Total synthesis of crotophorbolone

Article abstract of DOI:10.1039/d0sc02829k

As a natural diterpenoid, crotophorbolone possesses a challenging trans,trans-5/7/6 framework decorated with six contiguous stereogenic centers and is structurally and biogenetically related to tigliane-type diterpenoids with intriguing bioactivities such as phorbol and prostratin. Based on the convergent strategy, we completed an eighteen-step total synthesis of crotophorbolone starting from (-)-carvone and (+)-dimethyl-2,3-O-isopropylidene-l-tartrate. The key elements of the synthesis involve expedient installation of the six-membered ring and the five-membered ring with multiple functional groups at an early stage, cyclization of the seven-membered ring through alkenylation of the ketone between the five-membered ring and the six-membered ring, functional group-sensitive ring-closing metathesis and final selective introduction of hydroxyls at C20 and C4. This journal is

Full text of DOI:10.1039/d0sc02829k

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: T. Yu, Y. Sun, C.
Tu, T. Chen, S. Fu and B. Liu, Chem. Sci., 2020, DOI: 10.1039/D0SC02829K.
Volume
Number
9
1
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
7
January 2018
Pages 1-268
Chemical
Science
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
rsc.li/chemical-science
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Xinjing Tang et al.
Caged circular siRNAs for photomodulation of gene
expression in cells and mice
rsc.li/chemical-science

Page 1 of 6
Chemical Science
ARTICLE
View Article Online
DOI: 10.1039/D0SC02829K
Total Synthesis of Crotophorbolone
1
1
1
1
1
1
∗
Tianzi Yu , Ying Sun , Canhui Tu , Ting Chen , Shaomin Fu , and Bo Liu
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry and in
memory of Prof. Wei-Shan Zhou
As a natural diterpenoid, crotophorbolone possesses a challenging trans,trans-5/7/6
framework decorated with six contiguous stereogenic centers, which is structurally and
biogenetically related to tigliane-type diterpenoids with intriguing bioactivities such as
phorbol and prostratin. On the basis of convergent strategy, we completed an eighteen-step
total synthesis of crotophorbolone starting from (-)-carvone and (+)-dimethyl-2,3-O-
isopropylidene-L-tartrate. Key elements of the synthesis involve expedient installation of the
six-membered ring and the five-membered ring with multiple functional groups at early
stage, cyclization of the seven-membered ring through alkenylation of ketone between the
five-membered ring and the six-membered ring, functional group-sensitive ring-closing
4
metathesis and final selective introduction of hydroxyls at C20 and C .
Introduction
small family with about thirty members.[2a, 14] As illustrated,
crotophorbolone (1) possesses a trans, trans-5/7/6 tricyclic
ring system decorated with six contiguous stereogenic
centers involving two quaternary centers and four tertiary
centers. Crotophorbolone (1) is often regarded as a tigliane-
type diterpenoid due to its similar oxidation style to phorbol
(3) and its biogenesis from phorbol, although it shares similar
carbon skeleton with rhamnofolane-type diterpenoids.
Diterpenoid natural products are structurally versatile and
can be classified into different families, many of which are
biogenetically correlated. Among them, Hecker proposed
that tigliane might be regarded as biosynthetic precursor of
ingenane, daphnane and rhamnofolane (Scheme 1), and
this hypothesis was partially supported by co-occurrence of
these diterpenoids in the plant families of Euphorbiaceae and
[
1]
Accompanied by successful chemical syntheses of
[
2]
Thymelaeaceae.
Biosynthetically, tigliane could be
tigliane-type
phorbol,
diterpenoids
the Inoue group fulfilled the first total synthesis
involving
prostratin
and
[
5,11,12]
achievable initially from the abundant geranylgeranyl
pyrophosphate (GGPP) via formation of casbene and
of crotophorbolone.[15] In their pioneering work, an
impressive strategy was accomplished in thirty four linear
[
3]
lathyrane.
