C3-symmetric trisimidazoline-catalyzed enantioselective bromolactonization of internal alkenoic acids

Article abstract of DOI:10.1002/chem.201200647

A method for conducting enantioselective bromolactonization reactions of trisubstituted alkenoic acids, using the C₃-symmetric trisimidazoline 1 and 1,3-dibromo-5,5-dimethyl hydantoin as a bromine source, has been developed. The process generates chiral δ-lactones that contain a quaternary carbon. The results of studies probing geometrically different olefins show that (Z)-olefins rather than (E)-olefins are favorable substrates for the process. The method is not only applicable to acyclic olefin reactants but can also be employed to transform cyclic trisubstituted olefins into chiral spirocyclic lactones. Finally, the synthetic utility of the newly developed process is demonstrated by its application to a concise synthesis of tanikolide, an antifungal marine natural product. A catalytic, enantioselective bromolactonization of internal alkenoic acids has been developed by using C ₃-symmetric trisimidazoline (see scheme; DBDMH=1,3-dibromo-5,5- dimethyl hydantoin). Tri- and tetrasubstituted olefinic acids could be applied to give quaternary carbon containing δ-lactones as well as spiro lactones. The synthetic utility of the newly developed process is demonstrated by its application to a concise synthesis of tanikolide. Copyright

Full text of DOI:10.1002/chem.201200647

DOI: 10.1002/chem.201200647
C3-Symmetric Trisimidazoline-Catalyzed Enantioselective
Bromolactonization of Internal Alkenoic Acids
Kenichi Murai, Akira Nakamura, Tomoyo Matsushita, Masato Shimura, and
Hiromichi Fujioka*[a]
Abstract: A method for conducting
enantioselective bromolactonization re-
actions of trisubstituted alkenoic acids,
using the C3-symmetric trisimidazoline
1 and 1,3-dibromo-5,5-dimethyl hydan-
toin as a bromine source, has been de-
veloped. The process generates chiral
d-lactones that contain a quaternary
carbon. The results of studies probing
geometrically different olefins show
that (Z)-olefins rather than (E)-olefins
are favorable substrates for the process.
The method is not only applicable to
acyclic olefin reactants but can also be
employed to transform cyclic trisubsti-
tuted olefins into chiral spirocyclic lac-
tones. Finally, the synthetic utility of
the newly developed process is demon-
strated by its application to a concise
synthesis of tanikolide, an antifungal
marine natural product.
Keywords: alkenes
·
asymmetric
synthesis · lactones · organocataly-
sis · spiro compounds
Introduction
Halolactonization is an important transformation in synthet-
ic organic chemistry owing to the fact that it is utilized to
prepare synthetically useful halolactones,[1] which can be
employed as key intermediates in a number of different
transformations. Recently, several enantioselective halolac-
tonization reactions using organocatalysts have been de-
scribed.[2–4] For example, Borhan and co-workers developed
an enantioselective chlorolactonization reaction of 4-substi-
tuted-4-pentenoic acids that employs hydroquinidine 1,4-
phthalazinediyl diether ((DHQD)2PHAL) as the catalys-
t.[3a,b] A method for enantioselective bromolactonization of
conjugated (Z)-enynes, using a bifunctional catalyst com-
prised of a cinchona alkaloid bearing a urea moiety, was
also described by Tang and co-workers.[3c] A tertiary amino-
urea catalyzed enantioselective iodolactonization reaction
and an amino thiocarbamate catalyzed bromolactonization
process have also been devised by Jacobsen[3d] and Yeun-
g,[3e,f] respectively. We have also designed an enantioselec-
tive bromolactonization method (Scheme 1)[5] that is pro-
moted by the structurally unique, C3-symmetric trisimidazo-
line 1, developed in our earlier efforts.[6] By using this cata-
lyst, asymmetric reactions of 5-substituted-5-hexenoic acids
Scheme 1. Trisimidazoline 1 catalyzed bromolactonization.
take place to give d-lactones containing a quaternary carbon
center.
