Generating skeletal diversity from the C19-diterpenoid alkaloid deltaline: A ring-distortion approach

Article abstract of DOI:10.1002/chem.201500839

The development of new drugs calls for large collections of diverse molecules with considerable complexity. Ring distortion of natural products provides an efficient and facile approach to access new architectures with intriguing biological activities, by harnessing their inherent complexity. In this study, such a strategy has been explored on an abundant C₁₉-diterpenoid alkaloid, deltaline, enabling the synthesis of 32 new derivatives bearing a broad spectrum of unique scaffolds. Extensive spectroscopic studies including X-ray crystallographic analyses strongly supported the structures of the obtained novel skeletons, which present comparable opportunities with the great contributions made by nature for discovery of new lead compounds.

Full text of DOI:10.1002/chem.201500839

DOI: 10.1002/chem.201500839
Full Paper
&
Drug Discovery
Generating Skeletal Diversity from the C -Diterpenoid Alkaloid
19
Deltaline: A Ring-Distortion Approach
[
a]
Qi-Feng Chen, Feng-Peng Wang,* and Xiao-Yu Liu*
Abstract: The development of new drugs calls for large
collections of diverse molecules with considerable complexi-
ty. Ring distortion of natural products provides an efficient
and facile approach to access new architectures with intrigu-
ing biological activities, by harnessing their inherent com-
plexity. In this study, such a strategy has been explored on
an abundant C -diterpenoid alkaloid, deltaline, enabling the
synthesis of 32 new derivatives bearing a broad spectrum of
unique scaffolds. Extensive spectroscopic studies including
X-ray crystallographic analyses strongly supported the
structures of the obtained novel skeletons, which present
comparable opportunities with the great contributions
made by nature for discovery of new lead compounds.
19
Introduction
plexity, have been naturally employed as launch points to pro-
[7]
vide distinct derivatives. Recently, an elegant ring-distortion
approach was initiated by Hergenrother and co-workers, to
construct highly diverse collections of complex molecules from
Historically, natural products have long been an inspiration for
the development of organic chemical methodologies and
theories, promotion of modern spectroscopic technologies,
and more importantly, discovery of new drugs for treating dis-
[8]
readily available natural products (Figure 1). The new concept
[
1]
eases. Undoubtedly, natural products keep offering consider-
able opportunities for finding novel lead structures with thera-
[
2]
peutic efficacy in modern drug research. The main reason is
that natural products and their derivatives tend to possess
architecturally complex three-dimensional skeletons with rich
3
stereogenic centers and sp carbon atoms, allowing specific
modulation of the functions of biomacromolecules in living
systems. Nevertheless, as the most basic and essential element
of drug discovery, how to access such collections of natural-
product-like compounds with significant complexity and
diversity remains a notable and long-term challenge.
Since the traditional efforts of identification of new natural
products from the natural sources are uncertain, several crea-
tive strategies have been developed to realize collections of
complex molecules. Among them, diversity-oriented synthe-
Figure 1. Natural products investigated on the basis of ring-distortion
reactions by the Hergenrother group.
[
3]
[4]
[5]
sis, biology-oriented synthesis, function-oriented synthesis,
and synthesis of natural-product-inspired scaffolds/libraries,
has been concentrated on rapid scaffold diversification
through ring-distortion reactions (for example, ring cleavage,
expansion, fusion, and rearrangement), aiming at achieving
complexity-to-diversity, which serves as a superb complement
[6]
are established methods that focus on efficient generation of
complex and diversified structures from simple starting materi-
als. In contrast, natural products, with inherent structural com-
[9]
to the existing methods.
