A general asymmetric route to enantio-enriched isoflavanes via an organocatalytic annulation of o-quinone methides and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2018.05.016

Reported herein is a general approach to optically active isoflavanes based on a chiral amine-catalyzed [4 + 2] asymmetric annulation of o-quinone methides and aldehydes. A number of naturally occurring isoflavanes, including equol, sativan, isosativan, v

Full text of DOI:10.1016/j.tetlet.2018.05.016

Accepted Manuscript
A General Asymmetric Route to Enantio-enriched Isoflavanes via an Organo-
catalytic Annulation of o-Quinone Methides and Aldehydes
Jian Zhang, Shuangzhan Zhang, Huixin Yang, Ding Zhou, Xueting Yu, Wei
Wang, Hexin Xie
PII:
S0040-4039(18)30597-5
https://doi.org/10.1016/j.tetlet.2018.05.016
TETL 49963
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 March 2018
3 May 2018
7 May 2018
Please cite this article as: Zhang, J., Zhang, S., Yang, H., Zhou, D., Yu, X., Wang, W., Xie, H., A General Asymmetric
Route to Enantio-enriched Isoflavanes via an Organocatalytic Annulation of o-Quinone Methides and Aldehydes,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.016
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Tetrahedron Letters
A General Asymmetric Route to Enantio-enriched Isoflavanes via an Organocatalytic
Annulation of o-Quinone Methides and Aldehydes
Jian Zhang,#,a Shuangzhan Zhang,#,a Huixin Yang,a Ding Zhou,a Xueting Yu,a Wei Wanga,b and Hexin
Xiea,*
a
State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
b
Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Reported herein is a general approach to optically active isoflavanes based on a chiral amine-
catalyzed [4 + 2] asymmetric annulation of o-quinone methides and aldehydes. A number of
naturally occurring isoflavanes, including equol, sativan, isosativan, vestitol and medicarpin, as
well as isoflavane analogues were readily prepared with good to excellent enantioselectivities.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Isoflavanes
Asymmetric
Organocatalysis
o-Quinone methide
Isoflavanes, including equol,1 vestitol,2 and coluteol3, are a
small subgroup of isoflavonoids that widely found in leguminous
plants (Fig. 1). These natural products have attracted
considerable attention in the field of medicinal chemistry. For
instance, medicarpin4 are effective in the inhibition of a number
of bacteria,5 as well as pathogenic fungi.6 Equol, initially isolated
from fraction of pregnant mare urine, exhibits interesting
phytoestrogenic activity1c and potency in menopausal hormone
replacement therapy.1b
al. reported the first enantioselective synthesis of isoflavanes
with the chiral auxiliary strategy.10 The first enantioselective total
synthesis of (S)-equol was documented in 2006 by the Boulanger
laboratory,11 where the chiral auxiliary strategy was also
employed to construct the chiral center. Since then, several
approaches have been developed for the preparation of optically
active equol, such as allylic substitution,12 asymmetric
hydrogenation,13 and flavan-isoflavan rearrangement.14
Structurally, isoflavanes feature with a chiral 3-
phenylchroman backbone. Some of the isoflavanes naturally exist
in both enantiomers, but in different sources: some (S)-
enantiomers of isoflavanes were detected in Machaerium and
Dalbergia species while the (R)-enantiomers usually can be
found in Leguminosae and Papilionoideae.7 And, more
interestingly, these enantiomers typically exhibit different
physiological activities, for example, the (R)-equol shows higher
binding affinity to estrogen receptor  (ER) than the naturally
occurring (S)-equol whereas the (S)-enantiomer exhibits greater
binding affinity to estrogen receptor  (ER).8
Given the importance of these class of molecules, a number of
studies have been reported on the synthesis of these biologically
intriguing compounds. Early studies have been focused on the
synthesis of racemic form of isoflavanes. 8-9 In 1995, Versteeg et
# These authors contributed equally.
*Corresponding authors.
E-mail addresses: xiehexin@ecust.edu.cn (H. Xie)
Fig. 1. Selected examples of isoflavanes

