Enantioselective Catalytic [4+1]-Cyclization of ortho-Hydroxy-para-Quinone Methides with Allenoates

Article abstract of DOI:10.1002/chem.201901784

The first highly asymmetric catalytic synthesis of densely functionalized dihydrobenzofurans is reported, which starts from ortho-hydroxy-containing para-quinone methides. The reaction relies on an unprecedented formal [4+1]-annulation of these quinone methides with allenoates in the presence of a commercially available chiral phosphine catalyst. The chiral dihydrobenzofurans were obtained as single diastereomers in yields up to 90 % and with enantiomeric ratios up to 95:5.

Full text of DOI:10.1002/chem.201901784

A Journal of
Accepted Article
Title: Enantioselective Catalytic (4+1)-Cyclization of ortho-Hydroxy-
para-Quinone Methides with Allenoates
Authors: Katharina Zielke, Ondřej Kováč, Michael Winter, Jiří Pospíšil,
and Mario Waser
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To be cited as: Chem. Eur. J. 10.1002/chem.201901784
Link to VoR: http://dx.doi.org/10.1002/chem.201901784
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Enantioselective Catalytic (4+1)-Cyclization of ortho-Hydroxy-
para-Quinone Methides with Allenoates
Katharina Zielke,#[a] Ondřej Kováč,#[b] Michael Winter,[a] Jiří Pospíšil,[b,c] and Mario Waser*[a]
Abstract: We herein report the first highly asymmetric catalytic
synthesis of densely functionalized dihydrobenzofurans starting from
ortho-hydroxy-containing para-quinone methides. The reaction relies
on an unprecedented formal (4+1)-annulation of these quinone
methides with allenoates in the presence of a commercially available
chiral phosphine catalyst. The hereby accessed chiral
dihydrobenzofurans were obtained as single diastereomers in yields
up to 90% and with enantiomeric ratios up to 95:5.
(4+1)-cyclization with acceptors 2 in the presence of a
stoichiometric amount of PPh3 (Scheme 1C).[8] The (unexpected)
outcome of this reaction was in sharp contrast to other previously
described reactions between o-QMs
2
and (differently
substituted) allenoates, which all resulted in formal (4+2)-
annulations.[14] Unfortunately however, we were only able to carry
out this reaction in racemic manner, as even the use of a
stoichiometric amount of different commonly used chiral
phosphine catalysts gave low yields and poor enantioselectivities
only.[8] In especially we found that the in situ formed o-QMs 2
decomposed rather rapidly under the previously developed
reaction conditions, thus making a catalytic approach difficult.
Given these limitations in catalyst turnover and asymmetric
induction, we thought that maybe an alternative and slightly more
stable acceptor would be beneficial to address these challenges.
Thus, we decided to investigate if this methodology may also be
extended to the formal (4+1)-cyclization of the o-hydroxy-
containing p-QMs 3 with allenoates 4.[12] We reasoned that this
preformed and, compared to 2, more stable acceptor molecule
may be better suited to establish a truly catalytic as well as
asymmetric protocol, which would then allow for the first
enantioselective (4+1)-annulation of p-QMs 3 to access the highly
functionalized chiral dihydrobenzofurans 5 (Scheme 1D).
