Synthesis of the 6,6,5,7-tetracyclic core of daphnilongeranin B

Article abstract of DOI:10.1039/c3cc47873d

An efficient approach toward the synthesis of the 6,6,5,7-tetracyclic core of the daphnilongeranin B, a Daphniphyllum alkaloid, is reported. The bridged 6,6-bicyclic system was constructed using a gold(I) catalysed Conia-ene reaction, while the 5- and 7-membered rings were assembled by two diastereoselective Michael addition reactions, respectively. the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc47873d

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Synthesis of the 6,6,5,7-tetracyclic core of
daphnilongeranin B†
Cite this: Chem. Commun., 2014,
50, 5294
Xiaochun Xiong,‡abc Yong Li,‡b Zhaoyong Lu,b Ming Wan,b Jun Deng,b
Shuhang Wu,b Huawu Shao*a and Ang Li*b
Received 14th October 2013,
Accepted 11th December 2013
DOI: 10.1039/c3cc47873d
www.rsc.org/chemcomm
An efficient approach toward the synthesis of the 6,6,5,7-tetracyclic core
of the daphnilongeranin B, a Daphniphyllum alkaloid, is reported. The
bridged 6,6-bicyclic system was constructed using a gold(I) catalysed
Conia-ene reaction, while the 5- and 7-membered rings were assembled
by two diastereoselective Michael addition reactions, respectively.
Daphniphyllum alkaloids, isolated from the evergreen plant genus
Daphniphyllum, comprise a large (>250 members) and rapidly
growing family of polycyclic natural products.1 Consistent with
the fact the plant species has long been used in Chinese herbal
medicine,2 these compounds exhibit a variety of biological activ-
ities.3 From a chemical synthesis perspective, this collection of
molecules has attracted remarkable attention in the past deca-
des.1a,4–6 Notably, Heathcock and co-workers reported an excep-
tionally elegant synthesis of a Daphniphyllum alkaloid called methyl
homosecodaphniphyllate,5c which not only convincingly supports
their basic hypothesis for Daphniphyllum alkaloid biosynthesis,4
but also sets a landmark example for an ‘‘ideal synthesis’’.7
Among the Daphniphyllum alkaloids, the calyciphylline A-subfamily
members (e.g. 1–5, Fig. 1) containing a common 6,6,5,7-tetracyclic
Fig. 1 Structures of daphnilongeranin B and other representative molecules
of calyciphylline A-type Daphniphyllum alkaloids.
motif (Fig. 1) have been of increasing interest from a synthesis construct the functionalized cycloheptene moiety and a Claisen
perspective in recent years;6f–m daphnilongeranin B (2), isolated by rearrangement to establish the stereochemistry of the quaternary
Yue et al. from Daphniphyllum longeracemosum,8 has been a repre- C8.6g Liang and Yao exploited the functionalities and chirality of
(S)-carvone to assemble the 6,6,5-tricyclic moiety efficiently.6m Most
sentative target molecule. Wang and co-workers reported a creative
strategy leading to the syntheses of the 6,5,7-tricyclic6f and 6,6,5,7- recently, we accomplished the first total synthesis of daphenylline (5)
tetracyclic6j cores of 2. This work took advantage of a [2+2] photo- with a unique arene-containing structure.5j On the basis of our work
cycloaddition followed by a Grob fragmentation for the 7-membered on 5, we report here the synthesis of the 6,6,5,7-tetracyclic core of
ring formation. Dixon and co-workers disclosed a concise synthesis of daphnilongeranin B (2).
