Using heteroaryl-lithium reagents as hydroxycarbonyl anion equivalents in conjugate addition reactions with (S, S)-(+)-pseudoephedrine as chiral auxiliary; Enantioselective synthesis of 3-substituted pyrrolidines

Article abstract of DOI:10.1021/jo302438k

We have developed an efficient protocol for carrying out the stereocontrolled formal conjugate addition of hydroxycarbonyl anion equivalents to α,β-unsaturated carboxylic acid derivatives using (S,S)-(+)-pseudoephedrine as chiral auxiliary, making use of the synthetic equivalence between the heteroaryl moieties and the carboxylate group. This protocol has been applied as key step in the enantioselective synthesis of 3-substituted pyrrolidines in which, after removing the chiral auxiliary, the heteroaryl moiety is converted into a carboxylate group followed by reduction and double nucleophilic displacement. Alternatively, the access to the same type of heterocyclic scaffold but with opposite absolute configuration has also been accomplished by making use of the regio- and diastereoselective conjugate addition of organolithium reagents to α,β,γ,δ-unsaturated amides derived from the same chiral auxiliary followed by chiral auxiliary removal, ozonolysis, and reductive amination/intramolecular nucleophilic displacement sequence.

Full text of DOI:10.1021/jo302438k

Article
pubs.acs.org/joc
Using Heteroaryl-lithium Reagents as Hydroxycarbonyl Anion
Equivalents in Conjugate Addition Reactions with (S,S)‑(+)-
Pseudoephedrine as Chiral Auxiliary; Enantioselective Synthesis of
3‑Substituted Pyrrolidines
Beatriz Alonso, Marta Ocejo, Luisa Carrillo,* Jose L. Vicario,* Efraim Reyes, and Uxue Uria
́
Departamento de Química Organica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko Unibertsitatea
UPV/EHU, P.O. Box 644, E-48080 Bilbao, Spain
S
* Supporting Information
ABSTRACT: We have developed an efficient protocol for
carrying out the stereocontrolled formal conjugate addition of
hydroxycarbonyl anion equivalents to α,β-unsaturated carbox-
ylic acid derivatives using (S,S)-(+)-pseudoephedrine as chiral
auxiliary, making use of the synthetic equivalence between the
heteroaryl moieties and the carboxylate group. This protocol
has been applied as key step in the enantioselective synthesis
of 3-substituted pyrrolidines in which, after removing the chiral
auxiliary, the heteroaryl moiety is converted into a carboxylate
group followed by reduction and double nucleophilic displace-
ment. Alternatively, the access to the same type of heterocyclic
scaffold but with opposite absolute configuration has also been
accomplished by making use of the regio- and diastereose-
lective conjugate addition of organolithium reagents to α,β,γ,δ-unsaturated amides derived from the same chiral auxiliary followed
by chiral auxiliary removal, ozonolysis, and reductive amination/intramolecular nucleophilic displacement sequence.
INTRODUCTION
■
The pyrrolidine skeleton is a structural motif shared by many
different natural products and synthetic bioactive compounds.1
The ubiquitous occurrence of this heterocyclic moiety either as
itself or as a part of a more complex chemical entity has led to
active research toward the development of efficient procedures
for the stereocontrolled preparation of pyrrolidines incorporat-
ing different substitution patterns.2 In this context, simple 3-
alkyl- or 3-aryl-substituted pyrrolidines constitute a particularly
interesting subgroup of compounds with interesting pharmaco-
logic activities. Representative examples are depicted in Figure
1 and include several well-known pharmaceuticals such as
premafloxacin,3 an antibiotic for veterinary use that has also
shown potential for fighting against several cases of bacterial
resistance to commonly used antibiotics; β-homoproline,4
which is a conformationally restrained γ-amino acid that acts
as a potent inhibitor of the neuronal and glial uptake
mechanism of γ-aminobutyric acid neurotransmitter; and also
the antidepressant rolipram,5 which is based on a related 3-
Figure 1. Some representative examples of important 3-alkyl and 3-
aryl pyrrolidines.
arylpyrrolidin-2-one structure. In addition, this type of structure
can also be found in a few natural products such as, for
proceeding via enamine formation.7 However, despite their
example, leptothoracine and other simple N-alkylated 3-
methylpyrrolidines,6 which have been isolated from the poison
potential as lead compounds for drug discovery or as promising
gland of ants of the Leptothorax gender (Myrmicinae family). In
addition, β-proline and homoproline derivatives have also
found recent applicability as organocatalysts in several reactions
Received: November 9, 2012
Published: December 21, 2012
© 2012 American Chemical Society
614
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
candidates to be used as organocatalysts, the number of reports
dealing with the development of procedures for the
enantioselective preparation of these simple 3-substituted
pyrrolidine scaffolds is significantly smaller,8−10 especially
compared with the huge amount of information appearing in
the literature focused on the stereocontrolled preparation of
other more elaborated pyrrolidines.
shown in this Scheme, simultaneous disconnection of the two
C−N bonds shows that the pyrrolidine skeleton can be built up
from a conveniently functionalized diol that, in turn, should be
accessible from a highly enantioenriched 2-substituted 4-
hydroxybutanoate derivative. The enantioselective preparation
of this key intermediate was envisaged to be carried out by
conjugate addition of an heteroaryl-lithium reagent to α,β-
unsaturated amides that incorporates (S,S)-(+)-pseudoephe-
drine as the stereocontrolling element, also having in mind the
known feasibility of converting the heteroaryl moiety into a
carboxylate by means of an oxidative cleavage process.13 It has
to be pointed out that, in overall, this initial synthetic plan
called for the development of a convenient protocol for
carrying out the formal conjugate addition of hydroxycarbonyl
anion to α,β-unsaturated acid derivatives making use of the
synthetic equivalence between the heteroaryl moiety and the
carboxylate group and also by exploiting our background
knowledge on the use of pseudoephedrine as chiral auxiliary
linked to the Michael acceptor in conjugate addition
reactions.14
In general, the existing methodologies reported to date for
the stereoselective preparation of 3-alkyl or 3-aryl pyrrolidines
can be classified into two main different approaches. Most
reports focus on the construction of the five-membered
heterocyclic moiety by a ring-closure process,8 typically
involving an intramolecular reaction starting from a conven-
iently functionalized acyclic substrate that incorporates the
required functionalities that will interact between each other in
the cyclization reaction. Alternatively this ring-closing process
can also consist of a [3 + 2] cycloaddition reaction,9 in which
the simultaneous formation of two C−C bonds accounts for
the formation of the heterocyclic ring. The second most
frequently used approach comprises the functionalization of
commercially available pyrrolidines and related derivatives such
as proline, pyrrolidin-2-ones, or maleimides among others.10
We wish to report herein our efforts directed toward the
development of a practical and efficient protocol for the
preparation of 3-alkyl or 3-aryl pyrrolidines as highly
enantioenriched materials with a focus on their possible
applicability as efficient organocatalysts for transformations
proceeding via either enamine or iminium ion formation.11 For
this reason, we also decided to design a synthetic approach that
should be flexible enough to allow the incorporation of
substituents of different size and nature at the 3-position of the
pyrrolidine ring and that also should allow the enantioselective
preparation of both enantiomers, if possible, by using the same
chirality source. In this context, we planned the access to these
compounds by taking into account the possible application of
our previously reported methodology for carrying out the
conjugate addition of organometallic reagents to conjugated
amides using (S,S)-(+)-pseudoephedrine as chiral auxiliary as
key reaction with regard to the installation of the stereocenter
present at the final compounds (Scheme 1).12 In this report, we
As an alternative approach, we also planned access to the
same type of compounds by making use of our recently
reported methodology for carrying out the conjugate addition
of organolithium reagents to α,β,γ,δ-unsaturated amides also
incorporating the same chiral β-aminoalcohol (S,S)-(+)-pseu-
doephedrine as auxiliary (Scheme 2).15 In this case, the
Scheme 2
Scheme 1
simultaneous formation of the two C−N bonds for building up
the heterocycle was planned to be carried out by a cascade
reductive amination/intramolecular nucleophilic substitution
sequence, which in turn refers back to an α-substituted 4-
hydroxybutanal derivative as suitable precursor. We envisaged
that the formyl group at this key substrate could be formed by
ozonolysis starting from the corresponding alkene, the later
being accessible in a stereocontrolled fashion by applying our
aforementioned methodology for carrying out the regio- and
diastereoselective 1,4-addition of organolithium reagents to the
2,4-hexadienamide derived from (S,S)-(+)-pseudoephedrine.
It should be pointed out at this point that, comparing these
two approaches depicted in Schemes 1 and 2, in the second one
the alkyl/aryl substituent of the final 3-substituted pyrrolidine
would be incorporated at the organolithium reagent during the
conjugate addition reaction to the dienamide substrate, whereas
in the first one this substituent is supposed to be already
installed at the initial Michael acceptor, which has to be used as
the starting material. As a consequence of this and to the fact
that in both cases the same chirality source is intended to be
employed as stereocontrolling element in the generation of the
stereocenter that ultimately will be present at the 3-substituted
have shown that organolithiums add selectively in a 1,4-fashion
to α,β-unsaturated amides incorporating this chiral amino-
alcohol, furnishing the corresponding conjugate addition
products in good yields and diastereoselectivities, and therefore
we initially designed a first synthetic approach for the
preparation of a 3-substituted pyrrolidine derivatives according
to the retrosynthetic analysis indicated in Scheme 1. As is
615
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
Table 1. Diastereoselective Conjugate Addition of Heteroaryl-lithium Reagents to Crotonamide 1a Derived from (S,S)-
(+)-Pseudoephedrine
a
b
c
entry
HetArLi
product
additive
solvent
T (°C)
yield (%)
dr
d
1
2 (2 equiv)
2 (4 equiv)
2 (4 equiv)
2 (4 equiv)
2 (6 equiv)
2 (10 equiv)
2 (6 equiv)
2 (6 equiv)
2 (6 equiv)
3 (6 equiv)
4 (6 equiv)
4 (4 equiv)
5a
5a
5a
5a
5a
5a
5a
5a
5a
6a
7a
7a
LiCl (5 equiv)
LiCl (5 equiv)
LiCl (5 equiv)
None
THF
THF
THF
THF
THF
THF
THF
Toluene
Et2O
THF
THF
THF
−105
−105
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
<5
17
30
40
54
40
40
56
23
50
88
46
nd
2
96:4
3
96:4
4
86:14
96:4
5
LiCl (5 equiv)
LiCl (5 equiv)
TMEDA (6 equiv)
LiCl (5 equiv)
LiCl (5 equiv)
LiCl (5 equiv)
LiCl (5 equiv)
LiCl (5 equiv)
6
96:4
7
77:23
90:10
82:18
96:4
8
9
10
11
12
96:4
96:4
a
The heteroaryl-lithium reagents were prepared in situ by metalation of the corresponding heteroaryl bromide with n-BuLi for 1 h at 0 °C in the
b
c
required solvent. Yield after flash column chromatography. Determined by HPLC analysis of crude reaction mixture under conditions optimized
for a 1:1 mixture of C-4 epimers as standard (see Supporting Information). nd: not determined.
d
pyrrolidine skeleton, both approaches should result to be
enantiodivergent, each one providing the final pyrrolidine
compounds with opposite absolute configuration at their
stereocenter. This increases the synthetic utility of our
methodology.
diastereoselectivity (entry 3), and the key role played by the
presence of LiCl as an additive in the dr of the reaction was
confirmed with the results shown in entry 4 compared to entry
3 (the dr was increased from 86:14 to 96:4), which is also in
good agreement with what we had already found in the same
reaction with other organolithium reagents.12 Better yield of
conjugate addition product 5a was obtained by increasing the
amount of furyl-lithium to 6 equiv (entry 5), but no further
improvement was observed when a higher amount was
employed (entry 6). We also tested the use of TMEDA as
additive with the aim to increase the reactivity of the
organolithium reagent but with no success (entry 7). Also the
use of other solvents such as toluene or diethyl ether was
surveyed, but in those cases the diastereoselectivity of the
reaction decreased (entries 8 and 9). The use of more
nucleophilic furyl-lithium reagent such as 3 was next surveyed
(entry 10), and it was observed that, in this case, and under the
best reaction conditions found up to this moment (those
shown in entry 5), the reaction proceeded with similar yield
and diastereoselectivity. Remarkably, changing to the use of 2-
thienyl-lithium (4) as nucleophile led to an important
improvement in the yield of the reaction, maintaining an
excellent level of stereocontrol (entry 11). We finally tried to
carry out the reaction using lower amounts of the organo-
lithium reagent, but once again, lowering the amount of
nucleophile resulted in a drop in the yield of the reaction (entry
12).
RESULTS AND DISCUSSION
■
We started our work with the implementation of the synthetic
approach shown in Scheme 1, in which heteroaryl-lithium
reagents were planned to be used as hydroxycarbonyl anion
equivalents in conjugate addition reactions to α,β-unsaturated
enamides derived from (S,S)-(+)-pseudoephedrine. For this
reason, we started with the optimization of the reaction
conditions for this initial transformation using different
heteroaryl-lithium reagents as nucleophiles and (S,S)-(+)-pseu-
doephedrine crotonamide 1a as model substrate (Table 1).
Initially, we proceeded with the use of 2-furyl-lithium (2),
which was found to be the most widely used hydroxycarbonyl
anion equivalent in the literature.13 Disappointingly, when we
carried out the reaction between 2 and 1a under the reaction
conditions already reported by us12 for the general conjugate
addition of organolithium reagents to the same type of α,β-
unsaturated amides (5 equiv of LiCl as additive, in THF at
−105 °C, entry 1), no reaction was observed to occur,
providing unchanged starting material 1a after 7 h reaction
time. This result contrasts with the parent reaction using
phenyl-lithium, which we had observed to proceed in 86% yield
after 7 h reaction time (see ref 12). A small amount of the
expected conjugate addition product 5a was obtained when the
reaction was carried out using an excess of furyl-lithium reagent
(entry 2), and remarkably, in this case the reaction was also
found to proceed with an excellent level of diastereoselection.
The yield could be slightly improved by increasing the
temperature of the reaction with no negative effect on the
After all of these experiments we decided to survey the scope
of the reaction with regard to the substitution pattern at the
Michael acceptor, with the results shown in Table 2. In all cases
we assumed that the best reaction conditions for the
transformation were those shown in entries 5, 10, and 11 of
Table 1, which involved working in THF at −78 °C and in the
presence of LiCl as an additive. As can be seen in Table 2, when
616
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
substituted α,β-unsaturated carbonyl compounds toward
conjugate addition. The use of thienyl-lithium 4 led to better
results, providing good yields in all cases in which β-alkyl-
substituted α,β-unsaturated amides 1a−c were employed as
substrates (entries 9−11). Moreover, in this case, even though
the yield was also found to decrease when the size of the β-alkyl
substituent was increased, the effect was not as striking as when
we used heteroaryl-lithium reagents 2 and 3. Importantly, the
diastereoselectivity was not affected by the substitution pattern
at the α,β-unsaturated amide, and it was observed in all cases
that the reaction proceeded with excellent levels of stereo-
control. Finally, we could also carry out the reaction in this case
using cinnamide 1d as substrate (entry 12), providing the
corresponding conjugate addition product with only a 22%
yield but with excellent diastereoselectivity.
