Et2SBr.SbCl5Br: An effective reagent for direct bromonium-induced polyene cyclizations

Article abstract of DOI:10.1002/anie.200903834

It's all about reactivity: Although bromonium-induced cation-π cyclizations are commonly utilized by nature to fashion six-membered rings from a diverse set of polyene precursors, no general laboratory method exists that can achieve the same breadth of substrate scope. An easily synthesized and handled reagent is described (see scheme) that is capable of directly, broadly, and rapidly effecting such reactions in good yield with a variety of geraniol, farnesol, and nerol derivatives.

Full text of DOI:10.1002/anie.200903834

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DOI: 10.1002/anie.200903834
Biomimetic Synthesis
Et2SBr·SbCl5Br: An Effective Reagent for Direct Bromonium-Induced
Polyene Cyclizations**
Scott A. Snyder* and Daniel S. Treitler
Although biomimetic polyene cyclizations[1] have been honed
into powerful tools for complex molecule construction in the
half-century since the pioneering efforts of Stork and
Eschenmoser,[2] several limitations remain. For instance,
while nature can deploy heme- or vanadium-based enzymes[3]
to enantioselectively fashion an array of natural products,
such as 1–3 (Scheme 1),[4] from a broad range of appropriate
precursors, such as 4–6,[5] laboratory efforts to mirror the
same reactivity in racemic form with standard electrophilic
bromine sources, such as Br2, N-bromosuccinimide (NBS) or
2,4,4,6-tetrabromocyclohexa-2,5-dienone
(TBCO,
12),
broadly fail.[6–8] Electron-deficient forms of 7, for example,
are typically converted into elimination products (9) and/or
materials that incorporate exogenous nucleophiles such as
water or bromide (10), due to the low rate of intramolecular
cyclization within intermediate 8;[6a–d] attempts to counter
these results by precipitating bromide with added silver salts[7]
or by enhancing the electrophilicity of the halogen through
complexation (NBS/Ph3P)[9] are, at best, modestly successful.
Only a few electron-rich terpenes have been directly cyclized
in synthetically useful yields,[6f,g,9] though many materials in
this class,[6e,i] such as protected forms of cymopol (4), remain
challenging substrates (with typical cation–p product yields
ranging around 35%).[8,10] Here, we describe a simple and
readily handled reagent, 13, that overcomes these deficiencies
and smoothly effects bromonium-induced cation–p cycliza-
tions with a diverse set of compounds derived from geraniol,
farnesol, and nerol, including electron-deficient systems and a
protected form of cymopol (4).
Our efforts began with the search for novel classes of
brominating reagents under the operating assumption that a
highly activated, cationic source of electrophilic bromine free
from any additional nucleophilic species might have the best
Scheme 1. Natural products with rings that likely result from direct,
bromonium-induced cation–p cyclizations and the challenges in
achieving those reactions.
[*] Prof. Dr. S. A. Snyder, D. S. Treitler
Department of Chemistry, Columbia University, Havemeyer Hall
MC 3129, 3000 Broadway, New York, NY 10027 (USA)
Fax: (+1)212-932-1289
chance to enable controlled bromonium-induced cyclization
of a variety of terpenes, particularly those possessing electron-
deficient olefin nucleophiles.
E-mail: sas2197@columbia.edu
An extensive search of the literature revealed the
existence of a Br2 complex with Me2S and SbCl5 that
potentially fit these criteria; however, while structurally
characterized over 25 years ago, its reactivity with olefins,
or any other nucleophile, had not been explored.[11] Accord-
ingly, we prepared a number of compounds of this general
type, and discovered that admixing Br2 with a slight excess of
SbCl5 and Et2S in 1,2-dichloroethane at À308C led to the
immediate precipitation of an orange powder. Recrystalliza-
tion afforded pure 13 as an orange, plate-like solid.[12] With
this nearly odor-free, stable, and easily handled reagent in
Homepage: http://www.columbia.edu/cu/chemistry/groups/
snyder/
[**] We thank the NSF (CHE-0619638) for an X-ray diffractometer, Prof.
