Chemodivergent, Tunable, and Selective Iodine(III)-Mediated Bromo-Functionalizations of Polyprenoids

Article abstract of DOI:10.1021/acs.orglett.7b02125

Mild oxidation of bromides by iodine(III) reagents generated active electrophilic bromination species that were reacted with polyprenoids. By simple and minor variations of an I(III)/Br combination, the reactivity could be selectively steered toward dibro

Full text of DOI:10.1021/acs.orglett.7b02125

Letter
pubs.acs.org/OrgLett
Chemodivergent, Tunable, and Selective Iodine(III)-Mediated Bromo-
Functionalizations of Polyprenoids
Tatyana D. Grayfer, Pascal Retailleau, Robert H. Dodd, Joelle Dubois, and Kevin Cariou*
̈
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite
91198 Gif-sur-Yvette, France
́ ́
Paris-Sud, Universite Paris-Saclay, Avenue de la Terrasse,
S
* Supporting Information
ABSTRACT: Mild oxidation of bromides by iodine(III) reagents generated active electrophilic bromination species that were
reacted with polyprenoids. By simple and minor variations of an I(III)/Br combination, the reactivity could be selectively steered
toward dibromination, oxybromination, or bromocyclization, giving access to a wide array of brominated motifs.
rominated terpenoids of marine origin constitute a
particularly wide class of natural products that exhibit a
shown by Snyder with the development of a bromocyclization
specific BDSB reagent.7,8
B
vast array of structural diversity1 and potential therapeutic
applications.2 A myriad of motifs, arising from diverse
biosynthetic pathways,3 can be found in different families and
sometimes in the same molecule. For example, by just
considering the brominated moieties of the bromophycolide
A4 macrocycle (1, Figure 1), fragments arising from a
For our part we thought that it would be highly desirable to
design a general strategy that would demand only limited
modifications of the modus operandi to completely deviate the
reactivity in one or another chemical direction. Based on our
previous experience9 with iodine(III)-mediated bromination
reactions,10 we believed that when generating the active
bromination species by in situ oxidation of a bromide by a
hypervalent iodine(III) species,11 several parameters would be
easily tunable so as to govern the selectivity of the reaction. Thus,
running the reaction in a nonparticipating solvent in the absence
of an external nucleophile should favor bromocyclization9d
toward bromocyclohexenyl 5 (Scheme 1, eq 1), while adding an
alcohol to the reaction mixture would trigger an oxy-
bromination9a toward alkyl-bromohydrine 6 (Scheme 1, eq 2).
Initial experiments were performed on geranyl acetate 4a using
a combination of (diacetoxyiodo)benzene (DIB) and lithium
bromide in acetonitrile, which led to dibromo derivative 7a in
91% yield (Scheme 2). Running the same reaction in ethanol or
Figure 1. Examples of brominated terpenoids of marine origin.
Scheme 1. Chemoselective Iodine(III)-Mediated
Bromination of a Geranyl Derivative
carbobromination, a hydroxybromination, and an acyloxybromi-
nation (with the opposite regiochemistry) of a geranyl−geranyl
chain can be delineated. A carbobromination accounts for the
formation of cyclocymopol 2,5 but in this case the double bond
lies outside of the ring. Isocymobarbatol 36 stems from the same
linear precursor but through a formal cascade cyclization,
resulting in a tricyclic scaffold. This variability could be explained
by the intermediacy of one or several halogenating enzymes,3 but
raises complex chemo-, regio-, and stereoselectivity issues, which
remain challenging for organic chemists. One way to address this
challenge is to design specific reagents for one transformation, as
Received: July 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02125
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
decrease in yield, without changing the reaction course (Table 1,
entry 2). However, using this protocol and replacing the DIB by
its trifluoroacetoxy analog (PIFA) diverted the reactivity toward
bromocyclization giving 5b (as a mixture of isomers) and tricycle
8b in a 39% cumulated yield (Table 1, entry 3). This result could
be further improved by using the more soluble TMSBr to give
41% of 5b and 15% of 8b (Table 1, entry 4). Treatment of the
mixture of brominated cyclohexenes 5b with chlorosulfonic acid
in 2-nitropropane at −78 °C7,8 to give 8b led to a cumulated yield
of tricyclic adduct of 46%. Increasing the addition time (Table 1,
entry 5) or exchanging trimethylsilyl bromide for triethylsilyl
bromide (Table 1, entry 6) mostly led to complex mixtures of
adducts, including allyl bromide 10b and cyclopentene 11b.12
When alkylammonium bromide salts were used, the acyloxy-
bromination pathway was also observed (Table 1, entries 7 and
8), with 6b becoming the major product when tetrabutyl-
ammonium bromide was employed (Table 1, entry 8). This
could be further improved by slightly increasing the concen-
tration and the addition rate, to obtain 60% of 6b (Table 1, entry
9). Running the reaction in nitromethane with TESBr steered the
reactivity back toward cyclization (Table 1, entry 10), and using
the bulkier bis(tert-butylcarbonyloxy)iodobenzene completely
suppressed the oxybromination pathway (Table 1, entry 11). In
order to perform the reaction at a lower temperature (− 78 °C),
nitroethane was employed instead of nitromethane. This
prevented the formation of 10b, and directly submitting the
crude product to ClSO3H treatment gave 8b in 54% yield over
two steps (Table 1, entry 12). Eventually, performing the same
sequence with MeSO3H in the second step improved the yield up
Scheme 2. Solvent Effect in the DIB-Mediated Bromination of
Geranyl Acetate
in a water/acetonitrile mixture triggered the oxybromination
process yielding ethoxy and hydroxy adducts 6a and 6a′,
respectively, with satisfying yields. This reactivity switch
validated the second half of our premise, but despite extensive
screening,12 geranyl acetate, because of the deactivation of the
internal double bond, seemed unsuitable to probe the triggering
of the cyclization process.
