Catalytic desymmetrization of cyclohexadienes by asymmetric bromolactonization

Article abstract of DOI:10.1021/ol302908a

Asymmetric bromolactonization of prochiral cyclohexadiene derivatives with N-bromosuccimide proceeded in the presence of (DHQD)₂PHAL as a chiral catalyst to afford the corresponding bromolactones with up to 93% ee. This reaction was also applicable to the kinetic resolution of a racemic cyclic ene-carboxylic acid, where the starting material was recovered with high enantioselectivity.

Full text of DOI:10.1021/ol302908a

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6016–6019
Catalytic Desymmetrization of
Cyclohexadienes by Asymmetric
Bromolactonization
Kazutada Ikeuchi, Shunsuke Ido, Satoshi Yoshimura, Tomohiro Asakawa,
Makoto Inai, Yoshitaka Hamashima,* and Toshiyuki Kan*
School of Pharmaceutical Science, University of Shizuoka, 52-1 Yada, Suruga-ku,
Shizuoka 422-8526, Japan
hamashima@u-shizuoka-ken.ac.jp; kant@u-shizuoka-ken.ac.jp
Received October 22, 2012
ABSTRACT
Asymmetric bromolactonization of prochiral cyclohexadiene derivatives with N-bromosuccimide proceeded in the presence of (DHQD)2PHAL as a
chiral catalyst to afford the corresponding bromolactones with up to 93% ee. This reaction was also applicable to the kinetic resolution of a
racemic cyclic ene-carboxylic acid, where the starting material was recovered with high enantioselectivity.
Halolactonization of unsaturated carboxylic acids is a
versatile transformation in organic synthesis, particularly
for the preparation of natural products.1 Therefore, consid-
erable efforts have been made to develop efficient methods
for catalytic asymmetric halolactonization.2,3 In 2010, an
important breakthrough yielded an organocatalytic system
that is highly effective for halolactonization, with broad gen-
erality and excellent enantioselectivity (more than 90% ee).4
Since then, several groups have reported elegant systems
that use carefully designed organocatalysts.5 However,
the range of available substrates is still limited; only aryl-
substituted penteno- or hexenoic acid derivatives were
examined in most cases. During the course of our syn-
thetic studies on natural products,6 we became interested
in the asymmetric desymmetrization of cyclohexadiene
derivatives by bromolactonization (eq 1). This reaction
can construct three contiguous stereogenic centers at once,
including a chiral quaternary carbon center. Furthermore,
(1) (a) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1978, 8, 171.
(b) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321. (c) Robin, S.;
Rousseau, G. Tetrahedron 1998, 54, 13681. (d) Ranganathan, S.;
Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N. Tetrahedron
2004, 60, 5273.
(2) (a) Chen, G.; Ma, S. Angew. Chem., Int. Ed. 2010, 49, 8306.
(b) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Synlett 2011, 1335. (c) Castella-
nos, A.; Fletcher, S. P. Chem.;Eur. J. 2011, 17, 5766. (d) Denmark,
S. D.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51,
10938–10953.
(3) Selected early examples of asymmetric halolactonization: (a)
Kitagawa, O.; Hanano, T.; Tanabe, K.; Shiro, M.; Taguchi, T. J. Chem.
Soc., Chem. Commun. 1992, 1005. (b) Kitagawa, O.; Taguchi, T. Synlett
1999, 1191 and refereces therein. (c) Wang, M.; Gao, L. X.; Mai, W. P.;
Xia, A. X.; Wang, F.; Zhang, S. B. J. Org. Chem. 2004, 69, 2874.
(d) Ning, Z.; Jin, R.; Ding, J.; Gao, L. Synlett 2009, 2291.
(4) (a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B.
J. Am. Chem. Soc. 2010, 132, 3298. (b) Zhang, W.; Zheng, S.; Liu, N.;
Werness, J. B.; Guzei, I. A.; Tang, W. J. Am. Chem. Soc. 2010, 132, 3664.
(c) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am. Chem.
Soc. 2010, 132, 15474. (d) Veitch, G. E.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2010, 49, 7332. (e) Murai, K.; Matsushita, T.; Nakamura, A.;
Fukushima, S.; Shimura, M.; Fujioka, H. Angew. Chem., Int. Ed. 2010,
49, 9174.
(5) (a) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Org. Lett. 2011, 13, 2738.
(b) Yousefi, R.; Whitehead, D. C.; Mueller, J. M.; Staples, R. J.; Borhan,
B. Org. Lett. 2011, 13, 608. (c) Jaganathan, A.; Garzan, A.; Whitehead,
D. C.; Staples, R.; Borhan, B. Angew. Chem., Int. Ed. 2011, 50, 2593.
(d) Zhang, W.; Liu, N.; Schienebeck, C. M.; Decloux, K.; Zheng, S.;
Werness, J. B.; Tang, W. Chem.;Eur. J. 2012, 18, 7296. (e) Dobish,
M. C.; Johnston, J. N. J. Am. Chem. Soc. 2012, 134, 6068. (f) Chen, J.;
Kiat, Z. C.; Yeung, Y.-Y. J. Org. Chem. 2011, 77, 999. (g) Tan, C. K.;
Zhou, L.; Yeung, Y. Org. Lett. 2011, 13, 2738. (h) Tan, C. T.; Le, C.;
Yeung, Y. Chem. Commun. 2012, 48, 5793. (i) Li, G.-x.; Fu, Q.-q.;
Zhang, X.-m.; Tang, Z. Tetrahedron: Asymmetry 2012, 23, 245.
(j) Murai, K.; Nakamura, A.; Matsushita, T.; Shimura, M.; Fujioka,
H. Chem.;Eur. J. 2012, 18, 8448. (k) Jiang, X.; Tan, C. K.; Zhou, L.;
Yeung, Y.-Y. Angew. Chem., Int. Ed. 2012, 51, 7771.
(6) Inai, M.; Goto, T.; Furuta, T.; Wakimoto, T.; Kan, T. Tetrahe-
dron: Asymmetry 2008, 19, 2771.
r
10.1021/ol302908a
Published on Web 11/13/2012
2012 American Chemical Society