Gerard Parkin, Wesley Sattler, and Aaron Sattler for analyzing 13 and
36, and Dr. Andreas Schall for the preparation of 22. Financial
support was provided by Columbia University, an NSF CAREER
Award (CHE-0844593), the ACS Petroleum Research Fund (47481-
G), Amgen, Eli Lilly, the NSF (Predoctoral Fellowship to D.S.T.), and
the Camille and Henry Dreyfus Foundation (New Faculty Award to
S.A.S.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903834.
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hand,[13] we then proceeded to test its reactivity with a diverse
set of terpene-derived substrates.
As indicated in Table 1, a variety of electron-deficient
polyenes derived from geraniol[14] were smoothly cyclized
following the rapid addition of a CH3NO2 solution of 13
other major methods known in the literature[15] under either
the same reaction conditions (Br2/AgBF4 and TBCO) or
previously optimized protocols (NBS/PPh3).[9] In all cases, 13
provided far superior yields, the fastest and cleanest reactions,
and the simplest product purifications. Among these results,
entry 3 is perhaps the most significant as 13 alone proved
capable of cyclizing the highly electron-deficient 18 in any
measurable yield. It should be noted that every reaction using
these alternate methods was driven to completion, and that
the yields for these experiments derive from NMR analyses of
crude reaction mixtures since product isolation proved
challenging and/or impossible to achieve; as such, these
yields are likely artificially high relative to those observed
with 13 since those numbers reflect yields of isolated
compounds.[16]
Table 1: Exploration of the generality of direct, bromonium-induced
cation–p cyclizations using reagent 13 and available alternatives with
electron-deficient substrates.
Similar facility in initiating cation–p reactions was
observed when we exposed electron-rich substrates derived
from both geraniol and farnesol (Table 2) to the action of
BDSB (13).[14] For instance, not only was a polycyclization
smoothly achieved in 58% yield (entry 2), but even a
substrate bearing a highly electron-rich aromatic ring was
cyclized in 76% isolated yield without significant amounts of
competing aryl halogenation following 5 min of reaction time
at À258C.[17] As shown in Scheme 2, reagent 13 worked
equally well with even more complex and highly electron-rich
substrates such as 33,[18] providing in this case the means to
complete an efficient total synthesis of the natural product
4-isocymobarbatol (1) with the cation–p cyclization step
proceeding in 74% yield (53% overall yield from commercial
Table 2: Exploration of the generality of direct, bromonium-induced
cation-p cyclizations using reagent 13 and available alternatives with
electron-rich substrates.
[a] Isolated as a mixture of alkene stereoisomers. [b] All yields deriving
from this reagent were determined by NMR analysis using nitrobenzene
as an internal standard since the desired material co-elutes with
undesired side products. [c] Produced as a 3.8:1 mixture of separable
diastereomers at the C-4 position favoring the drawn product. [d] Pro-
duced as a 4.8:1 mixture of separable diastereomers at the bridgehead
methyl favoring the drawn product.
(1.0 equiv) to 0.1 mmol of the alkene starting material in
CH3NO2 (yielding a final reaction concentration of 0.1m). In
all cases, the bromonium-induced cation–p cyclization was
complete within 5 min, with the reaction temperature
employed in each case dictated by the nucleophilicity of the
internal alkene; a prolonged reaction was employed for
substrate 20 (entry 4) to effect the second, oxygen nucleo-
phile-based, cyclization. In an effort to obtain a quantitative
sense of the value and unique reactivity profile of 13 (BDSB)
over available alternatives, we next attempted to initiate
cation–p cyclizations of the same substrates with each of the
[a] Generated alongside some very minor diastereomers; [b] All yields
deriving from this reagent were determined by NMR analysis using
nitrobenzene as an internal standard since the desired material co-elutes
with undesired side products; [c] Yield includes partially cyclized
material; [d] Complete cyclization promoted by the addition of
CH3SO3H at the end of the reaction.
