Bicyclic Guanidine Catalyzed Asymmetric Tandem Isomerization Intramolecular-Diels-Alder Reaction: The First Catalytic Enantioselective Total Synthesis of (+)-alpha-Yohimbine

Article abstract of DOI:10.1002/asia.201500246

Hydroisoquinoline derivatives were prepared in moderate to good enantioselectivities via a bicyclic guanidine-catalyzed tandem isomerization intramolecular-Diels-Alder (IMDA) reaction of alkynes. With this synthetic method, the first enantioselective synthesis of (+)-alpha-yohimbine was completed in 9 steps from the IMDA products.

Full text of DOI:10.1002/asia.201500246

DOI: 10.1002/asia.201500246
Full Paper
Total Synthesis
Bicyclic Guanidine Catalyzed Asymmetric Tandem Isomerization
Intramolecular-Diels–Alder Reaction: The First Catalytic
Enantioselective Total Synthesis of (+)-alpha-Yohimbine
Wei Feng,[c] Danfeng Jiang,[a] Choon-Wee Kee,[a] Hongjun Liu,[b] and Choon-Hong Tan*[a]
Abstract: Hydroisoquinoline derivatives were prepared in
moderate to good enantioselectivities via a bicyclic guani-
dine-catalyzed tandem isomerization intramolecular-Diels–
Alder (IMDA) reaction of alkynes. With this synthetic
method, the first enantioselective synthesis of (+)-alpha-yo-
himbine was completed in 9 steps from the IMDA products.
Introduction
tacyclic rings, which contain five chiral centers. Several investi-
gations have been documented for the synthesis of yohim-
bine[2] and reserpine,[3] both racemic and enantioselective ver-
sions. However, less effort has been devoted to the synthesis
of alpha-yohimbine.[4] To the best of our knowledge, there is
no report on the enantioselective synthesis of alpha-yohim-
bine.
The yohimbine family of indole alkaloids (Figure 1), of which
alpha-yohimbine (1), yohimbine (2), and reserpine (3) are rep-
resentative members, have attracted extensive attention from
chemists due to their synthetically challenging structures and
pharmacological activities.[1] The synthesis of yohimbines is
challenging mainly due to difficulties in constructing the pen-
The most concise construction of the pentacyclic rings was
reported by Jacobsen and co-workers.[2k] An acyl-Pictet–Spen-
gler reaction was employed to construct the ring C, which was
followed by an intramolecular Diels–Alder reaction[2m] to form
the rings D and E. For the synthesis of alpha-yohimbine, the
most efficient method, developed by Martin and co-workers,
was to form the D and E rings using an intramolecular Diels–
Alder reaction, which was followed by oxidative cyclization to
form the ring C.[2h,4f] However, only racemic products were ach-
ieved. The only report on optical active alpha-yohimbine was
based on its isolation from Rauwolfia leaves.[4g] Here we report
our enantioselective synthesis of (+)-alpha-yohimbine and its
full characterization.
Figure 1. Monoterpenoid alkaloids.
[a] D. Jiang, Dr. C.-W. Kee, Dr. C.-H. Tan
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Science
Nanyang Technological University
Results and Discussion
We have been interested in the development of Brønsted-
base-catalyzed enantioselective transformations.[5] We have de-
veloped the synthesis of chiral allenoates through the enantio-
selective isomerization of alkynoates using bicyclic guanidine 4
as catalyst [Scheme 1, Eq. (1)].[5s] N-Phthalimido-protected 5-
aminoalkynoates underwent isomerization with high yield and
high enantioselectivity. We, thus, became interested to trap
such a chiral allene generated through an intramolecular-aza-
Michael reaction, in a tandem fashion, to construct the axially
chiral N-arylated 2-alkylidene lactam [Eq. (2)].[5t] The N-arylated
2-alkylidene lactam exists as an atropisomer due to the large
ortho-substitution on the aryl protecting group, which restricts
the rotation around the NÀC bond.
