Enantioselective Total Synthesis of Natural Isoflavans: Asymmetric Transfer Hydrogenation/Deoxygenation of Isoflavanones with Dynamic Kinetic Resolution

Article abstract of DOI:10.1021/acs.orglett.8b01034

A concise and highly enantioselective synthesis of structurally diverse isoflavans from a single chromone is described. The key transformation is a single-step conversion of racemic isoflavanones into virtually enantiopure isoflavans by domino asymmetric transfer hydrogenation/deoxygenation with dynamic kinetic resolution.

Full text of DOI:10.1021/acs.orglett.8b01034

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Total Synthesis of Natural Isoflavans: Asymmetric
Transfer Hydrogenation/Deoxygenation of Isoflavanones with
Dynamic Kinetic Resolution
Anton Keßberg, Tilo Lubken, and Peter Metz*
̈
Fakultat Chemie und Lebensmittelchemie, Organische Chemie I, Technische Universitat Dresden, Bergstrasse 66, 01069 Dresden,
̈
̈
Germany
S
* Supporting Information
ABSTRACT: A concise and highly enantioselective synthesis
of structurally diverse isoflavans from a single chromone is
described. The key transformation is a single-step conversion
of racemic isoflavanones into virtually enantiopure isoflavans
by domino asymmetric transfer hydrogenation/deoxygenation
with dynamic kinetic resolution.
lavonoids represent a wide range of secondary metabolites
shown to exhibit significant in vitro activity against the ameba
Naegleria fowleri,11 which triggers the rapidly fatal amebic
meningoencephalitis.12 Oh et al. reported that a number of
flavonoids from Erythrina milbraedii effectively reduce protein
tyrosine phosphatase 1 B activity.13 Among those, isoflavan 3
was the most potent agent identified, and as such, it might
prove useful for the therapy of type 2 diabetes or obesity.14
Tanaka et al. screened plants of the genus Erythrina for their
antibacterial activity against methicillin-resistant Staphylococcus
aureus and found eryzerin D (4) to be an effective agent.15
Further studies revealed promising activity of 4 against
vancomycin-resistant enterococci.16 The absolute configuration
of the natural product 4 has yet to be determined. Except for
equol (1), there is no synthetic access to the above-mentioned
isoflavans. Herein, we report an enantioselective total synthesis
of (S)-equol (1), manuifolin K (2), isoflavan 3, and eryzerin D
(4).
F
in plants with various health benefits.1 An important
subgroup of these natural products are isoflavans.
(S)-Equol (1), a potent phytoestrogenic isoflavan,2 was first
isolated from pregnant mares’ urine in 1932 (Figure 1).3 It was
Scheme 1 depicts the general retrosynthetic approach to
isoflavans 1−4. First, the natural products 1−4 can be traced
back to the respective phenols 5a−c. We envisioned that
enantiopure isoflavans 5a−c might be obtainable from the
racemic isoflavanones 6a−c in a single step through a domino
ATH/deoxygenation process involving an o-quinone methide
(I) as the crucial intermediate.9 In contrast to the previously
reported transformation of flavanones,9 the isoflavanones 6a−c
might readily racemize under the reaction conditions and, thus,
allow for a dynamic kinetic resolution.7b Finally, the
isoflavanones rac-6a−c should be attainable from chromone
717 by means of protecting group interchange, Suzuki coupling,
and conjugate reduction.
