Total synthesis of (+)-yohimbine via an enantioselective organocatalytic Pictet-Spengler reaction

Article abstract of DOI:10.1021/jo201657n

The binolphosphoric acid-catalyzed Pictet-Spengler reaction of an N-(5-oxy-2,4-pentadienyl)tryptamine derivative with methyl 5-oxo-2- (phenylseleno)pentanoate leads to the tetrahydro-β-carboline in a 92:8 enantiomeric ratio. This product is easily converted into the substrate for a stereoselective intramolecular Diels-Alder reaction of the type earlier reported by Jacobsen. These two key steps constitute the basis for a nine-step total synthesis of (+)-yohimbine from tryptamine. A similar asymmetric Pictet-Spengler reaction was applied to the synthesis of an intermediate in the recent total synthesis of corynantheidine by Sato.

Full text of DOI:10.1021/jo201657n

Article
pubs.acs.org/joc
Total Synthesis of (+)-Yohimbine via an Enantioselective
Organocatalytic Pictet−Spengler Reaction
Bart Herle, Martin J. Wanner, Jan H. van Maarseveen, and Henk Hiemstra*
́
Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
S
* Supporting Information
ABSTRACT: The binolphosphoric acid-catalyzed Pictet−
Spengler reaction of an N-(5-oxy-2,4-pentadienyl)tryptamine
derivative with methyl 5-oxo-2-(phenylseleno)pentanoate
leads to the tetrahydro-β-carboline in a 92:8 enantiomeric
ratio. This product is easily converted into the substrate for a
stereoselective intramolecular Diels−Alder reaction of the type
earlier reported by Jacobsen. These two key steps constitute
the basis for a nine-step total synthesis of (+)-yohimbine from tryptamine. A similar asymmetric Pictet−Spengler reaction was
applied to the synthesis of an intermediate in the recent total synthesis of corynantheidine by Sato.
Scheme 1. Synthetic Strategies toward (+)-Yohimbine
INTRODUCTION
■
Yohimbine (1) is one of the most well-known indole alkaloids
with a rich chemical and medicinal history.1 The first total
synthesis of the racemic compound was achieved more than 50
years ago by Van Tamelen and co-workers.2 Several other
racemic syntheses have been reported since, until the group of
Szantay published in 1986 the first preparation of the alkaloid
in enantiopure form by a second-order asymmetric trans-
formation step in the resolution of an intermediate.3 The first
asymmetric synthesis was reported by Momose and co-workers
in 1990,4 based on an asymmetric Michael-type cyclization. In
́
1994, Aube et al. published a synthesis of (+)-yohimbine from
the chiral pool compounds (+)-menthol and L-tryptophan.5
Our attention was drawn by the first catalytic enantiose-
lective total synthesis of yohimbine, recently reported by
Jacobsen and co-workers.6 In this work the alkaloid was
prepared in a fully stereocontrolled sequence of an acyl Pictet−
Spengler cyclization and an intramolecular Diels−Alder
reaction as the key steps, respectively (see Scheme 1). The
cyclization of tryptamine imine 2 was effected by acetyl chloride
and a chiral thiourea catalyst and proceeded via an N-
acyliminium intermediate to tetrahydro-β-carboline 3 in an er
of 97:3. The single stereocenter generated in this step
determined the outcome of the next key step, that is, the
intramolecular Diels−Alder reaction of 4, in which the
remaining four stereocenters of 1 were established. The
Jacobsen group has carefully studied this IMDA process
which appeared eminently suited to ensure high diastereose-
lectivity.
Recently, we discovered that the Pictet−Spengler cyclization
of N-monosubstituted tryptamines with various aldehydes in
the presence of catalytic amounts of enantiopure binolphos-
phoric acids may lead to tetrahydro-β-carbolines in good
enantiomeric excesses.7 This methodology was applied in the
enantioselective total synthesis of the indole alkaloid arboricine
(Scheme 2).8 It occurred to us that this strategy should also be
useful for the synthesis of (+)-yohimbine, if an enantioselective
reaction of tryptamine 5 with aldehyde 6 would provide
Pictet−Spengler product 7 in good er (see Scheme 1). The R1
and R2 substituents should be such that an E-alkene can be
readily formed from 7 so as to join the Jacobsen route in 4. The
greater efficiency of our method compared to Jacobsen’s
approach would then lie in the early attachment of the correct
substituent on nitrogen. Jacobsen required in the enantiose-
Received: August 8, 2011
Published: September 27, 2011
© 2011 American Chemical Society
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We then directed our attention to the aldehyde partner 6
(see Scheme 1) for the Pictet−Spengler reaction. Earlier
experience had taught us that β,γ-unsaturated aldehydes cannot
be used for this process, probably because the intermediate
iminium ion isomerizes to a conjugated and unreactive
enamine. This meant that a chemical equivalent of the required
dienophile double bond in 4 should be present in the aldehyde
6. We first chose to investigate dithioacetal aldehyde 11 which
has been used by Massiot et al. and later by Cook and co-
workers in Pictet−Spengler cyclizations with tryptamine and
tryptophan esters (see Scheme 3).10
The Pictet−Spengler reaction between freshly purified amine
10 and a slight excess of aldehyde 11 was carried out overnight
in toluene at 50 °C in the presence of powdered 4 Å molecular
sieves and 2 mol % of (R)-binolphosphoric acid 12a.11 These
optimized conditions are the result of an elaborate screening.
