Synthetic Study of Phainanoids. Highly Diastereoselective Construction of the 4,5-Spirocycle via Palladium-Catalyzed Intramolecular Alkenylation

Article abstract of DOI:10.1021/acs.orglett.7b01303

An efficient strategy to synthesize the western part of phainanoids is reported. The benzofuranone-based 4,5-spirocyclic motif is constructed diastereoselectively via a palladium-catalyzed intramolecular alkenylation. The computational study suggests that

Full text of DOI:10.1021/acs.orglett.7b01303

Letter
pubs.acs.org/OrgLett
Synthetic Study of Phainanoids. Highly Diastereoselective
Construction of the 4,5-Spirocycle via Palladium-Catalyzed
Intramolecular Alkenylation
Jiaxin Xie, Jianchun Wang, and Guangbin Dong*
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
S
* Supporting Information
ABSTRACT: An efficient strategy to synthesize the western part of phainanoids is reported. The benzofuranone-based 4,5-
spirocyclic motif is constructed diastereoselectively via a palladium-catalyzed intramolecular alkenylation. The computational
study suggests that the remarkably high diastereoselectivity is attributed to the stabilizing interaction between the 2′ carbonyl
moiety and the palladium catalyst in the favored transition state.
hainanoids, recently isolated from Phyllanthus hainanensis,
attractive targets for synthetic studies. Herein we describe our
initial efforts toward developing an efficient strategy to
construct the western part of the natural products. This
model study provides an important clue about how to construct
the benzofuranone-based 4,5-spirocycle in a highly diaster-
eoselective fashion.
P
are a class of novel triterpenoids that exhibit potent
immunosuppressive activities (Figure 1).1 For example, they
A simplified model compound (7) was chosen as the initial
target. The challenge to form the benzofuranone-based 4,5-
spirocyclic motif is twofold: (1) forming highly strained
multisubstituted cyclobutanes with an exocyclic olefin is a
nontrivial issue, and (2) control of the diastereoselectivity
during the ring closure step is another concern. After having
investigated a number of synthetic routes, we eventually
conceived the strategy of using an intramolecular alkenylation
to construct the cyclobutane ring (Scheme 1). The vinyl triflate
Scheme 1. Strategy for the Synthesis of 7
Figure 1. Phainanoids A−F and model compounds.
inhibit proliferation of T and B lymphocytes in vitro with IC50
values as low as 2.04 and 1.60 nM, respectively. From a
structural perspective, phainanoids possess a complex polycyclic
skeleton including 10 ring moieties and at least 13 chiral
centers. In particular, they all contain a unique benzofuranone-
based 4,5-spirocycle with a strained exocyclic olefin, which has
been unprecedented in other natural products.
A gross structure−activity analysis further reveals that such a
structural motif is crucial for the immunosuppressive activities.1
Thus, the intriguing chemical structures and promising
biological activities, in combination with their scarcity in nature
(5−20 mg/5 kg of dry plant material), make phainanoids highly
Received: May 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01303
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precursor 15 would come from an aldol condensation and
subsequent reduction between aldehyde 12 and benzofuran-
3(2H)-one (3-coumaranone, 13). Aldehyde 12 would be
rapidly accessed from commercially available β-keto ester 9.
