Total Synthesis of (-)-Xishacorene B from (R)-Carvone Using a C-C Activation Strategy

Article abstract of DOI:10.1021/jacs.8b05832

The activation of C-C bonds that are traditionally viewed as unreactive, when coupled with other bond-forming processes, can offer new approaches to the synthesis of complex molecular scaffolds. In this Communication, we demonstrate the conversion of carv

Full text of DOI:10.1021/jacs.8b05832

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Communication
Total Synthesis of (–)-Xishacorene B from (R)-
Carvone using a C–C Activation Strategy
Isabel Kerschgens, Alexander R Rovira, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 23 Jul 2018
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Total Synthesis of (–)-Xishacorene B from (R)-Carvone using a C–C Activation Strategy
Isabel Kerschgens, Alexander R. Rovira, and Richmond Sarpong*
9
Department of Chemistry, University of California, Berkeley, California 94720, United States
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Supporting Information Placeholder
ABSTRACT: The activation of C–C bonds that are tradi-
tionally viewed as unreactive, when coupled with other
bond-forming processes, can offer new approaches to the
synthesis of complex molecular scaffolds. In this manu-
A. Concept: C–C Bond Activation/Coupling of Carvone
O
O
O
Nu
Me
Me
Me
Me
Me
Nu
Nu
script, we demonstrate the conversion of carvone to unusual
E
Me
E
1
2
3
bicyclo[3.3.1] and [3.2.1] frameworks by exploiting a Pd(0)-
catalyzed C–C bond activation reaction and a radical cy-
clization process. This sequence is applied to a 10-step syn-
thesis of the diterpene xishacorene B.
Me
Me
B. Previous Work (Ref. 3a)
O
Me
Me
O
Br
HO
OH
Cp2TiCl2
Zn
Me
Me
Pd(0)
Me
O
HO
Me
Me
4
5
Me
6
The formation of carbon-carbon (C–C) bonds is para-
mount to the synthesis of complex organic molecules such
as terpenoid natural products,1 which consist primarily of a
carbon skeleton. Therefore, in developing strategies for the
total synthesis of terpenoids, significant emphasis is often
placed on methods that form new C–C bonds.2 As part of a
program to exploit readily-available, ‘chiral pool’ reagents
for terpene syntheses,3 we recognized that C–C activation of
carvone, when coupled with new C–C bond forming pro-
cesses, would yield novel structural frameworks that signif-
icantly expand the scope of complex molecules convention-
ally accessible from carvone (see 1®3, Figure 1A). We have
shown previously that this type of transformation can be re-
alized by converting epoxy carvone (4) to bis-hydroxylated
pinene derivatives (see 5, Figure 1B) using a method by Ber-
mejo,4 followed by Pd(0)-catalyzed cross coupling with vi-
nyl or aryl halides to provide access to structures such as 6,
which form the core of myriad natural products.
C. This work: Application to [3.3.1] Bicycles and Xishacorene B
Me
Me
Me
O
O
Me
Me
Me
Me
H
Me
Me
Me
HO
HO
Me
H
H
H
Me
R1
R1
R2
Me
R2
Me
Novel [3.3.1]
bicycles
xishacorene B (7)
OH
Me
OH
Me
Me
Me
HO
Me
HO
I
H
H
OH
OH
Me
5
9
8
Figure 1. Use of C–C activation starting from carvone for
natural product synthesis
Retrosynthetically, we envisioned xishacorene B (7, Fig-
ure 1C) arising from bicyclo[3.3.1]nonane 8. In turn, 8 could
be brought back to cyclobutanol 54 and vinyl iodide 9.6 We
commenced our synthetic studies by optimizing the cross
coupling of cyclobutanol 5 and vinyl iodide 9 (Table 1). On
the basis of the precedent of Uemura,7 this coupling likely
involves insertion of a Pd(0)-complex into 9 to provide a
Pd(II)-species that undergoes ligand exchange to form
alkenyl Pd-alkoxide 11. At this stage, β-carbon elimina-
tion/C–C bond activation would result in cleavage of the cy-
clobutanol to yield alkyl palladium intermediate 12. Reduc-
tive elimination to 13 would then complete the catalytic cy-
cle. Key to the success of this coupling sequence would be
to achieve reductive elimination from 12 over a competing
b-hydride elimination.8 We hypothesized that this would be
possible by the judicious
In this communication, we demonstrate that vinylated ad-
ducts related to 6 are easily advanced to unusual bicy-
clo[3.3.1]nonane frameworks in one or two steps. We show-
case the utility of this bicyclization sequence in a short syn-
thesis of the natural product xishacorene B (7).
