Enantioselective Spirocyclopropanation of para-Quinone Methides Using Ammonium Ylides

Article abstract of DOI:10.1021/acs.orglett.7b00869

The use of Cinchona alkaloid-based chiral ammonium ylides allows for the first highly enantioselective and broadly applicable spirocyclopropanation reactions of para-quinone methides. This strategy provides a straightforward protocol toward the chiral spiro[2.5]octa-4,7-dien-6-one skeleton, which is a frequently found structural motif in important biologically active molecules.

Full text of DOI:10.1021/acs.orglett.7b00869

Letter
pubs.acs.org/OrgLett
Enantioselective Spirocyclopropanation of para-Quinone Methides
Using Ammonium Ylides
Lukas Roiser and Mario Waser*
Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstr. 69, 4040 Linz, Austria
S
* Supporting Information
ABSTRACT: The use of Cinchona alkaloid-based chiral
ammonium ylides allows for the first highly enantioselective
and broadly applicable spirocyclopropanation reactions of
para-quinone methides. This strategy provides a straightfor-
ward protocol toward the chiral spiro[2.5]octa-4,7-dien-6-one
skeleton, which is a frequently found structural motif in
important biologically active molecules.
Scheme 1. Recent Michael-Initiated Cyclopropanation
Reports for the Synthesis of Spiro[2.5]octa-4,7-dien-6-ones
3 and the Herein Targeted Enantioselective Approach via
Chiral Ammonium Ylides Starting from Ammonium Salts 5
he spirocyclopropane motif is a recurring important
Tstructural element in a variety of natural (biologically
active) compounds.1 Among the different possible variations,
the spiro[2.5]octa-4,7-dien-6-one skeleton has become increas-
ingly relevant because of its presence in biologically active
natural products with, e.g., DNA-alkylating properties.2 In
addition to their interesting pharmacological properties,
spirocyclopropanes may also serve as versatile key-intermedi-
ates in the synthesis of complex (pharmaceutically interesting)
targets.3 One potentially powerful approach to access the
spiro[2.5]octa-4,7-dien-6-one motif is to start from quinoide-
type structures.4,5 Hereby two complementary strategies have
been reported, either by making use of para-quinone methides
as acceptors for cyclopropanation reactions4 or by reacting
quinone diazides with olefins.5 Quinone methides have become
a very privileged and unique class of acceptors for asymmetric
transformations over the course of recent years.6 While ortho-
quinone methides were successfully used for a variety of (4 +
n)-type cyclizations even with onium ylides,7 para-quinone
methides 1 have become increasingly important for vinylogous
enantioselective 1,6-addition reactions.8 In addition, very
recently the first reports describing the use of these reactive
substrates for Michael-initiated cyclopropanation reactions
either with α-bromo malonates (Scheme 1A)9 or sulfonium
ylides (Scheme 1B)4 have been reported, allowing for a
straightforward construction of the spiro[2.5]octa-4,7-dien-6-
one skeleton of compounds of general structure 3.
Our group has a fundamental interest in the use of
ammonium ylides for asymmetric three-membered ring-
forming reactions like epoxidation and aziridination10 as well
as in the synthesis of chiraI cyclopropanes.11 Ammonium ylides
have been very successfully used for asymmetric cyclo-
propanations over recent years.12 Therefore, the reports by
the groups of Yao and Lin4a and Fan4b (Scheme 1B) were
particularly inspiring for us because they clearly proved the
potential of sulfonium ylides for cyclopropanation reactions of
para-quinone methides. Interestingly, both groups were able to
achieve high yields and excellent diastereoselectivities using
dimethylsulfide-based ylides and with a broad substrate scope.
However, while Yao and Lin et al.4a realized that Aggarwal’s
chiral limonene-based sulfur ylide13 did not allow them to
facilitate this cyclopropanation reaction, Fan et al.4b reported a
single example using a chiral binaphthyl-derived sulfonium
Received: March 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00869
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Organic Letters
Letter
salt,14 which gave up to 90:10 enantiomeric ratio (er) in one
test reaction. Based on the high versatility of chiral ammonium
ylides for asymmetric cyclopropanation reactions,12 we became
interested in addressing the spirocyclopropanation of quinone
methides 1, aiming at developing the first highly enantiose-
lective and broadly applicable synthesis of the chiral targets 3
(Scheme 1C).