Thus it is intriguing to manifest chemical
interconversion among tigliane, ingenane, daphnane and
rhamnofolane to probe insightful information on biosynthetic
mechanism. In fact, the Wender group was able to transform
steps, featuring smart construction of
oxabicyclo[2.2.2]octane intermediate, followed
diastereoselective radical Michael addition to close the
a
unique
by
[
4]
crotophorbolone (1) to prostratin (2),
a tigliane-type
diterpenoid used as a potential adjuvant in highly active
[
5]
Scheme 1. Biogenic correlationship among tigliane, ingenane,
daphnane and rhamnofolane.
antiretroviral therapy (HAART) against HIV. Interestingly,
[
6]
acidic treatment of phorbol (3), a typical tigliane-type
diterpenoid, led to formation of crotophorbolone as a reaction
[
7]
product as early as in 1934, although the first isolation of 1
[
8]
from natural source had not been reported until 2010.
Allured by their impressive structures and bioactivities,
chemists have made numerous synthetic endeavors toward
natural ingenane-type, tigliane-type and daphnane-type
[
9]
diterpenoids, leading to chemical syntheses of ingenol and
[
10]
[11]
[5, 12]
its natural derivatives,
phorbol,
prostratin,
and
[
13]
resiniferatoxin. All of these natural diterpenoids embrace a
similar tricyclic scaffold embedded with multiple stereogenic
centers. Compared to tigliane-type and daphnane-type
diterpenoids, rhamnofolane-type diterpenoids belong to a
1
Key Laboratory of Green Chemistry & Technology of Ministry of Education,
College of Chemistry, Sichuan University 29 Wangjiang Rd., Chengdu,
Sichuan 610064 (China). Correspondence and requests for materials should
be addressed to B.L.(E-mail: chembliu@scu.edu.cn)
†
Electronic supplementary information (ESI) available: Experimental
procedures and details of the electrochemical apparatus employed. See DOI:
0.0000/xxxxxxxxxx
0
1

Chemical Science
Page 2 of 6
ARTICLE
a
Scheme 3. Synthesis of 5/7/6 tricyclic intermediate 21. View Article Online
Scheme 2. Retrosynthetic analysis.
DOI: 10.1039/D0SC02829K
middle cycloheptene, which was triggered by cleavage of a
bridgehead C-Se bond. Recently, we became interested in
developing a convergent synthetic strategy toward natural
[16]
daphnane-type and rhamnofolane-type diterpenoids,
on
the basis of our persistent research on total synthesis of
[
17]
terpenoids. Herein, we would like to present our efforts on
convergent total synthesis of crotophorbolone.
Retrosynthetically, crotophorbolone could be derived from
compound
isomerization (Scheme 2). Cleavage of the allylic alcohol at
20 and the C =C double bond in 4 would lead to its
precursor 5, which could be coupled from 6 and 7 through
nucleophilic addition. Fragments and could be
4 after oxidation of alcohols and alkene
C
6
7
6
7
a
synthesized from commercially available (-)-carvone and (+)-
dimethyl-2,3-O-isopropylidene-L-tartrate [(+)-8] respectively.
Reagents and conditions: (a) TBDPSCl, imidazole, DCM, rt, 3 h,
®
7
1
8%; (b) Na
2
S
2 4
O , NaHCO
3
, Adogen 464, PhMe/H
2
O (1/1), reflux,
.5 h; then IBX, EtOAc, 80 ℃, 12 h, 77%, dr 3.3:1; (c) LDA,
CHO, THF, -78 ℃ to -55 ℃, 2 h; then MsCl, Et N, DCM,
℃, 2 h, 59%; (d) LiHMDS, 3-bromo-2-methylpropene, HMPA, THF,
-78 ℃, 4 h, quant., dr > 20:1; (e) Me(MeO)NH•HCl, BuLi, THF, -
55 ℃, 1 h; (f) MeLi, THF, -78 to rt, 1.5 h, 72% over two steps; (g)
PhSeCH
0
2
3
Results & discussion
n
Accordingly, we started synthesis of the fully functionalized
six-membered ring 12 from compound 9 (Scheme 3),
feasibly produced after treating (-)-carvone with a copper-
K
2
CO
PhMe, rt, 5 h, 69%; (i) NH
Et N, THF, 0 ℃, 0.5 h, 85%; (j) BuLi, CeCl
TFA/THF/H O (3/4/4), rt, 3 h, 65% over two steps; (l) TPAP, NMO,
DCM, 0 ℃, 3 h, 72%; (m) cat. 19, C , reflux, 2 h, 88%; (n) Ba(OH)
MeOH/toluene (2/1), 55 ℃ , 10 min, 44%. TBDPSCl tert-
methyltrialkyl(C8-
3
, MeOH/EtOH (2/1), rt, 13 h, 72%; (h) Cu(OAc)
2 3 3
, PPh , PhSiH ,
[
18]
2
NH •H O, Et N, EtOH, 80 ℃, 20 h; then I
2
2
3
2
,
aluminium mixed oxide.
