Tandem semipinacol-type 1,2-carbon migration/aldol reaction toward the construction of [5-6-7] all-carbon tricyclic core of Calyciphylline A-type alkaloids

Article abstract of DOI:10.1021/ol302386g

A Lewis acid promoted tandem semipinacol-type 1,2-carbon migration/aldol reaction of trimethylsilane-protected vinylogous α-ketols with aldehyde or dimethyl acetals is reported. This reaction provides a direct and rapid way for the construction of 6-substituted spiro[4.5]decanes which extensively exist in Daphniphyllum alkaloids. By the use of this method, further construction of a [5-6-7] all-carbon tricyclic core of Calyciphylline A-type alkaloids was also completed.

Full text of DOI:10.1021/ol302386g

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5114–5117
Tandem Semipinacol-Type 1,2-Carbon
Migration/Aldol Reaction toward the
Construction of [5ꢀ6ꢀ7] All-Carbon Tricyclic
Core of Calyciphylline A‑Type Alkaloids
Ming Yang, Lin Wang, Zheng-He He, Shao-Hua Wang, Shu-Yu Zhang, Yong-Qiang Tu,*
and Fu-Min Zhang*
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn; zhangfm@lzu.edu.cn
Received August 28, 2012
ABSTRACT
A Lewis acid promoted tandem semipinacol-type 1,2-carbon migration/aldol reaction of trimethylsilane-protected vinylogous r-ketols with
aldehyde or dimethyl acetals is reported. This reaction provides a direct and rapid way for the construction of 6-substituted spiro[4.5]decanes
which extensively exist in Daphniphyllum alkaloids. By the use of this method, further construction of a [5ꢀ6ꢀ7] all-carbon tricyclic core of
Calyciphylline A-type alkaloids was also completed.
Calyciphylline A-type alkaloids, as important members
of Daphniphyllum alkaloids, are synthetically challenging
molecules.1,2 Because of their novel structural skeletons,
they have attracted numerous attention from organic
chemists.3 However, there has been no report about their
total synthesis until now. 6-Substituted spiro[4.5]decanes
which contain a spirocyclic all-carbon quaternary center, as
the key structural motifs, commonly exist in Calyciphylline
A-type alkaloids (Figure 1). How to directly and rapidly
construct this unit is the key and challenging step for the
syntheses of these molecules.
Recently, we have reported a chiral amine and Brønsted
acid catalyzed asymmetric semipinacol-type 1,2-carbon
migration4 of vinylogous R-ketols to synthesize chiral spiro-
[4.5]decane-1,7-diketones.5 This protocol offers a feasible
strategy for the construction of 6-substituted spiro[4.5]-
decanes via a tandem manner (Scheme 1). However, efforts
to utilize the enamine intermediate for the expected tandem
(1) Kobayashi, J.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936.
(2) For isolation of Calyciphylline A-type alkaloids, see: (a) Morita,
H.; Kobayashi, J. Org. Lett. 2003, 5, 2895. (b) Takatsu, H.; Morita, H.;
Shen, Y.-C.; Kobayashi, J. Tetrahedron 2004, 60, 6279. (c) Chen, X.;
Zhan, Z.-J.; Yue, J.-M. Helv. Chim. Acta 2005, 88, 854. (d) Yang, S.-P.;
Zhang, H.; Zhang, C.-R.; Cheng, H.-D.; Yue, J.-M. J. Nat. Prod. 2006,
69, 79. (e) Zhang, H.; Yang, S.-P.; Fan, C.-Q.; Ding, J.; Yue, J.-M.
J. Nat. Prod. 2006, 69, 553. (f) Di, Y.-T.; He, H.-P.; Lu, Y.; Yi, P.; Li, L.;
Wu, L.; Hao, X.-J. J. Nat. Prod. 2006, 69, 1074. (g) Li, Z.-Y.; Chen, P.;
Xu, H.-G.; Yang, Y.-M.; Peng, S.-Y.; Zhao, Z.-Z.; Guo, Y.-W. Org.
Lett. 2007, 9, 477. (h) Mu, S.-Z.; Li, C.-S.; He, H.-P.; Di, Y.-T.; Wang,
€
Y.; Wang, Y.-H.; Zhang, Z.; Lu, Y.; Zhang, L.; Hao, X.-J. J. Nat. Prod.
2007, 70, 1628. (i) Li, C.-S.; Di, Y.-T.; Zhang, Q.; Zhang, Y.; Tan, C.-J.;
Hao, X.-J. Helv. Chim. Acta 2009, 92, 653.
(3) For recent synthetic approaches toCalyciphylline A-typealkaloids,
ꢀ
see:(a) Sole, D.; Urbaneja, X.;Bonjoch, J. Org. Lett. 2005, 7, 5461. (b)Xu,
(4) For recent reviews on semipinacol rearrangement, see: (a) Snape,
T. J. Chem. Soc. Rev. 2007, 36, 1823. (b) Song, Z.-L.; Fan, C.-A.; Tu,
Y.-Q. Chem. Rev. 2011, 111, 7523. (c) Wang, B.; Tu, Y. Q. Acc. Chem.
Res. 2011, 44, 1207.
(5) Zhang, E.; Fan, C.-A.; Tu, Y.-Q.; Zhang, F.-M.; Song, Y.-L.
J. Am. Chem. Soc. 2009, 131, 14626.
C.; Liu, Z.; Wang, H.; Zhang, B.; Xiang, Z.; Hao, X.; Wang, D. Z. Org.
Lett. 2011, 13, 1812. (c) Sladojevich, F.; Michaelides, I. N.; Darses, B.;
Ward, J. W.; Dixon, D. J. Org. Lett. 2011, 13, 5132. (d) Darses, B.;
Michaelides, I. N.; Sladojevich, F.; Ward, J. W.; Rzepa, P. R.; Dixon,
D. J. Org. Lett. 2012, 14, 1684. (e) Xu, C.; Wang, L.; Hao, X.; Wang, D. Z.
J. Org. Chem. 2012, 77, 6307.
r
10.1021/ol302386g
Published on Web 09/19/2012
2012 American Chemical Society

