Synthetic studies towards daphniyunnine B: Construction of AC bicyclic skeleton with two vicinal all carbon quaternary stereocenters

Article abstract of DOI:10.1016/j.cclet.2019.06.049

The AC bicyclic skeleton of daphniyunnine B with the required 3 stereocenters (C4, C5 and C8) was accomplished in a concise route which featured two Claisen-type rearrangement reactions to construct the required vicinal all carbon quaternary stereocenters

Full text of DOI:10.1016/j.cclet.2019.06.049

Accepted Manuscript
Title: Synthetic studies towards daphniyunnine B:
Construction of AC bicyclic skeleton with two vicinal all
carbon quaternary stereocenters
Authors: Haiyu Sun, Guangmiao Wu, Xingang Xie
PII:
DOI:
Reference:
S1001-8417(19)30379-1
https://doi.org/10.1016/j.cclet.2019.06.049
CCLET 5080
To appear in:
Chinese Chemical Letters
Accepted date:
26 June 2019
Please cite this article as: Sun H, Wu G, Xie X, Synthetic studies towards
daphniyunnine B: Construction of AC bicyclic skeleton with two vicinal
all carbon quaternary stereocenters, Chinese Chemical Letters (2019),
https://doi.org/10.1016/j.cclet.2019.06.049
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Communication
Synthetic studies towards daphniyunnine B: Construction of AC bicyclic skeleton with
two vicinal all carbon quaternary stereocenters
Haiyu Sun, Guangmiao Wu, Xingang Xie 
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
ARTICLE INFO
ABSTRACT
The AC bicyclic skeleton of daphniyunnine B with the required 3 stereocenters (C4, C5
and C8) was accomplished in a concise route which featured two Claisen-type rearrangement
reactions to construct the required vicinal all carbon quaternary stereocenters (C5 and C8)
and an intramolecular iodo-cyclization reaction to assemble the cis-confused bicyclic lactam.
Article history:
Received 19 June 2019
Received in revised form 26 June 2019
Accepted 26 June 2019
Available online
Keywords:
Daphniyunnine B
Vicinal quaternary stereocenters
Claisen rearrangment
Intramolecular iodo-amidation reaction
Daphniphyllum alkaloids are a class of triterpene alkaloids with complex polycyclic skeletons and interesting bioactivities. Up to
now more than 320 members have been isolated and characterized from nature. According to their polycyclic skeletons,
daphniphyllum alkaloids can be divided into more than 20 subgroup and calyciphylline A type may be the most complex one [1]. As
shown in Fig. 1, calyciphylline A type daphniphyllum alkaloids share a unique compact 6,6,5,7,5-pentacyclic skeleton with 5-8 chiral
centers among which two are challenging vicinal all carbon quaternary stereocenters [2]. They have stimulated continuous interest in
the synthetic community and several elegant total syntheses have been reported [3,4]. Li and coworkers disclosed the first total
synthesis of daphenylline in 2013. In their elegant synthetic work, a gold catalyzed alkyne cyclization followed by an intramolecular
Michael addition process was used to construct the bridged 6,6,5-tricyclic motif and a photo induced olefin isomerization/6π
electrocyclization cascade followed by an oxidative aromatization process was utilized to construct the unique poly-substituted
phenyl ring [4a]. And based on the optimized route to prepare the common 6,6,5,7- tetracyclic intermediate in large scale, they
accomplished the total syntheses of several other members of calyciphylline A type alkaloids including longeracinphyllin A [4c],
daphnipaxianine A, himalenine D [4f], hybridaphniphylline B, daphnilongeranin B, daphniyunnine E and dehydrodaphnilongeranin B
[4g] in the following years. Yokoshima and Fukuyama group took advantage of the characteristic conformations of 5,6,7-tricyclic
intermediates to assemble the essential chiral side chain and they also accomplished the total synthesis of daphenylline [4b]. Based on
a novel catalytic, enantioselective prototropic shift/furan Diels−Alder (IMDAF) cascade reaction to construct the 5,6,7-tricyclic core,
Paton and Dixon group reported an elegant total synthesis of (-)-himalensine A [4d]. Zhai and co-workers completed the first total
synthesis of (-)-daphnilongeranin B and a bioinspired total synthesis of (-)-daphenylline in which an intermolecular Lu’s [3+2]
cycloaddition reaction was employed to construct the challenging spiral cyclic system [4e]. Qiu group accomplished a 19-steps
synthesis of daphenylline enabled by a stereoselective Mg(ClO4)2-catalyzed intramolecular amide addition cyclization and an
intramolecular Diels–Alder reaction to construct its 6,6,5,7-tetracyclic core architecture [4h]. Xu and coworkers disclosed a 14-steps
total synthesis of (-)-himalensine A in which an intramolecular Heck reaction was used to construct the challenging 2-
azabicyclo[3.3.1]nonane motif [4i]. Gao et al. developed a unified strategy to construct the 6,6,5,7-tetracyclic core framework of
calyciphylline A alkaloids which involved a Pd-catalyzed enolate alkenylation and a ring closing metathesis (RCM) reaction and they
also completed the total synthesis of himalensine A [4j]. So it is no doubt that calyciphylline A type daphniphyllum alkaloids have
served and continues to be a good platform to develop and test new synthetic methods and strategies. Inspired by all the above elegant
synthetic works and continuing with our long-term research interest in synthesis of bioactive natural products [5], we recently
initiated a synthetic program towards daphniyunnine B (Fig. 1), a representive member of calyciphylline A type of daphniphyllum
alkaloids [6].
Herein, we reported a concise synthesis of its AC bicyclic skeleton with the required 3 stereocenters (C4, C5, C8) which featured
two Claisen-type rearrangement reactions to construct the required vicinal all carbon quaternary stereocenters and an intramolecular
iodo-cyclization reaction to assemble the cis-confused bicyclic lactam.
———
 Corresponding author.
E-mail address: xiexg@lzu.edu.cn

