Enantioselective bromolactonization of aryl functionalized alkenoic acids

Article abstract of DOI:10.1016/j.tetlet.2020.151756

Aryl substituted 1,1-disubstituted alkenoic carboxylic acids were subjected to an enantioselective organocatalyzed protocol, yielding the corresponding δ-bromolactones in a regioselective manner. The products were isolated in good to high yields with enantiomeric excess in the range of 18–88%.

Full text of DOI:10.1016/j.tetlet.2020.151756

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Enantioselective Bromolactonization of Aryl Functionalized Alkenoic Acids
Renate Kristianslund Trond Vidar Hansen
PII:
S0040-4039(20)30184-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151756
TETL 151756
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
11 December 2019
11 February 2020
18 February 2020
Please cite this article as: Kristianslund Trond Vidar Hansen, R., Enantioselective Bromolactonization of Aryl
Functionalized Alkenoic Acids, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151756
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Enantioselective Bromolactonization of Aryl
Functionalized Alkenoic Acids
Leave this area blank for abstract info.
Renate Kristianslund and Trond Vidar Hansen
NO2
O
O
O2N
N
N
H
H
N(C5H11
)
2
Catalyst
CO2H
O
O
R
R
Br
-bromophthalimide
Acetone, -78 o
N
C
R: Me, OMe, F, CN, OH, NO2, Ac
18 - 88%
ee

Enantioselective Bromolactonization of Aryl Functionalized Alkenoic Acids
Renate Kristianslund and Trond Vidar Hansen*
Department of Pharmacy, Section for Pharmaceutical Chemistry, University of Oslo, P.O.
Box 1068, Blindern, N-0316 Oslo, Norway
E-mail: t.v.hansen@farmasi.uio.no
Abstract:
Aryl substituted 1,1-disubstituted alkenoic carboxylic acids were subjected to an
enantioselective organocatalyzed protocol, yielding the corresponding -bromolactones in a
regioselective manner. The products were isolated in good to high yields with enantiomeric
excess in the range of 18 to 88%.
Keywords: Bromolactonization, enantioselectivity, -bromolactones, organocatalysis, chiral
squaramide, H-bonding catalysis.
The electrophilic addition of halogens to alkenes is a classical synthetic reaction1 with
several advances recently reported affording a plethora of synthetically useful intermediates
and products.2,3 Among these electrophilic addition reactions, the halolactonization reaction
has been used in the total synthesis of various natural products.3b,4 The first catalytic
enantioselective bromolactonization of alkenoic acids was presented in 2010 by Fujioka and
co-workers,5 and additional reports continue to be presented.6
In connection with our interest in developing enantioselective bromo- and
iodolactonization protocols,7 we found that squaramides with H-bonding properties with a
chiral tertiary amine attached, provided high enantioinduction of the desired -halolactones.
Of note, using our bromolactonization protocol with a limited selection of aryl-alkenoic acids
under organocatalysis, enabled the stereoselective total synthesis of the sesquiterpenoids (+)-
sielboldianin A (1), (-)-boivinianin B (2) and (-)-gossonorol (3), as well as a formal synthesis
of yingzhaosu C (4) (Fig. 1).7b,d
3

OH
OH
HO
H
H
O
O
2
(-)-boivinianin B ( )
1
(+)-sielboldianin A ( )
Structure revised by total synthesis
OH
OH
Me
O
O
Me
Me
yingzhaosu C ( )
3
(-)-gossonorol ( )
4
Figure 1. Examples of sesquiterpenoids prepared utilizing enantioselective squaramide
catalyzed bromolactonizations.
Of interest, on both occasions,7b,d the organocatalyzed protocol was performed on multi-
gram scale showing its practicality in the total synthesis of 1-3. The greater chemical stability
of the C-Br bond relative to the C-I bond8 provides many advantages when using chiral
bromolactones compared to their iodo-congeners, such as increased chemical stability, ease of
purification often by recrystallization, as well as long-term storage. The utility of
enantioselective halolactonization protocols in the total synthesis of natural products has also
been demonstrated by other groups.9,10 Murai, Fujioka and co-workers used a trisimidazoline
catalyzed bromolactonization protocol in their synthesis of (-)-tanikolide, a metabolite of the
cyanobacterium Lyngbya majuscule.9 Martin and Klosowski successfully implemented their
method for organocatalyzed asymmetric iodolactonization in a total synthesis of (+)-
disparlure, constituting the shortest catalytic, enantioselective synthesis of this interesting
insect pheromone.10 Yeung and co-workers prepared a short synthesis of (+)-boivinianin A
based on a regio- and enantioselective organocatalyzed bromolactonization.11
The importance of stereoselective total synthesis for the structural elucidation of
natural products is well established.12 The development of organocatalysis for the preparation
of natural products is of current interest,13 due to the lack of sensitivity to moisture and
oxygen as well as the typically low toxicity of organocatalysts.14 An extension of the substrate
scope for our previously reported protocol is presented.
The different aryl substituted alkenoic acids were mainly obtained by using the Suzuki
reaction15 with aryl boronic acid 5a-5g and vinyl bromide 6 to yield methyl esters 7a-7g.
Basic hydrolysis of 7a-7g gave the corresponding carboxylic acids 8a-8g (Scheme 1).
4

