Formal enantioselective synthesis of tacamonine starting from asymmetrized 2-substituted propane-1,3-diols

Article abstract of DOI:10.1016/S0957-4166(99)00434-6

2-Substituted propanediols monoacetates, derived from enzymatic asymmetrization of the corresponding diols, have been obtained in high yields and enantiomeric excesses by using lipases and vinyl acetate as both solvent and acylating agent. These chiral bu

Full text of DOI:10.1016/S0957-4166(99)00434-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4057–4064
Formal enantioselective synthesis of tacamonine starting from
asymmetrized 2-substituted propane-1,3-diols
Bruno Danieli, Giordano Lesma,∗ Silvia Macecchini, Daniele Passarella and
Alessandra Silvani
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Centro CNR di Studio per le Sostanze
Organiche Naturali, via Venezian 21-20133 Milano, Italy
Received 16 September 1999; accepted 30 September 1999
Abstract
2-Substituted propanediols monoacetates, derived from enzymatic asymmetrization of the corresponding diols,
have been obtained in high yields and enantiomeric excesses by using lipases and vinyl acetate as both solvent and
acylating agent. These chiral building blocks have been transformed into the advanced intermediate 3, useful for
the enantioselective synthesis of tacamane alkaloids. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The strategy of using CS-symmetric precursors in the asymmetric synthesis of complex natural
molecules is based on the ability to identify simple symmetrical units as starting materials through
a correct retrosynthetic analysis.1 Following this concept, over the last decade, our group has been
interested1,2 in the applications of optically active C1-synthons, obtained through enzyme-mediated
transesterification or hydrolysis of the corresponding meso-precursors. However, for certain synthetic
purposes, examination of the target structure suggests more appropriate chiral synthons, possibly acces-
sible by enzymatic discrimination of enantiotopic groups linked to an achirotopic carbon atom, such as in
the case of 2-substituted propanediols or malonates. Following this approach, we report here an efficient
lipase-mediated preparation of the new chiral synthons 5 and 6 and their conversion into an advanced
intermediate for the enantiosynthesis of tacamane alkaloids.
Tacamonine 1, one of the few indole alkaloids of the tacamane type, was isolated in 1984 from
Tabernaemontana eglandulosa3 and has been found to show a structural similarity to eburnamonines,4
which are Hunteria alkaloids possessing vasodilator and hypotensive activities. Even if a great deal of
∗
Corresponding author. Tel: 0039-2-2367606; fax: 0039-2-2364369; e-mail: lesma@icil64.cilea.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00434-6

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effort has been devoted to the development of strategies for the synthesis of 1, few stereoselective routes
have been published to date.5,6
2. Results and discussion
We envisaged the optically active lactam 3 as a key synthetic intermediate for the enantiosynthesis of 1.
In the pioneering work of Levy et al.,7 3 has been prepared in racemic form by condensation of tryptamine
with 4-formyl hexanoate. The conversion to 1 was performed using standard chemistry, leading to all the
four possible tacamonine isomers, well before the isolation of the naturally occurring isomer 1. In our
retrosynthetic plan (Scheme 1), preparation of 3 could involve chemoselective nucleophilic attack of
chiral lactone 4 by tryptamine, subsequent cyclization of the produced hydroxyamide and homologation
of the C20 side chain. In turn, lactone 4 could be produced by two different approaches, both utilizing
enzymatic asymmetrization of 2-substituted 1,3-propanediols8 as the key step.
Scheme 1.
The PPL-catalyzed transesterification of diol 79a was reported by Tombo et al.9b leading to 5 in 70%
yield and 90% e.e. With the aim of improving both the yield and enantioselectivity of the process, we
carried out a comparative study using some commercially available enzymes (Table 1), and we found that,
using vinyl acetate both as solvent and acyl donor, and Amano PS lipase from Pseudomonas cepacea, a
substantial increase in the rate and enantioselection was achieved (Table 1).
In order to confirm its 2R absolute configuration, 5 was converted to 2-methylhexan-1-ol 8 through the
mesylate derivative, subsequent reduction with LiAlH4 and hydrogenation of the double bond (overall
yield 86%). The specific rotation was found to be [α]25=−10.5 (c=1, CHCl3) {lit.10 [α]25=−10.7 (c=1,
D
D
CHCl3)}, thus establishing the absolute configuration as 2S (Scheme 2) for 8.