Figure 1. Structure of isoflavans 1−4.
shown to be a selective estrogen receptor modulator,4 and it
exhibits antioxidant activity5 and is currently being investigated
as a drug for the treatment of benign prostatic hyperplasia.6
Despite its interesting bioactivity and structural simplicity,
catalytic protocols for the asymmetric synthesis of equol (1) are
scarce.7 Spurred by our recent success in the enantioselective
synthesis of flavanones,8 flavans,9 and isoflavanones7b by means
of asymmetric transfer hydrogenation (ATH), we envisioned
establishing an efficient protocol for the catalytic asymmetric
synthesis of isoflavans. We anticipated that a dynamic kinetic
resolution (DKR) of racemic isoflavanones by means of an
ATH/deoxygenation cascade might yield enantiopure isofla-
vans in a single step. In addition to (S)-equol (1), the isoflavans
2, 3, and 4 are interesting targets for this methodology. Initially
isolated from Maackia tenuifolia by Zhu et al. in 1998,10
manuifolin K (2) was later obtained from Dalea aurea and was
The preparation of (S)-equol (1) is depicted in Scheme 2.
Starting from chromone 7,17 a highly chemoselective cleavage
of the 5-O-MOM functionality and subsequent treatment with
methyl chloroformate afforded vinyl iodide 8 in excellent yield.
Received: April 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01034
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
furnished product 10 in very good yield. Finally, (S)-equol (1)
was obtained by simple hydrolysis of the acetal moieties with
99% enantiomeric excess.
Scheme 1. General Retrosynthetic Analysis of Isoflavans 1−4
Starting with chromone 8, we continued our investigation on
the domino ATH/deoxygenation with isoflavans 2 and 3 as the
targets (Scheme 3). While initial attempts to convert aryl
Scheme 3. Synthesis of Isoflavan 14
Scheme 2. Synthesis of (S)-Equol (1)
bromide 1122 to the corresponding boronic acid 12 failed, an in
situ quenching protocol by Li et al.23 allowed for convenient
handling and gave the best results. Suzuki coupling of 8 with 12
and subsequent treatment with L-Selectride gave rise to the
ATH substrate rac-6b. In order to maintain a reasonable
reaction time, a slightly higher catalyst loading was used,
compared to the domino ATH/deoxygenation of rac-6a. This
was largely because of the presence of the 2′-OMOM group.
Subsequent treatment with triflic anhydride allowed for a
convenient purification and gave rise to virtually enantiopure
isoflavan 13 in good yield over two steps. Finally,
deoxygenation at the 5-position and removal of the tosylate
group furnished product 14, which was further used to generate
both manuifolin K (2) and pyrano-isoflavan 3.
Commencing with isoflavan 14, manuifolin K (2) was readily
available in two steps (Scheme 4). Initially, prenyl ether 15 was
synthesized under Mitsunobu conditions24 in good yield and
short reaction time. The subsequent Claisen rearrangement was
carried out in acetic anhydride25 in order to avoid an abnormal
rearrangement.26 Due to partial MOM cleavage and acetylation,
the crude product mixture was submitted to solvolysis, followed
by acidic deblocking in order to obtain manuifolin K (2) as the
sole product27 with excellent enantiomeric excess and good
yield. Isoflavan 3 was also obtained from compound 14 in six
steps. The prenyl groups were introduced by means of Tsuji−
Trost allylation with allylic carbonate 1628 and subsequent
europium-catalyzed rearrangement.29,30 In comparison to the
perfect regioselectivity of the Claisen rearrangement of ether
15, this transformation exhibited moderate selectivity, favoring
the 5′-position over the 3′-position due to steric constraints.
However, both regioisomers were transformed to the single
product 17 using the same two-step protocol once again. Thus,
phenol 17 was obtained in good overall yield from isoflavan 14.