Due to the structural intricacy and variety, the polycyclic
diterpenes and their corresponding alkaloids have exhibited
all-pervasive biological functions and applications, and thus
[
a] Q.-F. Chen, Prof. Dr. F.-P. Wang, Dr. X.-Y. Liu
Key Laboratory of Drug Targeting and Drug Delivery
Systems of the Ministry of Education and
Department of Chemistry of Medicinal Natural Products
West China School of Pharmacy
[10]
attracted enormous research interests over centuries. As our
[10c,11]
ongoing pursuit of such fantastic molecules,
we disclose
herein the synthesis of complex and diverse scaffolds from the
Sichuan University, Chengdu 610041 (P. R. China)
E-mail: wfp@scu.edu.cn
C -diterpenoid alkaloid deltaline (1, Figure 2), by utilizing the
19
ring-distortion strategy.
xyliu@scu.edu.cn
Deltaline (also known as eldeline) was first isolated from
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500839.
[12]
Delphinium occidentale in 1936, and later found to be widely
Chem. Eur. J. 2015, 21, 1 – 6
1
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Scheme 1. Modifications on B- and F-rings from triol 11: a) 5% NaOH/MeOH,
RT, 1 h; b) Jones reagent, acetone, 08C, 0.5 h; c) 50% H
over 3 steps); d) Pb(OAc) , HOAc, RT, 0.5 h, 70%; e) H , PtO
0% (64% brsm); f) Jones reagent, acetone, 08C, 10 min, 65%. brsm=based
on recovered starting material.
2
SO
4
, RT, 24 h, 76%
(
4
2
2
, HOAc, RT, 12 h,
4
Besides the oxidative cleavage, the 7,8-vicinal diol was envis-
aged to be an appropriate substrate to participate in a Pinacol
[15o]
rearrangement event.
In this context, after having the corre-
sponding lactam from KMnO oxidation, we were pleased to
4
find that the use of 10% H SO solution under reflux realized
2
4
Figure 2. a) Structure of deltaline and b) overview of its skeletal
diversification through a ring-distortion strategy.
not only the cleavage of methylenedioxy group (i.e. 14), but
also the desired Pinacol rearrangement product 15 in one pot
(
Scheme 2). The so-obtained framework itself belongs to one
distributed and as one of the most abundant alkaloids in the
[
13]
plants from the genus Delphinium. This compound is distinc-
[14]
tive as a nicotinic acetylcholine receptor antagonist,
and
structurally characterized by its hexacyclic, cage-like framework
and densely oxygenated functionalities (one acetate, one
hydroxyl, one methylenedioxy, and three methoxy groups).
Previous explorations of the chemical reactivity of 1 and its
[15]
derivatives have been well documented in the literature,
whereas only simple transformations were concerned in most
cases. Therefore deltaline becomes an attractive platform for
complexity-to-diversity studies.
Results and Discussion
To begin with, the highly oxygenated B-ring provides vital syn-
thetic handles for creating diverse molecules. As illustrated in
Scheme 1, saponification followed by oxidation of the resulting
secondary alcohol delivered the C6 ketone. The corresponding
Scheme 2. Pinacol rearrangement of 7,8-diol and further diversification:
a) KMnO , acetone, H O, HOAc, RT, 1 h, 90%; b) 10% H SO , reflux, 5 h, 74%;
c) NaBH , THF, H O, RT, 22 h; d) Pb(OAc) , PhH, 08C, 4 h, 51% (81% brsm,
4
2
2
4
7
,8-diol 11 was then obtained by treatment with 50% H SO
4
2
4
2
4
[
15o]
over 2 steps), 1:1 d.r.; e) PCC, 4 ꢁ MS, CH Cl , RT, 14 h, 70%; f) NaBH , THF,
solution at room temperature.
According to the modified
2
2
4
[
16]
H
2
O, RT, 16 h, 89%; g) triphosgene, Py, CH
2
Cl
2
, À158C, 1.5 h, 5 (49%), 18
Edwards protocol, exposure of 11 to Pb(OAc) resulted in
4
(
19%). MS=molecular sieves, PCC=pyridinium chlorochromate.
the efficient formation of aminal 2, representing a ring expan-
sion product of the deltaline core. With its further conversion
into the ruptured intermediate 12 by catalytic hydrogenation,
a unique pentacyclic spiro-g-lactone 3 was thus generated in
the presence of Jones reagent. The reaction was postulated to
occur through acid 13 by a double oxidative cleavage with
loss of C7, followed by lactonization from 10-OH to the
carboxylic acid at C6. Full interpretation of the 1D and 2D
NMR spectroscopic data of 3 confirmed its structure (see the
Supporting Information).
