Ring-closing metathesis of allylic O,O- and N,O-acetals

Article abstract of DOI:10.1002/1615-4169(200208)344:6/7<736::AID-ADSC736>3.0.CO;2-8

A variety of allylic O,O- and N,O-acetals were synthesized using a mild palladium-catalyzed coupling of an alcohol or sulfonamide with an alkyl or aryl 1,2-propadienyl ether. The resulting linear acetals were used for the synthesis of unsaturated rings via ring-closing metathesis, in which the acetal carbon-a precursor for oxycarbenium or N-sulfonyliminium ions, respectively-served as a reactive center for further introduction of functional groups. The products-unsaturated oxygen and nitrogen heterocyclic scaffolds - offer multiple opportunities for derivatization as illustrated with the synthesis of substituted dihydropyrans, chromenes, enantiopure tetrahydropyridines and an enantiomerically pure quinolizidine amino acid.

Full text of DOI:10.1002/1615-4169(200208)344:6/7<736::AID-ADSC736>3.0.CO;2-8

FULL PAPERS
Ring-Closing Metathesis of Allylic O,O- and N,O-Acetals
Sape S. Kinderman,a Robin Doodeman,a Jetze W. van Beijma,a Jaap C. Russcher,b
Kim C. M. F. Tjen,a T. Martijn Kooistra,a Homayun Mohaselzadeh,a Jan H. van
Maarseveen,a Henk Hiemstra,a Hans E. Schoemaker,a, c Floris P. J. T. Rutjesa, b,*
a
Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The
Netherlands
b
NSR Center, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax: ( ‡ 31)-24-365-3393, e-mail: rutjes@sci.kun.nl
c
DSM Research, Life Science Products, PO Box 18, 6160 MD Geleen, The Netherlands
Received: February 4, 2002; Accepted: April 9, 2002
Abstract: A variety of allylic O,O- and N,O-acetals scaffolds offer multiple opportunities for derivatiza-
were synthesized using a mild palladium-catalyzed tion as illustrated with the synthesis of substituted
coupling of an alcohol or sulfonamide with an alkyl or dihydropyrans, chromenes, enantiopure tetrahydro-
aryl 1,2-propadienyl ether. The resulting linear acetals pyridines and an enantiomerically pure quinolizidine
were used for the synthesis of unsaturated rings via amino acid.
ring-closing metathesis, in which the acetal carbon a
precursor for oxycarbenium or N-sulfonyliminium
ions, respectively served as a reactive center for Keywords: allylic N,O-acetals; allylic O,O-acetals;
further introduction of functional groups. The prod- amidopalladation; oxypalladation; ring-closing meta-
ucts unsaturated oxygen and nitrogen heterocyclic thesis
Introduction
displayed in Scheme 1. In the type I precursors, only one
of the two olefinic moieties is part of the acetal function,
Ring-closing metathesishas emergedoverthe past decade while in the type II precursors the acetal is built up from
or so as a mild an general method for the construction of two olefinic side chains. Although ring-closing meta-
small to large sized unsaturated heterocyclic systems.[1] thesis of class II precursors is also highly valuable and
The mild, neutral conditions under which these reactions examples have been described in the literature,[6] this
are conducted in combination with the broad tolerance of paper focuses on the ring-closing metathesis of class I
the Ru- and Mo-catalysts towards virtually any functional type precursors. We anticipated that the latter approach,
group render this method especially valuable for the where olefin-containing alcohols and sulfonamides
synthesis of acid, base, and/or thermally labile hetero- were used to produce the required acetals, first of all
cyclic molecules. In recent years, with the emergence of would upon cyclization give rise to a double bond that
improved and highly active metathesis catalysts the can be used for additional transformations, but that
usefulness of this method has even been further extended
due to the fact that high reaction temperatures are often
no longer required.[2] Cyclic O,O-, and N,O-acetals
represent compound classes that are rather sensitive and
O
n
n
Type I
Type II
would be especially well suited for construction via a ring-
closing metathesis process. Interestingly, examples of
ring-closing metathesis of linear acetals are scarce in
literature; in fact, only a handful of such transformations
has been described.[3] In contrast with the occurrence of
these few examples, the resulting products are highly
desirable, functionalized, multipurpose heterocyclic com-
pounds,[4] which may serve as precursors for the synthesis
of natural products and other potentially biologically
relevant substances (Scheme 1).[5]
RO
X
R
X
1
2
n = 0, 1, 2
X = O, NSO2Ar
RCM
furans, pyrans, oxepines
and chromenes
n
pipecolic acids, azepines
and quinolizidines
RO
X
natural products
3
In principle, one can distinguish two types of allylic
Scheme 1. Allylic O,O- and N,O-acetal ring-closing meta-
O,O- and N,O-acetal precursors, both of which are thesis.
736
¹ 2002 WILEY-VCHVerlag GmbH& Co. KGaA, Weinheim 1615-4150/02/3446+7-736 748 $ 17.50-.50/0
Adv. Synth. Catal. 2002, 344, No. 6+7

Ring-Closing Metathesis of Allylic O,O- and N,O-Acetals
FULL PAPERS
Table 1. Oxypalladation of alkoxyallenes.
a
R1 OH
Entry
Alcohol
Allene (method)
Product
Yield [%]
98
R1
O
OR2
OR2
·
4 - 7
11 - 14
1
2
8 (A)
8: R2 = Me
9: R2 = Bn
10: R2 = Ph
MeO2C
OH
4
MeO2C
MeO2C
O
OMe
OBn
11
9 (B)
97
MeO2C
OH
O
a
n
n
5
12
OR2
OR2
R
NH
SO2R3
19 - 24
R
N
·
SO2R3
62[a]
6
3
4
9 (B)
9 (B)
25 - 30
OH
O
OBn
OBn
13
Scheme 2. Amido- and oxypalladation of alkoxyallenes. Re-
agents and conditions: (a) Method A: propadienyl ether 8
(3 equiv.), Pd(OAc)2 (5 mol %), dppp (5 mol %), Et3N
(1.5 equiv.), MeCN, sealed tube, reflux, 3 6 h. Method B:
propadienyl ether 9 or 10 (1.1 equiv.), Pd(OAc)2 (5 mol %),
dppp (5 mol %), Et3N (1.5 equiv.), MeCN, rt, 16 h.
63[a]
OH
O
7
14
[a] Reaction time less than 60 sec.
especially the presence of the alkoxy group adjacent to of the a-hydroxy ester 4 with methyl 1,2-propadienyl
the ring heteroatom would give access to the corre- ether (8) in refluxing acetonitrile catalyzed by Pd(OAc)2
sponding highly reactive oxycarbenium and N-sulfonyl- gave the desired acetal 11 in 97% yield (entry 1). Not
iminium cations[7] and hence ample opportunities for surprisingly, the product was obtained as a ca. 1:1
derivatization at this position. In this paper, we will mixture of diastereoisomers, which was the case in all of
underline the viability of this approach by describing an these acetalization reactions. The related tertiary alco-
efficient synthesis of members of several heterocyclic hol 5 also gave in nearly quantitative yield the corre-
compound classes such as amongst others pyrans, sponding acetal (12) using milder reaction conditions
chromenes, azepines, and pipecolic acids.
(room temperature instead of 80 8C, thus preventing
decomposition of the product) using benzyl 1,2-prop-
adienyl ether (9) as the allene source (entry 2). This new
example once again demonstrates the usefulness of this
type of acetal synthesis, since even very hindered
Results and Discussion
The synthesis of the ring-closing metathesis precursors tertiary alcohols react to provide the desired acetals.
was performed using a palladium-catalyzed coupling The same mild reaction conditions appeared extremely
between an alcohol or a sulfonamide and an alkyl 1,2- useful in the case of the substituted phenols 6 and 7.
propadienyl ether (Scheme 2). These metal-catalyzed Subjection of these alcohols to similar conditions led to
reaction conditions were especially developed to serve almost instantaneous product formation at room tem-
this purpose, since in most cases commonly used perature (5 mol % of catalyst), affording the acetals 13
combinations of reagents involving protic acids did not and 14 in 62 and 63% yield, respectively (entries 3 and
or only to a very small extent provide the required acid 4). Despite the fact that TLC indicated a clean
labile O,O- and N,O-allylic acetals. Generally, two conversion, the somewhat disappointing yields after
methods were used for the acetal formation, which isolation and purification by column chromatography
differ only in reaction temperature: with method A were probably the result of the labile nature of the
methyl 1,2-propadienyl ether (8) was used in refluxing phenolic acetals. Due to the good leaving group ability
acetonitrile (sealed tube), while with method B allenes 9 of the phenol substituent, these acetals are more prone
and 10 were used in the same solvent at room temper- to acid-catalyzed hydrolysis or isomerization reactions.
ature.[8] The usefulness of this palladium-mediated
In addition to the racemic olefinic substrates, an
coupling method for the construction of such acetals enantiomerically pure acetylenic substrate was pre-
has already been illustrated in publications from our pared, which might serve as a substrate for enyne ring-
group[3a, g,h] and from others.[3c]
closing metathesis. The synthesis commenced with the
Subjecting the secondary, tertiary and phenolic alco- readily available benzyl-protected (R)-glycidol 15
hols 4 7 to one of the electron-rich alkoxy-substituted (Scheme 3). Regioselective epoxide ring-opening with
allenes 8 10 in the presence of a catalytic amount of trimethylsilyl-protected ethynyllithium as the alkylating
Pd(OAc)2/dppp under basic conditions in dry acetoni- agent in the presence of BF3 ¥ OEt2 proceeded smoothly,
trile led to the desired ring-closing metathesis precur- giving the protected acetylenic alcohol 16 in 86% yield.
sors in reasonable to excellent yields (Table 1). Reaction The product was then coupled to methyl 1,2-propadien-
Adv. Synth. Catal. 2002, 344, 736 748
737

