Asymmetric total synthesis of crotophorbolone: Construction of the 5/7/6-fused ring system via an α-alkoxy bridgehead radical reaction

Article abstract of DOI:10.1246/bcsj.20160208

This account describes the development of a synthetic route to crotophorbolone (1). Compound 1 is classified as a derivative of the tigliane diterpenoids, and possesses a highly oxygenated 5/7/6-fused ABC-ring system. First, the six-membered C-ring fragment with five contiguous stereocenters was stereoselectively constructed from (R)-carvone. Nucleophilic addition of the three-carbon unit to the C-ring and stereoselective attachment of the five-membered A-ring through a π-allyl Stille coupling reaction provided the substrate for the key radical cyclization. Next, treatment of the O,Se-acetal with V-40 and (TMS)3SiH in refluxing toluene generated the α-alkoxy bridge-head radical, which participated in the endo-cyclization of the seven-membered B-ring with formation of the sterically congested bond in C9-stereospecific and C10-stereoselective manners. The C11-methyl group controlled the C10-stereochemical outcome via a long-range steric interaction, which was supported by the calculated transition state of the abbreviated α- alkoxy bridgehead radical structure. Finally, the functional groups on the 5/7/6-membered ring system were manipulated by Rh-catalyzed C2-olefin isomerization, C13-decarboxylative oxidation and C4-hydroxylation, completing the first total synthesis of 1 in 33 steps from (R)-carvone.

Full text of DOI:10.1246/bcsj.20160208

Advance Publication Cover Page
Asymmetric Total Synthesis of Crotophorbolone: Construction of the 5/7/6-Fused
Ring System via an -Alkoxy Bridgehead Radical Reaction
Daisuke Urabe, Taro Asaba, and Masayuki Inoue*
Advance Publication on the web July 6, 2016 by J-STAGE
doi:10.1246/bcsj.20160208
© 2016 The Chemical Society of Japan

Asymmetric Total Synthesis of Crotophorbolone: Construction of the 5/7/6-Fused
Ring System via an -Alkoxy Bridgehead Radical Reaction
Daisuke Urabe,1 Taro Asaba,1 Masayuki Inoue*1
1
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
E-mail: <Inoue@mol.f.u-tokyo.ac.jp >
Daisuke Urabe
Daisuke Urabe received his Ph.D. degree in 2006 from Nagoya University under the supervision of Professors Minoru
Isobe and Toshio Nishikawa. He carried out postdoctoral research with Professor Yoshito Kishi at Harvard University
(2006-2007). In 2008, he joined the Graduate School of Pharmaceutical Sciences at the University of Tokyo as an
assistant professor in the research group of Professor Masayuki Inoue, and was promoted to lecturer in 2013. He has
been honored with the Young Scientist’s Research Award in Natural Product Chemistry (2013), Thieme Chemistry Journal
Award 2014 and the Pharmaceutical Society of Japan Award for Young Scientists (2015
Taro Asaba
Taro Asaba recieved his B.S. degree in 2011 and M.S. degree in 2013 from the University of Tokyo. He then received
his Ph.D. in 2016 from the same university under the supervision of Professor Masayuki Inoue. He is currently working
for Eisai Co., Ltd.
Masayuki Inoue
Masayuki Inoue was born in Tokyo in 1971. He received a B.Sc. degree in Chemistry from the University of Tokyo in
1993. In 1998, he obtained his Ph.D. from the same university, working under the supervision of Prof. Kazuo Tachibana.
After spending two years with Prof. Samuel. J. Danishefsky at the Sloan-Kettering Institute for Cancer Research
(1998-2000), he joined the Graduate School of Science at Tohoku University as an assistant professor in the research
group of Prof. Masahiro Hirama. At Tohoku University, he was promoted to lecturer in 2003, and then to associate
professor in 2004. In 2007, he moved to the Graduate School of Pharmaceutical Sciences, The University of Tokyo as a
full professor. He has been honored with the Young Scientist’s Research Award in Natural Product Chemistry (2001),
the First Merck-Banyu Lectureship Award (2004), The Chemical Society of Japan Award for Young Chemists (2004),
Novartis Chemistry Lectureship 2008/2009, 5th JSPS Prize (2008) and the Mukaiyama Award 2014. His research
interests include the synthesis, design and study of biologically important molecules, with particular emphasis on the total
synthesis of structurally complex natural products.
