Stereoselective synthesis of heterocyclic cage compounds by domino conjugate additions

Article abstract of DOI:10.1002/1521-3765(20020104)8:1<208::AID-CHEM208>3.0.CO;2-0

Heterocyclic cage compounds have been stereoselectively synthesized from enantiopure [(S)R]-[(p-tolylsulfinyl)methyl]-p-quinols or their amine analogues and 2-(trimethylsilyloxy)furan in the presence of Bu₄NF. The method is particularly valuable not only because of the stereochemical control but also because the reactions occur in an experimentally simple one-pot procedure through a domino sequence of three consecutive conjugate additions. The intermediate 1,4-adducts could be isolated when the reaction was carried out in the presence of BF₃·OEt₂.

Full text of DOI:10.1002/1521-3765(20020104)8:1<208::AID-CHEM208>3.0.CO;2-0

FULL PAPER
Stereoselective Synthesis of Heterocyclic Cage Compounds by Domino
Conjugate Additions**
M. Carmen Carreno,* Carmen GarcÌa Luzo¬n, and MarÌa Ribagorda[a]
ƒ
¬
Dedicated to the late Professor Jesus H. RodrÌguez Ramos
Abstract: Heterocyclic cage compounds have been stereoselectively synthesized
from enantiopure [(S)R]-[(p-tolylsulfinyl)methyl]-p-quinols or their amine ana-
logues and 2-(trimethylsilyloxy)furan in the presence of Bu4NF. The method
is particularly valuable not only because of the stereochemical control but also
because the reactions occur in an experimentally simple one-pot procedure through a
domino sequence of three consecutive conjugate additions. The intermediate 1,4-
adducts could be isolated when the reaction was carried out in the presence of
BF3 ¥ OEt2.
Keywords:
dienones ¥ cage compounds ¥ dom-
ino reactions heterocycles
p-quinols ¥ sulfoxides
4-aminocyclohexa-2,5-
¥
¥
OH. The efficiency of the hydroxy group in directing the face
selectivity of 1,4-conjugate additions has also been pointed
out in reactions of achiral p-quinol derivatives.[8] A logical
extension of our work was to achieve consecutive diastereo-
selective conjugate additions to the dienone system in a single
step. The potential usefulness of the sequential 1,4-adducts as
building blocks for chiral targets prompted us to investigate
such a process. We reasoned that the use of a nucleophile such
as 2-(trimethylsilyloxy)furan,[9] which gives rise to a buteno-
lide fragment on reaction with electrophiles[10] and can later
act as a Michael acceptor,[11] could facilitate further trans-
formation of the initial 1,4-adducts.
In this paper we report the achievement of a highly
stereoselective synthesis of various tetracyclic cage com-
pounds[12] bearing two heterocyclic rings through the reaction
between [(S)R]-4-amino or 4-hydroxy-4-[(p-tolylsulfinyl)-
methyl]cyclohexa-2,5-dienone derivatives and 2-(trimethyl-
silyloxy)furan. This combination provides a short and simple
access to optically pure heterotetracyclic cage compounds not
accessible by other methods through a one-pot, domino, triple
conjugate addition process.
Introduction
Domino reactions leading to the stereoselective formation of
carbon carbon and carbon heteroatom bonds have been
the focus of intense studies.[1, 2] This interest stems from the
possibility of rapid and economic preparation of structurally
complex molecules from simple starting materials. The
sequential formation of increasing number of bonds is favored
when dense functionalization is present in such materials. For
instance, 1,4-dien-3-one derivatives have been efficiently used
to synthesize polycyclic systems through domino sequences
including [3‡2] cycloadditions with allylsilanes[3, 4] or succes-
sive Michael additions.[4b] Alkoxy substituted quinones and
quinoneimines[5] reacted with styrenes in the presence of
Lewis acids to form bridged compounds through domino
cycloadditions that take advantage of the dienone fragment.
The 2,5-cyclohexadienone system present in p-quinols is a
potential double Michael acceptor that has not been exploited
in domino reactions. Enantiopure [(S)R]-[(p-tolylsulfinyl)-
methyl]-p-quinols, which can be easily prepared by a method
described by our laboratory,[6, 7] show the dienone fragment, as
well as a sulfoxide, providing optical activity to the system,
which bears a prochiral cyclohexadienone moiety. Such p-
quinols have shown an excellent ability to direct the approach
of dienes in Diels Alder reactions[6] or organoaluminum
derivatives in conjugate additions[7] by the face containing the
Results and Discussion
Enantiopure 4-amino-4-[(p-tolylsulfinyl)methyl]cyclohexa-
2,5-dienone [(S)R]-7[13] and the 3-methyl-substituted ana-
logues 8 were easily accessible in high ee (>98%)[14a] by
addition of a-lithiocarbanion derived from [(S)R]-methyl p-
tolylsulfoxide[15] to quinoneimine monoacetals 1 and 2[16]
(Scheme 1). From the crude reaction mixture, hydrolysis of
the acetal groups of 3 and 4 was effected with an aqueous
¬
ƒ
[a] Prof. M. C. Carreno, C. G. Luzon, M. Ribagorda
¬
¬
Departamento de QuÌmica Organica (C-I), Universidad Autonoma
Cantoblanco, 28049 Madrid (Spain)
Fax : (‡34)91-397-3966
E-mail: carmen.carrenno@uam.es
[**] Supporting information for this article is available from the author.
208
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Chem. Eur. J. 2002, 8, No. 1

208 216
Table 1. Results of domino reactions of 7 10 with 11.
O
S
MeO
R
MeO OMe
R
OMe
O
O
p-Tol
OTMS
O
O
O
O
i)
O
+
O
11
R
X
4
X
BOCHN
NBOC
Bu4NF
CH2Cl2, RT
R
S
p-Tol
R
TolOS
HX
1: R = H
2: R = Me
O
TolOS
(R)
(12-15)b
S
(R)
(12-15)a
p-Tol
3: R = H
4: R = Me
1-24 h
O
[(S)R]-7: R = H; X = NH
ii)
[4R,(S)R]-8: R = Me; X = NH
[4S,(S)R]-8: R = Me; X = NH
[(S)R]-9: R = H; X = O [6,7]
O
O
[4R,(S)R]-10: R = Me; X = O [6,7]
iii)
4
4
R
H2N
R
Starting
material
R
H
X
Products
(ratio)
Yield
[%]
BOCHN
S
p-Tol
S
p-Tol
O
O
1
[(S)R]-7
NH
12a:12b
(1:1)
13a
67
[(S)R]-7: R = H
[4R,(S)R]-8: R = Me
[4S,(S)R]-8: R = Me
[(S)R]-5: R = H
[4R,(S)R]-6 / [4S,(S)R]-6
(77:23): R = Me
2
3
4
[4R(S)R]-8
[4S,(S)R]-8
[(S)R]-9
CH3
CH3
H
NH
NH
O
56
70
67
13b
Scheme 1. Synthesis of 4-amino-4-[(p-tolylsulfinyl)methyl]cyclohexa-2,5-
dienones. i) LDA, THF, À788C; ii) oxalic acid, THF:H2O, RT; iii) TFA,
CH2Cl2, RT.
14a:14b
(1:1)
15a
5
[4S,S)R]-10
CH3
O
67
solution of oxalic acid (10%) to afford N-Boc derivatives 5
and 6 in 80% and 82% overall yield, respectively. The latter
was characterized as a 77:23 mixture of epimers at C-4.
Diastereomers [4R,(S)R]-6 and [4S,(S)R]-6 could be separat-
ed by chromatography, and were isolated pure in 58% and
19% yield, respectively. N-Boc deprotection (TFA) of 5 and
the major diastereomer [4R,(S)R]-6 allowed the formation of
compounds [(S)R]-7 (97% yield) and [4R, (S)R]-8 (99%
yield), respectively. The minor epimer [4S,(S)R]-8 could also
be obtained pure by hydrolysis of [4S,(S)R]-6 (88% yield).
The absolute configuration of the stereogenic amino-
substituted carbons in diastereomers 8 could be assigned on
the basis of a comparative analysis of their 1H NMR
parameters with those of [(S)R]-7 and the p-quinols [(S)R]-
9, [4R,(S)R]-10 as well as the 3,5-dimethyl-substituted ana-
logue whose structure had been already assigned.[6a, 7a] The
most significant data correspond to the different chemical
shifts observed for the substituents situated at the olefinic b-
carbons (H and CH3). In the cyclohexadienone moiety of the
[4S,(S)R] epimer, the olefinic proton, which is situated on the
unsubstituted double bond, appears more shielded than in the
[4R,(S)R] diastereomers, whereas the methyl group is more
shielded in the latter.[17]
prepared as previously described.[6, 7] The results of the
reactions of 7 10 with 2-(trimethylsilyloxy)furan 11 promot-
ed by Bu4NF are given in Table 1. Under the conditions used
(CH2Cl2, RT), amino-substituted derivative 7 is rapidly
converted into a 1:1 mixture of two diastereomeric cage
compounds 12a and b in 67% total isolated yield (entry 1).
Under the same conditions, asymmetrically substituted cyclo-
hexadienone [4R,(S)R]-8 afforded diastereomer 13a[14b] ex-
clusively (56% yield, entry 2), whereas epimer [4S,(S)R]-8
was transformed stereospecifically into 13b (70% yield,
entry 3). The oxygenated derivative [(S)R]-9 behaved sim-
ilarly and gave rise to a 1:1 mixture of diastereomers 14a and
b (67% yield, entry 4), and the reaction of the 3-methyl
substituted p-quinol [4R,(S)R]-10 gave rise exclusively to 15a
(67% yield, entry 5). The transformation was faster when
compounds 7 and 9, which have an unsubstituted cyclo-
hexadienone moiety, were allowed to react.
