Diastereocontrolled multicomponent pathway to 3,4-heterocycle-annulated tetrahydro-β-carbolines

Article abstract of DOI:10.1016/j.tetasy.2005.02.008

A diastereoselective synthesis, using the Yonemitsu-type trimolecular condensation as the key step, has been used for the preparation of 3,4-heterocycle(furanone-, pyrrolidinone- and pyranone-) annulated tetrahydro-β-carbolines. The chirality of D-gly-cer

Full text of DOI:10.1016/j.tetasy.2005.02.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1329–1339
Diastereocontrolled multicomponent pathway to
3,4-heterocycle-annulated tetrahydro-b-carbolines
´
´
´
Emmanuel Dardennes, Arpad Kovacs-Kulyassa, Michel Boisbrun, Christian Petermann,
Jean-Yves Laronze and Janos Sapi*
` ´
FRE CNRS 2715 ‘Isolement, Structure, Transformations et Synthese de Substances Naturelles’, IFR 53 ‘Biomolecules’,
´
Faculte de Pharmacie, 51 rue Cognacq Jay, F-51096 Reims Cedex, France
Received 15 December 2004; accepted 8 February 2005
Abstract—A diastereoselective synthesis, using the Yonemitsu-type trimolecular condensation as the key step, has been used for the
preparation of 3,4-heterocycle(furanone-, pyrrolidinone- and pyranone-) annulated tetrahydro-b-carbolines. The chirality of D-gly-
ceraldehyde or that of the GarnerÕs aldehyde ensured a high and predictable diastereocontrol of the additional newly created
stereocentres.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
X
X
FG
The tetrahydro-b-carboline core is a commonly occurring
structural feature of numerous Vinca-, Harman-, Rauwol-
fia-type alkaloids and related synthetic compounds with
valuable biological properties.1 3,4-Annulated (tetrahy-
dro)-b-carboline derivatives2 were reported to be benzodi-
azepine,3 tyrosine-kinase4 or glucagon-like peptide (GLP-
1) receptor inhibitors.5 Such a family of tetrahydro-b-
carbolines is accessible from heterocycle-fused trypt-
amines via the well-established Pictet–Spengler6 and Bis-
chler–Napieralski7 cyclisation reactions. Furthermore,
heterocycle-fused tryptamines are considered as interme-
diates for the preparation of conformationally congested
serotonin and melatonin analogues.8
3
4
+
OHC
*
*
O
NH
O
O
+
(Ar-CHO)
*
Ar
+
N
H
N
H
O
Pictet-Spengler
cyclisation
3,4-heterocycle-annulated
multicomponent approach
tetrahydro-β-carbolines
Chemoselective deprotection, followed by internal
nucleophilic attack on the MeldrumÕs acid moiety afford-
ed functionalised indolylpropionic acid derivatives in a
diastereoselective manner. The carboxylic acid function
of the latter was relayed towards heterocycle-fused
tryptamines.
As part of our ongoing programme on the synthetic
application of the Yonemitsu multicomponent reac-
tion,9 we have recently proposed an alternative path-
way10 using a masked nucleophile function containing
chiral aldehydes as electrophile partners for the prepara-
tion of such 3,4-heterocycle annulated tetrahydro-b-
carbolines.
Herein, we report in full detail an efficient access for the
synthesis of new, chiral, nonracemic 3,4-furane-, pyrane-
and pyrrolidine-ring annulated 1-aryl-substituted tetra-
hydro-b-carboline derivatives.
2. Results and discussion
Our synthetic approach is based on a diastereoselective tri-
molecular condensation between indole, MeldrumÕs acid
and orthogonally protected11 polyfunctional aldehydes.
2.1. Synthesis of 3,4-furane-annulated tetrahydro-
b-carbolines
Chiral indolyl lactone-acid 5 was obtained in two
steps via 4, from indole 1, 2,3-O-isopropylidene-D-
glyceraldehyde 212 and MeldrumÕs acid 3 with high
*
Corresponding author. Tel.: +33 0326 91 80 22; fax: +33 0326 91 80
29; e-mail: janos.sapi@univ-reims.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.008

1330
E. Dardennes et al. / Tetrahedron: Asymmetry 16 (2005) 1329–1339
diastereocontrol, as described previously.13 The primary
hydroxyl group of 5 was protected and the carboxylic
acid ! amine (carbamate) interconversion14 was
achieved by means of three consecutive functional group
transformations (Scheme 1): treatment of 6 with diph-
enylphosphorylazide (DPPA) in the presence of triethyl-
O
HO
O
O
NH2
O
OHC
N
H
ent-2
ent-10
amine, followed by
a thermally induced Curtius
rearrangement provided the appropriate isocyanate spe-
cies, which was trapped by benzyl alcohol furnishing the
corresponding benzyl carbamate 7 in acceptable yield
(63% from 6).
Scheme 2. Reagents and conditions: see Scheme 1.
found that cyclisation of the related tryptamines with
a trans relative stereochemistry failed under kinetic con-
trol.18 As for 10 condensation with benzaldehyde
smoothly occurred although the intermediate Schiff-base
did not cyclise even in the presence of acid promoter.
However, when Pictet–Spengler condensation was con-
ducted in refluxing benzene–TFA mixture, the corre-
sponding diastereomeric tetrahydro-b-carbolines 11
(24%) and 12 (31%) were isolated after chromatography
(Scheme 3).
O
O
O
O
O
+
OHC
O
2
O
i
O
O
O
O
+
N
H
N
H
4
3
1
O
O
R1O
O
HO
O
R1O
HO
O
O
O
H
O
O
ii
iv
5
3
3
COOH
4
H
H
NHR2
11
H
NH
NH
i
+
10
H
5
H
N
N
N
H
N
H
H
H
7 R1= TBDMS, R2= Cbz
8 R1= TBDMS, R2= H
9 R1= H, R2= Cbz
5 R1= H
6 R1= TBDMS
v
iii
11
12
vi
Scheme 3. Reagents and conditions: (i) (a) PhCHO, MeOH, D;
(b) TFA, benzene, D, 55%.
vii
10 R1= R2= H
Scheme 1. Reagents and conditions: (i) cat. D,L-proline, CH3CN, 76%;
(ii) 10% HCl, THF, 92%; (iii) TBDMSCl, imidazole, CH2Cl2, DMF,
90%; (iv) (a) DPPA, Et3N, CH3CN, 0 ꢁC, (b) D, toluene, (c) BnOH,
toluene, D, 63%; (v) Pd–C, H2, EtOAc, 80%; (vi) AcOH–H2O–THF,
60 ꢁC, 97%; (vii) Pd–C, H2, MeOH, 80%.
The absolute configuration of the newly created stereo-
centre (C-5) in 12 could not be determined by using
NOE methods because of overlapping of the appropri-
ate signals. Nevertheless, the observed long-range cou-
pling (5J = 1.4 Hz) between H-5 (d = 5.30 ppm) and H-
11 (d = 4.19 ppm) suggested a relative cis-position for
these protons. Conversely, no H-5/H-11 long-range cou-
pling was observed in the more polar diastereomer 11.
From these observations we concluded the less polar
diastereomer 12 to have a (5S)-configuration and conse-
quently 11 to be its epimer (5R). Additionally, C-3 and
C-5 carbons of diastereomer 12 shifted downfield
(d = 54.8 and 57.6 ppm in acetone-d6, respectively) rela-
tive to those of the more polar diastereomer 11 (d = 53.1
and 55.2 ppm, respectively). It is known that these
carbon atoms in trans-1,3-disubstituted (numbering: b-
carboline skeleton) tetrahydro-b-carbolines are consis-
tently upfielded to those of the cis-isomer.19 From this
knowledge we concluded a cis relative stereochemistry
for the H-5 and H-3 protons in 12 and trans in 11. Such
a stereochemical arrangement supported the epimerisa-
tion of the C-3 carbon via imine–iminium species during
the Pictet–Spengler cyclisation.20
Acyl azide formation via a mixed anhydride15 failed. It is
important to note that acid 6 was very sensitive to decar-
boxylation; therefore unreacted starting material, re-
agents and eventually formed by-products had to be
removed by rapid flash chromatography on a short col-
umn. Without this purification, the overall yield dropped
to 30–35%. Debenzylation of carbamate 7 gave the corre-
sponding amine 8 in 80% yield. To obtain chiral furane-
annulated tryptamine 10, acid catalysed desilylation, fol-
lowed by debenzylation of 9 was proposed. As Curtius
rearrangements are known to proceed with retention,
the absolute configuration of tryptamine 10 remained un-
changed [(3R,4R,5S)], as supported by detailed NMR
experiments. Enantiomeric tryptamine ent-10 was pre-
pared starting from 2,3-O-isopropylidene-L-glyceralde-
hyde ent-216 via the same manipulations (Scheme 2).
