Lewis Acid-Catalyzed Ring-Opening Reactions of Semicyclic N,O-Acetals

Article abstract of DOI:10.1021/ol006990a

(Matrix Presented) Ring-opening reactions of semicyclic N,O-acetals with various nucleophiles such as silyl enol ethers are effectively catalyzed by a Lewis acid (TMSOTf). Reactions of 3-substituted N,O-acetals showed high diastereoselectivities. Syntheti

Full text of DOI:10.1021/ol006990a

ORGANIC
LETTERS
2001
Vol. 3, No. 3
477-480
Lewis Acid-Catalyzed Ring-Opening
Reactions of Semicyclic N,O-Acetals
Masaharu Sugiura and Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, CREST,
Japan Science and Technology Corporation (JST), Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received December 12, 2000
ABSTRACT
Ring-opening reactions of semicyclic N,O-acetals with various nucleophiles such as silyl enol ethers are effectively catalyzed by a Lewis acid
(TMSOTf). Reactions of 3-substituted N,O-acetals showed high diastereoselectivities. Synthetic utility of this method has been demonstrated
in the stereoselective synthesis of an anti-malarial agent, isofebrifugine.
In the presence of a Lewis acid, semicyclic acetals (1) such
as O-glycosides are known to react with various nucleophiles
to give cyclic ether products (2) via cyclic oxocarbenium
ion intermediates A (eq 1).1 Similarly, reactions of semi-
2).3 Meanwhile, reactions of other semicyclic N,O-acetals
(5), where the positions of nitrogen and oxygen of 3 are
inverted, are expected to proceed via formation of acyclic
iminium ion intermediates C to afford ring-opened products
(6) if an oxophilic Lewis acid is employed (eq 3). Although
it has been reported that N,N-dialkylaminofuranosides or
pyranosides reacted with excess Grignard reagents to give
ring-opened alkylation products4 and that N-galactosyl-N-
homoallylamine undergoes aza-Cope rearrangement pro-
moted by a stoichiometric amount of a Lewis acid,5 this type
of reaction has not been systematically explored. We have
recently reported that the second-type reactions (eq 2) were
effectively catalyzed by scandium trifluoromethanesulfonate.6
Herein we report the third-type reactions shown in eq 3 using
(2) Gabbutt, C. D.; Hepworth, J. D. In ComprehensiVe Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Eds.; Kirby, G. W., Volume Ed.; Pergamon: Oxford, 1995; Vol. 4,
pp 293-349.
(3) For reviews, see: (a) Hiemstra, H.; Speckamp, W. N. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 2, pp 1047-1082. (b) Speckamp, W. N.; Moolenaar,
M. J. Tetrahedron 2000, 56, 3817.
(4) (a) Nagai, M.; Gaudino, J. J.; Wilcox, C. S. Synthesis 1992, 163. (b)
Lay, L.; Nicotra, F.; Paganini, A.; Pangrazio, C.; Panza, L. Tetrahedron
Lett. 1993, 34, 4555. (c) Cipolla, L.; Lay, L.; Nicotra, F.; Pangrazio, C.;
Panza, L. Tetrahedron 1995, 51, 4679. (d) Cipolla, L.; La Ferla, B.; Peri,
F.; Nicotra, F. Chem. Commun. 2000, 1289. (e) Bortolussi, M. Cinquin,
C.; Bloch, R. Tetrahedron Lett. 1996, 37, 8729.
cyclic2 N,O-acetals (3) provide nitrogen-containing cyclic
compounds (4) via cyclic iminium ion intermediates B (eq
(1) For a recent review on C-glycosides, see: Du, Y.; Linhardt, R. J.;
Vlahov, I. R. Tetrahedron 1998, 54, 9913.
(5) Deloisy. S.; Kunz, H. Tetrahedron Lett. 1998, 39, 791.
(6) Okitsu, O.; Suzuki, R.; Kobayashi, S. Synlett 2000, 989.
10.1021/ol006990a CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/18/2001