21 Nanyang Link, Singapore 637371 (Singapore)
E-mail: choonhong@ntu.edu.sg
[b] Dr. H. Liu
Key Laboratory of Natural Medicine and Immunoengineering of Henan
Province
Henan University
Henan 475004 (China)
[c] Dr. W. Feng
Department of Chemistry
National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201500246.
This manuscript is part of a special issue on catalysis and transformation
of complex molecules. Click here to see the Table of Contents of the special
issue.
Encouraged by these results, we became interested to ex-
plore this concept further and attempted a tandem isomeriza-
Chem. Asian J. 2016, 11, 390 – 394
390
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 1. Tandem-isomerization intramolecular Diels–Alder reaction.
Entry 8 (PG, R)
Yield [%][a] d.r.[b] ee [%][c]
1
2
3
4
5
6
7
8
9
8a (Piv, Et)
89
75
91
89
80
83
3:1
4:1
60/60
83/83
8b (Piv, tBu)
8c (Boc, tBu)
8d (Cbz, tBu)
8e (Ts, tBu)[d]
8 f (4-BrBz, tBu)
8g ((1H-Indol-3-yl)-acetyl, tBu)[d] 72
8h (Boc, CEt3)
8i (Piv, CEt3)
3.3:1 79/77
4:1
2:1
77/77
76/80
2.5:1 65/65
4:1
4:1
3:1
68/69
87/88
87/88
80
80
Reactions were run on a 0.2 mmol scale with 10 mol% of catalyst in
10 mL of hexane at room temperature. [a] Isolated yield (9+10). [b] De-
termined by 1H NMR spectroscopy (9:10). [c] Determined by HPLC analy-
sis, 9/10. [d] The reaction was run in THF due to low solubility.
Scheme 1. Enantioselective isomerization of alkynoates.
tion intramolecular-Diels–Alder reaction [Eq. (3)]. This reaction
should lead to a bicyclic structure and with proper choice of
tether, which should then lead us to hydroisoquinolines,[6]
a class of biologically active compounds.
enantioselectivity (entry 9). The IMDA adducts 9b, 9c, and
10b, as well as the hydrogenation product of compound 9c,
1
were confirmed by X-ray crystallography and H and 13C NMR
spectroscopic analyses.[11] The absolute configurations of 9c
and 10c were determined by DFT calculation to be (5S, 6S, 9R)
and (5R, 6S, 9R).[9] To further support the result of the calcula-
tion, product 9e was re-crystallized to 93% ee, and determina-
tion of the absolute configuration of 9e by X-ray crystallogra-
phy[11] gave a result consistent with the calculation.
The key intermediate, alkynyl amine 8a, was prepared on
a gram scale (Scheme 2). We began the synthesis by alkylating
furfury amine 5 with propargyl bromide. The secondary amine
The IMDA adducts are hydroisoquinolines, which resemble
the lower two rings of alpha-yohimbine, with correctly placed
functional groups and chiral centers (Scheme 3). Retrosynthetic
Scheme 2. Preparation of key intermediate, alkynyl amide 8a.
6 was obtained in 80% yield together with 10% of dialkylated
byproduct.[7] Protection of the amine with pivaloyl chloride
went smoothly to give the protected-amine 7a in high yield.
Finally, amine 7a was coupled with diazo compounds in the
presence of CuI to provide alkynoate 8a in 75% yield.[8]
Bicyclic guanidine was found to catalyze the tandem-isomer-
ization intramolecular-Diels–Alder (IMDA) reaction of alkynyl
amine 8a (Scheme 2 and Table 1, entry 1). The IMDA adducts
were bicyclic hydroisoquinolines containing an oxo-bridge on
one of the rings. Several solvents were tested and hexane was
found to provide best yields and good levels of enantioselec-
tivity (see the Supporting Information). A good yield of 89%
with an 3:1 ratio of endo:exo adducts was obtained, with 8%
of starting material 8a recovered. A series of alkynoates 8b–
i were prepared containing different protecting groups for the
amine as well as ester group (Table 1, entries 2–9). In general,
amine protecting groups did not significantly affect the enan-
tioselectivities, while a bulky ester group such as a triethyl-
type ester led us to alkynoate 8i that gave the best level of
Scheme 3. Retrosynthetic analysis.
