Synthesis of tetrahydro-β-carbolines and studies of the Pictet-Spengler reaction

Article abstract of DOI:10.1016/S0040-4020(00)00165-4

Tetrahydro-β-carbolines have been prepared in a diastereomerically pure form by a short, efficient synthetic sequence consisting of reaction of α- aminoaldehydes with tryptamine. A study was made of the major factors affecting the stereoselectivity of the

Full text of DOI:10.1016/S0040-4020(00)00165-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2683±2692
Synthesis of Tetrahydro-b-carbolines and Studies of the
Pictet±Spengler Reaction
*
Pierre Ducrot, Cherif Rabhi and Claude Thal
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 11 October 1999; accepted 22 February 2000
AbstractÐTetrahydro-b-carbolines have been prepared in a diastereomerically pure form by a short, ef®cient synthetic sequence consisting
of reaction of a-aminoaldehydes with tryptamine. A study was made of the major factors affecting the stereoselectivity of the Pictet±
Spengler reaction. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
b-carbolines have never been obtained as unique
diastereoisomers.4 In previous work, we postulated a
hydrogen-bonded intermediate state to explain the cis
diastereoselectivity of the Pictet±Spengler reaction with
N-protected a-aminoaldehydes.3 In order to con®rm this
model and to access the trans series we varied the steric
bulk of the carbamate and furthermore used pyrrole as the
amine precursor and phthalimide as the amino-protecting
group. Indeed, these two groups are bulkier than the
carbamates and pyrrole cannot participate in hydrogen
bonding.
In the course of our study of Tyrosine Hydroxylase (TH)
gene inductors, we established the importance of the cis/
trans relative stereochemistry of E-azaeburnane compounds
of type 1±2 for biological activity.1 We then reported a new
diastereoselective synthesis of the racemic cis 1-amino-
indolo[2,3-a]quinolizidine 5b,2 followed by an improved
diastereoselective and enantioselective synthesis of (1)-
(1S, 12bR) amine 5b,3 key precursors in the synthesis of
the E-azaeburnanes 1±3 (Scheme 1).
We therefore report in the present paper a stereoselective
route to tetrahydro-b-carbolines 6 and 7, primary precursors
of the 1-aminoindolo[2,3-a]quinolizidines 4 and 5, together
with our studies of the diastereoselectivity of the Pictet±
Spengler reaction between tryptamine and variously
protected a-aminoaldehydes derived from l-glutamic acid.
As structure/activity relationship studies pointed out the
biological interest of the trans series, it became important
to either reverse the diastereoselectivity of the Pictet±
Spengler reaction, or alternatively to seek a new route.
Furthermore, pentacyclic compounds such as 3a and 3b
are interesting in their own right as well as being key pre-
cursors for some new series. In spite of many attempts to
reverse the diastereoselectivity of the reaction by modifying
both reaction conditions and protecting groups, trans
l-Glutamic acid was selectively protected as the oxazoli-
dinone 9, as described previously,5 allowing selective
Scheme 1.
Keywords: Pictet±Spengler reaction; a-aminoaldehydes; tryptamine.
* Corresponding author. Tel.: 133-1-69-82-31-08; fax: 133-1-69-07-72-47; e-mail: claude.thal@icsn.cnrs-gif.fr
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00165-4

2684
P. Ducrot et al. / Tetrahedron 56 (2000) 2683±2692
Scheme 2.
esteri®cation at the g position. Whereas iso-butene in acidic
media led to the desired tert-butyl ester 10a with reasonable
yields, attempts to improve this reaction by the addition of
tert-butanol to the activated carboxylic acid function
unfortunately led to the rearranged iso-butyl ester 10b.6,7
The oxazolidinones were hydrolysed using sodium
hydroxide in ethanol to give 11a,b in good yields. Both
tert-butyl and iso-butyl esters were then used in the follow-
ing steps to prepare hydroxamates 12a±c, known to be good
precursors of a-aminoaldehydes8 (Scheme 2).
the corresponding aldehydes 14a±f (Table 2), with good to
excellent yields.
Since the phtalimide group is incompatible with hydride
reduction, the N-phthaloyl derivative was prepared using a
different approach in four steps starting from the com-
mercially available N-phthaloyl-l-glutamic anhydride 15.
The latter was regioselectively opened with diethylamine9
(Scheme 3) and the free acid was transformed into the
mixed anhydride 17 which was then reduced quickly and
selectively in situ with sodium borohydride.10 The resulting
alcohol 18 was readily oxidized with PCC to form the
desired aldehyde 14g in 60% overall yield from acid 16.
Hydroxamates 12a±c were obtained in good yields by
addition of N-methoxy-N-methyl amine to the activated
carboxylic function. In order to allow introduction of
different protecting groups on the amine, the benzyl car-
bamates of 12a,b were then removed by hydrogenolysis in
good yields. Protecting groups were attached to the
amines 13a,b thus obtained to form the corresponding
hydroxamates 12d±f (Table 1).
Aldehydes 14a±g were then condensed with tryptamine
under a variety of conditions in an attempt to form
selectively cis and trans b-carbolines (Scheme 4, Table
3). Diastereomeric excesses of b-carbolines were measured
1
using H NMR and/or HPLC. Further cyclisation using
NaOMe in methanol led to the corresponding lactams 20
and 21 in good yields (68±90%), except for the N-Troc and
Reduction of hydroxamates 12a±f with lithiumaluminium
hydride, as previously described by Fehrentz et al.,8 led to
Table 2.
#
R1
R2
Cbz
Cbz
Boc
R3
14
Yield (%)
Table 1.
i
Ot-Bu
Oi-Bu
Ot-Bu
Ot-Bu
Oi-Bu
Ot-Bu
H
H
H
H
H
a
b
c
d
e
f
99
91
93
70
86
95
#
R1
R2
R3
Conditions
12 Yield (%)
ii
iii
iv
v
i
Ot-Bu CO2Me
Oi-Bu Troc
H
H
ClCO2Me/TEA
d
e
f
98
97
79
ii
iii Ot-Bu
ClCO2CH2CCl3 TEA
2,5-di-OMe-furan
AcOH/AcONa
CO2Me
Troc
Pyrrole
vi
Pyrrole

P. Ducrot et al. / Tetrahedron 56 (2000) 2683±2692
2685
Scheme 3.
N-phthaloyl derivative 7e and 6g, respectively, which did
not cyclise. Diastereomeric excesses of the lactams
con®rmed those of the corresponding b-carbolines.
In the N-Cbz series, low temperatures (below 2208C, entry
i, ii, viii, and ix) led exclusively to the cis tetrahydro-b-
carboline.11 A temperature increase produced the diastereo-
meric trans-product and tetracyclic compound 19 (entries
x±xiii). Formation of the latter was favoured by a short
reaction time at 408C (entry xii), whereas a higher tempera-
ture (entry xiii) led to degradation of starting materials. The
relative stereochemistry of compound 19 (assigned using 1H
NMR) thus shows that it is formed via the same intermediate
as the trans tetrahydro-b-carboline.
In the carbamate series (entries i±v), the cis b-carboline was
always the major diastereoisomer formed, the size of the
carbamate group providing little in¯uence on the course
of the reaction's diastereoselectivity. The best diastereo-
selectivity was observed with the benzyl carbamate, with
no in¯uence of the R1 ester group. Conversely, with either
pyrrole or phthalimide groups, the diastereoselectivity was
reversed (entries vi and vii).
Acidity had no effect on the diastereoselectivity of the
Scheme 4.
Table 3.
Entry
14
R2
R3
R1
Solvent
T (8C)
Time
TFA (equiv.)
617 (%)
6
7
19 (%)
i
ii
iii
iv
v
a
b
c
d
e
f
g
a
a
a
a
a
a
a
a
Cbz
Cbz
Boc
CO2Me
Troc
H
H
H
H
H
Ot-Bu
Oi-Bu
Ot-Bu
Ot-Bu
Oi-Bu
Ot-Bu
NEt2
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
CH2Cl2
CH2Cl2
240
240
240
240
240
250
rt
265
220
0
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 4h
2 h
1 h
35 min
15 min
7 min
1 h
2
2
2
2
2
2
2
2
2
2
2
2
2
5
15
81
77
71
73
74
62
68
68
69
66
61
54
51
61
51
0
0
10
9
14
100
93
0
100
100
90
91
86
0
0
0
0
0
0
0
0
0
0
5
9
30
5
8
,5
vi
pyrrole
phth
vii
viii
ix
x
xi
xii
xiii
xiv
xv
7
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
H
H
H
H
H
H
H
H
100
100
90
75
72
77
75
75
0
10
25
28
23
25
25
rt
40
60
rt
rt
1 h

2686
P. Ducrot et al. / Tetrahedron 56 (2000) 2683±2692
Scheme 5.
reaction (entry xi, xiv, and xv). Compound 19 results from
the attack of the nitrogen of the carbamate on the indol-
eninium intermediate, and provides a direct proof of the
formation of a spiro intermediate in the Pictet±Spengler
reaction.4
the reaction. Conversely, below 08C, the formation of the cis
b-carboline 7a was not observed.
These results are direct proof that a) formation of the tetra-
cyclic compound 19 is reversible and b) formation of the
spiroindoleninium intermediate is either irreversible or
considerably slower than the Wagner±Meerwein rearrange-
ment, otherwise we would have observed cis b-carboline.