since the products are highly functionalized, they should
be useful chiral building blocks in the synthesis of com-
plex natural products. Notably, when we started our
project, there had been no example of catalytic asym-
metric halolactonization of prochiral cyclic dienes.7 Quite
recently, however, Martin and his co-workers documen-
ted the first example of such a reaction in their paper on
asymmetric bromolactonization with their BINOL-
derived bifunctional catalyst. But, they examined only
one specific substrate, namely cyclohexa-2,5-dienecar-
boxylic acid, and the observed enantioselectivity was only
modest.8 Therefore, improvement in the reaction effi-
ciency in terms of the substrate range and enantio-
selectivity remains important. In this communication,
we report desymmetrization of prochiral cyclic dienes
by catalytic bromolactonization with (DHQD)2PHAL
to afford the corresponding lactones in up to 93% ee.
Moreover, we found that our catalytic system was applic-
able to a racemic cyclic ene-carboxylic acid; this is the first
example of kinetic resolution in halolactonization, to our
knowledge.
Figure 1. Selected examples of chiral catalysts examined.
of 3a. Next, we examined the protecting group of the
substrate. As shown in entries 2ꢀ4, the ee was greatly
improved by an appropriate protecting group. It is likely
that the bulkiness of the protecting group is important for
discriminating the two prochiral olefins. Reactions of 1c
and 1d reached completion within 1 h, and the desired
bromolactones were isolated in good yield with excellent
enantioselectivity (88 and 91% ee, respectively). Although
the ee was slightly improved at ꢀ60 °C (entry 5), we selected
ꢀ40 °C as the optimal reaction temperature because of the
shorter reaction time. The absolute configuration of2cwas
determined to be (1R,5S,6S) by comparing the optical
rotation with that of a reported compound after conver-
sion, as described below.
We also examined reactions catalyzed by related cinch-
ona alkaloids (entries 6, 7). Even though the same dihydro-
quinidine (DHQD) is incorporated, the reaction efficiency
changes dramatically, depending on the linker moiety. We
speculate that the nitrogen atom(s) of the phthalazine linker
would play an important role in determining the stereo-
selectivity, but this issue requires further study. Impor-
tantly, we were able to obtain the corresponding enan-
tiomer with a similar enantiomeric excess (86% ee) by
changing the catalyst3a topseudoenantiomeric 4 (entry 8).
Other brominating agents often examined in previous
reports4,5 were also tested with our substrate. Although the
reactions were less enantioselective, the reactions with
N-bromophthalimide (NBP), 2,4,4,6-tetrabromocyclohexa-
dienone (TBCO), and N,N0-dibromodimethyl hydantoin
(DBDMH) occurred to give the corresponding product
(NBP: 61%, 66% ee; TBCO: 72%, 81% ee; DBDMH:
91%, 61% ee). In contrast, N,N0-dichlorodimethylhydan-
toin (DCDMH) did not react with 1d. This is interest-
ing because the combination of 3a with DCDMH was
reported to be effective for the chlorolactonization of
With our synthetic targets in mind, we selected cyclic
dienoic acid 1 having a quaternary carbon center as a
model substrate, which was readily synthesized from ben-
zoic acid via reductive alkylation under Birch conditions,
followed by basic deprotection.9,10 As the brominating
agent, we chose relatively inexpensive N-bromosuccimide
(NBS), since we intended to carry out future synthetic
reactions on a large scale.
Based on previous reports,4,5 we examined the reaction
with various natural and unnatural chiral amines and less
polar solvent systems. We soon found that the dimeric
structure of cinchona alkaloid catalysts was essential to pro-
mote the reaction in an enantioselective manner (Figure 1).
On the other hand, monomeric cinchona alkaloid catalysts
gave negligible asymmetric induction.
As shown in Table 1, the reaction proceeded best in the
presence of (DHQD)2PHAL11 (3a) (10 mol %) in a 1:1
mixture of chloroform and n-hexane. It is noteworthy that
the protecting group of the primary alcohol of 1 had a sig-
nificant impact on the stereoselectivity. Although the reac-
tion of nonprotected 1a proceeded smoothly at ꢀ40 °C, a
racemic mixture of β-lactone 2a6 was formed (Table 1,
entry 1). This was not associated with a background reac-
tion, since no reaction proceeded at ꢀ40 °C in the absence
(7) For a stoichiometric reaction, see: Nishibayashi, Y.; Srivastava,
S. K.; Takada, H.; Fukuzawa, S.; Uemura, S. J. Chem. Soc., Chem.
Commun. 1995, 2321.
(8) Paull, D. H.; Fang, C.; Donald, J. R.; Pansick, A. D.; Martin,
S. F. J. Am. Chem. Soc. 2012, 134, 11128.
(9) (a) Kruger, T.; Vorndran, K.; Linker, T. Chem.;Eur. J. 2009, 15,
12082. (b) Hirai, S.; Nakada, M. Tetrahedron 2011, 67, 518.
(10) See Supporting Information for the preparation of compounds
1.
(11) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 448.
Org. Lett., Vol. 14, No. 23, 2012
6017

