One-pot construction of multi-substituted spiro-cycloalkanediones by an organocatalytic asymmetric epoxidation/semipinacol rearrangement

Article abstract of DOI:10.1002/asia.201100383

A one-pot preparation of chiral tri-oxygenated spirocycloalkanediones with up to 99 % ee features high stereoselectivity, the introduction of tri-oxygenated functional groups, and the efficient construction of at least two chiral centers. Copyright

Full text of DOI:10.1002/asia.201100383

DOI: 10.1002/asia.201100383
One-Pot Construction of Multi-Substituted Spiro-Cycloalkanediones by an
Organocatalytic Asymmetric Epoxidation/Semipinacol Rearrangement
Bao-Sheng Li, En Zhang, Qing-Wei Zhang, Fu-Min Zhang, Yong-Qiang Tu,* and
Xiao-Ping Cao*[a]
The construction of chiral spirocycloalkanedione cores,[1]
which are key intermediates in the synthesis of natural spi-
rocyclic compounds,[2] is an important task in organic syn-
thesis. The semipinacol rearrangement has proven to be one
of the most powerful procedures to access these units.[3] In
recent years, tremendous effort
the cinchona-derived amine d (Scheme 1), which has been
applied to a number of asymmetric reactions with high
enantioselectivity.[8] For example, List and co-workers ex-
plored the asymmetric epoxidation of enones using amine
d,[9] and Jørgensen and co-workers employed this d-promot-
has been made to investigate
semipinacol rearrangements for
this purpose and a series of
novel methodologies have been
developed, some of which have
been applied efficiently to the
synthesis of important natural
products.[4] However, the cata-
lytically effective asymmetric
semipinacol
rearrangement,
used for constructing chiral
units containing a quaternary
carbon,[5] especially multi-sub-
stituted spirocycloalkanediones,
still remains a challenge. Re-
cently, we have reported two
asymmetric semipinacol rear-
rangement reactions for the
construction of spirocyclic ke-
tones with high enantioselectiv-
ity.[6]
Scheme 1. Strategy to complex chiral spirocycloalkanediones via an asymmetric epoxidation/semipinacol rear-
rangement.
Organocatalysis has become a highly dynamic and rapidly
expanding field in organic chemistry.[7] One of the most
widely used organocatalysts over the past decade has been
ed, one-pot reaction in the synthesis of chiral allylic alco-
hols.[10] In our previous work, we have also successfully used
amine d to catalyze the semipinacol rearrangement of a,
generating chiral spirocyclic 1,4-diketones of type e with up
to 97% ee (Scheme 1a).[6b] We now present our studies on
the use of this amine (d) to explore a new asymmetric epox-
idation/semipinacol rearrangement in the efficient synthesis
of more-complex tri-oxygenated spirocycloalkanediones b.
We anticipated that the asymmetric epoxidation/semipinacol
rearrangement of vinylogous a-ketol a might be carried out
in a tandem or one-pot reaction (Scheme 1b) using amine d
as a catalyst, to produce tri-oxygenated-spirocycloalkane-
[a] B.-S. Li, Dr. E. Zhang, Q.-W. Zhang, Prof. Dr. F.-M. Zhang,
Prof. Dr. Y.-Q. Tu, Prof. Dr. X.-P. Cao
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
Fax : (+86)931-8915557
E-mail: tuyq@lzu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100383.
Chem. Asian J. 2011, 6, 2269 – 2272
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2269

COMMUNICATION
dione derivatives b. However, we were aware of some possi-
ble problems with this strategy. For example, the epoxida-
tion of enone a to give c would not be easy owing to the
presence of a bulky hydroxycycloalkyl substituent at the C-3
position. In addition, a mixture of two diastereoisomeric
products of b might be formed if the rearrangement of ep-
oxide c proceeded via competing SN1 and SN2-like processes
(Scheme 1b). Furthermore, under weakly acidic conditions,
a direct semipinacol rearrangement of enone a to form e (as
in Scheme 1a) might take place before epoxidation occur-
red.[6b] Herein, we report the development of this process
and its results.
room temperature to give the expected product 1b with
high stereoselectivity (99% ee) and in 30% yield (Table 1,
entry 1). With this result in hand, our subsequent efforts
were aimed at improving the yield of the rearrangement
step by screening other Brønsted acids. However, neither
trifluoroacetic acid (TFA) nor boric acid yielded the expect-
ed product 1b (Table 1, entries 2 and 3). We considered the
possibility that not only a Brønsted acid was required, but
also the presence of water was important in effecting this re-
arrangement, because the presence of a large amount of
water induced this reaction (Table 1, entries 2 and 3).
