Organohalogenite-Catalyzed Spiroketalization: Enantioselective Synthesis of Bisbenzannulated Spiroketal Cores

Article abstract of DOI:10.1002/adsc.201500390

A new core structure-motivated strategy for the intramolecular aromatic spiroketalization process was found and used for the enantioselective synthesis of bisbenzannulated spiroketals, the bioactive core of rubromycins, with high levels of enantioselectiv

Full text of DOI:10.1002/adsc.201500390

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DOI: 10.1002/adsc.201500390
Organohalogenite-Catalyzed Spiroketalization: Enantioselective
Synthesis of Bisbenzannulated Spiroketal Cores
Jijun Xue,a,* Hongrui Zhang,a Tian Tian,a Keshu Yin,a Dongxue Liu,a
Xianxing Jiang,b,* Ying Li,a,* Xiaojie Jin,a and Xiaojun Yaoa
a
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou, 730000 Gansu, Peopleꢀs Republic of China
E-mail: xuejj@lzu.edu.cn or liying@lzu.edu.cn
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Peopleꢀs Republic of China
b
E-mail: jiangxx5@mail.sysu.edu.cn
Received: April 20, 2015; Revised: November 2, 2015; Published online: January 18, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500390.
Abstract: A new core structure-motivated strategy
for the intramolecular aromatic spiroketalization
process was found and used for the enantioselective
synthesis of bisbenzannulated spiroketals, the bioac-
tive core of rubromycins, with high levels of enan-
tioselectivity (up to 98% ee) via an organohalogen-
ite-mediated asymmetric intramolecular aromatic
spiroketalization. This is the first organocatalytic
method for the construction of optically pure bis-
benzannulated spiroketals.
Keywords: asymmetric synthesis; organocatalysis;
organohalogen; spiroketalization
Core-scaffold-lead synthesis through rapid construc-
Figure 1. Important natural spiroketal products.
tion of chiral molecular complexity around the biolog-
ically relevant framework using a highly efficient
strategy is a key goal of organic and medicinal synthe-
sis. Benzannulated spiroketals, as a privileged struc-
tural moiety found in a large series of bioactive natu-
rally occurring alkaloids and pharmaceutically rele-
vant assays, such as Lysidicin[1] and rubromycins[2]
(Figure 1), exhibit a range of biological and pharma-
ceutical activities.[3] Although many strategies were
designed to construct spiroketals[4] and related natural
products,[5] the direct asymmetric catalytic approaches
to access them are still scarce.
Recently, List[6] and Nagorny[7] developed the asym-
metric catalytic construction of aliphatic spiroketals
by chiral phosphoric acid-catalyzed spiroketalizations
(a, Scheme 1), respectively. However, compared to
Scheme 1. Different catalytic strategies for spiroketalization.
the asymmetric formation of aliphatic spiroketals, the matic hydroxy groups have less nucleophilicity. There-
enantioselective construction of aromatic spiroketals fore, it is not surprising that the catalytic enantioselec-
represents a considerable challenge because the aro- tive synthesis of aromatic spiroketals has been rarely
370
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Organohalogenite-Catalyzed Spiroketalization
Table 1. Studies and optimization of the reaction paramet-
reported, and all of only two examples fall into the
more complex transition metal- or metal/phosphoric
acid combination-catalyzed strategies from Ding[8]
and Gong[9] group (b and c, Scheme 1), respectively.
The development of efficient methodologies that
enable cheaper, simpler, and more concise approaches
to access molecular complexity with exquisite levels
of stereocontrol remains a preeminent goal in modern
organic chemistry. Herein, we introduce an organoha-
logenite catalytic strategy as a new and convenient
platform for the core-structure-motivated design of
intramolecular aromatic spiroketalization processes.