Table 2. Diastereoselective Conjugate Addition of
Heteroaryl-lithium Reagents to α,β-Unsaturated Amides
Derived from (S,S)-(+)-Pseudoephedrine 1a−d
a
b
c
entry HetArLi
R1
R2
X
product yield (%)
dr
1
2
2
2
2
3
3
3
3
4
4
4
4
Me
Et
H
O
O
O
O
O
O
O
O
S
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
54
41
32
<5
50
44
39
<5
85
74
72
22
96:4
96:4
2
H
de
,
3
n-Pr
Ph
H
nd
nd
d
4
H
We next focused on the conversion of the heteroaryl moiety
into the target carboxylic group by the projected oxidative
cleavage of the heterocyclic ring (Scheme 3). We started by
subjecting furyl- and thienyl-containing adducts 5a and 7a to
standard conditions reported for converting electron-rich
aromatic groups into the carboxylate functionality,16 which
involved the use of NaIO4 as the oxidant in the presence of a
catalytic amount of RuCl3·xH2O, observing that a clean reaction
proceeded leading to the formation of a cleavage product in
which, in addition, the secondary alcohol moiety present at the
pseudoephedrine core had also undergone oxidation. We were
not able to completely purify this product, and for this reason,
we submitted the crude reaction mixture obtained after the
oxidative cleavage process to standard hydrolytic conditions,
leading to the formation of succinic acid (not isolated), which
was further subjected to esterification, forming dimethyl
succinate in ca. 20% overall yield for the three-step sequence.
We could use this sequence of reactions for the determination
of the absolute configuration of the stereogenic center created
during the conjugate addition step by chemical correlation.
Comparison of the obtained [α]20 value for 8 ([α]20 = +4.0
5
Me
Et
Me
Me
Me
Me
H
96:4
94:4
96:4
6
7
n-Pr
Ph
d
8
nd
9
Me
Et
96:4
97:3
97:3
97:3
10
11
12
H
S
n-Pr
Ph
H
S
H
S
a
The heteroaryl-lithium reagents were prepared in situ by metalation
of the corresponding heteroaryl bromide with n-BuLi for 1 h at 0 °C in
b
c
THF. Yield after flash column chromatography. Determined by
HPLC analysis of crude reaction mixture under conditions optimized
for a 1:1 mixture of C-4 epimers as standard (see Supporting
d
e
Information). nd: not determined. We were not able to find
conditions for the separation of two epimers.
furyl-lithium-type organolithium reagents 2 and 3 were
employed (entries 1−8), the yields were in all cases found to
be moderate at best, and also a dramatic drop in this parameter
was observed when progressively increasing the size of the β-
substituent at the α,β-unsaturated enamide from R1 = methyl to
R1 = ethyl and n-propyl (entries 1−3 and 5−7). Nevertheless,
with regard to stereocontrol, the reaction performed excellently,
furnishing high levels of diastereoselection in all cases. On the
other hand, when these organolithiums were tested as
nucleophiles in the conjugate addition with cinnamide 1d, no
reaction was observed even after prolonged stirring (entries 4
and 8), which was attributed to the lower reactivity of β-aryl-
D
D
(c 0.7, CH2Cl2)) with the reported in the literature for (R)-
dimethylsuccinate ([α]20D = +3.1 (c 2.9, CH2Cl2))17 allowed us
to establish the absolute configuration of 8 as (2R), which
could be extended by analogy to the rest of the adducts 5a−d,
6a−d, and 7a−d obtained in the asymmetric conjugate addition
of heteroaryl-lithium reagents to α,β-unsaturated amides 1a−d
derived from (S,S)-(+)-pseudoephedrine. This absolute config-
uration is also in agreement with previous results in our group
Scheme 3
617
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
dealing with the conjugate addition of different types of
nucleophiles to α,β-unsaturated carbonyl compounds using
pseudoephedrine as chiral auxiliary.12
This was finally converted into 3-methylpyrrolidines 16a and
16b by double nucleophilic displacement upon heating to 80
°C in the presence of benzylamine and tosylamide, respectively.
Optical purity of the final compounds was checked by chiral
HPLC on N-tosyl derivative 16b for which conditions could be
found for HPLC separation of the corresponding racemic
standard on a chiral stationary phase. The high ee obtained for
this compound matched that obtained for amides 5a and 7a
from which this compound was prepared and in which the
stereocenter had been installed by means of the diastereose-
lective conjugate addition of furyl-lithium and thienyl-lithium to
amide 1a. This final result indicates that all of the trans-
formations carried out on the adducts 5 and 7 proceeded with
no racemization.
At the same time, we also evaluated the alternative synthetic
approach proposed previously to reach the target 3-substituted
pyrrolidines, which has been previously outlined in Scheme 2
and which made use of the conjugate addition of organolithium
reagents to polyunsaturated amides derived from (S,S)-
(+)-pseudoephedrine as the key step with regard to the
stereocontrolled installation of the stereocenter. It should be
remembered here that this approach would lead to the
formation of the final 3-substituted pyrrolidines with
configuration opposite to that obtained for 16a and 16b.
We therefore started with the preparation of adducts 18a−d,
which were prepared by carrying out the conjugate addition
reaction of different alkyl-lithium reagents to α,β,γ,δ-unsatu-
rated amide 17, under our previously reported conditions
(Scheme 5 and Table 3).15 The reaction proceeded with good
yields and high diastereoselectivity, and as was pointed out in
our previous report, we observed only the exclusive formation
of the desired 1,4-addition products, and no byproduct arising
from the potential competitive 1,2- or 1,6-addition was formed
for the organolithium compounds used in this study. In this
respect, it should be noted that the reaction could not be
carried out using MeLi as the organolithium reagent (which
would lead after the complete synthetic route to the
corresponding 3-methylpyrrolidine) because in this case the
reaction furnished only the undesired 1,2-addition product, as
we had already stated previously.15 Nevertheless, with adducts
18a−d in hand, we next carried out the removal of the chiral
auxiliary by LAB-mediated reduction, isolating the correspond-
ing primary alcohols 19a−d in excellent yields in all cases.
Proceeding with the synthesis, these alcohols 19a−d were
mesylated, and the olefin moiety was converted into a formyl
group by the projected ozonolysis reaction, which proceeded
smoothly providing mesylated chiral α-substituted γ-hydrox-
yaldehydes 21a−d in excellent yields.
Alternatively, we also explored the possibility of carrying out
the oxidative cleavage of the heterocyclic moiety after removing
the chiral auxiliary in order to avoid the oxidation of the latter
(Scheme 3). For this reason, we proceeded first to carry out the
reduction of the pseudoephedrine amide moiety by using
lithium triamidoborate (LAB) under previously reported
conditions,18 obtaining primary alcohols 9a and 10a−d in
excellent yields in all cases. Next, these alcohols were protected
as the corresponding TBDPS-ethers 11a and 12a−c, and these
were subsequently subjected to oxidative cleavage conditions,
leading to the formation of the corresponding protected γ-
hydroxyacid derivatives 13a−c in good overall yields, although
in some cases the reaction also furnished minor amounts of the
corresponding unprotected derivative 13′ together with the
target compounds.
Once the protocol for using heteroaryl-lithium reagents as
hydroxycarbonyl anion equivalents undergoing stereocontrolled
conjugate addition using pseudoephedrine as chiral auxiliary
had been implemented, we next focused on the synthesis of our
target 3-substituted pyrrolidines by using this methodology as
key step with regard to the installation of the stereocenter.
Therefore, and according to what was planned based on the
retrosynthetic analysis shown in Scheme 1, we took O-TBDPS-
protected γ-hydroxy acid 13a and proceeded to carry out the
reduction of the carboxylate in order to obtain the
corresponding primary alcohol 14, which was subsequently
deprotected and reacted in situ with excess methanesulfonyl
chloride, leading to the formation of dimesylate 15 (Scheme 4).
Scheme 4
Scheme 5
618
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
Table 3. Conjugate Addition of Organolithium Reagents to Enamide 17 and Synthesis of Protected α-Substituted 4-
Hydroxyaldehydes 21
a
b
c
a
d
d
d
entry
R
product
yield (%)
dr
product
yield (%)
product
yield (%)
product
yield (%)
1
2
3
4
n-Bu
i-Pr
t-Bu
Ph
18a
18b
18c
60
65
86
80
88:12
88:12
93:7
19a
19b
19c
19d
91
94
80
99
20a
20b
20c
20d
90
91
94
99
21a
21b
21c
21d
80
85
99
85
18d
97:3
a
b
c
Results described in ref 15. Combined yield for both diastereoisomers after column chromatography purification. Determined by HPLC analysis
d
of crude reaction mixture under conditions optimized for a 1:1 mixture of epimers as standard (see Supporting Information). Yield after flash
column chromatography.
Scheme 6
We next faced the final reductive amination/cyclization step
that should lead directly to the formation of the target 3-
substituted pyrrolidines (Scheme 6), for which p-methoxyben-
zylamine was selected as the amine component in the reductive
amination step because of the known good ability of this group
to undergo hydrogenolysis faster than the parent benzyl group.
However, this final reductive amination/cyclization step
required some optimization because when this transformation
was carried out under the typical in situ Borch conditions or by
generating first the corresponding p-methoxybenzylimine
followed by NaBH4 reduction in a one-pot procedure at 0
°C, the final products were isolated with a significant decrease
in their enantiopurity when compared with the dr of their
corresponding precursors. When we tried to perform this imine
formation/NaBH4 reduction process at lower temperatures,
low conversions were observed even after prolonged reaction
times. For this reason and working under the hypothesis that
racemization was taking place by the presence of the imine/
enamine tautomeric equilibrium, we decided to apply modified
reaction conditions for this transformation that involved
formation of the imine at very low temperature (−78 °C),
which would in principle slow down the aforementioned
imine/enamine equilibrium, allowing reduction to take place
without racemization of the starting material. Working at such
low temperatures during the formation of the imine
intermediate required the incorporation of TiCl4 as Lewis
acid for the activation of the formyl moiety, which also
participates as water-scavenging reagent.19 After imine for-
mation was complete, NaBH4 was added to the reaction
mixture, and reduction of the imine and the subsequent
intramolecular nucleophilic displacement took place smoothly,
providing directly N-p-methoxybenzylated pyrrolidines 22a−d
in good yields and maintaining the stereochemical integrity of
the stereocenter present at the starting material. The optical
purity of the final pyrrolidines was determined after conversion
into the corresponding N-tosyl derivatives by hydrogenolytic
cleavage of the p-methoxybenzyl group followed by in situ
tosylation. This also established a procedure for removing the
N-alkyl substituent that also ensured our capability to obtain
free NH-containing 3-substituted pyrrolidines, which in this
particular case could not be isolated for purification and
characterization because of their high volatility.
CONCLUSIONS
■
In conclusion we have demonstrated that thienyl-lithium and
furyl-lithium can be employed as hydroxycarbonyl anion
equivalents in stereocontrolled conjugate addition reactions
using the aminoalcohol (S,S)-(+)-pseudoephedrine as chiral
auxiliary by making use of the chemical equivalency of these
heterocyclic moieties with the carboxylate group by means of
oxidative cleavage. This methodology has been successfully
applied to the synthesis of 3-substituted pyrrolidines by a set of
simple transformations, and alternatively, we have also shown
that the opposite enantiomers of the same type of chiral
heterocycles can also be accessed from the same chirality source
by means the regio- and diastereoselective conjugate addition of
organolithium reagents to α,β,γ,δ-unsaturated amides derived
from (S,S)-(+)-pseudoephedrine under conditions previously
developed in our group, followed by chiral auxiliary removal,
ozonolysis, and reductive amination/intramolecular nucleo-
philic displacement sequence.
EXPERIMENTAL SECTION
■
General Procedure for the Conjugate Addition of Hetero-
aryl-lithiums. A solution of organolithium (6.0 mmol) was carefully
added to a suspension of the corresponding enamide 1a−d (1.00
mmol) and LiCl (5.0 mmol) in dry THF (15 mL) at −78 °C, and the
reaction was stirred at this temperature for 4−7 h (TLC monitoring).
The mixture was allowed to warm to rt and quenched with a saturated
NH4Cl solution (15 mL). The mixture was extracted with CH2Cl2 (3
× 10 mL), the combined organic fractions were collected, dried over
Na2SO4, and filtered, and the solvent was removed in vacuo affording
the wanted amides after flash column chromatography purification.
(+)-(3R,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-3-
(furan-2-yl)-N-methylbutanamide (5a). Following the general
procedure amide 5a was prepared from enamide 1a (500 mg, 2.14
mmol), LiCl (460 mg, 10.7 mmol), and 2-furyl-lithium (17.0 mL of a
in situ prepared 0.74 M solution, 12.8 mmol) using dry THF (15 mL)
as solvent and isolated after FC purification (n-hexane/AcOEt 1:1) in
1
54% yield (350 mg, 1.16 mmol). H NMR (300 MHz, CDCl3) δ
(proportion of rotamers 1:3, *denotes minor rotamer signals): 0.95*
(d, 3H, J = 6.7 Hz), 1.05 (d, 3H, J = 6.7 Hz), 1.25−1.29 (m, 2H), 2.42
619
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
(dd, 1H, J = 15.1, 7.7 Hz), 2.70 (dd, 1H, J = 15.1, 6.3 Hz), 2.77 (s,
3H), 2.90* (s, 3H), 3.38−3.41 (m, 1H), 3.42−3.60* (m, 1H), 3.95−
4.09 (m, 1H), 4.10−4.18 (bs, 1H), 4.49−4.55 (m, 2H), 5.99 (d, 1H, J
= 3.1 Hz), 6.00* (d, 1H, J = 3.1 Hz), 6.16−6.26 (m, 1H), 7.21−7.32
(m, 6H). 13C NMR (75 MHz, CDCl3) δ (proportion of rotamers 1:3,
*denotes minor rotamer signals): 14.5, 15.4*, 19.0, 30.1, 40.1, 58.4,
58.9, 76.5, 104.0, 110.1, 126.5, 126.9*, 127.6, 128.3*, 128.7, 138.7,
141.7, 142.0, 142.8*, 159.1, 159.5*, 173.0*, 173.7. IR (cm−1): 3385
(OH), 1625 (CO). HRMS calcd for [C18H23NO3]+: 301.1678 (M+),
found 301.1683. MS (70 eV) m/z (%): 301 (12, M+), 194 (40), 148
(16), 126 (21), 121 (18), 95 (56), 81 (23), 79 (28), 72 (100), 67 (30),
59 (53). The dr (96:4) was determined by HPLC using Chiralpak IA
column, n-hexane/i-PrOH 97:3, flow rate 1.0 mL/min; τmajor = 61.98
4.05* (m, 1H), 4.17−4.30 (bs, 1H), 4.22−4.52 (m, 1H), 5.83−5.87
(m, 2H), 7.30−7.33 (m, 6H). 13C NMR (75 MHz, CDCl3) δ
(proportion of rotamers 1:3, *denotes minor rotamer signals): 13.5,
14.4, 15.3*, 18.9*, 19.0, 26.8, 30.2, 32.5*, 39.3*, 40.1, 57.9*, 58.4,
75.3*, 76.5, 104.3*, 104.5, 105.8, 126.4, 127.0*, 127.6, 128.3, 128.6*,
141.4*, 142.3, 150.3, 157.3, 157.9*, 172.5*, 173.7. IR (cm−1): 3385
(OH), 1625 (CO). HRMS calcd for [C19H25NO3]+: 315.1834 (M+),
found 315.1830. MS (70 eV) m/z (%): 315 (8, M+), 282 (100), 208
(38), 149 (30), 135 (82), 109 (89), 83 (42), 77 (20). The dr (96:4)
was determined by HPLC using Chiralpak IA column, n-hexane/i-
PrOH 97:3, flow rate 1.0 mL/min; τmajor = 32.95 min, τminor = 23.55
min. [α]20 +79.5 (c 1.02, CH2Cl2).