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concentration, with far more dilute solutions providing
superior yields and diastereoselectivities. Additionally, elec-
tron-rich substrate 25 was smoothly cyclized to tricycle 26 in
67% yield on 5.0 mmol scale under the same reaction
concentration as that of entry 8 in Table 3 at a reaction
temperature of À258C.[21]
Finally, although we do not yet fully understand the basis
for the unique chemical reactivity profile of BDSB (13) in
successfully initiating cation–p cyclizations far more smoothly
over available electrophilic bromine alternatives,[22] a few
initial observations are worth mentioning at this juncture. As
indicated in Figure 1, a preliminary X-ray crystal structure[23]
Scheme 2. Total synthesis of 4-isocymobarbatol (1) and a reaction with
nerol-derived substrate 35 using BDSB (13) to effect a biomimetic
cation–p cyclization: a) 32 (2.0 equiv), nBuLi (1.3m in hexanes,
1.7 equiv), THF, À788C, 30 min; then added to 31 (1.0 equiv), THF,
À408C to 08C, 2 h, 75%; b) 13 (1.1 equiv), CH3NO2, À258C, 5 min,
74%; c) HCl (concentrated, excess), THF, 258C, 5 h, 97%; d) 13
(1.1 equiv), CH3NO2, 08C, 5 min, 71%. MOM=methoxymethyl.
Figure 1. Preliminary X-ray crystal structure of BDSB (13) and compar-
ison to a known, related structure (37): a possible explanation for
superior reactivity.
of 13 reveals significantly tighter binding between the sulfur
atom and its electrophilic bromine counterpart relative to
other published Br2·sulfur adducts such as 37;[24] this alternate
distance is the likely basis for its unique reactivity, since 37 has
proven to be a source of molecular Br2 and ineffective for
cation–p cyclizations in our hands. Interestingly, though the
bromide atom that is part of the SbCl5Br anion within 13 is
oriented towards the electrophilic bromine atom attached to
sulfur, the extended bond distances suggest that it is
effectively sequestered. In terms of general capability to
effect other reactions, such as electrophilic aromatic substi-
tution, BDSB appears to be very comparable to NBS in terms
of its reaction with substrates that we have previously
explored.[25] However, NBS is more prone to provide small
quantities of overhalogenated materials that are absent in the
analogous reactions using BDSB.
materials). It also smoothly cyclized a terpene possessing an
alternate olefin geometry, namely polyene 35 derived from
nerol; as such, this result, coupled with those in both Table 1
and Table 2, illustrate that each of these BDSB-initiated
cyclizations proceeds through a tight, chair-like transition
state where the initial alkene geometry is expressed in the
relative stereochemistry of the products (i.e. the isoprene
cyclization rule is followed).[19,20] It is also worth noting that
while all of the reactions mentioned above were conducted on
a relatively small scale (0.1 mmol), we have been able to
successfully and smoothly perform the same transformation
on far larger quantities of material (5.0 mmol) for each of the
two substrates that we have attempted thus far (16 and 25). As
shown in Table 3, in our efforts to explore the large-scale
conversion of 16 into 17, the key to success is reaction
In conclusion, we have demonstrated that BDSB (13) is a
powerful reagent for electrophilic bromination, one that
finally enables the direct formation of cation–p cyclization
products with essentially every class of standard terpene
substrate in the absence of the difficult to separate side-
adducts formed with more classical reagents, as well as with
predictable stereoselectivity. Efforts to further explore the
complete reactivity profile of 13, render this transformation
asymmetric, and apply the lessons learned to analogous
chlorine- and iodine-based reactions, are the subject of
current study.
Table 3: Exploration of scaleability of BDSB-induced cyclizations with
substrate 16.
Scale [mmol] Concentration [m] BDSB equiv. Yield [%] d.r.
1
2
3
4
5
6
7
8
0.1
0.5
0.5
0.5
0.5
0.5
0.5
5.0
0.100
0.100
0.025
0.025
0.025
0.010
0.010
0.010
1.0
1.0
1.0
1.0[a]
1.1
1.0
1.1
1.1
80
61
70
71
74
78
84
75
3.8:1
4.3:1
4.7:1
4.6:1
4.3:1
5.1:1
5.0:1
5.3:1
Received: July 13, 2009
Published online: September 15, 2009
Keywords: biomimetic synthesis · bromine · isocymobarbatol ·
polyene cyclization · terpene
[a] Inverse order of addition (by adding a solution of 16 to a solution of
BDSB in CH3NO2).
.
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[9] A. Sakakura, A. Ukai, K. Ishihara, Nature 2007, 445, 900 – 903. It
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attempts to extend the developed system directly to bromine
afforded products in poor enantiomeric excess, revealing that the
problem of inducing asymmetry in this transformation is far from
a trivial one; these challenges, of course, are in addition to those
described for effecting bromonium-induced cyclizations in
racemic format as already described.
[10] Available two-step alternatives include iodonium-based cycliza-
tion followed by lithium exchange and bromine capture with
retention of configuration (cf. Ref. [9]), cyclization of bromohy-
drin precursors, or stoichiometric HgII-based cyclizations fol-
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Vidali, Chem. Eur. J. 2004, 10, 3822 – 3835; b) A. Murai, A.
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[4] For the original isolation of these natural products, see: a) M. E.
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shown below that could result from a bromonium-induced
cation–p cyclization of an isoprene-derived starting material.
[12] Use of Me2S and iPr2S leads to competent reagents for cation–p
cyclization; however, 13 is the most easily prepared and crystal-
lized. We propose giving compound 13 the acronym of BDSB for
bromodiethylsulfonium bromopentachloroantimonate.
Of these, many have potent biological activity, including
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[13] 13 has proven stable in a vial stored in a À208C refrigerator for
several months with no depreciation in chemical reactivity. It
appears only to be sensitive to prolonged exposure to moisture-
rich air. In terms of its solubility profile, 13 is fully soluble at
ambient temperature in CH3NO2, CH3CH2NO2, MeCN, DMSO,
DMF, and EtOAc, moderate to slightly soluble in CH2Cl2, 1,2-
dichloroethane, chloroform, and toluene, and insoluble in
benzene, hexanes, and pentane. We have observed that 13 is
soluble in acetone, methanol, ethanol, and THF, but reacts with
these solvents.
[5] For biosynthetic studies with the snyderols and the napyradio-
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Biol. Chem. 2007, 282, 16362 – 16368. For a recent, asymmetric
total synthesis of napyradiomycin A1, see: c) S. A. Snyder, Z.
Tang, R. Gupta, J. Am. Chem. Soc. 2009, 131, 5744 – 5745.
[6] For representative examples, see: a) E. E. van Tamelen, E. J.
Hessler, J. Chem. Soc. Chem. Commun. 1966, 411 – 413; b) T.
Kato, I. Ichinose, A. Kamoshida, Y. Kitahara, J. Chem. Soc.
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Martꢁn, C. Pꢂrez, M. A. Ramꢁrez, Tetrahedron Lett. 1976, 17,
137 – 138; d) T. Kato, I. Ichinose, J. Chem. Soc. Perkin Trans. 1
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[14] For the synthesis of these substrates, see the Supporting
Information.
[15] Although not reported to initiate cation–p cyclizations, bis(colli-
dine)halonium triflate and perchlorate salts have been utilized as
sources of electrophilic halogen. For selected examples, see:
a) R. U. Lemieux, A. R. Morgan, Can. J. Chem. 1965, 43, 2190 –
2197; b) J. W. Lown, A. V. Joshua, Can. J. Chem. 1977, 55, 122 –
130; c) Y. Tamaru, S. Kawamura, Z. Yoshida, Tetrahedron Lett.
1985, 26, 2885 – 2888; d) R. D. Evans, J. W. Magee, J. H. Schau-
ble, Synthesis 1988, 862 – 868; e) A. A. Neverov, R. S. Brown, J.
Org. Chem. 1998, 63, 5977 – 5982; f) X.-L. Cui, R. S. Brown, J.
Org. Chem. 2000, 65, 5653 – 5658. We prepared the bis(collidi-
ne)bromonium triflate reagent and explored its reactivity with
homogeranyl benzene (25) in CH3NO2 at À258C, finding that a
complex mixture of products was formed after 5 min of reaction
time with ca. 20% being the desired cation–p product (26). In
CH2Cl2, the yield of 26 was much lower.
