Asymmetric Syntheses of the Flavonoid Diels-Alder Natural Products Sanggenons C and O

Article abstract of DOI:10.1021/jacs.5b12778

Metal-catalyzed, double Claisen rearrangement of a bis-allyloxyflavone has been utilized to enable a concise synthesis of the hydrobenzofuro[3,2-b]chromenone core structure of the natural products sanggenon A and sanggenol F. In addition, catalytic, enantioselective [4+2] cycloadditions of 2′-hydroxychalcones have been accomplished using B(OPh)₃/BINOL complexes. Asymmetric syntheses of the flavonoid Diels-Alder natural products sanggenons C and O have been achieved employing a stereodivergent reaction of a racemic mixture (stereodivergent RRM) involving [4+2] cycloaddition.

Full text of DOI:10.1021/jacs.5b12778

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Communication
Asymmetric Syntheses of the Flavonoid Diels-
Alder Natural Products Sanggenons C and O
Chao Qi, Yuan Xiong, Vincent Eschenbrenner-Lux, Huan Cong, and John A. Porco
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12778 • Publication Date (Web): 06 Jan 2016
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Journal of the American Chemical Society
Asymmetric Syntheses of the Flavonoid Diels-Alder Natural
Products Sanggenons C and O
Chao Qi, ‡ Yuan Xiong, ‡ Vincent Eschenbrenner-Lux, Huan Cong, and John A. Porco, Jr. *
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Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts 02215
Supporting Information Placeholder
Scheme 1. Retrosynthetic Analyses for Sanggenons C and O
Abstract: Metal-catalyzed, double Claisen rearrangement of a
bis-allyloxyflavone has been utilized to enable a concise synthesis
of the hydrobenzofuro[3,2-b]chromenone core structure of the
natural products sanggenon A and sanggenol F. In addition,
catalytic, enantioselective [4+2] cycloadditions of 2′-
hydroxychalcones
have
been
accomplished
using
B(OPh)3/BINOL complexes. Asymmetric syntheses of the
flavonoid Diels-Alder natural products sanggenons C and O have
been achieved employing a stereodivergent reaction of a racemic
mixture (stereodivergent RRM) involving [4+2] cycloaddition.
Sanggenon-type natural products (Figure 1) are intriguing
synthetic targets due to their complex chemical structures and
potent biological activities.1 In particular, the congener sanggenon
C 2 has antitumor, antiviral, and anti-inflammatory properties 3
which underscores the compound as an attractive synthetic target.
Although chemical syntheses of related Diels-Alder type natural
products including sorocenol B4 and brosimones A and B5 have
been achieved, there are no reported catalytic, enantioselective
[4+2] cycloadditions of 2′-hydroxychalcones, nor are there
published reports of Diels-Alder cycloadditions of complex
flavonoid dienes. Herein, we report the first total syntheses of
sanggenon A (1) and sanggenol F (2), both featuring complex
benzofuro[3,2-b]chromenone structures. Further structural
complexity was obtained employing enantioselective [4+2]
cycloaddition to construct sanggenons C (3) and O (4). 6 In
particular, a unique stereodivergent reaction on a racemic mixture
(stereodivergent RRM) 7 was employed to obtain enantioenriched
sanggenons C (3) and O (4) in an efficient manner.
the chiral, racemic diene 7 as a promising strategy to synthesize
these two targets assuming that issues of endo/exo, face-, and
enantio-selectivity could be addressed. The requisite flavonoid
diene (7) may be derived from dehydrogenation of the prenyl
group of sanggenol F or its protected derivative (9).
Alternatively, the flavonoid diene may be derived from
5a,
9
Sanggenons C (3), D (5),8 and O (4) are apparent Diels-Alder
cycloadducts between
a flavonoid diene (7) and a 2′-
isomerization of the chromene ring in sanggenon A or the
hydroxychalcone (6) (Scheme 1). Among these compounds,
sanggenons C and O were shown to be endo cycloadducts and
epimers at C-2 and C-3. We considered stereodivergent RRM of
10
corresponding protected substrate (8).
