for
acyclic acetals with nucleophiles could provide us with AlCl3, the reactions proceeded well to afford the de-
valuable information on the reaction mechanism.[10] sired product 3 in moderate to high yields, and the
The obtained information would be very simple; if products were racemic in all cases (entries 1–7). Not
the reaction proceeds via the SN1 solvated or dissoci- only in CH2Cl2, but also in toluene and THF, the reac-
ated FIP mechanism, the product should be a race- tions proceeded to afford the racemic products (en-
mate, and if the reaction proceeds via the SN2 mecha- tries 8 and 9). It was also confirmed in these cases
nism or the SN1 CIP mechanism, the product should that the aldol-type reactions were faster than racemi-
retain an enantiomeric excess (ee).
zation of 1, and these results indicate that the aldol-
We synthesized chiral acetal 1 derived from 3-phe- type reaction of 1 with 2 also proceeded via the SN1
nylpropionaldehyde, which was purified by prepara- solvated or dissociated FIP mechanism.
tive HPLC with a chiral column (DAICEL CHIRAL-
CEL OD-H) to afford an optically pure form (>99%
ee). The aldol-type reaction of 1 with silicon enolate 2
prepared from acetophenone was conducted in the
Table 1. Racemization of optically active acetal 1.[a]
presence of 5 mol% of Me3SiOTf in dichloromethane
Entry Time
[min]
Yield of 3 ee of 3 Recovery of ee of 1
(Scheme 2).[3] The reaction proceeded at À788C for
4 h to afford only b-isopropyloxy ketone 3 selectively,
and the ketone was found to be completely racemic.
It is suggested that Me3SiOTf coordinated to the less
hindered MeO moiety rather than the i-PrO moiety
of 1, and that an oxocarbenium ion was formed and
attacked by 2 to afford racemic 3.
[%]
[%]
1 [%]
[%]
1
2
3
4
10
20
40
80
16
34
56
83
0
0
0
0
84
77
55
28
83
62
50
16
[a]
The reaction of 1 with 2 was conducted at À788C in
CH2Cl2 for the indicated time in the presence of
Me3SiOTf (1 mol%).
We then examined the possibility of racemization
of the starting acetal 1 under the reaction conditions
1928
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Lewis Acid-Mediated Acetal Substitution Reactions: Mechanism and Application
Table 2. Effect of solvents and Lewis acids.[a]
Table 3. Effect of solvents in the aldol-type reaction of 9.
Entry
Solvent
Lewis acid
Yield [%]
ee [%]
1
2
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
Me3SiOTf
RuCl3
FeCl3
TiCl4
TiCl4
AlCl3
SnCl4
Me3SiOTf
Me3SiOTf
78
73
84
46
78
0
43
40
55
0
0
0
0
0
–
0
0
0
Entry
Solvent
Yield [%]
ee [%]
4
5[b]
6
1
2
3
4
CH2Cl2
toluene
THF
91
95
94
91
0
0
0
0
7
8
9
hexane
[a]
The reaction of 1 with 2 was conducted at À788C for 4 h
using a Lewis acid (5 mol%), unless otherwise noted.
50 mol% of Lewis acid was used.
mechanism is the SN1 solvated or dissociated free ion
mechanism shown in Scheme 1.
Asymmetric Catalysis: We next undertook the task
of developing asymmetric catalysts for acetal substitu-
[b]
Nucleophilic additions using other substrates were tion reactions. Because the mechanism of these reac-
also investigated (Scheme 3 and Table 3). The aldol- tions has been proven to be the SN1 FIP mechanism,
type reaction of 1 with silicon enolate 5 derived from we faced a difficulty, namely, that selection of one
a thioester proceeded in the presence of Me3SiOTf face of a chiral ionic intermediate by an incoming at-
(5 mol%) in dichloromethane at À788C for 4 h to tacking nucleophile is needed to obtain an enantio-
afford the desired product 6 in 81% yield as a racemic pure adduct. Although several methods for chiral in-
form (Scheme 3). Allylation of 1 with allylsilane 5 duction have already been developed, examples using
also proceeded in the presence of Me3SiOTf chiral ionic pairs are rare, presumably because such
(5 mol%) to give homoallylic ether 8 in 62% yield, electronic or p-p electron interactions are weak in
and this product was also proven to be a racemic most cases.[12–16]
form. Furthermore, the same tendency was also ob-
We have previously developed a highly functional-
served in the reaction of aromatic aldehyde-derived ized chiral niobium catalyst and have demonstrated
acyclic acetal 9 (Table 3). Chiral acyclic acetal 9 (> its synthetic utility as a catalyst for Mannich reac-
99% ee) was treated with silicon enolate 2 in the pres- tions,[17] aza-Diels–Alder reactions,[18] and in the de-
ence of Me3SiOTf (5 mol%) in dichloromethane at symmetrization of meso-epoxides and meso-aziridines
À788C for 4 h to afford the desired adduct 10 in 91% with aniline nucleophiles.[19] A characteristic feature
yield, and this compound was found to be racemic. In of this catalyst system is its ability to discriminate be-
other solvents, completely racemic 10 was obtained in tween groups with closely matched steric and elec-
high yields. It was assumed that the aromatic moiety tronic demand, e.g., facial selectivity when prochiral
of 9 could stabilize the free oxocarbenium ion inter- substituents include ethyl and methyl groups.[19] This
mediate to accelerate the SN1-type reaction pathways property was demonstrated by the ability of the cata-
via solvated or dissociated free oxocarbenium ions.