Having found an efficient procedure for preparing 5 in high yield and e.e., we performed chemical
transformations in order to obtain the key intermediate 4. Compound 5 was reacted with ozone leading
to lactol 9 as a mixture of C2 epimers. Oxidation of 9 was strongly dependent upon the reagent and
conditions: reactions with KMnO4 and with CrO3–Py2 left the substrate substantially unaltered, while
a partial oxidation was achieved using catalytic tetra-n-propylammonium perruthenate (TPAP) in the
presence of N-methylmorpholine N-oxide. Finally, oxidation of 9 worked smoothly on a small scale
using freshly prepared AgCO3 supported on Celite, yielding 82% of 4. Since the Fetizon11 reagent is

B. Danieli et al. / Tetrahedron: Asymmetry 10 (1999) 4057–4064
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Table 1
Results of the lipase-catalyzed acetylation of 7 and 10
Scheme 2. (a) MsCl, pyridine; (b) LiAlH4, THF, 0°C; (c) H2, Pd (C), EtOH; (d) O3, MeOH/CH2Cl2, −78°C; (e) AgCO3/Celite,
benzene, ∆
expensive and not suitable for large scale preparations, the more direct approach depicted in Scheme 3
was examined.
Scheme 3. (a) aq. 10% H2SO4, THF; (b) Pd/BaSO4, quinoline, MeOH; (c) O3, MeOH/CH2Cl2, −78°C
At this stage, we have studied the enantioselective transesterification of 10, easily prepared by standard
methodologies.12 Under the same conditions already applied for the desymmetrization of 7, PPL proved
to be the most promising enzyme for providing monoacetate 6 with extremely high enantiomeric excess
and in good yield. Chemical correlation of 6 to 5 via desilylation and partial hydrogenation of the triple
bond indicated that 6 also possesses the 2R configuration. Ozonization of 6 afforded 4 in quantitative
yield, overcoming the difficulties related to the oxidation of lactol 9.
The attack of N-Boc-tryptamine 11 at the lactonic carbonyl group of 4 could be successfully effected in
refluxing THF, giving 12 in good yield. The next step in our synthetic plan was the transformation of the
hydroxyl group into an efficient leaving group, enabling the preparation of the lactam ring of intermediate
14 via cyclization in basic conditions. Thus, alcohol 12 was converted into mesylate 13 and then subjected
to deprotonation with tBuOK to give the desired cyclization product 14 in 75% yield. Finally, in order to
homologate the C20 acetoxymethyl side chain, the acetoxy group was hydrolyzed and then converted into
the corresponding tosylate 16. Cross-coupling condensation with dimethyllithium cuprate,13 followed by
N-Boc deprotection proceeded smoothly to give the desired chiral lactam 3 (Scheme 4).
Bischler–Napieralski cyclization of 3, followed by a few other steps affording the fifth ring has
been described7 to give a diastereoisomeric mixture of pseudovincamones, from which the natural

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Scheme 4. (a) THF, ∆; (b) MsCl, pyridine; (c) tBuOK, THF; (d) 0.5N NaOH, THF; (e) TsCl, Et3N, CH2Cl2, 0°C; (f) CuI, MeLi,
Et2O, −40°C; (g) TFA, CH2Cl2
all-cis isomer could be separated. Thus, the synthesis of 3 secured a formal enantioselective entry
to (+)-tacamonine. Despite this achievement, studies are in progress aimed at obtaining a completely
stereocontrolled formation of C3 and C14 stereocentres, with the required cis D/E ring junction, and
avoiding in this way the final step of diastereoisomeric separation.
3. Experimental14
3.1. Materials
Porcine pancreatic lipase (PPL, EC 3.1.1.3. of type II) was obtained from Sigma Chemical Co.,
Pseudomonas fluorescens lipase (PFL EC 3.1.1.3.) was purchased from Fluka and lipase Amano PS
from Pseudomonas cepacea was provided by Amano Pharmaceutica (Japan). All enzymes were used
without further purification.