The key for the synthesis of optically active isoflavanes relies
on the efficient construction of the 3-chiral center of chroman
(Scheme 1). We recently disclosed a chiral amine-catalyzed
enantioselective [4 + 2] annulation of aldehydes and in situ
oxidation-generated QMs for the synthesis of enantio-enriched 3-
substituted chromanols.17y We envisioned this asymmetric
process may serve as a general approach for the efficient
construction of 3-chiral center of isoflavanes.
We initialed our study with with substituted o-methylphenol
as o-QM precursor but the strategy of oxidative generation of o-
QM17y soon proved to be incompatible with this type of substrate.
We then moved to the desilylation/elimination process for the in
situ generation of the highly reactive o-QMs.17e, 17j Previous study
has indicated that, due to the low stability, fluoro was not a
suitable leaving group for the o-QM precursor with strong
electron-donating groups (e.g. methoxyl),17t we thus adopted
chloro-substituted 5a as the o-QM precursor. However, this type
of substrate requires stoichiometric amount of fluoride to
generate o-QM, which poses a potential problem for the amine-
catalyzed asymmetric process. A number of reaction conditions
have been tested and the results are summarized in Table 1. This
[4 + 2] annulation proceeded smoothly in the presence 1.1 equiv.
of tetrabutyl ammonium fluoride (TBAF) and p-nitrobenzoic acid
(PNBA), as well as chiral fluorinated pyrrolidine (cat. I) as
catalyst, giving chromanol 1aa in 44% yield and with 74% ee
(entry 1). And the amount of PNBA has marked impact on this
asymmetric reaction as the addition of 1.2 equivalent of PNBA
significantly enhanced the enantioselectivity to 84% ee, but,
unfortunately, only trace amount of product was obtained. As a
result, more additives were then tested and the combination of
NaH2PO4 and PNBA were found to be able to increase both yield
and enantioselectivity, delivering 1aa in 62% yield and with 85%
ee (entry 6). It is worth noting that potassium fluoride was
inefficient as fluoride source in this reaction, resulting in nearly
no desired product formation, which is likely due to the low
solubility of potassium fluoride in dichloromethane (DCM).
Furthermore, the use of aldehyde 4a, instead of 5a, as the
limiting reagent, led to much lower yield (16%, entry 8).
Scheme 1. Retro-synthesis analysis of isoflavanes.
ortho-Quinone methides (o-QMs) are a type of ephemeral
molecules with exceptionally high reactivities.15 Recently, this
class of molecules have been intensively investigated in the
asymmetric transformations16 and a large number of
enantioselective reactions have been developed, particularly with
small organic molecules as catalysts.17
The [4 + 2] cycloaddition of o-QMs and electron-rich olefins
has proven to be a reliable approach in the construction of
chroman scaffolds,18 for instance, equol and vestitol.9
Furthermore, by incorporation chiral auxiliary on the olefins, this
process has been applied in the enantioselective synthesis of a
number of chroman-containing natural products.19 Particularly,
highly enantio-enriched (-)-medicarpin and (-)-sophoracarpan A
were readily accessible with this enantioselective method.20
Nevertheless, construction of this type of molecules in a catalytic
asymmetric manner, avoiding pre-installation of chiral auxiliary
on the olefins and subsequent removal of auxiliary, still remains
as a more desirable approach. Herein, in our continuing research
interest on the chemistry of quinone methide,17t, 17y, 21 we report a
general asymmetric route for the synthesis of enantiomerically
enriched isoflavanes based on a chiral amine-catalyzed [4 + 2]
annulation of o-quinone methides and aldehydes. With this
approach, a range of optically active isoflavanes (e.g., equol,
vestitol, sativan, isosativan and medicarpin) and isoflavane
analogues were readily prepared in good to excellent
With enantio-enriched chromanol 1aa in hand, we turned our
attention to reduction of the hydroxyl group. The
TMSOTf/Et3SiH-mediated reduction was first tested for 1aa.
But, to our surprise, this reaction turned out to be less efficient,
enantioselectivities.
Table 1 Optimization of reaction conditionsa
Entry
1d
2e
3
Fluoride source (equiv.)
TBAF (1.1)
TBAF (1.1)
TBAF (1.1)
TBAF (1.1)
TBAF (1.5)
TBAF (1.1)
KF (1.0)
Additive
-
Yield (%)b
Ee(%)c
74
44
<5f
36
51
58
62
<5f
16
-
-
84
77
4g
5
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
71
71
6
7
8h
85
--
TBAF (1.1)
79
a Unless otherwise specified, the reaction was conducted with 5a (0.10 mmol) and 4a (0.3 mmol) in DCM (2.0 mL) in the presence of catalyst (0.03 mmol),
fluorine source (0.11 mmol), PNBA (0.03 mmol), additive (0.10 mmol) at -40 oC. b Isolated yields. c Ee was determined by chiral HPLC analysis of the
corresponding diols after reduction of 1aa with NaBH4. d 0.2 equiv of PNBA and 20 mol% of catalyst were used. e 1.2 equiv of PNBA and 20 mol% of catalyst
were used. f Based on TLC analysis. g At 0 oC. h 1.1 equiv of 5a and 1 equiv of 4a were used.

Scheme 2. Enantioselective synthesis of (S)-equol. a) 4a, cat. I,
TBAF, PNBA, NaH2PO4, DCM, -40 oC; b) NaBH4, MeOH, 0 oC; c)
DEAD, PPh3, THF, 0 oC to rt; d) Pd(OH)2/C, H2, MeOH/THF/H2O,
rt. DEAD: diethylazodicarboxylate
Scheme 4. Enantioselective synthesis of isoflavane analogues. a) 4d
o
or 4e, cat. I, TBAF, PNBA, NaH2PO4, DCM, -40 C; b) NaBH4,
o
o
MeOH, 0 C; c) DEAD, PPh3, THF, 0 C to rt; d) Pd(OH)2/C, H2,
MeOH/THF/H2O, rt.
Table 2. Minimum inhibitory concentration (μg/mL) of isoflavanes
and analogues against selected bacteria.a
Gram-positive
Gram-negative
Compound
B. subtilis S. aureus
E. coli P.
aeruginosa
>128
rac-sativan
(S)-sativan
rac-vestitol
(S)-vestitol
rac-8ad
(S)-8ad
rac-8ae
(R)-8ae
(S)-equol
>128
64
128
64
>128
>128
64
>128
64
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
128
128
>128
>128
64
64
>128
0.125
64
64
Scheme 3. Enantioselective synthesis of (S)-sativan, (S)-vestitol,
(S)-isosativan and (+)-medicarpin. a) 4b or 4c, cat. I, TBAF, PNBA,
Meropenem 0.125
0.0625 0.125
a B. subtilis: BR 151; S. aureus: ATCC 6538; E. coli: ATCC 25922; P.
aeruginosa: ATCC 15442. All experiments were triplicated.
o
o
NaH2PO4, DCM, -40 C; b) NaBH4, MeOH, 0 C; c) DEAD, PPh3,
o
THF, 0 C to rt; d) Pd(OH)2/C, H2, MeOH/THF/H2O, rt; e) Pb3O4,
AcOH, benzene, reflux; f) Pd(OH)2/C, H2, EtOH/THF; K2CO3,
EtOAc, rt.
Similarly, (S)-isosativan was readily prepared with 82% ee (97%
ee after recrystallization).
Moreover, starting from diol 6ac, (+)-medicarpin can be
efficiently constructed in 44% total yield and with 88% ee (95%
ee after recrystallization) via the Mitsunobu-oxidation-
hydrogenation-cyclization process.20
resulting in the reduced product 6aa in only 40% yield, which
may associate with the presence of benzyl-protecting group.
Further optimizations of this reaction, for instance, with
BF3·Et2O as Lewis acid, failed to yield satisfactory results.
Besides naturally occurring molecules, this synthetic
route is also feasible in the synthesis of other isoflavane
analogues. For instance, compound 8ad (R1 = Ph) was
readily prepared with 85% ee (90% ee after recrystallization)
after similar process (Scheme 4). It is worth noting that the
enantioselectivity of the product (8ae) can be as high as 95%
ee when 3-phenylpropanal (R1 = Bn, 4e) was employed as
substrate. These data further demonstrate this approach as a
general route for the synthesis of optically active isoflavanes.
We then switched to the reduction-Mitsunobu process for the
reduction of hydroxyl.7 As depicted in Scheme 2, the NaBH4-
mediated reduction of 1aa went smoothly, and the combination
of [4 + 2] annulation and reduction afforded diol 6aa in 49%
yield for two steps and with 85% ee after one column
chromatography purification.
A Mitsunobu reaction of 6aa followed by a Pd(OH)2-mediated
hydrogenation furnished equol with 85% ee and in 88% yield for