O
B(OH)2
R
R
R
Br
OMe
+
6
5a 5g
-
Pd(PPh3)4 (1 mol%), Na2CO3,
H2O, toluene, 80 °C
O
7a
7b
7c
7d
7e
: R = 3-OMe,4-Me: 46%
: R = 3-OH,4-Me: 13%
: R = 3-CN,4-Me: 36%
: R = 3-NO2: 32%
: R = 3-Ac: 49%
: R = 3,4,5-F: 39%
OMe
7f
7g
LiOH H2O
: R = 2-Me: 87%
THF/MeOH/H2O (3:1:1)
O
8a
8b
8c
8d
8e
: R = 3-OMe,4-Me: 95%
: R = 3-OH,4-Me: 95%
: R = 3-CN,4-Me: 95%
: R = 3-NO2: 91%
OH
8a 8g
-
: R = 3-Ac: 96%
8f
: R = 3,4,5-F: 94%
8g
: R = 2-Me: 95%
Scheme 1. Synthesis of substrates 8a-8g.
Substrate 9 was prepared by a Negishi reaction16 between triflate 10 and commercially
available zinc bromide 11 to produce 12 that was hydrolyzed to 9 (Scheme 2).
OTf
OEt
ZnBr
+
O
10
11
Pd-PEPPSITM-IPr (8%),
LiBr, NMI/DMI/THF
(1:1:1)
OEt
O
12
(31%)
LiOH
H2O
THF/EtOH/H2O (3:1:1)
OH
O
9
(96%)
Scheme 2. Synthesis of substrate 9.
Alkenoic acids not previously investigated in our protocol and carrying functionalities
amendable for further synthetic transformations were chosen, see Scheme 3. Catalyst 13 has
5

proven superior among those studied.7b,d In the presence of 1.5 equivalents of N-
bromophthalimide (NBP) in acetone (0.1 M) at -78 ºC, the desired products 14a-14g were all
formed regioselectively. For all products the S-configuration was assigned based on
comparison of the specific optical rotation values reported in the literature5 and by analogy
with our earlier published protocol.7b,7d In the absence of the chiral catalyst 13, the reaction
time is 24-48 hours and yields only racemic products.7e
NO2
O
O
O2N
N
N
H
H
N(C5H11 2
)
Catalyst (13)
13
(30 mol%),
O
NBP (1.5 equiv.),
Ar
OH
Ar
O
O
acetone (0.1 M),
-78 ºC, 24 hrs
Br
8a-8g
14a 14g
-
Ar =
MeO
HO
NC
O2N
14a
14b
14c
14d
Yield: 81%
Yield: 17%
Yield: 84%
Yield: 82%
ee: 88%
ee: 70%
ee: 88%
ee: 82%
O
F
F
F
14e
14f
14g
Yield: 96%
ee: 84%
Yield: 78%
ee: 82%
Yield: 36%
ee: 18%
Scheme 3. Squaramide catalyzed enantioselective bromolactonization of alkenoic acids 8a-8g.
Notably, using substrates with electron-donating groups in the meta-positions yielded
the corresponding bromolactones in fairly high enantioselectivities (70 and 88% ee, 14a and
14b, respectively, Scheme 3). For aryl substituents with dual π-donors and σ-withdrawers in
the meta-position, good enantioselective induction was expected, in light of the net reduced
electron density in the 1,1-disubstituted alkene moiety. Indeed, enantioselectivities of 70 and
88% ee were obtained for 14a and 14b (Scheme 3). This stands in sharp contrast to our
6