The structures of compounds 12 15 were characterized by
different spectroscopic techniques. The 1H NMR spectra
feature similar chemical shifts and coupling constants for all
the hydrogens of the cage moiety, except for the one situated
at C-6[18] that supports an O (in compounds 14 and 15) or NH
substituent (in compounds 12 and 13). The differences
observed in chemical shifts of the CH2SOTol ABsystem in
diastereomers 13a, 15a, and 13b, allowed the determination
of their relative configurations. Such an assignment was
confirmed in compound 13a,[19] which was a crystalline solid
and could be subjected to X-ray crystallographic analysis. Its
absolute configuration was established by taking into account
the R configuration of the starting sulfoxide. The most
significant spectral data for the configurational assignment
of 13a, 13b, and 15a are displayed in Figure 1. The con-
Enantiomerically pure [(S)R]-4-hydroxy-4-[(p-tolylsulfi-
nyl)methyl]cyclohexa-2,5-dienones 9 and 10 (Table 1) were
Abstract in Spanish: La sÌntesis estereoselectiva de compuestos
heterocÌclicos con estructura de tipo jaula se ha descrito a partir
¬
de [(S)R]-[(p-tolilsulfinil)metil]-p-quinoles o sus analogos
¬
nitrogenados enantiomericamente puros y 2-(trimetilsililoxi)-
¬
furano. El proceso, que tiene lugar en una unica etapa cuando
¬
se lleva a cabo en presencia de Bu4NF, transcurre a traves de
À
formation around the CH2 SO bond represented shows the
¬
una secuencia de reacciones domino en la que se producen tres
disposition found for 13a in the solid state (Figure 2), which is
the most stable rotamer due to the anti disposition of the
bulky p-tolyl substituent and the cage moiety. As can be seen,
the ABsystem of 13a appears at d ˆ 2.85 and 3.27. A
noticeable shielding effect of the sulfinyl oxygen situated anti
¬
adiciones conjugadas. Ademas de un eficaz control de la
¬
estereoselectividad, el metodo permite aislar alguno de los
¬
¬
intermedios de adicion 1,4- cuando la reaccion se lleva a cabo
en presencia de BF3 ¥ OEt2.
Chem. Eur. J. 2002, 8, No. 1
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209

ƒ
M. C. Carreno et al.
FULL PAPER
sented a NOE with the axial hydrogen a to the carbonyl group
of the cyclohexanone moiety (d ˆ 2.29). The slight differences
O
O
O
O
O
1
O
observed in the H NMR data of diastereomers 12a and 12b
NH
HN
HA
Me
or 14a and 14b did not allow unequivocal assignment of their
configurations.
The diastereomeric relationship between 14a and 14b was
confirmed by oxidation of a 1:1 mixture of 14a and 14b with
mCPBA (83% yield) that gave a single racemic sulfone 16
(Scheme 2).
Me
O
O
H
HA
HB
B 3.10
3.01
2.85
3.27
13a
13b
O
O
O
O
O
O
O
O
O
O
O
O
O
+
O
O
O
Me
O
i)
H
2.29
SOTol
TolOS
SO2Tol
NOE
NOE
HA
3.04
HB
14a
14b
-16
( )
3.46
Scheme 2. Oxidation of 14a and 14b to sulfone 16. i) mCPBA, CH2Cl2,
83%
15a
Figure 1. Significant spectral data for configurational assignment.
The following experimental evidence allowed a mechanistic
rationalization of the process. When p-quinol [4R,(S)R]-10
was treated with 2-(trimethylsilyloxy)furan 11 in the presence
[23]
of 1.5 equivalents of a mixture of TiCl4 and Ti(OiPr)4
instead of Bu4NF to trigger the reaction (Table 2, entry 1),
a,b-unsaturated lactone 17 was stereoselectively formed.
Chromatographic purification of the crude mixture gave only
10% yield of pure 17 due to its transformation into the
tricyclic derivative 18 (30% isolated yield), which resulted
from an intramolecular stereoselective conjugate addition of
the OH to the butenolide moiety of 17 in the presence of silica
gel. When BF3 ¥ OEt2 was present in the reaction medium,
[4R,(S)R]-10 gave a 63:4:30 mixture of 17, 18, and 15a, from
which 17 and 18 were isolated in 30 and 34% yield after flash
chromatography (Table 2, entry 2). These results suggested
that 17 and 18 were the precursors of 15a, which must be
formed from 18 through a new intramolecular conjugate
addition of the enolate derived from the lactone moiety to the
methyl-substituted conjugate position of cyclohexenone 18.
Two mechanistic pathways could be envisaged to explain the
Figure 2. ORTEP plot of compound 13a.
Table 2. Reaction of compounds 10 and 8 with 11.
O
to HA, appearing at d ˆ 2.85,[20] is observed. Conversely, the
deshielding observed for HB (d ˆ 3.27) must be a consequence
of the 1,3-parallel disposition of the CH3 group with respect to
this hydrogen[21] together with the gauche conformation of the
sulfinyl oxygen.[22] Confirmation of the absolute configuration
of 13a in this manner permitted reliable definition of the
stereochemistry of the diastereomer 13b, (Figure 1) whose
11
Additive
O
O
X
O
O
O
H
H
+
H
4
+
H
X
CH2Cl2
O
O
HX
X
O
SOTol
TolOS
O
SOTol
TolOS
H
[4R,(S)R]-10: X = O
[4R,(S)R]-8: X = NH
17: X = O
19: X = NH
18: X = O
20: X = NH
15a: X = O
13a: X = NH
Starting
material
Additive
(equiv)
T[a]
t
Products[a] Yield Product[d]
[%]
[8C] [h] (ratios)
À
CH2 SO ABsystem appears much less differentiated ( d ˆ
1
2
3
[4R,(S)R]-10 TiCl4/Ti(OiPr)4 À 78
6
17:18:15a 10
(90:0:0)[b] 30
17[e]
18
3.01 and 3.10). The shielding effect of the anti-sulfinyl oxygen
on HA is now attenuated by the gauche disposition of the NH
and the 1,3-parallel methyl group, which do not affect HB (d ˆ
3.10) and so HB appears less deshielded than in 13a.
Comparison of these spectral features with those of 15a
allowed its configurational assignment, which was confirmed
by NOESY experiments that displayed a NOE between HB
(d ˆ 3.46) and the CH3 group, whereas HA (d ˆ 3.04) pre-
(1.5/1.5)
[4R,(S)R]-10 BF3 ¥ OEt2
RT
RT
24 17:18:15a 30
17[f]
18
(3)
BF3 ¥ OEt2
(3)
(63:4:30)[c] 34
[4R,(S)R]-8
24 20:13a
37
20
(85:5)[b]
1
[a] Determined by H NMR spectroscopy from the crude product. [b] 10% of
10 or 8 was detected. [c] 3% of 10 was recovered. [d] Yield after flash column
chromatography. [e] Eluent: AcOEt. [f] Eluent: CH3CN/CH2Cl2.
210
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Heterocyclic Cage Compounds
208 216
formation of compound 17: an initial Diels Alder cyclo-
addition followed by an acid-catalyzed rearrangement[24] or a
1,4-conjugate addition of 2-(trimethylsilyloxy)furan through
its more nucleophilic position to the unsubstituted enone
moiety of 10. The former is unlikely since no Diels Alder
adducts were detected under any conditions. When the
reaction of amino derivative [4R,(S)R]-8 with 11 was run in
the presence of BF3 ¥ OEt2 (Table 2, entry 3), an 85:5 mixture
of tricyclic derivative 20 and the cage compound 13a were
formed, even though the conversion was not complete (10%
of starting material was recovered). Although compound 19,
the nitrogen analogue of 17, was not detected in this case, we
can assume a similar transformation from 19. Thus, once 19
has been formed, the higher nucleophilicity of the nitrogen
facilitates its immediate attack on the a,b-unsaturated lactone
moiety leading directly to 20 and 13a. Compound 20 was
isolated from this mixture in 40% yield. Although only 5% of
13a was detected under these conditions, this is additional
evidence of the intermediate formation of 19 and 20 en route
to 13a. All of these compounds were stereoselectively formed
since only one diastereomer of each was detected.
eoselective from the face of the OH group. Since cage
compound 13a was formed from 8 in the presence of BF3 ¥
OEt2 (Table 2, entry 3), we can assume that similar inter-
mediates are formed when the reactions are carried out in the
presence of Bu4NF. Although compounds 21 and 12 were not
detected in the reaction of 9 with 11 in the presence of Bu4NF,
similar intermediates must be formed en route to cage
compounds 12a and 12b. Under these conditions, an initial
Diels Alder reaction is not possible since cycloadducts only
rearrange in the presence of acids.[24]
In order to know the role of the sulfoxide in the process, we
decided to use p-quinamine 24 and p-quinol 25, which lack
such a group, in the reaction with 11 in the presence of Bu4NF.
Compound 24 was synthesized from N-Boc p-benzoquinone-
imine dimethylacetal[16] 1 by addition of MeLi followed by
hydrolysis of the acetal and N-Boc protecting groups (50%
overall yield); see Scheme 4. Derivative 25[8b] was obtained
similarly from p-benzoquinone dimethylacetal[25] 23 by 1,2-
addition of MeLi and hydrolysis of the acetal group, and
isolated in a 62% overall yield.
When unsubstituted cyclohexadienone 9 was treated with
11 in the presence of BF3 ¥ OEt2 two diastereomers 21a and
21b, resulting from an initial conjugate addition, were formed
in a 1:1 ratio (Scheme 3). After flash chromatography, a 1:1
mixture of tricyclic derivatives 22a and 22b could be isolated
in a 50% yield. Although two diastereomers are formed as a
O
OMe
MeO
i) ii)
Me
HX
X
1: X = N-Boc
23: X = O
X = N-Boc, 70%
24, X = NH
25, X = O, 62%
iii)
O
O
O
O
Me3Si
OTMS
Scheme 4. Synthesis of compounds 24 and 25. i) MeLi, THF, À788C;
ii) oxalic acid, THF:H2O; iii) TFA, CH2Cl2, RT, 71%.