D
(+)-(3R,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-N-
methyl-3-(5-methylfuran-2-yl)pentanamide (6b). Following the
general procedure amide 6b was prepared from enamide 1b (100 mg,
0.40 mmol), LiCl (93 mg, 2.0 mmol), and (5-methylfuran-2-yl)lithium
(4.0 mL of a in situ prepared 0.60 M solution, 2.40 mmol) using dry
THF (15 mL) as solvent and isolated after FC purification (n-hexane/
min, τminor = 54.30 min. [α]20 +71.3 (c 0.92, CH2Cl2).
D
(+)-(3R,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-3-
(furan-2-yl)-N-methylpentanamide (5b). Following the general
procedure amide 5b was prepared from enamide 1b (100 mg, 0.40
mmol), LiCl (95 mg, 2.0 mmol), and 2-furyl-lithium (3.3 mL of a in
situ prepared 0.74 M solution, 2.4 mmol) using dry THF (15 mL) as
solvent and isolated after FC purification (n-hexane/AcOEt 1:1) in
41% yield (50 mg, 0.17 mmol). 1H NMR (300 MHz, CDCl3) δ
(proportion of rotamers 1:3, *denotes minor rotamer signals): 0.84 (t,
3H, J = 7.3 Hz), 0.95* (d, 3H, J = 6.7 Hz), 1.00 (d, 3H, J = 6.7 Hz),
1.59−1.68 (m, 2H), 2.51 (dd, 1H, J = 15.1, 6.5), 2.66 (dd, 1H, J =
15.1, 7.7 Hz), 2.72 (s, 3H), 2.88* (s, 3H), 3.18−3.23 (m, 1H), 3.25−
3.35* (m, 1H), 3.99−4.11* (m, 1H), 4.12−4.44 (bs, 1H), 4.49−4.57
(m, 2H), 6.00 (d, 1H, J = 2.8 Hz), 6.06* (d, 1H, J = 2.1 Hz), 6.25−
6.28 (m, 1H), 7.23−7.39 (m, 6H). 13C NMR (75 MHz, CDCl3) δ
(proportion of rotamers 1:3, *denotes minor rotamer signals): 11.8,
14.2, 15.0*, 26.9, 37.5, 37.1, 38.5, 58.4, 76.5, 105.5, 110.1, 126.4,
126.9*, 127.6, 128.3, 128.7*, 140.9, 142.2, 157.3, 173.9. IR cm−1: 3381
(OH), 1620 (CO). HRMS calcd for [C19H25NO3]+: 315.1834 (M+),
found 315.1842. MS (70 eV) m/z (%): 315 (13, M+), 206 (21), 147
(60), 121 (64), 109 (50), 91 (25), 83 (100), 77 (22), 65 (16). The dr
(96:4) was determined by HPLC using Chiralpak IA column, n-
1
AcOEt 1:1) in 44% yield (60 mg, 0.18 mmol). H NMR (300 MHz,
CDCl3) δ (proportion of rotamers 1:3, *denotes minor rotamer
signals): 0.85 (t, 3H, J = 7.2 Hz), 0.94* (d, 3H, J = 6.7 Hz), 1.01 (d,
3H, J = 6.7 Hz), 1.58−1.69 (m, 2H), 2.23 (s, 3H), 2.48 (dd, 1H, J =
15.0, 6.7 Hz), 2.63 (dd, 1H, J = 15.0, 7.5 Hz), 2.75 (s, 3H), 2.87* (s,
3H), 3.09−3.14 (m, 1H), 3.17−3.30* (m, 1H), 3.95−4.10* (m, 1H),
4.16−4.19 (bs, 1H), 4.42−4.54 (m, 2H), 5.82−5.92 (m, 2H), 7.24−
7.34 (m, 5H). 13C NMR (75 MHz, CDCl3) δ (proportion of rotamers
1:3, *denotes minor rotamer signals): 11.7, 13.5, 14.4, 15.3*, 26.7*,
26.8, 37.2*, 37.4, 37.4*, 37.6, 38.6, 58.2*, 58.4, 75.3*, 76.4, 105.8,
106.0, 126.4, 126.9*, 127.3, 128.3, 128.6*, 141.2*, 142.3, 148.5*,
150.3, 156.1*, 156.1, 172.6*, 174.2. IR (cm−1): 3377 (OH), 1619
(CO). HRMS calcd for [C20H27NO3]+: 329.1991 (M+), found
329.1984. MS (70 eV) m/z (%): 329 (17, M+), 282 (100), 222
(23), 148 (21), 135 (76), 123 (41), 84 (18). The dr (96:4) was
determined by HPLC using Chiralpak IA column, n-hexane/i-PrOH
97:3, flow rate 1.0 mL/min; τmajor = 43.85 min, τminor = 38.43 min.
[α]20 +59.6 (c 0.98, CH2Cl2).
hexane/i-PrOH 97:3, flow rate 1.0 mL/min; τmajor = 56.28 min, τminor
=
43.65 min. [α]20 +71.4 (c 1.00, CH2Cl2).
(+D)-(3R,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-N-
methyl-3-(5-methylfuran-2-yl)hexanamide (6c). Following the
general procedure amide 6c was prepared from enamide 1c (100 mg,
0.38 mmol), LiCl (90 mg, 1.9 mmol), and (5-methylfuran-2-yl)lithium
(4.0 mL of a in situ prepared 0.60 M solution, 2.40 mmol) using dry
THF (15 mL) as solvent and isolated after FC purification (n-hexane/
D
(+)-(3R,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-3-
(furan-2-yl)-N-methylhexanamide (5c). Following the general
procedure amide 5c was prepared from enamide 1c (100 mg, 0.38
mmol), LiCl (90 mg, 1.98 mmol), and 2-furyl-lithium (3.1 mL of a in
situ prepared 0.74 M solution, 2.4 mmol) using dry THF (15 mL) as
solvent and isolated after FC purification (n-hexane/AcOEt 1:1) in
32% yield (40 mg, 0.12 mmol). 1H NMR (300 MHz, CDCl3) δ
(proportion of rotamers 1:3, *denotes minor rotamer signals): 0.88 (t,
3H, J = 7.2 Hz), 0.99 (d, 3H, J = 6.9 Hz), 1.15−1.39 (m, 2H), 1.54−
1.84 (m, 2H), 2.34−2.66 (m, 2H), 2.70 (s, 3H), 2.86* (s, 3H), 3.28−
3.35 (m, 1H), 3.36−3.50* (m, 1H), 4.02−4.09 (bs, 1H), 4.18−4.30*
(m, 1H), 4.41−4.57 (m, 2H), 6.00−6.05 (m, 1H), 6.25−6.28 (m, 1H),
7.25−7.39 (m, 6H). 13C NMR (75 MHz, CDCl3) δ (proportion of
rotamers 1:3, *denotes minor rotamer signals): 13.9, 14.3*, 14.4,
15.3*, 20.4, 25.3, 35.5, 35.6*, 35.9*, 36.1, 37.9*, 38.8, 64.3, 75.3*,
76.4, 105.0*, 105.4, 109.9*, 110.0, 126.5, 126.9*, 127.7, 128.4, 128.7*,
140.8, 142.3, 157.4, 159.4*, 172.8*, 173.9. IR cm−1: 3379 (OH), 1620
(CO). HRMS calcd for [C20H27NO3]+: 329.1991 (M+), found
329.1987. MS (70 eV) m/z (%): 329 (16, M+), 268 (99), 222 (31),
148 (30), 121 (67), 85 (96), 83 (100), 81 (37), 71 (20). [α]20D +72.6
(c 0.92, CH2Cl2).
1
AcOEt 1:1) in 39% yield (50 mg, 0.15 mmol). H NMR (300 MHz,
CDCl3) δ (proportion of rotamers 1:3, *denotes minor rotamer
signals): 0.86 (t, 3H, J = 7.2 Hz), 0.94* (d, 3H, J = 6.7 Hz), 0.98 (d,
3H, J = 6.7 Hz), 1.01−1.39 (m, 2H), 1.54−1.63 (m, 2H), 2.23 (s, 3H),
2.47 (dd, 1H, J = 14.9, 6.7 Hz), 2.64 (dd, 1H, J = 14.9, 7.4 Hz), 2.75
(s, 3H), 2.88* (s, 3H), 3.19−3.24 (m, 1H), 3.26−3.40* (m, 1H),
4.00−4.10* (m, 1H), 4.12−4.19 (bs, 1H), 4.42−4.57 (m, 2H), 5.82−
5.91 (m, 2H), 7.23−7.34 (m, 5H). 13C NMR (75 MHz, CDCl3) δ
(proportion of rotamers 1:3, *denotes minor rotamer signals): 13.5,
13.9, 14.0*, 14.4, 15.3*, 20.4, 35.3*, 35.6, 35.8, 36.0, 36.3*, 38.9,
58.2*, 58.4, 75.3*, 76.5, 105.6*, 105.8, 105.9, 126.5, 127.0*, 127.6,
128.3, 128.5*, 142.3, 150.2, 157.7, 174.0. IR (cm−1): 3374 (OH), 1620
(CO). HRMS calcd for [C21H29NO3]+: 343.2147 (M+), found
343.2146. MS (70 eV) m/z (%): 343 (15, M+), 282 (100), 234
(29), 147 (79), 137 (51), 135 (89), 107 (38), 95 (90), 71 (32). The dr
(96:4) was determined by HPLC using Chiralpak IA column, n-
hexane/i-PrOH 97:3, flow rate 1.0 mL/min;
(+)-(3R,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-N-
methyl-3-(5-methylfuran-2-yl)butanamide (6a). Following the
general procedure amide 6a was prepared from enamide 1a (100 mg,
0.34 mmol), LiCl (46 mg, 1.7 mmol), and (5-methylfuran-2-yl)lithium
(3.4 mL of a in situ prepared 0.60 M solution, 2.06 mmol) using dry
THF (15 mL) as solvent and isolated after FC purification (n-hexane/
(+)-(3R,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-N-
methyl-3-(thien-2-yl)butanamide (7a). Following the general
procedure amide 7a was prepared from enamide 1a (100 mg, 0.42
mmol), LiCl (46 mg, 1.7 mmol), and thienyl-lithium (2.6 mL of a 1 M
solution, 2.6 mmol) using dry THF (15 mL) as solvent and isolated
after FC purification (n-hexane/AcOEt 1:1) in 85% yield (115 mg,
1
AcOEt 1:1) in 50% yield (53 mg, 0.17 mmol). H NMR (300 MHz,
1
CDCl3) δ (proportion of rotamers 1:3, *denotes minor rotamer
signals): 0.94* (d, 3H, J = 6.7 Hz), 1.04 (d, 3H, J = 6.7 Hz), 1.25 (d,
3H, J = 6.9 Hz), 2.23 (s, 3H), 2.38 (dd, 1H, J = 15.0, 7.8 Hz), 2.48*
(dd, 1H, J = 15.2, 8.8 Hz), 2.67 (dd, 1H, J = 15.0, 6.8 Hz), 2.77 (s,
3H), 2.89* (s, 3H), 3.28−3.38 (m, 1H), 3.39−3−51* (m, 1H), 4.00−
0.36 mmol). H NMR (300 MHz, CDCl3) δ (proportion of rotamers
1:3, *denotes minor rotamer signals): 0.97* (d, 3H, J = 6.7 Hz), 1.03
(d, 3H, J = 6.7 Hz), 1.33−1.41 (m, 3H), 2.51 (dd, 1H, J = 15.1, 7.4
Hz), 2.64 (dd, 1H, J = 15.2, 6.6 Hz), 2.77 (s, 3H), 2.91* (s, 3H),
3.65−3.71 (m, 1H), 3.71−3.83* (m, 1H), 4.00−4.03 (m, 1H), 4.10−
620
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
4−18 (bs, 1H), 4.47−4.59 (m, 2H), 6.83 (d, 1H, J = 3.5 Hz), 6.86* (d,
1H, J = 6.4 Hz), 6.90 (dd, 1H, J = 5.0, 3.5 Hz), 6.92 (dd, 1H, J = 5.0,
0.9 Hz), 7.11−7.36 (m, 5H). 13C NMR (75 MHz, CDCl3) δ
(proportion of rotamers 1:3, *denotes minor rotamer signals): 14.5,
15.4*, 22.8, 26.9, 32.1, 32.3*, 43.2*, 43.5, 58.3*, 58.4, 75.2*, 76.4,
122.7, 122.8, 123.0*, 126.5, 126.6, 126.7*, 128.4, 128.7, 141.2*, 142.3,
150.4, 151.0*, 172.5*, 173.5. IR (cm−1): 3376 (OH), 1619 (CO).
HRMS calcd for [C18H24NO2S]+: 318.1527 [(M + H)+], found
318.1529. MS (70 eV) m/z (%): 318 [24, (M + H)+], 300 (100), 210
(35), 148 (26). The dr (96:4) was determined by HPLC using
Chiralpak IA column, n-hexane/i-PrOH 97:3, flow rate 1.0 mL/min;
Hz) 7.26−7.40 (m, 10H). 13C NMR (75 MHz, CDCl3) δ (proportion
of rotamers 1:3, *denotes minor rotamer signals): 14.2, 15.2*, 27.1,
41.1*, 41.7, 42.8, 43.1*, 58.1*, 58.4, 75.4*, 76.1, 123.7, 124.3, 126.6,
127.0, 127.7*, 127.8, 128.3, 128.4, 128.5, 128.6, 128.7*, 142.0, 143.7,
144.1*, 148.1, 172.7. IR (cm−1): 3395 (OH), 1620 (CO). HRMS
calcd for [C23H25NO2S]+: 379.1606 (M+), found 379.1608. MS (70
eV) m/z (%): 379 (4, M+), 339 (12), 338 (29), 337 (100), 317 (64),
183 (12), 139 (29), 97 (3). The er (97:3) was determined after
transformation to the alcohol 10d. [α]20 +50.2 (c 0.99, CH2Cl2).
Synthesis of (R)-Dimethyl 2-MeDthylsucccinate (8). To a
solution of amide 7a (0.08 g, 2,5 mmol) in CCl4/CH3CN/H2O
1:1:1.7 at room temperature were added NaIO4 (0.86 g, 37.5 mmol)
and RuCl3·H2O, in a catalytic amount. After 1 h of stirring, the layers
were separated, and the aqueous phase was extracted with CH2Cl2 (3
× 10 mL). The organic fractions were dried over Na2SO4 and filtered
through Celite. The solvent was removed in vacuo to yield the
corresponding carboxylic acid. This carboxylic acid intermediate was
dissolved in 1,4-dioxane (10 mL), the solution was cooled to 0 °C, and
H2SO4 4 M (10 mL) was slowly added. The mixture was refluxed for
12 h after which it was cooled to rt. Water was added (20 mL), and the
mixture was extracted with CH2Cl2 (3 × 10 mL). The organic
fractions were dried over Na2SO4, and the solvent was removed in
vacuo to yield the corresponding diacid compound, which was directly
subject to esterification by addition of TMSCHN2 (10 mmol) to a
cooled solution (0 °C) of the crude diacid in dry THF (10 mL). After
2 h, MeOH (2 mL) was added at once, and the mixture was stirred for
a further 45 min after which it was quenched with water (10 mL). The
mixture was extracted with CH2Cl2 (3 × 10 mL). The organic
fractions were dried over Na2SO4, and the solvent was removed in
vacuo to yield succinate 8 after flash column chromatography
τmajor = 33.29 min, τminor = 27.25 min. [α]20 +59.6 (c 0.98, CH2Cl2).
