Synthesis of Chiral Esters via Asymmetric Wolff Rearrangement Reaction

Article abstract of DOI:10.1021/acs.orglett.9b03227

The first asymmetric Wolff rearrangement reaction that directly converts α-diazoketones into broadly useful chiral α,α-disubstituted carboxylic esters with high enantioselectivities (up to 97.5:2.5 er) is reported. The cascade reaction proceeds through the seamless combination of visible-light-induced formation of the ketene intermediate and asymmetric ketene esterification using a readily available benzotetramisole-type catalyst.

Full text of DOI:10.1021/acs.orglett.9b03227

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Chiral Esters via Asymmetric Wolff Rearrangement
Reaction
Jing Meng, Wei-Wei Ding, and Zhi-Yong Han*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei 230026, China
S
* Supporting Information
ABSTRACT: The first asymmetric Wolff rearrangement
reaction that directly converts α-diazoketones into broadly
useful chiral α,α-disubstituted carboxylic esters with high
enantioselectivities (up to 97.5:2.5 er) is reported. The
cascade reaction proceeds through the seamless combination
of visible-light-induced formation of the ketene intermediate
and asymmetric ketene esterification using a readily available
benzotetramisole-type catalyst.
hiral carboxylic acid derivatives bearing two or more
mixture of the Wolff product and the O−H insertion product
Csubstituents at the α-carbons are important bioactive (Scheme 1a).3a Yang reported the asymmetric Wolff rearrange-
molecules. For instance, ibuprofen and other similar propionic
acid derivatives are widely used nonsteroidal anti-inflammatory
drugs. Flucythrinate is a pyrethroid insecticide and acaricide,
and clidanac is used to treat rheumatoid arthritis (Figure 1).1
As such, the synthesis and transformations of these compounds
are of high importance.
Scheme 1. Wolff Rearrangement for the Synthesis of α,α-
Disubstituted Carboxylic Acid Derivatives
Figure 1. Examples of bioactive α, α-disubstituted carboxylic acid
derivatives.
Wolff rearrangement,2 the transformation of α-diazoketones
to ketenes, provides a practical method for the synthesis of
carboxylic acid derivatives when conducted in the presence of
nucleophiles such as water, alcohols, or amines.3 The cascade
processes from α-diazoketones to carboxylic acid derivatives,
which are often regarded as Wolff rearrangement reactions as
well,4 are particularly useful in the Arndt−Eistert homologa-
tions as a one-carbon (methylene) extension method.3d
However, to the best of our knowledge, the catalytic
asymmetric transformation from achiral α-diazoketones to
chiral carboxylic acid derivatives is still unknown. The
challenges are not only the stereocontrol of the nucleophilic
addition to ketenes but also to avoid the side reactions such as
O−H and C−H insertions to the carbene intermediate. As a
typical example, light-induced Wolff rearrangement of α-
diazoketone 1a in the presence of methanol led to a 1:1
ment reaction using chiral diazoketones to give chiral β-amino
acid esters in poor to moderate yields and up to 10:1
diastereoselectivities (Scheme 1b).4 On the other hand, more
effects have been focused on the more reactive ketene
substrates via organocatalysis to prepare chiral α,α-disubsti-
tuted carboxylic acid derivatives.5 Pracejus first reported the
asymmetric addition of methanol to methylphenylketene
catalyzed by brucine and quinine derivatives at −110 °C
with moderate enantioselectivity.6 Applying planar-chiral
Received: September 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03227
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
DMAP drivatives, Fu’s group reported the highly enantiose-
lective esterifications of alkylarylketenes with methanol,
phenols, and enolizable diphenylacetaldehydes.7 Ye8 and
Smith9 have pioneered the NHC10-catalyzed asymmetric
ketene esterifications with moderate to excellent enantiose-
lectivities. Though with high enantioselectivities and broad
substrate scope, due to the instability of ketene substrates, the
widespread applications of these otherwise ideal methods are
restricted. Dynamic kinetic resolution of carboxylic acids and
their derivatives, represented by Birman,11 Shiina,12 and
Chi’s13 work, also features highly enantioselective and with
high yields but inevitably requires the presynthesis of the
racemic α,α-disubstituted carboxylic acids derivatives and often
demands an excess amount of bases or activation reagents.
