N,3,4-Trisubstituted pyrrolidines by electron transfer-induced oxidative cyclizations of N-allylic β-amino ester enolates

Article abstract of DOI:10.1016/j.tet.2009.10.034

Oxidative radical cyclizations starting from easily accessible N-allylic β-alanine esters are reported. Deprotonation generates the corresponding enolates, which are transformed efficiently into α-ester radicals by single electron transfer mediated by fer

Full text of DOI:10.1016/j.tet.2009.10.034

Tetrahedron 65 (2009) 10917–10929
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N,3,4-Trisubstituted pyrrolidines by electron transfer-induced oxidative
cyclizations of N-allylic b-amino ester enolates
,
a
a
b
Ullrich Jahn a , Frantisek Kafka , Radek Pohl , Peter G. Jones
*
ˇ
a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo namesti 2, 16610 Prague, Czech Republic
b Institut fu¨r Anorganische und Analytische Chemie, Technische Universita¨t Braunschweig, Hagenring 30, 38106 Braunschweig, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Oxidative radical cyclizations starting from easily accessible N-allylic
b-alanine esters are reported. De-
Received 13 August 2009
Received in revised form
22 September 2009
Accepted 9 October 2009
Available online 13 October 2009
protonation generates the corresponding enolates, which are transformed efficiently into
single electron transfer mediated by ferrocenium hexafluorophosphate. The stereochemistry of the radical
5-exo cyclization can be switched by the configuration of the enolate precursor. First examples of asym-
metric oxidative radical cyclizations using N-(1-phenylethyl)-substituted b-amino esters are reported. Only
two of the four possible diastereomers are formed from the (E)-enolate with high cis-selectivity. From (Z)-
enolates, an additional diastereomer is formed, which is likely to be formed only under chelation control.
Ó 2009 Elsevier Ltd. All rights reserved.
a
-ester radicals by
1. Introduction
1
R
2
PF
6
R
Pyrrolidines are important heterocyclic components of drugs and
natural products.1 They have gained importance as organocatalysts
or ligands.2 There are numerous methods for synthesizing pyrroli-
dines.3 Common strategies include intramolecular alkylations, [3þ2]
cycloadditions,4 intramolecular hydroaminations,5 transition metal-
catalyzed cycloisomerizations6 and other cyclization approaches,7
Tsuji–Trost-type reactions8 or modifications of prolines and N-acyl-
pyrrolidines9 and aza-Michael additions.10 Radical cyclizations con-
2
RN
Li
1
4
R
R
CO R
2
Fe
1
3
+
3
O
R
N
R
A
4
3
OR
R
2
2
stitute an important method for the access to pyrrolidines.11
A
2
R
R
1
4
1
4
R
CO R
R
number of reductive radical cyclization approaches exist for their
synthesis, which require, however, the preparation of functionalized
starting materials. There are also a few anionic cyclizations of
N-homoallyl glycinates that lead to 3-substituted prolines.12 The
scopeof this method ishoweverlimited.Morerecentlyapproachesto
pyrrolidine-3-carboxylates using metallo-ene reactions or radical
cyclizations using organometallic initiators such as diorganozinc
reagents have been developed.13 Traces of oxygen promote a radical
addition/5-exo cyclization process, in which the final radical is trap-
ped by the organometallic species to give organozinc intermediates,
which can be applied in a variety of subsequent polar reaction steps.
We have a longstanding interest in electron transfer-induced
oxidative tandem reactions.14 Recently, we developed an oxidative
tandem anionic-radical methodology for the synthesis of pyrroli-
dines (Scheme 1).15 In this process anionic conjugate additions of
2
CO R
2
3
3
R
N
R
R
N
R
C
B
N
O
TMP
N
O
=
N
4
4
1
1
R
2
R
R
4
CO R
2
2
NR
TMPO
R
4
CO R
2
3
3
R
R
N
R
OTMP
5 4-19 %
6 31-87 %
cis/trans 1:2.4 - 6.7:1
* Corresponding author. Tel.: þ420 220183219; fax: þ420 220183578.
E-mail address: jahn@uochb.cas.cz (U. Jahn).
Scheme 1. Tandem anion/radical sequence for the synthesis of pyrrolidines 6.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.034

10918
U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
lithium N-allylic amides 1 to
a
,b
-unsaturated esters 2, oxidative
2.1. Synthesis of the starting
b-amino esters 7
radical 5-exo cyclizations mediated by the single electron transfer
oxidant ferrocenium hexafluorophosphate 3 and oxygenations by
the stable free radical TEMPO 416 are combined. The pyrrolidines 6
were isolated in 31–87% yield with exclusive 2,3-trans and variable
3,4-diastereoselectivity.
To explore this hypothesis, N-allyl-
b
-alaninates 7 were synthe-
sized using an aza-Michael reaction of amines 1 themselves to 2
since they are less basic and enolate formation is not an issue. Initial
attempts applying a literature method18 failed for the reaction of 1a
with 2a. Thus, a new method was devised to obtain 7. Mixing
N-allylamines 1a–b with 2a or methyl acrylate 2b and 10 mol % of
anhydrous lithium chloride and stirring the inhomogeneous re-
Premature trapping of the initial a-ester radical B occurred only
to a limited extent. An inherent advantage of the methodology
compared to traditional radical-based approaches is that no prior
functionalization is required. The enolate A generated in the addi-
tion step serves as the trigger for the radical cyclization step (B/C).
Our interest in applying this methodology to the synthesis of nat-
ural products necessitated a more detailed investigation of the
structural features that determine the outcome of such sequences.
Here we report our results on oxidative SET-mediated tandem
addition/cyclization sequences and of oxidative radical 5-exo cy-
action mixture vigorously until completion (by TLC) gave the b-
alanine esters 7 (Scheme 3, Table 1). The reaction was slow at room
temperature (entries 1,4), but it proceeded smoothly in high yield at
50 ꢀC (entries 2,3,5,6). A control experiment under conditions
identical to entry 1 but in the absence of lithium chloride gave only
an 18% yield of 7a. A simple dilution with ether and filtration to
remove the catalyst gave the essentially pure
b
-amino esters 7a–d.
clization/oxygenation reactions of N-allylic
b-alanine derivatives
2
for the synthesis of 4-(piperidinyloxymethyl)pyrrolidine-3-car-
boxylates. We present an asymmetric version of these cyclizations
using 1-phenylethylamine as the chiral auxiliary17 and also a new
catalytic method of preparing the starting esters.
CO R
2
HN
10 mol% LiCl
1
1a,b
R
+
O
neat, 50 °C
N
R
2
1
OR
7a-d
2a,b
2. Results and discussion
2
CO R
2
MeOH, 20 °C, 68-92 h
Attempts to adapt the tandem conjugate addition/SET oxida-
tion/radical 5-exo cyclization/oxygenation reactions to lithium N,N-
diallylamide 1a and tert-butyl acrylate 2a, in analogy to our initial
conditions,15 met very limited success (Scheme 2). On addition of
2a to a solution of lithium N,N-diallylamide the reaction mixture
became inhomogeneous, in contrast to all earlier reactions. In the
following oxidation step, mediated by 3 in the presence of 4, con-
sumption of 3 was low. Products 5a and 6a were isolated in only
10% and 6% yield, respectively. To shed more light on the reaction
course, the reaction mixture was hydrolyzed after consumption of
N
Ph
2
2
7e R = tBu, 81%
7f R = Me, 70%
Scheme 3. Preparation of N-allyl-
b
-alanine esters 7.
1a and 2a. The expected b-amino ester 7a was obtained in a maxi-
Table 1
mum yield of only 30% after exploring a variety of different reaction
conditions and reagent ratios, but the mass balance of the reaction
was always low. This indicated that Michael-type polymerization
was the dominant pathway; thus Michael addition of 2a to 7a* was
faster than aza-Michael addition of 1a to 2a. It can, however, be
concluded that the radical cyclization step of 7* may be a viable
reaction step when decoupled from the conjugate addition.
N-Allylic b-alanine esters 7
Entry
R1
R2
Ratio 1:2
Temp (ꢀC)
Time (h)
7 (%)
1
2
3
4
5
6
All
All
All
Bn
Bn
Bn
tBu
tBu
Me
tBu
tBu
Me
1:1
20
50
40
20
50
40
23
29
45
50
90
50
7a (69)
7a (86)
7b (94)
7c (47)
7c (90)
7d (98)
1:1.2
1:1.5
1:1
1:1.5
1:1.5
However, when the amine is branched at the
a
-position as in
LiO
LiN
chiral N-allyl-1-phenylethylamines 1e,f, this method failed. Com-
pounds 7e and 7f were synthesized in 81 and 70% yield applying
a method developed by Denes and co-workers.19
2
OtBu
+
1a
O
N
OtBu
All
7a*
2.2. Oxidative radical cyclization/oxygenation reactions
2a
of b-amino esters 7a–f
All = Allyl
PF
6
The oxidative radical cyclizations were performed by deproto-
nation of N-allylic -alanine esters 7a–f with LDA in DME or THF for
TMP =
N
b
Fe
30 min, subsequent addition of 0.2 equiv of TEMPO 4, followed by
addition of a homogenized mixture of 3 and the remaining 4 at
ꢁ78 ꢀC against a stream of argon with vigorous stirring (Schemes 4
and 5, Tables 2 and 3). When the addition was complete, further 3
was added in small portions until the mixture became blue and
inhomogeneous. On average 1.5 equiv of 3 were necessary for
complete oxidation. From the cyclization reactions of achiral esters
7a–d, a diastereomeric mixture of the cyclized compounds cis- and
trans-6a–d was isolated as the major product in 28–65% yield. In
addition, the acyclic combination products 5a–f were isolated in 0–
49% yield, and in almost all cases starting ester 7 was recovered in
N
O
H O
2
3
4
OTMP
CO tBu
CO tBu
2
2
N
2
+
CO tBu
2
N
N
All
All
OTMP
5a 10 %
6a 6%
7a <30%
Scheme 2. Attempted tandem addition/cyclization with 1a and 2a.

U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
10919
Table 2
2
2
Cyclization results of 7a–d*a
CO R
CO R
LDA, additive,
2
2
–78 °C, 30 min,
Entry
7
Solvent Methodb Tc (ꢀC) 5 (%) 6 (%) 7d (%) cis/trans
1e
2e
3f
4
5
6
7
8
a
a
a
a
a
a
b
b
c
c
c
c
c
c
c
d
DME
DME
THF
DME
DME
DME
DME
THF
DME
DME
DME
DME
DME
DME
DME
DME
A
A
A
B
ꢁ78
ꢁ20
ꢁ78
ꢁ78
ꢁ20
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ25
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ20
ꢁ78
46
20
26
3
38
45
35
65
53
45
38
28
39
47
38
41
44
44
42
37
3
7
3.9:1
3.4:1
4.3:1
1:2.8
1:1.5
2:1
1:1.6
5.4:1
5.8:1
4.2:1
7:1
7:1
1:1.1
6:1
9:1
7:1
then 3, temp
N
N
R
1
1
18
22
27
24
d
9
R
7a-d
7a-d*
B
d
4
Ag
B
9
d
23
49
14
19
26
18
27
22
17
C
9e
10h
11i
12j
13h
14f
15f
16f
A
A
A
A
B
C
C
A
4
26
10
13
21
18
27
23
OTMP
OTMP
2
2
1
CO R
CO R
2
2
R N
2
CO R
+
+
+ 7a-d
2
a
Unless otherwise stated, 7 was deprotonated by 1.25 equiv of LDA at ꢁ78 ꢀC for
30 min in the absence or presence of additives in the stated solvent (Methods A–C).
TEMPO 4 (0.2 equiv) was added and a homogeneous mixture of 1.0 equiv of 3 and
0.8 equiv of 4 was added as a solid under a countercurrent of dry argon as 3 was
consumed. If the reaction was not complete as seen by consumption, further 3 was
added until the reaction mixture became blue and inhomogeneous.
N
N
R
OTMP
1
1
R
cis-6a-d
trans-6a-d
5a-d
recovered
Scheme 4. Oxidative radical 5-exo cyclization/oxygenation sequences of
enolates 7a–d*.
b-amino ester
b
Method A: In the absence of additives. Method B: HMPA (6.0 equiv) was added
before addition of ester. Method C: Anhydrous LiCl (7.0 equiv) was added from the
beginning.
c
2
Temperature for addition of 3,4.
Recovered 7.
TEMPO (1.0 equiv) was added first, followed by portion wise addition of 3 until
CO R
2
d
e
the reaction mixture became blue and inhomogeneous.
N
f
Reaction mixture was quenched by D2O, no deuterium incorporation was
detected in the products.
g
HMPA (6.0 equiv) was added after deprotonation of 7 and just before oxidation.
Experiment run in duplicate, outcome identical.
Double concentration of 7.
An excess of 2.0 equiv of LDA was used.
Ph
h
7e,f
i
j
LDA, additive,
–78 °C, 30 min,
then 3, 4, temp
Table 3
Cyclization results of 7e,fa
OTMP
CO R
OTMP
Entry
7
Solvent Method T (ꢀC) 5 (%) 6 (%) 7b (%) (1R,3S,4R):(1R,3R,4S):
(1R,3S,4S)
TMPO
R O C
2
2
2
CO R
2
2
2
1
2
3
4
e
e
e
f
f
f
DME
DME
THF
A
B
C
A
B
C
ꢁ20 Trace 52
26
36
11
16
26
10
1.2:1:trace
3:1:2
1.4:1:trace
1.5:1:trace
3.2:2:1
ꢁ78 8c
43
59
49
39
50
+ 5e,f
+ 7e,f
+
+
ꢁ78 16c
N
N
N
DME
DME
DME
ꢁ78
ꢁ78
d
d
5
6d
ꢁ78 11c
1.7:1:trace
Ph
6e,f
Ph
(1R,3S,4S)
Ph
(1R,3S,4R)
a
Unless otherwise stated, reaction conditions were identical to those of the cy-
clization of achiral substrates 7a–d (cf. Table 2).
(1R,3R,4S)
b
Recovered 7.
Diastereomeric ratio 1:1.
Reaction mixture was quenched by D2O, no deuterium incorporation was
c
Scheme 5. Oxidative radical cyclizations of chiral
b-alanine esters 7e,f.
d
detected in the products.
0–27% yield. Several factors influenced the reaction course and the
product ratios significantly. It proved useful to add only a part of 4
at the beginning and then add a mixture of 3 and 4, since this kept
the concentration of the persistent radical 4 lower and thus de-
creased the extent of premature trapping to 5.20
The tert-butyl esters 7a and 7c gave better yields than the cor-
responding methyl esters 7b and 7d (entries 1–6, 9–15 vs 7,8,16).
The yields were usually somewhat higher in DME than in THF,
while the amount of recovered 7 was higher in THF (entries 1,2 vs
3). The use of HMPA as an additive increased the yield of cyclized
products (entries 1,2 vs 4,5). Lithium chloride as an aggregate-
breaking additive led in some cases to slightly better yields of 6
(entries 14,15). An increase in temperature led to increased yields of
products 6 (entries 1 and 10 vs 2 and 11), while an increase of the
concentration of the enolate of 7 from 0.05 M to 0.1 M had no
significant effect on the product distribution (entry 11 vs 12). In an
attempt to shed light on the origin of the rather large amounts of
recovered ester 7, several reaction mixtures were quenched by
deuterium oxide (entry 3,14–16). However, no deuterium in-
corporation was found in recovered 7.
The stereoselectivity of the cyclization reaction proved to be
dependent on the nitrogen substituent and the reaction conditions.
From ester 7a the 3,4-cis isomer predominated (entries 1–3).
However, when HMPA was used as an additive prior to deproto-
nation, the diastereoselectivity was surprisingly reversed (entries
4,5). On the other hand no reversal of diastereoselectivity was ob-
served, when HMPA was added after the deprotonation was com-
plete (entry 6). Not surprisingly, the diastereoselectivity of the
cyclization decreased when the reaction temperature was in-
creased from ꢁ78 to ꢁ20 ꢀC (entries 1,4,10 vs 2,5,11).
The 3,4-cis diastereoselectivity of the oxidative cyclizations was
generally better using the N-benzyl substituent in 7c,d (entries 9–
16). The diastereoselectivity also changed on addition of HMPA, but

