The use of two optically active N-sulfinyl α-imino esters in the stereoselective aza-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tet.2009.01.090

Diastereoselective aza-Diels-Alder (aza-DA) reactions of ethyl (S)-N-(tert-butanesulfinyl)iminoacetate (2a) and ethyl (S)-N-(p-toluenesulfinyl)iminoacetate (2b) with different dienes including activated, non-activated, cyclic, and acyclic dienes in the pr

Full text of DOI:10.1016/j.tet.2009.01.090

Tetrahedron 65 (2009) 2806–2817
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The use of two optically active N-sulfinyl
aza-Diels–Alder reaction
a-imino esters in the stereoselective
,
Trygve Andreassen a, Marianne Lorentzen a, Lars-Kristian Hansen b, Odd R. Gautun a
*
a Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway
b Department of Chemistry, Faculty of Science, University of Tromsø, NO-9037 Tromsø, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Diastereoselective aza-Diels–Alder (aza-DA) reactions of ethyl (S)-N-(tert-butanesulfinyl)iminoacetate
(2a) and ethyl (S)-N-(p-toluenesulfinyl)iminoacetate (2b) with different dienes including activated, non-
activated, cyclic, and acyclic dienes in the presence of Lewis acids are described. Reactions with 2a were
found to be more selective. Reactions of unactivated dienes (acyclic and cyclic) with stoichiometric
amounts of TMSOTf as Lewis acid afforded the aza-DA adducts in modest yields and in diaster-
eoselectivities up to 99%. A strong preference for Re-approach was observed for 2a. Cyclic dienes gave the
exo adducts as major products. For the aza-DA reaction with activated Danishefsky type dienes poor
diastereoselectivities were observed. In these cases, the best results were obtained using stoichiometric
amounts of BF3$Et2O as Lewis acid (up to 69% de, 76% yield). The absolute configurations of six of the
addition products were established by chemical correlation with known compounds. Acidic cleavage of
Received 25 November 2008
Received in revised form 7 January 2009
Accepted 22 January 2009
Available online 30 January 2009
Keywords:
Asymmetric induction
Aza-Diels–Alder reactions
Sulfinimines
Non-activated dienes
the sulfinyl group occurred without racemization to optically active non-proteinogenic
ethyl esters.
a-amino acid
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
with this method is the removal of the p-toluenesulfonyl group (p-
Ts), which requires harsh conditions.4
The aza-Diels–Alder (aza-DA) reaction between dienes and
imines is a powerful synthetic method for preparation of highly
functionalized six-membered aza-cycles such as piperidines and
tetrahydroquinolines.1 In general, this reaction requires a highly
activated (electron-rich) diene like the Danishefsky’s diene and an
electron-poor imine. The aza-DA reaction is usually slow due to the
low reactivity of the imine functionality. The reactivity can often be
increased by incorporation of an electron-withdrawing substituent
on the imine and by addition of a Lewis acid to the reaction system.
Several asymmetric protocols have appeared, involving either
a diastereoselective aza-DA reaction applying chiral imines2 or
more recently, a catalytic enantioselective reaction.3
The chiral non-racemic N-sulfinylimino esters 2, which are the
sulfinyl analogs of 1 (see Fig. 1), have been described in the litera-
ture as ‘chiral glycine cation equivalents’ for the asymmetric syn-
thesis of a
-amino acids with excellent diastereoselectivities.5 The
chiral and electron-withdrawing sulfinyl group has been shown to
activate the C]N bond for nucleophilic addition with high and
predictable asymmetric induction, and is easily removed from the
product.6
Since the known aza-DA chemistry of chiral N-sulfinyl imines
(sulfinimines) as dienophiles was limited to only one report de-
scribing the reaction of 2-aryl substituted N-sulfinyl imines to the
highly activated (electron-rich) Rawal diene,7 an investigation of
the aza-DA reaction of 2a was initiated. We recently communicated
that 2a reacts with both activated and non-activated dienes in the
presence of BF3$OEt2.8 The aza-DA adducts were obtained in
In 2000, Jørgensen et al. reported excellent results for the cat-
alytic enantioselective aza-DA reaction by reacting the double ac-
tivated N-tosyl a-imino ester 1 (see Fig. 1) with different dienes
including activated, non-activated, cyclic, and acyclic dienes in the
presence of chiral BINAP–copper(I) complexes.3e The described
reaction provided an effective route to optically active non-pro-
R
S
teinogenic a-amino acids of the piperidine type. A major drawback
pTs
N
N
O
EtO2C
H EtO2C
H
1
2a: R = tBu
2b: R = pTol
* Corresponding author. Tel.: þ47 73 59 41 01; fax: þ47 73 59 42 56.
E-mail address: odd.gautun@chem.ntnu.no (O.R. Gautun).
Figure 1. Activated dienophiles for the aza-Diels–Alder reaction.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.090

T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
2807
modest yields and in diastereoselectivities ranging from poor for
OMe
the activated Danishefsky type dienes to excellent for the unac-
tivated acyclic dienes (up to 99% de). Here, we present a more de-
tailed report on this reaction with the a-imino ester dienophiles 2a
.
BF3 OEt2
2a
+
-78 °C, 17.5 h, DCM
(81% total yield)
OTMS
3b
and 2b. Assignment of the absolute configuration of the aza-DA
adducts, a model explaining the stereochemical outcome of the
reaction, and a study of the by-products in the reaction are
addressed. Finally, hydrolysis of the aza-DA adducts for removal of
the chiral sulfinyl auxiliary to afford optically active non-protei-
S
S
S
H
EtO2C
S
H
EtO2C
O
N
O
N
O
N
O
N
+
+
+
:
EtO2C
EtO2C
O
O
3
O
3
O
H
H
nogenic a-amino acid ethyl esters is presented.
H
CH
H
CH
H3C
H
H
H3C
(2R,3R,SS)-4b
(2R,3S,SS)-4b
(2S,3S,SS)-4b
ratio: 54
(2S,3R,SS)-4b
2. Results and discussion
:
26
:
16
4
2.1. The aza-Diels–Alder reaction
Scheme 2.
A series of Lewis acids (1 equiv) have previously been screened
as promoters for the diastereoselective aza-DA test reaction of 2a
(1 equiv) with the activated Danishefsky’s diene 3a (2 equiv),
shown in Scheme 1.8 The best result was obtained with a stoichio-
metric amount of BF3$OEt2 at ꢀ78 ꢁC for 1.5 h in dry dichloro-
methane, yielding an epimeric mixture of (2S,SS)-4a and (2R,SS)-4a
in ratio 5.4:1, and 76% combined yield. Using less than 1 equiv of
the Lewis acid provided inferior results, indicating that it was
consumed during the reaction. Recrystallization of the mixture
from 10% isopropanol in n-hexane provided the major isomer in
pure form, and an X-ray analysis established the relative configu-
ration shown in (2S,SS)-4a.8
Attempts to cleave off the sulfinyl group in (2S,SS)-4a with
concentrated HCl solution (aqueous) in methanol at room tem-
perature failed, resulting in several decomposition products.
However, repeating the experiment at 0 ꢁC afforded the desired
product (2S)-11a in 85% yield (see Scheme 1), and high purity
(>99% ee) according to chiral GC analysis. Interestingly, when
mixtures of (2S,SS)-4a and (2R,SS)-4a were treated with 1 M HCl
solution (aqueous) in THF at 0 ꢁC, a rate difference in cleavage of the
sulfinyl group was observed for the two compounds. In general, the
minor epimer (2R,SS)-4a was cleaved at a faster rate, as exemplified
in the experiment starting from an 81:19 mixture of (2S,SS)-4a and
(2R,SS)-4a and 10 min reaction time, giving 11a, (2S,SS)-4a, and
(2R,SS)-4a in ratio 11:77:12, respectively.
The aza-DA reaction of 2a with trans-1-methoxy-2-methyl-3-
(trimethylsilyloxy)-1,3-pentadiene (3b), in the presence of stoi-
chiometric amounts of BF3$OEt2 (ꢀ78 ꢁC,17.5 h), afforded a mixture
of four diastereomeric compounds as shown in Scheme 2. We were
able to separate (2S,3S,SS)-4b/(2R,3R,SS)-4b from (2S,3R,SS)-4b/
(2R,3S,SS)-4b by flash chromatography, and crystallization of the
former fraction yielded pure (2S,3S,SS)-4b. The absolute configu-
ration was established by X-ray.8 The relative configuration of
(2R,3R,SS)-4b was determined by 1H NMR spectroscopy, showing
a similar vicinal 1H–1H coupling constant (6.5 Hz) between H-2 and
H-3 as for (2S,3S,SS)-4b (6.0 Hz). The corresponding coupling con-
stants for (2S,3R,SS)-4b and (2R,3S,SS)-4b were found to be 1.7 Hz
and 2.3 Hz, respectively.
The absolute configurations of the latter two isomers could not
be determined, and the proposed structures in Scheme 2 are based
on the general preference for (S) configuration at the a-carbon (a to
the ester group) in these reactions (see stereochemical model dis-
cussed below). The stereochemical result shown in Scheme 2 de-
viates from the results obtained by Jørgensen et al., where a chiral
BINAP–copper(I) complex catalyzed the aza-DA reaction of tosyl
imine 1 with 3b, giving the trans adduct (corresponding to our
minor (2S,3R,SS)-4b and (2R,3S,SS)-4b) as the major product.3e
Their best result was a 10:1 ratio of the trans and cis adducts, and
the former diastereomer was isolated in 83% yield and 94% ee. The
cis adduct (corresponding to our (2S,3S,SS)-4b and (2R,3R,SS)-4b)
was isolated in 8% yield (racemic).
A series of Lewis acids including SnCl4, Zn(OTf)2, Cu(OTf)2,
Yb(OTf)3, trimethylsilyl trifluoromethanesulfonate (TMSOTf),
Mg(ClO4)2, AlBr3, and BF3$Et2O were screened as promoters
(1 equiv) for the stereoselective aza-DA reaction of 2a with non-
activated dienes (acyclic and cyclic). The survey pointed out
TMSOTf and BF3$Et2O to be the most selective and activating Lewis
acids for the reaction. The more promising results are presented in
Table 1. For comparison, results from reactions applying the p-tol-
uenesulfinylimino ester 2b as dienophile are included in Table 1. In
the presence of Lewis acids, some of the dienes underwent poly-
merization at rates competitive to the preferred aza-DA reactions.
For this reason, some excess diene (2 equiv) was generally used.
Especially for isoprene (3c), a significant improvement of the yield
was observed when using an even larger excess of 3c. The yield of
(2S,SS)-4c was raised from 25% (Table 1, entry 2) to 48% (Table 1,
entry 3) by increasing the amount of 3c from 2 to 20 equiv.
Without exception, all reactions with 2a were more selective
than the reactions with 2b, owing to the bulkiness of the tert-butyl
group. In general, the best diastereoselectivities were obtained in
reactions applying 2a in combination with TMSOTf. The tert-butyl
reactions of isoprene (3c, Table 1, entries 1–3) and 2,3-dime-
thylbutadiene (3d, Table 1, entries 5 and 6) provided only one ob-
servable diastereomer according to 1H NMR (400 MHz)
spectroscopy of respective crude products. Our results showed
better selectivities (>99% de) versus the reported enantioselective
aza-DA reaction of 1 with diene 3d catalyzed by chiral BINAP–
copper(I) complexes (up to 65% ee).3e
OMe
S
S
H
EtO2C
.
O
N
O
N
BF3 OEt2
The aza-DA reaction of 2a with (E)-1,3-pentadiene (3e, Table 1,
entry 9) and (E,E)-2,4-hexadiene (3f, Table 1, entry 10) afforded
mixtures of cis/trans adducts in 7 and 14% combined yields, re-
spectively. The diastereomeric products in both reactions could be
separated by flash chromatography. The proposed absolute con-
figurations shown in Table 1 were not determined, but were based
on NMR spectroscopy assigning the relative configuration between
the Me/CO2Et groups (see Fig. 2), and from the stereochemical
model discussed below showing a preference for (S) configuration
2a
+
+
EtO2C
-78 °C, 20 h, DCM
O
(2R,SS)-4a
O
OTMS
H
3a
(2S,SS)-4a
76% yield
ratio: 5.4
:
1
HN
H
HCl (aq.), MeOH, 0 °C, 5 h
(85% yield)
(2S,SS)-4a
O
EtO2C
(2S)-11a
Scheme 1.
at the a-carbon (a to the ester group).

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T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
Table 1
Aza-DA reactions of 2a,b (1 equiv) with non-activated dienes 3c–3h (2 equiv) promoted by Lewis acid (1 equiv) in CH2Cl2 under argon atm
Entry
Imine
Diene
Lewis acid
Conditions
Aza-Diels–Alder adducta
Yieldb (%)
R
S
R
S
O
N
O
N
+
EtO2C
EtO2C
(2R,SS)-4c
(2S,SS)-4c
1
2
3
4
2a (R¼t-Bu)
BF3$Et2O
TMSOTf
TMSOTf
TMSOTf
0 ꢁC, 1 h
Ratio: >99:<1
Ratio: >99:<1
Ratio: >99:<1
Ratio: 3:2
19
25
48c
18
2a
ꢀ78 ꢁC, 22 h
ꢀ78 ꢁC, 22 h
ꢀ78 ꢁC, 20 h
2a
3c
2b (R¼p-Tol)
R
S
R
S
O
N
O
N
+
EtO2C
EtO2C
(2S,SS)-4d
(2R,SS)-4d
5
6
7
8
2a (R¼t-Bu)
BF3$Et2O
TMSOTf
BF3$Et2O
TMSOTf
0 ꢁC, 2 h
ꢀ78 ꢁC, 5 h
0 ꢁC, 3.5 h
ꢀ78 ꢁC, 5.5 h
Ratio: >99:<1
Ratio: >99:<1
Ratio: 4:1
42
64
35
48
2a
2b (R¼p-Tol)
3d
2b
Ratio: 7:3
R
S
R
S
O
N
O
N
+
EtO2C
(2S,6S,SS)-4e
EtO2C
(2S,6R,SS)-4e
9
2a (R¼tBu)
TMSOTf
ꢀ78 ꢁC, 20 h
Ratio: 2:1
7d
3e
R
S
R
S
O
N
O
+
N
EtO2C
EtO2C
(2S,3R,6S,SS)-4f (2S,3S,6R,SS)-4f
10
2a (R¼t-Bu)
TMSOTf
ꢀ78 ꢁC, 23 h
Ratio: 97:3
14d
3f
R
S
R
S
R
S
O
O
O
N
N
N
+
+
EtO2C
EtO2C
H
H
(1S,3S,4R,SS)-4g
H
(1R,3S,4S,SS)-4g
CO2Et
(1R,3R,4S,SS)-4g
11
12
13
14
2a (R¼t-Bu)
BF3$Et2O
TMSOTf
BF3$Et2O
TMSOTf
ꢀ50 ꢁC, 25 h
ꢀ78 ꢁC, 18 h
ꢀ50 ꢁC, 0.5 h
ꢀ78 ꢁC, 17 h
Ratio: 88:12:0
Ratio: >99:<1:0
Ratio: 89:7:4
52
49
48
63
2a
2b (R¼p-Tol)
3g
2b
Ratio: 89:7:4
R
S
R
S
O
O
+
N
N
8d
EtO2C
EtO2C
H
(1S,3S,4R,SS)-4h
H
(1R,3S,4S,SS)-4h
15
2a (R¼t-Bu)
TMSOTf
ꢀ78 ꢁC, 16 h
Ratio: 87:13
3h
a
The product ratio was determined by 1H NMR (400 Hz) spectroscopy of the crude product.