Herein, with our continuous research interest in asymmetric
cascade reactions14 and inspired by recent progresses in the
area of Wolff rearrangement,2c,15 we report the first catalytic
asymmetric Wolff rearrangement reaction of achiral α-
diazoketones to give chiral α,α-disubstituted carboxylic acid
esters with high enantioselectivities (up to 97.5:2.5 er)
(Scheme 1c).
revealed that the incorporation of either an electron-with-
drawing group (2j and 2k) or a bulky group (2l) at the para
position all resulted in higher enantiomeric ratio. 2,6-
Disubstituted phenols 2m and 2n all led to the corresponding
product with poor enantioselectivity. Based on the above
results, our investigation was focused on 2,4-disubstituted
phenols (2o−2r). Gratifyingly, phenols with an electron-
donating group at the ortho position and an electron-
withdrawing group at the para position are optimal substrates
for the reaction, regarding both enantioselectivity and the yield
(2p−2r). Phenol 2r, a commercially available compound, gave
the corresponding chiral ester in 76% yield and 82:18
enantiomeric ratio. Diphenylmethanol 2s, a frequently used
alcohol for the dynamic kinetic resolution of carboxylic acids
or esters,8,13 only led to a trace amount of product.
With the optimal oxygen nucleophile 2r identified, the
reaction conditions were further optimized first through the
screening of chiral nucleophilic catalysts (Table 1). The results
a
Table 1. Reaction Optimization
The structure of the nucleophile has a significant influence
on the enantioselectivity of the ketene nucleophilic addition
reaction. Thus, our investigation was initiated with the
screening for ideal oxygen nucleophiles (Scheme 2). Blue
a
Scheme 2. Evaluation of Phenols and Diphenylmethanol
b
c
entry
solvent
THF
THF
THF
THF
THF
THF
THF
MTBE
DME
4
T (°C)
yield (%)
er
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4c
4c
4c
4c
40
40
40
40
40
40
40
40
40
40
40
76
63
62
43
71
53
68
70
60
65
82:18
58.5:41.5
88.5:11.5
50:50
53:47
60.5:39.5
58.5:41.5
90:10
91:9
92.5:7.5
93:7
9
10
11
2-Me-THF
2-Me-THF
d
80
a
Unless indicated otherwise, the reaction of 1 (0.1 mmol) and 2 (0.2
mmol) was carried out with 4c (20 mol %) in 2-methyltetrahy-
drofuran (2.0 mL) at 40 °C under irradiation of blue LEDs for 16 h.
a
Unless indicated otherwise, the reaction of 1 (0.1 mmol) and 2 (0.2
b
1
Determined by H NMR analysis of the crude reaction product.
mmol) were carried out with 4c (20 mol %), in 2-methyltetrahy-
drofuran (2.0 mL) at 40 °C under irradiation of blue LEDs for 16 h.
c
d
Determined by chiral HPLC. Isolation yield.
LED was applied for the light-induced Wolff rearrangement,3c
which features mild conditions and high yield, to generate the
ketene intermediate. The reaction of phenol 2a and 1-diazo-1-
phenylacetone 1a in the presence of a nucleophilic
benzotetramisole-type catalyst16,174a led to the desired
product in 66% yield, but no enantioselectivity was observed.
The presence of a substituent at the ortho position of the
phenol could render the reaction enantioselectivities (2b−2e),
and a methoxyl group resulted in the highest enantioselectivity
(2c), whereas the presence of a bulky tert-butyl group only led
to poor enantioselectivity (2e). Comparatively, functional
groups at the meta position of the phenol had much less effect
on the stereoselectivity of the reaction (2f−2g). Later on, the
examination of the substituents at the para position (2h−2l)
revealed that the enantiomeric ratio of 3a was significantly
affected by the structure of the Birman-type chiral Lewis bases
(entries 1−7). Notably, whereas the tert-butyl substituted
catalyst (S)-4d (entry 4) gave racemic product, (S)-4c bearing
a benzyl group (entry 3) proved to be the optimal catalyst
regarding of the enantioselectivity. Of note, a number of chiral
NHCs were also evaluated in the presence of additional base.
However, while up to 70% yield could be achieved, only poor
enantioselectivities were observed (see the Supporting
Information for details). A thorough examination of solvents
showed that ethers were ideal media for the cascade reaction,
and 2-Me THF gave the product with the highest enantiomeric
ratio (entry 10, see the Supporting Information for more
results). Further, performing the reaction at lower concen-
B
DOI: 10.1021/acs.orglett.9b03227
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tration could further improve the yield to 80% and the
enantiomeric ratio to 93:7 (entry 11).