10920
U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
not as dramatically as in case of the N-allyl unit (entry 12 vs 13). In
the presence of LiCl the diastereoselectivity increased with in-
creasing temperature (entry 15 vs 14). This is attributed to an in-
creased solubility of LiCl in DME at higher temperature and better
formation of mixed aggregates.21
The cyclization results for the chiral esters 7e,f are summarized
in Scheme 5 and Table 3. The yields of cyclized products were also
better for the tert-butyl ester 7e than for methyl ester 7f (entries 1–
3 vs 4–6). When the cyclization was performed according to
methods A and C, the simple cyclization diastereoselectivity was
very high, since only two cis-isomers out of the possible four di-
astereomers were formed (entries 1,2,4,5). The (1R,3S,4R)-
6e,f:(1R,3R,4S)-6e,f ratio was, however, low. In the presence of
HMPA as an additive, a 3,4-trans-diastereomer was formed to
information 1.5 equiv of N-oxoiminium hexafluorophosphate 1022
was added to a solution of enolate 7c* in the absence of 3 at ꢁ78 ꢀC in
THF (Scheme 7). It was indeed consumed instantaneously. After
workup, 60% of 5c was obtained and 16% of starting 7c was recovered,
but no trace of cyclized product 6c was detected. When the reaction
was run at ꢁ20 ꢀC (in duplicate), only 22% of 5c was obtained and
a much larger amount of 51% of 7c was recovered. A 6% yield of
cyclized product 6c and traces of an unknown compound, which was
never observed in the cyclization experiments and does not contain
the TMP unit, was also obtained from the reactions. Quenching by
D2O revealed no deuterium incorporation in 5c–7c.
LiO
OtBu
a
sizeable extent, to which the (1R,3S,4S)-configuration was
LDA, THF,
7c
assigned (entries 2,5). The acyclic oxygenation products 5e and 5f
were isolated as a diastereomeric mixture in a 1:1 ratio. Their
configuration was not assigned.
–78 °C,
N
25 min
Bn
7c*
The change of diastereoselectivity that accompanied the use of
HMPA as an additive was surprising and is potentially related to the
enolate geometry after deprotonation. To gain more information,
the enolate 7a* generated by deprotonation in DME was subjected
to trapping by chlorotrimethylsilane (Scheme 6). A mixture of silyl
ketene acetals 8a was isolated in 89% yield in a 6:1 (E/Z)-ratio. In
addition 11% of C-silylated ester 9a was detected. When the same
experiment was repeated in the presence of HMPA, no 8a was
isolated. The reaction mixtures of several experiments under
varying isolation conditions consisted only of C-silylated 9a and
starting material according to NMR analysis.
temp.
N
O
10
PF
6
TMPO
CO tBu
2
CO tBu
2
N
+ 7c +
Bn
OTMP
5c
N
Bn
6c
Temp.
recovered
16%
–78 °C
–20 °C
-
60%
22%
51%
6%
LiO
OtBu
Scheme 7. Reaction between enolate 7c and N-oxopiperidinium salt 10.
LDA, DME,
7a
–78 °C, 25 min
The configuration of products 6a–f was assigned in analogy to
the diastereomers D and E obtained from the tandem amide con-
jugate addition/radical cyclization/oxygenation reactions reported
earlier (Fig. 1, Table 4).15 The relative cis-configuration was con-
firmed for the major diastereomers of 6a, 6c and the two major
diastereomers (1R,3S,4R)-6e and (1R,3R,4S)-6e by ROESYanalysis. A
strong NOE effect between the tert-butyl and the piperidinyloxy-
methyl group was observed (Supplementary data). Such an NOE
effect was, however, not detected for (1R,3S,4S)-6e with 3,4-trans-
N
All
7a*
Me SiCl, –78 °C
80 min
3
89%
Me SiO
tBuO
3
tBuO C
OtBu
2
OSiMe
3
H
H
configuration. In addition, H5
investigated compounds.
b showed a clear NOE to H6 in all
Me Si
3
+
:
+
:
All N
(E)-8a
All N
(Z)-8a
All N
2
2
2
1 OTMP
9a
R
2
R
4
CO R
2
6
1
1
a
H
OTMP
CO R
OTMP
CO R
5
2
Scheme 6. Generation of silyl ketene acetals 8 after deprotonation of 7a (Curves in-
dicate NOE contacts).
3
2
2
b
R
N
H
2
2
R
D
a
b
a
b
H
H
H
Since several mechanisms for the SET oxidation and the further
course of the oxidative cyclizations of 7a–f can be envisaged, addi-
tional experiments were performed. It was determined in a control
experiment that 4 does not act as an oxidant for the enolate 7a*. Both
starting materials were recovered unchanged quantitatively. Fur-
thermore, 4 may be oxidized by 3 tothe N-oxopiperidinium ion 10 (cf.
Scheme 7), which may subsequently act as the actual oxidant for 7a*.
Since no interaction between 3 and 4 was noticeable in the solid state
(vide supra), 4 was dissolved in DME and an equimolar amount of 3
was added. After 60 min at ꢁ78 ꢀC and ꢁ20 ꢀC, 91 and 95% of 3 was
recovered unchanged by filtration from the blue inhomogeneous
mixture under inert conditions, while 82 and 96% of 4 were reiso-
lated after evaporation of the solvent. However, this does not prove
definitely that 3 is not oxidizing 4 to a small extent in equilibrium
thus driving the oxidative cyclization. To gain more detailed
5
5
2
2
N
H
N
R
1
OTMP
1
1
R
R
2
R
4
CO R
2
cis-6a-f
trans-6a-f
a
H
5
2
3
b
R
N
H
R
E
Figure 1. Structures and relative configurations of 6.
The N–O bond of the alkoxyamine function in 6 can be cleaved
reductively.15 Heating a mixture of cis- and trans-6a with zinc and
acetic acid to 80–90 ꢀC gave a mixture of the free alcohols cis- and
trans-11a and the bicyclic lactone 12a in 55% yield (Scheme 8). In the

U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
10921
C6
Table 4
Characteristic 1H and 13C NMR resonances of the diastereomeric 6 in ppm
Compound
H2
H2
H3
H4
H5a
H5b
H6
Da
cis-6a
cis-6b
cis-6c
d
d
2.5–2.8
2.94
3.03
2.96
3.06
2.93
3.06
3.02
3.18
2.2–2.5
2.61
2.69
2.61
2.69
2.93
2.75
2.6–2.9
2.61
2.69
2.61
2.69
2.69
2.78
2.60
2.68
2.5–2.9
2.54
2.69
2.54
2.69
2.58
2.70
3.1–3.5
3.04
3.03
2.96
2.95
3.16
3.20
2.68
2.72
2.7–3.1
2.69
2.69
2.68
2.69
2.75
2.72
2.2–2.4
2.29
2.23
2.41
2.31
2.41
2.36
2.56
2.35
2.3–2.6
2.41
2.40
2.45
2.45
2.60
2.62
3.7/3.8
<77
76.7
76.2
76.6
76.2
76.5
75.7
76.1
75.5
>78
78.7
78.4
78.7
78.5
78.3
78.1
2.54
2.57
2.61
2.61
2.58
2.58
2.73
2.71
d
2.94
3.03
2.87
2.95
2.73
2.79
2.93
3.17
d
3.62/3.80
3.59/3.74
3.66/3.78
3.61/3.73
3.73/3.82
3.70/3.80
3.71/3.78
3.64/3.76
3.7/3.85
3.72/3.72
3.74/3.74
3.72/3.72
3.60/3.73
3.78/3.78
3.76/3.76
cis-6d
(1R,3S,4R)-6e
(1R,3S,4R)-6f
(1R,3R,4S)-6e
(1R,3R,4S)-6f
Ea
trans-6a
trans-6b
trans-6c
trans-6d
(1R,3S,4S)-6e
(1R,3S,4S)-6f
2.61
2.69
2.68
2.69
2.71
2.67
2.72
3.03
2.87
3.06
2.74
2.75
a
Average values over all compounds in Ref. 15.
deprotection of the three component mixture of (1R,3S,4R)-6e,
(1R,3R,4S)-6e, and (1R,3S,4S)-6e, the same lactones (5R,3S,7R)-12e
and (5R,3R,7S)-12e were formed in a 3:1 diastereomeric ratio in 28%
yield, while the free trans-alcohol (1R,3S,4S)-11e was also obtained
in 18% yield. Although corresponding experiments were not per-
formed here, the N-allyl, N-benzyl and N-(1-phenylethyl) groups
can be deprotected in principle under reductive conditions.23
The constitution and absolute configuration of the major lactone
12e was proved unequivocally by X-ray crystallography (Fig. 2).24
The butyrolactone ring of the bicyclic system is almost planar
(mean deviation 0.006 Å), while the pyrrolidine ring prefers an
envelope conformation, in which the carbon atoms C2–C5 are al-
most coplanar (mean deviation 0.014 Å) and the nitrogen lies
0.65 Å out of the plane thus defined. Since the 1-phenylethyl group
in the starting material 7e has an (R)-configuration the configura-
tions of the bridge of the bicycle can be derived to (3S,7R). However,
in this case the anomalous dispersion of oxygen is sufficient to
determine the absolute configuration directly without recourse to
a known center. This result provides further support for the as-
signment of the absolute configurations to the other diastereomers
obtained in the oxidative cyclizations of 7e,f.
OTMP
OTMP
CO tBu
CO tBu
2
2
+
N
N
All
cis-6a
All
trans-6a
50 equiv. Zn
28% 6a
55%
O
AcOH/THF/H O 3:1:1
2
recovered
OH
OH
O
CO tBu
CO tBu
2
2
+
:
H
H
+
N
N
N
All
trans-11a
All
cis-11a
2.5
All
12a
:
1
1
TMPO
tBuO C
OTMP
CO tBu
OTMP
CO tBu
2
2
2
+
+
N
N
N
Ph
Ph
(1R,3R,4S)-6e
Ph
(1R,3S,4S)-6e
(1R,3S,4R)-6e
50 equiv. Zn
AcOH/THF/H O
4-18% 6e
46-74%
recovered
2
OH
O
O
O
O
CO tBu
2
+
+
H
H
H
H
5
N
Figure 2. Structure of (5R,3S,7R)-12e in the crystal.
N
N
Ph
(5R,3S,7R)-12e
Ph
(5R,3R,7S)-12e
Ph
(1R,3S,4S)-11e
The results of the oxidative cyclizations can be rationalized as
follows. Deprotonation of b-alanine esters 7a–f by LDA alone or in
the presence of lithium chloride gives predominately the (E)-enolate
(E)-7* as seen by the configuration of the silyl ketene acetal (E)-8a.
Two principal pathways are possible for the SET oxidation of 7*
(Scheme 9). The first consists of direct oxidation of 7* mediated by
Scheme 8. Reductive deprotection of the 2,2,6,6-tetramethylpiperidine unit in 6a and 6e.
case of 6e resulting from cyclization according to method C, both
major cyclized isomers led to lactones (5R,3S,7R)-12e and
(5R,3R,7S)-12e in 74% yield in a 1.6:1 diastereomeric ratio. During
ferrocenium hexafluorophosphate 3 giving an
a-ester radical 13,

10922
U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
3
LiO
N
O
OTMP
CO tBu
OtBu
OtBu
2
LDA
1. 5-exo
2. 4
7
N
R
N
R
1
1
7*
13
1
R
6
4
–20 °C
N
SET
PF
6
SET
polar oxygenation
caged radical pair
–78 and –20 °C
O
O
10
–78 and –20 °C
OtBu
combination
CO tBu
2
N
N
O
1
R
N
R
OTMP
1
5
13-4
Scheme 9. Mechanism of SET oxidation of enolates 7*.
which cyclizes to 6. This pathway is supported by a number of prior
investigations, in which 3 was used to trigger efficient radical cycli-
zations in the absence of 4.14d,25 In the presence of TEMPO 4, 3 may
competitively act as an oxidant for 4 generating oxoiminium ion 10
as an intermediate. This compound can be envisaged as a SEToxidant
for 7* affording radical 13 that will ultimately cyclize to 6.26
The latter pathway cannot be a significant contributor to the
outcome of the cyclization reactions. First, oxidation of 4 by 3 to 10 is
2
CO R
2
N
R
1
LDA, (LiCl),
LDA, HMPA,
DME, -78 °C
7a-d
THF or DME,
-78 °C
Li
2
OR
O
OR
1
1
R
R
2
N
N
Solv-H
OLi
(E)-7*
(Z)-7*
Path C
3
3
3
3
Li
O
Li
2
1
1
R
O
OR
2
CO R
2
R
CO R
1
2
2
N
N
1
R
2
OR
R
N
N
chair-13
boat-13
anti-chelate-13
syn-chelate-13
Path B
4
4
1
R
N
Path A
Path A
2
CO R
2
OTMP
5a-d
1
1
R
R
1
1
N
2
2
N
R
R
CO R
CO R
2
2
N
N
2
2
CO R
2
CO R
2
cis-14a-d
trans-14a-d
trans-15a-d
cis-15a-d
4
4
4
2
OTMP
2
1
CO R
R
2
1
N
R
CO R
2
N
OTMP
trans-6a-d
cis-6a-d
Scheme 10. Mechanistic and stereochemical rationalization of the cyclizations of 7a–d.

