Catalytic Asymmetric Conjugate Addition of Carboxylic Acids via Oxa-Michael Reaction of Peroxy Hemiacetals followed by Kornblum DeLaMare Fragmentation

Article abstract of DOI:10.1021/acs.orglett.6b02463

Disclosed herein an overall methodology constitutes an equivalent to the long sought after enantioselective intramolecular oxa-Michael (IOM) reaction of carboxylic acids. An organocatalyzed IOM reaction of in situ formed peroxy hemiacetals followed by a K

Full text of DOI:10.1021/acs.orglett.6b02463

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Conjugate Addition of Carboxylic Acids via
Oxa-Michael Reaction of Peroxy Hemiacetals followed by Kornblum
DeLaMare Fragmentation
Biswajit Parhi, Sanjay Maity, and Prasanta Ghorai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal By-pass Road, Bhauri, Bhopal 462066,
India
*
S Supporting Information
ABSTRACT: Disclosed herein an overall methodology constitutes an equivalent to the long sought after enantioselective
intramolecular oxa-Michael (IOM) reaction of carboxylic acids. An organocatalyzed IOM reaction of in situ formed peroxy
hemiacetals followed by a Kornblum DeLaMare type rearrangement cascade provides a broad class of chiral lactones in good
yields and with excellent enatioselectvities. Remarkably, the pure chiral lactones are obtained without any silica gel column
chromatography, and in many cases, the enantioselectivity is further increased by a simple hexane wash of the isolated solid
products.
ntramolecular oxa-Michael (IOM) reaction of α,β-unsatu-
rated carbonyls is one of the most fundamental and frequently
Scheme 1. Intramolecular Oxa-Michael Addition of (a)
Carboxylic Acid and (b) Peroxy Hemiacetals
I
employed methodologies for the construction of a variety of O-
1
heterocycles. Significant efforts have been directed toward the
development of catalytic asymmetric IOM reactions using
2
−4
alcohols as nucleophiles to furnish chiral cyclic ethers.
Remarkably, despite the considerable synthetic potential of the
analogous IOM reaction of carboxylic acids for the construction
5
of variety of lactones, the development of the asymmetric
variants has been entirely elusive to date. The complications stem
from the rapid self-promoted cyclization of carboxylic acids (pKa
in DMSO ≈ 4) with electrophilic enones and enals, even in the
6
absence of external catalyst (Scheme 1a). This phenomenon
prevents the development of their corresponding asymmetric
7
version.
To suppress the rapid cyclization, we hypothesized that a
masked carboxylic acid with higher pK would be useful. We
a
presumed that peroxy acetal intermediate II might provide a
chiral lactone if the Kornblum DeLaMare fragmentation of
9
of a base, which might enhance the reversibility of oxa-Michael
addition process and, thus, the loss of enantioselectivity.
Nevertheless, if the oxa-Michael addition and Kornblum
DeLaMare type rearrangement are achieved sequentially, the
overall methodology would be an equivalent of the long sought
after asymmetric oxa-Michael reaction of carboxylic acids where
the peroxy hemiacetals would serve as a masked synthon of
carboxylic acids. Notably, decomposition of a peroxide unit into
peroxy acetal to an ester could be conducted without
3
epimerization of the C stereocenter (Scheme 1b). Recently,
we reported a method for the enantioselective oxa-Michael
4
reaction of peroxy hemiacetals (I) in which the pK of OH group
a
8
is not significantly low (pK in DMSO ≈ 10 for I) to promote
rapid self-cyclization. Notably, the stereochemistry at the C
a
1
center in intermediate II would not be important if the absolute
3
stereochemistry at the C center remains same. However, finding
an appropriate condition for the Kornblum DeLaMare type
rearrangement is challenging as it usually occurs in the presence
Received: August 17, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02463
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Organic Letters
Letter
1
other functional groups remained an attractive strategy in organic
chemistry.
Developing enantioselective routes to 1-isochromanone
(94% based on H NMR) and enantioselectivity (97% ee). The
screening of solvents as well as catalyst loading was performed
(see the SI), and encouragingly, 25 mol % of FeCl ·6H O in
1
0
3
2
should be particularly rewarding, as this is a scaffold often
CH Cl as solvent was found to be the best condition for this
2 2
11
associated with bioactivity (Figure 1). Although they are rich
process (entry 8). It is also an important point to mention that a
loss of enantioslectivity was realized during the purification of 3a
via column chromatography on silica gel (see the SI). However,
filtration through a plug of silica followed by removal of solvent
provided a pure product (based on NMR).