OH
a
b
i)
SOTol
O
HO
SOTol
9
When treated with 2-(trimethylsilyloxy)furan 11 in the
presence of Bu4NF/CH2Cl2, 24 and 25 gave only but-2-
enolactone, whereas 7 and 9 were transformed in 1 h into cage
compounds under the same conditions. This lack of reactivity,
suggests that the sulfoxide plays an essential role in the
process. The easy transformation of 7 10 into 12 15 under
the experimental conditions used for these reactions (Bu4NF/
CH2Cl2), could only be due to the presence of the sulfoxide on
the side chain at C-4, which must increase the electrophilicity
of the cyclohexadienone framework. Thus, although this
group is not directly involved in the transformations, it plays
a double role: making the molecule optically active and
increasing the reactivity of the cyclohexadienone framework.
Although the experimental result is unequivocal, the origin of
such increased reactivity is not evident.
a
b
ii)
O
O
H
H
H
H
O
O
O
HO
OH
O
TolOS
SOTol
SiO2
21b
21a
1
:
1
SiO2
O
O
H
H
H
H
O
O
O
O
TolOS
O
O
SOTol
H
H
22a
22b
1
:
1
Stereochemistry: The stereoselectivity of the overall process
must be defined in the first 1,4-addition conjugate addition.
The p-facial diastereoselectivity of this reaction on the
cyclohexadienone fragment was the expected one according
to previous results on p-quinol derivatives,[7, 8a] and was
independent of the additive used to initiate the process. Steric
effects are at the origin of the preferred attack of 11 on the
face containing the OH of the cyclohexadienone system. The
configuration of the stereogenic carbon of the lactone frag-
12b
12a
Scheme 3. Sequential 1,4-additions in the reaction of 9 with 11. i) 11,
CH2Cl2, À788C; ii) BF3 ¥ OEt2 (8 equiv), 5 h.
consequence of the initial attack of 2-(trimethylsilyloxy)furan
11 to both prochiral conjugate positions of the unsubstituted
cyclohexadienone, such a reaction is highly p-facially diaster-
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211

ƒ
M. C. Carreno et al.
FULL PAPER
ment in 17 is consistent with the favored endo approach of
2-(trimethylsilyloxy)furan[26] to the enone, as shown in
Scheme 5. This attack gives rise to intermediate A, whose
O
O
O
O
Raney Ni
EtOH
O
O
X
X
R
TolOS
R
CH3
26: R = Me, X = NH
27: R = H, X = O
28: R = Me, X = O
13b
14a,b
15a
O
Scheme 6. Raney Ni desulfurization of heterocyclic cage compounds.
5
HO
SOTol
10
Conclusion
i)
O
O
A short and efficient asymmetric synthesis of a 7-aza-3-oxa or
3,7-dioxatetracyclo[6.4.0.02,6.05,9] skeleton from simple start-
ing materials has been described. The method is based on the
introduction of a homochiral p-tolylsulfinylmethyl substituent
at C-4 of a p-quinol or p-quinamine, which significantly
increases the acceptor character of the cyclohexadienone
system. The available evidence suggests that a domino
sequence of three conjugate additions occurs when a mixture
of 2-(trimethylsilyloxy)furan and enantiomerically pure com-
pounds is treated with Bu4NF; this gives rise to the stereo-
selective formation of tetracyclic cage compounds in a one-
pot reaction. The reactions described define a practical and
unprecedented method resulting in the formation of complex
structures with up to six stereogenic centers in a highly
stereocontrolled manner.
O
HO
SiMe3
O
17
H
O
O
O
SOTol
A
TolOS
ii)
O
O
O
H
O
H
O
O
18
O
H
O
Me
Me
SOTol
SOTol
15a
B
100% conversion
Scheme 5. Stereochemical course of domino conjugate additions. i) 11,
Bu4NF, CDCl3, RT; ii) Bu4NF, CDCl3.
protonation would yield 17. Compound 17 was detected when
this reaction was performed in a NMR sample tube (CDCl3 as
solvent). The preferred attack of 2-(trimethylsilyloxy)furan 11
on the more electrophilic C-5 conjugate position of 3-methyl-
substituted cyclohexadienones 8 and 10 was also expected on
the basis of its higher electrophilicity. The stereoselective 1,4-
addition of the OH or NH2 to the a,b-unsaturated lactone
may be rationalized through the favored disposition of the p-
systems, which results in the first reaction. As shown in
Scheme 5 for intermediate A, a second conjugate addition to
the butenolide led to the all-cis fused tricyclic intermediate B,
which was observed in the NMR experiment as the proto-
nated derivative 18. Compound 18 was isolated when the
reaction of 10 was carried out in the presence of TiCl4/
Ti(OiPr)4 or BF3 ¥ OEt2 (Table 2). The concave geometry of
intermediate B (Scheme 5) facilitates the attack of the
enolized lactone fragment on the cyclohexenone from the
face containing the oxygenated substituent. When these
reactions are carried out in the presence of Bu4NF, the
formation of negatively charged intermediates must be
responsible for the quick transformation observed. When
BF3 ¥ OEt2 or TiCl4/Ti(OiPr)4 are in the medium, the role of
the Lewis acids must be to activate the a,b-unsaturated
systems for the Michael type additions through coordination
Experimental Section
General: All reactions were monitored by TLC, which was performed on
precoated silica gel 60F254 plates. Flash column chromatography was
effected with silica gel 60 (230 240 mesh). 1H NMR spectra were recorded
at 200 or 300 MHz. 13C NMR were recorded at 50 or 75 MHz. Chemical
shifts are reported in ppm relative to TMS in CDCl3. All NMR spectra
were obtained in CDCl3 at room temperature. HRMS were measured at
70 eV. All reagents were purchased from Aldrich and were used without
further purification.
[(S)R]-4-(tert-Butoxycarbonyl)amino-4-[p-(tolylsulfinyl)methyl]cyclo-
hexa-2,5-dienone (5): A solution of [(S)R]-methyl-p-tolylsulfoxide (1.6 g,
10 mmol, 1 equiv) in THF (15 mL) was added at À788C to a solution of
LDA (1.2 equiv) in THF (20 mL). After 30 min of stirring, N-(tert-
butoxycarbonyl)-p-benzoquinonemonoimine dimethylacetal (1)[16] (3.0 g,
12 mmol, 1.1 equiv) in THF (20 mL) was added at À788C. The mixture was
stirred for 5 h. Hydrolysis was performed with saturated NH4Cl, the residue
was extracted with AcOEt, then the organic phase was dried (Na2SO4) and
concentrated to dryness. The resulting ketal derivative 3 was dissolved in
THF, then an aqueous solution of oxalic acid (10%) was added at RT. After
2 h, the solution was neutralized with saturated NaHCO3 and extracted
with AcOEt. The organic phase was dried (Na2SO4) and concentrated in
vacuo. The crude product was recrystallized from AcOEt as a white solid.
Yield: 3.0 g, 80%; m.p. 169 1708C; [a]2D0 ˆ ‡60.1(c ˆ 1 in CHCl3);
1H NMR (300 MHz): d ˆ 7.51 7.48 (AA', 2H; Tol), 7.33 7.31 (BB', 2H;
Tol), 7.30 (dd, J ˆ 10.1 and 3.1 Hz, 1H; H-3), 7.03 (dd, J ˆ 10.1 and 3.1 Hz,
1H; H-5), 6.33 (dd, J ˆ 10.1 and 1.9 Hz, 1H; H-2), 6.32 (s, 1H; NH), 6.23
(dd, J ˆ 10.1 and 1.9 Hz, 1H; H-6), 3.01 (brs, 2H; CH2SOTol), 2.39 (s, 3H;
Tol), 1.42 (s, 9H; tBu); 13C NMR (75 MHz): d ˆ 184.3 (CO), 154.2 (CO),
149.0 (C-3), 147.9 (C-5), 142.4 (C; Tol), 139.7 (C; Tol), 130.2 (2C; Tol), 129.4
(C-2), 128.7 (C-6), 123 (2C; Tol), 80.8 (C; tBu), 65.6 (CH2SOTol), 54.5 (C-
4), 28.2 (3C; tBu), 21.3 (Tol); elemental analysis calcd for C19H23NO4S: C
63.13, H 6.41, N 3.88, S 8.87; found C 62.73, H 6.29, N 3.31, S 9.25.
ˆ
to the C O.
The elimination of the sulfoxide group is important for
future applications of this methodology. This was quantita-
tively achieved in compounds 13b, 15a, 14a, and 14b upon
reaction with Raney nickel, which gave optically pure
compounds (À)-26 (80%) and (‡)-28 (92%) and racemic
derivative 27 (90%), respectively (Scheme 6).
[4R,(S)R] and [4S,(S)R] 4-(tert-Butoxycarbonyl)amino-3-methyl-4-
[p-(tolylsulfinyl)methyl]cyclohexa-2,5-dienone (6): A solution of [(S)R]-
methyl-p-tolylsulfoxide (775.0 mg, 5.03 mmol, 1 equiv) in THF (15 mL),
212
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0947-6539/02/0801-0212 $ 17.50+.50/0
Chem. Eur. J. 2002, 8, No. 1

Heterocyclic Cage Compounds
208 216
was added via cannula to a solution of LDA (1.2 equiv) at À788C in THF
(20 mL). After 30 min of stirring, N-(tert-butoxycarbonyl)-2-methyl-p-
benzoquinonmonoimine dimethylacetal 2[16] (1.53 g, 5.7 mmol, 1.1 equiv) in
THF (20 mL) was added at À788C. The mixture was stirred for 5 h.
