Total Synthesis of 1-Hydroxytaxinine

Article abstract of DOI:10.1002/anie.201906872

1-Hydroxytaxinine (1) is a cytotoxic taxane diterpenoid. Its central eight-membered B-ring possesses four oxygen-functionalized centers (C1, C2, C9, and C10) and two quaternary carbon centers (C8 and C15), and is fused with six-membered A- and C-rings. The densely functionalized and intricately fused structure of 1 makes it a highly challenging synthetic target. Reported here is an efficient radical-based strategy for assembling 1 from A- and C-ring fragments. The A-ring bearing an α-alkoxyacyl telluride moiety underwent intermolecular coupling with the C-ring fragment by a Et₃B/O₂-promoted decarbonylative radical formation. After construction of the C8-quaternary stereocenter, a pinacol coupling reaction using a low-valent titanium reagent formed the B-ring with stereoselective installation of the C1,C2-diol. Subsequent manipulations at the A- and C-rings furnished 1 in 26 total steps.

Full text of DOI:10.1002/anie.201906872

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition
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Accepted Article
Title: Total Synthesis of 1-Hydroxytaxinine
Authors: Yusuke Imamura, Shun Yoshioka, Masanori Nagatomo, and
Masayuki Inoue
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906872
Angew. Chem. 10.1002/ange.201906872
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http://dx.doi.org/10.1002/ange.201906872

10.1002/anie.201906872
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis of 1-Hydroxytaxinine
Yusuke Imamura+, Shun Yoshioka+, Masanori Nagatomo, and Masayuki Inoue*
Dedication ((optional))
Abstract: 1-Hydroxytaxinine (1) is a cytotoxic taxane diterpenoid. Its
AcO
10
11
OAc
AcO
A
O
OH
C
central 8-membered B-ring possesses four oxygen-functionalized
centers (C1, 2, 9, and 10) and two quaternary carbons (C8 and 15),
and is fused with 6-membered A- and C-rings. The densely
functionalized and intricately fused structure of 1 makes it a highly
challenging synthetic target. We developed an efficient radical-based
strategy for assembling 1 from A- and C-ring fragments. A-ring 5
bearing the -alkoxyacyl telluride moiety underwent intermolecular
coupling with C-ring 6 via a Et3B/O2-promoted decarbonylative radical
formation. After construction of the C8-quaternary stereocenters, a
pinacol coupling reaction of 4 using a low-valent titanium reagent
formed the B-ring of 3 with stereoselective installation of the C1,2-diol
system. Subsequent manipulations at the A- and C-rings furnished 1
in 26 total steps.
9
7
O
83 C
B
B
5
BzHN
Ph
O
A15
1
2
O
Ph
O
4
H
H
13
O
O
OAc
HO OAc 20
1-hydroxytaxinine (1)
HO OBz
taxol (2)
OH
O
O
O
O
pinacol
coupling
decarbonylative
radical coupling
8
9
8
C
O
B
2
C
5
NC
A
3
1
2
1
2
13
4
6
+
HO OH
O
O
3
4
O
O
O
TePh
10
9
9
11
15
1
OMe
11
+
O
A
10
1
O
1-Hydroxytaxinine (1, Scheme 1), isolated from stems of the
Japanese yew, Taxus cuspidata,[1] is cytotoxic to murine leukemia
L1210 cells and human epidermoid carcinoma KB cells (IC50 = 4.6
and 6.9 g/mL, respectively). This natural product belongs to a
family of taxane diterpenoids containing more than 400
congeners.[2] Many compounds in this family have biologically
important properties, and taxol (2),[3] one of the most bioactive
congeners, is used clinically to treat various cancers.[4]
As exemplified by the structures of 1 and 2, taxane diterpenoids
share a 6/8/6-membered carbon framework (ABC-ring system)
and differ in their substitution patterns of oxygen functionalities.