Although several useful methods have been developed
previously to carry out enantioselective halolactonization re-
actions, all of them are limited by the restricted range of re-
actant olefins. For example, 1,1-disubstituted olefins were
commonly employed as substrates to demonstrate the ap-
plicability of the developed methods (Figure 1).[3a,d,e,5] Thus
[a] Dr. K. Murai, A. Nakamura, T. Matsushita, M. Shimura,
Prof. Dr. H. Fujioka
Graduate School of Pharmaceutical Sciences
Osaka University
1-6, Yamada-oka, Suita
Osaka, 565-0871 (Japan)
Fax : (+81)6-6879-8229
E-mail: fujioka@phs.osaka-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200647.
Figure 1. Substrates for asymmetric halolactonization used in previous
works.
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FULL PAPER
far, among the wide range of other olefins, only conjugated
(Z)-enynes[3b] and 1,2-disubstituted olefins[3e] have been em-
ployed as substrates for enantioselective bromolactonization
reactions. In contrast, the reactivity profiles of internal ole-
fins have not been fully investigated, even though an expan-
sion of substrate scope would have a significant impact on
the applications of the halolactonization procedures in syn-
thetic organic chemistry.[7]
Here, we describe the results of recent studies carried out
to explore asymmetric bromolactonization reactions of
1,1,2-trisubstituted olefins promoted by trisimidazoline
1 (Figure 2). The observations made in this effort demon-
Scheme 3. Preparation of alkenoic acids 2g–k.
Figure 2. Substrates for asymmetric halolactonization used in this work.
mers was difficult. In another approach to the synthesis of
2g–j (Scheme 3), the olefinic esters 6g–j were prepared by
a sequence starting with hydrostannation of the correspond-
ing alkynes 7 with nBu3SnH in the presence of a catalytic
strate that acyclic and cyclic olefins in this group undergo
this process efficiently to generate bromolactones with high
levels of enantioselectivity. We have also demonstrated the
utility of this method by its application in a concise synthesis
of tanikolide, a natural product that incorporates a d-lactone
ring system with a quaternary carbon.
amount of [PdACTHNUGTRNEUNG(PPh3)4] followed by iodination to form (E)-
iodo-olefins 8a–d with high levels of stereoselectivity.[8] Ne-
gishi coupling reactions of 8a–d with the commercially avail-
able zinc reagent 9 were found to produce esters 6g–j in
good yields.[9,10] (E)-Alkenoic acid 2k was prepared in a simi-
lar manner from (Z)-iodo-olefin 11. Thus, treatment of 1-
phenyl-1-butyne (10) with NaI and CeCl3 produced (Z)-
iodo-olefin 11 with a moderate degree of regioselectivity.[11]
Purification by using column chromatography gave (Z)-
iodo-olefin 11 as a single stereoisomer in 50% yield. Negishi
coupling reaction with 9 followed by hydrolysis gave the
corresponding (E)-alkenoic acid 2k.
Results and Discussion
Synthesis of substituted ene-carboxylic acids: The scope of
the enantioselective bromolactonization reactions was ex-
plored by using various substituted alkenoic acids, such as
2a–k containing tri-substituted alkene moieties, a tetrasubsti-
tuted olefin 3, and substrates 4a–c bearing cyclic alkene
functionality. (Z)-Alkenoic acids 2a–f were readily prepared
for this purpose in a stereoselective manner by utilizing low
temperature Wittig olefination reactions of the correspond-
ing d-keto esters 5a–d followed by hydrolysis of the derived
esters 6a–f (Scheme 2).
The tetrasubstituted alkenoic acid 3 was prepared by
using the Wittig olefination reaction of ketoester 5a with
(CH3)2CHPPh3I. Finally, cyclic alkenoic acids 4a–c were
prepared by employing Pd-promoted coupling reactions be-
tween 9 and the corresponding triflates 13a–c (Scheme 4).