[
11d]
type of the naturally occurring C -diterpenoid alkaloids,
19
which may help to explain the excellent regioselectivity
observed during the rearrangement.
Further skeletal diversity would be achieved by elaborating
the newly formed six-membered ring (i.e. the rearranged F
ring) in 15. As a consequence, the 6,7-diol from NaBH4
reduction was directly subjected to Pb(OAc) , enabling the ring
4
cleavage of 15, with a concomitant hemiacetal formation be-
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
2
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
tween C6 aldehyde and the free alcohol at C10. Oxidation of
the epimeric hemiacetal 16 employing PCC gave rise to the
[
17]
stereochemically pure lactone 4, the structure of which was
unequivocally identified by X-ray crystallographic analysis. In-
terestingly, epimerization of C5 stereochemistry was observed
for compound 4. Since the b-orientation of H5 in both 16 and
its derivative 5 was verified by detailed NOE studies (see the
Supporting Information), it was suggested that the epimeriza-
tion occurred during the PCC oxidation, leading to the thermo-
dynamically more stable product. Additionally, reduction of 16
by NaBH4 afforded triol 17, which upon treatment with
triphosgene produced two unprecedented cyclic carbonates 5
[
18]
(49%) and 18 (19%).
[
15o]
Our previous studies have shown that,
by introducing
a leaving group at C6, an interesting sequence of transforma-
tions took place on compound 19 to furnish an unusual hepta-
cyclic core 20, through the forging of the pivotal NÀC6 bond,
accompanied by lactone formation, and methyl ether and
lactam cleavage (Scheme 3). The key intermediate 19, prepared
Scheme 4. Synthesis of 6 and diversification of its lactone cleavage deriva-
tives: a) triphosgene, Py, CH
c) LiAlH , THF, 508C, 24 h, 80%, 3:2 d.r.; d) Jones reagent, acetone, 408C,
24 h, 49%; e) 15 mmHg, 1808C, 15 min, 52%; f) TBSCl, imidazole, DMF, RT,
2 2
Cl , RT, 12 h, 65%; b) MsCl, Py, 508C, 5 h, 80%;
4
+
À
2
3 2 2 3
h, 79%; g) DMP, NaHCO , CH Cl , RT, 2 h, 86%; h) Me OS I , NaH, DMSO,
THF, 608C, 24 h, 62%. DMP=Dess–Martin periodinane, Ms=methane-
sulfonyl, TBS=tert-butyldimethylsilyl.
Scheme 3. Our previous synthesis of the heptacyclic compound 20.
from deltaline (1) over six steps, was an analogue of 15, with
the only difference at the C10-position. A similar transforma-
tion was envisioned to occur on compound 15, which was
rapidly synthesized in only two steps from 1. On the other
hand, the presence of 10-OH in this series offered more
choices for further diversification.