analysis shows that we could establish the (C3) chiral center at
the last step via oxidative cyclization.[2h] The indole moiety can
be installed by reductive amination using (indol-3-yl)acetalde-
hyde. The ring opening of the oxo-bridge of the IMDA adduct
followed by hydrogenation should then lead to the precursor
for the reductive amination step. The stereochemistry of the
two newly formed chiral centres (C15 and C20) is expected to
be controlled by the steric effect of the bulky ester group
during heterogeneous hydrogenation.
The IMDA adducts 9c underwent reductive opening of the
oxo-bridge using the Lautens’ condition,[10] which employ a cat-
Chem. Asian J. 2016, 11, 390 – 394
www.chemasianj.org
391
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
alytic amount of Ni(COD)2. Byproducts produced from olefin
hydroalumination and ester reduction were also detected. In-
creasing Ni(COD)2 to a stoichiometric amount and lowering
the reaction temperature led to a better yield of dialkene 11
(Scheme 4). Direct hydrogenation of 11 gave several products
with relatively low yields. However, when the hydroxyl group
is acetylated, the hydrogenation proceeded smoothly with Pt/
tioselective total synthesis of (+)-alpha-yohimbine. The syn-
thetic natural product was also fully characterized and con-
firmed by comparing the NMR data with those in the literatur-
e.[2h] The absolute configuration was confirmed to be as shown
in Scheme 4 by an X-ray crystallographic analysis of the HCl
salt of the synthetic natural product 1.[12]
Conclusions
In conclusion, a bicyclic guanidine-catalyzed asym-
metric tandem isomerization intramolecular-Diels–
Alder (IMDA) reaction of alkynoates provides a high
degree of enantioselective control in the synthesis of
substituted hydroisoquinolines. This method has
proved to be successful in the first catalytic enantio-
selective total synthesis of (+)-alpha-yohimbine.
Experimental Section
General
1H and 13C NMR spectra were recorded on a 500 MHz
Bruker DRX NMR spectrometer or an AMX500 (500 MHz)
spectrometer. Chemical shifts are reported in parts per
million (ppm). The residual solvent peak was used as an
internal reference. Low-resolution mass spectra were ob-
tained on a Finnigan/MAT LCQ spectrometer in the ESI
mode. High-resolution mass spectra were obtained on
a
Finnigan/MAT 95XL-T spectrometer. Enantiomeric
excess values were determined by chiral HPLC analysis
on a Dionex Ultimate 3000 HPLC unit, including an Ulti-
mate 3000 Pump and Ultimate 3000 variable detectors.
Optical rotations were recorded on a Jasco DIP-1000 po-
larimeter with a sodium lamp of wavelength 589 nm.
Flash chromatography separations were performed on
Scheme 4. Total synthesis of (+)-alpha-yohimbine.