On the other hand, it should be stated at this point that we
never observed the presence of a cis tetracyclic compound
22. This can be explained by the Felkin±Anh model since
under kinetic conditions, C3 attack only occurs on the less
hindered face of the iminium (model A). In this case the
geometry of the spiroindoleninium intermediate formed is
not favourable for nucleophilic attack by the carbamate's
nitrogen, and therefore a Wagner±Meerwein rearrangement
takes place, which leads to the cis b-carboline (Scheme 5).
Conversely, under thermodynamic conditions, C3 attack
leads to spiro intermediates in which the nucleophilic attack
is possible (model B).
Conclusion
We have achieved an improved and highly stereoselective
synthesis of protected 1-aminoindolo- [2,3-a]quinolizidin-
4-ones, key intermediates in the synthesis of 1-amino-
indolo[2,3-a]quinolizidines and E-azaeburnane compounds.
The use of bulky amino-protecting groups led to the trans
system, whereas smaller protecting groups led to the cis
series in accord with our previously published hypothesized
hydrogen-bonded intermediate.3
Under kinetic conditions the cis compound was formed
exclusively and, consequently under thermodynamic con-
ditions we were able to slightly reverse the diastereo-
selectivity and increase the proportion of the trans
compound generated. For these reactions, however, yields
were lower due to the formation of a new tetracyclic
compound, which is a direct proof of the spiroindoleninium
intermediate formation.
As previously mentioned, the longer the reaction time, the
lower was the yield of tetracyclic derivative 19. To
verify whether formation of the latter is reversible or not
and to investigate what stereochemistry the corresponding
rearranged b-carboline would have, we applied the Pictet±
Spengler reaction conditions to the isolated compound 19
(Table 4).
Experimental
We thus observed a total conversion to the trans b-carboline
6a at rt within two to four days, depending on the acidity of
Flash chromatography was performed using silica gel
(Merck, 230±400 Mesh). IR spectra were recorded on a
Nicolet 250 FT-IR instrument. UV spectra were recorded
on a Perkin±Elmer lambda 5 instrument. Optical rotations
were measured on a Perkin±Elmer 241 polarimeter. Mass
spectral measurements were obtained using an AEI MS50
Table 4.
Entry
TFA
T (8C)
Time
80 h
60 h
48 h
2 weeks
4 weeks
4 weeks
6a/7a
Yield
1
(EI), or Kratos MS-80 (CI, HRMS) spectrometer. H and
i
5
rt
rt
rt
0
220
240
100/0
100/0
100/0
Quantitative
Quantitative
Quantitative
Partial
13C NMR spectra were determined on Bruker AC-200, 250,
300 or 400 instruments. Chemical shifts are given as d
values with reference to Si(CH3)4 as internal standard, and
coupling constants are given in Hz. Elemental analyses were
performed at the ICSN, CNRS, Gif-sur-Yvette, France.
ii
iii
iv
v
10
15
5
10
15
No
No
vi

P. Ducrot et al. / Tetrahedron 56 (2000) 2683±2692
2687
4(S)-(2-Carboxyethyl)-5-oxo-oxazolidine 3-carboxylic
acid benzyl ester 9. See Ref. 5. aDˆ173 (248C, MeOH,
cˆ2.3). IR (CHCl3): nˆ3520 (OH); 3030; 1800 (CO); 1710
(CO); 1715 (CO); 1410. MS (EI) m/zˆ293 (M1); 275
(M2H2O); 249 (M2CO2); 204; 158; 140; 107; 91. HRMS
(C14H15NO6) calcd 293.0899, obs. 293.0898. 1H NMR
(CDCl3, 200 MHz): 8.90 (1H, bs, ex., CO2H); 7.70±7.20
(5H, m, Ph); 5.50±5.30 (4H, m, H2, CH2Ph); 4.30 (1H, t,
(100%, CH2Ph). Analysis (C17H23NO613.7% silica gel):
calcd C: 60.52; H: 6.87; O: 28.45; N: 4.15; obs. C: 59.28;
1
H: 6.79; O: 26.44; N: 3.82. H NMR (CDCl3, 200 MHz):
9.75 (1H, bs, CO2H); 7.35 (5H, s, Ph); 5.70 (1H, d, NH-Cbz,
JNH-4ˆ8 Hz); 5.10 (2H, s, CH2Ph); 4.40 (1H, m, H2); 2.40
(2H, t, H4, J2-3ˆ7 MHz); 2.30±1.90 (2H, m, H3); 1.45 (9H,
s, CH3 (t-Bu)). 13C NMR (CD3OD, 50.3 MHz): 175.5 (C1);
173.8 (C5); 154.0 (CONH); 138.3 (Cf); 129.4 (CHo); 129.0
(CHp); 128.8 (CHm); 81.8 (OC(CH3)3); 67.6 (CH2Ph); 54.5
(C2); 32.6 (C4); 28.3 (C(CH3)3); 28.0 (C3).
H4, J4-1 ˆ6 Hz); 2.60±2.10 (4H, m, H1 , H2 ). 13C NMR
(CD3OD, 50.3 MHz): 175.8 (CO2H); 173.8 (C5); 154.7
(CO Cbz); 137.1 (Cf ); 129.6 (CHo); 129.3 (CHp); 129.2
0
0
0
0
(CHm); 79.1 (C2); 68.8 (CH2Ph); 55.3 (C4); 30.0 (C2 );
0
27.0 (C1 ).
2(S)-Benzyloxycarbonylaminopentanedioic acid 5-iso-
butyl ester 11b. See Ref. 5. IR (CHCl3): nˆ3435; 3050±
2940; 1725 (CO). MS; (EI): m/zˆ337 (M1z; 292
(M2CO2H); 264; 230 (M2OBn); 107 (OBn, 100%); 91
4(S)-(2-tert-Butoxycarbonylethyl)-5-oxo-oxazolidine 3-
carboxylic acid benzyl ester 10a. See Ref. 5.
aD(ˆ127.9 (228C, EtOH, cˆ1.58). IR (CHCl3):
nˆ3030±2970; 1802 (CO); 1720 (CO); 1417. MS (CI1):
m/zˆ350 ([M1H]1); 294 (M2v,; 100%); 250 (M2t-
BuO2C); 107 (PhCH2O); 91 (PhCH2, 100%); 77. Analysis
(C18H23NO6): calcd C: 61.88; H: 6.64; O: 27.48; N: 4.01;
obs: C: 62.16; H: 6.83; O: 24.55; N: 3.51 1H NMR (CDCl3,
200 MHz): 7.40 (5H, s, Ph); 5.55 (1H, dl, H2); 5.20 (1H, d,
H2); 5.15 (2H, s, CH2Ph); 4.40 (1H, t, H4); 2.50±2.10 (4H,
1
(CH2Ph). H NMR (CDCl3, 200 MHz): 7.35 (5H, s, Ph);
5.80 (1H, d, NH-Cbz, JNH-4ˆ8 MHz); 5.10 (2H, s,
CH2Ph); 4.30 (1H, m, H2); 3.95 (2H, d, CH2 i-Bu,
Jˆ7.6 MHz); 2.50 (2H, m, H4); 2.20 (1H, m, CH i-Bu);
1.95 (2H, m, H3); 0.95 (6H, d, CH3 i-Bu). 13C NMR
(CD3OD, 50.3 MHz): 180.6 (C1); 173.6 (C5); 154.9
(CONH); 133.3 (Cf ); 128.7 (CHo); 128.2 (CHp); 127.7
(CHm); 70.1 (CH2Ph); 66.8 (OCH2 i-Bu); 53.6 (C2); 30.5
(C4); 27.8 (C3); 27.1 (CH i-Bu); 18.8 (CH3).
m, H2 , H1 ); 1.45 (9H, s, C(CH3)3). 13C NMR (CD3OD,
0
0
0
50.3 MHz): 171.9 (C3 ); 171.3 (C5); 158.0 (CO Cbz);
135.3 (Cf); 128.8 (CHo); 128.7 (CHp); 128.4 (CHm); 80.9
General procedure for hydroxamate formation
0
(OC(CH3)3); 77.8 (C2); 68.1 (CH2Ph); 54.2 (C4); 30.6 (C2 );
0
28.1 (C1 ); 26.0 (C(CH3)3).
To a stirred solution of 12.8 g (37.9 mmol) of acid 11 and
8.2 ml (74.6 mmol) of N-methylmorpholine in 160 ml
CH2Cl2 at 2158C were added dropwise 4.9 ml
(37.9 mmol) of iso-butyl chloroformate. After stirring for
30 min at the same temperature, 3.7 g (37.9 mmol) of
N.O-dimethylhydroxylamine hydrochloride were added.
After a further hour at 2158C, the reaction mixture was
allowed to warm to rt over 1 h. 150 ml of water was
added and the mixture was extracted with CH2Cl2. The
combined organic layers were then washed with brine,
dried over sodium sulfate, concentrated under reduced pres-
sure and puri®ed by chromatography (CH2Cl2 95/CH3OH 5)
to yield 11 g (78%) of a colorless oil.