D
(+)-(3R,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-N-
methyl-3-(thien-2-yl)pentanamide (7b). Following the general
procedure amide 7b was prepared from enamide 1b (100 mg, 0.40
mmol), LiCl (70 mg, 2.0 mmol), and thienyl-lithium (2.4 mL of a 1 M
solution, 2.4 mmol) using dry THF (15 mL) as solvent and isolated
after FC purification (n-hexane/AcOEt 1:1) in 74% yield (99 mg, 0.30
1
mmol). H NMR (300 MHz, CDCl3) δ (proportion of rotamers 1:3,
*denotes minor rotamer signals): 0.86 (t, 3H, J = 7.3 Hz), 0.96 (d, 3H,
J = 6.5 Hz), 1.55−1.65 (m, 1H), 1.72−1.79 (m, 1H), 2.57 (d, 1H, J =
7.3 Hz), 2.58 (d, 1H, J = 6.7 Hz), 2.72 (s, 3H), 2.85* (s, 3H), 3.39−
3.44 (m, 1H), 3.49−3.57* (m, 1H) 3.99−4.19 (m, 1H), 4.17−4.25
(bs, 1H), 4.45−4.52 (m, 2H), 6.81 (d, 1H, J = 3.4 Hz), 6.89 (dd, 1H, J
= 5.0, 3.4 Hz), 7.06 (d, 1H, J = 5.0 Hz), 7.23−7.34 (m, 5H). 13C NMR
(75 MHz, CDCl3) δ (proportion of rotamers 1:3, *denotes minor
rotamer signals): 12.0, 14.4, 15.4*, 30.1*, 30.3, 39.2, 39.4, 41.3*, 42.0,
58.1*, 58.4, 76.4, 122.9, 122.9*, 124.2, 126.5, 126.6*, 126.9, 127.5,
128.3, 128.6*, 141.2*, 142.4, 148.4, 148.9*, 172.3*, 173.5. IR (cm−1):
3419 (OH), 1620 (CO). HRMS calcd for [C19H26NO2S]+: 332.1684
[(M + H)+], found 332.1678. MS (70 eV) m/z (%): 332 [32, (M +
H)+], 315 (19), 314 (100), 225 (8), 224 (37), 148 (20). The dr (97:3)
1
purification in 20% yield (80 mg, 0.50 mmol). H NMR (300 MHz,
CDCl3) δ: 1.20 (d, 3H, J = 7.1 Hz), 2.39 (dd, 1H, J = 16.4, 6.1 Hz),
2.73 (dd, 1H, J = 16.4, 8.2 Hz), 2.87−2.94 (m, 1H), 3.66 (s, 1H), 3.68
(s, 1H). 13C NMR (75 MHz, CDCl3) δ: 16.9, 35.7, 37.4, 51.7, 51.9,
172.3, 175.7. IR (cm−1): 1639, 1675 (CO). HRMS calcd for
[C7H12O4]+: 160.0736 (M+), found 160.0733. MS (70 eV) m/z
(%): 101 (82), 74 (17), 59 (90), 72 (20), [α]20D +4.0 (c 0.7, CHCl3);
was determined after transformation to the alcohol 10b. [α]20 +43.2
D
(c 0.98, CH2Cl2).
(+)-(3R,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-N-
methyl-3-(thien-2-yl)hexanamide (7c). Following the general
procedure amide 7c was prepared from enamide 1c (100 mg, 0.38
mmol), LiCl (65 mg, 1.90 mmol), and thienyl-lithium (2.3 mL of a 1
M solution, 2.3 mmol) using dry THF (15 mL) as solvent and isolated
after FC purification (n-hexane/AcOEt 1:1) in 72% yield (95 mg, 0.27
lit.17 [α]20 +3.1 (c 2.9, CHCl3).
D
General Procedure for Reduction of Amides 5 and 7. n-BuLi
(4.54 mmol) was added over a solution of diisopropylamine (4.36
mmol) in dry THF (10 mL) at −78 °C, and the mixture was stirred
for 15 min. The reaction was warmed to 0 °C, and BH3·NH3 (4.45
mmol) was added at once. The mixture was stirred for 15 min at 0 °C
and another 15 min at room temperature, after which a solution of the
amide (0.89 mmol) in THF (5 mL) was added via canula at 0 °C and
the reaction was stirred for 2 h. Then the reaction was quenched with
1 M HCl (15 mL) and extracted with AcOEt (3 × 15 mL). The
organic fractions were collected, washed with satd NaHCO3, dried
over Na2SO4, and filtered, and the solvent was removed in vacuo,
affording alcohols as a colorless oil after flash column chromatography
purification.
(−)-(R)-3-(Furan-2-yl)butan-1-ol (9a). Following the general
procedure 9a was prepared starting from enamide 5a (1.00 g, 3.32
mmol), n-BuLi (17.0 mL of a 1 M solution, 17.0 mmol), i-Pr2NH
(2.28 mL, 16.2 mmol), and BH3·NH3 (0.504 g, 16.6 mmol) and was
isolated after FC purification (n-hexane/AcOEt 7:3) in 75% yield (350
mg, 2.50 mmol). 1H NMR (300 MHz, CDCl3) δ: 1.26 (d, 3H, J = 7.0
Hz), 1.70−1.90 (m, 3H), 2.94−2.98 (m, 1H), 3.55−3.68 (m, 2H),
5.98 (d, 1H, J = 2.6 Hz), 6.26−6.28 (dd, 1H, J = 2.6, 1.8 Hz), 7.25−
7.30 (bs, 1H). 13C NMR (75 MHz, CDCl3) δ: 19.3, 29.8, 38.7, 70.6,
103.7, 109.9, 140.8, 159.9. IR (cm−1): 3447 (OH). HRMS calcd for
[C8H13O2]+: 141.0915 [(M + H)+], found 141.0900. MS (70 eV) m/z
(%): 141 [26, (M + H)+], 123 (93), 122 (34), 95 (100). [α]20D −23.0
(c 0.99, CH2Cl2).
1
mmol). H NMR (300 MHz, CDCl3) δ (proportion of rotamers 1:3,
*denotes minor rotamer signals): 0.89 (t, 3H, J = 7.3 Hz), 0.99 (d, 3H,
J = 6.9 Hz), 1.22−1.34 (m, 2H), 1.55−1.73 (m, 2H), 2.59 (d, 1H, J =
6.5 Hz), 2.60 (d, 1H, J = 7.4 Hz), 2.73 (s, 3H), 2.87* (s, 3H), 3.52−
3.57 (m, 1H), 3.58−3.72 (bs, 1H), 3.99−4.05 (m, 1H), 4.42−4.57 (m,
2H), 6.82 (d, 1H, J = 3.3 Hz), 6.86* (d, 1H, J = 3.0 Hz), 6.90 (dd, 1H,
J = 4.5, 3.3 Hz), 6.97 (d, 1H, J = 4.5 Hz), 7.22−7.36 (m, 5H). 13C
NMR (75 MHz, CDCl3) δ (proportion of rotamers 1:3, *denotes
minor rotamer signals): 13.9, 14.4, 15.3*, 20.6, 26.5, 37.3*, 37.5, 39.4*,
39.5, 41.6*, 42.4, 58.4, 76.2, 122.8, 122.9, 124.0*, 124.2, 126.4, 126.6*,
126.9, 127.7, 128.3, 128.7*, 142.3, 148.8, 172.2*, 173.8. IR (cm−1):
3382 (OH), 1617 (CO). HRMS calcd for [C20H28NO2S]+: 346.1763
[(M + H)+], found 346.1741. MS (70 eV) m/z (%): 346 [46, (M +
H)+], 329 (28), 328 (100), 225 (8), 238 (33), 148 (10). The dr (97:3)
was determined after transformation to the alcohol 10c. [α]20 +58.7
D
(c 1.00, CH2Cl2).
(+)-(3S,1′S,2′S)-N-(1′-Hydroxy-1′-phenylpropan-2′-yl)-N,4,4-
trimethyl-3-phenyl-3-(thien-2-yl)propanamide (7d). Following
the general procedure amide 7d was prepared from enamide 1d (100
mg, 0.34 mmol), LiCl (60 mg, 1.85 mmol), and thienyl-lithium (2.0
mL of a 1 M solution, 2.0 mmol) using dry THF (15 mL) as solvent
and isolated after FC purification (n-hexane/AcOEt 1:1) in 22% yield
1
(28 mg, 0.07 mmol). H NMR (300 MHz, CDCl3) δ (proportion of
rotamers 1:3, *denotes minor rotamer signals): 0.73* (d, 3H, J = 6.7
Hz), 0.98 (d, 3H, J = 6.7 Hz), 2.33−2.41* (bs, 1H), 2.76 (s, 3H),
2.84* (s, 3H), 3.04 (d, 1H, J = 7.3 Hz), 3.07 (d, 1H, J = 8.3 Hz), 3.13*
(dd, 1H, J = 7.3, 5.2 Hz), 3.25* (dd, 1H, J = 15.0, 7.3 Hz), 3.70−3.90
(bs, 1H), 3.91−4.05* (m, 1H), 4.35−4.60 (m, 2H), 4.93 (dd, 1H, J =
7.4, 7.3 Hz), 6.82 (d, 1H, J = 3.6 Hz), 6.86* (d, 1H, J = 3.2 Hz), 6.92
(dd, 1H, J = 5.0, 3.6 Hz), 6.94−6.99* (m, 1H), 7.15 (d, 1H, J = 5.0
(−)-(R)-3-(Thien-2-yl)butan-1-ol (10a). Following the general
procedure 10a was prepared starting from enamide 7a (1.0 g, 3.32
mmol), n-BuLi (17 mL of a 1 M solution, 17.0 mmol), i-Pr2NH (2.28
mL, 16.2 mmol), and BH3·NH3 (500 mg, 16.6 mmol) using dry THF
(15 mL) as solvent and was isolated after FC purification (n-hexane/
1
AcOEt 7:3) in 78% yield (404 mg, 2.59 mmol). H NMR (300 MHz,
621
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
CDCl3) δ: 1.36 (d, 3H, J = 6.9 Hz), 1.86 (d, 1H, J = 6.6 Hz), 1.91 (d,
1H, J = 6.7 Hz), 2.23 (bs, 1H), 3.20−3.28 (m, 1H), 3.58−3.69 (m,
2H), 6.82−6.84 (m, 1H), 6.92 (dd, 1H, J = 5.0, 3.4 Hz), 7.07 (dd, 1H,
J = 5.0, 1.0 Hz). 13C NMR (75 MHz, CDCl3) δ: 23.3, 31.9, 42.0, 60.7,
122.6, 122.8, 126.5, 151.2. IR (cm−1): 3443 (OH). HRMS calcd for
[C8H13SO]+: 157.0687 [(M + H)+], found 157.0694. MS (70 eV) m/z
(%): 157 [18, (M + H)+], 156 (14, M+), 139 (100), 138 (12), 97 (56).
[α]20 −18.3 (c 1.01, CH2Cl2).
FC purification (n-hexane/AcOEt 9:1) in 84% yield (0.759 g, 2.00
mmol). 1H NMR (300 MHz, CDCl3) δ: 1.15 (s, 9H), 1.35 (d, 3H, J =
7.0 Hz), 1.89−1.92 (m, 1H), 2.10−2.17 (m, 1H), 3.20−3.27 (m, 1H),
3.80−3.85 (m, 2H), 6.03−6.05 (m, 1H), 6.36 (dd, 1H, J = 3.0, 1.9
Hz), 7.46−7.53 (m, 7H), 7.80−7.84 (m, 4H). 13C NMR (75 MHz,
CDCl3) δ: 19.3, 19.4, 27.0, 29.8, 38.7, 61.8, 103.7, 109.9, 127.7, 127.8,
129.6, 129.7, 134.0, 134.1, 135.5, 135.5, 140.7, 160.3. HRMS calcd for
[C24H31SiO2]+: 379.2093 [(M + H)+], found 379.2084. MS (70 eV)
(−D)-(R)-3-(Thien-2-yl)pentan-1-ol (10b). Following the general
procedure 10b was prepared starting from enamide 7b (100 mg, 0.30
mmol), n-BuLi (1.54 mL of a 1 M solution, 1.54 mmol), i-Pr2NH
(0.21 mL, 1.48 mmol), and BH3·NH3 (0.045 g, 1.51 mmol) using dry
THF (15 mL) as solvent and was isolated after FC purification (n-
hexane/AcOEt 7:3) in 75% yield (38 mg, 0.23 mmol). 1H NMR (300
MHz, CDCl3) δ: 0.86 (t, 3H, J = 7.3 Hz), 1.30 (bs, 1H), 1.53−1.80
(m, 3H), 1.82−2.05 (m, 1H), 3.20−3.30 (m, 1H), 3.49−3.77 (m, 2H),
6.81 (d, 1H, J = 3.1 Hz), 6.93 (dd, 1H, J = 5.1, 3.1 Hz), 7.15 (d, 1H, J
= 5.1 Hz). 13C NMR (75 MHz, CDCl3) δ: 11.9, 30.9, 39.4, 40.2, 60.9,
122.9, 123.9, 126.5, 149.1. IR (cm−1): 3456 (OH). HRMS calcd for
[C9H15OS]+: 171.0843 [(M + H)+], found 171.0851. MS (70 eV) m/z
(%): 171 [21, (M + H)+], 170 (37, M+), 153 (62), 141 (28), 126 (14),
125 (92), 111 (58), 97 (100), 85 (7). The er (97:3) was determined
by HPLC using Chiralcel OJ column, n-hexane/i-PrOH 95:5, flow rate
1.0 mL/min; τmajor = 8.96 min, τminor = 7.71 min. [α]20D −14.5 (c 1.00,
CH2Cl2).
m/z (%): 321 (100), 302 (18), 301 (79), 123 (36). [α]20 −12.0 (c
D
1.00, CH2Cl2).
(−)-(R)-tert-Butyldiphenyl-[3-(thien-2-yl)butoxy]silane (12a).
Following the general procedure 12a was prepared starting from
alcohol 10a (0.350 g, 2.24 mmol), TBDPSiCl (1.35 mL, 4.93 mmol),
imidazol (0.380 g, 5.60 mmol), and DMAP (cat.) and was isolated
after FC purification (n-hexane/AcOEt 8:2) in 95% yield (0.84 g, 2.13
mmol). 1H NMR (300 MHz, CDCl3) δ: 1.19 (s, 9H), 1.42 (d, 3H, J =
6.9 Hz), 1.97−2.00 (m, 2H), 3.42−3.49 (m, 1H), 3.76−3.82 (m, 2H),
6.86−6.89 (m, 1H), 7.00 (dd, 1H, J = 5.1, 3.4 Hz), 7.19 (dd, 1H, J =
5.1, 1.1 Hz,), 7.46−7.80 (m, 6H), 7.74−7.83 (m, 4H). 13C NMR (75
MHz, CDCl3) δ: 19.4, 23.4, 27.0, 31.7, 42.0, 61.8, 122.5, 122.8, 126.5,
127.7, 127.8, 129.6, 129.7, 134.0, 134.1, 135.5, 135.5, 151.6. HRMS
calcd for [C24H31OSSi]+: 395.1865 [(M + H)+], found 395.1852. MS
(70 eV) m/z (%): 395 [5, (M + H)+], 338 (18), 337 (100), 318 (14),
317 (67), 183 (7), 139 (32). [α]20 −8.1 (c 0.97, CH2Cl2).