Table 1. Identification of the Optimum Conditions and the
Best-Suited Chiral Amine Leaving Group for the Ammonium
Ylide-Mediated Synthesis of 3b
We decided to focus on amide-based ammonium ylide-
precursors 5a that would use trimethylamine as an achiral
amine leaving group for initial optimization experiments (Table
1, entries 1−5). This amine was chosen because of its
established superior leaving group ability for other cyclization
reactions.10
We soon found that using Cs2CO3 as a solid base in
combination with a slight excess of the acceptor 1a allowed for
a high yielding synthesis of the racemic spiro-target 3b with a
clear preference for the trans isomer (entry 5, Table 1).
Focusing on the development of an asymmetric protocol next,
we tested a series of rather simple Cinchona alkaloids. Very
interestingly, while free −OH containing derivatives like QD1
or Q1 gave only very little product formation (entries 6, 10),
the simple O-methylated analogues QD2 and Q2 turned out to
be much higher yielding (entries 7, 11). The same trend was
also observed when using the cinchonine and cinchonidine-
based Q3, Q4 and QD3, QD4 (entries 8, 9, 12, 13). Very
importantly, very high enantiomeric excesses for both
enantiomers of 3b could be achieved. However, we also
observed that the use of these chiral auxiliaries required longer
reaction times and a slightly larger excess of acceptor to achieve
a full conversion compared to the achiral approach when using
Me3N (2.5 equiv of 1a for 72 h at rt compared to 1.5 equiv of
1a for 24 h at rt). In addition, the trans/cis ratio of around 2.5:1
was still not what we desired (it should be noted that cis-3b was
obtained with the same very high enantiomeric excess as the
trans isomer). As we initially realized that the use of a stronger
base like t-BuOK allowed for very high diastereoselectivities in
the achiral attempts (entry 3), we also explored other bases for
the enantioselective reaction. However, the yields were not
satisfying in those cases. Nevertheless, we reasoned that the
higher trans-selectivity with stronger bases might be due to the
base-mediated isomerization of the cis-cyclopropane. Impor-
tantly we found that enantiomerically pure cis-3b could be
isomerized to trans-3b by treatment with either t-BuOK or
Cs2CO3 at elevated temperature. This latter observation then
inspired us to carry out the overall reaction at reflux, which
finally resulted in a protocol that allowed us to obtain 3b in
very high yield (98%) and with literally complete control of the
absolute (er > 99.8:0.2) and the relative configuration (dr >
40:1) (the chiral amine could also easily be recovered and
reused after the reaction by Al2O3 column chromatography). It
should be noted that attempts to carry out this reaction in a
catalytic fashion starting from α-bromoacetamides in the
presence of substoichiometric amounts of Q2 resulted in
almost the same high stereoselectivities but unfortunately were
limited with respect to yield (20−30%) and catalyst turnover,
as decomposition of the quinone methide 1a turned out to be
fast compared to the in situ formation of ammonium salt 5a
(details can be found in the Supporting Information).15
Having identified highly selective and high-yielding con-
ditions for the formation of chiral spiro[2.5]octa-4,7-dien-6-
ones 3, we next evaluated the application scope of this reaction
(Scheme 2). A variety of different acceptors and nucleophiles
were well tolerated, and in all cases, more or less complete
b
c
base
yield
dr
a
d
entry amine
(equiv)
cond.
(%)
(trans/cis) er (trans)
1
2
3
Me3N K2CO3
A
traces
(4×)
Me3N Cs2CO3
A
A
69
76
3.3:1
13:1
(4×)
Me3N t-BuOK
(2×)
Me3N DBU (3×)
4
5
A
B
55
86
2.8:1
2.5:1
Me3N Cs2CO3
(5×)
Cs2CO3
(5×)
Cs2CO3
(5×)
Cs2CO3
(5×)
Cs2CO3
(5×)
Cs2CO3
(5×)
Cs2CO3
(5×)
Cs2CO3
(5×)
6
QD1
QD2
QD3
QD4
Q1
C
C
C
C
C
C
C
C
D
9
6:1
n.d.
7
79
59
n.d.
3
1.8:1
3.3:1
2:98
8
2.5:97.5
9
10
11
12
13
14
3.1:1
2.5:1
2.7:1
n.d.
Q2
85
57
n.d.
98
>99.8:0.2
99.5:0.5
Q3
Q4
Cs2CO3
(5×)
Cs2CO3
(6×)
Q2
>40:1
>99.8:0.2
a
All reactions were carried out using 0.1 mmol 5a in CH2Cl2 (A: with
1 equiv 1a, rt, 24 h; B: with 1.5 equiv 1a, rt, 24 h; C: with 2.5 equiv 1a,
rt, 72 h; D: with 2.5 equiv 1a, reflux, 96 h. Isolated yields.