In this context, we document a highly enantioselective
synthesis of bisbenzannulated spiroketal cores by de-
veloping the first organocatalytic aromatic spiroketali-
zation (d, Scheme 1).
ers.[a]
In the past two decades, organohalo compounds
have been increasingly explored and proved to be
very versatile intermediates as environmentally
benign reagents[10] to replace expensive and toxic
heavy metal materials in halogenation,[11] oxida-
tion,[1c,12] and catalysis processes.[13] Amongst the most
challenges and interests for synthetic chemists is the
development of efficient organohalo catalysts that
allow the rapid construction of stereo- and skeleton-
chemically defined molecular complexity. There are
a number of efforts devoted to tandem reactions in-
volving organohalogen-mediated halogenation as
a transition process,[14,15,16] especially for halolactoniza-
tion[14] and related halocyclizations.[16] Notably, com-
pared with enantioselective halogenations and halo-
lactonizations, the catalytic asymmetric halocyclo-
etherification has attracted less attention, although it
may be more convenient and feasible for the enantio-
selective construction of spiroketals.
On the basis of the above considerations, our
recent efforts are to develop halocycloetherification
for the construction of spiroketals by using in-situ
generated hypoiodite catalysis system.[17] Herein, we
hope to expand our studies beyond the racemic com-
pounds and develop an efficient protocol through or-
ganocatalytic intramolecular aromatic spiroketaliza-
tion for accessing chiral bisbenzannulated spiroketals.
In this text, we present our preliminary results on this
topic.
Entry
Cat.
Solvent
X+ source
Yield[b]
ee[c]
1
2
3
4
5
6
7
8
3a[d]
3b[d]
3c
3d
3e
toluene
toluene
toluene
toluene
toluene
toluene
THF
21%
18%
14%
20%
7%
60%
10%
0%
10%
55%
54%
45%
61%
70%
6%
3%
7%
25%
0
35%
0%
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NBS
DBDMH
3f
3f
3f
3f
CHCl3
0%
5%
9
CH3CN
toluene
toluene
toluene
toluene
toluene
10
11
12
13
14
3f[e]
3f[f]
3f[g]
3f[f]
3f[f,h]
81%
84%
83%
98%
98%
[a]
Unless otherwise noted, the reaction was conducted with
4a (0.2 mmol) using 20.0 mol% catalysts and X+ source
(0.22 mmol) for 10.0 min at 258C. DHQD: dihydroquini-
dine, and DHQ: dihydroquinine.
[b]
[c]
Isolated yield.
The ee values were determined by HPLC, and the config-
uration was assigned by comparison of CD spectra and
X-ray crystal data of derivatives.
Using m-chloroperoxybenzoic acid (0.2 mmol).
At 08C.
To explore the possibility of the proposed intramo-
lecular bisbenzannulated spiroketalization process,
our investigation began with a screening of several or-
ganocatalysts to evaluate their catalytic activities
under the different reaction conditions. The model re-
action of substrate 4a was performed in the presence
of a 20 mol% loading of ligand (Table 1). Besides the
chiral catalysts 3a and 3b with diversely structured
scaffolds, organocatalysts 3c, 3d, 3e and 3f were also
[d]
[e]
[f]
At À208C.
[g]
[h]
At À408C.
Using 0.12 mmol DBDMH.
tested. While the desired product 5a could be ob- values were observed in the reactions (entries 1 and
tained in the presence of 3a or 3b with an amount of 2). In order to improve the yield and enantioselectivi-
m-chloroperoxybenzoic acid, only low yields and ee ty, organocatalysts 3c–3f and N-iodosuccimide (NIS)
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Jijun Xue et al.
The results of experiments under the optimized
conditions that probed the scope of the reaction are
summarized in Scheme 2. The catalytic intramolecular
bisbenzannulated spiroketalization in the presence of
20 mol% 3f with DBDMH was performed in toluene
at À208C. A variety of substrates 4 including those
bearing electron-withdrawing and electron-donating
substituents on the aryl ring were examined. Gratify-
ingly, all of the reactions could provide the excellent
enantioselectivities (93–98% ee). It is noteworthy that
the substituents on ring A or B can significantly influ-
ence yield of the reaction. In general, the results
showed that all reactions with aromatic substrates
proceeded quickly affording the desired products in
yields ranging from 52 to 92%.
