Enantioselective Construction of Cyclobutanes: A New and Concise Approach to the Total Synthesis of (+)-Piperarborenine B

Article abstract of DOI:10.1021/jacs.6b08279

A highly diastereoselective and enantioselective Cu(II)/SaBOX-catalyzed [2 + 2] cycloaddition of methylidenemalonate and multisubstituted alkenes was developed to furnish optically active cyclobutanes in high yields with >99/1 dr and up to >99% ee. By application of the newly developed method, the total synthesis of (+)-piperarborenine B was completed in eight steps from methylidenemalonate and olefin in 17% overall yield with >99/1 dr and 99% ee.

Full text of DOI:10.1021/jacs.6b08279

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Communication
Enantioselective Construction of Cyclobutanes: A New and
Concise Approach to the Total Synthesis of Piperarborenine B
Jiang-lin Hu, Liang-Wen Feng, Lijia Wang, Zuowei Xie, Yong Tang, and Xiaoge Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08279 • Publication Date (Web): 08 Sep 2016
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Enantioselective Construction of Cyclobutanes: A New and Concise
Approach to the Total Synthesis of (+)-Piperarborenine B
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JiangꢀLin Hu,† LiangꢀWen Feng,† Lijia Wang, † Zuowei Xie*, § Yong Tang*,† Xiaoge Li†
† The State Key Laboratory of Organometallic Chemistry and ShanghaiꢀHong Kong Joint Laboratory in Chemical Synthesis,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
§Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
Supporting Information Placeholder
high diastereoselectivities and excellent ees. In addition, optiꢀ
ABSTRACT: A highly diastereoselective and enantioselecꢀ
cally active (+)ꢀpiperarborenine B was synthesized by employꢀ
ing this newly developed method in 8 steps from methyliꢀ
denemalonate and olefin with 17% overall yield, >99/1 dr and
99% ee. Herein, we report these preliminary results.
tive Cu(II)/SaBOX catalyzed [2 + 2] cycloaddition of methyliꢀ
denemalonate with multisubstituted alkenes was developed to
furnish the optically active cyclobutanes in high yields with
>99/1 dr and up to >99% ee. By applying the newly developed
method, the total synthesis of (+)ꢀpiperarborenine B was comꢀ
pleted in 8 steps from methylidenemalonate and olefin with
17% overall yield, >99/1 dr and 99% ee.
The occurrence of cyclobutane frameworks in many natural
products and biologically active compounds (Figure 1) ,1 as
well as the possibility to transform cyclobutanes bearing mulꢀ
tiple functional groups to various synthetically useful and arꢀ
chitecturally complex structures,2 has aroused great interests to
build these fascinating structures.3 Although enantioselective
protocols have achieved remarkable breakthroughs,4ꢀ6 successꢀ
ful examples of asymmetric cyclobutanation are still limited
due to the fact that some of these methods still suffer from
limitations such as moderate diastereoselectivity and/or high
catalyst loading, as well as limited substrate scope. Accordingꢀ
ly, the appeal of developing new and effective enantioselective
methods for the construction of newꢀfashioned cyclobutanes is
urgent and necessary. Methylidenemalonate, which was first
prepared by Perkin in 1886,7 has been found to be a very reacꢀ
tive candidate in the [2 + 2] cycloaddition with electronꢀrich
alkenes to form donorꢀacceptor (DꢀA) cyclobutanes in the
presence of Lewis acid catalysts since 1983.2a,2b,8 Recently,
Johnson et al.,2a Pagenkopf et al.2b and Waser et al.8d indeꢀ
pendently developed racemic cyclobutanation reactions, using
Sc(OTf)3, Yb(OTf)3, or FeCl3·Al2O3 as catalysts. However, to
the best of our knowledge, the enantioselective version of this
reaction has not been realized yet. This can probably be asꢀ
cribed to the high symmetry of the methylidenemalonate molꢀ
ecule, the remote chiral delivery to the prostereogenic olefin,
and the resulting optically active DꢀA cyclobutanes being likeꢀ
ly to decompose into the racemic zwitterions promoted by
Lewis acids, which makes the enantioselective cyclobuꢀ
tanation reaction a challenging problem. In this work, we have
developed a Cu(II)/BOX (bisoxazoline) catalyzed [2 + 2] cyꢀ
cloaddition of methylidenemalonate with multisubstituted
alkenes, furnishing triꢀ and tetraꢀ substituted cyclobutanes with
Figure 1. Bioactive natural products containing cyclobu-
tane frameworks.