Introduction
The 2,3-dihydrobenzofuran scaffold is a prominent structural motif
found in numerous biologically active (natural) compounds[1] and
the development of novel synthesis strategies to access these
targets has been a heavily investigated topic over the last years.[2-
8]
One especially appealing approach to access chiral 2,3-
dihydrobenzofurans is the formal (4+1)-cyclization[9] between a
suitable C1 building block and a carefully chosen (maybe in situ
generated) acceptor-donor containing C4 building block. The
most versatile class of C4 building blocks used to obtain the
dihydrobenzofuran skeleton 1 via a formal (4+1)-cyclization are
ortho-quinone methides (o-QMs) 2.[10] These, usually in situ
generated, reactive compounds have recently been very
successfully used for racemic as well as highly stereoselective
(4+1)-annulations with either sulfonium or ammonium ylides,[4] a-
halocarbonyl compounds,[5] or with diazocompounds as C1
synthons (Scheme 1A).[6] Alternatively, the hydroxy-containing
para-quinone methides 3 have very recently emerged as powerful
building blocks for formal (4+n)-annulations as well.[7,11-13]
Interestingly however, their applicability for asymmetric (4+1)-
cyclizations to access dihydrobenzofurans 1 has so far been
rather limited, with highly asymmetric protocols still being rare
(Scheme 1B).[7] Two years ago we reported the first highly
enantioselective synthesis of compounds 1 by reacting preformed
chiral ammonium ylides with in situ formed o-QMs 2.[4c] More
recently we found that the highly functionalized allenoates 4 can
undergo a very unique (and up to then unprecedented) formal
[a]
[b]
[c]
DIin K. Zielke, DI M. Winter, Prof. M. Waser
Johannes Kepler University Linz, Institute of Organic Chemistry
Altenbergerstraße 69, 4040 Linz, Austria
E-mail: mario.waser@jku.at
Mgr. O. Kováč, Dr. J. Pospíšil
Department of Organic Chemistry,
Faculty of Science, Palacky University,
tř. 17. listopadu 1192/12, CZ-771 46 Olomouc, Czech Republic
Dr. J. Pospíšil
Laboratory of Growth Regulators,
The Czech Academy of Sciences, Institute of Experimental Botany
& Palacký University
Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic
These authors contributed equally
#
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Scheme
1.
Previous (4+1)-approaches
for the syntheses
of
side products; [d] complete conversion of 3a and large amounts of unidentified
dihydrobenzofurans (A-C) and the herein reported novel catalytic asymmetric
strategy (D).
side products; [e] 1 mmol scale reaction.
As decomposition of the acceptor 3a was obviously not very fast
in the first attempts with 2 equiv. of base we next used an excess
of allenoate 4a, which lead to a measurable increase in yield
(entry 3). The screening of different solvents revealed that toluene
allows for a slightly higher yield (entry 4), but also accompanied
with a more pronounced formation of various not identified side-
or decomposition products. Other solvents were not satisfying
(see entry 5 for one example) and we thus carried out further
optimizations with CH2Cl2. Very interestingly, lowering the amount
of base (entry 6) significantly improved the yield and suppressed
the side product formation. By testing other bases next, K2CO3
turned out to be the most promising (entry 7). It should be noted
that other simple trialkylphosphines were tested as well,[15] but in
analogy to our previous observation[8] these did not allow for this
(4+1)-annulation.
With these first high yielding conditions set, we next lowered the
amount of PPh3. Gratifyingly, and in sharp contrast to the reaction
with o-QMs 2,[8] the use of 20 mol% PPh3 allowed for the same
yield as when using a stoichiometric amount (compare entries 7
and 8). Further lowering of the catalyst amount unfortunately
slowed down the reaction measurably (entry 9). Considering the
beneficial effect of using less base when using Cs2CO3 (entry 6),
we finally also lowered the amount of K2CO3 (entries 10, 11), and
much to our surprise the reaction proceeded well even without
any base (entry 11; the reaction was reproduced several times on
different scales and also on 1 mmol scale).
Results and Discussion
Initial Optimization of the Racemic Reaction.
We started our investigations by carrying out the racemic reaction
between p-QM 3a and diethyl allenoate 4a in the presence of
PPh3 (Table 1 gives an overview of the most significant screening
results). Our first reactions were carried out in analogy to the
conditions developed for the annulation of o-QMs 2[8] (please note
that we previously used a twofold excess of the quinone methide
2 to compensate for its competing decomposition under the
reaction conditions). Gratifyingly the targeted dihydrobenzofuran
5a could be obtained as a single diastereomer in this initial
attempt already (entry 1). The relative configuration of the product
5a was confirmed by NOESY experiments (as shown in Scheme
3) and we also observed the same correlations for other products
5 later (Scheme 2). As the reaction was found to be rather slow,
with significant amounts of unreacted 3a being recovered
(indicating its increased stability compared to o-QMs 2), we next
increased the amount of base (entry 2), which however had a
detrimental effect (complete decomposition of starting materials).
Table 1: Initial screening with PPh3.
Development of an Asymmetric Catalytic Protocol.