U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
10923
2
H Me
H
Me
N
CO R
2
2
4
CO R
2
N
Ph
Ph
OTMP
17
(1R,3S,4R)-6e,f
2
H Me
Me
N
(E)-7e,f*
H
OR
3
2
CO R
2
N
Ph
Ph
OLi
chair-16
H Me
H
Me
N
O
OTMP
2
4
CO R
2
2
N
Ph
LDA, (LiCl),
THF or DME,
-78 °C
OR
Ph
18
(1R,3R,4S)-6e,f
2
CO R
2
7e,f
N
Ph
Li
Me
H Me
H Me
H
O
4
LDA, HMPA,
DME, -78 °C
OTMP
2
2
OR
N
N
N
Ph
Ph
Ph
2
CO R
CO R
2
2
3
20
(1R,3S,4S)-6e,f
anti-chelate-19
Li
Me
H
O
2
OR
N
Ph
3
Li
Me
H
OTMP
2
H Me
Me
H
O
(Z)-7e,f*
4
2
OR
N
N
N
2
Ph
Ph
Ph
CO R
CO R
2
2
22
(1R,3R,4R)-6e,f
anti-chelate-21
Scheme 11. Model for the formation of the stereoisomeric products 6e,f.
very slow at ꢁ78 and ꢁ20 ꢀC, if occurring at all, based on the control
experiments. Using isolated 10 as the stoichiometric oxidant for 7* in
the absence of 3 at ꢁ78 ꢀC gave only isoserine derivative 5 and not
a trace of cyclized 6. Compound 5 arises here either from a direct
polar oxygenation of 7* with 10. Alternatively, a SEToxidation of 7* to
a caged radical pair 13–4 is possible, which combines to 5 before cage
escape to free radicals 13 and 4 can occur. At ꢁ20 ꢀC, the reaction
between 10 and 7* was much less efficient, though 6% of 6c were
indeed formed. The ratio of isolated 5, 7 and 6 was, however, very
different from the cyclization reactions mediated by 3. Thus, 10 ox-
idizes 7* only to a small extent at the higher temperature to free
radical 13, which cyclizes to 6. Alternatively, cage escape from radical
pair 13–4 leading to 6 may be a somewhat more facile at ꢁ20 ꢀC
compared to ꢁ78 ꢀC. Taken these results together, direct oxidation of
7* by 3 and subsequent cyclization to 6 is much more plausible than
assuming a cyclization process invoking 10 as the oxidant.
oxygenation sequences reported earlier.15 Apparently, if a substituent
is missing in the 2-position of the enolates, the cyclization is slowed
down considerably sothat intermolecular coupling with 4 and radical
reduction of the a-ester radical compete to a more significant extent.
In contrast, deprotonation in the presence of HMPA is known to
lead to predominant formation of the corresponding (Z)-enolates
(Z)-7*.29 They are most probably chelated by the amino function in
the molecule. Enolates (Z)-7a–d* give on oxidation essentially the
same products 5a–d and 6a–d as the (E)-enolate. Interestingly, the
stereoselectivity of the cyclization varies with the enolate geometry
of 7a–d*. Enolates (E)-7* cyclize predominately via transition state
chair-13, while the minor isomer may arise via boat-13. The signif-
icantly different diastereoselectivity observed in the cyclizations in
the presence of HMPA suggests, that the chelate is at least to a rea-
sonable extent conserved on oxidation from (Z)-7* to chelate-13.
Cyclization to the major isomers trans-6a–d should occur via the
sterically favored transition state anti-chelate-13a–d and coupling of
resulting radicals trans-15a–d with 4. The minor isomers cis-6a–
d can arise either via cyclization of syn-chelate-13 or via equilibra-
tion of radicals chelate-13 to the open radicals chair- and boat-13 and
subsequent cyclization. An unambiguous determination of the ac-
tual pathways is, however, not possible for achiral substrates 7a–d.
The cyclization of the chiral substrates 7e,f provided valuable
insight into the reaction course since the exocyclic stereocenter of
the chiral N-(1-phenylethyl) group provides a bias for the radical
cyclization steps (Scheme 11). The cyclization of the (E)-enolates
7e,f* occurred with the best simple cis-cyclization diastereo-
selectivity and only two of the four possible isomers, namely
(1R,3S,4R)-6e,f and (1R,3R,4S)-6e,f, were isolated. The chiral aux-
iliary differentiates the orientations of substituents in radical chair-
16, thus the cyclization proceeds through two diastereomeric
transition states 17 and 18. The discrimination between them is,
however, poor. Transition state 17 is apparently lower in energy,
since it is free of steric interactions, while 18 seems to be slightly
disfavored because of a syn-pentane-type interaction30 between
the methyl and ester groups.
Enolates (E)-7* are certainly aggregated in solution, but cannot
be chelated by the amino group (Scheme 10). On SET oxidation by 3,
which is apparently quantitative,
a-ester radicals 13 result, for
which three reaction channels were observed. Most of radicals 13
undergo a 5-exo cyclization to radicals 14 followed by coupling with
TEMPO 4 to give pyrrolidine derivatives 6 (Path A). Another portion
of 13 is trapped by 4 prior to cyclization furnishing the protected
isoserine derivatives 5 (Path B). A third portion of 13 is reduced
leading to recovery of esters 7 (Path C). Path C cannot be related to
incomplete deprotonation or oxidation and re-formation of 7 by
protonation after the reaction, since considerable amounts of 7
were formed with even larger amounts of base. Furthermore,
deuterium incorporation was never observed on hydrolyzing the
reaction mixtures with deuterium oxide. Moreover, ferrocenium
hexafluorophosphate is also unlikely as a source of moisture, since
it is not hygroscopic.27 Thus, recovered 7 is most probably produced
by hydrogen atom transfer from the solvent or diisopropylamine,
which should be reasonably fast.28
It was surprising that 5 and 7 were produced to a larger extent
compared to the tandem lithium amide addition/cyclization/

10924
U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
Cyclization of the corresponding (Z)-enolates 7e,f* leads in
CH2]CH). 13C NMR (100 MHz, C6D6):
d
¼28.5 (q, C(CH3)3), 34.8 (t,
contrast to three diastereomers. This indicates clearly that a differ-
ent pathway operates. On oxidation of chelated 7e,f* a part of the
radical anti-chelate-19 cyclizes. In this case, however, only one di-
astereomer (1R,3S,4S)-6e,f is formed in large excess. Only anti-
chelate-19 has no unfavorable steric interactions during cyclization
to 20, while a strong steric interaction between the methyl group
and the N–CH2 group of the aminoester unit builds up in the al-
ternative cyclizing radical anti-chelate-21, thus preventing cycliza-
tion to the alternative trans-diastereomer (1R,3R,4R)-6e,f via 22.
The formation of the two cis-isomers (1R,3S,4R)-6e,f and
(1R,3R,4S)-6e,f cannot be attributed to cyclization via a chelated
radical such as syn-chelate-13 (cf. Scheme 10). In this case also one
of the two diastereomers is expected to be formed in larger excess,
since the same interactions as in anti-chelate-19 and anti-chelate-21
should affect the cyclizations. In the event, the cis-diastereomers
(1R,3S,4R)-6e,f and (1R,3R,4S)-6e,f were isolated in a similar ratio
as in the cyclizations of the corresponding (E)-enolates. Thus, it is
more likely that radical anti-chelate-19 relaxes to chair-16, which
cyclizes via 17 and 18 to similar diastereomeric mixtures as those
isolated from (E)-7e,f*.
CH2CH2CO), 49.9 (t, CH2CH2CO), 57.4 (t, CH2CH]), 79.9 (s, C(CH3)3),
117.2 (t, CH]CH2), 136.9 (d, CH]CH2), 171.8 (s, C]O). MS m/z, (%):
225 (Mþ, 40), 184 (85) [Mþ –CH2]CHCH2], 168 (80) [Mþ –C(CH3)3],
142 (70) [Mþ –(CH2]CHCH2)2], 128 (100) [CH2]CHCO2tBuþ], 110
(70) [All2NCHþ2 ], 81 (30), 68 (55). C13H23NO2 (225.33): calcd C 69.29,
H 10.29, N 6.22; found C 69.62, H 10.45, N 5.83.
4.1.2. tert-Butyl 3-(N-allyl-N-benzylamino)propanoate (7c). Yield
after flash chromatography (hexanes/EtOAc 10:1) as a colorless oil
1.652 g (90%) [Rf (hexanes/EtOAc 10:1)¼0.33]. IR (film); v [cmꢁ1]:
~
3036 (m), 2977 (m), 2930 (m), 2801 (m), 1726 (s), 1366 (m), 1251
(m), 1152 (s), 918 (m), 739 (m). 1H NMR (400 MHz, CDCl3):
d
¼1.37
(s, 9H, C(CH3)3); 2.34 (t, J¼7.1 Hz, 2H, CH2CO); 2.71 (t, J¼7.2 Hz, 2H,
NCH2CH2); 3.00 (d, J¼6.2 Hz, 2H, ]CHCH2); 3.51 (s, 2H, PhCH2N);
5.08 (m, 2H, CH2]CH); 5.79 (ddt, J¼6.4, 10.2, 16.7 Hz, 1H,
CH2]CH); 7.16–7.26 (m, 5H, ArH). 13C NMR (100 MHz, CDCl3):
d
¼28.3 (q, C(CH3)3), 34.2 (t, CH2CH2CO), 49.5 (t, CH2CH2CO), 56.8
(t, CH2CH]), 58.1 (t, PhCH2N), 80.41 (s, C(CH3)3), 117.5 (t,
CH]CH2), 127.1 (d, CHAr), 128.4 (d, CHAr), 129.1 (d, CHAr), 135.9 (d,
CH]CH2), 139.6 (s, CAr), 172.2 (s, C]O). MS m/z, (%): 275 (Mþ, 2),
218 (15) [Mþ –C(CH3)3], 184 (22) [Mþ –PhCH2], 160 (80)
[CH2]N(All)Bnþ], 128 (55) [CH2]CHCOOtBuþ], 91 (100) [C7Hþ7 ].
C17H25NO2 (275.39): calcd C 74.14, H 9.15, N 5.09; found C 74.02, H
9.22, N 4.95.
3. Conclusions
In the present study we showed that successful tandem lithium
amide conjugate addition/radical 5-exo cyclization/oxygenation
sequences require the presence of a substituent in 2-position of the
forming ring to be efficient. However, the synthesis of pyrrolidines
can nevertheless be accomplished by decoupling the tandem pro-
4.1.3. (R)-tert-Butyl 3-[N-allyl-N-(1-phenylethyl)amino]propanoate
(7e). Yield after flash chromatography (hexanes/EtOAc 5:1) as
~
a colorless oil 1.00 g (81%) [Rf (hexanes/EtOAc 5:1)¼0.38]. IR (film); v
cess into a two-step methodology. N-Allylic
b
-alanine derivatives
[cmꢁ1]: 2976 (m), 2930 (w), 2817 (w), 1728 (s), 1367 (m), 1256 (m),
were synthesized easily and in high yield by lithium chloride-cat-
alyzed aza-Michael addition of allylic amines to acrylates. They can
be transformed by an oxidative radical cyclization/oxygenation
sequence into N-protected 4-oxymethylpyrrolidine-3-carboxylates
in moderate to acceptable yields. It is surprising that for these
rather unbiased systems diastereoselectivities up to 9:1 can be
observed depending on the nitrogen protecting group. The selec-
tive generation of either (E)- or (Z)-enolates allows the control and
the switch of the diastereoselectivity from a moderate to high cis-
selectivity to a moderate trans-selectivity. The application of the 1-
phenylethyl group allows the asymmetric synthesis of pyrrolidines.
The cyclization proceeds with high cis-diastereoselectivity via two
similar chair-type transition states. The knowledge gained will be
applied in alkaloid synthesis by tandem lithium amide conjugate
addition/radical cyclization reactions.
1153 (s), 917 (m), 701 (m). 1H NMR (400 MHz, CDCl3):
d¼1.28 (d,
J¼6.7 Hz, 3H, CHCH3); 1.36 (s, 9H, C(CH3)3); 2.28 (t, J¼7.3 Hz, 2H,
CH2CO); 2.66 (dt, J¼7.3, 14.3 Hz, 1H, NCHHCH2); 2.79 (dt, J¼7.3,
14.3 Hz, 1H, NCHHCH2); 2.91 (dd, J¼6.3, 14.5 Hz, 1H, ]CHCHHN);
3.02 (dd, J¼6.3, 14.5 Hz, 1H, ]CHCHHN); 3.79 (q, J¼6.8 Hz, 1H,
CHCH3); 5.00 (dd, J¼1.2, 10.2 Hz, 1H, CHH]CH); 5.07 (dd, J¼1.6,
17.2 Hz,1H, CHH]CH); 5.73 (ddt, J¼6.3,10.2,16.6 Hz,1H, CH2]CH);
7.14–7.28 (m, 5H, ArH). 13C NMR (100 MHz, CDCl3):
d¼17.1 (q,
CHCH3), 28.4 (q, C(CH3)3), 34.7 (t, CH2CH2CO), 45.9 (t, CH2CH2CO),
53.4 (t, CH2CH]), 59.2 (d, CHCH3), 80.3 (s, C(CH3)3), 116.7 (t,
CH]CH2), 126.9 (d, CHAr), 127.9 (d, CHAr), 128.2 (d, CHAr), 137.1 (d,
CH]CH2),144.1 (s, CAr),172.4 (s, C]O). MS m/z, (%): 289 (Mþ, 2), 218
(35) [Mþ –CH3–(H3C)2C]CH2], 174 (30) [Mþ –CH2COOtBu], 146 (40)
[PhCH]NHAllþ], 128 (60) [CH2]CHCOOtBuþ], 105 (100)
[PhCHCHþ3 ], 70 (35). C18H27NO2 (289.41): calcd C 74.70, H 9.40, N
4.84; found C 74.58, H 9.51, N 4.77.
4. Experimental
4.1. N-Allylic
b-amino esters 7a–d (General procedure)
4.2. Pyrrolidine-3-carboxylates 6 via oxidative radical 5-exo
cyclizations of b-amino ester enolates (General procedures)
Amine 1 (1.0 equiv) was mixed with acrylate ester 2a or b (1.2–
1.5 equiv; see Table 1) and flame-dried lithium chloride (0.1 equiv)
under an argon atmosphere. The reaction mixture was heated to
50 ꢀC with vigorous stirring until finished by TLC. The reaction
mixture was cooled, diluted with ether and filtered through a pad
of silica gel. The filtrate was evaporated and the crude product was
purified by flash chromatography.
Method A. To a stirred solution of dry diisopropylamine (0.18 mL,
1.25 mmol) in 20 mL anhydrous DME or THF (See Table 2) butyl-
lithium (1.6 M in hexanes, 0.78 mL, 1.25 mmol) was added drop-
b-amino ester 7a–f
(1.0 mmol) in 0.6 mL of dry solvent was added dropwise. After
wise at ꢁ78 ꢀC. After 20 min, a solution of
30 min, TEMPO 4 (0.031 g, 0.2 mmol) was added as a solid. Sub-
sequently
a
thoroughly homogenized mixture of
4
(0.125 g,
4.1.1. tert-Butyl 3-(diallylamino)propanoate (7a). Yield after flash
0.8 mmol) and ferrocenium hexafluorophosphate
3 (0.331 g,
chromatography (hexanes/EtOAc 15:1) as a colorless oil 967 mg
1.0 mmol) was added in small portions with vigorous stirring at the
given temperature. Since discoloration of 3 was still fast at that
stage, further 3 (100–150 mg) was added in small portions, until
a dark blue-green color of reaction mixture persisted for 20 min.
The reaction mixture was quenched by saturated NH4Cl solution or
D2O (five drops), diluted with 20 mL of ether and filtered through
(86%) [Rf (hexanes/EtOAc 20:1)¼0.25]. IR (film); v [cmꢁ1]: 2978 (m),
~
2927 (m), 2808 (m), 1731 (s), 1367 (m), 1255 (m), 1157 (s), 918 (m).
1H NMR (400 MHz, C6D6):
d
¼1.43 (s, 9H, C(CH3)3); 2.35 (t, J¼7.4 Hz,
2H, CH2CO); 2.74 (t, J¼7.4 Hz, 2H, NCH2CH2); 3.07 (d, J¼6.4 Hz, 4H,
]CHCH2); 5.12 (dd, J¼1.0, 10.2 Hz, 2H, CHH]CH); 5.16 (dd, J¼1.7,
17.1 Hz, 2H, CHH]CH); 5.82 (ddt, J¼6.5, 10.2, 16.8 Hz, 2H,
a
pad of silica gel. The filtrate was evaporated, the crude