two steps (Scheme 2). No erosion of enantioselectivity was
observed over these processes. It is worth noting that the optical
purity of equol can be further boosted to 95% ee after one
recrystallization. The 1H NMR spectrum of this compound is
fully consistent with reported data (Table S1) and the absolute
configuration of the synthetic equol was determined to be S by
comparing its optical rotation with reported data (Table S6). The
stereo-chemical outcome of this asymmetric catalytic process is
in agreement with our previous observation.17y
Some isoflavanes (e.g., medicarpin) have proven to have
intriguing antimicrobial activities against a number of
bacterial pathogens.5 With these naturally occurring
isoflavanes and their analogues prepared, we further
investigated the antimicrobial activities of these compounds.
We incubated these molecules, along with Meropenem22 (as
positive control), in a serial of concentrations with a number
of clinically important Gram-negative bacteria (E. coli and
P. aeruginosa) and Gram-positive bacteria (B. subtilis and S.
aureus) to determine their minimum inhibitory
Encouraged by these results, we further capitalized with this
strategy in the synthesis other natural occurring isoflavanes. As
exhibited in Scheme 3, under standard [4 + 2] asymmetric
annulation protocol followed by subsequent reduction by NaBH4,
diols 6ab and 6ac were prepared in 64% and 60% yield (two
steps) and with 83% ee and 89% ee, respectively. Similarly,
enantio-enriched (S)-sativan and (S)-vestitol can be efficiently
synthesized with 83% ee, 88% ee (95% ee after one
concentrations (MICs). As shown in Table 2, these
compounds seem to be less effective against Gram-negative
bacterial pathogens. However, to our delight, some of these
chromans displayed intriguing activities against Gram-
positive bacterial. For example, (S)-sativan and (R)-8ae
exhibited MIC of 64 μg/mL against B. subtilis and S. aureus.
recrystallization) after the Mitsunobu-hydrogenation process.

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We thank the NNSFC (21472048), the “Thousand Plan”
Youth Program, and the Fundamental Research Funds for the
Central Universities for financial support.
Supplementary data
Experimental procedures, characterizations, 1H NMR and 13C
NMR spectra, HPLC traces are available in the online version.
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A General Asymmetric Route to Enantio-
enriched Isoflavanes via an Organocatalytic
Annulation of o-Quinone Methides and
Aldehydes
Leave this area blank for abstract info.
Jian Zhang,#,a Shuangzhan Zhang, #,a Huixin Yang,a Ding Zhou,a Xueting Yu,a Wei Wanga,b and Hexin Xie a,*

Research highlights
 A general asymmetric route to isoflavanes
was developed.
 Five optically active natural isoflavanes
were prepared.
 High synthetic efficiency