Total yield of isolated isomers.
Compound 3c (20 equiv) and 10 equiv of TMSOTf were added to 1 equiv 2a.
b
c
d
The proposed configurations were not determined, but rationalized by NOE experiments and from the stereochemical model discussed below.

T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
2809
CH3
N
CH3
N
H3C
H
CO2Et
LA
S
NOE
H
S
S
O
N
O
O
N
S
HNOE
O
NOE
H
CO2Et
(2S,6R,SS)-4e
CO2Et
CO2Et
tBu
CH3
(2S,3R,6S,SS)-4f
CH3
(2S,3S,6R,SS)-4f
(1S,3S,4R,SS)-4g
OEt
Figure 2. Relative configurations shown from NOE experiments.
LA
S
EtO2C
H
LA
H
b
N
b
a
N
CH2
CH3
CH3
O
O
a
N
LA
O
S
tBu
O
S
O
OEt
H
An exo preference was found for 2a in reactions with cyclo-
pentadiene (3g, Table 1, entries 11 and 12) and cyclohexadiene
(3h, Table 1, entry 15). The TMSOTf promoted reaction of 3g at
ꢀ78 ꢁC afforded only one observable diastereomer (1S,3S,4R,SS)-
4g (t-Bu) in 49% yield (entry 12), while BF3$Et2O provided an
88:12 mixture of the exo (1S,3S,4R,SS)-4g (t-Bu) and the endo
(1R,3S,4S,SS)-4g (t-Bu) in 52% combined yield (entry 11). The aza-
DA reaction of 2b with 3g afforded an 89:7:4 mixture of
(1S,3S,4R,SS)-4g (p-Tol), (1R,3S,4S,SS)-4g (p-Tol) and (1R,3R,4S,SS)-
4g (p-Tol), respectively (Table 1, entries 13 and 14). Re-
crystallization of the mixture from 10% isopropanol in n-hexane
afforded the major isomer almost pure (97% de). The exo prefer-
ence observed in reactions with unactivated cyclic dienes is in
accordance with results reported for the enantioselective aza-DA
reactions of 1 with 3g and 3h, catalyzed by chiral BINAP–copper(I)
complexes.3e Yields and enantioselectivities of the major exo aza-
DA adducts from 3g and 3h were reported up to 85% (83% ee) and
52% (95% ee), respectively.3e
tBu
- isobutylene
tBu
LA
8
CH2
S
H
O
N
CH2
O
H
10
- ethene
O
H
Scheme 3.
analog. Similar reactions with 2a were not observed. Ene reactions
with p-tolyl sulfoxide cation (formed in situ from p-toluenesulfi-
namide) have been reported,11 which can explain the formation of
the ene product 5. Ene product 5 was observed in low yields (2–12%)
when the reaction took place at ꢀ78 ꢁC, but at higher temperature
(0 ꢁC) the yield improved (27%, Table 2, entry 2). Chiral HPLC analysis
of 5 (Table 2, entry 1) showed that some degree of chiral induction
took place in these reactions (40% ee), indicating that the sulfur–
nitrogen bond could not have been completely broken during ad-
dition to the diene. Nucleophilic attack by an ethoxide rather than
diene would provide 7. This ethoxide would most likely come from
the ethyl ester group of the sulfinimine, but details around the re-
actionremainunclear. The thiosulfinate 6 was observedin all aza-DA
reactions with 2b in various amounts. In most reactions, the yields
were lower than 10%, but at higher temperatures (0 ꢁC) more 6 was
formed (28%, Table 2, entry 2). A decomposition of sulfinimine to
sulfenic acid,12 and a bimolecular dehydration of the sulfenic acid13
can explain the formation of 6.
2.2. By-products in the aza-Diels–Alder reaction
Several by-products were formed and identified during the
course of this work. Although not always structurally interesting,
attention to these products can provide new insight into the re-
action. We did notobserveanyimineeneby-products inourreaction
systems as reported for the chiral BINAP–copper(I) complex cata-
lyzed aza-DA of tosyl imine 1.3e Table 2 shows the most interesting
by-products encountered and the reaction conditions under which
they were formed. It should be pointed out that attempts to improve
the yields of these products were not undertaken. Formation of
products 5, 6,9 and 710 (Table 2, entries 1 and 2) must involve
breaking of the sulfur–nitrogen bond of 2b at some stage. It is ob-
vious that a potential p-tolyl sulfoxide cationdor radical, would be
more stabilized by resonance than the corresponding tert-butyl
The aza-DA adducts from cyclopentadiene reactions with 2a
were not particularly stable, and several by-products were iden-
tified (see Table 2, entries 3–5). Shortening the reaction time did
not provide higher yields. A rationale for the formation of 8 and
10 from the exo aza-DA product (1S,3S,4R,SS)-4g (t-Bu) is shown
Table 2
By-products from the aza-Diels–Alder reaction of sulfinimines 2a and 2b
Entry
Imine
Diene
Lewis acid
Conditions
By-products/yieldsa (%)
Aza-DA/yieldsb (%)
O
S
O
S
O
S
pTol
pTol
pTol
OEt
O
pTol
S
5
6
7
1
2
2b
2b
3c
3c
TMSOTf
TMSOTf
ꢀ78 ꢁC, 20 h
12 (40% ee):6:8
27:28:0
18
10
0
ꢁC, 1 h
S
EtO2C
H
EtO2C
H
NH
O
H
NH
S
NH
S
O
H
O
O
H
H
8
9
10
3
4
5
2a
2a
2a
3g
3g
3g
TMSOTf
BF3$Et2O
BF3$Et2O
ꢀ78 ꢁC, 15.5 h
ꢀ50 ꢁC, 25 h
rt, 17.5 h
17:0:11
13:0:3
38c:4c:0
44
52
0
a
Isolated yields.
Combined yield of aza-DA adducts.
Mixture of 8 and 9.
b
c

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T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
confirmed by calculations on different sulfinimines, both with and
without Lewis acids (LA) present.17 The model has earlier been
used to explain the stereochemical outcome of Lewis acid pro-
moted additions of both Grignard reagents5a and silyl nucleo-
philes18 to sulfinimines.
S
HN
O
O
CO2Et
NOE
NOE
H
H
H
H
NH
S
H
H
O
H
O
H
2.4. Configuration of the aza-Diels–Alder products
9
10
Figure 3. Structure determining NOE’s for 9 and 10.
The determination of the absolute configuration of the aza-DA
adducts (2S,SS)-4a and (2S,3S,SS)-4b has been described elsewhere.8
Absolute configurations of the major aza-DA adducts (2S,SS)-4c (t-Bu
and pTol), (2S,SS)-4d (t-Bu and p-Tol) and (1S,3S,4R,SS)-4g (t-Bu and
p-Tol) were established by chemical correlation with the known HCl
salt (2R)-12c (see Scheme 4),19 (2S)-13d (Scheme 5),3e and
(1S,3S,4R)-13g (Scheme 6),3e respectively.
in Scheme 3. Initiated by a Lewis acid (LA), the C–N bond breaks
to form an allylic cation, which is attacked by either the ester or
sulfinyl group. Rearrangement of a similar compound has been
reported by Kobayashi et al., although the hydrolyzed ester was
reported in this paper.14 Since our reactions were carried out in
anhydrous environment, we propose an alternative removal of the
ethyl group. The proposed mechanism for the formation of 8 in-
cludes an attack by the sulfinyl-sulfur lone pair, explaining the
inversion of the sulfinyl stereocentre. Similar nucleophilic attack
by the sulfur in tert-butanesulfinyl compounds has been sug-
gested by Davis et al., with the expulsion of isobutylene as an
important driving force.15 A similar rearrangement of the endo
product (1R,3S,4S,SS)-4g (t-Bu) would give 9. The absolute con-
figuration of 8 was determined by X-ray.16 The relative configu-
rations of 9 and 10 were found from NOE experiments. Structure
determining NOE’s are shown in Figure 3.
HCl x HN
EtO2C
i) TMSOTf, -78 °C, 19 h
HN
EtO2C
HCl
2a + 3c
ii) HCl, MeOH, r.t., 18 h
iii) K2CO3
(39% yield, 3 steps)
(100%)
(2S)-11c
(2S)-12c
ratio
pTs
(2S,SS)-4c: 3
+
mCPBA
N
HCl, MeOH
r.t., 4 h
(78%)
-20 °C, 5.5 h, DCM
(2R,SS)-4c: 2
(pTol)
EtO2C
(51%)
(2S)-13c
Scheme 4.
pTs
2.3. Stereochemical model
N
HN
EtO2C
pTsCl, Zn
(21%)
i) TMSOTf, -78 °C, 18 h
ii) HCl, MeOH, r.t., 18 h
(55% yield, two steps)
2a + 3d
EtO2C
Although most aza-Diels–Alder reactions are concerted, there
are many examples of stepwise Mannich–Michael type mecha-
nisms.1 Most of these examples involve electron-rich oxygenated
dienes or use of Brønsted acids as catalysts, leading to relative
stable intermediates. The absolute configurations of the major
cycloadducts (2S,SS)-4a, (2S,3S,SS)-4b, (2S,SS)-4c (t-Bu and p-Tol),
(2S,SS)-4d (t-Bu and p-Tol), and (1S,3S,4R,SS)-4g (t-Bu and p-Tol)
were determined (as described below). All major products had the
(2S)-11d
(2S)-13d
ratio
(2S,SS)-4d: 4
+
mCPBA
(2S)-13d
-20 °C, 5.5 h, DCM
(12%)
(2R,SS)-4d: 1
(pTol)
Scheme 5.
(S)-configuration at the
a-carbon atom (a to the ester group). A
strong preference for Re-approach was observed for 2a (t-Bu). In
fact, for all unactivated dienes, tert-butyl products were appar-
R
S
i) 4.0 M HCl in dioxane,
MeOH, r.t., 4 h
pTs
O
N
N
EtO2C
ently formed exclusively with (S)-configuration at the
a-carbon,
EtO2C
with the diastereomeric diversity originating from endo/exo ap-
proach. More evidently, tert-butyl reactions of isoprene (3c) and
2,3-dimethylbutadiene (3d) provided only one observable di-
astereomer, since endo/exo approaches lead to identical products
in these cases. The expected exo preference was found for
reactions with the cyclic dienes 3g and 3h,3e but the products
deriving from acyclic dienes 3b, 3e, and 3f showed the opposite
endo preference. Products from the activated Danishefsky’s dienes
3a and 3b are conspicuously less selective, forming diastereomers
ii) pTsCl, NEt3, DCM, 0 °C, 5 h
H
H
(67% yield, 2 steps)
(1S,3S,4R)-13g
(1S,3S,4R,SS)-4g
(R = tBu)
mCPBA, DCM, -20 °C, 2.5 h
(1S,3S,4R,SS)-4g
(R = pTol)
(1S,3S,4R)-13g
(46%)
Scheme 6.
The crude aza-DA adduct (2S,SS)-4c (t-Bu), obtained by reacting
2a with 20 equiv of 3c in the presence of 10 equiv TMSOTf, was
treated with concentrated aqueous HCl in methanol to afford the
HCl salt (2S)-12c (see Scheme 4). By controlling the pH of the water
phase, (2S)-12c was purified with extraction alone. Basic adjust-
ment afforded enantiopure (2S)-11c (according to chiral GC anal-
ysis), and was then transformed back to (2S)-12c in concentrated
aqueous HCl. Similarly, acidic removal of the tolylsulfinyl group in
a 3:2 mixture of (2S,SS)-4c (p-Tol) and (2R,SS)-4c (p-Tol) afforded
the enriched (2S)-12c in 78% yield. The tolylsulfinyl group in the
aza-DA mixture was also oxidized with m-CPBA at ꢀ20 ꢁC to the
enantiomerically enriched tosyl analog (2S)-13c in 51% yield.
Crude (2S,SS)-4d (t-Bu), obtained from the aza-DA reaction of 2a
with 3d (see Scheme 5), was hydrolyzed in accordance with the
method mentioned above for (2S,SS)-4c (t-Bu) to (2S)-11d, and then
tosylated under neutral conditions20 to the known (2S)-13d (>99%
with both configurations at the a-carbon atom. This could result
from a less selective, possibly stepwise, mechanism as suggested
by Kawe˛cki.7 However, we were not able to identify intermediate
products in these reactions. The stereochemical outcome of the
aza-DA reactions of 2a and 2b can be rationalized according to the
model shown in Figure 4. The shown conformation has been
CH3
H3C
H3C
N
Diene
C
endo or exo
O
LA
CO2Et
(S )
S
Figure 4. Stereochemical model.

T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
2811
As shown in Figure 6, the preferred conformer of the (S,SS)-dia
stereomer puts the tolyl group in the vicinity of the ester group,
leading to significant shielding of the ethyl (OCH2CH3) proton NMR
signals. The (R,SS)-diastereomer, however, does not show this ef-
fect. Table 3 shows the ethyl proton shifts for all tolyl aza-DA ad-
ducts described in this paper. A chemical shift at 3.6–3.7 for
R
S
S
S
O
O
O
N
N
N
EtO2C
EtO2C
EtO2C
NOE H
(1R,3S,4S,SS)-4h
NOEH
H
NOE
H
(1S,3S,4R,SS)-4h
H
(1R,3S,4S,SS)-4g
H
(R = tBu and pTol)
(1R,3S,4S,SS)-4g supports (S)-configuration at C-3
(a-C), and
a chemical shift at 4.29 for (1R,3R,4S,SS)-4 supports (R)-configu-
Figure 5. Proposed configurations for bicyclic aza-DA adducts.
ration at C-3.