Abstract
This account describes the development of a synthetic
route to crotophorbolone (1). Compound 1 is classified as a
1. Introduction
Plants of the Euphorbiaceae and Thymelaeaceae families
contain diverse isoprenoids.1 Diterpenoids occurring in these
plants attract significant attention as a source of drugs and
derivative of the tigliane diterpenoids, and possesses a highly
oxygenated 5/7/6-fused ABC ring system.
First, the
probes due to their pharmacologically useful bioactivities.
A
six-membered C-ring fragment with five contiguous
stereocenters was stereoselectively constructed from
(R)-carvone. Nucleophilic addition of the three-carbon unit to
the C-ring and stereoselective attachment of the five-membered
A-ring through the -allyl Stille coupling reaction provided the
substrate for the key radical cyclization. Next, treatment of
the O,Se-acetal with V-40 and (TMS)3SiH in refluxing toluene
generated the -alkoxy bridgehead radical, which participated
in the endo-cyclization of the seven-membered B-ring with
formation of the sterically congested bond in C9-stereospecific
and C10-stereoselective manners. The C11-methyl group
controlled the C10-stereochemical outcome via a long-range
steric interaction, which was supported by the calculated
transition state of the abbreviated -alkoxy bridgehead radical
considerable number of isolated diterpenoids are classified into
more than 20 skeletal types including tigliane, daphnane,
ingenane, jatrophane, lathyrane, and myrsinane.
To date, more than one hundred tigliane and daphnane
diterpenoids have been identified from Euphorbiaceae and
Thymelaeaceae, and many of them have been shown to exhibit
a remarkably broad range of selective biological activities.1
For instance, C12,13-diacylated derivative of phorbol, 2
a
tigliane, expresses tumor promoting activity (Figure 1), while
3
prostratin,
12-deoxyphorbol-13-acetate, shows latent
HIV-activating activity.4 The daphnane resiniferatoxin5 is a
potent activator of TRPV1,6 an ion channel protein in the
plasma membrane of sensory neurons, and possesses an
analgesic effect. These natural products share a highly
oxygenated 5/7/6-fused tricyclic ABC-ring system, and only
differ in the substitution patterns at the C12,13,14-positions.
Since the C1-11 substructure highlighted in gray is identical
among these compounds, the C12,13,14-functionalities are
structure.
Finally, the functional groups on the
5/7/6-membered ring system were manipulated by
Rh-catalyzed C2-olefin isomerization, C13-decarboxylative
oxidation and C4-hydroxylation, completing the first total
synthesis of 1 in 33 steps from (R)-carvone.

likely to function as important structural elements for
diversifying their biological functions.
efficient formation of the sterically congested C9-10 bond
between the A- and C-rings. To realize this, we decided to
incorporate the intramolecular -alkoxy bridgehead radical
reaction of 3a/b, which was designed to possess the
cyclopentenone and O,Se-acetal moieties as the radical
acceptor and donor, respectively. 15 The stereochemically
defined and highly reactive bridgehead radical generated from
oxabicyclo[2.2.2]octane 3a/b would undergo 7-endo
cyclization into 2 with C9-stereospecific connection of the
hindered bond. Installation of the C2-methyl group embedded
in the enone system, C4-hydroxylation of the A-ring and
oxidative cleavage of the C13-13' bond would transform 2 to
the target molecule 1.
Accordingly, this radical-based
strategy would simplify the stereochemical issues, because only
two stereocenters (C4,10) out of six would need to be
introduced upon conversion from 3a/b to 1. Two substrates
3a and 3b with the skipped diene structure were planned to be
assembled from the C-ring
functionalized five-membered
4
and the appropriately
A-ring fragment by
Horner-Wadsworth-Emmons olefination and -allyl Stille
coupling reaction, respectively. Pattern recognition of the
-oriented isopropenyl cyclohexane substructure within 4 led
us to utilize (R)-carvone as the starting material.16
Figure 1. Structures of crotophorbolone (1) and related natural
products
Crotophorbolone (1, Figure 1) was isolated as a degraded
compound of phorbol in 1934, and its structure was determined
in 1969.7 In 2010, 1 was identified from the dried plant roots
of Euphorbia fischeriana Steud, which has been used as a
traditional Chinese medicine for treatment of edema, ascites
and cancer.8 15,16-Dihydrocrotophorbolone, designated as
langduin A, was also identified from the same plant source.9
The structures of 1 and langduin A are the same as those of
phorbol, prostratin and resiniferatoxin except for the
C12,13,14-substitutions on the C-ring. Recently, Wender
demonstrated efficient conversion of 1 to prostratin through a
four-step manipulation of the C13,14-stereocenters.4
Tiglianes, daphnanes and their derivatives collectively have
attracted a great deal of attention from the synthetic community
due to their significant biological activities and architecturally
10
complex structures.
