Synthesis of optically active condensed tetrahydropyridines from α-amino esters

Article abstract of DOI:10.1055/s-2006-950192

Optically active condensed dihydropyridones 6 could be synthesized from α-amino esters 2 or 3 and o-bromobenzyl bromides or heterocyclic analogues 1. These products resemble isoquinoline and β-carboline alkaloid structures and could be stereoselectively t

Full text of DOI:10.1055/s-2006-950192

PAPER
2907
Synthesis of Optically Active Condensed Tetrahydropyridines from a-Amino
Esters
Synthesis of
Optic
e
ally Active
i
Conde
k
nse
d
T
etrahy
e
dropyridines Faltz, Christoph Bender, Jürgen Liebscher*
Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax +49(30)20937552; E-mail: liebscher@chemie.hu-berlin.de
Received 27 February 2006; revised 21 April 2006
unsatisfactory results. Condensed 3-hydroxytetrahydro-
Abstract: Optically active condensed dihydropyridones 6 could be
synthesized from a-amino esters 2 or 3 and o-bromobenzyl bro-
mides or heterocyclic analogues 1. These products resemble iso-
quinoline and b-carboline alkaloid structures and could be
pyridines, e. g. 4-hydroxytetrahydroisoquinolines, were
obtained either from corresponding condensed oxo
compounds by reduction5,18,19,22–26 or by addition of org-
stereoselectively transformed into condensed 4-hydroxytetrahydro- anometallics,5,17–19,25 by cyclization of 2-benzylamino-
acetaldehyde acetals27 or by Pictet–Spengler-type
pyridines 7 and 8 by reaction with Grignard reagents or reduction.
Treatment of condensed 4-allyl or 4-homoallyl-4-hydroxypyridines
8 with N-iodosuccinimide undergoes halocyclization to bridged tri-
reaction.28
We found an efficient way to condensed dihydropyridones.
It starts from a-amino acids like in the biosynthesis, but
only the C–C–N unit of the amino acid is incorporated
into the final pyridine ring while a C-3 unit is contributed
by an o-halobenzyl halide or a heterocyclic analogue (ret-
rosynthesis B in Scheme 1, X,Y = Hal).29–31 After primary
alkylation of the amino group of the N-protected a-amino
ester 3, the resulting N-(a-bromobenzyl)amino esters 5
were submitted to a bromo-lithium exchange by n-BuLi or
t-BuLi resulting in a cyclization to dihydroisoquinolin-4-
ones or their heterocyclic analogues 6 (Scheme 2,
Tables 1 and 2). Low temperatures (down to –100 °C)
were necessary to prevent racemization during the final
cyclization step. Occasionally, addition of the alkyllithi-
um to the carbonyl group of the product was observed as
side reaction resulting in the corresponding 4-alkyl-4-hy-
droxyisoquinolines and heterocyclic analogues 8 (see also
footnotes in Table 2).29 By choosing oxazole or thiazole
as the annulated heterocyclic 6p-ring, the corresponding
condensed dihydropyridones 6 (6p-system is 1,3-oxazole
or 1,3-thiazole) could be transformed into aminoglycitol
derivatives. Here, up to three new stereogenic centers
were created in a highly selective way.30,31 This overall
transformation of a-amino esters into aminoglycitols pro-
vided a novel way to amino sugars starting from a-amino
acids.30,31
cyclic tetrahydropyridines 9 and 10.
Key words: amino acids, carbolines, isoquinolines, asymmetric
synthesis, heterocycles
Condensed tetrahydropyridines such as tetrahydroiso-
quinolines or tetrahydro-b-carbolines are abundant in nat-
urally occurring alkaloids and have gained
pharmaceutical interest.1,2 Biosynthesis of such com-
pounds comprises a Pictet–Spengler-type cyclization of
phenylalanine or tryptophane according to retrosynthesis
A (see Scheme 1). Among such condensed N-heterocy-
cles, compounds are found with an oxygen atom as carbo-
nyl or hydroxy group in position
3
of the
tetrahydropyridine ring, i.e. position 4 of the condensed
system. Because of their importance, several syntheses
were developed for such 3-functionalized condensed tet-
rahydropyridines. Thus intramolecular Friedel–Crafts
acylation of benzylamino acids or a-heteroarylmethyl-
amino acids3–13 or of the corresponding esters and ni-
triles,14–18 intramolecular Dieckmann condensation of o-
ethoxycarbonylbenzylamino esters19,20 or Grignard reac-
tion of 4-hydroxyisoquinolinium salts21 lead to condensed
tetrahydropyridin-4-ones. With a few exceptions,22,23
these syntheses result in racemic mixtures and often give
Similar starting materials 1 and 2 and reactions could be
used in an interesting synthesis of optically active polycy-
clic bridged condensed tetrahydropyridines. N-Unsubsti-
tuted a-amino esters 2 were dibenzylated by o-
bromobenzyl bromides or heterocyclic analogues 1. The
resulting products 5 (R2 = o-bromobenzyl or heterocyclic
analogue) were submitted to a double cyclization via bro-
mo-lithium exchange. Alternatively, condensed dihydro-
pyridones 6 with an o-bromobenzyl or heterocyclic
analogous substituent R2 could be treated with butyllithi-
um.32,33 The products exhibited a novel mode of HIV-in-
hibition by blocking the RNase-H and DNA-polymerase
activity of the reverse transcriptase.32,33
COOH
N
N
NH2
O
X
retrosynthesis A
retrosynthesis B
R
O
R
+
HO
NH2
Y
Scheme 1
SYNTHESIS 2006, No. 17, pp 2907–2922
Advanced online publication: 15.08.2006
x
x.
x
x
.
2
0
0
6
DOI: 10.1055/s-2006-950192; Art ID: T03006SS
© Georg Thieme Verlag Stuttgart · New York

2908
H. Faltz et al.
PAPER
CO2Alk
R1
amino esters 2 were used in small excess. Reaction of
amino esters 2 with two equivalents of the alkylation re-
agent 1 promotes the double alkylation to become the ma-
jor reaction.32,33 The N-monobenzylated amino esters 4
could be N-Cbz-protected (5j) or allylated (5c, 5n) in high
yields providing an access (Method C) to products 5 as an
alternative to direct Route B.
AlkO2C
Br
Br
H2N
R1
2
6π
6π
Br
A
NH
1
4
CO2Alk
R1
C
R2-X
D
B
R2HN
3
Regardless of the kind of N-substituent at position 2, a cy-
clization of the N-alkylation products 5 via bromo-lithium
exchange to condensed dihydropyridones 6 was possible.
When R2 was H, i. e. 4 was used as starting material, two
equivalents of butyllithium had to be applied. Lowering of
the temperature from –78 to –100 °C increased the yield
(see product 6i). The use of t-BuLi instead of n-BuLi was
advantageous in some cases (see products 6i and 6m) but
gave rise to unwanted addition to the carbonyl group
yielding the corresponding hydroxy products 8 (R3 = t-
Bu, see 6b, 6g) in other cases. The transformation of the
NH-containing amino ester 4d into the carbazole 6b
would require three equivalents of t-BuLi. However, this
resulted in the formation of the corresponding tert-butyl-
hydroxytetrahydro-b-carboline 8 (R3 = t-Bu) almost to
the same extent (29%) as the envisaged b-carbolinone 6b
(33%). Thus it was better to use only two equivalents of t-
BuLi resulting in an increase of the yield from 33 to 52%
(see Table 2). Formation of the 4-alkyl-4-hydroxy prod-
uct 8 in the course of the cyclization of 5 to 6 was also ob-
served when n-BuLi was applied to a lesser extent than
with t-BuLi. For example, cyclization of 5b with n-BuLi
gave 12% of the isoquinolinone 6g and 46% of the corre-
sponding 4-butyl-4-hydroxyisoquinoline 7. With t-BuLi
no 6g could be obtained at all, but only the 4-tert-butyl-4-
hydroxyisoquinoline (58%). The conditions of the trans-
formation of amino esters 5 to condensed dihydropyri-
dones 6 did not violate the optical integrity as shown by
the b-carbolinone 6j, where only the enantiomer 6j could
be detected by HPLC (>99% ee, CHIRALCEL OD). The
structure of this compound could also be proved by X-ray
crystal analysis (Figure 1).
O
AlkO2C
Br
6π
R1
R2
R1
R2
D
6π
N
N
6
5
R1 = alkyl,
R1/R2 = (CH2)3
E–G
R
2 = H, PhSO2, allyl
R3
R1
HO
R3
R1
HO
6π
6π
R2
N
N
R2
8
7
R
2 = H
R2 = H
R3 = (CH2)n
R3 = (CH2)n
H
I
I
HO
HO
n
n
R1
R1
6π
6π
I
N
N
n = 1, 2
n = 1
10
9
Scheme 2 Reagents and conditions: Method A: MeCN, K2CO3, re-
flux, 5 h, 52–95%; Method B: MeCN, K2CO3, reflux, 5 h, 63–93%;
Method C, C1: MeCN or CH2Cl2, NaHCO3, reflux, 4–8 h or C2: r.t. 8
h, 87–95%; Method D: BuLi THF, –100 °C, 3–6 h (argon), 12–81%;
Method E: R3MgBr (5–7 equiv), THF, 0 °C–r.t., 8–12 h (argon), 18–
97%; Method F: NaBH4, EtOH, 0 °C–r.t., 5–10 h, 47–57%; Method
G: LiAlH4, THF, 0 °C–r.t., 12–20 h (argon), 22–93%; Method H:
NIS, THF, 0 °C–r.t., 12–20 h (argon), 56–66%; Method I: THF,
60 °C, 3 h, 98%
Here we give a full report on the synthesis of condensed
dihydropyridones 6 and their precursors i.e., the N-pro-
tected amino esters 5 and the N-unprotected members 4.
Furthermore, reactions of the condensed dihydropyri-
dones 6 with organometallics and with reducing reagents
resulting in a transformation of the carbonyl group into
hydroxy compounds 7 or 8 and halocyclization of allyl
and homoallyl compounds 8 to 1,3-bridged cyclization
products 9 and 10 are reported (Scheme 2).
A variety of a-amino esters 5 could be synthesized by
straightforward alkylation of N-protected amino esters or
proline ester with o-bromobenzyl bromides or heterocy-
clic analogues 1 (see Table 1, Method B). When N-unsub-
stituted a-amino esters 2 were reacted with the alkylating
reagents 1 to synthesize N-monosubstituted amino esters
4 (Method A), double alkylation occurred as side reaction
affording small amounts of dibenzylated products (see
footnotes in Table 1, compounds 4a, 4d–h) although the
Figure 1 X-ray crystal structure of 6j
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active Condensed Tetrahydropyridines
2909
Table 1 (S)-N-(o-Bromobenzyl)amino Esters and Heterocyclic Analogues 4 and 5 Prepared
No.