In the forward sense, aldehyde 12 was prepared in four steps
in high overall yields from β-keto ester 9 through a sequence of
methylation,2 triflation of the ketone, DIBAL-H reduction, and
Dess−Martin oxidation (Scheme 2). The aldol condensation
Table 1. Optimization of the Palladium-Catalyzed
Intramolecular Alkenylation of Ketone 15
a
Scheme 2. Preparation of Intermediate 15
entry
base (1.5 equiv)
solvent
yield of 7 (%)
1
2
3
4
5
6
7
LiHMDS
KHMDS
NaHMDS
LiOtBu
KOtBu
NaOtBu
Cs2CO3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
THF (0.05 M)
THF (0.05 M)
THF (0.05 M)
THF (0.05 M)
THF (0.05 M)
THF (0.05 M)
THF (0.05 M)
THF (0.05 M)
THF (0.10 M)
THF (0.20 M)
THF (0.05 M)
PhMe (0.05 M)
21
34
20
44
25
14
35
b
8
60
b
9
51 (2)
39 (12)
65
b
10
between 12 and 13 was found to be most efficient in the
presence of basic alumina,3 which provided enone 14 in 84%
yield with complete Z selectivity. Selective reduction of the
trisubstituted enone olefin in 14 in the presence of a vinyl
triflate moiety turned out to be challenging. A number of
copper or manganese hydride-mediated conjugate reduction
methods4 failed, likely because the α-oxygen substitution
reduces the electrophilicity of the enone CC bond. Attempts
to use homogeneous palladium-catalyzed reduction5 were also
unfruitful, probably as a result of the competing reactivity of the
vinyl triflate toward oxidative addition with a Pd(0) species.
Eventually, Pd/C-catalyzed hydrogenation (with a H2 balloon)
was found to chemoselectively reduce the enone olefin to
compound 15 in 91% yield when toluene/DCM (50:1) was
used as the optimal solvent combination [see the Supporting
Information (SI) for details].
bc
,
11
bc
,
12
trace
a
Reactions were conducted on a 0.05 mmol scale in a 4 mL vial sealed
with a PTFE-lined cap. Unless otherwise noted, 10 mol % Pd(OAc)2
and 20 mol % QPhos were used. Yields were determined by 1H NMR
analysis using 1,1,2,2-tetrachloroethane as the internal standard.
Recovery of starting material is noted in parentheses. Vials were
flame-dried. 5 mol % Pd(OAc)2 and 10 mol % QPhos were used.
b
c
QPhos, and 1.5 equiv of LiOtBu in THF, which provided 7 in
65% (57% isolated) yield (entry 11). The structure of 7 was
unambiguously confirmed by X-ray crystallography of the
corresponding 2,4-dinitrophenyl (DNP)-hydrazone derivative
(16) (eq 1).
With compound 15 in hand, the stage was set to explore the
key intramolecular alkenylation to construct the 4,5-spirocycle.
While palladium-catalyzed ketone alkenylations have been well-
established,6a the use of such a reaction in an intramolecular
setting to access four-membered rings remains elusive.6b The
challenge is anticipated to come from the difficulty of forming a
highly strained ring via reductive elimination. It is known that
reductive elimination benefits from using sterically hindered
ligands. For example, Helquist and co-workers have demon-
strated that various tert-butyl-substituted phosphine ligands
promote the palladium-catalyzed intermolecular alkenylation of
ketones, with QPhos being the most efficient.7 Hence, we
began exploring the intramolecular alkenylation of compound
15 using QPhos as the ligand (Table 1). To our delight, under
Helquist’s original conditions (LiHMDS, THF, rt), the desired
4,5-spirocycle 7 was obtained, albeit in merely 21% yield (entry
1). The choice of base proved to be critical, and LiOtBu was
later found to be the best (entry 4) among all the bases
examined (entries 1−7). Removing residual water in the
reaction vessel by flame drying significantly improved the yield
to 60% (entry 8). Reactions carried out at higher concen-
trations resulted in incomplete conversions of 15 (entries 9 and
10). Using toluene instead of THF shut down the product
formation at room temperature (entry 12). The optimal
conditions were established to be 5 mol % Pd(OAc)2, 10 mol %
It is noteworthy that the other possible diastereomer (7′)
was not observed during the intramolecular alkenylation. To
understand the origin of this diastereoselectivity, computational
studies using density functional theory (DFT) were carried out.
It was suggested that during the reductive elimination step, the
transition state that forms the desired diastereomer is 6.9 kcal/
mol lower in energy than the undesired one (Figure 2). The
stabilization is likely due to a favorable coordinative interaction
between the carbonyl π-bond electrons and the palladium (see
the SI for details).