the 6,5,7-tricyclic system, featuring a ring closing metathesis to
We began our synthesis (Scheme 1) with readily available
building block (Æ)-6.9 Enone sulfonamide 7 was obtained through
Mitsunobu reaction of 6 and o-nosylamine 8.5j 7 was then activated
by forming the corresponding silyl enol ether 9, which served as
the substrate for the devised Conia-ene reaction. After a series of
optimizations, we were delighted to find that the stable and
commercially available [Au(PPh3)]NTf2 displayed better catalytic
properties than the in situ mixture of [Au(PPh3)]Cl and AgOTf used
previously.10 10 mol% of this catalyst effected the cyclization at
22 1C, to afford the desired product 10 in 76% yield. This result
a Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy
of Sciences, Chengdu 610041, China. E-mail: shaohw@cib.ac.cn
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China. E-mail: ali@sioc.ac.cn
c University of Chinese Academy of Sciences, Beijing 100049, China
† Electronic supplementary information (ESI) available. CCDC 963869. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc47873d
‡ These authors contributed equally.
5294 | Chem. Commun., 2014, 50, 5294--5297
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Scheme 1 Synthesis of the 6,6,5,5-tetracyclic core of daphnilongeranin B. Reagents and conditions: (a) dimethyl malonate (1.2 eq.), NaH (1.2 eq.), THF, 60 1C, 4 h;
(b) aq. LiOH (1.1 eq., 1.0 M), MeOH, 22 1C, 12 h, 42% (2 steps); (c) 8 (1.1 eq.), PPh3 (1.1 eq.), DIAD (1.1 eq.), THF, 0 1C, 10 min, 84%; (d) TBDPSOTf (1.1 eq.), 2,6-lutidine
(1.2 eq.), CH2Cl2, À78 1C, 10 min; (e) Au(PPh3)NTf2 (0.1 eq.), toluene–MeOH (10 : 1), 22 1C, 76% (2 steps); (f) p-toluenethiol (1.5 eq.), K2CO3 (2.0 eq.), DMF, 1 h, 22 1C; (g) 11
(1.2 eq.), HOBt (2.0 eq.), EDCÁHCl (2.0 eq.), Et3N (3.0 eq.), CH2Cl2, 22 1C, 12 h, 78% (2 steps); (h) K2CO3 (5.0 eq.), MeCN, 100 1C, 3 h, 82%; (i) 15 (2.0 eq.), DBU (5.0 eq.),
CH2Cl2, 55 1C, 6 h, 64%; (j) HFÁpy–THF (1 : 5), 0 1C, 10 min; (k) DMP (1.5 eq.), CH2Cl2, 22 1C, 10 min, 81% (2 steps); (l) Et3N (10.0 eq.), CH2Cl2, 5 h, 60 1C; then t-BuOK
(2.0 eq.), t-BuOH, 0 1C, 10 min, 45%; (m) LiAlH(Ot-Bu)3 (1.5 eq.), CH2Cl2, À40 1C, 15 min; (n) TBSOTf (2.0 eq.), Et3N (5.0 eq.), CH2Cl2, À78 1C, 5 min, 67% (2 steps).
excludes the involvement of Ag(I) in the Conia-ene reaction. Nosyl attributable to the severe strain of the desired fused ring
deprotection of 10 with p-toluenethiol/K2CO3 furnished the corres- system. Finally, a second Michael addition reaction solved the
ponding secondary amine, which, without purification, underwent ring closure problem to an acceptable extent, as shown in
an amide coupling with carboxylic acid 11 under standard Scheme 1. Strong bases such as t-BuOK and LDA resulted in
EDCÁHCl–HOBt conditions. It should be noted that 11 was pre- severe decomposition of the substrate. Fortunately, heating 17
pared from known iodide 1211 through a sequence of malonate in the presence of a large excess of Et3N (essentially as a
alkylation and partial hydrolysis (Scheme 1). The resulting co-solvent) proved to be optimal to render tetracyclic
amide 13 was subjected to basic conditions (K2CO3 in MeCN) compound 18, together with a small portion of its C10 epimer,
at elevated temperature for an intramolecular Michael which was readily converted back to 18 by treating with t-BuOK
addition,5j,6g,h furnishing a ca. 8 : 1 C6 diastereomeric mixture for short reaction times. Thus, 18 was obtained in 45% overall
in favor of compound 14 (82% isolated yield).
