Lewis acid-catalyzed ring-opening reactions of semicyclic N,O-acetals possessing an exocyclic nitrogen atom: Mechanistic aspect and application to piperidine alkaloid synthesis

Article abstract of DOI:10.1021/ja0170448

Ring-opening reactions of semicyclic N,O-acetals possessing an exocyclic nitrogen atom with silicon-based nucleophiles (silyl enol ethers, ketene silyl acetals, allylic silanes, and trimethylsilyl cyanide) were systematically studied for the first time. I

Full text of DOI:10.1021/ja0170448

12510
J. Am. Chem. Soc. 2001, 123, 12510-12517
Lewis Acid-Catalyzed Ring-Opening Reactions of Semicyclic
N,O-Acetals Possessing an Exocyclic Nitrogen Atom: Mechanistic
Aspect and Application to Piperidine Alkaloid Synthesis
Masaharu Sugiura, Hiroyuki Hagio, Ryoji Hirabayashi, and Shuj Kobayashi*
Contribution from Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, CREST, Japan
Science and Technology Corporation (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
ReceiVed September 10, 2001
Abstract: Ring-opening reactions of semicyclic N,O-acetals possessing an exocyclic nitrogen atom with silicon-
based nucleophiles (silyl enol ethers, ketene silyl acetals, allylic silanes, and trimethylsilyl cyanide) were
systematically studied for the first time. It was found that the reactions were effectively catalyzed by a Lewis
acid, trimethylsilyl trifluoromethanesulfonate (TMSOTf), to afford 1,4- and 1,5-amino alcohols in high yields.
In reactions of 3-oxygen functionalized semicyclic N,O-acetals, high 1,2-syn-diastereoselectivity was obtained.
1
By H NMR experiment, the formation of the O-trimethylsilylated ring-opened product was observed as the
initial product. Furthermore, the epimerization between the diastereomers of a 3-benzyloxy semicyclic N,O-
acetal suggested the transient formation of an acyclic iminium ion species as a reactive intermediate. It was
also found that 3-acetoxy and 3-benzyloxy N,O-acetals showed a tendency for the larger nucleophile to provide
higher syn-selectivity, while 3-tert-butyldiphenylsilyloxy N,O-acetals showed the opposite tendency. These
stereochemical outcomes can be rationalized by assuming four transition state models for the acyclic iminium
ion intermediate. The synthetic utility of the reaction has been demonstrated in the diastereoselective synthesis
of piperidine alkaloids, (+)-isofebrifugine and (()-sedacryptine.
Introduction
X,Y-Acetals are functional groups consisting of an sp3-carbon
atom attached to two heteroatom groups, XR1 and YR2, where
X and Y are heteroatoms such as oxygen, nitrogen, sulfur,
phosphorus, and so on, and are widely utilized as versatile
intermediates in organic synthesis (Figure 1).1 On the basis of
the structural characteristics, it can be classified into three
groups: acyclic, cyclic, and semicyclic.2 Acyclic X,Y-acetals
consist of only an acyclic skeleton, while cyclic X,Y-acetals have
a cyclic structure including both X and Y heteroatoms in the
same ring system. Cyclic X,Y-acetals are especially utilized as
protecting groups of aldehydes or ketones such as 1,3-dioxane,
1,3-dioxolane, and 1,3-dithiane.3 On the other hand, semicyclic
X,Y-acetals possess a cyclic structure including either an X or
a Y heteroatom or neither of them in the ring system.
O-Glycoside is a naturally occurring representative of semicyclic
O,O-acetals.
Under acidic conditions (with a Brφnsted acid or a Lewis
acid), an X,Y-acetal can be activated to generate an R-heteroatom
substituted carbenium ion as a reactive intermediate, which
reacts with a nucleophile to form a substitution product. In this
process, the acid coordinates to a lone pair of one of the
heteroatoms (X or Y) to cleave the heteroatom-carbon bond
with the assistance of electron donation from a lone pair of the
other heteroatom. It is obvious that the reaction of unsym-
Figure 1. X,Y-Acetals.
metrical X,Y-acetals involves a chemoselective problem, namely
whether the X or Y hetereoatom is activated by the acid. The
selectivity would depend on the kind of heteroatom (O, N, S,
P, etc.), the type of substituents attached to the heteroatom (R1
and R2), and the type of acid and nucleophile used. Among
three structurally distinct X,Y-acetals (Figure 1), interesting is
the reaction of semicyclic X,Y-acetals possessing one of the
hetereoatoms in the ring system, since these can undergo two
types of reactions, i.e., substitution of the exocyclic heteroatom
group by a nucleophile or ring-opening addition of a nucleophile
(Scheme 1). Thus, four types of products are possible depending
on the positions (exocyclic or endocyclic) of the heteroatoms
X and Y.
