A Flexible and Divergent Strategy to Flavonoids with a Chiral A-Ring Featuring Intramolecular Michael Addition: Stereoselective Synthesis of (+)-Cryptocaryone, (+)-Cryptogione F, and (+)-Cryptocaryanones A and B, as Well as (+)-Cryptochinones A and C

Article abstract of DOI:10.1021/acs.orglett.8b00479

A flexible strategy has been developed to synthesize divergent flavonoids bearing a chiral A-ring. As two key steps, the coupling via a boron-mediated aldol condensation and the cyclization via a highly stereoselective intramolecular Michael addition of 1,3-diketone proceed under mild conditions; thus, the chiral flavonoids bearing C-7 oxy functional groups or olefinic bonds are both easily accessible. Using this approach, the first synthesis of (+)-cryptogione F, (+)-cryptocaryanone B, and (+)-cryptochinones A and C, as well as stereoselective synthesis of (+)-cryptocaryone and (+)-cryptocaryanone A, were achieved from 2-deoxy-d-ribose in high overall yields.

Full text of DOI:10.1021/acs.orglett.8b00479

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Flexible and Divergent Strategy to Flavonoids with a Chiral A‑Ring
Featuring Intramolecular Michael Addition: Stereoselective Synthesis
of (+)-Cryptocaryone, (+)-Cryptogione F, and (+)-Cryptocaryanones A
and B, as Well as (+)-Cryptochinones A and C
Xiaojing Liu, Junhao Jia, Yuanliang Jia, He Gu, Jingwen Luo, and Xiaochuan Chen*
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, People’s Republic of China
S
* Supporting Information
ABSTRACT: A flexible strategy has been developed to synthesize
divergent flavonoids bearing a chiral A-ring. As two key steps, the
coupling via a boron-mediated aldol condensation and the cyclization
via a highly stereoselective intramolecular Michael addition of 1,3-
diketone proceed under mild conditions; thus, the chiral flavonoids
bearing C-7 oxy functional groups or olefinic bonds are both easily
accessible. Using this approach, the first synthesis of (+)-cryptogione
F, (+)-cryptocaryanone B, and (+)-cryptochinones A and C, as well as
stereoselective synthesis of (+)-cryptocaryone and (+)-cryptocarya-
none A, were achieved from 2-deoxy-D-ribose in high overall yields.
molecules could be used as a chemotaxonomic marker. As the
first member of this group, cryptocaryone (2) was isolated from
Cryptocarya bourdilloni in 1972.1 Since 2001, more and more
flavonoids and biflavonoids bearing a chiral A-ring were
reported.2 Some members of these chiral flavonoids displayed
significant cytotoxicity against a series of human cancer
cells.2a−c,g,3 In recent years, the cell antiproliferation effect
and the mechanism of cryptocaryone on oral and androgen
refractory prostate cancer cells were studied exclusively.4 These
skeletal compounds were also found to possess a variety of
other bioactivities, such as anti-inflammatory,2e antimicrobial,2g
antituberculosis,2d tyrosine kinase inhibitory,2b glucose trans-
port inhibitory,3 and NF-kB inhibitory activity.5 Moreover,
several members bearing C-7 oxy functional groups, including
cryptochinones A (6) and C (7),2c can act as farnesoid X
receptor agonists.6 Therefore, these flavonoids and analogues
are a type of potential agent for the treatment of cancer and
other diseases.
lavonoids are a large family of natural products with
Fdiverse structures and important bioactivities. A special
group of chiral flavonoids such as 1−9, only isolated from
Cryptocarya species, are distinguished from other members by
their dearomative A-ring containing a C-5 acetic acid/lactone
group (see Figure 1). This unique feature of these skeletal
The increasing group member and bioactivity discovery
make these unique chiral flavonoids become attractive synthetic
targets. In 2010, the first synthesis of cryptocaryone and the
enantioselective synthesis of cryptocaryone and infectocaryone
(1)2a were reported by the Fujioka group7 and the Helmchen
group,8 respectively. The third member, cryptocaryanone A
(3),2a was synthesized by She and co-workers in 2012.9 Two
years later, an alternative approach to infectocaryone was also
developed by our laboratory.10All of the above syntheses are
achieved via the prior construction of chiral A-ring cores,
Received: February 9, 2018
Figure 1. Several flavonoids and biflavonoids bearing a chiral A-ring.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00479
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Letter
followed by the coupling with the appropriate partners
containing an aryl ring. Although these useful approaches to
the chiral flavonoids containing C-7 olefinic bond are
developed, those members with oxy groups at C-7, such as
cryptogione F (5),2e e.g., cryptochinones A and C, are not
conveniently synthesized yet. Herein, we describe a distinctive
and flexible strategy to the chiral flavonoids with more
structural variation, in which the chiral A-ring is constructed
in the final stage via an intramolecular Michael addition. Via
this approach, the first synthesis of cryptogione F, cryptocar-
yanone B,2a and cryptochinones A and C, as well as
stereoselective synthesis of cryptocaryone and cryptocaryanone
A, are achieved.
aldehyde, which was treated with (carbethoxymethylene)-
triphenylphosphorane (16) to result in the Z-conjugated ester
17 with good yield. To achieve better stereoselectivity in the
subsequent cyclization, we decided to construct unsaturated
lactone unit prior to the formation of the A-ring. Thus,
following the similar procedure in our synthesis of botryolide-
E,13 concurrent removal of the isopropylidene group in 17 and
lactonization smoothly occurred under acidic conditions to
afford the desired lactone 18. After protection of the remaining
alcohol functionality as TBS ether, terminal olefin 19 was
subjected to Wacker oxidation,14 which furnished the target
methyl ketone (20).
