Enantioselective Syntheses of (–)-Alloyohimbane and (–)-Yohimbane by an Efficient Enzymatic Desymmetrization Process

Article abstract of DOI:10.1002/ejoc.201601171

Enantioselective syntheses of (–)-alloyohimbane and (–)-yohimbane were accomplished in a convergent manner. The key step involves a modified mild protocol for the enantioselective enzymatic desymmetrization of a meso-diacetate. This provides convenient access to an optically active monoacetate in multi-gram quantities and in high enantiomeric purity. This monoacetate was converted to (–)-alloyohimbane. Reductive amination of the derived aldehyde caused isomerization to the trans-product and, ultimately, the formation of (–)-yohimbane.

Full text of DOI:10.1002/ejoc.201601171

DOI: 10.1002/ejoc.201601171
Full Paper
Enzymatic Desymmetrization
Enantioselective Syntheses of (–)-Alloyohimbane and
(–)-Yohimbane by an Efficient Enzymatic Desymmetrization
Process
Arun K. Ghosh*[a] and Anindya Sarkar[a]
Abstract: Enantioselective syntheses of (–)-alloyohimbane and in multi-gram quantities and in high enantiomeric purity. This
(–)-yohimbane were accomplished in a convergent manner. The monoacetate was converted to (–)-alloyohimbane. Reductive
key step involves a modified mild protocol for the enantio- amination of the derived aldehyde caused isomerization to the
selective enzymatic desymmetrization of a meso-diacetate. This trans-product and, ultimately, the formation of (–)-yo-
provides convenient access to an optically active monoacetate himbane.
Introduction
these molecules using enzymatic desymmetrization as the key
step. Of particular interest, we have developed a modified pro-
tocol, which provides convenient access to (1R, 6S)-6(hydroxy-
methylcyclohexenyl) methyl acetate in high optical purity in
multigram scales.
The yohimbine alkaloids, featuring a characteristic pentacyclic
indole ring framework, display a wide range of pharmacological
properties.[1,2] These alkaloids belong to the Rubiaceae family
and they are isolated from the bark of the Pausinystalia Yohimbe
tree in central Africa. Over the years, this family of alkaloids
has received much attention due to its antihypertensive and
antipsychotic activity.[3–6] Yohimbine (Figure 1) and related de-
rivatives have been used as traditional medicines, specifically as
adrenergic blocking agents for Angina pectoris and arterioscle-
rosis. They are also used as herbal medicines for the treatment
of impotency. Furthermore, yohimbines have been shown to
lower body fat and relieve symptoms of dry mouth.[7,8] The bio-
logical mechanism of action of the yohimbine family may be
due to its potent, competitive, and selective alpha-2-adrenergic
receptor antagonist properties.[9,10] They have been shown to
block dopamine pathways in schizophrenic patients. Also, they
weakly interact with alpha-1-adrenoreceptors. Not surprisingly,
the chemistry and biology of yohimbines have attracted im-
mense interest leading to many synthetic and biological stud-
ies. To date, several racemic syntheses,[11–13] as well as enantio-
selective syntheses[14–16] of yohimbine and related alkaloids
have been reported. Racemic[17–20] and enantioselec-
tive[16,21–26] syntheses of alloyohimbane and yohimbane, the
pentacyclic skeleton of yohimbine alkaloids have also been re-
ported in the literature. Stemming from our interest in the use
of polycyclic indoles in medicinal chemistry, we have devised
practical and enantioselective syntheses of (–)-yohimbane and
(–)-alloyohimbane. Herein we report convergent syntheses of
Figure 1. Structures of yohimbine and related compounds.
Results and Discussion
Our retrosynthetic analysis of (–)-alloyohimbane and (–)-yo-
himbane is shown in Figure 2. For the synthesis of (–)-alloyo-
himbane, we planned a Bischler–Napieralski reaction to con-
struct the pentacyclic indole framework from corresponding
lactams 5 and 6. A similar saturated lactam intermediate has
previously been converted to the corresponding yohimbane
derivative.[19,22] Lactam 5 would be obtained from nitrile deriva-
tive 7 through its conversion to the corresponding acid fol-
lowed by removal of the tert-butyloxycarbonyl group (Boc) and
amidation of the resulting amino acid. Nitrile derivative 7 can
be obtained by reductive amination of 3-indolyl acetaldehyde 8
and (1R, 6S)-6-(aminomethylcyclohexenyl)methyl acetate 9 and
[a] Department of Chemistry and Department of Medicinal Chemistry,
Purdue University,
560 Oval Drive, West Lafayette, Indiana, 47906, USA
E-mail: akghosh@purdue.edu
www.chem.purdue.edu/ghosh/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201601171.
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subsequent nitrile installation via standard synthetic steps. The
requisite optically active amine would be derived from the cor-
responding (1R, 6S)-6-(hydroxymethylcyclohexenyl)methyl acet-
ate 10. Optically active alcohol 10 can be obtained by enzy-
matic desymmetrization of the corresponding meso-diacetate.
For the synthesis of (–)-yohimbane, we planned to carry out
reductive amination of (1R, 6R)-6-(formylcyclohexenyl)methyl
acetate 11, which could be obtained by oxidation of alcohol 10
and in situ epimerization of the resulting aldehyde via an
enamine intermediate. Therefore, optically active alcohol 10
was envisioned to be useful for the syntheses of both alloyo-
himbane and yohimbane as well as their derivatives.
Scheme 1. Reagents and conditions: (a) PPL (5 % w/w), pH 7 buffer, 23 °C,
1
N NaHCO3 (84 %); (b) PPh3, diethyl azodicarboxylate, (PhO)2P(O)N3, 0 °C,
THF (92 %); (c) PPh3, H2O, THF, 60 °C; (d) K2CO3, MeOH, 0 °C; (e) PPh3, THF,
60 °C, then, H2O, 60 °C (78 % over two steps).
enzymatic hydrolysis of the meso-diacetate 12. Also, variability
in yields may have been due to non-enzymatic hydrolysis of
monoacetate 10. In an effort to minimize this competing non-
enzymatic reaction, we investigated a number of other organic
and inorganic bases that can effectively neutralize liberated
acetic acid without non-enzymatic side reactions. We found
that enzymatic desymmetrization of the meso-diacetate[27] in
the presence of 1
N NaHCO3 aqueous solution provided mono-
acetate 10 in high optical purity (> 95 % ee) with reproducible
yields (> 80 %). In a typical experiment, we carried out enzy-
matic desymmetrization of meso-diacetate 12 with 5 % (w/w)
PPL (Sigma, type II, crude) in pH 7 phosphate buffer at 23 °C in
Figure 2. Retrosynthetic analysis for yohimbanes.
Our synthesis of optically active alcohol 10 via desymmetri- the presence of 1
N aqueous NaHCO3 solution over the course
zation is shown in Scheme 1. Commercially available meso- of 24 h. We have carried out this enzymatic desymmetrization
1,2,3,6-tetrahydrophthalic anhydride was converted to meso-di- on 51 gram scale and obtained monoacetate 10 in 84 % yield
acetate 12 by LiAlH4 reduction followed by acetylation of the with > 95 % ee as determined by HPLC analysis (see Supporting
resulting diol as reported in the literature.[27] For optical resolu- Information for further details). Accordingly, we utilized this op-
tion, we planned to utilize commercially available and inexpen- tically active alcohol in a unified synthesis of (–)-alloyohimbane
sive porcine pancreatic lipase (PPL), an enzyme that hydrolyzes and (–)-yohimbane.
dietary triglycerides to monoglycerides and free fatty acids.[28]
This enzyme has been extensively utilized in the selective hy-
drolysis of esters in aqueous solution. As reported, exposure of
For the synthesis of (–)-alloyohimbane, alcohol 10 was sub-
jected to Mitsunobu azidation,[30,31] by using diphenylphos-
phoryl azide (DPPA) and triphenylphosphine in THF at 0 °C for
40 min to provide azide 13 in 92 % yield. Staudinger reduc-
tion,[32] of 13 with triphenylphosphine in aqueous THF at 60 °C,
provided desired amine 9 in only 18 % yield. Acetamide 14,
resulting from intramolecular acetate transfer, was obtained as
meso-diacetate 12 with PPL in 0.1
provided monoacetate 10 with high optical purity.[27,29] The re-
action protocol required continuous addition of 1 NaOH solu-
tion to neutralize the acetic acid released in the reaction.