Once the optimized reaction conditions for Kornblum
DeLaMare type rearrangement of intermediate IIa were
identified (Table 1, entry 8), we became interested in examining
the one-pot reaction development of the enantioselective oxa-
Michael reaction of peroxy hemiacetals (I) using catalyst 2a
followed by the decomposition of the peroxy acetal center to
provide the chiral lactone 3. As shown in Scheme 2, we examined
Scheme 2. Substrate Scope: 1-Isochromanones −
a c
Figure 1. 1-Isochromanone, phthalide, and γ-lactone moieties
containing bioactive molecules.
with biological significances, there are limited preceding
12
examples for their catalytic enantioselective synthesis. On the
other hand, chiral 3-substituted phthalides represent an
important structural motif featured in numerous natural
13a
products, registered drugs, and bioactive molecules. Owing
to their diverse biological activities, a number of approaches have
been developed to access this moiety with high enantioselectiv-
1
3
ity. Although many protocols have been proven to be effective
for a particular class of lactone, synthesis of a wider range lactones
has not been successful. Herein, we report the development of an
efficient, unified approach toward the synthesis of a wide variety
of lactones such as 1-isochromanones, 3-isochromanones,
phthalides, and γ-lactones with excellent enantioselectivities.
To test our hypothesis, we first examined the Kornblum
DeLaMare rearrangement of substrate IIa, which was prepared
4
a
t
using our previous method. In the presence of bases such as
Reaction conditions: 1 (0.1 mmol), BuOOH (0.5 mmol, 5 equiv), 2a
b
c
Et N and DBU (entries 1 and 2, Table 1) the desired lactone 3a
(0.005 mmol, 5 mol %) in toluene. Isolated products. Ee's were
3
d
was formed; unfortunately, the enantioselectivity was completely
lost. Therefore, we turned our attention to screen the various
Lewis acids such as InCl , ZnCl , FeCl ·6H O, Bi(OTf) ,
determined by HPLC analysis. Yield and ee after n-hexane wash.
e
Et O was used as solvent for the first step.
2
3
2
3
2
3
In(OTf) , etc. as catalyst (entries 3−7). Interestingly, as shown
3
in entry 5, FeCl ·6H O (10 mol %) provided the best conversion
3
2
the scope of the terminal aryl moieties of o-formyl
homochalcones. Overall, good to excellent yields and enantio-
selectivities were obtained with a range of substrates. Besides the
electron-neutral aryl group (3a), a variety of aryls substituted
with electron-rich grops, such as p-Me-(3b), p-MeO- (3c), as
well as electron-withdrawing groups, such as p-Cl- (3d), p-Br-
a
Table 1. Optimization of the Reaction Conditions
(
3e), p-I- (3f), p-F- (3g), and p-O N- (3h), were competent with
2
b
c
the present reaction conditions, generally giving 1-isochroma-
nones in moderate to good yields and in high enantioselectivities.
Heteroaromatic rings such as 2-furyl (3i) and 2-thiophene (3j)
also worked nicely to provide the desired products. Further, the
substitutions on the central aryl moiety were tested. Both
electron-donating (3k) and electron-withdrawing groups (3l) on
aryl ring afforded the desired products with high enantiose-
lectivity. Notably, all these products were purified without
performing a column chromatography. Interestingly, a simple
hexane wash increased the enantioselectivity to a considerable
extent, for example from 90% ee to >99% ee for 3a; from 97% ee
to >99% ee for 3b; from 97% ee to >99% ee for 3e; from 92% ee
to >99% ee for 3g, etc. Then, we focused on the o-homoformyl
chalcones (4) as substrates for analogues reaction (Scheme 3). In
entry
catalyst (mol %)
solvent
CH Cl
conv (%)
ee (%)
1
2
3
4
5
6
7
8
Et N (10)
3
31
100
8
0
0
2
2
DBU (10)
CH Cl
2
2
2
2
2
2
2
InCl (10)
CH Cl
92
93
97
80
78
97
3
2
ZnCl (10)
CH Cl
10
94
10
6
2
2
FeCl .6H O (10)
CH Cl
3
2
2
Bi(OTf) (10)
CH Cl
3
2
In(OTf) (10)
CH Cl
3
2
FeCl ·6H O (25)
CH Cl
2
100
3
2
2
a
All reactions are carried out on a 0.03 mmol scale. The reaction
mixture was filtered through a small plug of silica gel. NMR
conversions were calculated by using anisole as an internal standard.
b
c
The ee was determined by chiral HPLC analysis.