Xishacorene B is a member of a new family of diterpenes
recently isolated from the soft coral Sinularia polydactyla
(0.0008% yield of dry coral material) off the coast of the Xi-
sha Islands in China.5 Preliminary biological screening of
these secondary metabolites revealed that they have activity
as promoters of concanavalin A-induced T-lymphocyte pro-
liferation. Thus, these molecules may prove useful as a start-
ing point for the development of new small molecule im-
munopotentiators.
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Table 1. Optimization of the Pd-catalyzed C-C-activa-
tion/coupling sequence.
free hydroxy groups, providing an opportunity for in-situ
acyl-protection simply by choice of solvent (14, entry 7).
1
2
3
4
5
6
7
8
O
As shown in Figure 2, the optimized conditions are readily
extended to the coupling of 5 with a range of vinyl halides,
providing the corresponding adducts in good to excellent
yields. In general, vinyl iodides required lower reaction tem-
peratures to proceed, whereas vinyl bromides required
higher temperatures. In the coupling with 22, it is interesting
to note that the product of the cross-coupling provides the
skeleton of an isomer of the natural product cassiol.9
Me
Me
RO
R = H
13
14
Me
R = Ac
H
I
Me
OH
9
reductive
elimination
[Pd]0
OR
Me
oxidative addition
O
9
Me
HO
Me
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For the construction of bicyclic scaffolds including the
[3.3.1]-framework of the xishacorene family, we sought to
utilize the coupling products illustrated in Figure 2 in Muk-
aiyama-type hydrogen atom transfer (HAT) reactions. In-
spired by the work of Baran,10 Shenvi11 and others,12 a vari-
ety of HAT conditions that would lead to cyclization were
explored.
PdII
I
OH
H
12
10
PdII
ligand exchange
HO
Me
Me
OH
Me
PdII
Me
11
β-carbon elimination/
C-C activation
Me
OH
O
HO
Me
HO
5
The desired cyclization occurred with varying degrees of ef-
ficiency for several substrates (e.g., for 24 and 26, a 28%
yield and 32% yield, respectively, of the [3.2.1] bicycles
conversion[a]
entry
yield 13[a]
yield 14[a]
Pd-complex
solvent
1
2
3
4
5
6
7
> 98%
> 98%
67%
85%[b]
74%[c]
49%[d]
63%
-
Pd(PCy3)2
Pd(PCy3)2
Pd(PCy3)2
Pd(PPh3)4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
-
-
Table 2. Cyclization to bicyclo[3.3.1] and [3.2.1] bicy-
81%
-
cles.
73%
56%
-
-
Pd[P(tBu)2Ph]2 1,4-dioxane
Method A:
Fe(acac)3, Ph(i-PrO)SiH2, EtOH[a]
92%
63%
Pd(PCy3)2
Pd(PCy3)2
benzene
EtOAc
bicycle
enone
> 98%
17%
70%
Method B:
AIBN, HSnBu3, benzene, 80°C[b]
[a] Determined by 1H-NMR analysis using benzyl benzoate as an internal standard. [b]
Reagents and conditions: 5 mol% of Pd-complex, 1.5 equiv of vinyl iodide, 2.0 equiv
Cs2CO3, 30°C, 18 h. [c] 1.1 equiv vinyl iodide instead of 1.5 equiv [d] 18°C instead of
30°C.