Producta
Yield (%)
Method
Time
1H NMR (CDCl3)
d, J (Hz)
13C NMR (CDCl3)
d, J (Hz)
4a
89
A
1.27 (d, 3 H, J = 7.0, CH3), 1.93 (s, 1 H,
NH), 3.34 (q, 1 H, J = 7.0, CHN), 3.63 (s, 3 (CH3O), 56.0 (CHN), 124.0 (Car–
19.1 (CH3), 51.8 (CH2N), 51.9
Me
MeO2C
Br
5 hb
H, CH3O), 3.70 (d, 1 H, J = 13.9, CH2N),
3.83 (d, 1 H, J = 13.9, CH2N), 7.04–7.07
(m, 1 H, CHar), 7.18–7.23 (m, 1 H, CHar),
7.34 (dd, 1 H, J = 7.6, 1.6, CHar), 7.46 (dd,
1 H, J = 7.9, 1.2, CHar)
Br), 127.5 (CHar), 128.7 (CHar),
130.1 (CHar), 132.8 (CHar), 138.8
(Car), 175.9 (C=O)
NH
4b
89
A
0.85–0.90 (m, 6 H, 2 CH3), 1.18–1.91 [m, 2 19.0 (CH3), 19.7 (CH3), 32.1
i-Pr
MeO2C
Br
H, CH(CH3)2, NH], 2.95 (d, 1 H, J = 6.1,
CHN), 3.61 (s, 3 H, OCH3), 3.63 (d, 1 H,
J = 14.1, CH2N), 3.81 (d, 1 H, J = 14.1,
CH2N), 6.99–7.05 (m, 1 H, CHar), 7.17–
7.22 (m, 1 H, CHar), 7.36 (dd, 1 H,
J = 7.5, 1.1, CHar), 7.44 (d, 1 H, J = 7.9,
CHar)
[CH(CH3)2], 51.8 (OCH3), 52.8
(CH2N), 67.2 (CHN), 124.5 (Car–
Br), 127.7 (CHar), 128.9 (CHar),
130.5 (CHar), 133.1 (CHar), 139.5
(Car), 175.8 (C=O)
5 hc
NH
4c
69
A
5 h
0.88 (d, 6 H, J = 6.7, 2 CH3), 1.17 (t, 3 H,
J = 7.1, CH3CH2O), 1.71–1.93 [m, 2 H,
CH(CH3)2, NH], 3.57 (d, 1 H, J = 7.0,
14.3 (CH3CH2O), 18.6 (CH3), 19.4
(CH3), 31.7 [CH(CH3)2], 51.8
(CH2N), 55.9 (OCH3), 56.1 (CH3O),
i-Pr
EtO2C
Br
MeO
NH
CHN), 3.51 (d, 1 H, J = 14.2, CH2N), 3.65 60.4 (OCH2CH3), 66.5 (CHN),
(d, 1 H, J = 14.2, CH2N), 3.70 (s, 3 H,
OCH3), 3.77 (s, 3 H, OCH3), 4.09 (q, 2 H,
J = 7.1, OCH2CH3), 6.84 (s, 1 H, CHar),
6.93 (s, 1 H, CHar)
112.8 (CHar), 113.7 (Car–Br), 115.3
(CHar), 131.1 (Car), 148.2 (Car),
148.4 (Car), 175.0 (C=O)
MeO
4d
4e
68
A
1.28 (d, 3 H, J = 7.0, CH3), 1.71 (s, 9 H, 19.6 (CH3), 28.2 [(CH3)3C], 43.8
t-C4H9), 2.59 (s, 1 H, NH), 3.35 (s, 3 H, (CH2N), 51.6 (CH3O), 54.9 (CHN),
CH3O), 3.38 (q, 1 H, J = 7.0, CHN), 4.19 (d, 85.0 [C(CH3)3], 102.4 (Car–Br),
1 H, J = 14.6, CH2N), 4.28 (d, 1 H, J = 14.6, 115.8 (CHar), 119.4 (CHar), 123.3
Me
MeO2C
Br
2 hd
NH
CH2N), 7.21–7.34 (m, 2 H, CHar), 7.42–
7.51 (m, 1 H, CHar), 8.08 (d, 1 H, J = 8.1,
CHar)
(CHar), 125.5 (CHar), 128.0 (Car),
135.3 (Car), 135.4 (Car), 149.8
(CO2Bu-t), 175.9 (CO2Me)
N
Boc
52
A
0.96 (d, 3 H, J = 6.7, CH3), 0.98 (d, 3 H,
J = 6.3, CH3), 1.05 (t, 3 H, J = 7.1,
14.0 (CH3CH2), 18.4 [(CH3)2CH],
19.1 [(CH3)2CH), 28.2 [(CH3)3C],
i-Pr
EtO2C
Br
3 he
CH3CH2O), 1.79 (s, 9 H, t-C4H9), 1.89–2.02 32.0 [CH(CH3)2], 44.8 (CH2N), 60.1
[m, 1 H, CH(CH3)2], 2.65 (s, 1 H, NH), 3.09 (CH2O), 65.5 (CHN), 84.8
(d, 1 H, J = 5.3, CHN), 3.61–3.89 (m, 2 H, [C(CH3)3], 102.2 (Car–Br), 115.7
OCH2CH3), 4.24 (d, 1 H, J = 14.7, CH2N), (CHar), 119.3 (CHar), 123.2 (CHar),
NH
N
Boc
4.39 (d, 1 H, J = 14.7, CH2N), 7.32–7.39
125.4 (CHar), 128.0 (Car), 135.5
(m, 2 H, CHar), 7.55 (d, 1 H, J = 7.4, CHar), (Car), 135.8 (Car), 149.8 (CO2Bu-t),
8.16 (d, 1 H, J = 8.3, CHar)
174.9 (CO2Et)
4f
60
A
0.62 (d, 3 H, J = 6.8, CH3), 0.64 (t, 3 H,
J = 7.3, CH3CH2), 0.88–1.05 (m, 1 H, CH), (CH2CH3), 28.6 [(CH3)3C], 39.2
1.23–1.49 (m, 2 H, CH2CH3), 1.51 (s, 9 H, (CH), 45.1 (CH2N), 51.4 (CH3O),
11.9 (CH3CH2), 15.8 (CH3), 25.8
s-Bu
MeO2C
Br
3 hf
NH
t-C4H9), 2.34 (s, 1 H, NH), 2.91 (d, 1 H,
64.8 (CHN), 85.2 [C(CH3)3], 102.7
J = 5.8, CHN), 3.03 (s, 3 H, CH3O), 3.95 (d, (Car–Br), 116.1 (CHar), 119.7
1 H, J = 14.7, CH2N), 4.09 (d, 1 H, J = 14.7, (CHar), 123.6 (CHar), 125.8 (CHar),
N
Boc
CH2N), 7.05–7.12 (m, 2 H, CHar), 7.25–
7.26 (m, 1 H, CHar), 7.85–7.89 (m, 1 H,
CHar)
128.4 (Car), 135.9 (Car), 136.1 (Car),
150.2 (CO2Bu-t), 175.7 (CO2Me)
4g
67
A
0.74 (d, 3 H, J = 6.6, CH3), 0.82 (d, 3 H,
J = 6.6, CH3), 1.23–1.41 (m, 2 H,
CH2CHN), 1.44–1.58 [m, 1 H, CH(CH3)2], (CH2CHN), 44.7 (CH2N), 51.8
1.65 (s, 9 H, t-C4H9), 2.46 (s, 1 H, NH), (CH3O), 58.7 (CHN), 85.2
22.3 (CH3), 23.2 (CH3), 25.1
[CH(CH3)2], 28.6 [(CH3)3C], 43.5
i-Bu
MeO2C
Br
3 hg
NH
3.21–3.30 (m, 4 H, CH3O, CHN), 4.12 (d, 1 [C(CH3)3], 102.8 (Car–Br, 116.1
H, J = 14.7, CH2N), 4.24 (d, 1 H, J = 14.7, (CHar), 119.8 (CHar), 123.7 (CHar),
N
Boc
CH2N), 7.11–7.28 (m, 2 H, CHar), 7.35–
7.43 (m, 1 H, CHar), 7.98 (d, 1 H, J = 8.1,
CHar)
125.8 (CHar), 128.4 (Car), 135.8
(Car), 135.9 (Car), 150.2 (CO2Bu-t),
176.7 (CO2Me)
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

2910
H. Faltz et al.
PAPER
Table 1 (S)-N-(o-Bromobenzyl)amino Esters and Heterocyclic Analogues 4 and 5 Prepared (continued)
No.
Producta
Yield (%)
Method
Time
1H NMR (CDCl3)
d, J (Hz)
13C NMR (CDCl3)
d, J (Hz)
4h
65
A
1.26 (d, 3 H, J = 7.0, CH3CH), 1.99 (s, 1 H, 19.1 (CH3CH), 45.6 (CH2N), 51.9
NH), 3.35 (q, 1 H, J = 7.0, CHN), 3.66 (s, 3 (CH3O), 55.6 (CHN), 108.6 (Car–
Me
MeO2C
Br
3 hh
H, CH3O), 3.76 (d, 1 H, J = 14.6, CH2N),
Br), 124.7 (CHar), 129.9 (CHar),
NH
3.91 (d, 1 H, J = 14.6, CH2N), 6.84 (d, 1 H, 138.2 (Car), 175.7 (CO2Me)
J = 5.3, CHar), 7.13 (d, 1 H, J = 5.3, CHar)
S
4i
89
A
0.89 (d, 6 H, J = 6.8, [CH3)2CH], 1.22 (t, 3 14.7 (CH3CH2O), 18.8 (CH3), 19.7
H, J = 7.1, CH3CH2O), 1.82–1.91 [m, 2 H, (CH3), 32.1 [CH(CH3)2], 46.8
EtO2C
Br
i-Pr
3 hi
CH(CH3)2, NH], 2.97 (d, 1 H, J = 5.9,
(CH2N), 60.9 (CH2O), 66.6 (CHN),
N
CHN), 3.86 (d, 1 H, J = 14.7, CH2N), 3.94 108.6 (Car–Br), 125.0 (CHar), 130.2
(d, 1 H, J = 14.7, CH2N), 4.13 (q, 2 H,
J = 7.1, OCH2CH3), 6.84 (d, 1 H, J = 5.3,
CHar), 7.13 (d, 1 H, J = 5.3, CHar)
(CHar), 139.3 (Car), 175.2 (CO2Et)
S
5a
71
B
1.64–1.96 (m, 4 H, 2 proline CH2), 2.29–
2.35 (m, 1 H, proline CH2N), 2.91–2.92 (m, (CH3O), 53.3 (CH2N), 57.6 (CH2N),
23.3 (CH2), 29.3 (CH2), 51.7
MeO2C
Br
5 hj
1 H, proline CH2N), 3.19–3.24 (m, 1 H,
CHN), 3.48 (s, 3 H, OCH3), 3.61 (d, 1 H,
J = 14.0, CH2N), 3.79 (d, 1 H, J = 14.0,
CH2N), 6.90–6.93 (m, 1 H, CHar), 7.06–
7.11 (m, 1 H, CHar), 7.31–7.35 (m, 2 H,
CHar)
65.4 (CHN), 124.2 (Car–Br), 127.3
(CHar), 128.4 (CHar),131.0
(CHar),132.6 (CHar), 138.0 (Car),
174.6 (C=O)
N
5b
5c
93
B
1.21 (d, 3 H, J = 7.2, CH3), 3.34 (s, 3 H,
CH3O), 3.34 (q, 1 H, J = 7.2, CHN), 4.51 (d, (CH3O), 55.9 (CHN), 122.5 (Car–
1 H, J = 17.8, CH2N), 4.62 (d, 1 H, J = 17.8, Br), 127.8 (2 CHar), 128.9 (CHar),
CH2N), 7.02–7.08 (m, 1 H, CHar), 7.19–
7.28 (m, 1 H, CHar), 7.41–7.62 (m, 5 H,
CHar), 7.76–7.79 (m, 2 H, CHar)
17.1 (CH3), 49.6 (CH2N), 52.5
MeO2C
Br
Me
3 hk
N
129.2 (CHar), 129.4 (2 CHar), 128.0
(CHar), 132.8 (CHar), 133.3 (CHar),
137.4 (Car), 139.8 (Car), 171.7
(C=O)
SO2Ph
87
1.34 (d, 3 H, J = 7.2, CH3), 3.20–3.35 (m, 2 15.1 (CH3), 51.3 (CH3O), 53.9
H, NCH2CH), 3.63 (q, 1 H, J = 7.2, CHN), (CH2N), 54.2 (CH2N), 57.4 (CHN),
3.74 (s, 3 H, CH3O), 3.84 (d, 1 H, J = 16.4, 117.2 (CH2=CH), 123.9 (Car–Br),
CH2N), 3.90 (d, 1 H, J = 16.4, CH2N), 5.11 127.2 (CHar), 128.1 (CHar), 130.1
(dd, 1 H, J = 10.1, 1.4, CH2=CH), 5.23 (dd, (CHar), 132.5 (CHar), 136.4
1 H, J = 17.2, 1.6, CH2=CH), 5.77–5.90 (m, (CH=CH2), 139.2 (Car), 188.2
MeO2C
Br
Me
C1
8 hl
N
allyl
1 H, CH=CH2), 7.08–7.13 (m, 1 H, CHar),
7.28–7.33 (m, 1 H, CHar), 7.51–7.63 (m, 2
H, CHar)
(C=O)
5d
79
0.89–0.94 [m, 6 H, (CH3)2CH], 1.14 (t, 3 H, 13.8 (CH3CH2O), 19.4 (CH3), 20.1
J = 7.1, CH3CH2O), 2.04–2.09 [m, 1 H, (CH3), 28.7 [CH(CH3)2], 48.6
CH(CH3)2], 3.73–3.86 (m, 2 H, OCH2CH3), (CH2N), 55.9 (CH3O), 56.1 (CH3O),
3.88 (s, 3 H, CH3O), 3.91 (s, 3 H, CH3O), 60.6 (OCH2CH3), 66.3 (CHN),
4.22 (d, 1 H, J = 10.1, CHN), 4.64 (d, 1 H, 112.5 (Car–Br), 113.1 (CHar), 114.9
EtO2C
Br
i-Pr
B
3 hm
MeO
MeO
N
SO2Ph
J = 17.0, CH2N), 5.06 (d, 1 H, J = 17.0,
(CHar), 127.2 (2 CHar), 128.7 (2
CHar), 128.8 (Car), 132.7 (CHar),
CH2N), 6.99 (s, 1 H, CHar), 7.35 (s, 1 H,
CHar), 7.52–7.66 (m, 3 H, CHar), 7.89 (d, 2 139.6 (Car), 148.4 (Car), 148.6 (Car),
H, J = 7.9, CHar) 170.2 (C=O)
5e
86
B
1.75 (s, 9 H, t-C4H9), 1.91–2.20 (m, 4 H, 2 23.8 (CH2), 28.5 [(CH3)3C], 30.1
MeO2C
Br
CH2), 2.64–2.76 (m, 1 H, proline NCH2),
3.18–3.29 (m, 1 H, proline NCH2), 3.42–
3.47 (m, 1 H, CHN), 3.53 (s, 3 H, CH3O),
(CH2), 48.5 (CH2N), 51.8 (CH3O),
53.6 (CH2N), 64.3 (CHN), 84.6
[C(CH3)3], 102.2 (Car–Br), 115.5
2 hn
N
4.34 (d, 1 H, J = 13.6, CH2N), 4.51 (d, 1 H, (CHar), 119.8 (CHar), 123.3 (CHar),
J = 13.6, CH2N), 7.32–7.39 (m, 2 H, CHar), 125.6 (CHar), 128.2 (Car), 134.7
N
Boc
7.56–7.64 (m, 1 H, CHar), 8.07(dd, 1 H,
J = 0.8, 8.4, CHar)
(Car), 136.2 (Car), 150.0 (CO2Bu-t),
174.9 (CO2Me)
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active Condensed Tetrahydropyridines
2911
Table 1 (S)-N-(o-Bromobenzyl)amino Esters and Heterocyclic Analogues 4 and 5 Prepared (continued)
No.