aldol reaction failed.6 The reason might be the instability of
the enamine intermediate which can be quickly isomerized
to imine and quenched by water formed at the beginning to
give the diketone product. On the basis of these results,
we proposed that the use of proper Lewis acid would
probably initiate the semipinacol-type 1,2-carbon migra-
tion of trimethylsilane-protected vinylogous R-ketols
to give enolate intermediates which could further under-
go a Lewis acid promoted aldol reaction7 to construct
6-substituted spiro[4.5]decane-1,7-diones (Scheme 1). Here-
in, we present our preliminary results on this protocol and
its application in the synthesis of [5ꢀ6ꢀ7] all-carbon
tricyclic core of Calyciphylline A-type alkaloids.
As shown in Scheme 2, treatment of 2a with 1.2 equiv
of aldehyde 3 and 1.2 equiv of MeAlCl2 in CH2Cl2
at 0 °C, the tandem reaction could be finished within
20 min and provided 6-substituted spiro[4.5]decane-1,
7-diones 4 and 6, hemiketals 5 and 7 in 89% overall
yield [(4þ5):(6þ7) = 4.7:1]. It should be noted that other
Lewis acids, such as TiCl4, Et3Al, Et2AlCl, and TMSOTf,
were not effective for this reaction. The hemiketals 5 and
7 should be derived from corresponding diketones 4 and
6 under the Lewis acid conditions. This was confirmed
by the increased ratio of 5 and 7 upon prolonging the
reaction time. Among the products, the diketone 4 and
hemiketal 5 could not be thoroughly separated through
column chromatography, and the ratio of them was
about 10:1 which was indicated by 1H NMR. However,
the diketone 6 and hemiketal 7 were inseparable. Fur-
thermore, the relative configuration of hydroxyl dike-
tone 4 was verified at a late stage by X-ray structure of
16, of which the 6-H is cis to the 1-carbonyl group and
syn to the hydroxyl group.
Scheme 2. Study on Tandem Semipinacol-Type 1,2-Carbon
Migration/Aldol Reaction of Trimethylsilane-Protected
Vinylogous R-Ketol and Aldehyde
Figure 1. Selected Calyciphylline A-type alkaloids.
Scheme 1. Previous Work and Proposed Tandem
Semipinacol-Type 1,2-Carbon Migration/Aldol Reaction
To prevent the formation of the hemiketals, the alde-
hyde was replaced by dimethyl acetals.8 To our delight, the
tandem reaction could also take place under the standard
procedure, and the results are summarized in Table 1. Very
interestingly, unlike that for compound 4, the 6-H of the
major product 9 is trans tothe 1-carbonyl group and anti to
the methoxyl group, which was confirmed by the X-ray
crystallography analysis of compound 9h (Figure 2).9 This
result indicated that the aldol reaction might go through a
nonchelated transition state with the introduction of acetal
moiety. As shown in Table 1, trimethylsilane-protected
vinylogous R-ketol 2a could react with various dimethyl
acetals giving the corresponding 6-substituted spiro[4.5]-
decane-1,7-diones. Moderate to good yields and diastereo-
selectivities could be obtained. Normally, acetal substrates
with longer chains could give better diastereoselectivities
We first studied our proposed tandem semipinacol-
type 1,2-carbon migration/aldol reaction of trimethylsi-
lane-protected vinylogous R-ketol 2a with aldehyde 3.
(6) Recently, we also reported a one-pot reaction to construct chiral
6-hydroxy spiro[4.5]decane-1,7-diones: Li, B.-S.; Zhang, E.; Zhang,
Q.-W.; Zhang, F.-M.; Tu, Y.-Q.; Cao, X.-P. Chem. Asian J. 2011, 6,
2269.
(8) Trost, B. M.; Chen, D. W. C. J. Am. Chem. Soc. 1996, 118, 12541.
(9) CCDC-897943 for 9h and CCDC-852779 for 16 contain the 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.
(7) Mahrwald, R. Chem. Rev. 1999, 99, 1095.
Org. Lett., Vol. 14, No. 19, 2012
5115