The configurations of products were confirmed in
two ways. The first way is the CD spectrum
(Figure 2). The electronic circular dichroisms (ECDs)
Scheme 2. Investigations on the substrate scope. Unless
noted otherwise, the reaction was conducted with 4a
(0.2 mmol) using 20.0 mol% catalysts and X+ source
(0.12 mmol) for 10.0 min at À208C.
as a halogen source were investigated. Further screen-
ing of 3c–3f indicated that (DHQD)2AQN (3f) is the
best catalyst, furnishing the products in 60% yield
and 35% ee (entry 6). Subsequently, a survey of other
solvents was carried out with catalyst 3f (entries 6–9).
These results indicated that a substantial change of
the solvent has a significant effect on the reaction.
Among the solvents tested, toluene appeared to be
the most suitable reaction media in terms of chemical
yield and enantioselectivity. To our delight, the best
result was observed when the reaction was performed
in toluene at À208C by a further optimization of the
reaction temperature (54% yield and 84% ee,
entry 11). In addition, other halogen sources were
also attempted, such as N-bromosuccimide (NBS),
1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (en-
tries 13 and 14). As expected, the N-bromo reagent
gave much better results in terms of yield and stereo-
chemical outcome than the N-iodo reagent, and
DBDMH proved to be the most efficient halogen
source for catalytic intramolecular spiroketalization,
leading to excellent enantioselectivity and good yield
(98% ee and 70%, entry 14).
Figure 2. (a) The calculated CDs of 5a and 5i. (b) The calcu-
lated CD of 5c and experimental CD of 5c.
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Organohalogenite-Catalyzed Spiroketalization
salt intermediate 7, which will play dual roles in the
following transformation. The N-bromo quaternary
ammonium salt 7 not only could promote the enoliza-
tion of substrate 4a through the catalyst bearing terti-
ary amine moiety, but also could serve as an electro-
phile to react with the in situ formed enol 8a, thus
triggering an electrophilic bromo-addition process to
afford bromobenzofuranone 9a. The subsequent intra-
Scheme 3. Characterization of 5j with its derivatives.
of two possible candidate stereoisomers of 5a, 5c and molecular nucleophilic substitution of bromo inter-
5i were calculated (see the Supplorting Information). mediate 9a provides for the release of catalyst 3 to
The results indicated that the R-5a, 5c, and 5i have generate the final product 5a.
similar ECDs by comparison with R-5a CD spectrum
In summary, we have disclosed a new core-struc-
(a, Figure 2, the S-configuration products have the op- ture-motivated design of an intramolecular aromatic
posite curves). From the comparison of positive CEs spiroketalization process to synthesize bisbenzannu-
at 270 nm and 330 nm (b, Figure 2), the results also lated spiroketals with high levels of enantioselectivity
showed that the experimental spectrum of prepared (up to 98% ee) via an organohalogenite catalytic in-
5c could match the calculated ECD curve of S-5c. tramolecular aromatic spiroketalization. This repre-
Therefore, 5c prepared by our method herein, is sentative synthetic example demonstrates the inherent
more likely to have the S-configuration (Figure 2).
synthetic potential of this kind of organohalogenite
All the attempts to obtain the X-ray structures of catalytic strategy for bioactive natural products like
compounds 5 failed, so (2S,3R)-6j was prepared ac- rubromycins and lysidicins, and the total synthesis of
cording to the procedure reported by our group pre- these compounds using this protocol are underway.
viously.[18a] The X-ray structure of (2S,3R)-6j was then
obtained.[18b] The oxidation of (2S,3R)-6j gave (S)-5j
(Scheme 3), which was then compared with 5j pre- Experimental Section
pared from our method. The same specific optical ro-
tations were observed, which indicated that 5j herein General Procedure for Compound 5
should have the S-configuration.