We began our study by using sidearmꢀmodified bisoxazoꢀ
line (SaBOX) ligand L1 with two pendent benzyl groups as
sidearms9,10,11 copper perchlorate as catalyst, and 4ꢀ
methoxystyrene 2a as a model substrate (Table 1). When perꢀ
o
formed at room temperature or 0 C, the reaction proceeded
very fast and completed within a few minutes but without any
chiral induction (entries 1, 2). Lowing the reaction temperaꢀ
tures resulted in a dramatic increase of the enantioselectivity.
o
Notably, when the reaction was carried out at –70 C, 69% ee
was obtained with a significant decrease of the yield, despite a
full consumption of 2a (entry 3). However, further study of
this reaction has shown that this result was difficult to reproꢀ
duce (entry 3). Interestingly, when 3a with a 96% ee was subꢀ
jected to the above reaction conditions, 3a was recovered after
2 h in 80% yield but with only 50% ee (Scheme 1, eq. 1). A
cross experiment of 3a (96% ee) with 2m was also carried out,
however, only 3a with 62% ee was observed and no cross
cyclobutanation compound was detected (eq. 2). These results
suggest that the cyclobutane product 3a is probably decomꢀ
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posed into a pair of zwitterions at room temperature in the
With the reproducible reaction conditions in hand, we turned
our focus on further optimization of the Lewis acid, solvents
presence of Lewis acids,2a resulting in the racemization of 3a.
1
2
3
Table 1. Reaction Optimizationa
Scheme 1. Mechanistic studies
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yield
entry
Lewis acids
solvent
ee (%)c
L
(%)b
48
91
19
28
41
29
45
41
7
and ligands (Table 1). It was found that both Cu(OTf)2 and
Ni(ClO4)2 could afford the desired product (entries 5, 6).12
Interestingly, the yield was promoted to 45% without any loss
of the enantioselectivity, when 5 Å MS (molecule sieves) was
used instead of 4 Å MS as additive, (entry 7). Notably, when
THF was employed as solvent, a significant improvement of
the enantiocontrol was obtained with a 93% ee, but with a still
moderate yield (entry 8). We then switched to THF as solvent
to study the influence of ligands.12 As can be seen from Table
1, the substituent of the BOX (bisoxazoline) ligand has a great
impact on the stereocontrol. It was found that increasing the
steric demand of the R1 group led to a dramatic decrease of
both yield and enantioselectivity (entries 8ꢀ10). L4 bearing an
aromatic R1 group could not give a better enantioselectivity
(entry 11). Thus, the chiral BOX ligand L1 derived from Lꢀ
valinol was found to be best in terms of both ee value and
yield (41% yield, 93% ee, entry 8). When ligands L5ꢀL7 were
applied in the reaction, the sidearm effect of the ligands was
clearly revealed.10 For ligands L6 and L7 without sidearm
groups, a decrease of enantioselectivity was observed (entries
13ꢀ14). In addition, trisoxazoline (TOX) L8 containing a Lꢀ
valinol derived oxazolinyl group as sidearm could barely proꢀ
mote the reaction (entry 15). Since the sidearms of the ligands
played a key role in the enantiocontrol of the cyclobutanation,
we tried to modify the sidearms and synthesized ligands L9ꢀ
L11 with different pendant groups R2 and R3.12 All these ligꢀ
ands showed increased ee values and yields (entries 16ꢀ18) in
comparison with L1. Of the ligands tested, L9 bearing 2ꢀ
BrC6H4CH2 groups as sidearms gave the best result, leading to
the desired product in 82% yield with 97% ee (entry 16).
1d, f
2 e, f
3 f, g
4 f
5 f
6 f
7
8
9
10
11
12
13
14
15
16
17
18
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(OTf)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
0
0
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
63~69
72
70
0
72
93
71
56
63
92
82
83
ꢀ
Ni(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
7
10
39
22
48
trace
82
77
54
97
95
95
aReaction conditions: Lewis acid (0.04 mmol), L (0.048 mmol), 5
Å MS (100 mg), 1 (1.0 mmol), and 2a (0.4 mmol) in 4.0 mL of
solvent, After 1 or 2a was consumed, Et3N was added to quench
b
c
the reaction at the reaction temperature. Isolated yields. Deterꢀ
d
mined by HPLC using a chiral stationary. Reaction performed at
room temperature. eReaction performed at 0 oC. f 4 Å MS was used
as additive. g Without Et3N quench.