yield from 17. We then derived 18 into the corresponding
The next 7-membered ring closure proved to be the most diacetate 19 [LiAlH(Ot-Bu)3 reduction followed by acetylation
challenging transformation in the whole route. 14 was first with Ac2O at 40 1C] for X-ray crystallographic analysis (Fig. 2),12
converted to the corresponding aldehydes and halides via the which secured the connectivity of 18, as well as all its relative
intermediacy of the primary alcohol. However, the seemingly stereochemistry except for C8. In addition, the NOE studies on
straightforward intramolecular aldol or alkylation reaction 18 indicated a strong correlation between H-8 and H-3b.
failed to give any desired cyclization product, presumably due
to the steric and kinetic reasons. Thus, we decided to close
the ring in a sterically more friendly manner. An exo-cyclic
methylene was then introduced at C8 of 14 by treating with a
powerful electrophile, Eschenmoser’s salt 15, in the presence of
DBU at 55 1C. Desilylation of the resulting compound 16
followed by oxidation with Dess–Martin periodinane provided
aldehyde 17. The 1,3-dipolar cycloaddition reactions were
examined with the nitrone and nitrile oxide substrates
prepared from 17 but turned to be fruitless, which may be
Fig. 2 X-ray derived ORTEP of compound 19.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 5294--5297 | 5295

View Article Online
ChemComm
Communication
manipulation of the natural product. On the basis of these
endeavors, the total synthesis of daphnilongeranin B, as well as
the related calyciphylline A-subfamily members, is currently
underway in our laboratories.
We thank Prof. Xiao-Jiang Hao, Jian-Min Yue, and Biao Yu
for helpful discussions. Financial support was provided by the
Ministry of Science & Technology (2013CB836900) and the
National Natural Science Foundation of China (21290180,
21172235, and 21222202).
Notes and references
1 (a) J. Kobayashi and T. Kubota, Nat. Prod. Rep., 2009, 26, 936; (b) S.-P.
Yang and J.-M. Yue, Acta Pharmacol. Sin., 2012, 33, 1147.
2 Editorial Committee of the Administration Bureau of Traditional
Chinese Medicine in Chinese Materia in Zhonghua Bencao, Shanghai
Science & Technology Press, Shanghai, China, 1999, p. 865.
3 The biological activities of selected Daphniphyllum alkaloids:
(a) J. Kobayashi, Y. Inaba, M. Shiro, N. Yoshida and H. Morita,
J. Am. Chem. Soc., 2001, 123, 11402; (b) H. Morita, H. Takatsu,
Y.-C. Shen and J. Kobayashi, Tetrahedron Lett., 2004, 45, 901;
(c) H. Zhang, S.-P. Yang, C.-Q. Fan, J. Ding and J.-M. Yue, J. Nat.
Prod., 2006, 69, 553; (d) H. Morita, N. Ishioka, H. Takatsu,
T. Shinzato, Y. Obara, N. Nakahata and J. Kobayashi, Org. Lett.,
2005, 7, 459; (e) Y. Matsuno, M. Okamoto, Y. Hirasawa, N. Kawahara,
Y. Goda, M. Shiro and H. Morita, J. Nat. Prod., 2007, 70, 1516.
4 (a) R. B. Ruggeri and C. H. Heathcock, Pure Appl. Chem., 1989,
61, 289; (b) C. H. Heathcock, Angew. Chem., Int. Ed. Engl., 1992,
31, 665; (c) C. H. Heathcock, Proc. Natl. Acad. Sci. U. S. A., 1996,
93, 14323; (d) E. C. Cherney and P. S. Baran, Isr. J. Chem., 2011,
51, 391.