The chiral aldehydes (R)- and (S)-21 are conveniently
Our retrosynthetic strategy for these divergent flavonoids is
delineated (see Scheme 1). It was envisioned that 2−7 could be
prepared following She’s procedure9 (see Scheme 3).
Scheme 3. Synthesis of Aldehydes (R)- and (S)-21
Scheme 1. Retrosynthetic Analysis of Flavonoids 2−7
Regioselective opening of (S)-2-phenyloxirane ((S)-22) by
1,3-dithiane anion gave benzylic alcohol 23, which was
converted to 24 via treatment with MOMCl. The subsequent
removal of the 1,3-dithiane group afforded aldehyde (R)-21 in
higher yield than that reported in the literature, because of
employment of the MOM protecting group, instead of the TBS
group. Via the same route, (S)-21 was synthesized from (R)-22.
Next, we turned our attention to the aldol union of the
ketone and aldehyde subunits. Cinnamaldehyde (25) was first
tested in the coupling with methyl ketone 20. The aldol
reactions under basic conditions gave unsatisfactory results,
because of the occurrence of some side reactions of 20 such as
β-elimination and intramolecular nucleophilic attack. On the
other hand, in the boron-mediated aldol condensation
(Cy2BCl,15 Ipc2BCl15c,16) or the titanium-mediated aldol
condensation (TiCl415a,17), the target adducts were obtained.
After optimization of the reaction conditions, methyl ketone 20
was treated with Cy2BCl and Et3N at −78 °C to produce the
corresponding kinetic boron enolate, which reacted with 25 to
afford a mixture of diastereoisomeric adducts 26 and 27 in
good total yield. Although the aldol diastereoselectivity is not
high (diastereomeric ratio (dr) = 1.8:1), the absolute
configuration of the new stereogenic center was not important
to the overall synthetic plan. Thus, Dess−Martin periodinane
oxidation of the mixture afforded the 1,3-dione, which
isomerized to enol ketone 28 immediately. Following the
same procedures as applied to 25, chiral aldehydes (R)- and
(S)-21 were also converted to enol ketones 29 and 30,
respectively (see Scheme 4).
accessed from advanced intermediate 10 via modification or
dihydropyrone formation. The critical polysubstituted cyclo-
hexanone core of 10 could be constructed via a stereoselective
intramolecular Michael addition from the corresponding 1,3-
diketone substrates (11). The cyclization precursor 11
containing all carbons of the final targets should be generated
via an aldol condensation between appropriate aldehydes (12)
and methyl ketone (13), the latter of which could be prepared
readily from commercially available carbohydrates. Some cases
regarding the Michael addition of 1,3-diketones have been
reported;11 however, the reaction has not yet been employed in
the synthesis of chiral flavonoids.
Our synthesis began with the preparation of chiral ketone 13
from 2-deoxy-D-ribose 14 (see Scheme 2). According to the
literature procedures,12 14 was converted to the known
terminal alkene (15) with 72% yield in two steps. Swern
oxidation of primary alcohol 15 gave the corresponding
Scheme 2. Synthesis of Methyl Ketone 20
With cyclization precursors 28−30 prepared, the key
intramolecular Michael addition was investigated. Upon
treatment of 28 with Cs2CO3 in THF, the desired cis-
cyclization product 31 and its trans-isomer 32 were obtained
in 44% and 20% yield, respectively (Table 1, entry 1). The
stereochemistry of the two cyclic adducts were subsequently
identified by their transformation to the natural product and its
B
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Letter
ties of the synthetic samples were identical to those of the
natural products.1,2e
Scheme 4. Synthesis of Enol Ketones 28−30
Scheme 5. Synthesis of (+)-2 and (+)-5
Subsequently, we set out to utilize enol ketone 29 and 30 to
synthesize other chiral flavonoids via similar cyclization. Under
the same conditions as for 28 (Table 1, entry 6), the
intramolecular Michael addition of 29 furnished the resulting
cis- and trans-lactones 33 (68%) and 34 (13%); however, in the
cyclization of 30, 31 was also obtained in 12% yield, because of
β-elimination of the OMOM group besides two normal adducts
(35 (58%) and 36 (15%)). To suppress the elimination, we
must optimize the reaction conditions again. To our delight, the
temperature exerted a noticeable influence on the reaction, with
better results being obtained upon decreasing the temperature.