U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
10925
inhomogeneous mixture was preadsorbed on silica gel and purified
by flash chromatography.
TMP–C(CH3)2), 60.3 (s, TMP–C(CH3)2), 80.7 (s, C(CH3)3), 85.4 (d,
CHOTMP), 117.5 (t, CH]CH2), 135.9 (d, CH]CH2), 172.8 (s, C]O).
Method B. To a stirred solution of dry diisopropylamine (0.18 mL,
1.25 mmol) in 20 mL anhydrous DME or THF (See Table 2) butyl-
lithium (1.6 M in hexanes, 0.78 mL, 1.25 mmol) was added dropwise
at ꢁ78 ꢀC. After 20 min, HMPA (1.05 mL, 6.0 mmol) was added, fol-
4.2.3. Methyl 1-allyl-4-[(2,2,6,6-tetramethylpiperidin-1-yloxy)me-
thyl]pyrrolidine-3-carboxylate (6b). Isolated after flash chroma-
tography (hexanes/EtOAc 50:1 to 1:1) as a pale yellow oil. For yields
and diastereomeric ratios see Table 2. [Rf (hexanes/EtOAc
lowed by a solution of b-amino ester 7 (1.0 mmol) in 0.6 mL of dry
solvent. After 30 min, TEMPO 4 (0.031 g, 0.2 mmol) was added as
a solid. Subsequently a thoroughly homogenized mixture of 4
(0.125 g, 0.8 mmol) and 3 (0.331 g, 1.0 mmol) was added in small
portions with vigorous stirring at the given temperature. Since dis-
coloration of 3 was still fast at that stage, further 3 (100–150 mg) was
added in small portions, until a dark blue-green color of reaction
mixture persisted for 20 min. The reaction mixture was worked up
and purified as described in method A.
Method C. Lithium chloride (0.297 g, 7.0 mmol) was flame-dried
in a Schlenk flask. After cooling to room temperature the solvent
was added and the reaction was performed as described in
method A.
2:1)¼0.21]. IR (film); v [cmꢁ1]: 3078 (w), 2973 (m), 2929 (m), 2797
~
(w),1736 (s),1359 (m),1194 (s), 1046 (m), 919 (m). MS (ESI) m/z, (%):
339 (MþHþ, 100), 198 (15) [Mþ–TMP]. HRMS m/z, (C19H35N2O3;
MþHþ): calcd 339.2642; found 339.2643. 1H NMR (400 MHz,
CDCl3):
d¼0.99–1.05 (m, 24H, TMP–CH3, TMP–CH3*); 1.19 (m, 4H,
TMP–CH2, TMP–CH2*); 1.35 (m, 8H, TMP–CH2, TMP–CH2*); 2.23 (t,
J¼8.9 Hz, 1H, H5); 2.40 (m, 1H, H5*); 2.57 (m, 1H, H2); 2.69 (m, 5H,
H4, H2*, H3*, H4*, H5*); 2.96 (m, 2H, NCH2CH]*); 3.03 (m, 5H, H2,
H3, H5, H2*, NCH2CH]); 3.09 (m, 1H, NCH2CH]); 3.59 (m, 7H, H6,
OCH3, OCH3*); 3.74 (m, 3H, H6, H6*, H6*); 5.03 (d, J¼10.2 Hz, 2H,
CH]CH2, CH]CH2*); 5.14 (d, J¼17.1 Hz, 2H, CH]CH2, CH]CH2*);
5.84 (ddt, J¼6.6, 10.1, 17.0 Hz, 2H, CH]CH2, CH]CH2*). 13C NMR
(100 MHz, CDCl3):
d
¼17.2 (t, TMP–CCH2CH2), 20.09 (q, TMP–CH3),
4.2.1. tert-Butyl 1-allyl-4-[(2,2,6,6-tetramethylpiperidin-1-yloxy)-
methyl]pyrrolidine-3-carboxylate (6a). Isolated after flash chro-
matography (hexanes/EtOAc 50:1 to 1:1) as a pale yellow oil. For
yields and diastereomeric ratios see Table 2. [Rf (hexanes/EtOAc
20.10 (q, TMP–CH3), 33.1 (q, TMP–CH3), 33.2 (q, TMP–CH3), 39.8 (t,
TMP–CCH2), 40.2 (d, C4), 41.5 (d, C4*), 44.2 (d, C3), 46.0 (d, C3*), 51.6
(q, OCH3), 51.9 (q, OCH3*), 56.2 (t, C2), 56.7 (t, C2*), 56.9 (t, C5*), 57.6
(t, C5), 58.8 (t, CH2CH]*), 58.9 (t, CH2CH]), 59.8 (s, TMP–C(CH3)2),
59.9 (s, TMP–C(CH3)2), 76.2 (t, C6), 78.4 (t, C6*), 116.0 (t, CH]CH2*),
117.0 (t, CH]CH2), 135.51 (d, CH]CH2*), 135.55 (d, CH]CH2), 173.6
(s, C]O), 174.8 (s, C]O*). Resonances marked with * belong to 3,4-
trans-6b.
5:1)¼0.19]. IR (film); v [cmꢁ1]: 2975 (m), 2930 (m), 2794 (w), 1728
~
(s), 1367 (m), 1148 (s), 993 (m), 918 (m). MS (ESI) m/z, (%): 381
(MþHþ, 100), 325 (12) [MþHþ –H2C]C(CH3)2], 240 (5) [Mþ –TMP].
C22H40N2O3 (380.56): calcd C 69.43, H 10.59, N 7.36; found C 69.21,
H 10.75, N 7.12. 1H NMR (400 MHz, CDCl3):
d¼1.05–1.14 (m, 24H,
TMP–CH3, TMP–CH3*); 1.23 (m, 4H, TMP–CH2, TMP–CH2*); 1.34 (m,
8H, TMP–CH2, TMP–CH2*); 1.37 (s, 9H, C(CH3)3*); 1.38 (s, 9H,
C(CH3)3); 2.29 (t, J¼8.9 Hz, 1H, H5); 2.41 (dd, J¼6.1, 9.0 Hz, 1H, H5*);
2.54 (m, 2H, H2, H4*); 2.61 (m, 3H, H4, H2*, H3*); 2.69 (m, 1H, H5*);
2.72 (m,1H, H2*); 2.94 (m, 3H, H2, H3, NCH2CH¼*); 3.04 (m, 3H, H5,
NCH2CH¼, NCH2CH¼*); 3.13 (ddd, J¼1.1, 6.3, 13.2 Hz, 1H,
NCH2CH¼); 3.62 (dd, J¼8.6,10.7 Hz,1H, H6); 3.72 (m, 2H, H6*); 3.80
(dd, J¼4.7, 8.5 Hz, 1H, H6); 5.03 (dd, J¼1.6, 10.2 Hz, 2H, CH]CH2,
CH]CH2*); 5.14 (dd, J¼1.6, 17.1 Hz, 2H, CH]CH2, CH]CH2*); 5.84
(ddt, J¼6.5, 10.1, 16.7 Hz, 2H, CH]CH2, CH]CH2*). 13C NMR
4.2.4. Methyl 3-(N,N-diallylamino)-2-(2,2,6,6-tetramethylpiperidin-
1-yloxy)propanoate (5b). Pale yellow oil, for yields see Table 2. [Rf
(hexanes/EtOAc 10:1)¼0.65]. IR (film); v [cmꢁ1]: 3077 (w), 2975
~
(m), 2930 (m),1747 (s),1362 (m), 1176 (m),1041 (s), 918 (s). MS (ESI)
m/z, (%): 361 (100, MþNaþ), 339 (45, MþHþ). HRMS m/z,
(C19H35N2O3; MþHþ): calcd 339.2642; found 339.2639. 1H NMR
(400 MHz, CDCl3):
d
¼0.94–1.11 (m, 12H, TMP–CH3); 1.21 (m, 2H,
TMP–CH2); 1.35 (m, 4H, TMP–CH2); 2.75 (m, 2H, NCH2CHCO); 2.93
(dd, J¼7.1, 14.0 Hz, 2H, NCH2CH¼); 3.07 (dd, J¼5.8, 14.0 Hz, 2H,
NCH2CH¼); 3.63 (s, 3H, OCH3), 4.31 (dd, J¼5.8, 10.2 Hz, 1H,
CHOTMP); 5.04 (m, 4H, CH]CH2); 5.69 (ddt, J¼7.1, 10.1, 17.0 Hz, 2H,
(100 MHz, CDCl3):
d¼17.3 (t, TMP–CCH2CH2), 20.1 (q, TMP–CH3),
20.2 (q, TMP–CH3), 28.3 (s, C(CH3)3*), 28.4 (s, C(CH3)3), 33.4 (q,
TMP–CH3), 33.6 (q, TMP–CH3), 39.9 (t, TMP–CCH2), 40.1 (d, C4), 41.8
(d, C4*), 45.4 (d, C3), 46.7 (d, C3*), 56.1 (t, C2), 56.6 (t, C2*), 57.5 (t,
C5*), 58.4 (t, C5), 59.1 (t, CH2CH]*), 59.2 (t, CH2CH]), 59.8 (s,
TMP–C(CH3)2), 60.1 (s, TMP–C(CH3)2), 76.7 (t, C6), 78.7 (t, C6*), 80.5
(s, C(CH3)3*), 80.9 (s, C(CH3)3), 117.0 (t, CH]CH2*), 117.1 (t,
CH]CH2), 135.96 (d, CH]CH2*), 136.02 (d, CH]CH2), 172.7 (s,
C]O), 173.9 (s, C]O*). Resonances marked with * belong to 3,4-
trans-6a.
CH]CH2). 13C NMR (100 MHz, CDCl3):
d¼17.1 (t, TMP–CCH2CH2),
19.9 (q, TMP–CH3), 20.2 (q, TMP–CH3), 32.7 (q, TMP–CH3), 33.2 (q,
TMP–CH3), 40.3 (t, TMP–CCH2), 51.1 (q, OCH3), 54.1 (t, NCH2CHCO),
57.5 (t, NCH2CH]), 59.3 (s, TMP–C(CH3)2), 60.5 (s, TMP–C(CH3)2),
84.9 (d, CHOTMP), 117.2 (t, CH]CH2), 135.6 (d, CH]CH2), 173.4 (s,
C]O).
4.2.5. tert-Butyl 1-benzyl-4-[(2,2,6,6-tetramethylpiperidin-1-yloxy)-
methyl]pyrrolidine-3-carboxylate (6c). Isolated after flash chroma-
tography (hexanes/EtOAc 50:1 to 2:1) as a pale yellow oil. For yields
and diastereomeric ratios see Table 2. [Rf (hexanes/EtOAc
4.2.2. tert-Butyl 3-(N,N-diallylamino)-2-(2,2,6,6-tetramethylpiper-
7:1)¼0.15]. IR (film); v[cmꢁ1]: 2974 (m), 2930 (m), 2790 (w, br),1726
~
idin-1-yloxy)propanoate (5a). Pale yellow oil, for yields see Table 2.
[Rf (hexanes/EtOAc 20:1)¼0.28]. IR (film); v [cmꢁ1]: 3070 (w), 2976
(s),1366 (m),1147 (s), 735 (m), 698 (s). MS (ESI) m/z, (%): 431 (MþHþ,
100), 375 (3) [MþHþ –H2C]C(CH3)2]. C26H42N2O3 (430.62): calcd C
72.52, H 9.83, N 6.51; found C 72.79, H 10.01, N 6.21. 1H NMR
~
(m), 2931 (m), 1736 (s), 1365 (s), 1153 (s), 917 (s), 732 (s). MS (ESI)
m/z, (%): 403 (MþNaþ, 100), 381 (MþHþ, 100), 347 (5) [MþNaþ
–H2C]C(CH3)2], 325 (5) [MþHþ –H2C]C(CH3)2]. C22H40N2O3
(380.56): calcd C 69.43, H 10.59, N 7.36; found C 69.31, H 10.76, N
(400 MHz, CDCl3):
d¼0.96–1.05 (m, 24H, TMP–CH3, TMP–CH3*); 1.18
(m, 4H, TMP–CH2, TMP–CH2*); 1.32 (m, 8H, TMP–CH2, TMP–CH2*);
1.36 (s, 9H, C(CH3)3*); 1.37 (s, 9H, C(CH3)3); 2.41 (dd, J¼8.3, 8.7 Hz,
1H, H5); 2.45 (m, 1H, H5*); 2.54 (m, 1H, H4*); 2.61 (m, 3H, H2, H4,
H3*); 2.68 (m, 2H, H2*, H5*); 2.87 (m, 2H, H2, H2*); 2.96 (m, 2H, H5,
H3); 3.47 (d, J¼13.2 Hz, 1H, PhCH2*); 3.53 (d, J¼12.9 Hz, 1H, PhCH2);
3.66 (m, 3H, PhCH2, PhCH2*, H6); 3.72 (m, 2H, H6*); 3.78 (dd, J¼4.7,
8.4 Hz, 1H, H6); 7.16–7.27 (m, 10H, ArH, ArH*). 13C NMR (100 MHz,
7.17. 1H NMR (400 MHz, CDCl3):
d
¼1.02–1.10 (m, 12H, TMP–CH3);
1.22 (m, 2H, TMP–CH2); 1.36 (m, 4H, TMP–CH2); 1.40 (s, 9H,
C(CH3)3); 2.72 (m, 2H, NCH2CHCO); 2.93 (dd, J¼7.1, 14.0 Hz, 2H,
NCH2CH¼); 3.09 (dd, J¼5.9, 14.0 Hz, 2H, NCH2CH¼); 4.18 (dd, J¼5.7,
9.8 Hz, 1H, CHOTMP); 5.05 (ddd, J¼1.1, 9.9, 17.2 Hz, 4H, CH]CH2);
5.73 (ddt, J¼7.1, 10.1, 16.9 Hz, 2H, CH]CH2). 13C NMR (100 MHz,
CDCl3):
d
¼17.4 (t, TMP–CCH2CH2), 20.2 (q, TMP–CH3), 20.4 (q, TMP–
CDCl3):
d
¼17.4 (t, TMP–CCH2CH2), 20.1 (q, TMP–CH3), 20.3 (q, TMP–
CH3), 28.3 (s, C(CH3)3), 33.6 (q, TMP–CH3), 33.7 (q, TMP–CH3), 40.6
(t, TMP–CCH2), 55.0 (t, NCH2CHCO), 57.6 (t, NCH2CH]), 59.3 (s,
CH3), 28.3 (s, C(CH3)3*), 28.4 (s, C(CH3)3), 33.4 (q, TMP–CH3), 33.6 (q,
TMP–CH3), 39.9 (t, TMP–CCH2), 40.1 (d, C4), 41.7 (d, C4*), 45.5