Producta
Yield (%)
Method
Time
1H NMR (CDCl3)
d, J (Hz)
13C NMR (CDCl3)
d, J (Hz)
5f
87
B
1.67–2.06 (m, 4 H, proline CH2), 2.52–2.60 23.6 (proline CH2), 30.1 (proline
(m, 1 H, proline NCH2), 3.01–3.08 (m, 1 H, CH2), 49.2 (CH2N), 51.9 (CH3O),
proline NCH2), 3.29–3.34 (m, 1 H, CHN), 53.9 (CH2N), 54.3 (CH3O), 65.1
MeO2C
Br
2 ho
N
3.39 (s, 3 H, CH3O), 3.97 (s, 3 H, CH3O),
(CHN), 103.1 (Car–Br), 115.9
4.19 (d, 1 H, J = 13.6, CH2N), 4.29 (d, 1 H, (CHar), 119.9 (CHar), 123.8 (CHar),
J = 13.6, CH2N), 7.18–7.30 (m, 2 H, CHar), 126.0 (CHar), 128.4 (Car), 134.6
N
Moc
7.43 (m, 1 H, CHar), 7.99 (dd, 1 H,
(Car), 136.1 (Car), 152.0 (NCO2Me),
174.8 (CO2Me)
J = 8.4, 0.8, CHar)
5g
79
B
1.38 (d, 3 H, J = 7.2, CH3), 1.46 (s, 9 H, 16.5 (CH3), 28.6 [(CH3)3C], 45.2
t-C4H9), 3.48 (s, 3 H, CH3O), 4.22 (q, 1 H, (CH2N), 52.7 (CH3O), 58.8 (CHN),
Me
MeO2C
Br
4 hp
J = 7.2, CHN), 4.77 (d, 1 H, J = 14.4,
CH2N), 4.87 (d, 1 H, J = 14.4, CH2N),
85.3 [C(CH3)3], 105.3 (Car–Br),
115.7 (CHar), 120.1 (CHar), 123.6
N
SO2Ph
6.88–7.09 (m, 5 H, CHar), 7.19–7.22 (m, 1 (CHar), 126.3 (CHar), 127.5 (2
N
H, CHar), 7.39–7.42 (m, 2 H, CHar), 7.53–
7.56 (m, 1 H, CHar)
CHar), 128.1 (Car), 128.4 (2 CHar),
131.0 (Car), 132.2 (CHar), 135.7
(Car), 140.6 (Car), 149.6 (CO2Bu-t),
172.1 (CO2Me)
Boc
5h
68
B
0.99 (d, 3 H, J = 6.4, CH3), 1.18 (d, 3 H,
J = 6.7, CH3), 1.32 (t, 3 H, J = 7.1,
CH3CH2O), 1.66 (s, 9 H, t-C4H9), 2.32–2.58 28.6 [(CH3)3C], 41.5 (CH2N), 61.4
14.5 (CH3CH2), 20.1 [(CH3)2CH],
20.3 [(CH3)2CH], 27.9 [CH(CH3)3],
i-Pr
EtO2C
Br
4 hq
N
N
N
[m, 1 H, CH(CH3)2], 4.17–4.25 (m, 2 H,
OCH2CH3), 4.42 (d, 1 H, J = 11.1, CHN),
4.84 (d, 1 H, J = 13.8, CH2N), 5.16 (d, 1 H, (CHar), 119.9 (CHar), 123.4 (CHar),
J = 13.8, CH2N), 6.93–6.98 (m, 2 H, CHar), 126.2 (CHar), 127.2 (2 CHar), 127.8
7.16–7.41 (m, 6 H, CHar), 7.81–7.84 (m, 1 (Car), 128.1 (2 CHar), 130.2 (Car),
(CH2O), 66.9 (CHN), 85.2
[C(CH3)3], 106.2 (Car–Br), 115.7
SO2Ph
N
Boc
H, CHar)
131.9 (CHar), 135.7 (Car), 140.9
(Car), 149.6 (CO2Bu-t), 169.9
(CO2Et)
5i
74
B
0.84–0.90 (m, 6 H, 2 CH3), 0.99–1.11 (m, 1 11.3 (CH3CH2), 16.0 (CH3), 25.3
H, CH3CHC2H5), 1.59 (s, 9 H, t-C4H9), (CH2CH3), 28.1 [(CH3)3C], 33.7
1.79–2.07 (m, 2 H, CH2CH3), 3.64 (s, 3 H, (CH3CHC2H5), 41.4 (CH2N), 51.8
CH3O), 4.41 (d, 1 H, J = 10.9, CHN), 4.85 (CH3O), 65.5 (CHN), 84.8
(d, 1 H, J = 19.9, CH2N), 5.00 (d, 1 H,
J = 19.9, CH2N), 6.89–6.95 (m, 2 H, CHar), (CHar), 119.5 (CHar), 123.0 (CHar),
s-Bu
MeO2C
Br
4 hr
SO2Ph
[C(CH3)3], 105.7 (Car–Br), 115.3
N
Boc
6.93–7.36 (m, 6 H, CHar), 7.76 (d, 1 H,
J = 8.2, CHar)
125.8 (CHar), 126.9 (2 CHar), 127.5
(Car), 127.8 (2 CHar), 129.9 (Car),
131.6 (CHar), 135.4 (Car), 140.4
(Car), 149.2 (CO2Bu-t), 170.0
(CO2Me)
5j
95
–
14.3 [(CH3)2CH], 14.6 [(CH3)2CH],
19.4 (CH3CH2), 28.5 [(CH3)3C]
32.4 [CH(CH3)2], 45.1 (CH2N), 60.9
(CH2O), 64.8 (CHN), 67.9 (CH2O),
84.9 [C(CH3)3], 92.4 (Car–Br),
115.9 (CHar), 119.9 (CHar), 123.6
(CHar), 126.2 (CHar), 127.6 (Car),
128.3 (CHar), 128.7 (2 CHar), 129.1
(2 CHar), 132.1 (Car), 137.3 (Car),
138.4 (Car), 149.9 (CO2Bu-t), 156.4
(CO2C7H7), 171.1 (CO2Et)
i-Pr
cbz
EtO2C
Br
C2
8 hs
N
Boc
5k
78
B
1.75–1.91 (m, 4 H, proline CH2), 2.49–2.53 23.6 (proline CH2), 29.7 (proline
(m, 1 H, proline CH2N), 3.07–4.00 (m, 1 H, CH2), 51.3 (CH2N), 52.2 (CH3O),
proline CH2N), 3.31–3.36 (m, 1 H, CHN), 53.4 (CH2N), 64.7 (CHN), 110.0
3.64 (s, 3 H, CH3O), 3.86 (d, 1 H, J = 14.5, (Car–Br), 125.7 (CHar), 130.0
CH2N), 4.00 (d, 1 H, J = 14.5, CH2N), 6.84 (CHar), 136.6 (Car), 174.6 (CO2Me)
(d, 1 H, J = 5.3, CHar), 7.19 (d, 1 H, J = 5.3,
MeO2C
Br
3 ht
N
S
CHar)
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

2912
H. Faltz et al.
PAPER
Table 1 (S)-N-(o-Bromobenzyl)amino Esters and Heterocyclic Analogues 4 and 5 Prepared (continued)
No.
Producta
Yield (%)
Method
Time
1H NMR (CDCl3)
d, J (Hz)
13C NMR (CDCl3)
d, J (Hz)
5l
63
B
1.33 (d, 3 H, J = 7.4, CH3CH), 3.42 (s, 3 H, 17.2 (CH3CH), 44.5 (CH2N), 52.6
CH3O), 4.55–4.69 (m, 3 H, CH2N, CHN), (CH3O), 55.7 (CHN), 109.8 (Car–
6.79 (d, 1 H, J = 5.3, thiophene CHar), 7.18 Br), 126.6 (CHar), 127.8 (2 CHar),
(d, 1 H, J = 5.3, thiophene CHar), 7.41–7.53 129.4 (2 CHar), 129.8 (CHar), 133.3
Me
MeO2C
Br
3 hu
N
SO2Ph
i-Pr
(m, 3 H, CHar), 7.77–7.80 (m, 2 H, CHar)
(CHar), 136.9 (Car), 139.9 (Car),
171.8 (CO2Me)
S
5m
67
B
0.78 (d, 3 H, J = 6.6, CH3), 0.82 (d, 3 H,
J = 6.6, CH3), 1.05 (t, 3 H, J = 7.2,
CH3CH2O), 2.05–2.13 [m, 1 H, CH(CH3)2], (CH2N), 61.1 (CH2O), 66.3 (CHN),
3.66–3.86 (m, 2 H, OCH2CH3), 4.03 (d, 1 H, 110.5 (Car–Br), 127.0 (CHar), 127.9
14.3 (CH3CH2O), 19.8 (CH3), 20.1
(CH3), 29.3 [CH(CH3)2], 43.8
EtO2C
Br
3 hv
N
SO2Ph
J = 10.3, CHN), 4.61 (d, 1 H, J = 16.9,
(2 CHar), 129.2 (2 CHar), 129.6
S
CH2N), 5.07 (d, 1 H, J = 16.9, CH2N), 6.79 (CHar), 133.1 (CHar), 136.8 (Car),
(d, 1 H, J = 5.3, thiophene CHar), 7.18 (d, 1 140.0 (Car), 170.8 (CO2Et)
H, J = 5.3, thiophene CHar), 7.34–7.52 (m, 3
H, CHar), 7.74–7.77 (m, 2 H, CHar)
5n
87
1.26 (d, 3 H, J = 7.2, CH3CH), 3.19 (dd, 1 15.3 (CH3CH), 48.7 (CH2N), 51.3
H, J = 13.2, 6.9, NCH2CH), 3.28 (dd, 1 H, (CH3O), 54.2 (CH2N), 57.2 (CHN),
Me
MeO2C
Br
C1
5 hw
J = 13.2, 5.4, NCH2CH), 3.56 (q, 1 H,
107.9 (Car–Br), 117.4 (CH2=CH),
N
J = 7.2, CHN), 3.65 (s, 3 H, CH3O), 3.80 (d, 124.8 (CHar), 129.8 (CHar), 136.1
1 H, J = 15.6, CH2N), 3.87 (d, 1 H, J = 15.6, (CH=CH2), 140.2 (Car), 174.1
allyl
S
CH2N), 5.04 (dd, 1 H, J = 10.2, 1.3,
CH2=CH), 5.16 (dd, 1 H, J = 17.2, 1.5,
CH2=CH), 5.68–5.82 (m, 1 H, CH=CH2),
6.82 (d, 1 H, J = 5.3, CHar), 7.12 (d, 1 H,
J = 5.3, CHar)
(CO2Me)
a Satisfactory microanalyses obtained for 4a,b,d–i and 5a–n: C 0.38; H 0.15; Br 0.47; N 0.20; S 0.32.
b [a]D20 –26.9 (c = 1.15, CH2Cl2); + 8% N,N-dialkylation product.
c [a]D20 –47.8 (c = 1, CHCl3).
d [a]D20 –10.2 (c = 2.25, CH2Cl2). MS (90 eV): m/z (%) = 210 (36), 208 (35), 128 (20), 57 (100), 41 (39), 29 (10); + 9% N,N-dialkylation
product.
e [a]D20 +20.8 (c = 0.5, CH2Cl2); + 12% N,N-dialkylation product.
f Reactant ratio 1:1; + 13% N,N-dialkylation product.
g [a]D20 –3.28 (c = 1.4, CH2Cl2); reactant ratio 1/2 = 1:2; + 8% N,N-dialkylation product.
h [a]D20 –28.96 (c = 1.25, CH2Cl2); + 11% N,N-dialkylation product.
i [a]D20 –41.44 (c = 1.25, CH2Cl2). MS (90 eV): m/z (%) = 320 (M+, 1.16), 248 (24), 246 (24), 192 (13), 190 (14), 177 (100), 175 (96), 96 (16),
55 (12), 45 (18), 43 (14), 29 (19), 28 (15), 27 (11), 18 (13).
j [a]D20 –38.0 (c = 1, CH2Cl2).
k [a]D20 –29.12 (c = 1.25, CH2Cl2); mp 90–92 °C.
l [a]D20 –52.13 (c = 1.5, CH2Cl2). MS (90 eV): m/z (%) = 312 (M+, 1.13), 254 (17), 252 (17), 214 (21), 212 (23), 171 (97), 169 (100), 94 (20),
91 (29), 90 (50), 99 (41), 57 (18), 56 (35), 55 (27), 44 (17), 43 (29), 42 (21), 41 (28), 39 (15), 29 (18), 28 (22), 18 (17), 15 (29).
m [a]D20 –19.9 (c = 1, CH2Cl2).
n [a]D20 –32.0 (c = 1, CH2Cl2).
o [a]D20 –14.5 (c = 1, CH2Cl2).
p [a]D20 –21.6 (c = 1, MeOH); mp 115–117 °C. MS (90 eV): m/z = 311 (22), 309 (23), 210 (16), 208 (16), 129 (14), 128 (27), 77 (35), 57 (100),
56 (67), 41 (38), 29 (20), 18 (11).
q [a]D20 –94.8 (c = 1.1, CH2Cl2); mp 109–111 °C. MS (90 eV): m/z = 397 (10), 395 (9), 353 (28), 351 (29), 210 (20), 208 (21), 129 (15), 128
(29), 77 (34), 57 (100), 43 (10), 41 (40), 29 (30), 18 (25).
r [a]D20 –73.8 (c = 1, CH2Cl2); mp 113–115 °C.
s [a]D20 –24.1 (c = 1, CHCl3).
t [a]D20 –62.0 (c = 1, CH2Cl2).
u [a]D20 –36.3 (c = 1, CH2Cl2).
v [a]D20 –47.8 (c = 1, CHCl3).
w [a]D20 –46.0 (c = 1.25, CH2Cl2).
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active Condensed Tetrahydropyridines
2913
Table 2 Condensed Tetrahydropyridones 6 Prepared
No.