To a solution of compound 4 (0.2 mmol) and catalyst 3f
(0.04 mmol) in toluene (4.0 mL) was added the halogen
In fact, reducing our product 5j with LiAlH4 in
THF can give (2S,3R)-6j, which was characterized by
X-ray crystallography. This also proved that our prod-
uct is (S)-5j. Similarly, 5a has the S-configuration, too.
On the basis of the experimental results described
above and recent studies,[6,14c,15] a possible mechanism
is shown in Scheme 4. The 1,3-dibromo-5,5-dimethyl-
hydantoin reacts with organocatalyst (DHQD)2AQN
to form the chiral N-bromo quaternary ammonium
source (0.12 mmol), the resulting solution was then stirred
at an appropriate temperature. After the starting material
was completely consumed as monitored by TLC, the mix-
ture was filtered to remove the catalyst and the filtrate was
concentrated under vacuum. The crude residue was purified
by flash column chromatography (petroleum ether/EtOAc=
16:1, v/v) to give 5.
Acknowledgements
We are grateful for the financial support provided by Natural
Science Foundation of China (NSFC No. 21372107, 21202072
and 21272099).
References
[1] Y. Hu, X. Wu, S. Gao, S. Yu, Y. Liu, J. Qu, J. Liu, Y.
Liu, Org. Lett. 2006, 8, 2269.
[2] For the isolation of rubromycins: a) H. Brockmann, W.
Lenk, G. Schwantje, A. Zeeck, Chem. Ber. 1969, 102,
126–151; b) H. Brockmann, A. Zeeck, Chem. Ber. 1970,
103, 1709–1726; c) H. Brockmann, W. Lenk, G.
Schwantje, A. Zeeck, Tetrahedron Lett. 1966, 7, 3525–
3530.
[3] a) P. Traxler, H. Fritz, H. Fuhrer, W. J. Richter, J. Anti-
biot. 1980, 33, 967–978; b) C. Puder, S. Loya, A. Hizi,
A. Zeeck, Eur. J. Org. Chem. 2000, 729–735; c) A. A.
Scheme 4. The proposed mechanism.
Adv. Synth. Catal. 2016, 358, 370 – 374
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
373

COMMUNICATIONS
Jijun Xue et al.
Stierle, D. B. Stierle, K. G. Kelly, J. Org. Chem. 2006,
71, 5357–5360; d) M. Brasholz, S. Sçrgel, C. Azap,
H. U. Reibig, Eur. J. Org. Chem. 2007, 3801–3814; e) J.
Sperry, Z. E. Wilson, D. C. K. Rathwell, M. A. Brimble,
Nat. Prod. Rep. 2010, 27, 1117–1137.
[10] For a selected review of organohalo species, see: a) P. J.
Stang, V. V. Zhdankin, Chem. Rev. 1996, 96, 1123–1178;
b) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2002, 102,
2523–2584; c) T. Wirth, (Ed.), Hypervalent Iodine
Chemistry, in: Topics in Current Chemistry, Springer,
Berlin, 2003, vol. 224; d) J. A. Ma, D. Kahard, Chem.
Rev. 2004, 104, 6119–6146; e) V. V. Zhdankin, P. J.
Stang, Chem. Rev. 2008, 108, 5299–5358.
[11] Halogenation: a) M. Oestreich, Angew. Chem. 2005,
117, 2376–2379; Angew. Chem. Int. Ed. 2005, 44, 2324–
2327; b) V. A. Brunet, D. OꢀHagan, Angew. Chem.
2008, 120, 1198–1201; Angew. Chem. Int. Ed. 2008, 47,
1179–1182; c) U. Hennecke, Angew. Chem. 2012, 124,
4608–4610; Angew. Chem. Int. Ed. 2012, 51, 4532–4534.