In order to circumvent this hurdle, we decided to focus our
attention on the reactivity of the electron-rich homogeranyl-
benzene 4b (Table 1), which has been shown to cyclize more
readily toward mono- (5b) and/or tricyclic (8b) adducts under a
variety of conditions.7,8
We therefore screened numerous parameters12 in order to
generate the initial bromonium intermediate 9b and selectively
orientate its evolutions toward one of the many possible adducts
(5−8, allylbromide 10b and cyclopentene 11b).12 As with
geranyl acetate, the combination of DIB and LiBr in MeCN
mainly led to dibromo compound 7b in 63% yield (Table 1, entry
1).12 Halving the amount of bromide and adding it slowly as the
last reagent in order to prevent dibromination only led to a
Table 1. Optimization of the Iodine(III)-Mediated Dibromination, Oxybromination, and Bromocyclization of
a
Homogeranylbenzene 4b
a
b
A solution of MBr [2C] was slowly added to a solution of 4b [2C] containing the iodine(III) reagent. Resulting concentration after addition.
c
d
e
Isolated yields; for 8b overall yield after recyclization of 5b with ClSO3H is given in parentheses. Direct addition of LiBr and with 4 Å MS. And
f
g
h
7% of 10b. And traces of 10b. And 8% of 11b. The crude reaction mixture (5:2:1 ratio of tetra-, tri-, disubstituted olefins) was recyclized without
purification. Recyclization with MeSO3H, dr = 6:1.
i
B
DOI: 10.1021/acs.orglett.7b02125
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Letter
to 67% in a 6:1 diastereomeric ratio (Table 1, entry 13). This
thorough optimization helped define three sets of conditions to
selectively access dibromo-, oxybromo-, and cyclobromo-
derivatives. First, the scope of the former two processes was
evaluated.
Scheme 3. Bromocyclization of Homogeranyl- and
Homofarnesylarenes
In addition to the above-mentioned results on geranyl acetate
4a and homogeranylbenzene 4b, the combination of DIB and
LiBr selectively triggered the dibromination of o-homogerany-
lanisole 4c and geranylbenzene 4d to give 7a−d in good to
excellent yields (Table 2, entries 1−4). The same protocol could
Table 2. Scope of the Dibromination and the
Trifluoroacetoxybromination
a
b
entry
4, R
4a, OAc
7, yield %
6, yield %
1
2
3
4
5
6
91
63
52
55
63
77
60
56
64
57
4b, Bn
In the case of phenolic homogeranyl derivatives, PhI(OPiv)2-
mediated bromocyclization gave a good (59% to 68%) overall
yield of bromo-cyclized products,13 the distribution of which
varied depending on the initial substitution pattern (Scheme 4).
4c, o-MeOBn
4d, Ph
4, OH
c
d
4f, NHC(NZ)NHZ
52
25
a
Isolated yields for conditions A: PhI(OAc)2 (1.2 equiv), LiBr (2.4
Scheme 4. Bromocyclization of Homogeranylphenols
b
equiv), 4 Å MS in MeCN, at 0 °C for 5 min. Isolated yields for
conditions B: PhI(OCOCF3)2 (1.2 equiv) n-Bu4NBr (2.4 equiv) in
c
MeCN, at 0 °C for 5 min. At−78 °C, using TESBr instead of LiBr.
d
At−78 °C, with 13% of 6f and 31% of 12.
be applied to geraniol 4e to give 7e in 63% yield without any
detectable oxidation of the free alcohol (Table 2, entry 5).