For instance, in the presence of a Lewis acid, semicyclic O,O-
acetals 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).4,5 Similarly, reactions
of semicyclic N,O-acetals (3) provide aza-hetereocycle com-
pounds (4) via cyclic iminium ion intermediates B (eq 2).6 We
have also recently reported that the second type of reactions
(1) ComprehensiVe Organic Functional Group Transformations; Katritz-
ky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Kirby, G. W., Volume Ed.;
Pergamon: Oxford, 1995; Vol. 4.
(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) Greene, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: Now York, 1999.
(4) For a recent review on C-glycosides, see: Du, Y.; Linhardt, R. J.;
Vlahov, I. R. Tetrahedron 1998, 54, 9913.
10.1021/ja0170448 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/16/2001

Ring-Opening Reactions of Semicyclic N,O-Acetals
J. Am. Chem. Soc., Vol. 123, No. 50, 2001 12511
Scheme 1. Reaction Modes of Semicyclic X,Y-Acetals
lylamine underwent aza-Cope rearrangement promoted by a
stoichiometric amount of a Lewis acid.9 Accordingly, we
anticipated that if an oxophilic Lewis acid was employed, ring-
opening reaction would proceed via formation of acyclic
iminium ion intermediates C instead of cyclic intermediates such
as A to afford ring-opened products (6) (eq 3). We have indeed
found that this type of reaction was effectively catalyzed by a
Lewis acid.10 Herein, we report the first systematic study on
the reactions of semicyclic N,O-acetals 5, including the stereo-
chemical aspects of this reaction as well as the synthetic utility
in piperidine alkaloids synthesis.
Results and Discussion
Ring-Opening Reaction of 3-Unfunctionalized Semicyclic
N,O-Acetals. Benzyl (tetrahydropyran-2-yl)carbamate (5a),
which was readily prepared via an acid-catalyzed addition of
benzyl carbamate to 3,4-dihydro-2H-pyran,11 was first chosen
as one of the simplest semicyclic N,O-acetals. Reactions of 5a
with the silyl enol ether derived from acetophenone were
performed in the presence of a catalytic amount of a Lewis acid
(0.1 or 0.2 equiv) at 0 °C in dichloromethane (Table 1). Among
various Lewis acids tested (runs 1-5), trimethylsilyl trifluo-
romethanesulfonate (TMSOTf) was found to be the most
effective (runs 1 and 2), and ring-opened alcohol (1,5-amino
alcohol) 6a was obtained in high yields. A combination of
chlorotrimethylsilane or tin tetrachloride and silver perchlorate12
was also effective (runs 6 and 7).
were effectively catalyzed by scandium trifluoromethane-
sulfonate.7
Table 1. Effect of Lewis Acidsa
yield of
6a/%
run
LA (equiv)
TMSOTf (0.2)
TMSOTf (0.2)
SnCl4 (0.2)
BF3‚OEt2 (0.2)
TfOH (0.1)
time
1
2b
3
4
5
6
7
20 min
20 min
7 h
90
94
33
4
31
48
71
11 h
20 min
15 imn
15 min
TMSCl-AgClO4 (0.2 each)
SnCl4-AgClO4 (0.2 each)
a Reactions were carried out with 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
was used.
With TMSOTf as the catalyst, reactions with various nucleo-
philes were also investigated (Table 2). Allyltrimethylsilane,
trimethylsilyl cyanide, and other silyl enol ether and ketene silyl
acetal reacted smoothly to afford the desired adducts 6b-e in
excellent yields.
On the other hand, Lewis acid-catalyzed reactions of other
semicyclic N,O-acetals (5) (eq 3), where the positions of nitrogen
and oxygen of 3 are inverted, have been investigated less, though
it has been reported that N,N-dialkylaminofuranosides or pyra-
nosides reacted with excess Grignard reagents to give ring-
opened alkylation products,8 and that N-galactosyl-N-homoal-
(8) (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. Ring-opening reactions of
nucleosides by Grignard reagents or diisobutylaluminum hydride were also
reported, see: (f) Kawana, M. Chem. Lett. 1981, 1541. (g) Hirota, K.;
Monguchi, Y.; Kitade, Y.; Sajiki, H. Tetrahedron 1997, 53, 16683.
(9) Deloisy. S.; Kunz, H. Tetrahedron Lett. 1998, 39, 791.
(10) (a) Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3, 477. (b) Sugiura,
M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. Synlett 2001, 1225.