5 The total syntheses of Daphniphyllum alkaloids: (a) C. H. Heathcock,
S. K. Davidsen, S. Mills and M. A. Sanner, J. Am. Chem. Soc., 1986,
108, 5650; (b) R. B. Ruggeri, M. M. Hansen and C. H. Heathcock,
J. Am. Chem. Soc., 1988, 110, 8734; (c) S. Piettre and C. H. Heathcock,
Science, 1990, 248, 1532; (d) R. B. Ruggeri and C. H. Heathcock,
J. Org. Chem., 1990, 55, 3714; (e) C. H. Heathcock, R. B. Ruggeri and
K. F. McClure, J. Org. Chem., 1992, 57, 2585; ( f ) C. H. Heathcock,
J. A. Stafford and D. L. Clark, J. Org. Chem., 1992, 57, 2575;
(g) J. A. Stafford and C. H. Heathcock, J. Org. Chem., 1990,
55, 5433; (h) C. H. Heathcock, J. C. Kath and R. B. Ruggeri, J. Org.
Chem., 1995, 60, 1120; (i) M. E. Weiss and E. M. Carreira, Angew.
Chem., Int. Ed., 2011, 50, 11501; ( j) Z. Lu, Y. Li, J. Deng and A. Li,
Nat. Chem., 2013, 5, 679; (k) A. Shvartsbart and A. B. Smith, J. Am.
Chem. Soc., DOI: 10.1021/ja411539w.
Scheme 2 Functionalization of the tetracyclic core of daphnilongeranin B.
Reagents and conditions: (a) Crabtree’s cat. (0.2 eq.), H2 (balloon), CH2Cl2,
22 1C, 20 min, 82%; (b) HFÁpy–THF (1 : 4), 0 1C, 5 min; (c) MeOTf (10.0 eq.), 2,6-
di-tert-butylpyridine (20.0 eq.), 22 1C, 20 min; (d) LiClÁH2O (20.0 equiv.), DMSO,
170 1C, 5 h, 42% (3 steps); (e) allyl iodide (3.0 eq.), KHMDS (2.0 eq.), HMPA–THF
(1 : 10), À78 1C - 0 1C, 10 min; (f) mesitylene, 170 1C, 4 h, 64% (2 steps).
Reduction of 18 with LiAlH(Ot-Bu)3 followed by silylation
furnished compound 20.
We then functionalized this tetracyclic intermediate 20, as shown
in Scheme 2. Hydrogenation with Crabtree’s catalyst gave the desired
stereochemistry at C18, while Pd/C led to the opposite epimer
exclusively. These results were verified by NOE studies and consistent
with our observations in the daphenylline synthesis.5j Compound 21
and its desilylated analogue were found to be incompatible with the
Krapcho decarboxylation conditions and underwent skeletal decom-
position. Thus, the O-protecting group was switched to methyl, and
the subsequent demethoxycarbonylation occurred smoothly at
170 1C to furnish compound 22 in 42% yield for the three steps.5j,6g
The stereochemistry of C6 was confirmed by NOE studies (H6 and
H4, H6 and H21, respectively). Because ketone and olefin function-
alities are considerably stable under the Krapcho conditions as
Dixon et al.6g and we found,5j the removal of the methoxy-
carbonyl group should be planned at the very end of the
daphnilongeranin B synthesis, to avoid the incompatibility
problem of the protecting groups. Inspired by Dixon’s work,6g
we also installed the quaternary C8 using a Claisen rearrange-
ment strategy. Treatment of 20 with KHMDS and allyl iodide
gave the corresponding O-allylated compound as the single
detectable product, presumably due to the steric hindrance of
the ketone enolate. This allyl ether underwent a thermal
Claisen rearrangement to afford the C-allylated compound 23
in 64% yield for the two steps. The relative stereochemistry of
the quaternary C8 was determined by NOE studies (H13 and
H21), which is consistent with Dixon’s observations.6g
6 Selected recent synthetic approaches that are not covered in ref. 1a:
(a) S. Ikeda, M. Shibuya, N. Kanoh and Y. Iwabuchi, Org. Lett., 2009,
11, 1833; (b) T. B. Dunn, J. M. Ellis, C. C. Kofink, J. R. Manning and
L. E. Overman, Org. Lett., 2009, 11, 5658; (c) I. Coldham,
A. J. M. Burrell, H. D. S. Guerrand and N. Oram, Org. Lett., 2011,
´
´
13, 1267; (d) G. Belanger, J. Boudreault and F. Levesque, Org. Lett.,
2011, 13, 6204; (e) I. Coldham, L. Watson, H. Adams and
N. G. Martin, J. Org. Chem., 2011, 76, 2360; ( f ) C. Xu, Z. Liu,
H.-F. Wang, B. Zhang, Z. Xiang, X.-J. Hao and D. Z.-G. Wang, Org.