It is important to note that the 5-epimer of ent-10 has
been described by Dodd and co-workers by using a
Lewis acid catalysed regio- and stereoselective ring
opening of chiral aziridino-furasonide as key step.17
This poor C-5 diastereoselectivity could be slightly im-
proved to the detriment of the total yield by using a
higher excess of benzaldehyde and decreased quantity
of TFA. Silylether containing amine 8 gave the same tet-
rahydro-b-carbolines in lower yield along with trifluoro-
acetamido by-products.
Pictet–Spengler cyclisation of trans furane-fused trypt-
amine 10 proved to be troublesome. Previously we

E. Dardennes et al. / Tetrahedron: Asymmetry 16 (2005) 1329–1339
1331
2.2. Synthesis of 3,4-pyrane- and pyrrolidine-annulated
tetrahydro-b-carbolines
3 %
H
10 %
H
O
H
N
Continuing our studies on the synthesis of chiral 3,4-het-
erocycle fused tetrahydro-b-carbolines, it was interesting
to examine the diastereocontrol of newly formed stereo-
centres by using an orthogonally protected bifunctional
chiral aldehyde such as the GarnerÕs aldehyde 13.21
H
6
O
COOCH3
4
3
Boc
H
H
N
H
To this end, a three-component condensation of Gar-
nerÕs aldehyde 13 with indole 1, and MeldrumÕs acid 3
provided the unstable corresponding adduct 14 (90%)
in good (de >90%) diastereoselectivity.10 Depending on
the solvolysis conditions, chemoselective internal O- or
N-nucleophilic ring closures were envisaged (Scheme 4).
Figure 1. NOE interactions in compound 15.
reochemical correlation between the pyrano 15 and
pyrrolidino 16 series.
Pyrrolidine ester 16 could also be prepared from trimo-
lecular adduct 14 in a one-pot reaction (Scheme 4). A
third route to the key intermediate 16 has also been
developed: the DIBAL-H mediated reduction of the
N-benzyloxycarbonyl L-serinate derivative 1722 led to
the corresponding crude aldehyde, which was condensed
with indole 1 and MeldrumÕs acid 3, as usual, to yield
trimolecular derivative 18. Hydrogenolytic removal of
the Cbz-group with Pd–C failed in aprotic solvents
(ethyl acetate, THF, acetone) even at medium pressure
of hydrogen (10 bar). In contrast, debenzylation
smoothly took place in ethanol at normal pressure with
simultaneous solvolysis of the isopropylidene protecting
group. Treatment of the intermediate with an excess of
diazomethane provided 16, identical in all respects to
that obtained by the two previously mentioned methods.
O
O
+
N
O
H
O
O
1
3
O
+
+
NBoc
NCbz
CHO
13
COOCH3
i
17
v
O
NBoc
O
NCbz
O
O
O
O
O
O
O
O
N
H
N
H
18
14
ii
iv
vi
HO
Before conversion of the carboxylic acid into the carba-
mate, functional group transformations, for example,
protection of the primary alcohol to give 19, followed
by hydrolysis of the ester function, were realised
(Scheme 5). Acid 20 was transformed into carbamate
6
O
H
N
5
Boc-HN
O
O
5
3
3
4
4
COOCH3
COOCH3
iii
N
H
N
H
15
16
TBDMSO
R1O
H
N
H
N
O
O
Scheme 4. Reagents and conditions: (i) cat. D,L-proline, CH3CN, 90%;
(ii) (a) p-TsOH, MeOH, (b) CH2N2, 86%; (iii) TFA, CH2Cl2, 95%; (iv)
HCl–MeOH, 71% (v) (a) DIBAL-H, toluene ꢀ78 ꢁC, then 1 and 3, (b)
cat. D,L-proline, CH3CN, 57%; (vi) (a) Pd–C, H2, EtOH, (b) CH2N2,
63%.
iii
NHR
COOR2
N
H
N
H
21 R= Cbz
22 R= H
16 R1= H, R2= CH3
Mild isopropylidene deprotection of 14 in methanol
containing a catalytic amount of p-TsOH, smoothly
afforded the appropriate, very unstable d-lactone-acid,
which was immediately subjected to diazomethane-
assisted methylation. The absolute configuration of the
two newly created stereocentres of 15 was determined
by detailed NMR experiences. The large coupling con-
stant between H-3 and H-4 protons (3J = 11.6 Hz) is in
accordance with their trans relative stereochemistry,
while strong NOE interactions between the irradiated
NH and H-4 and H-6 protons evidenced equatorial po-
sition for the substituents and (R) absolute configura-
tion for C-4 carbon (Fig. 1).
iv
i
19 R1= TBDMS, R2= CH3
20 R1= TBDMS, R2= H
ii
v
H
N
H
HO
H
H
N
HO
O
O
12
H
NH
H
H
H
+
11
3
NH
H
H
5
N
N
H
H
23a
23b
Scheme 5. Reagents and conditions: (i) TBDMSCl, imidazole, DMF,
80%; (ii) KOH aq, 87%; (iii) (a) DPPA, Et3N, CH3CN, 0 ꢁC, (b) D,
THF, (c) BnOH, THF, D, 80%; (iv) Pd–C, H2, EtOAc, 97%; (v) (a)
PhCHO, dry MgSO4, (b) TFA, toluene, D, 67% (23a), 17% (23b).
Further hydrolysis of 15 with TFA removed the Boc
protecting group allowing ring contractile lactamisation
affording 16. This deprotection enabled us to set up ste-

1332
E. Dardennes et al. / Tetrahedron: Asymmetry 16 (2005) 1329–1339
21 by diphenylphosphoryl azide assisted acyl azide for-
mation, followed by a Curtius rearrangement in the
presence of benzyl alcohol. Deprotection of 21 by
hydrogenolysis led almost quantitatively to pyrroli-
dinone tryptamine 22.
protons in accord with their cis relative configuration.
No correlation was observed between H-5 and H-3.
Owing to the overlapping of angular protons
(d = 3.91 ppm) the trans C/D ring junction was deter-
mined by couplings measured between H-3 and H-11,
and neighbouring methylene protons H-2 and H-12,
respectively. Geminal protons H-2 were observed as
two doublets at d = 4.51 and 4.73 ppm, the upfield one
with two large coupling constants (JH-2a/H-2b = 10.9 Hz
and JH-2b/H-3 = 10.9 Hz), supporting H-3/H-2a trans
diaxial position. Similarly, trans diaxial arrangement
was observed between H-11 and H-12a (d = 2.61 ppm,
JH-12a/H-11 = 12.9 Hz) protons. Equatorial position of
H-12b was evidenced by a smaller JH-12b/H-11 = 5.3 Hz
coupling constant.
Pictet–Spengler cyclisation of 22 with benzaldehyde
under thermodynamic conditions provided 1,3,4-trisub-
stituted tetrahydro-b-carboline 23a in 67% yield, along
with some C-5 epimer 23b (17%). Investigation of the
stereochemical outcome by detailed NMR experiments
(e.g., JH-3/H-11 = 6.5 and 7.0 Hz for 23a and 23b, respec-
tively) confirmed the supposed C-3 epimerisation during
the thermally induced Pictet–Spengler cyclisation.20
Thus, the all-cis nature of H-5, H-3, H-11 and H-12 pro-
tons in 23a was established by long-range COSY and
NOESY experiments. In 23b the absence of a correla-
tion between H-5 and H-3, H-11 indicated that the
minor compound 23b had an opposite C-5 absolute
configuration. Additionally, Bailey and CookÕs empiri-
cal observations19 were in accordance with the relative
cis in 23a and trans in 23b, configurations concerning
the H-5 and H-3 protons.
As a preliminary result, a new type of tetrahydro-b-carb-
oline derivative 26 was obtained (65%) when the trimo-
lecular adduct 14 was treated with a saturated HCl–
MeOH solution at room temperature and the intermedi-
ate subsequently refluxed with syringaldehyde. The for-
mation of 26 can be explained by a multistep process
involving complete deprotection, methanolysis of the
MeldrumÕs acid moiety and final Pictet–Spengler cyclis-
ation. In fact, the 3,5-dimethoxy-4-hydroxyphenyl
appendage is commonly found in polycyclic compounds
of biological interest and chiral 1,2-aminoalcohol moiety
with neighbouring malonester function could be consid-
ered as anchoring points for further heterocyclisation.
The stereochemistry of the C-1 carbon of 26 was estab-
lished to be (S) owing to the correlation between the
H-1 and H-4 protons in the COSY and NOESY spectra.
