Access to electron-rich arene-fused hexahydroquinolizinones through a gold-catalysis-initiated cascade process

Article abstract of DOI:10.1002/anie.201203303

Golden Cascade: With a tethered, electron-rich arene as the internal nucleophile, a gold-catalyzed amide cyclization to an alkyne initiates a cascade process that ends with a Ferrier rearrangement. Electron-rich arene-bearing hexahydroquinolizin-2-ones are formed in good yields and can be converted into indole alkaloids in only a few steps. Copyright

Full text of DOI:10.1002/anie.201203303

Angewandte
Chemie
DOI: 10.1002/anie.201203303
N-Heterocycles
Access to Electron-Rich Arene-Fused Hexahydroquinolizinones
through a Gold-Catalysis-Initiated Cascade Process**
Lianzhu Liu and Liming Zhang*
We have recently developed a two-step, one-pot synthesis of
piperidine-4-ols.[1] In this reaction, the protonated cyclic
imidate intermediate A, which is prepared by a gold-cata-
lyzed[2] amide cyclization, is reduced by an external hydride
(e.g., catecholborane), which initiates a key Ferrier rear-
rangement[3] (Scheme 1a). We envisioned that a carbon
indolo[2,3-a]quinolizine skeleton with various indole alka-
loids, including dihydrocorynantheol,[4] yohimbine,[5] and
vincamine[6] (Scheme 2). Notably, the latter two are marketed
drugs for peripheral vasodilation.[7]
Scheme 2. Selected alkaloids containing the indolo[2,3-a]quinolizine
skeleton.
The formamide 1a was readily prepared from tryptamine
through a straightforward two-step sequence: alkylation with
but-3-yn-1-yl tosylate and formylation with ethyl formate.
When 1a was treated with IPrAuNTf2 (5 mol%) at ambient
temperature, desired product 2a could not be detected
(Table 1, entry 1). Instead, tricyclic formamide 3, which was
formed by a gold-catalyzed 8-exo-dig cyclization,[8] was
Scheme 1. A gold-catalysis-initiated cascade process toward bicyclic
piperidine-4-ones.
nucleophile could replace the hydride in this chemistry;
moreover, if such a nucleophile is attached to the amide
nitrogen atom, addition of reagent in the course of the
reaction is not needed. The reaction would constitute a gold-
catalysis-initiated cascade process and might provide an
efficient access to bicyclic piperidin-4-ones (e.g., 1, Sche-
me 1b). Herein, we disclose our implementation of this
strategy, which leads to an expedient synthesis of electron-
rich arene-fused hexahydroquinolizinones; its synthetic utility
is illustrated by a succinct and stereoselective synthesis of
dihydrocorynantheol without the use of any protecting group,
and a formal synthesis of yohimbine and b-yohimbine.
We chose tertiary formamide 1a as substrate, as the
formyl group would minimize steric hindrance for nucleo-
philic attack and the indole ring can act as a good neutral
carbon nucleophile. Importantly, the anticipated product 2a,
a tetracyclic piperidine-4-one, shares a common hexahydro-
Table 1: Initial discovery and condition optimization.[a]
Entry
Catalyst
Acid additive (equiv)
Yield [%][b]
[c]
1
2
3
4
5
6
7
8
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
Ph3PAuNTf2
BrettPhosAuNTf2
AuCl3
–
–
MsOH (2)
TsOH (2)
TFA (2)
AcOH (2)
TFA (2)
TFA (2)
TFA (2)
56[d]
64[d]
82[d]
[e]
–
83[d]
89[d] (87)[f]
12[d]
1
[a] [1a]=0.05m. [b] Yield estimated by H NMR spectroscopy with
diethyl phthalate as internal standard. [c] 12% of 3 formed after reaction
for 6 h. [d] 4 is the identifiable side product. [e] Reaction resulted in
a complex mixture of products. [f] Yield of isolated product. IPr=
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), Cy=cyclohexyl,
Ms=methanesulfonyl, Tf=trifluoromethanesulfonyl, TFA=trifluoro-
acetic acid, Ts=4-toluenesulfonyl.