An excess of the aldehyde is crucial for a successful reaction (if
the amine is in excess, the reaction simply does not proceed),
but too much aldehyde lowers the er. Furthermore, the (R)-
axial chirality in 12 is known to lead to the required (S)-
stereochemistry in the tetrahydro-β-carboline.7 The desired
product 13 was isolated in ca. 45% yield after chromatographic
purification, and the maximum er from a few runs was 76:24.
Scheme 2. Total Synthesis of (−)-Arboricine
lective Pictet−Spengler step an acetyl group, which is rather
difficult to be replaced by the desired diene substituent.6 This
article reports in detail a short total synthesis of (+)-yohimbine
along the above lines and serves to illustrate the general
synthetic utility of the asymmetric phosphoric acid-catalyzed
Pictet−Spengler cyclization.
RESULTS AND DISCUSSION
■
The first objective of our synthetic strategy was the preparation
of tryptamine 5 with the required diene substituent on the
amine nitrogen. We first investigated the use of the benzoate of
glutaconaldehyde,9 but its reductive amination with tryptamine
was unsuccessful due to predominant formation of the N-
benzoyl derivative of tryptamine. Apparently, we needed a
more robust protective group on the glutaconaldehyde and
chose the Boc group (eq 1).
Thus, the potassium salt of glutaconaldehyde (8) was
converted into its Boc derivative 9, which was readily purified
by recrystallization (mp 70 °C). Reductive amination of 9 with
tryptamine required extensive optimization (Scheme 3). Best
While clearly unsatisfactory, we continued with product 13 in
order to probe whether the following chemistry would work.
According to the Massiot protocol,10 one phenylthio group was
removed using thiophenol and a catalytic amount of base. The
resulting thioether 14 was converted into the corresponding
sulfoxide using m-chloroperbenzoic acid (1 equiv). Generation
of the dienophile required reflux of this sulfoxide in toluene.
Under these conditions the Diels−Alder reaction also took
place to furnish the diastereomeric cycloadducts 15a (endo) and
15b (exo) in a 3:1 ratio. While this result is in good agreement
with Jacobsen’s work,6 the selectivities and overall yield leave
much to be desired.
Scheme 3. Approach to Yohimbine Using Dithioacetal 11
We thus decided to modify our approach in order to attain a
better yield and diastereoselectivity. To this end we desired to
generate the dienophile at a much lower temperature and
introduce a protective group on the indole nitrogen before the
IMDA reaction.6 The phenylseleno aldehyde 16 was chosen
(Scheme 4) because the elimination of the selenoxide is known
to occur at rt so that the dienophile does not directly engage in
the Diels−Alder reaction.
The aldehyde 16 was made according to the procedure
reported by Clive et al.12 The Pictet−Spengler cyclization of
freshly purified amine 10 with aldehyde 16 was carried out
under identical conditions as with aldehyde 11 and produced
the desired product 17 as a mixture of diastereomers. This
mixture was directly treated in the same pot with di-tert-butyl
dicarbonate and DMAP at 40 °C for 2 h to give the Boc-
protected product 18 in 82% overall yield when using 2 mol %
of the octahydrobinolphosphoric acid catalyst 12b. Subse-
quently, 18 was subjected to oxidation with peracid at −78 °C.
After 2 h the mixture was warmed up to rt in the presence of
triethylamine, which led to to the elimination product 19 in
conditions were to stir the amine and the aldehyde for 2 h in
methanol as the solvent at −20 °C before adding NaBH4 as
reducing agent. After another hour at −20 °C the reaction was
quenched with acetone. Quick column chromatography gave
about 45% of product 10 as a rather unstable yellow oil which
should be kept cold, but was preferably used immediately in the
next reaction, that is, the asymmetric Pictet−Spengler
cyclization.
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Scheme 4. Synthesis of (+)-Yohimbine Using Selenide 16
Scheme 5. Synthesis of (−)-Corynantheidine by Sato
Scheme 6. Enantioselective Synthesis of Compound 23
catalyst 12b followed by indole nitrogen protection proceeded
as before and gave the tetrahydro-β-carboline 25 in 81% yield
from 24.
Selenoxide elimination led to 23 in excellent yield. The er of
23 was determined by HPLC to be 94:6 ([α]D = −18.3 (c 0.76,
CHCl3)), and its spectral data were identical to those
detemined by Sato et al.13 Thus, we have shortened the Sato
eight-step synthesis of 23 in 31% overall yield from tryptophan
into a four-step synthesis in 52% overall yield from
bromobutyne.
88% yield. The product was the pure (E)-isomer and showed
an er of 92:8 by chiral HPLC. The same process starting from
10 and 18 was also carried out with catalyst 12a, which led to a
similar yield of 19 in an er of 84:16.
