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Letter
pubs.acs.org/OrgLett

Enantioselective Total Synthesis of (−)-Nardoaristolone B via a
Gold(I)-Catalyzed Oxidative Cyclization
Anna Homs,†,§ Michael E. Muratore,†,§ and Antonio M. Echavarren*,†,‡
†

Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/Marcel·lı ́ Domingo s/n, 43007 Tarragona,
Spain

‡

S
* Supporting Information

ABSTRACT: The first enantioselective total synthesis of
(−)-nardoaristolone B is accomplished by the implementation of
an enantio- and diastereoselective copper(I)-catalyzed conjugate
addition/enolate trapping sequence and a gold(I)-catalyzed
oxidative cyclization (intermolecular oxidant), employed for the
first time in total synthesis.
mediate. Here we report the first enantioselective total
synthesis of nardoaristolone B (1) and additional studies on
the scope of the Au(I)-catalyzed oxidative cyclization of 1,6enynes.
Although the conjugate methylation of 2-methyl-2-cyclohexenone proceeded satisfactorily at −35 °C,5b the subsequent
α-alkylation proved to be challenging using methallyl bromide.
However, employing methallyl iodide under high concentration
and using 1:1 mixture of HMPA/THF before addition of MeLi
led to trisubstituted cyclohexanone 3 in 45−55% yield (Scheme
2). Employing the optimal chiral phosphoramidite ligand as
reported by Alexakis,5a the reaction proceeded with 91−92%
enantiomeric excess and 3:1 dr. Careful purification by standard
column chromatography allowed us to isolate 3 in essentially
pure form (>30:1 dr). The isomerization of exo-olefin 3 into
the corresponding trisubstituted endo-alkene 4 was not trivial,
and a range of conditions was screened.13 Fortunately, the use
of RhCl3·xH2O (5 mol %) in ethanol at 75 °C led to the
desired endo-olefin 4 in 74% yield. The conversion of
cyclohexanone 4 into enol triflate 5 was performed under
standard conditions (82% yield). Sonogashira cross-coupling of
5 with trimethylsilyl acetylene employing Pd(PPh3)2Cl2 (2 mol
%) and CuI (5 mol %) in a DMF/Et3N mixture, followed by
methanolysis of the TMS group led to 1,5-enyne 6 in
satisfactory yield (74% over two steps) (Scheme 2).
Pleasingly, 1,5-enyne underwent the desired gold(I)catalyzed oxidative cyclization using 8-methylquinoline Noxide (PNO5) and IPrAuNTf2 as catalyst in 1,2-dichloroethane
((CH2Cl)2) at 80 °C,9 albeit with low isolated yield (20%,
along with 25% of the simply cycloisomerized enyne 9). Careful
scrutiny of conditions revealed that the choice of the oxidant
was crucial in order to favor the desired oxidative cyclization
over the cycloisomerization. Thus, 3,5-dichloropyridine Noxide (PNO3) proved to be superior to all the other N-oxides

N

ardoaristolone B (1) was isolated in 2013 from
Nardostachys chinensis batal, a plant of the genus
Nardostachys endemic of the Himalayan mountains.1 The
synthesis of the racemic mixture has been recently reported.2
Closely related sesquiterpene (−)-aristolone (2) was isolated
much earlier, in 1955, from the roots of Aristochia debilis3 and
has been synthesized in racemic form by various research
groups.4 Nardoaristolone B (1) exhibits protective activity on
the injury of neonatal rat cardiomyocytes.
We were intrigued by the possibility of accessing 1 and other
members of the aristolone family by combining the highly
efficient Cu(I)-catalyzed asymmetric conjugate addition/αalkylation cascade of α,β-unsaturated cyclic ketones developed
by the groups of Alexakis and Cramer5−8 with the Au(I)catalyzed oxidative cyclization of enynes recently discovered by
Liu (Scheme 1).9 This last method, based on the gold(I)catalyzed oxidative functionalization of alkynes pioneered by
Toste10 and Zhang11,12 could offer direct access to this family of
compounds from cyclohexanone 4 as the common interScheme 1. Synthetic Plan toward Enantioenriched
(−)-Nardoaristolone B and (−)-Aristolone