Determined by NMR analysis of the crude product. Determined by
b
c
d
HPLC using a chiral stationary phase.
stereocontrol could be achieved. Gratefully, we were able to
obtain crystals of the bromo-substituted 3l, which were of
sufficient quality to unambiguously determine the absolute
configuration for that heavy atom-containing derivative by
anomalous single crystal X-ray analysis.15,16 By assuming a
similar mode of face-differentiation for the reactions with the
other test substrates, we therefore propose the same absolute
configuration given in Scheme 2. An interesting observation
was made when we attempted the synthesis of the
dimethylamino-containing cyclopropane 3k. This product was
clearly identified in the crude reaction mixture. However, after
silica gel column chromatography, we isolated the chiral alcohol
B
DOI: 10.1021/acs.orglett.7b00869
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Organic Letters
Letter
a
Scheme 2. Application Scope of the Asymmetric Ammonium Ylide-Mediated Synthesis of Spirocyclopropanes 3
a
Absolute configuration was determined by single crystal analysis of 3l15,16 and the other derivatives were proposed in analogy.
6h in reasonable yield and with a very high enantio- and
diastereoselectivity (Scheme 3). Further investigations proved
measurable but still a rather small erosion of the enantiopurity
(Δ = 1.8%), but with all of the other investigated trans-
formations with different cyclopropanes 3 and different
alcohols, they proceeded without any noticeable decrease in
er (see the Supporting Information).15
Scheme 3. Stereospecific Nucleophilic Ring Opening
Reactions of 315
In conclusion we have developed a highly asymmetric and
broadly applicable protocol for the straightforward synthesis of
chiral spiro[2.5]octa-4,7-dien-6-ones. Key to success for this
first ammonium ylide-based cyclopropanation of para-quinone
methides was the use of a simple Cinchona alkaloid-based
amine leaving group in combination with carefully fine-tuned
reaction conditions, which resulted not only in high enantio-
but also in very high diastereoselectivities. The hereby obtained
products can be used for stereospecific ring-opening reactions
as exemplified by the addition of simple alcohols.
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.7b00869.
that products 3 can, in general, easily be employed in
stereospecific cyclopropane ring-opening reactions with alco-
hols at room temperature (Scheme 3).15
Synthesis procedures, analytical details, and copies of
NMR spectra and HPLC data of all the compounds
(PDF)
Based on the proposed absolute configuration for trans-
cyclopropanes 3, addition of an alcohol should thus result in
compounds 6 with the configuration given in Scheme 3. Only
during the ring opening of one example did we observe a
Crystallographic data for 3l (CIF)
C
DOI: 10.1021/acs.orglett.7b00869
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Organic Letters
Letter
Reisinger, M.; Waser, M. RSC Adv. 2013, 3, 4552−4557. (d) Pichler,
AUTHOR INFORMATION
■
M.; Novacek, J.; Robiette, R.; Poscher, V.; Himmelsbach, M.;
Corresponding Author
*E-mail: mario.waser@jku.at.
ORCID
Monkowius, U.; Muller, N.; Waser, M. Org. Biomol. Chem. 2015, 13,
̈
2092−2099. (e) Roiser, L.; Robiette, R.; Waser, M. Synlett 2016, 27,
1963−1968. (f) Novacek, J.; Roiser, L.; Zielke, K.; Robiette, R.; Waser,
M. Chem. - Eur. J. 2016, 22, 11422−11428.
Mario Waser: 0000-0002-8421-8642
Notes
(11) (a) Waser, M.; Moher, E. D.; Borders, S. S. K.; Hansen, M. M.;
Hoard, D. W.; Laurila, M. E.; LeTourneau, M. E.; Miller, R. D.;
Phillips, M. L.; Sullivan, K. A.; Ward, J. A.; Xie, C.; Bye, C. A.; Leitner,
The authors declare no competing financial interest.
T.; Herzog-Krimbacher, B.; Kordian, M.; Mullner, M. Org. Process Res.
̈
Dev. 2011, 15, 1266−1274. (b) Herchl, R.; Waser, M. Tetrahedron Lett.
ACKNOWLEDGMENTS
2013, 54, 2472−2475.
■
(12) For impressive examples, see: (a) Johansson, C. C. C.;
Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S. C.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2006, 45, 6024−6028. (b) Papageorgiou, C. D.;
Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed.
2004, 43, 4641−4644.
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”). We are grateful to
Prof. Uwe Monkowius (JKU Linz) for his support with single
crystal X-ray analysis.
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(15) Further details can be found in the online Supporting
Information.
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