Unfortunately, it was not possible to synthesize alkenoic
acids 2g–j using this route because the stereoselectivities of
the Wittig olefination reactions were not sufficiently high
and chromatographic separation of the resulting stereoiso-
Scheme 4. Preparation of alkenoic acids 3 and 4a–c.
Screening of reaction conditions: Initial studies to explore
the new asymmetric bromolactonization reaction of internal
olefins were conducted with (Z)-alkenoic acid 2a (Table 1).
Scheme 2. Preparation of alkenoic acids 2a–f.
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H. Fujioka et al.
Table 1. Solvent effects.[a]
tions of exo alkenoic acids, reactions promoted by N-bromo-
succinimide (NBS) were observed to display comparable ef-
ficiencies to those induced by DBDMH. However, NBS was
not a suitable reagent for reactions of internal olefins owing
to its low reactivity with members of this family of alkenes
(Table 2, entry 2). Other bromine sources, such as N-bro-
mophthalimide (NBP), N-bromoacetamide (NBA), and
N,N’-dibromoisocyanuric acid (DBI)[14] were found to pro-
mote the bromolactonization reaction, however, lower levels
Entry
Solvent
Yield
[%]
ee
[%][b]
1
2
3
4
5
6
7
8
toluene
92
34
81
89
53
99
64
31
88
75
64
58
12
84
44
42
toluene/hexane=2:1
CH2Cl2/cyclohexane=1:2
CHCl3/hexane=1:3
THF/hexane=1:3
xylene
[3e]
of enantioselectivity were observed. Although NsNH2 and
AcOH[3a] have been used as additives in other asymmetric
halolactonizations, these substances had no effect on the
current process (Table 2, entries 6 and 7). The combined re-
sults show that the conditions used for the reaction de-
scribed in Table 2, entry 1, which are the same as those em-
ployed for exo olefins, are optimal for bromolactonization
reactions of internal olefins.
TBME
iPr2O
[a] Reagents and conditions: 2a (1 equiv), DBDMH (1 equiv),
1 (10 mol%), solvent (0.05m), 12 h. [b] Determined by HPLC; the ee
value of the major diastereomer is shown.
Effect of olefin geometry: The geometry of olefin substrates
for the bromolactonization reactions could significantly
affect selectivity. Consequently, to probe this issue, bromo-
lactonization reactions of (Z)-alkenoic acid 2a and (E)-alke-
noic acid 2k were explored (Scheme 5). As described above,
Under the previously developed conditions used for exo-ole-
fins, 2a reacted in the presence of 1,3-dibromo-5,5-dimethyl
hydantoin (DBDMH) and a catalytic amount of trisimidazo-
line 1 in toluene at À408C to form the desired bromolactone
15a in 92% yield with an enantiomeric excess (ee) of
88%.[12,13] Various solvent systems were explored in an
effort to improve the enantioselectivity of the process. We
had previously observed that, among several other solvents,
including dichloromethane (CH2Cl2), chloroform (CHCl3),
and tetrahydrofuran (THF), reactions in the less polar sol-
vent toluene proceeded with the highest efficiencies. Reac-
tions in varying polarity mixed solvent systems comprised of
toluene, CH2Cl2, CHCl3, and THF along with hexane or cy-
clohexane were observed to take place with low enantiose-
lectivities, perhaps because of the low solubilities of 1 and
DBDMH (Table 1, entries 2–5). The reaction in xylene dis-
played comparable, but slightly lower, selectivity (Table 1,
entry 6), and processes in less polar ethereal solvents, such
as tert-butyl methyl ether (TBME) or iPr2O, did not occur
with improved levels of asymmetric induction (Table 1, en-
tries 7 and 8).
Scheme 5. Effect of geometry.
