Catalytic Asymmetric Construction of α-Quaternary Cyclopentanones and Its Application to the Syntheses of (-)-1,14-Herbertenediol and (-)-Aphanorphine

Article abstract of DOI:10.1002/chem.201502700

A novel and efficient strategy to build α-benzylic quaternary cyclopentanones with excellent enantioselectivities (up to 96% ee) and high yields (up to 99% yield) has been developed, and its application demonstrated by the first catalytic asymmetric total synthesis of (-)-1,14-herbertenediol and the formal synthesis of (-)-aphanorphine. Herbertene rides again: A novel and efficient strategy to build α-quaternary cyclopentanones with high yields and excellent enantioselectivities (up to 96% ee) has been developed. Its application is demonstrated by the first catalytic asymmetric total synthesis of (-)-1,14-herbertenediol and the formal synthesis of (-)-aphanorphine.

Full text of DOI:10.1002/chem.201502700

DOI: 10.1002/chem.201502700
Communication
&
Synthetic Methods |Hot Paper|
Catalytic Asymmetric Construction of a-Quaternary
Cyclopentanones and Its Application to the Syntheses of
(À)-1,14-Herbertenediol and (À)-Aphanorphine
Dao-Yong Zhu,[a] Ming-Hui Xu,[a] Yong-Qiang Tu,*[a] Fu-Min Zhang,[a] and
Shao-Hua Wang*[a, b]
ous quaternary carbon centers on the cyclopentane ring with
one attached to a phenyl group. Since the 1990s, development
of strategies toward the synthesis of these natural products
with an all-carbon quaternary center has attracted much atten-
tion from organic chemists.[7] However, among the reported
strategies approaching these sesquiterpenes, most afford the
final products in racemic forms,[7e] and only few are catalytic
and asymmetric, such as the Pd-catalyzed asymmetric a-aryla-
tion of alkyl-substituted cyclopentanones developed by Buch-
wald,[8] and the asymmetric chlorination/ring expansion cas-
cade published by You.[9] Therefore, it is still highly desirable to
develop more efficient methodologies approaching the syn-
thesis of this kind of natural product.
Abstract: A novel and efficient strategy to build a-benzyl-
ic quaternary cyclopentanones with excellent enantiose-
lectivities (up to 96% ee) and high yields (up to 99%
yield) has been developed, and its application demon-
strated by the first catalytic asymmetric total synthesis of
(À)-1,14-herbertenediol and the formal synthesis of
(À)-aphanorphine.
Quaternary stereocenters are sterically hindered structural
units extensively found in a variety of natural products and
bioactive molecules, and their efficiently construction is gener-
ally a key step for organic synthesis.[1,2] For example, the
phenyl-substituted quaternary center at the a-position to the
carbonyl in cyclopentanone is a highly strained structural
motif, which is similar to groups found in herbertane-type ses-
quiterpenes,[3] such as (À)-herbertene,[4] (À)-1,14-herbertene-
diol,[5] and (À)-herbertenoid[6] (Figure 1). These molecules ex-
hibit special biological activities, such as anti-lipid-oxidation
and antifungal properties, and also share two unique contigu-
In connection with our long-standing interest in the asym-
metric construction of highly strained quaternary centers,[10]
we previously developed an organocatalytic asymmetric rear-
rangement of vinylogous g-ketol, which is efficient for the con-
struction of a series of chiral spirocyclic quaternary centers.[10f]
Thus we hypothesize that if such a reaction is effective for
a substrate with an acyclic and phenyl-substituted vinylogous
g-aldol, such as 1a (Scheme 1), a new and more efficient syn-
thesis of the herbertane-type sesquiterpenes might be achieva-
ble. Herein we present our efforts toward this methodology
development and its application to the first catalytic asymmet-
ric synthesis of (À)-1,14-herbertenediol and formal synthesis of
(À)-aphanorphine.