10926
U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
(d, C3), 46.9 (d, C3*), 56.0 (t, C2), 56.7 (t, C2*), 57.4 (t, C5*), 58.6 (t,
C5), 59.8 (s, TMP–C(CH3)2), 60.07 (s, TMP–C(CH3)2), 60.10 (t,
PhCH2*), 60.6 (t, PhCH2), 76.6 (t, C6), 78.7 (t, C6*), 80.4 (s, C(CH3)3*),
80.8 (s, C(CH3)3), 127.0 (d, CHAr*), 127.1 (d, CHAr), 128.38 (d, CHAr*),
128.43 (d, CHAr),128.8 (d, CHAr*),128.9 (d, CHAr),139.3 (s, CAr*),139.5
(s, CAr), 172.7 (s, C]O), 174.0 (s, C]O*). Resonances marked with *
belong to 3,4-trans-6c.
1H, CHOTMP); 5.05 (m, 2H, CH]CH2); 5.71 (ddt, J¼6.5, 10.2, 17.6 Hz,
1H, CH]CH2); 7.12–7.23 (m, 5H, ArH). 13C NMR (100 MHz, CDCl3):
d¼17.3 (t, TMP–CCH2CH2), 20.2 (q, TMP–CH3), 20.4 (q, TMP–CH3), 32.9
(q, TMP–CH3), 33.5 (q, TMP–CH3), 40.4 (t, TMP–CCH2), 51.3 (q, OCH3),
54.7 (t, NCH2CHCO), 57.1 (t, NCH2CH]), 59.1 (t, PhCH2N), 59.6 (s,
TMP–C(CH3)2), 60.7 (s, TMP–C(CH3)2), 85.0 (d, CHOTMP), 117.8 (t,
CH]CH2), 127.1 (d, CHAr), 128.3 (d, CHAr), 129.1 (d, CHAr), 135.4 (d,
CH]CH2), 139.3 (s, CAr), 173.5 (s, C]O).
4.2.6. tert-Butyl
3-(N-allyl-N-benzylamino)-2-(2,2,6,6-tetramethyl
piperidin-1-yloxy)propanoate (5c). Colorless oil, for yields see
4.2.9. tert-Butyl 1-(1-phenylethyl)-4-[(2,2,6,6-tetramethylpiperidin-
1-yloxy)methyl]pyrrolidine-3-carboxylates (6e). Isolated after flash
chromatography (hexanes/EtOAc 50:1–7:1) as a pale yellow oil. For
yields and diastereomeric ratios see Table 3. [Rf (hexanes/EtOAc
10:1)¼0.19].
Table 2. [Rf (hexanes/EtOAc 20:1)¼0.41]. IR (film); v [cmꢁ1]: 3064
~
(w), 2975 (m), 2930 (m), 1734 (s), 1365 (s), 1154 (s), 741 (m), 699
(m). MS (ESI) m/z, (%): 453 (MþNaþ, 70), 431 (MþHþ, 100), 160 (70)
[CH2]N(All)Bnþ]. C26H42N2O3 (430.62): calcd C 72.52, H 9.83, N
6.51; found C 72.73, H 9.99, N 6.27. 1H NMR (400 MHz, CDCl3):
4.2.9.1. (1R,3S,4R)-6e and (1R,3R,4S)-6e. IR (film); v [cmꢁ1]:
~
d
¼1.01–1.09 (m, 12H, TMP–CH3); 1.21 (m, 2H, TMP–CH2), 1.35 (m,
4H, TMP–CH2); 1.43 (s, 9H, C(CH3)3); 2.74 (dd, J¼5.0, 12.4 Hz, 1H,
NCHHCHCO); 2.82 (m, 2H, NCHHCHCO, NCHHCH]); 3.02 (dd,
J¼5.9, 14.1 Hz, 1H, NCHHCH]); 3.43 (d, J¼13.5 Hz, 1H, PhCHHN);
3.62 (d, J¼13.5 Hz, 1H, PhCHHN); 4.21 (dd, J¼5.0, 9.9 Hz, 1H,
CHOTMP); 5.03 (m, 2H, CH]CH2); 5.74 (m, 1H, CH]CH2); 7.14–7.25
2973 (m), 2930 (m), 2780 (w, br), 1727 (s), 1367 (m), 1146 (s), 701
(m). MS (ESI) m/z, (%): 445 (MþHþ, 100). C27H44N2O3 (444.65):
calcd C 72.93, H 9.97, N 6.30; found 73.14, H 10.19, N 5.92. 1H NMR
(600 MHz, CDCl3):
d
¼0.98–1.17 (m, 24H, TMP–CH3, TMP–CH3*);
1.29 (m, 2H, TMP–CH2, TMP–CH2*); 1.37 (d, J¼6.6 Hz, 3H, CHCH3*);
1.39 (d, J¼6.6 Hz, 3H, CHCH3); 1.38–1.45 (m, 8H, TMP–CH2, TMP–
CH2*); 1.42 (s, 9H, C(CH3)3); 1.44 (s, 9H, C(CH3)3*); 1.52 (m, 2H,
TMP–CH2, TMP–CH2*); 2.41 (dd, J¼7.8, 9.0 Hz, 1H, H5); 2.56 (dd,
J¼6.5, 8.7 Hz, 1H, H5*); 2.58 (dd, J¼7.3, 9.9 Hz 1H, H2); 2.60 (m, 1H,
H4*); 2.68 (dd, J¼5.9, 8.7 Hz, 1H, H5*); 2.69 (m, 1H, H4); 2.73 (dd,
J¼7.9, 9.9 Hz 1H, H2); 2.73 (dd, J¼8.4, 9.7 Hz, 1H, H2*); 2.93 (ddd,
J¼7.3, 7.9, 10.0 Hz, 1H, H3); 2.93 (dd, J¼9.1, 9.7 Hz, 1H, H2*); 3.02
(ddd, J¼7.4, 8.4, 9.1 Hz, 1H, H3*); 3.16 (dd, J¼6.5, 9.0 Hz, 1H, H5);
3.31 (d, J¼6.6 Hz, 1H, CHCH3); 3.34 (d, J¼6.6 Hz, 1H, CHCH3*); 3.71
(dd, J¼5.5, 8.4 Hz, 1H, H6*); 3.73 (dd, J¼6.1, 8.5 Hz, 1H, H6); 3.78
(dd, J¼4.6, 8.4 Hz, 1H, H6*); 3.82 (dd, J¼4.7, 8.5 Hz, 1H, H6); 7.19–
(m, 5H, ArH). 13C (100 MHz, CDCl3):
d¼17.3 (t, TMP–CCH2CH2), 20.3
(q, TMP–CH3), 20.4 (q, TMP–CH3), 28.4 (q, C(CH3)3), 33.7 (q, TMP–
CH3), 33.8 (q, TMP–CH3), 40.6 (t, TMP–CCH2), 55.6 (t, NCH2CHCO),
57.1 (t, NCH2CH]), 58.9 (t, PhCH2), 59.5 (s, TMP–C(CH3)2), 60.5 (s,
TMP–C(CH3)2), 80.9 (s, C(CH3)3), 85.4 (d, CHOTMP), 117.8 (t,
CH]CH2), 127.0 (d, CHAr), 128.2 (d, CHAr), 129.4 (d, CHAr), 135.5 (d,
CH]CH2), 139.2 (s, CAr), 172.6 (s, C]O).
4.2.7. Methyl 1-benzyl-4-[(2,2,6,6-tetramethylpiperidin-1-yloxy)-
methyl]pyrrolidine-3-carboxylate (6d). Isolated after flash chro-
matography (hexanes/EtOAc 50:1 to 2:1) as a pale yellow oil. For
yields and diastereomeric ratios see Table 2. [Rf (hexanes/EtOAc
7.35 (m, 10H, ArH, ArH*). 13C NMR (151 MHz, CDCl3):
d¼17.3 (t,
5:1)¼0.23]. IR (film); v [cmꢁ1]: 2973 (m), 2932 (m), 2792 (w, br),1735
TMP–CCH2CH2), 20.1 (q, TMP–CH3), 20.2 (q, TMP–CH3), 23.2 (q,
CHCH3*), 23.4 (q, CHCH3), 28.31 (q, C(CH3)3), 28.33 (q, C(CH3)3*),
33.3 (q, TMP–CH3), 33.6 (q, TMP–CH3), 39.8 (t, TMP–CCH2), 39.9 (d,
C4*), 40.1 (d, C4), 45.3 (d, C3), 45.5 (d, C3*), 54.4 (t, C2*), 55.2 (t, C2),
56.3 (t, C5*), 56.7 (t, C5), 59.8 (s, TMP–C(CH3)2), 60.0 (s, TMP–
C(CH3)2), 65.3 (d, CHCH3*), 65.7 (d, CHCH3), 76.1 (t, C6*), 76.5 (t, C6),
78.6 (s, C(CH3)3*), 80.7 (s, C(CH3)3), 126.93 (d, CHAr*), 126.96 (d,
CHAr), 127.3 (d, CHAr*), 127.4 (d, CHAr), 128.38 (d, CHAr*), 128.41 (d,
CHAr), 145.7 (s, CAr*), 145.8 (s, CAr), 172.6 (s, C]O*), 172.7 (s, C]O).
Resonances marked with * belong to (1R,3R,4S)-6e.
~
(s), 1362 (m), 1139 (s), 702 (m). MS (ESI) m/z, (%): 389 (MþHþ, 100),
288 (5). HRMS m/z, (C23H37N2O3; MþHþ): calcd 389.2799; found
389.2798. C23H36N2O3 (388.54): calcd C 71.10, H 9.34, N 7.21; found C
71.54, H 9.21, N 6.92. 1H NMR (400 MHz, CDCl3):
d¼0.96–1.04 (m,
24H, TMP–CH3, TMP–CH3*); 1.18 (m, 4H, TMP–CH2, TMP–CH2*); 1.35
(m, 8H, TMP–CH2, TMP–CH2*); 2.31 (t, J¼8.7 Hz, 1H, H5); 2.45 (dd,
J¼9.7, 12.9 Hz, 1H, H5*); 2.61 (dd, J¼8.1, 9.4 Hz, 1H, H2); 2.69 (m, 5H,
H4, H2*, H3*, H4*, H5*); 2.95 (m, 2H, H2, H5); 3.06 (dt, J¼7.9, 9.9 Hz,
2H, H3, H2*); 3.48 (d, J¼13.0 Hz,1H, PhCH2*); 3.59 (s, 3H, OCH3); 3.60
(m, 8H, PhCH2, PhCH2*, H6, H6*, OCH3*); 3.73 (dd, J¼6.2, 8.7 Hz, 2H,
H6, H6*); 7.16–7.27 (m, 10H, ArH, ArH*). 13C NMR (100 MHz, CDCl3):
4.2.9.2. (1R,3S,4S)-6e. 1H NMR (600 MHz, CDCl3):
d¼1.07 (s, 3H,
d¼17.3 (TMP–CCH2CH2), 20.16 (q, TMP–CH3), 20.18 (q, TMP–CH3),
TMP–CH3); 1.09 (s, 3H, TMP–CH3); 1.15 (s, 3H, TMP–CH3); 1.16 (s,
3H, TMP–CH3); 1.30 (m, 1H, TMP–CH2); 1.34 (d, J¼6.7 Hz, 3H,
CHCH3); 1.39–1.45 (m, 4H, TMP–CH2); 1.41 (s, 9H, C(CH3)3); 1.53 (m,
1H, TMP–CH2); 2.58 (m, 1H, H4); 2.60 (m, 1H, H5); 2.71 (m, 1H, H2);
2.74 (m, 1H, H2); 2.75 (m, 1H, H5); 2.93 (dt, J¼10.0, 7.6 Hz, 1H, H3);
3.21 (q, J¼6.7 Hz, 1H, CHCH3); 3.78 (m, 2H, H6); 7.19–7.35 (m, 5H,
33.2 (q, TMP–CH3), 33.3 (q, TMP–CH3), 39.9 (t, TMP–CCH2), 40.3 (d,
C4), 41.5 (d, C4*), 44.4 (d, C3), 46.1 (d, C3*), 51.5 (q, OCH3*), 51.7 (q,
OCH3), 56.4 (t, C2), 56.86 (t, C2*), 56.91 (t, C5*), 57.9 (t, C5), 59.91 (s,
TMP–C(CH3)2), 59.92 (s, TMP–C(CH3)2), 60.0 (t, PhCH2*), 60.5 (t,
PhCH2), 76.2 (t, C6), 78.5 (t, C6*), 127.08 (d, CHAr*), 127.13 (d, CHAr),
128.37 (d, CHAr*), 128.43 (d, CHAr), 128.8 (d, CHAr*), 128.9 (d, CHAr),
139.3 (s, CAr*), 139.4 (s, CAr), 173.8 (s, C]O), 174.0 (s, C]O*). Reso-
nances marked with * belong to 3,4-trans-6d.
ArH). 13C NMR (151 MHz, CDCl3):
d
¼17.0 (t, TMP–CCH2CH2), 20.06
(q, TMP–CH3), 20.10 (q, TMP–CH3), 23.04 (q, CHCH3), 28.0 (q,
C(CH3)3), 33.02 (q, TMP–CH3), 33.06 (q, TMP–CH3), 39.5 (t, TMP–
CCH2), 41.2 (d, C4), 46.4 (d, C3), 55.41 (t, C2 or C5), 55.47 (t, C2 or
C5), 59.5 (s, TMP–C(CH3)2), 59.6 (s, TMP–C(CH3)2), 65.0 (d, CHCH3),
78.3 (t, C6), 80.2 (s, C(CH3)3), 126.8 (d, CHAr), 127.1 (d, CHAr), 128.2
(d, CHAr), 145.6 (s, CAr), 173.9 (s, C]O).
4.2.8. Methyl 3-(N-allyl-N-benzylamino)-2-(2,2,6,6-tetramethylpi-
peridin-1-yloxy)propanoate (5d). Colorless oil, for yields see Table 2.
[Rf (hexanes/EtOAc 10:1)¼0.63]. IR (film); v [cmꢁ1]: 3064 (w), 2975
~
(m), 2930 (w),1744 (s),1361 (m),1040 (s), 740 (s), 698 (s). MS (ESI) m/
z, (%): 411 (MþNaþ, 80), 389 (MþHþ,100),160 (80) [CH2]N(All)Bnþ].
HRMS m/z, (C22H36N2O3Na; MþNaþ): calcd 411.2618; found 411.2616.
4.2.10. (R,R- and R,S)-tert-Butyl 3-[N-allyl-N-(1-phenylethyl)amino]-
2-(2,2,6,6-tetramethylpiperidin-1-yloxy)propanoates (5e). Colorless
oil, for yields see Table 3. [Rf (hexanes/EtOAc 10:1)¼0.49]. IR
1H NMR (400 MHz, CDCl3):
d
¼0.94–1.09 (m,12H, TMP–CH3); 1.22 (m,
(film); v [cmꢁ1]: 3062 (w), 2975 (m), 2931 (m), 1734 (s), 1365 (s),
~
2H, TMP–CH2), 1.35 (m, 4H, TMP–CH2); 2.78 (dd, J¼5.4, 12.4 Hz, 1H,
NCHHCHCO); 2.87 (m, 2H, NCHHCHCO, NCHHCH]); 3.03 (dd, J¼5.8,
14.2 Hz, 1H, NCHHCH]); 3.39 (d, J¼13.5 Hz, 1H, PhCHHN); 3.62 (s,
3H, OCH3); 3.64 (d, J¼13.0 Hz, 1H, PhCHHN); 4.34 (dd, J¼5.4, 10.4 Hz,
1148 (s), 916 (m), 701 (s). MS (ESI) m/z, (%): 467 (MþNaþ, 100),
445 (MþHþ, 50), 174 (70) [CH2]NAll(PhCHCH3)þ]. HRMS m/z,
(C27H44N2O3Na; MþNaþ): calcd 467.3244; found 467.3243. 1H