Fig. 1. Structures of calyciphylline A type daphniphyllum alkaloids.
In our synthetic plan, daphniyunnine B could be obtained from tricyclic ketone 1 by two lateral cyclization reactions and several
oxidation state adjustment manipulations (Scheme 1). As for compound 1, it could be approached via an intramolecular α-alkylation
of amide 2. The C-8 quaternary center of 2 was envisioned to be assembled by a Claisen rearrangement reaction of O-allylation
product of 1, 3-diketone 3 which was expected to be obtained from bicyclic lactam 4 via an aldol coupling reaction.
Scheme 1. Retrosynthetic analysis.
Our synthesis started with acid-promoted Johnson-Claisen rearrangement of the known cyclohexenol (±)-5. As Scheme 2 depicted,
the three-step process (rearrangement, basic hydrolysis and amidation) afforded primary amide (±)-6 in 43% overall yields. The
above three steps could be performed on 10 gram scale and only one column chromatography purification was needed. Then an
intramolecular iodo-cyclization under Levorse’s conditions [7] followed by a DBU-promoted elimination reaction smoothly gave
bicyclic lactam (±)-7 in 65% overall yields on 5 gram scale. N-Protection afforded compound (±)-8 in 90% yield which NOE
experiment further confirmed the cis-configuration of fused bicyclic lactam (see Supporting information for details). Subsequent
SeO2-assisted allylic oxidation and Swern oxidation of the obtained diastereomeric secondary alcohols gave the key bicyclic lactam
(±)-4 in high yield.
Scheme 2. Preparation of bicyclic lactam 4.
With the key bicyclic lactam (±)-4 in hand, we turned our attention to the assembling of the C-8 quaternary stereocenter (Scheme
3). A classic aldol reaction was utilized to combine (±)-4 and aldehyde 9. The obtained β-hydroxyl ketone (±)-10 was further
transformed into more active 1,3-diketone (±)-11 (existed as a mixture of (±)-11 and its enolization isomer (±)-12) in 80% yield. Then
compounds (±)-11 and (±)-12 were submitted to an allylation reaction to give a mixture of O-alkylation product (±)-13 and C-
alkylation product (±)-14 in 2.7:1 ratio and 95% total yields which could be easily seperated by column chromotography on silica gel.
To our delight, the relative stereochemistry between C5 and C8 of the minor product (±)-14 was determined to be the required one by
a comprehensive NOE experiment (see Supporting information for details). And the majar product 13 could also be transformed into
C-alkylation products easily via a heat-promoted Claisen rearrangement reaction affording (±)-14 in 70% yield.