Despite numerous studies, fully
chemical construction of tiglianes and daphnanes has been
hampered for many decades. Successful total syntheses of
this class of molecules were only reported by Wender’s group11
and Cha’s group,12 before our laboratory disclosed the total
synthesis of 1 in 2015. 13 Most recently, Baran’s group
described the biosynthesis-inspired elegant total synthesis of
phorbol.14
Our primary synthetic interest focused on establishing a new
efficient strategy for assembly of the C1-11 common motif of
the tigliane and daphnane diterpenoids. Development of such
a strategy would provide access to a number of structurally
related targets by minimum modifications of substrates and
reaction sequences. As the initial phase of this campaign, we
selected crotophorbolone (1) as the target molecule. In this
account, we describe the development of the strategy and
Scheme 1. Synthetic plan of crotophorbolone (1)
In this approach, the C10-stereocenter must be established
during the key radical cyclization (Scheme 2). Since the five
chiral centers are concentrated on the C-ring moiety, the
stereochemical information of the C-ring of 3 must be
transmitted to the achiral A-ring to produce the correct isomer
2 instead of its C10-diastereomer. Computational modeling
studies were thus performed to predict the C10-stereoselectivity.
To simplify the calculation, the radical intermediate I was used
as an abbreviated structure of 3a, whose methoxy, isopropenyl,
and OTIPS groups were replaced with H atoms. The two
transition states TS-1 and TS-2 from I were simulated at the
UM06-2X/6-31G(d) level of theory.17 TS-1, which leads to
the desired IIa, was found to be more stable than TS-2 by 4.1
kcal/mol. Close inspection of the three-dimensional structures
of TS-1 and TS-2 suggested that the equatorially oriented
C11-methyl group influenced the energy difference. While
the distances from H18 of the C11-methyl group of TS-2 to H1
(2.00 Å) and H2 (2.25 Å) are both within the sum of the van
der Waals radii (2.40 Å),18 TS-1 possesses only one such close
contact [H18-1 (2.24 Å), H18-10 (2.41 Å)]. On the basis of
the DFT calculations, we expected that the C10-stereocenter
would be controlled by the remote C11-stereocenter in a
1,9-relationship.
tactics for the total synthesis of 1.
The complex
5/7/6-tricyclic structure of 1 was constructed by efficient
coupling of simple fragments and powerful 7-endo cyclization
of
a specifically designed -alkoxy bridgehead radical
intermediate.
2. Synthetic plan of crotophorbolone
The three trans-fused rings of 1 with the two tertiary
hydroxy (C4, 9), allylic hydroxy (C20), ketone (C13) and
enone groups (C3) present a daunting synthetic challenge
(Scheme 1). Crucial to success of the total synthesis would be

Scheme 2. Calculated transition states of the cyclization at the
UM06-2X/6-31G(d) level. Values in parentheses are relative
free energies (G in kcal mol-1, 1 atm, 298 K)
3. Construction of the 5/7/6-fused ABC-ring system
3-1. Stereoselective synthesis of the C-ring fragment
The synthesis commenced with conversion of (R)-carvone 5
to 12 via introduction of the four new stereocenters (C8, 9, 11,
13) (Scheme 3). Treatment of 5 with TMSCl and MeMgBr in
the presence of catalytic FeCl3 regioselectively produced
dienoxysilane 6.19 Subsequent vinylogous Mukaiyama aldol
20
reaction of 6 by the action of BF3∙OEt2 and CH(OMe)3
attached the dimethyl acetal group at the C13-position in an
anti-selective manner to the bulky C14-isopropenyl group,
leading to 7 as the major product (dr = 5:1 at C13). The
kinetic enolate generated from 7 by LiN(i-Pr)2 underwent the
second aldol reaction at -78 ºC with formaldehyde that was
released in situ from A (2 equiv) and excess LiN(i-Pr)2.21 The
exclusive stereoselectivity in forming the C8-center of 8 was
again controlled by the C14-substituent. Importantly, the
double hydroxymethylation or the elimination of the hydroxy
group were not observed under these mild conditions. After
TIPS-protection of the primary hydroxy group of 8, the
conjugated C11-12 double bond was reduced under Birch
conditions to produce ketone 10 and alcohol 11 with the
thermodynamically stable equatorial C11-methyl group.