B
DOI: 10.1021/acs.orglett.6b02463
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Letter
general, good yields and high enantioselectivities were achieved
to provide the corresponding six-membered lactones (5a−d).
the corresponding 5-membered lactones (phthalides). It is
noteworthy that the reaction outcome is essentially unaffected by
the ring size of the product, as proven by the high yields and
optical purity of products 7. Terminal aryl moieties having a wide
range of functional groups such as p-Me- (7b), p-MeO-(7c), p-
Cl- (7d), p-Br- (7e), o-Br- (7f), p-I- (7g), p-F- (7h), o,p-di-F-
a
Scheme 3. Substrate Scope: 3-Isochromanone
(
7i), p-O N- (7j), and m-O N- (7k) worked efficiently to
2 2
provide the expected phthalides. Heteroaromatic groups such as
-furyl (7l) and 2-thiophene-yl (7m) also worked smoothly,
2
affording the desired products in good yields and high
enantioselectivities. We next investigated the substrate scope of
this reaction concerning differently substituted internal aryl
moiety of phthalides. Both electron-donating and electron-
withdrawing groups on aryl ring afforded products 7n−v with
outstanding enantioselectivity (up to >99% ee).
Notably, irrespective of the position of substitution, e.g., o-
7u−v), m- (7r−t), or p- (7q) to the formyl moiety of phthalides,
(
the reaction worked nicely to give the corresponding products in
good yields and with high enantioselectivities. Replacing the
internal phenyl moiety with naphthyl moiety was also
successfully reacted to provide 93% yield and up to 91% ee
a
Reaction conditions: same as Scheme 2.
To further explore the scope of the reaction, peroxy
hemiacetalization/oxa-Michael addition/decomposition was
performed with the o-formyl chalcones (6) (summarized in
Scheme 4). Overall, a smooth reaction was observed, providing
(
7w). To showcase the scalability and the practicality of the
process, we also performed a gram-scale reaction. For example, o-
formyl chalcone 6e (1.0 g, 3.2 mmol) was reacted under the
standard reaction conditions using 5 mol % catalyst loading, and
the desired phthalide (7e) was obtained in 93% yield and 87%
enantioselectivity. To illustrate the practical synthetic utility of
our methodology, we performed enantioselective synthesis of
lactones 7x, an advanced intermediate for the synthesis of
bioactive phthalide (S)-3-n-butyl phthalide (NBT). Moreover,
this shows a compatibility of the methodology with an aliphatic
α,β-ketone moiety. Besides the 1-isochromanone, 3-isochroma-
none, and phthalides, where the formyl group and enone moiety
are tethered with an aromatic moiety, this strategy was also tested
for the synthesis of chiral lactones in which the above two groups
are tethered with an aliphatic moiety. As shown in Scheme 5, β-
a
Scheme 4. Scope of Phthalides
Scheme 5. Chiral γ-Lactones −
a c
a
t
Reaction conditions: 8 (0.1 mmol), BuOOH (0.5 mmol, 5 equiv), 2a
b
(0.005 mmol, 5 mol %) in Et O. Yields shown are based on isolated
2
c
d
products. Ee’s were determined by HPLC analysis. After n-hexane
wash. The first step was carried out in toluene.
e
formyl enones (8) efficiently furnished the γ-lactones 9a−f with
high levels of stereocontrol. Notably, the synthesis of lactone 9g
having an alkyl substitution on the α,β-ketone moiety provided
an advanced intermediate for bioactive γ-heptalactone. The
absolute stereochemistry of the chiral 3-substituted phthalide
(
7a) was established by comparing optical rotation values with
3a
a
t
literature data (see the SI). This result unambiguously shows
the absolute configuration of product 7a to be the (R)-form. The
absolute configurations of all other compounds were assigned by
Reaction conditions: 1 (0.2 mmol), BuOOH (1.0 mmol, 5 equiv), 2a
b
c
(
0.01 mmol, 5 mol %) in toluene. Yields are isolated products. Ee’s
d
were determined by HPLC analysis. After n-hexane wash.
C
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Organic Letters
Letter
analogy. To explain the observed absolute stereochemistry of
product, a transition state similar to those previously proposed
for the squaramide/thiourea catalysts in the oxa-Michael reaction
(4) An enantioselective synthesis of peroxy acetals: Maity, S.; Parhi, B.;
Ghorai, P. Angew. Chem., Int. Ed. 2016, 55, 7723.