Merck 60 (0.040–0.063 mm) mesh silica gel. Hexane was
purified via simple distillation. MeCN was dried by using
a molecular sieve. Dichloromethane was distilled from CaH2 and
stored under N2 atmosphere. Other reagents and solvents were
commercial grade and were used as supplied without further pu-
rification, unless otherwise stated. Experiments involving moisture-
and/or air-sensitive components were performed under a positive
pressure of nitrogen in oven-dried glassware equipped with
a rubber septum inlet. Reactions requiring a temperature of À208C
were stirred in either Thermo Neslab CB-60 with Cryotrol tempera-
ture controller or Eyela PSL-1400 with digital temperature control-
ler cryobaths. Isopropanol was used as the bath medium. All ex-
periments were monitored by analytical thin layer chromatography
C as the catalyst at 708C. Bicyclic amine 13 was obtained as an
inseparable mixture of diastereomers with a d.r. of 8:1, as as-
1
sessed by using the H NMR spectrum of the crude reaction
product. The Boc group was easily removed using trifluoroace-
tic acid (TFA) in dichloromethane at 08C without affecting the
acetyl and triethyl ester. The diastereomers of 14 were still in-
separable. They were then subjected to the reductive amina-
tion directly. Unfortunately, the product 15 was inseparable
from the byproduct 2-(1H-indol-3-yl)ethanol which was gener-
ated from the reduction of 2-(1H-indol-3-yl)acetaldehyde. The
mixture of 15 and 2-(1H-indol-3-yl)ethanol underwent the sub-
sequent trans-esterification by treatment with camphorsulfonic
acid (CSA) in refluxing MeOH. The acetyl group was cleaved
and the triethyl ester was converted into the methyl ester in
a single step. A single diastereomer of indolyl amine 16 was
obtained in 31% yield over 4 steps. The enantiomeric purity
was maintained when indolyl amine 16 was analyzed with
chiral HPLC. Indolyl amine 16 was fully characterized, and the
stereochemistry was established by NOESY analysis and also
confirmed by comparing the 1H and 13C NMR spectroscopic
data with the reported data.[2h] The oxidative cyclization step
was followed by NaBH4 reduction to complete the first enan-
1
(TLC). Instrumentations H and 13C NMR spectra were recorded in
CDCl3 unless otherwise stated; 1H (500.1331 MHz) and 13C NMR
(125.7710 MHz) measurements with complete proton decoupling
1
and H NOESY NMR measurements were performed on a 500 MHz
Bruker DRX NMR spectrometer. All compounds synthesized were
stored at À348C.
Synthesis of compound 6
To a 200 mL round-bottomed flask was added a stirring bar,
10 mmol LiOH.H2O and 10 mL DMF (AR grade), followed by the ad-
dition of 30 mmol furfurylamine 5. The mixture was stirred vigo-
rously, and 10 mmol propargyl bromide in 30 mL of DMF was
added slowly over 1 h. After stirring for another 3 h, the mixture
Chem. Asian J. 2016, 11, 390 – 394
www.chemasianj.org
392
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
was filtered through Celite and washed thoroughly with diethyl
ether. The filtrate was washed four times with water. The combined
aqueous layer was extracted again with diethyl ether and the com-
bined organic layers were washed with brine and dried over
sodium sulfate, concentrated in vacuo, and purified by flash silica
gel chromatography (hexane:EtOAc=6:1) to afford 6 as a pale
yellow oil in 80% yield.
were added. Finally, Ac2O (0.9 mmol) was added, and the reaction
mixture was brought to room temperature. The reaction was moni-
tored by TLC until completion (usually around 10 h). Following re-
moval of the solvent in vacuo the crude mixture was purified by
flash silica gel chromatography (hexane:EtOAc, 10:1) to afford 12
was obtained as colorless oil in 80% yield.
Synthesis of 13
Synthesis of compound 7
Compound 12 (0.25 mmol, 110 mg) was dissolved in 2.5 mL of
EtOH in a 10 mL Schlenk flask, which was equipped with an adapt-
er attached with a H2 balloon, and Pt/C (50wt%, 55 mg) was
added. The system was evacuated and charged with H2 (4 times).
The reaction mixture was heated to 708C and was stirred for 4
Synthesis of 7a: To a solution of 6 (8 mmol) in dry CH2Cl2 (50 mL)
under nitrogen atmosphere was added Et3N (8.8 mmol, 1.1 equiv).
After the mixture was cooled to 08C, pivaloyl chloride was added
dropwise. Then the reaction mixture was warmed to room temper-
ature and stirred until full conversion as indicated by TLC (usually
around 1 h). The product 7a was obtained as a colorless oil in
95% yield following silica gel chromatography purification (hexa-
ne:EtOAc, 8:1) .
1
days. The reaction was monitored by H NMR spectroscopy of the
crude mixture until the reaction was complete. Subsequently, Pt/C
was filtered off and the filtrate was concentrated and used directly
1
in the next step without further purification. The H NMR spectrum
of the crude product shows that 13 was obtained as a mixture of
diastereomers (8:1).
