Asymmetric Total Synthesis of (+)-Waihoensene

Article abstract of DOI:10.1021/jacs.0c02143

The asymmetric total synthesis of (+)-waihoensene, which has a cis-fused [6,5,5,5] tetracyclic core bearing an angular triquinane, a cis-fused six-membered ring, and four contiguous quaternary carbon atoms, was achieved through a sequence of chemical reac

Full text of DOI:10.1021/jacs.0c02143

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Communication
Asymmetric Total Synthesis of (+)-Waihoensene
Yongzheng Qu, Zheyuan Wang, Zhongchao Zhang, Wendou Zhang, Jun Huang, and Zhen Yang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02143 • Publication Date (Web): 23 Mar 2020
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Asymmetric Total Synthesis of (+)-Waihoensene
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Yongzheng Qu,† Zheyuan Wang,† Zhongchao Zhang,† Wendou Zhang,† Jun Huang,*,† Zhen
Yang*,†,‡,§
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†Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen
Graduate School, Shenzhen, 518055, China;
‡Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National
Laboratory for Molecular Science, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871,
China;
§Shenzhen Bay Laboratory, Shenzhen 518055, China.
Supporting Information Placeholder
asymmetric conjugate addition8 of enone C. From inspection of the
ABSTRACT: The asymmetric total synthesis of (+)-
favorable transition state TSD-E and the 3D structure of enyne E (see
waihoensene, which has a cis-fused [6,5,5,5] tetracyclic core
E’ in Figure 1b), two of the three requisite quaternary stereogenic
bearing an angular triquinane, a cis-fused six-membered ring,
centers at C9a and C3a in the core of angular triquinane9 F could be
and four contiguous quaternary carbon atoms, was achieved
through a sequence of chemical reactions in a stereochemically
well-defined manner. The total synthesis features: 1) Cu-
constructed diastereoselectively by a sequence of Conia-ene type
reaction10 of diyne D and intramolecular Pauson-Khand reaction11
of enyne E. According to the results reported in Lee’s total synthesis
catalyzed
asymmetric
conjugated
1,4-addition;
2)
of waihoensene (1),5 one of the four requisites quaternary
stereogenic centers at C11a in intermediate G could be build up via
diastereoselective Conia-ene reaction; 3) diastereoselective
intramolecular Pauson-Khand reaction; 4) Ni-catalyzed
diastereoselective conjugated 1,4-addition; and 5) radical-
initiated intramolecular hydrogen atom transfer (HAT).
Control experiments and density functional theory
calculations support the proposed HAT process.
a
cuprate-mediated conjugated addition reaction. Thus, the
asymmetric total synthesis of (+)-waihoensene (1) could be
accomplished upon diastereoselective saturation of its C9−C15
double bond in G.
a) Total synthesis of ()-waihoensene by Lee and co-workers in 2017
Me
Me
Me
A
Me
Polyquinanes constitute an important class of carbocyclic
frameworks containing fused 5-membered rings (Figure 1) and are
found in various natural products, such as terpenoids and steroids.1
In 1997, Weavers and co-workers isolated (+)-waihoensene (1) from
the New Zealand podocarp, Podocarpus totara var waihoensis.2
Structurally, 1 contains a highly congested and cis-fused tetracyclic
core decorated with six contiguous stereogenic centers, among them
four are contiguous all-carbon quaternary carbon atoms (C3a, C5a,
C9a and C11a). Thus, 1 was widely regarded as a challenging target
for total synthesis.3
2
NHTs
N
D
C
Tandem [2+3]
cycloaddition
3a
9a
Me
B

Me
Me
Me
B
A
()-Waihoensene 1
b) This work (15 steps for (+)-Waihoensene)
O
O
Me
asymmetric
conjugate addition
3
Conia-ene
reaction
9a
9a
O
3a
5a
3a
3
Me
TSD-E
C
D
Given its structural complexity, 1 has been a focus of the
synthetic community for many years.4 In 2017, Lee and co-workers
published an impressive synthesis of (±)-waihoensene for the first
time in 18 steps, featuring a tandem [2+3] cycloaddition to construct
the BCD tricyclic ring with two contiguous quaternary stereogenic
centers5 (Figure 1a).
5a
Me
Pauson-Khand
reaction
5a
Me
3a
3
9a
3a
O
9a
O
O
F
E'
E
(DFT optimized structure)
We recently became interested in the total synthesis of complex
natural products bearing all-carbon quaternary stereogenic centers,6
and the total synthesis of 1 was a particular challenge involving such
a structure.7 Herein, we report our recent contribution for the
asymmetric total synthesis of 1 in 15 steps with 3.8% overall yield.
The cornerstone of our plan is the recognition of structural and
stereochemical relationships between substrates D, E and F and
their corresponding products E, F and G, which allowed us to
construct the key intermediates E, F and G in a highly
diastereoselective manner.
11a
Me
Me
Conjugate
addition
5a
Me
Me
Me
3a
9a
1
15
H
9
3
2
H
O
Me
F'
(DFT optimized structure)
G
1
(+)-Waihoensene
Figure 1: Total synthesis of (+)-waihoensene (1).
The total synthesis began with developing an asymmetric
approach for enantioselective synthesis of diyne 7. Initially, we
developed a six-step approach to prepare 7 in a racemic form (see
As shown in Figure 1b, the initial chiral quaternary stereogenic
center at C5a in diyne D could be installed via a Cu-catalyzed
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SI for details). We then decided to adopt Alexakis’ strategy12 for the
methylation at the C-3 and C-9 positions. As indicated by Snyder,7b
due to its lower steric hindrance, the C2 ketone group in 10 could be
selectively protected as its corresponding mono-ketal in 11, which
could then undergo a Wittig reaction to afford 12 bearing an exo-
cyclic olefin. To prove this theory, treatment of 10 with 2-ethyl-2-
methyl-1,3-dioxolane in the presence of a catalytic amount of TsOH
led to 11 in 91% yield, which then underwent a Wittig reaction,
followed by deketalization to give ketone 12 in 69% yield in two
steps.
1
2
3
4
5
6
asymmetric synthesis of 7 (Scheme 1). Enone 2 was reacted with the
Grignard reagent to afford 3.8c and then the C5a stereogenic center
in 4 was installed from 3 in a 61% overall yield, using the method
of Alexadis12. Allylation of enone 4 via Sakurai reaction,13 and
subsequent ozonolysis14 of olefin 5 afforded aldehyde 6 in a 58%
yield over the two steps. Chiral diyne 7 was then obtained in 72%
yield by reaction of aldehyde 6 with Ohira-Bestmann reagent,15
accompanied by in situ TMS-desilylation.
7
8
9
However, the diastereoselective hydrogenation of the exocyclic
olefin in 12 was found to be extremely difficult, and commonly used
transition metal catalysts (such as Pd/C, PtO2,25 Rh(PPh)3Cl26)
afforded the product bearing the opposite stereochemistry of C9 in
13, as the inherent concave-face of the exo-cyclic double bond in 12
is more sterically hindered than its convex-face. As a result, the
catalyst would approach the double bond from its convex-face,
leading to the product bearing the incorrect stereochemistry.
Recently, hydrogen atom transfer (HAT) reactions have emerged
as a powerful method for complex natural product total synthesis.27
We conjectured that the newly formed C9 carbon radical in 13a,
derived from a radical-mediated reductive reaction from 12, could
abstract a proton through an intramolecular HAT from the C3, due
to the close proximity (2.4 Å) of C3 and C9 and their position next
to the C2 carbonyl group. As a result, the diastereoselective
saturation of the C9–C15 double bond might be achieved (scheme
2).
Scheme 1. Asymmetric synthesis of diyne 7.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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46
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57
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59
60
Me
Me
Me
(R)
N
Ph
Ph
O
O
P
L
=
(R)
Me
Me
Me
TMS
b) CuTc
L, Me3Al
MgBr
TMS
TMS
O
a)
O
O
then n-BuOCH2NEt2
5a
c) m-CPBA
(61%, 91% ee
2 steps)
(98%)
OEt
Me
(-)-4
2
3
d) AllylTMS, BF3•Et2O (89%)
OHC
O
TMS
TMS
O
O
f) Bestmann
reagent
e) O3
5a
5a
5a
(65%)
(72%)
Me
Me
Me
6
7
5
Scheme 2. Total synthesis of (+)-waihoensene (1).
aReagents and conditions: (a) Grignard (2.0 equiv), THF, 0 °C to RT, 12 h,
98%; (b) CuTc (5 mol%), L (10 mol%), Me3Al (2.0 equiv), Et2O, -30 °C,
overnight; then nBuOCH2NEt2 (2.5 equiv), RT, 3 h; (c) mCPBA (1.5 equiv),
DCM, RT, 1 h, 61% for 2 steps, 91% ee; (d) Allyltrimethylsilane (1.5 equiv),
BF3●Et2O (1.1 equiv), DCM, -78 °C to RT, 30 min, 89%; (e) O3 (1 atm.),
DCM, -78 °C, 5 min, then PPh3 (1.0 equiv), RT, overnight, 65%; (f) Ohira-
Bestmann reagent (1.3 equiv), K2CO3 (2.3 equiv), MeOH, 0 °C to RT, 3 h,
b) Co2(CO)8
N2O
O
11a
3a
a) tBuOK
(83%)
Me
Me
9a
9
O
O
(59%, 93% ee)
3
2
O
7
Me
8
9
d) p-TsOH
72%. CuTc
=
Copper(I) thiophene-2-carboxylate; mCPBA
dimethyl
dichloromethane; THF =
= 3-
Me
c) Ni(acac)2
LiBr, Me2Zn
chloroperoxybenzoic acid; Ohira-Bestmann reagent
(acetyldiazomethyl)phosphonate; DCM
tetrahydrofuran.
=
O
O
Me
O
Me
Me
=
O
O
O
(81%)
(91%)
9
3
2
O
11
10
e) Ph3P+MeBr-, tBuOK (78%)
f) HCl (89%)
ORTEP of 9
With a streamlined synthesis of diyne 7 in hand, we turned our
attention to the synthesis of diketone 10 bearing the four contiguous
quaternary stereogenic centers (Scheme 2). The sequence began
with preparation of enyne 8, which was diastereoselectively
prepared in 83% yield as a single diastereomer via a Conia-ene type
Me
O
g) Fe(acac)3
PhSiH3
Me
O
Me
Me
Me
15
sp2 C
H
9
9
(75%)
3
Å
2
2.4
13
12
DFT optimized
structure of 13a
h) LiHMDS, MeI
(90%)
cyclization by treatment of 7 with a catalytic amount of BuOK.10f
t
Me
We envisaged that the enyne 8, which has Thorpe–Ingold
assistance,16 could be a good substrate for the proposed Pauson-
Khand (PK) reaction to form the 6-5-5-5 tetracyclic compound 9
bearing an angular triquinane core with three contiguous quaternary
chiral centers. To this end, we initially profiled several typical PK
reaction conditions, such as Co2(CO)8-mediated PK17 reaction in the
presence of trimethylamine N-oxide (TMANO),18 methyl
morpholine N-oxide (NMO)19 and tetramethyl thiourea (TMTU),20
as well as other transition metal-catalyzed PK reaction, such as
PdCl2/TMTU,21 and [Rh(CO)2Cl]2.22 However, in most cases, the
desired product 9 was only isolated in 22–38% yield (see SI for
details). We later found out that 9 could be obtained in 59% yield in
93% ee when the reaction was carried out in the presence of N-oxide
(N2O)23 in dichloroethane (DCE) at 80 °C for 20 h. The structure of
enone 9 was unambiguously confirmed by X-ray crystallo-graphic
analysis. Finally, a Ni-catalyzed methylation24 of 9 lead to the
formation of diketone 10 in 81% yield as a single diastereoisomer.
After the diastereoselective installation of the angular triquinane
motif, the remaining challenge was regio- and diastereo-selective
Me
i) Ph3P+MeBr-
Me
Me
tBuOK
Me
Me
Me
H
Me
H
Me
(90%)
H
H
O
Me
Me
()-waihoensene (1)
Me
1
14
aReagents and conditions: (a) tBuOK (0.5 equiv), DMSO, RT, 4 h, 83%. (b)
o
Co2(CO)8, N2O (1 atm), DCE, 80 C, 22h, 59%, 93% ee; (c) Ni(acac)2 (10
mol%), LiBr (3.0 equiv), Me2Zn (5.0 equiv), Et2O, 0 °C to RT, 48 h, 81%;
(d) 2-ethyl-2-methyl-3-dioxolane (5.0 equiv), PTSA•H2O (5 mol%), Et2O,
t
RT, 1 h, 91% (brsm 99%); (e) Ph3P+MeBr- (5.0 quiv), BuOK (4.9 equiv),
toluene, reflux, 1 h; then 15 (1.0 equiv), toluene, reflux, 19 h, 78% (brsm
90%); (f) HCl(1 M, 2.6 equiv) , THF, RT, overnight, 89%. (g) Fe(acac)3 (0.2
equiv.), PhSiH3 (1.0 equiv), EtOH, 60 °C, 75%. (h) lithium
bis(trimethylsilyl)amide (5.0 equiv), MeI (8.5 equiv), THF, -78 °C to RT, 27
h, 90%; (i) Ph3P+MeBr- (5.0 equiv), tBuOK (4.9 equiv), toluene, reflux, 1 h;
then 19 (1.0 equiv), toluene, reflux, 4 h, 90%. Ni(acac)2 = bis(2,4-
pentanediono)nickel; PTSA•H2O = p-toluenesulfonic acid monohydrate;
DMSO = dimethyl sulfoxide; DCE = dichloroethane.
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With this chemistry in mind, we first applied Shenvi’s protocol
In order to acquire a further appreciation for the observed
chemistry for the formation of 15 and 16 in Scheme 3, we carried
out a density functional theory (DFT) experiment to account for the
excellent diastereoselectivity (Figure 2). For the chair-like
conformation 13a, the small difference in the activation energy
between 1,4-HAT via a 5-membered transition state TS1 (the most
favored transition state, ΔΔG‡ = 0, for details, see SI) and 1,5-HAT
via a 6-membered transition state TS4 (ΔΔG‡ = 1.2 kcal/mol)
accounts for the results of deuterium labeling studies (scheme 3a).
For the boat-like conformation 13b, the energy barriers of both the
1,4-HAT transition state TS2 (ΔΔG‡ = 17.5 kcal/mol) and 1,5-HAT
transition state TS3 (ΔΔG‡ = 24.1 kcal/mol) are much higher than
that via TS1 and TS4, which indicates that TS2 and TS3 are not
favorable for the formation of 13 from 12.
1
2
3
4
5
6
7
8
for the treatment of 12 with catalyst Mn(dpm)3 in the presence of
PhSiH3 and TBHP.28 As expected, 13 was obtained in 67% yield as
the major isomer, together with a 10% yield of its diastereoisomer.
We then tested Baran’s conditions29 by using Fe(acac)3 as a catalyst
in the presence of PhSiH3. To our delight, 13 was obtained in 75%
yield as a single diastereoisomer, demonstrating the power of the
HAT reaction.
To complete the total synthesis of (+)-waihoensene, we adopted
Lee’s protocol5 to install the final methyl group. Ketone 13 was
treated with LiHMDS, and the resultant enolate was reacted with
methyl iodide to give 14 in 90% yield. Upon further treatment of 14
with methylene triphenylphosphonium ylide in refluxing toluene,
product 1 was obtained in 90% yield on a 100 mg scale. The 1H and
13C NMR spectra and specific rotation of the synthesized
waihoensene (1) were in agreement with those reported in the
literature2,5 ([]23 D = +49.33 , c = 0.15 in CHCl3; lit. []22 D =
+43.9, c = 0.09 in CHCl3), establishing the absolute stereochemistry
of (+)-waihoensene (1) for the first time.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
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42
43
44
45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
13a
a) conformational isomerization of
Me
Me
Me
Me
Me
13
13-iso
H
X
H
H
With regard to the critical role of HAT in our total synthesis, we
then carried deuterium experiments and control experiment (scheme
3). Accordingly, when 12 was treated with a catalytic amount of
H
O
O
Me
13b
13a
Boat-like
Chair-like
o
Fe(acac)3 in the presence of PhSiD3 (1.0 equiv.) in EtOH at 60 C
13
b) Calculated transition state leading to
for 1 h, deuterated ketone 15 was obtained in 75% yield as a single
diastereoisomer. When the same reaction was carried out in the
presence of deuterated ethanol (CD3CD2OD) at 60 oC for 1 h,
product 16 was obtained in 75% yield and deuterium atoms were
found in both C3 (29% D) and C1 (17% D) (D/H ≈ 1/3 in total) by
NMR spectroscopic analysis. This indicated that both [1,4] and
[1,5]-HAT processes by abstractions of protons from both C1 and
C3 carbons could occur in this radical-based reduction (when we
treated 13 with condition b in scheme 3, no deuterium atoms were
found in the product, see SI for details). We also envisaged that the
ketal 17, in which the protons at C1 and C3 position are less
activated compared with ketone 12, would afford different results.
Indeed, when 17 was subjected to the identical conditions listed in
Scheme 3b, 13-iso bearing the opposite stereochemistry at C9 was
obtained in 70% yield, together with a 9% yield of 13.
TS4
TS1
G‡ = 1.2
favorable
1,5-HAT
G‡ = 0
favorable
1,4-HAT
13-
c) Calculated transition state leading to
iso
TS2
TS3

G‡ = 24.1
G‡ = 17.5
disfavorable
1,4-HAT
disfavorable
1,5-HAT
Figure 2. Diastereoselective determined transition state calculation in
B3LYP-D3/6-31G**//B3LYP-D3/6-311++G** level in EtOH (SMD
solvation model).
Scheme 3. Deuterium labeling studies and control experiment.
a. Deuterium labeling studies
Me
Me
To account for the formation of 13-iso as the major product from
17 (Scheme 3b), we also carried out a DFT experiment, which
indicates that due to the protection of the ketone group in 12, the
resultant ketal 17 might proceed via both an intramolecular HAT
reaction and an intermolecular hydrogen-abstraction reaction to
afford products 13 and 13-iso (see SI for details).
In summary, the asymmetric total synthesis of (+)-waihoensene
has been achieved for the first time in 15 steps and 3.8% overall
yield. The key step in this total synthesis was identification of the
Fe(acac)3/PhSiH3-mediated intramolecular HAT reaction, which
enabled the diastereoselective saturation of the exo-cyclic double
bond of C9–C15 in 12 via both [1,4]- and [1,5]-HAT processes. The
total synthesis also features an enantioselective construction of the
angular triquinane core bearing four contagious quaternary
stereogenic centers via key steps: 1) a Cu-catalyzed asymmetric
conjugate addition; 2) a Conia-ene type reaction; 3) a Co-mediated
intramolecular PK reaction; and 4) a Ni-catalyzed alkylation.
Application of this synthetic strategy to the total synthesis of other
complex natural products is currently underway in our laboratories,
and will be reported in due course.
a) Fe(acac)3 (0.2 equiv.)
PhSiD3 (1.0 equiv.)
Me
D
Me
Me
1
1
H
3
3
EtOH, 60 °C
(75%)
O
O
15
12
Me
Me
b) Fe(acac)3 (0.2 equiv.)
PhSiH3 (1.0 equiv.)
Me
1
Me
H
D/H =
1
17% : 83%O
3
3
CD3CD2OD, 60 °C
(75%)
D/H =
O
12
29% : 71%
16
b. Control experiment
Me
Me
Me
O
c) Fe(acac)3
PhSiH3
Me
Me
Me
Me
1
Me
+
H
H
O
3
9
9
d) HCl
(79%, 2 steps)
(dr = 7.7 : 1)
O
O
17
13 (9%)
13-iso (70%
)
Based on the deuterium and control experiments, two difference
reaction pathways might account for the observed results, which are
associated with the chair-like conformation 13a and boat-like
conformation 13b (Figure 2). Our mechanistic analysis suggested
that HAT processes proceeded through the chair-like transition state
13a (see SI for details).
ASSOCIATED CONTENT
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Page 4 of 6
(8) (a) d’Augustin, M.; Palais, L.; Alexakis, A. Enantioselective
Supporting Information
Copper-Catalyzed Conjugate Addition to Trisubstituted
Cyclohexenones: Construction of Stereogenic Quaternary
Centers. Angew. Chem. Int. Ed. 2005, 44, 1376-1378. (b) d’Augustin,
M.; Alexakis, A. Copper-Catalyzed Asymmetric Conjugate
Addition of Trialkylaluminium Reagents to Trisubstituted
Enones: Construction of Chiral Quaternary Centers. Chem. Eur. J.
2007, 13, 9647-9662. (c) Palais, L.; Alexakis, A. Copper-Catalyzed
Asymmetric Conjugate Addition with Chiral SimplePhos Ligands.
Chem. Eur. J. 2009, 15, 10473-10485
1
2
3
4
5
6
7
8
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and compound characterizations (PDF);
X-ray diffraction of compound 9 (CIF), 11 (CIF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: zyang@pku.edu.cn
*E-mail: junhuang@pku.edu.cn
(9) (a) Renaud, J-L.; Aubert, C.; Malacria, M. Cobalt-Mediated
Cycloisomerization of δ-Substituted ε-Acetylenic β-Ketoesters
Construction of Angular Triquinane by a Sequence Ene/Pauson-
Khand Reactions. Tetrahedron 1999, 55, 5113-5128. (b) Ishizaki, M.;
Kyoumura, K.; Hoshino, O. An Effective Synthesis of Angular
Tricyclic Compounds Having Two Contiguous Quaternary
Centers by Intramolecular Pauson-Khand reaction of Exocyclic
Enynes Synlett 1999, 5, 587-589. (c) Ishizaki, M.; Iwahara, K.;
Niimi, Y.; Satoh H.; Hoshino, O. Investigation of the synthesis of
angular tricyclic compounds by intramolecular Pauson–Khand
reaction of exo- and endo-cyclic enynes. Tetrahedron 2001, 57,
2729–2738.
9
10
11
12
13
14
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17
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by the National Science
Foundation of China (Grant Nos. 21632002, 21702011 and
21871012), Shenzhen Basic Research Program (Grant Nos.
JCYJ20180302150314340 and JCYJ20170818090044432), and the
Scientific and Technological Innovation Project supported by
Qingdao National Laboratory for Marine Science and Technology
(Grant Nos. 2015ASKJ02, and LMDBKF201802). This paper is
dedicated to Professor Henry N. C. Wong on the occasion of his
70th birthday.
t
(10) For construction of quaternary stereogenic centers with BuOK–
mediated Conia-Ene Reaction, see (a) Hartrampf, F. W. W.;
Furukawa, T.; Trauner, D. A Conia-Ene-Type Cyclization under
Basic Conditions Enables an Efficient Synthesis of (-)-
Lycoposerramine R. Angew. Chem. Int. Ed. 2017, 56, 893-896.
Selected construction of quaternary stereogenic centers with
Conia-Ene Reaction from other groups: (b) Staben, S. T.;
Kennedy-Smith, J. J.; Toste, F. D. Gold(I)-Catalyzed 5-endo-dig
Carbocyclization of Acetylenic Dicarbonyl Compounds. Angew.
Chem., Int. Ed. 2004, 43, 5350-5352. (c) Yang, T.; Ferrali, A.;
Sladojevich, F.; Campbell, L.; Dixon, D. J. Brønsted Base/Lewis
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