2a reacted with a high level of enantioselectivity under the
optimal reaction conditions. On the other hand, the (E)-al-
kenoic acid 2k was observed to undergo the bromolactoni-
zation reaction to afford the bromolactone 15k with only
48% ee under these conditions.[13] This observation suggests
that (Z)-olefins are preferable substrates for asymmetric
bromolactonization reactions promoted by trisimidazoline 1.
We were interested in gaining information on the stereo-
chemistry of the quaternary carbon in bromolactones 15a
and 15k. For this purpose, the bromine atoms in these com-
pounds were removed under radical reduction conditions
with nBu3SnH and AIBN. Reductions of both 15a and 15k
were observed to afford preferentially the same lactone 16.
The results indicate that bromolactone formation selectively
occurs on the same face of the alkene, regardless of its ge-
ometry. The absolute facial selectivity of these processes
was determined from observations made in the tanikolide
synthesis described below.
The effect of the bromine source was also investigated by
using several commercially available reagents (Table 2, en-
tries 2–5). In our previous study on bromolactonization reac-
Table 2. Effect of bromine sources and additives.[a]
Entry
Br+ source
Additive
Yield
[%]
ee
[%][b]
1
2
3
4
5
6
7
DBDMH
NBS
NBP
NBA
DBI
none
none
none
none
none
NsNH2
AcOH
92
5
88
60
49
28
83
64
31
77
59
93
90
17
DBDMH
DBDMH
[a] Reagents and conditions: 2a (1 equiv), Br+ source (1 equiv),
1 (10 mol%), additive (1 equiv), toluene (0.05m), À408C, 12 h. [b] Deter-
mined by HPLC; the ee value of the major diastereomer is shown.
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Enantioselective Bromolactonization
FULL PAPER
Generality of asymmetric bromolactonization: The scope of
the bromolactonization reaction was investigated by utilizing
various (Z)-trisubstituted alkenoic acids. The results show
that the steric bulk of the alkene substituents does not
greatly influence either the reactivity or enantioselectivity
(Table 3, entries 1–3). Moreover, olefinic acid 2g, having an
first example of a catalytic asymmetric halolactonization re-
action of a tetrasubstituted olefinic acid.
Because they represent interesting synthetic targets,[16] the
formation of chiral spirocyclic lactones utilizing the method-
ology described above was probed. For this effort, bromo-
lactonization reactions of the endo-cyclic alkenoic acids 4a–
c, which have similar substitution patterns to (Z)-alkenoic
acids, were explored. As expected, indene derivatives 4a
and 4b underwent the reaction to give the respective spiro-
cyclic lactones with high enantioselectivities (Scheme 6,
Table 3. Scope of the reaction.[a]
Entry
Substrate (Z/E)
Product
Yield
[%]
ee
[%][b]
1
2
3
4
2a: R=Et (20:1)
2b: R=Me (20:1)
2c: R=nPr (20:1)
2g: R=(CH2)3OTBS (>20:1)
15a
15b
15c
15g
92
89
93
70
88
89
87
76
5
6
2h: R=pClC6H4 (>20:1)
2i: R=pBrC6H4 (>20:1)
15h
15i
99
96
90
88
Scheme 6. Synthesis of spiro lactones.
7
8
9
10
2d: R=pMeC6H4 (10:1)
2e: R=2-naphthyl (10:1)
2 f: R=pMeOC6H4 (12:1)
2j: R=Et (1:>20)
15d
15e
15 f
15j
80
93
64
97
81
78
0
Eq. (1)). Reactions of the endo-cyclic olefin within a lager
ring system, dihydronaphthalene derivative 4c, reacted with
good enantioselectivity (Scheme 6, Eq. (2)). The results
nicely demonstrate the preparative applicability of the bro-
molactonization process.