The key IMDA reaction of 19 was carried out on a 1 g scale
in toluene at 70 °C for 70 h and led to a 6:1 mixture of the
endo/exo isomers of the cycloadduct 20, fully in accord with the
results of Jacobsen et al., which only differ in the protective
groups.6 The isomers were easily separated on a column. The
major isomer 20a gave the pure enantiomer after one
recrystallization (mp 189 °C, [α]D = +49.7 (c 0.51, CHCl3),
yield 49%).
The final steps were easy. Removal of the Boc protective
groups occurred in quantitative yield on stirring 20a in a 1:1
mixture of trifluoroacetic acid and DCM for 2 h at rt.
Hydrogenation of the alkene in 21 with atmospheric hydrogen
in ethyl acetate in the presence of Pd/C as catalyst furnished
the alkaloid yohimbine (1) in virtually quantitative yield as off-
white crystals (mp 227−229 °C, [α]D = +51.8 (c 0.54, EtOH)).
Spectral and physical data were in full agreement with literature
data. The total synthesis of enantiopure (+)-yohimbine from
tryptamine involved nine steps (only six pots) and gave an
overall yield of 16%.
To illustrate the more general applicability of this approach
to indole alkaloids, we also investigated the synthesis of an
intermediate in the recent total synthesis of (−)-corynanthei-
dine (22) by Sato and co-workers.13 Tetrahydro-β-carboline 23
was made from L-tryptophan in eight steps including a Pictet−
Spengler reaction (Scheme 5). Six further steps (including a
nickel-catalyzed carboxylative cyclization) then furnished the
alkaloid 22. We set out to prepare optically active 23 from
tryptamine using an organocatalytic enantioselective Pictet−
Spengler reaction.
CONCLUSION
■
This article illustrates new applications in total synthesis for the
venerable Pictet−Spengler reaction, which was first reported a
century ago.14,15 When an achiral N-monosubstituted trypt-
amine is reacted with an achiral aldehyde in the presence of an
enantiopure binolphosphoric acid catalyst, the tetrahydro-β-
carboline product may show good to excellent enantiomeric
excess.16,17 We first discovered this useful process for N-
sulfenyltryptamines, which led to optically active NH
tetrahydro-β-carbolines.18 It also worked well for N-alkyltrypt-
amines as was proven in the key chirality introducing step of
the total syntheses of arboricine8 and now yohimbine and
corynantheidine. More examples can be expected in the near
future, increasing the relevance of asymmetric organocatalysis
in natural product synthesis.19
EXPERIMENTAL SECTION
■
General Remarks. All reactions were carried out in oven-dried
glassware with magnetic stirring under an atmosphere of nitrogen,
unless otherwise noted. Tetrahydrofuran (THF) was freshly distilled
from sodium and benzophenone. Toluene (used for the Pictet−
Spengler reaction) was stored over 4 Å molecular sieves. Other
commercial reagents and solvents were used as received. Powdered 4
Å molecular sieves were dried at 200 °C and 0.1 mbar.
1
All H NMR (at 400 MHz) and 13C NMR spectra (APT, at 100
Amine 24 was best prepared by amination of 1-bromo-2-
butyne with excess tryptamine (Scheme 6). The enantiose-
lective Pictet−Spengler cyclization using aldehyde 16 and
MHz) were recorded at rt in CDCl3 and calibrated to the residual
solvent signals. Analytical thin layer chromatography was performed
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1
using a Merck TLC plastic roll 500 × 20 cm silica gel 60 F254
.
the next reaction. H NMR δ: 8.14 (m, 1H) 7.61 (m, 2H), 7.42 (m,
1H), 7.29 (m, 4H), 7.12 (m, 1H), 6.04 (m, 2H), 5.72 (m, 1H), 4.23
(bm, 1H), 3.79 (m, 1H), 3.67 (m, 3H), 3.31 (m, 1H), 3.19 (m, 2H),
2.98 (m, 1H), 2.80 (m, 1H), 2.46 (dt, J = 16.4, 4.2 Hz, 1H), 2.33 (m,
1H), 2.20 (m, 1H), 2.05−1.92 (bm, 2H), 1.65−1.54 (2 × s, 9H). 13C
NMR δ: 173.4 (C), 173.3 (C), 150.6 (C), 150.0 (C), 139.08 (CH),
139.05 (CH), 136.5 (C), 136.2 (C), 135.9 (C), 135.7 (C), 135.52
(CH), 135.47 (CH), 135.42 (CH), 131.8 (CH), 129.29 (C), 129.23
(C), 128.84 (CH), 128.79 (CH), 128.25 (CH), 128.22 (CH), 128.1
(C), 127.9 (C), 126.68 (CH), 126.64 (CH), 123.80 (CH), 123.75
(CH), 122.5 (CH), 117.70 (CH), 117.67 (CH), 115.6 (CH), 114.5
(CH), 113.89 (C), 113.83 (C), 83.62 (C), 83.48 (C), 83.35 (C), 83.33
(C), 56.7 (CH), 55.26 (CH2), 55.21 (CH2), 51.79 (CH3), 51.75
(CH3), 43.7 (CH), 43.3 (CH), 41.5 (CH2), 41.4 (CH2), 32.4 (CH2),
32.2 (CH2), 31.1, 29.3 (CH2), 29.1 (CH2), 28.1 (3C, CH3), 27.5 (3C,
CH3), 16.57 (CH2), 16.52 (CH2). IR (thin film) ν: 1755, 1728 cm−1.