Table 1. Optimization of the Reaction Conditions
Scheme 1. Gram Scale Preparation of 3c and Further Trans-
formation
entry
R
catalyst
yield (%)
ee (%)
1
H (1a)
3a
3a
3a
3a
3a
3b
3c
4
70
84
87
93
91
66
57
91
0
45
2
Boc (1b)
TIPS (1c)
TBDPS (1d)
1d
3
91
4
88
5a
6
93
1d
77
7
8b
1d
24
1d
ꢀ86
a
ꢀ60 °C, 24 h. b (DHQ)2PHAL (4) was used.
4-phenyl-4-pentenoic acid.4a Taken together, these find-
ings indicate that the optimum reaction conditions vary
depending on the nature of the substrate, and the devel-
opment of a general catalytic system remains elusive.
As shown in Scheme 1, our reaction was easy to scale up.
The reaction could be carried out without any precautions
against air and moisture. It was also possible to reduce the
catalyst amount to as little as 3 mol %, and the desired
product was obtained without difficulty. It should be noted
that simple acidꢀbase liquidꢀliquid extraction was suffi-
cient to obtain the product in almost pure form. The
obtained3cwasreadilyconverted via a three-stepsequence
to epoxide 5, which is a key intermediate in our total synthesis
of (þ)-myriocin.6
Under the optimized reaction conditions, we next ex-
amined the effect of substituents on the cyclohexadiene
ring (Figure 2).12 A substrate having a methyl group at the
C4 position underwent the desired reaction to give 6 in
good yield with high enantioselectivity. Although the bulk-
ier MOM-oxy group retarded the reaction, reasonably
high asymmetric induction was observed for compounds
7 and 8. Reactions of less bulky substrates (9 and 10) were
less enantioselective. We also tested the reaction of the 3,5-
dimethylcyclohexadiene substrate. In this case, γ-lactone
11 was unexpectedly formed with only 37% ee, probably
due to the formation of an electronically more stable
tertiary carbocation intermediate.13
To further investigate the generality of the reaction,
we examined the formation of brominated γ-lactones
(Scheme 2). Thus, one-carbon-homologated cyclohex-
adiene derivatives 12 were prepared and subjected to
asymmetric bromolactonization. Under the same con-
ditions as described in Table 1, reactions of 12a and 12b
proceeded regioselectively, affording the corresponding
Figure 2. Desymmetrization of various cyclic dienes via asym-
metric bromolactonization.
γ-lactones 13a and 13b with excellent enantioselectivity
(92% ee, respectively).14,15
Finally, we demonstrated optical resolution16 of racemic
compounds by asymmetric bromolactonization, whichhas
never before been reported, to our knowledge. As shown in
Scheme 3, our catalytic system showed high enantio-
differentiation ability, allowing kinetic resolution of
cyclic ene-carboxylic acid 14 derived from 1-naphtha-
lenecarboxylic acid. In this reaction, (DHQD)2Pyr (3b)
(14) While the reaction catalyzed by 3a took place regioselectively,
spontaneous reaction at room temperature gave an inseparable 2:1
mixture of γ-lactone and δ-lactone.
(15) In contrast to the formation of β-lactones, it is likely that the
steric size of the substituent at the C1 position has minimal influence on
the enantioselectivity, because both substrates were converted in a
highly enantioselective manner. See also Figure 2.
(16) (a) Keith, M. J.; Larrow, F. J.; Jacobsen, N. E. Adv. Synth. Catal.
2001, 343, 5. (b) Robinson, D. E. J. E.; Bull, S. D. Tetrahedron:
Asymmetry 2003, 14, 1407. (c) Rendler, S.; Oestreich, M. Angew. Chem.,
Int. Ed. 2008, 47, 248. (d) Wills, M. Angew. Chem., Int. Ed. 2008, 47,
4264.
(12) To avoid the difficulty in the isolation and detection by UV light,
we chose a TBDPS group as a protecting group in Figure 2, even though
the TIPS-protected substrate gave the best enantioselectivity in Table 1.
(13) Barnett, W. E.; Needham, L. L. J. Org. Chem. 1975, 19, 2843.
(17) Reaction in CHCl3 gave unreacted 14 with 39% ee in the case of
3a, while 3b gave 78% ee at 50% conversion.
6018
Org. Lett., Vol. 14, No. 23, 2012