After silyl protection of the
n
3
, 12, THF, -78 ℃, 1 h; (k)
secondary alcohol, the intermediate underwent reduction
3
2
with sodium dithionite to give a mixture of compounds 10 and
[
19]
6
F
6
2
,
1
0′,
which was treated with IBX to afford the pure 10.
=
Coupling compound 10 and 2-(phenylselenyl)-acetaldehyde
®
[
20]
butyldiphenylsilyl chloride, Adogen
464
=
(11)
resulted in an aldol intermediate, and mesylation of
C10)ammonium chloride, IBX = 2-iodoxybenzoic acid, MsCl =
methanesulfonyl chloride, LiHMDS = lithium bis(trimethylsilyl)amide,
the resultant secondary alcohol led to elimination to produce
[21]
compound 12, as the equivalent of the fully functionalized
six-membered fragment 7.
TFA
=
trifluoroacetic acid, TPAP
=
tetrapropylammonium
perruthenate, NMO = N-methylmorpholine N-oxide.
Then synthesis of the five-membered fragment 17 began
with methallylation of compound (+)-8 with high yield and
[
22]
catalyst 19 to achieve high yield.[26] With compound 20 in
hand, we had expected that the desired trans-5,7-fused ring
diastereoselectivity.
Sequential Weinreb amidation and
nucleophilic addition with methyl lithium led to compound 14.
The following treatment with potassium carbonate resulted in
system with α-H at C10 would be constructed after alkene
[
23]
[15a, 27]
the functionalized cyclopentenone 16.
This process
isomerization from C
1
=C10 to C
1
=C
2
,
at least co-
involved inversion of the tertiary stereogenic center and
intramolecular aldol condensation to generate the
thermodynamically more stable cis-fused 5/5 bicyclic ring
system. Copper-catalyzed 1,4-reduction delivered an
intermediate, which was transformed to compound 17 as a
surrogate of the fragment 6 after formation of hydrazone and
subsequent iodination.
existing with the cis-5,7-fused ring system (21).
Unfortunately, we failed to gain the desired compound after
numerous trials. Treating 20 with Ba(OH)
2
in hot methanol
only led to compound 21 in 44% yield, while recovery or
decomposition of compound 20 was observed in other cases.
To introduce proper stereochemistry at C10, we decided to
inverse absolute configuration of the five-membered
fragment by starting synthesis from (-)-8 (Scheme 4). Thus
compound ent-17, prepared in the same synthetic procedure
as compound 17, was coupled with compound 12. The
resultant intermediate was converted into compound 22 after
acidic removal of acetonide. Then TPAP oxidation and RCM
cyclization smoothly afforded compound 23. In contrast to
Inspired by precedent synthetic studies,[24] we attempted
connection between the six-membered ring 12 and the five-
3
membered ring 17. In the presence of CeCl , the alkenyl
lithium generated from 17 and butyl lithium was added to the
ketone 12 to afford a diastereoselective adduct, acetonide of
which was removed to yield compound 18. It was then
converted into compound 20 with the desired 5/7/6 tricyclic
skeleton, after oxidation of the secondary alcohol and ring-
low conversion of 20 into 21 by using Ba(OH)
2
, treating 23
[
25]
with DBU promoted alkene isomerization to deliver
closing metathesis (RCM) in C
6
F
6
using Nolan’s ruthenium
2

Page 3 of 6
Chemical Science
ARTICLE
a
Scheme 4. Total synthesis of crotophorbolone.