(5) For racemic IOM of carboxylic acids, see: (a) Pahari, P.; Senapati,
2
−4
B.; Mal, D. Tetrahedron Lett. 2004, 45, 5109. (b) Mal, D.; Pahari, P.; De,
S. R. Tetrahedron 2007, 63, 11781. (c) Karmakar, R.; Pahari, P.; Mal, D.
Tetrahedron Lett. 2009, 50, 4042. (d) Fuwa, H.; Ichinokawa, N.; Noto,
K.; Sasaki, M. J. Org. Chem. 2012, 77, 2588. (e) Lin, J.-B.; Xu, S.-M.; Xie,
J.-K.; Li, H.-Y.; Xu, P.-F. Chem. Commun. 2015, 51, 3596.
of enone is presumed.
In summary, a catalytic enantioselective strategy to suppress
the rapid cyclization for enantioselective intramolecular oxa-
Michael reactions of carboxylic acids was developed. The
enantioenriched lactones were synthesized via a tandem peroxy
acetalization/asymmetric oxa-Michael addition/Lewis acid cata-
lyzed Kornblum DeLaMare type rearrangement of o-homo-
formyl chalcones or o-formylhomochalcones. A simple hexane
wash was enough to purify these enantiopure products in good
yields and excellent enatioseleectvities (up to >99 ee). Notably,
the synthetic design was highly flexible and can be readily
adapted to various other substrates enabling direct access to a
broad range of chiral lactones. Further investigations toward the
scope and limitations of this methodology are in progress.
(
6) The only report where a domino oxidation of 2-alkenyl
benzaldehydes is followed by asymmetric oxa-Michael addition of in
situ generated carboxylate anion to α,β-unsaturated “esters”: Youn, S.
W.; Song, H. S.; Park, J. H. Org. Lett. 2014, 16, 1028.
(
7) The pK value of benzoic acid in DMSO is ∼4. For reference, see:
a
March, J. Advanced Organic Chemistry, 4th ed.; John Wiley & Sons, 1992;
pp 250−252.
(
8) The pK value of alkoxy hemiacetals in DMSO is ∼10 (ref 6). We
a
expect a similar pK value for peroxi-hemiacetals.
a
(9) For Kornblum DeLaMare rearrangement, see: (a) Kornblum, N.;
DeLaMare, H. E. J. Am. Chem. Soc. 1951, 73, 880. (b) Staben, S. T.;
Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12658.
ASSOCIATED CONTENT
Supporting Information
(
c) Pramanik, S.; Ghorai, P. Org. Lett. 2013, 15, 3832. (d) Yaremenko,
I. A.; Vil’, V. A.; Demchuk, D. V.; Terent’ev, A. O. Beilstein J. Org. Chem.
016, 12, 1647.
10) Decomposition of peroxide for the synthesis of other
■
*
S
2
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02463.
(
functionalities: (a) Willand-Charnley, R.; Puffer, B. W.; Dussault, P.
H. J. Am. Chem. Soc. 2014, 136, 5821. (b) Liu, W.; Li, Y.; Liu, K.; Li, Z. J.
Am. Chem. Soc. 2011, 133, 10756. (c) Zheng, X.; Lu, S.; Li, Z. Org. Lett.
Experimental procedures and characterization data (PDF)
NMR spectra for all products (PDF)
2
2
4
013, 15, 5432. (d) Zheng, X.; Lv, L.; Lu, S.; Wang, W.; Li, Z. Org. Lett.
014, 16, 5156. (e) Cheng, J.-K.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137,
2.
AUTHOR INFORMATION
Corresponding Author
■
*
(
11) Importance of 1-isochromanone: (a) Haritakun, R.; Sappan, M.;
Suvannakad, R.; Tasanathai, K.; Isaka, M. J. Nat. Prod. 2010, 73, 75.
b) Xu, L.; He, Z.; Xue, J.; Chen, X.; Wei, X. J. Nat. Prod. 2010, 73, 885.
(c) Li, Y.; Plitzko, I.; Zaugg, J.; Hering, S.; Hamburger, M. J. Nat. Prod.
010, 73, 768.
12) Synthesis of chiral 1-isochromanone: (a) Superchi, S.; Minutolo,
E-mail: pghorai@iiserb.ac.in.
(
Notes
2
(
The authors declare no competing financial interest.
F.; Pini, D.; Salvadori, P. J. Org. Chem. 1996, 61, 3183. (b) Rioz-
Martınez, A.; de Gonzalo, G.; Torres Pazmino, D. E.; Fraaije, M. W.;
Gotor, V. J. Org. Chem. 2010, 75, 2073. (c) Chen, J.; Zhou, L.; Tan, C.