3.2. General methods
Analytical liquid chromatography was carried out with a Kontron HPLC system equipped with a UV
detector and a Chiracel ODH HPLC column, using n-hexane:iPrOH (97:3) as an eluant. Progress of the
acetylations was monitored by HPLC analysis, and the reactions were stopped when they came to a near
standstill. All separations were carried out under flash-chromatographic (FC) conditions on silica gel 60
(230–400 mesh) using the indicated eluents. The organic extracts were dried over anhydrous Na2SO4
prior to solvent removal on a rotary evaporator.
3.3. General procedure for the enzymatic acetylation of 2-(but-3-enyl)-propane-1,3-diol 7 and 2-(4-
dimethylphenyl silanyl-but-3-ynyl)-propane-1,3-diol 10
To a solution of 7 or 10 (1 mmol) in dry vinyl acetate (10 ml) was added an appropriate enzyme
(PPL, 45670 units/mmol substrate; PFL, 236 units/mmol substrate; Amano PS lipase, 5400 units/mmol

B. Danieli et al. / Tetrahedron: Asymmetry 10 (1999) 4057–4064
4061
substrate) and the mixture was shaken at room temperature. After the appropriate time, the enzyme was
filtered off, the solvent was evaporated, and the reaction product purified by FC. The optical purities of
monoacetates 5 and 6 were determined by chiral HPLC (after conversion into its p-nitrobenzoic ester for
5).
3.3.1. (2R)-2-(Acetoxymethyl)hex-5-en-1-ol 5
Oil; Rf (AcOEt:hexane, 1:1) 0.43; [α]25=+11.1 (c=1, CHCl3), [α]23565=+36.3 (c=1, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 5.86–5.71 (m, 1H), 5.08–4.93 (m, 2H), 4.19 (dd, 1H, J=11.0, 4.5 Hz), 4.09 (dd, 1H,
J=11.0, 6.5 Hz), 3.61 (dd, 1H, J=11.0, 4.5 Hz), 3.52 (dd, 1H, J=11.0, 7.0 Hz), 2.18–2.08 (m, 2H), 2.06
(s, 3H), 1.95 (br s, 1H), 1.88–1.78 (m, 1H), 1.52–1.32 (m, 2H); HRMS calcd for C9H16O3: 172.1099,
found 172.1113. Anal. calcd for C9H16O3: C, 62.76; H, 9.37. Found: C, 62.68; H, 9.48.
3.3.2. (2R)-2-(Acetoxymethyl)-6-dimethylphenylsilyl-hex-5-yn-1-ol 6
25
1
Oil; Rf (AcOEt:hexane, 1:1) 0.40; [α] =+10.8 (c=1, CHCl3); H NMR (300 MHz, CDCl3) δ 7.65
D
(m, 2H), 7.36 (m, 3H), 4.19 (dd, 1H, J=11.2, 5.0 Hz), 4.12 (dd, 1H, J=11.2, 6.2 Hz), 3.63 (dd, 1H,
J=11.2, 4.5 Hz), 3.55 (dd, 1H, J=11.2, 5.5 Hz), 2.38 (t, 2H, J=7.2 Hz), 2.07 (s, 3H), 2.03–1.93 (m, 1H),
1.70–1.52 (m, 2H), 0.4 (s, 6H); HRMS calcd for C17H24O3Si: 304.1495, found 304.1508. Anal. calcd for
C17H24O3Si: C, 67.06; H, 7.95; O, 15.76. Found: C, 67.21; H, 8.01; O, 15.70.
3.4. (5S)-2-Hydroxy-5-(acetoxymethyl)tetrahydropyran 9
A solution of 5 (600 mg, 3.5 mmol) in MeOH (15 ml) and CH2Cl2 (8 ml) was cooled to −78°C.