Hydrolysis was performed with saturated NH4Cl, and the residue was
extracted with AcOEt. The organic phase was dried (Na2SO4) and
concentrated in vacuo. An aqueous solution of oxalic acid (10%, 2 mL)
was added at RT to the resulting acetal derivatives 4, which were dissolved
in THF (20 mL). After 2 h of stirring, the solution was neutralized with
saturated NaHCO3. The organic phase was extracted with AcOEt, dried
(Na2SO4), and concentrated in vacuo to give a mixture of [4R,(S)R]-6 and
[4S,(S)R]-6 (77:23, 82% overall yield), which could be separated by column
chromatography (hexane/AcOEt 4:1) to afford [4R,(S)R]-6 (1.1 g, 58%
yield) and [4S,(S)R]-6 (360 mg, 19% yield) as white solids.
(brs, 3H; CH3), 1.83 (brs, 2H; NH2); 13C NMR (50 MHz): 184.9 (CO),
160.5 (C-3), 151.9 (C-5), 142.1 (C; Tol), 140.0 (C; Tol), 130.1 (2C; Tol),
128.2 (C-2), 127.3 (C-6), 123.9 (2C; Tol), 67.8 (CH2SOTol), 52.9 (C-4), 21.3
(Tol), 18.3 (CH3); HRMS (FAB ‡ ) calcd for C15H17NO2S: m/z: 276.1061
‡
[M] , found 276.1058.
[1R,2R,5S,6R,8S,9R,(S)R] and [1S,2S,5R,6S,8R,9S,(S)R]-8-[(p-tolyl-
sulfinyl)methyl]-3-oxa-7-azatetracyclo [6.4.0.02,6.05,9]dodecane-4,11-dione
(12a/12b): 2-(Trimethylsilyloxy)furan 11 (20.3 mg, 0.13 mmol, 1.2 equiv)
and Bu4NF (1m in THF, 130 mL, 1.1 equiv) were sequentially added at RT to
a solution of 7 (30 mg, 0.11 mmol, 1 equiv) in dry CH2Cl2 (0.5 mL). After
1 h of stirring, a saturated aqueous solution of NaCl was added. The
solution was extracted with AcOEt, and the combined organic phases were
dried (Na2SO4). Removal of the solvent in vacuo afforded a residue, which
was purified by column chromatography (CH3CN/CH2Cl2 4:1). Com-
pounds 12a and 12b were obtained as white solids as a 1:1 mixture of two
diastereomers. Yield: 25.5 mg, 67%; 1H NMR (300 MHz): 7.59 7.56 (AA',
2H; Tol, two diastereomers), 7.38 7.36 (BB', 2H; Tol, two diastereomers),
4.80 4.79 (m, 1H; H-2, two diastereomers), 4.58 4.54 (m, 1H; H-6, two
diastereomers), 3.36, 3.07 (ABsystem, J ˆ 14.1 Hz, 2H; CH2SOTol, one
diastereomer), 3.32, 3.03 (ABsystem J ˆ 13.7 Hz, 2H; CH2SOTol, one
diastereomer), 3.13 (brs, 1H; H-1, two diastereomers), 2.90 2.30 (m, 6H;
two diastereomers), 2.46 (s, 3H; Tol, two diastereomers); 13C NMR
(75 MHz): 203.8 (CO; two diastereomers), 175.8 (CO), 175.7 (CO), 142.5
(Tol; two diastereomers), 140.1 (Tol; two diastereomers), 130.4 (2C, Tol;
two diastereomers), 123.9 (2C, Tol; two diastereomers), 81.1 (C-2), 80.0 (C-
2), 64.3 (C-8), 64.2 (C-8), 63.9 (CH2SOTol; two diastereomers), 58.9 (C-6),
58.7 (C-6), 45.9 (C-5), 45.8 (C-5), 45.2 (C-1), 44.5 (C-1), 44.1 (C-9), 43.7 (C-
9), 36.8 (C-12), 36.7 (C-10), 35.5 (C-12), 35.4 (C-10), 21.4 (Tol; two
diastereomers); HRMS(EI) calcd for C18H19NO4S: m/z: 345.1036, found
345.1034.
[4R,(S)R]-6: M.p. 136 1378C; [a]2D0 ˆ ‡60.1 (c ˆ 1 in CHCl3); 1H NMR
(200 MHz): 7.48 7.44 (AA', 2H; Tol), 7.39 (d, J ˆ 11.2 Hz, 1H; H-5), 7.29
7.26 (BB', 2H; Tol), 6.91 (brs, 1H; NH), 6.39 (dd, J ˆ 11.2 and 2.1 Hz, 1H;
H-6), 6.07 (brs, 1H; H-2), 3.15 and 2.42 (ABsystem, J ˆ 13.3 Hz, 2H;
CH2SOTol), 2.41 (s, 3H; Tol), 1.91 (d, J ˆ 1.6 Hz, 3H; CH3), 1.37 (s, 9H;
tBu); 13C NMR (75 MHz): 184.7 (CO), 160.3 (CO), 154.1 (C-3), 150.6 (C-5),
142.9 (C; Tol), 140.1 (C; Tol), 129.9 (2C; Tol), 130 (CH), 127.8 (CH), 124.0
(2C; Tol), 80.78 (C; tBu), 67.2 (CH2SOTol), 57.7 (C-4), 28.4 (3C; tBu), 21.7
(Tol), 18.8 (CH3); elemental analysis calcd for C20H25NO4S: C 63.97, H 6.71,
N 3.73, S 8.54; found C 63.98, H 6.68, N 3.55, S 8.65.
[4S,(S)R]-6: M.p. 121 1228C; [a]2D0 ˆ ‡30 (c ˆ 1 in CHCl3); 1H NMR
(300 MHz): 7.51 7.47 (AA', 2H; Tol), 7.34 7.30 (BB', 2H; Tol), 6.92 (d,
1H, J ˆ 10.2 Hz; H-5), 6.63 (brs, 1H; NH), 6.24 6.15 (m, 2H; H-6 and
H-2), 3.00, 2.80 (ABsystem, J ˆ 13.4 Hz, 2H; CH2SOTol), 2.39 (s, 3H; Tol),
2.21 (s, 3H; CH3), 1.38 (s, 9H; tBu); 13C NMR (75 MHz): 184.7 (CO), 159.1
(CO), 154.0 (C-3), 151.1 (C-5), 142.0 (C; Tol), 139.2 (C; Tol), 129.5 (2C;
Tol), 128.1 (CH), 127 (CH), 123.4 (2C; Tol), 80.6 (C; tBu), 65.7
(CH2SOTol), 57.3 (C-4), 27.7 (3C; tBu), 21.2 (Tol), 19.2 (CH3).
[1R,2R,5S,6R,8R,9R,(S)R]-9-Methyl-8-[(p-tolylsulfinyl)methyl]-3-oxa-
7-azatetracyclo[6.4.0.02,6.05,9]dodecane-4,11-dione (13a): 2-(Trimethylsilyl-
oxy)furan 11 (33.7 mg, 0.21 mmol, 1.8 equiv) and Bu4NF (1m in THF,
132 mL, 0.13 mmol, 1.1 equiv) were sequentially added at room temper-
ature to a solution of [4R,(S)R]-8 (32 mg, 0.12 mmol, 1 equiv) in dry CH2Cl2
(0.5 mL). After 24 h of stirring, a saturated aqueous solution of NaCl was
added. Extractions were carried out with AcOEt, and the combined
organic phases were dried (Na2SO4). Removal of the solvent in vacuo
afforded a residue that was purified by column chromatography (CH3CN/
CH2Cl2 3:1) to give 13a as a white solid. Yield: 24 mg, 56%; m.p. 249
[(S)R]-4-amino-4-[p-(tolylsulfinyl)methyl]cyclohexa-2,5-dienone (7): TFA
(10 equiv) was added to a solution of 5 (3 g, 8.3 mmol, 1 equiv) in CH2Cl2
(40 mL). The mixture was stirred at RT for 2 h, and an aqueous solution of
NaOH (2m) was added slowly at 08C until the pH was basic. The product
mixture was extracted with AcOEt, and the combined organic phases were
washed with brine and dried (Na2SO4). After removal of the solvent in
vacuo, the residue was recrystallized from AcOEt to afford a white solid.
Yield: 2.1 g, 97%; m.p. 162 1638C; [a]2D0 ˆ ‡146 (c ˆ 1 in CHCl3);
1H NMR (300 MHz): 7.54 7.50 (AA', 2H; Tol), 7.35 7.31 (BB', 2H;
Tol), 7.15 (dd, J ˆ 9.6 and 3.2 Hz, 1H; H-3), 6.99 (dd, J ˆ 9.6 and 3.2 Hz,
1H; H-5), 6.27 (dd, J ˆ 9.6 and 1.6 Hz, 1H; H-2), 6.19 (dd, J ˆ 9.6 and
1.6 Hz, 1H; H-6), 3.10, 2.75 (ABsystem, J ˆ 13.4 Hz, 2H; CH2SOTol), 2.41
(s, 3H; Tol), 2.01 (brs, 2H; NH2); 13C NMR (75 MHz): 184 (CO), 151.0 (C-
3), 150.8 (C-5), 142.2 (C; Tol), 140.3 (C; Tol), 130.1 (2C; Tol), 128.0 (C-2),
127.8 (C-6), 123.8 (2C; Tol), 67.2 (CH2SOTol), 53.0 (C-4), 21.3 (Tol).