Remarkable enhancement of stereoselectivity and inhibition of
β-elimination both were achieved by performing the reactions
at −20 °C to afford the target cis-adduct predominantly. Under
the optimized conditions, 29 and 30 cyclized with higher dr
value to afford cis-fused lactones 33 and 35 in good yield,
respectively (see Scheme 6).
a
Table 1. Optimization of the Cyclization of 28
temperature time
yield of
31 (%)
yield of
entry
base
solvent
(°C)
(h)
32 (%)
1
2
3
4
5
6
7
8
9
Cs2CO3
K2CO3
K2CO3
K2CO3
DBU
THF
rt
rt
3
55
48
24
1
44
48
40
34
65
83
71
50
38
60
20
15
17
14
11
8
THF
acetone
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
THF
rt
rt
Scheme 6. Synthesis of (+)-3, (+)-4, (+)-6, and (+)-7
rt
DBU
0
1
DBU
0
2
7
DBU
0
4
12
10
10
DBU
DMF
0
4
b
10
DBU
CH2Cl2
−20
8
a
General conditions: 28/base = 1/1.1, concentration (c) = 0.05 M.
20% of 28 was recovered.
b
epimer. Under K2CO3-mediated conditions, the cyclization of
28 showed similar yield and dr values. However, prolonged
reaction times are necessary for full consumption of 28 (entries
2−4 in Table 1). Gratifyingly, the velocity and stereoselectivity
of the reaction were remarkably improved when DBU was used
as a base. The cyclization of 28 could completed within 1 h in
CH2Cl2 at room temperature to afford 31 and 32 in a ratio of
6:1 (entry 5 in Table 1). The better results were obtained by
decreasing the temperature to 0 °C, and the target 31 was
produced in 83% yield, together with a small amount of 32
(8%) (Table 1, entry 6). Increased reaction times led to a
decrease in yield, likely due to the slow deterioration of
products (Table 1, entry 7). In other solvents, such as
tetrahydrofuran (THF) or dimethylformamide (DMF), the
catalytic effect of DBU decreased to give inferior results (see
entries 8 and 9 in Table 1). Lower reaction temperature did not
show an improvement in the stereoselectivity, but the reaction
ran sluggishly (Table 1, entry 10).
Finally, construction of the B-ring was achieved by TFA-
mediated cleavage of the MOM protecting group in 33,
concomitant formation of hemiacetal, and dehydration to
produce hydropyranone (37). After deprotection of the TBS
group, the resulting alcohol (38) was subjected to one-pot
sulfonylation and elimination to furnish (+)-cryptocaryanone A.
Following the similar manipulation involving closure of the B-
ring and removal of the TBS group, the other adduct (35) was
transformed to (+)-cryptochinone A, which underwent O-
methylation using MeI and Ag2O to give (+)-cryptochinone C
(7-O-methylcryptochinone A). On the other hand, (+)-crypto-
After optimizing conditions to provide useful quantities of
31, the transformation of this key intermediate to 2 and 5 is
easy. The silyl group of 31 was removed smoothly with HF·Py
to give (+)-cryptogione F. Further β-elimination of the
hydroxyl group in 5 with Burgess reagent18 furnished
(+)-cryptocaryone (see Scheme 5). The spectroscopic proper-
C
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In summary, we have developed a versatile synthetic strategy
to flavonoids with a chiral A-ring featuring boron-mediated
aldol condensation and highly stereoselective intramolecular
Michael addition. Because of the high nucleophilicity of the 1,3-
diketone substrates, the construction of the A-ring at the final
stage can proceed under mild conditions, which allows one to
tolerate the oxy functional groups, which are prone to β-
elimination. Therefore, the chiral flavonoids bearing C-7 oxy
functional groups or olefinic bonds are both easily accessible.
The utility of the flexible strategy has been demonstrated by the
first synthesis of cryptogione F, cryptocaryanone B, and
cryptochinones A and C, as well as stereoselective synthesis
of cryptocaryone and cryptocaryanone A, in good overall yields.
More of this type of chiral flavonoids should be accessed via the
versatile approach by fine-tuning methyl ketone partners.
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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.8b00479.
(12) (a) Takahashi, K.; Morita, H.; Honda, T. Tetrahedron Lett. 2012,
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1
Detailed experimental procedures and copies of H and
13C NMR spectra of the compounds (PDF)
(13) Liu, X.; Chen, R.; Duan, F.; Jia, J.; Zhou, Y.; Chen, X.
Tetrahedron Lett. 2017, 58, 3947−3950.
AUTHOR INFORMATION
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■
Corresponding Author
*E-mail: chenxc@scu.edu.cn.
ORCID
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Xiaochuan Chen: 0000-0003-3901-0524
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Natural
Science Foundation of China (No. 21172153). Compound
characterization was performed by the Comprehensive
Specialized Laboratory Training Platform, College of Chem-
istry, Sichuan University, as well as Prof. Xiaoming Feng’s
group at Sichuan University.
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