Table 1. Screening for sequential transformation from 2V6ietwoA2rt8ic/l2e8O′n. line
DOI: 10.1039/D0SC02829K
[
a]
Entry
1
Conditions in the epoxidation step
Result
Oxone (1.5 equiv.), NaHCO
3
(3.0 equiv.)
28′ (67%)
28′ (57%)
acetone, 0 ℃
2
3
4
5
6
3
MeReO (0.25 equiv.), pyridine (2.5 equiv.),
2 2
H O
(2.5 equiv.), MeCN/AcOH (19/1), 0 ℃
[
b]
NaHCO
3
(2 equiv.), DCM, dropwise addition
N. R.
m
of CPBA (1.05 equiv.) in DCM, -78 ℃
NaHCO
3
(2 equiv.), DCM, dropwise addition
28/28′
m
of CPBA (1.05 equiv.) in DCM, -40 ℃
(1/1.4) 67%
NaHCO
3
(2 equiv.), DCM, dropwise addition
28/28′
m
of CPBA (1.05 equiv.) in DCM, 0 ℃
(1.4/1) 59%
[
c]
NaHCO
3
(2 equiv.), DCM, one-batch
28 (38%)
28′ (37%)
m
[c]
addition of CPBA (1.05 equiv.), 0 ℃
[
a]
[b]
[c]
Overall isolated yield from 27.
N. R. = no reaction.
Overall
m
isolated yield from 26. CPBA = meta-chloroperbenzoic acid.
rearrangement.[30] Notably, allylic positions adjacent to C
and C15=C16 were inert, probably due to electron-deficient
property of C =C and shielding effect of neighbouring
TBDPS ether near C15=C16 respectively.
To introduce hydroxyl at C , we decided to examine
=C
2
1
1
2
4
feasibility of a three-step sequence involving silyl enolation,
diastereoselective epoxidation and global deprotection to
afford the desired compound 28. Crude 27 was firstly in situ
obtained by silylation of compound 26. As summarized in
3 2 2
table 1, in the presence of Oxone or MeReO /H O ,
epoxidation of crude 27 only resulted in the undesired cis-
product 28′ after desilylation (entries 1-2). Although
application of meta-chloroperbenzoic acid ( CPBA) at -78 ℃
a
n
Reagents and conditions: (a) BuLi, CeCl
TFA/THF/H O (3/4/4), rt, 4 h, 86% over two steps; (c) TPAP, NMO,
DCM, 0 ℃, 2.5 h, 78%; (d) cat. 19, C , reflux, 3 h, 96%; (e) DBU,
MeOH, 0 ℃ to rt, 1.5 h, 94%; (f) SmI , THF, 0 ℃, 20 min, 63% (brsm
0%); (g) TPP, O , hv, DCE, 12 h, PPh ; then Re , 15 min, 32%
brsm 45%) after two cycles; (h) TMSOTf, Et N, DCM, 0 ℃,3 h, 72%;;
i) see table 1, then 40% HF/MeCN (1/4), 60 ℃, 4 h, 28/28′ =
8%/37%; (j) Dess-Martin periodinane, NaHCO , DCM, rt, 3 h,
, MeOH, -40 ℃, 10 min, 92%. DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene, TPP 5,10,15,20-
3
, 12, THF, -78 ℃, 1 h; (b)
2
m
6 6
F
afforded no reaction (entry 3), epoxidation with it at higher
temperature did take place, which was followed by global
desilylation to afford a mixture of diastereomers 28 and 28′
with almost 1:1 ratios (entries 4-5). To our delight, we found
2
9
(
(
2
3
2 7
O
3
m
3
3
direct addition of CPBA in one batch into the DCM solution
n
4 4
quant.; (k) Bu N·BH
of crude 27 at 0 ℃ provided the optimal result, eventually
producing 28 in 38% yield and 28′ in 37% yield from 26
=
tetraphenylporphyrin, DCE = 1,2-dichloroethane, brsm = based on
recovery of starting material.