Synthesis of compound 8
Synthesis of 8a: Compound 7a (6 mmol) was dissolved in MeCN
(AR grade) under N2 atmosphere, and CuI (0.6 mmol) was added to
the solution. The mixture was stirred for 10 min. Then ethyl diazoa-
cetate (9 mmol) was added and the mixture was stirred for 10 h.
Subsequently, the solvent was removed. Purification of the result-
ing residue by silica gel chromatography (hexane:EtOAc=10:1) af-
forded 8a as a colorless oil in 75% yield. The IMDA products (9a
and 10a) were obtained in 10% yield.
Synthesis of 14
The mixture of 13 was dissolved in 3 mL CH2Cl2 and cooled to 08C.
Then 0.75 mL TFA was added, and the reaction mixture was stirred
at 08C for 10 min. The reaction was monitored by TLC. After the re-
action was completed, the reaction was quenched with saturated
NaHCO3 and extracted with CH2Cl2 for 4 times. The combined or-
ganic layers were dried over Na2SO4, concentrated, and dried
under vacuum. The crude product 14 (a mixture of diastereomers
of 8:1 as assessed by 1H NMR spectroscopy) was used directly in
the next step.
General procedure for the IMDA reaction
Synthesis of 9a and 10a: Substrate 8 (0.2 mmol) was dissolved in
10 mL distilled hexane. Subsequently, 10 mol% of catalyst was
added and the mixture was stirred at room temperature. The reac-
tion was monitored by TLC until the starting material was com-
pletely consumed. The solvent was removed in vacuo and purifica-
tion of the resulting residue by flash chromatography (hexane:E-
tOAc, 10:1) afforded 9 and 10 in 72–88% yields and 60–88% ee.
The two cycloadducts can be separated using flash chromatogra-
phy.
Synthesis of compound 15
Compound 14 (crude product), HOBz, and NaCNBH3 were mixed in
5 mL toluene in a 50 mL round-bottomed flask under N2 atmos-
phere. The reaction mixture was stirred for 30 min at room temper-
ature. Then 2-(1H-indol-3-yl)acetaldehyde (freshly prepared from
methyl 2-(1H-indol-3-yl)acetate via DIBAL-H reduction) in 5 mL tol-
uene was added and the reaction mixture was stirred at room tem-
perature overnight. Subsequently, the reaction mixture was
quenched with saturated NaHCO3 and extracted with CH2Cl2 for
4 times. The combined organic layers were dried over Na2SO4 and
concentrated. Purification of the residue by silica gel chromatogra-
phy (hexane:EtOAc, 2:1) afforded a mixture of 15 and 2-(1H-indol-
3-yl)ethanol, of which the latter is produced from the reduction of
Synthesis of compound 11
In a glovebox, 9c (2 mmol) was added to a 100 mL round-bot-
tomed flask, followed by addition of PPh3 (8 mmol ) and Ni(COD)2
(2 mmol). The mixture was then dissolved in 20 mL dry toluene.
After stirring in the glovebox for 1 h at room temperature, the
flask was sealed with a rubber septum and taken out of the glove-
box. Under a N2 balloon, the mixture was cooled to 08C. Subse-
quently, 2.5 mmol of DIBAL-H (1m in toluene) was diluted with
20 mL dry toluene and added to the mixture slowly over 1 h using
a syringe pump. After addition, the reaction was monitored by TLC
until complete conversion. The reaction was then quenched with
saturated NH4Cl solution and extracted with CH2Cl2 (4”50 mL). The
combined organic layers were dried over Na2SO4 and concentrated.
Purification of the residue by flash silica gel chromatography af-
forded 11 (hexane:EtOAc, 4:1) as a colorless oil in 50% yield.
1
the aldehyde, as evidenced by H NMR spectroscopy of the crude
reaction mixture. The mixture could not be separated and was
used directly in the next step.