Having established high yielding and robust catalytic procedures
for the racemic synthesis of 5a we next focused on the use of
chiral phosphine catalysts. As already mentioned before, we were
not able to identify a suited asymmetric catalyst for our previous
(4+1)-annulation of o-QMs 2. However, given the fact that p-QM
3a performed very well in the racemic reaction and also allowed
for a catalytic approach, we were confident that the well-described
bulky chiral phosphines A[16] or B[17] may allow for a truly catalytic
enantioselective protocol (Table 2). We first used the binaphthyl-
based phosphines A1-3, but unfortunately neither of them allowed
for any product formation (entries 1-3). Gratifyingly however, by
switching to the commercially available chiral spiro phosphine B
((R)-SITCP)[17] we observed a very clean and reasonably
enantioselective product formation when using 20 mol% of this
catalyst under base-free conditions in CH2Cl2 (entry 4). Lowering
the reaction temperature to 0 °C unfortunately did not allow for
product formation anymore (entry 5). When carrying out the
reaction in the presence of two equiv. of K2CO3, the outcome was
only slightly affected in this solvent (entry 6).
Entrya
3a : 4a
PPh3
Base (eq.)
Solvent
Yield
(%)b
1
2 : 1
2 : 1
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 eq.
Cs2CO3 (2 eq.)
Cs2CO3 (10 eq.)
Cs2CO3 (2 eq.)
Cs2CO3 (2 eq.)
Cs2CO3 (2 eq.)
Cs2CO3 (0.2 eq.)
K2CO3 (2 eq.)
K2CO3 (2 eq.)
K2CO3 (2 eq.)
K2CO3 (0.5 eq.)
-
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
16c
-
2
1 eq.
3
1 eq.
33c
45d
-
4
1 eq.
5
1 eq.
6
1 eq.
63
7
1 eq.
82
8
0.2 eq.
0.1 eq.
0.2 eq.
0.2 eq.
81
9
49
10
11
89
90 (86)e
[a] All reactions were carried out on 0.1 mmol scale (based on the p-QM 3a):
[b] Isolated yield; [c] Incomplete conversion of 3a and noticeable amounts of
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lower yields and K3PO4 giving no product at all). We thus tested if
any further improvement in the presence of 2 equiv. of K2CO3 may
be possible (entries 8-11). However, lowering of the reaction
temperature was possible to some extent only (entries 9, 10), but
reducing the catalyst loading to 10 mol% was unfortunately not
possible anymore (entry 11). Accordingly, the best-suited and
most robust catalytic enantioselective approach to access 5a as
a single diastereomer was to carry out the reaction in toluene at
10 °C in the presence of 2 equiv. K2CO3 by using 20 mol% of the
commercially available phosphine catalyst B (entry 9, the reaction
was reproduced by different persons on 0.05 - 0.1 mmol 3a scale
giving identical results).
Table 2: Development of an enantioselective catalytic protocol.
Application Scope.
Having established a high yielding and robust catalytic procedure
for the synthesis of dihydrobenzofuran 5a, we next tested the use
of differently substituted quinone methides 3 and allenoates 4
(Scheme 2).
Entrya
PR3
(mol%)
Solvent
Base
(eq.)
Temp.
(°C)
Yield
(%)b
e.r.c
1
2
3
4
5
6
A1 (20%)
A2 (20%)
A3 (20%)
B (20%)
B (20%)
B (20%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-
-
-
-
-
25
25
25
25
0
-
-
-
-
-
-
84
-
88:12
-
K2CO3
(2 eq.)
25
70
87:13
7
8
B (20%)
B (20%)
Toluene
Toluene
-
25
25
87
90
94:6
92:8
K2CO3
(2 eq.)
9
B (20%)
B (20%)
B (10%)
Toluene
Toluene
Toluene
K2CO3
(2 eq.)
10
0
89
-
94:6
10
11
K2CO3
(2 eq.)
-
-
K2CO3
(2 eq.)
10
-
[a] All reactions were carried out on 0.1 mmol scale (based on 3a): [b] Isolated
yield; [c] Determined by HPLC using a chiral stationary phase with the (+)-
enantiomer as the major product. The relative configuration was assigned by
NOESY experiments (see Scheme 4) but the absolute configuration could not
be determined yet.