(entry 6). Finally, oxidation with Dess-Martin periodinane
gave compound 29, and selective reduction of the aldehyde
accomplished total synthesis of crotophorbolone (1).
compound 24 in 94% yield, as a cis-5/7 ring system with
identical stereochemistry at C10 to that of 1. At this stage,
directly inverting stereochemistry of the quaternary
a
Scheme 5. Thermodynamic stability of 25 over 30′.
stereogenic center at C
2
2
4
was infeasible. So the α-OH at C
4 was cleaved with samarium (II) iodide to afford compound
5, whose relative stereochemistry was unambiguously
4
in
established by single crystal X-ray diffraction. Subsequently,
we proposed that a primary allylic alcohol at C20 be
selectively introduced to generate compound 26 in the
presence of other two alkenes. However, oxidation with
stoichiometric selenium dioxide in THF at 50 ℃ resulted in
2
6′ instead, while its application in other solvents, as well as
t
the combination of catalytic SeO
2
and BuOOH, led to
decomposition of 25. Then White’s protocol with Pd(OAc)
2
-
[
28]
sulfoxide catalysis was attempted,
but no reaction was
observed. Finally, 26 was facilitated by means of Schenk ene
reaction with singlet oxygen, followed by Re O -mediated
2 7
a
[
29]
2
Reagents and conditions: (a) SmI , THF, 0 ℃, 20 min, 74%; (b)
DBU, MeOH, rt-40 ℃, 16 h, 63%.
3

Chemical Science
Page 4 of 6
ARTICLE
The authors declare no competing interests.
View Article Online
DOI: 10.1039/D0SC02829K
Surprisingly, similar to that of 24, treatment of 21 with SmI
2
Acknowledgements
in THF led to 25 as the sole isolable product. It indicated the
unexpected thermodynamic stability of 25 over 30′ although
both compounds embrace cis-fused 5/7 ring systems, which
was further evidenced by base-mediated conversion of 30
into 25 without 30′ detected (Scheme 5).
We acknowledge financial support from the NSFC
(21925106, 21672153, 21921002) and
fundamental research funds for the central universities. We
thank the Analytical & Testing Center of Sichuan University
for NMR recording and X-ray diffraction work. We are
grateful to Dr. Daibing Luo at Sichuan University for his help
in single crystal analysis.
4
Actually, to properly install the hydroxyl at C , we first
attempted deprotonation of compound 26 and coupled the
resulting enolate with different oxaziridines involving the
Davis’ reagent (+)-31 (Scheme 6A). Unfortunately, under
those conditions, either no reaction was observed, or only
trace amount of 32′ with cis-5/7 ring system was generated
instead of the desired 32. Supposing that protection of free
alcohols and enhancement of opposite steric hindrance
might induce favored diastereoselective hydroxylation, we
transformed 26 to 33 to test the practicability (Scheme 6B).
In most cases, enolation of 33 with strong bases, followed by
treatment with oxaziridine, led to either no reaction or
decomposition of the reactant. The best 20% (brsm 31%)
yield of the desired compound 34 was achieved when 33
was subjected to sodium hexamethyldisilazide (NaHMDS)
and (+)-31 in THF at 0 ℃ . Fortunately, a three-step
manipulation was developed to successfully transform 26 to
Notes and references
[
[
1] a) E. Hecker, Pure Appl. Chem., 1977, 49, 1423-1431;
b) W. Adolf, E. Hecker, Isr. J. Chem., 1977, 16, 75-83.
2] a) H. B. Wang, X. Y. Wang, L. P. Liu, G. W. Qin, T. G.
Kang, Chem. Rev., 2015, 115, 2975-3011; b) G.
Appendino, Progress in the chemistry of organic natural
products., 2016, 102, 1-90; c) Y. X. Jin, L. L. Shi, D. P.
Zhang, H. Y. Wei, Y. Si, G. X. Ma, J. Zhang, Molecules.,
2
019, 24; d) S. G. Liao, H. D. Chen, J. M. Yue, Chem.