To examine the influence of adjacent stereocenters and
fused-ring structures on the 4,5-spirocycle formation, we sought
B
DOI: 10.1021/acs.orglett.7b01303
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Scheme 4. Synthesis of Compound 8 from Compound 24
Figure 2. DFT-calculated diastereochemistry-determining transition
states for the palladium-catalyzed intramolecular alkenylation. Energies
were calculated at the M06/SDD−6-311+G(d,p)/SMD(thf) level of
theory with geometries optimized at the B3LYP/SDD−6-31G(d)
level.
to synthesize a more complex model compound (8, Figure 1)
with a hexacyclic core structure of phainanoids. A strategy of
employing a vinyl oxirane-mediated polyene cyclization8 was
conceived to prepare the precursor for the intramolecular
alkenylation (Scheme 3). While aldehyde 19 has been
Scheme 3. Synthesis of Compound 24
alcohol 25 with a trans-decaline core in 70% yield. Treatment of
alcohol 25 with Dess−Martin periodinane gave ketone 26, the
structure of which was further confirmed by X-ray crystallog-
raphy. Subsequent triflation of ketone 26 followed by the Pd/
C-catalyzed chemoselective hydrogenation uneventfully pro-
vided compound 28. Finally, the Pd(OAc)2/QPhos-catalyzed
intramolecular alkenylation, to our surprise, was more effective
in toluene than in THF (vide supra). At an elevated reaction
temperature (60 °C), 4,5-spirocycle 8 was ultimately isolated in
83% yield with a >20:1 diastereomeric ratio (see the SI for
optimization details). The X-ray structure of 8 was also
obtained.
In summary, we have disclosed a general and practical route
to access the western part of phainanoids, which contains a
unique 4,5-spirocyclic ether motif. The synthesis features a
highly diastereoselective palladium-catalyzed intramolecular
alkenylation to construct a strained system, which should
have broad implications beyond the synthesis itself. Total
syntheses of phainanoids and their analogues are currently
under investigation in our laboratory.
synthesized previously,9 a modified route was developed from
inexpensive geranyl acetate (17) through a three-step sequence
involving copper-catalyzed allylic coupling, chemoselective
epoxidation, and oxidative cleavage of the epoxide. Under
Still’s modified Horner−Wadsworth−Emmons olefination
conditions,10 (Z)-olefin 21 was obtained selectively in 79%
yield. Subsequent treatment of ester 21 with DIBAL-H led to
allylic alcohol 22 in quantitative yield. Directed epoxidation of
the allylic alcohol followed by Parikh−Doering oxidation
efficiently yielded the corresponding epoxy aldehyde 23. The
subsequent basic-alumina-promoted aldol condensation be-
tween aldehyde 23 and 3-coumaranone (13) smoothly
delivered vinyl epoxide 24. It should be noted that all of
these reactions could be performed on gram scales.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01303.
Experimental procedures, spectral data, crystallographic
data, and DFT computational data (PDF)
With an effective route to 24, the Lewis acid-mediated
polyene cyclization was then explored (Scheme 4). Gratifyingly,
the reaction occurred rapidly with SnCl4, furnishing tricyclic
X-ray crystallographic data for compound 8 (CIF)
X-ray crystallographic data for compound 16 (CIF)
X-ray crystallographic data for compound 26 (CIF)
C
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Organic Letters
Letter
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gbdong@uchicago.edu.
ORCID
Guangbin Dong: 0000-0003-1331-6015
Author Contributions
J.X. conducted all of the experiments. J.W. performed the DFT
computational study. J.X. and G.D. wrote the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Kinship Foundation (Searle Scholar Program)
and the Alfred P. Sloan Foundation for research funding. Dr.
Vincent Lynch (University of Texas at Austin) and Mr. Ki-
Young Yoon (University of Chicago) are acknowledged for X-
ray crystallography. Dr. Siu Yin Lee (University of Chicago) is
thanked for editing the manuscript. We also acknowledge Dr.
Gang Lu (University of Pittsburgh) for DFT advice.
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DOI: 10.1021/acs.orglett.7b01303
Org. Lett. XXXX, XXX, XXX−XXX