Over-reduced 11 was in turn oxidized to 10 by TPAP.22 The
three large coupling constants among the C8, 11, and
13-protons (J
= 12.4, 13.3, 12.4 Hz) confirmed the
Scheme 3. Stereoselective synthesis of the C-ring fragment 4
stereostructure of 10. The sterically demanding lithiated vinyl
ether B in turn approached the C9-ketone of 10 equatorially,
furnishing the pentasubstituted cyclohexane 12.
Next, the caged C9,13'-bis-acetal structure 4 was built from
12 through a six-step functional group manipulation. Upon
activation with CSA, the axial C9-alcohol of 12 participated in
acetal exchange with the C13'-dimethyl acetal to provide
oxabicyclo[2.2.2]octane 13 (dr
=
1:1 at C13').
The
C9-O,Se-acetal was then constructed by conversion of the
C9-vinyl ether of 13.15a Vinyl ether 13 was chemoselectively
oxidized by m-CPBA to carboxylic acid 17. This single step
included a series of reactions in one flask. Thus, the vinyl
ether was first epoxidized with m-CPBA to generate 14, the
hydrolysis of which afforded the hydroxy ketone intermediate
15. The highly electrophilic hydroxy ketone 15 rapidly

underwent Baeyer-Villiger oxidation in situ with excess
m-CPBA, and the resultant hemiacetal 16 was hydrolyzed into
carbonate by using catalytic Pd(PPh3)4 and stoichiometric CuCl,
LiCl and Et3N in DMSO at 80 ºC resulted in the formation of a
1:1 mixture of 3b and its stereoisomer in 26% combined yield.
The application of the same reaction conditions to the more
reactive 29 again was ineffective, leading to decomposition of
29 without isolable products. After screening of additives to
avoid the unwanted side reactions and decomposition,
copper(I)-thiophene-2-carboxylate (CuTC) 31 was found to
significantly accelerate and selectively promote the -allyl
Stille coupling reaction. When 29 was treated with F, CuTC
and K2CO3 in the presence of catalytic Pd(PPh3)4 in DMF, the
C-C bond formation proceeded even at 0 °C to afford 3b with
no geometrical alteration.
carboxylic acid 17.
After mesylation of 17, the
mesyloxycarbonyl group of 18 was converted to the PhSe
group of 20 in one-pot by Barton ester formation 23 and
subsequent photo-irradiation in the presence of (PhSe)2.24
Remarkably, the seven events from vinyl ether 13 to
O,Se-acetal 20 were realized in three steps, thereby shortening
the synthetic route to 20. Removal of the TIPS group of 20,
followed by chromatographic separation, gave rise to (13'R)-21
and (13'S)-21. Finally, (13'R)-21 and (13'S)-21 were subjected
to SO3·pyridine oxidation, yielding the C-ring fragments
(13'R)-4 and (13'S)-4, respectively. The C13'-configuration of
(13'S)-4 was assigned by NOE experiments.
3-2. Attachment of the A-ring
Attachment of the A-ring substructure was realized by two
different coupling methods, resulting in preparation of
substrates 3a and 3b with CN and CH2OTIPS groups at C6,
respectively. Scheme 4A illustrates the synthesis of 3a from
the C13’-diastereomeric mixture of 4. In this approach, the
25
E-selective Horner-Wadsworth-Emmons olefination
was
accomplished by using the C-ring aldehyde 4 and the A-ring
phosphonate D. Use of diphenyl phosphonate D instead of its
dialkyl phosphate counterpart was crucial for the requisite
E-C6-7 regiochemistry.26 Specifically, the phosphonium ylide
derived from D and NaN(TMS)2 reacted with 4 at 0 °C to yield
a 2.2:1 E/Z-mixture of 22, providing desired 22a and its isomer
22b in 48% and 22% yields, respectively, after separation by
HPLC.
An NOE experiment of 22b established the
Z-geometry of its C6-7 double bond. The TBS group of the
thus obtained E-isomer 22a was removed with TBAF in
CH3CN at 60 C, and the resultant hydroxy group of 23 was
oxidized with the Dess-Martin reagent27 to the ketone of 3a.