(11) Related reactions of benzamides have been reported: Chen, J.;
Crooks, P. A.; Hussain, A. Int. J. Pharm. 1995, 123, 95.
(5) Endocyclic cleavage in acid-catalyzed methanolysis and hydrolysis
of a pyranoside (a semicyclic O,O-acetal) has been reported; (a) Liras, J.
L.; Anslyn, E. V. In Molecular Design and Bioorganic Catalysis; Wilcox,
C. S., Hamilton, A. D., Eds.; NATO SAI Ser.; Kluwer Academic
Publishers: Boston, MA, 1996; Vol. 478, pp 1-15. (b) Liras, J. L.; Anslyn,
E. V. J. Am. Chem. Soc. 1994, 116, 2645.
(6) For reviews on the chemistry of N-acyliminium ions and related
intermediates, see: (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe
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.
(7) (a) Okitsu, O.; Suzuki, R.; Kobayashi, S. Synlett 2000, 989. (b) Okitsu,
O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809.
(12) For a leading reference see: Mukaiyama, T.; Takashima, T.;
Katsurada, M.; Aizawa, H. Chem. Lett. 1991, 533.

12512 J. Am. Chem. Soc., Vol. 123, No. 50, 2001
Table 2. Reactions with Various Nucleophilesa
Sugiura et al.
Scheme 3. Obervation of the Initial Product
the initial O-silylated product. Note that newly formed TMSOTf
after one catalytic cycle is different from the original TMSOTf.
In other words, use of a catalytic amount of TMSOTf and a
trimethylsilylated nucleophile must be the key to making this
reaction catalytic.
time/
yield/
%
NuSiMe3 (equiv)
min
product (6)
CH2dCHCH2SiMe3 (2)
Me3SiCN (2)
CH2dC(t-Bu)(OSiMe3) (1.5)
Me2CdC(OMe)(OSiMe3) (1.5)
120 6b(R ) CH2CHdCH2)
15 6c(R ) CN)
20 6d(R ) CH2COt-Bu)
20 6e(R ) CMe2CO2Me)
91
99
89
99
a All reactions were carried out with 5a (0.2 mmol), a nucleophile,
and TMSOTf (0.2 equiv) in dichloromethane at 0 °C.
Table 3. Effect of Substituents on the Nitrogen Atoma
product (6)
(% yield)
run no.
substrate (5)
5a (R ) OCH2Ph)
1
2
3
4
5
6
6a (90)
6f (88)
6g (86)
6h (53)
6i (82)
6j (74)
5b (R ) O(9-fluorenylmethyl)
5c (R ) OCH2CHdCH2)
5d (R ) O(2-naphthyl)
5e (R ) Ph)
Figure 2. Assumed catalytic cycle.
5f (R ) CH2CH2Ph)
Reactions of 3-Oxygen-Functionalized Semicyclic N,O-
Acetals. We next focused on elucidation of the stereochemical
aspects of this reaction. For this purpose, 3-acetoxy, 3-benzyl-
oxy, and 3-tert-butyldiphenylsilyloxy semicyclic N,O-acetals
(5h, 5i, and 5j, respectively) were prepared via TMSOTf-
promoted nucleophilic substitution of ester 7 and 9 or ether 8
with benzyl carbamate (Scheme 4). The substituted THP’s 7-9
were prepared in 2 steps from 3,4-dihydro-2H-pyran. Since
benzyl carbamate is a relatively weak nucleophile, an addition
of 4 Å molecular sieves was essential to prevent the formation
of hydrolyzed products. N,O-Acetals 5h, 5i, and 5j were
obtained as diastereomeric mixtures and used without separation.
Stereochemical assignments were performed by 1H NMR
observation of the coupling constants between H2 and H3
protons (J2,3 ) ca. 9 Hz for trans and ca. 2 Hz for cis).
a Reactions were carried out with 5a-f (0.2 mmol), the silyl enol
ether (1.2 equiv), and TMSOTf (0.2 equiv) in dichloromethane at 0
°C.
Scheme 2. The THF System
Other substituents on the nitrogen atom of the N,O-acetal were
next examined (Table 3). Synthetically useful deprotectable
N-alkoxycabonyl groups, 9-fluorenylmethoxycarbonyl (run 2)
and allyloxycarbonyl (run 3), are tolerant in this reaction.
Moreover, N-aroyl and N-alkanoyl N,O-acetals also reacted
smoothly (runs 5 and 6). A five-membered analogue 5g also
provided the ring-opened alcohol (1,4-amino alcohol) 6k in high
yield (Scheme 2).