Sanggenol F core
structure (9) may arise from olefin cross metathesis of precursor
10. We envisioned that 10 may be derived from metal-catalyzed
double Claisen rearrangement11 of bis-allyloxyflavone ether 11
followed by hemiketalization.
Figure 1. Structures of Sanggenon-Type Natural Products
Synthesis of the requisite bis-allyloxyflavone substrate 11
commenced with tetra-MOM group protection of the
commercially available compound morin (12) and subsequent 5-
allylation to afford the protected intermediate 13 (Scheme 2).
Selective 3-MOM deprotection was accomplished using NaI and a
12
catalytic amount of aqueous HCl.
In this transformation,
protonation of the 4-carbonyl and O-3 of substrate 13 appears to
activate the 3-MOM group for chemoselective deprotection.
Finally, 3-allylation and global MOM deprotection afforded the
desired bis-allyloxyflavone ether substrate 11 in 33% overall yield
(five steps).
A number of rare earth metal triflates were evaluated for
double rearrangement of bis-allyloxyflavone substrate 11 (Table
1).13 Among the metal triflates, Yb(OTf)3 was found to produce
the double rearrangement product 15 in 72% yield. In this reaction,
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Scheme 3. Syntheses of Sanggenol F and Sanggenon A
Scheme 2. Synthesis of Morin Di-allyl Ether
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Conditions: (a) TBSOTf (3.2 equiv.), NEt3 (3.0 equiv.), CH2Cl2, r.t., 6h;
(b) Grubbs’ 2nd gen. cat. (10 mol%), isobutene, 40 °C, 24h, 92% 2 steps;
(c) NEt3•3HF (8.0 equiv.), CH3CN, 0°C, 3h, 91%. (d) DDQ (1.2 equiv.),
THF, 60 °C, 12h, 78%.
Conditions: (a) MOMCl (5 equiv.), DIPEA (5 equiv.), CH2Cl2, 0 °C to
r.t., 55%; (b) allyl-Br (1.2 equiv.), Cs2CO3 (1.2 equiv.), DMF, 65°C, 12h,
93%; (c) NaI (0.8 equiv.), 1N HCl (0.1 equiv.), 40 °C, 12h, 73%; (d)
allyl-Br (2.0 equiv.), Cs2CO3 (2.0 equiv.), DMF, 65 °C, 12h, 96%; (e)
conc. HCl, MeOH, 40 °C, 93%.
benzoquinone (DDQ) 10,18 to afford (±)-sanggenon A (1) in 78%
yield.
We next evaluated (±)-sanggenon A (1) as a diene precursor for
[4+2] cycloaddition. Treatment of 1 under Brønsted acidic,
hexafluoro-2-propanol (HFIP) was used as
a polar, non-
coordinating14 cosolvent to solubilize the polar rearrangement
substrate. Other rare earth triflates were found to produce the
double rearrangement product 15 along with the single
rearrangement product 16 in varying ratios. Based on examination
of a DFT molecular model13 for substrate 11, there are two
possible chelation sites between O-3, O-4 (2.85 Å) and O-5, O-4
(2.72 Å) through either five or six-membered arrangements.
Selective binding to either or both chelation pockets may occur
depending on the ionic radius15 of the Lewis acid to enable 3-allyl
rearrangement and/or 5-allyl rearrangement.16 Different modes of
chelation by rare earth metal triflates may explain the product
distributions observed in Table 1. For example, La(OTf)3 with a
larger ionic radius (103.2 Å) may preferentially chelate between
O-3 and O-4 with a larger binding pocket to afford the 3-allyl
rearrangement product 16 as the major product. The product of
mono-aromatic Claisen rearrangement (not shown) was not
observed during the screening.