U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
10927
NMR (400 MHz, CDCl3):
d
¼0.99–1.04 (m, 24H, TMP–CH3, TMP–
22.7 (q, CHCH3), 32.6 (q, TMP–CH3), 32.8 (q, TMP–CH3), 39.3 (t,
TMP–CCH2), 40.7 (d, C4), 45.7 (d, C3), 51.5 (OCH3); 54.8 (t, C5),
55.5 (t, C2), 59.4 (s, TMP–C(CH3)2), 59.5 (s, TMP–C(CH3)2), 64.8 (d,
CHCH3), 78.1 (t, C6), 126.6 (d, CHAr), 126.8 (d, CHAr), 128.0 (d,
CHAr), 145.0 (s, CAr), 174.8 (s, C]O). Traces of the other trans-di-
astereomer were detected.
CH3*); 1.19 (m, 4H, TMP–CH2, TMP–CH2*); 1.26 (d, J¼6.8 Hz, 3H,
CHCH3*); 1.27 (d, J¼6.8 Hz, 3H, CHCH3); 1.34 (m, 8H, TMP–CH2,
TMP–CH2*); 1.43 (s, 9H, C(CH3)3); 1.44 (s, 9H, C(CH3)3*); 2.58 (dd,
J¼5.2, 12.4 Hz, 1H, NCHHCHCO*); 2.80 (dd, J¼7.4, 14.3 Hz, 1H,
NCHHCH]); 2.83 (d, J¼7.5 Hz, 2H, NCH2CHCO); 2.89 (m, 1H,
NCHHCHCO*); 2.93 (m, 1H, NCHHCH]); 3.01 (dd, J¼7.2, 14.3 Hz,
1H, NCHHCH]*); 3.08 (ddt, J¼1.4, 5.4, 14.3 Hz, 1H, NCHHCH]);
3.84 (q, J¼6.8 Hz, 2H, CHCH3, CHCH3*); 4.14 (dd, J¼7.4, 7.9 Hz, 1H,
CHOTMP); 4.21 (dd, J¼5.3, 10.6 Hz, 1H, CHOTMP*); 5.03 (m, 4H,
CH]CH2, CH]CH2*); 5.70 (m, 2H, CH]CH2, CH]CH2); 7.13–7.30
4.2.12. (R,R-nand R,S)-Methyl 3-[N-allyl-N-(1-phenylethyl)amino]-2-
(2,2,6,6-tetramethylpiperidin-1-yloxy)propanoate (5f). Pale yellow
~
oil, for yields see Table 3. [Rf (hexanes/EtOAc 10:1)¼0.49]. IR (film); v
[cmꢁ1]: 3064 (w), 2973 (m), 2932 (m), 1745 (s), 1200 (m), 1042 (m),
700 (m). MS (ESI) m/z, (%): 403 (MþHþ, 100), 174 (45)
[CH2]NAll(PhCHCH3)þ]. HRMS m/z, (C24H39N2O3; MþHþ): calcd
(m, 10H, ArH, ArH*). 13C NMR (100 MHz, CDCl3):
d
¼15.8 (q,
CHCH3*), 17.3 (t, TMP–CCH2CH2), 18.4 (q, CHCH3), 20.3 (q, TMP–
CH3), 20.4 (q, TMP–CH3), 28.40 (q, C(CH3)3*), 28.44 (q, C(CH3)3),
33.6 (q, TMP–CH3), 33.9 (q, TMP–CH3), 40.6 (t, TMP–CCH2), 51.6 (t,
NCH2CHCO*), 52.4 (t, NCH2CHCO), 53.5 (t, NCH2CH]*), 54.4 (t,
NCH2CH]), 59.2 (d, CHCH3*), 59.4 (d, CHCH3), 59.5 (s, TMP–
C(CH3)2), 60.5 (s, TMP–C(CH3)2), 80.8 (s, C(CH3)3*), 80.9 (s,
C(CH3)3), 85.4 (d, CHOTMP), 85.8 (d, CHOTMP*), 117.0 (t,
CH]CH2*), 117.1 (t, CH]CH2), 126.9 (d, CHAr), 127.0 (d, CHAr*),
128.06 (d, CHAr), 128.12 (d, CHAr*), 128.3 (d, CHAr), 128.4 (d, CHAr),
136.7 (d, CH]CH2*), 136.9 (d, CH]CH2), 142.2 (s, CAr), 143.6 (s,
CAr*), 172.8 (s, C]O), 172.9 (s, C]O*). Resonances marked with *
belong to one diastereomer (configuration not assigned).
403.2955; found 403.2965. 1H NMR (400 MHz, CDCl3):
d
¼0.92–1.08
(m, 24H, TMP–CH3, TMP–CH3*); 1.20 (m, 4H, TMP–CH2, TMP–CH2*);
1.25 (d, J¼6.8 Hz, 3H, CHCH3*); 1.26 (d, J¼6.9 Hz, 3H, CHCH3); 1.34
(m, 8H, TMP–CH2, TMP–CH2*); 2.68 (dd, J¼5.4, 12.8 Hz, 1H,
NCHHCHCO*); 2.84 (m, 2H, NCH2CHCO); 2.89 (m,1H, NCHHCHCO*);
2.96 (m, 4H, NCH2CH], NCH2CH]*); 3.56 (s, 3H, OCH3); 3.65 (s, 3H,
OCH3*); 3.83 (q, J¼6.9 Hz, 2H, CHCH3, CHCH3*); 4.31 (m, 2H,
CHOTMP, CHOTMP*); 5.01 (m, 4H, CH]CH2, CH]CH2*); 5.67 (m,
2H, CH]CH2, CH]CH2*); 7.13–7.25 (m, 10H, ArH, ArH*). 13C NMR
(100 MHz, CDCl3):
d
¼14.7 (q, CHCH3*),17.0 (q, CHCH3), 17.3 (t, TMP–
CCH2CH2), 20.2 (q, TMP–CH3), 20.5 (q, TMP–CH3), 33.0 (q, TMP–
CH3), 33.4 (q, TMP–CH3), 40.4 (t, TMP–CCH2), 40.5 (t, TMP–CCH2),
51.1 (t, NCH2CHCO*), 51.24 (q, OCH3*), 51.25 (q, OCH3), 51.9 (t,
NCH2CHCO), 53.8 (t, NCH2CH]*), 54.3 (t, NCH2CH]), 58.6 (d,
CHCH3*), 59.5 (s, TMP–C(CH3)2), 60.1 (d, CHCH3), 60.8 (s, TMP–
C(CH3)2), 85.2 (d, CHOTMP*), 85.8 (d, CHOTMP), 116.9 (t, CH]CH2*),
117.1 (t, CH]CH2), 126.9 (d, CHAr), 127.0 (d, CHAr*), 128.0 (d, CHAr),
128.09 (d, CHAr*), 128.14 (d, CHAr), 128.2 (d, CHAr*), 136.8 (d,
CH]CH2), 137.0 (d, CH]CH2*), 142.7 (s, CAr*), 143.7 (s, CAr), 173.5 (s,
C]O), 173.7 (s, C]O*). Resonances marked with * belong to one
diastereomer (configuration not assigned).
4.2.11. Methyl 1-(1-phenylethyl)-4-[(2,2,6,6-tetramethylpiperidin-1-
yloxy)methyl]pyrrolidine-3-carboxylates (6f). Isolated after flash
chromatography (hexanes/EtOAc 50:1 to 2:1) as a pale yellow oil.
For yields and diastereomeric ratios see Table 3. [Rf (hexanes/EtOAc
3:1)¼0.41].
4.2.11.1. (1R,3S,4R)-6f and (1R,3R,4S)-6f. IR (film); v [cmꢁ1]:
~
2973 (m), 2931 (m), 2782 (w, br), 1736 (s), 1454 (m), 1164 (s), 702
(s). MS (ESI) m/z, (%): 403 (MþHþ, 100). HRMS m/z, (C24H39N2O3;
MþHþ): calcd 403.2955; found 403.2954. 1H NMR (600 MHz,
CDCl3):
d
¼1.01–1.15 (m, 24H, TMP–CH3); 1.30 (m, 4H, TMP–CH2,
4.2.13. Silyl ketene acetals (8a) by trapping of the enolate resulting
from deprotonation of 7a. To a stirred solution of dry diisopropyl-
amine (0.18 mL, 1.25 mmol) in 15 mL anhydrous DME butyllithium
(1.6 M in hexanes, 0.78 mL, 1.25 mmol) was added dropwise at
TMP–CH2*); 1.38 (d, J¼6.6 Hz, 3H, CHCH3*); 1.40 (d, J¼6.6 Hz, 3H,
CHCH3); 1.43 and 1.54 (2 m, 8H, TMP–CH2, TMP–CH2*); 2.35 (dd,
J¼7.2, 9.1 Hz, 1H, H5*); 2.36 (t, J¼8.7 Hz, 1H, H5); 2.58 (dd, J¼7.9,
9.8 Hz, 1H, H2); 2.68 (m, 1H, H4*); 2.71 (m, 1H, H2*); 2.72 (m, 1H,
H5*); 2.78 (m, 1H, H4); 2.79 (dd, J¼7.9, 9.8 Hz, 1H, H2); 3.06 (dt,
J¼7.9, 10.0 Hz, 1H, H3); 3.17 (m, 1H, H2*); 3.18 (m, 1H, H3*); 3.20
(dd, J¼6.9, 8.7 Hz, 1H, H5); 3.32 (d, J¼6.6 Hz, 1H, CHCH3); 3.34 (d,
J¼6.6 Hz, 1H, CHCH3*); 3.64 (s, 3H, CH3O); 3.64 (dd, J¼7.7, 8.8 Hz,
1H, H6*); 3.69 (s, 3H, CH3O*); 3.70 (t, J¼8.6 Hz, 1H, H6); 3.76 (dd,
J¼6.4, 8.8 Hz, 1H, H6*); 3.80 (dd, J¼6.1, 8.6 Hz, 1H, H6); 7.21–7.36
ꢁ78 ꢀC. After 20 min
a solution of tert-butyl 3-(N,N-diallyl-
amino)propanoate 7a (0.226 g, 1.0 mmol) in 0.9 mL of dry DME was
added at ꢁ78 ꢀC. After 25 min chlorotrimethylsilane (0.16 mL,
1.25 mmol) was added and the mixture was stirred at ꢁ78 ꢀC for
80 min. The solvent was carefully removed under high vacuum. The
solid white residue was washed with dry hexane (5ꢂ5 mL) and fil-
tered under inert conditions. The solvent was removed in high vac-
uum and the remaining highly sensitive colorless oil (0.344 g) was
dissolved in C6D6, transferred to an NMR tube and analyzed.
(m, 10H, ArH, ArH*). 13C NMR (151 MHz, CDCl3):
d
¼16.8 (t, TMP–
CCH2CH2), 19.67 (q, TMP–CH3), 19.72 (q, TMP–CH3), 22.7 (q,
CHCH3*), 22.9 (q, CHCH3), 32.6 (q, TMP–CH3), 32.8 (q, TMP–CH3),
39.3 (t, TMP–CCH2), 39.7 (d, C4*), 39.8 (d, C4), 43.6 (d, C3), 43.9 (d,
C3*), 51.3 (q, OCH3), 51.4 (q, OCH3*), 54.4 (t, C2*), 55.2 (t, C2), 55.80
(t, C5), 55.81 (t, C5*), 59.4 (s, TMP–C(CH3)2), 59.5 (s, TMP–C(CH3)2),
65.0 (d, CHCH3*), 65.3 (d, CHCH3), 75.5 (t, C6*), 75.7 (t, C6), 126.7
(d, CHAr* and CHAr), 126.80 (d, CHAr*), 126.86 (d, CHAr), 128.04 (d,
CHAr), 128.05 (d, CHAr*), 144.9 (s, CAr*), 145.1 (s, CAr), 173.48 (s,
C]O*), 173.52 (s, C]O). Resonances marked with * belong to
(1R,3R,4S)-6f.
4.2.14. (E)-1-tert-Butoxy-3-(N,N-diallylamino)-1-(trimethylsilyloxy)-
propene (E–8a). 1H NMR (500 MHz, C6D6):
d
¼0.13 (s, 9H, Si(CH3)3);
1.26 (s, 9H, C(CH3)3); 3.10 (ddd, J¼1.5, 1.8, 6.4 Hz, 4H, CH2CH]CH2);
3.17 (d, J¼7.2 Hz, 2H, NCH2CH]); 4.05 (t, J¼7.2 Hz, 1H,
All2NCH2CH]); 5.04 (ddt, J¼1.5, 2.3, 10.2 Hz, 2H, CH2CH]CHH);
5.16 (ddt, J¼1.8, 2.3, 17.2 Hz, 2H, CH2CH]CHH); 5.91 (ddt, J¼6.4,
10.2, 17.2 Hz, 2H, CH2CH]CH2). 13C NMR (125 MHz, C6D6): 0.0 (q,
Si(CH3)3), 29.3 (q, C(CH3)3), 49.8 (t, NCH2CH]C), 56.8 (t,
CH2CH]CH2), 78.4 (s, C(CH3)3), 87.80 (d, NCH2CH]C), 116.6 (t,
CH2CH]CH2), 137.4 (d, CH2CH]CH2), 154.4 (s, NCH2CH]C).
4.2.11.2. (1R,3S,4S)-6f. 1H NMR (600 MHz, CDCl3):
d
¼1.08 (s,
3H, TMP–CH3); 1.12 (s, 3H, TMP–CH3); 1.15 (s, 3H, TMP–CH3); 1.16
(s, 3H, TMP–CH3); 1.30 (m, 1H, TMP–CH2); 1.37 (d, J¼6.6 Hz, 3H,
CHCH3); 1.40–1.45 (m, 4H, TMP–CH2); 1.53 (m, 1H, TMP–CH2);
2.62 (m, 1H, H5); 2.67 (m, 1H, H2); 2.70 (m, 1H, H4); 2.72 (m, 1H,
H5); 2.75 (m, 2H, H2, H3); 3.24 (q, J¼6.7 Hz, 1H, CHCH3); 3.76 (m,
2H, H6); 7.21–7.36 (m, 5H, ArH). 13C NMR (151 MHz, CDCl3):
4.2.15. (Z)-1-tert-Butoxy-3-(N,N-diallylamino)-1-(trimethylsilyloxy)-
propene (Z–8a). 1H NMR (500 MHz, C6D6):
d
¼0.17 (s, 9H, Si(CH3)3);
1.21 (s, 9H, C(CH3)3); 3.09 (m, 4H, CH2CH]CH2); 3.18 (d, J¼7.2 Hz,
2H, NCH2CH]C); 4.10 (t, J¼7.2 Hz, 1H, NCH2CH]C); 4.99 (ddt,
J¼1.5, 2.3, 10.1 Hz, 2H, CH2CH]CHH); 5.08 (ddt, J¼1.8, 2.3, 17.1 Hz,
2H, CH2CH]CHH); 5.81 (dddd, J¼5.7, 6.9, 10.1, 17.1 Hz, 2H,
d
¼16.8 (t, TMP–CCH2CH2), 19.7 (q, TMP–CH3), 19.8 (q, TMP–CH3),