As we anticipated, when dioxane and water (v/v 1:2) were
used as a mixed solvent, rearrangement of epoxide 1c pro-
ceeded sluggishly with 5% TFA at 508C and gave the prod-
uct 1b in 60% yield after 36 hours (Table 1, entry 4). In-
creasing the amount of TFA to 10 equivalents reduced the
reaction time to 6 hours and enhanced the yield of product
1b to 84% (Table 1, entry 5). Likewise, the use of tetrahy-
drofuran and water as a mixed solvent also effected this re-
arrangement with 99% ee, and in 69% yield (Table 1,
entry 6). Subsequently, we examined other mixed solvents,
such as 1,4-dioxane with dichloromethane or methanol
(Table 1, entries 7 and 8), but no product 1b was observed.
A survey of mixed solvents revealed that water as a co-sol-
vent was essential to this rearrangement reaction. Further-
more, changing the ratio of dioxane/water from 1:1 to 1:3
was examined to find the optimal conditions, and dioxane/
water in a ratio of 1:2 was found to give the best yield.
To further explore the substrate scope and generality of
this one-pot procedure (Scheme 1b), a series of vinylogous
a-ketol substrates, a (prepared through the coupling of vari-
ous enones with cyclobutanone or cyclopentanone deriva-
tives),[12] were subjected to asymmetric epoxidation with
H2O2 followed by in situ acidification in the general process
described below. The results are shown in Table 2. Substitu-
tion at the C-3’ position of the cyclobutanol moiety of sub-
strate 1a with both six- and seven-membered spiro-rings
(Table 2, entries 2 and 3) were effectively converted into the
desired product using this procedure, with comparable
yields of 56% and 60%, respectively. The introduction of
cis-mono-substituents 4-BrC6H4 and Ph at the C-3’ position
(Table 2, entries 4 and 5) led to 3:1 diastereoisomeric mix-
tures of 4b/4b’ and 5b/5b’ in total yields of 55% and 57%,
respectively.
We initially attempted to develop the tandem asymmetric
epoxidation/semipinacol rearrangement of the vinylogous a-
ketol a. However, the reaction of 1a with 2.5 equivalents of
H2O2 (30% w/w in H2O), using amine d as the catalyst, in
the presence of water-stable Lewis acids ScCAHTUNGTRENNNUG
[11]
ACHTUNGTRENNUNG
solvents at 358C. Fortunately, the intermediate epoxide 1c
was produced with several solvents, such as 1,4-dioxane, tet-
rahydrofuran, or ethyl acetate. Among these solvents, 1,4-di-
oxane gave the highest ee (98%) and yield (68%).[12] In
these cases, a trace amount of the competing semipinacol re-
arrangement product e was also observed.
Based on the experimental results above, we turned our
attention to promoting the subsequent semipinacol rear-
rangement of epoxide 1c into product 1b so as to accom-
plish a one-pot procedure (Scheme 1b).[13] Thus, epoxide 1c
served as the substrate in a search for appropriate rear-
rangement conditions. We treated 1c with a variety of
Brønsted or Lewis acids in 1,4-dioxane,[14] and the results
(Table 1) indicated that several Lewis acids, such as Mg-
ACHTUNGTRENNUNG(ClO4)2, LiClO4·3H2O, AlCl3, and SnCl4, were ineffective in
promoting this rearrangement at 508C. Gratifyingly, when
concentrated hydrochloric acid (4 equiv) was used; however,
the reaction went to completion smoothly within 4 hours at
Table 1. Screening rearrangement conditions from 1c to 1b.[a]
Both major isomers, 4b and 5b, were produced in excel-
lent optical purities (98% ee and 99% ee, respectively).The
absolute configuration of (À)-4b was unambiguously con-
firmed by X-ray crystallography,[15] and, based on this infor-
mation, the absolute configuration of other products 1b–3b
and 5b in Table 2 were deduced. However, trans-mono-sub-
stitution with a phenyl group at the C-3’ position of 1a re-
sulted in poor 1:1 diastereoselectivity and a low total yield
of 40% (Table 2, entry 6). When 3’,3’-diphenyl-substituted
1a was subjected to the reaction conditions, we did not ob-
serve the expected product b, and e was the sole product,
probably owing to steric hindrance caused by the bulky 3’,3’-
diphenyl substitution during the initial epoxidation step.
entry
Solvent
Acid
Yield [%][e]
ee [%][f]
1
2
3
4
5
6
7
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
HCl[b]
TFA[c]
30
n.d.
n.d.