62
11
3
15l
85
65
Total synthesis of tanikolide: To further demonstrate its
preparative potential, the bromolactonization process was
utilized as a key step in a concise route for the synthesis of
tanikolide,[17,18] which is a metabolite of the cyanobacterium
Lyngbya majuscule. In addition, this effort provided infor-
mation about the absolute configuration of the chiral carbon
formed in the bromolactone product. The synthetic strategy
used to prepare tanikolide is given in Scheme 7. We envis-
[a] Reagents and conditions: alkenoic acid (1 equiv), DBDMH (1 equiv),
1 (10 mol%), toluene (0.05m), À408C. [b] Determined by HPLC; the ee
value of the major diastereomer is shown.
alkyl side chain bearing an OTBS moiety that can be used
as a functional handle in further transformations, reacts
smoothly to form the corresponding bromolactone, albeit
with only a moderate degree of enantioselectivity (Table 3,
entry 4). Substrates containing various aromatic rings were
found to react smoothly under the optimal conditions, giving
bromolactones with moderate to good enantioselectivities
(Table 3, entries 5–8). However, substrate 2 f, possessing an
electron-rich p-methoxybenzene group, reacted to give the
corresponding bromolactone 15 f in racemic form (Table 3,
entry 9).[15]
The presence of aromatic moieties on the olefin was
found to play an important role in determining the enantio-
selectivities of the reaction, as shown by the decrease in the
levels of enantioselectivity in reactions of nonaromatic ring
substituted olefin substrates (Table 3, entry 10). Finally, bro-
molactonization also took place when the tetrasubstituted
alkenoic acid 3 was used as the reactant (Table 3, entry 11),
although the enantioselectivity of the process was only mod-
erate. Importantly, to the best of our knowledge, this is the
Scheme 7. Possible synthetic routes.
aged that two asymmetric bromolactonization-based routes
could be used to synthesize the quaternary carbon contain-
ing target. In one, olefin 18 bearing a protected hydroxy-
methyl group (CH2OR with R=protecting group, such as
TBS) would be subjected to bromolactonization (Route a)
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H. Fujioka et al.
to produce a bromolactone intermediate. However, because
alkyl substituted olefins were found not to be appropriate
substrates for the bromolactonization reaction, an alterna-
tive route employing the phenyl substituted alkenoic acid 19
as a key intermediate was selected for the synthesis of tani-
kolide (Route b).
The concise synthetic sequence used to prepare tanikolide
is illustrated in Scheme 8. Initially, d-keto-ester 5a was
transformed into the alkenoic acid 19 by using a Wittig ole-
route described above, is negative. This observation there-
fore shows that the absolute configuration of the quaternary
carbon center in bromolactone 20 is S, a configuration that
is in accord with those found in products of previously re-
ported asymmetric bromolactonization reactions of exo ole-
fins. Other bromolactones described in this manuscript were
assigned the same configuration by analogy.
Conclusion
In the investigation described above, we have expanded tri-
simidazoline 1 catalyzed asymmetric bromolactonization re-
actions of alkenoic acids to include internal olefins as sub-
strates. In particular, (Z)-olefins were found to be suitable
substrates for these processes, giving products in high yields
and with high levels of enantioselectivity. The applicability
of the asymmetric bromolactonization process to the synthe-
sis of chiral spirocyclic lactones was also demonstrated. Fi-
nally, a concise total synthesis of (À)-tanikolide was ach-
ieved by using the developed reaction as a key step. This
constitutes, to the best of our knowledge, the first example
of an organocatalytic asymmetric halolactonization reaction
employed in natural product synthesis. We believe the meth-
odology developed in this effort will serve as a valuable tool
for the synthesis of a wide range of functionalized chiral lac-
tone derivatives.