3. Conclusion
O
S
In conclusion, diastereoselective aza-Diels–Alder (aza-DA) re-
actions of ethyl (S)-N-(tert-butanesulfinyl)iminoacetate (2a) and
ethyl (S)-N-(p-toluenesulfinyl)iminoacetate (2b) in the presence of
stoichiometric amounts of Lewis acids have been presented. A
range of dienes have been applied. The reactions with 2a were
found to be the most selective. Reactions of unactivated dienes with
TMSOTf as Lewis acid afforded aza-DA adducts in modest yield and
diastereoselectivities up to 99%. A strong preference for the Re-
approach was observed for 2a. Cyclic dienes gave exo adducts as
major products. For the aza-DA reactions with activated Dani-
shefsky type dienes, poor diastereoselectivities were observed. In
these cases the best results (up to 69% de, 76% yield) were obtained
with BF3$Et2O as Lewis acid. Treatment of selected aza-DA adducts
with HCl resulted in cleavage of the sulfinyl group without race-
N
N
CO2Et
S
H
CO2Et
(S,S )
H
O
(R,S )
S
S
Figure 6. Model explaining observed shielding for (S,SS)-isomers in 1H NMR.
ee, HPLC).3e The configuration of a 4:1 mixture of (2S,SS)-4d (p-Tol)
and (2R,SS)-4d (p-Tol) was established by an m-CPBA oxidation to
the enantiomerically enriched (2S)-13d.
The absolute configuration of (1S,3S,4R,SS)-4g (t-Bu) was de-
termined by cleavage of the sulfinyl group5e and subsequent tosy-
lation to the known N-tosyl compound (1S,3S,4R)-13g3e in 67%
total yield (see Scheme 6). The configuration of (1S,3S,4R,SS)-4g (p-
Tol) was assigned by oxidation to (1S,3S,4R)-13g.
mization, yielding optically active non-proteinogenic
esters.
a-amino ethyl
The relative configurations of the other isomers of 4g and 4h,
disregarding the configuration at the a-carbon atom (a to the ester
4. Experimental
group), were found from NOE experiments. The structure de-
termining NOE’s are summarized in Figure 5. From the stereo-
chemical model discussed above we assume (S)-configuration at
4.1. General remarks
All reactions were performed under an argon or nitrogen at-
mosphere. Tetrahydrofuran (THF) was distilled under nitrogen
from Na/benzophenone. Dichloromethane was distilled under
nitrogen from calcium hydride. Sulfinimines 2a and 2b were
prepared according to the literature.5a The racemic sulfinimines
were also prepared to provide reference compounds for chiral GC
and HPLC analysis. Melting points were determined on a Buchi
535 apparatus and are uncorrected. TLC was performed on Merck
silica gel 60 F254 plates, using UV light at 312 nm and a 5% alco-
holic molybdophosphoric acid for detection. Silica gel for flash
chromatography was purchased from Merck. Optical rotations
were measured with a Perkin–Elmer 241 Polarimeter. Enantio-
meric excesses were determined by HPLC analysis, using Daicels
columns Chiralcel OD-H and OJ and Chiralpak AD (250ꢂ4.6 mm),
or by GC using CP Chirasil Dex CB column. 1H and 13C NMR
spectra (Bruker Avance DPX instruments 300/75 MHz and 400/
100 MHz) were obtained from solutions of CDCl3, and chemical
shifts are in parts per million and referenced to TMS via the lock
signal of the solvent. 1H and 13C NMR signals were assigned by 2D
correlation techniques (COSY, HSQC, HMBC, NOESY). IR spectra
were run on a Thermo Nicolet FT-IR NEXUS instrument, and only
the strongest/structurally most important peaks are listed. The
mass spectra were recorded on a Finnigan MAT 95ꢂL mass
spectrometer. The electron-impact mass spectra, MS (EI), were
recorded at 50 eV with a direct inlet, and the electron spray
ionization mass spectra, MS (ESI), at 4.7 kV for low resolution
spectra and 10 kV for high resolution spectra. The high resolution
mass spectra, HRMS (EI) and (ESI), were obtained by using per-
fluorokerosene (PFK) and polyethyleneimine (PEI) as standards,
respectively, to provide the reference masses. The elemental
analyses were performed at the Mikroanalytisches labor Beller,
Go¨ttingen, Germany.
the
a-carbon, and with (S)-configuration fixed at sulfur, the fol-
lowing structures shown in Figure 5 are proposed.
The configurations of the p-toluene isomers (1R,3S,4S,SS)-4g
and (1R,3R,4S,SS)-4g were deduced by the following reasoning: the
aza-DA adducts are formally sulfinamides with the nitrogen taking
part in a cyclic structure. Focusing only on the substituents from the
parent sulfinimine, the sulfoxy group on nitrogen and the ester
group on the neighboring carbon (a-C), some general observations
can be rationalized for the aza-DA adducts of p-toluensulfinimine.
To reduce van der Waals strain, the bulky sulfoxy group would
preferably adopt an orientation trans to the ester group (see Fig. 6).
Considering the rotation of the N–S bond, there is general prefer-
ence for a staggered orientation of the sulfinamides, with the ni-
trogen lone pair anti to the sulfoxide oxygen.21 This can be
attributed to a stabilizing interaction between the nitrogen lone
pair and the anti bonding s-orbital of the S–O bond. In our work,
compounds with (S)-configuration on sulfur were prepared, with-
out any sign of racemization. This leads to two diastereomeric ar-
rangements (ignoring the remaining part of the molecule), due to
(R) or (S)-configuration of the carbon
a
to the ester group (see
Fig. 6).
Table 3
Configuration at a-C versus OCH2CH3 proton shift
p-Tol aza-DA adducts
(S)/ppm
(R)/ppm
(2S,SS)-4cþ(2R,SS)-4c
(2S,SS)-4dþ(2R,SS)-4d
(1S,3S,4R,SS)-4g
4.15
4.13
3.67, 3.62
3.7–3.6
4.22
4.22
(1R,3S,4S,SS)-4g
(1R,3R,4S,SS)-4g
4.29

2812
T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
4.2. General procedure for aza-Diels–Alder reactions
butylsulfinyl)-3,5-dimethyl-4-oxo-1,2,3,4-tetrahydropyridine-2-
carboxylate, (2R,3S,SS)-4b
Sulfinimine 2 (1.2–1.5 M in CH2Cl2, 0.25 mmol) was dissolved in
dried CH2Cl2 (2 mL) and cooled down to the specified temperature
(see Table 1) under an argon atmosphere. The diene 3 (1.4–
2.0 equiv) and the Lewis acid (1.0–1.2 equiv) were added via syringe
and the resultant mixture was stirred. After the appropriate re-
action time (see Table 1), the reaction mixture was quenched by the
addition of a phosphate buffer (pH¼7, 3 mL), and allowed to warm
to room temperature. The mixture was extracted with CH2Cl2
(4ꢂ4 mL) and the combined organics were dried (MgSO4) and
concentrated. The crude product was analyzed by 1H NMR spec-
troscopy to determine the diastereomeric ratio and, thereafter,
purified by flash chromatography.
The asymmetric aza-DA reaction between sulfinimine 2a
(0.52 mmol) and the dimethyl substituted Danishefsky’s diene 3b
(0.99 mmol) according to the general procedure (2ꢂscale) at
ꢀ78 ꢁC for 17.5 h afforded a 54:26:16:4 mixture of (2S,3S,SS)-4b,
(2R,3R,SS)-4b, (2S,3R,SS)-4b, and (2R,3S,SS)-4b, respectively. Flash
chromatography (EtOAc/n-hexane, 1:2) separated (2S,3S,SS)-4b/
(2R,3R,SS)-4b from (2S,3R,SS)-4b/(2R,3S,SS)-4b (total yield:
126.2 mg, 81%). Recrystallization of the main fraction from Et2O/n-
pentane yielded (2S,3S,SS)-4b pure as white crystals (55.4 mg, 35%),
and the absolute configuration was established by X-ray analysis.8
Data for (2S,3S,SS)-4b: Rf (EtOAc/n-hexane, 1:1)¼0.3. Mp 87–88 ꢁC
rt
(from Et2O/n-pentane). [
a]
ꢀ123 (c 1.0, CHCl3). HPLC (Chiralpak
D
AD, i-PrOH/n-hexane, 5:95, 1.0 ml minꢀ1, 230 nm): tR 11.3 min. 1
NMR (400 MHz):
H
d
7.24 (m, 1H, H-6), 4.24 (dd, 1H, J¼6.0, 1.3 Hz, H-
4.2.1. Ethyl (2S,SS)-1-(tert-butylsulfinyl)-4-oxo-1,2,3,4-tetrahydro-
pyridine-2-carboxylate, (2S,SS)-4a, and ethyl (2R,SS)-1-(tert-
butylsulfinyl)-4-oxo-1,2,3,4-tetrahydropyridine-2-carboxylate,
(2R,SS)-4a
2), 4.20 (q, 2H, J¼7.1 Hz, OCH2), 2.94 (qd, 1H, J¼7.1, 6.0 Hz, H-3), 1.74
(d, 3H, J¼1.0 Hz, Me-5), 1.30 (d, 3H, J¼7.1 Hz, Me-3), 1.26 (s, 9H, t-
Bu), 1.25 (t, 3H, J¼7.1 Hz, OCH2CH3). 13C NMR (100 MHz):
d 193.3 (C-
4), 168.0 (CO2Et), 137.4 (C-6), 113.1 (C-5), 64.4 (C-2), 61.9 (OCH2),
59.6 (CMe3), 41.9 (C-3), 21.9 (CMe3), 13.97 (OCH2CH3), 12.9 (Me-5),
11.3 (Me-3). IR (KBr tablet): 3037 (w), 2988 (m), 1737 (s), 1688 (s),
1606 (s), 1381 (m), 1366 (m), 1293 (m), 1194 (s), 1093 (s), 1027 (m),
941 (m), 914 (m), 879 (m) cmꢀ1. MS (EI) m/z (% rel int.): 301 (Mþ, 1),
245 (63), 197 (87), 125 (22), 124 (100), 123 (32). HRMS (EI) calcd for
C14H23NO4S 301.1348, found 301.1336. Anal. Calcd for C14H23NO4S:
C, 55.79; H, 7.69; N, 4.65; S, 10.64. Found: C, 55.68; H, 7.63, N, 4.64;
The asymmetric aza-DA reaction between sulfinimine 2a
(0.52 mmol) and the Danishefsky’s diene 3a (1.0 mmol) according
to the general procedure (2ꢂscale) at ꢀ78 ꢁC for 20 h afforded
a 5.4:1 mixture of (2S,SS)-4a and (2R,SS)-4a, which were not sep-
arable by flash chromatography (EtOAc/n-hexane,1:1). The mixture
was isolated as a pale yellow viscous oil (total yield: 108.3 mg, 76%).
Crystallization of the mixture from 10% i-PrOH in n-hexane affor-
ded the major isomer in pure form (white solid), and an X-ray
analysis established the relative configuration to be that shown in
(2S,SS)-4a.8 Anal. Calcd of the mixture C12H19NO4S: C, 52.73; H,
7.01; N, 5.12; S, 11.73. Found: C, 52.69; H, 7.02; N, 5.05; S, 11.79. Data
S, 10.65. HPLC (Chiralpak AD, i-PrOH/n-hexane, 5:95, 1.0 ml minꢀ1
,
230 nm) of a racemic sample (2R*,3R*,RS*)-4b: tR 11.3 and 13.3 min.
Data for (2R,3R,SS)-4b: Rf (EtOAc/n-hexane, 1:1)¼0.3. HPLC (Chir-
alpak AD, i-PrOH/n-hexane, 5:95, 1.0 ml minꢀ1
, 230 nm): tR
for (2S,SS)-4a: Rf (EtOAc/n-hexane, 1:1)¼0.1. Mp¼127–128 ꢁC (from
13.9 min. 1H NMR (400 MHz):
d 7.10 (m, 1H, H-6), 4.51 (dd, 1H,
rt
10% i-PrOH/n-hexane). [
a]
ꢀ166 (c 0.30, CHCl3). HPLC (Chiralpak
D
J¼6.5, 1.3 Hz, H-2), 4.16 (m, 2H, OCH2), 2.99 (qd, 1H, J¼7.1, 6.5 Hz, H-
3), 1.73 (d, 3H, J¼1.0 Hz, Me-5), 1.27 (d, 3H, J¼7.1 Hz, Me-3), 1.27 (s,
9H, t-Bu), 1.24 (t, 3H, J¼7.2 Hz, OCH2CH3). 13C NMR (100 MHz):
AD, i-PrOH/n-hexane, 10:90, 1.0 ml minꢀ1, 230 nm): tR 23.3 min. 1H
NMR (400 MHz):
d
7.52 (dd, 1H, J¼8.2, 1.4 Hz, H-6), 5.42 (dd, 1H,
J¼8.2, 1.3 Hz, H-5), 4.37 (ddd, 1H, J¼7.0, 2.1, 1.4 Hz, H-2), 4.25 (q, 2H,
J¼7.1 Hz, OCH2), 3.05 (ddd, 1H, J¼16.8, 2.1, 1.3 Hz, trans-H-3), 2.86
(dd, 1H, J¼16.8, 7.0 Hz, cis-H-3), 1.28 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.26
d
193.1 (C-4), 168.5 (CO2Et), 143.1 (C-6), 118.8 (C-5), 61.5 (OCH2),
60.1 (CMe3), 59.3 (C-2), 42.1 (C-3), 22.1 (CMe3), 14.01 (OCH2CH3),
12.7 (Me-5), 11.1 (Me-3). HPLC (Chiralpak AD, i-PrOH/n-hexane,
5:95, 1.0 ml minꢀ1, 230 nm) of a racemic sample (2R*,3R*,SS*)-4b: tR
12.7 and 13.9 min. Data for (2S,3R,SS)-4b: Rf (EtOAc/n-hexane,
1:1)¼0.25. HPLC (Chiralpak AD, i-PrOH/n-hexane, 5:95,
(s, 9H, t-Bu). 13C NMR (100 MHz):
d 190.10 (C-4), 169.0 (CO2Et),
142.8 (C-6), 106.2 (C-5), 62.8 (OCH2), 59.78 (CMe3), 59.4 (C-2), 38.3
(C-3), 21.7 (CMe3), 14.04 (OCH2CH3). IR (KBr tablet): 3050 (w), 3001
(m), 2979 (m), 2912 (m), 1740 (s), 1649 (s), 1577 (s), 1479 (m), 1421
(m), 1337 (m), 1295 (s), 1234 (s), 1194 (s), 1096 (s), 1042 (s), 1021
(m), 992 (s), 930 (m) cmꢀ1. MS (EI) m/z (% rel int.): 274 (Mþ1, 1), 217
(13),169 (18),144 (86), 96 (100), 95 (19), 78 (13), 68 (33), 67 (22), 57
(21), 41 (89), 39 (15). HRMS (EI) calcd for C12H19NO4S 273.1035
(Mþ), found 273.1039. HPLC (Chiralpak AD, i-PrOH/n-hexane, 10:90,
1.0 mL minꢀ1, 230 nm) of a racemic sample (2R*,RS*)-4a: tR 24.6 and
30.5 min. Data for (2R,SS)-4a: Rf (EtOAc/n-hexane, 1:1)¼0.1. HPLC
(Chiralpak AD, i-PrOH/n-hexane, 10:90, 1.0 ml minꢀ1, 230 nm): tR
1.0 ml minꢀ1, 230 nm): tR 17.8 min. 1H NMR (400 MHz):
d 7.33 (m,
1H, H-6), 4.22 (q, 2H, J¼7.1 Hz, OCH2), 4.12 (app. t, 1H, J¼1.6 Hz, H-
2), 3.08 (qd, 1H, J¼7.5, 1.7 Hz, H-3), 1.74 (d, 3H, J¼1.0 Hz, Me-5), 1.31
(d, 3H, J¼7.5 Hz, Me-3), 1.27 (s, 9H, t-Bu), 1.26 (t, 3H, J¼7.1 Hz,
OCH2CH3). 13C NMR (100 MHz):
d 194.4 (C-4), 169.4 (CO2Et), 139.1
(C-6), 111.8 (C-5), 65.2 (C-2), 62.5 (OCH2), 60.1 (CMe3), 43.1 (C-3),
22.1 (CMe3), 17.5 (Me-3), 14.0 (OCH2CH3), 13.1 (Me-5). HPLC (Chir-
alpak AD, i-PrOH/n-hexane, 5:95, 1.0 ml minꢀ1, 230 nm) of a race-
mic sample (2R*,3S*,RS*)-4b: tR 15.1 and 17.7 min. Data for
(2R,3S,SS)-4b: Rf (EtOAc/n-hexane, 1:1)¼0.25. HPLC (Chiralpak AD,
i-PrOH/n-hexane, 5:95, 1.0 ml minꢀ1, 230 nm): tR 15.2 min. 1H
17.9 min. 1H NMR (400 MHz):
d
7.29 (dd,1H, J¼8.0,1.5 Hz, H-6), 5.31
(dd, 1H, J¼8.0, 1.3 Hz, H-5), 4.70 (ddd, 1H, J¼7.2, 2.1, 1.5 Hz, H-2),
4.20 (q, 2H, J¼7.1 Hz, OCH2), 3.04 (ddd, 1H, J¼17.1, 2.1, 1.3 Hz, H-3A),
2.90 (dd, 1H, J¼17.1, 7.2 Hz, H-3B), 1.26 (t, 3H, J¼7.1 Hz, OCH2CH3),
NMR (400 MHz):
d
7.12 (m, 1H, H-6), 4.32 (dd, 1H, J¼2.3, 1.5 Hz, H-
2), 4.18 (m, 1H, OCHH), 4.16 (m, 1H, OCHH), 2.98 (qd, 1H, J¼7.4,
2.3 Hz, H-3), 1.72 (d, 3H, J¼1.0 Hz, Me-5), 1.33 (d, 3H, J¼7.4 Hz,
Me-3), 1.27 (s, 9H, t-Bu), 1.25 (overlap, 3H, OCH2CH3). 13C NMR
1.26 (s, 9H, t-Bu). 13C NMR (100 MHz):
d 190.12 (C-4), 168.9 (CO2Et),
147.9 (C-6), 105.0 (C-5), 62.4 (OCH2), 59.77 (CMe3), 52.6 (C-2), 39.0
(C-3), 21.8 (CMe3), 14.02 (OCH2CH3). HPLC (Chiralpak AD, i-PrOH/n-
hexane, 10:90, 1.0 ml minꢀ1, 230 nm) of a racemic (2R*,SS*)-4a: tR
18.2 and 41.0 min.