Rev., 2009, 109, 1092-1140; e) H. A. Abdelgadir, J.
Van Staden, South African Journal of Botany., 2013, 88,
204-218; f) R. K. Devappa, H. P. S. Makkar, K. Becker,
J. Am. Oil Chem. Soc., 2011, 88, 301-322; g) F. J.
Evans, C. J. Soper, Lloydia-the Journal of Natural
Products., 1978, 41, 193-233.
2
8 as illustrated in scheme 4.
[
3] R. J. Schmidt, Bot. J. Linn. Soc., 1987, 94, 221–230.
Scheme 6. Attempts to install β-OH at C4.
[4] G. A. Miana, M. Riaz, S. Shahzad-ul-Hussan, R. Z.
Paracha, U. Z. Paracha, Mini-Reviews in Medicinal
Chemistry., 2015, 15, 1122-1130.
[
[
[
5] P. A. Wender, J. M. Kee, J. M. Warrington, Science.,
2
008, 320, 649-652.
6] G. Goel, H. P. S. Makkar, G. Francis, K. Becker,
International Journal of Toxicology., 2007, 26, 279-288.
7] a) B. Flaschentrager, F. F. Falkenhausen, Justus
Liebigs Ann. Chem., 1934, 514, 252-260; b) H. W.
Thielmann, E. Hecker, Justus Liebigs Ann. Chem.,
1
969, 728, 158-183.
[
8] H. B. Wang, W. J. Chu, Y. Wang, P. Ji, Y. B. Wang, Q.
Yu, G. W. Qin, J. Asian Nat. Prod. Res., 2010, 12,
1
038-1043.
9] a) R. Liu, J. Feng, B. Liu, Acta Chim. Sinica., 2016, 74,
4-43 and references cited therein; b) Y. Li, M. Wei, M.
[
2
Dai, Tetrahedron., 2017, 73, 4172-4177; c) L. V.
Nguyen, A. B. Beeler, Org. Lett., 2018, 20, 5177-5180;
d) Z. G. Brill, Y.-M. Zhao, V. H. Vasilev, T. J. Maimone,
Tetrahedron., 2019, 75, 4212-4221; e) K. Watanabe, Y.
Suzuki, K. Aoki, A. Sakakura, K. Suenaga, H. Kigoshi,
J. Org. Chem., 2004, 69, 7802-7808; f) X. Liu, J. Liu, J.
Zhao, S. Li, C. C. Li, Org. Lett., 2017, 19, 2742-2745; g)
K. Murai, S.-i. Katoh, D. Urabe, M. Inoue, Chem. Sci.,
Conclusions
In general, we have completed
a convergent total
2
013, 4, 2364-2368; h) J. K. Cha, O. L. Epstein,
synthesis of crotophorbolone in eighteen longest linear steps.
The synthesis features expedient construction of the fully
functionalized substructures, i.e. the six-membered fragment
Tetrahedron., 2006, 62, 1329-1343; i) S. Chow, T.
Krainz, P. V. Bernhardt, C. M. Williams, Org. Lett.,
2
019, 21, 8761-8764; j) A. Pascual-Escudero, M.
1
2 through diastereoselective hydroxylation and vinylation,
González-Esguevillas, S. Padilla, J. Adrio, J. C.
Carretero, Org. Lett., 2014, 16, 2288-2231; k) A. J.
Catino, A. Sherlock, P. Shieh, J. S. Wzorek, D. A.
Evans, Org. Lett., 2013, 15, 3330-3333; l) C. Stewart,
R. McDonald, F. G. West, Org. Lett., 2011, 13, 720-723;
m) G. L. Carroll, R. D. Little, Org. Lett., 2000, 2, 2873-
the five-membered fragment 17 through selective
methallylation and aldol condensation, and the 5/7/6 tricyclic
framework through nucleophilic coupling and RCM
cyclization. Selective installation of alcohols at C20 and C4
proved challenging but accessible. Undoubtedly, our
discovery on stability of 25 over 30′ would benefit design of
concise routes in future total synthesis of crotophorbolone
and other structurally and biosynthetically related
diterpenoids.
