Chiral Fe(ii) complex catalyzed enantioselective [1,3] O-to-C rearrangement of alkyl vinyl ethers and synthesis of chromanols and beyond

Article abstract of DOI:10.1039/d0sc04340k

A highly efficient enantioselective [1,3] O-to-C rearrangement of racemic vinyl ethers that operates under mild conditions was developed. This method with chiral ferrous complex catalyst provided an efficient access to a wide range of chromanols with high yields and excellent enantioselectivities. In addition, an important urological drug (R)-tolterodine and others were easily obtained after simple transformations.

Full text of DOI:10.1039/d0sc04340k

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Chiral Fe(II) complex catalyzed enantioselective
[1,3] O-to-C rearrangement of alkyl vinyl ethers and
synthesis of chromanols and beyond†
Cite this: DOI: 10.1039/d0sc04340k
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Lifeng Wang,
Pengfei Zhou,
Qianchi Lin,
Shunxi Dong,
Xiaohua Liu
*
and Xiaoming Feng
Received 7th August 2020
Accepted 7th September 2020
A highly efficient enantioselective [1,3] O-to-C rearrangement of racemic vinyl ethers that operates under
mild conditions was developed. This method with chiral ferrous complex catalyst provided an efficient
access to a wide range of chromanols with high yields and excellent enantioselectivities. In addition, an
important urological drug (R)-tolterodine and others were easily obtained after simple transformations.
DOI: 10.1039/d0sc04340k
rsc.li/chemical-science
realize an enantioselective [1,3] O-to-C rearrangement from
racemic vinyl alkyl ethers is challenging, and a concerted [1,3]
Introduction
alkyl rearrangement is required to proceed antarafacial which is
highly unlikely under thermal conditions.
The [1,3] and [3,3] O-to-C rearrangements are powerful methods
widely used in the formation of valuable compounds.1 Asym-
metric catalytic [3,3] O-to-C rearrangement2 allows stereo-
chemistry to be efficiently relayed through a cyclic transition
state, and is more established than its [1,3] counterpart. In
comparison, the stereochemistry in [1,3] O-to-C rearrangement
is critical, but the development of enantioselective [1,3] O-to-C
rearrangement is much slower however.3 Generally, there are
three catalytic activation methods for [1,3]-rearrangement of
vinyl ether and its variants. Chiral nucleophilic organocatalysts
have been generally used for O-carboxyl shi in Steglich-type
(Black) rearrangements.4 Transition metal catalysed reactions
have been described but none of these are enantioselective
thereof.5 Thirdly, chiral Brønsted acids and Lewis acids6 seem to
be powerful in asymmetric [1,3] rearrangements of both aryl
ethers7 and vinyl ethers.8 For instance, Terada and coworkers
investigated asymmetric aza-Petasis–Ferrier rearrangement of
hemiaminal vinyl ethers using chiral phosphoric acid catalysts
Substituted chromanols or chromanones are important
structural motifs in many natural products and pharmaceuti-
cals.10 Despite some asymmetric catalytic examples were re-
ported for the construction of chromanols,11 developing new
methods remain highly desirable in order to expand the
substrate generality. In recent years, in situ generated o-quinone
(Scheme
1a).8a
Stereoselective
hydroalkoxylation/[1,3]-
rearrangement of racemic ynamides through kinetic resolu-
tion was accomplished by Ye's group (Scheme 1b).8b The
stereochemistry of the chiral substrates in the rearrangement
could be transferred through zwitterion pairs.9 This result has
also been conrmed in the work related to [1,3]-rearrangement
of Z-amino enol ethers generated from the insertion of achiral
or chiral benzyl alcohols to triazoles (Scheme 1c).8c There is no
report that describes enantioselective catalysis in [1,3] O-to-C
rearrangement of unsubstituted racemic vinyl ethers. To
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan University, Chengdu 610064, China. E-mail: liuxh@scu.edu.cn;
xmfeng@scu.edu.cn
† Electronic supplementary information (ESI) available: 1H, 13C{1H} and 19F{1H}
Scheme
1
Catalytic enantioselective [1,3]-rearrangement of vinyl
NMR, HPLC spectra, CD spectra (PDF). See DOI: 10.1039/d0sc04340k
ethers.