Interestingly, when changing to toluene (other solvents like THF
were found to be not suited), we were able to improve the
enantioselectivity significantly (entries 7-9). At room temperature
reactions in the presence of K2CO3 as well as under base-free
conditions performed very similarly, with a slightly higher e.r. in
the absence of base (compare entries 7 and 8). However, when
we investigated the application scope later on, we realized that
the base-mediated conditions were more robust when using
differently substituted starting materials 3, while not all of those
allowed for good conversions under base-free conditions. Other
bases were found to be less satisfactory (with e.g. Cs2CO3 giving
Scheme 2. Application scope (Conditions: 0.05 - 0.2 mmol 3, 2 equiv. 4, 2 equiv.
K2CO3, 20 mol% B, toluene (0.025 M), 10 °C, min. 20 h; All yields are isolated
yields and enantiomeric ratios were determined by HPLC using a chiral
stationary phase with the (+)-enantiomer being the major product in each case).
First, we could show that replacement of one of the allenoate ethyl
ester groups for a benzyl ester was tolerated very well (see
product 5b). Then it turned out that a dimethyl-based p-QM 3 can
be used as well to obtain the enantioenriched product 5c (albeit
with a slightly lower selectivity than for the parent t-Bu-based 5a).
Interestingly, substituents in the
5 and 6-position of the
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benzofuran backbone were tolerated very well (see compounds
5d, 5e, 5f, 5i, 5j, 5k, 5m). In contrast, substituents in positions 4
and 8 turned out to be more limiting and product 5g was only
accessible with a rather low enantiomeric ratio of 79:21.
Surprisingly, compound 5h was not formed at all under the
asymmetric conditions (even with longer reaction times). We were
however able to obtain racemic 5h in high yield when using PPh3
as an achiral catalyst. Very interestingly, while we found initially
that benzyl ester containing allenoates were tolerated similarly
well as ethyl ester-based ones (see targets 5a and 5b), we found
that t-butyl esters resulted in somewhat lower enantiomeric ratios
compared to ethyl and benzyl esters (compare 5k and 5l as well
as 5m, 5n, and 5o). All asymmetric reactions were initially carried
out on 0.05 mmol scale of the limiting agent 3 and we also
reproduced selected reactions on up to 0.2 mmol scale without
affecting the outcome, thus indicating that the asymmetric
procedure is of similar robustness as the racemic one (Table 1,
entry 11).
Mechanistic Considerations.
Mechanistically this is a rather complex reaction and it should be
admitted that so far we only have some hints that may allow us to
postulate the mechanistic scenario depicted in Scheme 4. This
proposal is also based on our recent observations made for the
racemic (4+1)-annulation of o-QMs 2 where we found that
intramolecular rapid proton transfers are crucial to explain the
outcome of this (4+1)-cyclization.[8]
All substrate combinations gave the (+)-enantiomer as the major
product, but unfortunately we were so far not able to obtain suited
crystals of any of the products 5 to determine the absolute
configuration by means of single crystal X-ray analysis.
It has been described by others that the t-butyl groups of the
phenol derivatives obtained by addition of nucleophiles to QMs
can be cleaved off under (Lewis) acidic conditions.[7a,11c] We thus
carried out a few (unoptimized) test reactions to see if a similar
debutylation is also possible on the highly functionalized diester-
containing dihydrobenzofuranes 5 (Scheme 3). Carrying out the
reaction at elevated temperature lead to quick decomposition only.
In contrast, at room temperature the slow formation of the
debutylated diester 6a was observed by MS. Interestingly
however, the major reaction product was found to be the
debutylated monoester 7a that was formed in around 30% after
one day and around 50-60% after 3 days (accompanied with
some decomposition products) and which could also be isolated
after column chromatography (NMR clearly confirmed that the
ester group on the stereogenic center was hydrolysed). It should
be noted that no further attempts to optimize this reaction were
undertaken, but this result clearly shows that the highly
functionalized compounds 5a can be used for further
transformations and that the two ester groups have different
reactivities.
Scheme 4. Postulated mechanism and NOESY results to determine the relative
configuration.
Addition of the phosphine to the allenoate is supposed to give the
required zwitterion I after proton transfer on the primary addition
product. Following the reaction between PPh3 and 4a by 31P NMR
shows the appearance of two new signals around 27 ppm (the
parent PPh3 peak is at -5 ppm) substantiating the formation of
alkylated phosphine species (these addition products
decomposed very quickly in the absence of any electrophile).
Upon addition of the quinone methide 3a immediately a strong red
colour evolves, which can be rationalized by the 1,6-addition of I
to 3a to give the phenolate II. Similar colour changes can also be
observed when adding different nucleophiles to other p-QMs,
substantiating the assumed initial 1,6-addition. With respect to the
nature of the electrophile 3a one could however also postulate
that a prototropic shift from the phenol to the para-QM moiety
gives an ortho-QM in situ, which then reacts with I to give III
directly).[18] However, we found compound 3a being rather stable
under basic conditions and we never observed any other species
or got any experimental hint that supports this pathway, but it
should not be ruled out completely with the current state of
knowledge. The phenolate II then needs to undergo two proton
transfer reactions towards the betaine IV, which then finally can
react to the product 5a via an SN2’ type cyclization. We have
recently shown for the cyclizations of o-QMs 2 that these proton
transfers are rather likely processes and we reason that the
Scheme 3. AlCl3-mediated transformations of rac-5a.
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organic layers were evaporated to dryness (under reduce pressure) and
the products were purified by silica gel column chromatography (gradient
of heptanes and EtOAc) giving the corresponding dihydrobenzofurans 5 in
the reported yields and enantiopurities (Syntheses of racemic samples
were carried out in analogy using PPh3 instead).
presence of a base is beneficial for these reactions, which would
be an explanation why the herein presented (4+1)-cyclization is
more robust under basic conditions. This beneficial effect of base
became especially pronounced in those cases where no electron-
donating ring substituent para to the OH group is present (these
reactions usually proceeded
a bit slower as well). This
Dihydrobenzofuran 5a. Obtained as a yellow residue in 89% and e.r. =
94:6. [ꢀ]ꢂꢁꢃ = 64.6 (c = 0.15, CHCl3, e.r. = 94:6); 1H NMR (300 MHz, δ,
CDCl3, 298 K): 0.82 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.36 (s,
18H), 1.89 (d, J = 7.2 Hz, 3H), 3.52-3.77 (m, 2H), 4.26-4.36 (m, 2H), 5.11
(s, 1H), 5.24 (s, 1H), 6.40 (q, J = 7.1 Hz, 1H), 6.83 (s, 2H), 6.94 (t,
J = 7.3 Hz, 1H), 7.01-7.09 (m, 2H), 7.19-7.26 (m, 1H) ppm. 13C NMR
(75 MHz, δ, CDCl3, 298 K): 13.4, 14.2, 15.5, 30.2, 34.2, 55.8, 60.8, 61.1,
94.0, 110.2, 121.8, 125.7, 126.1, 128.9, 129.4, 130.0, 132.7, 133.2, 135.1,
153.0, 158.1, 167.2, 168.4 ppm; HRMS (ESI): m/z calcd for C31H40O6:
509.2898 [M+H]+; found: 509.2897. The enantioselectivity was
determined by HPLC (YMC Chiral Art Cellulose-SB, eluent: hexane:i-
observation supports a scenario where the final ring-closure may
be the rate-determining step, which also rationalizes why slightly
larger amounts of catalyst were necessary to obtain satisfying
catalyst turnover.
With respect to the observed stereoselectivity it is likely that the
catalyst controls the absolute configuration in the 1,6-addition
step. An alternative may be a less selective 1,6-addition followed
by base-mediated isomerization of the benzylic position on one of
the chiral catalyst-bound intermediates II or III. However, as the
observed enantioselectivity was more or less the same under
basic and base-free conditions (compare with Table 2), this option
seems less likely. The diastereoselectivity is then controlled in the
final proton transfer - cyclization sequence. Given the fact that
SN2’ reactions usually proceed via cis-orientation of nucleophile
and leaving group[19] the proton transfer towards IV is supposed
to be highly selective, and may be steered by electrostatic
attraction between the phenolate anion and the phosphonium
cation in the nonpolar reaction solvent. However, it should clearly
be pointed out that this is just a mechanistic hypothesis and
although we were able to observe the presence of some alkylated
phosphonium species by 31P NMR during the reaction, none of
these intermediates could be isolated or more carefully analysed.