Producta
Yield (%)
BuLi
Precursor
1H NMR (CDCl3)
d, J (Hz)
13C NMR (CDCl3)
d, J (Hz)
O
6a
23b
n-BuLi
4b
0.89 (d, 3 H, J = 6.8, CH3), 1.00 (d, 3 H,
J = 6.9, CH3), 2.21 (br s, 1 H, NH), 2.44–
2.50 [m, 1 H, CH(CH3)2], 3.19 (d, 1 H,
J = 4.8, CHN), 4.05 (d, 1 H, J = 16.5,
17.6 (CH3), 19.8 (CH3), 27.2
[CH(CH3)2], 46.7 (CH2N), 68.7
(CHN), 125.6 (CHar), 127.1 (CHar),
127.2 (CHar), 131.3 (Car), 133.3
i-Pr
NH
CH2N), 4.13 (d, 1 H, J = 16.5, CH2N), 7.12 (CHar), 143.7 (Car) 197.1 (C=O)
(d, 1 H, J = 7.6, CHar), 7.25–7.30 (m, 1 H,
CHar), 7.38–7.44 (m, 1 H, CHar), 7.95 (dd, 1
H, J = 7.8, 1.1, CHar)
6b
6c
52c
t-BuLi
4d
1.35 (d, 3 H, J = 6.9, CH3), 1.63 (s, 9 H, 15.4 (CH3), 28.2 [(CH3)3C], 43.9
O
Me
NH
t-C4H9), 1.98 (s, 1 H, NH), 3.45 (q, 1 H,
J = 6.9, CHN), 4.35 (d, 1 H, J = 19.0,
(CH2N), 57.6 (CHN), 85.8
[C(CH3)3), 115.0 (Car), 115.2 (CHar),
CH2N), 4.57 (d, 1 H, J = 19.0, CH2 N), 7.21– 121.5 (CHar), 124.6 (CHar), 125.1
N
7.32 (m, 2 H, CHar), 7.98–8.05 (m, 1 H,
CHar), 8.11–8.20 (m, 1 H, CHar)
(CHar), 125.6 (Car), 135.6 (Car),
150.2 (CO2Bu-t), 151.1 (Car), 196.3
(C=O)
Boc
61d
t-BuLi
4e
0.95 (d, 3 H, J = 6.8, CH3), 1.01 (d, 3 H,
18.5 (CH3), 20.3 (CH3), 27.1
O
i-Pr
NH
J = 6.9, CH3), 1.63 (s, 9 H, t-C4H9), 2.06 (s, [CH(CH3)2], 28.6 [(CH3)3C], 44.2
1 H, NH), 2.36–2.49 [m, 1 H, CH(CH3)2],
3.10 (d, 1 H, J = 5.5, CHN), 4.29 (d, 1 H,
J = 19.0, CH2N), 4.54 (d, 1 H, J = 19.0,
(CH2N), 67.6 (CHN), 86.1
[C(CH3)3], 115.6 (CHar), 116.1 (Car),
121.9 (CHar), 124.9 (CHar), 125.5
N
CH2N), 7.25–7.28 (m, 2 H, CHar), 8.06–8.13 (CHar), 126.1 (Car), 136.0 (Car),
Boc
(m, 1 H, CHar), 8.17–8.21 (m, 1 H, CHar)
149.9 (CO2Bu-t), 151.3 (Car), 196.2
(C=O)
6d
41e
n-BuLi
4f
0.88 (t, 3 H, J = 7.4, CH3CH2), 0.98 (d, 3 H, 12.3 (CH3CH2), 16.8 (CH3), 25.6
J = 6.9, CH3), 1.15–1.59 (m, 2 H, CH2CH3), (CH2CH3), 28.6 [(CH3)3C], 33.8
O
s-Bu
NH
1.63 (s, 9 H, t-C4H9), 1.90 (br s, 1 H, NH),
2.11–2.24 (m, 1 H, CH), 3.16 (d, 1 H,
J = 5.3, CHN), 4.28 (d, 1 H, J = 19.0,
(CH), 44.2 (CH2N), 67.1 (CHN),
86.1 [C(CH3)3], 115.6 (CHar), 116.2
(Car), 121.9 (CHar), 124.9 (CHar),
N
CH2N), 4.54 (d, 1 H, J = 19.0, CH2N), 7.19– 125.4 (CHar), 126.1 (Car), 136.0
Boc
7.28 (m, 2 H, CHar), 8.02–8.10 (m, 1 H,
CHar), 8.14–8.23 (m, 1 H, CHar)
(Car), 150.2 (CO2Bu-t), 151.2 (Car),
196.4 (C=O)
6e
60f
n-BuLi
4g
62
t-BuLi
4g
1.14 (d, 3 H, J = 6.5, CH3), 1.17 (d, 3 H,
J = 6.6, CH3), 1.63–1.71 [m, 1 H,
CH(CH3)2], 1.87 (s, 9 H, t-C4H9), 1.89–2.12 (CH2CHN), 43.1 (CH2N), 59.9
(m, 2 H, CH2CHN), 2.21 (s, 1 H, NH), 3.56– (CHN), 85.7 [C(CH3)3], 115.0 (Car),
3.61 (m, 1 H, CHN), 4.53 (d, 1 H, J = 19.1, 115.2 (CHar), 121.4 (CHar), 124.5
CH2N), 4.65 (d, 1 H, J = 19.1, CH2N), 7.43– (CHar), 125.0 (CHar), 125.7 (Car),
21.6 (CH3), 23.4 (CH3), 25.0
[CH(CH3)2), 28.2 [(CH3)3C], 38.0
O
i-Bu
NH
N
Boc
7.53 (m, 2 H, CHar), 7.26–7.29 (m, 1 H,
CHar), 7.36–8.39 (m, 1 H, CHar)
135.6 (Car), 149.4 (CO2Bu-t), 150.8
(Car), 196.9 (C=O)
6f
23g
t-BuLi
4i
0.89 (d, 3 H, J = 6.8, CH3), 1.00 (d, 3 H,
J = 6.9, CH3), 2.30 (br s, 1 H, NH), 2.42–
2.50 [m, 1 H, CH(CH3)2], 3.10 (d, 1 H,
J = 4.9, CHN), 4.11 (d, 1 H, J = 17.2,
CH2N), 4.26 (d, 1 H, J = 17.2, CH2N), 7.03 (C=O)
(d, 1 H, J = 5.2, CHar), 7.33 (d, 1 H, J = 5.2,
CHar),
18.1 (CH3), 20.3 (CH3), 27.1
[CH(CH3)2], 44.0 (CH2N), 68.1
(CHN), 123.9 (CHar), 125.3 (CHar),
136.7 (Car), 155.2 (Car), 193.5
O
i-Pr
NH
S
6g
12h
n-BuLi
5b
1.35 (d, 3 H, J = 7.4, CH3), 4.05 (q, 1 H,
J = 7.4, CHN), 4.60 (d, 1 H, J = 17.9,
CH2N), 4.93 (d, 1 H, J = 17.9, CH2N), 7.10– CHar), 127.8 (CHar), 128.4 (CHar),
7.20 (m, 4 H, CHar), 7.27–7.44 (m, 2 H, 129.1 (Car), 129.4 (2 CHar), 133.1
CHar), 7.52–7.56 (m, 2 H, CHar), 7.63–7.66 (CHar), 134.6 (CHar), 138.1 (Car),
15.4 (CH3), 43.0 (CH2N), 58.3
(CHN), 126.1 (CHar), 127.4 (2
O
Me
N
SO2Ph
(m, 1 H, CHar)
139.4 (Car), 194.4 (C=O)
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

2914
H. Faltz et al.
PAPER
Table 2 Condensed Tetrahydropyridones 6 Prepared (continued)
No.
Producta
Yield (%)
BuLi
Precursor
1H NMR (CDCl3)
d, J (Hz)
13C NMR (CDCl3)
d, J (Hz)
6h
61i
t-BuLi
5d
0.92 [d, 3 H, J = 6.6, (CH3)2CH)], 1.09 [d, 3 19.0 (CH3), 20.6 (CH3), 27.9
O
H, J = 6.6, (CH3)2CH], 1.91–2.03 [m, 1 H,
CH(CH3)2], 3.73 (s, 3 H, CH3O), 3.85 (s, 3
H, CH3O), 3.97 (d, 1 H, J = 10.2, CHN),
[CH(CH3)2], 43.2 (CH2N), 56.0
(CH3O), 56.2 (CH3O), 67.3 (CHN),
106.7 (CHar), 108.2 (CHar), 122.6
i-Pr
MeO
MeO
N
SO2Ph
4.54 (d, 1 H, J = 18.6, CH2N), 4.90 (d, 1 H, (Car), 126.9 (2 CHar), 128.8 (2 CHar),
J = 18.6, CH2N), 6.46 (s, 1 H, CHar) 7.03 (s, 132.2 (Car), 132.6 (CHar), 139.3
1 H, CHar), 7.14–7.28 (m, 3 H, CHar), 7.49– (Car), 148.5 (Car), 154.1 (Car), 191.7
7.52 (m, 2 H, CHar)
(C=O)
6i
54j
n-BuLi
5e
59
1.64 (s, 9 H, t-C4H9), 1.78–1.84 (m, 2 H, pro- 24.2 (proline CH2), 26.9 (proline
line CH2), 2.04–2.31 (m, 2 H, proline CH2), CH2), 30.5 [(CH3)3C], 52.7 (CH2N),
2.59–2.63 (m, 1 H, CHN), 3.05–3.24 (m, 2 55.5 (CH2N), 70.0 (CHN), 88.2
O
N
H, proline CH2N), 4.03 (dd, 1 H,
[C(CH3)3], 117.6 (CHar), 118.4 (Car),
N
t-BuLi
J = 18.3, 2.6, CH2N), 4.69 (d, 1 H, J = 18.3, 123.9 (CHar), 126.9 (CHar), 127.4
5e
23
CH2N), 7.25–7.28 (m, 2 H, CHar), 7.99–8.03 (CHar), 127.8 (Car), 128.3 (Car),
Boc
(m, 1 H, CHar), 8.15–8.17 (m, 1 H, CHar)
138.3 (Car), 151.9 (CO2Bu-t), 196.7
n-BuLi
(C=O)
5e
at –78 °C
6j
81k
n-BuLi
5g
1.34 (d, 3 H, J = 7.3, CH3), 1.68 (s, 9 H, t-
16.0 (CH3), 28.6 [(CH3)3C], 41.1
O
Me
N
C4H9), 4.60 (q, 1 H, J = 7.3, CHN), 4.66 (d, (CH2N), 58.1 (CHN), 87.1
1 H, J = 19.8, CH2N), 4.56 (d, 1 H, J = 19.8, [C(CH3)3], 114.3 (Car), 115.5 (CHar),
CH2N), 7.21–7.26 (m, 5 H, CHar), 7.61–7.64 121.8 (CHar), 125.2 (Car), 125.3
SO2Ph
N
(m, 2 H, CHar), 7.93–7.98 (m, 2 H, CHar)
(CHar), 126.1 (CHar), 127.1 (2 CHar),
129.5 (2 CHar), 133.3 (CHar) 135.9
(Car), 139.4 (Car), 145.5 (Car), 149.5
(CO2Bu-t), 192.2 (C=O)
Boc
6k
65l
n-BuLi
5h
72
t-BuLi
5h
0.94 (d, 3 H, J = 6.6, CH3), 1.10 (d, 3 H,
J = 6.6, CH3), 1.68 (s, 9 H, t-C4H9), 1.89–
2.01 [m, 1 H, CH(CH3)2], 4.01 (d, 1 H,
J = 10.0, CHN), 4.67 (d, 1 H, J = 20.4,
CH2N), 5.53 (d, 1 H, J = 20.4, CH2N), 7.14– 121.8 (CHar), 125.0 (CHar), 125.3
7.24 (m, 5 H, CHar), 7.55–7.58 (m, 2 H,
CHar), 7.90–7.95 (m, 2 H, CHar)
19.5 (CH3), 21.3 (CH3), 28.6
[(CH3)3C], 29.1 [CH(CH3)2], 42.2
(CH2N), 68.2 (CHN), 87.1
O
i-Pr
N
SO2Ph
[C(CH3)3], 115.0 (Car), 115.4 (CHar),
N
(Car), 125.8 (CHar), 127.1 (2 CHar),
129.3 (2 CHar), 133.1 (CHar), 135.8
(Car), 139.3 (Car), 144.9 (Car), 149.5
(CO2Bu-t), 192.2 (C=O)
Boc
6l
63m
n-BuLi
5k
1.75–1.86 (m, 2 H, proline CH2), 2.05–2.13 22.3 (proline CH2), 25.0 (proline
O
(m, 2 H, proline CH2), 2.52–2.61 (m, 1 H,
CHN), 3.04–3.10 (m, 2 H, proline CH2N),
CH2), 50.6 (CH2N), 53.5 (CH2N),
69.0 (CHN), 124.3 (CHar), 124.8
N
3.83 (dd, 1 H, J = 15.9, 2.3, CH2N), 4.29 (d, (CHar), 136.7 (Car), 153.3 (Car),
1 H, J = 15.9, CH2N), 7.06 (d, 1 H, J = 5.2, 192.5 (C=O)
CHar), 7.34 (d, 1 H, J = 5.2, CHar)
S
6m
6n
66n
n-BuLi
5l
1.37 (d, 3 H, J = 7.4, CH3CH), 4.56 (q, 1 H, 17.0 (CH3CH), 42.0 (CH2N), 59.2
O
Me
J = 7.4, CHN), 4.62 (d, 1 H, J = 18.5,
(CHN), 126.0 (CHar), 126.2 (CHar),
CH2N), 5.18 (d, 1 H, J = 18.5, CH2N), 6.95– 128.4 (2 CHar), 130.6 (2 CHar),
N
SO2Ph
6.99 (m, 2 H, CHar), 7.20–7.37 (m, 3 H,
CHar), 7.54–7.57 (m, 2 H, CHar)
134.4 (CHar), 135.6 (Car), 140.2
(Car), 149.9 (Car), 191.0 (C=O)
S
75o
t-BuLi
5m
0.94 (d, 3 H, J = 6.6, CH3), 1.11 (d, 3 H,
J = 6.6, CH3), 1.56–2.10 [m, 1 H,
CH(CH3)2], 3.95 (d, 1 H, J = 10.2, CHN),
19.5 (CH3), 20.2 (CH3), 28.3
[CH(CH3)2], 41.9 (CH2N), 68.1
(CHN), 124.8 (CHar), 125.0 (CHar),
O
i-Pr
N
SO2Ph
4.60 (d, 1 H, J = 19.0, CH2N), 5.19 (d, 1 H, 127.2 (2 CHar), 129.3 (2 CHar),
J = 19.0, CH2N), 6.90–6.94 (m, 2 H, CHar), 133.2 (CHar), 135.2 (Car), 139.1
7.16–7.22 (m, 2 H, CHar), 7.28–7.33 (m, 1 H, (Car), 148.3 (Car), 188.8 (C=O)
CHar), 7.50–7.53 (m, 2 H, CHar)
S
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active Condensed Tetrahydropyridines
2915
Table 2 Condensed Tetrahydropyridones 6 Prepared (continued)
No.