10928
U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
CH2CH]CH2). 13C NMR (125 MHz, C6D6): 1.4 (q, Si(CH3)3), 28.7 (q,
C(CH3)3), 49.6 (t, NCH2CH]C), 57.0 (t, CH2CH]CH2), 79.0 (s,
C(CH3)3), 87.75 (d, NCH2CH]C), 117.0 (t, CH2CH]CH2), 137.3 (d,
CH2CH]CH2), 153.8 (s, NCH2CH]C).
CH]CH2), 135.33 (d, CH]CH2*), 135.45 (d, CH]CH2), 172.9 (s,
C]O), 173.9 (s, C]O*). Resonances marked with * belong to minor
3,4-trans-11a.
4.3.2. N-Allylhexahydrofuro[3,4-c]pyrrol-1-one
(400 MHz, CDCl3):
(12a). 1H NMR
¼2.33 (m, 1H, H2); 2.58 (m, 1H, H5); 2.79 (m,
4.2.16. tert-Butyl 3-(N,N-diallylamino)-2-(trimethylsilyl)propanoate
d
(9a). 1H NMR (500 MHz, C6D6):
d
¼0.03 (s, 9H, Si(CH3)3); 1.39 (s, 9H,
1H, H5); 3.01 (m, 4H, NCH2CH], H3, H4); 3.17 (d, J¼9.4 Hz, 1H, H2);
4.03 (dd, J¼3.5, 9.2 Hz, 1H, H6); 4.43 (t, J¼9.2 Hz, 1H, H6); 5.04 (m,
C(CH3)3); 2.22 (dd, J¼3.6, 11.1 Hz, 1H, CHSi(CH3)3); 2.43 (dd, J¼3.6,
13.0 Hz, 1H, CHHCHSi); 2.92 (ddt, J¼1.3, 7.1, 15.4 Hz, 2H,
CHHCH]CH2); 3.08 (dd, J¼11.1, 13.0 Hz, 1H, NCHHCHSi); 3.10 (m,
2H, CHHCH]CH2); 4.99 (ddt, J¼1.3, 2.3, 10.1 Hz, 2H, CH2CH]CHH);
5.08 (ddt, J¼1.3, 2.3, 17.1 Hz, 2H, CH2CH]CHH); 5.77 (ddt, J¼7.1,
10.1, 17.1 Hz, 2H, CH2CH]CH2). 13C NMR (125 MHz, C6D6): –2.3 (q,
Si(CH3)3), 28.4 (q, C(CH3)3), 37.8 (d, CHSi), 51.6 (t, NCH2CHSi), 56.80
(t, CH2CH]CH2), 78.2 (s, C(CH3)3), 116.9 (t, CH]CH2), 136.7 (d,
CH]CH2), 173.4 (s, C]O).
1H, CH]CHH); 5.13 (m, 1H, CH]CHH); 5.80 (m, 1H, CH]CH2). 13
C
NMR (100 MHz, CDCl3):
d
¼37.8 (d, C4), 43.9 (d, C3), 57.35 (t,
NCH2CH]), 57.70 (t, C5), 60.8 (t, C2), 74.0 (t, C6), 117.40 (t,
CH]CH2), 135.41 (d, CH]CH2), 179.8 (s, C]O). The same num-
bering as in monocyclic compounds was used for assignment.
4.4. Reductive N–O bond cleavage of 6e obtained
according to method C
4.2.17. tert-Butyl 3-(N-allyl-N-benzylamino)-2-(2,2,6,6-tetramethyl-
piperidin-1-yloxy)propanoate (5c) by oxygenation of 7c with 2,2,6,
6-tetramethyl-1-oxopiperidinium hexafluorophosphate (10). To
a stirred solution of dry diisopropylamine (0.18 mL, 1.25 mmol) in
10 mL anhydrous THF, butyllithium (1.4 M in hexanes, 0.90 mL,
1.25 mmol) was added dropwise at ꢁ78 ꢀC. After 15 min, a solution
of 7c (0.276 g, 1.0 mmol) in 0.6 mL of dry THF was added dropwise.
After 30 min,10 (0.302 g, 1.0 mmol) was added in portions and after
its dissolution further 0.150 g (0.5 mmol) of 10. The reaction mixture
was stirred at ꢁ78 ꢀC for 60 min, quenched with saturated NH4Cl
solution (four drops), diluted with ether (20 mL) and filtered
through a pad of silica gel. Evaporation of the filtrate yielded 0.558 g
of an orange oil, which was preadsorbed on silica gel and purified by
flash chromatography (hexanes/EtOAc 20:1 gradient to 5:1) to give
0.259 g (60%) of 5c and 0.044 g (16%) of 7c.
A 1.8:1 diastereomeric mixture of (1R,3S,4R)-6e and (1R,3R,4S)-
6e (0.207 g, 0.47 mmol) was dispersed in a mixture of 2.9 mL acetic
acid and 1.0 mL water. THF was added dropwise until a homoge-
neous solution was formed (3.0 mL). Zinc dust (1.53 g, 23.30 mmol,
50 equiv) was added with vigorous stirring and the reaction mixture
was heated at 85–90 ꢀC for 7 h. The mixture was cooled to room
temperature, diluted with CH2Cl2 (15 mL) and filtered. The filtrate
was neutralized with saturated K2CO3 solution to a pH of ca. 10. The
organic layer was separated, washed twice with water, dried over
MgSO4 and evaporated to give 118 mg of colorless oil. The aqueous
layer and washing solutions were combined, treated with 2 M NaOH
solution to pH 13 and extracted with ether (3ꢂ10 mL). The ethereal
extract was washed with brine and dried over MgSO4. Evaporation
yielded 2 mg of colorless semi-solid residue, which was combined
with main product. The crude product was purified by flash chro-
matography (hexanes/EtOAc 5:1 gradient to EtOAc) to give 8 mg
(4%) recovered (1R,3S,4R)-6e and (1R,3R,4S)-6e, followed by 81 mg
(74%) of a partly separable 1.6:1 diastereomeric mixture of lactones
(5R,3S,7R)-12e and (5R,3R,7S)-12e.
4.3. Reductive N–O bond cleavage of 6a
The diastereomeric mixture of 6a (0.222 g, 0.58 mmol; 3.5:1 cis/
trans) was dissolved in a mixture of 1.2 mL THF and 1.2 mL water.
Then, 3.6 mL of acetic acid was added and the mixture was warmed
at 70 ꢀC. Zinc dust (1.89 g, 29.0 mmol) was added with vigorous
stirring. The temperature was increased to 80–85 ꢀC and stirring was
continued. According to TLC (hexanes/EtOAc/Et3N 100:100:1) the
starting material appeared to be consumed after 60 min. The re-
action mixture was cooled to room temperature, diluted with CH2Cl2
(20 mL) and filtered. The filtrate was neutralized with saturated
K2CO3 solution until a pH of ca. 10 was reached. The layers were
separated. The organic layer was washed twice with water, dried
over MgSO4 and evaporated to give 0.151 g of a yellow oil, which was
purified by flash chromatography (hexanes/iPrOH/Et3N 200:100:1).
At first 62 mg (28%) of 6a was recovered as a 3.2:1 cis/trans-di-
astereomeric mixture [Rf(hexanes/iPrOH/Et3N 200:100:1)¼0.75],
followed by 72 mg (55%) of an inseparable mixture of alcohols cis-
and trans-11a and lactone 12a in a ratio of 2.5:1:1 [Rf (hexanes/
iPrOH/Et3N 200:100:1)¼0.3–0.4 (streaky)].
4.4.1. N-((R)-1-phenylethyl)hexahydrofuro[3,4–c]pyrrol-1-ones
(12e). IR (film); v [cmꢁ1]: 2973 (m), 2918 (m), 2798 (m), 1766 (s),
~
1476 (m), 1362 (m), 1132 (s), 1046 (m), 1002 (s), 765 (m), 702 (m).
MS (ESI) m/z, (%): 254 (MþNaþ, 17), 232 (MþHþ, 100). HRMS m/z,
(C14H18NO2; MþHþ): calcd 232.1332; found 232.1331. To simplify
assignment, hydrogen and carbon numbers identical to those of the
monocyclic derivatives are applied. 1H NMR (400 MHz, CDCl3):
d¼1.29 (d, J¼6.7 Hz, 3H, CH3CH and CH3CH*); 2.16 (dd, J¼6.5, 9.8 Hz,
1H, H5); 2.27 (dd, J¼7.1, 9.6 Hz, 1H, H2*); 2.37 (dd, J¼7.7, 9.1 Hz, 1H,
H2); 2.38 (m, 1H, H5*); 2.51 (d, J¼9.9 Hz, 1H, H5); 2.90 (m, 5H, H4,
H2*, H3*, H4*, H5*); 2.99 (ddd, J¼1.2, 7.8, 9.5 Hz, 1H, H3); 3.14 (q,
J¼6.7 Hz, 1H, CH3CH); 3.18 (q, J¼6.6 Hz, 1H, CH3CH*); 3.40 (d,
J¼9.1 Hz, 1H, H2); 3.90 (dd, J¼4.2, 9.1 Hz, 1H, H6); 4.08 (dd, J¼3.5,
9.1 Hz, 1H, H6*); 4.37 (t, J¼9.0 Hz, 1H, H6); 4.43 (dd, J¼8.1, 9.1 Hz,
1H, H6*); 7.12–726 (m, 10H, ArH). 13C NMR (100 MHz, CDCl3):
d
¼23.1 (q, CH3CH*), 23.4 (q, CH3CH), 37.5 (d, C4), 37.8 (d, C4*), 43.7
(d, C3*), 43.9 (d, C3), 55.8 (t, C2), 56.2 (t, C2*), 59.0 (t, C5*), 60.0 (t,
C5), 64.1 (d, CH3CH*), 64.3 (d, CH3CH), 74.0 (t, C6*), 74.2 (t, C6), 127.1
(d, CHAr* and CHAr), 127.30 (d, CHAr), 127.33 (d, CHAr*), 128.65 (d,
CHAr),128.67 (d, CHAr*),144.6 (s, CAr*),145.2 (s, CAr),179.8 (s, C]O*),
180.1 (s, C]O). Resonances marked with an * belong to minor
(5R,3R,7S)-12e.
4.3.1. tert-Butyl 1-allyl-4-(hydroxymethyl)pyrrolidine-3-carboxylates
(11a). 1H NMR (400 MHz, CDCl3):
d
¼1.38 (s, 9H, C(CH3)3*); 1.41 (s,
9H, C(CH3)3); 2.33 (m, 1H, H2*); 2.43 (m, 1H, H2); 2.46 (m, 2H, H4*,
H5*); 2.58 (m, 1H, H4); 2.79 (m, 5H, H2, H5 , H5 , H2*, H3*); 3.01
a
b
(m, 6H, NCH2CH], NCH2CH]*, H3, H5*); 3.17 (br s, 2H, OH); 3.57
(dd, J¼4.8, 10.3 Hz, 1H, H6*); 3.64 (m, 3H, H6, H6*); 5.04 (m, 2H,
CH]CHH, CH]CHH*); 5.13 (m, 2H, CH]CHH, CH]CHH*); 5.80 (m,
4.5. Reductive N–O bond cleavage of 6e obtained
according to method B
2H, CH]CH2, CH]CH2*). 13C NMR (100 MHz, CDCl3):
d
¼28.2 (q,
C(CH3)3*), 28.3 (q, C(CH3)3), 42.8 (d, C4), 43.8 (d, C4*), 45.7 (d, C3),
46.9 (d, C3*), 55.9 (t, C5), 56.7 (t, C5*), 57.40 (t, C2*), 57.68 (t, C2),
58.6 (t, CH2CH]*), 58.8 (t, CH2CH]), 63.3 (t, C6), 66.6 (t, C6*), 81.1
(s, C(CH3)3*), 81.5 (s, C(CH3)3), 117.3 (t, CH]CH2*), 117.46 (t,
A 3:1:2 diastereomeric mixture of (1R,3S,4R)-6e, (1R,3R,4S)-6e,
and (1R,3S,4S)-6e (0.130 g, 0.29 mmol) was dispersed in a mixture
of 1.8 mL acetic acid and 0.6 mL water. THF was added dropwise