Sape S. Kinderman et al.
FULL PAPERS
Me3Si
Me3Si
b
a
O
BnO
BnO
BnO
OH
16 (86%)
O
OMe
15
17 (88%)
18 (52%)
c
Figure 1. Ruthenium catalysts.
Scheme 3. Enyne acetal synthesis. Reagents and conditions:
(a) BF3 ¥ OEt2 (1.5 equiv.), 1-trimethylsilylethynyllithium
(1.5 equiv.), THF, 78 8C. (b) Methyl propadienyl ether,
Pd(OAc)2/dppp 5 mol %, Et3N (1.5 equiv.), MeCN, sealed
tube, reflux, 4 h. (c) K2CO3 (5 equiv.), MeOH, rt, 16 h.
Table 3. Allylic O,O-acetal ring-closing metathesis.
À
Entry Precursor
Conditions[a]
Product
Yield [%]
74
1
2
11
12
31, rt, 4 h
33, rt, 6 h
Table 2. Amidopalladation of alkoxyallenes.
MeO2C
MeO2C
O
34
OMe
OBn
Allene
Product (R3)
25 (C6H4CH3)
26 (C6H4CH3)
27 (pC6H4NO2)
28 (pC6H4NO2)
29 (C6H4CH3)
30 (pC6H4NO2)
Yield [%]
Entry Amide
n
0
1
0
1
1
2
R
H
Method
8
9
64
82
96
84
62
90
1
2
3
4
5
6
19
20
21
22
23
24
A
B
B
B
B
B
77
78
O
35
H
9
CH2OBn
CO2Me
CO2Me
CO2Me
9
3
13
32, 80 °C, 4 h
O
O
OBn
36
10
9
4
5
14
17
31, rt, 8 h
87
OBn
37
-
yl ether in refluxing acetonitrile using 5 mol % of
Pd(OAc)2/dppp as the catalyst affording the acetal 17
in a yield of 88%. This compound could serve as a
substrate for enyne metathesis, but also the correspond-
ing desilylated compound 18 which was obtained upon
treatment of 17 with K2CO3 in MeOH.
The linear N,O-acetals were all prepared via the same
method and are displayed in Table 2. Reaction of N-
tosylallylamine (19) with methyl 1,2-propadienyl ether
31, 40 °C, 16 h
-
BnO
O
OMe
6
18
31, rt, 2 h
36
38
[a] Catalyst 31 was used in CH2Cl2, catalysts 32 and 33 were used in toluene.
at reflux temperature in acetonitrile afforded the resents a new method for the formation of N-sulfonyl-
product 25 in a reasonable yield of 64% (entry 1). protected N,O-acetals, which are not readily accessible
Analogously, but under milder conditions (allene 9, via other pathways.[11]
room temperature) its homologue 20 was converted into
Having these precursors in hand, we set out to explore
the N,O-acetal 26 in 82% yield. The racemic vinyl- both the ring-closing and the enyne metathesis reac-
glycinol-derived[9] sulfonamide 21 (Ns ˆ 4-nitrobenze- tions. Whenever possible we used the mildest conditions
nesulfonyl), and the enantiomerically pure sulfonylated to complete the metathesis process: in most cases the
unsaturated amino acids 22 and 24[10] were successfully ruthenium-based Grubbs catalyst 31 (Figure 1) was used
reacted with benzyl propadienyl ether (9) at room (5 mol %), either at room temperature or at reflux
temperature to give the desired products (27, 28, and 30, temperature in dichloromethane.
respectively) in very good yields (entries 3, 4, and 6).
In reactions where this catalyst gave an unsatisfactory
The conversion of the allylglycine-derived sulfonamide rate or yield, we turned to the more active, dihydroimi-
23 with phenyl 1,2-propadienyl ether (10) proceeded dazolidene-substituted ruthenium catalyst 33 (5 mol %),
smoothly at room temperature, albeit that the yield of with which reactions were performed in toluene at
the resulting N,O-acetal 29 was somewhat lower (62%) elevated temperatures. The metathesis results of the
presumably due to the better leaving group ability of the O,O-acetal precursors are listed in Table 3.
phenoxy moiety (entry 5). In the cases of the enantio-
In these oxygen series, acetal 11 gave the dihydropyr-
merically pure precursors, it was demonstrated with an product 34 (1:1 mixture of cis/trans isomers) in a good
chiral HPLC that the coupling reaction proceeded yield of 74% (entry 1).[3a] A comparable result was
without loss of stereochemical integrity at the amino obtained with the a-methyl-substituted analogue 12,
acid stereocenter (at the acetal center, a 1:1 mixture of which upon treatment with catalyst 33 gave the corre-
diastereoisomers was formed). Considering these ex- sponding product 35 in 77% yield as a 1:1 mixture of cis/
amples, it should be emphasized that this Pd-catalyzed trans-isomers that could be separated by column chro-
condensation of sulfonamides with alkoxyallenes rep- matography (entry 2). The phenolic acetal precursors 13
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Ring-Closing Metathesis of Allylic O,O- and N,O-Acetals
FULL PAPERS
Table 4. Allylic N,O-acetal ring-closing metathesis.
a
Conditions[a]
Yield [%]
95
Entry Precursor
Product
MeO
O
CO2Me
O
CO2Me
O
CO2Me
46 (65%)
34
45
1
2
25
26
31, rt, 2 h
31, rt, 4 h
OMe
39
N
Ts
a
BnO
O
CO2Me
O
CO2Me
68
42
89
60
70
35
47 (47%, 1:3)
N
OBn
40
Ts
b
b
BnO
BnO
O
CO2Me
C
C
O
CO2Me
31, 60 °C[b], 16 h
OBn
3
4
5
6
27
28
29
30
N
N
N
35
48 (49%, 1:1.25)
OBn
Ns
41
O
O
MeO2C
N
OBn
42
31, rt, 16 h
49 (75%)
36
Ns
Scheme 4. Oxycarbenium ion chemistry. Reagents and con-
ditions: (a) BF3 ¥ OEt2 (2 equiv.), allyltrimethylsilane
(2 equiv.), CH2Cl2, 0 8C to rt, 1 h. (b) BF3 ¥ OEt2 (2 equiv.),
trimethylsilyl cyanide (2 equiv.), CH2Cl2, 0 8C to rt, 1 h.
31, 40 °C, 16 h
31, rt, 16 h
MeO2C
MeO2C
N
OPh
43
Ts
prevent aromatization to the corresponding pyrrole.
The successful construction of this labile system dem-
onstrates once more the mildness of the metathesis
process. A similar level of instability was encountered in
ring-closing precursor 27 (entry 3). This time, a higher
temperature was required to obtain the desired product
41 in 42% yield. The use of more active catalysts such as
N
OBn
44
Ns
[a] Catalyst 31 was used in CH2Cl2.
[b] Toluene was used as the solvent.
and 14 could both be ring-closed in a satisfactory yield 32 or 33 did not improve the yield, but instead led to
(78 and 87%, respectively); we observed that in the more extensive decomposition. The product was formed
former case use of catalyst 32 (4 mol %) at higher as an approximately 1:1 mixture of cis/trans-isomers,
temperature was preferred, since with catalyst 31, more indicating that both precursor diastereoisomers cyclized
than 10 mol % of catalyst had to be added portionwise at a comparable rate. The six-membered ring precursors
over a period of several hours in order to reach the same 26, 28, and 29 all gave products (40, 42, and 43) of a
conversion. (entries 3 and 4). The enyne ring-closing significantly higher stability and yields ranging from
metathesis reactions were studied using catalyst 31 60 89% (entries 2, 4, and 5). Interestingly, the ester
(5 mol %) in dichloromethane at room temperature or functionality of 28 had a positive effect on the cycliza-
at 40 8C. Enyne metathesis of such acetal precursors tion process, resulting in a clear increase of the yield of
would yield interesting multifunctionalized acetal-diene 42 compared to 40. In contrast, partial hydrolysis upon
systems, which may be used in a variety of ways for silica gel purification of the more labile phenol-substi-
further derivatization. While the trimethylsilyl-protect- tuted N,O-acetal 43 was probably the reason for the
ed acetylenic precursor 17 appeared unreactive under somewhat lower yield in this case. Furthermore, we were
these reaction conditions (entry 5), the corresponding pleased that the seven-membered ring 44 in this series
deprotected acetylene 18 gave the desired diene in a was smoothly formed at room temperature in a good
reasonable 36% yield. Application of this series of yield of 70% (entry 6).
reactions onto the corresponding homologous acetal
The products resulting from the ring-closing meta-
(obtained starting from addition of trimethylsilyl-pro- thesis reactions proved to be useful building blocks for
tected propargyllithium onto 15) unfortunately did only further derivatization. This was illustrated with the
result in trace amounts of the seven-membered ring synthesis of substituted dihydropyrans[3a,12] and chro-
diene.
menes[3h,13] in the cyclic, unsaturated oxygen-acetal
The first example in the nitrogen series was the series. Lewis acid treatment of these cyclic acetals will
formation of the acid-sensitive five-membered 2,5- lead to conjugated oxycarbenium ion intermediates
dihydropyrrole system 39 from precursor 25 in 95% (viz. 45), which in principle, can undergo 1,2- and 1,4-
isolated yield (Table 4, entry 1). This five-membered type additions of suitable nucleophiles. The reactivity of
ring was rapidly formed in 2 hours at room temperature, these allylic acetals was studied, of which some exam-
but the product had to be purified with great care to ples are shown in Scheme 4.
Adv. Synth. Catal. 2002, 344, 736 748
739