Producta
Yield (%)
BuLi
Precursor
1H NMR (CDCl3)
d, J (Hz)
13C NMR (CDCl3)
d, J (Hz)
6o
53p
t-BuLi
5n
1.26 (d, 3 H, J = 7.1, CH3CH), 3.21–3.24 (m, 12.2 (CH3CH), 45.8 (CH2N), 56.3
2 H, NCH2CH), 3.45 (q, 1 H, J = 7.1, CHN), (CH2N), 62.8 (CHN), 118.9
3.99 (d, 1 H, J = 17.1, CH2N), 4.16 (d, 1 H, (CH2=CH), 123.9 (CHar), 124.6
O
Me
N
allyl
J = 17.1, CH2N), 4.88–5.15 (m, 2 H,
CH2=CH), 5.73–5.82 (m, 1 H, CH=CH2),
7.07 (d, 1 H, J = 5.2, CHar), 7.33 (d, 1 H,
J = 5.2, CHar)
(CHar), 134.4 (CH=CH2), 151.4
(Car), 173.3 (Car), 193.5 (C=O)
S
a Satisfactory microanalyses obtained for 6a–m: C 0.48; H 0.40; S 0.38. Exceptions: 6a: C –0.58; 6b: C –0.85; 6d: H –0.57; 6h: C –1.37.
b Plus 41% of the corresponding hydroxyisoquinoline 8 (R3 = n-Bu); Rf 0.51 (CHCl3–MeOH, 9:1).
c Plus 10% of the corresponding hydroxy-b-carboline 8 (R3 = t-Bu); Rf 0.32 (CHCl3–MeOH, 97:3); [a]D20 +31.4 (c = 1, CH2Cl2).
d White solid; mp 168 °C; Rf 0.36 (CH2Cl2–acetone, 8:2); [a]D20 –11.4 (c = 1, CH2Cl2). MS (90 eV): m/z (%) = 328 (M+, 0.61), 229 (24), 201
(30), 157 (29), 129 (21), 128 (15), 72 (12), 57 (100), 55 (12), 43 (23), 41 (42), 39 (14), 29 (26), 28 (11), 27 (13).
e Rf 0.41 (CH2Cl2–acetone, 95:5); [a]D20 –97.3 (c = 1, MeOH).
f White solid; mp 129–130 °C; Rf 0.50 (CH2Cl2–acetone, 95:5); [a]D20 –9.3 (c = 1, CH2Cl2).
g Plus 18% of the debrominated starting material; Rf 0.26 (CH2Cl2–acetone, 95:5).
h Plus 46% of the alcohol 8 (R3 = n-Bu). Use of t-BuLi gave no 6, but 58% of the corresponding alcohol 8 (R3 = t-Bu); Rf 0.25 (hexanes–
EtOAc, 7:3).
i Rf 0.37 (hexanes–EtOAc, 1:1); [a]D20 –44.0 (c = 1, CH2Cl2).
j Pale yellow solid; mp 143 °C; Rf 0.24 (CH2Cl2–acetone, 95:5); [a]D20 +45.7 (c = 1, MeOH).
k Rf 0.69 (CH2Cl2–acetone, 95:5); ee >99.9% determined by HPLC (Chiracel OD; 0.5 mL/min, hexane–i-PrOH, 9:1); [a]D20 –15.8 (c = 1,
MeCN).
l Rf 0.2 (hexanes–EtOAc, 7:3); [a]D20 –34.6 (c = 1, CH2Cl2).
m Rf 0.28 (CH2Cl2–acetone, 95:5).
n Plus 21% of the hydroxy product 8 (R3 = n-Bu); white solid; mp 140–142 °C; Rf 0.84 (CH2Cl2–acetone, 95:5); [a]D20 +24.8 (c = 1, CH2Cl2).
MS (90 eV): m/z (%) = 307 (M+, 1.17), 166 (53), 125 (39), 124 (100), 97 (36), 96 (56), 77 (47), 70 (18), 51 (27), 45 (19), 18 (15).
o Rf 0.26 (hexanes–EtOAc, 7:3); [a]D20 –4.7 (c = 1, MeOH).
p Plus 22% of starting material; colorless oil; Rf 0.20 (hexanes–EtOAc, 7:3); [a]D20 +31.3 (c = 1.15, CH2Cl2).
Since the chiral centre of the condensed dihydropyridones The assignment of the reduction product of a 3-methyl-2-
6 is incorporated into a relatively rigid ring, an efficient tosyl-1,2,3,4-tetrahydrobenzo[h]isoquinolin-4-one to the
asymmetric 1,2-induction can be expected in addition re- trans-series 7 by Gellert et al.23 rather than to 8 seems to
actions to the adjacent carbonyl group. Thus, the incom- be questionable in light of our results. The authors owe
ing nucleophile should be directed opposite to the further proof for the configuration of their product.
substituent R1. Indeed, reaction with Grignard reagents
gave the corresponding alcohols 8 as major diastereomers
often in high diastereomeric ratios (Table 3, see also ref-
The NMR spectral data of compounds 7 and 8 prepared
are listed in Table 5.
Blough et al. reported a halocyclization of racemic 4-al-
lyl-1,2,3,4-tetrahydroisoquinoline in the presence of N-io-
dosuccinimide.34 Interestingly, a five-membered ring was
formed similar to 9 (R1 = H) under kinetic control at 0–
20 °C, which could be transformed into the six-membered
product 10 (R1 = H) by heating. Remarkably, the tetrahy-
dro-b-carbolines 8c, 8d, 8e gave the six-membered cy-
clization products 10 already at low temperatures (0–
20 °C, Table 6, Method H). Obviously the substituent R1
affects the outcome of the reaction. Possibly the bulk of
the substituent R1 hampers the formation of the five-mem-
bered ring thus directing the cyclization to the more spa-
tial six-membered ring by 6-endo-trig mode. On the other
hand, the iodocyclization of the thiophene derivative 8j
gave a separable mixture of the corresponding five-mem-
bered 9a (27%) and the six-membered cyclization product
10a (56%). The former could be transformed into the ring-
expanded product 10a by heating in THF at 60 °C for 3
hours (Method I) indicating that 9 can serve as intermedi-
ates for 10. When lower homologous 4-vinyltetrahydro-b-
carbolines 8h and 8i (R3 = vinyl) were treated with N-io-
erences 30 and 31). As expected, bulkier substituents R1
are more effective than the methyl group (Table 3, com-
pare 8c/8d, 8f/8g). In the case of the addition of homoal-
lylmagnesium bromide to the methyl substituted dihydro-
b-carbolinone 6b, the two epimers 7f and 8f could be sep-
arated by column chromatography and characterized in
pure form. In the other cases the major diastereomer was
obtained in pure state by column chromatography. A sim-
ilar effect of the size of the substituent R1 on the stereose-
lectivity was observed when condensed dihydropyridones
6 were reduced with sodium borohydride or lithium alu-
minum hydride to condensed hydroxytetrahydropyridines
8 (R3 = H, Table 4, Methods F, G). The cis-configuration
of condensed hydroxytetrahydropyridines was proved
with 8b and 8l by NOE effects showing the proximity of
the substituent R3 at position 4 and the H atom at the ad-
jacent position 3. On the other hand, Grignard reactions
and reductions of condensed dihydropyridones 6 [R1/
R2 = (CH2)3] derived from proline gave the opposite dias-
tereomers 7, as found before with similar systems.3,22,24,31
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

2916
H. Faltz et al.
PAPER
Table 3 Condensed 4-Alkyl-4-hydroxy-1,2,3,4-tetrahydropyridines 7 and 8 (R3 ≠ H) by Grignard Reaction
R3
N
Product
R2
R1
R3MgX
EtMgBr
dr
Yield (%)a
HO
R1
R2
6π
7a
-(CH2)3-
>95:5
74
R3
R1
HO
N
R2
N
Boc
8a
8b
8c
SO2Ph
i-Pr
Me
Me
>95:5
76:24
82:18
53b
58
H
H
BnMgCl
63
MgBr
8d
8e
H
H
H
H
H
H
i-Pr
s-Bu
Me
>95:5
>95:5
62:38
89:11
93:7
67
81
8f/7f
8g
48c
72
MgBr
i-Pr
Me
8h
8i
18d
24e
MgBr
i-Pr
>95: 5
HO R3
7b
7c
-(CH2)3-
-(CH2)3-
EtMgBr
PhMgBr
95:5
95:5
97f
53f
R1
N
R2
S
8j
H
i-Pr
95:5
63
MgBr
a Isolated yield after chromatography.
b Additional indole-deprotected product was obtained in 22%.
c Plus 26% starting material, diastereomers could be separated by flash
chromatography.
d Plus 60% starting material.
e Plus 58% starting material.
f Racemic starting material was used.
dosuccinimide, which would lead to four- or five-mem- the CHI signal of the ring expanded product 10 resonanc-
bered cyclization products 9 (n = 0) or 10 (n = 0) es at 22–24 ppm. Products 9 and 10 were formed as single
respectively, only the starting materials were re-isolated. diastereomers. The configuration of 10 could be deter-
This confirms that four-membered ring formation or 5- mined by NOESY. The configuration at the iodomethyl-
endo-trig cyclization is disfavored in these cases. On the substituted carbon atom of 9 could not be elucidated.
other hand, the higher homologous (n = 2) 4-homoal-
In summary, a series of optically active condensed tet-
lyltetrahydro-b-carbolines 8f and 8g underwent entirely
rahydropyridines could be synthesized starting from a-
6-exo-trig cyclization upon treatment with N-iodosuccin-
amino esters and o-bromobenzyl bromides or heterocyclic
imide at low temperatures (0–20 °C) affording the smaller
analogues. Addition of Grignard reagents or reduction oc-
curred with high stereoselectivity giving access to con-
densed hydroxypyridines. Allyl- and homoallyl-
substituted condensed hydroxypyridines undergo iodocy-
clization to interesting new bridged condensed tetrahy-
dropyridines. All these products represent new alkaloid-
like structures.
ring systems 9e and 9f. No ring expansion to 10 occurred
under thermal treatment of these products 9e, 9f (THF,
NaI, reflux). Obviously, no steric driving force is found in
these larger six-membered rings 9, which would have ex-
panded to the seven-membered 10 (n = 2). Structures 9
and 10 can be easily differentiated by 13C NMR spectros-
copy where the CH2I signals of 9 appear at 6 ppm while
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active Condensed Tetrahydropyridines
2917
Table 4 Condensed 4-Hydroxytetrahydropyridines 7 and 8 (R3 = H) by Reduction
Product
OH
R1
R2
Reducing Agent
Yield (%)
dra
R1
R2
6π
N
7d
-(CH2)3-
LiAlH4/THF
NaBH4/EtOH
65
56
91:9
>95:5
HO
R1
R2
N
N
Boc
8k
8l
i-Pr
SO2Ph
allyl
LiAlH4/THF
22b
>95:5
Me
LiAlH4/THF
NaBH4/EtOH
66
57
87:13
91:9
8m
8n
i-Pr
allyl
allyl
LiAlH4/THF
93
>95:5
i-Bu
LiAlH4/THF
NaBH4/EtOH
61
47
92:8
94:6
7e
-(CH2)3-
LiAlH4/THF
82
>95:5c
OH
R1
N
R2
S
a Determined by NMR of the crude product.
HO
b Additional N-deprotected product was obtained in 48% yield.
i-Pr
N
SO2Ph
N
c Racemic starting material was used.
H
Table 5 NMR Data of Condensed 4-Alkyl-4-hydroxy-1,2,3,4-tetrahydropyridines 7 and 8 Prepared
Producta
1H NMR (CDCl3)
13C NMR (CDCl3)
d, J (Hz)
d, J (Hz)
7ab
1.16 (t, 3 H, J = 7.5, CH3CH2), 1.85 (s, 9 H, t-C4H9), 2.01–2.39 9.6 (CH3), 22.5 (CH2), 23.3 (CH2), 27.6 [C(CH3)3], 29.9
(m, 4 H, proline CH2), 2.56 (q, 2 H, J = 7.5, CH2CH3), 2.78– (CH2), 51.4 (CH2N), 55.6 (CH2N), 73.9 (CHN), 75.1 (Cq–
2.88 (m, 1 H, CHN), 3.32–3.51 (m, 2 H, proline CH2), 3.53 (d, OH), 87.2 [C(CH3)3], 112.1 (CHar), 114.0 (Car), 116.2
1 H, J = 14.2, CH2N), 4.28 (d, 1 H, J = 14.2, CH2N), 7.09–7.14 (CHar), 121.8 (CHar), 122.1 (CHar), 127.9 (Car), 128.7 (Car),
(m, 2 H, CHar), 7.44 (d, 1 H, J = 7.6, CHar), 7.92 (d, 1 H, J = 7.5, 138.6 (Car), 151.8 (CO2Bu-t)
CHar)
7bc
7cd
0.89 (t, 3 H, J = 7.6, CH3CH2), 1.77–2.03 (m, 8 H, proline CH2, 8.9 (CH3CH2), 22.8 (CH2), 23.1 (CH2), 29.1 (CH2), 52.4
CH2CH3), 2.29–2.35 (m, 1 H, CHN), 2.49–2.58 (m, 1 H, pro- (CH2N), 54.8 (CH2N), 71.7 (CHN), 74.5 (Cq–OH), 122.5
line CH2N); 3.14–3.26 (m, 1 H, proline CH2N), 3.37 (d, 1 H,
J = 14.4, CH2N), 4.11 (d, 1 H, J = 14.4, CH2N), 7.02 (d, 1 H,
J = 5.2, CHar), 7.08 (d, 1 H, J = 5.2, CHar)
(CHar), 125.8 (CHar), 135.3 (Car), 141.7 (Car)
1.13–1.25 (m, 1 H, proline CH2), 1.37–1.52 (m, 1 H, proline
22.2 (CH2), 24.3 (CH2), 52.2 (CH2N), 54.2 (CH2N), 72.4
CH2), 1.60–1.72 (m, 1 H, proline CH2), 1.76–1.89 (m, 1 H, pro- (CHN), 76.2 (Cq–OH), 123.7 (CHar), 125.3 (CHar), 126.8
line CH2), 2.26–2.35 (m, 1 H, CHN), 2.67–2.72 (m, 1 H, pro- (CHar), 127.2 (4 CHar), 135.7 (Car), 142.5 (Car), 142.6 (Car)
line CH2N), 3.11–3.18 (m, 1 H, proline CH2N), 3.49 (d, 1 H,
J = 14.4, CH2N), 4.27 (d, 1 H, J = 14.4, CH2N), 6.74 (d, 1 H,
J = 5.2, CHar), 7.06 (d, 1 H, J = 5.2, CHar), 7.16–7.28 (m, 3 H,
CHar), 7.39–7.46 (m, 2 H, CHar)
7de
–
24.4 (proline CH2), 28.1 (proline CH2), 28.6 [(CH3)3C],
52.2 (CH2N), 54.5 (CH2N), 68.4 (CHOH), 71.3 (CHN),
84.6 [C(CH3)3], 115.8 (CHar), 119.3 (Car), 120.3 (CHar),
123.2 (CHar), 124.2 (CHar), 128.1 (Car), 135.0 (Car), 136.6
(Car), 150.6 (CO2Bu-t)
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