Thus, it was envisioned that poisoning the catalyst may inhibit
the racemization. As expected, the ee of cyclobutane 3a was
maintained under the reaction conditions for 2 h after being
Under the optimized conditions, the substrate scope was
next explored (Table 2). Using methylidenemalonate 1, a
broad range of alkenes worked well. For substituted styrenes 2a-
2c, with electronꢀdonating groups such as MeOꢀ or BnOꢀ in
paraꢀposition of the phenyl, the corresponding D–A cyclobuꢀ
tanes (3a, 3b) were isolated in 82–91% yields with 96% ee,
respectively. 3,4ꢀDisubstituted piperonyl alkene 2c worked
well in this reaction with the same enantioselectivity. Thienyl
substituted cyclobutane 3d could also be furnished in 95% ee.
The absolute configuration of 3d was confirmed by singleꢀ
o
quenched by NEt3 at – 70 C (eq. 3). On the basis of these
results, we improved the workꢀup procedure by quenching the
reaction with NEt3 at – 70 oC after the reaction was completed.
Under these conditions, the ee was enhanced slightly and
could be readily reproduced (entry 7). Remarkably, by means
of quenching the reaction at low temperature, the racemization
of the resulting DꢀA cyclobutanes was effectively suppressed,
which provides a promising solution in the enantioselective
catalysis involving enantioꢀlabile compounds.
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crystal Xꢀray analyses.13 For 1,1ꢀdisubstituted alkenes 2e-2f,
the desired products were obtained with up to 72% yields and
up to 96% ee, when the reaction was carried out at – 80 oC,
toxicity against cancer cell lines (Pꢀ388, HTꢀ29, and A549,
IC50 < 1.46 ꢁg/mL)1c,1e, and thus has received research interꢀ
ests in the area of organic synthesis.14 In 2011, Baran and coꢀ
workers applied an elegant sequential cyclobutane CꢀH arylaꢀ
tion strategy in their total synthesis of racemic piperarborenine
B.14a,15 With cyclobutane 3m in hand, we attempted the enanꢀ
tioselective total synthesis of piperarborenine B (Scheme 2).
By deprotection of 3m with TBAF, TBS was removed to give
4 in a quantitative yield. Swern oxidation of 4 resulted in the
formation of aldehyde 5 which was further oxidized by oxone
to form acid 6. Condensation of 6 with 7 by EDCI led to amꢀ
ide 8. With the amide directing group, the 3,4,5ꢀ
trimethoxylphenyl group could be installed selectively to afꢀ
ford 10. After removing one of the ester groups in 10 by using
LiCl, a single diastereoisomer 11 was obtained. Boc protection
of the amideand subsequent hydrolysis of the amide and ester
group afforded a diacid which was amidated to give (+)ꢀ
piperarborenine B. Thus, by employing the current reaction,
total synthesis of (+)ꢀpiperarborenine B could be acomplished
in 8 steps from methylidenemalonate and 2m with 17% overꢀ
all yield and 99% ee. During the preparation of this paper, a
beautiful work on the enantioselective total synthesis of (+)ꢀ
piperarborenine B was reported by Fox and coꢀworkers in 10
steps from veratraldehyde with 8% overall yield and 92%
ee.14b
1
2
3
4
5
6
7
8
Table 2. Substrate Scopea
9
CO2Me
CO2Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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CO2Me
CO2Me
CO2Me
CO2Me
S
CO2Me
CO2Me
O
OMe
O
OBn
3a
3d
3c
3b
yieldb: 82%, eec: 97%
yield: 25%, ee: 95%
yield: 60%, ee: 96%
yield: 91%, ee: 96%
CO2Me
CO2Me
CO2Me
CO2Me
Me
CO2Me
CO2Me
CO2Me
Me
CO2Me
Et
Me
O
OMe
OMe
3h
yield: 84%, ee: 98%
dr: >95/5
Me
O
3e d
3f d
3g
yield: 89%, ee: 97%
dr : >95/5
yield: 52%, ee: 94%
CO2Me
yield: 72%, ee: 96%
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Bn
BnH2C
Cy
TBSOH2C
OMe
OMe
OMe
OMe
Scheme 2. Total Synthesis of (+)-Piperarborenine Ba
3if
3j
3k
3l
yield: 87%, ee: >99% yield: 91%, ee: 97%
yield: 50%, ee: 99%
dr: 93/7
yield: 91%, ee: 99%
dr: >99/1
dr: >95/5
dr: >99/1
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
TBSOH2C
TBSOH2C
OMe
OMe
Me
OMe
O
O
3o g
3m
3n
yield: 68%, ee: 99%
dr: >99/1
yield: 92%, ee: 96%
dr: >99/1
yield: 74%, ee: 95%
dr: >99/1
aReaction conditions: Cu(ClO4)2·6H2O (0.04 mmol), L9 (0.048
mmol), 5 Å MS (100 mg), 1 (1.0 mmol), and 2 (0.4 mmol) in
o
b
4.0 mL of THF, quenched by Et3N at –70 C. Isolated yield.