Treatment of trimolecular condensation product 14 with
70% aqueous acetic acid at room temperature provided
pyrane-fused tryptamine 24 (82%), as a result of selective
isopropylidene deprotection, followed by internal ring
opening of the MeldrumÕs acid appendage and decarbox-
ylation (Scheme 6). The trans relative configuration of H-
4 (d = 3.63 ppm) and H-5 (d = 4.27 ppm) protons (pyra-
none numbering) in 24 was supported by the observed
large coupling constant (J = 8.9 Hz). Pyranone-annu-
lated tetrahydro-b-carboline 25 was prepared in 49%
yield by stirring a solution of 24 with benzaldehyde in
the presence of the desiccating agent (MgSO4) and
TFA at room temperature. The stereochemistry of 25
was determined by combined NMR methods. NOESY
experiments showed correlation between H-5 and H-11
3. Conclusion
In summary, a diastereoselective synthesis using the
Yonemitsu-type trimolecular condensation as key step
has been developed for the preparation of 3,4-fura-
none-, pyrrolidinone- and pyranone-annulated tetrahy-
dro-b-carbolines of biological interest. We have shown
that the chirality of D-glyceraldehyde or that of the Gar-
nerÕs aldehyde ensured a high and predictable enantio-
control of the additional newly created stereocentres.
Application of this strategy using multifunctional chiral
aldehydes to the synthesis of polycyclic compounds is in
progress.
O
O
O
5
2
O
ii
12
BocNH
4
H
H
3
5
11
NH
H
i
N
H
N
H
14
24
25
4. Experimental
COOCH3
iii
OH
H3COOC
3
4
General: Melting points were determined on a Reichert
Thermovar hot-stage apparatus and are uncorrected. IR
spectra were measured with a BOMEM FTIR instru-
NH
H
1
N
H
ment. H NMR (300 MHz) and 13C NMR (75 MHz)
1
spectra were recorded on Bruker AC 300 spectrometer
using TMS as internal standard. All mass spectrometric
measurements were run on VG Autospec apparatus.
Optical rotations were measured in a 10 cm pathlength
cell at 21 ꢁC using a Perkin–Elmer 241 polarimeter.
Reactions were monitored using Merck precoated plates
(Kieselgel 60 F254). Column chromatography was
OCH3
CH3O
OH
26
Scheme 6. Reagents and conditions: (i) AcOH aq, rt, 82%; (ii) (a)
PhCHO, CH2Cl2, dry MgSO4, (b) TFA, rt, 49%; (iii) (a) HCl–MeOH,
CH2Cl2, rt, (b) syringaldehyde, CH2Cl2, D, 65%.

E. Dardennes et al. / Tetrahedron: Asymmetry 16 (2005) 1329–1339
1333
performed on SDS Chromagel (silica gel 35–70 or 70–
200 lm) support.
123.0, 127.6, 137.0, 169.4, 172.4 ppm; MS (FAB, magic
bullet) m/z (%) = 298 (M+Na+, 55), 276 (M+H+, 100),
275 (M+Å, 70); HRMS (FAB, magic bullet) for
C14H13NO5 calcd: 275.0794. Found: 275.0800.
4.1. (S,S)-5-[(2,2-Dimethyl-1,3-dioxolan-4-yl)-(1H-indol-
3-yl)-methyl]-2,2-dimethyl-1,3-dioxan-4,6-dione, 4
4.4. (3R,4R,5R)-5-Hydroxymethyl-4-(1H-indol-3-yl)-2-
oxotetrahydrofuran-3-carboxylic acid, ent-5
To a solution of 2,3-O-isopropylidene-D-glyceraldehyde
2 (502 mg, 3.86 mmol) in acetonitrile (50 mL) were
added successively indole 1 (226 mg, 1.93 mmol), Mel-
drumÕs acid 3 (278 mg, 1.93 mmol) and D,L-proline
(11 mg, 0.096 mmol). The reaction mixture was stirred
at room temperature under N2 for 36 h, the solvent
was evaporated and the residue was purified by column
chromatography (hexane–ethyl acetate 8:2) to afford 4
(550 mg, 76%), as a yellowish solid. Mp: 65 ꢁC (hexane);
[a]D = ꢀ33.2 (c 1.22, CHCl3); IR (KBr) m = 3408, 2988,
Yield: 91%. Mp: 86–87 ꢁC (ether); [a]D = ꢀ137.1 (c 0.84,
MeOH); HRMS (FAB, magic bullet) for C14H13NO5
calcd: 275.0794. Found: 275.0781.
4.5. (3S,4S,5S)-5-(tert-Butyldimethylsilanyloxymethyl)-
4-(1H-indol-3-yl)-2-oxotetrahydrofuran-3-carboxylic
acid, 6
1773 and 1740 cmꢀ1
;
1H NMR (CDCl3): d = 1.09 (s,
To an ice-cooled solution of acid 5 (697 mg, 2.53 mmol)
in dry DMF (2 mL) and dry CH2Cl2 (13 mL), imidazole
(431 mg, 6.33 mmol) and tert-butyldimethylsilyl chlo-
ride (TBDMSCl) (955 mg, 6.34 mmol) were added and
the reaction mixture stirred at room temperature under
N2 for 20 h. After quenching with methanol (1 mL), the
solution was diluted with CH2Cl2 and washed with 10%
HCl solution. The aqueous phase was extracted with
CH2Cl2 (3 · 10 mL); the combined organic phases were
washed with water, dried over Na2SO4, evaporated and
the residue was purified by column chromatography
(heptane–ethyl acetate 7:3!1:1, 0.5% acetic acid) to
provide 6 (886 mg, 90%) as a white amorphous solid.
Mp: 63–64 ꢁC (hexane); [a]D = +115.9 (c 0.96, CHCl3);
3H), 1.34 (s, 3H), 1.39 (s, 3H), 1.61 (s, 3H), 3.68 (d,
1H, J = 2.8 Hz), 3.99 (dd, 1H, J = 8.1, 7.0 Hz), 4.26
(dd, 1H, J = 8.1, 5.9 Hz), 4.35 (dd, 1H, J = 9.0,
2.8 Hz), 5.08 (ddd, 1H, J = 9.0, 7.0, 5.9 Hz), 7.11–7.16
(m, 3H), 7.25 (d, 1H, J = 6.0 Hz), 7.66 (d, 1H,
J = 6.0 Hz), 8.32 (br s, 1H) ppm; 13C NMR (CDCl3):
d = 25.7, 26.8, 27.9, 28.2, 40.1, 48.9, 68.0, 77.1, 105.6,
109.7, 111.1, 111.8, 119.1, 120.0, 122.3, 123.8, 127.0,
135.5, 165.4, 165.5 ppm; MS (EI) m/z (%) = 373 (M+Å,
12), 300 (4), 273 (8), 272 (7), 258 (7), 196 (6), 187 (8),
170 (100); HREIMS for C20H23NO6 calcd: 373.1525.
Found: 373.1549.
4.2. (R,R)-5-[(2,2-Dimethyl-1,3-dioxolan-4-yl)-(1H-indol-
3-yl)-methyl]-2,2-dimethyl-1,3-dioxan-4,6-dione, ent-4
IR (film) m = 3410, 2955, 2930, 2859, 1771, 1723 cmꢀ1
;
1H NMR (CDCl3): d = ꢀ0.10 (s, 3H), ꢀ0.04 (s, 3H),
0.85 (s, 9H), 3.43 (d, 1H, J = 11.3 Hz), 3.74 (dd, 1H,
J = 11.3, 2.2 Hz), 4.34 (d, 1H, J = 12.8 Hz), 4.60 (dd,
1H, J = 12.8, 8.0 Hz), 4.98 (dd, 1H, J = 8.0, 2.2 Hz),
7.13–7.27 (m, 3H), 7.40 (d, 1H, J = 8.0 Hz), 7.52 (d,
1H, J = 8.0 Hz), 8.22 (br s, 1H), 9.37 (br s, 1H) ppm;
13C NMR (CDCl3): d = ꢀ6.2, ꢀ6.1, 17.9, 25.5, 39.9,
51.2, 62.0, 81.0, 109.3, 111.5, 118.0, 119.7, 122.2,
122.3, 126.4, 136.1, 172.1, 172.6 ppm; MS (FAB, magic
bullet) m/z (%) = 412 (M+Na+, 100); HRMS (FAB,
magic bullet) for C20H27NO5NaSi (M+Na)+ calcd:
412.1556. Found: 412.1565.
Yield: 66%. Mp: 65 ꢁC (hexane); [a]D = +34.8 (c 1.27,
CHCl3); HREIMS for C20H23NO6 calcd: 373.1525.
Found: 373.1541.