[12] Oxidation–lactonization: a) T. Dohi, A. Maruyama, N.
Takenaga, K. Senami, Y. Minamitsuji, H. Fujioka, S. B.
Caemmerer, Y. Kita, Angew. Chem. 2008, 120, 3847–
3850; Angew. Chem. Int. Ed. 2008, 47, 3787–3790;
b) M. Uyanik, T. Yasui, K. Ishihara, Angew. Chem.
2010, 122, 2221–2223; Angew. Chem. Int. Ed. 2010, 49,
2175–2177.
[4] For examples of the construction of spiroketals, see:
a) X. Li, A. R. Chianese, T. Vogel, R. H. Crabtree, Org.
Lett. 2005, 7, 5437–5440; b) S. P. Waters, M. W. Fennie,
M. C. Kozlowski, Org. Lett. 2006, 8, 3243–3246; c) C. C.
Lindsey, K. L. Wu, T. R. R. Pettus, Org. Lett. 2006, 8,
2365–2367; d) K. L. Wu, S. Wilkinson, N. O. Reich,
T. R. R. Pettus, Org. Lett. 2007, 9, 5537–5540; e) G. L.
Zhou, J. R. Zhu, Z. X. Xie, Y. Li, Org. Lett. 2008, 10,
721–724; f) M. A. Marsini, Y. Huang, C. C. Lindsey,
K. L. Wu, T. R. R. Pettus, Org. Lett. 2008, 10, 1477–
1480; g) Y. Zhang, J. J. Xue, Z. J. Xin, Z. X. Xie, Y. Li,
Synlett 2008, 940–944; h) J. Barluenga, A. Mendoza, F.
´
Rodríguez, F. J. Fananµs, Angew. Chem. 2009, 121,
1672–1675; Angew. Chem. Int. Ed. 2009, 48, 1644–1647;
i) T. A. Wenderski, M. A. Marsini, T. R. R. Pettus, Org.
Lett. 2011, 13, 118–121; j) Z. Sun, G. A. Winschel, P.
Nagorny, Synlett 2013, 24, 661; k) L. Cala, F. J. FaÇanµs,
F. Rodríguez, Org. Biomol. Chem. 2014, 12, 5324.
[5] For selected examples of the synthesis of natural prod-
ucts, see: a) D. Qin, R. X. Ren, T. Siu, C. Zheng, S. J.
Danishefsky, Angew. Chem. 2001, 113, 4845–4849;
Angew. Chem. Int. Ed. 2001, 40, 4709–4713; b) T. Siu,
D. Qin, S. J. Danishefsky, Angew. Chem. 2001, 113,
4849–4852; Angew. Chem. Int. Ed. 2001, 40, 4713–4716;
c) S. Akai, K. Kakiguchi, Y. Nakamura, I. Kuriwaki, T.
Dohi, S. Harada, O. Kubo, N. Morita, Y. Kita, Angew.
Chem. 2007, 119, 7602–7605; Angew. Chem. Int. Ed.
2007, 46, 7458–7461; d) S. E. Denmark, C. S. Regens, T.
Kobayashi, J. Am. Chem. Soc. 2007, 129, 2774–2774;
e) P. Buchgraber, T. N. Snaddon, C. Wirtz, R. Mynott,
R. Goddard, A. Füsttner, Angew. Chem. 2008, 120,
8578–8582; Angew. Chem. Int. Ed. 2008, 47, 8450–8454;
f) X. Wu, J. Zhou, B. B. Snider, Angew. Chem. 2009,
121, 1309–1312; Angew. Chem. Int. Ed. 2009, 48, 1283–
1286; g) D. C. K. Rathwell, S. H. Yang, K. Y. Tsang,
M. A. Brimble, Angew. Chem. 2009, 121, 8140–8144;
Angew. Chem. Int. Ed. 2009, 48, 7996–8000; h) K. Wu,
E. V. Mercado, T. R. R. Pettus, J. Am. Chem. Soc. 2011,
133, 6114–6117; i) T. Y. Yuen, S. H. Yang, M. A. Brim-
ble, Angew. Chem. 2011, 123, 8500–8503; Angew.