Scheme 3. Synthesis of bicyclic compound 14.
In summary, the compact AC bicyclic skeleton of daphniyunnine B with the required three stereocenters has been
accomplished in 12 steps from known cyclohexenol (±)-5. Our synthesis featured two highly effective Claisen-type
rearrangement reactions to assemble the requisite two vicinal all carbon quaternary stereocenters (C5 and C8) and an
intramolecular iodo-cyclization reaction to assemble the cis-confused bicyclic lactam. Further synthetic works towards
daphniyunine B is undertook in this laboratory now and will be reported in due course.
Acknowledgment
We wish to thank the generous financial support from the National Natural Science Foundation of China (Nos. 21102062, 21472079).
References
[1] (a) J. Kobayashi, T. Kubota, Nat. Prod. Rep. 26 (2009) 936−962;
(b) H.F. Wu, X.P. Zhang, L.S. Ding, et al., Planta Med. 79 (2013) 1589−1598l;
(C) A.K. Chattopadhyay, S. Hanessian, Chem. Rev. 117 (2017) 4104−4146.
[2] B. Kang, P. Jakubec, D. Dixon, J. Nat. Prod. Rep. 31 (2014) 550−562.
[3] (a) D. Sole, X. Urbaneja, J. Bonjoch, Org. Lett. 7 (2005) 5461−5464;
(b) F. Diaba, A. Martinez-Laporta, G. Coussanes, I. Fernandez, J. Bonjoch, Tetrahedron 71 (2015) 3642−3651;
(c) G. Coussanes, J. Bonjoch, Org. Lett. 19 (2017) 878−881;
(d) F. Sladojevich, I.N. Michaelides, D. Benjamin, J.W. Ward, D.J. Dixon, Org. Lett. 13 (2011) 5132−5135;
(e) C. Xu, L. Wang, X. Hao, D.Z.G. Wang, J. Org. Chem. 77 (2012) 6307−6313;
(f) V. Wang, C. Xu, L. Chen, X. Hao, D.Z.G. Wang, Org. Lett. 16 (2014) 1076−1079;
(g) M. Yang, L. Wang, Z.H. He, et al., Org. Lett. 14 (2012) 5114−5117;
(h) Y. Yao, G. Liang, Org. Lett. 14 (2012) 5499−5501;
(i) A.A. Ibrahim, A.N. Golonka, A.M. Lopez, J.L. Stockdill, Org. Lett. 16 (2014) 1072−1075;
(j) D. Ma, H. Cheng, C. Huang, L. Xu, Tetrahedron Lett. 56 (2015) 2492−2495;
(k) H. Shao, W. Bao, Z.R. Jing, et al., Org. Lett. 19 (2017) 4648−4651.
[4] (a) Z.Y. Lu, Y. Li, J. Deng, A. Li, Nat. Chem. 5 (2013) 679−684;
(b) R. Yamada, Y. Adachi, S. Yokoshima, T. Fukuyama, Angew. Chem. Int. Ed. 55 (2016) 6067−6070;
(c) J. Li, W.H. Zhang, F. Zhang, Y. Chen, A. Li, J. Am. Chem. Soc. 139 (2017) 14893−14896;
(d) H. Shi, I.N. Michaelides, B. Darses, et al., J. Am. Chem. Soc. 1392017) 17755−17758;
(e) X.M. Chen, H.J. Zhang, X.K. Yang, et al., Angew. Chem. Int. Ed. 57 (2018) 947−951;
(f) Y.H. Chen, W.H. Zhang, L. Ren, J. Li, A. Li, Angew. Chem. Int. Ed. 57 (2018) 952−956;
(g) W.H. Zhang, M. Ding, J. Li, et al., J. Am. Chem. Soc. 140 (2018) 4227−4231;
(h) B. Xu, B.Y. Wang, W. Xun, F.Y.G. Qiu, Angew. Chem. Int. Ed. 58 (2019) 5754−5757;
(i) Y.Y. Chen, J.P. Hu, L.D. Guo, et al., Angew. Chem. Int. Ed. 58 (2019) 7390−7394;
(j) J.X. Zhong, K.W. Chen, Y.Y. Qiu, H.B. He, S.H. Gao, Org. Lett. 21 (2019) 3741−3745.
[5] (a) Z.M. Wang, Z.M. Xing, L. Liu, et al., ChemistrySelect 1 (2016) 2225−2227;
(b) H. Zhang, S.Q. Ma, Z.M. Xing, et al., Org. Chem. Front. 4 (2017) 2211−2215;
(c) L. Liu, H.Y. Song, P. Chen, et al., Org. Chem. Front. 5 (2018) 3013−3017;
(d) T. Li, G.M. Wu, S.B. Feng, et al., Tetrahedron 75 (2019), doi: https://doi.org/10.1016/j.tet.2019.06.017
[6] (a) H. Zhang, S.P. Yang, C.Q. Fan, J. Ding, J.M. Yue, J. Nat. Prod. 69 (2006) 553−557;
(b) Y.T. Di, H.P. He, Y. Lu, et al., J. Nat. Prod. 69 (2006) 1074−1076.
[7] K. Spencer, T.L. Anthony, J. Org. Chem. 53(1988) 4006−4014.

Graphical Abstract
The AC bicyclic skeleton of daphniyunnine B with the required two vicinal all carbon quaternary stereocenters (C-5 and C-8) was
accomplished in 12 steps from the known cyclohexenol (±)-5.