2918
H. Faltz et al.
PAPER
Table 5 NMR Data of Condensed 4-Alkyl-4-hydroxy-1,2,3,4-tetrahydropyridines 7 and 8 Prepared (continued)
Producta
1H NMR (CDCl3)
13C NMR (CDCl3)
d, J (Hz)
d, J (Hz)
7ef
1.58–1.75 (m, 1 H, proline CH2), 1.77–1.98 (m, 1 H, proline
CH2), 2.09–2.23 (m, 2 H, proline CH2), 2.25–2.34 (m, 1 H, pro- (CHN), 68.2 (CHCq–OH), 72.6 (CHN), 123.6 (CHar),
22.1 (proline CH2), 28.4 (proline CH2), 51.6 (CH2N), 54.2
line CH2N), 2.48–2.59 (m, 1 H, CHN), 2.64 (br s, 1 H, OH),
3.12–3.19 (m, 1 H, proline CH2N), 3.32 (d, 1 H, J = 14.3,
CH2N), 3.99 (d, 1 H, J = 14.3, CH2N), 4.44 (d, 1 H, J = 7.8,
CHOH), 6.99 (d, 1 H, J = 5.1, CHar), 7.10 (d, 1 H, J = 5.1, CHar)
124.1 (CHar), 135.2 (Car), 139.3 (Car)
8ag
0.73 [d, 3 H, J = 6.9, (CH3)2CH], 0.95 (t, 3 H, J = 7.4,
CH3CH2), 1.01 [d, 3 H, J = 6.6, (CH3)2CH], 1.61 (s, 9 H, t-
C4H9), 1.76–1.87 [m, 1 H, CH(CH3)2], 1.92 (q, 2 H, J = 7.4,
8.6 (CH3CH2), 21.6 [(CH3)2CH], 23.2 [(CH3)2CH], 28.6
[C(CH3)3], 29.6 [(CH3)2CH], 35.2 (CH2CH3), 43.3 (CH2N),
63.4 (CHN), 75.6 (Cq–OH), 85.0 [C(CH3)3], 115.8 (CHar),
CH2CH3), 4.14 (d, 1 H, J = 6.5, CHN), 4.38 (d, 1 H, J = 18.1, 120.6 (Car), 121.5 (CHar), 123.3 (CHar), 124.5 (CHar), 127.2
CH2N), 4.88 (d, 1 H, J = 18.1, CH2N), 7.11–7.18 (m, 2 H,
(2 CHar), 127.9 (Car), 129.2 (Car), 129.4 (2 CHar), 132.9
CHar), 7.42–7.47 (m, 3 H, CHar), 7.77–8.02 (m, 4 H, CHar)
(CHar), 136.4 (Car), 140.9 (Car), 150.3 (CO2Bu-t)
8bh
1.17 (d, 3 H, J = 6.6, CH3), 1.55 (s, 9 H, t-C4H9), 2.45 (br s, 1 14.3 (CH3), 28.2 [C(CH3)3], 43.0 (CH2COH), 44.3 (CH2N),
H, OH), 2.79 (q, 1 H, J = 6.6, CHN), 3.09 (d, 1 H, J = 13.8, 54.4 (CHN), 72.7 (Cq–OH), 84.2 [C(CH3)3], 115.7 (CHar),
CH2N), 3.66–3.72 (m, 2 H, CH2COH), 3.94 (d, 1 H, J = 13.8, 118.7 (Car), 120.3 (CHar), 123.0 (CHar), 123.8 (CHar), 126.4
CH2N), 6.76–6.79 (m, 2 H, CHar), 7.00–7.03 (m, 2 H, CHar), (CHar), 127.9 (Car), 128.2 (2 CHar), 129.9 (2 CHar), 136.1
7.17–7.24 (m, 3 H, CHar), 7.78–7.83 (m, 1 H, CHar), 8.11–8.18 (Car), 136.9 (Car), 137.1 (Car), 150.0 (CO2Bu-t)
(m, 1 H, CHar)
8ci
8dj
1.16 (d, 3 H, J = 6.5, CH3), 1.57 (s, 9 H, t-C4H9), 2.53–2.62 (m, 14.0 (CH3), 28.2 [(CH3)3C], 40.9 (CH2COH), 45.3 (CH2N),
3 H, CH2COH, OH), 2.91 (q, 1 H, J = 6.5, CHN), 3.15 (br s, 1 55.1 (CHN), 71.2 (Cq–OH), 84.2 [C(CH3)3], 115.6 (CHar),
H, OH), 3.93 (s, 2 H, CH2N), 4.80 (d, 1 H, CH2=CH), 4.94 (d, 117.8 (CH2=CH), 119.0 (Car), 120.0 (CHar), 122.9 (CHar),
1H, CH2=CH), 5.20–5.36 (m, 1 H, CH=CH2), 7.16–7.20 (m, 2 123.7 (CHar), 127.4 (Car), 133.8 (CH=CH2), 136.0 (Car),
H, CHar), 7.69–7.72 (m, 1 H, CHar), 8.08–8.11 (m, 1 H, CHar) 136.8 (Car), 150.0 (CO2Bu-t)
0.99 (d, 3 H, J = 6.8, CH3), 1.04 (d, 3 H, J = 6.9, CH3), 1.59 (s, 15.7 (CH3), 21.8 (CH3), 24.2 [CH(CH3)2], 26.7 [(CH3)3C],
9 H, t-C4H9), 2.09 (s, 1 H, OH), 2.21–2.32 [m, 2 H, CH(CH3)2, 39.7 (CH2COH), 44.9 (CH2N), 62.0 (CHN), 72.1 (Cq–OH),
OH], 2.59 (d, 1 H, CHN), 2.69–2.80 (m, 1 H, CH2COH), 5.15– 82.6 [C(CH3)3], 114.0 (CHar), 116.3 (CH2=CH), 118.2
5.26 (m, 1 H, CH2COH), 3.89 (d, 1 H, J = 17.5, CH2N), 4.23 (d, (Car), 118.3 (CHar), 121.3 (CHar), 122.2 (CHar), 125.9 (Car),
1 H, J = 17.5, CH2N), 4.87 (d, 1 H, J = 10.1, CH2=CH), 4.95 (d, 132.6 (CH=CH2), 134.9 (Car), 136.7 (Car), 150.0 (CO2Bu-t)
1 H, J = 16.8, CH2=CH), 5.19–5.30 (m, 1 H, CH=CH2), 7.16–
7.19 (m, 2 H, CHar), 7.63–7.71 (m, 1 H, CHar), 8.10–8.18 (m, 1
H, CHar)
8ek
0.89 (t, 3 H, J = 7.2, CH3CH2), 1.04 (d, 3 H, J = 6.9, CH3), 1,59 13.1 (CH3CH2), 19.6 (CH3), 24.3 (CH2CH3), 28.6
(s, 9 H, t-C4H9), 1.74–1.98 (m, 2 H, CHCH2CH3), 2.16–2.25
(m, 1 H, CHC2H5), 2.62 (s, 1 H, NH), 2.96–2.80 (m, 1 H,
[(CH3)3C], 33.5 (CH), 41.8 (CH2COH), 46.8 (CH2N), 64.9
(CHN), 73.7 (Cq–OH), 84.6 [C(CH3)3], 116.0 (CHar), 118.3
CH2COH), 3.11–3.22 (m, 1 H, CH2COH), 3.65 (d, 1 H, CHN), (CH2=CH), 119.7 (Car), 120.3 (CHar), 123.2 (CHar), 124.2
3.87 (d, 1 H, J = 17.3, CH2N), 4.26 (d, 1 H, J = 17.3, CH2N),
4.79 (d, 1 H, J = 10.1, CH2=CH), 4.93 (d, 1 H, J = 16.8,
CH2=CH), 5.14–5.29 (m, 1 H, CH=CH2), 7.11–7.23 (m, 2 H,
CHar), 7.69 (m, 1 H, CHar), 8.11 (m, 1 H, CHar)
(CHar), 127.6 (Car), 134.5 (CH=CH2), 136.5 (2 Car), 150.5
(CO2Bu-t)
8fl
1.17 (d, 3 H, J = 6.7, CH3), 1.58 (s, 9 H, t-C4H9), 1.88–1.99 (m, 14.6 (CH3), 28.2 [(CH3)3C], 29.4 (CH2), 35.1 (CH2COH),
3 H, CH2, OH), 2.04–2.28 (m, 3 H, CH2COH, NH), 2.83 (q, 1 44.8 (CH2N), 59.2 (CHN), 73.5 (Cq–OH), 84.1 [C(CH3)3],
H, J = 6.7, CHN), 4.11 (d, 1 H, CH2N), 4.25 (d, 1 H, CH2N),
4.77–4.92 (m, 2 H, CH2=CH), 5.61–5.79 (m, 1 H, CH=CH2),
114.3 (CH2=CH), 115.1 (CHar), 120.7 (Car), 120.0 (CHar),
122.7 (CHar), 123.6 (CHar), 127.9 (Car), 135.2 (Car), 135.9
7.09–7.21 (m, 2 H, CHar), 7.68–7.76 (m, 1 H, CHar), 8.03–8.09 (Car), 138.9 (CH=CH2), 150.2 (CO2Bu-t)
(m, 1 H, CHar)
8gm
0.94 (d, 3 H, J = 6.8, CH3), 1.01 (d, 3 H, J = 6.9, CH3), 1.54 (s, 17.4 (CH3), 23.7 (CH3), 25.9 [CH(CH3)2], 28.4 [C(CH3)3],
9 H, t-C4H9), 1.61–1.78 [m, 1 H, CH(CH3)2], 2.01–2.20 (m, 2 29.4 (CH2), 35.3 (CH2COH), 46.6 (CH2N), 63.8 (CHN),
H, CH2), 2.38–2.56 (m, 3 H, CH2COH, NH), 3.42–3.60 (m, 1 73.7 (Cq–OH), 84.1 [C(CH3)3], 114.4 (CH2=CH), 115.5
H, CHN), 3.86 (d, 1 H, J = 17.5, CH2N), 4.20 (d, 1 H, J = 17.5, (CHar), 119.6 (Car), 119.7 (CHar), 122.9 (CHar), 123.7
CH2N), 4.77–4.82 (m, 2 H, CH2=CH), 5.50–5.68 (m, 1 H,
(CHar), 127.3 (Car), 136.0 (2 Car), 138.1 (CH=CH2), 150.0
CH=CH2), 7.11–7.15 (m, 2 H, CHar), 7.59–7.68 (m, 1 H, CHar), (CO2Bu-t)
8.06 (d, 1 H, J = 7.6, CHar)
8hn
0.99 (d, 3 H, J = 6.6, CH3), 1.48 (s, 9 H, t-C4H9), 2.28 (s, 1 H, 14.0 (CH3), 28.2 [(CH3)3C], 45.8 (CH2N), 57.5 (CHN),
OH), 2.70 (q, 1 H, J = 6.6, CHN), 3.98 (d, 1 H, J = 17.3,
CH2N), 4.09 (d, 1 H, J = 17.3, CH2N), 5.24 (d, 1 H, J = 10.4,
71.8 (Cq–OH), 84.2 [C(CH3)3], 115.4 (CHar), 115.6
(CH2=CH), 119.0 (Car), 120.1 (CHar), 122.7 (CHar), 123.8
CH2=CH), 5.43 (d, 1 H, J = 13.8, CH2=CH), 5.69–5.82 (m, 1 H, (CHar), 127.4 (Car), 135.9 (Car), 136.4 (Car), 140.6
CH=CH2), 6.95–7.11 (m, 2 H, CHar), 7.50 (d, 1 H, CHar), 7.98 (CH=CH2), 150.3 (CO2Bu-t)
(d, 1 H, CHar)
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active Condensed Tetrahydropyridines
2919
Table 5 NMR Data of Condensed 4-Alkyl-4-hydroxy-1,2,3,4-tetrahydropyridines 7 and 8 Prepared (continued)
Producta
1H NMR (CDCl3)
13C NMR (CDCl3)
d, J (Hz)
d, J (Hz)
8io
0.98 [d, 6 H, J = 6.9, (CH3)2CH], 1.59 (s, 9 H, t-C4H9), 2.09–
2.18 [m, 1 H, CH(CH3)2], 2.45–2.53 (m, 1 H, CHN), 4.01 (d, 1 47.7 (CH2N), 67.4 (CHN), 74.7 (Cq–OH), 84.1 [C(CH3)3],
H, CH2N), 4.53 (d, 1 H, CH2N), 5.38 (d, 1 H, CH2=CH), 5.57 116.3 (CHar), 116.4 (CH2=CH), 120.6 (Car), 120.9 (CHar),
18.3 (CH3), 24.7 (CH3), 26.9 [CH(CH3)2], 29.2 [C(CH3)3],
(d, 1 H, CH2=CH), 5.84–5.97 (m, 1 H, CH=CH2), 7.02–7.19
(m, 2 H, CHar), 7.53–7.61 (m, 1 H, CHar), 8.07–8.12 (m, 1 H,
CHar)
123.4 (CHar), 124.7 (CHar), 128.1 (Car), 136.8 (2 Car), 142.1
(CH=CH2), 151.3 (CO2Bu-t)
8jp
8kq
8lr
0.95 [d, 3 H, J = 7.2, (CH3)2CH], 0.98 (d, 3 H, J = 7.2,
(CH3)2CH)], 2.18–2.44 [m, 2 H, (CH3)2CH, NH], 2.61–2.84
(m, 3 H, CH2COH, CHN), 3.80 (d, 1 H, J = 15.8, CH2N), 3.96 117.9 (CH2=CH), 123.1 (CHar), 124.9 (CHar), 133.8
(d, 1 H, J = 15.8, CH2N), 4.89 (d, 1 H, J = 10.1, CH2=CH), 4.99 (CH=CH2), 138.0 (Car), 140.4 (Car)
(d, 1 H, J = 17.1, CH2=CH), 5.27–5.37 (m, 1 H, CH=CH2), 6.98
17.1 (CH3), 23.2 (CH3), 25.9 [CH(CH3)2], 42.1
(CH2CqOH), 46.0 (CH2N), 63.5 (CHN), 72.4 (Cq–OH),
(d, 1 H, J = 5.2, CHar), 7.05 (d, 1 H, J = 5.2, CHar)
0.81 (d, 3 H, J = 6.3, CH3), 1.08 (d, 3 H, J = 6.6, CH3), 1.59 (s, 21.6 (CH3), 21.8 (CH3), 27.2 [CH(CH3)2], 28.6 [(CH3)3C],
9 H, t-C4H9), 2.15–2.28 [m, 1 H, CH(CH3)2], 2.39 (d, 1 H,
J = 8.6, OH), 3.73–3.82 (m 1 H, CHN), 4.61 (d, 1 H, J = 17.1, 115.8 (CHar), 117.7 (CHar), 120.6 (CHar), 123.4 (CHar),
CH2N), 4.82 (d, 1 H, J = 17.1, CH2N), 4.95–5.04 (m, 1 H, 124.7 (CHar), 127.3 (2 CHar), 128.4 (CHar), 129.5 (2 CHar),
CHOH), 7.08–7.22 (m, 2 H, CHar), 7.35–7.50 (m, 3 H, CHar), 133.1 (CHar), 136.2 (Car), 141.3 (2 Car), 150.2 (CO2Bu-t)
7.68–8.01 (m, 4 H CHar)
45.2 (CH2N), 65.2 (CHOH), 66.8 (CHN), 85.1 [C(CH3)3],
1.26 (d, 1 H, J = 6.6, CH3), 1.56 (s, 9 H, t-C4H9), 2.09 (br s, 1 13.9 (CH3), 28.2 [(CH3)3C], 51.1 (CH2N), 56.0 (CH2N),