Synthesis of compound 16
The mixture of 15 and 2-(1H-indol-3-yl)ethanol was dissolved in
4 mL MeOH in a sealed tube. Next, CSA (0.25 mmol) was added
and the mixture was heated to 808C. After 24 h, the mixture was
cooled to room temperature and MeOH was removed in vacuo.
The resulting mixture was dissolved in CH2Cl2 and neutralized with
1m NaOH. Extraction was done with CH2Cl2 for 4 times. The com-
bined organic layers were dried over Na2SO4 and concentrated in
vacuo. Purification of the resulting residue by flash silica gel chro-
matography (hexane:EtOAc, 1:1 followed by DCM:MeOH, 20:1) af-
forded compound 16 as a white foam in 31% yield over 4 steps.
Synthesis of compound 12
In a dry round-bottomed flask, 11 (0.6 mmol) was dissolved in
12 mL of dry CH2Cl2 under a N2 atmosphere. The reaction mixture
was cooled to 08C and Et3N (0.9 mmol) and DMAP (0.06 mmol)
Chem. Asian J. 2016, 11, 390 – 394
www.chemasianj.org
393
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[4] For alpha-yohimbine synthesis: a) L. Tçke, K. Honty, L. Szabó, G. Blaskó,
C. Szµntay, J. Org. Chem. 1973, 38, 2496–2500; b) L. Tçke, Z. Gombos,
G. Blaskó, K. Honty, L. Szabó, J. Tamµs, C. Szµntay, J. Org. Chem. 1973,
38, 2501–2509; c) C. Szµntay, K. Honty, L. Tçke, L. Szabó, Chem. Ber.
1976, 109, 1737–1748; d) E. Wenkert, T. D. J. Halls, G. Kunesch, K. Orito,
R. L. Stephens, W. A. Temple, J. S. Yadv, J. Am. Chem. Soc. 1979, 101,
5370–5376; e) K. Honty, E. Baitz-Gacs, G. Blaskó, C. Szµntay, J. Org.
Chem. 1982, 47, 5111–5114; f) S. F. Martin, H. Rüeger, Tetrahedron Lett.
1985, 26, 5227–5230; g) A. von Stoll, A. Hofmann, R. Brunner, Helv.
Chim. Acta 1955, 38, 270–283.
Synthesis of compound 1
Compound 16 (28 mg, 0.08 mmol) was dissolved in 1.5 mL EtOH,
then an aqueous solution of Hg(OAc)2 and EDTA-2Na (1:1, 2.4 mL
of a 0.1m solution in water, 0.24 mmol) was added. The resulting
solution was heated to 858C and refluxed for 3 h. Then the mixture
was cooled to 08C and 2.5 mL 25% HClO4 was added. The mixture
was then stirred at 08C for 10 min and extracted with CH2Cl2 (4”
5 mL). The combined organic layers were washed with brine, dried
over Na2SO4 and concentrated in vacuo. The residue was re-dis-
solved in MeOH/H2O (9:1, v/v, 2.5 mL). The pH was adjusted to 6
using 5% NaHCO3 solution. The mixture was cooled to 08C, and
NaBH4 (0.6 mmol, 25 mg) was added. The reaction was brought to
room temperature and stirred for an additional hour. The solvents
were removed under reduced pressure, and the residue was parti-
tioned between cold 10% NH4OH and CH2Cl2. The aqueous layer
was extracted with CH2Cl2 for 4 times, and the combined organic
layers were dried (Na2SO4) and evaporated under reduced pressure.
The residue was purified by flash silica gel chromatography
(hexane/ETOAc 1:1, then CH2Cl2/MeOH 20:1) to afford 1 as a white
foam in 30% yield.