60
84
69
99
–
–
96
99
99
–
boric acid[c]
TFA[d]
1,4-dioxane/water
1,4-dioxane/water
THF/water
1,4-dioxane/CH2Cl2
1,4-dioxane/MeOH
TFA[c]
TFA[c]
TFA[c]
n.d.
n.d.
TFA[c]
–
[a] All Reactions (except entry 1) were performed with 0.1 mmol of ep-
oxide 1c in 1 mL solvent at 508C. [b] 4 equiv acid was added. [c] 10 equiv
acid was added. [d] 0.02 equiv acid was added. [e] Yield of isolated prod-
uct. [f] ee of product 1b was determined by chiral HPLC analysis. THF=
tetrahydrofuran, TFA=trifluoroacetic acid, n.d.=not detected.
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Chem. Asian J. 2011, 6, 2269 – 2272

One-Pot Construction of Multi-Substituted Spiro-Cycloalkanediones
Table 2. One-pot synthesis of asymmetric spirocycloalkanediones.[a]
seven-membered ring in 10a and used as a substrate in this
protocol. Its reaction also gave a good yield (70%) of prod-
uct 10b with 93% ee (Table 2, entry 10).
Entry
Substrate
Product[c]
Yield
[%][d]
ee
[%][e]
The above results (Table 2) showed that the correspond-
ing trioxygenated spirocycloalkanedione products b could
be obtained with moderate total yields (40–75%) and excel-
lent stereoselectivities (93–99% ee). In all cases, no other
spiro-isomer was observed, indicating that the rearrange-
ment step proceeded well in a concerted SN2-type process.
These types of multi-substituted spirocycloalkanediones,
which contain tri-oxygenated functional groups and two ad-
jacent chiral centers (including one all-carbon quaternary
center), are versatile building blocks for the synthesis of
many important molecules.[2] For example, the spirojatamol
and erythrodiene-type natural products would be readily
synthesized through conversion of the hydroxy and carbonyl
groups adjacent to the spirocenter into fully reduced alkyl
groups.[2]
1
2
1a R1, R2 =H
2a R1, R2 =
(CH2)5
1b R1, R2 =H
2b R1, R2 =
(CH2)5
66
56
99
99
3
3a R1, R2 =
(CH2)6
3b R1, R2 =
(CH2)6
60
99
98
99
94
4[b]
5[b]
6[b]
4a (R1 =H,
R2 =4-BrC6H4)
5a (R1 =H,
R2 =C6H5)
6a (R1 =C6H5,
R2 =H)
4b/4b’
55
57
40
ACHTUNGTRENNUNG
5b/5b’
5b/5b’
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
In summary, a new and efficient one-pot procedure for
the synthesis of various trioxygenated-spirocycloalkanedione
cores has been developed based on an asymmetric epoxida-
tion/semipinacol rearrangement. The significant features of
this transformation include the excellent stereoselectivity
and high efficiency in an aqueous medium.
7
75
51
46
70
99
99
99
93
7a
8a
7b
8b
8
Experimental Section
Experimental Details
9
A mixture of substrate a (0.15–0.51 mmol, 0.1m in 1,4-dioxane), catalyst
d (0.1 equiv) and TFA (0.2 equiv) was stirred in 1,4-dioxane at RT for
10 min, and then H2O2 (30% w/w in H2O, 2.5 equiv) was added. The re-
action was heated to 35–508C for 20–72 h. After completed conversion of
enone into the epoxide had been established by TLC analysis, TFA
(10 equiv) and water was added at 508C. The reaction was stirred for 6–
36 h, cooled to RT, and a saturated solution of NaHCO3 (4 mL) was
added. The reaction mixture was extracted with Et2O (15 mLꢁ3), dried
(MgSO4), and concentrated under reduced pressure. The residue was pu-
rified by column chromatography on silica gel.
9a
9b
10
10a
10b
[a] For experimental details, see the Supporting Information. [b] For en-
tries 4–6, the ee values of 4b and 5b were described; The d.r. (given in
parentheses) were determined by chiral HPLC. [c] Preparation of the
racemates is described in the Supporting Information. [d] Total yield of
isolated product. [e] ee values in parentheses were determined by chiral
HPLC.
Acknowledgements
We gratefully acknowledge financial support from the NSFC (Grant Nos.