M phosphate buffer (pH 7)
N
Although this protocol provided optically active alcohol 10, a major product in 48 % yield. Acetate 13 was therefore con-
the observed enantiomeric excess (ee) and reaction yields verted to amino alcohol 15 by exposure to K2CO3 in MeOH at
proved variable, particularly during large scale preparations. We 0 °C for 1 h followed by Staudinger reduction to provide 15 in
presume that the erosion of ee could be due to competing non- 78 % yield over two steps.
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Our initial coupling of amine 15 with 3-indolyl acetalde- The spectroscopic data of our synthetic (–)-alloyohimbane and
hyde[33] did not provide satisfactory results. As shown in observed specific rotation {[α]2D0 = –78.8 (c = 0.3 EtOH)} are in
Scheme 2, reductive amination of 15 with 3-indolyl acetalde- complete agreement with the synthetic (–)-alloyohimbane re-
hyde was carried out with sodium cyanoborohydride in MeOH ported in the literature.[22]
in the presence of acetic acid. However, this reductive amin-
ation provided amine 16 in poor yields under a variety of reac-
tion conditions, presumably due to the instability of 3-indolyl
acetaldehyde. In an alternative route, amine 15 was coupled
with 3-indolylacetic acid by using 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt)
in THF at 23 °C for 12 h to provide amide 17 in 75 % yield.
Reduction of this amide with LiAlH4 in THF at 80 °C for 12 h
afforded amine 16 in 74 % yield.
Scheme 3. Reagents and conditions: (a) Boc2O, CH2Cl2, 23 °C; (b) PPh3, DIAD,
THF, Me2C(OH)CN, 23 °C (83 % over two steps); (c) 20 % aq. NaOH, EtOH (1:1),
reflux (76 %); (d) CF3CO2H, CH2Cl2, 23 °C; (e) EDCI, HOBt, NEtiPr2, CH2Cl2, 23 °C
(45 % over two steps); (f) POCl3, CH2Cl2, 50 °C, then, NaBH4, MeOH/H2O, 0 °C
(74 %); (g) H2, 10 % Pd-C, EtOAc, 23 °C (91 %).
The synthesis of (–)-yohimbane, 2 from (1R, 6S)-6-(hydroxy-
Scheme 2. Reagents and conditions: (a) 3-indolyl acetaldehyde 8, AcOH,
methylcyclohexenyl)methyl acetate 10 is shown in Scheme 4.
MeOH, Na(CN)BH3, 23 °C (24 %); (b) 3-indolylacetic acid, EDC, HOBt, NEtiPr2,
Swern oxidation of alcohol 10 provided aldehyde 20, which was
THF, 23 °C (75 %); (c) LiAlH4, THF, 80 °C (74 %).
immediately subjected to reductive amination with tryptamine
in the presence of acetic acid and sodium cyanoborohydride at
23 °C for 10 h. To our delight, the reductive amination condi-
tions led to the formation of epimerized product 21 along with
unepimerized product 22 in a 9:1 diastereomeric ratio as deter-
mined by 1H NMR spectroscopy. Swern oxidation conditions
provided predominantly cis-aldehyde 20 and only trace
amounts of epimerized trans-aldehyde 11 as determined by 1H-
The synthesis of (–)-alloyohimbane from amine 16 is shown
in Scheme 3. Amine 16 was protected as the Boc derivative by
treatment with 0.95 equiv. of Boc2O in CH2Cl2 at 23 °C for 5 h.
These conditions provided predominantly the corresponding N-
Boc derivative and only trace amounts of the corresponding
tert-butylcarbonate. The free alcohol was converted to cyanide
7 by using a Mitsunobu reaction with acetone cyanohydrin[34]
in the presence of diisopropyl azodicarboxylate (DIAD) and tri-
phenylphosphine in THF at 23 °C for 6 h. Cyanide derivative 7
was obtained in 83 % yield over two steps. Compound 7 was
treated with 20 % aqueous NaOH in ethanol at reflux for 18 h
to provide acid 18 in 76 % yield. The Boc group was cleaved by
exposure to trifluoroacetic acid in CH2Cl2 at 23 °C for 1 h and
reaction of the resulting amino acid with EDC and HOBt in the
presence of diisopropylethylamine at 23 °C for 18 h afforded
lactam 5 in 45 % yield over the two steps. The lactam was con-
verted to (–)-dehydroalloyohimbane 19 by a Bischler–Napieral-
ski reaction[22] with phosphorus oxychloride in CH2Cl2 (1:1) at
50 °C for 4 h followed by sodium borohydride reduction of the
resulting iminium ion to provide 19 as a single isomer in 74 %
yield. The stereochemical outcome was dictated by the existing
ring stereochemistry and preferred hydride attack from the
sterically less hindered α-face. Catalytic hydrogenation of olefin
19 over 10 % Pd/C in ethyl acetate under a H2-filled balloon at
23 °C for 1 h furnished (–)-alloyohimbane (–)-1 in 91 % yield.
Scheme 4. Reagents and conditions: (a) (COCl)2, DMSO, NEt3, –78 °C, CH2Cl2
(93 %); (b) AcOH, MeOH, Na(CN)BH3, 23 °C (73 %).
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NMR spectroscopy. The reductive amination provided epimer- tion of the acetate afforded the corresponding alcohol in 96 %
ized product 21 as the major product presumably due to epi- yield and this alcohol was then converted to cyanide 26 in 94 %
merization via an imine-enamine pathway. As shown in Fig- yield. The cyanide was then hydrolyzed to carboxylic acid 27 as
ure 3, initial imine 23 isomerized to the more stable trans-imine described above. Carboxylic acid 27 was subjected to trifluoro-
25 via enamine 24 under the reaction conditions. Interestingly, acetic acid and the resulting amino acid was converted to
hydrogenation of the cis-aldehyde with tryptamine and 10 % lactam 6 in 42 % yield over two steps. Lactam 6 was then
Pd-C in methanol at 23 °C for 24 h resulted in significantly less treated with phosphorus oxychloride in CH2Cl2 at 50 °C for 4 h
epimerization and the corresponding saturated cis-isomer of 22 followed by treatment with NaBH4 to afford pentacyclic indole
was formed as the major product (7:3 diastereomeric ratio). Ad- derivative 28 in 72 % yield. Catalytic hydrogenation of 28 with
ditionally, the acetate group was hydrolyzed under these reac- 10 % Pd-C under a H2-filled balloon furnished (–)-yohimbane 2
tion conditions.
in 92 % yield. The spectroscopic data of our synthetic
(–)-yohimbane {[α]2D0 = –77.6 (c = 0.22, EtOH)} is in complete
agreement with the synthetic (–)-yohimbane {[α]2D2 = –81 (c =
0.5, EtOH)} reported in the literature.[23]
Conclusions
In summary, we have developed stereoselective syntheses of
(–)-yohimbane and (–)-alloyohimbane which feature enantio-
selective enzymatic desymmetrization with sodium hydrogen
carbonate to neutralize the acetic acid formed. To the best of
our knowledge, this procedure has not been reported in the
literature and should serve as an excellent technique for large-
scale synthesis of optically active starting materials due to the
mild basicity of sodium hydrogen carbonate. Epimerization dur-
ing reductive amination was used to our advantage and utilized
for the synthesis of (–)-yohimbane. Different stereochemical
consequences attained by reductive amination and amide cou-
pling reactions enabled efficient paths to the pentacyclic cores
of yohimbine alkaloids. The strategically positioned unsaturated
site in pentacyclic indole derivatives 19 and 28 can be used
conveniently to synthesize yohimbol, yohimbine, alloyohimb-
ine, corynanthine and related alkaloids. The efficacy and brevity
of this synthesis underscores the value of enantioenriched
products that are easily accessible by enzymatic desymmetriza-
tion.
Figure 3. Plausible epimerization pathway.