Scheme 4. Preparations of 3-Oxygen Functionalized
Semicyclic N,O-Acetals
1H NMR analysis of the TMSOTf-catalyzed reaction of 5a
in CDCl3 showed that the initial product formed was O-
trimethylsilylated ether O-TMS-6a, which was easily hydrolyzed
to the alcohol 6a by addition of water (Scheme 3).13 This result
strongly suggests a mechanism for this reaction involving
coordination of TMSOTf to the ring-oxygen followed by ring-
opening activation to form an acyclic iminium ion intermediate
(Figure 2). After the nucleophilic addition of a trimethylsilylated
nucleophile to the iminum ion intermediate, TMSOTf is
regenerated by the attack of the triflate anion onto the trimeth-
ylsilyl group of the nucleophile along with the formation of
(13) Although the 1H NMR spectra of O-TMS-6a 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
O-TMS-6a and 3.60 ppm (t) for 6a.

Ring-Opening Reactions of Semicyclic N,O-Acetals
J. Am. Chem. Soc., Vol. 123, No. 50, 2001 12513
Table 4. Reactions of 3-Oxygen-Functionalized Semicyclic N,O-Acetals 5h-j with Various Uncleophilesa
a Reactions were carried out with 5h-j (ca. 0.2 mmol), a nucleophile (2 equiv), and TMSOTf (0.2 equiv) in acetonitrile at the indicated temperature.
Scheme 5. Determination of Relative Configurations
We first tested the reaction of 5h with the silyl enol ether
derived from acetophenone in dichloromethane. Unlike the
3-unsubstituted N,O-acetals, 5h required a stoichiometric amount
of TMSOTf in dichloromethane for complete consumption to
give a 58:42 diastereomeric mixture of product 6m in 60% yield.
We presumed that a polar solvent would stabilize the iminium
ion intermediate to promote the reaction. Among solvents thus
tested, acetonitrile and nitromethane were found to be effective,
promoting the reaction catalytically to afford the ring-opened
product in 76% and 77% yields, respectively. In terms of
stereoselectivity, acetonitrile showed higher syn-selectivity (91%
syn) than nitromethane (82% syn). With acetonitrile as the
optimal solvent, we then investigated the reactions of 5h, 5i,
and 5j with various nucleophiles (Table 4). With a silyl enol
ether, a ketene silyl acetal, allyltrimethylsilane, and trimethylsilyl
cyanide, ring-opened products 6l-w were obtained in good to
high yields with moderate to high syn-diastereoselectivity.
Furthermore, it was found that 3-acetoxy and 3-benzyloxy N,O-
acetals 5h and 5i showed a tendency for the larger nucleophile
to provide higher syn-selectivity, while 3-tert-butyldiphenylsi-
lyloxy N,O-acetals 5j showed the opposite tendency.
The relative configurations of the major diastereomers of 6m
(R1 ) Ac) and 6q (R1 ) Bn) were determined respectively as
syn after converting to cis-piperidines 10 (R1 ) Ac) or 11 (R1
) Bn)7 via PCC-oxidation and reductive cyclization (Scheme
5). The syn-configuration of 6m (R1 ) Ac) was further
confirmed after transformation to oxazolidin-2-one 12 upon base
treatment. The 1H NMR coupling constant between the H4 and
(R1 ) TBDPS) was determined to be syn by formation of trans-
H5 protons of this type of oxazolidin-2-one is known to be cis
> trans.14 Thus, the major diastereomer of 12 derived from 6m
12. Moreover, the major isomers of allylation prodoucts of 6n
(R1 ) Ac) and of 6v (R1 ) TBDPS) were also assigned to be
was found to be trans, which is consistent with the formation
syn via a similar transformation to oxazolidone 13, while the
major isomer of 6r (R1 ) Bn) was determined to be syn by the
synthesis of isofebrifugine (vide infra). The configuration of
other products was tentatively assigned on the basis of analogy.
Stereochemical Courses. Before discussing the origin of the
stereochemical outcomes, we had to answer the question whether
of cis-10 from 6m. Similarly, the major diastereomer of 6u
(14) For example, see: (a) Dufour, M.-N.; Jouin, R.; Poncet, J.; Pantaloni,
A.; Castro, B. J. Chem. Soc., Perkin Trans. 1 1986, 1895. (b) Kano, S.;
Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Tetrahedron Lett. 1987, 28, 6331.
(c) Kiyooka, S.-I.; Nakano, M.; Shiota, F.; Fujiyama, R. J. Org. Chem.
1989, 54, 5409.