As expected, exposure of 15 to triphosgene or MsCl in the
presence of pyridine furnished the heptacyclic system 6 (con-
firmed by X-ray crystallography) with remarkable efficiency
(Scheme 4). Cleavage of the lactone in 6 by reduction with
LiAlH gave rise to tetraol 21 as a pair of inseparable diastereo-
4
mers. The latter, after being converted to carboxylic acid 22,
underwent vacuum pyrolysis to generate a novel pentacyclic
lactam 7, the structure of which was unambiguously deter-
mined by the X-ray crystallographic data. The reaction was
proposed to be initiated by a Grob-fragmentation-like pathway
Scheme 5. Synthesis of diverse skeletons 8, 9, 27, and 28 from 6: a) NBS,
HOAc, RT, 1 h, 93%; b) 6.5% HBr/HOAc, 858C, 50 h, 79%; c) 5% NaOH/
MeOH, RT, 3 h; d) PivCl, DMAP, Py. RT, 3 h; e) MsCl, Py., RT, 2 h, 80% (over
3
steps); f) NaH, CH
Me S, Et N, RT, 3.5 h, 28 (61%), 8 (26%); h) 0.25% NaOH/MeOH, RT, 5 h;
i) MsCl, Py, RT, 2 h, 89% (over 2 steps); j) O , CH Cl
, À788C, 10 min; then
2
Cl
2
, RT, 6 h, 66%; g) O
3
, CH
2
Cl
2
, À788C, 10 min; then
2
3
3
2
2
[
19]
and terminated with a lactam formation. On the other hand,
Me S, Et N, RT, 2 h, 8 (60%); k) O , CH Cl , À788C, 10 min; then Me S, pTsOH,
2
3
3
2
2
2
[
20]
elaboration of tetraol 21 to the spiroepoxide 24 was ach-
ieved in three steps: 1) selective silyl protection of the primary
alcohol, 2) oxidation of the secondary hydroxyl groups to ke-
tones, and 3) epoxide formation at C7 carbonyl group through
RT, 3 h, 55%. DMAP=4-dimethylaminopyridine, NBS=N-bromosuccinimide,
Piv=pivaloyl, pTsOH=para-toluenesulfonic acid.
[
21]
the Corey–Chaykovsky protocol. Note that the desilylation
occurred slowly under the reaction conditions and reached
completion with prolonged time. In addition, the selective
manner in the production of spiroepoxide 24 was also
impressive, which was speculated to be dependent on the
steric effect of the substrate.
diversity, through distortions of the C/D rings. Specifically,
manipulations of N-ethyl and methoxy groups led to the antici-
[15k,22]
pated acetates 25 (Scheme 5).
A three-step procedure
was then applied to secure the important precursor 26, with
an 80% overall yield. At this stage, an impressive Grob frag-
mentation proceeded smoothly in the presence of sodium hy-
dride at room temperature, giving access to the ring cleavage
product 27. It is noteworthy that the olefinic ketone 27
As a versatile intermediate, compound 6 offered further
entries to novel derivatives with conceivable complexity and
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
3
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
became particularly attractive due to its latent reactivity
towards ozonolysis and subsequent transformations.
Accordingly, subjecting 27 to ozone followed by quenching
the reaction with Me S and Et N (Scheme 5) gave two separa-
2
3
ble products, 8 (26%) and 28 (61%). Intramolecular aldol addi-
tion of the resultant dialdehyde from ozonolysis accounted for
[
23]
the generation of both products,
the structures of which
were established by extensive spectroscopic analyses, includ-
ing X-ray crystallography of 28. As shown in Scheme 6, con-
Scheme 7. Generating diversity from intermediate 31: a) 6.5% HBr/HOAc,
8
58C, 65 h, 84%; b) 5% NaOH/MeOH, RT, 4 h, 98%; c) triphosgene, Py.,
CH Cl , RT, 15 h, 70%; d) PivCl, DMAP, Py, RT, 3 h, 92%; e) Jones reagent,
acetone, 08C, 10 min, 98%; f) H /HCO H (1:1), RT, 2.5 h, 71%.
2
2
2
O
2
2
[
17]
to deliver the lactone 10, promoted by a mixture of H O
2
2
[24]
and HCO H. The location of the newly established lactone
2
1
1
was assigned on the basis of H, H-COSY and HMBC
experiments.
Scheme 6. Possible pathways for the formation of 8, 9, and 28.
Conclusions
In summary, we have described an expedient access to highly
complex and diverse scaffolds from the naturally occurring C -
struction of the C9ÀC12 bond along with the elimination of
a pivalic acid afforded 8 (Scheme 6, path a), whereas the as-
sembly of the C9ÀC13 bond with ensuing hemiacetal forma-
tion allowed for the production of 28 (Scheme 6, path b). With-
1
9
diterpenoid alkaloid deltaline, by means of a ring-distortion
strategy. The endeavors of distorting different rings have
generated not only the skeletal diversity, but also an array of
widespread structural moieties embedded in these carbon
frameworks, which further demonstrates the versatility of the
promising protocol. All the 32 products described in this study
are new compounds, prepared within ten synthetic steps and
on 12–9200 mg scales (see the Supporting Information), thus
providing entries to identify potentially new chemotypes.