Hence, the developed sequence established the cis-relationship
of the radical donor (C-ring) and acceptor (A-ring), and
constructed the skipped diene structure. Despite the coupling
efficiency, the inevitable HPLC-purification of E-olefin 22a
limited the scalable synthesis of 3a (below 50 mg), and the
C6-cyanide moiety remained to be reduced at a later stage of
the total synthesis. Accordingly, an alternative route was
planned for preparation of 3b with the C6-oxidation level
corresponding to the targeted 1.
Compound 3b with the trialkyl-substituted C6-7 double bond
was prepared from (13'R)-4 by employing a stereoselective
-allyl Stille coupling reaction (Scheme 4B). Although not
shown, the diastereomeric (13’S)-4 was also utilized as an
intermediate for the total synthesis of crotophorbolone (1).
Before the pivotal Stille reaction, (13'R)-4 was regioselectively
converted to allylic chloride 29 in six steps. Aldehyde
(13'R)-4 was transformed to diol 24 (dr = 14:1 at C7) by
nucleophilic addition of vinyl lithium E. The two hydroxy
Scheme 4. Synthesis of substrates 3a and 3b for the key
cyclization
3-3. Stereoselective 7-endo radical cyclization
As shown in Schemes 3 and 4, the O,Se-acetal structure at the
bridgehead position was retained from 20 to 3a and 3b.
Despite its inertness towards nucleophilic, oxidative and
transition metal reagents, the O,Se-acetal in both 3a and 3b
served as the reactive radical generating functional group
(Table 1). For instance, treatment of 3a with Ph3SnH and
AIBN in refluxing benzene afforded the -alkoxy bridgehead
radical III, which stereospecifically reacted in a 7-endo manner
according to the electronic guidance of the ,-unsaturated
ketone to afford 2a (entry 1). As expected from the
calculations, the C10-stereocenter was completely controlled to
deliver the tricyclic ring system 2a as the sole isomer after the
C4-stereoselective hydrogen transfer from Ph3SnH. However,
the premature reduction of radical III occurred to generate 30a
groups of 24 were then acetylated to afford bis-acetate 25.
A
reagent combination of Pd(0) and KOAc isomerized
disubstituted olefin 25 into trisubstituted olefin 26 via -allyl
formation and site-selective addition of acetate to the less
congested primary position.28 After saponification of 26, the
more exposed C20-hydroxy group of the resultant diol 27 was
regioselectively capped with the bulky TIPS group, and the
remaining C5-hydroxy group of 28 was chlorinated to give 29.
These two transformations enabled selective activation of C5
over C20 for the -allyl Stille coupling reaction.29 However,
the resulting C6-7 geometry30 was partially isomerized under
the standard thermal conditions for coupling with F. For
example, the-allyl Stille coupling of the corresponding allyl

as a side product (19% yield), and the cyclization to the desired
2a was inefficient (19% yield). When a higher temperature
was applied to the reaction [Ph3SnH, V-40 (G), toluene, 110 ºC,
entry 2], the yield of 2a was increased to 31%, and that of 30a
was decreased to 15% yield. Switching Ph3SnH to less
reactive hydrogen donors Bu3SnH (entry 3) and (TMS)3SiH
(entry 4) decelerated the direct reduction of radical III,
resulting in formation of 2a in 39% and 62% yields,
respectively. Remarkably, formation of 30a was completely
suppressed upon the use of (TMS)3SiH. The same reaction
conditions [(TMS)3SiH, V-40 (G), toluene, 110 ºC, entry 5]
were successfully applied to the alternative substrate 3b,
leading to the tricycle 2b in even higher yield (69%). The
stereochemistries at C4, 9 and 10 of 2b were assigned based on
NOE experiments.
Whereas the C10-stereochemical outcome was consistent
throughout the entries, the C6-substituents of 3a and 3b
affected the yields of the products 2a and 2b (62% in entry 4 vs.