lyst to perform kinetic resolution of non-terminal un-
These experimental results indicate that Lewis acid- symmetrical epoxides bearing a methyl group.[19] We
mediated acetal substitution reactions with silicon nu- reasoned that given this highly controlled asymmetric
cleophiles proceed via solvated or dissociated free ox- environment in which discrimination between small
ocarbenium ion intermediates, that is, the reaction steric differences is achievable, it might be possible to
apply this system to the desymmetrization of simple
prochiral compounds such as acetals.
The chiral Nb catalyst was first used in the aldol-
type reaction of the dimethyl acetal 11a prepared
from p-anisaldehyde with the silicon enolate derived
from S-ethyl thioacetate in a toluene-CH2Cl2 (1:1)
mixed solvent system (Table 4, entry 1). To our de-
light, the desired reaction proceeded smoothly with
moderate enantioselectivity (59% ee). During optimi-
zation of the reaction conditions, it was found that a
coordinating additive, THF, could improve the enan-
tioselectivity to 77% ee (entry 2).[20] In the presence
of THF, the reaction gave the desired product in good
Scheme 3. Aldol-type and allylation reactions.
yield with high enantioselectivity even when toluene,
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Table 4. Catalytic asymmetric aldol reactions of acetals.
Entry
R
Solvent
Yield [%]
ee [%]
1[a]
2[a,b]
3[a,b]
4[a,c]
5[a]
6
4-MeOC6H4 (11a)
11a
11a
11a
11a
11a
11a
11a
4-MeC6H4 (11b)
4-MeSC6H4 (11c)
3,4-(MeO)2C6H3 (11d)
2-thienyl (11e)
3,4-(OCH2O)C6H3 (11f)
(E)-PhCH=CH (11g)
C6H5 (11h)
toluene-CH2Cl2 (1:1)
toluene-CH2Cl2 (1:1)
toluene
94
90
87
83
91
88
88
81
81
86
78
78
92
83
55
N.R.
59
77
87
90
90
91
91
83
82
85
89
89
83
92
62
-
toluene
toluene-Et2O (1:1)
toluene-Et2O (1:1)
toluene-Et2O (1:1)
toluene-Et2O (1:1)
toluene-Et2O (1:1)
toluene-Et2O (1:1)
toluene-Et2O (1:1)
toluene-Et2O (1:1)
toluene-Et2O (1:3)
toluene-Et2O (1:1)
Et2O
7[d]
8[e]
9
10
11
12
13
14
15[a,f]
16[a,f]
PhCH2CH2 (11i)
Et2O
[a]
10 mol% Nb catalyst.
THF (5 mol%) was added.
THF (20 mol%) was added.
2.5 mol% Nb catalyst, at 0.4M.
1 mol% Nb catalyst, at 0.7M.
The reaction time was 48 h.
[b]
[c]
[d]
[e]
[f]
a less polar solvent, was used as the sole solvent acetal derived from benzaldehyde also proceeded;
(entry 3). The amount of THF was also crucial; the however, the yield and the selectivity were moderate
enantioselectivity was further improved to 90% ee (entry 15). The reaction of the dimethyl acetal derived
when 20 mol% of THF was employed (entry 4). We from 3-phenylpropanal did not proceed under these
then searched for solvent systems again, and finally conditions (entry 16).[21]
found that Et2O was very effective as a cosolvent, and
In summary, we have conducted a mechanistic
the highest ee (91%) was obtained without THF addi- study of aldol-type reactions of acyclic acetals. The re-
tive (entry 5). Under these reaction conditions, the actions of an optically active acetal proceeded
catalyst loading was successfully reduced, and 5 mol% smoothly to afford the desired adducts in racemic
of the Nb catalyst was found to work well and the forms. By comparison of the ees of the products with
highest ee was obtained (91%) (entry 6). A further the ees of the recovered acetals, we concluded that
decrease in the amount of the catalyst was also possi- the aldol-type reactions proceeded not via direct dis-
ble in more concentrated reaction conditions (en- placement (SN2) or CIP (SN1) but by a solvated or dis-
tries 7 and 8). The substrate scope was then investi- sociated free oxocarbenium ion (SN1) mechanism.
gated, and dimethyl acetals derived from electron-rich Further study to achieve asymmetric catalysis of the
aromatic aldehydes bearing methyl, methoxy, and acetal substitution reactions was then carried out, and
methylthio groups reacted smoothly under the opti- it was found that a chiral Nb complex prepared from
mum reaction conditions with good to high enantiose- Nb
ACHTUNGRTENN(UNG OMe)5 and a tetradentate BINOL derivative
lectivities (entries 9–14). The reaction of the dimethyl could achieve high enantioselectivities. Asymmetric
1930
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Lewis Acid-Mediated Acetal Substitution Reactions: Mechanism and Application
References
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lectivities in a toluene-Et2O solvent system. Further
studies to improve the substrate scope and to develop
other asymmetric reactions of acetals are now in
progress.