4.3. (3S,4S,5S)-5-Hydroxymethyl-4-(1H-indol-3-yl)-2-
oxotetrahydrofuran-3-carboxylic acid, 5
To a solution of 4 (767 mg, 2.06 mmol) in THF
(12.5 mL), 10% HCl solution (7 mL) was added drop-
wise and the reaction mixture stirred at room tempera-
ture for 30 min. After evaporation of THF, the residue
was partitioned between satd Na2CO3 solution
(20 mL) and ethyl acetate (20 mL). The organic phase
was extracted with satd NaHCO3 solution (2 · 10 mL),
the combined aqueous layers acidified with solid citric
acid to pH = 5 and this acidic solution further extracted
with ethyl acetate (3 · 15 mL). The combined organic
layers were dried over Na2SO4, filtered, evaporated
and the residue purified by column chromatography
(hexane–ethyl acetate 1:1 with 0.5% acetic acid) and
then crystallised in anhydrous diethyl ether to give acid
5 (520 mg, 92%). Mp: 87–88 ꢁC (ether); [a]D = +138.6 (c
0.82, MeOH); IR (KBr) m = 3410, 2924, 1769,
4.6. (3R,4R,5R)-5-(tert-Butyldimethylsilanyloxymethyl)-
4-(1H-indol-3-yl)-2-oxotetrahydrofuran-3-carboxylic
acid, ent-6
Yield: 87%. Mp: 63–64 ꢁC (hexane); [a]D = ꢀ120.0 (c
1.00, CHCl3); HRMS (FAB, magic bullet) for
C20H27NO5NaSi (M+Na)+ calcd: 412.1556. Found:
412.1533.
4.7. (3R,4R,5S)-[5-(tert-Butyldimethylsilanyloxymethyl)-
4-(1H-indol-3-yl)-2-oxotetrahydrofuran-3-yl]-carbamic
acid benzyl ester, 7
1736 cmꢀ1 1H NMR (acetone–d6): d = 3.49 (dd, 1H,
;
J = 12.3, 3.1 Hz), 3.70 (dd, 1H, J = 12.3, 2.6 Hz), 4.43
(d, 1H, J = 12.2 Hz), 4.71 (dd, 1H, J = 12.2, 8.1 Hz),
5.16 (m, 1H), 7.13 (m, 1H), 7.19 (m, 1H), 7.47 (s, 1H),
7.49 (d, 1H, J = 7.8 Hz), 7.75 (d, 1H, J = 7.8 Hz),
10.34 (br s, 1H) ppm; 13C NMR (acetone-d6): d = 40.3,
51.8, 61.3, 81.8, 109.8, 111.7, 118.6, 119.4, 122.0,
To an ice-cooled solution of 6 (96 mg, 0.247 mmol) in
acetonitrile (3 mL) were added triethylamine (52 lL,
0.371 mmol) and DPPA (108 lL, 0.499 mmol) under
N2 and the resulting mixture stirred for 3 h while
being warmed to room temperature. After evapora-
tion of the solvent the residue was purified by flash

1334
E. Dardennes et al. / Tetrahedron: Asymmetry 16 (2005) 1329–1339
chromatography (cyclohexane–ethyl acetate 1:1). The
crude azide obtained was dissolved in dry toluene
(3 mL) and the solution heated at 70 ꢁC under N2. After
1 h heating benzyl alcohol (31 lL, 0.300 mmol) was
added via syringe and the heating prolonged for a fur-
ther 20 h. After cooling the solvent was evaporated,
and the residue purified by column chromatography
(heptane–ethyl acetate 8:2!7:3) giving 7 as a white solid
(77 mg, 63%). Mp: 78–79 ꢁC (heptane); [a]D = +96.2 (c
0.68, CHCl3); IR (film) m = 3370, 2956, 2928, 2857,
were evaporated and the residue purified by column
chromatography (ethyl acetate–heptane 1:1!6:4) to
afford 9 (83 mg, 97%), as a white solid. Mp: 87–88 ꢁC
(heptane); [a]D = +86.3 (c 0.76, CH2Cl2); IR (film)
1
m = 3434, 3368, 3320, 2926, 1775, 1701, 1528 cmꢀ1; H
NMR (CDCl3): d = 2.95 (br s, 1H) 3.33 (d, 1H,
J = 12.1 Hz), 3.56 (d, 1H, J = 12.1 Hz), 4.26 (dd, 1H,
J = 12.4, 8.3 Hz), 4.86 (d, 1H, J = 8.3 Hz), 4.93 (s,
2H), 5.26 (dd, 1H, J = 12.4, 9.1 Hz), 5.76 (d, 1H,
J = 9.1 Hz), 7.06–7.44 (m, 10H), 8.62 (s, 1H) ppm; 13C
NMR (CDCl3): d = 41.1, 54.1, 61.4, 67.4, 80.4, 108.9,
111.8, 118.0, 119.9, 122.5, 123.1, 127.1, 127.9, 128.1,
128.4, 135.7, 136.3, 156.5, 175.7 ppm; MS (EI) m/z
(%) = 380 (M+Å, 27), 272 (26), 229 (75), 198 (25), 184
(15), 173 (61), 156 (32), 144 (27), 130 (100), 117 (63);
HREIMS for C21H20N2O5 calcd: 380.1372. Found:
380.1388.
1
1779, 1705, 1524 cmꢀ1; H NMR (CDCl3): d = ꢀ0.04
(s, 3H), ꢀ0.01 (s, 3H), 0.92 (s, 9H), 3.40 (d, 1H,
J = 11.4 Hz), 3.73 (dd, 1H, J = 11.4, 1.6 Hz), 4.14 (dd,
1H, J = 12.0, 8.3 Hz), 4.93 (d, 1H, J = 8.3 Hz), 5.00
(AB system, 1H, J = 12.4 Hz), 5.05 (AB system, 1H,
J = 12.4 Hz), 5.49 (dd, 1H, J = 12.0, 9.4 Hz), 5.67 (d,
1H, J = 9.4 Hz), 7.17–7.54 (m, 10H), 8.73 (s, 1H) ppm;
13C NMR (CDCl3): d = ꢀ6.0, ꢀ5.9, 18.1, 25.7, 42.7,
53.8, 62.0, 67.2, 79.5, 109.2, 111.6, 118.0, 119.9, 122.4,
123.2, 127.1, 127.9, 128.1, 128.4, 135.9, 136.3, 156.4,
175.1 ppm; MS (EI) m/z (%) = 494 (M+Å, 18), 437 (10),
409 (8), 393 (9), 319 (13), 286 (92), 275 (17), 156 (22),
130 (57), 117 (100); HREIMS for C27H34N2O5Si calcd:
494.2237. Found: 494.2226.
4.11. (3S,4S,5R)-(5-Hydroxymethyl-4-(1H-indol-3-yl)-
2-oxotetrahydrofuran-3-yl)-carbamic acid benzyl ester,
ent-9
Yield: 97%. Mp: 86–87 ꢁC (heptane); [a]D = ꢀ88.6 (c
0.77, CH2Cl2); HREIMS for C21H20N2O5 calcd:
380.1372. Found: 380.1361.
4.8. (3S,4S,5R)-[5-(tert-Butyldimethylsilanyloxymethyl)-
4-(1H-indol-3-yl)-2-oxotetrahydrofuran-3-yl]-carbamic
acid benzyl ester, ent-7
4.12. (3R,4R,5S)-(3-Amino-4-(1H-indol-3-yl)-5-hydroxy-
methyl)-dihydrofuran-2-one, 10
Yield: 70%. Mp: 77–78 ꢁC (heptane); [a]D = ꢀ95.8 (c
0.68, CHCl3); HREIMS for C27H34N2O5Si calcd:
494.2237. Found: 494.2195.
A solution of 9 (136 mg, 0.358 mmol) and triethylamine
(three drops) in methanol (7 mL) was hydrogenated over
10% Pd–C (30 mg) for 2.5 h. The catalyst was filtered on
a Celite pad and the filtrate purified by column chroma-
tography (toluene–methanol 9:1!8:2 with 0.2% Et3N)
to give 10 (70 mg, 80%), as a white solid. Mp: 170–
172 ꢁC; [a]D = +186.1 (c 0.63, MeOH); IR (KBr)
m = 3431, 3397, 3368, 3053, 2928, 2866, 1769,
4.9. (3R,4R,5S)-(3-Amino-5-(tert-butyldimethylsilanyl-
oxymethyl)-4-(1H-indol-3-yl))-dihydrofuran-2-one, 8
A solution of 7 (172 mg, 0.348 mmol) and triethylamine
(three drops) in ethyl acetate (5 mL) was hydrogenated
over 10% Pd–C (25 mg) for 24 h. The catalyst was re-
moved by filtration, the filtrate evaporated and the res-
idue purified by chromatography (ethyl acetate–
heptane 1:1!6:4 with 0.5% Et3N) to yield 8 (100 mg,
80%), as a white solid. Mp: 185–187 ꢁC (heptane);
[a]D = +136.4 (c 0.68, CH2Cl2); IR (film) m = 3378,
1622 cmꢀ1 1H NMR (CD3OD): d = 3.35 (dd, 1H,
;
J = 12.1, 3.4 Hz), 3.53 (dd, 1H, J = 12.1, 2.6 Hz), 4.06
(dd, 1H, J = 12.4, 8.4 Hz,), 4.51 (d, 1H, J = 12.4 Hz),
4.95 (m, 1H), 7.05 (dt, 1H, J = 7.5, 1.1 Hz), 7.14 (dt,
1H, J = 7.5, 1.1 Hz), 7.38 (s, 1H), 7.42 (d, 1H,
J = 8.0 Hz), 7.58 (d, 1H, J = 8.0 Hz) ppm; 13C NMR
(CD3OD) = 44.6, 54.7, 61.8, 82.4, 109.6, 112.6, 119.0,
120.3, 122.9, 123.9, 128.7, 138.2, 179.2 ppm; MS (EI)
m/z (%) = 246 (M+Å, 18), 173 (78), 158 (18), 144 (27),
130 (100), 117 (70); HREIMS for C13H14N2O3 calcd:
246.1004. Found: 246.0996.
2930, 2859, 1773, 1644 cmꢀ1
;
1H NMR (CDCl3):
d = ꢀ0.08 (s, 3H), ꢀ0.04 (s, 3H), 0.84 (s, 9H), 1.86 (br,
2H), 3.42 (dd, 1H, J = 11.6, 1.5 Hz), 3.71 (dd, 1H,
J = 11.6, 2.7 Hz), 3.89 (dd, 1H, J = 12.0, 8.3 Hz), 4.38
(d, 1H, J = 12.0 Hz), 4.81 (m, 1H), 7.12–7.26 (m, 3H)
7.40 (d, 1H, J = 7.9 Hz), 7.53 (d, 1H, J = 7.9 Hz), 8.47
(s, 1H) ppm; 13C NMR (CDCl3): d = ꢀ5.9, 18.1, 25.8,
44.7, 54.6, 61.9, 79.6, 110.2, 111.5, 118.1, 119.8, 122.0,
122.5, 127.3, 136.3, 178.7 ppm; MS (EI) m/z (%) = 360
(M+Å, 1), 275 (56), 230 (12), 183 (18), 159 (42), 130
(38), 117 (100); HREIMS for C19H28N2O3Si calcd:
360.1869. Found: 360.1889.
4.13. (3S,4S,5R)-(3-Amino-4-(1H-indol-3-yl)-5-hydroxy-
methyl)-dihydrofuran-2-one, ent-10
Yield: 65%. Mp: 168–170 ꢁC (heptane); [a]D = ꢀ185.5 (c
0.59, MeOH); HREIMS for C13H14N2O3 calcd:
246.1004. Found: 246.0981.
4.14. (3S,5R,11R,12S)-12-Hydroxymethyl-5-phenyl-
3,4,5,11-tetrahydrofuro[3,4-c]-b-carboline-2(12H)-one,
11, and (3S,5S,11R,12S)-12-hydroxymethyl-5-phenyl-
3,4,5,11-tetrahydrofuro[3,4-c]-b-carboline-2(12H)-one, 12
4.10. (3R,4R,5S)-(5-Hydroxymethyl-4-(1H-indol-3-yl)-2-
oxotetrahydrofuran-3-yl)-carbamic acid benzylester, 9
A solution of 7 (111 mg, 0.225 mmol) in a mixture of
acetic acid (4 mL), water (1.5 mL) and THF (1.5 mL)
was heated to 60 ꢁC for 20 h. After cooling, the solvents
A solution of 10 (31.0 mg, 0.126 mmol) and benzalde-
hyde (19 lL, 0.188 mmol) in methanol (3 mL) was

E. Dardennes et al. / Tetrahedron: Asymmetry 16 (2005) 1329–1339
1335
heated to reflux under N2 for 1.5 h. After cooling, the
solvent was evaporated and the residue co-evaporated
with dry benzene. The resulting yellow solid was dis-
solved in dry benzene (7 mL) and to this solution,
1.71 (s, 9H), 1.83 (s, 3H), 2.05 (s, 3H), 4.17 (dd, 1H,
J = 9.3, 6.3 Hz), 4.46 (s, 1H), 4.98 (br s, 1H), 5.12 (br
s, 1H), 5.34 (br d, 1H, J = 4.0 Hz), 7.38–7.52 (m, 4H),
7.86 (br s, 1H), 8.32 (d, 1H, J = 5.2 Hz) ppm; 13C
NMR (C6D6, 343 K): d = 27.3, 28.0, 28.2, 28.3, 28.5,
39.6, 48.7, 61.0, 66.2, 80.2, 94.5, 104.6, 111.3, 112.3,
119.7, 120.2, 122.4, 125.3, 128.6, 135.9, 153.2, 165.4,
166.3 ppm; MS (FAB, gly) m/z (%) = 474 ((M+H)+, 6),
473 (M+Å, 21), 472 (7), 414 (9), 359 (30), 301 (43), 273
(27), 245 (35), 200 (29), 187 (32), 185 (24), 170 (100).
˚
molecular sieves (4 A) and TFA (19 lL, 0.245 mmol)
added and the mixture stirred and heated to reflux under
N2 for 3 h. The cooled solution was washed with satd
K2CO3 solution (10 mL). The aqueous phase was ex-
tracted with ethyl acetate (7 mL) and the combined
organic layers dried over Na2SO4, filtered and purified
by column chromatography (toluene–ethyl acetate
8:2!7:3 with 0.5% of Et3N) to afford the (5S)-isomer
12 (13.2 mg, 31%), as a white solid. Mp: 250–252 ꢁC
(hexane–CH2Cl2); [a]D = +105.3 (c 0.26, acetone); IR
(KBr) m = 3449, 3416, 3391, 3312, 3265, 2861, 1780,
4.16. (3R,4R,5R)-5-tert-Butoxycarbonylamino-4-(1H-
indol-3-yl)-2-oxo-tetrahydropyran-3-carboxylic acid
methyl ester, 15
1456 cmꢀ1
;
1H NMR (acetone-d6): d = 2.85 (s, 1H),
A solution of 14 (404 mg, 0.85 mmol) and p-TsOH
(10 mg, 0.05 mmol) in methanol (10 mL) was stirred at
room temperature for 1 h 15 min. Then freshly prepared
ethereal diazomethane solution was added to the reac-
tion mixture and allowed to stand at 0–5 ꢁC for
30 min. The solvents were removed under reduced pres-
sure and the residue heated under reflux in CH2Cl2
(10 mL) in the presence of p-TsOH (10 mg) for 6 h.
The solvent was evaporated and the crude product puri-
fied by chromatography (cyclohexane–ethyl acetate 1:1),
crystallised in hexane–CH2Cl2 to give 15 (283 mg, 86%),
as white crystals. Mp: 147–149 ꢁC (hexane–CH2Cl2);
[a]D = ꢀ18.6 (c 1.00, CHCl3); IR (film) m = 3397, 2928,
3.61 (m, 2H), 4.02 (d, 1H, J = 7.3 Hz), 4.19 (ddd, 1H,
J = 8.6, 7.3, 1.4 Hz), 5.30 (d, 1H, J = 1.4 Hz), 5.36 (dt,
1H, J = 8.6, 3.4 Hz), 7.07 (m, 2H), 7.29–7.45 (m, 6H)
7.57 (dd, 1H, J = 6.8, 2.0 Hz), 9.76 (br s, 1H) ppm; 13C
NMR (acetone-d6): d = 36.2, 54.8, 57.6, 60.8, 82.4,
103.8, 111.3, 117.8, 119.3, 121.4, 126.5, 128.1, 128.4,
128.8, 136.1, 136.6, 140.0, 174.4 ppm; MS (EI) m/z
(%) = 335 ((M+1)+, 23), 334 (M+Å, 100), 333 (35), 259
(32), 257 (45), 245 (44), 220 (39), 219 (60), 169 (77);
HREIMS for C20H18N2O3 calcd: 334.1317. Found:
334.1289.
Continuing the chromatography with toluene–ethyl ace-
tate 1:1 then heptane–acetone 1:1 (both containing 0.5%
Et3N) the more polar isomer 11 [(5R)-isomer] (10.2 mg,
24%) was collected. Mp: 111–112 ꢁC (hexane–CH2Cl2);
[a]D = +98.0 (c 0.20, acetone); IR (KBr) m = 3433,
1753–1697, 1520, 1460 cmꢀ1 1H NMR (acetone-d6):
;
d = 1.26 (s, 9H), 3.51 (s, 3H), 3.95 (dd, 1H, J = 11.6,
8.6 Hz), 4.22 (d, 1H, J = 11.6 Hz), 4.30–4.38 (m, 2H),
4.63 (dd, 1H, J = 10.8, 3.8 Hz), 6.46 (d, 1H,
J = 7.2 Hz), 7.03 (t, 1H, J = 7.9 Hz), 7.11 (t, 1H, J =
7.9 Hz), 7.31 (d, 1H, J = 2.3 Hz), 7.39 (d, 1H,
J = 7.9 Hz), 7.70 (d, 1H, J = 7.9 Hz), 10.23 (br s,
1H) ppm; 13C NMR (acetone-d6): d = 27.7, 38.4, 50.5,
51.9, 53.8, 70.6, 78.6, 111.8, 113.6, 119.1, 119.2, 121.8,
123.0, 126.7, 137.1, 155.5, 167.4, 168.7 ppm; MS (EI)
m/z (%) = 388 (M+Å, 5), 332 (12), 271 (63), 213 (45),
212 (100), 201 (46), 170 (81); HREIMS for
C20H24N2O6 calcd: 388.1634. Found: 388.1627.