4(S)-(2-Isobutoxycarbonylethyl)-5-oxo-oxazolidine 3-car-
boxylic acid benzyl ester 10b. To a stirred solution of 9
(2.6 g, 8.90 mmol) in 30 ml CH2Cl2 at 2158C were added
successively 1.50 ml (10.7 mmol) of triethylamine then
dropwise 1.20 ml (10.7 mmol) of iso-butyl chloroformate.
After stirring for 15 min, 1.25 ml (13.3 mmol) of tert-buta-
nol were added, and the temperature was allowed to increase
to rt over 2 h. The reaction mixture was extracted with a
saturated solution of sodium carbonate, washed with brine
and dried over sodium sulfate. The combined organic layers
were then concentrated under reduced pressure, and puri®ed
by chromatography (CH2Cl2 97/CH3OH 3) to yield 3.0 g
(96%) of a colorless oil. aDˆ1358 (228C, MeOH, cˆ1.4).
IR (CHCl3): nˆ3030±2970; 1800 (CO); 1780 (CO); 1410.
MS (EI): m/zˆ349 (M1); 305 (M2CO2); 293 (M2v,;
100%); 276 (M2i-BuO); 107 (PhCH2O); 91 (100%); 77.
HRMS (C18H23NO6): calcd 349.1525; obs. 349.1528.
Analysis: calcd C: 61.88; H: 6.64; O: 27.48; N: 4.01; obs.
4(S)-Benzyloxycarbonylamino-4-(methoxymethylcarba-
moyl) butyric acid tert-butyl ester 12a. aDˆ212.9 (248C,
MeOH, cˆ0.6). IR (CHCl3): nˆ3015 (NH); 1720 (CO);
1510; 1370. MS (CI1) m/zˆ381 ([M1H]1, 100%); 325
(3812.v); 217; 91. Analysis (C19H28N2O6): calcd C:
59.99; H: 7.42; O: 25.23; N: 7.36; obs. C: 60.24; H: 7.24;
O: 25.05; N: 7.31. 1H NMR (CDCl3, 200 MHz): 7.50±7.20
(5H, m, Ph); 5.90 (1H, d ex., NH-Cbz, JNH-4ˆ8 Hz); 5.10
(2H, s, CH2Ph); 4.80±4.70 (1H, m, H4); 3.80 (3H, s, OCH3);
3.20 (3H, s, NCH3); 2.20 (2H, t, H2, J2-3ˆ7 Hz); 2.10±1.70
(2H, m, H3); 1.30 (9H, s, CH3 (t-Bu)). 13C NMR (CD3OD,
50.3 MHz): 172.0 (C1); 168.3 (C5); 156.3 (CO Cbz); 136.5
(Cf ); 126.0 (CHo, CHm, CHp); 80.5 (OC(CH3)3); 66.8
(CH2Ph); 61.6 (OCH3); 50.6 (C4); 32.2 (NCH3); 31.3 (C2);
28.1 (CH3 t-Bu); 27.8 (C3).
1
C: 62.36; H: 6.66; O: 24.86; N: 3.46. H NMR (CDCl3,
200 MHz): 7.60±7.20 (5H; m, Ph); 5.55 (1H, bd, H2);
5.25 (1H, d, H2); 5.20 (2H, s, CH2Ph); 5.05 (1H, d,
0
CH(CH3)2); 4.40 (1H, t, H4); 2.75 (2H, t, H2 ); 2.30 (2H,
0
m, CH2 (i-Bu)); 2.00 (2H, m, H1 ); 1.00 (6H, d, CH3 (i-Bu));
13
0
C NMR (CD3OD, 50.3 MHz): 173.0 (C3 ); 172.6 (C5);
157.3 (CO Cbz); 136.9 (Cf); 129.9 (CHo); 129.7 (CHp);
129.4 (CHm); 79.3 (OCH2. i-Bu); 72.0 (C2); 68.9 (CH2Ph);
0
0
54.9 (C4); 30.0 (C2 ); 28.7 (CH, i-Bu); 26.9 (C1 ); 20.3 (CH3
(i-Bu)).
4(S)-Benzyloxycarbonylamino-4-(methoxymethylcarba-
moyl) butyric acid isobutyl ester 12b. IR (CHCl3):
nˆ3015 (NH); 1720 (CO); 1510; 1370. MS (CI1):
m/zˆ381 ([M1H]1, 100%); 325 (3812.v); 217; 91; 57.
Analysis (C19H28N2O6): calcd C: 59.99; H: 7.42; O: 25.23;
N: 7.36; obs. C: 59.63; H: 7.31; O: 24.54; N: 7.38. 1H NMR
2(S)-Benzyloxycarbonylaminopentanedioic acid 5-tert-
butyl ester 11a. See Ref. 5. aDˆ212 (248C, MeOH,
cˆ1.6). IR (CHCl3): nˆ3435; 3050±2940; 1715 (CO).
MS; (EI): m/zˆ337 (M1); 292 (M2CO2H); 264; 91

2688
P. Ducrot et al. / Tetrahedron 56 (2000) 2683±2692
(CDCl3, 200 MHz): 7.30 (5H, bs, Ph); 5.80 (1H, d ex., NH-
Cbz, JNH-4ˆ8 Hz); 5.10 (2H, s, CH2Ph); 4.80 (1H, m, H4);
3.80 (2H, d, CH2 (i-Bu), Jˆ8 Hz); 3.75 (3H, s, OCH3); 3.20
(3H, s, NCH3); 2.40 (2H, t, H2, J2-3ˆ7 Hz); 2.10 (1H, m, CH
(i-Bu)); 1.90 (2H, m, H3); 0.95 (6H, d, CH3 (i-Bu), Jˆ8 Hz).
13C NMR (CD3OD, 50.3 MHz): 172.5 (C1); 169.1 (C5);
156.4 (CO); 137.3 (Cf); 126.2 (CHo, CHm); 126.1 (CHp);
72.4 (OCH2 i-Bu); 67.1 (CH2Ph); 61.3 (OCH3); 50.9 (C4);
32.8 (NCH3); 31.4 (C2); 27.8 (C3); 27.2 (CH i-Bu); 19.2
(CH3 i-Bu).
of triethylamine. After stirring for 2 h, the reaction mixture
was hydrolysed by addition of 100 ml of a 1N hydrochloric
acid solution, and extracted with CH2Cl2. The combined
organic layers were then washed with brine, dried over
sodium sulfate, ®ltered, concentrated under reduced
pressure, and puri®ed by chromatography AcOEt 70/
heptane 30) to yield 490 mg (98%) of a colorless oil. IR
(CHCl3): nˆ3423; 3027; 2981; 2941; 1721 (CO); 1686
(CO); 1659 (CO); 1509; 1478; 1424; 1369. MS (CI1):
m/zˆ305 ([M1H]1, 100%); 275; 249 (M2v,); 98.
1
HRMS (C13H24N2O6): calcd 305.1706, obs. 305.1702. H
4(S)-tert-Butoxycarbonylamino-4-(methoxymethylcarba-
moyl) butyric acid tert-butyl ester 12c. IR (CHCl3):
nˆ3015 (NH); 1720 (CO); 1510; 1370. MS (SIMS):
m/zˆ347 ([M1H]1); 291 (M2.v); 235; 191; 173.
NMR (CDCl3, 250 MHz): 5.55 (1H, d, NHCO2,
JNH-4ˆ8.2 Hz); 4.70 (1H, m, H4); 3.80 (3H, s, OCH3);
3.70 (3H, s, OCH3); 3.20 (3H, s, NCH3); 2.30 (2H, t, H2,
J2-3ˆ8 Hz); 2.20±1.75 (2H, m, H3); 1.40 (9H, s, CH3 t-Bu).
13C NMR (CD3OD, 62.9 MHz): 171.7 (C1); 170.9 (C5);
160.4 (CONH); 80.2 (OC(CH3)3); 61.2 (OCH3); 51.9
(OCH3); 50.2 (C4); 46.9 (NCH3); 30.9 (C2); 27.7
(C(CH3)3); 27.3 (C3).
1
HRMS (C16H30N2O6); calcd 347.2183; obs. 347.2191. H
NMR (CDCl3, 250 MHz): 5.26 (1H, d ex, NH-Boc,
JNH-4ˆ9.2 Hz); 4.80±4.60 (1H, m, H4); 3.78 (3H, s,
OCH3); 3.21 (3H, s, NCH3); 2.33 (2H, t, H2, J2-3ˆ7.2 Hz);
2.10±1.6 (2H, m, H3); 1.45 (18H, s, CH3). 13C NMR
(CD3OD, 50.3 MHz): 172.2 (C1); 169.0 (C5); 155.6 (CO
Boc); 80.5 (OC(CH3)3); 79.9 (C(CH3)3); 61.3 (OCH3);
50.0 (C4); 32.2 (NCH3); 31.5 (C2); 28.4 (C(CH3)3); 28.1
(C(CH3)3); 27.9 (C3).
4(S)-(Methoxymethylcarbamoyl)-4-(2,2,2-trichloro-
ethoxycarbonylamino) butyric acid isobutyl ester 12e.