1
2508C; [a]2D0 ˆ ‡140 (c ˆ 1.05 in MeOH); H NMR (200 MHz): 7.62 7.59
(AA', 2H; Tol), 7.41 7.38 (BB', 2H; Tol), 4.86 (dd, J ˆ 8.0 and 4.9 Hz, 1H;
H-2), 4.49 (brt, J ˆ 4.9 Hz, 1H; H-6), 3.27, 2.85 (ABsystem, J ˆ 13.1 Hz,
2H; CH2SOTol), 3.03 2.93 (m, 1H; H-1), 2.70 2.49 [m, 3H; H-12a, H-12e,
H-10e), 2.43 (s, 3H; Tol), 2.32 (d, J ˆ 4.9 Hz, 1H; H-5), 2.15 (part Bof AB '
system, J ˆ 16.3 Hz, 1H; H-10a), 1.09 (s, 3H; CH3); 13C NMR (50 MHz):
204.1 (CO), 175.6 (CO), 142.5 (Tol), 139.9 (Tol), 130.3 (2C; Tol), 124.0 (2C;
Tol), 82.0 (C-2), 66.3 (C-8), 63.1 (C-6), 56.5 (CH2SOTol), 50.5 (C-5), 48.8
(C-9), 44.9 (C-1), 44.3 (C-10), 36.3 (C-12), 25.5 (CH3), 21.4 (Tol).
[4R,(S)R]-4-Amino-3-methyl-4-[p-(tolylsulfinyl)methyl]cyclohexa-2,5-di-
enone [4R,(S)R]-(8): TFA (10 equiv) was added to a solution of [4R,(S)R]-
6 (1.1 g, 2.9 mol, 1 equiv) in CH2Cl2 (50 mL). The mixture was stirred at RT
for 1 h, then aqueous NaOH (2m) was added slowly at 08C until the pH was
basic. The mixture was extracted with AcOEt. The combined extracts were
washed with brine and dried (Na2SO4). After removal of the solvent in
vacuo, the residue was recrystallized from AcOEt to afford a white solid.
Yield: 694 mg, 87%; m.p. 118 1198C; [a]2D0 ˆ ‡130 (c ˆ 1 in CHCl3);
1H NMR (300 MHz): 7.47 7.44 (AA', 2H; Tol), 7.34 (d, J ˆ 10.1 Hz, 1H;
H-5), 7.30 7.28 (BB', 2H; Tol), 6.25 (dd, J ˆ 10.1 and 2 Hz, 1H; H-6), 6.04
(brs, 1H; H-2), 3.20, 2.65 (ABsystem, J ˆ 13.3 Hz, 2H; CH2SOTol), 2.36 (s,
3H; Tol), 1.99 (d, J ˆ 1.2 Hz, 3H; CH3), 1.95 (brs, 2H; NH2); 13C NMR
(50 MHz): 184.9 (CO), 159.9 (C-3), 151.9 (C-5), 142.0 (C; Tol), 140.6 (C;
Tol), 130.0 (2C; Tol), 127.4 (C-2), 127.2 (C-6), 123.7 (2C; Tol), 66.9
(CH2SOTol), 55.1 (C-4), 21.2 (Tol), 18.5.
[1S,2S,5R,6S,8R,9S,(S)R]-9-Methyl-8-[(p-tolylsulfinyl)methyl]-3-oxa-7-
azatetracyclo[6.4.0.02,6.05,9] dodecane-4,11-dione (13b): 2-(Trimethylsilyl-
oxy)furan 11 (37.5 mg, 0.24 mmol, 1.8 equiv) and Bu4NF (1m in THF,
156 mL, 1.2 equiv) were sequentially added at RT to a solution of [4S,(S)R]-
8 (37 mg, 0.13 mmol, 1 equiv) in dry CH2Cl2 (0.5 mL). After 24 h of stirring,
a saturated aqueous solution of NaCl was added. Extraction was carried out
with AcOEt, and the combined organic phases were dried (Na2SO4).
Removal of the solvent in vacuo, afforded a crude product which was
purified by column chromatography (CH3CN/CH2Cl2 3:1) to give 13b as a
white solid. Yield: 33 mg, 70%; m.p. 203 2048C; [a]2D0 ˆ ‡170 (c ˆ 1 in
CHCl3); 1H NMR (200 MHz): 7.58 7.55 (AA', 2H; Tol), 7.38 7.35 (BB',
2H; Tol), 4.84 (dd, J ˆ 8.0 and 4.8 Hz, 1H, H-2), 4.52 (brt, J ˆ 4.8 Hz, 1H;
H-6), 3.10, 3.01 (ABsystem, J ˆ 13.1 Hz, 2H; CH2SOTol), 3.01 2.98 (m,
1H; H-1), 2.68 2.62 [m, 3H; H-12a, H-12e, H-10e), 2.42 (s, 3H; Tol), 2.36 (d,
J ˆ 4.8 Hz, 1H; H-5), 2.16 (part Bof AB ' system, J ˆ 16.0 Hz, 1H; H-10a),
1.09 (s, 3H; CH3); 13C NMR (75 MHz): 204.6 (CO), 175.5 (CO), 142.3 (Tol),
140.7 (Tol), 130.3 (2C; Tol), 123.8 (2C; Tol), 81.4 (C-2), 66.5 (C-8), 63.5 (C-
6), 58.0 (CH2SOTol), 51.7 (C-5), 48.9 (C-9), 45.7 (C-10), 45.0 (C-1), 36.3 (C-
12), 25.6 (CH3), 21.5 (Tol): HRMS(EI) calcd for C19H21NO4S: m/z:
359.1191, found 359.1189.
[4S,(S)R]-4-Amino-3-methyl-4-[p-(tolylsulfinyl)methyl]cyclohexa-2,5-di-
enone [4S,(S)R]-(8): Starting from [4S,(S)R]-6 (360 mg, 0.96 mmol,
1 equiv) and following the procedure for the synthesis of [4R,(S)R]-8, the
diastereomer [4S,(S)R]-8 was obtained as a white solid. Yield: 262 mg,
99%; m.p. 168 1698C; [a]2D0 ˆ ‡242 (c ˆ 1 in CHCl3); 1H NMR
(300 MHz): 7.49 7.46 (AA', 2H; Tol), 7.31 7.28 (BB', 2H; Tol), 7.03 (d,
J ˆ 10.6 Hz, 1H; H-5), 6.16 (dd, J ˆ 10 and 1.8 Hz, 1H; H-6), 6.13 (brs, 1H;
H-2), 3.05, 2.93 (ABsystem, J ˆ 13.3 Hz, 2H; CH2SOTol), 2.39 (s, 3H), 2.13
[1S, 2R, 5S, 6R, 8S, 9R, (S)R] and [1R, 2S, 5R, 6S, 8R, 9S, (S)R]-8-
[(p-Tolylsulfinyl)methyl]-3,7-dioxa tetracyclo[6.4.0.02,6.05,9]dodecane-4,11-
Chem. Eur. J. 2002, 8, No. 1
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0801-0213 $ 17.50+.50/0
213

ƒ
M. C. Carreno et al.
FULL PAPER
dione (14a/14b): 2-(Trimethylsilyloxy)furan 11 (167 mg, 1.07 mmol,
1.5 equiv) and Bu4NF (1m in THF, 1.4 mL, 1.5 equiv), were sequentially
added at RT to a solution of [(S)R]-9 (270 mg, 1.03 mmol, 1 equiv), in dry
CH2Cl2 (4 mL). After 1 h of stirring, a saturated aqueous solution of NaCl
was added. Extractions were carried out with AcOEt, and the combined
organic phases were dried (Na2SO4). Removal of the solvent in vacuo
(AcOEt) gave 17 as a pale yellow oil (yield: 18 mg, 30%) and 18 as a yellow
oil (yield: 24 mg, 40%).
TiCl4/Ti(OiPr)4: Ti(OiPr)4 (59.6 mg, 0.21, 1.5 equiv), TiCl4 (39.8 mg, 0.21,
1.5 equiv), and 2-(trimethylsilyloxy)furan 11 (32.8 mg, 0.21 mmol,
1.5 equiv) were sequentially added at À788C to a solution of [4R,R(S)]-
10 (40 mg, 0.14 mmol, 1 equiv) in dry CH2Cl2 (0.5 mL). After 6 h stirring, a
saturated aqueous solution of NaCl was added. Extractions were carried
out with AcOEt, and the combined organic phases dried (Na2SO4) and
concentrated in vacuo to give a 90:10 mixture of 17/18/15a/10. Purification
by column chromatography (AcOEt) gave 17 as a pale yellow oil (yield:
6 mg, 10%) and 18 as a yellow oil (yield: 18 mg, 30%).
afforded
a residue, which was purified by column chromatography
(Hexane/AcOEt/CH3CN 1:1:0.2) to give 14a:14b as a white solid as a 1:1
mixture of two diastereomers. Yield: 239 mg, 67%; 1H NMR (300 MHz):
7.60 7.57 (AA', 2H; Tol, two diastereomers), 7.38 7.35 (BB', 2H; Tol, two
diastereomers), 5.45 (brt, 1H, J ˆ 4.9 Hz; H-6, two diastereomers), 4.98
4.83 (m, 1H; H-2, two diastereomers), 3.39, 3.10 (ABsystem, J ˆ 15 Hz,
2H; CH2SOTol, two diastereomers), 3.19, 2.94 (m, 3H; two diastereomers),
2.75 (dd, J ˆ 10 and 4.1 Hz, 2H; two diastereomers), 2.62 2.32 (m, 2H; two
diastereomers), 2.42 (s, 3H; Tol, two diastereomers); 13C NMR (75 MHz):
203.1 (CO), 174.1 (CO; two diastereomers), 174.0 (CO), 142.3 (Tol, two
diastereomers), 140.5 (Tol, two diastereomers), 130.3 (2C; two diaster-
eomers), 123.8 (2C; two diastereomers), 82.9 (C-8; two diastereomers),
81.8 (C-6; two diastereomers), 80.4 (C-2; two diastereomers), 60.4
(CH2SOTol), 60.3 (CH2SOTol), 46.8 (C-5), 45.4 (C-5), 45.3 (C-1), 45.0
(C-1), 44.0 (C-9), 42.7 (C-9), 36.8 (C-12; two diastereomers), 35.6 (C-10),
35.5 (C-10), 21.4 (Tol; two diastereomers); HRMS(EI) calcd for C18H17O5S:
m/z: 346.0871, found 346.0874.