Amine 21 was converted to (–)-yohimbane as shown in
Scheme 5. Treatment of amine 21 with Boc2O provided the
corresponding Boc-protected amine in 92 % yield. Saponifica-
Experimental Section
All reactions were carried out under an atmosphere of Ar in oven-
dried (120 °C) glassware with magnetic stirring unless otherwise
noted. Solvents, reagents and chemicals were purchased from com-
mercial suppliers. Solvents were distilled as follows: dichloro-
methane from calcium hydride, tetrahydrofuran from sodium/
benzophenone, and methanol from activated magnesium. Purifica-
tion of reaction products was carried out by flash chromatography
by using Silicycle silica gel 230–400 mesh, 60 Å pore diameter. Ana-
lytical thin layer chromatography was performed on glass-backed
thin-layer silica gel chromatography plates (0.25 mm thickness,
60 Å, F-254 indicator). Visualization was realized with UV light and
ethanolic phosphomolybdic acid solution or ethanolic acidic
p-anisaldehyde solution followed by heating. Optical rotations were
measured by using a Perkin–Elmer 341 polarimeter with a sodium
lamp and are reported as follows: [α]TD(°C) (c =g/100 mL, solvent).
Infrared spectra were recorded with a Varian 2000 Infrared spectro-
Scheme 5. Reagents and conditions: (a) Boc2O, NEt3, CH2Cl2, 23 °C; (b) K2CO3,
MeOH, 0 °C; (c) PPh3, DIAD, Me2C(OH)CN, THF, 23 °C (83 % over three steps);
(d) 20 % aq. NaOH, EtOH (1:1), reflux (81 %); (e) CF3CO2H, CH2Cl2, 23 °C;
(f) EDCI, HOBt, NEtiPr2, CH2Cl2, 23 °C (42 % over two steps); (g) POCl3, CH2Cl2,
50 °C, then, NaBH4, MeOH/H2O, 0 °C (72 %); (h) H2, 10 % Pd-C, EtOAc, 23 °C
(92 %).
photometer and are reported as cm–1 1H NMR spectra were re-
.
corded at room temperature with a Bruker ARX-400 spectrometer
and are reported in ppm relative to solvent signals (CDCl3 at δ =
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7.26 ppm, CD3OD at δ = 3.31 ppm) as an internal standard. Data
are reported as (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, dd = doublet of doublets, ddd = doublet of doublet
of doublets, td = triplet of doublets, qd = quartet of doublets, dt =
doublet of triplets, dq = doublet of quartets, brs = broad singlet;
coupling constant(s) in Hz; integration). Proton-decoupled 13C NMR
spectra were recorded with a Bruker ARX-400 spectrometer and are
reported in ppm by using the solvent as the internal standard
(CDCl3 at δ = 77.16 ppm, CD3OD at δ = 49.00 ppm). Low and High
resolution mass spectra were obtained at the Purdue University De-
partment of Chemistry Mass Spectrometry Center.
H), 1.89–1.78 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.9,
125.7, 125.3, 63.0, 40.1, 36.9, 34.1, 27.8, 26.6, 23.0 ppm. LRMS-ESI:
m/z = 183.2. HRMS (ESI) m/z calcd. for C10H17NO2Na [M + Na]+:
206.1157, found 206.1155.
[(1R,6S)-6-(Aminomethyl)cyclohex-3-en-1-yl]methanol (15): To a
solution of azido-acetate 13 (1.02 g, 4.9 mmol) in methanol (30 mL)
was added potassium carbonate (672 mg, 4.9 mmol), and stirred
for 2 h. Methanol was removed under reduced pressure, dichloro-
methane was added and the mixture was washed with water. The
organic layer was washed with brine, dried with sodium sulfate and
the solvent was evaporated to produce 774 mg (4.7 mmol, 96 %
yield) of the corresponding alcohol as a pale yellow viscous liquid.
Rf 0.75 (40 % ethyl acetate/hexanes). 1H NMR (400 MHz, CDCl3): δ =
5.72–5.52 (m, 2 H), 3.63 (dd, J = 10.8, 6.9 Hz, 1 H), 3.55 (dd, J = 10.8,
6.7 Hz, 1 H), 3.40 (dd, J = 12.2, 6.3 Hz, 1 H), 3.23 (dd, J = 12.1, 8.1 Hz,
1 H), 2.22–2.01 (m, 4 H), 2.00–1.81 (m, 2 H) ppm.
[(1R,6S)-6-(Hydroxymethyl)cyclohex-3-en-1-yl]methyl Acetate
(10): To a suspension of diacetate 12 (51 g, 0.23 mol) in 0.1
Phosphate buffer (650 mL, pH 7) was added PPL (2.55 g, Sigma type
II, crude). 1 Sodium hydrogen carbonate solution (690 mL) was
M
N
added and the heterogeneous mixture was stirred for 24 h. The
mixture was then filtered through Celite®. The filtrate was extracted
with dichloromethane (× 3). The organic layer was washed with
brine, dried with sodium sulfate, filtered and the solvent evapo-
rated. The residue was purified by chromatography on silica gel
(25 % to 30 % ethyl acetate/hexanes) to obtain 10 (34.7 g, 0.19 mol,
84 % yield) as a colorless oil. Rf 0.6 (50 % ethyl acetate/hexanes).
[α]2D0 = –20.1 (c = 2.0, CHCl3); lit.[1] [α]2D3 = –17.0 (c = 0.42, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 5.75–5.54 (m, 2 H), 4.19 (dd, J = 11.0,
6.0 Hz, 1 H), 3.95 (dd, J = 11.0, 8.0 Hz, 1 H), 3.68 (dd, J = 10.8, 7.1 Hz,
1 H), 3.59 (dd, J = 10.7, 6.9 Hz, 1 H), 2.29–2.08 (m, 3 H), 2.06 (s, 3
H), 2.01–1.68 (m, 3 H), 1.80 (br. s, 1 H, OH) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.5, 125.8, 125.3, 65.1, 63.9, 37.4, 33.4, 27.2, 26.1,
21.2 ppm. LRMS-ESI: m/z = 207.2 [M + Na]+.
The azido-alcohol (750 mg, 4.5 mmol) obtained above was dis-
solved in tetrahydrofuran (25 mL) and triphenylphosphine (2.35 g,
9 mmol) was added. The mixture was heated at 60 °C for 1 h. A few
drops of water were added, and further heated at 60 °C for 1 h. The
solvent and water were removed under vacuum, and the residue
was purified by column chromatography by using 5–20 % (5 % am-
monia/methanol)/dichloromethane to obtain amino-alcohol 15
(513 mg, 3.63 mmol, 81 % yield) as a yellow oil in 78 % yield over
two steps. Rf 0.3 [20 % (5 % ammonia/methanol)/dichloromethane].
[α]2D0 = –7.95 (c = 2, Methanol). 1H NMR (400 MHz, CD3OD): δ = 5.62
(s, 2 H), 3.57 (dt, J = 10.0, 5.0 Hz, 1 H), 3.45 (dd, J = 10.9, 6.2 Hz, 1
H), 2.70 (dd, J = 12.5, 6.0 Hz, 1 H), 2.57 (dd, J = 12.6, 7.1 Hz, 1 H),
2.17–1.89 (m, 6 H) ppm. 13C NMR (101 MHz, CD3OD): δ = 126.9,
126.6, 63.3, 43.1, 39.0, 28.8, 27.8 ppm. LRMS (TWA-CI): m/z = 142.25
[M + H]+. HRMS (ESI) m/z calcd. for C8H16NO [M + H]+: 142.1232,
found 142.1226.
[(1R,6S)-6-(Azidomethyl)cyclohex-3-en-1-yl]methyl Acetate (13):
To a solution of alcohol 10 (1.25 g, 6.8 mmol) and PPh3 (3.6 g,
13.6 mmol) in tetrahydrofuran (65 mL) at 0 °C was added diethyl
azodicarboxylate (5.3 mL, 13.6 mmol) and the solution was stirred
for 5 min. Diphenyl phosphoryl azide (2.9 mL, 13.6 mmol) was then
added at room temperature and the solution was stirred for 20 min.
The solvent was evaporated and the crude mixture was purified
over silica gel by using 5 % ethyl acetate/hexanes to yield 13 (1.3 g,
6.2 mmol, 92 % yield) as a yellow liquid. Rf 0.25 (5 % ethyl acetate/
N-{[(1S,6R)-6-(Hydroxymethyl)cyclohex-3-en-1-yl]methyl}-2-(1H-
indol-3-yl)acetamide (17): A solution of indole-3-acetic acid
(666 mg, 3.82 mmol) and HOBt hydrate (703 mg, 5.2 mmol) in dry
tetrahydrofuran (15 mL) was cooled to 0 °C. EDCI·HCl (732 mg,
3.82 mmol) was added and the mixture was stirred for 1 h at 0 °C.