Sape S. Kinderman et al.
FULL PAPERS
a
a
H
BnO
N
CO2Me
N
CO2Me
N
CO2Me
BnO
N
CO2Me
Ns
42
Ns
55 (100%)
b,c
Ns
Ns
42
50
b,c
e
d
R
N
CO2Me
R
N
H
CO2H
H
H
H
Ns
N
CO2H
N
CO2Me
N
CO2Me
53: R = H (61%)
54: R = propargyl (52%)
51: R = H (88%)
52: R = propargyl (75%)
56 (50%)
58 (50%)
57 (77%)
Scheme 5. Substituted pipecolic acid synthesis. Reagents and
conditions: (a) BF3 ¥ OEt2 (3 equiv.), triethylsilane (3 equiv.)
or allenyltributyltin (3 equiv.), CH2Cl2, 78 8C to rt, 4 h. (b)
PhSH(3 equiv.), K 2CO3 (4 equiv.), MeCN, rt, 24 h. (d) LiOH
(1.1 equiv), MeOH/H2O (1:1), rt, 24 h.
Scheme 6. Quinolizidine amino acid synthesis. Reagents and
conditions: (a) BF3 ¥ OEt2 (3 equiv.), allyltributyltin (3 equiv.),
CH2Cl2, 78 8C to rt, 4 h. (b) PhSH(3 equiv.), K 2CO3
(4 equiv.), MeCN, rt, 24 h. (c) allyl bromide (2 equiv.), K2
CO3 (2 equiv.), MeCN, 60 8C, 30 h. (d) 32, toluene, 80 8C, 6 h.
(e) LiOH(1.1 equiv), MeOH/H 2O (3:1), rt, 24 h.
À
À
The acetals were treated with the Lewis acid BF3 ¥
OEt2 at 0 8C and in spite of the use of different
nucleophiles, in all cases solely 1,2-substitution was intermediate. Deprotection of both cyclic amino esters
observed. In the first example, allyltrimethylsilane using standard reaction conditions (thiophenolate-
addition onto acetal 34 provided the allyl-substituted mediated sulfonamide cleavage, followed by lithium
dihydropyran 46 as a single trans-diastereoisomer in hydroxide-induced saponification and subsequent puri-
65% yield. Most likely, the ester substituent on the fication via ion exchange chromatography) yielded the
planar intermediate 45 forces the nucleophile to come in free pipecolic amino acids 53 and 54 without detectable
from the opposite site. Inversely, the comparable a- racemization and epimerization, respectively. Thus
methyl-substituted acetal 35 showed much lower dia- compound 53, which is identical to the natural product
[16]
À
stereoselectivity upon reaction with allyltrimethylsilane baikiain, was obtained {[a]D: 182.6 (c 0.3, H2O; lit.
À
and trimethylsilyl cyanide giving products 47 and 48 in
201.6 (c 1, H2O)}, representing a novel pathway
47 and 49% yield. The low to virtually non-existing towards its synthesis.[16]
selectivity clearly reflects the difference in size between
In addition, a novel enantiomerically pure quinolizi-
a proton and a methyl substituent on the side of the dine amino acid was synthesized using similar N-
electrophile, but also the difference in bulk between the sulfonyliminium ion chemistry and a second ring-closing
allylsilane and the cyanide on the side of the nucleo- metathesis step (Scheme 6). Treatment of the N,O-
À
phile. Moreover, in the aromatic series the benzopyran acetal 42 with BF3 ¥ OEt2 at 78 8C in situ gave the
acetal 36 gave under the same reaction conditions the 2- conjugated N-sulfonyliminium ion 50, which was
cyano-2H-chromene 49 in 75% isolated yield.
trapped in this case by the allyltributylstannane as the
The unsaturated sulfonamide-derived acetals proved nucleophile to give the addition product. In spite of the
to be good precursors for the synthesis of enantiomeri- fact that four possible isomers can be formed in this
cally pure substituted pipecolic acids via N-sulfonylimi- reaction (1,2- and 1,4-addition, cis and trans with respect
nium ion chemistry (Scheme 5).
to the ester group), a single diastereoisomer (55) was
À
Therefore, precursor 42 was treated at 78 8C with obtained. The selectivity was strongly influenced by the
BF3 ¥ OEt2 and the resulting intermediate N-sulfonyli- nature of the nucleophile (allyltrimethylsilane instead
minium ion species 50 was reacted in situ with the of the more reactive allyltributylstannane gave a ca. 3:1
nucleophiles triethylsilane and allenyltributylstan- mixture of 1,2- and 1,4-regioisomers) and the reaction
nane.[14] This approach afforded the protected pipecolic temperature (at higher temperatures, lower selectivities
acids 51 and 52 in 88 and 75% yield, respectively, in a were obtained). The cis-stereochemistry of the adduct
completely regioselective fashion without any detect- was assigned on the basis of 1HNMR NOE studies after
able formation of the corresponding 1,4-adducts. In the deprotection to the free amino acid, which showed a
latter case, the product was proven to consist only of the 10% enhancement of H6 upon irradiation of H2 and vice
cis-adduct after deprotection to the corresponding free versa.[17] Successive sulfonamide cleavage by the thio-
amino acid and comparison with deprotected 55 (vide phenolate anion, followed by allylation using standard
infra).[3g] The cis-relation between the allyl and the ester conditions afforded the diallyl compound 56 in 50%
group is most probably a result of so-called chirality over these two steps. Remarkably, subjection of this
relay:[15] the ester substituent forces the arylsulfonamide triolefin to the ruthenium catalyst 31 in dichlorome-
moiety to point downwards, thus preventing the nucle- thane gave almost no product formation. In contrast, the
ophile to attack from the bottom face of the planar more active catalyst 32 showed a good reactivity in
740
Adv. Synth. Catal. 2002, 344, 736 748

Ring-Closing Metathesis of Allylic O,O- and N,O-Acetals
FULL PAPERS
1HNMR and 77.0 ppm for 13C NMR). Mass spectra were
measured using a JEOL JMS SX/SX102A four-sector mass
spectrometer, coupled to a JEOL MS-MP7000 data system.
Melting and boiling points are uncorrected. Melting points
were determined with B¸chi melting point B-545. Methyl 1,2-
propadienyl ether 8,[18] benzyl 1,2-propadienyl ether 9, and
phenyl 1,2-propadienyl ether 10 were prepared following the
procedure described by Brandsma et al.[14,19]
toluene at 80 8C and afforded the unsaturated, bicyclic
quinolizidine skeleton 57 in 77%. Strikingly, use of only
1% of catalyst 32 was sufficient to complete the reaction
in six hours, compared to virtually no reactivity of
catalyst 31 at all at 40 8C. Finally, the ester was
saponified to give the free, conformationally restricted
quinolizidine amino acid 58. Beside the fact that this
compound represents a new tertiary amino acid, it may
also be applied as an enantiopure building block for
alkaloid synthesis.
General Methods for the Oxy- and Amidopalladation
Method A: In a sealed tube was added to a solution of the
sulfonamide or alcohol (0.3 M) in dry acetonitrile under a
nitrogen atmosphere Et3N (1.5 equiv.), Pd(OAc)2 (5 mol %),
dppp (5 mol %), and the alkyl 1,2-propadienyl ether (3 equiv.).
The mixture was heated at 100 8C for the indicated time. The
crude mixture was cooled and quenched with H2O, and the
product was extracted with diethyl ether. The organic layers
were washed with brine, dried over MgSO4 and concentrated
under vacuum. The crude oil was purified by column chroma-
tography as indicated.
Method B: To a solution of the sulfonamide or alcohol
(0.1 M) in dry acetonitrile under a nitrogen atmosphere was
added Et3N (1.5 equiv.), Pd(OAc)2 (5 mol %), dppp
(5 mol %), and the alkyl 1,2-propadienyl ether (1.1 equiv).
The reaction mixture was stirred at room temperature for the
indicated time and worked up identical to method A.
Conclusions
In this paper, we demonstrated the efficient trans-
formation of various alcohols and sulfonamides into
allylic O,O-acetals or N,O-acetals under mild palladi-
um-catalyzed conditions. The sensitive allylic acetals
appeared to be suitable substrates for ring-closing and
enyne metathesis as shown by many examples. The
usefulness of these cyclic acetals was illustrated with the
synthesis of substituted dihydropyran derivatives and
the synthesis of a substituted chromene derivative. Their
usefulness was further underlined by application in the
synthesis of several novel unsaturated pipecolic acid
derivatives and a new quinolizidine-type amino acid,
which may be used as an enantiopure building block in
alkaloid synthesis. In conclusion, the combination of
allylic acetal formation, ring-closing metathesis and
acid-mediated functionalization constitutes straightfor-
ward and efficient methodology that may be widely used
in the synthesis of strongly functionalized building
blocks, potentially biologically active compounds, and
natural products.
Methyl 2-(1-Methoxyallyloxy)pent-4-enoate (11)
2-Hydroxypent-4-enoic acid methyl ester 4 (2.00 g, 15.4 mmol)
was reacted with methyl 1,2-propadienyl ether according to
method A. Column chromatography (petroleum ether/diethyl
ether, 1:1) afforded 11 as a colorless oil; yield: 3.01 g (98%); IR
À
1
(film): n ˆ 1068, 1129, 1205, 1754, 2834, 2935, 3079 cm ;
1HNMR (400 MHz, CDCl 3): isomer 1: d ˆ 5.84 5.73 (m,
2H), 5.47 5.29 (m, 2H), 5.14 5.06 (m, 2H), 4.93 (d, J ˆ 4.5 Hz,
1H), 4.27 (d, J ˆ 6.3 Hz, 1H), 3.71 (s, 3H), 3.30 (s, 3H), 2.50 (q,
J ˆ 5.9 Hz, 2H); isomer 2: d ˆ 5.84 5.73 (m, 2H), 5.47 5.29
(m, 2H), 5.14 5.06 (m, 2H), 4.86 (d, J ˆ 5.1 Hz, 1H), 4.10 (t,
J ˆ 6.3 Hz, 1H), 3.71 (s, 3H), 3.36 (s, 3H), 2.50 (q, J ˆ 5.9 Hz,
2H); 13C NMR (100 MHz, CDCl3): both diastereoisomers: d ˆ
134.0, 133.8, 132.8, 132.6, 119.3, 119.2, 118.1, 117.9, 102.7, 101.5,
Experimental Section
General information
‡
73.9, 72.9, 53.5, 52.8, 51.6, 37.3; HRMS (EI ): calcd. for
Unless otherwise noted, materials were purchased from
commercial suppliers and used without purification. Toluene,
dichloromethane and acetonitrile were freshly distilled from
calcium hydride. Tetrahydrofuran and diethyl ether were
freshly distilled from sodium with benzophenone as indicator.
Triethylaminewasstored over potassiumhydroxide pellets and
used as such. All air and moisture sensitive reactions were
carried out under an inert atmosphere of dry nitrogen, except
for the ring-closing metathesis reactions, which were stirred
under a dry argon atmosphere. Column chromatography was
performed using Aldrich silica gel (70 230 mesh, 60 ä). Rf
values were obtained by using thin layer chromatography
(TLC) on silica gel-coated plastic sheets (Merck silica gel 60
F254) with the indicated solvents. Infrared spectra were
recorded on a Bruker IFS 28 spectrophotometer. Nuclear
magnetic resonance (NMR) spectra were obtainedon a Bruker
ARX 400 or a Varian Inova-500. Spectra are reported in units
of ppm on the d scale, relative to chloroform (7.26 ppm for
‡
À
(M OMe) : 169.0865; found: 169.0850.
Methyl 2-(1-Benzyloxyallyloxy)-2-methylpent-4-
enoate (12)
2-Hydroxy-2-methylpent-4-enoic acid methyl ester 5 (0.29 g,
2.0 mmol) was reacted with benzyl 1,2-propadienyl ether
according to method B. Column chromatography (heptane/
ethyl acetate 3:1) gave the 12 as a slightly yellow oil; yield:
0.58 g (97%); 1HNMR (300 MHz, CDCl 3): both diaster-
eoisomers: d ˆ 7.35 7.21 (m, 5H), 6.00 5.69 (m, 2H), 5.50
5.24 (m, 3H), 5.12 5.06 (m, 2H), 4.68 4.45 (m, 2H), 3.62 and
3.55 (s, 3H), 2.56 (m, 2H), 1.52 and 1.44 (s, 3H); 13C NMR
(50 MHz, CDCl3): both diastereoisomers: d ˆ 175.1, 139.8,
139.6, 137.0, 136.8, 134.1, 133.9, 129.8, 129.2, 119.6, 119.3, 119.2,
98.5, 98.2, 80.7, 79.6, 67.7, 67.0, 66.0, 52.5, 44.4, 44.1, 23.1, 21.2.
Adv. Synth. Catal. 2002, 344, 736 748
741