3389, 3319, 3281, 2924, 2854, 1768, 1454 cmꢀ1 1H
;
NMR (acetone-d6) d = 2.88 (br s, 1H), 3.48 (dd, 1H,
J = 12.1, 4.4 Hz), 3.80 (dd, 1H, J = 12.1, 3.7 Hz), 3.95
(d, 1H, J = 7.1 Hz), 4.23 (dd, 1H, J = 7.1, 7.0 Hz), 5.18
(ddd, 1H, J = 7.0, 4.4, 3.4 Hz), 5.33 (s, 1H), 7.09 (m,
2H), 7.25–7.37 (m, 6H), 7.68 (dd, 1H, J = 6.7, 1.6 Hz),
9.97 (br s, 1H) ppm; 13C NMR (acetone-d6): d = 37.1,
53.1, 55.2, 62.2, 83.5, 105.2, 112.3, 119.5, 120.2, 122.5,
127.8, 128.8, 129.3, 136.8, 137.5, 141.7, 176.3 ppm; MS
(EI) m/z (%) = 335 ((M+1)+, 17), 334 (M+Å, 68), 333
(15), 316 (52), 257 (36), 245 (100), 244 (90), 243 (50),
219 (47), 218 (45), 169 (77), 168 (57), 149 (67); HREIMS
for C20H18N2O3 calcd: 334.1317. Found: 334.1348.
4.17. (3S,4R,5R)-5-Hydroxymethyl-4-(1H-indol-3-yl)-2-
oxo-pyrrolidine-3-carboxylic acid methyl ester, 16
From 14: To a solution of HCl–MeOH (10 mL) was
added dropwise at 0 ꢁC a solution of 14 (200 mg,
0.47 mmol) in MeOH (4 mL). Stirring was continued
at 0 ꢁC for 1 h 30 min, then the solvent was evaporated.
The residue was treated with triethylamine at 0 ꢁC
(pH >8) and evaporated again. The solid residue was
purified by flash chromatography (toluene–ethyl ace-
tate–methanol 6:3:1) affording 16 (96 mg, 71%), as white
crystals.
4.15. (R,R)-4-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxane-5-yl)-
(1H-indol-3-yl)-methyl]-2,2-dimethyl-oxazolidine-3-car-
boxylic acid tert-butyl ester, 14
MeldrumÕs acid 3 (524 mg, 3.64 mmol) and a catalytic
amount of D,L-proline were added to a solution of Gar-
nerÕs aldehyde 13 (1.00 g, 4.37 mmol) in acetonitrile
˚
(15 mL) with molecular sieves (4 A). After 30 min stir-
ring, indole 1 (426 mg, 3.64 mmol) was added to the
reaction mixture and stirring continued overnight. After
removal of the solvent under reduced pressure the resi-
due was purified by chromatography (CH2Cl2 then
cyclohexane–ethyl acetate 6:4) to give 14 (1.55 g, 90%),
a quite unstable foam. [a]D = ꢀ1.31 (c 3.66, CH2Cl2);
From 15: To a solution of 15 (126 mg, 0.325 mmol) in
CH2Cl2 (5 mL) TFA (0.40 mL, 5.4 mmol) was added
and the reaction mixture stirred at room temperature
for 2.5 h. After evaporation to dryness, triethylamine
(five drops) was added, evaporated again under reduced
pressure and the residue purified by flash chromatogra-
phy (toluene–ethyl acetate–methanol 6:3:1) to afford 16
(89 mg, 97%), as white crystals.
IR (film) m = 3400, 3358, 2982, 1745, 1682, 1458 cmꢀ1
;
1H NMR (C6D6, 343 K): d = 1.20 (s, 3H), 1.47 (s, 3H),

1336
E. Dardennes et al. / Tetrahedron: Asymmetry 16 (2005) 1329–1339
From 18: A solution of 18 (1.04 g, 2.06 mmol) in ethanol
(25 mL) and acetic acid (five drops) was hydrogenated
over 10% Pd–C (100 mg) at room temperature for
20 h. The catalyst was removed by filtration and the fil-
trate evaporated to dryness. The residue was dissolved
in methanol (12 mL), treated with an excess of freshly
prepared ethereal diazomethane solution and allowed
to stand at 0 ꢁC for 30 min. After evaporation of the sol-
vents, the residue was purified by chromatography
giving 16 (375 mg, 63%), as a white solid. Mp:
206–207 ꢁC (MeOH–ether); [a]D = ꢀ226 (c 0.60,
MeOH); IR (KBr) m = 3366, 1730, 1701, 1456,
4.19. (3S,4R,5R)-5-(tert-Butyldimethylsilanyloxymethyl)-
4-(1H-indol-3-yl)-2-oxo-pyrrolidine-3-carboxylic acid
methyl ester, 19
To an ice-cooled solution of 16 (474 mg, 1.65 mmol) in
dry DMF (5 mL), imidazole (281 mg, 4.13 mmol) and
TBDMSCl (298 mg, 1.98 mmol) were added. The reac-
tion mixture was allowed to stir overnight and then a
second batch of TBDMSCl (298 mg) was added. After
24 h the mixture was diluted with ethyl acetate
(20 mL), extracted with water (10 mL) and satd NH4Cl
solution (3 · 5 mL). The organic layer was dried over
Na2SO4, filtered, evaporated and the crude product
was purified by chromatography (cyclohexane–ethyl
acetate 1:1) to give 19 (529 mg, 80%), as a white solid.
Mp: 154 ꢁC; [a]D = ꢀ166.3 (c 0.80, CHCl3); IR (film)
m = 3375, 3340, 3279, 2920, 1740, 1698, 1468,
1431 cmꢀ1 1H NMR (DMSO-d6): d = 3.05 (m, 2H),
;
3.63 (s, 3H), 3.96 (m, 1H), 4.05 (d, 1H, J = 12.0 Hz),
4.30 (dd, 1H, J = 12.0, 7.9 Hz), 4.58 (t, 1H, J =
4.7 Hz), 7.01 (t, 1H, J = 7.8 Hz), 7.11 (t, 1H,
J = 7.8 Hz), 7.23 (d, 1H, J = 1.5 Hz), 7.37 (d, 1H, J =
7.8 Hz), 7.63 (d, 1H, J = 7.8 Hz), 8.27 (s, 1H), 10.99 (s,
1H) ppm; 13C NMR (DMSO-d6): d = 38.9, 52.1, 52.3,
56.3, 61.8, 110.3, 111.5, 118.5, 118.7, 121.3, 122.8,
126.9, 136.3, 170.9, 171.9 ppm; MS (EI) m/z (%) = 289
((M+H)+, 12), 288 (M+Å, 43), 257 (25), 229 (100), 201
(80), 197 (27), 170 (73); HREIMS for C15H16N2O4
calcd: 288.1110. Found: 288.1127.
1435 cmꢀ1
;
1H NMR (CDCl3): d = ꢀ0.13 (s, 3H),
ꢀ0.10 (s, 3H), 0.81 (s, 9H), 3.26 (dd, 1H, J = 10.6,
5.8 Hz), 3.34 (dd, 1H, J = 10.6, 3.1 Hz), 3.74 (s, 3H),
3.97 (d, 1H, J = 10.8 Hz), 4.12 (m, 1H), 4.53 (dd, 1H,
J = 10.8, 7.9 Hz), 6.16 (br s, 1H), 7.11–7.26 (m, 3H),
7.39 (d, 1H, J = 8.0 Hz), 7.57 (d, 1H, J = 7.7 Hz), 8.25
(br s, 1H) ppm; 13C NMR (CDCl3): d = ꢀ5.7, 18.0,
25.8, 38.7, 52.6, 52.7, 57.0, 63.5, 111.4, 111.5, 118.6,
120.0, 121.9, 122.6, 126.9, 136.4, 170.1, 172.5 ppm; MS
(EI) m/z (%) = 403 ((M+H)+, 8), 402 (M+Å, 2), 388 (2),
372 (2), 346 (82), 313 (23), 283 (15), 202 (23),
197 (21), 196 (37), 170 (59), 144 (24), 130 (100); HRE-
IMS for C21H30N2O4Si calcd: 402.1975. Found:
402.1939.