U. Jahn et al. / Tetrahedron 65 (2009) 10917–10929
10929
4563; (e) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712; (f) Miura,
K.; Hosomi, A. Synlett 2003, 143–155.
8. Selected reviews: (a) Hyland, C. Tetrahedron 2005, 61, 3457–3471; (b) Trost, B.
M. J. Org. Chem. 2004, 69, 5813–5837.
9. Selected recent reviews: (a) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069–1084;
(b) O’Brien, P.; Bilke, J. L. Angew. Chem., Int. Ed. 2008, 47, 2734–2736; (c) Huang,
P.-Q. Synlett 2006, 1133–1149.
10. Reviews: (a) Balme, G.; Bouyssi, D.; Lomberget, T.; Monteiro, N. Synthesis 2003,
2115–2134; (b) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003,
4101–4111; (c) Rodriguez, J. Synlett 1999, 505–518.
11. Reviews: (a) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603–1618; (b) Majumdar, K. C.;
Basu, P. K.; Chattopadhyay, S. K. Tetrahedron 2007, 63, 793–826; (c) Aurre-
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until a homogeneous solution was formed (3.0 mL). Zinc dust
(0.95 g, 14.6 mmol, 50 equiv) was added with vigorous stirring and
the reaction mixture was heated at 85 ꢀC for 3 h. The mixture was
cooled to room temperature, diluted with CH2Cl2 (15 mL) and fil-
tered. The filtrate was neutralized with saturated K2CO3 solution to
a pH of ca. 10. The organic layer was separated, washed twice with
water, dried over MgSO4 and evaporated to give 87 mg of an oil,
which was purified by flash chromatography (hexanes/EtOAc 7:1 to
EtOAc) to give a 3:1:2 mixture of (1R,3S,4R)-6e, (1R,3R,4S)-6e and
(1R,3S,4S)-6e (23 mg, 18%) and
a partly separable 3:1 di-
astereomeric mixture of lactones (5R,3S,7R)-12e and (5R,3R,7S)-12e
(19 mg, 28%) and (1R,3S,4S)-11e (16 mg, 18%).
4.5.1. tert-Butyl 4-(hydroxymethyl)-1-(1-phenylethyl)pyrrolidine-3-
carboxylate (11e). 1H NMR (400 MHz, CDCl3):
d
¼1.31 (d, J¼6.7 Hz,
3H, CH3CH); 1.35 (s, 9H, C(CH3)3); 2.36 (dd, J¼6.4, 8.3 Hz, 1H, H2);
2.47 (m, 1H, H4); 2.51 (dd, J¼7.3, 8.2 Hz, 1H, H5); 2.60 (br s, 1H OH);
2.74 (dt, J¼4.2, 8.3 Hz, 1H, H3); 2.78 (t, J¼8.4 Hz, 1H, H2); 2.83 (dd,
J¼2.4, 8.5 Hz, 1H, H5); 3.14 (q, J¼6.6 Hz, 1H, CH3CH); 3.58 (ddd,
J¼0.6, 4.2, 10.2 Hz, 1H, H6); 3.70 (dd, 1H, J¼4.5, 10.2 Hz, H6); 7.13–
7.27 (m, 5H, ArH). 13C NMR (100 MHz, CDCl3):
d
¼23.2 (q, CH3CH),
14. Jahn, U.; Dinca, E. Chem.dEur. J. 2009, 15, 58–62; (b) Jahn, U.; Rudakov, D. Org.
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Jahn, U. Chem. Commun. 2001, 1600–1601.
15. Jahn, U.; Mu¨ller, M.; Aussieker, S. J. Am. Chem. Soc. 2000, 122, 5212–5213.
16. For a recent review on synthetic applications of TEMPO, see: Vogler, T.; Studer,
A. Synthesis 2008, 1979–1993.
28.2 (q, C(CH3)3), 43.6 (d, C4), 46.8 (d, C3), 56.0 (t, C2 or C5), 56.1 (t,
C2 or C5), 65.2 (d, CH3CH), 67.2 (t, C6), 81.1 (s, C(CH3)3), 127.2 (d,
CHAr), 127.33 (d, CHAr), 128.6 (d, CHAr), 144.9 (s, CAr), 174.1 (s, C]O).
17. Reviews: (a) Juaristi, E.; Leon-Romo, J.-L.; Reyes, A.; Escalante, J. Tetrahedron:
Asymmetry 1999, 10, 2441–2495; (b) Juaristi, E.; Escalante, J.; Leon-Romo, J. L.;
Reyes, A. Tetrahedron: Asymmetry 1998, 9, 715–740.
Acknowledgements
18. Cabral, J.; Laszlo, P.; Mahe´, L.; Montaufier, M.-T.; Randriamahefa, S. L. Tetrahe-
This work was supported by the Academy of Sciences of the
Czech Republic (Z4 055 0506).
dron Lett. 1989, 30, 3969–3972.
19. Denes, F.; Perez-Luna, A.; Chemla, F. J. Org. Chem. 2007, 72, 398–406.
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Rec. 2005, 5, 27–35; (b) Studer, A. Chem.dEur. J. 2001, 7, 1159–1164.
Supplementary data
21.
b-Amino ester enolates have not been investigated in detail with regard to the
formation of mixed aggregates with lithium halides, their formation is docu-
mented with ketones, see for instance: (a) Henderson, K. W.; Dorigo, A. E.; Liu,
Q.-Y.; Williard, P. G.; von Rague-Schleyer, P.; Bernstein, P. R. J. Am. Chem. Soc.
1996, 118, 1339–1347; (b) Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc.
1991, 113, 9571–9574; (c) Jackman, L. M.; Lange, B. C. J. Am. Chem. Soc. 1981, 103,
4494–4499.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2009.10.034.
References and notes
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24. Crystal data for (5R,3S,7R)-12e: C14H17NO2, orthorhombic, P212121, a¼5.
5570(2), b¼11.8157(3), c¼18.5313(4) Å, Z¼4, T¼100 K. A colorless tablet 0.
25ꢂ0.15ꢂ0.06 mm was used to record a total of 23458 data to 2
q
(max) 151ꢀ
using Cu K
a radiation on an Oxford Diffraction Nova O diffractometer. The
structure was refined using the program SHELXL-97 (G.M. Sheldrick, Acta Cryst.
2008, A64, 112–122) to wR2 0.080, R1 0.030 (all data) for 2512 independent
data and 155 parameters. The Flack parameter refined to 0.06(18), thus de-
termining the absolute configuration on the basis of the anomalous dispersion
of oxygen. Complete crystallographic data have been deposited with the
Cambridge Crystallographic Data Center as supplementary publication no.
CCDC 747054. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: (internat.) 1 44 1223/336
033; E-mail: deposit@ccdc.cam.ac.uk].
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was not observed during storage. However, 3 is dried routinely prior to use in high
vacuum at room temperature for 1–2 h. For the preparation of 3, see: Ref. 25a.
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