[*] Dr. L. Liu, Prof. Dr. L. Zhang
Department of Chemistry and Biochemistry, University of California
Santa Barbara, CA (USA)
E-mail: zhang@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~zhang/index.html
[**] The authors thank NIGMS (R01 GM084254) and UCSB for generous
financial support, and Sigma–Aldrich for generous donation of
BrettPhosAuNTf2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203303.
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Table 2: The reaction scope.[a]
detected in a small amount. To our delight, when MsOH
(2 equiv) was added, the desired product 2a was formed in
56% yield after 24 hours. The main side product was the
corresponding methyl ketone 4, formed by gold-catalyzed
alkyne hydration. To gain insight into the reaction mecha-
nism, the reaction was run in CDCl3 and monitored by
1H NMR spectroscopy. Surprisingly, the initial gold-promoted
cyclization and subsequent protodeauration[9] were facile and
efficient, even at 08C, and the formamide 1a was converted to
the 1,3-oxazin-3-ium intermediate C (see Table 1, footnote) in
approximately 80% NMR yield after only 40 minutes.
Because the Ferrier rearrangement is supposed to be fast,
this result suggested that the cyclization of C is very slow,
which is unexpected.
Entry
1
2
Yield
[%][b]
1
2
3
1b
1c
1d
1e
2b 82
2c 84
2d 83
2e 82
To further improve the reaction, we subsequently
screened other acid additives (Table 1, entries 3–5). Trifluoro-
acetic acid (TFA) turned out to be the most effective additive,
and the indole-fused hexahydroquinolizinone 2a was formed
in 82% yield (Table 1, entry 4). Among the other examined
[10]
gold catalysts, BrettPhosAuNTf2 provided a slightly better
yield (Table 1, entry 7), while use of AuCl3 resulted in a very
low yield (entry 8).
4
With the optimized reaction conditions in hand, the scope
of this gold-catalysis-initiated cascade reaction was explored.
Different substituents on the indole benzenoid ring, including
an electron-donating 5-MeO (Table 2, entry 1), electron-
withdrawing 6-F (entry 2) and 5-Cl (entry 3), and a 5-Me
(entry 4), were tolerated, and the reactions afforded indole-
fused hexahydroquinolizinones in good yields. The form-
amide 1 f, which was easily prepared from tryptophan ethyl
ester, also reacted smoothly, and the tetracyclic keto ester
product 2 f was formed in 79% yield, although the diastereo-
selectivity was low (a/b = 2/3; Table 2, entry 5). The tolerance
of the reaction toward substituents on the but-3-yn-1-yl group
was then studied. The reaction occurred smoothly with
a phenyl group in a position to the nitrogen atom (Table 2,
entry 6). Notably, the reaction was highly diastereoselective,
and product 2g, with the phenyl group cis to the indole ring,
was isolated as the only diastereoisomer in 72% yield. When
a 4-benzyloxybut-1-yl group replaced the phenyl group, the
reaction proceeded with the same yield of isolated product
and equally excellent stereoselectivity (Table 2, entry 7). A
cyclohexyl group at the propargylic position posed no
problem, and the cyclized product was isolated in 81%
yield, albeit with a low diastereoselectivity (a/b = 2.4/1;
Table 2, entry 8). Because of the general interest in indole
alkaloids, all the examples thus far used indole rings as the
tethered nucleophiles. This, however, is not a limitation to the
chemistry. For example, electron-rich benzene rings, such as
methoxybenzene (Table 2, entry 9) and benzo[1,3]dioxole
(entry 10), participated in the cascade, giving the benzene-
fused hexahydroquinolizin-2-ones in synthetically useful
yields.
5
1 f
1g
1h
1i
2 f 79
2g 72
2h 72
2i 81
2j 68
2k 61[c]
6
7
8
9
1j
10
1k
[a] [1]=0.05m. [b] Yield of isolated product. [c] TFA (5 equiv), 4 days.