Moreover, it is particularly remarkable that, utility of simple
chemical methods and reagents enables efficient and facile
transformations in complex molecular settings. Most
importantly, creation of novel skeletons and their derivatives in
this study sets the stage for an in-depth exploration of the
biological and medicinal applications.
out adding bases (such as Et N) into the reaction mixture was
3
insignificant to alter the ratio between compounds 8 and 28.
To improve the yield of 8, a mesylate was installed at C16 to
replace the pivalate, serving as a better leaving group. As
a result, the facile formation of enal moiety prevented the
addition from C13 to C9, thereby producing hexacyclic 8
exclusively.
Furthermore, the possible impact of acidic additive on the
profile of products was investigated (Scheme 5). As expected,
addition of pTsOH into the reaction mixture gave an entirely
different spot, which was identified as the heptacycle 9 and
confirmed by an X-ray crystallographic study. The key to the
formation of a characteristic 1,3-dioxepane-4,7-diol unit in 9
relied on
a consecutive acetalization process from the
Experimental Section
dialdehyde 29 after hydration (Scheme 6).
Without bothering the N-ethyl group, direct O-demethyla-
tion followed by saponification of compound 6 furnished triol
All the experimental details are presented in the Supporting
Information.
31 (Scheme 7). Treating the latter with triphosgene yielded
a ring-fusion product 32. In addition, we envisioned that a ring
expansion version might be generated by a Baeyer–Villiger
oxidation of the C7 ketone. Despite numerous efforts, the car-
bonyl group at C7 was revealed to be inert to the oxidation
conditions, probably due to its spatially crowded environment
in the rigidly heptacyclic nucleus. In contrast, the C14 ketone
displayed positive reactivity towards related oxidants. There-
fore, selective protection of the sterically less hindered hydrox-
yl group at C16 in the intermediate 31 was achieved, similar to
that described in Scheme 5. After Jones oxidation of C14 alco-
hol, the expected Baeyer–Villiger reaction took place smoothly
Acknowledgements
Financial support for this work was provided by the National
Natural Science Foundation of China (81273387) and Start-up
Funds of Sichuan University. We are grateful to Prof. Daibing
Luo and Dr. Daichuan Ma (Sichuan University) for X-ray
analysis.
Keywords: alkaloids · deltaline · drug discovery · natural
products · X-ray crystallography
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
4
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
[
[
1] D. A. Dias, S. Urban, U. Roessner, Metabolites 2012, 2, 303–336.
2] a) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2012, 75, 311–335; b) G. M.
Cragg, D. J. Newman, Biochim. Biophys. Acta 2013, 1830, 3670–3695;
c) M. S. Butler, A. A. B. Robertson, M. A. Cooper, Nat. Prod. Rep. 2014, 31,
pp. 151–247; b) F.-P. Wang, X.-T. Liang in The Alkaloids: Chemistry and
Biology, Vol. 59 (Ed.: G. A. Cordell), Elsevier, New York, 2002, pp. 1–280;
c) F.-P. Wang, Q.-H. Chen, X.-T. Liang in The Alkaloids: Chemistry and Biol-
ogy, Vol. 67 (Ed.: G. A. Cordell), Elsevier, New York, 2009, pp. 1–78; d) F.-
P. Wang, Q.-H. Chen in The Alkaloids: Chemistry and Biology, Vol. 69 (Ed.:
G. A. Cordell), Elsevier, New York, 2010, pp. 1–577.
1612–1661.
[
[
3] a) S. L. Schreiber, Science 2000, 287, 1964–1969; b) M. D. Burke, S. L.
Schreiber, Angew. Chem. Int. Ed. 2004, 43, 46–58; Angew. Chem. 2004,
[12] J. F. Couch, J. Am. Chem. Soc. 1936, 58, 684–685.