(−)-(R)-tert-Butyldiphenyl-[D3-(thien-2-yl)pentoxy]silane
(12b). Following the general procedure 12b was prepared starting
from alcohol 10b (0.250 g, 1.47 mmol), TBDPSiCl (0.95 mL, 3.67
mmol), imidazol (0.300 g, 4.41 mmol), and DMAP (cat.) and was
isolated after FC purification (n-hexane/AcOEt 9:1) in 93% yield
(0.558 g, 1.36 mmol). 1H NMR (300 MHz, CDCl3) δ: 0.92 (t, 3H, J =
7.3 Hz), 1.13 (s, 9H), 1.51−2.05 (m, 3H), 2.05−2.20 (m, 1H), 3.13−
3.18 (m, 1H), 3.66−3.77 (m, 2H), 6.78−6.82 (m, 1H), 6.96 (dd, 1H, J
= 5.0, 3.4 Hz), 7.17 (dd, 1H, J = 5.0, 0.8 Hz), 7.30−7.51 (m, 6H),
7.60−7.77 (m, 4H). 13C NMR (75 MHz, CDCl3) δ: 12.0, 19.3, 26.9,
30.8, 39.2, 42.1, 61.7, 122.7, 123.9, 126.4, 127.6, 127.7, 129.5, 129.7,
134.0, 134.1, 135.6, 135.6, 149.5. HRMS calcd for [C25H33OSSi]+:
409.2021 [(M + H)+], found 409.2039. MS (70 eV) m/z (%): 409 [5,
(M + H)+], 353 (15), 351 (100), 331 (78), 199 (10), 183 (14),
(−)-(R)-3-(Thien-2-yl)hexan-1-ol (10c). Following the general
procedure 10c was prepared starting from enamide 7c (0.49 g, 1.43
mmol), n-BuLi (7.20 mL of a 1 M solution, 7.20 mmol), i-Pr2NH
(0.98 mL, 6.95 mmol), and BH3·NH3 (0.216 g, 7.10 mmol) using dry
THF (50 mL) as solvent and was isolated after FC purification (n-
hexane/AcOEt 7:3) in 76% yield (0.20 g, 1.08 mmol). 1H NMR (300
MHz, CDCl3) δ: 0.88 (t, 3H, J = 7.3 Hz), 1.25−1.30 (m, 2H), 1,59−
1.96 (m, 5H), 3.04−3.08 (m, 1H), 3.51−3.63 (m, 2H), 6.80 (d, 1H, J
= 3.3 Hz), 6.91 (dd, 1H, J = 5.0, 3.3 Hz), 7.14 (d, 1H, J = 5.0 Hz). 13C
NMR (75 MHz, CDCl3) δ: 13.9, 20.5, 37.5, 40.3, 40.5, 60.8, 122.8,
123.9, 126.4, 149.2. IR (cm−1): 3339 (OH). HRMS calcd for
[C10H17OS]+: 185.1000 [(M + H)+], found 185.0985. MS (70 eV) m/
z (%): 185 [5, (M + H)+], 153 (62), 141 (28), 126 (14), 125 (92),
111 (58), 97 (100), 85 (7). The er (97:3) was determined by HPLC
using Chiralcel OJ column, n-hexane/i-PrOH 95:5, flow rate 1.0 mL/
min; τmajor = 8.96 min, τminor = 7.71 min. [α]20D −6.5 (c 1.16, CH2Cl2).
(−)-(S)-3-Phenyl-3-(thien-2-yl)propan-1-ol (10d). Following
the general procedure 10d was prepared starting from enamide 7d
(100 mg, 0.26 mmol), n-BuLi (1.34 mL of a 1 M solution, 1.34 mmol),
i-Pr2NH (0.18 mL, 1.29 mmol), and BH3·NH3 (0.040 g, 1.32 mmol)
using dry THF (15 mL) as solvent (41 mg, 0.18 mmol) and was
isolated after FC purification (n-hexane/AcOEt 7:3) in 72% yield (41
mg, 0.18 mmol). 1H NMR (300 MHz, CDCl3) δ: 2.25−2.43 (m, 2H),
3.58−3.64 (m, 2H), 4.40 (t, 1H, J = 7.7 Hz), 6.86−6.88 (m, 1H),
6.91−6.94 (m, 1H), 7.14−7.17 (m, 2H), 7.23−7.32 (m, 5H). 13C
NMR (75 MHz, CDCl3) δ: 39.9, 42.0, 60.7, 123.7, 123.9, 126.6, 126.7,
126.9, 128.0, 146.1, 148.9. IR (cm−1): 3440 (OH). HRMS calcd for
[C13H15OS]+: 219.0843 [(M + H)+], found 219.0843. MS (70 eV) m/
z (%) 219 [10, (M + H)+], 218 (38, M+), 200 (25), 173 (100), 141
(13), 135 (90), 117 (20), 105 (49), 91 (17). (The er (97:3) was
determined by HPLC using Chiralcel OJ column, n-hexane/i-PrOH
90:10, flow rate 1.0 mL/min; τmajor = 49.37 min, τminor = 40.76 min.).
153(28). [α]20 −7.1 (c 1.80, CH2Cl2).
D
(−)-(R)-tert-Butyldiphenyl-[3-(thien-2-yl)hexoxy]silane (12c).
Following the general procedure 12c was prepared starting from
alcohol 10c (0.150 g, 0.82 mmol), TBDPSiCl (0.53 mL, 2.03 mmol),
imidazol (0.166 g, 2.44 mmol), and DMAP (cat.) and was isolated
after FC purification (n-hexane/AcOEt 9:1) in 90% yield (0.311 g,
1
0.738 mmol). H NMR (300 MHz, CDCl3) δ: 0.93 (t, 3H, J = 7.3
Hz), 1.13 (s, 9H), 1.31−1.36 (m, 2H), 1.55−1.65 (m, 2H), 1.69−1.74
(m, 1H), 1.85−2.05 (m, 1H), 3.15−3.36 (m, 1H), 3.56−3.81 (m, 2H),
6.78 (d, 1H, J = 3.0 Hz), 6.94 (dd, 1H, J = 4.9, 3.5 Hz), 7.15 (d, 1H, J
= 4.9 Hz), 7.33−7.52 (m, 6H), 7.65−7.75 (m, 4H). 13C NMR (75
MHz, CDCl3) δ: 14.0, 19.3, 20.5, 26.9, 37.1, 40.2, 40.5, 61.6, 122.6,
123.8, 126.3, 127.6, 127.7, 129.5, 129.6, 134.0, 134.1, 135.6, 135.6,
149.8. HRMS calcd for [C26H35OSSi]+: 423.2178 [(M + H)+], found
423.2198. MS (70 eV) m/z (%): 423 [9, (M + H)+], 365 (100), 345
(95), 265 (20), 199 (20), 183 (30), 165(12). [α]20 −7.0 (c 1.48,
D
CH2Cl2).
General Procedure for the Synthesis of Carboxylic Acids 13.
To a solution of the silane 12 (25 mmol) in H2O/CH3CN/CCl4
1.7:1:1 at room temperature were added NaIO4 (375 mmol) and
RuCl3·H2O (cat.). The reaction was stirred at that temperature for 1 h
and then was quenched with NH4Cl (5 mL) and extracted with
CH2Cl2 (3 × 15 mL). The organic fractions were collected, dried over
Na2SO4, and filtered through Celite, and the carboxylic acid 13 was
isolated after the solvent was removed in vacuo.
[α]20 +6.5 (c 1.00, CH2Cl2).
D
General Procedure for the Synthesis of Silanes 11 and 12.
To a solution of the alcohol 9 or 10 (2.5 mmol) in dry THF were
added TBDPSCl (5.0 mmol), imidazole (5.60 mmol), and DMAP
(cat.). The reaction was stirred at room temperature for 18 h, and then
it was quenched with NH4Cl (5 mL) and extracted with CH2Cl2 (3 ×
15 mL). The organic fractions were collected, dried over Na2SO4, and
filtered, and the solvent was removed in vacuo, affording the silane
after flash column chromatography purification.
(−)-(R)-tert-Butyldiphenyl-[3-(furan-2-yl)butoxy]silane (11a).
Following the general procedure 11a was prepared starting from
alcohol 9a (0.330 g, 2.36 mmol), TBDPSiCl (1.35 mL, 5.18 mmol),
imidazol (0.40 g, 5.89 mmol), and DMAP (cat.) and was isolated after
(R)-4-(tert-Butyldiphenylsililoxy)-2-methylbutyric Acid
(13a).20 Following the general procedure 13a was prepared starting
from 12a (0.65 g, 1.72 mmol), NaIO4 (5.51 g, 25.8 mmol), and
1
RuCl3·H2O (cat.) in 78% yield (0.478 g, 1.34 mmol). H NMR (300
MHz, CDCl3) δ: 0.96 (s, 9H), 1.17 (d, 3H, J = 7.0 Hz), 1.62−1.70 (m,
1H), 2.00−2.09 (m, 1H), 2.72−2.79 (m, 1H), 3.68−3.74 (m, 2H),
7.26−7.44 (m, 6H), 7.62−7.71 (m, 4H). 13C NMR (75 MHz, CDCl3)
622
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
δ: 16.8, 19.1, 26.8, 35.8, 36.1, 61.5, 127.7, 129.6, 133.6, 133.7, 134.6,
135.6, 182.3. HRMS calcd for [C21H28O3Si]+: 356.1808 (M+), found
356.1794. MS (70 eV) m/z (%): 356 (4, M+), 297 (100), 277 (86),
259 (23), 219 (14), 199 (23).
General Procedure for the Synthesis of Pyrrolidines 16. A
mixture of the dimesilate 15 (0.23 mmol) and the corresponding
amine (1.48 mmol) was warmed at 80 °C. After 8 h the reaction was
cooled to room temperature and was solved in CH2Cl2 (5 mL) and
satd NaHCO3 (5 mL). The organic fractions were collected, dried
over Na2SO4, and filtered, and the solvent was removed in vacuo,
affording the pyrrolidines 16 after flash column chromatography
purification.
(−)-(R)-4-(tert-Butyldiphenylsililoxy)-2-ethylbutyric Acid
(13b). Following the general procedure 13b was prepared starting
from 12b (0.130 g, 0.32 mmol), NaIO4 (1.36 g, 6.37 mmol), and
RuCl3·H2O (cat.) and was isolated after FC purification (n-hexane/
1
(−)-(3R)-N-Benzyl-3-methylpyrrolidine (16a). Following the
general procedure 16a (0.03 g, 0.16 mmol) was isolated by FC
purification (n-hexane/AcOEt 2:8) in 70% yield starting from
dimesilate 15 (0.060 g, 0.23 mmol) and benzylamine (0.20 mL, 1.84
AcOEt 7:3) in 50% yield (59 mg, 0.16 mmol). H NMR (300 MHz,
CDCl3) δ: 0.94 (t, 3H, J = 7.4 Hz), 1.04 (s, 9H), 1.50−1.76 (m, 3H),
1.90−2.00 (m, 1H), 2.55−2.58 (m, 1H), 3.70 (t, 2H, J = 6.1 Hz),
7.26−7.42 (m, 6H), 7.62−7.72 (m, 4H). 13C NMR (75 MHz, CDCl3)
δ: 11.6, 19.1, 25.1, 26.7, 34.0, 43.5, 61.8, 127.7, 129.6, 133.7, 135.6,
133.6, 182.3. HRMS calcd for [C22H29O2Si]+: 353.1937 [(M −
OH)+], found 353.1954. MS (70 eV) m/z (%): 353 [32, (M − OH)+],
1
mmol). H NMR (300 MHz, CDCl3) δ: 1.03 (d, 3H, J = 6.7 Hz),
1.31−1.36 (m, 1H), 1.99−2.03 (m, 2H), 2.04−2.30 (m, 1H), 2.33−
2.50 (m, 1H), 2.61−2.77 (m, 1H), 2.82 (m, 1H, J = 8.8, 7.5 Hz), 3.57
(d, 1H, J = 12.9 Hz), 3.62 (d, 1H, J = 12.9 Hz), 7.20−7.36 (m, 5H).
13C NMR (75 MHz, CDCl3) δ: 20.4, 31.8, 32.6, 54.1, 60.8, 62.2, 126.8,
128.1, 128.8, 141.1. HRMS calcd for [C12H18N]+: 176.1439 [(M +
H)+], found 176.1434. MS (70 eV) m/z (%): 176 [100, (M + H)+],
175 (80, M+), 98 (21), 91 (29), 84 (19). [α]20D −8.4 (c 1.44, EtOH),
313 (22), 235 (70), 215 (27), 199 (100). [α]20 −6.6 (c 1.00,
D
CH2Cl2).
(−)-(R)-4-(tert-Butyldiphenylsililoxy)-2-propylbutyric Acid
(13c). Following the general procedure 13c was prepared starting
from 12c (0.210 g, 0.50 mmol), NaIO4 (2.12 g, 9.95 mmol), and
RuCl3·H2O (cat.) and was isolated after FC purification (n-hexane/
lit.21 [α]20 −8.6 (c 1.75, EtOH).
D
1
(−)-(3R)-N-Tosyl-3-methylpyrrolidine (16b). Following the
general procedure 16b (0.090 g, 0.36 mmol) was isolated by FC
purification (n-hexane/AcOEt 2:8) in 73% yield starting from
dimesilate 15 (0.13 g, 0.50 mmol) and tosylamine (0.20 mL, 1.84
AcOEt 7:3) in 50% yield (96 mg, 0.25 mmol). H NMR (300 MHz,
CDCl3) δ: 0.92 (t, 3H, J = 7.2 Hz), 1.04 (s, 9H), 1.31−1.76 (m, 4H),
1.80−2.00 (m, 2H), 2.61−2.66 (m, 1H), 3.69 (t, 2H, J = 6.2 Hz),
7.26−7.91 (m, 10H). 13C NMR (75 MHz, CDCl3) δ: 13.9, 19.1, 20.3,
26.8, 34.2, 34.4, 41.7, 61.8, 127.6, 129.6, 133.5, 133.7, 133.6, 135.6,
181.7. HRMS calcd for [C23H31SiO2]+: 367.2094 [(M − OH)+], found
367.2106. MS (70 eV) m/z (%): 367 [51, (M − OH)+], 327 (27), 249
1
mmol). H NMR (300 MHz, CDCl3) δ: 0.90 (d, 3H, J = 6.7 Hz),
1.27−1.37 (m, 1H), 1.86−1.94 (m, 1H), 2.06−2.14 (m, 1H), 2.42 (s,
3H), 2.70−2.76 (m, 1H), 3.22−3.38 (m, 1H), 3.40−3.43 (m, 2H),
7.30 (d, 2H, J = 8.1 Hz), 7.70 (d, 2H, J = 8.1 Hz). 13C NMR (75 MHz,
CDCl3) δ: 17.6, 21.5, 33.2, 33.3, 47.6, 54.7, 127.5, 129.5, 134.1, 143.2.
HRMS calcd for [C12H18NO2S]+: 240.1058 [(M + H)+], found
240.1068. MS (70 eV) m/z (%): 240 [100, (M + H)+], 239 (19), 148
(99), 229 (41), 199 (100), 129 (45). [α]20 −4.4 (c 1.00, CH2Cl2).
D
Synthesis of (+)-(R)-(tert-Butyldiphenylsililoxy)-2-methylbu-
tan-1-ol (14). To a solution of the carboxylic acid 13a (0.5 g, 1.40
mmol) in dry THF (15 mL) at room temperature was added borane
(2.1 mL, 4.21 mmol), and the mixture was stirred at this temperature.