Sape S. Kinderman et al.
FULL PAPERS
1-(1-Benzyloxyallyloxy)-2-vinylbenzene (13)
5-Benzyloxy-4-(1-methoxyallyloxy)pent-1-
ynyl]trimethylsilane (17)
According to general procedure B, phenol
6 (0.50 g,
4.19 mmol) was reacted with benzyl 1,2-propadienyl ether.
Column chromatography (petroleum ether/ethyl acetate, 40:1)
According to method A, alcohol 16 was reacted with methyl
1,2-propadienyl ether. Column chromatography (petroleum
ether/diethyl ether, 20:1) afforded 17 as slightly yellow colored
afforded 13 as a colorless oil; yield:0.69 g (2.60 mmol, 62%); IR
À
1
1
(film): n ˆ 3029, 1230, 985 cm ; HNMR (C 6D6, 400 MHz):
d ˆ 7.45 (dd, J ˆ 1.6, 7.7 Hz, 1H), 7.36 (dd, J ˆ 11.2, 17.8 Hz,
1H), 7.20 7.18 (m, 2H), 7.12 7.03 (m, 4H), 7.00 (dt, J ˆ 1.6,
7.3 Hz, 1H), 6.84 (dt, J ˆ 0.7, 8.2 Hz, 1H), 5.91 (ddd, J ˆ 4.3,
10.7, 17.3 Hz, 1H), 5.73 (dd, J ˆ 1.4, 17.8 Hz, 1H), 5.56 (d, J ˆ
4.3 Hz, 1H), 5.41 (td, J ˆ 1.3, 17.4 Hz, 1H), 5.21 (dd, J ˆ 1.4,
11.1 Hz, 1H), 5.07 (td, J ˆ 1.2, 10.7 Hz, 1), 4.64 (d, J ˆ 11.8 Hz,
1H), 4.43 (d, J ˆ 11.8 Hz, 1H); 13C NMR (C6D6, 50 MHz): d ˆ
155.3, 138.9, 135.6, 132.9, 129.7, 129.3, 129.2 (2'), 128.7 (2'),
128.4, 127.4, 123.1, 119.7, 117.6, 115.3, 101.7, 68.3; HRMS
(FAB): calcd. for C18H18O2: 266.1307; found: 266.1306.
oil; yield: 0.79 g (88%); [a]D: ‡ 9.1 (c 1, CH2Cl2); IR (film): n ˆ
À
2957, 2176, 1250, 840 cm ; 1HNMR (400 MHz, CDCl 3): both
1
diastereoisomers: d ˆ 7.35 7.26 (m, 5H), 5.84 (m, 1H), 5.39
(m, 1H), 5.30 and 5.29 (s, 1H), 5.05 (m, 1H), 4.60 and 4.55 (s,
2H), 3.96 (m, 1H), 3.64-3.57 (m, 2H), 3.36 and 3.33 (s, 3H), 2.58-
2.51 (m, 2H), 0.13 (s, 9H); 13C NMR (100 MHz, CDCl3): both
diastereoisomers: d ˆ 138.1, 134.9, 128.3, 128.2, 118.6, 103.4,
103.3, 102.3, 102.1, 86.3, 86.2, 73.5, 73.4, 73.3, 52.6, 52.4, 23.7,
‡
À
0.1; HRMS (FAB): calcd. for C19H29O3Si (MH ): 333.1886;
found: 333.1886.
[2-(1-Methoxyallyloxy)pent-4-ynyloxymethyl]benzene
(18)
1-Isopropenyl-2-(1-benzyloxyallyloxy)benzene (14)
To a solution of 17 (0.67 g, 2.55 mmol) in methanol (5 mL) was
added K2CO3 (35 mg, 10.3 mmol). After stirring for 16 h, the
reaction mixture was poured into saturated aqueous NH4Cl
(5 mL). After layer separation, the aqueous layer was extract-
ed with CH2Cl2 (3 Â 10 mL). The combined organic layers were
dried over MgSO4 and concentrated. Column chromatography
(petroleum ether/diethyl ether, 20:1) afforded 18 as a yellowiÀsh
According to general procedure B, phenol
7 (346 mg,
2.58 mmol) was reacted with benzyl 1,2-propadienyl ether.
Column chromatography (petroleum ether/ethyl acetate, 20:1)
afforded acetal 14 as a colorless oil; yield: 447 mg (63%); IR
À
1
1
(film): n ˆ 3075, 3029, 2917, 1219, 979 cm ; HNMR (C 6D6,
400 MHz): d ˆ 7.24 7.20 (m, 3H), 7.16 7.01 (m, 5H), 6.86 (dt,
J ˆ 1.2, 7.4 Hz, 1H), 5.93 (ddd, J ˆ 4.3, 10.7, 17.4 Hz, 1H), 5.60
(td, J ˆ 1.1, 4.3 Hz, 1H), 5.44 (td, J ˆ 1.4, 17.4 Hz, 1H), 5.16 (m,
2H), 5.10 (td, J ˆ 1.3, 10.7 Hz, 1H), 4.65 (d, J ˆ 11.8 Hz, 1H),
4.47 (d, J ˆ 11.8 Hz, 1H), 2.20 (s, 3H); 13C NMR (C6D6,
50 MHz): d ˆ 153.8, 144.2, 137.8, 134.5, 134.2, 129.4 (2'), 128.0
(2'), 127.5, 127.4, 127.2, 121.9, 118.4, 116.3, 115.0, 100.2, 66.7,
23.2; HRMS (FAB): calcd. for C19H20O2: 280.1463; found:
280.1465.
1
oil; yield: 0.25 g (52%); IR (film): n ˆ 3296, 2936 cm ;
1HNMR (400 MHz, CDCl 3): both diastereoisomers: d ˆ
7.34 7.26 (m, 5H), 5.79 (m, 1H), 5.44 (m, 1H), 5.30 and 5.29
(s, 1H), 5.02 (m, 1H), 4.57 and 4.55 (s, 2H), 3.96 (m, 1H), 3.64
3.57 (m, 2H), 3.35 and 3.34 (s, 3H), 2.57-2.48 (m, 2H), 1.98 and
1.97 (s, 1H); 13C NMR (100 MHz, CDCl3): both diastereoisom-
ers: d ˆ 138.0, 134.7, 128.3, 127.4, 118.6, 102.3, 102.0, 88.9, 72.9,
73.2, 73.3, 68.6, 52.6, 52.5, 23.2; HRMS (FAB): calcd. for
‡
C16H21O3 (MH ): 261.1491; found: 261.1491.
N-Allyl-N-(1-methoxy-allyl)-4-
methylbenzenesulfonamide (25)
(S)-1-Benzyloxy-5-trimethylsilylpent-4-yn-2-ol (16)
To a solution of trimethylsilylacetylene (2.7 g, 27.5 mmol) in
dry THF (35 mL) at 78 8C was slowly added n-butyllithium
(17.5 mL, 27.9 mmol). The solution was allowed to warm to
N-Tosylallylamine (19, 1.0 g, 4.8 mmol) and methyl 1,2-prop-
adienyl ether were reacted according to method A. Column
chromatography (petroleum ether/diethyl ether, 9:1) afforded
25 as a yellowish oil; yield: 0.86 g (64%); IR (film): n ˆ 2833,
À
À
30 8C in 30 min. The reaction mixture was again cooled to
78 8C and BF3 ¥ OEt2 (3.75 mL, 30.5 mmol) was added,
À
1
1345 cm ; 1HNMR (400 MHz, CDCl 3): d ˆ 7.70 (d, J ˆ
8.3 Hz, 2H), 7.27 (d, J ˆ 8.0 Hz, 2H), 5.74 (m, 1H), 5.57 (m,
1H), 5.46 (dt, J ˆ 4.3, 1.3 Hz, 1H), 5.33 (dt, J ˆ 17.2, 1.5 Hz,
1H), 5.21 (dt, J ˆ 10.5, 1.5 Hz, 1H), 5.11 (dq, J ˆ 17.2, 1.4 Hz,
1H), 5.02 (dq, J ˆ 10.1, 1.3 Hz, 1H), 3.75 (m, 2H), 3.31 (s, 3H),
2.4 (s, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 143.2, 137.8,
135.0, 133.8, 129.5, 127.1, 118.5, 117.1, 88.3, 55.4, 45.3, 22.0;
À
followed by stirring at this temperature for 30 min. A solution
of benzyl glycidol 15 (3.0 g, 18.3 mmol) in THF (15 mL) was
À
added and the mixture was stirred at 78 8C for 2 h. The
reaction was quenched by adding saturated aqueous NH4Cl
(50 mL) and allowed to warm to room temperature. The layers
were separated and the aqueous layer was extracted with CH2
Cl2 (3 Â 50 mL). The combined organic layers were dried over
MgSO4 and concentrated. Column chromatography (petrole-
um ether/ethyl acetate 4:1) afforded 16 as a slightly yellow oil;
‡
HRMS (FAB): calcd. for C14H20NO3S (MH ): 282.1164; found:
282.1164.
yield: 4.1 g (86%); [a]D ˆ‡ 10.5 (c 10, CH2Cl2); IR (film): n ˆ
À
1
1
3417, 2126, 1249, 840 cm ; HNMR (400 MHz, CDCl 3): d ˆ
7.38 7.26 (m, 5H), 4.57 (s, 2H), 3.98 3.93 (m, 1H), 3.61 (dd,
J ˆ 9.6, 3.9 Hz, 1H), 3.50 (dd, J ˆ 9.6, 6.5 Hz, 1H), 2.50 (dd, J ˆ
6.1, 3.8 Hz, 2H), 2.43 (br, 1H), 0.15 (s, 9H); 13C NMR
(100 MHz, CDCl3): d ˆ 137.7, 128.3, 127.7, 102.4, 87.2, 73.3,
N-(1-Benzyloxyallyl)-N-but-3-enyl-4-
methylbenzenesulfonamide (26)
N-Tosyl-3-butenylamine (20, 1.0 g, 4.43 mmol) was reacted
with benzyl 1,2-propadienyl ether according to method B.
Column chromatography (pentane/diethyl ether, 4:1 1:1)
À
72.7, 68.7, 24.9, 0.09.
742
Adv. Synth. Catal. 2002, 344, 736 748