DIBAL-H=diisobutylaluminium hydride, DMSO=dimethylsulfoxide,
Py=pyridine.
been synthesized through many elegant total synthesis
approaches.[11] The ethyl formamide substrate 6a was easily
prepared in 72% overall yield in two steps from tryptamine
and 2-ethylbut-3-yn-1-yl tosylate (Scheme 3), which in turn
was synthesized in 44% yield in two steps[12] from cheap
commercially available 1-pentyne. Compound 6a underwent
the cascade reaction smoothly, and the hexahydroindolo[2,3-
a]quinolizinone 7a was isolated in 87% yield, albeit as
With the relatively general reaction scope of this cascade
approach in hand, we turned our attention to the investigation
of its utility in the synthesis of indole alkaloids that feature the
hexahydroindolo[2,3-a]quinolizine skeleton. We first chose
dihydrocorynantheol, which was first isolated from the bark
of the Amazonian tree A. marcgravianum Woodson and has
2
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a separable mixture of yohimbine and b-yohimbine through
a chemoselective Dieckmann reaction[14] and a subsequent Pt-
catalyzed hydrogenation.[15]
In summary, we have developed an efficient synthesis of
electron-rich arene-fused hexahydroquinolizinones. In this
cascade reaction, a gold-catalyzed amide cyclization to
ꢀ
a tethered C C bond initiates a subsequent Friedel–Crafts-
type cyclization followed by a Ferrier rearrangement. When
an indole ring is employed as the tethered nucleophile, this
reaction provides a rapid access to the hexahydroindolo[2,3-
a]quinolizine skeleton, which is the common core structure in
various indole alkaloids. This new method enables a succinct
and stereoselective synthesis of dihydrocorynantheol and
a formal synthesis of yohimbine and b-yohimbine.
Experimental Section
General procedure for the gold catalysis-initiated cascade reaction: A
formamide, BrettPhosAuNTf2 (0.05 equiv), and trifluoroacetic acid
(2.0 equiv) were dissolved in anhydrous methylene chloride (0.1m) in
a flame-dried vial. The mixture was stirred at RT typically for 24 h.
Ammonium hydroxide ( ꢁ 14.8n, the same volume as methylene
chloride) was added to quench the reaction. The organic phase was
separated and the aqueous phase was extracted with methylene
chloride. The combined organic phases were dried with anhydrous
sodium sulfate. After filtration and concentration, the resulting
residue was purified by flash chromatography on silica gel (eluent:
ethyl acetate/MeOH/NH4OH = 10:1:0.1).
Scheme 3. Stereoselective total synthesis of dihydrocorynantheol, and
formal synthesis of yohimbine and b-yohimbine. Reagents and con-
ditions: a) K2CO3, CH3CN, 858C, 36 h; b) ethyl formate, 808C, 8 h;
c) BrettPhosAuNTf2 (5 mol%), TFA (2 equiv), CH2Cl2, RT, 24 h;
d) methyl(dimethoxyphosphinyl)acetate, NaH, benzene; e) Pd/C, H2,
MeOH, RT, 2 h; then DIBAL-H, CH2Cl2, 08C, 3 h; f) methyl(dimethoxy-
phosphinyl)acetate, NaH, benzene; g) Pd(OH)2/C, HCl, THF, 4 h; then
SO3·Py, Et3N, DMSO, RT, 10 h; h) KOH, I2, MeOH, 08C, 4 h.
Received: April 30, 2012
Published online: && &&, &&&&
Keywords: alkaloids · cascade reactions · catalysis · gold ·
indoles
.
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subjected to the Horner–Wadsworth–Emmons (HWE) reac-
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excellent yield. Apparently, under basic reaction conditions,
the axial ethyl group in the b isomer of 7a was epimerized to
the more stable equatorial position, either before or after the
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
N-Heterocycles
Golden Cascade: With a tethered, elec-
tron-rich arene as the internal nucleo-
phile, a gold-catalyzed amide cyclization
to an alkyne initiates a cascade process
that ends with a Ferrier rearrangement.
Electron-rich arene-bearing hexahydro-
quinolizin-2-ones are formed in good
yields and can be converted into indole
alkaloids in only a few steps.
L. Liu, L. Zhang*
&&&& — &&&&
Access to Electron-Rich Arene-Fused
Hexahydroquinolizinones through
a Gold-Catalysis-Initiated Cascade
Process
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!