(100 MHz, selected signals):
d 169.4 (CO2Et), 144.3 (C-6), 62.1
(OCH2), 60.2 (C-2), 60.2 (CMe3), 43.7 (C-3), 21.9 (CMe3), 17.5
(Me-3), 13.5 (Me-5).
4.2.2. Ethyl (2S,3S,SS)-1-(tert-butylsulfinyl)-3,5-dimethyl-4-oxo-
1,2,3,4-tetrahydropyridine-2-carboxylate, (2S,3S,SS)-4b, ethyl
(2R,3R,SS)-1-(tert-butylsulfinyl)-3,5-dimethyl-4-oxo-1,2,3,4-
tetrahydropyridine-2-carboxylate, (2R,3R,SS)-4b, ethyl (2S,3R,SS)-
1-(tert-butylsulfinyl)-3,5-dimethyl-4-oxo-1,2,3,4-tetrahydro-
pyridine-2-carboxylate, (2S,3R,SS)-4b, and ethyl (2R,3S,SS)-1-(tert-
4.2.3. Ethyl (2S,SS)-1-(tert-butylsulfinyl)-4-methyl-1,2,3,6-
tetrahydropyridine-2-carboxylate, (2S,SS)-4c (t-Bu)
The asymmetric aza-DA reaction between sulfinimine 2a and
isoprene (3c) according to the general procedure (described above)
afforded only (2S,SS)-4c (t-Bu) as aza-DA adduct. The crude product
was purified by flash chromatography (EtOAc/n-hexane, 1:5). Data

T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
2813
for (2S,SS)-4c (t-Bu): viscous colorless oil. Rf (EtOAc/n-hexane,
1445 (m), 1152 (m), 1085 (s), 1050 (s) cmꢀ1. HRMS (EI) calcd for
C12H14OS 206.0760 (Mþ), found 206.0763.
rt
1:1)¼0.35. [
a
]
D
ꢀ36 (c 1.59, CH2Cl2). GC [CP Chirasil Dex CB, 80 ꢁC
(0 min)–4 ꢁC minꢀ1–190 ꢁC (2 min)]: tR 18.0 min. 1H NMR
(400 MHz):
d
5.34 (m, 1H, H-5), 4.39 (dd, 1H, J¼6.5, 1.6 Hz, H-2),
4.2.5. Ethyl (2S,SS)-1-(tert-butylsulfinyl)-4,5-dimethyl-1,2,3,6-
tetrahydropyridine-2-carboxylate, (2S,SS)-4d (t-Bu)
The asymmetric aza-DA reaction between sulfinimine 2a and
2,3-dimethylbutadiene (3d) according to the general procedure
(described above) afforded only (2S,SS)-4d (t-Bu) as aza-DA adduct.
The crude product was purified by flash chromatography (EtOAc/n-
4.20 (q, 2H, J¼7.1, OCH2), 3.82 (app. dp, 1H, J¼18, 2.4 Hz, H-6), 3.60
(br d, 1H, J¼18 Hz, H-6), 2.45 (br d, 1H, J¼17 Hz, H-3), 2.36 (br d, 1H,
J¼17 Hz, H-3), 1.69 (s, 3H, Me-4), 1.27 (t, 3H, J¼7.1 Hz, OCH2CH3),
1.17 (s, 9H, t-Bu). 13C NMR (100 MHz):
d 172.0 (CO2Et), 131.3 (C-
4), 117.6 (C-5), 61.2 (OCH2), 59.0 (CMe3), 51.8 (C-2), 45.1 (C-6), 32.0
(C-3), 23.5 (Me-4), 22.3 (CMe3), 14.0 (OCH2CH3). IR (thin film, NaCl):
2958 (m), 2928 (m), 1736 (s), 1448 (m), 1362 (m), 1194 (s), 1077 (s),
917 (m) cmꢀ1. Anal. Calcd for C13H23NO3S: C, 57.11; H, 8.48; N, 5.12.
Found: C, 57.21;ꢀH1, 8.62, N, 5.10. GC [CP Chirasil Dex CB, 80 ꢁC
(0 min)–4 ꢁC min –190 ꢁC (2 min)] of a racemic sample (2R*,R*S)-
4c (t-Bu): tR 17.8 and 17.9 min.
hexane, 1:5). Data for (2S,SS)-4d (t-Bu): viscous colorless oil. Rf
rt
(EtOAc/n-hexane, 1:1)¼0.45. [
a
]
ꢀ23.7 (c 1.0, CHCl3). GC [CP
D
Chirasil Dex CB, 110 ꢁC (0 min)–1 ꢁC minꢀ1–150 ꢁC (0 min)–
15 ꢁC minꢀ1–180 ꢁC (5 min)]: tR 32.0 min. 1H NMR (400 MHz):
d
4.32 (dd, 1H, J¼6.5, 0.9 Hz, H-2), 4.18 (q, 2H, J¼7.1 Hz, OCH2), 3.71
(br d, 1H, J¼17 Hz, H-6), 3.40 (br d, 1H, J¼17 Hz, H-6), 2.47 (br d, 1H,
J¼17 Hz, H-3), 2.32 (br d, 1H, J¼17 Hz, H-3), 1.63 (s, 3H, Me-4), 1.57
4.2.4. Ethyl (2S,SS)-4-methyl-1-(p-tolylsulfinyl)-1,2,3,6-
tetrahydropyridine-2-carboxylate, (2S,SS)-4c (p-Tol), ethyl (2R,SS)-
4-methyl-1-(p-tolylsulfinyl)-1,2,3,6-tetrahydropyridine-2-
carboxylate, (2R,SS)-4c (p-Tol), and 2-(p-tolylsulfinylmethyl)-1,3-
butadiene, 5
(s, 3H, Me-5), 1.26 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.17 (s, 9H, t-Bu). 13
C
NMR (100 MHz): d 172.0 (CO2Et), 123.1 (C-4), 122.5 (C-5), 61.1
(OCH2), 58.9 (CMe3), 52.4 (C-2), 49.4 (C-6), 33.0 (C-3), 22.4 (CMe3),
18.9 (Me-4), 15.9 (Me-5), 14.2 (OCH2CH3). IR (thin film, NaCl): 2925
(m), 1736 (s), 1448 (m), 1362 (m), 1193 (s), 1135 (m), 1081 (s), 915
(m) cmꢀ1. MS (EI) m/z (% rel int.): 287 (M, 1), 231 (49), 183 (34), 182
(87), 158 (20), 157 (22), 110 (100), 108 (45), 57 (34). Anal. Calcd for
C14H25NO3S: C, 58.50; H, 8.77; N, 4.87; S, 11.16. Found: C, 58.42; H,
8.77; N,ꢀ41.94; S, 11.10. GC [CP Chirasil Dex CB, 110 ꢁC (0 min)–
1 ꢁC min –150 ꢁC (0 min)–15 ꢁC minꢀ1–180 ꢁC (5 min)] of a race-
mic sample (2R*,RS*)-4d (t-Bu): tR 31.7 and 32.0 min.
The asymmetric aza-DA reaction between sulfinimine 2b and
isoprene (3c) according to the general procedure (described above)
afforded an inseparable mixture of (2S,SS)-4c (p-Tol) and (2R,SS)-4c
(p-Tol). In addition, various amounts of 5, 6,9 and 710 were formed
dependent on the reaction conditions applied (see Table 2, entries 1
and 2). The mixture of (2S,SS)-4c (p-Tol) and (2R,SS)-4c (p-Tol) was
purified by flash chromatography (EtOAc/n-hexane, 3:7) and
obtained as a colorless oil. Anal. Calcd of the mixture C16H21NO3S: C,
62.51; H, 6.89; N, 4.56; S, 10.43. Found: C, 62.31; H, 6.75; N, 4.46; S,
10.28. IR of the mixture (thin film, NaCl): 2923 (m), 2852 (m), 1738
(s), 1446 (m), 1380 (m), 1338 (m), 1279 (m), 1197 (s), 1093 (s), 1072
(s) cmꢀ1. Data for (2S,SS)-4c (p-Tol): Rf (EtOAc/n-hexane, 3:7)¼0.2.
HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm):
4.2.6. Ethyl (2S,SS)-4,5-dimethyl-1-(p-tolylsulfinyl)-1,2,3,6-
tetrahydropyridine-2-carboxylate, (2S,SS)-4d (p-Tol),
and ethyl (2R,SS)-4,5-dimethyl-1-(p-tolylsulfinyl)-1,2,3,6-
tetrahydropyridine-2-carboxylate, (2R,SS)-4d (p-Tol)
The asymmetric aza-DA reaction between sulfinimine 2b and
2,3-dimethylbutadiene (3d) according to the general procedure
(described above) afforded an inseparable mixture of (2S,SS)-4d (p-
Tol) and (2R,SS)-4d (p-Tol). The mixture was purified by flash
chromatography (EtOAc/n-hexane, 15:85): colorless oil. Anal. Calcd
of the mixture C17H23NO3S: C, 63.52; H, 7.21; N, 4.36. Found: C,
63.51; H, 7.24; N, 4.16. IR of the mixture (thin film, NaCl): 2981 (m),
2917 (m), 2859 (m), 1738 (s), 1491 (m), 1446 (m), 1384 (m), 1285
(m), 1197 (s), 1135 (m), 1092 (s), 1071 (s), 1023 (s) cmꢀ1. Data for
(2S,SS)-4d (p-Tol): Rf (EtOAc/n-hexane, 1:1)¼0.40. HPLC (Chiralpak
AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1): tR 33.2 min. 1H NMR
tR 35.8 min. 1H NMR (300 MHz):
d
7.57 (app. d, 2H, J¼8.2 Hz, tolyl),
7.29 (app. d, 2H, J¼8.2 Hz, tolyl), 5.35 (app. s, 1H, H-5), 4.27 (dd, 1H,
J¼6.5, 2.2 Hz, H-2), 4.15 (q, 2H, J¼7.1 Hz, OCH2), 3.99 (d, 1H,
J¼17.1 Hz, H-6), 3.56 (d, 1H, J¼17.1 Hz, H-6), 2.65–2.38 (m, 2H, H-3),
2.41 (s, 3H, ArCH3), 1.70 (s, 3H, Me-4), 1.25 (t, 3H, J¼7.1 Hz,
OCH2CH3). 13C NMR (100 MHz):
d 171.0 (CO2Et), 141.2 (Ar), 140.4
(Ar), 131.1 (C-4), 129.7 (Ar), 126.5 (Ar), 118.0 (C-5), 61.2 (OCH2), 55.5
(C-2), 42.8 (C-6), 32.7 (C-3), 23.4 (Me-4), 21.3 (ArCH3), 14.1
(OCH2CH3). HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98,
1.0 ml minꢀ1, 230 nm) of a racemic sample (2R*,RS*)-4c (p-Tol): tR
35.8 and 44.9 min. Data for (2R,SS)-4c (p-Tol): Rf (EtOAc/n-hexane,
(300 MHz):
d
7.57 (app. d, 2H, J¼8.2 Hz, tolyl), 7.29 (app. d, 2H,
J¼8.2 Hz, tolyl), 4.21 (d, 1H, J¼7.2 Hz, H-2), 4.13 (q, 2H, J¼7.2 Hz,
OCH2), 3.90 (app. d, 1H, J¼16.9 Hz, H-6), 3.38 (app. d, 1H, J¼16.9 Hz,
H-6), 2.63–2.36 (m, 2H, H-3), 2.41 (s, 3H, ArCH3), 1.64 (s, 3H, Me-4),
1.54 (s, 3H, Me-5), 1.23 (t, 3H, J¼7.2 Hz, OCH2CH3). 13C NMR
3:7)¼0.2. HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1
,
230 nm): tR 47.5 min. 1H NMR (300 MHz):
d 7.64 (app. d, 2H,
J¼8.2 Hz, tolyl), 7.32 (app. d, 2H, J¼8.2 Hz, tolyl), 5.31 (app. s, 1H, H-
5), 4.47 (dd,1H, J¼6.1, 2.4 Hz, H-2), 4.22 (q, 2H, J¼7.1 Hz, OCH2), 3.56
(d,1H, J¼17.1 Hz, H-6), 3.38 (d,1H, J¼17.1, H-6), 2.65–2.38 (m, 2H, H-
3), 2.42 (s, 3H, ArCH3), 1.70 (s, 3H, Me-4), 1.30 (t, 3H, J¼7.1 Hz,
(100 MHz):
d 171.1 (CO2Et), 141.1 (Ar), 140.6 (Ar), 129.6 (Ar), 126.5
(Ar), 122.9 (C-4), 122.8 (C-5), 61.0 (OCH2), 55.5 (C-2), 47.0 (C-6), 33.9
(C-3), 21.3 (ArCH3), 18.8 (Me-5), 15.8 (Me-4), 14.1 (OCH2CH3). HPLC
(Chiralpak AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1) of a racemic
sample (2R*,RS*)-4d (p-Tol): tR 33.3 and 37.2 min. Data for (2R,SS)-4d
(p-Tol): Rf (EtOAc/n-hexane,1:1)¼0.40. HPLC (Chiralpak AD, i-PrOH/
OCH2CH3). 13C NMR (100 MHz):
d 171.4 (CO2Et), 141.22 (Ar), 140.7
(Ar), 130.6 (C-4), 129.7 (Ar), 126.5 (Ar), 118.1 (C-5), 61.3 (OCH2), 57.9
(C-2), 39.4 (C-6), 32.8 (C-3), 23.4 (Me-4), 21.3 (ArCH3), 14.2
(OCH2CH3). HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98,
n-hexane, 2:98, 1.0 ml minꢀ1 230 nm): tR 31.5 min. 1H NMR
,
1.0 ml minꢀ1, 230 nm) of a racemic sample (2R*,SS*)-4c (p-Tol): tR
(300 MHz):
d
7.65 (app. d, 2H, J¼8.4 Hz, tolyl), 7.32 (app. d, 2H,
rt
43.9 and 47.6 min. Data for 5: Rf (EtOAc/n-hexane, 3:7)¼0.12. [
a]
J¼8.4 Hz, tolyl), 4.41 (dd, 1H, J¼6.3, 2.5 Hz, H-2), 4.22 (q,
2H, J¼7.2 Hz, OCH2), 3.38 (app. d, 1H, J¼17 Hz, H-6), 3.25 (app. d,
1H, J¼17 Hz, H-6), 2.63–2.36 (m, 2H, H-3), 2.42 (s, 3H, ArCH3),
1.64 (s, 3H, Me-4), 1.49 (s, 3H, Me-5), 1.29 (t, 3H, J¼7.2 Hz,
D
ꢀ56.5 (c 0.4, CHCl3). HPLC (Chiralpak AD, i-PrOH/n-hexane, 10:90,
1.0 ml minꢀ1, 230 nm): 40% ee, tR 8.9 (minor) and 10.5 (major) min.
1H NMR (300 MHz):
d
7.51 (app. d, 2H, J¼8.1 Hz, tolyl), 7.31 (app. d,
2H, J¼8.1 Hz, tolyl), 6.37 (dd, 1H, J¼17.6, 10.8 Hz, H-3), 5.33 (d, 1H,
J¼17.6 Hz, H-4), 5.23 (m, 1H, H-1), 5.19 (m, 1H, H-4), 5.00 (app. s,1H,
H-1), 3.79 (dd, 1H, J¼12.5, 0.8 Hz, CH2), 3.56 (dd, 1H, J¼12.5, 0.6 Hz,
OCH2CH3). 13C NMR:
d 171.6 (CO2Et), 141.1 (Ar), 140.3 (Ar), 129.5
(Ar), 126.5 (Ar), 123.0 (C-4), 122.6 (C-5), 61.2 (OCH2), 58.2 (C-2),
43.2 (C-6), 33.8 (C-3), 21.3 (ArCH3), 18.8 (Me-4), 15.9 (Me-5), 14.1
(OCH2CH3). HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98,
1.0 ml minꢀ1, 230 nm) of a racemic sample (2R*,SS*)-4d (p-Tol): tR
31.5 and 42.5 min.
CH2), 2.41 (s, 3H, ArCH3). 13C NMR (100 MHz):
d 141.7 (Ar), 140.7
(Ar), 137.0 (C-3), 135.7 (C-2), 129.7 (Ar), 124.4 (Ar), 122.7 (C-1), 115.4
(C-4), 61.5 (CH2), 21.4 (ArCH3). IR (KBr tablet): 2932 (w), 1727 (m),

2814
T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
4.2.7. Ethyl (2S,6S,SS)-1-(tert-butylsulfinyl)-6-methyl-1,2,3,6-
tetrahydropyridine-2-carboxylate, (2S,6S,SS)-4e, and ethyl
(2S,6R,SS)-1-(tert-butylsulfinyl)-6-methyl-1,2,3,6-
230 nm): tR 11.2 min. 1H NMR (400 MHz):
d 5.62 (m, 1H, H-4), 5.60
(m, 1H, H-5), 4.24 (m, 1H, H-6), 4.12 (app. q, 2H, J¼7.1 Hz, OCH2),
3.93 (br d, 1H, J¼5.4 Hz, H-2), 2.79 (m, 1H, H-3), 1.37 (d, 3H,
J¼6.9 Hz, Me-6), 1.26 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.18 (s, 9H, t-Bu),
tetrahydropyridine-2-carboxylate, (2S,6R,SS)-4e
The asymmetric aza-DA reaction between sulfinimine 2a and
(E)-1,3-pentadiene (3e) according to the general procedure affor-
ded a mixture of (2S,6S,SS)-4e and (2S,6R,SS)-4e, which were
separated by flash chromatography (two columns: first EtOAc/n-
1.08 (t, 3H, J¼6.9 Hz, Me-3). 13C NMR (100 MHz):
d 171.2 (CO2Et),
60.4 (OCH2), 58.9 (C-2), 48.4 (C-6), 20.2 (Me-6), 19.2 (Me-3),
14.1 (OCH2CH3). HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98,
1.0 ml minꢀ1, 230 nm) of a racemic sample (2R*,3R*,6S*,RS*)-4f: tR
11.2 and 15.9 min.
hexane, 1:1, and then Et2O/n-pentane. 1:1). Data for (2S,6S,SS)-4e:
rt
viscous colorless oil. Rf (EtOAc/n-hexane, 1:1)¼0.4. [
a
]
ꢀ50 (c
D
0.77, CHCl3). HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98,
4.2.9. Ethyl (1S,3S,4R,SS)-2-(tert-butylsulfinyl)-2-azabicyclo
[2.2.1]hept-5-ene-3-carboxylate, (1S,3S,4R,SS)-4g (t-Bu), and ethyl
(1R,3S,4S,SS)-2-(tert-butylsulfinyl)-2-azabicyclo[2.2.1]-hept-5-
ene-3-carboxylate, (1R,3S,4S,SS)-4g (t-Bu)
1.0 ml minꢀ1, 230 nm): tR 12.0 min. 1H NMR (400 MHz):
d
5.84
(app. ddt, 1H, J¼10.4, 6.4, 3.4 Hz, H-4), 5.59 (app. dtd, 1H, J¼10.4,
3.0, 0.8 Hz, H-5), 4.51 (dd, 1H, J¼6.8, 1.3 Hz, H-2), 4.19 (dq, 1H,
J¼10.6, 7.2 Hz, OCH2), 4.17 (dq, 1H, J¼10.6, 7.2 Hz, OCH2), 3.98 (m,
1H, H-6), 2.54 (app. dd, 1H, J¼17.2, 6.4 Hz, H-3), 2.35 (app. ddtd,
1H, J¼17.2, 6.8, 3.1, 2.4 Hz, H-3), 1.28 (t, 3H, J¼7.2 Hz, OCH2CH3),
1.25 (s, 9H, t-Bu), 1.24 (d, 3H, J¼7.2 Hz, Me-6). 13C NMR (100 MHz):
The asymmetric aza-DA reaction between sulfinimine 2a and
cyclopentadiene (3g) according to the general procedure afforded
either (1S,3S,4R,SS)-4g (t-Bu) pure or as a mixture of (1S,3S,4R,SS)-
4g (t-Bu) and (1R,3S,4S,SS)-4g (t-Bu). In addition various amounts
of 8, 9, and 10 were formed dependent on the reaction conditions
applied (see Table 2, entries 3–5). The crude product was purified
by flash chromatography (EtOAc/n-hexane, 1:5). The mixture of
(1S,3S,4R,SS)-4g (t-Bu) and (1R,3S,4S,SS)-4g (t-Bu) was inseparable.
Anal. Calcd of the mixture C13H21NO3S: C, 57.54; H, 7.80; N, 5.16; S,
11.82. Found: C, 57.25; H, 7.64; N, 5.20; S, 12.10. Data for
d
173.0 (CO2Et), 128.8 (C-5), 123.4 (C-4), 61.2 (OCH2), 58.3 (CMe3),
55.0 (C-6), 48.7 (C-2), 26.3 (C-3), 22.9 (CMe3), 22.7 (Me-6), 14.1
(OCH2CH3). IR (thin film, NaCl): 3034 (w), 2979 (m), 2954 (m),
2931 (m), 1735 (s), 1456 (m), 1368 (m), 1283 (m), 1210 (m), 1189
(s), 1135 (m), 1103 (m), 1075 (s), 1040 (m), 970 (m) cmꢀ1. Anal.
Calcd for C13H23NO3S: C, 57.11; H, 8.48; N, 5.12; S, 11.73. Found: C,
57.05; H, 8.34; N, 5.06; S, 11.57. HPLC (Chiralpak AD, i-PrOH/n-
(1S,3S,4R,SS)-4g (t-Bu): viscous colorless oil. Rf (EtOAc/n-hexane,
rt
hexane, 2:98, 1.0 mL minꢀ1
,
230 nm) of
a
racemic sample
1:1)¼0.35. [
a
]
D ꢀ134 (c 1.17, CHCl3). HPLC (Chiralpak AD, i-PrOH/n-
(2R*,6R*,RS*)-4e: tR 10.2 and 12.1 min. Data for (2S,6R,SS)-4e: vis-
cous colorless oil. Rf (EtOAc/n-hexane, 1:1)¼0.3. HPLC (Chiralpak
AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm): tR 14.2 min. 1H
hexane, 2:98, 1.0 ml minꢀ1
,
230 nm): tR 18.2 min. 1H NMR
(400 MHz):
d
6.50 (dd, 1H, J¼5.6, 2.1 Hz, H-6), 6.35 (m, 1H, H-5),
4.28 (m, 1H, H-1), 4.21 (dq, 1H, J¼10.9, 7.1 Hz, OCH2), 4.18 (dq, 1H,
J¼10.9, 7.1 Hz, OCH2), 3.62 (s, 1H, H-3), 3.32 (m, 1H, H-4), 2.10 (ddd,
1H, J¼8.7, 1.9, 1.5 Hz, H-7syn), 1.35 (app. d, 1H, J¼8.7 Hz, H-7anti),
1.28 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.14 (s, 9H, t-Bu). 13C NMR
NMR (400 MHz):
d
5.78 (dddd, 1H, J¼10.2, 4.3, 3.5, 2.0 Hz, H-4),
5.64 (app. ddt, 1H, J¼10.2, 3.0, 2.0 Hz, H-5), 4.28 (m, 1H, H-2), 4.24
(dq, 1H, J¼10.8, 7.1 Hz, OCH2), 4.18 (m, 1H, H-6), 4.16 (dq, 1H,
J¼10.8, 7.1 Hz, OCH2), 2.62 (m, 1H, H-3), 2.39 (m, 1H, H-3), 1.35 (d,
3H, J¼7.1 Hz, Me-6), 1.28 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.23 (s, 9H, t-
(100 MHz): d 173.0 (CO2Et), 136.5 (C-5), 135.2 (C-6), 68.5 (C-1), 61.0
(OCH2), 57.4 (CMe3), 53.5 (C-3), 50.5 (C-4), 45.1 (C-7), 22.7 (CMe3),
14.2 (OCH2CH3). IR (thin film, NaCl): 3067 (w), 2957 (m), 1743 (s),
1448 (m), 1362 (m), 1243 (m), 1188 (s), 1081 (m), 1061 (m), 963 (m),
Bu). 13C NMR (100 MHz, selected signals):
d 131.3 (C-5), 123.7 (C-
4), 61.2 (OCH2), 59.1 (CMe3), 53.6 (C-2), 48.4 (C-6), 27.2 (C-3), 23.5
(CMe3), 20.1 (Me-6), 14.2 (OCH2CH3). HPLC (Chiralpak AD, i-PrOH/
875 (s) cmꢀ1
. HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98,
n-hexane, 2:98, 1.0 ml minꢀ1
,
230 nm) of
a
racemic sample
1.0 ml minꢀ1, 230 nm) of a racemic sample (1R*,3R*,4S*,R*S)-4g (t-
Bu): tR 18.3 and 25.7 min. Data for (1R,3S,4S,SS)-4g (t-Bu): viscous
colorless oil. Rf (EtOAc/n-hexane, 1:1)¼0.35. HPLC (Chiralpak AD, i-
PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm): tR 20.9 min. 1H NMR
(2R*,6S*,R*S)-4e: tR 14.4 and 17.2 min.
4.2.8. Ethyl (2S,3R,6S,SS)-1-(tert-butylsulfinyl)-3,6-dimethyl-
1,2,3,6-tetrahydropyridine-2-carboxylate, (2S,3R,6S,SS)-4f, and
ethyl (2S,3S,6R,SS)-1-(tert-butylsulfinyl)-3,6-dimethyl-1,2,3,6-
tetrahydropyridine-2-carboxylate, (2S,3S,6R,SS)-4f
The asymmetric aza-DA reaction between sulfinimine 2a and
(E,E)-2,4-hexadiene (3f) according to the general procedure affor-
ded a mixture of (2S,3R,6S,SS)-4f and (2S,3S,6R,SS)-4f, which were
separated by flash chromatography (EtOAc/n-hexane, 1:5). Data for
(400 MHz):
d
6.45 (app. dd, 1H, J¼5.6, 3.0 Hz, H-6), 6.20 (app. dd,
1H, J¼5.6, 2.8 Hz, H-5), 4.47 (d,1H, J¼3.5 Hz, H-3), 4.43 (m,1H, H-1),
4.13 (q, 2H, J¼7.1 Hz, OCH2), 3.49 (m, 1H, H-4), 1.90 (app. dt, 1H,
J¼8.5, 1.5 Hz, H-7syn), 1.55 (app. d, 1H, J¼8.5 Hz, H-7anti), 1.25 (t,
3H, J¼7.1 Hz, OCH2CH3), 1.17 (s, 9H, t-Bu). 13C NMR (100 MHz):
d
172.1 (CO2Et), 137.5 (C-5), 136.6 (C-6), 73.7 (C-1), 60.8 (OCH2), 57.7
(CMe3), 52.7 (C-3), 48.7 (C-7), 22.9 (CMe3), 14.3 (OCH2CH3). HPLC
(Chiralpak AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm) of
a racemic sample (1R*,3S*,4S*,SS*)-4g (tBu): tR 16.7 and 21.0 min.