Compound 1 has six oxygen-substituted carbons (C1, 2, 5, 9, 10,
and 13). The presence of two quaternary carbons (C8, 15) and
two olefins (C4, 11) in this densely oxygenated skeleton further
heightens the synthetic challenge of 1. Whereas 2 has been
chemically constructed by 10 research groups,[5,6] the total
synthesis of 1 was only reported in a dissertation from Kishi's
group in 1998.[7] In this report, Ni(II)/Cr(II)-mediated coupling[8]
was applied for the construction of the 8-membered B-ring and 1
was synthesized in 38 steps (longest linear sequence). Herein,
we describe a new radical-based strategy for the total synthesis
of 1. A combination of intermolecular and intramolecular radical
coupling reactions permitted us to efficiently annulate the B-ring
from A- and C-ring fragments.
O
8
O
O
7
5
Scheme 1. Structures of 1-hydroxytaxinine (1) and taxol (2) and synthetic plan
for 1.
Radical reactions are compatible with diverse oxygen
functionalities and applicable to the formation of sterically
hindered C–C bonds, thereby serving as methods to forge the
complex architectures of highly oxygenated terpenoids.[9] In this
context, we developed a series of powerful coupling reactions of
-alkoxy carbon radicals.[10,11] Our continued interest in these
reactions motivated us to devise an efficient radical-based
convergent route to 1 from chiral 5 and achiral 6 (Scheme 1).[12]
A-ring 5 and C-ring 6 were designed to have an acetonide-
protected C9,10-diol and C2-nitrile groups as stereocontrolling
and reactivity-enhancing elements, respectively. Decarbonylative
radical formation from -alkoxyacyl telluride 5 would generate the
corresponding
[13]
C9--alkoxy
radical,
which
would
stereoselectively add to 2-cyano-2-cyclohexen-1-one (6) to link
the C8–C9 bond. After construction of the C8-quaternary carbon,
pinacol coupling of ketoaldehyde 4 was to be applied for both
cyclization of the 8-membered B-ring and installation of the C1,2-
stereocenters of 3.[14] Subsequent adjustment of the C3-, C4-,
C5-, and C13-functional groups at the A- and C-rings would
transform 3 to target 1. Retrosynthetically, the key radical
precursor 5 was further simplified into methyl acrylate (8) and 2,2-
dimethylcyclohexane-1,3-dione (7), which has the preinstalled
C15-quaternary carbon. Hence, 1 was to be assembled from
three commercially available components 6, 7, and 8.
[☆]
Y. Imamura,[+] Dr. D. Yoshioka,[+] Dr. M. Nagatomo, and Prof. Dr. M.
Inoue
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: inoue@mol.u-tokyo.ac.jp
These authors contributed equally to this work
Supporting information and the ORCID identification number(s) for
the author(s)of this article can be found under:
https://doi.org/10.1002/anie.XXXXX.
[+]
This article is protected by copyright. All rights reserved.

10.1002/anie.201906872
Angewandte Chemie International Edition
COMMUNICATION
O
OMe
O
O
OMe
OH
e.
OMe
9
10
11
9
HO
8
a. (CH2OH)2
(+)-CSA
c. NH2NH2
d. I2
O
g. Me2C(OMe)2
PPTS
O
O
I
10
11
Pd(PPh3)4
f. AD-mix-
R1
12
12
O
O
O
O
1
O
O
O
O
12
O
7
b. LiN(SiMe3)2
MeI
9: R1 = H
11
13
(96% ee)
10: R1 = Me
C
O
O
O
O
O
O
O
O
O
O
9
CN
10
TePh
OMe
8
8
9
9
9
6
6
j. , Et3B, air
; DDQ
h. LiOH
C
C
O
O
A
A
A
A
O
O
O
–EtTePh
–CO
i. iBuOCOCl;
(PhTe) 2, NaBH4
O
O
CN
CN
OBEt2
O
O
O
O
O
O
B
A
5
14
15
15
( 96% ee)
(>99% ee)
recrystallization
k. MeMgBr, CuI;
NaBH4
p. CrO3
O
O
O
O
O
10
O
O
O
9
2
l. MsCl;
DBU
m. iBu2AlH;
aq. HCl
n. TiCl4, Zn
pyridine
11
8
8
N NH
B
5
1
2
1
4
O
O
13
CN
CN
O
O
HO OR2
OH
O
O
O
16
17
4
3: R2 = H
o. Ac2O
18: R2 = Ac
O
O
O
O
O
O
O
O
HO
Ph
t.