To a stirred solution of 350 mg (1.42 mmol) of hydroxamate
13a in 20 ml of CH2Cl2 at 2408C were added successively
240 ml (1.74 mmol) of 2,2,2-trichloroethyl chloroformate,
and 243 ml (1.74 mmol) of triethylamine dropwise. After
1 h, the reaction mixture was hydrolysed by addition of
10 ml of 1N solution of hydrochloric acid, and extracted
with CH2Cl2. The combined organic layers were then
washed with brine, dried over sodium sulfate, ®ltered,
concentrated under reduced pressure, and puri®ed by chro-
matography (AcOEt 70/heptane 30) to yield 582 mg (97%)
of a colorless oil. IR (CHCl3): nˆ1817; 1784; 1733; 1652;
1466; 1382; 710. MS (CI1): m/zˆ421 ([M1H]1 100%);
General procedure for Cbz hydrogenolysis
To a stirred solution of 1.37 g (3.62 mmol) of hydroxamate
12a in 30 ml of MeOH were added sucessively 46 mg of
10% palladium on charcoal, and 977 mg (18.1 mmol) of
anhydrous ammonium formate. After stirring for 2 h at rt,
the reaction mixture was ®ltered over celite. The organic
layer was then concentrated under reduced pressure to yield
882 mg (99%) of an amorphous white solid, which was used
without any further puri®cation.
1
365 (4212.v). H NMR (CDCl3, 250 MHz): 5.82 (1H,
d. ech. NHCO2, JNH-4ˆ8.8 Hz); 4.90±4.60 (3H, m, H4,
CO2CH2); 3.87 (2H, d, CH2 (i-Bu), Jˆ6.5 Hz); 3.80 (3H,
s, OCH3); 3.25 (3H, s, NCH3); 2.45 (2H, t, H2, J2-3ˆ7 Hz);
2.20 (1H, m, CH(CH3)2); 2.00 (2H, m, H3); 1.00 (9H, d, CH3
(i-Bu), Jˆ6.5 Hz); 13C NMR (CD3OD, 62.9 MHz): 172.9
(C1); 171.6 (C5); 154.4 (CO Troc); 95.5 (CCl3); 74.8 (CH2
Troc); 70.9 (OCH2 i-Bu); 61.8 (OCH3); 50.9 (C4); 32.3
(NCH3); 31.2 (C2); 29.9 (C3); 27.8 (CH i-Bu); 19.2 (CH3
i-Bu).
4(S)-Amino-4-(methoxymethylcarbamoyl)-butyric acid
tert-butyl ester 13a. MS (SIMS): m/zˆ247 ([M1H]1
1
100%), 191 (M2.v), 173 (M2t-BuO), 102. RMN H;
CDCl3; 200 MHz; 4.40; 1H; t; H4; J4-3ˆ6 Hz 3.80; 3H; s;
OCH3; 3.25; 3H; s; NCH3; 2.40; 2H; t; H2; J2-3ˆ8 Hz 2.00;
2H; q; H3; 1.45; 9H; s; CH3 (t-Bu). 13C NMR (CD3OD;
75.5 MHz 172.1 (C1), 169.6 (C5), 97.8 (OC(CH3), 62.3
(OCH3), 51.2 (C4), 32.8 (NCH3), 31.2 (C2), 28.3 (C(CH3),
27.2 (C3).
4(S)-(Methoxymethylcarbamoyl)-4-pyrrol-1-yl-butyric
acid tert-butyl ester 12f. To a stirred solution of 720 mg
(2.93 mmol) of hydroxamate 13a in 20 ml of acetic acid was
added 1.05 g (12.8 mmol) of sodum acetate. The reaction
mixture was heated to re¯ux, and 380 ml (2.93 mmol) of
2,5-dimethoxytetrahydrofuran was added dropwise. After
re¯uxing a further 10 min, the reaction mixture was cooled
to rt, and hydrolysed by addition of 50 ml of water, and
extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over sodium sulfate, ®ltered,
concentrated under reduced pressure, and puri®ed by
chromatography (AcOEt 50/heptane 50) to yield 686 mg
(79%) of a yellow oil. IR (CHCl3): nˆ3478; 3025; 2982;
2940; 1723 (CO); 1665 (CO); 1488; 1458; 1392; 1369. MS
(EI): m/zˆ296 (M1); 240 (M2v,; 100%); 208
4(S)-Amino-4-(N-methoxy-N-methylcarbamoyl)-butyric
acid isobutyl ester 13b. IR (CHCl3): nˆ3478; 3050; 1720
(CO); 1657 (CO); 1509; 1229; 1148. MS (SIMS): m/zˆ247
([M1H]1 100%); 191; 173 (M2i-BuO). 1H NMR (CDCl3,
300 MHz): 4.50 (1H, t, H4, J4-3ˆ6.0 Hz); 4.05 (2H, d, CH2
(i-Bu), Jˆ7.2 Hz); 3.95 (3H, s, OCH3); 3.45 (3H, s, NCH3);
2.70 (2H, t, H2); 2.35 (2H, m, H3); 2.10 (2H, m, CH(CH3)2);
0.95 (6H, d, CH3 (i-Bu), Jˆ7.5 Hz). 13C NMR (CD3OD,
75.5 MHz): 170.9 (C1); 168.3 (C5); 82.4 (OCH2 i-Bu);
61.1 (OCH3); 51.4 (C4); 31.8 (NCH3); 31.3 (C2); 28.1 (CH
i-Bu); 26.9 (C3); 18.6 (CH3 i-Bu).
4(S)-Methoxycarbonylamino-4-(methoxymethylcarba-
moyl) butyric acid tert-butyl ester 12d. To a stirred solu-
tion of 402 mg (1.63 mmol) of hydroxamate 13a in 20 ml of
CH2Cl2 at rt, were successively added 140 ml (1.81 mmol)
of methyl chloroformate and dropwise 254 ml (1.81 mmol)
1
(M2CON(Me)OMe). H NMR (CDCl3, 200 MHz): 6.80
0
0
0
0
0
0
(2H, t, H2 , J2 -3 ˆ1.7 Hz); 6.10 (2H, t, H3 , J3 -2 ˆ1.7 Hz);
5.20 (1H, t, H4, J4-3ˆ7.6 Hz); 3.40 (3H, s, OCH3); 3.20 (3H,

P. Ducrot et al. / Tetrahedron 56 (2000) 2683±2692
2689
s, NCH3); 2.30±2.00 (4H, m, H2, H3); 1.40 (9H, s, CH3
(t-Bu). 13C NMR (CD3OD, 50.3 MHz): 171.8 (C1); 169.9
5-Oxo-4(S)-(2,2,2-Trichloroethoxycarbonylamino) penta-
noic acid isobutyl ester 14e. MS (CI1): m/zˆ362
1
(C5); 119.8 (C2 ); 108.3 (C3 ); 80.2 (C(CH3)3); 61.1 (OCH3);
56.3 (C4); 32.0 (NCH3); 30.8 (C2); 27.9 (C3); 27.8
(C(CH3)3).
([M1H]1); 306 (M2v,). H NMR (CDCl3, 200 MHz):
0
0
9.60 (1H, s, CHO); 5.45 (1H, bd, NHCO2); 4.70 (2H, m,
CH2CCl3); 4.05 (1H, m, H4); 3.80 (2H, d, OCH2 (i-Bu));
2.45 (2H, bt, H2); 2.10 (1H, m, CH (i-Bu)); 2.05 (2H, m,
H3); 1.40 (6H, d, CH3 (i-Bu), Jˆ8 Hz).
General procedure for reduction of hydroxamates
5-Oxo-4(S)-Pyrrol-1-yl-pentanoic acid tert-butyl ester
14f. H NMR (CDCl3, 200 MHz): 9.60 (1H, s, CHO); 6.60
To a stirred solution of 2.0 g (5.22 mmol) of hydroxamate in
50 ml Et2O at 2208C were added portionwise 278 mg
(7.31 mmol) of LiAlH4. After 2 h 40 min the reaction
mixture was slowly hydrolysed by addition of a 3% aqueous
solution of sodium hydrogenosulfate, ®ltered and extracted
with Et2O. The combined organic layers were then washed
successively with a solution of 1N hydrochloric acid, a
saturated solution of sodium hydrogenocarbonate, and
brine. The combined organic layers were then dried over
sodium sulfate, ®ltered, and concentrated under reduced
pressure to yield 1.66 g (99%) of a colorless oil which
was used without further puri®cation.
1
0
(2H, t, H2 ); 6.20 (2H, t, H3 ); 4.40 (1H, m, H4); 2.40±1.80
0
(4H, m, H2, H3); 1.40 (9H, bs, CH3 (t-Bu)).
4(S)-Diethylcarbamoyl-2-(1,3-dioxo-1,3-dihydroisoindol-
2-yl) butyric acid 16. To a stirred solution of 2.0 g
(7.72 mmol) of N-phthaloyl glutamic anhydride in 10 ml
of THF at rt was added dropwise a solution of 0.84 ml
(8.13 mmol) of diethylamine in 5 ml of THF. After re¯ux-
ing for 2 h, the reaction mixture was cooled to rt, and the
resulting white precipitate was ®ltered and washed succes-
sively with 5 ml of THF, 10 ml of cooled (2208C) Et2O, and
dried under reduced pressure to yield 1.64 g (64%) of a
white amorphous solid. IR (CHCl3): nˆ3478; 3400±2450;
1751; 1625; 1467; 1385. MS (EI): m/zˆ332 (M1); 287
(M2CO2H); 259 (M273); 232 (M2CONEt2); (CI1):
m/zˆ333 ([M1H]1 100%); 315 (M2H2O); 287
(M2CO2H); 186. HRMS (C17H20N2O5): calcd 333.1443,
4(S)-Benzyloxycarbonylamino-5-oxo-pentanoic acid tert-
butyl ester 14a. aDˆ223 (248C, MeOH; cˆ0.9). IR
(CHCl3): nˆ3430 (NH); 3025; 2965 (CH3); 1700 (CO);
1710 (CO); 1510 (NH). MS (CI1), m/zˆ322 ([M1H]1,
100%); 304 (3222H2O); 266 (3222.v; 100%); 107
(PhCH2O); 91. HRMS (C17H23NO5): calcd 322.1649, obs.