The optimized reaction conditions were first applied to an
array of α-diazoketones bearing various alkyl groups in the
reaction with phenol 3r (Scheme 3). Generally, a range of alkyl
Scheme 4. Employing the Current Asymmetric Wolff
Rearrangement Reaction for the Synthesis of Bioactive
Compounds
a
Scheme 3. Substrate Scope
(R)-ibuprofen ester 3ab, 3ac bearing a difluoromethoxyl group
at the para position (the core structure of flucythrinate) and
3ad (the basic skeleton of lipoxygenase inhibitor Bay-x 1005)18
could be afforded through the cascade reaction with high to
excellent enantioselectivities. With a cyclic α-diazo ketone
substrate, Wolff rearrangement could provide the one-carbon
ring-contracted product.19 Under the standard reaction
conditions, 1-diazo-2-tetrlong 5 could also undergo the cascade
reaction to give chiral 1-indancarboxylic acid ester, the core
structure of clidanac,1a albeit with moderate yield and
enantioselectivity (Scheme 4b). The ester group of the
product (e.g., 3ab) can be easily removed by using the well-
established method in high yield (Scheme 4c).
Control experiments were performed to further understand
the mechanism of the reaction (Scheme 5). Visible-light
a
Unless indicated otherwise, the reaction of 1 (0.1 mmol) and 2 (0.2
mmol) were carried out with 4c (20 mol %) in 2-methyltetrahy-
drofuran (2.0 mL) at 40 °C under irradiation of blue LEDs for 16 h.
Scheme 5. Control Experiments and Proposed Mechanism
for the Reaction
groups could be well tolerated, giving the corresponding chiral
esters with high to excellent enantioselectivities (3b−3f).
Noteworthy, isopropyl-substituted substrate is preferable to
achieve higher stereoselectivity (3f, 96.5:3.5 er). The scope of
the aryl groups were then examined through the reactions of 2r
with α-aryl-α-diazomethylisopropylketones and α-aryl-α-diaz-
oacetones. For all of the tested α-aryl-α-diazoketones, high to
excellent enantioselectivities could be obtained. The sub-
stitution pattern of the aryl ring of the α-aryl-α-diazoketones,
either para (3g−3m), ortho (3n−3q), or meta (3r−3x), and
the electronic properties of the substituent as well, exhibited
very limited effect on the yield and enantioselectivity of the
reaction. Other aryl groups, such as 2-naphthyl (3y) and 2, 4-
dichlorophenyl (3z), are also tolerated, affording the desired
product with moderate to good yield and high enantiose-
lectivity. Substrate bearing a heterocycle (i.e., 2-thiophene-yl)
also gave the correct product with high er but in much lower
yield (3aa). The low yield might be due to undesired reactions
associated with the electron-rich thiophene moiety.
irradiation of α-diazoketone 1a alone overnight led to
complete conversion to phenyl methyl ketene I, which was
confirmed by NMR analysis. One-pot addition of phenol 2r in
the presence of catalyst 4c afforded 3a in 61% yield and 59:41
er (Scheme 5a). The severe decrease of the enantioselectivity
implies the existence of an uncatalyzed racemic background
reaction. On the other hand, under our cascade reaction
The asymmetric Wolff rearrangement reaction may offer an
effective way for the preparation of bioactive α-alkyl-α-
arylcarboxylic acid derivatives. As illustrated in Scheme 4a,
C
DOI: 10.1021/acs.orglett.9b03227
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) (a) Kirmse, W. Eur. J. Org. Chem. 2002, 2002, 2193−2256.
(b) Coquerel, Y.; Rodriguez, J.. In Molecular Rearrangements in
Organic Synthesis; Wiley, 2015; pp 59−84. (c) Ciszewski, L. W.;
Rybicka-Jasinska, K.; Gryko, D. Org. Biomol. Chem. 2019, 17, 432−
448. (d) Tomioka, H.; Okuno, H.; Izawa, Y. J. Org. Chem. 1980, 45,
5278−5283. (e) Csizmadia, I. G.; Font, J.; Strausz, O. P. J. Am. Chem.
Soc. 1968, 90, 7360−7361. (f) Cui, G.; Thiel, W. Angew. Chem., Int.
Ed. 2013, 52, 433−436. (g) Wolff, L. Justus Liebigs Ann. Chem. 1902,
325, 129−195.
conditions, the reactive ketene intermediate is generated slowly
and directly trapped by the nucleophic catalyst, leading to the
chiral product with high stereoselectivity. Under the standard
reaction conditions, compared to substrate 1a, α-diazoketone
1a′ could undergo aryl-migrative Wolff rearrangement,
generating the same phenyl methyl ketene I, and provided
chiral ester 3a with identical enantioselectivity and slightly
lower yield (Scheme 5b). The above results all support that the
reaction proceeds through the ketene intermediate. As for the
chiral amine-catalyzed ketene esterification step, it is widely
accepted that there could be two mechanistic pathways:7c,9,20
(1) initial formation of an amine alcohol (phenol) complex as
a “chiral nucleophile”, which reacts with the ketene cabonyl
(Scheme 5c), and (2) nucleophilic attack of the amine catalyst
to the ketene to form a C1 ammonium enolate21 intermediate,
which undergoes an asymmetric proton-transfer process with
the phenol (Scheme 5d). When phenol 2r and catalyst 4c are
(3) (a) Ogata, Y.; Sawaki, Y.; Ohno, T. J. Am. Chem. Soc. 1982, 104,
216−219. (b) Tomioka, H.; Okuno, H.; Kondo, S.; Izawa, Y. J. Am.
Chem. Soc. 1980, 102, 7123−7125. (c) Bernardim, B.; Hardman-
Baldwin, A. M.; Burtoloso, A. C. B. RSC Adv. 2015, 5, 13311−13314.
(d) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091−1160.
(4) Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts,
E. Org. Lett. 2000, 2, 2177−2179.
(5) Paull, D. H.; Weatherwax, A.; Lectka, T. Tetrahedron 2009, 65,
6771−6803.
(6) Pracejus, H. Justus. Liebigs. Ann. Chem. 1960, 634, 9.
(7) (a) Fu, G. C. Acc. Chem. Res. 2000, 33, 412−420. (b) Schaefer,
C.; Fu, G. C. Angew. Chem., Int. Ed. 2005, 44, 4606−4608. (c) Wiskur,
S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176−6177. (d) Hodous,
B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10006−10007.
(8) Wang, X. N.; Lv, H.; Huang, X. L.; Ye, S. Org. Biomol. Chem.
2009, 7, 346−350.
1
mixed, there is no evidence by H NMR for formation of an
ion pair, which was observed in the chiral DMAP-catalyzed
addition of phenol to ketenes reported by Fu.7c This is
probably due to the weaker basity of the benzotetramisole-type
catalyst. As such, the second pathway of nucleophilic catalysis
is highly favored for the current reaction.
In conclusion, we have developed the first asymmetric Wolff
rearrangement reaction that directly transforms α-diazoketones
into chiral esters using a commercially available phenol
derivative. The cascade reaction consists of a visible-light-
induced Wolff rearrangement, which slowly generates the
ketene intermediate, and subsequent chiral benzotetramisole-
catalyzed asymmetric ketene esterification. The current
method allows for effective access to the broadly useful α,α-
disubstituted carboxylic esters with up to 97.5:2.5 er.
́
(9) Concellon, C.; Duguet, N.; Smith, A. D. Adv. Synth. Catal. 2009,
351, 3001−3009.
(10) (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007,
́
107, 5606−5655. (b) Marion, N.; Díez-Gonzalez, S.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 2988−3000. (c) Liu, B.; Yan, J.;
Huang, R.; Wang, W.; Jin, Z.; Zanoni, G.; Zheng, P.; Yang, S.; Chi, Y.
R. Org. Lett. 2018, 20, 3447−3450.
(11) (a) Yang, X.; Liu, P.; Houk, K. N.; Birman, V. B. Angew. Chem.,
Int. Ed. 2012, 51, 9638−9642. (b) Yang, X.; Birman, V. B. Angew.
Chem., Int. Ed. 2011, 50, 5553−5555.
(12) Shiina, I.; Ono, K.; Nakata, K. Catal. Sci. Technol. 2012, 2,
2200−2205.
ASSOCIATED CONTENT
* Supporting Information
■
(13) Chen, X.; Fong, J. Z. M.; Xu, J.; Mou, C.; Lu, Y.; Yang, S.; Song,
B.-A.; Chi, Y. R. J. Am. Chem. Soc. 2016, 138, 7212−7215.
(14) (a) Li, L. L.; Ding, D.; Song, J.; Han, Z. Y.; Gong, L. Z. Angew.
Chem., Int. Ed. 2019, 58, 7647−7651. (b) Meng, J.; Fan, L.-F.; Han,
Z.-Y.; Gong, L.-Z. Chem. 2018, 4, 1047−1058. (c) Meng, J.; Li, X.-H.;
Han, Z.-Y. Org. Lett. 2017, 19, 1076−1079.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03227.
Complete experimental procedures and characterization
data for the prepared compounds (PDF)
(15) (a) Liu, D.; Ding, W.; Zhou, Q. Q.; Wei, Y.; Lu, L. Q.; Xiao, W.
J. Org. Lett. 2018, 20, 7278−7282. (b) Li, M.-M.; Wei, Y.; Liu, J.;
Chen, H.-W.; Lu, L.-Q.; Xiao, W.-J. J. Am. Chem. Soc. 2017, 139,
14707−14713. (c) Liu, J.; Li, M. M.; Qu, B. L.; Lu, L. Q.; Xiao, W. J.
Chem. Commun. 2019, 55, 2031−2034.
(16) (a) Merad, J.; Pons, J.-M.; Chuzel, O.; Bressy, C. Eur. J. Org.
Chem. 2016, 2016, 5589−5610. (b) Birman, V. B.; Li, X. Org. Lett.
2006, 8, 1351−1354. (c) Birman, V. B.; Li, X. Org. Lett. 2008, 10,
1115−1118. (d) Yang, X.; Birman, V. B. Adv. Synth. Catal. 2009, 351,
2301−2304. (e) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A.
M. Z.; Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714−2720.
(f) Simal, C.; Lebl, T.; Slawin, A. M.; Smith, A. D. Angew. Chem., Int.
Ed. 2012, 51, 3653−3657.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hanzy2014@ustc.edu.cn.
ORCID
Zhi-Yong Han: 0000-0002-9225-5064
Notes
The authors declare no competing financial interest.
(17) (a) Schwarz, K. J.; Yang, C.; Fyfe, J. W. B.; Snaddon, T. N.
Angew. Chem., Int. Ed. 2018, 57, 12102−12105. (b) Schwarz, K. J.;
Pearson, C. M.; Cintron-Rosado, G. A.; Liu, P.; Snaddon, T. N.
Angew. Chem., Int. Ed. 2018, 57, 7800−7803. (c) Spoehrle, S. S. M.;
West, T. H.; Taylor, J. E.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem.
Soc. 2017, 139, 11895−11902. (d) Jiang, X.; Beiger, J. J.; Hartwig, J.
F. J. Am. Chem. Soc. 2017, 139, 87−90. (e) Schwarz, K. J.; Amos, J. L.;
Klein, J. C.; Do, D. T.; Snaddon, T. N. J. Am. Chem. Soc. 2016, 138,
5214−5217. (f) Song, J.; Zhang, Z. J.; Chen, S. S.; Fan, T.; Gong, L.
Z. J. Am. Chem. Soc. 2018, 140, 3177−3180. (g) Song, J.; Zhang, Z. J.;
Gong, L. Z. Angew. Chem., Int. Ed. 2017, 56, 5212−5216.
(18) Hatzelmann, A.; Fruchtmann, R.; Mohrs, K. H.; Raddatz, S.;
ACKNOWLEDGMENTS
We are grateful for the financial support from NSFC (Grant
Nos. 21831007, 21772184, and 21971231).
■
REFERENCES
■
(1) (a) Noguchi, S.; Kishimoto, S.; Minamida, I.; Obayashi, M.;
Kawakita, K. Chem. Pharm. Bull. 1971, 19, 646−648. (b) Bodor, N.;
Woods, R.; Raper, C.; Kearney, P.; Kaminski, J. J. J. Med. Chem. 1980,
23, 474−480. (c) Addor, R.; Berkelhammer, G. In Annual Reports in
Medicinal Chemistry; Hess, H.-J., Ed.; Academic Press, 1982; Vol. 17,
pp 311−321.
Mu
̈
ller-Peddinghaus, R. Biochem. Pharmacol. 1993, 45, 101−111.
D
DOI: 10.1021/acs.orglett.9b03227
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(19) Lowe, G.; Ridley, D. D. J. Chem. Soc., Chem. Commun. 1973,
328−329.
(20) (a) Brady, W. T.; Vaughn, W. L.; Hoff, E. F. J. Org. Chem. 1969,
34, 843−845. (b) Tille, A.; Pracejus, H. Chem. Ber. 1967, 100, 196.
(c) Lillford, P. J.; Satchell, D. P. N. J. Chem. Soc. B 1968, 889−897.
̈
̈
(d) Jahme, J.; Ruchardt, C. Tetrahedron Lett. 1982, 23, 4011−4014.
(e) Cannizzaro, C. E.; Strassner, T.; Houk, K. N. J. Am. Chem. Soc.
2001, 123, 2668−2669.
(21) (a) Lectka, T.; France, S.; Guerin, D. J.; Miller, S. J. Chem. Rev.
2003, 103, 2985−3012. (b) Gaunt, M. J.; Johansson, C. C. C. Chem.
Rev. 2007, 107, 5596−5605. (c) Smith, A.; Douglas, J.; Churchill, G.
Synthesis 2012, 44, 2295−2309. (d) Morrill, L. C.; Smith, A. D. Chem.
Soc. Rev. 2014, 43, 6214−622.
E
DOI: 10.1021/acs.orglett.9b03227
Org. Lett. XXXX, XXX, XXX−XXX