Received: December 7, 2014
Published: January 7, 2015
© 2015 American Chemical Society

461

DOI: 10.1021/ol503531n
Org. Lett. 2015, 17, 461−463

Letter

Organic Letters

obtained under standard cycloisomerization conditions in the
absence of any oxidant (Table 1, entry 6). The competitive
formation of cycloisomerization product 9, along with 7, in
these reactions suggests that both products result from a
common cyclopropyl gold(I) intermediate.15 However, the
alternative mechanism involving an earlier oxidation of the
terminal alkyne to form an α-oxo gold(I) carbene intermediate
that leads to 7 by intramolecular cyclopropanation, in parallel
with a simple gold(I)-catalyzed cycloisomerization, cannot be
excluded.9
With the optimal conditions in hand, we performed an
oxidative cyclization in the presence of only 5 mol % of
IPrAuNTf2 and 3,5-dichloropyridine N-oxide. The desired
product 7 was isolated in good yield (74%) along with 15% of
cycloisomerized product 9. The last step consisted in the allylic
oxidation, which was accomplished in high yield (93%) using a
Pd-catalyzed radical oxidation in the presence of Pearlman’s
catalyst (Pd(OH)2/C) and t-BuOOH16 (Scheme 3). The

Scheme 2. Synthesis of 1,5-Enyne 6

Scheme 3. Last Step in the Synthesis of (−)-Nardoaristolone
B

screened (Table 1, entries 3 and 11).13,14 Interestingly, using
isomeric 2,6-dichloropyridine N-oxide (PNO4) led exclusively
to diene 9 (Table 1, entry 4), whereas a complex mixture was
Table 1. Screening of Conditions for the Gold(I)-Catalyzed
Oxidative Cyclization of 6

entry

[Au]

oxidant

yield of 7/9a,b (%)

1
2
3
4
5
6
7
8c
9
10
11

IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
(JohnPhos)AuCl/AgNTf2
tBuXPhosNTf2
[(ArO)3P]AuCl/AgNTf2
IMesAuNTf2
IPrAuNTf2d

PNO1
PNO2
PNO3
PNO4
PNO5
none
PNO3
PNO3
PNO3
PNO3
PNO3

spectroscopic data are in excellent agreement with the ones
reported for the isolated compound and further support for the
structure was obtained by X-ray diffraction analysis.17
Having accomplished the first total synthesis of nardoaristolone B, we were very keen on applying our strategy to a
higher enyne in order to gain access to the core of the
aristolone family of natural products. Our synthetic effort first
involved the conversion of key intermediate enol triflate 5 into
the corresponding 1,6-enyne 8. Although the direct Kumada
cross-coupling of 5 with propargylmagnesium bromide in the
presence of various Pd- or Ni-based catalysts did not take place,
we uncovered an unprecedented Kumada cross-coupling of
TMS-protected propargylmagnesium bromide with enol
triflates. This coupling proceeded smoothly on our model
system (4-tert-butylcyclohexanone-derived enol triflate) employing only 2 mol % of Pd(PPh3)4 and 2 equiv of freshly
prepared Grignard reagent.13 However, the cross-coupling was
significantly slower on 5 and 20 mol % of Pd complex as well as
4 equiv of Grignard reagent were necessary to obtain full
conversion at 23 °C. Under these conditions, the crosscoupling of 5 proceeded smoothly to afford 8 in 77% yield after
methanolysis of the TMS group (Scheme 4). This substrate was
then treated under a variety of conditions in order to prepare
aristolone; however all attempts resulted in the formation of 6aformyl-6-deoxonardoaristolone 10 in 65% yield when employing IPrAuNTf2 as catalyst.15 Although (−)-aristolone (2) was

31/5
20/36
74/15
0/55
20/25
complex mixture
43/15
18/15
55/2
55/2
74 (74)e/15

a

Yields determined by 1H NMR analysis of the crude mixture using
diphenylmethane as internal standard. bFull conversion of starting
material was observed unless otherwise stated. c13% unreacted starting
material were also visible. d5 mol % of catalyst; Ar = 2,4-(tBu)2C6H3.
e
Isolated yield.