[5] For selected reviews, see: a) T. Ishikawa, T. Kumamoto, Synthesis 2006,
5, 737–752; b) D. Leow, C.-H. Tan, Chem. Asian J. 2009, 4, 488–507;
c) X. Fu, C.-H. Tan, Chem. Commun. 2011, 47, 8210–8222. For examples
from other groups, see: d) E. J. Corey, M. J. Grogan, Org. Lett. 1999, 1,
157–160; e) T. Kita, A. Georgieva, Y. Hashimoto, T. Nakata, K. Nagasawa,
Angew. Chem. Int. Ed. 2002, 41, 2832–2834; Angew. Chem. 2002, 114,
2956–2958; f) T. Ishikawa, T. Isobe, Chem. Eur. J. 2002, 8, 552–557; g) Y.
Sohtome, Y. Hashimoto, K. Nagasawa, Adv. Synth. Catal. 2005, 347,
1643–1648; h) M. Terada, H. Ube, Y. Yaguchi, J. Am. Chem. Soc. 2006,
128, 1454–1455; i) M. Terada, M. Nakano, H. Ube, J. Am. Chem. Soc.
2006, 128, 16044–6055; j) M. Terada, T. Ikehara, H. Ube, J. Am. Chem.
Soc. 2007, 129, 14112–14113; k) C. Palomo, M. Oiarbide, R. López,
Chem. Soc. Rev. 2009, 38, 632–653; l) Z. Yu, X. Liu, L. Zhou, L. Lin, X.
Feng, Angew. Chem. Int. Ed. 2009, 48, 5195–5198; Angew. Chem. 2009,
121, 5297–5300; m) T. Misaki, G. Takimoto, T. Sugimura, J. Am. Chem.
Soc. 2010, 132, 6286–6287; n) T. Takeda, M. Terada, J. Am. Chem. Soc.
2013, 135, 15306–15309. For representative publications from our
group, see: o) J. Shen, T. Nguyen, Y.-P. Goh, W. Ye, X. Fu, J. Xu, C.-H. Tan,
J. Am. Chem. Soc. 2006, 128, 13692–13693; p) D. Leow, S. Lin, S. K. Chit-
timalla, X. Fu, C.-H. Tan, Angew. Chem. Int. Ed. 2008, 47, 5641–5645;
Angew. Chem. 2008, 120, 5723–5727; q) X. Fu, W.-T. Loh, Y. Zhang, T.
Chen, T. Ma, H. Liu, J. Wang, C.-H. Tan, Angew. Chem. Int. Ed. 2009, 48,
7387–7390; Angew. Chem. 2009, 121, 7523–7526; r) Z. Jiang, Y. Pan, Y.
Zhao, T. Ma, R. Lee, Y. Yang, K.-W. Huang, M. W. Wong, C.-H. Tan, Angew.
Chem. Int. Ed. 2009, 48, 3627–3631; Angew. Chem. 2009, 121, 3681–
3685; s) H. Liu, D. Leow, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2009,
131, 7212–7213; t) H. Liu, W. Feng, C.-W. Kee, D. Leow, W.-T. Loh, C.-H.
Tan, Adv. Synth. Catal. 2010, 352, 3373–3379; u) T. Ma, X. Fu, C.-W. Kee,
L. Zong, Y. Pan, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2011, 133,
2828–2831.
Acknowledgements
We gratefully acknowledge the financial support of grants
from NTU (M4080946.110 and RG 6/12M40110018.110).
Keywords: alkaloids
·
alkyne
·
chiral guanidine
·
intramolecular-Diels–Alder reaction · total synthesis
[1] For leading references and reviews of the monoterpenoid alkaloids of
the indole family, see: a) J. E. Saxton in Specialist Periodical Reports, The
Alkaloids, The Royal Society of Chemistry, Burlington House, London,
1983, 13, 221–237; b) T. E. Gaffney, C. A. Chidsey, E. Braunwald, Circ.
Res. 1963, 12, 264–268.
[6] a) J. D. Scott, R. M. Williams, Chem. Rev. 2002, 102, 1669–1730; b) M.
Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104, 3341–3370;
c) D. L. Comins, R. S. Al-awar, J. Org. Chem. 1992, 57, 4098–4103; d) D. L.
Comins, C. A. Brooks, R. S. Al-awar, R. R. Goehring, Org. Lett. 1999, 1,
229–231.