r. catecholborane
NaOAcꞏ3H2O
2,4,6-Cl3C6H2COCl
s. OsO4, NMO
OH
O
8
3
5
5
5
3
4
4
5
O
Ph
X
H
H
H
13
O
O
O
O
OH
OH
HO OAc
HO OAc
HO OAc
HO OAc
19: X = O
20
Cin
23
22
21
q. TsNHNH2
AcO
: X = NNHTs
u. PCC
OAc
O
O
O
O
AcO
OAc
O
H
x.Et3N S N CO2Me
O
11
v. MeMgBr
15
1
4
4
OCin
OH
4
4
1
R3 = H
H
OCin
OCin
OH
OCin
O
H
H
H
OAc
OH
OAc
O
O
O
Y
O
HO OAc
24: Y = O
25
HO OAc
26
20
O2S
C
28
olefination
NHCO2Me
: Y = CH2
w. CF3CO2H;
Ac2O
O
H
AcO
OAc
AcO
OAc
x.Et3N S N CO2Me
O
R
3 = SiHMe2
B
C
4
A
1
8
OCin
OH
OCin
z. HFꞏpyridine
H
H
O
O
R3O OAc
HO OAc
1-hydroxytaxinine (1)
: R3 = H
27
y. Me2HSiCl
29: R3 = SiHMe2
15 (CCDC 19092621)
1 (CCDC 19092620)
Scheme 2. Total synthesis of 1-hydroxytaxinine. Reagents and conditions: a) (CH2OH)2, (+)-10-camphorsulfonic acid (CSA), toluene, 50 °C, 67%; b) LiN(SiMe3)2,
MeI, THF, –78 °C to RT, 98%; c) NH2NH2H2O, Et3N, EtOH, 100 °C, 76%; d) I2, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), Et2O, RT, 72%; e) 8, Et3N, Pd(PPh3)4 (3
mol%), DMF, 80 °C, 94%; f) AD-mix- (2 equiv), methanesulfonamide (MsNH2), H2O, tBuOH, RT; g) 2,2-dimethoxypropane, pyridinium p-toluenesulfonate (PPTS),
CH2Cl2, RT, 41% (2 steps, 96% ee); h) LiOHH2O, THF, H2O, RT; i) iBuOCOCl, N-methylmorpholine (NMM), THF; (PhTe)2, NaBH4, THF, MeOH, 0 °C to RT, 91%
(2 steps). j) 6 (2 equiv), Et3B (3 equiv), air, benzene, 50 °C; 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), 2,6-lutidine, 50 °C, 15 (96% ee): 65%; recrystallization
(hexane, EtOAc, 60 °C), 15 (>99% ee): 76%; k) MeMgBr, CuI, Me2S, toluene, –20 °C; NaBH4, EtOH, RT; l) methanesulfonyl chloride (MsCl), Et3N, benzene, RT;
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 100 °C, 17:C8-epi-17 = 7:1; m) iBu2AlH, hexane, 20 °C; 1 M aq. HCl, RT, 61% (3 steps); n) TiCl4 (4 equiv), Zn (10
equiv), pyridine, THF, 50 °C; o) Ac2O, N,N-dimethyl-4-aminopyridine (DMAP), pyridine, CH2Cl2, RT, 18: 45% (2 steps), C2-epi-3: 6% (2 steps); p) CrO3, 3,5-
dimethylpyrazole (3,5-DMP), CH2Cl2, RT, 55%; q) p-toluenesulfonyl hydrazide (TsNHNH2), AcOH, RT, 94%; r) catecholborane, THF, 0 °C; NaOAc3H2O, CHCl3,
85 °C, 21: 47%, C3-epi-21: 21%; s) OsO4 (10 mol%), N-methylmorpholine N-oxide (NMO), acetone, H2O, RT, 76%; t) cinnamic acid, 2,4,6-trichlorobenzoyl chloride,
Et3N, DMAP, toluene, RT; u) pyridinium chlorochromate (PCC), MS4A, CH2Cl2, RT, 76% (2 steps); v) MeMgBr, THF, 60 °C to 30 °C, 12% recovered 24; w)
CF3CO2H, MeOH, 50 °C; Ac2O, DMAP, pyridine, CH2Cl2, RT, 34% (2 steps); x) Et3NSO2NCO2Me, toluene, 120 °C, 28: 16%, 1: 13%; y) Me2HSiCl, imidazole, DMF,
0 °C, 89%; z) HFpyridine, THF, RT, 56% (2 steps from 29).