a catalytic amount of a Lewis acid, and their synthetic utility
and high stereoselectivity are described.
Furthermore, five-membered analogue 5b was also shown
to provide the ring-opened product 6f in high yield (Scheme
At the outset, we chose benzyl N-(tetrahydropyran-2-yl)-
carbamate (5a) as one of the simplest semicyclic N,O-acetals
and the silyl enol ether derived from acetophenone as a
nucleophile (Table 1). Pyran 5a was readily prepared via
1).
Scheme 1. THF System
Table 1. Effect of Lewis Acidsa
We next focused on the elucidation of the stereochemical
aspect of this reaction. For this purpose, 3-substituted semi-
cyclic N,O-acetals 5c and 5d were prepared via TMSOTf-
promoted substitution of ester 7 or ether 8 with benzyl
carbamate (Scheme 2). Since benzyl carbamate is a weak
run
LA (equiv)
time
yield of 6a /%
1
2b
3
4
5
6
7
TMSOTf (0.2)
TMSOTf (0.2)
SnCl4 (0.2)
BF3‚OEt2 (0.2)
TfOH (0.1)
TMSCl-AgClO4 (0.2)
SnCl4-AgClO4
20 min
20 min
7 h
90
94
33
4
31
48
71
11 h
20 min
15 min
15 min
Scheme 2. Preparations of 3-Substituted THP Substrates
a Reactions were carried out using 5a (0.2 mmol), the silyl enol ether
(1.2 equiv), and a Lewis acid (0.1 or 0.2 equiv) in dichloromethane at 0
°C, unless otherwise noted. b Two equivalents of the silyl enol ether were
used.
acid-catalyzed addition of benzyl carbamate to 3,4-dihydro-
2H-pyran.7 The reactions were carried out using a catalytic
amount of a Lewis acid (0.1-0.2 equiv) at 0 °C in
dichloromethane. Among the various Lewis acids tested (runs
1-5), trimethylsilyl trifluoromethanesulfonate (TMSOTf)
was found to be the most effective (runs 1 and 2), and ring-
opened alcohol 6a was obtained in high yields. A combina-
tion of chlorotrimethylsilane or tin tetrachloride and silver
perchlorate8 was also effective (runs 6 and 7).
nucleophile, an addition of 4 Å molecular sieves was
essential to prevent the formation of the hydrolyzed products.
We then investigated the reaction of 5c with the silyl enol
ether derived from acetophenone (Table 3). Unlike 5a, 5c
Under these optimal conditions for 5a, reactions with
various nucleophiles were also investigated (Table 2).
Allyltrimethylsilane, trimethylsilyl cyanide, and other silyl
enolates reacted smoothly to afford the desired adducts 6b-e
in excellent yields.
Table 3. Reactions of 3-Substituted Substratesa
Table 2. Reactions with Various Nucleophilesa
products
yield/ syn/
run R1 R2
R3
Ph
(6)
conditions
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
-23 °C, 2 h
0 °C, 5 h
0 °C, 30 min
-23 °C, 1 h
0 °C, 3 h
%
anti
1b Ac
2c
H
6g
60
77
76
45
61
87
67
59
94
58/42
82/18
91/9
93/7
94/6
94/6
94/6
94/6
94/6
3
4
5
H
t-Bu
6h
6i
6j
6k
6l
time/
min
yield/
%
6
Me MeO
NuSiMe3 (equiv)
product (6)
7
8
9
Bn
H
H
Ph
t-Bu
CH2dCHCH2SiMe3
120 6b (R ) CH2CHdCH2)
15 6c (R ) CN)
20 6d (R ) CH2COt-Bu)
20 6e (R ) CMe2CO2Me)
91
99
89
99
Me3SiCN (2)
Me MeO
-23 °C, 40 min
CH2dC(t-Bu)(OSiMe3) (1.5)
Me2CdC(OMe)OSiMe3) (1.5)
a Reactions were carried out using 5c or 5d (0.1 mmol), a nucleophile
(2 equiv), and TMSOTf (0.2 equiv) in acetonitrile, unless otherwise noted.
b One equivalent of TMSOTf was used in dichloromethane as a solvent.c
Nitromethane was used as a solvent.
a All reactions were carried out using 5a (0.2 mmol), a nucleophile, and
TMSOTf (0.2 equiv) in dichloromethane at 0 °C.
478
Org. Lett., Vol. 3, No. 3, 2001