(2S,3R,6S,SS)-4f: viscous colorless oil. Rf (EtOAc/n-hexane, 1:1)¼0.4.
rt
[
a]
ꢀ87 (c 1.35, CHCl3). HPLC (Chiralpak AD, i-PrOH/n-hexane,
D
2:98, 1.0 ml minꢀ1, 230 nm): tR 10.6 min. 1H NMR (400 MHz):
d 5.59
(m, 2H, H-4 and H-5), 4.38 (d, 1H, J¼6.3 Hz, H-2), 4.17 (dq, 1H,
J¼10.8, 7.1 Hz, OCH2), 4.14 (dq, 1H, J¼10.8, 7.1 Hz, OCH2), 4.03 (app.
qd, 1H, J¼7.1, 3.1 Hz, H-6), 2.58 (m, 1H, H-3), 1.30 (d, 3H, J¼7.1 Hz,
Me-6), 1.27 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.24 (s, 9H, t-Bu), 1.07 (d, 3H,
4.2.10. Ethyl (3S,3aS,6aS,RS)-1-oxo-3,3a,4,6a-tetrahydro-2H-
cyclopenta[d]isothiazole-3-carboxylate (8) and ethyl
(3S,3aR,6aR,RS)-1-oxo-3,3a,4,6a-tetrahydro-2H-
cyclopenta[d]isothiazole-3-carboxylate (9)
J¼7.5 Hz, Me-3). 13C NMR (100 MHz):
d
170.9 (CO2Et), 128.3 (C-4),
The general procedure for the asymmetric aza-DA reaction was
followed by reacting 2a with 3g using BF3$OEt2 as the Lewis acid
and 17.5 h reaction time at room temperature (Table 2, entry 5).
Flash chromatography (EtOAc/n-hexane, 1:1) purification of the
crude product, after work up, provided an inseparable mixture
(viscous oil) of 8 and 9 (ratio 9.5:1, 22.4 mg, 42% total yield).
Compound 8 was further purified by recrystallization from EtOAc/
n-hexane, providing colorless crystals (9.3 mg, 17%). Data for 8: Rf
128.1 (C-5), 60.5 (OCH2), 58.1 (CMe3), 54.7 (C-6), 53.0 (C-2), 31.8 (C-
3), 23.4 (CMe3), 23.0 (Me-6), 17.3 (Me-3), 14.2 (OCH2CH3). IR (thin
film, NaCl): 3029 (w), 2972 (m), 2933 (m), 1744 (s), 1458 (m), 1367
(m), 1156 (s), 1073 (s), 1029 (m), 979 (m) cmꢀ1. MS (ESI) m/z (% rel
int): 310 (MþþNa, 16), 288 (Mþþ1, 2), 185 (10), 184 (100). HRMS
(ESI) calcd for C14H25NNaO3S 310.1447 (MþþNa), found 310.1447.
HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm)
of a racemic sample (2R*,3S*,6R*,RS*)-4f: tR 8.7 and 10.6 min. Data
for (2S,3S,6R,SS)-4f: viscous colorless oil. Rf (EtOAc/n-hexane,
(acetone)¼0.5. GC [CP Chirasil Dex CB, 80 ꢁC (0 min)–4 ꢁC minꢀ1
–
190 ꢁC (2 min)]: tR 24.2 min. 1H NMR (400 MHz):
d 5.92 (app. dq,
1:1)¼0.3. HPLC (Chiralpak AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1
,
1H, J¼5.8, 2.0 Hz, H-5), 5.85 (app. dq, 1H, J¼5.8, 2.3 Hz, H-6), 5.12

T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
2815
(dd, 1H, J¼5.8, 1.0 Hz, H-3), 4.68 (br s, 1H, NH), 4.32 (dq, 1H,
J¼10.8, 7.1 Hz, OCH2), 4.25 (dq, 1H, J¼10.8, 7.1 Hz, OCH2), 4.17 (m,
1H, H-6a), 3.57 (app. ddtd, 1H, J¼9.1, 7.5, 5.7, 1.2 Hz, H-3a), 2.61
(app. ddtd, 1H, J¼17.6, 9.1, 2.2, 0.9 Hz, H-4), 2.18 (app. dddt, 1H,
J¼17.6, 5.6, 3.3, 2.4 Hz, H-40), 1.32 (t, 3H, J¼7.1 Hz, OCH2CH3). 13C
10% i-PrOH in n-hexane afforded the major isomer (1S,3S,4R,SS)-4g
(p-Tol) as a white solid (97% de). Data for (1S,3S,4R,SS)-4g (p-Tol):
Rf (EtOAc/n-hexane, 25:75)¼0.1. Mp¼78–79 ꢁC (from 10% i-PrOH in
rt
n-hexane). [
a
]
þ20.7 (c 1.07, CH2Cl2). 1H NMR (400 MHz):
d 7.53
D
(app. d, 2H, J¼8 Hz, tolyl), 7.23 (app. d, 2H, J¼8 Hz, tolyl), 6.53 (dd,
1H, J¼5.2, 2.2 Hz, H-6), 6.35 (m, 1H, H-5), 4.62 (m, 1H, H-1), 3.69
(dq, 1H, J¼10.8, 7.1 Hz, OCH2), 3.62 (dq, 1H, J¼10.8, 7.1 Hz, OCH2),
3.42 (s, 1H, H-3), 3.13 (br s, 1H, H-4), 2.36 (s, 3H, ArCH3), 2.22 (br d,
1H, J¼8.6 Hz, H-7), 1.45 (br d, 1H, J¼8.6 Hz, H-7), 0.94 (t, 3H,
NMR (100 MHz):
d 170.0 (CO2Et), 137.9 (C-5), 123.9 (C-6), 85.6
(C-6a), 64.5 (C-3), 61.7 (OCH2), 41.8 (C-3a), 35.9 (C-4), 14.24
(OCH2CH3). IR (thin film, NaCl): 3447 (br), 3135 (br), 1733 (s), 1379
(m), 1265 (m), 1255 (m), 1243 (m), 1218 (m), 1107 (m), 1037
(s) cmꢀ1. MS (ESI) m/z (% rel int.): 238 (MþþNa, 100), 216 (Mþþ1,
26). HRMS (ESI) calcd for C9H14NO3S 216.0689 (Mþþ1), found
216.0684. HRMS (ESI) calcd for C9H13NNaO3S 238.0508 (MþþNa),
found 238.0509. The absolute configuration of 8 was corroborated
by X-ray crystallographic analysis.16 GC [CP Chirasil Dex CB, 80 ꢁC
(0 min)–4 ꢁC minꢀ1–190 ꢁC (2 min)] of racemic 8: tR 23.6 and
24.4 minꢀ. 1Data for 9: GC [CP Chirasil Dex CB, 80 ꢁC (0 min)–
4 ꢁC min –190 ꢁC (2 min)]: tR 23.4 min. 1H NMR (400 MHz):
J¼7.1 Hz, OCH2CH3). 13C NMR (100 MHz):
d 171.7 (CO2Et), 141.1 (Ar),
140.7 (Ar), 135.5 (C-6), 135.3 (C-5), 129.03 (Ar), 125.77 (Ar), 67.2 (C-
1), 60.6 (OCH2), 53.0 (C-3), 49.7 (C-4), 46.2 (C-7), 21.2 (ArCH3), 13.7
(OCH2CH3). IR (KBr tablet): 2990 (m), 2959 (m), 2929 (m), 1724 (s),
1474 (m), 1449 (m), 1370 (m), 1252 (m), 1234 (m), 1191 (s), 1167 (s),
1094 (s), 1069 (s), 1053 (s), 1024 (m), 964 (s) cmꢀ1. MS (EI) m/z (%
rel int): 305 (Mþ, 3), 257 (7), 240 (12), 232 (11), 166 (11), 141 (5),
140 (15), 139 (100), 138 (3), 123 (86), 120 (5), 94 (5), 93 (84), 92
(17), 91 (16), 77 (5), 67 (7), 66 (22), 65 (15). Anal. Calcd for
C16H19NO3S: C, 62.93; H, 6.27; N, 4.59; S, 10.50. Found: C, 62.97; H,
6.32, N, 4.35; S, 10.22. Data for (1R,3S,4S,SS)-4g (p-Tol): 1H NMR
d
6.14 (app. dq, 1H, J¼5.8, 1.9 Hz, H-5), 5.65 (app. dq, 1H, J¼5.8,
2.3 Hz, H-6), 4.63 (m, 1H, H-6a), 4.60 (m, 1H, NH), 4.47 (dd, 1H,
J¼8.0, 1.8 Hz, H-3), 4.26 (overlap, 2H, OCH2), 3.27 (dddd, 1H, J¼9.6,
8.9, 8.0, 4.0 Hz, H-3a), 2.76 (app. ddtd, 1H, J¼17.6, 8.9, 2.4, 1.6 Hz,
H-4), 2.56 (overlap, 1H, H-40), 1.32 (overlap, 3H, OCH2CH3). 13C
(400 MHz):
d
7.55 (app. d, 2H, J¼8.3 Hz, tolyl), 7.21 (overlap, 2H,
tolyl), 6.63 (dd, 1H, J¼5.5, 3.0 Hz, H-6), 6.16 (dd, 1H, J¼5.5, 2.6 Hz,
H-5), 4.62 (overlap, 1H, H-1), 4.32 (d, 1H, J¼3.2H, H-3), 3.7–3.6
(overlap, 2H, OCH2), 3.42 (overlap, 1H, H-4), 2.35 (s, 3H, ArCH3),
2.06 (br d, 1H, J¼8.4 Hz, H-7), 1.63 (br d, 1H, J¼8.4 Hz, H-7), 0.92
(overlap, 3H, OCH2CH3). 13C NMR (100 MHz, selected signals):
NMR (100 MHz):
d 171.1 (CO2Et), 137.6 (C-5), 123.4 (C-6), 78.7 (C-
6a), 67.1 (C-3), 61.9 (OCH2), 44.8 (C-3a), 37.3 (C-4), 14.17
(OCH2CH3).
4.2.11. Ethyl (3S,3aS,6aS,RS)-1-oxo-3,3a,4,6a-tetrahydro-2H-
cyclopenta[d]isothiazole-3-carboxylate (8) and 2-methyl-N-
(2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]-furan-3-yl)
propane-2-sulfinamide (10)
The asymmetric aza-DA reaction between sulfinimine 2a and
3g using TMSOTf as the Lewis acid at ꢀ78 ꢁC for 15.5 h (Table 2,
entry 3) afforded a mixture of 8 and 10 after flash chromatogra-
phy (EtOAc/n-hexane, 1:1). Further purification by flash chro-
d
137.8 (C-6), 137.1 (C-5), 129.01 (Ar), 125.82 (Ar), 69.8 (C-1), 60.3
(OCH2), 52.3 (C-3), 49.0 (C-7), 47.3 (C-4), 14.2 (OCH2CH3). Data for
(1R,3R,4S,SS)-4g (p-Tol): 1H NMR (400 MHz):
7.72 (app. d, 2H,
d
J¼8 Hz, tolyl), 7.33 (app. d, 2H, J¼8 Hz, tolyl), 6.44 (dd, 1H, J¼5.6,
2.4 Hz, H-6), 6.32 (m, 1H, H-5), 4.29 (q, 2H, J¼7.1 Hz, OCH2), 3.92
(m, 1H, H-1), 3.74 (s, 1H, H-3), 3.42 (overlap, 1H, H-4), 2.43 (s, 3H,
ArCH3), 1.75 (br d, 1H, J¼8.9 Hz, H-7), 1.35 (t, 3H, J¼7.1 Hz,
OCH2CH3), 1.32 (overlap, 1H, H-7). 13C NMR (100 MHz):
d 171.9
matography (acetone/pentane, 1:4) allowed separation of
8
(CO2Et), 141.2 (Ar), 141.0 (Ar), 138.0 (C-6), 133.8 (C-5), 129.5 (Ar),
126.2 (Ar), 62.0 (C-1), 61.5 (C-3), 61.3 (OCH2), 49.2 (C-4), 45.8 (C-7),
21.3 (ArCH3), 14.2 (OCH2CH3).
(9.0 mg, 17%) and 10 (6.6 mg, 11%). For analytical data of 8 see
Section 4.2.10. Data for 10: colorless viscous oil, Rf (acetone)¼0.6.
GC [CP Chirasil Dex CB, 80 ꢁC (0 min)–3 ꢁC minꢀ1–190 ꢁC (2 min)]:
tR 29.67 min. 1H NMR (400 MHz):
d
6.10 (m, 1H, H-5), 5.91 (app.
4.2.13. Ethyl (1S,3S,4R,SS)-2-(tert-butylsulfinyl)-2-azabicyclo[2.2.2]
oct-5-ene-3-carboxylate, (1S,3S,4R,SS)-4h, and ethyl (1R,3S,4S,SS)-
2-(tert-butylsulfinyl)-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate,
(1R,3S,4S,SS)-4h
ddt, 1H, J¼5.8, 2.6, 1.8 Hz, H-6), 5.59 (app. dp, 1H, J¼7.8, 1.6 Hz, H-
6a), 3.95 (dd, 1H, J¼7.7, 2.0 Hz, H-3), 3.92 (br s, 1H, NH), 3.10 (app.
qd, 1H, J¼7.7, 1.5 Hz, H-3a), 2.81 (app. dddt, 1H, J¼17.4, 7.1, 2.5,
2.1 Hz, H-4), 2.72 (m, 1H, H-40), 1.27 (s, 9H, t-Bu). 13C NMR
The asymmetric aza-DA reaction between sulfinimine 2a and
1,3-cyclohexadiene (3h) provided an inseparable mixture of
(1S,3S,4R,SS)-4h and (1R,3S,4S,SS)-4h. The crude mixture was pu-
rified by flash chromatography (EtOAc/n-hexane, 1:5) yielding
a viscous colorless oil. Analytical data of the mixture: IR (thin film,
NaCl): 3053 (w), 2955 (m), 2929 (m), 1745 (s), 1461 (m), 1363 (m),
1258 (m), 1176 (s), 1085 (s), 1061 (m), 892 (m) cmꢀ1. MS (EI) m/z (%
rel int.): 229 (32), 164 (22), 149 (58), 108 (22), 80 (100), 79 (40), 57
(32). MS (ESI) m/z (% rel int.): 308 (MþþNa, 50), 183 (10), 182 (100).