322.1672. 1H NMR (CDCl3, 200 MHz): 9.55 (1H, s, CHO);
7.30 (5H, s, Ph); 5.80 (1H, d ex. NHCO, JNH-4ˆ8 Hz); 5.05
(2H, s, CH2Ph); 4.40±4.30 (1H, m, H4); 2.30 (2H, t, H2,
J2-3ˆ7 Hz); 2.10±1.70 (2H, m, H3); 1.40 (9H, s, CH3
(t-Bu). 13C NMR (CD3OD, 50.3 MHz): 198.9 (C5); 172.0
(C1); 156.2 (CO Cbz); 136.2 (Cf ); 128.5 (CHo); 128.2
(CHp); 128.0 (CHm); 80.9 (OC(CH3)3); 67.1 (CH2Ph); 52.6
(C4); 30.9 (C2); 28.0 (CH3 t-Bu); 24.1 (C3).
1
obs. 333.1451. H NMR (CDCl3, 250 MHz): 10.80 (1H,
0
0
bs, CO2H); 7.85 (2H, m, H4 Pht); 7.70 (2H, m, H5 Pht);
4.90 (1H, m, H4); 3.40±3.15 4H, m, CH2 (Et)); 2.80±2.30
(4H, m, H3, H2); 1.10 (6H, m, CH3 (Et)). 13C NMR (CD3OD,
50.3 MHz): 176.5 (C5); 174.5 (C1); 169.0 (CO Pht); 134.4
0
0
0
(C5 ); 132.5 (C3 ); 124.1 (C4 ); 54.3 (C4); 42.2 (CH3 Et); 32.6
(C2); 25.6 (C3); 11.2 (CH3 Et).
4(S)-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-5-hydroxy-
pentanoic acid diethylamide 18. To a stirred solution of
1.22 g (3.07 mmol) of 16 in 25 ml of THF at 2158C were
successively added 338 ml (3.07 mmol) of N-methyl-
morpholine, and 399 ml (3.07 mmol) of iso-butyl chloro-
formate. After stirring for 1 min at 2158C, a solution of
350 mg (9.21 mmol) of sodium borohydride in 5 ml of
water was added at once. The reaction mixture was stirred
for 15 s then hydrolysed with 20 ml water, and extracted
with AcOEt. The combined organic layers were then
washed with brine, dried over sodium sulfate, ®ltered and
concentrated under reduced pressure to yield 1.02 g (88%)
of a colorless oil which was used without further puri®ca-
tion. IR (CHCl3): nˆ3627; 3602±3190; 3088; 2981; 2937;
2877; 2460; 1773 (CO); 1713; 1635; 1483; 1468; 1438. MS
(EI): m/zˆ318 (M1z); 300 (M218); 287 (M2CH2OH); 246
4(S)-Benzyloxycarbonylamino-5-oxo-pentanoic acid iso-
butyl ester 14b. IR (CHCl3): nˆ3430 (NH); 3020; 1700
(CO); 1710 (CO); 1500 (NH). MS (CI1), m/zˆ322
([M1H]1, 100%); 304 (3222H2O); 266 (3222.v;
1
100%); 107 (PhCH2O); 91. H NMR (CDCl3, 200 MHz):
9.60 (1H, s, CHO); 7.30 (5H, s, Ph); 5.70 (1H, d, ex.,
NHCO, JNH-4ˆ8 Hz); 5.10 (2H, s, CH2Ph); 4.40±4.30
(1H, m, H4); 3.90 (2H, d, CH2 i-Bu, Jˆ7.6 Hz); 2.35 (2H,
t, H2, J2-3ˆ7 Hz); 2.20 (1H, m, CH i-Bu); 2.00±1.85 (2H, m,
H3); 1.00 (6H, d, CH3 i-Bu). 13C NMR (CD3OD, 50.3 MHz):
198.0 (C5); 172.5 (C1); 155.8 (CO Cbz); 136.1 (Cf ); 128.6
(CHo); 128.3 (CHp); 128.0 (CHm); 68.3 (CH2Ph); 66.7
(OCCH2 i-Bu); 53.2 (C4); 30.5 (C2); 27.3 (CH i-Bu); 24.2
(C3); 19.1 (CH3 i-Bu).
1
(M2NEt2); 186; 128. H NMR (CDCl3, 200 MHz): 7.80
4(S)-4-tert-Butoxycarbonylamino-5-oxo-pentanoic acid
tert-butyl ester 14c. MS (CI1): m/zˆ288 ([M1H]1); 232
(M2v,); 176 (M22xv,; 100%); 132. 1H NMR (CDCl3,
200 MHz): 9.50 (1H, s, CHO); 5.40 (1H, dl, NHCO); 4.00
(1H, m, H4); 2.30 (2H, bt, H2); 2.05 (2H, m, H3); 1.40 (18H,
bs, CH3 (t-Bu)).
0
0
(2H, m, H4 Pht); 7.75 (2H, m, H5 Pht); 4.40 (1H, m, H4);
4.10±3.85 (2H, m, H5); 3.25±3.05 (5H, m, CH2 (Et), OH);
2.30±1.90 (4H, m, H2, H3); 1.00 (3H, t, CH3 (Et)); 0.90 (3H,
t, CH3 (Et). 13C NMR (CD3OD, 50.3 MHz): 170.9 (CO);
168.9 (CO Pht); 133.9 (CH Pht); 131.7 (Cf Pht); 123.1
(CH Pht); 62.6 (C5); 53.7 (C4); 41.9 (CH2CH3); 40.2
(CH2CH3); 29.6 (C2); 24.1 (C3); 14.0 (CH2CH3); 12.9
(CH2CH3).
4(S)-4-(Methoxycarbonyl)amino-5-oxo-pentanoic acid
tert-butyl ester 14d. H NMR (CDCl3, 200 MHz): 9.55
1
(1H, bs, CHO); 5.50 (1H, bd, NHCO2); 3.60 (3H, s,
OCH3); 4.10 (1H, m, H4); 2.25 (2H, t, H2); 1.95 (2H, m,
H3); 1.35 (9H, s, CH3 (t-Bu)).
4(S)-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-5-oxo-penta-
noic acid diethylamide 14g. To a stirred solution of

2690
P. Ducrot et al. / Tetrahedron 56 (2000) 2683±2692
0
(C1 ); 157.1 (CO Cbz); 136.4 (C8a); 132.6 (Cf Cbz); 128.7
(C9a); 128.5 (CHo); 128.2 (C4b); 127.9 (CHp); 127.5 (CHm);
121.8 (C7); 119.4 (C6); 118.1 (C8); 111.4 (C5); 110.9 (C4a);
41.8 mg (131 mmol) of alcohol 18 in 10 ml of CH2Cl2 at rt,
Ê
were successively added 150 mg of 4A molecular sieves,
and 142 mg (655 mmol) of PCC. After 1 h of stirring at rt,
the reaction mixture was ®ltered over Celite, concentrated
under reduced pressure, and puri®ed by chromatography
(AcOEt 80/heptane 20) to yield 23 mg (68%) of a light
yellow oil. 1H NMR (CDCl3, 200 MHz): 9.70 (1H, s,
0
80.9 (OC(CH3)3); 66.6 (CH2Ph); 56.2 (C1); 52.6 (C4 ); 43.6
0
0
(C3); 32.3 (C2 ); 28.2 (C(CH3)3); 27.3 (C4); 21.9 (C3 ). Chiral
HPLC (hexane 98/ethanol 2): RT1ˆ32 min; RT2ˆ40 min;
eeˆ24%.
0
0
CHO); 8.85 (2H, m, H4 Pht); 8.75 (2H, m, H5 Pht); 4.80
(1H, m, H4); 3.40±3.10 (4H, m, CH2 (Et)); 2.55±2.15 (4H,
m, H2, H3); 1.05 (6H, m, CH3 (Et)).
3a(R)-4(S)-5a(S)-1,2,3,3a,4,5-Hexahydro-4-(tert-butoxy-
carbonylpropyl)-5-(benzyloxycarbonyl)-pyrrolo[20,30:
3,4]pyrrolo[2,3-b]indole 19. aDˆ240 (248C, MeOH,
cˆ1.0). IR (CHCl3): nˆ3437 (NH); 3028±2990±2975;
1710 (CO); 1520; 1426; 1216. UV (EtOH): lˆ211; 242;
298. MS (CI1): m/zˆ464 ([M1H]1); 391 (M2Ot-Bu); 301;
161. HRMS (C27H33N3O4): calcd 463.2463, 464.2542; obs.
General procedure for the Pictet±Spengler reaction
To a stirred solution of 848 mg (2.64 mmol) of aldehyde and
465 mg (2.90 mmol) of tryptamine in 20 ml CH2Cl2 held at
the desired temperature, was added dropwise a solution of
0.41 ml (5.80 mmol) of tri¯uoroacetic acid in 5 ml CH2Cl2.