than the shorter ones. Acetals derived from propargyl or
aromatic aldehydes afforded better yields than those from
aliphatic aldehydes (Table 1, entries 4, 8, and 9 compared
with entries 1ꢀ3 and 5ꢀ7). The results might be due to the
elimination of methanol by dimethyl acetals of aliphatic
aldehydes which could quench the enolate intermediate.10
In addition, acetals bearing a silyl ether could also parti-
cipate well in this tandem reaction with good yields
(Table 1, entries 9 and 11). Also, geminal dimethyl sub-
stituents at the C-5 position on the cyclohexanone of
trimethylsilane-protected vinylogous R-ketol showed no
retardation of this tandem reaction (Table 1, entries 10
and 11). However, efforts to construct two continuous all-
carbon quaternary centers by this tandem reaction failed
(Table 1, entry 12). Although we mainly focused on the
syntheses of 6-substituted spiro[4.5]decanes, we had also
tried to synthesize otherringsystems. Unfortunately, when
we changed the cyclobutanol to cyclopentanol or cyclo-
hexanol, the semipinacol-type 1,2-carbon migration could
not occur. When the substrate with the cycloheptyl instead
of the cyclohexyl core ring was subjected to the reaction,
the major product was the spiro[4.6]undecane-1,7-dione.
At last, it should be noted that for all products in Table 1,
the major isomers of 9a, 9e, and 9gꢀk could be easily
separated by silica gel column chromatography from the
remaining isomers; the diastereomers of 9bꢀc and 9f could
be partially separated; however, the diastereomers of 9d
were inseparable.
Figure 2. X-ray structure of 9h.
After successful development of the tandem semipina-
col-type 1,2-carbon migration/aldol reaction, we applied
it to the synthesis the [5ꢀ6ꢀ7] all-carbon tricyclic core of
Calycphyilline A-type alkaloids from the corresponding
6-substituted spiro[4.5]decane-1,7-diones. Compound 4
(mixed with 5) of the first studied tandem reaction was
chosen as the starting material (Scheme 3). Selective reduc-
tion of the cyclohexanone moiety of the mixture with
NaBH(OAc)3 in acetic acid at room temperature11 fol-
lowed by protection of the 1,3-diol using 2,2-dimethox-
ypropane provided ketones 10 in 41% yield and 11 in 17%
yield over two steps. Ketones 10 and 11 were then con-
verted into enol triflates 12 and 13 by quenching the
corresponding potassium enolates with PhNTf2 in 86%
and 83% yield, respectively. Treatment of 12 or 13 with
Pd(OAc)2 under the reductive condition afforded [5ꢀ6ꢀ7]
tricyclic product 14 in 90% yield or 15 in 86% yield
successfully.12 The relative stereochemistry of 14 was con-
firmed by X-ray diffraction of crystalline diol 16 obtained
by desilylation and deprotection of 14 (Scheme 4).9
Table 1. Tandem Semipinacol-Type 1,2-Carbon Migration/Al-
dol Reaction of Trimethylsilane-Protected Vinylogous R-Ketol
and Dimethyl Acetalsa
Scheme 3. Synthesis of the [5ꢀ6ꢀ7] All-Carbon Tricyclic Core
of Calyciphylline A-Type Alkaloids
Inconclusion, we havedevelopeda tandem semipinacol-
type 1,2-carbon migration/aldol reaction of trimethylsilane-
protected vinylogous R-ketols with aldehyde or dimethyl
a For experimental details, see the Supporting Information. b Combined
yield of isolated product after column chromatography. c The dr value
was determined by 1H NMR.
(11) Saksena, A. K.; Mangiaracina, P. Tetrahedron Lett. 1983, 24,
273.
(12) Burns, B.; Grigg, R.; Sridharan, V.; Worakun, T. Tetrahedron
Lett. 1988, 29, 4325.
(10) For the elimination of methanol by dimethyl acetals, see:
Gassman, P. G.; Burns, S. J.; Pfister, K. B. J. Org. Chem. 1993, 58, 1449.
5116
Org. Lett., Vol. 14, No. 19, 2012