PrOH = 95:5, 0.5 mL/min, 10 °C, retention times: tmajor = 9.4 min, tminor
11.0 min).
=
Acknowledgements
This work was supported by the Austrian Science Funds (FWF):
Project No. P26387-N28. The NMR spectrometers used were
acquired in collaboration with the University of South Bohemia
(CZ) with financial support from the European Union through the
EFRE INTERREG IV ETC-AT-CZ program (project M00146,
"RERI-uasb"). O. Kováč was supported from Internal Grant
Agency of Palacky University (IGA_PrF_2019_027). J. Pospíšil
was supported from European Regional Development Fund
Project “Centre for Experimental Plant Biology” (No.
CZ.02.1.01/0.0/0.0/16_019/0000738).
Conclusions
The first highly asymmetric catalytic formal (4+1)-annulation of o-
hydroxy-p-quinone methides 3 with allenoates 4 was developed.
The outcome of this reaction is in sharp contrast to other recently
reported reactions between quinone methides
3
and
allenoates.[12] Key to success was the use of the commercially
available chiral phosphine B as a catalyst under carefully
optimized reaction conditions. This methodology allowed for the
so far unprecedented synthesis of the chiral dihydrobenzofurans
5 as single diastereomers in yields up to 90% and with
enantiomeric ratios up to 95:5.
Keywords: Allenoates • Enantioselectivity • Diastereoselectivity •
Organocatalysis • Annulation
1
For illustrative reviews and selected examples please see: (a) R. S. Ward, Nat.
Prod. Rep., 1999, 16, 75-96; (b) S. Apers, D. Paper, J. Bürgermeister, S.
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Experimental Section
2
3
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D. Sheppard, J. Chem. Res. 2011, 35, 377-385.
General details can be found in the online supporting information. This
document also contains detailed synthesis procedures and analytical data
of novel compounds and reaction products as well as copies of NMR
spectra and HPLC traces.
For selected recent examples employing complementary synthesis strategies
see: (a) E. D. Coy, L. Jovanovic, M. Sefkow, Org. Lett., 2010, 12, 1976-1979; (b)
J. Mangas-Sanchez, E. Busto, V. Gotor-Fernandez, V. Gotor, Org. Lett., 2010,
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(e) A. Lu, K. Hu, Y. Wang, H. Song, Z. Zhou, J. Fang, C. Tang, J. Org. Chem., 2012,
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28, 239-244; (i) Y. Cheng, Z. Gang, W. Li, P. Li, Org. Chem. Front. 2018, 5, 2728-
General asymmetric (4+1)-cyclization procedure: A mixture of the para-
quinone methide
3 (0.05-0.2 mmol), K2CO3 (2 equiv.), and chiral
phosphine B (20 mol%) was cooled to 10°C and a solution of the allenoate
4 (2 equiv.) in dry toluene (20 ml per mmol 4) was added. The resulting
mixture was stirred at 10°C under an Ar atmosphere for approximately 20
h. The mixture was diluted by adding CH2Cl2 (5 ml), filtrated over a pad of
Na2SO4 and the residue was rinsed with CH2Cl2 (5 x 5 ml). The combined
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2733; (j) T. Zhou, T. Xia, Z. Liu, L. Liu, J. Zhang, Adv. Synth. Catal. 2018, 360,
4475-4479.
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4
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5
6
7
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8
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10.1002/chem.201901784
Chemistry - A European Journal
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The first highly asymmetric synthesis of densely functionalized
dihydrobenzofurans via an organocatalytic (4+1)-cyclization of ortho-hydroxy-
para-quinone methides with allenoates was developed.
Katharina Zielke, Ondřej
Kováč, Michael Winter,
Jiří Pospíšil and Mario
Waser*
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Enantioselective
Catalytic (4+1)-
Cyclization of ortho-
Hydroxy-para-Quinone
Methides with
Allenoates
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