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methide has emerged as a popular synthon in chiral acids results,14 most of the chiral N,N0-dioxide-metal complexes,
promoted reactions.12 We envision that highly enantioselective except for lanthanide metal complexes, adopt similar octahe-
[1,3] O-to-C arrangement is available from racemic 2-vinyl- dral geometry. We initially proposed that such a sharp contrast
oxymethylphenols in the presence of a chiral Lewis acid catalyst in outcomes between Fe(OTf)3 and Fe(OTf)2 might raise from
(Scheme 1d). In view of the excellent performance of chiral N,N0- the metal cation radii, and Fe(III) has shorter radii than these
dioxide-metal complex catalysts in asymmetric catalysis,13,14 we other metal salts (entry 4 vs. entries 1–3). X-ray single crystal
utilized chiral Lewis acids for the asymmetric [1,3] O-to-C analysis of Fe(OTf)3, Fe(OTf)2 and Sc(OTf)3 of chiral N,N0-diox-
rearrangement of racemic 2-vinyloxymethylphenols to synthe- ides16 show that the former has a more compact cavity around
size chromanols. In this report, we demonstrate that a readily the metal center, where the distance between the four oxygens
available chiral iron(II) catalyst achieve extremely high enan- of the ligand and metal ion as Fe(III) is shorter than Fe(II) and
tioselective rearrangement of racemic vinyl alkyl ethers, and Sc(III). We probably would have thought that the condensed
establish that an array of chromanols and the corresponding chiral metal complex might not be benecial to the coordina-
chromanones could be obtained, one of which is transformed tion of the two oxygen-containing species from the substrate or
into an important urological drug (R)-tolterodine.15
the intermediates, leading to sharply reduced yield and ee
values. However, later we found that when small amount of
water was added in connect with the use of Fe(OTf)3 at 10 mol%
catalyst loading, the yield and enantioselectivity dramatically
recovered (entry 5 vs. entry 4). The inuence of water became
inapparent when the catalyst loading of Fe(OTf)3/L-PiPr2 was
reduced to 1 mol%, and a yield of 63% with 98% ee were still
obtained without extra water (entry 6). We rationalized that
water might participate in the catalytic cycle, and accelerate the
recovery of the metal catalyst. Fe(III) iron has stronger Lewis
acidity than Fe(II), and there is closer interaction between Fe(III)
and the intermediate species, abating the occurrence of the
rearrangement step and its regeneration. The existence of
a certain amount of water could overcome the unfavorable issue
of Fe(III) catalyst at high catalyst loading. Ferric salts with other
Results and discussion
Racemic 2-(phenyl(vinyloxy)methyl)phenol 1a was selected as
the model substrate. Upon investigating routine parameters, we
found that a Fe(OTf)2/chiral N,N0-dioxide L-PiPr2 catalyst can
promote the enantioselective [1,3] O-to-C rearrangement,
delivering chromanol 2a in 93% yield and 98% ee (Table 1, entry
1). The use of Sc(OTf)3 as the metal salt resulted in slightly lower
yield and enantioselectivity (entry 2). Whereas, an extremely low
yield of the product with moderate enantioselectivity was ob-
tained if Zn(OTf)2 was used (entry 3). Interestingly, racemic
product was observed in poor yield in the presence of Fe(OTf)3
instead of Fe(OTf)2 (entry 4). According to our current research
Table 1 Optimization of the reaction conditionsa
Entry
Variation from “standard conditions”
Yield (%)
ee (%)
1
2
3
None
Sc(OTf)3
Zn(OTf)2
Fe(OTf)3
93
86
13
19
71
63
93
84
80
80
86
67
98
90
69
0
99
98
99
98
94
91
96
0
4
5b
6
Fe(OTf)3 + H2O
Fe(OTf)3 in 1 mol% catalyst loading
1 mol% catalyst loading
0.1 mol% catalyst loading
L-RaPr2
L-PrPr2
L-PiMe2
Ph-Box
7
8
9
10
11
12
a “Standard condition”: 1a (0.1 mmol), and L-PiPr2/Fe(OTf)2 (1/1, 10 mol%) in CH2Cl2 (0.1 M) at 35 ꢀC for 2 h. Isolated yield of 2a. Ee was determined
b
by HPLC analysis on a chiral stationary phase. H2O (5 mL).