1
Compound 17: H NMR (300 MHz): 7.59 7.55 (AA', 2H; Tol), 7.41 7.37
(BB', 2H; Tol), 7.32 (dd, J ˆ 5.9 and 1.6 Hz, 1H; H-4'), 6.06 (dd, J ˆ 5.9 and
2.1 Hz, 1H; H-3), 5.84 (brs, 1H; H-4'), 5.80 (ddd, J ˆ 4.3, 2.1 and 1.6 Hz,
1H; H-5), 5.58 (s, 1H; OH), 3.84 3.78 (m, 1H; H-1'), 3.20 3.80 (AB
system, J ˆ 13.9 Hz, 2H; CH2SO2Tol), 2.49 2.44 (m, 2H; Heq/ax-6'), 2.44 (s,
3H; Tol), 2.07 (d, J ˆ 1.6 Hz, 3H; CH3); 13C NMR (75 MHz): 193.7 (CO),
172.0 (CO), 162.3 (C-3'), 153.6 (C-4'), 143.3 (Tol), 138.5 (Tol), 130.6 (2C;
Tol), 128.1 (C-4), 124 (2C; Tol), 122.5 (C-3), 81.8 (C-5), 74.3 (C-2'), 61.1
(CH2SOTol), 45.2 (C-6'), 33.8 (C-1×), 21.5 (Tol), 18.8 (CH3).
1
Compound 18: H NMR (200 MHz): 7.52 7.48 (AA', 2H; Tol), 7.36 7.32
(BB', 2H; Tol), 6.04 (brs, 1H; H-6), 5.13 (t, J ˆ 4.4 Hz, 1H; H-3a), 4.93
(brt, J ˆ 4.8 Hz, 1H; H-8b), 3.24 2.90 (m, 4H), 2.86 (m, 3H), 2.42 (s, 3H),
1.98 (s, 3H; CH3); 13C NMR (75 MHz): 193.9 (CO), 173.7 (CO), 142.2 (Tol),
140.3 (Tol), 130.5 (C-6), 130.3 (2C, Tol), 124.0 (C-5), 123.9 (2C, Tol), 87.0
(C-3a), 82.6 (C-8b), 66.3 (CH2SOTol), 56.7 (C-4a), 46.8 (C-8a), 37.1 (C-3),
33.5 (C-8), 21.4 (Tol), 18.1 (CH3).
[1R,2R,5S,6R,8R,9R,(S)R]-9-Methyl-3,7-dioxa-8-[(p-tolylsulfinyl)meth-
yl]tetracyclo[6.4.0.02,6.05,9]dodecane-4,11-dione (15a): 2-(Trimethylsilyl-
oxy)furan 11 (59.0 mg, 0.37 mmol, 1.8 equiv) and Bu4NF (1m in THF,
228 mL, 1.1 equiv) were sequentially added at RT to a solution of [4R,(S)R]-
10 (60 mg, 0.21 mmol, 1 equiv) in dry CH2Cl2 (0.5 mL). After 24 h of
stirring, a saturated aqueous solution of NaCl was added. Extractions were
carried out with AcOEt, and the combined organic phases were dried
(Na2SO4). Removal of the solvent in vacuo afforded a residue whose
purification by column chromatography (CH3CN/CH2Cl2 3:1) gave 15a as a
white solid. Yield: 52 mg, 67%; m.p. 228 2298C; [a]2D0 ˆ ‡237 (c ˆ 0.36 in
CHCl3); 1H NMR (500 MHz): 7.62 7.61 (AA', 2H; Tol), 7.41 7.40 (BB',
2H; Tol), 5.39 (t, J ˆ 5.02 Hz, 1H; H-6), 4.95 (dd, J ˆ 7.9 and 4.9 Hz, 1H;
H-2), 3.46 3.04 (ABsystem, J ˆ 14.6 Hz, 2H; CH2SOTol), 3.02 3.0 (m,
1H; H-1), 2.81 (part A of ABX system (H-12eq) and part A of AB system
(H-10eq)), J ˆ 18.4 Hz, 2H), 2.69 (part Bof ABX system (H-12 ax)), J ˆ 18.3
and 6.2 Hz, 1H), 2.52 (d, J ˆ 5.1 Hz, 1H; H-5), 2.47 (s, 3H; Tol), 2.29 (part
Bof ABsystem, J ˆ 18.4, 1H; H-10ax), 1.18 (s, 3H; CH3); 13C NMR
(75 MHz): 203.1 (CO), 174.1 (CO), 142.3 (Tol), 140.5 (Tol), 130.3 (2C; Tol),
124 (2C; Tol), 84.9 (C-8), 81.1 (C-6), 80.4 (C-2), 58.3 (CH2SOTol), 51.8 (C-
5), 50.1 (C-9), 45.1 (C-10), 44.2 (C-1), 36.4 (C-12), 25.4 (CH3), 21.4 (Tol);
HRMS(EI) calcd for C19H20O5S: m/z: 360.1031, found 360.1029.
[3aR,4aR,8aR,8bR,(S)R]-5-Methyl-4a-[(p-tolylsulfinyl)methyl]-3a,4,4a,
8,8a,8b-hexahydro-2H-furo[3,2-b]indole-2,7(3H)-dione (20): 2-(Trimeth-
ylsilyloxy)furan 11 (30.0 mg, 0.19 mmol, 1.2 equiv) and BF3OEt2 (68.1 mg,
0.48, 3 equiv) were sequentially added at RT to a solution of [4R,(S)R]-8
(45.7 mg, 0.16 mmol, 1 equiv) in dry CH2Cl2 (0.5 mL). After 24 h of stirring,
a saturated aqueous solution of NaCl was added. Extractions were carried
out with AcOEt, and the combined organic phases dried (Na2SO4) and
concentrated in vacuo to give a 85:5:10 mixture of 20/13a/8. Purification by
column chromatography (AcOEt) gave of 20 as a pale yellow oil. Yield:
22 mg, 37%; 1H NMR (200 MHz): 7.53 7.50 (AA', 2H; Tol), 7.38 7.35
(BB', 2H; Tol), 5.92 (brs, 1H; H-6), 5.19 (t, J ˆ 6.0 Hz, 1H; H-8b), 4.32
(brt, J ˆ 6,2 Hz, 1H; H-3a), 3.30 (brt, J ˆ 6.8 Hz, 1H; H-8a), 3.21, 3.69 (AB
system, J ˆ 13.9 Hz, 2H; CH2SOTol), 3.0 (part A of ABsystem, J ˆ
18.2 Hz, 1H; H-8), 2.76 (m, 2H; H-8 and H-3), 2.42 (s, 3H; Tol), 2.39
(part Bof AB ' system, J ˆ 17.0 Hz, 1H; H-3), 2.0 (d, J ˆ 1.2 Hz, 3H; CH3);
13C NMR (50 MHz): 193.7 (CO), 175.3 (CO), 142.6 (Tol), 139.5 (Tol), 130.4
(2C; Tol), 128.9 (C-6), 125.3 (C-5), 123.8 (2C; Tol), 87.4 (C-8b), 64.8 (C-4a),
61.9 (CH2SOTol), 55.8 (C-3a), 46.5 (C-8a), 37.8 (C-3), 33.8 (C-8), 21.4 (Tol),
19.0 (CH3).
[1S*,2R*,5S*,6R*,8S*,9R*]-8-[(p-Tolylsulfonyl)methyl]-3,7-dioxatetra-
cyclo [6.4.0.02,6.05,9]dodecane-4,11-dione (16): A solution of m-chloroper-
oxybenzoic acid (50 70% w/w, 24 mg, 0.07 0.10 mmol, 1.4 2 equiv) in
CH2Cl2 (10 mL) was added to a solution of a mixture of 14a and 14b (1:1,
18 mg, 0.052 mmol, 1 equiv) in CH2Cl2 (0.5 mL) at 08C. The reaction
mixture was stirred for 1 h and then washed with saturated aqueous Na2SO3
and NaHCO3. The combined organic phases were dried (Na2SO4) and
concentrated in vacuo. The residue was purified by crystallization (AcOEt)
to afford 16 as a white solid. Yield: 16 mg, 83%; m.p. 218 2198C; 1H NMR
([D6]DMSO, 300 MHz): 7.81 7.78 (AA', 2H; Tol), 7.43 7.40 (BB', 2H;
Tol), 5.28 (brt, J ˆ 4.8 Hz, 1H; H-6), 4.78 (dd, J ˆ 7.0 and 5.2 Hz, 1H; H-2),
4.26, 4.18 (ABsystem, J ˆ 15.3 Hz, 2H; CH2SO2Tol), 2.8 2.6 (m, 6H), 2.40
(s, 3H; Tol), 2.32 2.24 (m, 2H); 13C NMR ([D6]DMSO, 75 MHz): 205.0
(CO), 175.2 (CO), 144.5 (Tol), 138.2 (Tol), 129.8 (2C; Tol), 128.0 (2C; Tol),
82.0 (C-8), 81.5 (C-6), 79.9 (C-2), 54.8 (CH2SOTol), 44.3 (2C; C-5 and C-1),
43.3 (C-9), 36.8 (C-12), 35.4 (C-10), 21.2 (Tol).