HRMS (FAB) calcd for C37H47N2O7Se [M + H]+ 711.2552, found
711.2550 m/z.
(S)-tert-Butyl 2-((2E,4E)-5-((tert-Butoxycarbonyl)oxy)penta-
2,4-dien-1-yl)-1-((E)-4-methoxy-4-oxobut-2-en-1-yl)-3,4-dihy-
dro-1H-pyrido[3,4-b]indole-9(2H)-carboxylate (19). To a stirred
solution of 18 (1.82 g, 2.57 mmol) in DCM (2.5 mL) at −78 °C was
added m-chloroperbenzoic acid (≤77%, from Aldrich, 691 mg, 3.084
mmol, 1.2 equiv). After being stirred for 2 h at −78 °C triethylamine
(1.08 mL, 7.71 mmol, 3 equiv) was added. The solution was then
allowed to slowly warm up to rt by removal of the cooling bath, which
led to a color change from yellow to red. Once at ambient temperature
the mixture was concentrated and subjected to flash chromatography
(10:10:3 hexanes/DCM/ethyl acetate) to yield 19 as an almost
colorless oil in 88%. The er was determined to be 92:8 by chiral HPLC
(OD-H, 1% isopropanol in n-heptane, 0.5 mL/min), retention time
(minor): 24.1 min, retention time (major): 30.9 min. 1H NMR δ: 8.16
(d, 8.0 Hz, 1H), 7.45 (d, J = 6.6, 1H), 7.29 (m, 2H), 7.15 (m, 2H),
6.08 (m, 2H), 5.92 (d, J = 15.7 Hz, 1H), 5.76 (m, 1H), 4.48 (dd, J =
10.5, 3.0 Hz, 1H) 3.77 (s, 3H), 3.35 (m, 1H), 3.23 (m, 2H), 3.05 (dd,
J = 14.2, 5.6 Hz, 1H), 2.84 (m, 1H), 2.75 (m, 1H), 2.57 (m, 1H), 2.51
(dd, J = 16.6, 5.0 Hz, 1H), 1.66 (s, 9H), 1.54 (s, 9H). 13C NMR δ:
166.8 (C),150.5 (C), 150.0 (C), 147.5 (CH), 139.1 (CH), 135.8 (C),
135.4 (C), 131.3 (CH), 129.1 (C), 126.8 (CH), 124.0 (CH), 122.5
(CH), 121.6 (CH), 117.8 (CH), 115.6 (CH), 114.4 (CH), 114.4 (C),
83.8 (C), 83.4 (C), 56.1 (CH), 55.2 (CH2), 51.3 (CH3), 41.4 (CH2),
36.8 (CH2), 28.1 (3C, CH3), 27.5 (3C, CH3), 16.6 (CH2). IR (thin
film) ν: 1755, 1725 cm−1. HRMS (FAB) calcd for C31H41N2O7 [M +
H]+ 553.2914, found 553.2908 m/z.
(1R,2S,4aR,13bS,14aS)-13-tert-Butyl 1-Methyl-2-((tert-
butoxycarbonyl)oxy)-1,4a,5,7,8,13b,14,14a-octahydroindolo-
[2′,3′:3,4]pyrido[1,2-b]isoquinoline-1,13(2H)-dicarboxylate
(20). Compound 19 (360 mg, 0.65 mmol) was dissolved in dry
toluene (90 mL) and heated to 70 °C for 70 h. The mixture was then
cooled to rt and the solvent removed in vacuo. According to 1H NMR
a 6:1 mixture of diastereomers 20a and 20b was formed. This mixture
was dissolved again in a 1:1 mixture of DCM and hexanes and
separated by column chromatography (eluent 10:10:3 hexanes/DCM/
ethyl acetate). The pure diastereomer 20a was obtained in 70% yield.