12514 J. Am. Chem. Soc., Vol. 123, No. 50, 2001
Scheme 6. Control Experiments
Sugiura et al.
the diastereomeric ratios of N,O-acetals reflected those of the
ring-opened products. To confirm this point, each diastereomer
of the substrate 5i was once separated by preparative TLC on
silica gel and independently subjected to the reaction conditions
with acetophenone-silyl enol ether and TMSOTf (Scheme 6).
As a result, almost the same syn-stereoselectivities were obtained
from both the trans and cis isomers. This result is consistent
with the mechanism via formation of an acyclic iminium
intermediate, where the chiral C2 carbon center of the N,O-
acetal converted to a prochiral center (see Figure 2).
Furthermore, when each diasteromer of 5i was independently
treated with TMSOTf in the absence of a nucleophile at 0 °C
for 10 min, epimerization to a trans/cis ) 60/40 diastereomeric
mixture was observed from both the trans and cis isomers. It is
suggested that the epimerization between the trans and cis
isomers occurs via a transient acyclic iminium ion intermediate
which also can be the reactive intermediate of the ring-opening
reaction (Figure 3).15
Figure 4. Assumed transition state models.
nucleophile and the stereoselectivity. On the other hand, in a
bulky 3-silyloxy system, the smaller nucleophile tends to provide
the higher selectivity. The steric bulkiness of the 3-silyloxy
group might prevent the hydrogen bonding and, therefore, two
competitive nonchelation transition states, TS3 and TS4, where
the 3-silyloxy group is perpendicular to the plane of the CdN
double bond of the iminum ion intermediates for stereoelectronic
reasons, could be involved in this case. Since the conformation
of TS4 has a larger allylic strain between the alkyl side chain
and the proton bound to the iminium nitrogen, TS3 could be
favored and then the nucleophile could attack from the opposite
side of the silyloxy group to give the syn-product selectively.16
It is reasonable that, in TS3, the smaller nucleophile has the
advantage of overcoming the steric repulsion against the alkyl
side chain to show higher selectivity.
Synthetic Application. From the synthetic point of view, the
present reaction provides a powerful tool for the preparation of
a wide variety of 1,4- and 1,5-amino alcohols. In addition, the
reaction is applied to the stereoselective synthesis of the 2,3-
cis-substituted aza-hetereocycles such as piperidines17 (eq 4).
This outcome is complementary to the Lewis acid-catalyzed
reactions of 2,3-diacyloxy or 2-alkoxy-3-acyloxy piperidine
derivatives with nucleophiles which provide preferably 2,3-
trans-substituted piperidines (eq 5).7 To exploit this stereocon-
trol, our methodology has successfully been applied to diaste-
reoselective syntheses of piperidine alkaloids, i.e., an antimalarial
agent, (+)-isofebrifugine and (()-sedacryptine.
Figure 3. Epimerization of the semicyclic N,O-acetal.
Considering the above mechanistic studies, the diastereofacial
selection of the acyclic iminum intermediates by a nucleophile
is the key to explaining the stereochemical outcomes. We
assumed four transition state models TS1-TS4 depending on
the protecting groups (Figure 4). For the 3-acyloxy and 3-alkoxy
systems, a chelation model TS1 possessing a hydrogen bond
between the proton bound to the iminium nitrogen and the
3-oxygen functional group is likely, and then a nucleophile could
attack from the less hindered side (from the side of hydrogen)
to give the syn-product. In TS1, the bulkier nucleophile could
cause larger steric repulsion against the alkyl side chain and,
therefore, could show higher selectivity. This tendency was
actually observed in the 3-acetoxy and 3-benzyloxy systems.
In addition, for the 3-acyloxy system, five-membered dioxo-
carbenium ion intermediate TS2 might also be involved in
neighboring group participation of the 3-acyloxy group. This
dioxocarbenium ion would have the trans-configuration for
steric reasons, and then an SN2-type attack of a nucleophile
would provide the syn-product. However, in TS2, it is difficult
to explain the relationship between the steric bulkiness of the
(+)-Isofebrifugine. (+)-Febrifugine and (+)-isofebrifugine,
isolated first from the Chinese plant Dichroafebrifuga18 and later
(16) Nagai et al. suggested a similar transition state model for the
R-alkoxy-N,N-dibenzyliminium ion system (see ref 8a).
(17) For a recent review on stereoselective synthesis of piperidines, see:
Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(15) (a) Lockhoff, O.; Stadler, P. Carbohydr. Res. 1998, 314, 13. (b)
Cheng, X.; Hii, K. K. Tetrahedron Lett. 2001, 57, 5445.

Ring-Opening Reactions of Semicyclic N,O-Acetals
J. Am. Chem. Soc., Vol. 123, No. 50, 2001 12515
Figure 5. (+)-Febrifugine and (+)-isofebrifugine.