Ozone was bubbled into the solution until persistence of a blue colour. After further bubbling of O3 for
5 min, Me2S (2.5 ml) and pyridine (30 µl) were added. After 2 min the flask was put under a nitrogen
atmosphere, allowed to warm to rt, and stirred for 2 h. The solution was concentrated under reduced
pressure, the residue was dissolved in AcOEt and washed with water to give, after evaporation of the
solvent, crude 9 (525 mg, 86%, mixture of epimers A:B, 1:1) which was used as such at once for further
reactions: oil; Rf (AcOEt:hexane, 7:3) 0.28; [α]25=−5.1 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
5.12 (br s, 0.5HB), 4.75 (dd, J=8.4, 2.4 Hz, 0.5HA), 3.99 (dd, J=12.2, 5.6 Hz, 0.5HeqA), 3.95–3.85 (m,
2H), 3.77 (dd, J=11.2, 9.1 Hz, 0.5HeqB), 3.61 (dd, J=11.2, 4.2 Hz, 0.5HaxB), 3.28 (dd, J=12.2, 9.0 Hz,
0.5HaxA), 2.02 (s, 3H), 2.00–1.85 (m, 2H), 1.75–1.55 (m, 2H), 1.50–1.35 (m, 1H); 13C NMR (75.4 MHz,
CDCl3) δ 171.0, 95.4, 92.0, 66.7, 65.4, 64.9, 62.6, 34.4, 34.2, 30.8, 29.2, 24.0, 20.8, 20.7; EIMS m/z
(relative intensity) 174 (2, M+), 157 (100), 114 (53). Anal. calcd for C8H14O4: C, 55.16; H, 8.11. Found:
C, 55.21; H, 8.01.
3.5. (5S)-5-(Acetoxymethyl)tetrahydropyran-2-one 4
Method A: A mixture of 9 (500 mg, 2.87 mmol) and Ag2CO3/Celite (22.8 mmol, freshly prepared
according to a literature procedure11) in benzene (90 ml) was heated under reflux for 8 h. The solid
was collected by filtration, washed with CH2Cl2, and the combined filtrates evaporated to give, after
purification by FC (eluent: AcOEt), pure 4 (406 mg, 82%).
Method B: Into a solution of 6 (500 mg, 1.6 mmol) in MeOH (15 ml) and CH2Cl2 (8 ml) ozone was
bubbled until persistence of a blue colour. After further bubbling of O3 for 5 min, the flask was put under
a nitrogen atmosphere and stirred for 2 h. The solution was concentrated, the residue was dissolved in
AcOEt and washed with aq. NaHCO3 to give, after evaporation of the solvent and purification by FC
(eluent: AcOEt), pure 4 (267 mg, 97%): oil; Rf (AcOEt:hexane, 7:3) 0.19; [α]25=+4.0 (c=1, CHCl3); 1H
D

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B. Danieli et al. / Tetrahedron: Asymmetry 10 (1999) 4057–4064
NMR (300 MHz, CDCl3) δ 4.37 (ddd, J=11.5, 6.8, 2.3 Hz, 1H), 4.14 (dd, J=11.4, 8.0 Hz, 2H), 3.99 (dd,
J=11.5, 7.8 Hz, 1H), 2.60 (m, 2H), 2.33 (m, 1H), 2.08 (s, 3H), 2.07 (m, 1H), 1.68 (m, 1H); 13C NMR
(75.4 MHz, CDCl3) δ 70.6, 64.7, 32.7, 28.9, 22.2, 21.2; EIMS m/z (relative intensity) 172 (15, M+), 130
(100), 112 (45). Anal. calcd for C8H12O4: C, 65.45; H, 5.50. Found: C, 65.58; H, 5.70.