Our initial investigation focused on screening catalysis sys-
tems. Firstly, our previously well recognized cinchona alkaloid-
based organocatalyst[10f] Cat. A1 (Scheme 1), was used to pro-
mote the rearrangement of 1a with an E double bond, which
was readily prepared from a known method (for details, see
the Supporting Information).[11] However, both the enantiose-
lectivity (16%) and yield (46%) of the reaction were unsatisfac-
tory (Scheme 1). Furthermore, in the presence of some other
secondary amine catalysts (Cat. A2–A4; Scheme 1),[12] only rac-
emic product was obtained.[13] The results might be attributed
to the presence of a less hindered carbonyl group, which
would affect the enantioselectivity during the rearrangement
step. On the basis of the above results and considerations, we
envisioned that such a disadvantage might be overcome
through the use of a catalyst such as chiral silver phosphates
(CSPs), which could interact with the substrate through a dual
activation mode.[14]
Figure 1. Selected herbertane-type sesquiterpenes.
[a] D.-Y. Zhu, M.-H. Xu, Prof. Dr. Y.-Q. Tu, Prof. Dr. F.-M. Zhang,
Prof. Dr. S.-H. Wang
State Key Laboratory of Applied Organic Chemistry & College of Chemistry
and Chemical Engineering, Lanzhou University, Lanzhou and Collaborative
Innovation Center of Chemical Science and Engineering
Tianjin (P. R. China)
Fax: (+86)931-8912582
E-mail: tuyq@lzu.edu.cn
[b] Prof. Dr. S.-H. Wang
School of Pharmacy, Lanzhou University, and Key Laboratory of Drug
Targeting and Drug Delivery System, Ministry of Education
Sichuan University, Chengdu (P. R. China)
E-mail: wangshh@lzu.edu.cn
Following above assumption, we carried out the reaction
under the catalysis of three typical CSPs. Fortunately, when we
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502700.
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Communication
substituents on the phenyl ring
showed some influence on the
enantioselectivity of the reac-
tion. In the case of substrates
with substituents at the para or
meta position of the phenyl ring,
the ee values of the correspond-
ing products were usually excel-
lent (2b–g, 2i, 2j). In contrast,
the ee values were much lower
for substrates with a substituent
at the ortho position of the
phenyl ring (2h and 2l). To fur-
ther quantify the utility of such
a method, we also carried out
the reaction of 1 f on 2 mmol
scale and the product 2 f was
readily obtained in 92% yield
and 90% ee.
Encouraged by above experi-
mental results, the utility of this
method was further demonstrat-
ed with the synthesis of herber-
tane-type sesquiterpenes by
Scheme 1. Design of the catalytic asymmetric reaction.
using it as
a
key step
(Scheme 2).[3] For example, 1,14-
tested the reaction of 1a in the presence of CSP catalyst c1,
the reaction could proceed successfully in toluene at room
temperature to give the desired product 2a in 40% yield
and 45% ee (Table 1, entry 1). Further screening of another
two common CSPs, c2 and c3, did not give better results
(Table 1, entries 1 and 2). Next, screening of different sol-
vents with c1 as catalyst indicated that CHCl3 was the best
choice, giving the desired product 2a in 91% yield and
82% ee (Table 1, entry 6). We also attempted to improve the
enantioselectivity of this reaction by lowering the tempera-
ture of the reaction system; the desired product 2a could
be obtained in 93% ee at À258C (Table 1, entries 9–12). The
influence of molecular sieves on this transformation was also
tested, and the use of 5 Š MS slightly increased the ee value
to 95% (Table 1, entry 15).
Table 1. Optimization of the reaction conditions.[a]
Entry
Cat.
Solvent
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
c1
c2
c3
c1
c1
c1
c1
c1
c1
c1
c1
c1
c1
c1
c1
toluene
toluene
toluene
CH2Cl2
DCE
25
25
25
25
25
25
25
0
0
À10
À20
À25
À25
À25
À25
6
6
6
2
2
40
33
trace
92
90
91
90
90
95
95
95
97
97
97
97
45
14
NA
70
70
82
55
76
86
89
92
93
93
93
95
With the optimized reaction conditions in hand (Table 1,
entry 15), the substrate scope of the asymmetric semipinacol
rearrangement reaction was explored. A series of olefin alde-
hydes with different aryl substituents at the b-position was
tested as substrates in this reaction (Table 2), giving the ex-
pected products in good to excellent yields and ee values.