[7] V. Sai Sudhir, R. B. Nasir Baig, S. Chandrasekaran, Eur. J. Org. Chem. 2008,
2423–2429.
[8] A. Suµrez, G. C. Fu, Angew. Chem. Int. Ed. 2004, 43, 3580–3582; Angew.
Chem. 2004, 116, 3664–3666.
[2] For general reviews of synthetic approaches toward yohimbine alka-
loids, see: a) M. E. Kuehne, R. S. Muth, J. Org. Chem. 1991, 56, 2701–
2712. For examples of yohimbine synthesis see: b) E. E. van Tamelen, M.
Shamma, A. W. Burgstahler, J. Wolinsky, R. Tamm, P. E. Aldrich, J. Am.
Chem. Soc. 1958, 80, 5006–5007; c) E. E. van Tamelen, M. Shamma, A. W.
Burgstahler, J. Wolinsky, R. Tamm, P. E. Aldrich, J. Am. Chem. Soc. 1969,
91, 7315–7333; d) L. Tçke, K. Honty, C. Szµntay, Chem. Ber. 1969, 102,
3248–3259; e) G. Stork, R. N. Guthikonda, J. Am. Chem. Soc. 1972, 94,
5109–5110; f) E. Wenkert, J. St. Pyrek, S. Uesato, Y. D. Vankar, J. Am.
Chem. Soc. 1982, 104, 2244–2246; g) O. Miyata, Y. Hirata, T. Naito, I. Ni-
nomiya, J. Chem. Soc. Chem. Commun. 1983, 1231–1232; h) S. F. Martin,
H. Rüeger, S. A. Williamson, S. Grzejszczak, J. Am. Chem. Soc. 1987, 109,
6124–6134; i) Y. Hirai, T. Terada, Y. Okaji, T. Yamazaki, T. Momose, Tetra-
hedron Lett. 1990, 31, 4755–4756; j) J. AubØ, S. Ghosh, M. Tanol, J. Am.
Chem. Soc. 1994, 116, 9009–9018; k) D. J. Mergott, S. J. Zuend, E. N. Ja-
cobsen, Org. Lett. 2008, 10, 745–748; l) B. HerlØ, M. J. Wanner, J. H. van
Maarseveen, H. Hiemstra, J. Org. Chem. 2011, 76, 8907–8912. For exam-
ple of IMDAs in total synthesis: m) F. Matsuura, R. Peters, M. Anada, S. S.
Harried, J. Hao, Y. Kishi, J. Am. Chem. Soc. 2006, 128, 7463–7465.
[3] For a review of reserpine synthesis: a) E.-F. Chen, J. Huang, Chem. Rev.
2005, 105, 4671–4706. For more recent approaches, see: b) N. S. Raja-
paksa, M. A. McGowan, M. Rienzo, E. N. Jacobsen, Org. Lett. 2013, 15,
706–709; c) A. G. Barcan, A. Patel, K. N. Houk, O. Kwon, Org. Lett. 2012,
14, 5388–5391; d) J. Huang, F.-E. Chen, Helv. Chim. Acta 2007, 90, 1366–
1372.
[9] M. Kwit, M. D. Rozwadowska, J. Gawron´ski, A. Grajewska, J. Org. Chem.
2009, 74, 8051–8063.
[10] M. Lautens, S. Ma, P. Chiu, J. Am. Chem. Soc. 1997, 119, 6478–6487.
[11] CCDC 1029362,
CCDC 1029365,
CCDC 1029364,
CCDC 1029363,
CCDC 1052979 contain the supplementary crystallographic data for
compounds 9b, 10b, and 9c, and the hydrogenation product of 9c
and 9e. This data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] CCDC 1052980 contains the supplementary crystallographic data for
compound 1. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Manuscript received: March 15, 2015
Accepted Article published: April 30, 2015
Final Article published: June 12, 2015
Chem. Asian J. 2016, 11, 390 – 394
www.chemasianj.org
394
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim