Total synthesis of (±)-Cephanolides B and C via a palladium-catalyzed cascade cyclization and late-stage sp3 C-H bond oxidation

Article abstract of DOI:10.1021/jacs.8b03015

Herein, we report the first total syntheses of complex cephalotaxus diterpenoids cephanolide B and C from commercially available 5-bromo-2-methylanisole. Key to the success of this synthetic route is a palladium-catalyzed cascade cyclization reaction, which allowed us to efficiently forge the 6-5-6 cis-fused tricyclic ring systems found in the entire family of cephalotaxus diterpenoids. Additionally, site-selective late-stage sp³ C-H bond oxidation served as a key strategic element in the chemical synthesis of cephanolide C.

Full text of DOI:10.1021/jacs.8b03015

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Total Synthesis of (±)-Cephanolides B and C via a Palladium-
Catalyzed Cascade Cyclization and Late-stage sp3 C–H Bond Oxidation
Lun Xu, Chao Wang, Ziwei Gao, and Yu-Ming Zhao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03015 • Publication Date (Web): 09 Apr 2018
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Total Synthesis of (±)-Cephanolides B and C via a Palladium-Cata-
lyzed Cascade Cyclization and Late-stage sp3 C–H Bond Oxidation
Lun Xu,‡ Chao Wang,‡ Ziwei Gao, and Yu-Ming Zhao*
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Key Laboratory of Applied Surface and Colloid Chemistry of MOE & School of Chemistry and Chemical Engineering,
Shaanxi Normal University, 620 West Chang’an Ave, Xi’an, 710119, China
ABSTRACT: Herein, we report the first total syntheses of complex cephalotaxus diterpenoids cephanolide B and C from commer-
cially available 5-bromo-2-methylanisole. Key to the success of this synthetic route is a palladium-catalyzed cascade cyclization
reaction, which allowed us to efficiently forge the 6-5-6 cis-fused tricyclic ring systems found in the entire family of cephalotaxus
diterpenoids. Additionally, site-selective late-stage sp3 C–H bond oxidation served as a key strategic element in the chemical synthesis
of cephanolide C.
Introduction
remaining members of this family, including cephanolides A-D
(2-5), have not been synthesized and successful routes to these
molecules may shed further light on their biosynthetic relation-
ships. In developing a general synthetic route to this family, we
were drawn to a palladium-catalyzed Heck-type/carbonylative
C–H activation cascade between aryl halide 7 and a one-carbon
unit provided by carbon monoxide (Figure 1b). We viewed this
highly efficient construction of the cephalotaxus diterpene pen-
tacyclic core as an ideal platform to explore the entire family
from a common synthetic intermediate. Herein, we document
the realization of this maneuver which has resulted in the first
total syntheses of cephanolide B (3), and C (4).
Plants of the Cephalotaxaceae family produce an extensive
array of structurally diverse natural products with a variety of
biological properties, particularly potent antitumor activity.1
Among these secondary metabolites, cephalotaxus diterpenoids
represent a relatively rare and structurally fascinating class of
natural products. The first member of the cephalotaxus diterpe-
noids, harringtonolide (1) (also named hainanolide2b), was iso-
lated from the seeds of cephalotaxus harringtonia in 1978 by
Buta et. al and was later shown to have potent activity against
human KB cells (IC50 = 43 nM).2a,4 To date, over 25 diterpenes
with rigid polycyclic frameworks related structurally, and pre-
sumably biosynthetically, to 1 have been isolated many of
which also possess significant biological activities.3 Very re-
cently, Yue and co-workers isolated new structurally unique
norditerpenoids cephanolides A-D (2-5) from cephalotaxus
sinensis, a finding which sheds light on plausible biosynthetic
scenarios among this large family (Figure 1a).3f Compared with
other cephalotaxus diterpenoids, cephanolides A-D represent
the first examples which have a rarely encountered aromatic
benzenoid ring (A-ring) in this family.
Structurally, cephalotaxus diterpenoids possesses a complex
rigid tetracyclic carbon skeleton featuring a cis-fused tricarbo-
cycle (BCD-system), a cyclohexane ring bearing five or six
contiguous stereogenic centers (D-ring), and a bridging lactone
unit (E-ring). These fascinating architectural attributes, as well
as the aforementioned biological activities, have made diterpe-
noids from Cephalotaxaceae attractive and challenging targets
for total synthesis. From the viewpoint of the synthetic chemist,
these molecules also provide an ideal platform for the develop-
ment of new synthetic strategies and the discovery of novel syn-
thetic methodologies. In this context, great effort has been de-
voted to the total synthesis of 1 resulting in several model stud-
ies and three impressive total syntheses.5,6 In 1998, Mander and
co-workers disclosed the total synthesis of 1, featuring an ele-
gant intramolecular arene cyclopropanation followed by ring
expansion strategy,5a work which was a breakthrough in cepha-
lotaxus chemistry. Recently, the groups of Tang and Zhai de-
veloped efficient total syntheses of 1 through unique intramo-
lecular cycloaddition strategies, respectively.5b,c However, the
Figure 1. (a) Representative cephalotaxus diterpenoids. (b) A pal-
ladium-catalyzed cascade cyclization for rapid polycycle assembly.
Result and discussion
Our synthetic studies commenced with the preparation of
pentacyclic precursor 12 (Scheme 1). Commercially available
5-bromo-2-methylanisole underwent sequential Negishi-cou-
pling with alkyl zinc bromide 8,7 and following aromatic
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iodination, ester 9 was generated in 88% over two-steps.
Page 2 of 7
were examined under carbon monoxide atmosphere; To our sur-
prise, the desired cascade reaction proceeded smoothly and only
one cyclized product was obtained. Unfortunately, further
structural analysis revealed that the product of the annulation
was undesired diastereomer 13, not 6. The structure of 13 was
unambiguously confirmed by single crystal X-ray diffraction.
Interestingly, incorporation of one equivalent of Ag2CO3 as ad-
ditive could generate the desired 6 as a minor product along
with majority of 13 in 34% combined yield (6:13 = 1:1.6). Ex-
tensive optimization through varying silver salts, ligand, bases,
and solvent, all failed to improve this outcome. Molecular mod-
eling suggests that the face of alkene (C1=C10 double bond)
which is closer to the lactone unit in 12, is sterically less hin-
dered, thus resulting in the above-mentioned diastereoselectiv-
ity. Taking this analysis in account, we sought to alter the steric
constraints surrounding the alkene diastereofaces. It was found
that simple reduction of lactone 12 into 14 followed by PPTS-
catalyzed acetal formation gave 15 as a single diastereomer. An
X-ray crystal structure of 15 shows the orientation of methoxy
group at C-18, which increases the steric hindrance of one face
of the alkene. Much to our delight, subjecting 15 to the palla-
dium-catalyzed cascade cyclization conditions afforded 16 as a
single diastereomer in 91% yield. Oxidation of this material
[BF3∙OEt2, m-CPBA] then afforded 6.11 Notably, multigram
quantities of 6 are readily prepared in our laboratory through
this sequence, which is envisioned to serve as the foundation
for syntheses of multiple cephalotaxus diterpenes.
1
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3
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6
7
8
Formylation of this material [LDA, HCO2Me] followed by
Cu(OTf)2-catalyzed Robinson annulation with 3-penten-2-one
afforded an inseparable 4:1 mixture of 10 and its diasteromer in
78% overall yield. Pleasingly, stereoselective Luche reduction
of this mixture afforded easily chromatographically separable
allylic alcohols thus resulting in the isolation of 11 as a single
diasteromer. Hydrolysis of 11 with aq NaOH in MeOH at 70 oC
followed by an EDCI coupling provided the desired precursor
lactone 12 in 62% overall yield. It should be noted that this
seven-step sequence, which required only four chromato-
graphic purifications, allowed for the preparation of multigram
quantities of 12 in the absence of any substantive optimization.
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With substantial amounts of 12 in hand, we were in a position
to test the crucial C–C bond-forming reaction, a palladium-cat-
alyzed cascade annulation of 12 in the presence of carbon mon-
oxide. Though palladium-catalyzed Mizoroki–Heck reactions
between aryl halides and alkenes are well-exploited,8,9 as are
carbonylative processes,10 to the best of our knowledge, there is
only one literature precedence wherein the transformation ter-
minated with an annulative formal C–H activation.10a,e Moreo-
ver, this reaction only worked with thiophenes and furans. A
palladium-catalyzed this type of carbonylative annulation reac-
tions which terminate with a phenyl ring have not been devel-
oped (Scheme 1, 126). Initially, standard palladium-catalyzed
o
Heck conditions [cat. Pd(OAc)2, PPh3, K2CO3, PhMe, 90 C]
Scheme 1. Synthesis of common pentacyclic core intermediate 6.a
aReagents and conditions: (a) 8 (1.5 equiv), Pd(OAc)2 (2.0 mol %), SPhos (4.0 mol %), THF, 50 oC, 8 h, 90%; (b) AgOAc (1.0 equiv), I2
(1.0 equiv), HOAc, 12 h, rt, 98%; (c) LDA (1.5 equiv, 1.0 M in THF), HCOOMe (3.0 equiv), –78 oCrt, 5 h; (d) 3-penten-2-one (1.5 equiv),
Cu(OTf)2 (0.2 equiv), THF, 50 oC, 7 days, 78% over two steps; (e) NaBH4 (0.8 equiv), CeCl3∙7H2O (1.2 equiv), MeOH, 0 oC, 2 h, 65%; (f)
o
o
NaOH (10 equiv), MeOH/H2O (v/v = 1:1), 70 C, 12 h; (g) EDCI (1.2 equiv), DMAP (0.2 equiv), CH2Cl2, 0 Crt, 12 h, 62% over two
steps; (h) Pd(OAc)2 (5.0 mol %), Ph3P (10 mol %), Ag2CO3 (1.05 equiv), K2CO3 (2.0 equiv), CO (1 atm), PhMe, 90 oC, 18 h, 13% 6, 21%
13; (i) DIBAL-H (2.0 equiv), CH2Cl2, –78 oC, 12 h, 90%; (j) PPTS (0.1 equiv), MeOH, 50 oC, 7 h, 58%, 81% (brsm); (k) Pd(OAc)2 (2.0 mol
%), Ph3P (4.0 mol %), CO (1 atm), K2CO3 (2.0 equiv), PhMe, 90 oC, 18 h, 91%; (l) BF3∙OEt2 (1.2 equiv), m-CPBA (1.5 equiv), CH2Cl2, 0
oC, 1 h, then Et3N (3.0 equiv), 0 oCrt, 5 min, 94%. SPhos = 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, LDA = lithium diisoprop-
ylamide, EDCI = N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, DMAP = 4-(dimethylamino)pyridine, DIBAL-H = diisobutylaluminum
hydride, PPTS = pyridinium p-toluenesulfonate, m-CPBA = 3-chloroperbenzoic acid.
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Table 1. A preliminary substrate scope of palladium-catalyzed cascade annulation.a,b
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aReactions were performed on a 0.1 mmol scale, Pd(OAc)2 (10 mol %), Ph3P (20 mol %), K2CO3 (2.0 equiv), CO (1 atm), PhMe (0.07
M), 90 oC, 18 h. bIsolated yield. cDetermined by 1H NMR analysis. n.d = not detected.
Without a doubt, the efficient preparation of pentacyclic in-
termediate 6 can be attributed to the novel palladium-catalyzed
cascade reaction. To the best of our knowledge, this is the first
example of a palladium-catalyzed cascade reaction of this kind
wherein the process terminates with aryl ring attachment.10a,e To
further understand the nature of this cascade reaction, a prelim-
inary study of substrate scope was conducted under similar con-
substrates 17d and 17e were synthesized and examined under
standard conditions (entry 4). To our disappointment, only 17d
afforded the desired cascade product 18d and in very low yield
(< 5%). Interestingly, acid 24 or 25 was isolated from the reac-
tion in both cases, which is likely generated by the hydrolysis
of acylpalladium intermediate. Ether bridged bicyclic alkene
substrate 17f could also give an inseparable 2:1 mixture of dia-
stereoisomers in 84% combined yield favoring 18f (entry 5).
The selectivity shown here was consistent with our previous
analysis for the face-selectivity of alkene 12 (see Scheme 1).
Finally, three lactone bridged bicyclic alkene substrates (17g-
17i), which have differing aromatic electronic character, were
prepared and investigated (entry 6-8). Much to our delight, all
of these bicyclic substrates afforded the desired products (18g-
18i) under standard condition. However, it was easy to find that
the reaction efficiency was highly dependent on the electroneg-
ativity of aromatic ring.
o
ditions [cat. Pd(OAc)2, PPh3, K2CO3, PhMe, 90 C] and these
results are summarized in Table 1. As predicted, substrates con-
taining monocyclic alkenes, whether activated enones or rela-
tively neutral allylic alcohols and their TBS derivatives (entry
1-3) all failed to afford any desired products (18a-18c). Analy-
sis of side-products formed in these reactions resulted in the ob-
servation of tricyclic products (19-23). These experimental re-
sults supported the proposal that a palladium-catalyzed Heck-
type cyclization was involved in the initial step of cascade re-
action (vide infra). Subsequently, disubstituent terminal alkene
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Scheme 2. Potential mechanism for palladium-catalyzed cascade annulation.
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Mechanistically, this pivotal cascade reaction probably takes
place by an intramolecular Heck-type cyclization, followed by
CO insertion and Friedel–Crafts acylation sequence. However,
a potential palladacycle involved aryl sp2 C–H bond activation
pathway in the final stage of sequence couldn’t be ruled out in
this case (Scheme 2). Generally, there are two potential mecha-
nisms which have received the most support in the reaction of
palladium-catalyzed aryl sp2 C–H bond functionalization: (i)
concerted metalation-deprotonation (CMD) with simple, elec-
tron-deficient benzenes (path a or path b)12 and (ii) electrophilic
aromatic substitution (SEAr) with electron-rich, nucleophilic ar-
omatic ring (path c). Moreover, the CMD involved mechanism
normally favors reaction with electron-deficient, C–H acidic
benzenes, which constitutes a complete inversion of reactivity
compared to the SEAr pathway.12b In the contrast, the electron-
withdrawing group on the aromatic ring dramatically reduces
the reactivity of the ring to further attack in SEAr, thus resulting
in a much lower reaction efficiency. Based on the above exper-
imental observation and general reactivity displayed in palla-
dium chemistry, it seems that the processes, involving initial
Heck-type cyclization to generate σ-alkylpalladium (II) species,
sequential CO insertion, and a final Friedel–Crafts acylation of
acylpalladium (II) intermediate, may be operative in this palla-
dium-catalyzed cascade reaction.
After the preliminary substrate evaluation of the palladium-
catalyzed cascade process, we turned our attention to the total
synthesis of cephanolides B (3) and C (4) (Scheme 3). Toward
this end, ionic reduction of ketone 6 [TfOH, Et3SiH, CH2Cl2]
generated lactone 26 in 70% yield. Demethylation of 26 with
BBr3 smoothly afforded cephanolide B (3) in nearly quantita-
tive yield (95%). Gratifyingly, single crystals of 3, suitable for
X-ray diffraction, could be grown thus allowing for unambigu-
ous structure determination.
aReagents and conditions: (a) TfOH (10.0 equiv), Et3SiH (10.0
equiv), CH2Cl2, rt, 40 h, 70%; (b) BBr3 (8.0 equiv), CH2Cl2, –78
oCrt, 6 h, 95%; (c) DDQ (2.0 equiv), 1:1 CH2Cl2/H2O (v/v), rt, 8
o
h, 75%; (d) PCC (4.0 equiv), NaOAc (5.0 equiv), PhH, 70 C, 12
h, 64%; (e) BCl3 (5.0 equiv), TBAI (4.0 equiv), CH2Cl2, –78  –
40 oC, 4 h; (f) Tf2O (1.2 equiv), pyr. (1.5 equiv), CH2Cl2, 0 oC, 1 h,
57% over two steps; (g) Pd(OAc)2 (10 mol%), dppp (10 mol%),
Scheme 3. Completion of the syntheses of Cephanolides B
and C from common pentacycle 6.a
o
Et3SiH (2.5 equiv), DMF, 60 C, 8 h, 91%. DDQ = 2,3-dichloro-
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5,6-dicyano-1,4-benzoquinone, PCC = pyridinium chlorochro-
NHPI, 2-ethylbutyraldehyde, O2, CH3CN,
4
5
24%
20%
50 oC, 5 h; then Ph3P, CH2Cl2, rt, 5 h
1
2
3
mate, TBAI = tetrabutylammonium iodide, pyr. = pyridine, dppp =
1,3-bis(diphenylphosphino)propane, DMF = N,N-dimethylforma-
mide.
NHPI, trimethylacetaldehyde, O2, CH3CN,
50 oC, 5 h; then Ph3P, CH2Cl2, rt, 5 h
4
5
6
7
8
9
6d
7e
8d
9
DDQ, CH3CN/H2O (1:1), rt, 10 h
DDQ, THF/H2O (1:1), rt, 10 h
DDQ, dioxane/H2O (1:1), rt, 10 h
DDQ, CH2Cl2/H2O (1:1), rt, 10 h
30%
--
After completing the synthesis of cephanolide B, we then
turned our attention to the more heavily oxidized member
cephanolide C (4) which poses additional challenges (Scheme
3). Strategically, an ideal synthetic approach to this target would
be the direct late-stage sp3 C–H oxidation of an intermediate
similar to 3, a tactic which nature may employ in the construc-
tion of this molecule.3f Considering the steric and electronic na-
ture of the sp3 C–H bonds in 26,13 we expected that a benzylic
oxidation would take place regioselectively to install the chal-
lenging C-10 oxygenation. Initially, a Cu-catalyzed Kharasch–
Sosnovsky reaction was investigated but proved to be fruitless,
leading only to highly complex reaction mixtures (Table 2, en-
try 1). Taking inspiration from the general observations of Ishii
and others,14 NHPI-catalyzed aerobic oxidation of 26 was ex-
amined. Gratefully, the desired 27 could be obtained after the
in-situ reduction of the terminal peroxide with Ph3P, but in only
18% yield (entry 2). Optimization of various initiators to im-
prove the yield of 27 was unsuccessful (entry 3-5). Fortunately,
it was found that oxidation of 26 with DDQ in a mixture of
CH3CN/H2O at room temperature afforded the desired 27 in
moderated yield, along with recovery of 26 (entry 6). Encour-
aged by this result, extensive studies were carried out and re-
vealed that solvent had a crucial effect on the reaction efficiency
(entry 7 and 8). Ultimately it was discovered that stirring 26
with DDQ in a mixture of CH2Cl2/H2O (v/v = 1:1) at room tem-
perature afforded 27 in synthetically useful yield (75%). More-
over, the structure and stereochemistry of 27 were unambigu-
ously confirmed by X-ray crystallographic analysis confirming
the stereochemistry at C-10. Next, the C-7 benzylic position
could be oxidized using a chromium-based protocol [PCC,
NaOAc, PhH] successfully, affording ketone 28 in 64% yield.15
With the proper oxygenation in place, all that remained to com-
plete the synthesis of cephanolide C (4) was the removal of the
methoxy group from the benzene ring. This was accomplished
with cleavage of methyl ether with BCl3,16 followed by triflation
with Tf2O to give triflate 29 in 57% yield over two-steps. Fi-
nally, palladium-catalyzed reduction of 29 with Et3SiH afforded
cephanolide C (4) in 91% yield.17 The spectral properties of
synthetic 4 were in good agreement with those of the natural
isolate.
28%
75%
aReactions were performed on a 0.06 mmol scale. bIsolated yield.
cDecomposed. >85% (brsm). No reaction. NHPI = N-hydroxy-
phthalimide, AIBN = 2,2'-azobis(2-methylpropionitrile), DDQ =
2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
d
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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In summary, we have achieved the first chemical syntheses
of the complex cephalotaxus diterpenoids natural products
cephanolide B (3) and cephanolide C (4) in a longest linear se-
quence of 13 and 17 steps, respectively. The synthesis featured
a novel palladium-catalyzed cascade annulation reaction, which
enabled rapid construction of common pentacyclic skeleton 6
of cephalotane-type diterpenoids. In addition, a regioselective
and successive late-stage sp3 C–H bond oxidation served as key
element to install the challenging C-10 and C-7 oxygenation.
We anticipate that the palladium-catalyzed annulation de-
scribed herein may find use in the synthesis of other complex,
polycyclic natural products. Moreover, Further application of
this chemistry to the synthesis of other cephalotaxus diterpe-
noids is underway and will be reported in due course.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications
website.
X-ray crystallographic data for 3 (CIF)
X-ray crystallographic data for 6 (CIF)
X-ray crystallographic data for 13 (CIF)
X-ray crystallographic data for 15 (CIF)
X-ray crystallographic data for 27 (CIF)
Experimental procedures and spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Author
*ymzhao@snnu.edu.cn
Table 2. Optimization of late-stage site-selective oxidation
of 26 at C-10.a
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the National Science Foundation of
China (21202074, 21672134), Shaanxi Provincial Natural Science
Foundation (2017JM2001), Fundamental Research Funds for the
Central Universities (GK201803033),“100 Talents Program” of the
Shaanxi Province (Y.-M. Z.), and generous start-up funds from
Shaanxi Normal University. We thank Prof. Thomas J. Maimone
at UC Berkeley for helpful discussions during the preparation of
this manuscript. Dr. Huaming Sun at Shaanxi Normal University is
acknowledged for X-ray crystallographic analysis.
Entry Conditions
Yieldb
CuX (X = Cl, Br), PhCOOOtBu, PhH, 50
1c
--
oC, 5 h
NHPI, AIBN, O2, CH3CN, 75 oC, 5 h; then
Ph3P, CH2Cl2, rt, 2 h
2
18%
26%
o
NHPI, CH3CHO, O2, CH3CN, 50 C, 5 h;
3
then Ph3P, CH2Cl2, rt, 5 h
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