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10.1002/anie.201906872
Angewandte Chemie International Edition
COMMUNICATION
A-ring fragment 5 was prepared from 7 and 8 in nine steps
(Scheme 2). One of the two carbonyl groups of 7 was protected
as the dioxolane of 9 using ethylene glycol and camphorsulfonic
acid (CSA). The remaining ketone of 9 was -methylated with
LiN(SiMe3)2 and MeI, and transformed to the vinyl iodide of 11
through generation of the corresponding hydrazone and its
treatment with I2 in the presence of 1,5-diazabicyclo[4.3.0]non-5-
ene (DBN).[15] The Pd(0)-catalyzed Heck reaction between 11
and 8 extended the carbon chain at C11, leading to the -
unsaturated ester 12.[16] The less substituted C9-olefin of diene
12 was regio- and enantioselectively dihydroxylated by employing
AD-mix- to provide 13 (96% ee).[17,18] After acetonide protection
of the resulting vicinal diol 13, methyl ester 14 was saponified with
aqueous LiOH. The activated ester was formed using iBuOCOCl
and N-methylmorpholine (NMM) and changed in situ into an -
alkoxyacyl telluride of 5 by attack of the TePh anion generated
from NaBH4 and (PhTe)2.[13]
at 50 °C allowed for the formation of tricycle 3 with the desired
C1,2-stereochemistry (entry 2). After acetylation, however, 18
was isolated in variable yields (0%-33%) due to competing
reduction of the C2-aldehyde of 4 to a primary alcohol. Because
of the low yield and reproducibility, we turned our attention to
other low-valent metal reagents. When 4 was subjected to
[27]
VCl3(THF)3 (entry 3) or NbCl3(DME)[28] (entry 4), no reaction
occurred, indicating their inadequacy for single-electron reduction
of 4. Considerable experimentations and optimizations revealed
that the low-valent titanium reproducibly provided the desired
tricycle 3 (entry 5).[29] Treatment of 4 with TiCl4 (4 equiv) and Zn
(10 equiv) at 50 °C in THF in the presence of pyridine resulted in
the formation of 3 and C2-epi-3 as the major and minor
components, respectively.[30]
Upon acetylation of the
diastereomeric mixture with Ac2O and DMAP, the secondary C2-
OH of 3 was acetylated chemoselectively over the tertiary C1-OH
to give 18 (45%) along with the unreacted C2-epi-3 (6%). The
three-dimensional structure of 18 was unambiguously confirmed
by X-ray crystallographic analysis (Figure S4).[22] Thus, all four
oxygen functionalities on the 8-membered B-ring (C1, 2, 9, and
10) were successfully installed at this stage.
Next, the adduct 15 was produced by radical coupling between
A-ring 5 and C-ring 6, and subsequent oxidative C8-olefin
regeneration. Specifically, treatment of 5 and 6 (2 equiv) with Et3B
(3 equiv) in benzene at 50 °C under air effected the formation of
the
C8–C9
bond,[19]
and
2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ) was introduced to the reaction mixture to
provide 15 as a single C9-isomer in 65% yield.[20] In this reaction,
an ethyl radical generated from Et3B/O2 promotes homolytic
cleavage of the C–Te bond to afford an acyl radical, which
undergoes the spontaneous release of carbon monoxide to form
Table 1. Investigation of pinacol coupling reactions of 4.