HRMS (ESI) calcd for C14H23NNaO3S 308.1291 (MþþNa), found
308.1288. Anal. Calcd for C14H23NO3S: C, 58.92; H, 8.12; N, 4.91; S,
11.24. Found: C, 59.02; H, 8.12; N, 4.79; S, 11.06. Data for
(1S,3S,4R,SS)-4h: Rf (EtOAc/n-hexane, 1:1)¼0.35. HPLC (Chiralpak
AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm): tR 18.3 min. 1H
(100 MHz): d 175.2 (C-2), 136.5 (C-5), 129.2 (C-6), 88.0 (C-6a), 58.4
(C-3), 56.2 (CMe3), 44.1 (C-3a), 37.3 (C-4), 22.4 (CMe3). IR (thin
film, NaCl): 3442 (br), 3279 (br), 1774 (s), 1641 (m), 1365 (m), 1134
(m), 1042 (s), 991 (m) cmꢀ1. MS (ESI) m/z (% rel int.): 266 (MþþNa,
18), 244 (Mþþ1, 100), HRMS (ESI) calcd for C11H18NO3S 244.1002
(Mþþ1), found 244.1001. HRMS (ESI) calcd for C11H17NNaO3S
266.0821 (MþþNa), found 266.0819. GC [CP Chirasil Dex CB, 80 ꢁC
(0 min)–3 ꢁC minꢀ1–190 ꢁC (2 min)] of racemic 10: tR 29.66 and
29.81 min.
4.2.12. Ethyl (1S,3S,4R,SS)-2-(p-tolylsulfinyl)-2-azabicyclo[2.2.1]
hept-5-ene-3-carboxylate, (1S,3S,4R,SS)-4g (p-Tol), ethyl
(1R,3S,4S,SS)-2-(p-tolylsulfinyl)-2-azabicyclo[2.2.1]hept-5-ene-3-
carboxylate, (1R,3S,4S,SS)-4g (p-Tol), and ethyl (1R,3R,4S,SS)-2-
(p-tolylsulfinyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate,
(1R,3R,4S,SS)-4g (p-Tol)
The asymmetric aza-DA reaction between sulfinimine 2b and
cyclopentadiene (3g) according to the general procedure yielded
mixtures of (1S,3S,4R,SS)-4g (p-Tol), (1R,3S,4S,SS)-4g (p-Tol), and
(1R,3R,4S,SS)-4g (p-Tol) dependent on the reaction conditions ap-
plied (see Table 1, entries 13 and 14). Separation of the di-
astereomers by flash chromatography (EtOAc/n-hexane, 15:85 to
25:75) did not succeed, but recrystallization of the mixture from
NMR (400 MHz):
d
6.52 (ddd, 1H, J¼8.2, 5.1, 1.5 Hz, H-6), 6.47 (ddd,
1H, J¼8.2, 6.7, 1.6 Hz, H-5), 4.20 (dq, 1H, J¼10.8, 7.1 Hz, OCH2), 4.18
(dq, 1H, J¼10.8, 7.1 Hz, OCH2), 4.03 (dd, 1H, J¼3.3, 1.6 Hz, H-3), 3.92
(m, 1H, H-1), 3.02 (m, 1H, H-4), 2.20 (dddd, 1H, J¼12.9, 9.6, 5.6,
2.7 Hz, H-7syn), 1.63 (app. ddt, 1H, J¼12.6, 9.6, 2.9 Hz, H-8syn), 1.38
(m, 1H, H-7anti), 1.28 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.12 (s, 9H, t-Bu),
1.09 (m, 1H, H-8anti). 13C NMR (100 MHz):
d 127.2 (CO2Et), 134.6
(C-5), 133.0 (C-6), 60.8 (OCH2), 57.5 (CMe3), 54.8 (C-1), 52.7 (C-3),
33.8 (C-4), 24.3 (C-7), 22.4 (CMe3), 20.5 (C-8), 14.3 (OCH2CH3). HPLC
(Chiralpak AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm) of

2816
T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
a racemic sample (1R*,3R*,4S*,RS*)-4h: tR 18.3 and 20.2 min. Data for
(1R,3S,4S,SS)-4h: Rf (EtOAc/n-hexane, 1:1)¼0.35. HPLC (Chiralpak
AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm): tR 15.5 min. 1H
4.3.3. The HCl salt of ethyl (S)-4-methyl-1,2,3,6-tetrahydropyridine-
2-carboxylate, (2S)-12c
NMR (400 MHz):
d
6.56 (ddd, 1H, J¼8.1, 6.7, 1.9 Hz, H-6), 6.19 (app. t,
(a) Enantiopure (2S)-11c (12.5 mg, 0.0739 mmol) was added to
aqueous HCl (concd, w0.5 mmol) and dried under high vacuum
1H, J¼7 Hz, H-5), 4.26 (d, 1H, J¼2.9 Hz, H-3), 4.11 (q, 2H, J¼7.1 Hz,
OCH2), 4.06 (m, 1H, H-1), 3.10 (m, 1H, H-4), 2.28 (dddd, 1H, J¼13, 9,
4, 3 Hz, H-7syn), 1.74 (dddd, 1H, J¼13, 9, 5, 2 Hz, H-8syn), 1.39 (m,
1H, H-8anti), 1.26 (m, 1H, H-7anti), 1.23 (t, 3H, J¼7.1 Hz, OCH2CH3),
overnight to give (2S)-12c (15.2 mg, 100%) as a white solid. Data
rt
for (2S)-12c: [
a
]
ꢀ79 (c 0.76, EtOH) {lit. data for the (R)-en-
D
25
antiomer: [
a
]
þ113.7 (c 1.0, EtOH)}.19 1H NMR (300 MHz):
D
1.14 (s, 9H, t-Bu). 13C NMR (100 MHz):
d
172.3 (CO2Et), 134.3 (C-6),
d 10.2 (br s, 1H, NH), 9.98 (br s, 1H, NH), 5.42 (app. s, 1H, H-5),
131.6 (C-5), 60.7 (OCH2), 57.3 (CMe3), 54.3 (C-1), 53.1 (C-3), 34.4 (C-
4), 26.0 (C-7), 22.8 (CMe3), 20.4 (C-8), 14.2 (OCH2CH3). HPLC
(Chiralpak AD, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm) of
a racemic sample (1R*,3S*,4S*,SS*)-4h: tR 14.0 and 15.5 min.
4.31 (app. q, 2H, J¼7.0 Hz, OCH2), 4.16 (br s, 1H, H-2), 3.96 (app.
d, 1H, J¼15.9 Hz, H-6), 3.38 (m, 1H, H-6), 2.65 (m, 2H, H-3), 1.78
1
(s, 3H, H-5), 1.32 (t, 3H, J¼7.0 Hz, OCH2CH3). The H NMR data
are compatible with data reported for the racemic (2R*)-12c.23
(b) A mixture of (2S,SS)-4c (p-Tol) and (2R,SS)-4c (p-Tol, in ratio
3:2, 14.2 mg, 0.046 mmol) was dissolved in MeOH (3 mL),
added aqueous HCl (concd, 12 drops), and stirred at room
temperature for 4 h. The reaction mixture was concentrated in
vacuo to afford a colorless oil, which precipitated by addition of
diethyl ether to provide (2S)-12c (7.4 mg, 78%) as a white salt.
4.3. Chemical derivatization of the aza-DA products
4.3.1. Ethyl (2S)-4-oxo-1,2,3,4-tetrahydropyridine-2-
carboxylate, (2S)-11a
Diastereomerically pure (2S,SS)-4a (7.4 mg, 0.027 mmol) was
dissolved in MeOH (2 mL) and cooled to 0 ꢁC. Aqueous HCl (concd,
w20 equiv) was added and the resultant solution stirred at 0 ꢁC for
5 h before neutralization with phosphate buffer (pH 7, 1.5 mL). The
mixture was extracted with CH2Cl2 (4ꢂ4 mL) and the combined
organic layer was dried (MgSO4). The solution was filtered, con-
centrated, and the residue purified by flash chromatography
rt
25
[
a]
D ꢀ68.3 (c 0.74, EtOH) {lit. data for the (R)-enantiomer: [
a]
D
þ113.7 (c 1.0, EtOH)}.19
4.3.4. Ethyl (2S)-4-methyl-1-(p-tosyl)-1,2,3,6-tetrahydropyridine-
2-carboxylate, (2S)-13c
A mixture of (2S,SS)-4c (p-Tol) and (2R,SS)-4c (p-Tol, in ratio 3:2,
19.7 mg, 0.064 mmol) was dissolved in CH2Cl2 (2 mL) and cooled to
ꢀ20 ꢁC under argon atmosphere. A solution of m-CPBA (32.1 mg,
0.186 mmol) in CH2Cl2 (3 mL) was cannulated into the mixture. The
resultant mixture was stirred for 5.5 h, and then water (2 mL) and
an aqueous saturated solution of K2CO3 (3 mL) was added. The
mixture was extracted with CH2Cl2 (3ꢂ5 mL). The combined or-
ganic layer was washed with brine (3 mL), dried (MgSO4), filtered,
and concentrated. The residue was purified by flash chromatogra-
(EtOAc), providing (2S)-11a (3.9 mg, 85%) as a white solid. Data for
rt
(2S)-11a: [
a
]
þ276 (c 0.39, CHCl3). GC [CP Chirasil Dex CB, 110 ꢁC
D
(0 min)–2 ꢁC minꢀ1–180 ꢁC (2 min)]: >99% ee, tR 18.1. 1H NMR
(400 MHz):
d
7.22 (ddd, 1H, J¼7.5, 6.3, 0.5 Hz, H-6), 5.41 (br s, 1H,
NH), 5.09 (app. d, 1H, J¼7.5 Hz, H-5), 4.34 (ddd, 1H, J¼12.8, 6.0,
1.4 Hz, H-2), 4.28 (dq, 1H, J¼10.7, 7.1 Hz, OCH2), 4.26 (dq, 1H, J¼10.7,
7.1 Hz, OCH2), 2.78 (app. ddt, 1H, J¼16.4, 6.0, 0.9 Hz, H-3), 2.71 (dd,
1H, J¼16.4, 12.8 Hz, H-3), 1.31 (t, 3H, J¼7.1 Hz, OCH2CH3). The 1H
NMR data is compatible with data reported for the racemic (2R*)-
11a.22 GC [CP Chirasil Dex CB, 110 ꢁC (0 min)–2 ꢁC minꢀ1–180 ꢁC
(2 min)] of racemic (2R*)-11a: tR 18.1 and 18.7 min.
phy (EtOAc/n-hexane, 18:85) yielding (2S)-13c (10.6 mg, 51%) as
rt
a colorless oil. Data for (2S)-13c: [
a
]
þ18.7 (c 0.33, CHCl3), HPLC
D
(Chiralcel OJ, i-PrOH/n-hexane, 10:90, 1.0 ml minꢀ1, 230 nm): 42%
ee, tR 23.2 (R) and 33.4 (S) min. 1H NMR (300 MHz):
d
7.69 (app. d,
4.3.2. Ethyl (S)-4-methyl-1,2,3,6-tetrahydropyridine-2-
carboxylate, (2S)-11c
2H, J¼8.3 Hz, tolyl), 7.28 (app. d, 2H, J¼8.3 Hz, tolyl), 5.33 (s, 1H, H-
5), 4.87 (dd, 1H, J¼6.6, 1.7 Hz, H-2), 4.04–3.88 (m, 3H, H-6/OCH2),
3.78 (d, 1H, J¼17.5 Hz, H-6), 2.51–2.35 (m, 2H, H-3), 2.42 (s, 3H,
ArCH3), 1.66 (s, 3H, Me-4), 1.08 (t, 3H, J¼7.1 Hz, OCH2CH3). 13C NMR
The aza-DA product (2S,SS)-4c (t-Bu) was prepared according to
the general procedure (Section 4.2) using TMSOTf (10 equiv) as the
Lewis acid and a large excess of isoprene (3c, 20 equiv.) at ꢀ78 ꢁC for
19 h. The crude product was dissolved in MeOH (3 mL), added
aqueous HCl (concd, w5 mmol), and stirred at room temperature for
18 h. The solution was concentrated, added water (5 mL) and aque-
ous HCl (concd, one drop), and washed with diethyl ether (9ꢂ5 mL)
to remove impurities. The aqueous phase was basified with K2CO3
and extracted with diethyl ether (6ꢂ5 mL). The combined organic
phases from the latter extractions were dried (MgSO4), filtered, and
(100 MHz): d 170.4 (CO2Et), 143.2 (Ar), 136.6 (Ar), 130.3 (C-4), 129.4
(Ar), 127.3 (Ar), 116.9 (C-5), 61.2 (OCH2), 53.1 (C-2), 42.1 (C-6), 32.3
(C-3), 23.2 (Me-4), 21.5 (ArCH3), 13.9 (OCH2CH3). IR (thin film,
NaCl): 2976 (w), 1742 (s), 1343 (s), 1197 (s), 1155 (s), 1099 (s) cmꢀ1
.
Anal. Calcd for C16H21NO4S: C, 59.42; H, 6.54; N, 4.33; S, 9.91.
Found: C, 59.20; H, 6.57, N, 4.29; S, 9.93.
4.3.5. Ethyl (S)-4,5-dimethyl-1,2,3,6-tetrahydropyridine-2-
carboxylate, (2S)-11d
concentrated to provide (2S)-11c (16.7 mg, 39% yield from sulfini-
rt
mine 1a) as a colorless viscous oil. Data for (2S)-11c: [
a
]
D ꢀ83 (c 0.2,
The aza-DA adduct (2S,SS)-4d (t-Bu) was prepared according to
the general procedure (Section 4.2) using TMSOTf as the Lewis acid
at ꢀ78 ꢁC for 18 h. The crude product was hydrolyzed according to
the procedure described in Section 4.3.2, afforded (2S)-11d
(25.4 mg, 55% yield from sulfinimine 1a) as a colorless viscous oil.