69% in entry 5). The bulkier TIPS-protected hydroxymethyl
group of 3b in comparison to the CN group of 3a would
preorganize the reacting A-ring to be proximal to the C9-radical
by destabilizing the non-productive linear conformation, and/or
kinetically protecting the potentially reactive C6-7 double
bond.32
4. Total synthesis of crotophorbolone
4-1. Functionalization of the A-ring
With the tricyclic framework 2b in hand, the C2-, C4- and
C13-functionalizations from 2b were explored to complete the
total synthesis of 1. Installations of the olefinic C2-methyl
and C4-hydroxy groups of 1 to the A-ring were first
investigated (Scheme 5). Ketone 2b was regioselectively
transformed to TMS-enol ether 31, which was homologated
with Eshenmoser’s reagent to provide enone 32 after
elimination of the dimethyl amino group with silica gel.33
Internalization of the exo-olefin of 32 into the more stable
endo-olefin of 33 was effectively catalyzed by RhCl3.34 The
next C4-hydroxylation was problematic, because it was
necessary to perform the oxidation at the sterically shielded
angular position without touching the three other potentially
oxidizable olefins. After screening hydroxylating reagents,
Davis’ reagent H35 was found to serve as the oxidant of the
enolate derived from 33 and NaN(TMS)2.36 However, the
hydroxy group was exclusively introduced from the -face,
providing the undesired cis-fused isomer 34 (31% yield). The
structure of 34 was determined by NOESY experiments.
Therefore, the C4-reduction (3 → 2) and C4-oxidation (33 →
34) both took place from the -faces of the molecules,
indicating that the C4-stereochemical outcome originated from
the intrinsic three-dimensional structure of the acetal-bridged
ring system. According to these data and considerations, we
planned to open the C13’-acetal and install a bulky protecting
group at the C9-hydroxy group prior to the C4-hydroxylation in
order to block the -face and reverse the C4-stereoselectivity.
Most importantly, the present cyclization connected the
tetrasubstituted and trisubstituted carbons of 1, and established
the three contiguous stereocenters (C4,9,10) in a single step.
The alternative diastereomers, the 6-exo cyclization adduct, or
the isomerized product of the skipped olefin were not observed
in any entries, demonstrating the high stereo-, regio- and
chemoselectivities of the radical reaction.
Table 1. Optimization of the radical cyclization
entry
substrate
reductant
products
2a: 19%
30a: 19%
2a: 31%
30a: 15%
2a: 39%
30a: 15%
1a,b 3a: R1 = CN
Ph3SnH
Ph3SnH
Scheme 5. Functionalization of the A-ring
2a
3a
4a
5
3a: R1 = CN
4-2. C13-decarboxylative oxidation
Acid hydrolysis of 33 opened the cyclic acetal and partially
deprotected the C20-hydroxy group, which was re-capped with
the TIPS group to afford 36 (Scheme 6). The extra carbon
C13’ was exchanged to the C13-hydroxy group by radical
oxidation. Thus, oxidation of aldehyde 36 to carboxylic acid
37 and subsequent silylation of the C9-tertiary hydroxy group
3a: R1 = CN
n-Bu3SnH
(TMS)3SiH
3a: R1 = CN
2a: 62%
3b: R1 = CH2OTIPS
(TMS)3SiH
2b: 69%
a
b
with TMSOTf gave rise to 38.
The latter reaction
A 1:1 diastereomixture at C13’ was used.
The reaction was
concomitantly induced the C4-epimerization through TMS-enol
formation and protonation from the -face. The trans-fused
AB-ring system was elucidated by the NOE correlation of the
methylated 39. Although the C4-epimerization was not a
performed in refluxing benzene using AIBN as a radical initiator.

The contrasting stereoselective outcomes of the
C4-hydroxylation of 33 and 43 were considered to originate
from the C9-oxygen-based functional groups (Scheme 7). As
discussed in Section 4-1, while the oxidant approached from
the less hindered -face of the tricyclic framework of 33’, the
bulky TMS-group at C9-O of 43’ would override this intrinsic
steric bias by blocking the -face, thereby allowing installation
of the -oriented C4-OH.
prerequisite for construction of the targeted 1, this result
implied higher accessibility of reagents from the -face of the
molecule as compared to the cyclic acetal intermediates.
Carboxylic acid 38 was stereoselectively transformed to
C13-secondary alcohol 42 by the following one-pot sequence:
i) Barton ester formation with I and EDCI·HCl; ii) peroxide
formation by photo-irradiation in the presence of oxygen and
t-BuSH; and iii) reductive alcohol formation by P(OEt)3.37
The adjacent C14-isopropenyl group directed oxygen to
approach from the less hindered -face, producing the
-oriented C13-hydroxy group having a large coupling
constant between the two axial protons H13 and H14 (J = 10.1
Hz). The thus constructed hydroxy group of 42 was protected
as the TES ether, affording 43.