The er of 20a was determined to be 92:8 by chiral HPLC (OD-H, 1%
isopropanol in n-heptane, 0.5 mL/min), retention time (minor): 24.1
min, retention time (major): 30.9 min. After recrystallization a single
enantiomer was obtained in 49% yield (176 mg, 70% yield for the
recrystallization): mp 189 °C; [α]D20 +49.7 (c 0.51, CHCl3). 1H NMR
δ 8.20 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.28 (dt, J = 7.2,
1.4 Hz, 1H), 7.25 (dt, J = 7.0, 1.1 Hz, 1H), 5.88−5.80 (m, 2H), 5.38
(dt, 4.0, 1.2 Hz, 1H), 4.34 (d, 9.8 Hz, 1H), 3.65 (s, 3H), 3.23−3.16
(m, 2H), 2.90−2.76 (m, 4H), 2.62 (dd, J = 11.2, 4 Hz, 1H), 2.40 (dt, J
= 12.5, 2.6 Hz, 1H), 2.27 (bt, 11.2 Hz, 1H), 2.12 (dq, 11.4, 3.0 Hz,
1H), 1.75 (s, 9H), 1.50 (s, 9H), 1.29 (q, J = 11.7 Hz, 1H). 13C NMR
δ: 170.4 (C), 152.8 (C), 150.1 (C), 136.8 (C), 136.3 (C), 134.5 (CH),
128.9 (C), 124.3 (CH), 123.8 (CH), 122.4 (CH), 117.6 (CH), 115.5
(CH), 115.3 (C), 84.2 (C), 82.0 (C), 68.7 (CH), 59.3 (2C, CH2),
58.5 (CH), 51.4 (CH3), 49.2 (CH), 46.3 (CH2), 36.9 (CH), 35.8
(CH), 30.2 (CH2), 27.8 (3C, CH3), 27.7 (3C, CH3). IR (thin film) ν:
Chromatographic purification refers to flash chromatography over
Biosolve 60 Å (0.032−0.063 mm) silica gel. The er determinations
were carried out using HPLC with a Chiralcel OD-H columns (Chiral
Technologies Europe, 0.46 cm × 25 cm). Melting points are
uncorrected.
tert-Butyl (1E,3E-5-Oxopenta-1,3-dien-1-yl)carbonate (9).
Glutaconaldehyde potassium salt9 (8) (17.0 g, 125 mmol) was
dissolved as well as possible in dry DMSO (300 mL) at 50 °C under
vigorous mechanical stirring. Then, under continuous stirring, di-tert-
butyl dicarbonate (34.8 g, 159.5 mmol, 1.28 equiv) dissolved in dry
DMSO (60 mL) was added as quickly as possible. A dark red gel was
immediately formed, which hindered stirring. Diethyl ether (300 mL)
was added after 10 min and vigorous stirring was continued for 1 h.
Water was then added whereupon the gel immediately dissolved,
releasing heat and gas. The reaction mixture was extracted a few times
with diethyl ether and the combined extracts dried over sodium sulfate.
The solvent was removed in vacuo and the residue dissolved in
toluene. The solvent was again evaporated in vacuo to remove all of
the tert-butanol. The pure compound 9 was obtained after
recrystallization from hexanes in 64% yield as pale yellow needles:
mp 68−72 °C. 1H NMR δ: 9.57 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 12.3
Hz, 1H), 7.12, (dd, J = 15.2, 11.6 Hz, 1H), 6.24 (t, J = 11.6 Hz, 1H),
6.22, (dd, J = 15.2, 7.9 Hz, 1H), 1.56 (s, 9H). 13C NMR δ: 193.0
(CH), 149.6 (C), 148.0 (CH), 146.9 (CH), 131.3 (CH), 112.4 (CH),
84.8 (C), 27.3 (3C, CH3). IR (thin film) ν: 1764, 1686, 1648, 1122
cm−1. HRMS (FAB) calcd for C10H15O4 [M + H]+ 199.0970; found
199.0966 m/z. Elemental anal. calcd for C10H14O4 C 60.59, H 7.12;
found C 60.28, H 7.09.
(1E,3E)-5-((2-(1H-Indol-3-yl)ethyl)amino)penta-1,3-dien-1-yl
tert-butyl Carbonate (10). A mixture of methanol (480 mL), Boc-
protected glutaconaldehyde 9 (9.90 g, 50 mmol), and tryptamine (8.01
g, 50 mmol) was stirred for 2 h at −20 °C. Then sodium borohydride
(2.85 g, 75 mmol, 1.5 equiv) was added, and the solution was stirred
for another hour at −20 °C. Acetone (5 mL) was added, and the
solution was allowed to warm to rt. Ethyl acetate was then added, and
the volatiles removed in vacuo. The residue was directly brought onto
a short column and the product purified (eluent 85:10:5 ethyl acetate/
methanol/triethylamine). The unstable product 10 was obtained as
yellow oil, which turned dark red (near black) over time. The
compound decomposed at higher temperatures and should be kept as
1
cool as possible. H NMR δ: 8.05 (bs, 1H), 7.62 (d, J = 7.8 Hz, 1H),
7.40 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz,
1H), 7.08 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.06 (dd, J = 14, 11 Hz,
1H), 5.99 (t, J = 11 Hz, 1H), 5.74 (dt, J = 7.4, 6.3 Hz, 1H), 3.31 (d, J
= 6.3 Hz, 2H), 3.00 (m, 4H), 1.53 (s, 9H), one NH signal is not
discernible. 13C NMR δ: 150.6 (C), 139.1 (CH), 136.3 (C), 131.2
(CH), 127.2 (C), 125.9 (CH), 122.1 (CH), 121.7 (CH), 119.0 (CH),
118.7 (CH), 114.4 (CH), 113.3 (C), 111.2 (CH), 83.5 (C), 51.2
(CH2), 49.1 (CH2), 27.5 (3C, CH3), 25.5 (CH2). IR (thin film) ν:
1754 cm−1. HRMS (FAB) calcd for C20H27N2O3 [M + H]+ 343.2022,
found 343.2023 m/z.