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counteranions or HOTf as additive was really no good for the perform smoothly no matter what electron-donating or
outcomes (see ESI† for details). Finally, an excellent result (93% electron-withdrawing substituents at meta- or para-position of
yield with 99% ee) was achieved if 1 mol% of Fe(OTf)2/L-PiPr2 the aryl group, delivering the corresponding products 2c–2g in
catalyst was employed (entry 7), and an even lower loading of good yields (76–94% yield) and excellent ee values (96–99% ee).
Fe(OTf)2 and chiral ligand L-PiPr2 can be used, without loss in The ortho-methyl aryl group substituted chromanol 2b was ob-
enantioselectivity in the presence of 0.1 mol% of catalyst (entry tained in 70% yield and 97% ee. Moreover, alkyl substituted 2-
8). Other families of N,N0-dioxide ligands are also acceptable vinyloxymethylphenols were also tolerated, affording the
under these conditions, regardless the amino acid backbone desired products 2h–2k in 77–92% yields and 88–99% ee. In
and the amide substituents (entries 9–11). The Ph-Box ligand addition, the effects of the substituent R2 at the phenol unit
could promote the reaction but gave racemic product (entry 12). were investigated. Either electron-withdrawing or electron-
With the optimized conditions in hand, we next explored the donating substituents at para-position of the hydroxyl group
substrate scope (Table 2). The [1,3] rearrangement reaction can of phenol provided the corresponding products 2o–2s in
excellent yields (94–99% yield) and enantioselectivities (98–99%
ee). It was noteworthy that the catalyst loading in the reaction of
the substrate 1q containing a para-uoro-substituent can
decrease to 0.1 mol%. Substituent at meta-position to the
Table 2 Substrate scope of the reactiona
hydroxyl group was also tolerable (2n). Nevertheless, the effect
of steric hindrance around the hydroxyl group of phenol unit
was obvious (2l, 2m, and 2t). In these cases, good yield and
enantioselectivity were available at higher catalyst loading
(5 mol%) or employing Sc(OTf)3 as the metal precursor. Grati-
fyingly, naphthyl substituted substrates were proved to be
suitable substrates in the reaction, giving the corresponding
products 2u and 2v in fair yield and excellent enantioselectiv-
ities with 10 mol% of L-RaPr2/Fe(OTf)2 catalyst, albeit in
moderate yields.
With respect to the synthetic utility of this new method, an
enantioselective synthesis of (R)-tolterodine, an urological drug,
has been started in the case of a gram-scale rearrangement of 1o
in the presence of 1 mol% of Fe(OTf)2/L-PiPr2, and the carbon–
carbon formation proceeded well in 96% yield and 96% ee
(Scheme 2a). Subsequently, chroman-2-ol 2o underwent reduc-
tive amination in the presence of diisopropylamine and sodium
cyanoborohydride to furnish (R)-tolterodine in 72% yield. Its
absolute conguration was determined to be R by comparing
the optical rotation with the literature value.15e Thus, the
stereochemistry of the product 2o and 3o was assigned as (R)-
isomers. The conguration of other products was assigned by
comparing with the CD spectrum of the compound 3o.