Table 2. Optimization of C4-hydroxylation
entry
1
oxidant
yielda
43% (62%)
H
2
3
0%b
ent-H
27% (34%)
J
a
b
The yields in parentheses are calculated based on recovered 43.
52% of 43 was recovered.
Scheme 6. Installation of the C13-oxygen functionality
Scheme 7. Explanation for the stereoselectivity of the
C4-hydroxylation
4-3. C4-Hydroxylation
The C4-hydroxylation was re-examined by using 43 as a new
substrate (Table 2). Gratifyingly, the sodium enolate derived
from 43 and NaN(TMS)2 reacted with Davis’ reagent H at
-78 °C to deliver the desired C4-stereoisomer 44 in 43% yield
without forming the undesired C4-epimer (entry 1). It was
worthy of note that the yield of 44 was greatly affected by the
oxidant. The use of the enantiomer of H (ent-H) resulted in
no detectable formation of 44, and 52% of the starting 43 was
recovered (entry 2), while the simple oxidant J38 afforded 44 in
4-4. Completion of the total synthesis
Crotophorbolone (1) was synthesized from 44 in three
additional steps (Scheme 8). In the reaction of 44 with TFA in
a mixture of H2O and THF at 0 ºC, the most labile TES group
of trisilylated 44 was chemoselectively removed, and the
liberated C13-alcohol of 45 was oxidized to the corresponding
ketone of 46 using the Dess-Martin reagent. Finally, HCl in
aqueous MeOH deprotected disilylated 46, giving rise to
crotophorbolone (1). Analytical data of the fully synthetic 1
including the specific rotation, IR, NMR, and HRMS, matched
those of natural 1.
27% yield (entry 3).
These results clarified that the
three-dimensional structures of both the substrate and the
oxidant were crucial to the efficient C4-hydroxylation.

Schmidt, E. Hecker, Tetrahedron Lett. 1976, 17, 1737. b) G. A.
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Scheme 8. Total synthesis of crotophorbolone (1)
8 H.-B. Wang, W.-J. Chu, Y. Wang, P. Ji, Y.-B. Wang, Q. Yu,
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5. Summary
9
Q.-G. Ma, W.-Z. Liu, X.-Y. Wu, T.-X. Zhou, G.-W. Qin,
In summary, we achieved the first total synthesis of the highly
complex diterpenoid crotophorbolone (1) with the 5/7/6-ring
system in 33 total steps from (R)-carvone. Design of the
unique oxabicyclo[2.2.2]octane 3b as the key intermediate
enabled us to utilize the stereochemically predestined -alkoxy
bridgehead radical for cyclization of the central
seven-membered ring of 2b. This transformation proved the
power and generality of the bridgehead radical reaction for
stereoselective construction of the hindered bond within the
Phytochemistry 1997, 44, 663.
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densely functionalized natural product.
Other notable
methodological features of the synthesis include: i)
stereoselective installations of four stereocenters from
(R)-carvone 5; ii) chemoselective construction of the bicyclic
bisacetal structure 20 equipped with the PhSe group; iii)
regioselective formation of the differentially functionalized
C6-trisubstituted olefin 29; iv) efficient coupling of A-ring F
and C-ring 29 by the allyl Stille coupling using CuTC; and
v) highly optimized C2, C4- and C13-functionalization
protocols for conversion of 2b to 1. The present strategy
would be applicable to the unified synthesis of biologically
active tiglianes and daphnanes that possess the same C1-11
moiety as 1. Future investigations in our laboratory will
involve such studies.
We thank Mr. Yuki Katoh for conducting preliminary studies on
this project. This research was financially supported by the
Funding Program Grant-in-Aids for Scientific Research (A)
(JSPS) to M.I., and (C) (JSPS) and on Innovative Areas
(MEXT) to D.U. A fellowship to T.A. from Graduate
Program for Leaders in Life Innovation (MEXT) is gratefully
acknowledged.
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Graphical Abstract
Asymmetric Total Synthesis of Crotophorbolone: Construction of the 5/7/6-Fused Ring System via an -Alkoxy Bridgehead Radical
Reaction
Daisuke Urabe, Taro Asaba, Masayuki Inoue*
This account details the asymmetric total synthesis of crotophorbolone with a highly oxygenated 5/7/6-fused ABC ring system. The
assembly of the complex structure is highlighted by two key C-C bond formations: the -allyl Stille coupling between the
five-membered A- and six-membered C-rings, and -alkoxy bridgehead radical cyclization of the seven-membered B-ring.