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Experimental Section
General Procedure for Me3SiOTf-Catalyzed Reaction
of Optically Active Non-Symmetrical Acetals with
Nucleophiles
A
dichloromethane solution (1.5 mL) of an acetal
(0.525 mmol), a nucleophile (0.500 mmol) in a two-neck 10-
mL flask was cooled at À788C, and 25 mL of a Me3SiOTf so-
lution (1.0M in dichloromethane) were then added, and the
whole was stirred for 4 h at the same temperature. The reac-
tion mixture was quenched by saturated aqueous NaHCO3,
and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layers were washed with brine, and dried over
anhydrous Na2SO4. After filtration and concentration under
reduced pressure, the obtained crude mixture was purified
on preparative TLC to give the desired product. The ee was
determined by HPLC analysis using a chiral column.
Typical Procedure for Asymmetric Aldol-Type
Reactions of meso-Acetals
[5] Reactions using optically active acetals: a) P. A. Bar-
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A
solution of NbACTHGUNTERNNU(G OMe)5 (0.02 mmol) and ligand 13
(0.022 mmol) in toluene (1.0 mL) was heated at 608C. The
mixture was stirred at the same temperature for 3 h, and
then it was allowed to cool down to room temperature. The
catalyst solution was concentrated and dried under reduced
pressure for 30 min, and toluene (1.0 mL) was then added,
and it was stirred for 10 min. After cooling down the solu-
tion at À458C, an acetal (0.40 mmol) in Et2O (0.5 mL) and
a silicon enolate (0.48 mmol) in Et2O (0.5 mL) were succes-
sively added. The reaction mixture was stirred for 24 h at
the same temperature. After the reaction was stopped by
adding saturated aqueous NaHCO3, and the mixture was ex-
tracted twice with CH2Cl2, and the organic layers were com-
bined and dried over anhydrous Na2SO4. After filtration and
concentration under reduced pressure the residue obtained
was purified by preparative TLC (hexane: ethyl acetate=4:
1) to afford the desired product. The enantioselectivity of
the reaction was determined with chiral column HPLC anal-
ysis.
[8] I. Mori, K. Ishihara, L. A. Flippin, K. Nozaki, H. Ya-
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[11] Other than those reports, there have been several
papers in which oxocarbenium ions are written in
schemes or figures of acetal substitution reactions. In
all such cases, however, no definitive evidence of exis-
tence of the oxocarbenium ions is shown to the best of
our knowledge. Moreover, it is not clear that such oxo-
carbenium ions are the contact ion pair or the solvated
or dissociated ion pair.
Acknowledgements
This work was partially supported by CREST, SORST,
ERATO (JST), a Grant-in-Aid for Science Research from
the Japan Society for the Promotion of Science (JSPS) and
Global COE Program (Chemistry Innovation through Coop-
eration of Science and Engineering), The University of
Tokyo, and MEXT, Japan.
Adv. Synth. Catal. 2011, 353, 1927 – 1932
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Shu¯ Kobayashi et al.
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[12] Our preliminary report: K. Arai, Y. Yamashita, M. M.
Salter, S. Kobayashi, Asymmetric Nucleophilic Substi-
tuion Reaction to Acyclic Acetals Using a Chiral Niobi-
um Catalyst, in: The 88th Annual Meeting of the Chem-
ical Society of Japan, March 28, 2008.
[15] Example of intermolecular asymmetric synthesis using
acyclic acetals: N. Umbayashi, Y. Hamashima, M. So-
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Chem. Int. Ed. 2008, 47, 4196–4199.
[16] Examples of intermolecular asymmetric synthesis via
oxocarbenium ion, see S. E. Reisman, A. G. Doyle,
E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130, 7198–
7199.
[17] S. Kobayashi, K. Arai, H. Shimizu, Y. Ihori, H. Ishitani,
Y. Yamashita, Angew. Chem. 2005, 117, 771–774;
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[18] V. Jurcꢂk, K. Arai, M. M. Salter, Y. Yamashita, S. Ko-
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[19] a) K. Arai, M. M. Salter, Y. Yamashita, S. Kobayashi,
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ˇ
´
[13] Intramolecular fashion: a) I. Covic, S. Mꢁller, B. List, J.
ˇ
´
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[14] Examples of intramolecular asymmetric synthesis using
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[20] Cf. R. Fujiyama, K. Goh, S-i. Kiyooka, Tetrahedron
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[21] We have not obtained information (SN1 or SN2) on the
mechanism of the reactions using a chiral Nb catalyst,
because the reactions of 1 or 9 with 7 did not proceed
in the presence of the Nb catalyst.
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Adv. Synth. Catal. 2011, 353, 1927 – 1932