462

DOI: 10.1021/ol503531n
Org. Lett. 2015, 17, 461−463

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Scheme 4. Synthesis and Fate of 1,6-Enyne 8

ASSOCIATED CONTENT

S
* Supporting Information

Experimental procedures and characterization data for compounds 1 and 3−10 as well as the X-ray crystal structure of 1.
This material is available free of charge via the Internet at
http://pubs.acs.org.

■

REFERENCES

(1) Liu, M. A.; Duan, Y.-H.; Hou, Y.-L.; Li, C.; Gao, H.; Dai, Y.; Yao,
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(b) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M.
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(8) For other selected asymmetric conjugate addition/enolate
trapping methods, see: (a) Li, K.; Alexakis, A. Tetrahedron Lett.
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Chem. 2006, 71, 5737−5742. (c) Germain, N.; Guénée, L.; Mauduit,
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2006−2009.
(9) Vasu, D.; Hung, H.-H.; Bhunia, S.; Gawade, S. A.; Das, A.; Liu,
R.-S. Angew. Chem., Int. Ed. 2011, 50, 6911−6914.
(10) Witham, C. A.; Mauleón, P.; Shapiro, N. D.; Sherry, N. D.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838−5839.
(11) (a) Qian, D.; Zhang, J. Chem. Commun. 2011, 47, 11152−
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(12) Ji, K.; Zheng, Z.; Wang, Z.; Zhang, L. Angew. Chem., Int. Ed.
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(13) See the Supporting Information for a comprehensive survey of
conditions.
(14) It is interesting to note that when 8-methylquinoline N-oxide
was replaced by 3,5-dichloropyridine N-oxide, cyclopentadienyl
aldehydes were obtained from 1,5-enynes: Hung, H.-H.; Liao, Y.-C.;
Liu, R.-S. J. Org. Chem. 2013, 78, 7970−7976.
(15) An analogous oxidation of a cyclopropyl gold(I) carbene was
demonstrated to occur in the cyclization of 1,6-enynes with Ph2SO as
the oxidant.10
(16) Yu, J.-Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232−3233.
(17) CCDC 1037494 (1) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(18) (a) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108,
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47, 902−912.

not prepared via our original strategy, the preparation of
enantioenriched cyclohexanone 4 constitutes a formal synthesis
of (−)-2, since racemic 2 has already been prepared from (±)-4
in five steps.4b
Under all the conditions examined, the gold(I)-catalyzed
reaction of 1,6-enyne 8 proceeded exclusively by the 6-exo-dig
mode. It is interesting that this result is in contrast to that
observed in the reaction 1-ethynyl-2-allylbenzene, which
yielded a 6-membered ring ketone by a 6-endo-dig oxidative
cyclization.9 This different behavior can be ascribed to the
different substitution pattern of the alkene, which usually
controls the outcome in gold(I)-catalyzed cycloisomerizations
of 1,6-enynes.18
In conclusion, we have developed the first enantioselective
synthesis of (−)-nardoaristolone B (1) in seven steps and
14−17% overall yield. Our expedient strategy, by implementation of an enantio- and diastereoselective conjugate addition/
enolate alkylation and the first example of a gold(I)-catalyzed
oxidative cyclization of enynes in total synthesis, is perfectly
suited for the rapid preparation of analogues of this natural
product.

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Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: aechavarren@iciq.es.
Author Contributions
§

These authors contributed equally.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS
We thank MINECO (Severo Ochoa Excellence Accreditation
2014-2018 (SEV-2013-0319), project CTQ2013-42106-P, and
FPI predoctoral Fellowship to A.H.), the European Research
Council (Advanced Grant No. 321066), the AGAUR (2014
SGR 818), and the ICIQ Foundation. M.E.M. acknowledges
the receipt of a COFUND postdoctoral fellowship (Marie
Curie program).
463

DOI: 10.1021/ol503531n
Org. Lett. 2015, 17, 461−463