Furthermore, the chromanols 2u and 2v were oxidized with PCC
a
Unless otherwise stated, all reactions were performed with 1 (0.2
mmol) and L-PiPr2/Fe(OTf)2 (1/1, 1 mol%) in CH2Cl2 (0.1 M) at 35 ꢀC.
Isolated yield of the product 2. Ee was determined by HPLC analysis
based on the related derivative 3. L-PiPr2/Fe(OTf)2 (5 mol%). L-
PiPr2/Sc(OTf)3 (5 mol%). L-PiPr2/Fe(OTf)2 (0.1 mol%). L-RaPr2/
Fe(OTf)2 (10 mol%) in CH2ClCH2Cl. L-RaPr2/Fe(OTf)2 (10 mol%) in
b
c
d
e
f
Scheme 2 (a) Scale-up synthesis of 2o and concise synthesis of (R)-
tolterodine; (b) further transformation of chromanols 2u and 2v.
CHCl3.
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to the corresponding chromanones 3u and 3v in excellent yields water in the catalytic system assists the formation of acetal,
and enantioselectivities. The chromanone 3u was reported to affording the chiral chromanol product 2o and regenerating the
exhibit activity as an inhibitor of Sir2.17 Subsequently, ring- chiral catalyst. Additionally, the chiral ligand was found to
opened amination reaction of chromanones 3u and 3v using reduce the generation of 2-methyl-4H-benzo[d][1,3]dioxine
piperidine yields ROR-g-modulator analogs 4u and 4v with good byproduct (see ESI† for details).
results (Scheme 2b).18
As the second most abundant metal on earth, iron salts are
popular Lewis acids and metal complexes catalysts.19 In most
Conclusions
cases, ferric salt was used instead of ferrous salt because the In summary, we have successfully developed a highly efficient
former is classied hard acid according to Pearson's HSAB [1,3] O-to-C rearrangement of racemic vinyl alkyl ethers using
principle. We conducted HRMS spectra to probe into the a chiral N,N0-dioxide/Fe(OTf)2 complex. Various important
difference of the two iron species toward water (see ESI† for chiral chromanols were obtained with high yields and excellent
details). The signals in response to the complexes of iron salt, enantioselectivities (up to 99% yield and 99% ee). The catalyst
chiral ligand and water showed that higher peaks was found loading is as low as 0.1–5.0 mol% in most cases. Moreover, this
from the system of Fe(OTf)2 than Fe(OTf)3. It might indicate that methodology has been applied in the highly efficient synthesis
the ferrous catalyst is a slightly sensitive to moisture than the of an important urological drug (R)-tolterodine. Further inves-
corresponding ferric catalyst. Trace amount of water might be tigations on other type of rearrangements are currently
brought from the catalysts and other reaction components into underway.
the reaction system.
Based on the stereo-outcome of the chiral catalysts and our
Conflicts of interest
previous work,16d a possible catalytic model was proposed
(Scheme 3). At rst, the N,N0-dioxide L-PiPr2 and the two oxygen There are no conicts to declare.
atoms of 1o coordinated to the Fe(II) center, which undergoes
the heterolytic cleavage of alkyl C–O bond to generate enolate
anion and o-quinone methide cation, depreciating the formal
Acknowledgements
stereo-arrangement. The activation of protonated o-quinone We appreciate the National Natural Science Foundation of
methide further increases its electrophilicity, so the efficiency of China (No. U19A2014 and 21625205) for nancial support.
the chiral catalyst is extremely high. Recoordination of the
ethenolate and o-quinone methide to the chiral Lewis acid
center occurs, followed by bond recombination through 1,4-
Notes and references
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the bulky 2,6-diisopropylphenyl group of L-PiPr2, thus enolate
anion would prefer to attack from the Re-face of o-quinone
methide to generate (R)-intermediate. Next, the trace amount of
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