cDetermined by HPLC using a chiral stationary. dCu(OTf)2
(0.04 mmol), L1 (0.048 mmol) as catalyst, 2.0 mL THF as
o
1
f
solvent, reaction at –
80 C. e Determined by H NMR. Reacꢀ
tion at ꢀ50 C. gThe absolute configuration of 3o has not been
o
determined.
using Cu(OTf)2 as the catalyst. Notably, a variety of trans diꢀ
substituted alkenes 2k-2g proved to be suitable substrates for
the current catalytic system, giving the corresponding products
in good yields with excellent diastereoselectivity and enantiꢀ
oselectivity (93/7–>99/1 dr, 97–>99% ee). To test the funcꢀ
tional group tolerance of the reaction, a TBS protected hyꢀ
droxyl group was introduced into the substrates, affording 3l-
3n in 68ꢀ92% yields with >99/1 dr and 96–>99% ee. The abꢀ
solute configuration of 3g was determined by vibrational cirꢀ
cular dichroism (VCD).12 To our delight, the triꢀsubstituted
alkene 2o was also compatible with this reaction, delivering
cyclobutane 3o, bearing a fullꢀcarbon chiral center in 74%
yield with >99/1 dr and 93% ee. Unfortunately, 2ꢀsubstituted
methylidenemalonate proved to be inert under the current reꢀ
action conditions.12
aReagent and conditions: (a) TBAF (1.5 equiv), THF, rt, 99%;
(b) DMSO (2.0 equiv), (COCl)2 (1.3 equiv), 92%; (c) Oxone
(0.9 equiv), DMF; (d) EDCI (1.2 equiv), DMAP (2.4 equiv), 7
(1.1 equiv), DCM, 79% 2 steps; (e) 9 (2.0 equiv), Pd(OAc)2
(0.3 equiv), Ag2CO3 (1.5 equiv), PivOH (1.0 equiv), toluene,
130 oC, 72h, 70% b.r.s.m; (f) LiCl (10 equiv), H2O (10 equiv),
o
DMSO, 130 C, 48h, 93%; (g) (Boc)2O (1.5 equiv), DMAP
(0.1 equiv), MeCN; then LiOH (6 equiv), H2O2 (10 equiv),
THF/H2O; (COCl)2, DMF, THF, 2h; 12 (3 equiv) , toluene, 4
Å MS, 80 oC, 12h, 69%.
In summary, the first asymmetric [2 + 2] cycloaddition of
dimethyl methylidene malonate with polysubstituted olefins
has been developed using Cu(II)/SaBOX as the catalyst, givꢀ
ing optically active cyclobutanes in high yields with >99/1 dr
Piperarborenine B (Figure 1), which was isolated from the
stem of Piper arborescens in 2004, has shown in vitro cytoꢀ
3
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P. A. Org. Lett. 2006, 8, 5597–5600. (f) Chaumontet, M.; Piccardi, R.;
and up to >99% ee. The reaction has a broad substrate scope,
in which monoꢀ, diꢀ, and triꢀsubstituted alkenes all work well.
This newly developed method has been applied to the enantiꢀ
oselective total synthesis of (+)ꢀpiperarborenine B which was
completed in 8 steps from methylidenemalonate and 2m with
17% overall yield and 99% ee. Further application of this reacꢀ
tion is an onꢀgoing project in our laboratory.
Audic, N.; Hitce, J.; Peglion, J. ꢀL.; Clot, E.; Baudoin, O. J. Am.