Lett., 2011, 13, 1812; (g) F. Sladojevich, I. N. Michaelides, B. Darses,
J. W. Ward and D. J. Dixon, Org. Lett., 2011, 13, 5132; (h) C. Kourra,
F. Klotter, F. Sladojevich and D. J. Dixon, Org. Lett., 2012, 14,
1016–1019; (i) B. Darses, I. N. Michaelides, F. Sladojevich,
J. W. Ward, P. R. Rzepa and D. J. Dixon, Org. Lett., 2012, 14, 1684;
( j) C. Xu, L. Wang, X.-J. Hao and D. Z.-G. Wang, J. Org. Chem., 2012,
77, 6307; (k) B.-W. Fang, H.-J. Zheng, C.-G. Zhao, P. Jing, H.-L. Li,
X.-G. Xie and X.-G. She, J. Org. Chem., 2012, 77, 8367; (l) M. Yang,
L. Wang, Z.-H. He, S.-H. Wang, S.-Y. Zhang, Y.-Q. Tu and
F.-M. Zhang, Org. Lett., 2012, 14, 5114; (m) Y.-M. Yao and
G.-X. Liang, Org. Lett., 2012, 14, 5499; (n) S. Hanessian, S. Dorich
and H. Menz, Org. Lett., 2013, 15, 4134.
In summary, we have developed an efficient synthesis of the
6,6,5,7-tetracyclic system of daphnilongeranin B, a Daphniphyllum
alkaloid. A gold(I) catalysed Conia-ene reaction and two diastereo-
selective Michael addition reactions played the key roles in the
construction of the carbon skeleton. Functionalization studies on
compound 20 provide considerable information for the late stage
7 T. Gaich and P. S. Baran, J. Org. Chem., 2010, 75, 4657.
8 S.-P. Yang, H. Zhang, C.-R. Zhang, H.-D. Cheng and J.-M. Yue, J. Nat.
Prod., 2006, 69, 79.
9 S. A. Snyder, D. A. Wespe and J. M. von Hof, J. Am. Chem. Soc., 2011,
133, 8850.
5296 | Chem. Commun., 2014, 50, 5294--5297
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
10 (a) S. T. Staben, J. J. Kennedy-Smith, D. Huang, B. K. Corkey,
R. L. LaLonde and F. D. Toste, Angew. Chem., Int. Ed., 2006,
(d) N. Huwyler and E. M. Carreira, Angew. Chem., Int. Ed., 2012,
51, 13066.
45, 5991. The applications of this methodology to natural product 11 J.-E. Nystroem, T. D. McCanna, P. Helquist and R. Amouroux,
synthesis: (b) X. Linghu, J. J. Kennedy-Smith and F. D. Toste, Angew. Synthesis, 1988, 56.
Chem., Int. Ed., 2007, 46, 7671; (c) K. C. Nicolaou, G. S. Tria, 12 CCDC 963869 contains the supplementary crystallographic data of
D. J. Edmonds and M. Kar, J. Am. Chem. Soc., 2009, 131, 15909;
compound 19.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 5294--5297 | 5297