[1S,2R,(S)R]- and [1R,2S,(S)R]-5-{2-Hydroxy-5-oxo-2-[[p-tolylsulfinyl]-
methyl}-3-cyclohexenyl}-2(5H)-furanone (21a/21b), and [3aR,4aR,
8aS,8bR,(S)R]- and [3aS, 4aS, 8aR, 8bS,(S)R]-4a-[(p-tolylsulfinyl)meth-
yl]-3a, 8a, 8b-tetrahydrofuro[3, 2-b]benzofuran-2, 7(3H,4aH)-dione
(22a/22b): 2-(Trimethylsilyloxy)furan 11 (14.2 mg, 0.09 mmol, 1.2 equiv)
and BF3OEt2 (86.3 mg, 0.60 mmol, 8 equiv) were sequentially added at RT
to a solution of [(S)R]-9 (20.5 mg, 0.076 mmol, 1 equiv) in dry CH2Cl2
(0.3 mL). After 5 h of stirring, a saturated aqueous solution of NaCl was
added. Extractions were carried out with AcOEt, and the combined
organic phases dried (Na2SO4) and concentrated in vacuo to give a 1:1
mixture of 21a:21b, which gave 22a:22b after purification by column
chromatography (AcOEt) as a pale yellow oil (yield: 13.1 mg, 50%).
Compound 21a/21b: 1H NMR (200 MHz): 7.61 7.52 (m, 2H; Tol, two
diastereoisomers), 7.41 7.32 (m, 2H; Tol, two diastereoisomers), 6.94 (d,
J ˆ 10.2 Hz, 1H; H-3', two diastereoisomers), 6.19 6.08 (m, 1H; H-4, two
diastereoisomers), 5.92 (d, J ˆ 10.2 Hz, 1H; H-4', two diastereoisomers),
5.73 5.68 (m, 1H; H-2, two diastereoisomers), 5.59 5.53 (m, 1H; H-5, two
diastereoisomers), 3.43 and 2.12 (ABsystem, J ˆ 14 Hz, 2H; CH2SOTol),
3.39 3.23 (m, 1H; H-1', one diastereoisomer), 3.25, 3.17 (ABsystem, J ˆ
14 Hz, 2H; CH2SOTol, one diastereoisomer), 2.78 2.73 (m, 1H; H-1', one
diastereoisomer), 2.58 2.29 (m, 2H; H-6', two diastereoisomers), 2.42
(3H, Tol, two diastereoisomers).
[1S,2R,(S)R]-5-{2-Hydroxy-3-methyl-5-oxo-2-[(p-tolyl)sulfinyl]methyl}-
3-cyclohexenyl}-2(5H)-furanone (17) and [3aR,4aR,8aS,8bR,(S)R]-5-
Methyl-4a-[(p-tolylsulfinyl)methyl]-3a,8a,8b-tetrahydrofuro[3,2-b]benzo-
furan-2,7(3H, 4aH)-dione (18):
BF3OEt2: 2-(Trimethylsilyloxy)furan 11 (39.0 mg, 0.25 mmol, 1.5 equiv)
and BF3OEt2 (68.5 mg, 0.48 mmol, 3 equiv) were sequentially added at RT
to a solution of [4R,(S)R]-10 (44.4 mg, 0.161 mmol, 1 equiv) in dry CH2Cl2
(0.5 mL). After 24 h of stirring, a saturated aqueous solution NaCl was
added. Extractions were carried out with AcOEt, and the combined
organic phases dried (Na2SO4) and concentrated in vacuo to give a
63:4:30:3 mixture of 17/18/15a/10. Purification by column chromatography
Compound 22a/22b: 1H NMR (200 MHz): 7.57 7.53 (AA', 2H; Tol, one
diastereoisomer), 7.56 7.51 AA' 2H; Tol, one diastereoisomer), 7.37 7.33
214
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Chem. Eur. J. 2002, 8, No. 1

Heterocyclic Cage Compounds
208 216
(BB', 2H; Tol, two diastereoisomers), 6.73 (dd, J ˆ 10 and 1.9 Hz, 1H; H-5,
one diastereoisomer), 6.44 (dd, J ˆ 10.1 and 1.9 Hz, 1H; H-5, one
diastereoisomer), 6.23 (d, J ˆ 10 Hz, 1H; H-6, one diastereoisomer), 6.02
(d, J ˆ 10.1 Hz, 1H; H-6, one diastereoisomer), 5.18 5.12 (m, 1H; H-8b,
two diastereoisomers), 4.95 (t, J ˆ 6.5 Hz, 1H; H-3a, two diastereoisomers),
3.25, 2.98 (ABsystem, J ˆ 14 Hz, 2H; CH2SOTol), 3.91 3.85 (m, 1H;
H-8a, one diastereoisomer), 3.40 3.03 (m, 1H; H-8a, one diastereoisom-
er), 3.08, 2.92 (ABX system, JAB ˆ 13.5 and JBX ˆ 5 Hz, 2H; two diaster-
(1S*,2R*,5S*,6R*,8S*,9R*)-8-Methyl-3,7-dioxatetracyclo[6.4.0.02,6.05,9]-
dodecane-4,11-dione (27): Compound 27 was obtained from a 1:1 mixture
of 14a and 14b (60 mg) by following the general method and purified by
1
crystallization (CH2Cl2/Hexane). Yield: 90%; m.p. 193 1948C; H NMR
(200 MHz): 5.27 (brt, J ˆ 4.9 Hz, 1H), 4.83 (dd, J ˆ 7.2 and 4.8 Hz, 1H),
2.93 (dd, J ˆ 11.3 and 4.8 Hz, 1H), 2.79 2.70 (m, 1H), 2.66 (t, J ˆ 2.0 Hz,
1H; H-9), 2.56 2.40 (m, 3H), 2.29 2.23 (m, 1H), 1.63 (s, 3H); 13C NMR
(75 MHz): 203.9, 174.8, 83.1, 81.0, 46.4, 45.6, 45.0, 37.3, 35.8, 17.8;
‡
eoisomers, H-8), 2.78, 2.65 (ABX system, JAB ˆ 17.1, JAX ˆ 5.7 and JBX
ˆ
HRMS(FAB ‡ ) calcd for C11H12O4 [M‡1] : m/z: 209.0813, found 209.0815.
(1S,2R,5S,6R,8R,9R)-8,9-dimethyl-3,7-dioxatetracyclo[6.4.0.02,9.05,9]do-
decane-4,11-dione (28): Compound 28 was obtained from 15a (40 mg)
according to the general method and purified by crystallization (AcOEt/
Hexane). Yield: 92%; m.p. 211 2128C; [a]2D0 ˆ ‡9 (c ˆ 0.6 in CHCl3);
1H NMR (200 MHz): 5.22 (brt, J ˆ 4.8 Hz, 1H; H-6), 4.81 (dd, J ˆ 6.6 and
4.8 Hz, 1H; H-2), 2.76 2.66 (m, 2H; H-10 and H-12), 2.49 2.41 (m, 2H;
H-5 and H-12), 2.28 2.16 (m, 2H; H-1 and H-10), 1.51 (s, 3H; C8-CH3),
1.12 (s, 3H; C9-CH3); 13C NMR (75 MHz): 204.4 (CO), 174.8 (CO), 85.2 (C-
8), 81.1 (C-6), 80.6 (C-2), 52.0 (C-5), 48.5 (C-9), 47.5 (C-1), 45.3 (C-10), 36.5
2 Hz, 2H; two diastereoisomers, H-2), 2.41 (3H; Tol, two diastereoiso-
mers); 13C NMR (50 MHz): 194.1, 193.9, 174.0, 173.8, 146.3, 145.9, 142.1,
140.5, 140.4, 130.9, 130.4, 130.2, 123.8, 86.7, 86.4, 68.0, 47.0, 44.2, 37.5, 37.4,
33.6, 33.3, 21.3, 20.9.
4-(tert-Butoxycarbonyl)amino-4-methylcyclohexa-2,5-dienone
(N-Boc-
24): A solution of N-(tert-Butoxycarbonyl)-p-benzoquinoneimine dimeth-
ylacetal 1,[16] (2.5 g, 9.4 mmol, 1 equiv) in THF (15 mL) was added via
cannula to a solution of MeLi (1.6m in diethyl ether, 6.7 ml, 10 mmol,
1.1 equiv) in THF (20 mL) at À788C. The mixture was stirred 5 h and then
hydrolyzed with a saturated aqueous solution of NH4Cl. The mixture was
concentrated with AcOEt, and the organic phase dried (Na2SO4) and
concentrated to dryness. The resulting acetal derivative was dissolved in
THF, and then an aqueous solution of oxalic acid (10%) was added at RT.
After 2 h of stirring, the solution was neutralized with saturated NaHCO3
and extracted with AcOEt. The organic phase was dried (Na2SO4) and
concentrated in vacuo. The crude product was recrystallized from AcOEt
as a white solid. Yield: 1.5 g, 70%; m.p. 1198C; 1H NMR (200 MHz): 6.80
(d, J ˆ 9.8 Hz, 2H; H-3 and H-5), 6.18 (dd, J ˆ 9.8 and 1.6 Hz, 2H; H-2 and
H-6), 1.34 (s, 3H; CH3), 1.33 (s, 9H; tBu); 13C NMR (75 MHz): 185.1 (CO),
152.4 (2C), 127.8 (2C), 80.5 (C-4), 52.0 (C-tBu), 28.1 (3C, tBu), 26.8 (CH3).
‡
(C-12), 25.6 (CH3), 14.8 (CH3); HRMS calcd for C12H14O4 [M] : m/z:
222.0892, found 222.0891.
Acknowledgement
¬
¬
¬
We thank the Direccion General de Investigacion CientÌfica y Tecnica
(Grant PB98 0062) for financial support. M.R. thanks the Ministerio de
¬
Educacion, Cultura y Deportes for a fellowship.