1. conditions
2. Ac2O, DMAP
3 + C2-epi-3
18 + C2-epi-3
4
entry
conditions
results[a]
18 (0%)
-alkoxy radical
A
and loses the C9-stereochemical
1
2
3
4
5
SmI2 (10 equiv), THF, RT
information.[21] The acetonide-protected 1,2-diol of A redefines
the correct C9-stereochemistry upon 1,4-radical addition,[13b] as
enone 6 only approaches from the opposite side of the bulky C10-
substituent of A. Subsequently, Et3B captures the resultant
radical intermediate to form boron enolate B, and subsequent
DDQ-oxidation furnishes enone 15. Thus-obtained 15 (96% ee)
was recrystallized to afford enantiopure 15, and its absolute
structure was determined by X-ray crystallographic analysis.[22]
Prior to construction of the substrate 4 for another key radical
reaction, the C8-quaternary center was stereoselectively installed
from 15 through nucleophilic 1,4-addition of MeMgBr in the
presence of CuI and Me2S in toluene (d.r. = 7:1).[23,24] The
following NaBH4-reduction of the C4-ketone in one pot gave rise
to alcohol 16. The X-ray structure of 15 suggests that the bulky
A-ring structure would block the bottom face of the C8-double
bond and the desired C8-stereochemistry would be established
by the favorable top face addition of the nucleophile. The
secondary alcohol of 16 was then sequentially treated with
methanesulfonyl chloride (MsCl) and Et3N, and with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), resulting in the formation
of -unsaturated nitrile 17 by elimination of the mesylate. Nitrile
17 was reduced to the corresponding imine with
diisobutylaluminum hydride, and the following acidic work-up
simultaneously hydrolyzed the C2-imine and C1-acetal to
produce the requisite ketoaldehyde 4. It is important to note that
the C2-nitrile group has multiple roles in this route: it enhances
the reactivity of two 1,4-acceptors 6 and 15 as an electron-
withdrawing group, and serves as a precursor of the C2-aldehyde
of 4.
SmI2 (10 equiv), THF, 50 °C
18 (0-33%)
No reaction
No reaction
18 (45%)
VCl3(THF)3 (5 equiv), Zn, CH2Cl2, RT
NbCl3(DME) (10 equiv), THF, RT
TiCl4 (4 equiv), Zn (10 equiv), pyridine,
THF, 50 °C
C2-epi-3 (6%)
[a] yield over 2 steps.
H
18
O
H
17
NOE
NOE
1
O
O
H
H
H
A
O
H
O
1
2
10
A
9
9
11
O
11
O
10
O
17
H
H
4a : 4b = 2 : 1
(in THF-d8, RT)
H
H
C
16
H
H
18
C
H
H
H
TiCl4, Zn
4a
4b
: minor
: major
pyridine
O
O
9
O
O
H
H
H
Tin+
O
O
OTin+
H
9
9
O
2
1
Tin+
O
Tin+
O
1
1
H
H
H
2
2
Tin+
O
H
O
Tin+
H
16
D/E
F
G
3
C2-epi-
3
3
3
C1,2-epi- /C1-epi-
Scheme 3. Two stable conformers of ketoaldehyde 4 in THF-d8 and rationale
for the C1,2-stereoselectivity of the pinacol coupling reaction.
The C1,2-stereochemical outcome of the intramolecular radical
coupling can be explained by steric interactions of the four
titanium-coordinated radical intermediates D, E, F, and G that
lead to C1,2-epi-3, C1-epi-3, C2-epi-3, and 3, respectively
(Scheme 3). As the C16-H becomes proximal to the C-ring, D
The stage was set for exploring the pinacol coupling reactions
for stereoselective cyclization of the 8-membered B-ring (Table
1).[25] Whereas application of SmI2 at room temperature did not
generate the cyclized compound (entry 1),[26] the same conditions
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10.1002/anie.201906872
Angewandte Chemie International Edition
COMMUNICATION
and E are significantly disfavored compared with F and G. G is
considered to be energetically more favorable than F due to steric
repulsion of the pseudo-axial C2O-functionality, ultimately
resulting in the generation of 3 as the major isomer. On the other
hand, the temperature dependency of the cyclization efficiency
(e.g., entries 1 and 2, Table 1) would originate from the hindered
rotation of the C10–C11 bond. Namely, detailed NMR analysis of
4 at room temperature in THF-d8 revealed that it exists as a 2 : 1
mixture of conformers 4a and 4b because of the high rotational
barrier around the C10–C11 bond (Scheme 3).[31] The relative
orientations between the A- and C-rings of 4a and 4b match those
of D/E and F/G, respectively. As only 4b would lead to productive
cyclization via the intermediacy of F/G, a higher temperature
would be required to facilitate the conformational change from 4a
to 4b.