After 5 h, the reaction mixture was slowly hydrolysed by
addition of a saturated solution of sodium carbonate. The
reaction mixture was then extracted with CH2Cl2, and
washed with brine. The combined organic layers were
dried over sodium sulfate, ®ltered, concentrated under
reduced pressure, and puri®ed by chromatography
(AcOEt 80/heptane 20, then AcOEt 100%, then AcOEt
90/MeOH 10) to yield 1.85 g (77%) of an amorphous
beige solid.
1
463.2466, 464.2513. H NMR (CDCl3, 200 MHz): 7.50±
7.30 (5H, m, H arom.); 7.20±7.00 (2H, m, H8, H10); 6.80
(1H, t, H9, J7-6ˆJ7-8ˆ8 Hz); 6.60 (1H, d, H7, J5-6ˆ8 Hz);
5.50 (1H, bs, ex., H3); 5.41 (1H, bs, ex., H6); 5.30±5.00
(3H, m, CH2Ph, H5a); 4.00 (1H, m, H4); 3.60 (1H, bs,
0
H3a); 3.20 (2H, t, H2, J10-9ˆ6 Hz); 2.30±2.00 (4H, m, H2 ,
H1); 1.80±1.50 (2H, m, H3 ); 1.30 (9H, s, CH3 (t-Bu)). 13C
0
NMR (CD3OD, 50.3 MHz): 172.4 (CO ester); 154.8 (CO
Cbz); 136.6 (Cf ); 131.3 C6a); 128.7 (CHo. CHp); 128.2
(CHm); 128.0 (C10a); 122.9 (C8); 119.3 (C9); 119.2 (C10);
109.2 (C7); 83.9 (C5a); 80.3 (OC(CH3)3); 74.5 (C3a); 67.3
0
0
(CH2Ph); 65.4 (C4); 47.2 (C2); 32.6±29.4 (C2 , C3 , C1); 29.7
(C10b); 28.1 (C(CH3)3). Chiral HPLC (hexane 98/ethanol 2):
RT1ˆ21 min; RT2ˆ29 min; eeˆ60%.
1(R)-40(S)-Benzyloxycarbonylamino-40-(1,2,3,4-tetra-
hydro-1H-b-carbolin-1-yl) butyric acid isobutyl ester
7b. IR (CHCl3): nˆ3300 (NH); 3020±2980±2970; 1700
(CO); 1510. MS (EI): m/zˆ463 (M1z; 390 (M2Ot-Bu);
288; 171 (100%); 144; 130; 91. 1H NMR (CDCl3,
200 MHz): 8.85 (1H, bs, ex., H9); 7.50 (1H, d, H5,
J5-6ˆ8 Hz); 7.40±6.90 (8H, m, H arom.); 5.70 (1H, m,
ex., H2); 4.90 (2H, s, CH2Ph); 4.30 (1H, m, ex., NHCO2);
1(R)-40(S)-Benzyloxycarbonylamino-40-(1,2,3,4-tetra-
hydro-1H-b-carbolin-1-yl) butyric acid tert-butyl ester
7a. aDˆ120 (258C, MeOH, cˆ1.0). IR (CHCl3): nˆ3300
(NH); 3020±2980±2970; 1700 (CO); 1510. UV (EtOH):
lˆ225; 280. MS (EI): m/zˆ464 ([M1H]1z; 462
([M2H]1z; 391 (M2Ot-Bu); 171; 91; (CI1): m/zˆ464
([M1H]1); 390 (M2Ot-Bu); 298; 171 (100%); 143; 130;
117; 91. HRMS (C27H33N3O4): calcd 463.2463, obs.
1
463.2458. H NMR (CDCl3, 200 MHz): 8.55 (1H, bs, ex.,
H9); 7.60±7.00 (9H, m, H arom.); 5.90±5.60 (1H, m, ex.,
0
H2); 5.10 (2H, s, CH2Ph); 4.95 (1H, d, H1, J1-4 ˆ7 Hz); 4.60
0
4.20 (2H, m, H1, H3); 3.95 (1H, m, H4 ); 3.85 (2H, d, CH2
0
(1H, d, ex., NH (Cbz), JNH-4 ˆ7 Hz); 4.40±4.10 (2H, m, H3);
0
0
0
0
0
0
(i-Bu), Jˆ8 Hz); 3.75±2.15 (5H, m, H3 , H2 , CH (i-Bu));
3.50±3.40 (1H, m, H4 ); 2.43 (2H, t, H2 , J2 -3 ˆ7 Hz); 1.90±
1.60 (4H, m, H3 , H4); 1.45 (9H, s, CH3 (t-Bu)). 13C NMR
0
2.10 (2H, m, H4); 0.95 (6H, d, CH3 (i-Bu), Jˆ8 Hz). 13C
0
NMR (CD3OD, 50.3 MHz): 172.9 (C1 ); 157.1 (CO Cbz);
0
(CD3OD, 50.3 MHz): 172.7 (C1 ); 156.9 (CO Cbz); 136.3
136.4 (C8a); 132.6 (Cf Cbz); 128.7 (C9a); 128.5 (CHo);
128.2 (C4b); 127.9 (CHp); 127.5 (CHm); 121.8 (C7);
119.4 (C6); 118.1 (C8); 111.4 (C5); 110.9 (C4a); 72.5
(C8a); 136.6 (Cf Cbz); 132.8 (C9a); 128.2±127.2 (CHo,
CHm, CHp, C4b); 121.3 (C7); 118.9 (C6); 117.7 (C8); 110.5
0
(C4a); 80.4 (OC(CH3)3); 66.2 (CH2Ph); 56.1 (C1); 52.6 (C4 );
0
(OCH2 i-Bu); 66.6 (CH2Ph); 56.2 (C1); 52.6 (C4 ); 43.6
0
0
43.3 (C3); 32.2 (C2 ); 27.9 (C(CH3)3); 27.2 (C4); 22.5 (C3 ).
Chiral HPLC (hexane 98 / ethanol 2): RT1ˆ42 min;
RT2ˆ45 min; ee.99%.
0
0
(C3); 32.3 (C2 ); 27.3 (C4); 26.9 (CH i-Bu); 21.9 (C3 );
19.4 (CH3 i-Bu).
1(R)-40(S)-tert-Butoxycarbonylamino-40-(1,2,3,4-tetra-
hydro-1H-b-carbolin-1-yl) butyric acid tert-butyl ester
7c. IR (CHCl3): nˆ3435 (NH); 3035±2850; 1764 (CO);
1704 (CO); 1499; 1456; 1368; 1151. MS (EI): m/zˆ429
(M1z; 355 (M2t-BuOH); 298; 282; 171 (100%). HRMS
1(S)-40(S)-Benzyloxycarbonylamino-40-(1,2,3,4-tetra-
hydro-1H-b-carbolin-1-yl) butyric acid tert-butyl ester
6a. aDˆ215 (24, MeOH, cˆ1.0). IR (CHCl3): nˆ3300
(NH); 3020±2980±2970; 1700 (CO); 1510. UV (EtOH):
lˆ225; 280. MS (EI): m/zˆ463 (M1; 390 (M2Ot-Bu);
288; 171 (100%); 144; 130; 91. HRMS (C27H33N3O4):
calcd 463.2463, obs. 463.2444. Analysis: calcd C: 69.97,
H: 7.17, O: 13.81, N: 9.06; obs., C: 69.69, H: 7.33, O:
1
(C24H35N3O4): calcd 429.2627, obs. 429.2623. H NMR
(CDCl3, 200 MHz): 8.70 (1H, s, H9); 7.45 (1H, d, H5,
J5-6ˆ7.6 Hz); 7.25 (1H, d, H8, J8-7ˆ7.6 Hz); 7.10 (2H, m,
H6, H7); 5.25 (1H, bd, NHCO2); 4.20 (1H, d, H1,
1
13.98, N: 8.76. H NMR (CDCl3, 200 MHz): 8.85 (1H, bs,
0
0
J1-4 ˆ8 Hz); 4.10 (1H, m, H4 ); 3.4 (1H, ddd, H3eq
,
,
ex., H9); 7.50 (1H, d, H5, J5-6ˆ8 Hz); 7.40±6.90 (8H, m, H
arom.); 5.70 (1H, m, ex., H2); 4.90 (2H, s, CH2Ph); 4.30
(1H, m, ex., NHCO2); 4.20 (2H, m, H1, H3); 3.95 (1H, m,
Jˆ2.4 Hz, Jˆ4.8 Hz, Jˆ12 Hz); 3.05 (1H, ddd, H4ax
Jˆ4.9 Hz, Jˆ9.6 Hz, Jˆ9.6 Hz); 2.90±2.60 (2H, m, H3,
0
H4); 2.40 (2H, t, H2 ); 2.10 (1H, bs, H2); 1.90 (2H, m,
0
0
0
H4 ); 3.85±2.20 (4H, m, H3 , H2 ); 2.10 (2H, m, H4); 1.40
(9H, s, CH3 (t-Bu)). 13C NMR (CD3OD, 50.3 MHz): 172.9
0
H3 ); 6c: 9.00 (1H, s, H9); 7.30 (1H, d, H8); 5.75 (1H, bd,

P. Ducrot et al. / Tetrahedron 56 (2000) 2683±2692
2691
NHCO2). 13C NMR (CD3OD, 50.3 MHz): 172.9 (C1 ); 156.6
(CO Boc); 136.3 (C8a); 133.2 (C9a); 127.4 (C4b); 121.3 (C7);
0
0
(C1); 38.4 (C4 ); 30.0 (C3); 28.5 (C2 ); 27.7 (C(CH3)3);
0
23.4 (C4); 22.6 (C3 ).