Scheme 8. Total synthesis of tanikolide.
fination and base-mediated hydrolysis protocol. The mixture
of geometric isomers of 19 (Z/E=20:1) was subjected to
asymmetric bromolactonization to give the bromolactone 20
in good yield. Radical reduction with nBu3SnH and AIBN
was used to remove the bromine to afford the corresponding
lactone 21 in 91% yield. At this stage, the enantiomeric
excess (ee) of lactone 21 was determined to be 90% (HPLC
analysis). The final steps in the synthesis of tanikolide in-
volved transformation of the phenyl into a hydoxymethyl
group. Thus, the benzene moiety in 21 was oxidized to the
corresponding carboxylic acid 22 by using RuCl3/NaIO4.[19]
One-pot mixed anhydride formation with 22 and reduction
using NaBH4 led to generation of the alcohol moiety in the
target tanikolide in 52% yield from 21. The enantiomeric
purity of tanikolide was determined from its benzoyl ester
to be 90% ee, an observation that suggests that racemization
does not occur in the last two steps of the synthetic route.
Although the results of several studies focusing on the syn-
thesis of tanikolide have already been reported, the alterna-
tive approach described here features a novel method to
generate d-lactones containing a quaternary carbon. In addi-
tion, this is the first strategy developed for synthesis of this
natural product that relies on an asymmetric organocatalytic
halolactonization reaction.
Experimental Section
Typical procedure for the bromolactonization; (S)-6-[(S)-1-Bromoprop-
yl]-6-phenyltetrahydro-2H-pyran-2-one (15a): A solution of ene-carbox-
ylic acid 2a (66.6 mg, 0.305 mmol) and trisimidazoline
1 (22.3 mg,
0.0305 mmol) in toluene (6.1 mL) was stirred for 10 min at RT and the re-
sulting solution was cooled to À408C. DBDMH (87.3 mg, 0.305 mmol)
was then added in one portion to the solution and the reaction mixture
was stirred at À408C for 12 h. Upon completion, the reaction was
quenched with sat. aq. Na2S2O5 at À408C, and the organic layer was ex-
tracted with EtOAc. The extracts were washed with brine, dried with
Na2SO4, and concentrated in vacuo. The residue was purified by SiO2
column chromatography (hexane/AcOEt=2:1) to give 15a (83.5 mg,
92%) as colorless oil; [a]D19 =À4.09 (c=0.92, CHCl3, 88% ee); 1H NMR
(400 MHz, CDCl3): d=7.49–7.47 (m, 2H), 7.40–7.31 (m, 3H), 4.08 (dd,
J=11.6, 2.0 Hz, 1H), 2.73 (dt, J=14.8, 4.0 Hz, 1H), 2.46–2.30 (m, 2H),
2.20 (ddd, J=17.2, 12.8, 4.8 Hz, 1H), 1.98–1.94 (m, 1H), 1.88–1.80 (m,
1H), 1.65–1.59 (m, 1H), 1.30–1.21 (m, 1H), 0.96 ppm (t, J=7.2 Hz, 3H);
13C NMR (100.5 MHz, CDCl3): d=170.4, 138.3, 128.5, 128.4, 126.8, 87.8,
66.4, 29.4, 29.0, 25.9, 16.2, 12.9 ppm; IR (KBr): n˜ =2968, 1736, 1449, 1240,
1043 cmÀ1; HRMS (FAB): m/z calcd for C14H17BrO2: 297.0490 [M+H]+;
found: 297.0497; HPLC (DAICEL CHIRALCEL OJ; hexane/iPrOH=
92:8; flow rate=1.0 mLminÀ1
; 210 nm): Rt =23.8 (major), 29.7 min
(minor).
Acknowledgements
This work was financially supported by Grant-in-Aid for Scientific Re-
search (B) and for Young Scientists (B) from JSPS.
The optical rotation of natural tanikolide is reported to
be positive and the absolute configuration of the quaternary
carbon center in the natural product is known to be R. In
contrast, the optical rotation of tanikolide, prepared by the
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Enantioselective Bromolactonization
FULL PAPER
[12] Although the bromolactone was obtained as inseparable diastereo-
mers when the starting alkenoic acid was an Z/E mixture, the ee
value of the major diastereomer was unambiguously determined by
HPLC analysis because each peak was separated.
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Received: February 27, 2012
Published online: May 23, 2012
Chem. Eur. J. 2012, 18, 8448 – 8453
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8453