3.6. (4R)-N-[2-(N-Boc-indol-3-yl)ethyl]-4-acetoxymethyl-5-hydroxypentanamide 12
A solution of N-Boc-tryptamine (670 mg, 2.6 mmol) in THF (5 ml) was added to a solution of 4 (370
mg, 2.2 mmol) in THF (4 ml). After heating at 60°C for 4 h, the solvent was evaporated and the residue
was flash-chromatographed (eluent: AcOEt:hexane, 9:1) to give pure 12 (866 mg, 76%): oil; Rf (AcOEt)
0.30; [α]25=+6.8 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7
D
Hz, 1H), 7.41 (s, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 5.60 (br s, 1H), 4.11 (dd, J=12.0, 4.8
Hz, 1H), 4.04 (dd, J=12.0, 6.3 Hz, 1H), 3.64–3.57 (m, 2H), 3.56–3.51 (m, 2H), 2.91 (t, J=6.7 Hz, 2H),
2.36 (br s, 1H), 2.32–2.12 (m, 2H), 2.02 (s, 3H), 1.82–1.75 (m, 1H), 1.75–1.62 (m, 2H), 1.66 (s, 9H); 13
C
NMR (75.4 MHz, CDCl3) δ 173.1, 171.7, 149.8, 135.6, 130.3, 124.5, 122.6, 119.0, 117.9, 115.8, 93.9,
64.9, 62.3, 40.0, 39.4, 33.5, 28.4, 25.2, 23.1, 21.0; EIMS m/z (relative intensity) 432 (4, M+), 187 (21),
143 (100). Anal. calcd for C24H34N2O6: C, 64.55; H, 7.68; N, 6.27. Found: C, 64.51; H, 7.65; N, 6.14.
3.7. (4S)-N-[2-(N-Boc-indol-3-yl)ethyl]-4-acetoxymethyl-5-mesyloxypentanamide 13
To a solution of 12 (600 mg, 1.4 mmol) in pyridine (6 ml), methanesulfonyl chloride (243 mg, 1.7
mmol) was added. After stirring at rt for 30 min, the reaction mixture was poured into aq. NaHCO3 and
extracted with AcOEt; the organic phase was washed with 1N HCl and then with brine to give, after
25
1
evaporation, pure 13 (650 mg, 91%): oil; Rf (AcOEt) 0.60; [α] =+4.2 (c=1, CHCl3); H NMR (300
D
MHz, CDCl3) δ 8.15 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.32 (t, J=7.5 Hz, 1H),
7.24 (t, J=7.5 Hz, 1H), 5.65 (br s, 1H), 4.19 (d, J=6.5 Hz, 2H), 4.15 (dd, J=12.0, 4.5 Hz, 1H), 4.11
(dd, J=12.0, 6.5 Hz, 1H), 3.58 (q, J=7.0, 2H), 2.99 (s, 3H), 2.91 (t, J=7.0 Hz, 2H), 2.23 (t, J=7.1 Hz,
2H), 2.04 (s, 3H), 2.15–2.03 (m, 1H), 1.79–1.66 (m, 2H), 1.66 (s, 9H); 13C NMR (75.4 MHz, CDCl3) δ
172.4, 170.9, 149.7, 135.5, 130.4, 124.5, 122.5, 118.9, 117.5, 115.3, 83.6, 68.9, 63.0, 39.4, 37.3, 33.0,
28.2, 25.0, 23.7, 20.8, 14.2; HRMS calcd for C25H36N2O8S: 524.2192, found 524.2205. Anal. calcd for
C25H36N2O8S: C, 57.23; H, 6.92; N, 5.34; O, 24.40. Found: C, 57.12; H, 6.98; N, 5.32; O, 24.32.
3.8. (5R)-1-[2-(N-Boc-indol-3-yl)ethyl]-5-acetoxymethyl-piperidin-2-one 14
To a solution of 13 (600 mg, 1.2 mmol) in THF (15 ml), 1 M tBuOK in THF (1.76 ml, 1.8 mmol)
was added dropwise. After stirring at rt for 2 h, the reaction mixture was diluted with aq. NH4Cl and
extracted with AcOEt; the solvent was evaporated to give, after FC (eluent: AcOEt:hexane, 8:2), pure 14
(373 mg, 75%): oil; Rf (AcOEt) 0.50; [α]25=+27.9 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.12
D
(d, J=8.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H),
4.01 (dd, J=11.0, 5.4 Hz, 1H), 3.86 (dd, J=11.0, 7.9 Hz, 1H), 3.73–3.54 (m, 2H), 3.21 (dd, J=11.8, 4.6
Hz, 1H), 3.05–2.94 (m, 3H), 2.56–2.32 (m, 2H), 2.15–2.01 (m, 1H), 2.00 (s, 3H), 1.92–1.80 (m, 1H), 1.66
(s, 9H), 1.60–1.48 (m, 1H); 13C NMR (75.4 MHz, CDCl3) δ 171.2, 169.8, 150.2, 136.1, 131.1, 125.0,
123.1, 119.6, 118.4, 115.8, 84.0, 66.1, 51.7, 48.6, 34.1, 31.6, 28.8, 24.5, 23.4, 21.3; EIMS m/z (relative
intensity) 414 (13, M+), 243 (52), 187 (100). Anal. calcd for C26H28N2O5: C, 69.62; H, 6.30; N, 6.24.