(1S)-tert-Butyl 2-((2E,4E)-5-((tert-Butoxycarbonyl)oxy)penta-
2,4-dien-1-yl)-1-(4-methoxy-4-oxo-3-(phenylselenyl)butyl)-
3,4-dihydro-1H-pyrido[3,4-b]indole-9(2H)-carboxylate (18).
To a stirred solution of freshly purified 10 (1.076 g, 3.14 mmol) in
dry toluene (15.5 mL) was added catalyst 12b (59.7 mg, 0.63 mmol, 2
mol %). After a clear solution was obtained powdered molecular sieves
4 Å (5.5 g) and a solution of 1612 (989 mg, 3.45 mmol) in dry toluene
(5 mL) were added, and the mixture was stirred overnight at 50 °C.
The conversion was monitored through TLC (10:10:3 hexanes/
DCM/ethyl acetate). When the reaction was complete, di-tert-butyl
dicarbonate (1.026 g, 4.71 mmol) and DMAP (114.9 mg, 0.94 mmol,
30 mol %) were added, and the mixture was stirred for 2 h at 40 °C.
After the reaction was complete the orange suspension was filtered
over Celite, giving a reddish filtrate. The filtrate was concentrated in
vacuo and directly purified by column chromatography (10:10:3
hexanes/DCM/ethyl acetate). The product 18 was obtained as a light
yellow foam in 82% yield over two steps as a ca. 58:42 mixture of
1
diastereomers (according to H NMR). The er was determined after
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1734 cm−1. HRMS (FAB) calcd for C31H41N2O7 [M + H]+ 553.2914,
found 553.2916 m/z. Elemental anal. calcd for C31H40N2O7 C 67.37,
H 7.30, N 5.07; found C 67.39, H 7.29, N 5.07.
and the mixture was heated to 40 °C for 2 h. Hexanes and silica gel
were added, and the mixture was brought onto a column as a slurry.
Column chromatography (85:15 hexanes/ethyl acetate) afforded 25
(469 mg, 0.81 mmol) as a colorless oil in 81% yield (a 1:1 mixture of
diastereomers). 1H NMR δ: 8.13 (d, J = 7.9 Hz, 0.5H), 8.09 (d, J = 7.7
Hz, 0.5H), 7.64−7.61 (m, 2H), 7.41 (td, J = 7.5, 0.7 Hz, 1H), 7.35−
7.21 (m, 5H), 4.48 (d, J = 9.8 Hz, 1H), 3.89 (dd, J = 8.4, 6.9 Hz,
0.5H), 3.82 (dd, J = 8.6, 6.9 Hz, 0.5H), 3.65 (s, 1.5H), 3.62 (s, 1.5H),
3.40 (m, 2H), 3.18 (m, 2H), 2.84−2.75 (m, 1H), 2.52 (m, 0.5H), 2.48
(m, 0.5H), 2.33−2.08 (m, 2H), 2.05−1.98 (m, 1H), 1.95−1.87 (m,
0.5H), 1.84 (t, J = 2.3 Hz, 3H), 1.78−1.65 (m, 0.5H), 1.69 (s, 4.5H),
1.69 (s, 4.5H). 13C NMR δ: 173.4 (C), 173.3 (C), 150.1 (C), 150.0
(C), 136.2 (C), 135.94 (C), 135.92 (C), 135.7 (C), 135.43 (CH),
135.37 (CH), 129.18 (C), 129.12 (C), 128.80 (CH), 128.77 (CH),
128.18 (C), 128.15 (CH), 128.0 (C), 123.84 (CH), 123.78 (CH),
122.5 (CH), 117.75 (CH), 117.73 (CH), 115.6 (CH), 113.91 (C),
113.80 (C), 83.7 (C), 83.5 (C), 79.67 (C), 79.60 (C), 76.04 (C),
76.00 (C), 56.7 (CH), 56.5 (CH), 51.77 (CH3), 51.72 (CH3), 43.5
(CH), 43.3 (CH), 42.83 (CH2), 42.76 (CH2), 41.7 (CH2), 41.6
(CH2), 32.2 (CH2), 32.0 (CH2), 28.88 (CH2), 28.85 (CH2), 28.16
(3C, CH3), 28.11 (3C, CH3), 16.65 (CH2), 16.60 (CH2), 3.51 (CH3),
3.50 (CH3). IR (thin film) ν: 1727 cm−1. HRMS (FAB) calcd for
C31H37N2O4Se [M + H]+ 581.1921, found 581.1929 m/z.
(S,E)-tert-Butyl 2-(But-2-yn-1-yl)-1-(4-methoxy-4-oxobut-2-
en-1-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-9(2H)-carboxylate
(23). To a stirred solution of 25 (413 mg, 0.71 mmol) in dry DCM (7
mL) at −78 °C was added m-chloroperbenzoic acid (≤77%, from
Aldrich, 191.5 mg, 0.85 mmol). After 2 h at −78 °C triethylamine
(0.298 mL, 2.14 mmol) was added, and the mixture was allowed to
warm up to rt. After stirring for 30 min at rt, hexanes (7 mL) were
added and the mixture was brought as such onto a silica gel column.