A solution of amino-alcohol 15 (490 mg, 3.47 mmol) and DIPEA
(1.81 mL, 10.4 mmol) in tetrahydrofuran (10 mL) was then added at
room temp., and the reaction mixture was stirred for 12 h. The
solvent was evaporated and the residue was dissolved in ethyl acet-
ate. The solution was washed with saturated aqueous sodium
hydrogen carbonate, brine and dried with Na2SO4. Ethyl acetate
was evaporated and the residue was purified over silica gel by using
75 % ethyl acetate/hexanes to ethyl acetate to furnish light yellow
solid 17 (850 mg, 2.85 mmol, 75 % yield). Rf 0.19 (ethyl acetate).
hexanes). [α]2D5 = –1.7 (c = 0.35, CHCl3). IR: ν = 3028, 2900,
˜
2845, 2094, 1976, 1737, 1653, 1439, 1396, 1387, 1336, 1035, 922,
1
909 cm–1. H NMR (400 MHz, CDCl3): δ = 5.57 (s, 2 H), 4.02 (dd, J =
11.0, 7.0 Hz, 1 H), 3.93 (dd, J = 11.1, 7.3 Hz, 1 H), 3.31 (dd, J = 12.1,
6.3 Hz, 1 H), 3.18 (dd, J = 12.0, 8.3 Hz, 1 H), 2.22–2.02 (m, 4 H), 1.99
(s, 3 H), 1.94–1.79 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
170.9, 125.0, 124.9, 64.6, 52.4, 34.4, 33.8, 27.0, 26.5, 20.8 ppm. HRMS
(ESI) m/z calcd. for C10H15N3O2Na [M + Na]+: 232.1062, found
232.1058.
1
[α]2D0 = +32.7 (c = 2, CHCl3). H NMR (400 MHz, CDCl3): δ = 9.26 (s,
1 H), 7.51 (d, J = 7.8 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.19 (t, J =
7.3 Hz, 1 H), 7.10 (t, J = 7.4 Hz, 1 H), 7.05 (s, 1 H), 6.39 (s, 1 H), 5.50
(q, J = 9.9 Hz, 2 H), 3.70 (s, 2 H), 3.58–3.48 (m, 1 H), 3.39 (ddd, J =
25.9, 11.7, 5.7 Hz, 3 H), 2.87 (dt, J = 13.1, 6.3 Hz, 1 H), 2.00–1.80 (m,
4 H), 1.79–1.60 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 172.8,
127.0, 125.7, 125.2, 124.3, 122.4, 119.8, 118.5, 111.7, 108.3, 63.4, 40.1,
36.9, 34.0, 33.4, 27.8, 26.3 ppm. LRMS (ESI): m/z = 321.3 [M + Na]+.
HRMS (ESI) m/z calcd. for C18H22N2O2Na [M + Na]+: 321.1279, found
321.1569.
N-{[(1S,6R)-6-(Hydroxymethyl)cyclohex-3-en-1-yl]methyl}-
acetamide (14): To a solution of azide 13 (60 mg, 0.29 mmol) in
tetrahydrofuran (4 mL) was added triphenylphosphine (151 mg,
0.58 mmol), followed by few drops of water. The solution was
heated at 60 °C for 2 h. The solvent was evaporated, and the residue
was purified over silica gel with 5–10 % (5 % ammonia/methanol)/
dichloromethane to afford acetamide 14 as a brown oil (25 mg,
0.14 mmol, 48 % yield) along with amino-acetate 9 (vide article)
(10 mg, 0.05 mmol, 18 % yield). Analytical data for 9 could not be
collected because it gradually converted to 14 under purification
conditions and upon standing. Analytical data for 14: Rf 0.1 [5 %
[(1R,6S)-6-({[2-(1H-Indol-3-yl)ethyl]amino}methyl)cyclohex-3-
en-1-yl]methanol (16): To a solution of amide 17 (800 mg,
(5 % ammonia/methanol)/dichloromethane]. [α]2D5 = +27.1 (c = 1.9, 2.68 mmol) in tetrahydrofuran (40 mL) was added LiAlH4 (407 mg,
CHCl3). 1H NMR (400 MHz, CD3OD): δ = 5.73–5.53 (m, 2 H), 3.62 (dd, 10.7 mmol). The suspension was stirred at 80 °C for 12 h. The mix-
J = 10.8, 6.1 Hz, 1 H), 3.48 (dd, J = 10.8, 7.5 Hz, 1 H), 3.24 (dd, J =
ture was cooled to 0 °C and ethyl acetate was added until bubbling
13.3, 5.5 Hz, 1 H), 3.14–3.03 (m, 1 H), 2.20–1.96 (m, 5 H), 1.94 (s, 3 ceased. 5
N
NaOH solution (9 mL) was added, followed by solid
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sodium sulfate. The mixture was filtered through Celite® and the
filtrate was evaporated. The residue was taken in ethyl acetate,
washed with water and brine. The solvent was evaporated, and
the residue was purified over silica gel with 5 % (5 % ammonia/
methanol)/dichloromethane to afford amino-alcohol 16 (561 mg,
1.97 mmol, 74 % yield) as a yellow oil. Rf 0.5 [10 % (5 % ammonia/
for 18 h. The mixture was cooled to 0 °C, acidified to pH 3 by careful
addition of saturated aqueous citric acid, and then extracted with
ethyl acetate (× 3). The organic layer was washed with brine, dried
with Na2SO4, filtered and the solvent was evaporated. The residue
was purified by silica gel chromatography with 60 % ethyl acetate/
hexanes to obtain carboxylic acid 18 (341 mg, 0.83 mmol, 76 %
methanol)/dichloromethane]. [α]2D0 = –20.7 (c = 1.46, CHCl3). 1H yield) as a yellow amorphous solid. Rf 0.2 (60 % ethyl acetate/hex-
1
NMR (400 MHz, CDCl3): δ = 8.92 (s, 1 H), 7.61 (d, J = 7.6 Hz, 1 H),
anes). [α]2D0 = +28.9 (c = 1.9, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.36 (d, J = 7.9 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 1 H), 7.12 (d, J = 7.2 Hz, 8.22 (s, 1 H), 7.60 (d, J = 8.3 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.23–
1 H), 6.98 (s, 1 H), 5.75–5.51 (m, 2 H), 4.40 (s, 1 H), 3.75–3.53 (m, 2
H), 3.07–2.80 (m, 4 H), 2.74 (t, J = 10.7 Hz, 1 H), 2.42 (d, J = 12.2 Hz,
1 H), 2.29–2.15 (m, 2 H), 2.08–1.78 (m, 5 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 136.4, 127.2, 126.6, 124.6, 122.2, 122.0, 119.2, 118.7,
113.1, 111.2, 64.6, 50.3, 49.3, 39.1, 37.1, 30.8, 25.3, 25.1 ppm. LRMS
7.16 (m, 1 H), 7.12 (t, J = 7.1 Hz, 1 H), 6.98 (s, 1 H), 5.61 (s, 2 H), 3.60
(dq, J = 15.4, 8.1, 7.5 Hz, 1 H), 3.46 (dd, J = 14.2, 8.9 Hz, 1 H), 3.35
(dt, J = 13.5, 6.8 Hz, 1 H), 3.12–2.95 (m, 2 H), 2.90 (dd, J = 14.8,
5.6 Hz, 1 H), 2.55 (d, J = 10.3 Hz, 1 H), 2.37–2.06 (m, 4 H), 2.04–1.76
(m, 3 H), 1.44 (m, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 177.2,
(ESI): m/z = 285.3 [M + H]+. HRMS (ESI) m/z calcd. for C18H25N2O [M 157.1, 136.4, 127.5, 125.6, 125.4, 122.2, 122.1, 119.5, 118.7, 113.1,
+ H]+: 285.1967, found 285.1961.
111.4, 80.6, 48.4, 35.8, 33.7, 30.9, 29.8, 28.6, 26.3, 24.5 ppm. LRMS
(ESI): m/z = 435.3 [M + Na]+. HRMS (ESI) m/z calcd. for C24H32N2O4
[M + Na]+: 435.2260, found 435.2256.
tert-Butyl [2-(1H-Indol-3-yl)ethyl]{[(1S,6S)-6-(cyanomethyl)-
cyclohex-3-en-1-yl]methyl}carbamate (7): To a solution of amino-
alcohol 16 (450 mg, 1.58 mmol) in dichloromethane (10 mL) was
added di-tert-butyl dicarbonate (Boc anhydride, 328 mg, 1.5 mmol).