4.18. (R,R)-4-[(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-
(1H-indol-3-yl)-methyl]-2,2-dimethyl-oxazolidine-3-car-
boxylic acid benzyl ester, 18
To a ꢀ78 ꢁC cooled solution of ester 17 (1.06 g,
3.60 mmol) in dry toluene (12 mL), a 1.5 M DIBAL
solution in toluene (3.60 mL, 5.40 mmol) was added
via syringe over a period of 50 min. Stirring continued
at ꢀ78 ꢁC for 30 min, after which the cold solution
was quenched by the dropwise addition of methanol
(1.60 mL). The resulting mixture was poured into an
ice-cold 1 M HCl solution (20 mL). The two phases were
separated, and the aqueous phase extracted with ethyl
acetate (3 · 10 mL). The combined organic layers were
washed with satd NaHCO3 solution and brine, dried
(Na2SO4) and evaporated to afford the crude aldehyde
(1.10 g).
4.20. (3S,4R,5R)-[5-(tert-Butyldimethylsilanyloxy-
methyl)-4-(1H-indol-3-yl)-2-oxo-pyrrolidin-3-yl]-
carbamic acid benzyl ester, 21
To an ice-cooled solution of 19 (427 mg, 1.06 mmol) in
THF (25 mL) were added 1.8 mL and 1 h later 1.8 mL
0.6 M KOH solution (2.16 mmol) and the reaction mix-
ture stirred for 5 h. A third portion of 1.8 mL 0.6 M
KOH (1.08 mmol) was added and the stirring continued
at room temperature overnight. The mixture was treated
with 5% citric acid solution (3 mL). The organic solvent
was removed by evaporation, with the remaining aque-
ous solution acidified by the addition of 5% citric acid
solution (10 mL) and extracted with ethyl acetate
(3 · 20 mL). The organic layer was dried over Na2SO4,
concentrated and the crude product purified by flash
chromatography (ethyl acetate–acetic acid 98:2) to give
acid 20 (350 mg, 87%), as a white foam. [a]D = ꢀ201.9
(c 0.52, CHCl3); IR (film) m = 3379, 2930, 2859, 1722,
To the solution of the latter in acetonitrile (20 mL) were
added indole 1 (420 mg, 3.60 mmol), MeldrumÕs acid
3
(518 mg, 3.60 mmol) and D,L-proline (40 mg,
0.35 mmol) and the reaction mixture stirred at room
temperature under N2 for 15 h. After evaporation of
the solvent the residue was purified by column chroma-
tography (CH2Cl2 then cyclohexane–acetone 8:2!7:3)
to give 18 (1.04 g, 57% for two steps), as an amorphous,
unstable solid. Mp: 74–75 ꢁC (ether); [a]D = +11.0 (c
3.14, CH2Cl2); IR (film) m = 3412, 3344, 1774, 1741,
1697, 1427 cmꢀ1
;
1H NMR (CDCl3): d = ꢀ0.17 (s,
1695, 1458, 1404 cmꢀ1
;
1H NMR (C6D6, 343 K):
3H), ꢀ0.14 (s, 3H), 0.79 (s, 9H), 3.26 (dd, 1H,
J = 10.8, 5.2 Hz), 3.33 (dd, 1H, J = 10.8, 3.0 Hz), 3.97
(d, 1H, J = 11.2 Hz), 4.12 (m, 1H), 4.42 (dd, 1H,
J = 11.2, 8.0 Hz), 6.67 (br s, 1H), 7.08 (d, 1H
J = 2.0 Hz), 7.13 (dt, 1H, J = 7.8, 1.0 Hz), 7.22 (dt,
1H, J = 7.8, 1.0 Hz), 7.38 (d, 1H, J = 7.8 Hz), 7.52 (d,
1H, J = 7.8 Hz), 8.20 (br s, 1H) ppm; 13C NMR
(CDCl3): d = ꢀ5.9, ꢀ5.8, 17.9, 25.7, 38.5, 52.0, 57.4,
63.1, 110.9, 111.6, 118.4, 119.6, 122.2, 122.4, 126.9,
136.4, 171.9, 174.7 ppm.
d = 1.13 (s, 3H), 1.42 (s, 3H), 1.81 (s, 3H), 2.06 (s,
3H), 4.11 (dd, 1H, J = 9.4, 6.0 Hz), 4.34 (dd, 1H,
J = 2.3 Hz), 4.93 (d, 1H, J = 9.4 Hz), 5.17 (m, 1H),
5.25 (AB system, 1H, J = 12.3 Hz), 5.31 (dd, 1H,
J = 6.4, 2.3 Hz), 5.43 (AB system, 1H, J = 12.3 Hz),
7.31–7.55 (m, 10H), 8.16 (d, 1H, J = 7.7 Hz) ppm; MS
(FAB, NBA) m/z (%) = 507 ((M+H)+, 10), 506 (M+Å,
9) 449 (8), 448 (5), 170 (100); HRMS (FAB, NBA) for
C28H30N2O7 calcd: 506.2053. Found: 506.2075.

E. Dardennes et al. / Tetrahedron: Asymmetry 16 (2005) 1329–1339
1337
To a solution of 20 (150 mg, 0.387 mmol) in acetonitrile
(10 mL) were added DPPA (0.17 mL, 0.78 mmol) and
triethylamine (82 lL, 0.58 mmol) at 0 ꢁC. The mixture
was stirred and allowed to warm up to room tempera-
ture (2.5 h). The solvent was carefully evaporated and
the residue was rapidly purified by flash chromatogra-
phy (cyclohexane–ethyl acetate 1:1) providing acyl
azide, which was dissolved in dry THF (5 mL) and
refluxed under N2 for 1 h. Benzyl alcohol (81 lL,
0.78 mmol) was added via syringe to the hot reaction
mixture and the heating was continued under N2 for
24 h. The solvents were then evaporated and the crude
product was purified by chromatography (cyclohex-
ane–ethyl acetate 1:1) and crystallised from ethyl acetate
to give 21 (154 mg, 80%), as a white solid. Mp: 144–
148 ꢁC (ethyl acetate); [a]D = ꢀ147.0 (c 0.60, CHCl3);
1H NMR (CDCl3): d = ꢀ0.13 (s, 3H), ꢀ0.11 (s, 3H),
0.82 (s, 9H), 3.29 (m, 2H), 3.91 (dd, 1H, J = 9.9,
9.6 Hz), 3.99 (m, 1H), 5.03 (s, 2H), 5.09 (m, 1H), 5.44
(d, 1H, J = 9.9 Hz), 6.62 (br s, 1H), 7.09–7.27 (m, 7H),
7.37–7.50 (m, 3H), 8.43 (br s, 1H) ppm; 13C NMR
(CDCl3): d = ꢀ5.8, ꢀ5.7, 18.0, 25.7, 42.6, 54.4, 55.4,
63.0, 67.0, 110.1, 111.5, 118.2, 119.6, 122.2, 123.2,
127.3, 127.9, 128.0, 128.4, 136.0, 136.4, 156.8,
175.4 ppm; MS (EI) m/z (%) = 493 (M+Å, 1), 436 (1),
402 (1), 329 (25), 328 (100), 286 (20), 285 (83), 211
(20), 184 (30), 170 (35); HREIMS for C27H35N3O4Si
calcd: 493.2397. Found: 493.2378.
aldehyde (64 lL, 0.632 mmol) under N2 and the reaction
mixture stirred at room temperature for 1.5 h. Then dry
toluene (4 mL) and TFA (33 lL, 0.430 mmol) were
added and the reaction mixture heated under reflux for
19 h. The solvent was evaporated, the residue was dis-
solved in ethyl acetate (10 mL) and washed with satd
NaHCO3 solution. The aqueous phase was extracted
with ethyl acetate (2 · 10 mL) and the combined organic
layers dried over Na2SO4, filtered, evaporated and puri-
fied by flash chromatography (cyclohexane–ethyl
acetate–methanol 5:4:1) to give 23a (47 mg, 67%),
as a white solid. Mp: 170–175 ꢁC (ethyl acetate);
[a]D = ꢀ171.7 (c 0.24, CHCl3); IR (film) m = 3249,
1
2910, 1692, 1455 cmꢀ1; H NMR (CDCl3): d = 1.85 (br
s, 1H), 3.46 (m, 2H), 3.77 (d, 1H, J = 6.5 Hz), 3.95 (br
dd, 1H, J = 6.7, 6.5 Hz), 4.30 (br d, 1H, J = 8.1 Hz),
5.14 (d, 1H, J = 1.4 Hz), 6.59 (br s, 1H), 7.08–7.26 (m,
3H) 7.36 (s, 5H), 7.43 (d, 1H, J = 6.6 Hz), 7.69 (br s,
1H) ppm; 13C NMR (CDCl3): d = 36.6, 56.7, 58.2,
58.3, 60.7, 105.4, 111.4, 118.1, 120.3, 122.4, 126.7,
128.7, 129.1, 129.3, 135.7, 136.1, 138.5, 175.6 ppm; MS
(EI) m/z (%) = 334 ((M+1)+, 9), 333 (M+Å, 37), 332
(22), 315 (13), 303 (9), 256 (29), 245 (63), 244 (22),
243 (20), 231 (17), 220 (19), 219 (32), 169 (100);
HREIMS for C20H19N3O2 calcd: 333.1477. Found:
333.1468.