2
876.
[
10] a) J. D. Winkler, M. B. Rouse, M. F. Greaney, S. J.
Harrison, Y. T. Jeon, J. Am. Chem. Soc., 2002, 124,
9
726-9728; b) K. Tanino, K. Onuki, K. Asano, M.
Miyashita, T. Nakamura, Y. Takahashi, I. Kuwajima, J.
Am. Chem. Soc., 2003, 125, 1498-1500; c) A. Nickel, T.
Maruyama, H. Tang, P. D. Murphy, B. Greene, N.
Yusuff, J. L. Wood, J. Am. Chem. Soc., 2004, 126,
Conflicts of interest
4

Page 5 of 6
Chemical Science
ARTICLE
1
2
6300-16301; d) I. Kuwajima, K. Tanino, Chem. Rev.,
005, 105, 4661-4670; e) T. Ohyoshi, S. Funakubo, Y.
[25] C. Samojlowicz, M. Bieniek, A. Zarecki, R.
V
K
ie
a
w
d
A
y
rt
r
ic
o
le
v
O
,
n
K
line
.
DOI: 10.1039/D0SC02829K
Grela, Chem. Commun., 2008, 6282-6284.
Miyazawa, K. Niida, I. Hayakawa, H. Kigoshi, Angew.
Chem. Int. Ed., 2012, 51, 4972-4975; f) L. Jorgensen, S.
J. McKerrall, C. A. Kuttruff, F. Ungeheuer, J. Felding, P.
S. Baran, Science., 2013, 341, 878-882; g) S. J.
McKerrall, L. Jorgensen, C. A. Kuttruff, F. Ungeheuer,
P. S. Baran, J. Am. Chem. Soc., 2014, 136, 5799-5810;
h) Y. Jin, C. H. Yeh, C. A. Kuttruff, L. Jorgensen, G.
Dunstl, J. Felding, S. R. Natarajan, P. S. Baran, Angew.
Chem. Int. Ed., 2015, 54, 14044-14048.
[26] L. Jafarpour, H. J. Schanz, E. D. Stevens, S. P. Nolan,
Organometallics., 1999, 18, 5416-5419.
[27] X. Huang, L. Song, J. Xu, G. Zhu, B. Liu, Angew.
Chem. Int. Ed., 2013, 52, 952-955.
[28] a) M. S. Chen, M. C. White, J. Am. Chem. Soc., 2004,
126, 1346-1347; b) M. S. Chen, N. Prabagaran, N. A.
Labenz, M. C. White, J. Am. Chem. Soc., 2005, 127,
6970-6971.
[29] A. A. Ghogare, A. Greer, Chem. Rev., 2016, 116, 9994-
[
11] a) P. A. Wender, H. Kogen, H. Y. Lee, J. D. Munger, R.
10034.
S. Wilhelm, P. D. Williams, J. Am. Chem. Soc., 1989,
[30] I. Volchkov, D. Lee, Chem. Soc. Rev., 2014, 43, 4381-
4394.
1
11, 8957-8958; b) P. A. Wender, F. E. McDonald, J.
Am. Chem. Soc., 1990, 112, 4956-4958; c) P. A.
Wender, K. D. Rice, M. E. Schnute, J. Am. Chem. Soc.,
1
997, 119, 7897-7898; d) K. Lee, J. K. Cha, J. Am.
Chem. Soc., 2001, 123, 5590-5591; e) S. Kawamura, H.
Chu, J. Felding, P. S. Baran, Nature., 2016, 532, 90-93.
12] a) G. Tong, Z. Liu, P. Li, Chem., 2018, 4, 2944-2954.
b) G. Tong, Z. Ding, Z. Liu, Y. Ding, L. Xu, H. Zhang, P.
Li, J. Org. Chem., 2020, 85, 4813-4837.
[
[
13] a) P. A. Wender, C. D. Jesudason, H. Nakahira, N.
Tamura, A. L. Tebbe, Y. Ueno, J. Am. Chem. Soc.,
1
997, 119, 12976-12977; b) P. A. Wender, N.