The solution was stirred for 5 h at room temperature. The solvent
was evaporated under reduced pressure and the residue was puri-
fied over silica gel by using 15 % ethyl acetate/hexanes to yield the
N-boc derivative (535 mg, 1.39 mmol, 88 % yield) along with traces
of the corresponding tert-butylcarbonate (O-Boc derivative). Rf 0.25
(4aS,8aS)-2-[2-(1H-Indol-3-yl)ethyl]-1,4,4a,5,8,8a-hexahydroiso-
quinolin-3(2H)-one (5): To a solution of carboxylic acid 18
(165 mg, 0.4 mmol) in dichloromethane (2 mL) at 0 °C was added
trifluoroacetic acid (0.67 mL). The solution turned from yellow to
orange as it was gradually warmed to room temperature. After 1 h,
the reaction mixture was concentrated in vacuo. The residue was
taken in dichloromethane (4 mL), and diisopropylethylamine
(0.35 mL, 2 mmol) was added at 0 °C. HOBt hydrate (73 mg,
0.48 mmol) was then added, followed by EDCI·HCl (84 mg,
0.44 mmol). Diisopropylethylamine (0.35 mL, 2 mmol) was added
again and the solution was warmed to room temperature. After
18 h, water was added to the reaction mixture, and it was extracted
with ethyl acetate (× 3). The combined organic layers washed with
brine, dried with Na2SO4, filtered and the solvent was evaporated.
The residue was subjected to silica gel chromatography with ethyl
acetate to afford lactam 5 (74 mg, 0.25 mmol, 45 % yield) as a white
1
(40 % ethyl acetate/hexanes). [α]2D0 = +7.8 (c = 0.5, CHCl3). H NMR
(400 MHz, CDCl3): δ = 8.04 (s, 1 H), 7.62 (d, J = 7.5 Hz, 1 H), 7.36 (d,
J = 8.1 Hz, 1 H), 7.19 (d, J = 7.4 Hz, 1 H), 7.12 (t, J = 7.4 Hz, 1 H),
6.99 (s, 1 H), 5.81–5.46 (m, 2 H), 3.86–3.40 (m, 5 H), 3.36–3.20 (m, 1
H), 3.07–2.89 (m, 2 H), 2.18 (s, 1 H), 2.00 (d, J = 15.3 Hz, 3 H), 1.77
(d, J = 14.2 Hz, 1 H), 1.61 (d, J = 19.2 Hz, 2 H), 1.44 (s, 9 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 156.4, 136.3, 127.3, 126.0, 125.6,
121.9, 119.2, 118.6, 113.1, 111.2, 79.8, 63.4, 49.3, 47.2, 37.1, 33.1,
28.3, 27.9, 26.6, 24.5 ppm.
1
solid. Rf 0.1 (ethyl acetate). [α]2D0 = –18.1 (c = 0.16, CHCl3); H NMR
To a solution of the above Boc-protected amino-alcohol (500 mg,
1.3 mmol) in dry tetrahydrofuran (8 mL) was added triphenylphos-
phine (1.02 g, 3.9 mmol), followed by dropwise addition of diiso-
propyl azodicarboxylate (0.77 mL, 3.9 mmol) at 0 °C. The solution
turned cloudy after 5 min. After 5 more minutes, acetone cyano-
hydrin (0.6 mL, 6.5 mmol) was added and the reaction mixture
turned clear yellow. The solution was warmed to room temperature
and stirred for 6 h. The mixture was then poured into water and
extracted with ethyl acetate (× 3). The organic layer was washed
with brine, dried with Na2SO4, filtered and the solvents evaporated
to dryness. The residue was purified by silica gel chromatography
(5 % to 30 % ethyl acetate/hexanes) to yield pale yellow amorphous
solid 7 (480 mg, 1.22 mmol, 94 % yield). Rf 0.6 (40 % ethyl acetate/
(400 MHz, CDCl3): δ = 8.31 (s, 1 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.36 (d,
J = 8.1 Hz, 1 H), 7.23–7.09 (m, 2 H), 7.03 (s, 1 H), 5.58 (s, 2 H), 3.72
(dt, J = 14.7, 7.7 Hz, 1 H), 3.61 (dt, J = 13.6, 7.6 Hz, 1 H), 3.17 (qd,
J = 12.0, 5.5 Hz, 2 H), 3.04 (t, J = 6.2 Hz, 2 H), 2.38 (qd, J = 17.8,
5.8 Hz, 2 H), 2.21–2.06 (m, 4 H), 1.90–1.80 (m, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 169.1, 136.2, 127.4, 124.7, 124.4, 122.0, 121.8,
119.2, 118.7, 113.0. 111.1, 50.9, 48.0, 35.7, 30.0, 29.3, 28.0, 26.1,
22.8 ppm. LRMS-ESI: m/z = 317.3 [M + Na]+. HRMS (ESI) m/z calcd.
for C19H22N2ONa [M + Na]+: 317.1630, found 317.1628.
(–)-Dehydroalloyohimbane (19): To a solution of the lactam 5
(45 mg, 0.15 mmol) in dichloromethane (1 mL) was added phos-
phorus oxychloride (1 mL). The mixture was heated for 4 h at 50 °C.
The reaction was then cooled to room temperature and phosphorus
oxychloride was removed in vacuo. The residue was dissolved in
methanol/water (9:1) (1 mL) and cooled to 0 °C. Sodium boro-
hydride was added until the pH > 7. Then 1 mL of saturated aque-
ous ammonium chloride solution and ice were added to the reac-
tion mixture. The mixture was then extracted with dichloromethane
(× 3). The combined organic layers were washed with brine, dried
with Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was purified by silica gel chromatography with 30 %
ethyl acetate/hexanes to obtain 19 (31 mg, 0.11 mmol, 74 % yield).
Rf 0.3 (30 % ethyl acetate/hexanes). [α]2D0 = –59.2 (c = 1.00, CHCl3);
1H NMR (400 MHz, CDCl3): δ = 7.73 (s, 1 H), 7.47 (d, J = 7.6 Hz, 1 H),
7.27 (d, J = 6.8 Hz, 1 H), 7.10 (dt, J = 14.8, 7.0 Hz, 2 H), 5.80–5.41
(m, 2 H), 3.24 (d, J = 10.7 Hz, 1 H), 3.04–2.90 (m, 2 H), 2.83 (d, J =
11.2 Hz, 1 H), 2.73–2.51 (m, 4 H), 2.43 (d, J = 17.9 Hz, 1 H), 2.08–
1.95 (m, 3 H), 1.90–1.69 (m, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
1
hexanes). [α]2D0 = –4.0 (c = 0.42, CHCl3). H NMR (400 MHz, CDCl3):
δ = 8.29 (s, 1 H), 7.62 (d, J = 6.5 Hz, 1 H), 7.36 (d, J = 7.5 Hz, 1 H),
7.24–7.16 (m, 1 H), 7.16–7.05 (m, 1 H), 6.97 (s, 1 H), 5.62 (s, 2 H),
3.58 (dt, J = 14.0, 7.2 Hz, 1 H), 3.50–3.19 (m, 2 H), 3.14–2.91 (m, 3
H), 2.14 (dd, J = 36.6, 21.1 Hz, 6 H), 1.99 (d, J = 19.5 Hz, 1 H), 1.86–
1.63 (m, 1 H), 1.52 (s, 3 H), 1.46 (s, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 156.2, 136.4, 125.6, 124.6, 122.3, 122.0, 119.6, 118.8,
111.4, 79.7, 48.0, 35.0, 31.4, 29.5, 28.6, 26.6, 26.3, 22.1 ppm. LRMS-
ESI: m/z = 416.3 [M + Na]+. HRMS (ESI) m/z calcd. for C24H31N3O2Na
[M + Na]+: 416.2314, found 416.2308.