Chem. Int. Ed. 2011, 50, 8350–8353; j) A. N. Lowell,
M. W. Fennie, M. C. Kozlowski, J. Org. Chem. 2011, 76,
6488; k) R. Bandichhor, A. N. Lowell, M. C. Kozlowski,
J. Org. Chem. 2011, 76, 6475.
[13] Catalysis: a) C. M. Starkes, J. Am. Chem. Soc. 1971, 93,
195–199; b) T. Ooi, M. Kameda, K. Maruoka, J. Am.
Chem. Soc. 1999, 121, 6519–6520; c) T. Ooi, M.
Kameda, K. Maruoka, J. Am. Chem. Soc. 2003, 125,
5139–5151.
[14] Halolactonization: a) M. Uyanik, H. Okamoto, T.
Yasui, K. Ishihara, Science 2010, 328, 1376–1379; b) L.
Zhou, C. K. Tan, X. J. Jiang, F. Chen, Y. Y. Yeung, J.
Am. Chem. Soc. 2010, 132, 15474–15476; c) D. C.
Whitehead, R. Yousefi, A. Jaganathan, B. Borhan, J.
Am. Chem. Soc. 2010, 132, 3298–3300; d) G. E. Veitch,
E. N. Jacobsen, Angew. Chem. 2010, 122, 7490–7493;
Angew. Chem. Int. Ed. 2010, 49, 7332–7335; e) G. F.
Chen, S. M. Ma, Angew. Chem. 2010, 122, 8484–8486;
Angew. Chem. Int. Ed. 2010, 49, 8306–8308; f) R. You-
sefi, D. C. Whitehead, J. M. Mueller, R. J. Staples, B.
Borhan, Org. Lett. 2011, 13, 608–611; g) M. Wilking, C.
Muck-Lichtenfeld, C. G. Daniliuc, U. Hennecke, J. Am.
Chem. Soc. 2013, 135, 8133–8136.
[15] Halogenation–semipinacol: 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.
[16] Halocycloetherification: a) S. H. Kang, S. B. Lee, C. M.
Park, J. Am. Chem. Soc. 2003, 125, 15748–15749;
b) D. S. Huang, X. Q. Liu, L. J. Li, Y. D. Cai, W. G. Liu,
Y. A. Shi, J. Am. Chem. Soc. 2013, 135, 8101–8104;
c) A. Sakakura, A. Ukai, K. Ishihara, Nature 2007, 445,
900–903.
[17] a) W. Wei, Y. Wang, J. Yin, J. Xue, Y. Li, Org. Lett.
2012, 14, 1158–1161; b) W. Wei, L. Li, X. Lin, H. Li, J.
Xue, Y. Li, Org. Biomol. Chem. 2012, 10, 3494–3499.
[18] a) T. Tian, L. Q. Li, J. J. Xue, J. Zhang, Y. Li, J. Org.
Chem. 2015, 80, 4189–4200; b) CCDC 1432820 contains
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
[6] I. Coric, B. List, Nature 2012, 483, 315–319.
[7] Z. Sun, G. A. Winschel, A. Borovika, P. Nagorny, J.
Am. Chem. Soc. 2012, 134, 8074–8077.
[8] Z. M. Wang, Z. B. Han, Z. Wang, K. L. Ding, Angew.
Chem. 2012, 124, 960–964; Angew. Chem. Int. Ed. 2012,
51, 936–940.
[9] H. Wu, Y. P. He, L. Z. Gong, Org. Lett. 2013, 15, 460–
463.
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
Crystallographic Data
Centre via
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