116, 48–60; c) D. S. Tan, Nat. Chem. Biol. 2005, 1, 74–84; d) W. R. Gallo-
[13] For selected reports, see: a) S. W. Pelletier, N. V. Mody, O. D. Dailey Jr.,
Can. J. Chem. 1980, 58, 1875–1879; b) S. W. Pelletier, O. D. Dailey Jr.,
N. V. Mody, J. D. Olsen, J. Org. Chem. 1981, 46, 3284–3293; c) Q. P.
Jiang, W. L. Sung, Heterocycles 1985, 23, 11–15; d) S. W. Pelletier, S. A.
Ross, P. Kulanthaivel, Tetrahedron 1989, 45, 1887–1892; e) C. Y. Zhang,
W. L. Sung, D. H. Chen, Fitoterapia 1993, 64, 188–189; f) F.-Z. Chen, D.-L.
Chen, Q.-H. Chen, F.-P. Wang, J. Nat. Prod. 2009, 72, 18–23.
[14] a) P. Dobelis, J. E. Madl, J. A. Pfister, G. D. Manners, J. P. Walrond, J. Phar-
macol. Exp. Ther. 1999, 291, 538–546; b) K. D. Welch, J. A. Pfister, F. G.
Lima, B. T. Green, D. R. Gardner, Toxicol. Appl. Pharmacol. 2013, 266,
366–374.
[15] a) M. Carmack, J. P. Ferris, J. Harvey, P. T. Magat, E. W. Martin, D. W. Mayo,
J. Am. Chem. Soc. 1958, 80, 497; b) P. Kulanthaivel, S. W. Pelletier, Tetra-
hedron Lett. 1987, 28, 3883–3886; c) P. Kulanthaivel, S. W. Pelletier, Tet-
rahedron 1988, 44, 4313–4320; d) A. S. Narzullaev, M. S. Yunusov, A. M.
Moisenkov, S. S. Sabirov, Khim. Prir. Soedin. 1989, 372–375; e) H. K.
Desai, H. P. Chokshi, S. W. Pelletier, J. Nat. Prod. 1989, 52, 1296–1302;
f) X. Liang, H. K. Desai, B. S. Joshi, S. W. Pelletier, Heterocycles 1990, 31,
1889–1894; g) S. K. Srivastava, B. S. Joshi, M. G. Newton, D. Lee, S. W.
Pelletier, Tetrahedron Lett. 1995, 36, 519–522; h) Y. Bai, H. K. Desai, S. W.
Pelletier, J. Nat. Prod. 1995, 58, 929–933; i) Y.-M. He, C.-L. Zou, Q.-H.
Chen, F.-P. Wang, J. Asian Nat. Prod. Res. 2007, 9, 713–720; j) C.-L. Zou,
X.-Y. Liu, F.-P. Wang, Q.-H. Chen, Chem. Pharm. Bull. 2008, 56, 250–253;
k) C.-L. Zou, H. Ji, G.-B. Xie, D.-L. Chen, F.-P. Wang, J. Asian Nat. Prod. Res.
2008, 10, 1063–1067; l) C.-L. Zou, L. Cai, H. Ji, G.-B. Xie, F.-P. Wang, X.-X.
Jian, L. Song, X.-Y. Liu, D.-L. Chen, Q.-H. Chen, Tetrahedron 2008, 64,
7594–7604; m) L. Wang, Q.-H. Chen, F.-P. Wang, Nat. Prod. Commun.
2012, 7, 721–724; n) L. Wang, Q.-F. Chen, F.-P. Wang, Nat. Prod.
Commun. 2012, 7, 1583–1586; o) P. Tang, L. Wang, Q.-F. Chen, Q.-H.
Chen, X.-X. Jian, F.-P. Wang, Tetrahedron 2012, 68, 5031–5036; p) P.