2-[(1S,6S)-6-({[2-(1H-Indol-3-yl)ethyl](tert-butoxycarbonyl)-
amino}methyl)cyclohex-3-en-1-yl]acetic Acid (18): To 7 (430 mg,
1.09 mmol) was added 1:1 20 % aqueous sodium hydroxide/ethanol
(6 mL). The mixture was stirred at room temperature for 1 h, fol-
lowed by addition of water (1 mL). The reaction was then refluxed
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δ = 136.1, 135.6, 126.2, 123.4, 121.3, 119.5, 118.2, 110.8, 108.3, 60.7,
60.4, 53.3, 33.3, 32.2, 32.0, 31.4, 25.7, 22.0 ppm. LRMS (ESI): m/z =
279.4 [M + H]+. HRMS (ESI) m/z calcd. for C19H23N2 [M + H]+:
279.1861, found 279.1857.
Reductive Amination Under Hydrogenation Conditions: To a so-
lution of aldehyde 20 (63 mg, 0.35 mmol) in dry methanol (2 mL)
under Ar was added tryptamine (55 mg, 0.35 mmol). Molecular
sieves (150 mg, 4 Å, powdered, oven-dried) were then added, fol-
lowed by 10 % Pd-C (19 mg). The Ar balloon was replaced with an
H2 balloon, and the reaction was stirred for 24 h at room tempera-
ture. The mixture was then filtered through Celite®, the methanol
was removed under reduced pressure, and the residue was purified
with 5 %(5 % ammonia/methanol)/dichloromethane to afford satu-
rated cis-amine (31 mg, 0.11 mmol, 31 % yield) and saturated trans-
(–)-Alloyohimbane (1): A 2-neck round-bottomed flask was evacu-
ated and filled with Ar. 10 % Pd/C (5 mg) was added under Ar.
0.5 mL of ethyl acetate was added down the sides of the flask to
wash down any Pd/C in the walls. A solution of 19 (8 mg,
0.029 mmol) in 0.5 mL ethyl acetate was then added. The mixture
was stirred. The flask was evacuated and re-filled with Ar three
times. An H2 balloon was then attached. The flask was evacuated
and filled with H2 three times. After 2 h, the balloon was removed
and the flask was filled with Ar. The mixture was filtered through
Celite® and the solvent was concentrated in vacuo. The residue was
purified by chromatography over silica gel (30 % ethyl acetate/hex-
anes) to yield (–)-Alloyohimbane 1 (7.4 mg, 0.026 mmol, 91 % yield).
Rf 0.3 (20 % ethyl acetate/hexanes). [α]2D0 = –78.8 (c = 0.3, Ethanol);
1H NMR (400 MHz, CDCl3): δ = 7.75 (s, 1 H), 7.47 (d, J = 7.6 Hz, 1 H),
7.30 (d, J = 7.7 Hz, 1 H), 7.10 (dt, J = 17.9, 7.1 Hz, 2 H), 3.24–3.18
(m, 1 H), 3.00–2.93 (m, 2 H), 2.79 (d, J = 11.3 Hz, 1 H), 2.68 (d, J =
14.9 Hz, 1 H), 2.52 (dq, J = 14.3, 8.7, 6.1 Hz, 2 H), 2.01–1.86 (m, 3 H),
1.75–1.57 (m, 5 H), 1.42 (ddd, J = 16.8, 9.8, 5.7 Hz, 2 H), 1.38–1.26
(m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 135.9, 135.4, 127.4,
121.1, 119.3, 118.0, 110.6, 108.1, 61.7, 60.3, 53.3, 36.5, 34.7, 31.8,
30.4, 26.4, 21.6, 20.8 ppm. LRMS (ESI): m/z = 281.4 [M + H]. HRMS
(ESI) m/z calcd. for C19H25N2 [M + H]+: 281.2018, found 281.2009.
1
amine (13 mg, 0.045 mmol, 13 % yield). H NMR for saturated trans
amine (400 MHz, CDCl3): δ = 9.00 (s, 1 H), 7.54 (d, J = 7.8 Hz, 1 H),
7.38 (t, J = 7.6 Hz, 1 H), 7.16 (d, J = 7.7 Hz, 1 H), 7.13 (d, J = 5.0 Hz,
1 H), 7.07 (d, J = 7.7 Hz, 1 H), 3.48 (dd, J = 11.1, 2.3 Hz, 1 H), 3.43–
3.27 (m, 1 H), 3.24–3.18 (m, 2 H), 3.15–3.10 (m, 1 H), 3.07–3.00 (m,
1 H), 2.76–2.73 (m, 1 H), 1.70–1.53 (m, 3 H), 1.45–1.37 (m, 2 H), 1.26–
1.18 (m, 2 H), 1.16–0.99 (m, 3 H), 0.78–0.68 (m, 1 H) ppm. LRMS
(APCI): m/z = 287 [M + H]+. 1H NMR for saturated cis amine
(400 MHz, CDCl3): δ = 8.41 (s, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.36 (d,
J = 8.1 Hz, 1 H), 7.20 (t, J = 7.3 Hz, 1 H), 7.12 (t, J = 7.4 Hz, 1 H),
7.01 (d, J = 1.9 Hz, 1 H), 3.67–3.55 (m, 1 H), 3.55–3.48 (m, 1 H), 2.99–
2.93 (m, 2 H), 2.93–2.86 (m, 1 H), 2.86–2.75 (m, 1 H), 2.52–2.40 (m,
1 H), 1.79 (s, 2 H), 1.62–1.46 (m, 3 H), 1.46–0.99 (m, 6 H) ppm. LRMS
(ESI): m/z = 287.4 [M + H]+.
tert-Butyl [2-(1H-Indol-3-yl)ethyl]{[(1S,6S)-6-(cyanomethyl)-
cyclohex-3-en-1-yl]methyl}carbamate (26): To a solution of amine
21 (800 mg, 2.45 mmol) in dichloromethane (10 mL) was added
triethylamine (0.38 mL, 2.7 mmol). The mixture was cooled to 0 °C.
A solution of di-tert-butyl dicarbonate (Boc anhydride, 589 mg,
2.7 mmol) in dichloromethane (5 mL) was then added. The reaction
was stirred for 90 min. The solvent was evaporated and the residue
was purified by silica gel chromatography with 15 % ethyl acetate/
hexanes to obtain the –Boc protected amino-acetate (961 mg,
[(1R,6S)-6-Formylcyclohex-3-en-1-yl]methyl Acetate (20): To a
solution of oxalyl chloride (0.76 mL, 8.69 mmol) in dichloromethane
(10 mL) at –78 °C was added dropwise a solution of dry dimethyl
sulfoxide (1.23 mL, 17.4 mmol) in dichloromethane (10 mL). The
mixture was stirred at –78 °C for 5 min. A solution of the alcohol 10
(800 mg, 4.35 mmol) in dichloromethane (10 mL) was then added
dropwise to the mixture. After 30 min, triethylamine (2.43 mL,
17.4 mmol) was added and the mixture was stirred at –78 °C for
10 min. The reaction was then warmed to room temperature. The
2.25 mmol, 92 % yield). Rf 0.6 (40 % ethyl acetate/hexanes). [α]D20
=
–20.9 (c = 2, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 1 H),
7.63 (d, J = 7.4 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.19 (t, J = 7.3 Hz,
1 H), 7.12 (t, J = 7.5 Hz, 1 H), 6.99 (s, 1 H), 5.61 (d, J = 11.6 Hz, 2 H),
4.01 (dd, J = 13.2, 5.1 Hz, 2 H), 3.48 (d, J = 5.3 Hz, 2 H), 3.21 (s, 2
H), 3.00 (s, 2 H), 2.15–2.05 (m, 3 H), 2.03 (s, 3 H), 1.89 (d, J = 9.9 Hz,
1 H), 1.84–1.77 (m, 2 H), 1.51–1.41 (m, 9 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.2, 155.9, 136.2, 127.4, 125.7, 124.9, 122.1, 121.8,
119.1, 118.6, 112.9, 111.1, 79.3, 66.5, 64.7, 48.4, 33.9, 32.5, 28.4, 26.0,
25.4, 22.6, 23.7, 20.9 ppm.
mixture was washed successively with water, 2N HCl, water, brine
and dried with Na2SO4. The solvent was evaporated to obtain alde-
hyde 20 (736 mg, 4.05 mmol, 93 % yield) as a colorless oil. Rf 0.8
(50 % ethyl acetate/hexanes); 1H NMR (400 MHz, CDCl3): δ = 9.69
(s, 1 H), 5.74–5.54 (m, 2 H), 4.23–3.85 (m, 2 H), 2.59 (q, J = 7.8, 7.1 Hz,
2 H), 2.31–2.17 (m, 3 H), 2.05–1.98 (m, 1 H), 1.96 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 202.9, 170.2, 125.2, 124.5, 64.1, 46.9,
32.5, 26.5, 22.4, 20.3 ppm.