K.; Yeung, Y.-Y. J. Org. Chem. 2012, 77, 999.
(13) Aymmetric synthesis of phthalides: (a) Karmakar, R.; Pahari, P.;
Mal, D. Chem. Rev. 2014, 114, 6213. (b) Zhang, B.; Xu, M.-H.; Lin, G.-Q.
Org. Lett. 2009, 11, 4712. (c) Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am.
Chem. Soc. 2009, 131, 15608. (d) Chang, H.-T.; Jeganmohan, M.;
Cheng, C.-H. Chem. - Eur. J. 2007, 13, 4356. (e) Xing, C.-H.; Liao, Y.-X.;
He, P.; Hu, Q.-S. Chem. Commun. 2010, 46, 3010. (f) Zhang, H.; Zhang,
S.; Liu, L.; Luo, G.; Duan, W.; Wang, W. J. Org. Chem. 2010, 75, 368.
ACKNOWLEDGMENTS
■
This work has been supported by CSIR, New Delhi, and IISER
Bhopal. B.P. thanks CSIR, New Delhi, and S.M. thanks UGC,
New Delhi, India, for fellowships.
REFERENCES
■
(
1) For recent reviews on oxa-Michael reactions, see: (a) Nising, C. F.;
e, S. Chem. Soc. Rev. 2008, 37, 1218. (b) Hintermann, L. Top.
Organomet. Chem. 2010, 31, 123. (c) Nising, C. F.; Bras
Rev. 2012, 41, 988.
2) For selected recent examples of enantioselective IOM of alcohols,
see: (a) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007,
Bras
̈
̈
e, S. Chem. Soc.
(g) Zhong, F.; Luo, J.; Chen, G.-Y.; Dou, X.; Lu, Y. J. Am. Chem. Soc.
(
2
012, 134, 10222. (h) Song, X.; Hua, Y.-Z.; Shi, J.-G.; Sun, P.-P.; Wang,
M.-C.; Chang, J. J. Org. Chem. 2014, 79, 6087. (i) Egami, H.; Asada, J.;
Sato, K.; Hashizume, D.; Kawato, Y.; Hamashima, Y. J. Am. Chem. Soc.
1
1
29, 3830. (b) Li, D. R.; Murugan, A.; Falck, J. R. J. Am. Chem. Soc. 2008,
30, 46. (c) Reyes, E.; Talavera, G.; Vicario, J. L.; Badia, D.; Carrillo, L.
2
015, 137, 10132.
Angew. Chem., Int. Ed. 2009, 48, 5701. (d) Gu, Q.; Rong, Z.-Q.; Zheng,
C.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 4056. (e) Asano, K.;
Matsubara, S. J. Am. Chem. Soc. 2011, 133, 16711. (f) McGarraugh, P.
G.; Brenner-Moyer, S. E. Org. Lett. 2011, 13, 6460. (g) Rubush, D. M.;
Morges, M. A.; Rose, B. J.; Thamm, D. H.; Rovis, T. J. Am. Chem. Soc.
2
012, 134, 13554. (h) Okamura, T.; Asano, K.; Matsubara, S. Chem.
Commun. 2012, 48, 5076. (i) Wu, W.; Li, X.; Huang, H.; Yuan, X.; Lu, J.;
Zhu, K.; Ye, J. Angew. Chem., Int. Ed. 2013, 52, 1743. (j) Asano, K.;
Matsubara, S. Org. Lett. 2012, 14, 1620. (k) Fukata, Y.; Miyaji, R.;
Okamura, T.; Asano, K.; Matsubara, S. Synthesis 2013, 45, 1627. (l) Lu,
Y.; Zou, G.; Zhao, G. ACS Catal. 2013, 3, 1356. (m) Azuma, T.; Murata,
A.; Kobayashi, Y.; Inokuma, T.; Takemoto, Y. Org. Lett. 2014, 16, 4256.
(
n) Ooi, T. ACS Catal. 2015, 5, 6980.
3) Our contributions toward organocatalyzed enantioselective oxa-
Michael reactions: (a) Ravindra, B.; Das, B. G.; Ghorai, P. Org. Lett.
014, 16, 5580. (b) Ravindra, B.; Maity, S.; Das, B. G.; Ghorai, P. J. Org.
(
2
Chem. 2015, 80, 7008. (c) Parhi, B.; Gurjar, J.; Pramanik, S.; Midya, A.;
Ghorai, P. J. Org. Chem. 2016, 81, 4654.
D
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