CHCl3). GC [CP Chirasil Dex CB, 80 ꢁC (0 min)–1 ꢁC minꢀ1–110 ꢁC
(0 min)–20 ꢁC minꢀ1–180 ꢁC (3 min)]: >99% ee, tR 13.1 min. 1H NMR
(400 MHz):
d
5.43 (m,1H, H-5), 4.20 (q, 2H, J¼7.2 Hz, OCH2), 3.56 (dd,
1H, J¼8.2, 6.1 Hz, H-2), 3.42 (m, 1H, H-6), 3.38 (m, 1H, H-6), 2.22 (m,
1H, H-3), 2.20 (m, 1H, H-3), 1.70 (m, 3H, Me-4), 1.29 (t, 3H, J¼7.2 Hz,
Data for (2S)-11d: 1H NMR (400 MHz):
d
4.19 (app. q, 2H, J¼7.1 Hz,
OCH2CH3). 13C NMR (100 MHz):
d
173.4 (CO2Et), 131.5 (C-4), 120.1
OCH2), 3.53 (app. t, 1H, J¼7.1 Hz, H-2), 3.35–3.20 (m, 2H, H-6), 2.25–
(C-5), 60.9 (OCH2), 55.3 (C-2), 44.2 (C-6), 32.7 (C-3), 23.3 (Me-4),14.2
(OCH2CH3). IR (thin film, NaCl): 3346 (br), 2925 (m), 1736 (s), 1448
(m),1376 (m), 1181 (s),1035 (m) cmꢀ1. MS (EI) m/z (rel int.): 169 (Mþ,
8), 148 (20), 96 (100), 94 (24). MS (ESI) m/z (% rel int.): 170 (Mþþ1,
100). HRMS (ESI) calcd for C9H16NO2 170.1176 (Mþþ1), found
170.1178. GC [CP Chirasil Dex CB, 80 ꢁC (0 min)–1 ꢁC minꢀ1–110 ꢁC
(0 min)–20 ꢁC minꢀ1–180 ꢁC (3 min)] of racemic (2R*)-11c: tR 12.7
and 13.1 min.
2.15 (m, 2H, H-3), 1.97 (br s, 1H, NH),1.64 (m, 3H, Me-4),1.57 (m, 3H,
Me-5), 1.28 (t, 3H, J¼7.1 Hz, OCH2CH3). 13C NMR (100 MHz):
d 173.6
(CO2Et), 125.2 (C-5), 123.3 (C-4), 60.8 (OCH2), 55.8 (C-2), 49.4 (C-6),
33.8 (C-3), 18.7 (Me-4), 16.0 (Me-5), 14.2 (OCH2CH3). IR (thin film,
NaCl): 3438 (br), 2985 (m), 2917 (m), 1736 (s), 1638 (s), 1447 (m),
1373 (m), 1303 (m),1182 (s), 1131 (m),1031 (m) cmꢀ1. MS (EI) m/z (%
rel int.): 183 (Mþ, 15), 124 (29), 110 (100), 108 (45), 107 (68), 94 (20).
HRMS (EI) calcd for C10H17NO2 183.1259 (Mþ), found 183.1253.

T. Andreassen et al. / Tetrahedron 65 (2009) 2806–2817
2817
4.3.6. Ethyl (2S)-4,5-dimethyl-1-(p-tosyl)-1,2,3,6-
References and notes
tetrahydropyridine-2-carboxylate, (2S)-13d
1. Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y.; Weinreb, S. M. Org. React. 2005, 65,
141–599.
(a) The amine (2S)-11d (22.4 mg, 0.12 mmol) was tosylated by
following the general procedure described by Murty et al.20 The
crude product was purified by flash chromatography (EtOAc/n-
hexane, 1:10) providing (2S)-13d (8.4 mg, 21%) as a light yel-
low, viscous oil. Data for (2S)-13d: Rf (EtOAc/n-hexane,
2. For examples of the diastereoselective aza-Diels–Alder reactions with chiral
imines, see: (a) Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. Engl. 1989, 28,
1067–1068; (b) Waldmann, H.; Braun, M.; Dra¨ger, M. Angew. Chem., Int. Ed.
Engl. 1990, 29, 1468–1471; (c) Waldmann, H.; Braun, M.; Dra¨ger, M. Tetrahe-
dron: Asymmetry 1991, 2, 1231–1246; (d) Waldmann, H.; Braun, M. J. Org.
Chem. 1992, 57, 4444–4451; (e) Waldmann, H.; Braun, M.; Weymann, M.;
Gewehr, M. Tetrahedron 1993, 49, 397–416; (f) Hattori, K.; Yamamoto, H. Tet-
rahedron 1993, 49, 1749–1760; (g) Devine, P. N.; Reilly, M.; Oh, T. Tetrahedron
Lett. 1993, 34, 5827–5830; (h) Kitazume, T.; Murata, K.; Okabe, A.; Takahashi,
Y.; Yamazaki, T. Tetrahedron: Asymmetry 1994, 5, 1029–1040; (i) Kitazume, T.;
Shibano, H. J. Fluorine Chem. 1997, 82, 185–188; (j) Bailey, P. D.; Smith, P. D.;
Pederson, F.; Clegg, W.; Rosair, G. M.; Teat, S. J. Tetrahedron Lett. 2002, 43,
1067–1070.
rt
rt
1:10)¼0.1. [
a]
þ16.6 (c 0.15, CHCl3) {lit. 65% ee, [
a
]
þ17.4 (c
D
D
0.4, CHCl3)}.3e HPLC (Chiralcel OJ, i-PrOH/n-hexane, 2:98,
1.0 ml minꢀ1, 230 nm): >99% ee, tR 36.6 min. HPLC (Chiralcel
OJ, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm) of racemic
(2R*)-13d: tR 27.8 and 37.0 min.
(b) A mixture of (2S,SS)-4d (p-Tol) and (2R,SS)-4d (p-Tol, in ratio
4:1, 27.5 mg, 0.086 mmol) was oxidized according to the pro-
cedure shown in Section 4.3.4. Flash chromatography (EtOAc/
3. For examples of the catalytic enantioselective aza-Diels–Alder reactions, see:
(a) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357–7360; (b) Ko-
bayashi, S.; Komiyama, H.; Ishitani, H. Angew. Chem., Int. Ed. 1998, 37,
979–981; (c) Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 1998, 37, 3121–3124; (d) Kobayashi, S.; Kusakabe, K.-i.; Ko-
miyama, S.; Ishitani, H. J. Org. Chem. 1999, 64, 4220–4221; (e) Yao, S.; Saaby,
S.; Hazell, R. G.; Jørgensen, K. A. Chem.dEur. J. 2000, 6, 2435–2448; (f)
Manchen˜o, O. G.; Arraya´s, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2004, 126,
n-hexane,1:10) of the crude product afforded (2S)-13d (3.6 mg,
rt
12%) as a colorless oil. Data for (2S)-13d: [
a]
þ13.4 (c 0.36,
D
rt
CHCl3), {lit. 65% ee, [
a]
þ17.4 (c 0.40, CHCl3)}.3e HPLC (Chir-
D
alcel OJ, i-PrOH/n-hexane, 2:98, 1.0 ml minꢀ1, 230 nm): 72% ee,
tR 30.8 (R) and 40.6 (S) min.
´
456–457; (g) Guillarme, S.; Whiting, A. Synlett 2004, 711–713; (h) Sunden,
H.; Ibrahem, I.; Eriksson, L.; Co´ rdova, A. Angew. Chem., Int. Ed. 2005, 44,
4877–4880; (i) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2006,
45, 4796–4798; (j) Liu, H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org.
Lett. 2006, 8, 6023–6026; (k) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem.
Soc. 2006, 128, 8418–8420.
4.3.7. Ethyl (1S,3S,4R)-2-(p-tosyl)-2-azabicyclo[2.2.1]hept-5-ene-
4. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th
ed.; John Wiley & Sons: New Jersey, 2007.
3-carboxylate, (1S,3S,4R,SS)-13g
5. (a) Davis, F.; McCoull, W. J. Org. Chem. 1999, 64, 3396–3397; (b) Jacobsen, M. F.;
Skrydstrup, T. J. Org. Chem. 2003, 68, 7112–7114; (c) Jayathilaka, L. P.; Deb, M.;
Standaert, R. F. Org. Lett. 2004, 6, 3659–3662; (d) Kong, J.-R.; Cho, C.-W.; Kri-
sche, M. J. Am. Chem. Soc. 2005, 127, 11269–11276; (e) Beenen, M.; Weix, D. J.;
Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304–6305; (f) Grigg, R.; McCaffrey, S.;
Sridharan, V.; Fishwick, C. W. G.; Kilner, C.; Korn, S.; Baiely, K.; Blacker, J. Tet-
rahedron 2006, 62, 12159–12171; (g) Dai, H.; Lu, X. Org. Lett. 2007, 9, 3077–
3080; (h) Andreassen, T.; Hansen, L.-K.; Gautun, O. R. Eur. J. Org. Chem. 2008,
4871–4876.
6. For reviews covering asymmetric synthesis with the use of sulfinimines, see:
(a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13–18; (b) Ell-
man, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–995; (c)
Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60, 8003–8030; (d) Davis,
F. A.; Yang, B.; Deng, J.; Wu, Y.; Zhang, Y.; Rao, A.; Fang, T.; Goswami, R.;
Prasad, K. R.; Nolt, M. B.; Anilkumar, G. Phosphorus, Sulfur Silicon Relat. Elem.
2005, 180, 1109–1117; (e) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62,
8869–8905.
7. Kawe˛ cki, R. Tetrahedron: Asymmetry 2006, 17, 1420–1423.
8. Andreassen, T.; Håland, T.; Hansen, L.-K.; Gautun, O. R. Tetrahedron Lett. 2007,
48, 8413–8415.
9. Lanfranchi, D. A.; Gilles, H. J. Org. Chem. 2006, 71, 4854–4861.
10. Yoshino, T.; Imori, S.; Togo, H. Tetrahedron 2006, 62, 1309–1317.
11. Krasnova, L. B.; Yudin, A. K. J. Org. Chem. 2004, 69, 2584–2587.
12. (a) Davis, F. A.; Friedman, A. J.; Kluger, E. W. J. Am. Chem. Soc. 1974, 96, 5000–
5001; (b) Davis, F. A.; Friedman, A. J.; Nadir, U. K. J. Am. Chem. Soc. 1978, 100,
2844–2852.
13. Block, E.; O’Connor, J. J. Am. Chem. Soc. 1974, 96, 3929–3944.
14. Kobayashi, T.; Ono, K.; Kato, H. Bull. Chem. Soc. Jpn. 1992, 65, 61–65.
15. Davis, F. A.; Qu, J.; Srirajan, V.; Joseph, R.; Titus, D. D. Heterocycles 2002, 58,
251–258.
16. Inquiries concerning X-ray analysis should be addressed to L.K.H (e-mail: lars-
kristian.hansen@chem.uit.no). CCDC 687785 for 8 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
17. (a) Dobrowolski, J.; CzKawe˛cki, R. J. Mol. Struct. 2005, 734, 235–239; (b)
Bharatam, P. V.; Uppal, P.; Kaur, A.; Kaur, D. J. Chem. Soc., Perkin Trans. 2
2000, 43–50; (c) Tietze, L. F.; Schuffenhauer, A. Eur. J. Org. Chem. 1998,
1629–1637.
(a) Pure (1S,3S,4R,SS)-4g (t-Bu, 0.130 g, 0.48 mmol) was dissolved
with stirring in MeOH (4 mL) and treated with 4.0 M HCl in
dioxane (0.610 mL, 2.44 mmol) at room temperature for 4 h.5e
The reaction mixture was concentrated under reduced pres-
sure. The residue was dissolved with stirring by addition of dry
CH2Cl2 (2 mL) and triethylamine (0.214 mL, 1.54 mmol), and
then cooled to 0 ꢁC. A solution of p-TsCl (92.7 mg, 0.486 mmol)
in dry CH2Cl2 (3 mL) was cannulated into the mixture. The
resultant mixture was stirred for 5 h at 0 ꢁC and then warmed
to room temperature. The reaction mixture was concentrated
under reduced pressure, and the residue was purified by flash
chromatography (EtOAc/n-hexane, 15:85 to 20:80) affording
(1S,3S,4R,SS)-13g (0.103 g, 67%) as a white solid. Data for
rt
(1S,3S,4R,SS)-13g: Rf (EtOAc/n-hexane, 1:5)¼0.1.[
a
]
D
ꢀ241.1 (c
rt
1.0, CHCl3), {lit. 83% ee, [
(400 MHz):
a]
ꢀ195.7 (c 1.0, CHCl3)}.3e 1H NMR
D
d
7.77 (app. d, 2H, J¼8.3 Hz, Ts), 7.28 (m, 2H, Ts),
6.26 (m, 1H, H-5 or H-6), 6.21 (app. dd, 1H, J¼5.6, 2.1 Hz, H-5 or
H-6), 4.59 (m, 1H, H-1), 4.18 (app. q, 2H, J¼7.1 Hz, OCH2), 3.50
(m,1H, H-3), 3.32 (m, 1H, H-4), 2.43 (s, 3H, Ts), 2.06 (app. dt,1H,
J¼8.7, 1.7 Hz, H-7syn), 1.47 (app. d, 1H, J¼8.7 Hz, H-7anti), 1.26
(t, 3H, J¼7.1 Hz, OCH2CH3).
(b) The p-tolylsulfinyl aza-DA adduct (1S,3S,4R,SS)-4g (p-Tol,
0.068 mmol, 97% de) was oxidized according to the procedure
shown in Section 4.3.4. Flash chromatography (EtOAc/n-hex-
ane, 15:85) of the crude product afforded (1S,3S,4R,SS)-13g in
rt
46% yield as a white solid. Data for (1S,3S,4R,SS)-13g: [
a
]
D ꢀ244
rt
(c 0.5, CHCl3) {lit. 83% ee, [
a
]
ꢀ195.7 (c 1.0, CHCl3)}.3e HPLC
D
(Chiralcel OD-H, i-PrOH/n-hexane, 5:95, 0.5 mL minꢀ1
,
230 nm): 97% ee, tR 27.2 (major) and 35.4 min (minor).
18. Prakash, G. K. S.; Mandahl, M.; Olah, G. A. Org. Lett. 2001, 3, 2847–2850.
19. Danilewicz, J.C. WO 96/33993, 1996; Chem. Abstr. 1997, 126, 47558.
20. Murty, M. S. R.; Reddy, N. R.; Yadav, J. S. J. Sulfur Chem. 2006, 27, 589–593.
21. Basch, H. In The Chemistry of Sulfinic Acids, Esters and Their Derivatives; Patai, S.,
Ed.; John Wiley & Sons Ltd: Chichester, UK, 1990; pp 9–34.
22. Revuelta, J.; Chicchi, S.; Brandi, H. J. Org. Chem. 2005, 70, 5636–5642.
23. Zhang, W.; Xie, W.; Fang, J.; Wang, P. G. Tetrahedron Lett. 1999, 40,
7929–7933.
Acknowledgements
We thank the Norwegian Research Council (Grant 160099 to
T.A.) for generous financial support. We also thank Mrs. Julie Jack-
son and Associate Professor Rudolf Schmid (NTNU) for performing
the mass spectrometric measurements.