Chem. Soc. 2008, 130, 15157–15166. (g) Adachi, M. A.; Yamauchi,
E.; Komada, T.; Isobe, M. Synlett 2009, 20, 1157–1161. (h) de Nanꢀ
teuil, F.; Waser, J. Angew. Chem., Int. Ed. 2013, 52, 9009–9013.
(4) For photoꢀpromoted enantioselective [2 + 2] reactions, see (a)
Guo. H,; Herdtweck. H.; Bach, T. Angew. Chem., Int. Ed. 2010, 49,
7782–7785. (b) Muller, C.; Bauer, A.; Maturi, M. M.; Cuquerella, M.
C.; Miranda, M. A.; Bach, T. J. Am. Chem. Soc. 2011, 133, 16689–
16697. (c) Du, J. N.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P.; Sci-
ence 2014, 344, 392–396. (d) Conner, M. L.; Xu, Y.; Brown, M. K. J.
Am. Chem. Soc. 2015, 137, 3482–3485.
(5) For organocatalytic enantioselective [2 + 2] reactions, see (a)
Albrecht, Ł.; Dickmeiss, G.; Acosta, F. C.; Escrich, C. R.; Davis, R.
L.; Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134, 2543–2546. (b)
Talavera, G.; Reyes, E.; Vicario, J. L.; Carrillo, L. Angew. Chem., Int.
Ed. 2012, 51, 4104–4107.
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ASSOCIATED CONTENT
9
Experimental procedures, complete characterization data, includꢀ
ing NMR spectra and HPLC data as well as CIF data of 3d. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
(6) (a) Hayashi, Y.; Narasaka, K. Chem. Lett. 1989, 793–796. (b)
Hayashi, Y.; Niihata, S.; Narasaka, K. Chem. Lett. 1990, 2091–2094.
(c) Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Niihata, S. J. Am. Chem.
Soc. 1992, 114, 8869–8885. (d) Narasaka, K.; Hayashi, K.; Hayashi,
Y. Tetrahedron 1994, 50, 4529–4542. (e) Canales, E.; Corey, E. J. J.
Am. Chem. Soc. 2007, 129, 12686–12687. (f) Xu, Y.; Conner, M. L.;
Brown, M. K. Angew. Chem. Int. Ed., 2015, 54, 11918–11928. (g)
GuisánꢀCeinos, M.; Parra, A.; MartínꢀHeras, V.; Tortosa, M., Angew.
Chem. Int. Ed., 2016, 55, 6969ꢀ6972.
(7) (a) Perkin, W. H. Ber. Dtsch. Chem. Ges. 1886, 19, 1053–1057;
(b) De Keyser, J. ꢀL.; De Cock, C. J. C.; Poupaert, J. H.; Dumont, P. J.
Org. Chem. 1988, 53, 4859–4862.
(8) (a) Komiya, Z.; Nishida, S., J. Org. Chem. 1983, 48, 1500–
1509. (b) Baar, M. R.; Ballesteros, P.; Roberts, B. W., Tetrahedron
Lett. 1986, 27, 2083–2086. (c) Yamazaki, S.; Tanaka, M.; Inoue, T.;
Morimoto, N.; Kumagai, H.; Yamamoto, K., J. Org. Chem. 1995, 60,
6546–6551. (d) DeꢀNanteuil, F.; Waser, J., Angew. Chem. Int. Ed.
2013, 52, 9009–9013.
Corresponding Author
tangy@mail.sioc.ac.cn; zxie@cuhk.edu.hk
ACKNOWLEDGMENT
We are grateful for the financial support from the National Natuꢀ
ral Sciences Foundation of China (No. 21421091, 21432011, and
21272250); the National Basic Research Program of China (973
Program) (2015CB856600); the NSFC/RGC Joint Research
Scheme (21461162002 to Y.T. and N_CUHK442/14 to Z.X.), and
the Chinese Academy of Sciences. We also thank Dr. Sebastian
Schaubach for the assistance in English editing.
REFERENCES
(1) For selected examples, see (a) Nakamura, M.; Chi, Y. M.; Yan,
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(2) For leading examples on the ringꢀopening/annulation reactions
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(10) For reviews on sidearm strategy, see: (a) Zhou, J.; Tang, Y.
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(11) For recent uses of sidearm modified BOX (SaBOX) Ligand,
see: (a) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem.
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(12) For details, see the Supporting Information.
(13) The crystallographic data of 3d can be found in Supporting Inꢀ
formation.
(14) (a) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011,
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(3) For selected racemic examples of cyclobutanation, see (a)
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