entry
enone
method
product
yield
O
Me
H
Ph
choice of ligands on the Pd complex. We identified
Pd(PCy3)2 as the optimal palladium complex, and tempera-
tures of 30–40 °C as well as the use of cyclobutanol 5 bear-
ing free hydroxy groups to be ideal (Table 1, entry 1). The
highest yields for the coupling were obtained using 1.5
equivalents of vinyl iodide 9. Lowering the amount of 9 to
1.1 equivalents and the reaction temperature to 18 °C re-
sulted in lower yields (entries 2 and 3). Using benzene as a
solvent (entry 6) gave the product in lower yield relative to
1,4-dioxane. Interestingly, with EtOAc as the solvent, the
cross-coupling proceeded with attendant acylation of the
Me
Me
Me
HO
28%[c]
1
A
Me
H
O
24
25
OH
OH
Ph
O
Me
H
H
Me
Me
Me
Me
Me
HO
32%
75%
89%
2
3
4
A
O
26
27
Me
O
Me
Me
H
AcO
Br
Me
Me
B
Figure 2. Scope of the Pd-catalyzed C–C-activa-
H
28
29
O
OAc
tion/coupling sequence
OH
Me
O
Me
H
O
RX, Pd(PCy3)2, Cs2CO3,
1,4-dioxane, 40°C[a]
Me
Me
Me
H
HO
HO
Me
H
Me
Me
AcO
Br
Me
B
Me
5
R
30
31
Me
O
OAc
Ph
Br
Me
Br
Me
I
Br
Br
Ph
Me
Me
Ph
78%[c]
89%[b]
53%[b]
16
69%
68%
Unsuccessful HAT-substrates:
O
O
O
15
17
18
19
Me
Me
Me
H
Me
H
Me
Me
HO
HO
HO
Br
OH
Me
Me
Br
OTBS
I
I
OTBS
H
32
33
13
OTBS
50%[b]
22
Me
HO
HO
38%[b][c]
53%[b]
21
77%
20
23
[a] Detailed conditions: 1 equiv Fe(acac)3, 2–2.5 equiv Ph(i-PrO)SiH2, EtOH (0.1 M – 0.2 M),
0°C – rt, 2 h. [b] Detailed conditions: 0.2 equiv AIBN, 4 equiv HSnBu3, benzene (0.1 M),
80°C, 50 min. [c] Isolated as an inseparable mixture containing minor side products.
[a] Detailed conditions: 1.5 – 3 equiv vinyl halide, 0.5 – 0.1 equiv Pd(PCy3)2, 2 equiv
Cs2CO3, 1,4-dioxane (0.2 M), 40°C, 18 h. [b] Elevated temperature required, see the SI for
details. [c] Isolated as inseparable mixture of alkene isomers, see the SI for details.
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Scheme 1. Synthesis of xishacorene B and 1-epi-xishacorene B (46).
OH
OAc
A.
O
O
Me
Me
Pd(PCy)2, 9,
Cs2CO3
H
AIBN,
n-Bu3SnH
H
Me
Me
1
LiAlH4
HO
HBr
Me
Me
AcO
Br
Me
Me
5
Me
Me
1,4-dioxane,
30°C
AcOH, 0°C→RT
benzene, 80°C
THF, 0°C
H
H
H
OH
O
HO
OAc
Me
13
34
35
8
Me
1
d.r.: 1:1
73%
d.r.: 1.1:1
48%
88%
98%
DCC⋅MeI
THF, 55°C
I
92% total yield
OH
9
OAc
Me
(major diastereomer drawn, no separation)
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
PO(OEt)2
42
Me
9
Me
H
Me
KOt-Bu
DMSO, 100°C
PCC, NaOAc
KOt-Bu
Me
Me
Me
Me
Me
Me
HO
THF, 0°C
Me
Me
MS 3 Å,
CH2Cl2, 0°C
Me
12
15
H
15
OH
36
I
7
41
40
O
88%
xishacorene B
75%
61%
55%
Me
(diastereomers separated)
I
Me
H
H
Me
Me
H
[α]20D= – 19.5 (c = 0.58, MeOH)
Me
Me
Me
Me
[α]20D= – 11.3 (c = 0.20, MeOH) [ref. 5]
Me
Me
Me
12
15
O
I
15
H
H
O
I
O
37
38
39
(From DMP oxidation of 36)
B.
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
I
PCC, NaOAc
42, KOt-Bu
KOt-Bu
DMSO, 100°C
Me
HO
Me
Me
THF, 0°C
MS 3 Å,
CH2Cl2, 0°C
H
OH
I
O
43
44
45
46
Me
58%
88%
81%
Me
were obtained, see entries 1 and 2 in Table 2). More chal-
lenging substrates such as 32 and 33 could not be cleanly
transformed to the corresponding bicycles. In particular,
enone 13, an intermediate in the xishacorene synthesis
(Scheme 1), only gave small amounts of the Mukaiyama-
type cyclization product along with numerous side products.
Various HAT conditions using Fe, Co, or Mn-complexes,13
a range of silanes, and various solvents also resulted in com-
peting side reactions including reduction of the enone double
bond or both double bonds in the substrate to give insepara-
ble mixtures of reduction products.
photoredox conditions15 did not result in any conversion of
starting material.