required a stoichiometric amount of TMSOTf for complete
consumption in dichloromethane, giving a ca. 1:1 dia-
stereomeric mixture of product 6g (run 1). A polar solvent
such as acetonitrile or nitromethane, which was presumed
to stabilize the iminium ion intermediate, was found to
promote a catalytic reaction and to improve the yield and
stereoselectivity (runs 2-4). Using the conditions in aceto-
nitrile, reactions of 5c with other silyl enolates provided
alcohols 6h and 6i with high syn-diastereoselectivities (runs
5 and 6). In addition, reactions of 3-benzyloxypyran 5d also
proceeded catalytically in acetonitrile to give ring-opened
products 6j-l with high syn-diastereoselectivities (runs 7-9).
The configuration of the major diastereomers of 6g and
6j were determined, respectively, as syn after converting to
cis-piperidines 9 or 106 via PCC-oxidation and reductive
cyclization (Scheme 3).
Scheme 3. Determination of Relative Stereochemistries
Figure 1.
1H NMR analysis of the TMSOTf-catalyzed reaction of
5a in CDCl3 showed that the initial product formed was
O-trimethylsilylated ether 11 which was easily hydrolyzed
to the alcohol 6a by the addition of water (Scheme 4).9 This
benium ion intermediate could be involved, giving a trans-
product preferentially.6 While the 3-benzyloxy substituent
of 5d could not participate as an iminium ion intermediate,
TS2 would be favorable between the two competitive
transition states TS2 and TS3, since the conformation of TS3
has a large allylic strain between the alkyl side chain and
the proton bound to the iminium nitrogen.10 It would be also
possible that the hydrogen bonding between the proton bound
to the iminium nitrogen and the 3-benzyloxy group could
fix the conformation of the transition state (see, TS4) and a
nucleophile would attack from the less hindered side to give
the syn-product.
Scheme 4. Observation of the Initial Product
result strongly suggests a mechanism of this reaction
involving coordination of the Lewis acid to the ring-oxygen
followed by ring-opening activation to form an acyclic
iminium ion intermediate (see, eq 3).
Synthetic utility of the present reaction has been demon-
strated in a facile synthesis of an anti-malarial alkaloid,
isofebrifugine11 (Scheme 5). Using a quinazoline-containing
The stereochemical course of the present reaction can be
rationalized as shown in Figure 1. In 3-acetoxy system 5c,
five-membered dioxocarbenium ion intermediate TS1 could
be involved in neighboring group participation of the
3-acetoxy group. This dioxocarbenium ion would have the
trans-configuration due to steric reason, and then an SN2-
type attack of a nucleophile would provide the syn-product.
This is a good contrast to the reaction of the 3-acetoxy cyclic
piperidine system where the cis-fused bicyclic dioxocar-
Scheme 5. Synthesis of Isofebrifugine
(7) Related reactions of benzamides have been reported: Chen, J.;
Crooks, P. A.; Hussain, A. Int. J. Pharm. 1995, 123, 95.
(8) For a leading reference: Mukaiyama, T.; Takashima, T.; Katsurada,
M.; Aizawa, H. Chem. Lett. 1991, 533.
(9) Although the 1H NMR spectra of 11 and 6a are quite similar, the
chemical shifts for the methylene proton adjacent to the silyloxy group or
the hydroxyl group are distinguishable, i.e., 3.55 ppm (t) for 11 and 3.60
ppm (t) for 6a.
Org. Lett., Vol. 3, No. 3, 2001
479

silyl enol ether11a as a nucleophile, 3-benzyloxy N,O-acetal
5d was converted to acyclic alcohol 6m in good yield. A
slight excess of TMSOTf was required presumably due to
the basicity of the quinazoline nitrogen. Further transforma-
tions of 6m accomplished a diastereoselective synthesis of
isofebrifugine.
nucleophiles were effectively catalyzed by a Lewis acid to
afford acyclic alcohols 6 with high diastereoselectivities. The
stereoselective synthesis of isofebrifugine provided an ex-
ample of their synthetic utility. Further applications and
mechanistic studies are now in progress.
In summary, we have demonstrated that ring-opening
reactions of semicyclic N,O-acetals 5 with silicon-based
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan.
(10) Nagai et al. suggested a similar transition state model for R-alkoxy-
N,N-dibenzyliminium ion system (see, ref 4a).
(11) For recent syntheses of isofebrifugine and/or febrifugine, see: (a)
Burgess, L. E.; Gross, E. K. M.; Jurka, J. Tetrahedron Lett. 1996, 37, 3255.
(b) Kobayashi, S; Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron Lett. 1999,
40, 2175. (c) Kobayashi, S; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.;
Wataya, Y. J. Org. Chem. 1999, 64, 6833. (d) Takeuchi, Y.; Abe, H.;
Harayama, T. Chem. Pharm. Bull. 1999, 47, 905. (e) Takeuchi, Y.; Hattori,
M.; Abe, H.; Harayama, T. Synthesis 1999, 1814. (f) Takeuchi, Y.; Azuma,
K.; Takakura, K.; Abe, H.; Harayama, T. Chem. Commun. 2000, 1643. (g)
Taniguchi, T.; Ogasawara, K. Org. Lett. 2000, 2, 3193.
Supporting Information Available: Experimental pro-
cedures and physical data of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL006990A
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Org. Lett., Vol. 3, No. 3, 2001