Buschmann, N. B. Cardin, L. R. Jones, C. Kan, J. M.
Kee, J. A. Kowalski, K. E. Longcore, Nat. Chem., 2011,
3
, 615-619; c) S. Hashimoto, S.-i. Katoh, T. Kato, D.
Urabe, M. Inoue, J. Am. Chem. Soc., 2017, 139,
6420-16429.
14] A. Vasas, J. Hohmann, Chem. Rev., 2014, 114, 8579-
612
15] a) T. Asaba, Y. Katoh, D. Urabe, M. Inoue, Angew.
Chem. Int. Ed., 2015, 54, 14457-14461; b) D. Urabe, T.
Asaba, M. Inoue, Bull. Chem. Soc. Jpn., 2016, 89,
1
[
[
8
1
137-1144.
[
[
16] a) J. Feng, H. Yin, Y. Man, S. Fu, B. Liu, Chin. J.
Chem., 2018, 36, 831-836; b) J. Feng, T. Yu, Z. Zhang,
J. Li, S. Fu, J. Chen, B. Liu, Chem. Commun., 2018, 54,
7
665-7668.
17] a) C. Yuan, B. Du, L. Yang, B. Liu, J. Am. Chem. Soc.,
013, 135, 9291-9294; b) L. Song, G. Zhu, Y. Liu, B.
Liu, S. Qin, J. Am. Chem. Soc., 2015, 137, 13706-
3714; c) H. Deng, W. Cao, R. Liu, Y. Zhang, B. Liu,
2
1
Angew. Chem. Int. Ed., 2017, 56, 5849-5852; d) C.
Yuan, B. Du, H. Deng, Y. Man, B. Liu, Angew. Chem.
Int. Ed., 2017, 56, 637-640; e) B. Du, Z. Huang, X.
Wang, T. Chen, G. Shen, S. Fu, B. Liu, Nat. Commun.,
2
019, 10, 1892.
[
18] A. Leticia Garcia-Cabeza, R. Marin-Barrios, R. Azarken,
F. Javier Moreno-Dorado, M. J. Ortega, H. Vidal, J. M.
Gatica, G. M. Massanet, F. M. Guerra, Eur. J. Org.
Chem., 2013, 2013, 8307-8314.
[
[
[
[
[
19] F. Camps, J. Coll, J. Guitart, Tetrahedron., 1986, 42,
4
603-4609.
20] H. J. Reich, F. Chow, J. Chem. Soc., Chem. Commun.,
975, 790-791.
21] C. J. Kowalski, J. S. Dung, J. Am. Chem. Soc., 1980,
02, 7950-7951.
22] R. Naef, D. Seebach, Angew. Chem. Int. Ed., 1981, 20,
030-1031.
23] a) A. I. Meyers, B. A. Lefker, Tetrahedron. Lett., 1987,
8, 1745-1748; b) A. I. Meyers, B. A. Lefker,
1
1
1
2
Tetrahedron., 1987, 43, 5663-5676; c) A. I. Meyers, C.
A. Busacca, Tetrahedron. Lett., 1989, 30, 6977-6980.
24] a) L. A. Paquette, F. Gallou, Z. Zhao, D. G. Young, J.
Liu, J. Yang, D. Friedrich, J. Am. Chem. Soc., 2000,
[
1
22, 9610-9620; b) T. V. Ovaska, S. E. Reisman, M. A.
Flynn, Org. Lett., 2001, 3, 115-117; c) O. L. Epstein, J.
K. Cha, Angew. Chem. Int. Ed., 2005, 44, 121-123.
5

Chemical Science
Page 6 of 6
ARTICLE
View Article Online
Entry for the Table of Contents
DOI: 10.1039/D0SC02829K
Convergent total synthesis of crotophorbolone was
accomplished in 18 longest linear steps by combining
all facilely accessible fragments. Unexpected
thermodynamic stability of a cis,trans-5/7/6 tricycle
was observed, benefiting future synthetic design of
rhamnofolane-,
diterpenoids.
tigliane-
and
daphnane-type
6