previous reports of using a methoxy-group in the para-position, which results in only 9% ee of
the ensuing bromolactone.7b
Aryl alkenoic acids with electron-withdrawing groups in the meta-position were well
tolerated in this protocol, affording the bromolactone products 14c-14e in both high yields
(82-96%) and good enantioselectivities (82-88% ee), Scheme 3. Of interest, the nitrile, nitro
and acetyl functionalities may all be utilized for further synthetic transformations by
nucleophilic addition or by reduction. Investigation of substrates with an ortho-substituent was
of interest as this has not been previously examined.7b Consequently, an ortho-tolyl alkenoic
acid was then subjected to the established method, but unfortunately this afforded the
bromolactone 14g in only 18% ee and 36% yield. In comparison to the para-tolyl substrate
(79% ee, 91% yield),7b ortho-substituents are seemingly not well tolerated in this protocol.
When the aryl group of the alkenoic acid was replaced with a cyclohexene substituent in
conjugation with the 1,1-disubstituted alkene moiety, the enantioselectivity was severely
reduced (14% ee, 86% yield, 14h, Scheme 4). The S-configuration was also assigned to 14h
using specific rotation values and by comparison with the literature.5 Previously, it has also
been demonstrated that aliphatic substrates with an iso-propyl or a cyclohexyl substituent on
the alkene, result in poor enantiomeric excess of the products using this method (24 and 21%
ee, respectively).7b
O
1) Pd(PPh3)4 (1 mol%)
B(OH)2
O
OH
+
Na2CO3, toluene, 80 °C
2) LiOH, THF/MeOH/H2O
(3:1:1)
Br
OMe
6
8h
5h
13
(30 mol%),
NBP (1.5 equiv.),
acetone (0.1 M),
-78 ºC
O
O
Br
14h
Yield: 86%
ee: 14%
Scheme 4. Synthesis and squaramide catalyzed enantioselective bromolactonization of
alkenoic acid 8h.
7

In summary, an extension of the alkenoic acids investigated in our organocatalyzed
enantioselective bromolactonization protocol has been presented. Such efforts are in demand
for advancing the use of organocatalyzed enantioselective bromolactonization reactions in
natural product total synthesis. As previously, only -bromolactones were obtained, further
supporting the excellent regioselectivity earlier reported. The enantiomeric excess of the
products formed from aryl functionalized 1,1-disubstituted alkenoic acids, were determined to
be in the range of 18-88% ee. The two alkenoic acids 8h and 9 with aliphatic substituents
gave products 14h and 15, respectively, with low enantiomeric excess of 14 and 38% ee,
respectively.
Acknowledgment
The Norwegian Research Council is gratefully acknowledged for funding of a doctoral
fellowship to R. K. (FRIPRO-FRINATEK 230470).
Supplementary data
Supplementary data include experimental procedures and characterization data, copies of 1H-
and 13C-NMR spectra, as well as copies of chromatograms of HPLC analyses.
References:
1. (a) Snyder, S. A.; Treitler, D. S., Brucks, A. P. Aldrichimica Acta 2011, 44, 27-40; (b)
Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8, 171-197.
2. (a) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321-3408; (b) Cresswell, A. J.;
Eey S. T. C.; Denmark, S. E. Nat. Chem. 2015, 7, 146-152.
3. (a) Ranganathan, S.; Muraleedharan, K. M.,; Vaish, N. K.; Jayaraman, N.
Tetrahedron, 2004, 60, 5273-5308; (b) Nolsøe, J. M. J.; Hansen, T. V. Eur. J. Org.
Chem. 2014, 15, 3051-3065; (c) Kristianslund, R.; Tungen, J. E.; Hansen, T. V. Org.
Biomol. Chem., 2019, 19, 3079-3092.
4. Selected reviews concerning halolactonization reactions used in natural product
synthesis: (a) Laya, M. S.; Banerjee, A. K.; Cabrera, E. V. Curr. Org. Chem. 2009, 13,
720-730; (b) French, A. N.; Bissmire, S.; Wirth, T. Chem. Soc. Rev. 2004, 33, 354-
362.
8

5. Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka, H.,
Angew. Chem. Int. Ed. Engl. 2010, 49, 9174-9177.
6. (a) Gieuw, M. H.; Ke, Z.; Yeung, Y.-Y. Chem. Rec., 2017, 17, 287-311 and references
cited therein; (b) Jiang, X.; Liu, S.; Yang, S.; Jing, M.; Xu, L.; Yu, P.; Wang, Y.;
Yeung, Y.-Y. Org. Lett. 2018, 20, 3259-3262; (c) Klosowski, D. W.; Hethcox, J. C.;
Paull, D. H.; Fang, C.; Donald, J. R.; Shugrue, C. R.; Pansick, A. D.; Martin, S. F. J.
Org. Chem. 2018, 83, 5954-5968; (d) Balkrishna, S. J.; Kumar, S.; Kumar, A.; Panini,
P.; Kumar, S., Proc. Natl. Acad. Sci., India, Sect. A Phys. Sci. 2016, 86, 589-600.
7. (a) Tungen, J. E.; Nolsøe, J. M. J.; Hansen, T. V. Org. Lett. 2012, 14, 5884-5887; (b)
Aursnes, M.; Tungen, J. E.; Hansen, T. V. J. Org. Chem. 2016, 81, 8287-8295; (c)
Kristianslund, R.; Aursnes, M.; Tungen, J. E.; Hansen, T. V. Tetrahedron Lett. 2016,
57, 5232-5236; (d) Kristianslund, R.; Aursnes, M.; Tungen, J. E.; Görbitz, C. H.;
Hansen, T. V. J. Nat. Prod. 2018, 81, 1007-1013; (e) Tungen, J. E.; Kristianslund, R.
K.; Vik, A.; Hansen, T. V. J. Org. Chem. 2019, 84, 11373-11381; (f) Filipova, L.;
Hansen, T. V.; Stenstrøm, Y. Tet. Lett., 2014, 55, 419-422.
8. (a) Luo, Y. R. Handbook of Bond Dissociation Energies in Organic Compounds; CRC
Press: Boca Raton, FL, 2002. (b) Carey, F. A.; Sundberg, R. J. Advanced Organic
Chemistry: Part A: Structure and Mechanisms, 5th ed.; Springer: New York, 2007; p
258.
9. Murai, K.; Nakamura, A.; Matsushita, T.; Shimura, M.; Fujioka, H. Chem. Eur. J.
2012, 18, 8448-8453.
10. Klosowski, D. W.; Martin, S. F. Org. Lett. 2018, 20, 1269-1271.
11. Jiang, X.; Tan, C. K.: Zhou, L.; Yeung, Y.-Y. Angew. Chem. Int. Ed. Engl. 2012, 51,
7771-7775.
12. Nicolaou, K. C.; Snyder, S. A. Angew. Chem. Int. Ed. Engl. 2005, 44, 1012-1044.
13. (a) Sun, B.-F. Tetrahedron Lett. 2015, 56, 2133-2140; (b) Abbasov, M. E.; Romo, D.
Nat. Prod. Rep. 2014, 31, 1318-1327; (c) de Figueiredo, R. M.; Christmann, M. Eur.
J. Org. Chem. 2007, 2575-2600; (d) Marqués-López, E.; Herrera, R. P.; Christmann,
M. Nat. Prod. Rep., 2010, 27, 1138-1167; (e) Merad, J.; Lalli, C.; Bernadat, G.;
Maury, J.: Masson, G. Chem. Eur. J. 2017, 24, 3925-3943.
14. MacMillan, D. W. C. Nature, 2008, 455, 304-308.
15. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
16. Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Eur. J. Org. Chem. 2010,
4343-4354.
9

Highlights:
 An extension of an organocatalyzed bromolactonization protocol is presented
 Several aryl substituted 1,1-disbustituted alkenoic carboxylic acids were investigated
 The protocol is regioselective and the products were isolated in good to high chemical
yields
 The enantioselectivity varied and depended on the substitution on the aryl ring
Declaration of interests
☒ The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in this
paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
10