[(1R,6R)-6-({[2-(1H-Indol-3-yl)ethyl]amino}methyl)cyclohex-3-
en-1-yl]methyl Acetate (21): To a solution of aldehyde 20 (700 mg,
3.85 mmol) and tryptamine (801 mg, 5 mmol) in methanol (25 mL)
was added glacial acetic acid (0.22 mL, 3.85 mmol) and 4 Å molec-
ular sieves (1.5 g, powdered, activated). The orange solution was
stirred for 1 h. Sodium cyanoborohydride was then added and the
reaction was stirred for 10 h. The mixture was then filtered and the
methanol was evaporated. The residue was purified by silica gel
To a solution of the above amino-acetate (800 mg, 1.88 mmol) in
methanol (10 mL) was added potassium carbonate (260 mg,
1.88 mmol). The mixture was stirred for 2 h at room temperature.
The methanol was evaporated, water was added and extracted with
dichloromethane (× 3). The combined organic layers were washed
with water, brine, dried with sodium sulfate and the solvent was
evaporated. The residue was purified by silica gel chromatography
chromatography with ethyl acetate to obtain the secondary amine (30 % to 40 % ethyl acetate/hexanes) to obtain the amino-alcohol
21 (917 mg, 2.81 mmol, 73 % yield) as an orange semi-solid. Rf 0.2
(694 mg, 1.8 mmol, 96 % yield). Rf 0.3 (40 % ethyl acetate/hexanes).
1
[5 %(5 % ammonia/methanol)/dichloromethane]. [α]2D0 = –30.7 (c =
[α]2D0 = –7.7 (c = 1.7, CHCl3); H NMR (400 MHz, CDCl3): δ = 8.07 (s,
1
7.0, Methanol). H NMR (400 MHz, CD3OD): δ = 7.60 (d, J = 7.8 Hz,
1 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.20 (t, J =
7.4 Hz, 1 H), 7.12 (t, J = 7.3 Hz, 1 H), 6.99 (s, 1 H), 5.66–5.57 (m, 2
H), 3.58–3.47 (m, 5 H), 3.02–2.98 (m, 3 H), 2.19–2.02 (m, 2 H), 1.98
(m, 2 H), 1.78 (d, J = 15.9 Hz, 1 H), 1.67–1.56 (m, 2 H), 1.44 (s, 9
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.9, 136.2, 127.4, 125.5,
125.0, 121.9, 121.8, 119.2, 118.7, 113.4, 111.1, 79.4, 63.4, 50.3, 48.7,
1 H), 7.39 (d, J = 8.1 Hz, 1 H), 7.16–7.00 (m, 3 H), 5.56 (s, 2 H), 3.93
(h, J = 5.6 Hz, 2 H), 3.20–3.07 (m, 4 H), 2.97 (dd, J = 12.5, 5.0 Hz, 1
H), 2.78 (dd, J = 12.6, 9.0 Hz, 1 H), 2.15 (d, J = 18.1 Hz, 1 H), 2.05–
1.98 (m, 5 H), 1.90–1.76 (m, 3 H) ppm. 13C NMR (101 MHz, CD3OD):
δ = 172.7, 137.7, 127.8, 125.9, 124.6, 124.0, 122.6, 120.0, 118.9, 112.4,
110.1, 66.5, 51.7, 49.7, 34.8, 32.5, 26.6, 25.9, 22.9, 20.9 ppm. LRMS 47.1, 37.4, 33.1, 28.3, 26.5, 24.5 ppm. LRMS (ESI): m/z = 407.3 [M +
(ESI): m/z = 327 [M + H]+. HRMS (ESI) m/z calcd. for C20H27N2O2 [M Na]+. HRMS (ESI) m/z calcd. for C23H32N2O3Na [M + Na]+: 407.2311,
+ H]+: 327.2073, found 327.2062.
found 407.2303.
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To a solution of the above alcohol (615 mg, 1.6 mmol) in dry tetra- 0.4 [5 %(5 % ammonia/methanol)/dichloromethane]. [α]2D0 = –13.2
1
hydrofuran (10 mL) was added triphenylphosphine (1.26 g,
4.8 mmol), followed by dropwise addition of diisopropyl azodicarb-
oxylate (0.94 mL, 4.8 mmol) at 0 °C. The solution turned cloudy
(c = 1, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.67 (dq,
J = 7.8, 0.9 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.22–7.16 (m, 1 H),
7.13 (td, J = 7.5, 7.1, 1.0 Hz, 1 H), 7.06 (d, J = 2.2 Hz, 1 H), 5.65 (t,
after 5 min. After 5 more minutes, acetone cyanohydrin (0.73 mL, J = 4.7 Hz, 2 H), 3.77–3.57 (m, 2 H), 3.23 (dd, J = 12.2, 4.2 Hz, 1 H),
8 mmol) was added. The solution was warmed to room temperature
and stirred for 6 h. The mixture was then poured into water and
extracted with ethyl acetate (× 3). The organic layer was washed
with brine, dried with sodium sulfate, filtered and the solvents evap-
orated to dryness. The residue was purified by silica gel chromatog-
raphy (5 % to 30 % ethyl acetate/hexanes) to yield yellow liquid 26
(592 mg, 1.5 mmol, 83 % yield over the three steps). Rf 0.7 (40 %
ethyl acetate/hexanes). [α]2D5 = –7.1 (c = 3.9, CHCl3); 1H NMR
(400 MHz, CDCl3): δ = 8.49 (s, 1 H), 7.61 (t, J = 7.1 Hz, 1 H), 7.35 (d,
J = 8.0 Hz, 1 H), 7.17 (t, J = 7.3 Hz, 1 H), 7.11 (t, J = 7.0 Hz, 1 H),
6.97 (s, 1 H), 5.63–5.55 (m, 2 H), 3.61–3.50 (m, 1 H), 3.31 (s, 1 H),
3.16–2.89 (m, 3 H), 2.34–1.91 (m, 6 H), 1.83 (m, 1 H), 1.68 (s, 2 H),
1.48 (m, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 156.1, 136.4,
127.4, 125.5, 125.0, 124.4, 122.2, 121.9, 119.2, 118.6, 112.8, 111.4,
79.8, 71.4, 47.8, 34.8, 34.4, 28.4, 26.3, 26.1, 22.0, 21.2 ppm. LRMS
(ESI): m/z = 416.3 [M + Na]+. HRMS (ESI) m/z calcd. for C24H31N3O2Na
[M + Na]+: 416.2314, found 413.2304.
3.13–2.96 (m, 2 H), 2.99–2.88 (m, 1 H), 2.64 (dd, J = 17.6, 4.8 Hz, 1
H), 2.21 (dt, J = 14.6, 3.6 Hz, 1 H), 2.10–2.02 (m, 2 H), 1.81–1.71 (m,
2 H), 1.67–1.63 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.5,
132.3, 132.2, 128.7, 128.6, 125.8, 125.1, 122.1, 119.4, 118.8, 111.3,
54.5, 48.2, 39.4, 33.8, 32.8, 32.0, 28.8, 23.1 ppm. LRMS-ESI: m/z =
293.5 [M – H]. HRMS (ESI) m/z: calcd. for C19H22N2ONa [M + Na]+:
317.1630, found 317.1626.
(4aS,13bS,14aS)-1,4,4a,5,7,8,13,13b,14,14a-Decahydroindolo-
[2′,3′:3,4]pyrido[1,2-b]isoquinoline (28): To a solution of lactam 6
(67 mg, 0.23 mmol) in dichloromethane (1 mL) was added freshly
distilled phosphorus oxychloride (1 mL). The mixture was heated
for 4 h at 50 °C. The reaction was then cooled to room temperature
and the phosphorus oxychloride was evaporated in vacuo. The resi-
due was dissolved in methanol/water (9:1, 1 mL) and cooled to 0 °C.