H, OH), 2.78–2.84 (m, 1 H, CHN), 3.1 (dd, 1 H, J = 13.7, 7.2, 57.7 (CHN), 66.4 (CHOH), 83.9 [C(CH3)3], 115.6 (CHar),
CH2N), 3.43 (dd, 1 H, J = 13.7, 5.9, CH2N), 3.53 (d, 1 H,
J = 17.4, CH2N), 3.98 (d, 1 H, J = 17.4, CH2N), 4.58 (d, 1 H,
117.8 (Car), 118.1 (CH2=CH), 118.5 (CHar), 122.9 (CHar),
123.9 (CHar), 128.2 (Car), 134.8 (Car), 134.9 (CH=CH2),
J = 2.2, CHOH), 5.12–5.22 (m, 2 H, CH2=CH), 5.79–5.93 (m, 136.1 (Car), 150.1 (CO2Bu-t)
1 H, CH=CH2), 7.15–7.24 (m, 2 H, CHar), 7.57–7.62 (m, 1 H,
CHar), 8.07–8.10 (m, 1 H, CHar)
8ms
1.05 (d, 1 H, J = 6.6, CH3), 1.08 (d, 1 H, J = 6.5, CH3), 1.57 (s, 20.6 (CH3), 21.0 (CH3), 26.1 [CH(CH3)2], 28.6 [(CH3)3C],
9 H, t-C4H9), 2.13–2.28 [m, 1 H, CH(CH3)2], 2.32–2.40 (m, 1 50.6 (CH2N), 51.1 (CH2N), 62.9 (CHN), 68.4 (CHOH),
H, CHN), 2.99–3.10 (m, 1 H, CH2N), 3.41–3.49 (m, 1 H,
CH2N), 3.48 (d, 1 H, J = 18.1, CH2N), 4.36 (d, 1 H, J = 18.1,
CH2N), 4.90 (d, 1 H, J = 2.4, CHOH), 5.03–5.13 (m, 2 H,
CH2=CH), 5.69–5.81 (m, 1 H, CH=CH2), 7.16–7.25 (m, 2 H,
CHar), 7.53–7.60 (m, 1 H, CHar), 8.09–8.18 (m, 1 H, CHar)
84.4 [C(CH3)3], 116.0 (CHar), 116.6 (CH2=CH), 118.1
(Car), 118.4 (CHar), 123.4 (CHar), 124.4 (CHar), 128.7 (Car),
136.1 (Car), 136.7 (Car), 138.1 (CH=CH2), 150.7 (CO2Bu-t)
8nt
0.86 (d, 3 H, J = 6.6, CH3), 0.94 (d, 3 H, J = 6.5, CH3), 1.40–
1.51 (m, 1 H, CH2CHN), 1.56 (s, 9 H, t-C4H9), 1.59–1.68 (m, 1 36.7 (CH2CHN), 51.0 (CH2N), 54.4 (CH2N), 59.6 (CHN),
H, CH2CHN), 1.80–1.94 [m, 1 H, CH(CH3)2], 2.18 (br s, 1 H, 63.4 (CHOH), 83.9 [C(CH3)3], 115.5 (CHar), 117.5
22.3 (CH3), 23.8 (CH3), 24.9 [CH(CH3)2], 28.2 [(CH3)3C],
OH), 2.70–2.79 (m, 1 H, CHN), 3.19–3.32 (m, 2 H, CH2N),
3.46 (d, 1 H, J = 17.1, CH2N), 4.08 (d, 1 H, J = 17.1, CH2N),
4.69 (d, 1 H, J = 2.3, CHOH), 5.02–5.19 (m, 2 H, CH2=CH),
5.70–5.86 (CH=CH2), 7.11–7.21 (m, 2 H, CHar), 7.52–7.60 (m,
1 H, CHar), 8.05–8.12 (m, 1 H, CHar)
(CH2=CH), 117.9 (Car), 118.4 (CHar), 123.0 (CHar), 123.9
(CHar), 128.3 (Car), 135.0 (Car), 135.9 (CH=CH2), 136.1
(Car), 150.2 (CO2Bu-t)
a Satisfactory microanalyses obtained for 8b–j,l–n and 7d,e: C 0. 0.42; H 0.22; N 0.49; S 0.31. Exceptions: 7d: C –0.6; 8b: C –0.73;
8c: N –0.83; 8g: C –0.75; 8h: N –0.97; 8m: H –0.81.
b Recorded in CD3OD; Rf 0.48 (CHCl3–MeOH, 9:1).
c Rf 0.45 (CHCl3–MeOH, 9:1).
d Rf 0.49 (CHCl3–MeOH, 9:1).
e Rf 0.17 (CHCl3–MeOH, 9:1).
f Rf 0.34 (CHCl3–MeOH, 9:1).
g Rf 0.59 (CH2Cl2–acetone, 95:5); [a]D20 +29.6 (c = 1, CH2Cl2).
h Rf 0.21 (CHCl3–MeOH, 9:1); [a]D20 +76.2 (c = 1.25, CH2Cl2).
i Rf 0.23 (CHCl3–MeOH, 9:1); [a]D20 +85.5 (c = 1, CH2Cl2).
j Rf 0.54 (CHCl3–MeOH, 9:1).
k Rf 0.53 (CHCl3–MeOH, 9:1).
l Rf 0.26 (CHCl3–MeOH, 9:1), [a]D20 +50.0 (c = 1.1, CH2Cl2).
m Rf 0.13 (CHCl3–MeOH, 9:1).
n Rf 0.21 (CHCl3–MeOH, 9:1), [a]D20 +29.7 (c = 1.65, CH2Cl2).
o Rf 0.50 (CHCl3–MeOH, 9:1).
p Rf 0.23 (CHCl3–MeOH, 9:1).
q Rf 0.25 (hexane–EtOAc, 7:3).
r Rf 0.25 (CHCl3–MeOH, 97:3); [a]D20 +39.9 (c = 1.2, CH2Cl2).
s Rf 0.44 (hexane–EtOAc, 7:3); [a]D20 +33.9 (c = 1.3, CH2Cl2).
t Rf 0.46 (hexane–EtOAc, 7:3).
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

2920
H. Faltz et al.
PAPER
Table 6 Iodocyclization Products 9 and 10a
n
1
R1
9
10
1H NMR (CDCl3)
13C NMR (CDCl3)
d, J (Hz)
6π
Yield (%) Yield (%) d, J (Hz)
Method
Method
i-Pr
9a
27
H
–
0.93 (d, 3 H, J = 6.6, CH3), 1.05 (d, 3 5.7 (CH2I), 19.8 (CH3), 22.3 (CH3),
H, J = 6.5, CH3), 1.62–1.68 [m, 1 H, 25.9 [CH(CH3)2], 42.8 (CH2COH),
CH(CH3)2], 1.93 (dd, 1 H,
J = 12.2, 6.1, CH2COH), 2.32 (dd, 1 (CHN), 79.8 (Cq–OH), 122.7
H, J = 12.2, 10.2, CH2COH), 2.75 (d, (CHar), 124.5 (CHar), 129.4 (Car),
51.0 (CH2N), 61.7 (CHCH2I), 75.1
S
1 H, J = 10.5, CHN), 3.04 (dd, 1 H,
J = 9.4, 9.2, CH2I), 3.18 (dd, 1 H,
J = 9.4, 6.6, CH2I), 3.79–3.88 (m, 1
H, CHCH2I), 3.93 (d, 1 H, J = 18.2,
CH2N), 4.03 (d, 1 H, J = 18.2,
145.2 (Car)
CH2N), 6.95 (d, 1 H, J = 5.0, CHar),
7.10 (d, 1 H, J = 5.0, CHar)
1
–
10ab
56
H
98
I
0.89 (d, 3 H, J = 6.7, CH3), 1.00 (d, 3 21.7 (CH3), 22.1 (CH3), 23.3
H, J = 6.6, CH3), 1.53–1.67 [m, 1 H, (CHI), 27.5 [CH(CH3)2], 47.6
CH(CH3)2], 1.95 (s, 1 H, OH), 2.21
(dd, 1 H, J = 12.2, CH2COH), 2.35
(dd, 1 H, J = 12.2, CH2COH), 2.49
(CH2COH), 53.2 (CH2N), 66.6
(CH2CHI), 70.6 (CHN), 76.6 (Cq–
OH), 123.8 (CHar), 124.0 (CHar),
(d, 1 H, J = 9.3, CHN), 3.16 (dd, 1 H, 135.6 (Car), 139.5 (Car)
J = 12.7, CH2CHI), 3.36 (dd, 1 H,
J = 12.7, CH2CHI), 3.62 (d, 1 H,
J = 18.2, CH2N), 3.74 (m, 1 H, CHI),
4.14 (d, 1 H, J = 18.1, CH2N), 6.95
(d, 1 H, J = 5.1, CHar), 7.11 (d, 1 H,
J = 5.1, CHar)
1
Me
–
10b
66
H
1.06 (d, 3 H, J = 6.8, CH3), 1.62 (s, 9 12.5 (CH3), 22.6 (CHI), 28.3
H, t-C4H9), 2.1 (s, 1 H, OH), 2.22 (dd, [(CH3)3Cq], 47.6 (CH2COH), 49.5
1 H, J = 12.0, CH2COH), 2.74 (dd, 1 (CH2N), 60.5 (CHN), 65.6
H, J = 12.0, CH2COH), 3.03 (q, 1 H, (CH2CHI), 72.9 (Cq–OH), 84.6
N
Boc
J = 6.8, CHN), 3.19–3.40 (m, 2 H,
[C(CH3)3], 115.6 (CHar), 116.9
CH2CHI), 3.81–3.99 (m, 2 H, CH2N, (Car), 120.1 (CHar), 123.0 (CHar),
CHI), 4.34 (d, 1 H, J = 18.4, CH2N), 124.0 (CHar), 127.1 (Car), 134.8
7.12–7.26 (m, 2 H, CHar), 7.76 (d, 1 (Car), 136.0 (Car), 150.2 (CO2Bu-t)
H, CHar), 8.07 (d, 1 H, CHar)
1
i-Pr
–
10cc
62
H
0.93 (d, 3 H, J = 6.7, CH3), 1.03 (d, 3 22.4 (CH3), 22.7 (CH3), 23.8
H, J = 6.5, CH3), 1.62 (s, 9 H, t-
C4H9), 1.68–1.80 [m, 1 H,
(CHI), 27.7 [CH(CH3)2], 28.7
[(CH3)3C], 48.5 (CH2COH), 52.0
(CH2N), 66.8 (CH2CHI), 71.4
(CHN), 75.5 (Cq–OH), 84.8
CH(CH3)2], 1.98 (s, 1 H, OH), 2.22
(dd, 1 H, J = 12.1, CH2COH), 2.49
(d, 1 H, J = 9.4, CHN), 2.71 (dd, 1 H, [C(CH3)3], 115.9 (CHar), 118.1
J = 12.1, CH2COH), 3.18 (dd, 1 H,
CH2CHI), 3.39 (dd, 1 H, CH2CHI),
(Car), 120.8 (CHar), 123.3 (CHar),
124.2 (CHar), 127.5 (Car), 135.8
3.73–3.91 (m, 2 H, CH2N, CHI), 4.27 (Car), 136.3 (Car), 150.9 (CO2Bu-t)
(d, 1 H, J = 18.6, CH2N), 7.09–7.22
(m, 2 H, CHar), 7.83 (d, 1 H, CHar),
8.05 (d, 1 H, CHar)
1
s-Bu
–
10d
48
H
0.71 (t, 3 H, J = 7.2, CH3CH2), 0.99 10.9 (CH3CH2), 18.3 (CH3), 23.8
(d, 3 H, J = 6.6, CH3), 1.16–1.28 (m, (CHI), 27.5 (CH2CH3), 28.7
2 H, CH2CH3), 1.50–1.61 (m, 1 H,
[(CH3)3C], 33.4 (CH3CHC2H5),
CH3CHC2H5), 1.62 (s, 9 H, t-C4H9), 48.6 (CH2COH), 52.2 (CH2N),
1.98 (s, 1 H, OH), 2.25 (dd, 1 H,
J = 12.0, CH2COH), 2.64 (d, 1 H,
J = 9.1, CHN), 2.81 (dd, 1 H,
J = 12.0, CH2COH), 3.12 (dd, 1 H,
CH2CHI), 3.40 (dd, 1 H, CH2CHI),
66.8 (CH2CHI), 69.1 (CHN), 75.5
(Cq–OH), 84.8 [C(CH3)3], 115.9
(CHar), 118.2 (Car), 120.8 (CHar),
123.3 (CHar), 124.2 (CHar), 127.5
(Car), 135.9 (Car), 136.4 (Car), 150.7
3.81–3.92 (m, 2 H, CH2N, CHI), 4.26 (CO2Bu-t)
(d, 1 H, J = 18.8, CH2N), 7.11–7.25
(m, 2 H, CHar), 7.82 (d, 1 H, CHar),
8.08 (d, 1 H, CHar)
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active Condensed Tetrahydropyridines
2921
Table 6 Iodocyclization Products 9 and 10a (continued)
n
R1
9
10
1H NMR (CDCl3)
13C NMR (CDCl3)
d, J (Hz)
6π
Yield (%) Yield (%) d, J (Hz)
Method
Method
2
Me
9e
85
H
–
1.33 (d, 3 H, J = 7.0, CH3), 1.61 (s, 9 8.1 (CH2I), 11.2 (CH3), 27.5 (CH2),
H, t-C4H9), 1.72–2.02 (m, 4 H, 2
CH2), 2.97 (q, 1 H, J = 7.0, CHN),
28.3 [C(CH3)3], 30.0 (CH2COH),
45.8 (CH2N), 53.8 (CHCH2I), 61.1
3.11–3.23 (m, 2 H, CH2I), 3.83–4.09 (CHN), 69.9 (Cq–OH), 84.2
(m, 2 H, CH2N, CHCH2I), 4.18 (d, 1 [C(CH3)3], 115.5 (CHar), 120.0
H, J = 18.4, CH2N), 7.06–7.20 (m, 2 (CHar), 122.0 (Car), 122.8 (CHar),
H, CHar), 7.67–7.73 (m, 1 H, CHar),
8.08 (d, 1 H, CHar)
123.7 (CHar), 126.5 (Car), 135.7
(Car), 136.0 (Car), 150.8 (CO2Bu-t)
2
i-Pr
9fd
66
H
–
1.00–1.05 (m, 6 H, 2 CH3), 1.14–1.22 9.0 (CH2I), 22.0 (CH3), 22.3 (CH3),
[m, 1 H, CH(CH3)2] 1.62 (s, 9 H, t-
C4H9), 1.72–2.05 (m, 4 H, 2 CH2),
2.36 (q, 1 H, J = 9.5, CHN), 2.88–
27.5 (CH2), 27.6 [CH(CH3)2], 28.3
[C(CH3)3], 37.7 (CH2COH), 40.1
(CH2N), 64.4 (CHCH2I), 72.9 (Cq–
2.99 (m, 1 H, CHCH2I), 3.10 (dd, 1 H, OH), 73.3 (CHN) 84.1 [C(CH3)3],
CH2I), 3.22 (dd, 1 H, CH2I), 3.68 (d, 115.4 (CHar), 118.4 (Car), 120.4
1 H, J = 18.6, CH2N), 3.96 (d, 1 H,
(CHar), 122.7 (CHar), 123.4 (CHar),
J = 18.6, CH2N), 7.09–7.20 (m, 2 H, 127.4 (Car), 135.1 (Car), 135.9 (Car),
CHar), 7.81 (d, 1 H, CHar), 8.08 (d, 1 150.9 (CO2Bu-t)
H, CHar)
a Satisfactory microanalyses obtained for 9a,f and 10a–c: C 0.48; H 0.35; N 0.27; S 0.38. Exception: 9f: C + 0.6.