0
118.9 (C6); 117.6 (C8); 111.2 (C5); 110.3 (C4a); 80.6
0
(C(CH3)3); 79.4 (C(CH3)3); 56.6 (C1); 51.2 (C4 ); 43.6
1(S)-40(S)-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-N,N-di-
ethyl-40-(1,2,3,4-tetrahydro-1H-b-carbolin-1-yl) butyra-
mide 6g( IR (CHCl3): nˆ3470; 3050; 1708; 1629; 1394;
1365; 1270; 1142. MS (SIMS): m/zˆ459 ([M1H]1, 100%);
442; 287; 171; 144. 1H NMR (CDCl3, 200 MHz): 9.4 (1H, s,
0
0
(C3); 32.4 (C2 ); 28.1 (2 C(CH3)3); 27.1 (C4); 22.0 (C3 );
0
6c: 173.1 (C1 ); 156.1 (CO Boc); 121.5 (C7); 119.1 (C6);
0
117.9 (C8); 56.4 (C1); 53.2 (C4 ); 43.0 (C3).
1(R)-40(S)-Methoxycarbonylamino-40-(1,2,3,4-tetrahydro-
1H-b-carbolin-1-yl) butyric acid tert-butyl ester 7d. IR
(CHCl3): nˆ3423; 3027±2920; 1715 (CO); 1660; 1509;
1480; 1370; 1155. MS (CI1): m/zˆ388 ([M1H]1); 386
([M2H]1); 171; 161; 144. HRMS (C21H29N3O4): calcd
388.2229, obs. 388.2229. 1H NMR (CDCl3, 200 MHz):
8.65 (1H, bs, H9); 7.45 (1H, d, H5, J5-6ˆ8 Hz); 7.35 (1H,
d, H8, J8-7ˆ8 Hz); 7.20±6.95 (2H, m, H6, H7, 5.55 (1H, bd,
ex., NHCO2); 4.20 (3H, m, H1, H3); 3.45 (3H, s, OCH3);
ex., H9); 7.80 (2H, m, H4 Pht); 7.70 (2H, m, H5 Pht); 7.45
(1H, d, H5, J5-6ˆ8 Hz); 7.40 (1H, d, H8, J8-7ˆ8 Hz); 7.15
00
00
(1H, t, H7, J7-6ˆJ7-8ˆ8 Hz); 7.05 (1H, t, H6, J7-6ˆJ7-8
ˆ
0
0
8 Hz); 4.70 (1H, m, H4 ); 4.45 (1H, d, H1, J1-4 ˆ9.6 Hz);
3.45±2.95 (6H, m, H3 CH2 (Et)); 2.85±2.60 (3H, m, H4,
0
H3 ); 2.55±2.20 (3H, m, H2 , H3 ); 2.05 (bs, 1H, H2);
0
0
1.15±0.95 (m, 6H, CH3 (NEt2)); 7g: 8.95 (1H, s, ex., H9);
0
4.95 (1H, m, H4 ); 4.55 (1H, d, H1). 13C NMR (CD3OD,
0
50.3 MHz): 171.1 (C1 ); 169.3 (CO Pht); 136.2 (C8a);
0
3.40 (1H, m, H4 ); 3.10±2.90 (1H, m, H2 ); 2.50±2.10 (3H,
0
134.2 (CH Pht); 133.8 (Cf Pht); 131.9 (C9a); 127.3 (C4b);
123.5 (CH Pht); 121.7 (C7); 119.2 (C6); 118.0 (C5); 111.5
0
m, H2 , H3 ); 2.00±1.90 (1H, m, H4); 1.45 (9H, s, CH3
0
0
(C8); 110.0 (C4a); 54.6 (C1); 53.9 (C4 ); 42.1 (CH2 Et); 41.8
(t-Bu)); 6d: 9.05 (1H, bs, H9); 5.80 (1H, bd, ex., NHCO2).
0
C NMR (CD3OD, 50.3 MHz): 172.9 (C1 ); 157.4 (CO);
136.2 (C8a); 127.3 (C9a); 117.9 (C4b); 121.4 (C7); 118.9
(C6); 117.7 (C8); 111.3 (C5); 110.4 (C4a); 80.7
13
0
0
(C3); 40.6 (CH2 Et); 29.9 (C2 ); 25.4 (C3 ); 22.8 (C4); 14.2
(CH3 Et); 13.2 (CH3 Et).
0
(OC(CH3)3); 56.2 (OCH3); 52.4 (C1); 52.0 (C4 ); 43.5 (C3);
General procedure for lactam cyclisations
0
32.3 (C2 ); 28.0 (C(CH3)3); 27.3 (C4); 22.0 (C3 ); 6d:
0
0
173.2 (C1 ); 156.2 (CO); 53.6 (C1); 43.1 (C3); 24.7 (C4);
0
22.7 (C2 ).
To a stirred solution of 345 mg (745 mmol) of b-carboline
in 20 ml MeOH at rt were added 4 mg (814 mmol) of
NaOMe. After 24 h, the reaction mixture was concentrated
under reduced pressure, diluted in 50 ml AcOEt and washed
successively with a solution of 1 N hydrochloric acid, 5%
sodium hydrogenocarbonate solution, and brine. The
combined organic layers were then dried over sodium
sulfate, ®ltered, concentrated under reduced pressure and
puri®ed by chromatography (AcOEt 90/heptane 10) to
yield 261 mg (90%) of a beige amorphous solid.
1(R)-40(S)-(1,2,3,4-Tetrahydro-1H-b-carbolin-1-yl)-40-
(2,2,2-trichloroethoxycarbonylamino) butyric
acid
isobutyl ester 7e. IR (CHCl3): nˆ3435 (NH); 3010±
2970; 1722 (CO); 1735 (CO); 1510; 1136. MS (CI1):
m/zˆ504 ([M1H]1); 421 (100%); 391; 319; 171. HRMS
1
(C22H28N3O4Cl3): calc 504.1224, obs. 504.1245. H NMR
(CDCl3, 200 MHz): 8.60 (1H, s, H9); 7.45 (1H, d, H5,
J5-6ˆ7.6 Hz); 7.20 (1H, d, H8, J8-7ˆ7.6 Hz); 7.10 (2H, m,
H6, H7); 5.90 (1H, d, H1); 4.50 (2H, s, CH2 (Troc)); 4.30
1(S)-12b(R)-(4-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo-
[2,3-a]quinolizin-1-yl) carbamic acid benzyl ester 21a.
aDˆ159 (248C, MeOH, cˆ0.6). IR (CHCl3): nˆ3435
(NH); 3320 (NH); 3015±2980±2950; 1710 (CO); 1635
(CvN); 1510 (CvC); 1125 (C-O). UV (EtOH): lˆ214;
242; 298. MS (EI): m/zˆ389 (M1z; 298 (M2PhCH2); 281
(M2PhCH2OH); 238 (M2NH2Cbz; 100%); 171; 107
(PhCH2O); 91; 77; (CI1) m/zˆ390 ([M1H]1); 312; 282;
256; 249; 212; 152; 147; 91. HRMS (C23H23N3O3): calcd
389.1734, obs. 389.1751. 1H NMR (CDCl3, 300 MHz): 9.54
(1H, s, ex., NH12); 7.50±6.90 (9H, m, H arom.); 6.20 (1H,
02d, ex., NHCO2, JNH-1ˆ6 Hz); 5.20 (2H, d, CH2Ph); 4.45
(1H, bs, H12b); 2.70 (5H, m, H6, H3, H1); 2.40 (4H, m, H7,
H2). 13C NMR (CD3OD, 50.3 MHz): 169.4 (C4); 156.9 (CO
Cbz); 136.9 (C11a); 136.0 (Cf); 130.0 (C12a); 128.3 (CHo);
127.7 (CHp); 127.2 (CHm); 126.6 (C7b); 122.2 (C10); 119.4
(C9); 118.4 (C8); 111.3 (C11); 111.0 (C7a); 66.5 (CH2Ph);
58.2 (C12b); 46.4 (C1); 40.1 (C6); 27.4 (C3); 24.6 (C2); 20.6
(C7). Chiral HPLC (hexane 98/ethanol 2): RT1ˆ12 min;
RT2ˆ16 min; ee.99%.