IR (film) m = 3285, 2928, 2856, 1705, 1530, 1460 cmꢀ1
;
Compound 23b: Yield: 12 mg (17%). Mp: 161–163 ꢁC
(CH2Cl2); [a]D = ꢀ155.6 (c 0.22, MeOH); IR (film)
m = 3397, 2920, 1692, 1454 cmꢀ1
;
1H NMR
(CDCl3 + acetone-d6): d = 3.50 (m, 2H), 3.79 (m, 1H),
3.95–4.05 (m, 1H), 4.40 (m, 1H), 5.21 (s, 1H), 6.85 (s,
1H), 7.05–7.21 (m, 2H), 7.25–7.55 (m, 7H), 8.85 (s,
1H) ppm; 13C NMR (CDCl3 + acetone-d6): d = 36.3,
56.5, 57.9, 58.0, 60.6, 104.9, 111.2, 117.7, 119.5, 121.7,
126.5, 128.5, 128.6, 128.7, 135.6, 136.1, 138.8,
175.1 ppm; MS (EI) m/z (%) = 334 (10), 333 (M+Å, 45),
332 (10), 316 (14), 302 (15), 285 (12), 256 (16), 245
(100), 230 (14), 219 (25), 169 (92); HREIMS for
C20H19N3O2 calcd: 333.1477. Found: 333.1425.
4.21. (3S,4S,5R)-[3-Amino-5-(tert-butyldimethylsilanyl-
oxymethyl)-4-(1H-indol-3-yl)]-pyrrolidin-2-one, 22
Carbamate 21 (120 mg, 0.243 mmol) dissolved in ethyl
acetate (7 mL) was hydrogenated over 10% Pd–C
(25 mg) catalyst at room temperature for 31 h. After fil-
tration of the catalyst and evaporation of the solvent the
residue was purified by chromatography (CH2Cl2–
MeOH 9:1) to afford amine 22 (85 mg, 97%), as an
amorphous solid. [a]D = ꢀ211 (c 0.89, CHCl3); IR (film)
m = 3273, 2933, 2854, 1703, 1460 cmꢀ1
;
1H NMR
4.23. (4R,5R)-[4-(1H-Indol-3-yl)-2-oxo-tetrahydropyran-
5-yl]-carbamic acid tert-butyl ester, 24
(CDCl3): d = ꢀ0.13 (s, 3H), ꢀ0.12 (s, 3H), 0.81 (s,
9H), 2.23 (br s, 2H), 3.26 (m, 2H), 3.70 (dd, 1H,
J = 11.1, 8.0 Hz), 3.90 (m, 1H), 3.98 (d, 1H,
J = 11.1 Hz), 6.58 (br s, 1H), 7.05–7.25 (m, 3H), 7.37
(d, 1H, J = 7.9 Hz), 7.51 (d, 1H, J = 7.8 Hz), 8.93 (br
s, 1H) ppm; 13C NMR (CDCl3): d = ꢀ5.7, 17.8, 25.7,
43.9, 54.9, 55.8, 63.3, 110.6, 111.5, 118.2, 119.3, 122.0,
122.1, 127.3, 136.5, 178.3 ppm; MS (EI) m/z (%) = 360
((M+H)+, 10), 359 (M+Å, 29), 303 (11), 302 (35), 287
(23), 285 (43), 257 (27), 230 (39), 227 (27), 170 (40);
HREIMS for C19H29N3O2Si calcd: 359.2029. Found:
359.2016.
A solution of 14 (519 mg, 1.10 mmol) in 70% acetic acid
(10 mL) was stirred at room temperature until the disap-
pearance of the starting material (ca. 1.5 h). After evap-
oration of the solvent, the resulting brown syrup was
dissolved in ethyl acetate (10 mL), heated under reflux
for 2.5 h, evaporated to dryness and the residue was
purified by column chromatography (cyclohexane–ethyl
acetate 6:4) to yield 24 (298 mg, 82%), as a white solid.
Mp: 177–178 ꢁC (CH2Cl2); [a]D = ꢀ15.6 (c 0.64,
CHCl3); IR (film) m = 3395, 3340, 1730, 1692,
1526 cmꢀ1 1H NMR (CDCl3): d = 1.42 (s, 9H), 2.87
;
4.22. (3S,5R,11S,12R)-12-Hydroxymethyl-5-phenyl-
3,4,5,11-tetrahydropyrrolo[3,4-c]-b-carboline-2(12H)-
one, 23a and (3S,5S,11S,12R)-12-hydroxymethyl-5-
phenyl-3,4,5,11-tetrahydropyrrolo[3,4-c]-b-carboline-
2(12H)-one, 23b
(dd, 1H, J = 17.8, 6.9 Hz), 3.13 (dd, 1H, J = 17.8,
6.4 Hz), 3.63 (m, 1H), 4.18 (dd, 1H, J = 11.4, 5.2 Hz),
4.27 (dddd, 1H, J = 8.9, 6.1, 5.2, 3.7 Hz), 4.49 (dd, 1H,
J = 11.4, 3.7 Hz), 4.87 (d, 1H, J = 6.1 Hz), 7.07 (d, 1H,
J = 2.2 Hz), 7.17 (t, 1H, J = 7.8 Hz), 7.25 (t, 1H, J =
8.1 Hz), 7.40 (d, 1H, J = 8.1 Hz), 7.72 (d, 1H,
J = 7.8 Hz), 8.22 (br s, 1H) ppm; 13C NMR
(CDCl3 + CD3OD): d = 27.7, 33.7, 33.8, 48.7, 70.2,
To a solution of 22 (75 mg, 0.228 mmol) in dry CH2Cl2
(4 mL) were added desiccated MgSO4 (15 mg) and benz-

1338
E. Dardennes et al. / Tetrahedron: Asymmetry 16 (2005) 1329–1339
79.5, 111.3, 114.3, 118.3, 118.9, 121.2, 121.7, 125.7,
136.6, 155.9, 172.2 ppm; MS (EI) m/z (%) = 330 (M+Å,
10), 274 (9), 257 (7), 229 (16), 213 (92), 188 (28), 170
(28); HREIMS for C18H22N2O4 calcd: 330.1580. Found:
330.1579.
Acknowledgements
The authors thank the French Ministry of Education,
Research and Technology (MENRT) for a Ph.D.
fellowship to E.D. A.K.-K. thanks French Ministry of
Education, Research and Technology (MENRT) and
University of Reims for a three-year (1999–2002)
assisted professor position. Mass-spectroscopic mea-
surements by P. Sigaut and D. Patigny are gratefully
acknowledged.
4.24. (3R,5S,11R)-5-Phenyl-3,4,5,11-tetrahydropyr-
ano[3,4-c]-b-carboline-13(2,12H)-one, 25
To a solution of 24 (137 mg, 0.415 mmol) in dry CH2Cl2
(10 mL) were added desiccated MgSO4, benzaldehyde
(128 lL, 1.26 mmol) and TFA (0.30 mL, 3.91 mmol)
and the mixture stirred overnight at room temperature
under N2. After evaporation of the solvent the crude res-
idue was purified by chromatography (ethyl acetate–
cyclohexane 7:3) to give 25 (65 mg, 49%), as a white
solid. Mp: 155–159 ꢁC (ethyl acetate–cyclohexane);
[a]D = +128.7 (c 0.46, MeOH); IR (film) m = 3384,
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2919, 2851, 1725, 1677, 1455 cmꢀ1; H NMR (DMSO-
d6): d = 2.71 (dd, 1H, J = 17.3, 12.0 Hz), 3.75 (dd, 1H,
J = 17.3, 5.0 Hz), 3.91 (m, 2H), 4.48 (t, 1H,
J = 10.3 Hz), 4.59 (dd, 1H, J = 10.3, 4.5 Hz), 6.04 (br
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J = 7.0 Hz), 7.33 (d, 1H, J = 8.0 Hz), 7.44 (m, 2H),
7.55 (m, 3H), 7.68 (d, 1H, J = 8.0 Hz), 11.00 (br s,
1H) ppm; 13C NMR (DMSO-d6): d = 30.7, 34.7, 53.0,
58.2, 60.5, 109.4, 109.5, 112.1, 119.6, 119.7, 122.1,
124.6, 127.6, 129.2, 130.1, 130.3, 137.0, 168.0 ppm; MS
(EI) m/z (%) = 318 (M+Å, 100), 271 (19), 259 (18), 241
(43), 230 (33); HREIMS for C20H18N2O2 calcd:
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1730, 1613, 1516 cmꢀ1; H NMR (CD3OD): d = 3.27–
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3.32 (m, 4H), 3.51–3.71 (m 5H), 3.74–3.81 (m, 7H),
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