Benzopyran 18 was synthesized through oxidative cyclization
using DDQ.31 Surprisingly, no regioisomeric product was
observed next to 18. Finally, acid-promoted cleavage of the
acetal moieties furnished the target compound 3 in moderate
Construction of the isoflavanone rac-6a was achieved in two
steps by Suzuki coupling18 with 4-(methoxymethoxy)-
phenylboronic acid19 and conjugate reduction of the resulting
isoflavone. The crucial ATH of ketone rac-6a was studied using
a chiral ruthenium catalyst20 and a mixture of triethylamine and
formic acid as the hydrogen source. To our delight, the desired
ATH/deoxygenation cascade proceeded smoothly at low
catalyst loading and gave rise to the virtually enantiopure
product (S)-5a in 90% yield. Reductive removal of the free
hydroxyl group by treatment of compound 5a with triflic
anhydride and subsequent palladium-catalyzed deoxygenation21
B
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propargylation32 and subsequent prenylation under Mitsunobu
conditions.24 A cascade of domino Claisen/Cope rearrange-
ment, followed by annulation33 of the pyran moiety, comprising
five pericyclic transformations, gave rise to chromone 21 in a
single step in satisfying yield. Europium catalysis29,30 was crucial
for this reaction in order to ensure the domino Claisen/Cope
process occurred first and, thus, counter to the usual
regioselectivity of the annulation reaction.34 Treatment of
product 21 with methyl chloroformate gave rise to chromone
22. Finally, Suzuki coupling of vinyl iodide 22 with 2,4-
bis(methoxymethoxy)phenylboronic acid35 and subsequent
conjugate reduction furnished isoflavanone rac-6c.
Scheme 4. Synthesis of Isoflavans 2 and 3
Scheme 6 illustrates the ATH/deoxygenation of isoflavanone
rac-6c and the final steps toward eryzerin D (4). Isoflavan (R)-
Scheme 6. Synthesis of Eryzerin D (4)
yield due to the unstable nature of structure 3. Unexpectedly,
the spectroscopic data of the synthetic sample 3 did not match
the reported data.13 A thorough review of the published
information revealed that Oh et al. in fact isolated eryzerin D
(4) rather than isoflavan 3.
Synthesis of the structurally challenging ATH substrate rac-
6c, required for eryzerin D (4), is depicted in Scheme 5.
Starting with chromone 7, treatment with concentrated HCl
allowed the clean removal of both MOM functionalities. Ether
20 was obtained by means of a highly chemoselective
5c was obtained with 98% ee, applying the same reaction
conditions used for the transformation of isoflavanone rac-6b.
Unfortunately, in situ racemization of compound (S)-6c proved
to be quite slow, and thus, complete conversion of rac-6c was
not achieved. While reduction of substrate rac-6c was not
impeded by the addition of Lewis and Brønsted acids or bases,
racemization was not accelerated either. Nonetheless, enantio-
selective reduction of the highly functionalized isoflavanone rac-
6c yielded 40% of the fairly unstable product (R)-5c, which was
submitted to further transformation right away. Treatment of
5c with triflic anhydride and subsequent deoxygenation gave
rise to isoflavan 23 in good yield. Finally, eryzerin D (4) was
obtained by removal of the MOM groups. In accordance with
the chemical behavior of isoflavans 3 and 5c, the combination
of a pyran moiety and free phenolic hydroxyl groups led to the
fairly unstable properties of 4. With isoflavan 4 in hand,
comparison of specific rotation and CD spectrum of the
synthetic sample with the literature data15 revealed the absolute
configuration of eryzerin D (4) to be R. Furthermore, NMR
and MS data are in good agreement with the data reported by
Oh et al.13,36
Scheme 5. Synthesis of ATH Substrate rac-6c
In summary, we have accomplished the first enantioselective
total synthesis of manuifolin K (2), eryzerin D (4), and
isoflavan 3. Our results verify the R configuration for the natural
product 4, and the absolute configuration of isoflavan 2 was
unambiguously established. In addition, the published structure
of compound 3 was revised to be identical to that of eryzerin D
(4). Furthermore, a new catalytic protocol for the asymmetric
total synthesis of equol (1) was established. Central to our
C
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Huijsduijnen, R. H.; Bombrun, A.; Swinnen, D. Drug Discovery Today
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01034.
■
S
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2009, 131, 16045−16047.
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902.
Experimental procedures, spectroscopic data, and 1H and
13C NMR spectra (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: peter.metz@chemie.tu-dresden.de.
ORCID
Peter Metz: 0000-0002-0592-9850
Notes
The authors declare no competing financial interest.
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