0
(1H, m, H4 ); 3.90 (2H, d, CH2 (i-Bu)); 3.35 (1H, dd, H3eq);
3.00 (1H, dd, H4ax); 2.95±2.60 (2H, m, H3ax, H4eq); 2.55 (2H,
0
0
t, H2 ); 2.25 (1H, m, CH (i-Bu)); 2.00 (2H, m, H3 ); 1.00 (6H,
d, CH3 (i-Bu)); 6e: 8.95 (1H, s, H9); 7.50 (1H, d, H5); 7.35
(1H, d, H8); 6.15 (1H, d, H1). 13C NMR (CD3OD,
0
50.3 MHz): 173.6 (C1 ); 155.4 (CO Troc); 136.4 (C8a);
132.2 (C9a); 127.4 (C4b); 122.0 (C4a); 121.8 (C7); 119.3
(C6); 118.0 (C8); 111.2 (C5); 95.6 (CCl3); 74.2 (OCH2
0
Troc); 71.0 (OCH2 i-Bu); 56.2 (C1); 52.9 (C4 ); 43.5 (C3);
0
30.9 (C2 ); 27.8 (C4); 27.5 (CH i-Bu); 22.0 (C3 ); 19.2 (CH3
0
0
i-Bu); 6e: 122.0 (C7); 74.7 (OCH2 Troc); 53.6 (C4 ); 43.1
0
(C3); 30.6 (C2 ); 22.8 (C3 ).
0
1(S)-40(S)-Pyrrol-1-yl-40-(1,2,3,4-tetrahydro-1H-b-car-
bolin-1-yl) butyric acid tert-butyl ester 6f( IR (CHCl3):
nˆ3410 (NH); 3025±2930; 1718 (CO); 1614; 1491; 1370;
1155; 1091. MS (EI): m/zˆ379 (M1z; 322 (M2t-Bu); 306;
287; 171 (100%). 1H NMR (CDCl3, 200 MHz): 7.45 (1H, d,
0
H5); 7.05 (3H, m, H6, H7, H8); 6.60 (2H, t, H2 ); 6.40 (1H, s,
0
0
H9); 6.15 (2H, t, H3 ); 4.20 (1H, d, H1, J1-4 ˆ8 Hz); 4.10 (1H,
0
m, H4 ); 3.25±3.30 (2H, m, H3eq. H4ax); 2.80.2.60 (3H, m,
1(S)-12b(S)-(4-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo-
[2,3-a]quinolizin-1-yl)-carbamic acid benzyl ester 20a.
IR (CHCl3): nˆ3422 (NH); 3070 (NH); 3007; 1687
(CO); 1645 (CvN); 1513 (CvC); 1135 (C±O). MS (EI):
m/zˆ389 (M1z; 298 (M2CH2Ph); 171; 91. HRMS
0
0
H3ax, H4eq, H3 ); 2.20±1.90 (2H, m, H2 , NH); 1.80 (1H, bs,
0
H3 ); 1.40 (9H, s, CH3 (t-Bu)); 13C NMR (CD3OD,
00
50.3 MHz): 167.3 (CO); 130.1 (C8a); 129.5 (CH2 ); 128.6
00
(CH3 ); 121.3 (C9a); 118.7 (C7); 117.6 (C4b); 110.4 (C6);
108.7 (C8); 108.3 (C5); 106.5 (C4a); 80.1 (C(CH3)3); 67.8
1
(C23H23N3O3): calcd 389.1734, obs. 389.1735. H NMR

2692
P. Ducrot et al. / Tetrahedron 56 (2000) 2683±2692
(CDCl3, 200 MHz): 9.20 (1H, bs, ex., NH (Ind); 7.40 (1H, d,
H8, J8-9ˆ8 Hz); 7.30 (5H, bs, H Cbz); 7.25 (1H, d, H11, J11-
H8, J8-9ˆ10.5 Hz); 7.10 (3H, m, H9, H10, H11); 6.85 (2H, t,
0 0
H2 ); 6.40 (2H, t, H3 ); 6.30 (1H, s, NH Ind); 5.20 (1H, m,
H6eq); 5.10 (1H, d, H12b, J12b-1ˆ10.5 Hz); 4.15 (1H, ddd, H1,
J1-12bˆ10.5 Hz, J1-2ˆ4 Hz); 3.95±2.55 (3H, m, H6ax, H3);
2.50±2.30 (4H, m, H7, H2). 13C NMR (CD3OD,
75.5 MHz): 167.9 (CO); 136.6 (C11a); 130.2 (C7b); 126.0
ˆ8 Hz); 7.10 (1H, t, H10); 7.05 (1H, t, H9); 5.55 (1H, bs,
10
ex., NH Cbz); 5.15 (2H, s, CH2Ph); 4.95 (1H, m, H6eq); 4.65
(1H, d, H12b, J12b-1ˆ5.9 Hz); 4.15 (1H, m, H1); 2.95±2.20
(5H, m, H3, H6ax, H7); 2.05±1.70 (2H, m, H2). 13C NMR
(CD3OD, 50.3 MHz): 168.9 (C4); 156.6 (CO Cbz); 136.2
(C11a); 135.9 (Cf ); 131.7 (C12a); 128.9 (CHo); 128.7
(CHp); 128.4 (CHm); 124.6 (C7b); 122.4 (C10); 119.8 (C9);
118.4 (C8); 111.5 (C11); 110.3 (C7a); 67.8 (CH2Ph); 60.1
(C12b); 51.6 (C1); 41.9 (C6); 30.1 (C3); 26.3 (C2); 20.9
(C7). Chiral HPLC (hexane 98 / ethanol 2): RT1ˆ18 min;
RT2ˆ20 min; eeˆ46%.
0
(C12a); 125.7 (C11); 122.3 (C9); 119.7 (C8); 118.3 (C2 );
0
110.9 (C10); 110.0 (C3 ); 60.1 (C1); 58.8 (C12b); 40.7 (C6);
31.5 (C3); 28.6 (C2); 21.0 (C7).
Acknowledgements
We wish to thank Professor P. Potier for his interest in this
work and Dr R. Dodd for the very careful reading of the
manuscript.
1(S)-12b(S)-(4-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo-
[2,3-a]quinolizin-1-yl)-carbamic acid tert-butyl ester 21c.
IR (CHCl3): nˆ3439 (NH); 3015±2980±2950; 1795 (CO);
1641 (CvN); 1506 (CvC); 1157. MS (EI): m/zˆ355 (M1z;
298 (M2t-Bu); 281 (M2t-BuO); 238 (M2NH2Boc, 100%);
107 (PhCH2O); 91; 77. HRMS (C20H25N3O3): calc
355.1896, obs. 355.1887. 1H NMR (CDCl3, 200 MHz):
8.85 (1H, bs, ex., NH Ind); 7.45 (1H, d, H8, J8-9ˆ8 Hz);
7.30 (1H, d, H11, J11-10ˆ8 Hz); 7.20 (1H, t, H10); 7.10 (1H,
t, H9); 5.30 (1H, d, ex., NHCO2, JNH-1ˆ9.6 Hz); 5.15 (1H,
dt, H6eq, Jˆ12 Hz, Jˆ4 Hz); 4.95 (1H, d, H12b, J12b-1ˆ5 Hz);
4.75 (1H, m, H1); 2.85 (1H, m, H6ax); 2.70 (2H, m, H7); 2.65
(2H, m, H3); 2.15 (2H, m, H2). 13C NMR (CD3OD,
50.3 MHz): 169.0 (C4); 156.5 (CO Boc); 136.9 (C11a);
130.1 (C7b); 126.7 (C12a); 123.6 (7a); 122.3 (C9); 119.5
(C10); 118.4 (C8); 111.4 (C11); 80.6 (OC(CH3)3); 58.8
(C12b); 45.5 (C1); 40.2 (C6); 28.2 (C(CH3)3); 27.5 (C2);
24.7 (C7); 20.7 (C3).
References
1. Schmitt, P.; Melnyk, P.; Bourde, O.; Demuynck, L.; Pujol, J.-F.;
Thal, C. Med. Chem. Res. 1993, 3, 24±33.
2. Melnyk, P.; Ducrot, P.; Demuynck, L.; Thal, C. Tetrahedron
Lett. 1993, 34, 5085±5088.
3. Melnyk, P.; Ducrot, P.; Thal, C. Tetrahedron 1993, 49, 8589±
8596.
4. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797±1842.
5. Itoh, M. Chem. Pharm. Bull. 1969, 17, 1679±1686.
6. King, F. E.; Kidd, D. A. A. J. Chem. Soc. 1949, 3315±3319.
7. Craig, J. C.; Bhargava, H. N.; Everhart, E. T.; LaBelle, B.;
Ohnsorge, U.; Webster, R. V. J. Org. Chem. 1988, 53, 1167±1170.
8. Fehrentz, J.; Castro, B. Synthesis 1983, 676±678.
9. Friedman, O. M.; Chatterji, R. J. Am. Chem. Soc. 1959, 81,
3750±3752.
1(S)-12b(S)-1-Pyrrol-1-yl-2,3,4,6,7,12,12b-hexahydro-1H-
indolo[2,3-a]quinolizin-4-one 20f. IR (CHCl3): nˆ3423
(NH); 3050±2950; 2355; 1642 (CO). MS (CI1): m/zˆ305
([M1H]1); 328; 170. HRMS (C19H19N3O): calcd 305.1518,
10. Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J.
Tetrahedron Lett. 1991, 32, 923±926.
11. Enantiomerically pure (ee .99%) as further proved by chiral
HPLC of the 1-amino[2,3-a]quinolizidine, see Ref. 3.
1
obs. 305.1521. H NMR (CDCl3, 200 MHz): 7.50 (1H, d,