Among the substrates screened, the electronic effect of the
substituents on the phenyl ring did not clearly affect the
enantioselectivity; substrates with either an electron-donat-
ing or an electron-withdrawing group at the para position of
the phenyl ring (1b–e) could afford the desired products in
excellent ee values. However, with regards to reaction yield
and rate, it was clear that the more electron-withdrawing
the substituent was, the lower the yield and longer the reac-
tion time were (Table 2, 1b–e). Interestingly, the position of
CHCl3
CCl4
2
2
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
12
12
18
18
24
24
24
24
9
10
11
12
13[d]
14[e]
15[f]
[a] Reaction conditions: 1a (0.1 mmol), catalyst (0.005 mmol), and solvent
(1.0 mL) stirred at a given temperature under argon atmosphere for 24 h.
[b] Yield of isolated product. [c] Determined by HPLC analysis. [d] 40 mg of
3 Š molecular sieves were added. [e] 40 mg of 4 Š molecular sieves were
added. [f] 40 mg of 5 Š molecular sieves were added. DCE=1,2-dichloro-
ethane.
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in a THF/methanol solvent mixture. Next, hydrogenation of
ester 5 with 10% Pd/C followed by demethylation of the
phenyl ring by boron tribromide furnished the tricyclic inter-
mediate 6 as a single product in nearly quantitative yield. Fi-
nally, syn-methylation of compound 6 followed by lithium alu-
minum hydride reduction led to (À)-1,14-herbertenediol,[5]
which also confirmed the absolute configuration of the prod-
uct 2l. The absolute configurations of other products (2a–k,
2m, 2n) could also be deduced from this result. Furthermore,
the formal synthesis of (À)-aphanorphine was also carried out
through a simple decarbonylation of the aldehyde 2g, which
gave Ogasawara’s intermediate 8 in 60% yield.[15]
Table 2. Substrate scope of the catalytic asymmetric semipinacol rearran-
gement.[a]
In conclusion, a novel and efficient asymmetric semipinacol
rearrangement of olefin aldehyde was developed, which could
afford a series of cycloalkanones with an all-carbon quaternary
stereocenter in excellent enantioselectivity (up 96% ee). The
application of the methodology was well demonstrated by the
first catalytic asymmetric total synthesis of (À)-1,14-herbertene-
diol and the formal synthesis of (À)-aphanorphine.
Experimental Section
General procedure: To a solution of compound 1 (0.1 mmol) in an-
hydrous CHCl3 (1.0 mL) at À208C or À258C under argon was
added 5 Š molecular sieves (40 mg) and catalyst (0.05 mmol,
3.6 mg). The reaction mixture was stirred until the disappearance
of compound 1 by TLC monitoring. The mixture concentrated
under vacuum and purification of the residue by column chroma-
tography on silica gel to afford product 2.
Acknowledgements
This work was supported by the NSFC (No. 21202073,
21290180, 21272097, 21372104 and 21472077), the “111” Pro-
gram of MOE, the Project of MOST (2012ZX 09201101-003), the
Fundamental Research Funds for the Central Universities (lzujb-
ky-2014-k20 and lzujbky-2015-k12), and the Opening Project of
Key Laboratory of Drug Targeting and Drug Delivery System,
Ministry of Education (Sichuan University).
Keywords: asymmetric synthesis
·
enantioselectivity
·
organocatalysis · quaternary stereocenters · sesquiterpenes
[a] Reaction conditions (unless otherwise stated):
1 (0.1 mmol), c1
[1] For recent reviews, see: a) C. J. Douglas, L. E. Overman, Proc. Natl. Acad.
Sci. USA 2004, 101, 5363–5367; b) D. J. Ramon, M. Yus, Curr. Org. Chem.
2004, 8, 149–183; c) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347,
1473–1482; d) B. M. Trost, C. Jiang, Synthesis 2006, 369–396; e) P. G.
Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2007, 5969–5994;
f) O. Riant, J. Hannedouche, Org. Biomol. Chem. 2007, 5, 873–888; g) M.
Bella, T. Gasperi, Synthesis 2009, 1583–1614; h) C. Hawner, A. Alexakis,
Chem. Commun. 2010, 46, 7295–7306; i) J. P. Das, I. Marek, Chem.
Commun. 2011, 47, 4593–4623.
[2] a) A. Y. Hong, M. R. Krout, T. Jensen, N. B. Bennett, A. M. Harned, B. M.
Stoltz, Angew. Chem. Int. Ed. 2011, 50, 2756–2760; Angew. Chem. 2011,
123, 2808–2812; b) A. Y. Hong, B. M. Stoltz, Eur. J. Org. Chem. 2013,
2745–2759.
(0.005 mmol), and CHCl3 (1.0 mL) stirred at À25 or À208C under argon at-
mosphere for 24 h; the ee values of compounds 2a–n were determined
from the corresponding compounds 3a–n (for details, see the Supporting
Information). [b] The reaction was carried out on 2 mmol scale.
herbertenediol[5] could be synthesized asymmetrically in seven
steps from compound 2l. Firstly, in the presence of Wilkinson’s
catalyst, decarbonylation of the aldehyde 2l could give com-
pound 3l in moderate yield. Then the ketone 3l was treated
with sodium hexamethyldisilazide (NaHMDS) and PhNTf2 to
afford corresponding vinyl triflate 4, which was converted into
ester 5 through a carbomethoxylation catalyzed by [Pd(PPh3)4]
[3] a) H. Irita, T. Hashimoto, Y. Fukuyama, Y. Asakawa, Phytochemistry 2000,
55, 247–253; b) A. Matsuo, S. Yuki, M. Nakayama, J. Chem. Soc. Perkin
Trans. 1 1986, 701–710; c) Y. Fukuyama, Y. Kiriyama, M. Kodama, Tetra-
Chem. Eur. J. 2015, 21, 15502 – 15505
www.chemeurj.org
15504
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[8] a) J. Šhman, J. P. Wolfe, M. V. Trout-
man, M. Palucki, S. L. Buchwald, J.
Am. Chem. Soc. 1998, 120, 1918–
1919; b) T. Hamada, A. Chieffi, J.
Šhman, S. L. Buchwald, J. Am.
Chem. Soc. 2002, 124, 1261–1268.
[9] Q. Yin, S.-L. You, Org. Lett. 2014, 16,
1810–1813.
[10] a) B. Wang, Y.-Q. Tu, Acc. Chem. Res.
2011, 44, 1207–1222; b) Z.-L.
Song, C.-A. Fan, Y.-Q. Tu, Chem.
Rev. 2011, 111, 7523–7556; c) S.-H.
Wang, B.-S. Li, Y.-Q. Tu, Chem.
Commun. 2014, 50, 2393–2408;
d) Z.-M. Chen, Q.-W. Zhang, Z.-H.
Chen, H. Li, Y.-Q. Tu, F.-M. Zhang,
J.-M. Tian, J. Am. Chem. Soc. 2011,
133, 8818–8821; e) H. Li, F.-M.
Zhang, Y.-Q. Tu, Q.-W. Zhang, Z.-M.
Chen, Z.-H. Chen, J. Li, Chem. Sci.
2011, 2, 1839–1841; f) E. Zhang,
C.-A. Fan, Y.-Q. Tu, F.-M. Zhang, Y.-L.
Song, J. Am. Chem. Soc. 2009, 131,
14626–14627.
[11] X. Creary, P. A. Inocencio, T. L. Un-
Scheme 2. Syntheses of (À)-1,14-herbertenediol and (À)-aphanorphine.
deriner, R. Kostromin, J. Org. Chem.
1985, 50, 1932–1938.
[12] a) K. L. Jensen, G. Dickmeiss, H.
hedron Lett. 1996, 37, 1261–1264; d) Y. Fukuyama, Y. J. Asakawa, J.