With [3.3.1] bicycle 35 in hand, treatment with LiAlH4 ef-
fected global reduction of the two ester groups and the ke-
tone carbonyl to give triol 8 in 98% yield.16 Subjecting triol
8 to 5 equivalents of DCC·MeI17 at 55 °C in THF selectively
converted the two primary alcohols to the corresponding io-
dides in the presence of the secondary alcohol at C12.18 The
secondary alcohol group was confirmed by DMP oxidation
of the resulting diiodide (36) to afford ketone 37. At this
stage, the two C1-epimers that had been carried along fol-
lowing the radical cyclization step (see 34®35) could be
separated. Upon treatment of the desired isomer (36) with
KOt-Bu at elevated temperature, elimination of the C9 pri-
mary iodide occurred to form a vinyl group. It is presumed
that Williamson-etherification by displacement of the C15
iodide by the C12 hydroxyl yields oxetane intermediate
39,19,20 which gives alcohol 40 following elimination in an
overall transposition of the C12 hydroxyl.21 Xishacorene B
was accessed from 40 using a two-step sequence involving
oxidation of the primary hydroxyl to aldehyde 41 (using pyr-
idinium chlorochromate) followed by Horner-Wadsworth-
Emmons olefination with phosphonate 42. The optical rota-
tion of synthetic 7 was found to differ from the reported
value of the isolated material (synthetic: –19.5; natural: –
11.3). We theorize this might arise from the poor solubility
of the very lipophilic 7 in MeOH.
Ultimately, a more effective two-step sequence was iden-
tified for bicyclization that began with installation of a ter-
tiary bromide through hydrobromination of the more elec-
tron-rich double bond using HBr in AcOH.14 Cyclization to
provide 29 or 31 proceeded smoothly under radical condi-
tions (AIBN, n-Bu3SnH, 80 °C) in good yields (see Table 2,
Method B).
In the context of the synthesis of xishacorene B, bromina-
tion of 13 (Scheme 1, A) proceeded with concomitant acyl-
ation of both hydroxy groups to give 34 in 73% yield as a
1:1-diastereomeric ratio of epimers about the Br-bearing car-
bon. The radical cyclization proceeded smoothly in 92%
yield to give 35 as a 1.1:1 diastereomeric mixture at C1
slightly favoring the desired diastereomer. Attempts to im-
prove the diastereomeric ratio using other initiation condi-
tions (e.g., lauroyl peroxide as an initiator) have not been
successful, whereas some other methods including
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Synthesis of the C1 epimer of xishacorene B (7) was also
realized using the same sequence but starting with bicycle
43, the epimer of 36 (Scheme 1B).
L. D.; Williams, D. E.; Andersen, R. J.; Jancar, S.; Berlinck,
R. G. S.; Sarpong, R. Nat. Chem. 2018, NCHEM-
17102265B.
4 Bermejo, F. A.; Mateos, A. F.; Escribano, A. M.; Lago,
R. M.; Burón, L. M.; López, M. R.; González, R. R. Tetra-
hedron 2006, 62, 8933.
1
2
3
4
5
6
7
8
In conclusion, we have demonstrated the utility of a C–C
activation/cross-coupling sequence for the construction of
complex molecular frameworks. Specifically, carvone can
be converted in two steps to a hydroxylated pinene deriva-
tive that sets the stage for a key cross-coupling. A Pd-cata-
lyzed cyclobutanol C–C cleavage/coupling with vinyl hal-
ides followed by radical-mediated C–C bond construction
provided rapid access to a variety of [3.3.1] bicycles. Using
this approach, the first total synthesis of the marine diterpene
xishacorene B has been achieved in 10 steps from carvone
without using any protecting groups. Future studies will fo-
cus on applying this strategy to the synthesis of xishacorene
congeners and their derivatives as well as the investigation
of their bioactivity.
5
Ye, F.; Zhu, Z.-D.; Chen, J.-S.; Li, J.; Gu, Y.-C.; Zhu,
W.-L.; Li, X.-W.; Guo, Y.-W. Org. Lett. 2017, 19, 4183.
6 Original contribution: Wipf, P.; Lim, S. Angew. Chem.
Int. Ed. 1993, 32, 1068. Procedure used from: Schaubach,
S.; Gebauer, K.; Ungeheuer, F.; Hoffmeister, L.; Ilg, M. K.;
Wirtz, C.; Fürstner, A. Chem. Eur. J. 2016, 22, 8494.
7 a) Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S.
J. Am. Chem. Soc. 2003, 125, 8862. b) Nishimura, T.; Matsu-
mura, S.; Maeda, Y.; Uemura, S. Tetrahedron Lett. 2002, 43,
3037. c) Nishimura, T.; Matsumura, S.; Maeda, Y.; Uemura,
S. Chem. Commun. 2002, 50.
9
10
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12
13
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
Competing b-hydride elimination has been observed to
varying extent at elevated temperatures.
ASSOCIATED CONTENT
9 Shiraga, Y.; Okano, K.; Akira, T.; Fukaya, C.; Yoko-
yama, K.; Tanaka, S.; Fukui, H.; Tabata, M. Tetrahedron
1988, 44, 4703.
Supporting Information.
10 a) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc.
2014, 136, 1304. b) Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C.-M.;
Baran, P. S. Nature 2014, 516, 343.
The Supporting Information is available free of charge on
the ACS Publications website at http://pubs.acs.org.
11
Obradors, C.; Martinez, R. M.; Shenvi, R. A. J. Am.
Experimental detail and spectroscopic data.
Chem. Soc. 2016, 138, 4962.
12 a) George, D. T.; Kuenstner, E. J.; Pronin, S. V. J. Am.
Chem. Soc. 2015, 137, 15410. b) Xu, G.; Elkin, M.; Tantillo,
D.; Newhouse, T.; Maimone, T. Angew. Chem. Int. Ed.
2017, 56, 12498.
AUTHOR INFORMATION
Corresponding Author
*rsarpong@berkeley.edu
13
Specifically, Fe(acac)3, Co(acac)3, Co(dmp)2,
Notes
Mn(acac)3 and the Co-complex used in Ref. 12b were inves-
tigated as catalysts for this process.
The authors declare no competing financial interest.
14
a) Tabuchi, T.; Urabe, D.; Inoue, M. J. Org. Chem.
ACKNOWLEDGMENTS
2016, 81, 10204. b) Hagiwara, K.; Tabuchi, T.; Urabe, D.;
This work was supported by the National Science Foun-
dation (NSF, CHE-1566430 to R.S.). The Swiss National
Science Foundation is kindly acknowledged for an Early
Postdoc. Mobility Fellowship to support I. K.
(P2BSP2_168732). Aduro Biotech is kindly acknowledged
for a Postdoc Fellowship for A. R. R. Dr. Marcus Blümel is
kindly acknowledged for generous donations of 5.
Inoue, M. Chem. Sci. 2016, 7, 4372.
15 a) Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J.
Angew. Chem. Int. Ed. 2011, 50, 9655. b) Schnermann, M.
J.; Overman, L. E. Angew. Chem. Int. Ed. 2012, 51, 9576.
16 The configuration of the secondary hydroxyl at C12 in
8 was determined by NOE-experiments.
17 Scheffold, R.; Saladin, E. Angew. Chem. Int. Ed. 1972,
11, 229.
18 Holtsclaw, J.; Koreeda, M. Org. Lett. 2004, 6, 3719.
19 For a review on oxetanes in synthesis see: a) Bull, J. A.;
Croft, R. A.; Davis, O. A.; Doran, R.; Morgan, K. F. Chem.
Rev. 2016, 116, 12150. b) Mahal, A. Eur. J. Chem. 2015, 6,
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R. J. Am. Chem. Soc. 2015, 137, 6327. c) Finkbeiner, P.;
Murai, K.; Röpke, M.; Sarpong, R. J. Am. Chem. Soc. 2017,
139, 11349. d) Kuroda, Y.; Nicacio, K. J.; da Silva, I. A.;
Leger, P. R.; Chang, S.; Gubiani, J. R.; Deflon, V. M.; Na-
gashima, N.;Rode, A.; Blackford, K.; Ferreira, A. G.; Sette,
21 We are grateful to an insightful reviewer for suggesting
this pathway for the formation of 40.
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radical
cyclization
Me
Me
R1
Me
Me
O
Me
Me
R1
R2
R2
HO
Me
X
RO
Me
Novel bridged
bicycles
xishacorene B
Pd(0)-
coupling
RO
Me
C–C activation
New bonds
10-step synthesis
enantiospecific
protecting group free
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