Sodium borohydride was added until the pH > 7. Then 1 mL of
saturated ammonium chloride and ice were added to the reaction
mixture. The mixture was then extracted with dichloromethane
(× 3). The combined organic layers were washed with brine, dried
with sodium sulfate, filtered and concentrated in vacuo. The crude
2-[(1S,6S)-6-({[2-(1H-Indol-3-yl)ethyl](tert-butoxycarbonyl)-
amino}methyl)cyclohex-3-en-1-yl]acetic Acid (27): To compound
26 (500 mg, 1.27 mmol) was added 20 % aqueous sodium hydrox- residue was purified by silica gel chromatography with 90 % ethyl
ide (4 mL) and ethanol (4 mL, to make the solution homogeneous).
The mixture was stirred at room temperature for 1 h, followed by
addition water (1 mL). The reaction was then refluxed for 12 h. The
mixture was cooled to 0 °C, acidified to pH 3 by careful addition of
saturated aqueous citric acid, and then extracted with ethyl acetate
(× 3). The combined organic layers were dried with sodium sulfate,
filtered and the solvent was evaporated. The residue was purified
acetate/toluene to obtain 28 (46 mg, 0.16 mmol, 72 % yield). Rf 0.4
(90 % ethyl acetate/toluene). [α]2D0 = –55.3 (c = 0.49, CHCl3); 1H NMR
(400 MHz, CDCl3): δ = 7.74 (br. s, 1 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.30
(d, J = 7.9 Hz, 1 H), 7.13–7.08 (m, 2 H), 5.69 (d, J = 2.5 Hz, 2 H),
3.38–3.34 (m. 1 H), 3.13–2.96 (m, 3 H), 2.74 (dd, J = 3.5, 7.8 Hz, 1 H),
2.63 (td, J = 11.1, 4.4 Hz, 1 H), 2.53–2.27 (m, 1 H), 2.21–2.08 (m, 3
H), 1.92–1.69 (m, 3 H), 1.61–1.49 (m, 1 H), 1.47–1.35 (m, 1 H) ppm.
by silica gel chromatography with 60 % ethyl acetate/hexanes to 13C NMR (101 MHz, CDCl3): δ = 136.2, 134.9, 127.6, 126.5, 126.2,
obtain carboxylic acid 27 (424 mg, 1.03 mmol, 81 % yield) as a
121.5, 119.6, 118.3, 110.8, 108.4, 62.0, 60.2, 53.3, 37.0, 36.9, 32.2,
colorless oil. Rf 0.2 (60 % ethyl acetate/hexanes). [α]2D0 = +28.9 (c = 30.7, 29.6, 21.8 ppm. LRMS-ESI: m/z = 279.4 [M + H]+. HRMS (ESI)
1
1.9, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1 H), 7.62 (d, J =
7.2 Hz, 1 H), 7.34 (d, J = 7.0 Hz, 1 H), 7.22–7.15 (m, 1 H), 7.15–7.04
(m, 1 H), 6.96 (s, 1 H), 5.68–5.50 (m, 2 H), 3.66–3.38 (m, 2 H), 3.37–
3.08 (m, 2 H), 2.99 (s, 2 H), 2.61–2.06 (m, 5 H), 1.86 (dd, J = 42.4,
9.0 Hz, 3 H), 1.54–1.37 (m, 9 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 178.7, 156.2 136.4, 127.6, 125.0, 122.0, 119.3, 118.8, 113.3, 111.3,
79.7, 48.5, 38.2, 35.0, 31.3, 28.6, 28.0, 24.4 ppm. LRMS (ESI): m/z =
411.3 [M – H]. HRMS (ESI) m/z calcd. for C23H32N2O3Na [M + Na]+:
435.2260, found 435.2249.
m/z calcd. for C19H23N2 [M + H]+: 279.1861, found 279.1857.
(4aS,13bS,14aS)-1,2,3,4,4a,5,7,8,13,13b,14,14a-Dodecahydro-
indolo[2′,3′:3,4]pyrido[1,2-b]isoquinoline [(–)-Yohimbane (2)]: A
2-neck round-bottomed flask was evacuated and filled with Ar. 10 %
Pd/C (8 mg) was added under Ar. 0.5 mL of ethyl acetate was added
down the sides of the flask to wash down any Pd/C in the walls. A
solution of 28 (21 mg, 0.075 mmol) in 0.5 mL ethyl acetate was
then added. The mixture was stirred. The flask was evacuated and
filled with Ar three times and a H2 balloon was then attached. The
flask was evacuated and re-filled with H2 three times. After 2 h, the
balloon was removed and the flask was filled with Ar. The mixture
was filtered through Celite® and the solvent was removed in vacuo.
The residue was purified by chromatography over silica gel (90 %
Ethyl acetate/Toluene) to yield (–)-Yohimbane 2 (19 mg,
(4aS,8aS)-2-[2-(1H-Indol-3-yl)ethyl]-1,4,4a,5,8,8a-hexahydroiso-
quinolin-3(2H)-one (6): To a solution of the carboxylic acid 27
(300 mg, 0.73 mmol) in dichloromethane (3 mL) at 0 °C was added
trifluoroacetic acid (1 mL). The solution turned yellow to orange to
purple as it was gradually warmed to room temperature. After 1 h,
the reaction mixture was concentrated in vacuo. The residue was
taken in dichloromethane (4 mL), and diisopropylethylamine
0.069 mmol, 92 % yield). Rf 0.3 (40 % ethyl acetate/hexanes). [α]D20
–77.6 (c = 0.22, ethanol); 1H NMR (400 MHz, CDCl3): δ = 7.73 (s, 1
=
(0.64 mL, 3.65 mmol) was added at 0 °C. HOBt hydrate (134 mg, H), 7.47 (d, J = 7.3 Hz, 1 H), 7.30 (d, J = 7.7 Hz, 1 H), 7.10 (dt, J =
0.88 mmol) was then added, followed by EDCI·HCl (154 mg, 14.6, 6.7 Hz, 2 H), 3.29 (d, J = 10.7 Hz, 1 H), 3.09 (dt, J = 13.2, 6.3 Hz,
0.8 mmol). Additional diisopropylethylamine (0.64 mL, 3.65 mmol)
was added and the solution was warmed to room temperature.
After 48 h, water was added to the reaction mixture, and it was
extracted with ethyl acetate (× 3). The combined organic layers
were washed with brine, dried with sodium sulfate, filtered and
the solvent was evaporated. The residue was subjected to silica
gel chromatography (50 % to 75 % ethyl acetate/hexanes) to afford
lactam 6 (90 mg, 0.31 mmol, 42 % yield) as an amorphous solid. Rf
1 H), 3.04–2.95 (m, 1 H), 2.95–2.80 (m, 1 H), 2.72 (d, J = 15.3 Hz, 1
H), 2.62 (dt, J = 11.0, 5.8 Hz, 1 H), 2.13 (t, J = 10.9 Hz, 1 H), 2.00 (d,
J = 12.1 Hz, 1 H), 1.80–1.60 (m, 4 H), 1.50–1.41 (m, 1 H), 1.31 (m, 4
H), 1.16–0.99 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 135.9,
135.0, 127.4, 121.1, 119.2, 118.0, 110.6, 108.0, 62.0, 60.2, 53.1, 41.9,
36.9, 32.8, 30.3, 26.3, 25.9, 21.7 ppm. LRMS (ESI): m/z = 281.3 [M +
H]+. HRMS (ESI) m/z calcd. for C19H25N2 [M + H]+: 281.2018, found
281.2005.
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Financial support of this work was provided by the National
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Keywords: Alkaloids · Bischler–Napieralski · Enzymatic
resolution · Indoles · Polycycles · Enantioselectivity ·
Cyclization
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Received: September 19, 2016
Published Online: ■
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Enzymatic Desymmetrization
Enantioselective syntheses of (–)-allo-
yohimbane and (–)-yohimbane are de-
scribed. The key step involves a mild
enantioselective enzymatic desymme-
trization of a meso-diacetate. The re-
sulting monoacetate is an intermedi-
ate for the synthesis of (–)-alloyohim-
bane. Reductive amination of the de-
rived aldehyde induces an isomeriza-
tion, which leads to the trans-product
and, ultimately, to (–)-yohimbane.
A. K. Ghosh,* A. Sarkar .................. 1–10
Enantioselective Syntheses of (–)-Al-
loyohimbane and (–)-Yohimbane by
an Efficient Enzymatic Desymmetri-
zation Process
DOI: 10.1002/ejoc.201601171
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