20872055, 20972060, 20732002, and 20972059), the “973” program of
(2010CB833200), and the “111” program.“
Enone 7a, which has a larger C3-cyclopentanol moiety,
was examined using this procedure, and this substrate was
found to give the highest yield (75%) of product 7b ob-
tained for any substrate in our study (Table 2, entry 7). Sub-
stitution on the ring of the cyclohexenone moiety with a six-
membered spirocycle at the C-5 position was investigated
and the desired product 8b was produced in a moderate
51% yield (Table 2, entry 8). X-ray crystal structures of (À)-
4b and (À)-7b[15] were obtained, and, based on this informa-
tion and the absolute configuration of 4b, the absolute con-
figurations of products 7b, 8b, 9b, and 10b were elucidated.
A C-5 dimethyl-substituted substrate gave only a low yield
(46%) of product 9b (Table 2, entry 9). Finally, the six-
membered cyclohexenone ring of 7a was expanded to a
Keywords: asymmetric synthesis · chiral quaternary carbon ·
epoxidation · semipinacol rearrangement · spiro compounds
[1] a) B. M. Trost, D. C. Lee, J. Am. Chem. Soc. 1988, 110, 6556; b) J.
Huang, A. J. Frontier, J. Am. Chem. Soc. 2007, 129, 8060; c) L. E.
Overman, D. A. Watson, J. Org. Chem. 2006, 71, 2600; d) T. Jin, M.
Himuro, Y. Yamamoto, Angew. Chem. 2009, 121, 6007; Angew.
Chem. Int. Ed. 2009, 48, 5893; e) H.-S. Yeom, Y. Lee, J. Jeong, E.
So, S. Hwang, J.-E. Lee, S. S. Lee, S. Shin, Angew. Chem. 2009, 121,
1655; Angew. Chem. Int. Ed. 2010, 49, 1611.
[2] a) M. Lachia, F. Dꢂnꢃs, F. Beaufils, P. Renaud, Org. Lett. 2005, 7,
4103; b) D. E. White, L. C. Stewart, R. H. Grubbs, B. M. Stoltz, J.
Chem. Asian J. 2011, 6, 2269 – 2272
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2271

Y.-Q. Tu, X.-P. Cao et al.
COMMUNICATION
Am. Chem. Soc. 2008, 130, 810; c) D. F. Taber, M. I. Sikkander, P. H.
Storck, J. Org. Chem. 2007, 72, 4098; d) C. Pathirana, W. Fenical, E.
Corcoran, J. Clardy, Tetrahedron Lett. 1993, 34, 3371.
Y. Chen, J. Hang, L. Tang, P. Mcdaid, L. Deng, Acc. Chem. Res.
2004, 37, 621.
[9] a) X. Wang, C. M. Reisinger, B. List, J. Am. Chem. Soc. 2008, 130,
6070; b) S.-S. Jew, J.-H. Lee, B.-S. Jeong, M.-S. Yoo, M.-J. Kim, Y.-J.
Lee, J. Lee, S.-h. Choi, K. Lee, M. S. Lah, H.-g. Park, Angew. Chem.
2005, 117, 1407; Angew. Chem. Int. Ed. 2005, 44, 1383; c) X. Lu, Y.
Liu, B. Sun, B. Cindric, L. Deng, J. Am. Chem. Soc. 2008, 130, 8134.
[10] a) H. Jiang, N. Holub, K. A. Jørgensen, Proc. Natl. Acad. Sci. USA
2010, 107, 20630.
[11] a) A. T. Placzek, J. L. Donelson, R. Trivedi, R. A. Gibbs, S. K. De,
Tetrahedron Lett. 2005, 46, 9029; b) O. Monasson, M. Ginisty, G.
Bertho, C. Gravier-Pelletier, Y. L. Merrer, Tetrahedron Lett. 2007,
48, 8149; c) V. K. Aggarwal, G. Hynd, W. Picoul, J.-L. Vasse, J. Am.
Chem. Soc. 2002, 124, 9964.
[3] a) T. J. Snape, Chem. Soc. Rev. 2007, 36, 1823; b) Y. Q. Tu, L. D.
Sun, P. Z. Wang, J. Org. Chem. 1999, 64, 629; c) L. A. Paquette,
D. R. Owen, R. T. Bibart, C. K. Seekamp, A. L. Kahane, J. C.
Lanter, M. A. Corral, J. Org. Chem. 2001, 66, 2828; d) G. R. Dake,
M. D. B. Fenster, M. Fleury, B. O. Patrick, J. Org. Chem. 2004, 69,
5676; e) B. M. Trost, D. W. C. Chen, J. Am. Chem. Soc. 1996, 118,
12541.