thermal, or photochemical conditions in the presence of silica-
19
supported silver nanoparticles (AgNP’s)
and 2′-
hydroxychalcone (cf. 20) as dienophile did not lead to the desired
[4+2] cycloaddition; only severe decomposition of (±)-sanggenon
A was observed. Accordingly, we elected to prepare a protected
variant of sanggenon A to serve as a diene equivalent. Specifically,
transformation of the prenyl flavonoid (±)-17 to chromene (±)-18
was investigated. Treatment of (±)-17 with DDQ in THF cleanly
afforded chromene (±)-18 (73%) (Scheme 4). However, severe
decomposition of 17 was observed when halogenated solvents
(e.g. CH2Cl2, CHCl3, or PhCl) were employed. As DDQ is a
strong electron-acceptor, 20 a charge-transfer complex may be
produced when an electron-donating solvent such as THF is
employed.21 The formation of such a complex may modulate the
22
reactivity of DDQ
which appears to largely suppress
decomposition observed using oxidative conditions with
halogenated solvents. We anticipated that TBS-protected
chromene 18 could generate the desired diene 19 in situ through
retro 6π-electrocyclization followed by deprotonation/protonation
(formal 1,7 hydrogen shift).23 Accordingly, (±)-chromene 18 was
employed in cycloadditions with acetylated 2′-hydroxychalcone
Table 1. Evaluation of Lewis Acids for Double Rearrange-
ment of 11a
Scheme 4. Syntheses of (±)-Sanggenons C and O
entryb M(OTf)x
ionic radii (pm)c
yield% (15, 16 )d
1
2
3
4
5
Yb(OTf)3
Y(OTf)3
Gd(OTf)3
Nd(OTf)3
La(OTf)3
86.8
90.0
93.8
98.3
103.2
72%, 0%
60%, 36%
48%, 40%
38%, 62%
0%, 70%
a Please see the Supporting Information for complete experimental details.
b All reactions were carried out with substrate 11 (0.13 mmol) and M(OTf)3
c
(15 mol% ) at 0.1 M in CH2Cl2/HFIP (4:1) at 50 °C. For effective ionic
radius, see ref. 15. d Isolated yield determined using purified 15 and 16.
After obtaining the desired hydrobenzofuro[3,2-b]chromenone
core structure (±)-15 via double rearrangement, we investigated
syntheses of the derived natural products 1 and 2. Although the
17
prenyl group could be installed by cross-metathesis
of
hemiacetal (±)-15 to directly access (±)-sanggenol F (2), we found
that silylation of (±)-15 followed by cross metathesis produced the
tri-silyl protected (±)-sanggenol F (±)-17 in excellent yield. This
sequence enabled purification of the final product from residual
ruthenium byproducts. Desilylation of (±)-17 afforded (±)-2
which was dehydrogenated with 2,3-dichloro-5,6-dicyano-1,4-
Conditions: (a) DDQ (1.5 equiv.), THF, 60 °C, 73%; (b) 20 (1.2 equiv),
AgNP (0.25 mol%), AcOH (2 equiv.), DCE, 65 °C, 3d (c) sat. Na-
HCO3, MeOH, r.t., 12h; (d) NEt3•3HF (8.0 equiv.), CH3CN, r.t., 12h,
36% (3 steps), sanggenon C (3): sanggenon O (4) = 4:1.