Tang, Q.-F. Chen, L. Wang, Q.-H. Chen, X.-X. Jian, F.-P. Wang, Tetrahedron
2012, 68, 5668–5676; q) P. Tang, L. Wang, Q.-F. Chen, Q.-H. Chen, X.-X.
Jian, F.-P. Wang, Tetrahedron 2012, 68, 6249–6256.
way, A. Isidro-Llobet, D. R. Spring, Nat. Commun. 2010, 1, 80; e) C. J.
O’Connor, H. S. G. Beckmann, D. R. Spring, Chem. Soc. Rev. 2012, 41,
4
444–4456.
4] a) S. Wetzel, R. S. Bon, K. Kumar, H. Waldmann, Angew. Chem. Int. Ed.
011, 50, 10800–10826; Angew. Chem. 2011, 123, 10990–11018; b) H.
Lachance, S. Wetzel, K. Kumar, H. Waldmann, J. Med. Chem. 2012, 55,
989–6001.
5] P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2008,
1, 40–49.
2
5
[
[
4
6] a) H. E. Pelish, N. J. Westwood, Y. Feng, T. Kirchhausen, M. D. Shair, J. Am.
Chem. Soc. 2001, 123, 6740–6741; b) B. C. Goess, R. N. Hannoush, L. K.
Chan, T. Kirchhausen, M. D. Shair, J. Am. Chem. Soc. 2006, 128, 5391–
5403; c) K. J. Frankowski, V. Setola, J. M. Evans, B. Neuenswander, B. L.
Roth, J. Aubꢂ, Proc. Natl. Acad. Sci. USA 2011, 108, 6727–6732; d) H.
Oguri, T. Hiruma, Y. Yamagishi, H. Oikawa, A. Ishiyama, K. Otoguro, H.
Yamada, S. Omura, J. Am. Chem. Soc. 2011, 133, 7096–7105; e) H. Mizo-
guchi, H. Oikawa, H. Oguri, Nat. Chem. 2014, 6, 57–64; f) M. C. McLeod,
G. Singh, J. N. Plampin III, D. Rane, J. L. Wang, V. W. Day, J. Aubꢂ, Nat.
Chem. 2014, 6, 133–140; g) J. Zhang, J. Wu, B. Hong, W. Ai, X. Wang, H.
Li, X. Lei, Nat. Commun. 2014, 5, 4614.
[
7] For recent reviews, see: a) K. C. Morrison, P. J. Hergenrother, Nat. Prod.
Rep. 2014, 31, 6–14; b) O. Robles, D. Romo, Nat. Prod. Rep. 2014, 31,
3
2
18–334; c) J. Szychowski, J.-F. Truchon, Y. L. Bennani, J. Med. Chem.
014, 57, 9292–9308; for recent examples, see: d) B. R. Balthaser, M. C.
Maloney, A. B. Beeler, J. A. Porco Jr., J. K. Snyder, Nat. Chem. 2011, 3,
69–973; e) J. Li, J. S. Cisar, C.-Y. Zhou, B. Vera, H. Williams, A. D. Rodrꢃ-
9
guez, B. F. Cravatt, D. Romo, Nat. Chem. 2013, 5, 510–517; f) O. E. Hutt,
T. L. Doan, G. I. Georg, Org. Lett. 2013, 15, 1602–1605; g) C. Ding, Y.
Zhang, H. Chen, C. Wild, T. Wang, M. A. White, Q. Shen, J. Zhou, Org.
Lett. 2013, 15, 3718–3721; h) A. J. Grenning, J. K. Snyder, J. A. Porco Jr.,
Org. Lett. 2014, 16, 792–795; i) Q. Michaudel, G. Journot, A. Regueiro-
Ren, A. Goswami, Z. Guo, T. P. Tully, L. Zou, R. O. Ramabhadran, K. N.
Houk, P. S. Baran, Angew. Chem. Int. Ed. 2014, 53, 12091–12096; Angew.
Chem. 2014, 126, 12287–12292.
[16] O. E. Edwards, M. Los, L. Marion, Can. J. Chem. 1959, 37, 1996–2006.