Found: C, 69.70; H, 6.42; N, 6.28.

B. Danieli et al. / Tetrahedron: Asymmetry 10 (1999) 4057–4064
4063
3.9. (5R)-1-[2-(N-Boc-indol-3-yl)ethyl]-5-hydroxymethyl-piperidin-2-one 15
To a stirred solution of 14 (300 mg, 0.72 mmol) in THF (5 ml), aq. 0.5N NaOH (2.2 ml, 1.09 mmol)
was added. After 2 h at rt, the reaction was acidified with 1N HCl and extracted with AcOEt to give pure
15 (242 mg, 90%): oil; Rf (CHCl3:MeOH, 95:5) 0.40; [α]25=+28.4 (c=1, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 8.12 (d, J=8.3 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.41 (s, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.23 (t,
J=7.8 Hz, 1H), 3.64 (t, J=7.5 Hz, 2H), 3.58 (dd, J=10.5, 7.2 Hz, 1H), 3.47 (dd, J=10.5, 5.5 Hz, 1H),
3.32 (dd, J=12.0, 5.1 Hz, 1H), 3.08 (dd, J=12.0, 9.1 Hz, 1H), 2.96 (t, J=8.5 Hz, 2H), 2.53–2.31 (m, 2H),
2.03–1.91 (m, 1H), 1.91–1.80 (m, 1H), 1.66 (s, 9H), 1.58–1.46 (m, 1H); EIMS m/z (relative intensity)
373 (15, MH+), 188 (35), 143 (100). Anal. calcd for C24H26N2O4: C, 70.91; H, 6.45; N, 6.89. Found: C,
71.00; H, 6.47; N, 6.94.
3.10. (5R)-1-[2-(N-Boc-indol-3-yl)ethyl]-5-tosyloxymethyl-piperidin-2-one 16
A solution of 15 (97 mg, 0.26 mmol) in CH2Cl2 (4 ml), cooled to 0°C, was treated with Et3N (138 µl,
1.0 mmol) and p-toluenesulfonyl chloride (99 mg, 0.52 mmol). After stirring at rt overnight, the reaction
mixture was quenched with aq. NH4Cl and extracted with AcOEt to give, after FC (eluent: CHCl3:MeOH,
99:1), pure 16 (123 mg, 90%): oil; Rf (CHCl3:MeOH, 95:5) 0.48; [α]25=+19.1 (c=1, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 8.12 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.3 Hz, 1H), 7.41 (s,
1H), 7.32 (d, J=8.8 Hz, 2H), 7.31 (t, J=7.5 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 3.94 (dd, J=9.5, 5.5 Hz,
1H), 3.83 (dd, J=9.5, 7.5 Hz, 1H), 3.68–3.49 (m, 2H), 3.26 (dd, J=12.0, 5.0 Hz, 1H), 3.01 (dd, J=12.0,
9.2 Hz, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.50–2.29 (m, 2H), 2.43 (s, 3H), 2.22–2.09 (m, 1H), 1.83–1.76 (m,
1H), 1.66 (s, 9H), 1.55–1.49 (m, 1H); EIMS m/z (relative intensity) 526 (64, M+), 472 (45), 426 (100).
Anal. calcd for C31H32N2O6S: C, 66.41; H, 5.76; N, 5.00; O, 17.12. Found: C, 66.33; H, 5.69; N, 5.08;
O, 17.29.