Scheme 2. Formation of Optically Active γ-Lactonesa
Scheme 3. Kinetic Resolution by Asymmetric Bromolactonization.a
a The absolute stereochemistry was tentatively assigned by analogy to
the reaction shown in Scheme 1.
was superior to (DHQD)2PHAL (3a).17 The reaction
with 0.5 equiv of NBS afforded β-lactone 15 with 86%
ee, with the remaining starting material 14 being re-
covered as the corresponding methyl ester with similar
enantioselectivity (84% ee). Thus, we next examined
the amount of NBS. When 0.6 equiv of NBS was re-
acted with 14, 15 was isolated in 55% yield with 78% ee.
Gratifyingly, the starting carboxylic acid 14 was ob-
tained in 39% yield with excellent enantioselectivity
(92% ee). Since a variety of unsymmetrically substi-
tuted cyclohexadienes can be synthesized from com-
mercially available benzoic acid derivatives, we expect
that kinetic resolution by bromolactonization would
be a potentially useful method to access novel chiral
building blocks.
In summary, we have developed a catalytic desymme-
trization of cyclohexadiene derivatives via asymmetric
bromolactonization. Not only β-lactones but also γ-lac-
tones were produced in a highly enantioselective manner.
Additionally, the reaction was applicable to kinetic resolu-
tion of racemic cyclic ene-carboxylic acids. Since the pro-
ducts are densely functionalized, this reaction is expected
to be valuable in synthetic studies of complex natural
products. Recently, we have completed the total synthesis
a The absolute stereochemistry was tentatively assigned by analogy to
the reaction shown in Scheme 1.
of (ꢀ)-sphingofungin E from the epoxide 5, the results of
which to be reported in due course.
Acknowledgment. This study was supported by the
Uehara Memorial Foundation, a Grant-in-Aid for Scien-
tific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts”, and a Grant-
in-Aid for Scientific Research on Priority (12045232) from
The Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available. Experimental pro-
cedures and analytical data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
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