After 3.5 h the solution was cooled at 0 °C, water was added (10 mL,
and the mixture was extracted with CH2Cl2 (3 × 15 mL). The organic
fractions were collected, dried over Na2SO4, and filtered, and the
solvent was removed in vacuo, affording the alcohol 14 after flash
column chromatography purification (hexane/AcOEt 8:2) in 72%
(7). [α]20 +8.1 (c 1.05, CH2Cl2). Mp: 90−92 °C (hexane/AcOEt
D
8:2). The ee (92% ee) was calculated by HPLC: Chiralpak IA, 0.70
mL/min, hexane/i-PrOH 98/02. Mayor isomer: tR = 35.5 min. Minor
isomer: tR = 36.8 min.
General Procedure for the Synthesis of Mesilates 20. To a
solution of the corresponding alcohol 1915 (1.00 mmol) in dry
CH2Cl2 (20 mL) at 0 °C were added Et3N (3.00 mmol),
methanesulfonyl chloride (3.00 mmol), and DMAP (cat.). After 2 h
of stirring at room temperature the reaction was quenched with 2 M
KOH (10 mL) and extracted with CH2Cl2 (3 × 15 mL). The organic
fractions were dried over Na2SO4 and filtered, and the solvent was
removed in vacuo, affording the mesilates 20 after flash column
chromatography purification.
1
yield (0.36 g, 1.05 mmol). H NMR (300 MHz, CDCl3) δ: 0.92 (d,
3H, J = 6.8 Hz), 1.09 (s, 9H), 1.51−1.56 (m, 1H), 1.61−1.68 (m, 1H),
1.84−1.90 (m, 1H), 2.60−2.70 (bs, 1H), 3.50−3.52 (m, 2H), 3.73−
3.81 (m, 2H), 7.39−7.51 (m, 6H), 7.70−7.75 (m, 4H). 13C NMR (75
MHz, CDCl3) δ: 17.1, 19.2, 26.8, 33.8, 36.7, 62.5, 68.2, 127.7, 129.7,
135.6, 133.5. IR (cm−1): 3340 (OH). HRMS calcd for [C21H31O2Si]+:
343.2093 [(M + H)+], found 343.2095. MS (70 eV) m/z (%): 343 [8,
(M + H)+], 285 (39), 239 (35), 228 (100), 199 (70), 179 (29), 166
(+)-(S,E)-3-Butylhex-4-enyl Methanesulfonate (20a). Follow-
ing the general procedure 20a (0.38 g, 1.61 mmol) was obtained in
90% yield starting from alcohol 19a (0.28 g, 1.79 mmol), Et3N (0.76
mL, 5.38 mmol), MsCl (0.42 mL, 5.38 mmol), and DMAP (0.02 g,
0.18 mmol) as a colorless oil after flash column chromatography
(40), 69 (13). [α]20 +5.0 (c 0.94, CH2Cl2).
D
Synthesis of (+)-(R)-2-Methylbutane-1,4-diyl Dimethanesul-
fonate (15). To a solution of the alcohol 14 (0.3 g, 0.87 mmol) in dry
THF (15 mL) was added TBAF (3.50 mL of a 1 M solution in THF,
3.5 mmol), and the mixture was stirred for 18 h. The reaction was
quenched with water (10 mL) and extracted with CH2Cl2 (3 × 15
mL). The organic fractions were collected, dried over Na2SO4, and
filtered, and the solvent was removed in vacuo. To a solution of the
crude in dry CH2Cl2 (10 mL) at 0 °C were added Et3N (0.54 mL, 3.85
mmol), methanesulfonyl chloride (0.3 mL, 3.85 mmol), and DMAP
(cat.). After 14 h of stirring at room temperature the reaction was
quenched with 2 M KOH (5 mL) and extracted with CH2Cl2 (3 × 15
mL). The organic fractions were collected, dried over Na2SO4, and
filtered, and the solvent was removed in vacuo. Sulfonate 15 was
isolated after flash column chromatography purification FC (hexane/
1
purification (hexane/AcOEt 8:2). H NMR (300 MHz, CDCl3) δ:
0.85 (t, 3H, J = 6.1 Hz), 1.19−1.33 (m, 6H), 1.46−1.58 (m, 1H), 1.63
(d, 3H, J = 6.3 Hz), 1.69−1.86 (m, 1H), 1.98−2.05 (m, 1H), 2.95 (s,
3H), 4.09−4.24 (m, 2H), 5.06 (dd, 1H, J = 15.0, 9.1 Hz), 5.34−5.46
(m, 1H). 13C NMR (75 MHz, CDCl3) δ: 13.9, 17.8, 22.5, 29.1, 34.3,
35.1, 37.1, 39.1, 68.8, 126.4, 133.8. IR (cm−1): 2927 (CC), 1355
(SO2), 1175 (SO2). HRMS calcd for [C11H22O3S]+: 234.1290, found
234.1283. MS (70 eV) m/z (%): 234 (1, M+), 218 (38), 138 (53), 123
(59), 109 (94), 96 (98), 81 (99), 79 (100), 67 (99), 55 (98). [α]20
D
+13.4 (c 1.0, CH2Cl2).
(+)-(R,E)-3-Isopropylhex-4-enyl Methanesulfonate (20b).
Following the general procedure 20a (0.39 g, 1.79 mmol) was
obtained in 91% yield starting from alcohol 19b (0.28 g, 1.97 mmol),
Et3N (0.83 mL, 5.37 mmol), MsCl (0.45 mL, 5.37 mmol), and DMAP
(0.02 g, 0.18 mmol) as a colorless oil after flash column
chromatography purification (hexane/AcOEt 8:2). 1H NMR (300
MHz, CDCl3) δ: 0.83 (d, 3H, J = 6.7 Hz), 0.87 (d, 3H, J = 6.7 Hz),
1.49−1.62 (m, 2H), 1.67 (dd, 3H, J = 6.3, 1.4 Hz), 1.82−1.93 (m,
2H), 2.97 (s, 3H), 4.08−4.27 (m, 2H), 5.09−5.17 (m, 1H), 5.36−5.47
(m, 1H). 13C NMR (75 MHz, CDCl3) δ: 17.9, 18.8, 20.4, 31.6, 32.0,
1
AcOEt 2:8) in 20% yield (0.090 g, 0.35 mmol). H NMR (300 MHz,
CDCl3) δ: 1.04 (d, 3H, J = 6.8 Hz), 1.63−1.70 (m, 1H), 1.87−1.96
(m, 1H), 2.08−2.14 (m, 1H, CH), 3.01 (s, 3H), 3.12 (s, 3H), 4.04−
4.15 (m, 2H), 4.26−4.34 (m, 2H). 13C NMR (75 MHz, CDCl3) δ:
16.1, 29.8, 32.2, 37.3, 37.4, 67.4, 73.5. HRMS calcd for [C7H17O6S2]+:
261.0466 [(M + H)+], found 261.0466. MS (70 eV) m/z (%): 261 [8,
(M + H)+], 192 (5), 174 (8), 165 (100), 125 (13), 105 (42). [α]20
D
+0,5 (c 1.00, CH2Cl2).
623
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
37.2, 45.4, 69.2, 127.6, 131.3. IR (cm−1): 2958 (CC), 1355 (SO2),
1176 (SO2). HRMS calcd for [C9H17]+: 125.1331 [(M − OMs)+],
found 125.1323. MS (70 eV) m/z (%): 125 [89, (M − OMs)+], 124
(−)-(R)-3-Formyl-4,4-dimethylpentyl Methanesulfonate
(21c). Following the general procedure 21c (0.19 g, 0.89 mmol)
was obtained in a quantitative yield starting from mesilate 20c (0.21 g,
0.89 mmol) and Me2S (0.30 mL, 4.05 mmol) as a colorless oil after
(10), 123 (17), 109 (11), 97 (55), 83 (31), 81 (14), 69 (100). [α]20
D
1
flash column chromatography purification (hexane/AcOEt 7:3). H
+17.8 (c 1.0, CH2Cl2).
NMR (300 MHz, CDCl3) δ: 1.01 (s, 9H), 1.82−1.92 (m, 1H), 2.06−
2.18 (m, 1H), 2.23−2.35 (m, 1H), 2.96 (s, 3H), 4.04−4.11 (m,1H),
4.17−4.24 (m, 1H), 9.81 (s, 1H). 13C NMR (75 MHz, CDCl3) δ:
24.3, 27.9, 33.6, 37.3, 57.7, 68.5, 204.9. IR (cm−1): 1716 (CO),
1349 (SO2), 1174 (SO2). HRMS calcd for [C8H15O]+: 127.1123 [(M
− OMs)+], found 127.1126. MS (70 eV) m/z (%): 127 [100, (M −
(+)-(S,E)-3-tert-Butylhex-4-enyl Methanesulfonate (20c). Fol-
lowing the general procedure 20c (0.32 g, 1.38 mmol was obtained in
94% yield starting from alcohol 19c (0.23 g, 1.47 mmol), Et3N (0.62
mL, 4.41 mmol), MsCl (0.34 mL, 4.41 mmol), and DMAP (0.02 g,
0.14 mmol) as a colorless oil after flash column chromatography
1
purification (hexane/AcOEt 8:2). H NMR (300 MHz, CDCl3) δ:
OMs)+], 83 (15), 71 (16), 70 (24). [α]20 −32.0 (c 1.0, CH2Cl2).
D
0.84 (s, 9H), 1.38−1.50 (m, 1H), 1.67 (dd, 3H, J = 6.3, 1.3 Hz), 1.72−
1.80 (m, 1H), 1.92−2.02 (m, 1H), 2.97 (s, 3H, CH3S), 4.04−4.12 (m,
1H), 4.19−4.26 (m, 1H), 5.11−5.19 (m, 1H), 5.34−5.46 (m, 1H). 13C
NMR (75 MHz, CDCl3) δ: 17.9, 27.6, 28.7, 32.6, 37.2, 49.6, 69.6,
128.0, 130.9. IR (cm−1): 2958 (CC), 1354 (SO2), 1176 (SO2).
HRMS calcd for [C10H19]+: 139.1487 [(M − OMs)+], found
139.1481. MS (70 eV) m/z (%): 139 [70, (M − OMs)+], 123 (11),
(−)-(R)-3-Formyl-3-phenylpropyl Methanesulfonate (21d).
Following the general procedure 21d (0.27 g, 1.10 mmol) was
obtained in 85% yield starting from mesilate 20d (0.33 g, 1.29 mmol)
and Me2S (0.48 mL, 6.49 mmol) as a colorless oil after flash column
chromatography purification (hexane/AcOEt 7:3). 1H NMR (300
MHz, CDCl3) δ: 2.08−2.12 (m, 1H), 2.48−2.52 (m, 1H), 2.93 (s,
3H), 3.71−3.80 (m, 2H), 4.06−4.14 (m, 1H), 4.21−4.28 (m, 1H),
7.16−7.41 (m, 5H), 9.66 (s, 1H). 13C NMR (75 MHz, CDCl3) δ:
28.2, 36.3, 53.9, 66.3, 127.2, 128.0, 128.4, 133.4, 198.0. IR (cm−1):
1720 (CO), 1351 (SO2), 1172 (SO2). HRMS calcd for
[C11H14O4S]+: 242.0613 (M+), found 242.0615. MS (70 eV) m/z
(%): 242 (2, M+), 222 (18), 192 (17), 191 (99), 147 (100), 117 (57),
95 (20), 91 (14) 75 (28). [α]20 −69.6 (c 1.0, CH2Cl2).
111 (51), 83 (100), 82 (21), 69 (25). [α]20 +19.3 (c 1.0, CH2Cl2).
D
(+)-(S,E)-3-Phenylhex-4-enyl Methanesulfonate (20d). Fol-
lowing the general procedure 20d (0.46 g, 1.82 mmol) was obtained in
>99% yield starting from alcohol 19d (0.32 g, 1.82 mmol), Et3N (0.62
mL, 4.41 mmol), MsCl (0.34 mL, 4.41 mmol), and DMAP (0.02 g,
0.18 mmol) as a colorless oil after flash column chromatography
1
General Procedure for the DSynthesis of Pyrrolidines 22. Over
a cooled (−78 °C) solution of the aldehyde 21 (1.00 mmol) in THF
(10 mL) were added p-methoxybenzylamine (1.10 mmol) and Et3N
(3 mmol). Then, a solution of TiCl4 (1.0 mmol) in CH2Cl2 was
carefully added, and the reaction was stirred at this temperature for 5
min at −78 °C and 10 min at −20 °C. A solution of NaBH4 (4.5
mmol) in anhydrous MeOH (10 mL) was slowly added to the reaction
mixture (30 min), and the reaction was stirred for 2 h at −20 °C. The
reaction was quenched with a satd Na2CO3 solution (15 mL), and the
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined
organic fractions were collected, dried over Na2SO4, and filtered, and
the solvent was removed in vacuo affording the wanted pyrrolidines
after flash column chromatography purification.
purification (hexane/AcOEt 8:2). H NMR (300 MHz, CDCl3) δ:
1.65 (d, 3H, J = 6.2 Hz), 2.09 (d, 1H, J = 6.6 Hz), 2.14 (d, 1H, J = 6.6
Hz), 2.94 (s, 3H), 3.38−3.44 (m, 1H), 4.09−4.24 (m, 2H, CH2O),
5.52−5.55 (m, 2H), 7.18−7.34 (m, 5H). 13C NMR (75 MHz, CDCl3)
δ: 17.9, 34.8, 37.0, 44.7, 68.4, 126.0, 126.5, 127.3, 128.6, 133.3, 143.3.
IR (cm−1): 2936 (CC), 1354 (SO2), 1173 (SO2). HRMS calcd for
[C13H18O3S]+: 254.0977 (M+), found 254.0959. MS (70 eV) m/z (%):
158 [33, (M − OMs)+], 143 (100), 131 (76), 129 (78), 128 (74), 115
(73), 103 (20), 91 (79), 79 (70), 77 (40). [α]20 +25.1 (c 1.0,
D
CH2Cl2).
General Procedure for the Synthesis of Aldehydes 21. Ozone
was bubbled through a cooled solution at −78 °C of mesilate 20a−d
(1.0 mmol) in dry CH2Cl2 (20 mL), until the solution turned light
blue. Then, dimethyl sulfide (5.00 mmol) was added, and the reaction
mixture was stirred at −78 °C for 2 h. The reaction was quenched with
water (20 mL) and extracted with CH2Cl2 (3 × 10 mL). The organic
fractions were dried over Na2SO4 and filtered, and the solvent was
removed in vacuo, affording the aldehyde 21a−d after flash column
chromatography purification.
(+)-(S)-3-Butyl-N-(p-methoxybenzyl)pyrrolidine (22a). Fol-
lowing the general procedure 22a (0.20 g, 0.83 mmol) was obtained
in 75% yield after FC purification (n-hexane/AcOEt/Et3N 7:2.8:0.2)
starting from aldehyde 21a (0.25 g, 1.13 mmol), p-methoxybenzyl-
amine (0.16 mL, 1.24 mmol), Et3N (1 mL, 3.39 mmol), TiCl4 (1.24
mL of a 1.0 M solution in CH2Cl2, 1.24 mmol), and NaBH4 (0.19 g,
5.10 mmol) in MeOH. 1H NMR (300 MHz, CDCl3) δ: 0.88 (t, 3H, J
= 6.4 Hz), 1.16−1.42 (m, 7H), 1.92−2.04 (m, 2H), 2.07−2.17 (m,
1H), 2.33−2.41 (m, 1H), 2.64−2.72 (m, 1H), 2.77−2.83 (m, 1H),
3.50 (d, 1H, J = 12.6 Hz), 3.52 (d, 1H, J = 12.6 Hz),, 3.79 (s, 3H), 6.84
(d, 2H, J = 8.4 Hz), 7.23 (d, 2H, J = 8.4 Hz). 13C NMR (75 MHz,
CDCl3) δ: 14.0, 22.7, 30.5, 30.7, 35.4, 37.5, 53.8, 55.1, 60.1, 60.5,
113.5, 129.9, 131.3, 158.5. IR (cm−1): 2922 (CC), 1245 (C−O).