Ring-Closing Metathesis of Allylic O,O- and N,O-Acetals
FULL PAPERS
afforded 26 as a colorless oil; yield: 1.34 g (82%); IR (film): n ˆ
5.46 (m, 2H), 5.10 5.04 (m, 2H), 4.43 4.48 and 4.33 4.30 (m,
1H), 3.72 and 3.62 (s, 3H), 3.04 2.99 (m, 1H), 2.58 2.55
(m,1H), 2.43 and 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3):
one diastereoisomer: d ˆ 170.9, 156.8, 143.6, 137.6, 134.7, 133.7,
129.3, 129.4, 127.7, 122.0, 120.0, 117.4, 115.9, 86.1, 57.9, 52.2,
À
1
1
2930, 1341, 1163 cm ; HNMR (500 MHz, CDCl 3): d ˆ 7.72
(d, J ˆ 7.3 Hz, 2H), 7.28 7.38 (m, 7H), 5.70 5.75 (m, 1H), 5.68
(s, 1H), 5.43 5.52 (m, 2H), 5.26 (d, J ˆ 10.3 Hz, 1H), 5.00 5.06
(m, 2H), 4.73 (d, J ˆ 12.0 Hz, 1H), 4.57 (d, J ˆ 12.2 Hz, 1H),
3.25 3.30 (m, 1H), 3.09 3.15 (m, 1H); 13C NMR (125 MHz,
CDCl3): d ˆ 143.4, 137.8, 137.6, 135.1, 133.8, 129.7, 128.3, 127.7,
127.6, 127.0, 119.0, 116.6, 86.4, 69.4, 43.1, 35.0, 21.5; HRMS
‡
35.6, 21.4; HRMS (FAB): calcd. for C22H26NO5S (MH ):
416.1532; found: 416.1531.
‡
(FAB): calcd. for C21H26NO3S (MH ): 372.1633; found:
372.1637.
Methyl 2-[(1-Benzyloxyallyl)-(4-
nitrobenzenesulfonyl)amino]hex-5-enoate (30)
N-(1-Benzyloxyallyl)-N-(1-benzyloxymethylallyl)-4-
nitrobenzenesulfonamide (27)
Methyl
(S)-2-(4-nitrobenzenesulfonylamino)hex-5-enoate
(24, 0.1 g, 0.305 mmol) was reacted with benzyl 1,2-propadien-
yl ether according to method B. Column chromatography
(petroleum ether/diethyl ether, 4:1 1:1) afforded 30 as a
N-(1-Benzyloxymethylallyl)-4-nitrobenzenesulfonamide (21,
0.30 g, 0.81 mmol) was reacted with benzyl 1,2-propadienyl
ether according to method B. Column chromatography (pen-
tane/diethyl ether, 2:1) afforded 27 as a white, waxy solid; yield:
colorless oil; yield: 0.13 g (90%); IR (film): n ˆ 2951, 1745,
À
1
1531, 1351, 1165 cm ; 1HNMR (400 MHz, CDCl 3): both
diastereoisomers: d ˆ 8.27 (d, J ˆ 8.8 Hz, 2H), 8.03 (d, J ˆ
8.9 Hz, 2H), 7.37 7.24 (m, 5H), 5.75 5.64 (m, 2H), 5.53
5.44 (m, 2H), 5.32 5.29 (m, 1H), 5.02 4.94 (m, 2H), 4.73 (d,
J ˆ 11.9 Hz, 1H), 4.59 4.54 (m, 1H), 4.23 4.16 (m, 1H), 3.66
and 3.60 (s, 3H), 2.40 2.32 (m, 1H), 2.31 2.13 (m, 1H), 2.07
1.95 and 1.78 1.72 (m, 2H); 13C NMR (100 MHz, CDCl3): one
diastereoisomer: d ˆ 171.2, 147.0, 136.7, 137.0, 133.4, 129.0,
128.7, 128.3, 127.6, 123.9, 119.6, 115.8, 86.7, 70.2, 56.9, 52.2, 31.1,
0.40 g (96%); IR (film): n ˆ 3066, 3033, 2871, 1533, 1350,
À
1
1
1165 cm ; HNMR (400 MHz, CDCl 3): both diastereoisom-
ers: d ˆ 8.15 (m, 2H), 7.96 (m, 2H), 7.37 7.06 (m, 10H), 6.15
6.80 (m, 1H), 6.80 5.61 (m, 1H), 5.56 5.20 (m, 2H), 4.65 4.31
(m, 5H), 3.93 3.79 (m, 1H); 13C NMR (100 MHz, CDCl3):
both diastereoisomers: d ˆ 149.5, 147.5, 137.5, 137.0, 135.2,
134.7, 134.4, 134.0, 128.6, 128.2, 128.1, 126.9, 123.7, 119.6, 119.2,
119.0, 118.4, 87.0, 73.0, 70.4, 58.9, 47.1, 15.1; HRMS (FAB):
‡
30.6; HRMS (FAB): calcd. for C23H27N2O7S (MH ): 475.1539;
found: 475.1535.
‡
calcd. for C27H28N2O6SNa (MNa ): 531.1566; found: 531.1548.
Methyl 2-[(1-Benzyloxyallyl)-(4-
nitrobenzenesulfonyl)amino]pent-4-enate (28)
General Method for the Ring-Closing Metathesis
Reactions
Methyl (S)-2-(4-nitrobenzenesulfonylamino)pent-4-enoate
(22, 2.58 g, 8.19 mmol) and benzyl 1,2-propadienyl ether
were reacted following method B. Column chromatography
(pentane/diethyl ether, 1:1 1:4) afforded 28 as a colorless oil;
The substrate was dissolved in degassed dichloromethane or
toluene in a concentration of approximately 0.01 M. Argon
was bubbled through the solution for 10 min, after which the
ruthenium catalyst (see: Tables, 5 mol % in most cases) was
added. The reaction mixture was stirred for the indicated time
(see Tables) and then stirred openly exposed to air to destroy
the active catalyst. The solvent was then removed under
vacuum and the crude product purified by column chromatog-
raphy as indicated.
yield: 3.17 g (84%); IR (film): n ˆ 2952, 1745, 1530, 1350,
À
1
1
1164 cm ; HNMR (400 MHz, CDCl 3): both diastereoisom-
ers: d ˆ 8.26 (d, J ˆ 8.8 Hz, 2H), 8.04 (d, J ˆ 8.9 Hz, 2H), 7.35
7.24 (m, 5H), 5.83 5.63 (m, 1H), 5.54 5.43 (m, 2H), 5.32 5.27
(m, 1H), 5.15 4.99 (m, 2H), 4.76 (d, J ˆ 12.0 Hz, 1H), 4.64 (d,
J ˆ 12.0 Hz, 1H), 4.57 4.52 (m, 1H), 4.24 4.20 (m, 1H), 3.68
and 3.6 (s, 3H), 3.05 2.97 (m, 1H), 2.75 2.69 and 2.46 2.39
(m, 1H); 13C NMR (100 MHz, CDCl3): both diastereoisomers:
d ˆ 170.5, 149.8, 146.5, 136.7, 134.3, 128.8, 128.3, 127.5, 123.8,
119.6, 117.9, 86.4, 70.0, 57.4, 52.2, 35.8; HRMS (FAB): calcd. for
Methyl 6-Methoxy-3,6-dihydro-2H-pyran-2-
carboxylate (34)
‡
C22H25N2O7S (MH ): 461.1382; found: 461.1363.
Precursor 11 (1.0 g, 5.0 mmol) was reacted following the
general method. Column chromatography (petroleum ether/
diethyl ether, 4:1 1:1) afforded 34 as a colorless oil; yield:
0.63 g (3.7 mmol, 74%); IR (film): n ˆ 1050, 1111, 1179, 1217,
Methyl 2-[(1-Phenoxyallyl)(4-
toluenesulfonyl)amino]pent-4-enoate (29)
À
1
1735, 2828, 2954 cm ; 1HNMR (400 MHz, CDCl 3): both
diastereoisomers: d ˆ 6.02 5.98 (m, 1H), 5.77 5.73 (m,
0.5H), 5.66 (dd, J ˆ 10.2, 2.0 Hz, 0.5H), 5.00 (t, J ˆ 1.8 Hz,
0.5H), 4.97 4.96 (m, 0.5H), 4.49 (dd, J ˆ 9.3, 6.0 Hz, 0.5H),
4.97 4.96 (m, 0.5H), 3.77 and 3.74 (s, 3H), 3.46 and 3.44 (s, 3H),
2.45 2.44 (m, 0.5H), 2.34 2.28 (m, 1.5H); 13C NMR
(100 MHz, CDCl3): both diastereoisomers: d ˆ 171.5, 171.2,
127.5, 127.4, 126.0, 125.2, 97.0, 95.8, 69.3, 65.6, 55.5, 55.3, 52.1,
Methyl (S)-2-(4-toluenesulfonylamino)pent-4-enoate (23,
1.00 g, 3.53 mmol) was reacted with phenyl 1,2-propadienyl
ether according to method B. Column chromatography (pen-
tane/diethyl ether, 4:1 2:1) afforded 29 as a colorless oil; yield:
0.90 g (62%); IR (film): n ˆ 3469, 1744, 1596, 1492, 1346, 1226,
À
1
1160 cm ; 1HNMR (500 MHz, CDCl 3) both diastereoisomers:
d ˆ 7.68 (m, 2H), 7.18 7.30 (m, 4H), 7.01 (t, J ˆ 7.3 Hz, 1H),
6.94 6.85 (m, 1H), 6.80 (d, J ˆ 7.8 Hz, 1H), 6.35 6.33 (m, 1H),
6.17 6.08 and 5.90 6.00 (m, 1H), 5.85 5.78 (m, 1H), 5.56
‡
‡
51.9, 27.3, 25.8; HRMS (EI ): calcd. for C16H21O3 (M ):
172.0736; found: 172.0737.
Adv. Synth. Catal. 2002, 344, 736 748
743