the first time. It demonstrates that the newly developed
tandem reaction is a potentially useful method in the
total synthesis of polycyclic nature products which contain
the structural motif of 6-substituted spiro[4.5]decane.
Further studies toward a total synthesis of Calyciphylline
A-type alkaloids using this protocol are underway in our
laboratory.
Scheme 4. Relative Stereochemistry of 16
Acknowledgment. This work was supported by NSFC
(Grant Nos. 21072085, 20921120404, 21102061, 20972059,
21202073, 21290180 and 21272097), the National Basic
Research Program of China (“973” Program, Grant No.
2010CB833203), Key National S&T Program “Major New
Drug Development”of Ministry of Health of China
(2012ZX09201101-003), and “111” Program of MOE. We
thank Prof. Yuan-Jiang Pan of Zhejiang University for high-
resolution mass spectrometry analysis of compounds 12ꢀ15.
Supporting Information Available. NMR spectra of
products and X-ray crystallographic data for 9h and 16.
This material is available free of charge via the Internet at
http://pubs.acs.org.
acetals. 6-Substituted spiro[4.5]decane-1,7-diones could be
easily and rapidly synthesized by this protocol. Subse-
quently, the [5ꢀ6ꢀ7] all-carbon tricyclic core of Calyci-
phylline A-type alkaloids has been rapidly constructed for
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
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