[17] L. Silva, A. C. Gomes, J. M. L. Rodilla, Nat. Prod. Commun. 2011, 6, 497–
504.
[18] H. Zhang, H.-B. Liu, J.-M. Yue, Chem. Rev. 2014, 114, 883–898.
[19] For a related Grob fragmentation via vacuum pyrolysis, see: L. Wang,
Q.-F. Chen, F.-P. Wang, Nat. Prod. Commun. 2013, 8, 1701–1704.
[20] a) S. Mo, A. Krunic, B. D. Santarsiero, S. G. Franzblau, J. Orjala, Phyto-
chemistry 2010, 71, 2116–2123; b) C. Li, M. Jiang, M.-P. La, T.-J. Li, H.
Tang, P. Sun, B.-S. Liu, Y.-H. Yi, Z. Liu, W. Zhang, Mar. Drugs 2013, 11,
1565–1582.
[
[
8] a) R. W. Huigens III, K. C. Morrison, R. W. Hicklin, T. A. Flood, M. F. Richter,
P. J. Hergenrother, Nat. Chem. 2013, 5, 195–202; b) R. J. Rafferty, R. W.
Hicklin, K. A. Maloof, P. J. Hergenrother, Angew. Chem. Int. Ed. 2014, 53,
220–224; Angew. Chem. 2014, 126, 224–228; c) R. W. Hicklin, T. L. Lꢄpez
Silva, P. J. Hergenrother, Angew. Chem. Int. Ed. 2014, 53, 9880–9883;
Angew. Chem. 2014, 126, 10038–10041.
9] J.-P. Krieger, G. Ricci, D. Lesuisse, C. Meyer, J. Cossy, Angew. Chem. Int.
Ed. 2014, 53, 8705–8708; Angew. Chem. 2014, 126, 8849–8852.
[
10] For selected reviews, see: a) L. N. Mander, Nat. Prod. Rep. 2003, 20, 49–
[21] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353–1364.
[22] F.-P. Wang, L. Xu, Tetrahedron 2005, 61, 2149–2167.
[23] For a similar transformation on a different scaffold, see ref. [14].
[24] M. Zhu, X.-Y. Liu, Q.-H. Chen, F.-P. Wang, J. Asian Nat. Prod. Res. 2012, 14,
441–449.
69; b) H.-D. Sun, S.-X. Huang, Q.-B. Han, Nat. Prod. Rep. 2006, 23, 673–
698; c) F.-P. Wang, Q.-H. Chen, X.-Y. Liu, Nat. Prod. Rep. 2010, 27, 529–
570; d) E. C. Cherney, P. S. Baran, Isr. J. Chem. 2011, 51, 391–405; e) Z.-L.
Zhou, Y.-X. Yang, J. Ding, Y.-C. Li, Z.-H. Miao, Nat. Prod. Rep. 2012, 29,
57–475; f) K. Wada in Studies in Natural Products Chemistry, Vol. 38
Ed.: Atta-ur-Rahman), Elsevier, Amsterdam, 2012, pp. 191–223; g) J. R.
4
(
Hanson, Nat. Prod. Rep. 2015, 32, 76–87.
[11] For reviews, see: a) F.-P. Wang, X.-T. Liang in The Alkaloids: Chemistry and
Received: March 2, 2015
Physiology, Vol. 42 (Ed.: G. A. Cordell), Academic, San Diego, 1992,
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Drug Discovery
Q.-F. Chen, F.-P. Wang,* X.-Y. Liu*
& – &&
&
A ring-distortion strategy has been
applied to the synthesis of 32 distinct
molecules with significant complexity
and diversity, from the C -diterpenoid
ported the structures of the obtained
novel skeletons, which present compa-
rable opportunities with the great
contributions made by nature for the
discovery of new lead compounds.
Generating Skeletal Diversity from the
C -Diterpenoid Alkaloid Deltaline: A
Ring-Distortion Approach
19
19
alkaloid deltaline (see scheme). Exten-
sive spectroscopic studies strongly sup-
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!