protected the sterically encumbered C1-OH of 27 with its
dimethylsilyl group in the presence of Me2HSiCl and
imidazole,[38,39] and 29 was treated with Burgess reagent and
subsequently with HFpyridine. This alternative protocol enabled
the formation of the targeted 1-hydroxytaxinine (1) in 56% yield
over 2 steps from 29 without forming 28. The X-ray structure in
Scheme 2 shows the structural integrity of the synthesized 1,[22]
which was further validated by the matched physical data (1H
NMR, 13C NMR, IR, []D and HRMS) of 1 with those reported
previously.[1,40]
In summary, we achieved an asymmetric total synthesis of 1-
hydroxytaxinine
(1)
in
26
total
steps
from
2,2-
dimethylcyclohexane-1,3-dione (7). The two powerful radical
reactions annulated the B-ring from the judiciously designed A-
and C-ring substrates and streamlined the overall synthetic
sequence. Because of their flexibility and robustness, the
strategy and tactics developed here would potentially be
applicable to the synthesis of highly oxygenated taxane
diterpenoids, including taxol (2).
The last stage of the total synthesis involved carefully optimized
functional group transformations at the C3, C4, C5, and C13
positions from the 6/8/6-membered ring system 18 (Scheme 2).
First, the C5- and C13-allylic methylenes of 18 were
simultaneously oxidized using CrO3 and 3,5-dimethylpyrazole to
produce bis-enone 19.[32] The C5-enone of 19 was then used as
a handle for introducing the C3-hydrogen and C5-olefin. Thus,
the addition of p-toluenesulfonyl hydrazide and AcOH changed
the less hindered C5-carbonyl group of diketone 19 into the
corresponding sulfonyl hydrazone of 20, which was subjected to
catecholborane and NaOAc.[33] As a result, 1,2-reduction of
hydrazone 20 occurred from the more exposed top face and
induced the elimination of a p-tolylsulfinate. The following allylic
diazene rearrangement transferred the C3-hydrogen from the
bottom face and shifted the olefin location, giving rise to the
selective formation of 21 (47%) along with its epimer C3-epi-21
(21%).
Dihydroxylation of the disubstituted C5-olefin of diene 21 using
catalytic OsO4 and stoichiometric N-methylmorpholine N-oxide
(NMO) proceeded stereoselectively from the bottom side to
generate 22 presumably because the top side approach of the
osmium reagent would cause a severe 1,3-diaxial interaction with
the C8-methyl group. The less hindered C5-OH of diol 22 was in
turn converted to the cinnamoyl ester of 23 using the Yamaguchi
reagent system,[34] and the remaining C4-OH of 23 was oxidized
to the C4-ketone of 24 with pyridinium chlorochromate (PCC).
Olefination of 24, however, did not give 25 under a variety of
conditions using Wittig, Peterson, Takai, or Tebbe reagent. The
shielded and base-sensitive nature of the -acetoxy C4-ketone of
24 would be responsible for the failure of this simple
transformation.
Acknowledgements
This research was financially supported by Grants-in-Aid for
Scientific Research (S) (JP17H06110), for Scientific Research on
Innovative Areas (JP17H06452) to M.I., for Scientific Research
(C) (JP16K08156), for Early Career Scientists (JP19K15554), and
for Scientific Research on Innovative Areas (JP18H04384) to M.N.
from JSPS. Fellowships from MEXT (WISE Program) to Y.I. and
from JSPS (JP14J12384) to S.Y. are gratefully acknowledged.
Determination of the X-ray crystallographic structures was
financially supported by the Nanotechnology Platform of MEXT
(JP12024046).
Conflict of interest
The authors declare no conflict of interest.
Keywords: Natural products • Tellurium • Terpenoids • Total
synthesis • Radical reactions
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Table of Contents
COMMUNICATION
Yusuke Imamura, Shun Yoshioka,
Masanori Nagatomo, and Masayuki
Inoue*
Page No. – Page No.
Total Synthesis of 1-Hydroxytaxinine
1-Hydroxytaxinine, a cytotoxic taxane diterpenoid, possesses a highly oxygenated
6/8/6-membered ring (ABC-ring) system. Decarbonylative intermolecular radical
coupling and low-valent titanium-promoted intramolecular radical cyclization were
employed as the two key reactions to annulate the B-ring from A- and C-ring
fragments. Subsequent manipulations at the A- and C-rings furnished 1-
hydroxytaxinine in 26 total steps.
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