Scheme 7. Synthesis of (+)-Isofebrifugine (1)
from the common hydrangea,19 have attracted considerable atten-
tion due to their potentially powerful antimalarial activity.20
Among several synthetic efforts,21 we have achieved the catalytic
asymmetric synthesis of these compounds and revised their
absolute configurations as shown in Figure 5.21b,c In our contin-
uous interest in developing synthetic methodologies of nitrogen-
containing compounds such as febrifugine analogues, we first
undertook the synthesis of isofebrifugine utilizing the methodol-
ogy developed herein (Scheme 7). The optically pure 3-ben-
zyloxy N,O-acetal (3S)-5i was prepared from D-arabinose in
seven steps.22 The reaction of (3S)-5i with the quinazolinone-
containing silyl enol ether21a was carried out in the presence of
2.5 equiv of TMSOTf. The slight excess amount of the Lewis
acid was required due to the basicity of the quinazolinone
moiety. Without epimerization, the desired syn-adduct 6x was
obtained in good yield with satisfactory diastereoselectivity. The
ring formation of 6x via an oxidation/reductive cyclization
sequense provided piperidine 15. Finally, deprotection of the
N-benzyloxy carbonyl and benzyl ether groups in one pot under
refluxing 6 N aqueous HCl furnished (+)-isofebrifugine in good
yield (11 steps from D-arabinose).
The stereoselective synthesis of (+)-isofebrifugine was also
accomplished via ring-opening allylation (Scheme 8). The
TMSOTf-catalyzed reaction of (3S)-5i with allyltrimethylsilane
at -20 °C afforded the optically active ring-opened product
(S)-6r in good yield. Epoxidation of (S)-6r followed by an
introduction of 4-hydroxyquinazoline gave diol 16 as a diaster-
eomeric mixture. Oxidation of both hydroxyl groups of 16 with
Dess-Martin periodinane and a sequential piperidine ring
formation by triethylsilane reduction gave cis-piperidine 15 (vide
supra). Compared with the former synthesis, the key ring-
opening allylation of this route requires only a catalytic amount
Scheme 8. Synthesis of (+)-Isofebrifugine (2)
(18) (a) Koepfly, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem.
Soc. 1947, 69, 1048. (b) Koepfly, J. B.; Mead, J. F.; Brockman, J. A., Jr.
J. Am. Chem. Soc. 1947, 69, 1837. (c) Koepfly, J. B.; Mead, J. F.; Brockman,
J. A., Jr. J. Am. Chem. Soc. 1948, 70, 1048.
(19) (a) Ablondi, F.; Gordon, S.; Morton, J., Jr., II; Williams, J. H. J.
Org. Chem. 1952, 17, 14. (b) Kato, M.; Inada, M.; Itahana, H.; Ohara, E.;
Nakamura, K.; Uesato, S.; Inouye, H.; Fujita, T. Shoyakugaku Zasshi 1990,
44, 288.
(20) (a) Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.; Lu, G.; Thou,
T. C. Science 1946, 103, 59. (b) Chou, T.-Q.; Fu, F. Y.; Kao, Y. S. J. Am.
Chem. Soc. 1948, 70, 1765. (c) Frederick, A. K., Jr.; Spencer, C. F.; Folkers,
K. J. Am. Chem. Soc. 1948, 70, 2091.
(21) 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. (h) Ooi,
H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett.
2001, 3, 953.
of the Lewis acid. Moreover, the later introduction of the
quinazolinone part may provide a variation of this step in the
synthesis of febrifugine analogues.
(()-Sedacryptine. Sedacryptine was isolated from Sedum
acre as a minor alkaloid along with sedinine.23 Although three
total syntheses including two diastereoselective asymmetric
syntheses have been reported so far,24 these syntheses need an
(22) (a) Tanaka, D.; Yoshino, T.; Kouno, I.; Miyashita, M.; Irie, H.
Tetrahedron 1993, 49, 10253. (b) Charette, A. B.; Mellon, C.; Motamedi,
M. Tetrahedron Lett. 1995, 36, 8561.

12516 J. Am. Chem. Soc., Vol. 123, No. 50, 2001
Scheme 9. Retrosynthetic Analysis of Sedacryptine
Sugiura et al.