Sape S. Kinderman et al.
FULL PAPERS
d ˆ 138.2, 137.5, 128.0, 127.0, 125.8, 124.3, 114.1, 114.0, 97.8,
Methyl 6-Benzyloxy-2-methyl-3,6-dihydro-2H-pyran-
2-carboxylate (35)
96.1, 73.3, 72.4, 70.9, 65.7, 55.1, 25.9, 25.8; HRMS (FAB): calcd.
‡
for C16H21O3 (MH ): 261.1491; found: 261.1491.
Precursor 12 (137 mg, 0.47 mmol) was reacted following the
general method. Column chromatography (heptane/ethyl
acetate, 9:1 3:1) afforded 35 as two separated diastereoisom-
ers; yield: 95 mg (0.36 mmol, 77%). Diastereoisomer 1:
1HNMR (300 MHz, CDCl 3): d ˆ 7.37 7.22 (m, 5H), 6.08
5.68 (m, 1H), 5.74 5.68 (m, 1H), 5.09 5.07 (m, 1H), 4.75
(AB, J ˆ 12.2, 76.0 Hz, 2H), 3.55 (s, 3H), 2.76 (m, 1H), 2.08 (dq,
J ˆ 2.2, 2.5, 17.6 Hz, 1H), 1.50 (s, 3H); 13C NMR (50 MHz,
CDCl3): d ˆ 183.9, 138.7, 128.9, 128.3, 128.3, 128.1, 124.7, 94.3,
73.0, 69.8, 52.8, 32.4, 27.5. Diastereoisomer 2: 1HNMR
(300 MHz, CDCl3): d ˆ 7.39 7.24 (m, 5H), 6.00 5.94 (m,
1H), 5.76 5.70 (m, 1H), 5.43 5.41 (m, 1H), 4.76 (AB, J ˆ 11.8,
73.8 Hz, 2H), 3.75 (s, 3H), 2.60 (m, 1H), 2.26 (m, 1H), 1.58 (s,
3H); 13C NMR (50 MHz, CDCl3): d ˆ 175.0, 138.6, 128.9, 128.5,
128.1, 127.3, 126.2, 94.9, 76.2, 69.8, 53.0, 33.1, 25.7.
2-Methoxy-1-(4-toluenesulfonyl)-2,5-dihydro-1H-
pyrrole (39)
Precursor 25 (0.5 g, 1.78 mmol) was reacted according to the
general procedure. Column chromatography (petroleum
ether/diethyl ether, 9:1) gave 39 as a brown oil; yield: 0.43 g
À
1
1
(1.69 mmol, 95%); IR (film): n ˆ 2934, 1339 cm ; HNMR
(C6D6, 400 MHz): d ˆ 7.76 (d, J ˆ 8.3 Hz, 2H), 6.78 (d, J ˆ
8.0 Hz, 2H), 5.97 (d, J ˆ 3.4 Hz, 1H), 5.22 5.15 (m, 2H), 3.88
(dd, J ˆ 15.5, 2.1 Hz, 1H), 3.68 (m, 1H), 3.12 (s, 3H), 1.88 (s,
3H); 13C NMR (C6D6, 100 MHz): d ˆ 143.7, 130.0, 128.3, 128.0,
127.9, 127.6, 127.5, 96.7, 55.1, 53.1; HRMS (FAB): calcd. for
‡
C12H16NO3S (MH ): 254.0851; found: 254.0851.
2-Benzyloxy-2H-chromene (36)
6-Benzyloxy-1-(4-toluenesulfonyl)-1,2,3,6-
tetrahydropyridine (40)
Precursor 13 (0.20 g, 0.76 mmol) was reacted according to the
general procedure. Column chromatography (petroleum
ether/ethyl acetate, 40:1) afforded 36 as a slightly brown oil;
Precursor 26 (0.2 g, 0.54 mmol) was reacted according to the
general procedure. Column chromatography (pentane/diethyl
ether, 4:1 2:1) afforded 40 as a colorless oil; yield: 0.13 g
yield: 0.14 g (0.59 mmol, 78%); IR (film): n ˆ 3032, 2919, 1202,
À
1
1
1031 cm ; HNMR (C 6D6, 400 MHz): d ˆ 7.20 (m, 2H), 7.05
(m, 3H), 6.97 (m, 2H), 6.85 (br. d, J ˆ 7.2 Hz, 1H), 6.77 (m, 1H),
6.36 (d, J ˆ 9.2 Hz, 1H), 5.55 (m, 2H), 4.74 (d, J ˆ 12.1 Hz, 1H),
4.50 (d, J ˆ 12.1 Hz, 1H); 13C NMR (C6D6, 50 MHz): d ˆ 151.7,
137.9, 129.0, 127.8, 127.5 (2Â), 127.1 (2Â), 126.7, 126.1, 121.1,
120.8, 119.8, 116.4, 94.2, 68.8; HRMS (FAB): calcd. for
(0.37 mmol, 68%); IR (film): n ˆ 3533, 3022, 2828, 1595, 1450,
À
1322, 1156 cm ; 1HNMR (CDCl 3, 500 MHz): d ˆ 7.72 (d, J ˆ
1
8.3 Hz, 2H), 7.39 7.32 (m, 5H), 7.27 (d, J ˆ 8.0 Hz, 2H), 5.85
5.78 (m, 2H), 5.52 (d, J ˆ 3.7 Hz, 1H), 4.80 (d, J ˆ 11.7 Hz, 1H),
4.64 (d, J ˆ 12.0 Hz, 1H), 3.83 3.80 (m, 1H), 3.45 3.39 (m,
1H), 2.43 (s, 3H), 1.78 1.76 (m, 2H); 13C NMR (CDCl3,
125 MHz): d ˆ 143.3, 138.3, 137.9, 129.5, 129.2, 128.3, 128.0,
127.6, 126.9, 124.7, 79.5, 69.6, 37.6, 23.0, 21.4; HRMS (FAB):
‡
C16H15O2 (MH ): 239.1072; found: 239.1060.
‡
calcd. for C19H22NO3S (MH ): 344.1320; found: 344.1316.
2-Benzyloxy-4-methyl-2H-chromene (37)
Precursor 14 (0.44 g, 1.58 mmol) was reacted according to the
general method. Column chromatography (petroleum ether/
ethyl acetate, 20:1) afforded 37 as a brown oil; yield: 0.33 g
2-Benzyloxy-5-benzyloxymethyl-1-(4-
nitrobenzenesulfonyl)-2,5-dihydro-1H-pyrrole (41)
À
1
(1.31 mmol, 84%); IR (film): n ˆ 3031, 2915, 1215, 1037 cm ;
1HNMR (C 6D6, 400 MHz) d ˆ 7.23 7.20 (m, 2H), 7.12 7.04
(m, 6H), 6.85 6.81 (m, 1H), 5.58 (d, J ˆ 3.8 Hz, 1H), 5.42 (m,
1H), 4.78 (d, J ˆ 12.1 Hz, 1H), 4.53 (d, J ˆ 12.1 Hz, 1H), 1.76 (s,
3H); 13C NMR (C6D6, 50 MHz): d ˆ 151.3, 138.6, 132.1, 128.9,
127.9 (2Â), 127.5 (2Â), 127.1, 123.6, 121.0, 118.6, 117.3, 116.5,
Precursor 27 (0.1 g, 0.2 mmol) was reacted following the
general method, except that catalyst 31 was used in toluene at
60 8C. Column chromatography (pentane/diethyl ether, 2:1)
yielded 41 as a colorless oil; yield: 40.0 mg (0.084 mmol, 42%);
À
1
IR (film): n ˆ 2920, 1715, 1529 cm ; 1HNMR (CDCl 3,
400 MHz): both diastereoisomers: d ˆ 8.15 (m, 2H), 7.97 (m,
2H), 7.45 7.07 (m, 10H), 6.11 (m, 1H), 5.76 (m, 1H), 4.61 4.30
(m, 6H), 3.68 (m, 2H); 13C NMR (CDCl3, 100 MHz): both
diastereoisomers: d ˆ 137.4, 132.5, 128.6, 128.3, 128.3, 127.8,
127.7, 127.6, 127.5, 127.3, 123.9, 94.4, 73.4, 72.4, 68.0, 65.7, 65.3,
‡
94.4, 68.8, 17.3; HRMS (FAB): calcd. for C17H16O2 (MH ):
252.1150; found: 252.1158.
2-Benzyloxymethyl-6-methoxy-4-vinyl-3,6-dihydro-
2H-pyran (38)
‡
29.6; HRMS (FAB): calcd. for C25H24N2O6SNa (MNa ):
503.1253; found: 503.1250.
Precursor 18 (0.24 g, 0.92 mmol) was reacted as indicated in the
general procedure. Column chromatography (petroleum
ether/diethyl ether, 20:1) afforded the dihydropyran 38 as a
colorless oil; yield: 85.0 mg (0.33 mmol, 36%); IR (film): n ˆ
Methyl 6-Benzyloxy-1-(4-nitrobenzenesulfonyl)-
1,2,3,6-tetrahydropyridine-2-carboxylate (42)
À
1
3088, 3030, 2825, 1652 cm ; 1HNMR (CDCl 3, 400 MHz): both
diastereoisomers: d ˆ 7.39 7.26 (m, 5H), 6.37 (dd, J ˆ 17.5,
10.7 Hz, 1H), 5.70 and 5.63 (s, 1H), 5.29 and 5.24 (d, J ˆ 6.8 Hz,
1H), 5.14 (s, 1H), 5.11 and 5.03 (s, 1H), 4.62 (m, 2H), 4.18 4.04
(m, 1H), 3.72 3.58 (m, 2H), 3.49 and 3.46 (s, 3H), 2.22 2.16
(m, 2H); 13C NMR (100 MHz, CDCl3): both diastereoisomers:
Precursor 28 (3.1 g, 6.7 mmol) was reacted according to the
general method. Column chromatography (pentane/diethyl
ether, 1:1 1:4) afforded 42 as a white solid; yield: 2.59 g
(6.0 mmol, 89%); mp 106 108 8C; IR (film): n ˆ 3105, 2952,
À
1
1743, 1529, 1349, 1167 cm ; 1HNMR (CDCl 3, 400 MHz): both
744
Adv. Synth. Catal. 2002, 344, 736 748