Column chromatography (85:15, hexanes/ethyl acetate) yielded the
product 23 (280 mg, 0.66 mmol) as a colorless oil in 93%. The er was
determined to be 94:6 by chiral HPLC (OD-H column, 0.3%
isopropanol in n-heptane, 0.5 mL/min), retention time (minor): 38.8
min, rentention time (major): 45.1 min. [α]D20 −18.3 (c 0.76, CHCl3)
(lit.13 [α]D22 −15.8 (c 0.52, CHCl3)). 1H NMR δ: 8.14 (d, J = 8.1 Hz,
1H), 7.44 (m, 1H), 7.33−7.23 (m, 2H), 7.21−7.13 (m, 1H), 6.00 (dt,
J = 15.8, 1.5 Hz, 1H), 4.47 (dd, J = 9.9, 2.2 Hz, 1H), 3.75 (s, 3H), 3.42
(dd, J = 2.4, 2.2 Hz, 2H), 3.21 (dd, J = 8.8, 3.4 Hz, 2H), 2.87−2.81 (m,
1H), 2.80−2.74 (m, 1H), 2.63−2.56 (m, 1H), 2.55 (dt, J = 13.1, 3.1
Hz, 1H), 1.86 (t, J = 2.3 Hz, 3H), 1.70 (s, 9H). 13C NMR δ: 166.9
(C), 150.0 (C), 147.4 (CH), 135.9 (C), 134.9 (C), 129.0 (C), 124.0
(CH), 122.5 (CH), 121.6 (CH), 117.8 (CH), 115.6 (CH), 114.5 (C),
83.8 (C), 80.0 (C), 75.7 (C), 56.0 (CH), 51.2 (CH3), 42.9 (CH2),
41.8 (CH2), 36.7 (CH2), 28.1 (3C, CH3), 16.7 (CH2), 3.4 (CH3). IR
(thin film) ν: 1723 cm−1. HRMS (FAB) calcd for C25H31N2O4 [M +
H]+ 423.2284, found 423.2287 m/z.
( 1 R , 2 S , 4 a R , 1 3 b S , 1 4 a S ) - M e t h y l 2 - H y d r o x y -
1,2,4a,5,7,8,13,13b,14,14a-decahydroindolo[2′,3′:3,4]pyrido-
[1,2-b]isoquinoline-1-carboxylate (21). To a solution of crystal-
line 20a (140 mg, 0.25 mmol) in DCM (2.5 mL) was added dropwise
trifluoroacetic acid (2.5 mL, 32.6 mmol). After being stirred for 2 h the
reaction mixture was diluted with ethyl acetate (20 mL) and then
poured into a saturated sodium bicarbonate solution (20 mL). The
organic layer was washed four times with saturated sodium bicarbonate
and dried on sodium sulfate. Removal of the solvent in vacuo gave 21
as a white solid in quantitative yield (88.1 mg, 0.25 mmol): mp 126−
130 °C; [α]D20 +75.5 (c 0.50, CHCl3). 1H NMR δ: 8.21 (s, 1H), 7.49
(d, J = 7.3 Hz, 1H), 2.27 (d, J = 8.6 Hz, 1H), 7.16−7.08 (m, 2H),
5.94−5.89 (m, 1H), 5.71 (d, J = 9.9 Hz, 1H), 4.47 (t, J = 4.2 Hz, 1H),
3.82 (s, 3H), 3.36 (d, J = 9.8 Hz, 1H), 3.11−3.07 (m, 1H), 3.07−3.03
(m, 1H), 3.02−2.96 (m, 1H), 2,74 (dd, 15.0 Hz, 4.1 Hz, 1H), 2.67−
2.60 (m, 2H), 2.54 (dt, J = 12.3 Hz, 2.6 Hz, 1H), 2.28−2.23 (t, J =
10.9 Hz, 1H), 2.19 (q, J = 11.1 Hz, 1H), 1.90 (dq, J = 11.3, 3.0 Hz,
1H), 1.37 (q, J = 11.9 Hz, 1H). 13C NMR δ: 173.2 (C), 135.8 (C),
134.3 (C), 132.3 (CH), 127.7 (CH), 127.1 (C), 121.1 (CH), 119.1
(CH), 117.9 (CH), 110.8 (CH), 107.7 (C), 65.1 (CH), 60.0 (CH),
59.6 (CH2), 52.8 (CH2), 51.8 (CH3), 50.4 (CH), 40.6 (CH), 34.6
(CH), 32.7 (CH2), 21.6 (CH2). IR (thin film) ν: 3366, 1725 cm−1.
HRMS (FAB) calcd for C21H25N2O3 [M + H]+ 353.1865, found
353.1860 m/z.