HRMS calcd for [C16H25NO]+: 247.1936 (M+), found 247.1933. MS
(70 eV) m/z (%): 247 (10, M+), 126 (12), 121 (100), 87 (16), 85
(35), 84 (38), 82(11), 71 (19), 69 (10), 57 (22), 55 (13). [α]20D +3.5
(c 1.0, CH2Cl2).
(−)-(S)-3-Formylheptyl Methanesulfonate (21a). Following
the general procedure 21a (0.15 g, 0.63 mmol) was obtained in
80% yield starting from mesilate 20a (0.20 g, 0.79 mmol) and Me2S
(0.29 mL, 3.94 mmol) as a colorless oil after flash column
chromatography purification (hexane/AcOEt 7:3). 1H NMR (300
MHz, CDCl3) δ: 0.87 (t, 3H, J = 6.1 Hz), 1.26−1.29 (m, 4H), 1.41−
1.53 (m, 1H), 1.61−1.73 (m, 1H), 1.75−1.90 (m, 1H), 1.99−2.13 (m,
1H,), 2.41−2.49 (m, 1H), 2.93 (s, 3H), 4.14−4.27 (m, 2H), 9.53 (s,
1H). 13C NMR (75 MHz, CDCl3) δ: 13.7, 22.5, 27.7, 28.2, 28.7, 37.1,
47.9, 67.6, 203.6. IR (cm−1): 1721 (CO), 1353 (SO2), 1174 (SO2).
HRMS calcd for [C9H18O4S]+: 222.0926 (M+), found 222.0926. MS
(70 eV) m/z (%): 222 (1, M+), 126 (5), 99 (7), 86 (25), 83 (39), 79
(+)-(R)-3-Isopropyl-N-(p-methoxybenzyl)pyrrolidine (22b).
Following the general procedure 22b (0.24 g, 1.02 mmol) was
obtained in 97% yield after FC purification (n-hexane/AcOEt/Et3N
7:2.8:0.2) starting from aldehyde 21b (0.22 g, 1.06 mmol), p-
methoxybenzylamine (0.15 mL, 1.15 mmol), Et3N (0.44 mL, 3.15
mmol), TiCl4 (1.15 mL of a 1.0 M solution in CH2Cl2, 1.15 mmol),
(100), 70 (11), 55 (90). [α]20 −6.87 (c 1.0, CH2Cl2).
D
(+)-(R)-3-Formyl-4-methylpentyl Methanesulfonate (21b).
Following the general procedure 21b (0.14 g, 0.639 mmol) was
obtained in 85% yield starting from mesilate 20b (0.18 g, 0.81 mmol)
and Me2S (0.30 mL, 4.05 mmol) as a colorless oil after flash column
chromatography purification (hexane/AcOEt 7:3). 1H NMR (300
MHz, CDCl3) δ: 0.94 (d, 3H, J = 6.9 Hz), 0.99 (d, 3H, J = 6.9 Hz),
1.73−1.84 (m, 1H), 2.03−2.18 (m, 2H,), 2.34−2.41 (m, 1H), 2.97 (s,
3H), 4.12−4.29 (m, 2H), 9.67 (s, 1H). 13C NMR (75 MHz, CDCl3)
δ: 19.1, 20.0, 24.7, 28.1, 37.2, 53.8, 68.3, 204.1. IR (cm−1): 1723 (C
O), 1352 (SO2), 1174 (SO2). HRMS calcd for [C7H13O]+: 113.0967
[(M − OMs)+], found 113.0968. MS (70 eV) m/z (%): 112 [42, (M
− OMs)+], 97 (100), 84 (10), 83 (11), 79 (12), 69 (13), 67 (11).
1
and NaBH4 (0.18 g, 4.72 mmol) in MeOH. H NMR (300 MHz,
CDCl3) δ: 0.85 (d, 3H, J = 6.6 Hz), 0.88 (d, 3H, J = 6.6 Hz), 1.38−
1.50 (m, 2H), 1.78−1.98 (m, 2H), 2.01−2.06 (m, 1H), 2.29−2.37 (m,
1H), 2.69−2.83 (m, 2H), 3.50 (d, 1H, J = 12.6 Hz), 3.56 (d, 1H, J =
12.6 Hz), 3.78 (s, 3H, OCH3), 6.84 (d, 2H, J = 8.4 Hz), 7.23 (d, 2H, J
= 8.4 Hz). 13C NMR (75 MHz, CDCl3) δ: 21.0, 21.2, 28.9, 32.9, 45.2,
54.0, 55.0, 58.8, 60.2, 113.4, 129.8, 131.5, 158.4. IR (cm−1): 2954
(CC), 1245 (C−O). HRMS calcd for [C15H24NO]+: 234.1858 [(M
+ H)+], found 234.1852. MS (70 eV) m/z (%): 234 [100, (M + H)+],
[α]20 +8.0 (c 1.0, CH2Cl2).
D
624
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
233 (63, M+), 232 (54), 218 (11), 149 (8), 126 (19), 121 (41), 112
(3). [α]20 +10.6 (c 2.0, CH2Cl2).
was obtained in 72% yield after FC purification (n-hexane/AcOEt 8:2)
starting from pyrrolidine 22b (0.08 g, 0.36 mmol), Et3N (0.14 mL,
1.03 mmol), p-toluenesulfonylchloride (0.19 g, 1.03 mmol), and a
(+)-(R)D-3-tert-Butyl-N-(p-Methoxybenzyl)pyrrolidine (22c).
Following the general procedure 22c (0.22 g, 0.89 mmol) was
obtained in 83% yield after FC purification (n-hexane/AcOEt/Et3N
7:2.8:0.2) starting from aldehyde 21c (0.24 g, 1.08 mmol), p-
methoxybenzylamine (0.16 mL, 1.19 mmol), Et3N (0.45 mL, 3.24
mmol), TiCl4 (1.19 mL of a 1.0 M solution in CH2Cl2, 1.19 mmol),
1
catalytic amount of DMAP (4.19 mg, 0.03 mmol). H NMR (300
MHz, CDCl3) δ: 0.84 (d, 6H, J = 6.6 Hz), 1.29−1.43 (m, 2H), 1.62−
1.76 (m, 1H), 1.86−1.95 (m, 1H), 2.43 (s, 3H), 2.78 (t, 1H, J = 9.6
Hz), 3.10−3.23 (m, 1H), 3.33−3.47 (m, 2H), 7.31 (d, 2H, J = 8.1 Hz),
7.70 (d, 2H, J = 8.1 Hz). 13C NMR (75 MHz, CDCl3) δ: 20.9, 21.3,
21.5, 30.0, 31.8, 46.4, 48.1, 52.1, 127.5, 129.6, 134.0, 143.2. IR (cm−1):
2957 (CC), 1344 (SO2), 1162 (SO2). HRMS calcd for
[C14H22NO2S]+: 268.1371, found 268.1370. MS (70 eV) m/z (%):
1
and NaBH4 (0.18 g, 4.72 mmol) in MeOH. H NMR (300 MHz,
CDCl3) δ: 0.84 (s, 9H), 1.49−1.60 (m, 1H), 1.72−1.84 (m, 1H),
1.98−2.06 (m, 1H), 2.09−2.17 (m, 1H), 2.27−2.35 (m, 1H), 2.62−
2.73 (m, 2H), 3.47 (d, 1H, J = 12.6 Hz), 3.57 (d, 1H, J = 12.6 Hz),
3.78 (s, 3H), 6.84 (d, 2H, J = 8.5 Hz), 7.23 (d, 2H, J = 8.5 Hz). 13C
NMR (75 MHz, CDCl3) δ: 25.9, 27.4, 31.9, 48.3, 54.6, 55.1, 55.7, 60.2,
113.4, 129.7, 131.5, 158.4. IR (cm−1): 2955 (CC), 1245 (C−O).
HRMS calcd for [C16H26NO]+: 248.2014 [(M + H)+], found
248.2019. MS (70 eV) m/z (%): 248 [100, (M + H)+], 247 (69,
268 [100, (M + H)+], 267 (10, M+), 176 (3), 112 (15), 91 (1). [α]20
D
−23.5 (c 0.2, CHCl3). The er (88:12) was determined by HPLC using
Chiralcel OJH column, n-hexane/i-PrOH 98:2, flow rate 1.00 mL/
min; τmajor = 27.44 min, τminor = 25.36 min.
(+)-(R)-3-tert-Butyl-N-(p-toluenesulfonyl)pyrrolidine (ent-
16e). Following the general procedure ent-16e (0.07 g, 0.26 mmol)
was obtained in 50% yield after FC purification (n-hexane/AcOEt 8:2)
starting from pyrrolidine 22c (0.11 g, 0.44 mmol), Et3N (0.19 mL,
1.33 mmol), p-toluenesulfonylchloride (0.25 g, 1.33 mmol), and a
catalytic amount of DMAP (5.44 g, 0.04 mmol). 1H NMR (300 MHz,
CDCl3) δ: 0.81 (s, 9H), 1.39−1.61 (m, 1H), 1.70−1.91 (m, 2H), 2.43
(s, 3H), 2.93 (t, 1H, J = 9.6 Hz), 3.04−3.13 (m, 1H), 3.25−3.35 (m,
1H), 3.36−3.43 (m, 1H), 7.31 (d, 2H, J = 8.2 Hz), 7.71 (d, 2H, J = 8.2
Hz). 13C NMR (75 MHz, CDCl3) δ: 21.5, 26.6, 27.3, 31.2, 48.3, 48.9,
49.4, 127.5, 129.6, 133.8, 143.2. IR (cm−1): 2923 (CC), 1346
(SO2), 1164 (SO2). HRMS calcd for [C15H24NO2S]+: 282.1527 [(M +
H)+], found 282.1520. MS (70 eV) m/z (%): 282 [100, (M + H)+],
261 (10, M+), 190 (7), 126 (15), 91 (1). [α]20D +7.9 (c 1.0, CH2Cl2).
The er (97:3) was determined by HPLC using Chiralcel OJH column,
n-hexane/i-PrOH 98:2, flow rate 0.85 mL/min; τmajor = 20.31 min,
τminor = 17.57 min.
M+), 246 (60), 232 (22), 140 (20), 121 (33). [α]20 +5.5 (c 1.0,
D
CH2Cl2).
(+)-(R)-N-(p-Methoxybenzyl)-3-phenyl Pyrrolidine (22d). Fol-
lowing the general procedure 22d (0.17 g, 0.63 mmol) was obtained in
80% yield after FC purification (n-hexane/AcOEt/Et3N 7:2.8:0.2)
starting from aldehyde 21d (0.20 g, 0.78 mmol), p-methoxybenzyl-
amine (0.11 mL, 0.85 mmol), Et3N (0.33 mL, 2.34 mmol), TiCl4 (0.58
mL of a 1.0 M solution in CH2Cl2, 0.85 mmol), and NaBH4 (0.13 g,
3.51 mmol) in MeOH. 1H NMR (300 MHz, CDCl3) δ: 1.90−2.01 (m,
1H), 2.34−2.46 (m, 1H,), 2.55 (dd, 1H, J = 9.0, 7.9 Hz), 2.69−2.78
(m, 1H), 2.83−2.92 (m, 1H), 3.09 (dd, 1H, J = 9.0, 7.9 Hz), 3.37−
3.48 (m, 1H), 3.68 (s, 2H), 3.84 (s, 3H), 6.93 (d, 2H, J = 8.7 Hz),
7.21−7.28 (m, 1H), 7.33−7.36 (m, 6H). 13C NMR (75 MHz, CDCl3)
δ: 33.1, 43.2, 54.4, 55.1, 59.8, 62.1, 113.5, 125.9, 127.2, 128.2, 129.8,
131.3, 145.6, 158.5. IR (cm−1): 2932 (CC), 1248 (C−O). HRMS
calcd for [C18H22NO]+: 268.1701 [(M + H)+], found 268.1689. MS
(70 eV) m/z (%): 268 [35, (M + H)+], 267 (60, M+), 266 (18), 163
(+)-(R)-3-Phenyl-N-(p-toluenesulfonyl)pyrrolidine (ent-16f).
Following the general procedure ent-16f (0.06 g, 0.22 mmol) was
obtained in 50% yield after FC purification (n-hexane/AcOEt 8:2)
starting from pyrrolidine 22d (0.10 g, 0.37 mmol), Et3N (0.16 mL,
1.12 mmol), p-toluenesulfonylchloride (0.21 g, 1.12 mmol), and a
(7), 160 (12), 122 (8), 121 (100), 91 (2). [α]20 +17.0 (c 0.5,
D
CH2Cl2).
General Procedure for the Hydrogenolysis and Synthesis of
p-Toluenesulfonylpyrrolidines ent-16. A catalytic amount of
Pd(OH)2 (40 mol %) was added to a solution of the corresponding
pyrrolidine 22 (1.00 mmol) in MeOH (10 mL), and the mixture was
stirred at rt under 100 psi pressure of H2 (TLC monitoring). Then the
mixture was filtered, and the solvent was removed in vacuo. The
reaction crude was disolved in CH2Cl2 (10 mL) at 0 °C, and Et3N
(3.00 mmol) and p-toluenesulfonylchloride (3.00 mmol) and a
catalytic amount of DMAP (0.10 mmol) were added. The reaction
mixture was stirred at rt for 16 h, quenched with 2 M KOH (10 mL),
and extracted with CH2Cl2 (3 × 10 mL). The organic fractions were
collected, dried over Na2SO4, and filtered, and the solvent was
removed in vacuo. The wanted pyrrolidines ent-16 were obtained after
flash column chromatography purification.
1
catalytic amount of DMAP (4.57 mg, 0.04 mmol). H NMR (300
MHz, CDCl3) δ: 1.79−1.93 (m, 1H), 2.17−2.23 (m, 1H), 2.45 (s,
3H), 3.16−3.25 (m, 2H), 3.31−3.40 (m, 1H), 3.49−3.57 (m, 1H),
3.69−3.79 (m, 1H), 7.12 (m, 2H), 7.18−7.32 (m, 3H), 7.36 (m, 2H),
7.75 (d, 2H, J = 8.1 Hz). 13C NMR (75 MHz, CDCl3) δ: 21.5, 32.8,
43.7, 47.8, 54.0, 126.9, 127.5, 128.6, 129.7, 133.9, 140.6, 143.4. IR
(cm−1): 2968 (CC), 1342 (SO2), 1160 (SO2). HRMS calcd for
[C17H19NO2S]+: 301.1136 (M+), found 301.1137. MS (70 eV) m/z
(%): 302 [100, (M + H)+], 300 (4), 210 (1), 184 (3), 148 (6), 146
(12). Mp (°C): 89−92 (AcOEt/hexane 1:1) [α]20 +6.3 (c 0.5,
D
EtOH); lit.22 [α]20 −6.6, c 1.16, EtOH, for S isomer. The er (97:3)
D
was determined by HPLC using Chiralpak IA column, n-hexane/i-
PrOH 98:2, flow rate 0.85 mL/min; τmajor = 31.25 min, τminor = 29.66
min.
(+)-(S)-3-Butyl-N-(p-toluenesulfonyl)pyrrolidine (ent-16c).