Finally, the more challenging bis(benzyloxycarbamate)-guani-
dine 4f could be selectively dibrominated to yield 7f by using a
reverse addition protocol at −78 °C (Table 2, entry 6). The same
substrates were also submitted to the PIFA/n-Bu4NBr
combination to give the α-bromo trifluoroacetyl adducts 6.
Geranyl acetate led to 6a″ and geraniol to 6e in 77% and 57%
yield, respectively (Table 2, entries 1 and 5). In addition to 4b,
the other aryl derivatives 4c and 4d reacted equally well to give
the oxybrominated adducts in 56% and 64% yield (Table 2,
entries 3 and 4). Only guanidine 4f reacted sluggishly to yield the
desired trifluoroacetoxy adduct 6f in only 25% yield (Table 2,
entry 6) along with 13% of 7f and 31% of cyclic guanidine 12 (see
Scheme 5). Finally, it was demonstrated that selective cleavage of
the trifluoroacetoxy group of 6b could be achieved with NaBH4
to give the corresponding bromohydrine in 79% yield.12
We then turned our attention toward the third protocol and
studied the cyclization of several homogeranyl and geranyl
derivatives. First, homogeranylarenes were reacted under the
optimized conditions, followed by treatment with sulfonic acid or
with tin(IV) chloride, to provide the corresponding tricycles
(Scheme 3). Para-toluene 4g, para-anisole 4h, and ortho-anisole
4c derivatives led to the desired bromo-octahydrophenanthrenes
8g, 8h, and 8c with 40% to 60% yields and moderate to good
diastereoselectivities.
Starting from ortho-phenol 4k, in addition to the monocyclic
cyclohexenes 5k and the expected tricycle 8k, compound 13
embedding a seven-membered ring was also isolated.14 For meta-
phenol 4l, the cyclohexenes 5l were obtained in 36% yield and
the two brominated polycycles arising from para and ortho
addition (8l + 8l′ = 23% yield) were also formed.
Finally, the behavior of geranyl compounds was explored
(Scheme 5). Geranyl-benzene 4d led to bromocyclohexenes 5d
in 43% yield as a mixture of endo/exo adducts. The analogous
cyclohexenes 5m were obtained in slightly higher yield (51%)
from o-geranylanisole 4m along with 24% of bromo-hexahy-
droxanthene 14 arising from a cascade cyclization and
concomitant loss of a methyl group.
As could be expected, this isocymobarbatol-like adduct
became the major product when o-geranylphenol 4n was
subjected to the PhI(OPiv)2/TESBr combination. 3-Bromo-
chromane 15, resulting from a phenoxybromination of the
internal double bond, was also observed as a minor adduct. This
change in chemoselectivity might hint at an active participation
of the heteroatom in the cyclization process, presumably via
The reaction proceeded even better with meta-anisyl substrate
4i, although the two adducts arising from para and ortho addition
(8i + 8i′ = 73% yield) were formed. Finally, homofarnesyl-
benzene 4j was reacted to give bromotetracycle 8j in a low but
satisfying yield, considering that one C−Br and three C−C
bonds are formed in the sequence.
C
DOI: 10.1021/acs.orglett.7b02125
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Letter
Scheme 5. Bromocyclization of Geranyl Derivatives
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initial ligand exchange between the phenol and the ester on the
hypervalent iodine center, followed by oxy-halogenation of the
proximal double bond. This was further exemplified by the
reaction of guanidine 4f which smoothly led to 12 in 75% yield.
Indeed, it is the only substrate that we studied for which the
reaction mainly occurred on the internal double bond.
Overall we have shown that by using a combination of a
(bisacyloxy)iodobenzene and a bromide source, three different
electrophilic brominations of terpenoids with different outcomes
could be triggered. Simple adjustments in the nature of the
reagents (all commercially available) and the procedure
(temperature, rate, and order of addition) could steer the
reactivity toward dibromination, oxy-bromination, or bromocyc-
lization, including cascade processes. This strategy grants access
to various motifs that can be found in several families of natural
products. Studies in this direction as well as the implementation
of this methodology for other halides are currently being
pursued.
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02125.
Comprehensive optimization studies, experimental pro-
cedures, analytical data, and copies of NMR spectra for all
new compounds (PDF)
Crystallographic data for 5d (CIF)
Crystallographic data for 8b (CIF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kevin.cariou@cnrs.fr.
ORCID
Kevin Cariou: 0000-0002-5854-9632
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank CNRS and ICSN, for financial support. T. D.
G. thanks ICSN for a PhD fellowship.
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DOI: 10.1021/acs.orglett.7b02125
Org. Lett. XXXX, XXX, XXX−XXX