Scheme 10. Diastereoselective Synthesis of
(()-Sedacryptine
Figure 6. Assumed transition state for the formation of 2,6-cis-
piperidine 17.
selectivity. The 2,6-cis-isomer could be separated by silica gel
chromatography. The 2,6-cis-configuration was confirmed by
1
the H NMR measurement of NOE enhancement between one
of the methylene protons at C1′ and one of the methylene
protons at C1′′ (in DMSO-d6 at 80 °C, 5.5% enhancement of
the H1′ proton on the irradiation at H1′′ and 4.0% enhancement
of the H1′′ proton on the irradiation at H1′ were observed). On
the other hand, no NOE enhancement between H2 and H6
protons was observed, implying the piperidine has a rather rigid
conformation with the diaxial substituents at C2 and C6 and
the equatorial substituent at C3. A nucleophilc attack to a cyclic
iminium ion intermediate from the axial direction has been
proposed to be favored due to the stereoelectronic effect.25
Moreover, the C2 or C6 substituent in N-acyl piperidine is
known to locate in a pseudoaxial position because of steric
repulsion between the C2 or C6 substituent and the planar N-acyl
group.25 In our case, the cyclic iminium ion intermediate would
have a pseudoaxial 2-oxopropane group at C2 and a pseu-
doequatorial tert-butyldiphenylsilyloxy group at C3 as depicted
in Figure 6 and, therefore, the nucleolphile would attack from
the axial direction to give 2,6-cis-piperidine 17 selectively. With
the 2,3,6-all-cis-isomer 17 in hand, further transformations to
sedacryptine were performed. First, a chemoselective acetal
protection of the methyl ketone moiety26 afforded mono-acetal
18. Use of the neopentyl glycol derivative was a key to
decreasing polarity of the acetal product, since the separation
of the corresponding ethylene glycol derived acetal from the
unreacted starting ketone 17 was difficult. The stereoselective
reduction of the phenyl ketone part of 18 with Li(tert-
BuO)3AlH27 followed by LAH reduction of the N-benzyloxy-
carbonyl group to the N-methyl group, deprotection of the tert-
butyldiphenylsilyl group by TBAF, and acid hydrolysis of the
acetal protection furnished almost pure (()-sedacriptine, which
was further purified by alumina TLC. All NMR spectroscopic
data for the synthetic sedacryptine were completely consistent
with those of the litereature.28 While we have shown efficient
racemic synthesis of sedacryptine, enantioselective synthesis of
inversion of the stereogenic center or include key steps with
low diastereoselectivity. As shown in our retrosynthetic analysis
(Scheme 9), we anticipated that the ring-opening reaction of 5j
with the silyl enol ether derived from acetone followed by
oxidation/Lewis acid-catalyzed nucleophilic substitution of the
ring-opened product 6y would construct the sedacryptine
skeleton 17 stereoselectively.
(25) For example, see: (a) Palasz, P. D.; Utley, J. H. P. J. Chem. Soc.,
Perkin Trans. 2 1984, 807. (b) Irie, K.; Tanaka, T.; Saito, S. J. Chem. Soc.,
Chem. Commun. 1985, 633. (c) Comins, D. L.; Foley, M. A. Tetrahedron
Lett. 1988, 29, 6711. (d) Driessens, F.; Hootele´, C. Can. J. Chem. 1991,
69, 211. (e) Herdeis, C.; Held, W. A.; Kirfel, A. Libigs. Ann. Chem. 1994,
1117.
The synthesis of sedacryptine is summarized in Scheme 10.
The ring-opening reaction of 5j with acetone-silyl enol ether
provided adduct 6y in high yield with high syn-diastereoselec-
tivity as expected. Subsequent SO3‚Py-DMSO oxidation of 6y
and BF3‚OEt2 promoted nucleophilic substitution with acetophe-
none-silyl enol ether to give piperidine 17 with good 2,6-cis-
(26) (a) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,
21, 1357. (b) Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1985, 50, 3946.
(27) The stereoselective reduction of a phenyl ketone moiety by this
reagent in a similar system has been reported: Herdeis, C.; Held, W. A.;
Kirfel, A.; Schwabenla¨nder, F. Liebigs. Ann. 1995, 1295.
(23) Hootele´, C.; Colau, B.; Halin, F. Tetrahedron Lett. 1980, 21, 5061.
(24) (a) Natsume, M.; Ogawa, M. Heterocycles 1983, 20, 601 (racemate).
(b) Akiyama, E.; Hirama, M. Synthesis 1996, 100 (optically active). (c)
Plehiers, M.; Hootele´, C. Can. J. Chem. 1996, 74, 2444 (optically active).
(28) (a) See ref 24c for 1H NMR. (b) For 13C NMR: Colau, B.; Hootele´,
C.; Tourwe, D. Tetrahedron 1984, 40, 2171 .