3.11. (5R)-1-[2-(N-Boc-indol-3-yl)ethyl]-5-ethyl-piperidin-2-one 17
A suspension of CuI (145 mg, 0.76 mmol) in dry Et2O (4 ml), cooled to −10°C, was treated with a 1.6
M solution of MeLi in Et2O (950 µl, 1.5 mmol). During this addition a yellow precipitate formed first,
which, upon completion of the addition, dissolved completely forming a brown solution. After stirring for
10 min at −10°C, this solution was added to a solution of 16 (80 mg, 0.152 mmol) in Et2O (2 ml), cooled
to −40°C. The temperature was allowed to rise slowly to rt and the mixture was stirred overnight. After
dilution with aq. NH4Cl and Et2O, the mixture was stirred for 1 h to give two homogeneous phases, which
were separated. After usual work up and FC (eluent: CHCl3:MeOH, 99:1), pure 17 (46 mg, 81%) was
25
1
obtained: oil; Rf (CHCl3:MeOH, 95:5) 0.53; [α] =+29.3 (c=1, CHCl3); H NMR (300 MHz, CDCl3)
D
δ 8.12 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.41 (s, 1H), 7.30 (t, J=7.3 Hz, 1H), 7.24 (t, J=7.3
Hz, 1H), 3.70–3.52 (m, 2H), 3.17 (dd, J=12.0, 5.5 Hz, 1H), 2.96 (t, J=7.6 Hz, 2H), 2.88 (dd, J=12.0, 9.5
Hz, 1H), 2.47 (ddd, J=12.8, 6.0, 3.8 Hz, 1H), 2.33 (ddd, J=12.8, 11.0, 6.2 Hz, 1H), 1.90–1.81 (m, 1H),
1.66 (s, 9H), 1.62–1.54 (m, 1H), 1.44–1.32 (m, 1H), 1.26 (q, J=7.0 Hz, 2H), 0.85 (t, J=7.0 Hz, 3H); 13
C
NMR (75.4 MHz, CDCl3) δ 170.4, 150.3, 136.1, 131.2, 125.0, 123.7, 123.1, 119.7, 118.6, 115.8, 84.0,
54.6, 48.5, 36.2, 32.3, 28.8, 27.6, 26.6, 23.4, 11.9; EIMS m/z (relative intensity) 370 (6, M+), 187 (41),
143 (100). Anal. calcd for C25H28N2O3: C, 74.23; H, 6.98; N, 6.93. Found: C, 74.11; H, 7.10; N, 6.98.

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B. Danieli et al. / Tetrahedron: Asymmetry 10 (1999) 4057–4064
3.12. (5R)-1-[2-Indol-3-yl-ethyl]-5-ethyl-piperidin-2-one 3
At 0°C, 17 (46 mg, 0.12 mmol) was dissolved in CH2Cl2 (2 ml) and TFA (0.5 ml) was added. After
stirring for 1 h at rt, the solution was poured into aq. 10% NaOH and extracted with CH2Cl2 to give 3 (29
mg, 85%): oil; Rf (CHCl3:MeOH, 95:5) 0.21; [α]25=+21.0 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3)
D
δ 8.12 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.39 (s, 1H), 7.30 (t, J=7.3 Hz, 1H), 7.24 (t, J=7.3
Hz, 1H), 3.72–3.53 (m, 2H), 3.17 (dd, J=12.0, 5.4 Hz, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.87 (dd, J=12.0, 9.5
Hz, 1H), 2.45 (ddd, J=12.8, 6.0, 3.7 Hz, 1H), 2.31 (ddd, J=12.8, 11.0, 6.2 Hz, 1H), 1.93–1.80 (m, 1H),
1.62–1.52 (m, 1H), 1.46–1.32 (m, 1H), 1.26 (q, J=7.0 Hz, 2H), 0.85 (t, J=7.0 Hz, 3H); 13C NMR (75.4
MHz, CDCl3) δ 170.4, 150.3, 136.0, 131.3, 125.0, 123.7, 123.4, 118.5, 117.9, 115.8, 83.0, 54.3, 48.5,
35.2, 32.3, 27.1, 26.6, 23.4, 11.8; HRMS calcd for C17H22N2O: 207.1732, found 207.1725. Anal. calcd
for C17H22N2O: C, 75.52; H, 8.21; N, 10.36. Found: C, 75.68; H, 8.15; N, 10.34.
Acknowledgements
This work was supported by the Ministero dell’Università e della Ricerca Scientifica e Tecnologica
(MURST).
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