4-Amino-4-methylcyclohexa-2,5-dienone (24): TFA (10 equiv) was added
to a solution of N-Boc-24 (1.5 g, 6.7 mmol, 1 equiv) in CH2Cl2. The mixture
was stirred at RT for 1 h, and NaOH (2m) was added slowly at 08C until the
pH was basic. The mixture was extracted with AcOEt. The combined
extracts were washed with brine and dried (Na2SO4). After removal of the
solvent in vacuo, the residue was crystallized from AcOEt to give an unstable
white solid that must be used immediately after the synthesis. Yield:
585 mg, 71%; 1H NMR (200 MHz): 6.75 (dd, J ˆ 10.1 and 1.7 Hz; 2H), 5.98
(dd, J ˆ 10.1 and 2.0 Hz; 2H), 1.51 (brs, 1H; NH), 1.26 (s; 3H); 13C NMR
(75 MHz): 185.2 (CO), 154.9 (2C), 126.2 (2C), 50.4 (C-4), 26.9 (CH3).
[1] Reviews: a) L. F. Tietze, Chem. Rev. 1996, 96, 115 136; b) T.-L. Ho,
Tandem Organic Reactions, Wiley-Interscience, Chichester, 1992;
c) G. H. Posner, Chem. Rev. 1986, 86, 831 834.
[2] For recent references see: a) U. Jahn, M. M¸ller, S. Aussieker, J. Am.
Chem. Soc. 2000, 122, 5212 5213; b) C. Schneider, O. Reese, Angew.
Chem. 2000, 112, 3074 3076; Angew. Chem. Int. Ed. 2000, 39, 2948
2950; c) K. R. Prabhu, P. S. Sivanand, S. Chandrasekaran, Angew.
Chem. 2000, 112, 4486 4489; Angew. Chem. Int. Ed. Engl. 2000, 39,
4316 4319.
4-Hydroxy-4-methylcyclohexa-2,5-dienone (25):[8b] Compound 25 was
obtained by following the procedure used to synthesize N-Boc-24 starting
from p-benzoquinone dimethylacetal 23[24] (600 mg, 1 equiv) in THF
(15 mL) and MeLi (1.6m in ether) (2.6 mL, 1.1 equiv), and allowing them
to react for 3 h. The resulting acetal derivative was dissolved in THF, then
an aqueous solution of oxalic acid (10%) was added at RT. After 1.5 h of
stirring, the solution was neutralized with a saturated aqueous solution of
NaHCO3, followed by extraction with AcOEt. The organic phase was dried
(Na2SO4) and concentrated in vacuo. Purification by column chromatog-
raphy (AcOEt/hexane 3:2) gave 25 as a light yellow oil. Yield: 302 mg,
62%; 1H NMR (200 MHz): 6.83 (dd, J ˆ 8.4 and 1.6 Hz, 2H; H-3 and H-5),
5.98 (dd, J ˆ 8.4 and 1.8 Hz, 2H; H-2 and H-6), 1.39 (s, 3H, CH3).
[3] 2,5-Dialkylydenencyclopentanones: a) H.-J. Knˆlker, E. Baum, R.
Graf, P. G. Jones, O. Spiess, Angew. Chem. 1999, 111, 2742 2745;
Angew. Chem. Int. Ed. 1999, 38, 2583 2585; b) H.-J. Knˆlker, P. G.
Jones, R. Graf, Synlett 1996, 1155 1158.
[4] Acyclic 1,4-dienone derivatives: a) S. Giese, L. Kastrup, D. Stiens,
F. G. West, Angew. Chem. 1999, 111, 2046 2049; Angew. Chem. Int.
Ed. 2000, 39, 1970 1972; b) H. Hagiwara, A. Okano, H. Uda, J.
Chem. Soc. Chem. Commun. 1985, 1047.
[5] T. A. Engler, C. M. Scheibe, R. Iyengar, J. Org. Chem. 1997, 62, 8274
8275, and references therein.
ƒ
¬
¬
[6] a) M. C. Carreno, M. Perez Gonzalez, K. N. Houk, J. Org. Chem. 1997,
¬
¬
62, 9128 9137; b) M. C. Carrenƒo, M. Perez Gonzalez, J. Fischer,
Tetrahedron Lett. 1995, 36, 4893 4896.
General method for desulfinylation: Activated Raney-Ni (1 2 equiv) was
added at RT to a solution of the sulfinyl compound (1 equiv) in EtOH
(0.2m). The reaction was monitored by TLC. When the starting material
could no longer be observed, the mixture was filtrated through Celite.
Concentration of the filtrate in vacuo gave quantitative yield of the crude
desulfinylated compound. Purification was done by recrystallization (the
solvent is indicated in each case).
¬
¬
ƒ
[7] a) M. C. Carreno, M. Perez Gonzalez, M. Ribagorda, K. N. Houk, J.
ƒ
¬
Org. Chem. 1998, 63, 3687 3693; b) M. C. Carreno, M. Perez
Gonzalez, M. Ribagorda, J. Fischer, J. Org. Chem. 1996, 61, 6758
¬
6759.
[8] a) K. A. Swiss, D. C. Liotta, C. A. Maryanoff, J. Am. Chem. Soc. 1990,
112, 9393 9394; b) P. Wipf, Y. Kim, J. Am. Chem. Soc. 1994, 116,
11678 11688.
(1S,2S,5R,6S,8S,9S)-9,8-Dimethyl-3-oxa-7-azatetracyclo [6.4.0.02,6.05,9]-
dodecane-4,11-dione (26): Compound 26 was obtained from 13b (20 mg)
by following the general method and purified by recrystallization (AcOEt/
Hexane). Yield: 80%. [a]2D0 ˆ À8.5 (c ˆ 0.4 in CHCl3); 1H NMR
(200 MHz): 5.22 (brt, J ˆ 4.8 Hz, 1H; C-2), 4.81 (dd, J ˆ 6.6 and 4.8 Hz,
1H; C-6), 2.69, 2.23 (ABsystem, J ˆ 18.7 Hz, 2H; 2H-10), 2.65, 2.43 (ABX
system, J ˆ 17.7, 6.0, and 2.2 Hz, 2H; 2H-12), 2.31 (d, J ˆ 4.3 Hz, 1H; H-5),
2.17 2.10 (m, 1H; H-1), 1.38 (s, 3H; C8-CH3), 1.09 (s, 3H; C9-CH3);
13C NMR (75 MHz): 205.4 (CO), 176.3 (CO), 81.6 (C-2), 65.3 (C-8), 63.3 (C-
6), 52.5 (C-5), 48.3 (C-10), 47.8 (C-9), 45.2 (C-1), 36.5 (C-12), 25.8 (CH3),
[9] For a study of nucleophilicities of silyl enol ethers see: J. Burfeindt, M.
Patz, M. M¸ller, H. Mayr, J. Am. Chem. Soc. 1998, 120, 3629 3634.
[10] For a review of reactions of trialkylsilyloxyfurans, see: G. Casiraghi, G.
Rassu, Synthesis 1995, 607 626.
[11] For a recent instance, see: S. Hanessian, B. Reddy, Tetrahedron 1999,
55, 3427 3443.
[12] Cage compounds through domino reactions: a) D. Giomi, R. Nesi, S.
Turchi, E. Mura, J. Org. Chem. 2000, 65, 360 364; b) H.-C. Lin, H.-J.
Wu, Tetrahedron 2000, 56, 341 350, and references therein.
[13] By analogy with p-quinols, we use the name p-quinamines for the
4-amino analogues. Such a name was proposed in 1928 by Fries: K.
Fries, G. Ohemes, Justus Liebigs Ann. Chem. 1928, 462, 1 24.
‡
14.8 (CH3); HRMS calcd for C12H15NO3 (M ): m/z: 221.1051, found
221.1051.
Chem. Eur. J. 2002, 8, No. 1
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0801-0215 $ 17.50+.50/0
215

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M. C. Carreno et al.
FULL PAPER
¬
[21] E. Pretsch, T. Clerc, J. Seibl, W. Simon, Tablas para la Determinacion
[14] Enantiomeric excesses were determined by HPLC analysis of the
products by using commercially available chiral columns with
isopropylalcohol/hexanes as eluent: a) 99%ee (Chiralpack OD col-
umn); b) 99%ee (Chiralpack AD column).
¬
¬
¬
Estructural por Metodos Espectroscopicos, Springer Iberica, Barcelo-
na, 1998.
ƒ
[22] M. C. Carreno, J. L. GarcÌa Ruano, A. M. MartÌn, C. Pedregal, J. H.
¬
¬
¬
[15] G. Solladie, J. Hutt, A. Girardin, Synthesis 1987, 173 175.
RodrÌguez, A. Rubio, J. Sanchez, G. Solladie, J. Org. Chem. 1990, 55,
2120 2128.
ƒ
[16] M. C. Carreno, M. Ribagorda, J. Org. Chem. 2000, 65, 1231 1234.
[17] For a detailed discussion see reference [7a].
[23] This mixture gives Cl2Ti(OiPr)2 as reactive species: M. Reetz in
Organometallics in Synthesis–A Manual (Ed.: M. Schlosser), Wiley,
New York, 1994, pp. 198 282.
[18] Carbon numbering follows IUPAC nomenclature rules.
[19] Crystallographic data (excluding structure factors) have been depos-
ited with the Cambridge Crystallographic Data Centre as supple-
mentary publications no. CCDC 154385. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK, (fax: (‡44)123-336033; e-mail: deposit@
ccdc.cam.ac.uk).
ƒ
[24] F. Farina, M. C. Paredes, J. Valderrama, Tetrahedron Lett. 1992, 48,
4629 4640.
[25] D. R. Henton, R. L. McCreery, J. S. Swenton, J. Org. Chem. 1980, 45,
369 378.
[26] K. E. Harding, M. T. Coleman, L. T. Liu, Tetrahedron Lett. 1991, 32,
[20] R. Lett, A. Marquet, Tetrahedron 1974, 30, 3379 3392.
3795 3798.
Received: June 5, 2001 [F3312]
216
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0947-6539/02/0801-0216 $ 17.50+.50/0
Chem. Eur. J. 2002, 8, No. 1