Following the general procedure ent-16c (0.08 g, 0.27 mmol) was
obtained in 75% yield after FC purification (n-hexane/AcOEt 8:2)
starting from pyrrolidine 22a (0.09 g, 0.36 mmol), Et3N (0.15 mL,
1.09 mmol), p-toluenesulfonylchloride (0.21 g, 1.09 mmol), and a
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all compounds prepared. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
catalytic amount of DMAP (4.45 mg, 0.04 mmol). H NMR (300
MHz, CDCl3) δ: 0.84 (t, 3H, J = 6.6 Hz), 1.18−1.25 (m, 6H), 1.30−
1.40 (m, 1H), 1.85−2.02 (m, 2H), 2.41 (s, 3H), 2.72−2.78 (m, 1H),
3.13−3.22 (m, 1H), 3.28−3.35 (m, 1H), 3.38−3.44 (m, 1H), 7.29 (d,
2H, J = 8.4 Hz), 7.69 (d, 2H, J = 8.4 Hz). 13C NMR (75 MHz, CDCl3)
δ: 13.88, 21.5, 22.6, 30.2, 31.5, 32.7, 38.8, 47.5, 53.3, 127.5, 129.5,
133.9, 143.2. IR (cm−1): 2925 (CC), 1344 (SO2), 1161 (SO2).
HRMS calcd for [C15H23NO2S]+: 281.1449 (M+), found 281.1454.
MS (70 eV) m/z (%): 281 (8, M+), 280 (12), 184 (47), 155 (38), 126
(100), 91 (46), 85 (14), 83 (24), 65 (10). [α]20D +7.9 (c 1.0, CH2Cl2).
The er (88:12) was determined by HPLC using Chiralcel OJH
column, n-hexane/i-PrOH 98:2, flow rate 0.85 mL/min; τmajor = 28.95
min, τminor = 26.65 min.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: marisa.carrillo@ehu.es; joseluis.vicario@ehu.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the University of the Basque Country (UFI
QOSYC 11/22 and fellowship to M.O.), the Spanish Ministerio
(−)-(R)-3-Isopropyl-N-(p-toluenesulfonyl)pyrrolidine (ent-
16d). Following the general procedure ent-16d (0.07 g, 0.26 mmol)
625
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
de Ciencia e Innovacion (project CTQ2008-00136), and the
Basque Government (Grupos IT328-10 and fellowships to B.A.
and U.U.) for financial support. The authors also acknowledge
PETRONOR, S.A. (Muskiz, Bizkaia) for the generous gift of
solvents.
Article
Y.; White, A. J. P. J. Org. Chem. 2009, 74, 5041. (c) Mitsumori, S.;
Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F.,
III J. Am. Chem. Soc. 2006, 128, 104. (d) Terakado, D.; Takano, M.;
Oriyama, T. Chem. Lett. 2005, 34, 962.
́
(8) (a) McDonald, R. I.; Wong, G. W.; Neupane, R. P.; Stahl, S. S.;
Landis, C. R. J. Am. Chem. Soc. 2010, 132, 14027. (b) Verendel, J. J.;
Zhou, T.; Li, J.-Q.; Paptchikhine, A.; Lebedev, O.; Andersson, P. G. J.
Am. Chem. Soc. 2010, 132, 8880. (c) Vogel, S.; Bantreil, X.; Maitro, G.;
Prestat, G.; Madec, D.; Poli, G. Tetrahedron Lett. 2010, 51, 1459.
(d) Mazuela, J.; Coll, M.; Pamies, O.; Dieguez, M. J. Org. Chem. 2009,
74, 5440. (e) Garcia-Garcia, P.; Ladepeche, A.; Halder, R.; List, B.
Angew. Chem., Int. Ed. 2008, 47, 4719. (f) Blanchet, J.; Pouliquen, M.;
Lasne, M.-C.; Rouden, J. Tetrahedron Lett. 2007, 48, 5727. (g) Duan,
W.-L.; Imazaki, Y.; Shintani, R.; Hayashi, T. Tetrahedron 2007, 63,
8529. (h) Wee, A. G. H.; Duncan, S. C.; Fan, G. Tetrahedron:
Asymmetry 2006, 17, 297. (i) Stoncius, A.; Nahrwold, M.; Sewald, N.
Synthesis 2005, 1829. (j) Timmons, C.; Guo, L.; Liu, J.; Cannon, J. F.;
Li, G. J. Org. Chem. 2005, 70, 7634. (k) Back, T. G.; Parvez, M.; Zhai,
H. J. Org. Chem. 2003, 68, 9389. (l) Johnson, T. A.; Jang, D. O.; Slafer,
B. W.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2002, 124, 11689.
(m) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.;
Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215. (n) Andres, C.;
Duque-Soladana, J. P.; Pedrosa, R. J. Org. Chem. 1999, 64, 4273.
(o) Coldham, I.; Hufton, R.; Snowden, D. J. J. Am. Chem. Soc. 1996,
118, 5322. (p) Westrum, L, J.; Meyers, A. I. Tetrahedron Lett. 1994, 35,
973 . See also refs 3d, e, 4h−l, 5b−g, and 6b, c.
(9) (a) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1995, 60, 3221.
(b) Stack, J. A.; Heffner, T. A.; Geib, S. J.; Curran, D. P. Tetrahedron
1993, 49, 995. (c) Negron, G.; Roussi, G.; Zhang, J. Heterocycles 1992,
34, 293.
(10) (a) Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi,
T. Angew. Chem., Int. Ed. 2005, 44, 4611. (b) Horiuchi, T.; Ohta, T.;
Shirakawa, E.; Nozaki, K.; Takaya, H. J. Org. Chem. 1997, 62, 4285.
(c) Westrum, L. J.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 973.
(d) Meyers, A. I.; Snyder, L. J. Org. Chem. 1993, 58, 36.
(11) For some references from our group dealing with the use of
chiral pyrrolidines as catalysts in organocatalytic reactions under
iminium or enamine activation, see: (a) Fernandez, M.; Reyes, E.;
Vicario, J. L.; Badía, D.; Carrillo, L. Adv. Synth. Catal. 2012, 354, 371.
(b) Fernandez, M.; Uria, U.; Reyes, E.; Vicario, J. L.; Carrillo, L. J. Am.
Chem. Soc. 2012, 134, 11872. (c) Uria, U.; Vicario., J. L.; Badía, D.;
Carrillo, L.; Reyes, E. Org. Lett. 2011, 13, 336. (d) Alonso, B.; Reyes,
E.; Vicario, J. L.; Badía, D.; Carrillo, L. Chem.Eur. J. 2011, 17, 6048.
(e) Reyes, E.; Talavera, G.; Vicario, J. L.; Badía, D.; Carrillo, L. Angew.
Chem., Int. Ed. 2009, 48, 5701. (f) Ruiz, N.; Reyes, E.; Vicario, J. L.;
Badía, D.; Carrillo, L.; Uria, U. Chem.Eur. J. 2008, 14, 9357.
(12) (a) Reyes, E.; Vicario, J. L.; Carrillo, L.; Badía, D.; Iza, A.; Uria,
U. Org. Lett. 2006, 8, 2535. (b) Reyes, E.; Vicario, J. L.; Carrillo, L.;
Badía, D.; Uria, U.; Iza, A. J. Org. Chem. 2006, 71, 7763.
REFERENCES
■
(1) For some selected reviews, see: (a) Stocker, B. L.; Dangerfield, E.
M.; Win-Mason, A. L.; Haslett, G. W.; Timmer, M. S. M. Eur. J. Org.
Chem. 2010, 1615. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem.,
́
Int. Ed. 2007, 46, 8748. (c) Najera, C.; Sansano, J. M. Org. Biomol.
Chem. 2009, 7, 4567. (d) Bellina, F.; Rossi, R. Tetrahedron 2006, 62,
7213. (e) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
́
(2) (a) Najera, C.; Sansano, J. M.; Yus, M. J. Braz. Chem. Soc. 2010,
21, 377. (b) Kissane, M.; Maguire, A. R. Chem. Soc. Rev. 2010, 39, 845.
(c) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484.
(d) Huang, P.-Q. Synlett 2006, 1133. (e) Husinec, S.; Savic, V.
́
Tetrahedron: Asymmetry 2005, 16, 2047. (f) Najera, C.; Sansano, J. M.
Angew. Chem., Int. Ed. 2005, 44, 6272. (g) Pyne, S. G.; Davis, A. S.;
Gates, N. J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.; Tang, M. Synlett
2004, 2670. (h) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003,
3693.
(3) (a) Watts, J. L.; Salmon, S. A.; Sanchez, M. S.; Yancey, R. J., Jr.
Antimicrob. Agents Chemother. 1997, 41, 1190. (b) Zerva, L.; Marshall,
S. A.; Jones, R. N. J. Antimicrob. Chemother. 1996, 38, 742.
(c) Domagala, J. M.; Hagen, S. E.; Joannides, T.; Kiely, J. S.;
Laborde, E.; Schroeder, M. C.; Sesnie, J. A.; Shapiro, M. A.; Suto, M.
J.; Vanderroest, S. J. Med. Chem. 1993, 36, 871. For examples of the
asymmetric synthesis of premafloxacin, see: (d) Sakai, T.; Kawamoto,
Y.; Tomioka, K.; Sakai, T.; Kawamoto, Y.; Tomioka, K. J. Org. Chem.
2006, 71, 4706. (e) Fleck, T. J.; McWhorter, W. W., Jr.; DeKam, R. N.;
Pearlman, B. A. J. Org. Chem. 2003, 68, 9612.
(4) (a) Katarzynska, J.; Mazur, A.; Bilska, M.; Adamek, E.; Zimecki,
M.; Jankowski, S.; Zabrocki, J. J. Peptide Sci. 2008, 14, 1283. (b) Kim,
Y. J.; Kaiser, D. A.; Pollard, T. D.; Ichikawa, Y. Bioorg. Med. Chem. Lett.
2000, 10, 2417. (c) N’Goka, V.; Schlewer, G.; Linget, J. M.; Chambon,
J. P.; Wermuth, C. G. J. Med. Chem. 1991, 34, 2547. (d) Nielsen, L.;
Brehm, L.; Krogsgaard-Larsen, P. J. Med. Chem. 1990, 33, 71.
(e) Krogsgaard-Larsen, P.; Hjeds, H.; Falch, E.; Jorgensen, F. S.;
Nielsen, L. Adv. Drug Res. 1988, 17, 381. (f) Krogsgaard-Larsen, P.;
Falch, E.; Larsson, O. M.; Schousboe, A. Epilepsy Res. 1987, 1, 77.
(g) Krogsgaard-Larsen, P.; Falch, E.; Hjeds, H. Prog. Med. Chem. 1985,
22, 67.
For some asymmetric syntheses of β-homoproline, see:
(h) Fustero, S.; Monteagudo, S.; Sanchez-Rosello, M.; Flores, S.;
Barrio, P.; del Pozo, C. Chem.Eur. J. 2010, 16, 9835. (i) Felluga, F.;
Gombac, V.; Pitacco, G.; Valentin, E. Tetrahedron: Asymmetry 2004,
15, 3323. (j) Thomas, C.; Orecher, F.; Gmeiner, P. Synthesis 1998,
1491. (k) Galeazzi, R.; Geremia, S.; Mobbili, G.; Orena, M.
Tetrahedron: Asymmetry 1996, 7, 79. (l) Galeazzi, R.; Mobbili, G.;
Orena, M. Tetrahedron 1996, 52, 1069.
(5) (a) Schmiechen, R.; Horowski, R.; Palenschat, D.; Paschelke, G.;
Wachtel, H.; Kehr, W. U.S. Patent 4 193 926, 1980. For some recent
asymmetric syntheses of rolipram, see: (b) Furutachi, M.; Mouri, S.;
Matsunaga, S.; Shibasaki, M. Chem. Asian J. 2010, 5, 2351. (c) Vakulya,
B.; Varga, S.; Soos, T. J. Org. Chem. 2008, 73, 3475. (d) Hynes, P. S.;
Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389. (e) Palomo, C.;
Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S. Angew. Chem.,
Int. Ed. 2007, 46, 8431. (f) Deng, J.; Duan, Z.-C.; Huang, J.-D.; Hu, X.-
P.; Wang, D.-Y.; Yu, S.-B.; Xu, X.-F.; Zheng, Z. Org. Lett. 2007, 9,
4825. (g) Lubkoll, J.; Wennemers, H. Angew. Chem., Int. Ed. 2007, 46,
6841.
(13) Aprile, C.; Gruttadauria, M.; Amato, M. E.; D’Anna, F.; Lo Meo,
P.; Riela, S.; Noto, R. Tetrahedron 2003, 59, 2241.
(14) (a) Etxebarria, J.; Vicario, J. L.; Badía, D.; Carrillo, L. J. Org.
Chem. 2004, 69, 2588. (b) Etxebarria, J.; Vicario, J. L.; Badía, D.;
Carrillo, L.; Ruiz, N. J. Org. Chem. 2005, 70, 8790.
(15) Ocejo, M.; Carrillo, L.; Badía, D.; Vicario, J. L.; Fernan
́
dez, N.;
Reyes, E. J. Org. Chem. 2009, 74, 4404.
(16) For a review covering oxidative cleavage of furane rings
mediated by RuCl3, see: (a) Merino, P.; Tejero, T.; Delso, I.; Matute,
R. Curr. Org. Chem. 2007, 11, 1076. For several examples, see:
(b) Trost, B. M.; Yeh, S. C. Org. Lett. 2002, 4, 3513. (c) Trost, B. M.;
Yeh, S. C. Org. Lett. 2002, 4, 3513. (d) Borg, G.; Chino, M.; Ellman, J.
A. Tetrahedron Lett. 2001, 42, 1433.
(6) (a) Veith, H. J.; Reder, V. E.; Buschinger, A. Helv. Chim. Acta
1995, 78, 73. For examples on asymmetric syntheses see: (b) Jawaid,
S.; Farrugia, L. J.; Robins, D. J. Tetrahedron: Asymmetry 2004, 15,
3979. (c) Lin, J.; Chan, W. H.; Lee, A. W. M.; Wong, W. Y.; Huang, P.
Q. Tetrahedron Lett. 2000, 41, 2949.
́
(17) Guibe-Jampel, E.; Rousseau, G.; Salaun, J. J. Chem Soc., Chem.
Commun. 1987, 1080.
(18) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J. Synlett
1997, 457. (b) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron
Lett. 1996, 37, 3623. See also: (c) Whitlock, G. A.; Carreira, E. M.
Helv. Chim. Acta 2000, 83, 2007 and refs 12 and 14.
(7) (a) Tsandi, E.; Kokotos, C. G.; Kousidou, S.; Ragoussis, V.;
Kokotos, G. Tetrahedron 2009, 65, 1444. (b) Armstrong, A.; Bhonoah,
626
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627

The Journal of Organic Chemistry
Article
(19) Barney, C. L.; Huber, E. W.; McCarthy, J. R. Tetrahedron Lett.
1990, 31, 5547.
(20) Lienard, B. M. R.; Garau, H.; Horsfall, L.; Karsisiotis, A. I.;
Bamblon, C.; Lassaux, P.; Papamicael, C.; Roberts, G. C. K.; Galleni,
M.; Dideberg, O.; Frere, J.-H.; Schofield, C. J. Org. Biomol. Chem.
2008, 6, 2282.
(21) Molander, G. A; Pack, S. K. J. Org. Chem. 2003, 68, 9214.
(22) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1995, 60, 3221.
627
dx.doi.org/10.1021/jo302438k | J. Org. Chem. 2013, 78, 614−627