b [a]D20 –76.9 (c = 1, CH2Cl2).
c [a]D20 –39.3 (c = 1, CH2Cl2).
d [a]D20 +88.0 (c = 1, CH2Cl2).
NaHCO3. The mixture was stirred at r.t. for 8 h and the organic
Starting materials were purchased from Aldrich, Lancaster, Acros,
and Merck. TLC analysis was performed on Merck silica gel 60 F254
plates and visualized with UV illumination and charring with phos-
phomolybdic acid in EtOH (5%, v/v) or 0.3% ninhydrin in EtOH.
Column chromatography was conducted with Merck silica gel 60
(400–639 mesh). Melting points were determined on a Boetius hot-
stage apparatus and are uncorrected. 1H NMR and 13C NMR spectra
were recorded at 300 and 75.5 MHz, respectively, on a Bruker AC-
300 in CDCl3 with TMS as internal standard. Mass spectra were
measured at 70 eV. Optical rotations were determined with a Perk-
inElmer polarimeter 241 (d = 2 mm). Enantiomeric purity was
proved by analytical HPLC on cellulose carbamate (CHIRALCEL
OD).
phase was separated. The aqueous phase was extracted with CH2Cl2
(3 × 30 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column chroma-
tography.
Condensed Tetrahydropyridones 6; General Procedure
Method D: A solution of the N-alkylated amino ester 4 or 5 (2.5
mmol) in anhyd THF (120 mL) under argon was cooled to –100 °C.
A 1.7 M solution of t-BuLi in pentane (5 mmol) or 1.6 M solution
of n-BuLi in hexanes (3 mmol) was added dropwise while the tem-
perature was maintained below –98 °C. After the addition, the solu-
tion was stirred at –100 °C for 3 to 6 h and then quenched with sat.
aq NH4Cl at this temperature. The mixture was stirred at r.t. until the
appearing precipitate dissolved. The organic layer was separated
and the aqueous phase was extracted with CH2Cl2 (5 ×). The com-
bined organic layers were dried (Na2SO4), the solvent removed in
vacuo and the residue purified by column chromatography.
N-(2-Bromobenzyl)amino Esters and Heterocyclic Analogues 4;
General Procedure
Method A: A mixture of o-bromobenzyl bromide or the correspond-
ing heterocyclic analogue 1 (0.02 mol), K2CO3 (2.76 g, 0.02 mmol),
amino ester 2 (0.026 mol) and MeCN (250 mL) was refluxed for 5
h. After cooling down to r. t., the suspension was filtered and the so-
lution was concentrated in vacuo. The residue was purified by col-
umn chromatography.
Condensed 4-Alkyl-4-hydroxy-1,2,3,4-tetrahydropyridines and
Heterocyclic Analogues 7 and 8 (R ≠ H) by Grignard Reaction;
General Procedure
Method E: A solution of the condensed dihydropyridone 6 (0.80
mmol) in anhyd THF (15 mL) was kept under argon and cooled to
0 °C. The Grignard reagent R3MgBr (4.0 mmol or 5.6 mmol for
NH-containing 6) was added dropwise. After stirring for 8 to 12 h,
the mixture was poured onto ice and the organic phase separated.
The aqueous phase was extracted with CH2Cl2 (5 ×). The combined
organic layers were dried (Na2SO4) and the solvent removed in vac-
uo. The residue was purified by column chromatography.
N-(2-Bromobenzyl)amino Esters and Heterocyclic Analogues 5;
General Procedures
Method B: Analogous to Method A, but using N-substituted amino
ester 3.
Method C1: NaHCO3 (0.84 g, 0.01 mol) and allyl bromide (4.84 g,
0.04 mol) were added to a solution of the N-(o-bromobenzyl)amino
ester or the corresponding heterocyclic analogue 4 (0.01 mol) in
MeCN (150 mL). After reflux (4–8 h) the mixture was cooled to r.t.
and filtered. The solution was concentrated in vacuo and the residue
purified by column chromatography.
Condensed 4-Hydroxy-1,2,3,4-tetrahydropyridines and
Heterocyclic Analogues 7 and 8 (R = H) by Reduction;
General Procedures
Method C2: A solution of the bromoindolmethylamino ester 4 (5
mmol) in CH2Cl2 (30 mL) was added under vigorous stirring to a so-
lution of carbobenzyloxy chloride (0.89 g, 5.2 mmol) in sat. aq
Method F: NaBH4 (0.85 g, 2.25 mmol) was added to a solution of
the condensed dihydropyridone 6 (1.5 mmol) in EtOH (60 mL) at
0 °C. The mixture was allowed to warm slowly to r.t. and was then
Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York

2922
H. Faltz et al.
PAPER
stirred for 5 to 10 h (TLC). After the reaction had gone to comple-
tion, the mixture was quenched with sat. aq NH4Cl. The organic lay-
er was separated and the aqueous phase was extracted with CH2Cl2
(5 ×). The combined organic layers were washed with H2O and
dried (Na2SO4). After evaporation of the solvent in vacuo, the re-
maining material was purified by column chromatography giving a
solid.
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Method G: A solution of the condensed dihydropyridone 6 (1.5
mmol) in anhyd THF (20 mL) was added to a solution of LiAlH4
(0.068 g, 1.8 mmol) in anhyd THF (40 mL) under argon at 0 °C. The
mixture was allowed to warm slowly to r.t. and was stirred for 12 to
18 h (TLC). After the reaction had gone to completion, the mixture
was quenched with ice. The organic layer was separated and the
aqueous phase was extracted with CH2Cl2 (5 ×). The combined or-
ganic layers were washed with water and dried (Na2SO4). After
evaporation of the solvent in vacuo the remaining material was pu-
rified by column chromatography giving a solid.
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Iodocyclization Products 9 and 10; General Procedure
Method H: A solution of the hydroxytetrahydropyridine 8 (1.3
mmol) in anhyd THF (5 mL) was added dropwise into a solution of
N-iodosuccinimide (0.382 g, 1.7 mol) in anhyd THF (15 mL) under
argon at 0 °C. The mixture was allowed slowly to warm up to r.t.
and was stirred for 12 to 20 hours (TLC). The solvent was removed
in vacuo and the remaining yellowish solid was purified by column
chromatography.
Method I: A solution of the iodocyclization product 9a (0.150 g,
0.413 mmol) in THF (10 mL) was stirred at 60 °C for 3 h. After
evaporation of the solvent, the pure product was obtained in quanti-
tative yield.
X-ray Crystal Data for the Dihydro-b-carboline 6j35
Empirical formula: C23H24N2O5S, formula weight: 440.50, temper-
ature: 200 (2) K, wavelength: 0.71073 A, crystal system: monoclin-
ic, space group: P 21, unit cell dimension: a = 10.704 (2) Å, a = 90°,
b = 6.8991 (6) Å, b = 100.40 (2)°, c = 14.796 (2) Å, g = 90 deg, vol-
ume: 1074.7 (2) Å3, Z = 2, rcalcd = 1.361 Mg/m3, absorption coeffi-
cient: 0.189 mm–1, F (000): 464, crystal size: 0.45 × 0.42 × 0.30
mm, max. and min. transmission: 0.9456 and 0.9200, q-range for
data collection: 2.17 to 24.17 deg, index ranges: –12 £ h £ 12–7 £ k
£ 7–16 £ 1 £ 16; reflections collected: 7595, independent reflec-
tions: 3351 [R(int) = 0.0795], refinement method: full-matrix least-
squares on F2, Data/restraints/parameters: 3351/1/376, goodness-
of-fit on F2: 0.998, final R indices [I > 2s (I)]: R1 = 0.0303
wR2 = 0.0750, R indices (all data): R1 = 0.0332 wR2 = 0.0762, ab-
solute structure parameter: –0.05 (6), largest diff.-map peak and
hole: 0.157 and –0.160 e·A–3.
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D. T. J. Org. Chem. 1970, 35, 1100.
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101, 907.
(29) Faltz, H.; Radspieler, A.; Liebscher, J. Synlett 1997, 1071.
(30) Swaleh, S.; Liebscher, J. Tetrahedron Lett. 1999, 40, 2099.
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(32) Faltz, H.; Liebscher, J. Synlett 1998, 1355.
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Hübscher, U.; Ramadan, K.; Liebscher, J. Eur. J. Org.
Chem. 2004, 3484.
Acknowledgment
We gratefully acknowledge financial support by the Deutsche For-
schungsgemeinschaft and the Fonds der Chemischen Industrie. We
thank Dr. Burkhard Ziemer for X-ray crystal analysis.
(34) Blough, B. E.; Mascarella, S. W.; Rothman, R. B.; Carroll,
F. I. J. Chem. Soc., Chem. Commun. 1993, 759.
(35) Full details have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC 606388. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK.
References
(1) The Alkaloids: Chemistry and Physiology, Vol. 1–15;
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Synthesis 2006, No. 17, 2907–2922 © Thieme Stuttgart · New York