(+)-Yohimbine (1). To a stirred solution of crude 21 (100 mg,
0.284 mmol) in ethyl acetate (6 mL) was added 10% Pd/C (30.2 mg,
0.028 mmol Pd). The mixture was flushed with hydrogen gas and then
stirred overnight under a 1 atm hydrogen pressure. The mixture was
worked up by filtration over Celite and washing the filter with a
mixture of ethyl acetate and methanol, yielding yohimbine (1) as off-
white crystals (101 mg, quantitative yield): mp 227−229 °C (lit.5
233−235 °C); [α]D20 +51.8 (c 0.54, EtOH) (lit.5 [α]D20 +52.3 (c 0.59,
EtOH)). 1H NMR δ: 7.76 (bs, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.33 (d, J
= 7.9 Hz, 1H), 7.18−7.09 (m. 2H), 4.25 (bs, 1H), 3.84 (s, 3H), 3.37
(dd, J = 11.5, 1,9 Hz, 1H), 3.13−3.09 (m, 1H), 3.06−2.94 (m, 3H),
2.77−2.72 (m, 1H), 2.66 (dt, J = 11.2, 4.6 Hz, 1H), 2.38 (dd, J = 11.5,
2.0 Hz, 1H), 2.28 (m, 1H), 2.09−1.98 (m, 3H), 1.60 (m, 3H), 1.46−
1.44 (m, 1H), 1.40 (m, 1H). 13C NMR δ: 175.5 (C), 135.8 (C), 134.2
(C), 127.2 (C), 121.3 (CH), 119.3 (CH), 118.0 (CH), 110.6 (CH),
108.1 (C), 66.8 (CH), 61.2 (CH2), 59.7 (CH), 52.7 (CH2), 52.2
(CH), 51.8 (CH3), 40.6 (CH), 36.6 (CH), 34.2 (CH2), 31.3 (CH2),
23.2 (CH2), 21.6 (CH2). IR (thin film) ν: 3369, 1724 cm−1. HRMS
(FAB) calcd for C21H27N2O3 [M + H]+ 355.2022, found 355.2017 m/
z.
N-(2-(1H-Indol-3-yl)ethyl)but-2-yn-1-amine (24). 1-Bromo-2-
butyne (1.33 g, 10 mmol) was added to a solution of tryptamine (8.0
g, 50 mmol) in acetonitrile (200 mL). The mixture was stirred at rt for
18 h, and after cooling in ice the solids were removed by filtration. The
filtrate was then concentrated in vacuo and the residue chromato-
graphed (eluent EtOAc, EtOAc/MeOH 95:5 and EtOAc/MeOH
90:10, respectively) to give 24 (1.55 g, 7.32 mmol, 73%) as a slightly
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1H and 13C NMR spectra of compounds 1, 9, 10, 17, 18, 19,
20a, 21, 23, 24, and 25. This material is available free of charge
via the Internet at http://pubs.acs.org.
colored solid: mp 95−99 °C. H NMR δ: 8.02 (bs, 1H), 7.66 (d, J =
7.9 Hz, 1H), 7.37 (d, J = 8.16 Hz, 1H), 7.22 (m, 1H), 7.14 (m, 1H),
7.08 (d, J = 2.2 Hz, 1H), 3.40 (bs, 2H), (3.0−3.1 (m, 4H), 1.80 (t, J =
2.3 Hz, 3H). 13C NMR δ: 136.3 (C), 127.3 (C), 121.9 (CH), 121.8
(CH), 119.0 (CH), 118.8 (CH), 113.6 (C), 111.6 (CH), 78.9 (C),
77.1 (C), 48.7 (CH2), 38.4 (CH2), 25.5 (CH2), 3.34 (CH3). IR (neat)
ν: 3412, 1455 cm−1. HRMS (FAB) calcd for C14H17N2 [M + H]+
213.1392, found 213.1394 m/z.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: h.hiemstra@uva.nl.
(1S)-tert-Butyl 2-(But-2-yn-1-yl)-1-(4-methoxy-4-oxo-3-
(phenylselenyl)butyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-
9(2H)-carboxylate (25). Amine 24 (212 mg, 1.00 mmol) and
catalyst 12b (17.3 mg, 2 mol %) were dissolved in dry toluene (5 mL).
Powdered molecular sieves 4 Å (1.5 g) and aldehyde 1612 (315 mg,
1.10 mmol) dissolved in dry toluene (2.5 mL) were added, and the
mixture was stirred overnight at 50 °C. Then, di-tert-butyl dicarbonate
(327.3 mg, 1.50 mmol) and DMAP (36.6 mg, 0.30 mmol) were added,
ACKNOWLEDGMENTS
■
We thank J. A. J. Geenevasen and J. W. H. Peeters for their
generous help in collecting all NMR and mass spectral data and
acknowledge The Netherlands Research School Combination
Catalysis for financially supporting our organocatalytic research.
8911
dx.doi.org/10.1021/jo201657n|J. Org. Chem. 2011, 76, 8907−8912

The Journal of Organic Chemistry
Article
DEDICATION
■
This paper is dedicated to the memory of Professor Hans
Wynberg, a pioneer of organocatalysis, deceased May 25, 2011.
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