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combined yield, 10 : 1 endo/exo ratio, and in >99% and 41% ee,
Scheme 5. Model Reaction and Proposed Active Complex
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respectively (Scheme 5a). A bright orange color change was
observed when the borate catalyst and 2′-hydroxychalcone were
combined, leading us to hypothesize that a borate-substrate
complex (cf. 26) may be generated as an active species for [4+2]
cycloaddition. By mixing 2′-hydroxychalcone 21, (S)-BINOL 23,
and B(OPh)3 in CH2Cl2, we obtained borate complex 26, the
structure of which was confirmed by single X-ray crystal structure
analysis.13 The predicted absolute stereochemistry of the
corresponding endo cycloadduct 24 based on the expected face
selectivity of complex 26 was also confirmed by X-ray
crystallography.13 We found that 1 equivalent of phenol was also
bound to the borate complex as shown in the X-ray crystal
structure (Scheme 5b). The bound phenol could serve to further
activate the chalcone for cycloaddition and may also protonate the
cycloadduct to turnover the boron/BINOL catalyst for additional
catalytic cycles. Wulff and coworkers have reported a hydrogen-
bonded complex of a boroxinate catalyst and a protonated
iminium substrate.26b We also found that treatment of crystalline
26 with diene 22 led to similar results to produce 24 in high
enantioselectivity.13 The latter result reinforces the involvement of
borate complex 26 in the catalytic asymmetric Diels-Alder
cycloaddition which is also supported by literature precedent.28
We next applied this catalytic system to a stereodivergent RRM
strategy to synthesize enantioenriched sanggenons C and O.
Based on the model reaction (cf. Scheme 5), a catalytic amount of
B(OPh)3 and (R)-BINOL 23 were used to mediate asymmetric
[4+2] cycloaddition of diene precursor (±)-18 and dienophile 20
(Scheme 6). After sequential deprotection of both acetate and
silyl protecting groups, promising enantioselectivities were
observed. A number of BINOL ligands were evaluated; best
results were obtained when B(OPh)3 and (R)-BINOL 23 were
employed. A mixture of cycloadducts were observed which was
followed by consecutive deprotections (NaHCO3; NEt3•3HF) to
afford sanggenon C (3) and sanggenon O (4) in 2: 1 ratio and 98%,
93% ee respectively. The high endo/exo selectivity (cf. Scheme 5)
suggested that minimal amounts of exo diasteromers were
generated which we were not able to isolate and characterize. In
this transformation, we expected four different stereoisomers:
sanggenon C (3) and ent-sanggenon O (4) from (2R, 3R)-18; ent-
sanggenon C (3) and sanggenon O (4) from (2S, 3S)-18 (Scheme
6). As shown in the (R)-BINOL/B(OPh)3/chalcone complex 27,
the re face of the chalcone dienophile is blocked by the bulky
bromo substituent. As a result, the derived dienes (2R, 3R)-19 and
(2S, 3S)-19 approach from the si face of the chalcone 20 to afford
sanggenon C (3) and sanggenon O (4). Using (S)-BINOL 23 as
catalyst, ent-sanggenon C (3) and ent-sanggenon O (4) were
isolated in a 2 : 1 ratio and in 99%, 93% ee, respectively.13 We
also noticed that in the stereodivergent RRM, sanggenon C is
produced in both high enantiomeric excess and diastereomeric
ratio relative to sanggenon O. This result suggests that
for [4+2] Cycloaddition
20 in the presence of AgNP’s to yield a mixture of two endo
cycloadducts and minimal production of exo diastereomers. The
mixture of endo cycloadducts was sequentially treated with
aqueous NaHCO3 and NEt3•3HF to yield a mixture of (±)-
sanggenons C (3) and O (4) in 36% yield over 3 steps in a 4 : 1
diastereomeric ratio.