[7] a) L. E. Wolinsky, D. J. Faulkner, J. Org. Chem. 1976, 41, 597 –
600; b) T. R. Hoye, M. J. Kurth, J. Org. Chem. 1978, 43, 3693 –
3697.
[8] A. Tanaka, T. Oritani, Biosci. Biotechnol. Biochem. 1995, 59,
516 – 517. A graphical summary of all of the bromonium-induced
cyclizations in Refs. [6–8] can be found at the end of the
Supporting Information to provide a full sense of the true state-
of-the-art in these reactions in racemic format.
[16] As a point of internal calibration to verify that our results with
these alternate reagents are valid and have not been skewed in
any way, we note that three of the yields in Table 1 directly
parallel literature precedent, namely entries 2 and 5 for Br2/
AgBF4 and entry 1 for TBCO. Each of these precedents is fully
elucidated in the Supporting Information.
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[17] A substrate related to 29 was reported in Ref. [9] to cyclize with
NBS/Ph3P under the utilized conditions in 71% yield; we have
been unable to achieve similar results despite several attempts.
Rather than offer any questioning of this precedent, we would
argue instead here that our protocol provides for easier
execution since temperature control over the course of 30 h is
not required.
proton-initiated cation–p cyclization, was observed in each case
in up to 12% overall yield. On large scale, this side-product
could be suppressed to < 5% by using dilute reaction concen-
trations (0.01m) and adding 2 equivalents of pulverized CaCO3
to the reaction media prior to BDSB addition. It could also be
suppressed by adding a cold solution of BDSB very quickly to
the substrate.
[18] Compound 33 has also been prepared by using the cuprate
nucleophile derived from 32; see Ref. [6i]. We observed that the
lithiated form was better yielding overall for this bond con-
struction with none of the very difficult to separate SN2’ adducts
generated.
[19] In all cases, the stereochemistry of products was confirmed by
NMR analysis as well as comparison to published character-
ization data. In particular, at least in terms of NMR analyses, any
alteration in the axial or equatorial disposition of groups
attached to the carbocycle are highly diagnostic signals. To
verify the nerol cyclization case, we obtained a crystal structure
for 36 (a picture of which is shown in the Supporting
Information) since precedent for cyclizations with these sub-
strates is sparse.
[22] Conceptually, the reagent described herein can be defined as
Lewis base activation of a Lewis acid. For a review on this
important mode of promoting reactivity from one of its leading
practitioners, see: S. E. Denmark, G. L. Beutner, Angew. Chem.
2008, 120, 1584 – 1663; Angew. Chem. Int. Ed. 2008, 47, 1560 –
1638. For a recent paper on the use of this approach to attempt
enantioselective addition of chalcogens such as sulfur onto
alkenes, see: S. E. Denmark, W. R. Collins, M. D. Cullin, J. Am.
Chem. Soc. 2009, 131, 3490 – 3492.
[23] The crystal structure of 13 is noted as preliminary since disorder
resulting from halide exchanges between the halogen atoms
attached to the antimony counterion prevents a consistent unit
cell.
[24] G. Allegra, G. E. Wilson, E. Benedetti, C Pedone, R. Albert, J.
Am. Chem. Soc. 1970, 92, 4002 – 4007.
[25] a) S. A. Snyder, A. L. Zografos, Y. Lin, Angew. Chem. 2007, 119,
8334 – 8339; Angew. Chem. Int. Ed. 2007, 46, 8186 – 8191; b) S. A.
Snyder, S. P. Breazzano, A. G. Ross, Y. Lin, A. L. Zografos, J.
Am. Chem. Soc. 2009, 131, 1753 – 1765.
[20] Products 17 and 36 are believed to result upon work-up through
a reaction between water and the acetate-bridged cationic
intermediate formed following cation–p cyclization. This mech-
anism was first advanced by Faulkner in his groupꢄs studies with
compound 16 using Br2/AgBF4 (cf. Ref. [7a]).
[21] For the reaction of 25, as well as all the other substrates in
Table 2, one minor and characterizable side-product, that of
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