[4] a) M. D. B. Fenster, G. R. Dake, Org. Lett. 2003, 5, 4313; b) C.-A.
Fan, Y.-Q. Tu, Z.-L. Song, E. Zhang, L. Shi, M. Wang, B. Wang, S.-
Y. Zhang, Org. Lett. 2004, 6, 4691.
[5] In Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis (Eds: J. Christoffers, A. Baro.), Wiley-VCH, Weinheim,
Germany, 2005; a) C. J. Douglas, L. E. Overman, Proc. Natl. Acad.
Sci. USA 2004, 101, 5363; b) B. M. Trost, C. Jiang, Synthesis 2006,
369; c) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem.
2007, 5969; d) M. Bella, T. Gasperi, Synthesis 2009, 1583.
[12] For details, Please see supporting information.
[13] a) S.-y. Tosaki, R. Tsuji, T. Ohshima, M. Shibasaki, J. Am. Chem.
Soc. 2005, 127, 2147; b) T. Nemoto, H. Kakei, V. Gnandesikan, S.-y.
Tosaki, T. Ohshima, M. Shibasaki, J. Am. Chem. Soc. 2002, 124,
14544.
[6] a) Q.-W. Zhang, C.-A. Fan, H.-J. Zhang, Y.-Q. Tu, Y.-M. Zhao, P.
Gu, Z.-M. Chen, Angew. Chem. 2009, 121, 8724; Angew. Chem. Int.
Ed. 2009, 48, 8572; b) E. Zhang, C.-A. Fan, Y.-Q. Tu, F.-M. Zhang,
Y.-L. Song, J. Am. Chem. Soc. 2009, 131, 14626.
[7] a) Recent Developments in Asymmetric Organocatalysis (Ed: H. Pel-
lissier), Royal Society of Chemistry, 2010; b) Enantioselective Orga-
nocatalysis: Reactions and Experimental Procedures (Ed: P. I.
Dalko), Wiley-VCH, Weinheim, Germany, 2007; c) S. Mukherjee,
J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471, and
references therein.
[8] In Cinchona Alkaloids in Synthesis & Catalysis: Ligands, Immobili-
zation and Organocatalysis (Ed: C. E. Song.), Wiley-VCH, Wein-
heim, Germany, 2009; a) L.-Y. Wu, G. Bencivenni, M. Mancinelli,
A. Mazzanti, G. Bartoli, P. Melchiorre, Angew. Chem. 2009, 121,
7332; Angew. Chem. Int. Ed. 2009, 48, 7196; b) M. W. Paix¼o, N.
Holub, C. Vila, M. Nielsen, K. A. Jørgensen, Angew. Chem. 2009,
121, 7474; Angew. Chem. Int. Ed. 2009, 48, 7338; c) W. Chen, W.
Du, Y.-Z. Duan, Y. Wu, S.-Y. Yang, Y.-C. Chen, Angew. Chem.
2007, 119, 7811; Angew. Chem. Int. Ed. 2007, 46, 7667; d) S.-K. Tian,
[14] a) K. Aplander, R. Ding. M. Krasavin, U. M. Lindstrçm, J. Wenner-
berg, Eur. J. Org. Chem. 2009, 810; b) M. Kokubo, C. Ogawa, S. Ko-
bayashi, Angew. Chem. 2008, 120, 7015; Angew. Chem. Int. Ed.
2008, 47, 6909; c) R. Ding, K. Katebzadeh, L. Roman, K.-E. Berg-
quist, U. M. Lindstrçm, J. Org. Chem. 2006, 71, 352; d) K. Suda, T.
Kikkawa, S.-i. Nakajima, T. Takanami, J. Am. Chem. Soc. 2004, 126,
9554; e) Z.-J. Zheng, X.-Z. Shu, K.-G. Ji, S.-C. Zhao, Y.-M. Liang,
Org. Lett. 2009, 11, 3214; f) S.-J. Jeon, P. J. Walsh, J. Am. Chem. Soc.
2003, 125, 9544; g) Y. Kita, S. Kitagaki, Y. Yoshida, S. Mihara, D.-F.
Fang, M. Kondo, S. Okamoto, R. Imai, S. Akai, H. Fujioka, J. Org.
Chem. 1997, 62, 4991.
[15] For ORTEPs of (À)-4b and (À)-7b, please see the Supporting Infor-
mation. CCDC 800896 (À)-4b and CCDC 814514 (À)-7b contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallograph-
ic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: April 15, 2011
Published online: June 15, 2011
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