Ring-Closing Metathesis of Allylic O,O- and N,O-Acetals
FULL PAPERS
diastereoisomers: d ˆ 8.29 and 8.14 (d, J ˆ 8.9 Hz, 2H), 7.99 (d,
J ˆ 8.9 Hz, 2H), 5.97 5.92 and 5.89 5.85 (m, 1H), 5.78 5.76
and 5.75 5.73 (m, 1H), 5.70 and 5.49 (d, J ˆ 3.6 Hz, 1H), 4.76
4.67 (m, 2H), 4.54 and 4.23 (d, J ˆ 11.4 Hz, 1H), 3.83 and 3.52 (s,
3H), 2.69 2.46 (m, 1H), 1.92 1.88 (m, 1H); 13C NMR (CDCl3,
100 MHz): both diastereoisomers: d ˆ 170.7, 150.0, 149.8,
146.5, 146.0, 137.2, 136.8, 128.7, 128.2, 128.2, 128.1, 127.8,
127.6, 127.5, 127.4, 127.2, 125.2, 124.1, 123.7, 123.3, 82.3, 79.3,
69.5, 68.1, 55.5, 52.8, 50.8, 27.0, 23.5; HRMS (FAB): calcd. for
colorless oil; yield: 34 mg (65%); IR (film): n ˆ 2954, 2928,
À
1740, 1216, 1179, 1104 cm ; 1HNMR (CDCl 3, 400 MHz): d ˆ
1
5.89 5.79 (m, 2H), 5.70 (dq, J ˆ 10.4, 2.0 Hz, 1H), 5.14 5.06
(m, 2H), 4.48 (t, J ˆ 2.3 Hz, 1H), 4.50 4.43 (m, 1H), 3.75 (s,
3H), 2.40-2.28 (m, 4H); 13C NMR (CDCl3, 100 MHz): d ˆ
172.2, 134.0, 128.9, 122.6, 117.3, 71.5, 68.9, 52.0, 39.2, 26.8;
‡
‡
HRMS (EI ): calcd. for C20H22NO5S (M ): 182.0943; found:
182.0946.
‡
C20H20N2O7SNa (MNa ): 455.0889; found: 455.0882.
Methyl 6-Allyl-2-methyl-3,6-dihydro-2H-pyran-2-
carboxylate (47)
Methyl 6-Phenoxy-1-(4-toluenesulfonyl)-1,2,3,6-
tetrahydropyridine-2-carboxylate (43)
To a solution of 35 (one diastereoisomer, 65 mg, 0.248 mmol)
and allyltrimethylsilane (78.8 mL, 0.5 mmol) in dry CH2Cl2
(5 mL) at 0 8C, was added BF3 ¥ OEt2 (63 mL, 0.5 mmol). After
stirring for 3 h with the temperature going from 0 8C to room
temperature, saturated aqueous NaHCO3 (10 mL) and diethyl
ether (10 mL) were added and the layers were separated. The
organic layer was washed with brine (5 mL), dried over MgSO4
and concentrated. Column chromatography (heptane/ethyl
acetate, 4:1) afforded 47 as a colorless oil; yield: 23 mg (47%);
1HNMR (CDCl 3, 300 MHz): 3:1 mixture of diastereoisomers:
d ˆ 5.92 5.56 (m, 3H), 5.19 5.03 (m, 2H), 4.45 and 4.23 (m,
1H), 3.75 and 3.71 (s, 3H), 2.68-2.25 and 2.12-2.02 (m, 4H), 1.48
and 1.43 (s, 3H); 13C NMR (CDCl3, 50 MHz): d ˆ 175.4, 134.8,
127.6, 123.0, 118.0, 70.3, 65.8, 53.0, 40.1, 32.8, 21.5.
Precursor 29 (0.88 g, 2.27 mmol) was reacted as indicated in the
general procedure. Column chromatography (pentane/diethyl
ether, 4:1 2:1) afforded 43 as a colorless oil; yield: 0.53 g
(1.37 mmol, 60%); IR (film): n ˆ 1749, 1600, 1495, 1357, 1228,
À
1
1164 cm ; 1HNMR (C 6D6, 500 MHz): d ˆ 7.66 (d, J ˆ 8.3 Hz,
2H), 7.09 7.06 (m, 2H), 6.99 (d, J ˆ 7.8 Hz, 2H), 6.85 6.83 (m,
2H), 6.68 (d, J ˆ 8.3 Hz, 2H), 6.46 (s, 1H), 5.55 5.54 (m, 2H),
4.62 (d, J ˆ 6.8 Hz, 1H), 3.10 (s, 3H), 2.43 2.40 (m, 1H), 1.96
1.90 (m, 1H), 1.86 (s, 3H); 13C NMR (C6D6, 125 MHz): d ˆ
171.3, 170.6, 143.5, 138.6, 130.2, 129.4, 128.7, 128.4, 123.3, 122.6,
117.6, 78.9, 51.9, 51.6, 25.1, 21.5; HRMS (FAB): calcd. for
‡
C20H22NO5S (MH ): 388.1219; found: 388.1236.
Methyl 7-Benzyloxy-1-(4-nitrobenzenesulfonyl)-
2,3,4,7-tetrahydro-1H-azepine-2-carboxylate (44)
Methyl 6-Cyano-2-methyl-3,6-dihydro-2H-pyran-2-
carboxylate (48)
Precursor 30 (0.11 g, 0.23 mmol) was reacted according to the
general method. Column chromatography (petroleum ether/
diethyl ether, 4:1 1:1) gave 44 as a colorless oil; yield: 72 mg,
To a solution of 35 (one diastereoisomer, 57 mg, 0.218 mmol)
and Me3SiCN (58 mL, 0.44 mmol) in dry CH2Cl2 (5 mL) at 0 8C,
was added BF3 ¥ OEt2 (55 mL, 0.44 mmol). After stirring for 2 h
with the temperature going from 0 8C to room temperature,
saturated aqueous NaHCO3 (10 mL) and diethyl ether
(10 mL) were added and the layers separated. The organic
layer was washed with brine (5 mL), dried over MgSO4 and
concentrated. Column chromatography (heptane/ethyl ace-
tate, 4:1) afforded 48 as a slightly yellow oil; 21 mg (49%);
1HNMR (CDCl 3, 300 MHz): 1:1.25 mixture of diastereoisom-
ers: d ˆ 6.13 5.98 (m, 1H), 5.75 5.66 (m, 1H), 5.46 5.42 and
5.19 5.15 (m, 1H), 3.79 and 3.73 (s, 3H), 2.81 2.72 (ddt, J ˆ
17.6, 11.3, 1.4, 1.1 Hz, 0.57H), 2.70 2.60 (dddd, J ˆ 17.6, 5.8,
2.7, 1.4, 1.1 Hz, 0.43H), 2.33 2.07 (dddd, J ˆ 48.0, 17.6, 6.0,
2.8 Hz, 1H), 1.52 and 1.50 (s, 3H); 13C NMR (CDCl3, 50 MHz):
both diastereoisomers: d ˆ 173.1, 127.7, 127.2, 121.1, 120.5,
117.4, 117.1, 72.5, 71.9, 61.8, 61.3, 53.0, 52.6, 32.6, 32.1, 25.9.
(0.16 mmol, 70%); IR (film): n ˆ 2952, 1745, 1531, 1349,
À
1
1
1163 cm ; HNMR (CDCl , 400 MHz): both diastereoisom-
3
ers: d ˆ 8.3 and 8.08 (d, J ˆ 8.8 Hz, 2H), 8.21 and 7.98 (d, J ˆ
8.8 Hz, 2H), 7.35 7.24 (m, 4H), 7.09 7.07 (m, 1H), 5.86 5.82
(m, 0.5H), 5.74 5.66 (m, 1H), 5.61 (d, J ˆ 5.9 Hz, 0.5H), 5.56 (s,
0.5H), 5.51 5.46 (m, 0.5H), 4.82 4.74 (m, 1H), 4.62 4.55 (m,
1H), 4.32 (d, J ˆ 11.6 Hz, 0.5H), 4.21 (d, J ˆ 11.6 Hz, 0.5H), 3.78
and 3.65 (s, 3H), 2.58 2.52 (m, 0.5H), 2.49 2.22 (dm, 3H),
1.82 1.75 (m, 0.5H); 13C NMR (CDCl3, 100 MHz): both
diastereoisomers: d ˆ 171.5, 171.3, 146.6, 145.6, 137.3, 136.8,
134.2, 131.9, 129.0, 128.5, 128.3, 128.2, 128.0, 127.8, 127.7, 127.6,
127.3, 126.9, 123.9, 123.7, 85.5, 84.3, 71.1, 69.5, 60.0, 57.6, 52.4,
29.3, 29.0, 26.9, 23.8.
Methyl 6-Allyl-3,6-dihydro-2H-pyran-2-carboxylate
(46)
2H-Chromene-2-carbonitrile (49)
To a solution of 34 (50 mg, 0.291 mmol) and allyltrimethylsi-
lane (92.4 mL, 0.58 mmol) in dry CH2Cl2 (3 mL) at 0 8C, was
added BF3 ¥ OEt2 (75 mL, 0.58 mmol). After stirring for 30 min
at 0 8C, the mixture was allowed to warm to room temperature
in 1 h. Saturated aqueous NaHCO3 (10 mL) was added and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (2 × 5 mL) and the combined organic layers were dried
over MgSO4 and concentrated. Column chromatography
(petroleum ether/diethyl ether, 4:1 1:1) afforded 46 as a
To a solution of 36 (50.5 mg, 0.21 mmol) and Me3SiCN (58 mL,
0.44 mmol) in dry CH2Cl2 (5 mL) at 0 8C, was added BF3 ¥ OEt2
(55 mL, 0.44 mmol). The solution was allowed to warm to room
temperature and saturated aqueous NaHCO3 (10 mL) was
added. The layers were separated and the aqueous layer was
extracted with CH2Cl2 (5 mL). The combined organic layers
were washed with brine (5 mL), dried over MgSO4 and
concentrated. Column chromatography (petroleum ether/
ethyl acetate, 40:1) afforded 49 as a colorless oil; yield: 26 mg
Adv. Synth. Catal. 2002, 344, 736 748
745