Ring-Opening Reactions of Semicyclic N,O-Acetals
J. Am. Chem. Soc., Vol. 123, No. 50, 2001 12517
powder (activated by using a domestic microwave oven, 300 mg/1
mmol of 7, 8, or 9) in dichloromethane (0.2 M) was added dropwise
TMSOTf (1 equiv) at room temperature. After being stirred for 10-
30 min, the mixture was quenched with saturated aqueous NaHCO3,
diluted with ethyl acetate, and filtered through a Celite pad. After
separation of the organic layer, the aqueous layer was extracted with
ethyl acetate (2×) and washed with brine. The combined organic layers
were dried over anhydrous MgSO4 and concentrated in vacuo. The
residue was purified by silica gel chromatography to give a 3-oxygen-
fuctionalized semicyclic N,O-acetal 5h-j.
General Procedure for TMSOTf-Catalyzed Ring-Opening Reac-
tions of Semicyclic N,O-Acetals. To a solution of semicyclic N,O-
acetal 5 (1 equiv.) and a nucleophile (a silyl enol ether, a ketene silyl
acetal, an allylic silane, or trimethylsilyl cyanide, 1.2-2 equiv) in
dichloromethane or acetonitrile (0.1 M) was added dropwise trimeth-
ylsilyl trifluoromethanesulfonate (TMSOTf, 0.2 equiv) at 0 °C or room
temperature. After being stirred at that temperature for the indicated
time, the mixture was quenched with saturated aqueous NaHCO3 and
extracted with ethyl acetate (2×). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concentrated in
vacuo. The residue was purified by preparative TLC to give a ring-
opened product 6.
(+)- or (-)-sedacryptine would be readily performed starting
from L- or D-arabinose according to the transformation shown
in Schemes 7 and 10.
Conclusion
In summary, we have revealed that ring-opening reactions
of various types of semicyclic N,O-acetals 5 with silicon-based
nucleophiles such as silyl enol ethers, ketene silyl acetals, allylic
silanes, and trimethylsilyl cyanide were effectively catalyzed
by a Lewis acid (TMSOTf) to afford acyclic 1,4- and 1,5-amino
alcohols 6 with high diastereoselectivities. The stereochemical
outcomes were mechanistically rationalized. This is the first
systematic study of the reactions of the semicyclic N,O-acetals
5 under Lewis acidic conditions, showing quite different reaction
modes and stereoselectivity from those in the reactions of other
semicyclic acetals 1 and 3. Furthermore, the synthetic utility of
this methodology has been demonstrated in the stereoselective
syntheses of (+)-isofebrifugine and (()-sedacryptine.
Experimental Section
NMR Experiment: TMSOTf-Catalyzed Reaction of 5a with
1-Phenyl-1-(trimethylsilyloxy)ethylene in CDCl3. In a dry NMR tube
with a septum, 5a (14.3 mg, 0.06 mmol) was dissolved in CDCl3 (dried
over 4 Å molecular sieves pellet, 0.6 mL). 1-Phenyl-1-(trimethylsily-
loxy)ethylene (12 mg, 1.0 equiv) and TMSOTf (2.2 µL, 0.2 equiv)
were successively introduced to the solution. Then the reaction had
been monitored by a NMR spectrometer. The gradual consumption of
5a and the formation of O-TMS-6a were observed and the reaction
was almost completed after 45 min. Addition of water (5 µL) to this
mixture showed an immediate formation of alcohol 6a.
General Procedure for the Preparation of 3-Unsubstituted
Semicyclic N,O-Acetals (5a-f). To a solution of a carbamate or an
amide (1-3 mmol) and 3,4-dihydro-2H-pyran (1-1.2 equiv) in
dichloromethane (1.0 M) was added p-toluenesulfonic acid monohydrate
(1 mol %) at room temperature. The reaction mixture was stirred for
1-3 h. The mixture was quenched with saturated aqueous NaHCO3
and extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by recrystallization and/or silica gel chromatog-
raphy to give a 3-unsubstituted semicyclic N,O-acetal 5a-f. (Benzyl
carbamate was purchased from Tokyo Chemical Industry Co., Ltd. and
was used without purification. 9H-Fluoren-9-ylmethyl carbamate, allyl
carbamate, and naphthalen-2-yl carbamate were prepared according to
the literature procedure.29)
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
General Procedure for the Preparation of 3-Oxygen-Function-
alized Semicyclic N,O-Acetals (5h-j). To a suspension of 7, 8, or 9
(1 equiv), benzyl carbamate (1.1 equiv), and 4 Å molecular sieves
Supporting Information Available: Full experimental
procedure and compound characterizations (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(29) Loev, B.; Kormendy, M. F.; Goodman, M. M. Org. Synth. Coll.
Vol. 5 1973, 162.
JA0170448