24
Unfortunately, our previously developed conditions for
asymmetric Claisen rearrangement11 failed to give useful levels of
enantioselectivity employing bis-allyloxyflavone substrate 11. We
considered that sanggenons C and O are both endo cycloadducts
with the same absolute configurations for the chiral cyclohexene
moiety and epimers at both C-2 and C-3. Accordingly, we
proposed that enantioselective [4+2] cycloaddition of chiral,
racemic substrate 18 and dienophile 20 should efficiently deliver
two natural products simultaneously utilizing a stereodivergent
process. In our initial studies,25 we found that borate complexes
derived from chiral 1,1'-bi-2-naphthol (BINOL)
used in catalytic, enantioselective [4+2] cycloadditions of 2′-
hydroxychalcones. A two dimensional screen was conducted
5b, 26
could be
using
a number of borates (B(OPh)3, tris(p-chlorophenyl),
tris(pentafluorophenyl), and tris(hexafluoroisopropyl) borate) and
BINOL ligands. We found that asymmetric [4+2] cycloaddition of
the model dienophile 2′-hydroxychalcone 21 and diene 2227 using
a
catalytic amount of (S)-3,3'-dibromoBINOL 23 and
triphenylborate afforded the [4+2] cycloadducts 24 and 25 in 91%
Scheme 6. Asymmetric Syntheses of Sanggenons C and O
Conditions: (a) B(OPh)3 (20 mol%), 23 (22 mol%), 80 °C, 48h; (b) sat. NaHCO3, MeOH, r.t.,12h; (c) NEt3•3HF (8.0 equiv.), CH3CN, r.t., 12h.
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matched/mismatched cycloadditions may also be operative based
analyses. NMR (CHE-0619339) and MS (CHE-0443618)
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on differential interactions of the chiral borate catalyst with both
enantiomers of diene 19.
facilities at Boston University are supported by the NSF. Work at
the BU-CMD is supported by R24GM111625.
In order to understand the greater preference for formation of
sanggenon
C
vs.
O
(cf. Scheme 4), and the higher
enantioselectivity observed for sanggenon C, we conducted
computational studies of dienophile complex 27 using and both
enantiomers of a simplified variant of the diene (19’, TMS instead
REFERENCES
of TBS groups) to analyze the interacting complex of reagents
29
engaging in Diels-Alder cycloaddition.13,
Simplified
cycloaddition models A and B are shown in Scheme 6 with the
lowest energy conformer of diene 19. It appears that cycloaddition
through model A is favored in comparison to the corresponding
model B using (R)-BINOL which results in greater amounts of
sanggenon C derivatives and therefore favored production of (2R,
3R) stereoisomers in the product mixture. Our preliminary
reaction assembly calculations 30 (See Supporting Information)
show that there are significant steric interactions between the
prenyl and phenyl group on the chalcone dienophile which are
likely responsible for the significantly increased energy in
assemblies related to model B. Based on the X-ray structure of
the chiral borate complex (cf. Scheme 5), we predicted that the
use of (R)-BINOL as catalyst should yield (3’’S, 4’’R, 5’’S) for
both sanggenons C and O. This prediction is in agreement with
absolute stereochemistry determinations reported by Nomura and
coworkers for the natural products.2b
In summary, we have achieved the first asymmetric syntheses
of the flavonoid Diels-Alder natural products sanggenons C and O.
The syntheses employ a Lewis acid-promoted double Claisen
rearrangement to construct the hydrobenzofuro[3,2-b]chromenone
core scaffold of sanggenon A and sanggenol F. The first catalytic
enantioselective [4+2] cycloadditions of 2′-hydroxychalcones
have been developed using BINOL-boron catalysis. The high
enantioselectivity and diastereoselectivity of this catalytic system
enabled a stereodivergent reaction of a chiral, racemic flavonoid
diene precursor to afford enantioenriched sanggenons C and O.
Preliminary calculations of the interactions of diene-dienophile
complexes support the stereochemical outcomes observed in
stereodivergent cycloadditions. Further studies on the chemistry
and biology of Diels-Alder natural products, as well as a complete
energetic profiling of the key stereodivergent RRM, are ongoing
and will be reported in due course.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
characterization data for all new compounds described herein,
including CIF files for compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
porco@bu.edu
Author Contributions
‡C.Q. and Y.X. contributed equally to this paper.
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
We thank the National Institutes of Health (GM-073855 and GM-
099920), Vertex Pharmaceuticals (graduate fellowship to C. Q.),
and AstraZeneca (graduate fellowship to H.C.) for research
support. We thank Dr. Jeffrey Bacon (Boston University) and
Matthew Benning (Bruker AXS) for X-ray crystal structure
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