Chem. Soc. Perkin Trans. 1 1991, 2737–2741.
Jiang, Ł. Albrecht, K. A. Jørgensen, Acc. Chem. Res. 2012, 45, 248–264;
b) J.-M. Tian, Y.-H. Yuan, Y.-Q. Tu, F.-M. Zhang, X.-B. Zhang, S.-H. Zhang,
S.-H. Wang, X.-M. Zhang, Chem. Commun. 2015, 51, 9979–9982.
[13] See the Supporting Information, p. S8.
[14] a) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science 2007, 317, 496–
499; b) G. L. Hamilton, T. Kanai, F. D. Toste, J. Am. Chem. Soc. 2008, 130,
14984–14986; c) Q.-W. Zhang, C.-A. Fan, H.-J. Zhang, Y.-Q. Tu, Y.-M.
Zhao, P.-M. Gu, Z.-M. Chen, Angew. Chem. Int. Ed. 2009, 48, 8572–8574;
Angew. Chem. 2009, 121, 8724–8726; d) Y. Wang, K. Zheng, R. Hong, J.
Am. Chem. Soc. 2012, 134, 4096–4099; e) B. Liu, T.-Y. Liu, S.-W. Luo, L.-Z.
Gong, Org. Lett. 2014, 16, 6164–6167.
[15] a) N. Gulavita, A. Hori, Y. Shimizu, P. Laszlo, J. Clardy, Tetrahedron Lett.
1988, 29, 4381–4384; b) S. Takano, K. Inomata, T. Sato, M. Takahashi, K.
Ogasawara, J. Chem. Soc. Commun. 1990, 290–292; c) K. Yasuyuki, F.
Junko, O. Yusuke, S. Yoshinari, K. G. Jnaneshwara, F. Hiromichi, J. Org.
Chem. 2003, 68, 5917–5924.
[4] For asymmetric syntheses of herbertene, see: a) A. Nayek, S. Ghosh, Tet-
rahedron Lett. 2002, 43, 1313–1315; b) A. Abad, C. Agullo, A. C. Cunat,
R. H. Perni, J. Org. Chem. 1999, 64, 1741–1744; c) M. Tori, T. Miyako, M.
Sono, Tetrahedron: Asymmetry 1997, 8, 2731–2738; d) S. Takano, M.
Moriya, K. Ogassawara, Tetrahedron Lett. 1992, 33, 329–332.
[5] For earlier syntheses of herbertene-1,14-diol, see: a) Y. Fukuyama, K.
Matsumoto, Y. Tonoi, R. Yokoyama, H. Takahashi, H. Minami, H. Okazaki,
Y. Mitsumoto, Tetrahedron 2001, 57, 7127–7135; b) A. Srikrishna, M. S.
Rao, Tetrahedron Lett. 2002, 43, 151–154; c) T. Paul, A. Pal, P. D. Gupta,
D. Mukherjee, Tetrahedron Lett. 2003, 44, 737–740; d) S. Acherar, G.
Audran, F. Fotiadu, H. Monti, Eur. J. Org. Chem. 2004, 2004, 5092–5099.
[6] L. Harinantenaina, D. N. Quang, T. Nishizawa, T. Hashimoto, C. Kohchi,
G. I. Soma, Y. Asakawa, Phytomedicine 2007, 14, 486–491.
[7] a) D. Lebœuf, C. M. Wright, A. J. Frontier, Chem. Eur. J. 2013, 19, 4835–
4841; b) A. Srikrishna, P. C. Ravikumar, H. S. Krishnan, Synthesis 2008, 10,
1527–1534; c) A. Srikrishna, P. C. Ravikumar, Synthesis 2007, 1, 65–74;
d) A. Srikrishna, L. B. Vasantha, Tetrahedron Lett. 2005, 46, 4879–4881;
e) P. D. Gupta, A. Pal, A. Roy, D. Mukherjee, Tetrahedron Lett. 2000, 41,
7563–7566.
Received: July 9, 2015
Published online on September 4, 2015
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