Sape S. Kinderman et al.
FULL PAPERS
À
(75%); IR (film): n ˆ 2930, 2360, 1240 cm ; 1HNMR (CDCl 3,
400 MHz): d ˆ 7.23 (dt, J ˆ 7.8, 1.3 Hz, 1H), 7.10 (dd, J ˆ 7.5,
1.6 Hz, 1H), 7.02 (dt, J ˆ 7.4, 0.5 Hz, 1H), 6.94 (br d, J ˆ 8.1 Hz,
1H), 6.69 (d, J ˆ 9.5 Hz, 1H), 5.77 (dd, J ˆ 9.5, 4.7 Hz, 1H), 5.67
(dd, J ˆ 4.7, 0.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d ˆ
150.8, 130.5, 127.9, 127.4, 123.2, 120.5, 116.7, 116.1, 116.0,
1
(S)-1,2,3,6-Tetrahydropyridine-2-carboxylic Acid
(Baikiain, 53)
To a solution of 51 (150 mg, 0.47 mmol) in DMF (10 mL) was
added K2CO3 (196 mg, 1.42 mmol) and thiophenol (58.2 mL,
0.57 mmol), followed by stirring at room temperature for 24 h.
The solvent was removed and the crude mixture was lyophi-
lized. The residue was again dissolved in methanol (2 mL) and
H2O (2 mL) was added, followed by lithium hydroxide
(1.1 equiv.). The mixture was stirred for 24 h. Diethyl ether
(5 mL) was added and a white solid precipitated, which was
filtered off. The aqueous layer was then lyophilized to yield 53
‡
62.4; HRMS (FAB): calcd. for C10H7NO (MH ): 157.0528;
found: 157.0538.
À
as an amorphous solid; yield: 32.5 mg (61%); [a]D: 182.6 (c
0.3, H2O); IR (KBr): n ˆ 2924, 1712, 1404, 1189 cmÀ1; 1HNMR
(CD3OD, 400 MHz): d ˆ 6.01 (br s, 1H), 5.80 5.78 (m, 1H),
4.07 4.03 (m, 1H), 3.74 (br s, 2H), 3.31 (br s, 3H), 2.76 2.72
(m, 1H), 2.53 2.46 (m, 1H); 13C NMR (D2O, 100 MHz): d ˆ
173.6, 128.0, 122.6, 58.0, 44.7, 28.4. Data were identical to
literature values.[16]
Methyl (S)-1-(4-Nitrobenzenesulfonyl)-1,2,3,6-
tetrahydropyridine-2-carboxylate (51)
To a solution of 42 (50 mg, 0.116 mmol) and triethylsilane
(55.5 mL, 0.347 mmol) in CH2Cl2 (1 mL) at 78 8C, was added
À
BF3 ¥ OEt2 (44 mL, 0.347 mmol). After 1 h at this temperature,
the solution was allowed to warm to room temperature and
quenched by adding saturated aqueous NaHCO3 (5 mL).
Diethyl ether (10 mL) was added and the layers were
separated. The organic layer was washed with H2O (5 mL)
and brine (5 mL), dried over MgSO4 and concentrated.
Recrystallization of the crude product afforded 51 as a white
(S,S)-6-Prop-2-ynyl-1,2,3,6-tetrahydropyridine-2-
carboxylic Acid (54)
To a solution of 52 (1.47 g, 4.05 mmol) in DMF (50 mL) was
added K2CO3 (1.68 g, 12.15 mmol) and thiophenol (500 mL,
4.86 mmol), followed by stirring at room temperature for 24 h.
The solvent was removed by lyophilization. The crude residue
was again dissolved in methanol (10 mL) and H2O (10 mL) was
added, followed by lithium hydroxide (2.0 equiv.). The result-
ing mixture was stirred for 24 h. Diethyl ether (10 mL) was
added and a white solid precipitated, which was filtered off.
The aqueous layer was then lyophilized to afford 54 as an
solid; yield: 33 mg (88%); mp 119 120 8C; [a]D: ‡ 21 (c 1, CH2
À
1
Cl2); IR (film): n ˆ 1711, 1531, 1352, 1168 cm ; 1HNMR
(CDCl3, 400 MHz): d ˆ 8.34 (d, J ˆ 8.8 Hz, 2H), 7.97 (d, J ˆ
8.8 Hz, 2H), 5.77 5.74 (m, 1H), 5.67 5.64 (m, 1H), 4.91 4.89
(m, 1H), 4.14 (d, J ˆ 16.7 Hz, 1H), 3.80 (d, J ˆ 16.7 Hz, 1H),
3.52 (s, 3H), 2.62 2.61 (m, 2H); 13C NMR (CDCl3, 100 MHz):
d ˆ 170.1, 149.0, 144.7, 128.4, 124.0, 122.8, 122.5, 52.9, 52.3, 42.2,
‡
27.7; HRMS (FAB): calcd. for C13H15N2O6S (MH ): 327.0651;
À
amorphous solid; yield: 344 mg (52%); [a]D: 106.8 (c 0.5,
found: 327.0650.
MeOH); IR (KBr): n ˆ 3184, 3012, 2659, 2526, 1601, 1409 cm-1;
1HNMR (CD 3OD, 400 MHz): d ˆ 6.08 6.01 (m, 1H), 5.81 (d,
J ˆ 9.3 Hz, 1H), 4.00 3.98 (m, 1H), 3.72 3.66 (m, 1H), 2.74
2.56 (dm, 4H), 2.43 2.34 (m, 1H); 13C NMR (CD3OD,
100 MHz): d ˆ 173.8, 128.3, 124.9, 78.6, 73.9, 57.8, 54.3, 27.6,
‡
23.4; HRMS (FAB): calcd. for C9H12NO2 (MH ): 166.0868;
found: 166.0866.
Methyl (S,S)-1-(4-Nitrobenzenesulfonyl)-6-prop-2-
ynyl-1,2,3,6-tetrahydropyridine-2-carboxylate (52)
To a solution of 42 (40 mg, 0.095 mmol) and allenyltributyl-
stannane (94 mg, 0.286 mmol) in CH2Cl2 (1 mL) at 78 8C, was
Methyl (S,S)-6-Allyl-1-(4-nitrobenzenesulfonyl)-
1,2,3,6-tetrahydropyridine-2-carboxylate (55)
À
added BF3 ¥ OEt2 (36 mL, 0.286 mmol). After 3 h at this
temperature, the solution was allowed to warm to room
temperature and quenched by adding saturated aqueous
NaHCO3 (5 mL). Diethyl ether (10 mL) was added and the
layers were separated. The organic layer was washed with H2O
(5 mL) and with brine (5 mL), dried over MgSO4 and
concentrated. Column chromatography (petroleum ether/
diethyl ether, 4:1 1:1) afforded 52 as a white solid; yield:
To a solution of 42 (1.00 g, 2.31 mmol) and allyltributylstan-
À
nane (2.15 mL, 6.93 mmol) in CH2Cl2 (20 mL) at 78 8C was
added BF3 Â OEt2 (0.87 mL, 6.94 mmol). This mixture was
À
stirred at 78 8C for 4 h and allowed to warm to room
temperature. The reaction was quenched with saturated
aqueous NaHCO3 (20 mL) and diethyl ether (20 mL) was
added. The layers were separated and the aqueous layer was
extracted with Et2O (3 Â 20 mL). The organic layers were
washed with brine (20 mL), dried over MgSO4 and concen-
trated. Column chromatography (pentane/diethyl ether, 2:1)
afforded 55 as a white solid; yield: 0.88 g (100%); mp 113
114 8C; [a]D: ‡ 59.1 (c 1, CH2Cl2); IR (film): n ˆ 3105, 2953,
26 mg (75%); mp 112 114 8C; [a]D: ‡ 83.5 (c 1.05, CH2Cl2); IR
À
(film): n ˆ 3290, 1742, 1530, 1351, 1167 cm ; 1HNMR (CDCl 3,
1
400 MHz): d ˆ 8.36 (d, J ˆ 8.8 Hz, 2H), 8.03 (d, J ˆ 8.8 Hz, 2H),
6.01 5.97 (m, 1H), 5.83 5.78 (m, 1H), 4.84 (d, J ˆ 6.2 Hz, 1H),
4.38 (dd, J ˆ 6.8, 3.4 Hz, 1H), 3.72 (s, 3H), 2.83 2.81 (m, 1H),
2.79 2.63 (m, 1H), 2.58 2.51 (m, 1H), 2.10 2.03 (m, 2H);
13C NMR (CDCl3, 100 MHz): d ˆ 170.6, 149.0, 145.7, 128.2,
125.0, 124.4, 123.1, 71.2, 60.3, 52.7, 52.4, 52.0, 25.9, 24.6; HRMS
À
1
1741, 1531, 1216, 1095, 923 cm ; 1HNMR (CDCl 3, 400 MHz):
d ˆ 8.4 (d, J ˆ 8.8 Hz, 2H), 8.1 (d, J ˆ 8.8 Hz, 2H), 5.84 5.66
(m, 3H), 5.10 5.06 (m, 2H), 4.83 (d, J ˆ 6.3 Hz, 1H), 4.30 4.26
(m, 1H), 3.72 (s, 3H), 2.64 (dd, J ˆ 17.8, 5.8 Hz, 1H), 2.55 2.48
(m, 1H), 2.22 (dt, J ˆ 13.6, 9.0 Hz, 1H), 2.08 2.01 (m, 1H);
‡
(FAB): calcd. for C16H17N2O6S (MH ): 365.0807; found:
365.0809.
746
Adv. Synth. Catal. 2002, 344, 736 748

Ring-Closing Metathesis of Allylic O,O- and N,O-Acetals
FULL PAPERS
13C NMR (CDCl3, 100 MHz): d ˆ 170.7, 149.8, 146.0, 133.7,
(D2O, 400 MHz): d ˆ 6.04 (m, 1H), 5.99 5.68 (m, 2H), 4.21 (m,
2H), 4.08 (m, 1H), 3.73 (m, 1H), 2.80-2.58 (m, 3H), 2.41 (m,
1H); 13C NMR (D2O, 100 MHz): d ˆ 137.7, 128.4, 126.8, 126.6,
122.6, 66.5, 60.8, 53.5, 32.0, 30.3; HRMS (FAB): calcd. for
128.1, 125.4, 124.0, 122.6, 118.0, 53.4, 52.3, 51.6, 40.2, 24.0;
‡
HRMS (FAB): calcd. for C13H20O2N (MH ): 367.0964; found:
367.0975.
‡
C10H14O2N (MH ): 180.1025; found: 180.1021.
Methyl (S,S)-1,6-Diallyl-1,2,3,6-tetrahydropyridine-2-
carboxylate (56)
Acknowledgements
To a solution of 55 (487 mg, 1.32 mmol) in acetonitrile (20 mL)
was added K2CO3 (551 mg, 3.98 mmol) and thiophenol
(164 mL, 1.59 mmol). This suspension was stirred for 24 h,
during which more thiophenol was added (2 Â 75 mL). After
evaporation of the acetonitrile, the product was purified by
column chromatography (pentane/diethyl ether, 1:2) to yield
the free amine methyl 6-allyl-1,2,3,6-tetrahydropyridine-2-
carboxylate (yield: 178 mg, 74%) as a colorless oil, which was
dissolved again in dry acetonitrile (10 mL), followed by the
addition of K2CO3 (271 mg, 1.96 mmol) and allyl bromide
(178 mg, 1.47 mmol). The solution was stirred at 60 8C for 24 h
during which additional allyl bromide (89 mg, 0.74 mmol) was
added. The solvent was removed under vacuum and the crude
product was purified by column chromatography (pentane/
diethyl ether, 20:1), to afford 56 as a yellow oil; yield: 147 mg
This research is financially supported (in part) by the Council
for Chemical Sciences of the Netherlands Organization for
À
Scientific Research (CW NWO). DSM Research is kindly
acknowledged for providing a research grant to K. C. M. F. Tjen.
References and Notes
[1] For review articles, see: a) A. F¸rstner, Angew. Chem.
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Tetrahedron 1998, 54, 4413. d) A. F¸rstner, Top. Organo-
met. Chem. 1998, 1, 37.
(50%); [a]436: ‡ 60.2 (c 1.05 CH2Cl2); IR (film): n ˆ 2923, 1735,
[2] For several investigations into new RCM catalysts, see:
a) J. Huang, E. D. Stevens, S. P. Nolan, J. L. Petersen, J.
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À
1459 cm ; 1HNMR (CDCl 3, 400 MHz): d ˆ 5.75 (m, 4H), 5.11
1
ˆ
ˆ
(m, 4H), 3.70 (s, 3H), 3.53 (d, J 5.1 Hz, 1H), 3.42 (d, J 1.3 Hz,
2H), 3.24 (m, 1H), 2.41 (m, 2H), 2.20 (m, 2H); 13C NMR
(CDCl3, 125 MHz): d ˆ 135.9, 131.1, 128.8, 122.2, 118.9, 116.2,
58.9, 57.8, 55.7, 51.9, 37.8, 30.1; HRMS (FAB): calcd. for
‡
C13H20O2N (MH ): 222.1494; found: 222.1491.
Methyl (S,S)-3,6,9,9a-Tetrahydro-4H-quinolizine-4-
carboxylate (57)
A solution of 56 (147 mg, 0.665 mmol) in dry toluene (30 mL)
was degassed using argon. Ruthenium catalyst 32 (5.7 mg,
1 mol %) was added and the solution was heated at 80 8C for
6 h. Air was bubbled through the solution to destroy the active
catalyst and the solvent was removed under vacuum. Column
chromatography (pentane/diethyl ether, 2:1) gave 57 as a white
À
solid; yield: 99 mgÀ(77%); [a]D: 74 (c 0.98, CH2Cl2); IR (film):
1
n ˆ 3025, 1742 cm ; 1HNMR (CDCl 3, 500 MHz): d ˆ 5.58 (m,
4H) 3.76 (s, 3H), 3.37 (d, J ˆ 15.1 Hz, 1H), 3.18 (dd, J ˆ 6.8 Hz,
3.9 Hz, 1H), 2.96 (m, 1H), 2.82 (m, 1H), 2.54 (dd, J ˆ 2.4 Hz, 1.7
Hz, 1H), 2.23 (m, 3H); 13C NMR (CDCl3, 125 MHz): d ˆ 173.4,
129.0, 125.5, 124.6, 122.4, 64.2, 56.6, 52.0, 51.9, 32.7, 30.0;
‡
HRMS (FAB): calcd. for C11H16O2N (MH ): 194.1181; found:
194.1181.
(S,S)-3,6,9,9'-Tetrahydro-4H-quinolizine-4-carboxylic
Acid (58)
A solution of ester 57 (50 mg, 0.259 mmol) in methanol/H2O
(3:1, 4 mL) was treated with lithium hydroxide (11.9 mg,
0.28 mmol) and stirred for 24 h. The crude solution was
purified using a strong basic Amberlite column (IRA-416):
washing with 5% NH3/H2O and collecting with acetic acid
(1 M) as the eluent. After lyophilizing off the aqueous acetic
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acid, the free amino acid 58 was obtained as a white solid; yield:
À
1
1
23 mg (50%); IR (film): n ˆ 3030, 1738, 1169 cm ; HNMR
Adv. Synth. Catal. 2002, 344, 736 748
747

Sape S. Kinderman et al.
FULL PAPERS
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748
Adv. Synth. Catal. 2002, 344, 736 748