Enantiospecific Solvolytic Functionalization of Bromochlorides

Article abstract of DOI:10.1021/jacs.7b07792

Herein, we report that under mild solvolytic conditions, enantioenriched bromochlorides can be ionized, stereospecifically cyclized to an array of complex bromocyclic scaffolds, or intermolecularly trapped by exogenous nucleophiles. Mechanistic investigations support an ionic mechanism wherein the bromochloride serves as an enantioenriched bromonium surrogate. Several natural product-relevant motifs are accessed in enantioenriched form for the first time with high levels of stereocontrol, and this technology is applied to the scalable synthesis of a polycyclic brominated natural product. Arrays of nucleophiles including olefins, alkynes, heterocycles, and epoxides are competent traps in the bromonium-induced cyclizations, leading to the formation of enantioenriched mono-, bi-, and tricyclic products. This strategy is further amenable to intermolecular coupling between cinnamyl bromochlorides and a diverse set of commercially available nucleophiles. Collectively, this work demonstrates that enantioenriched bromonium chlorides are configurationally stable under solvolytic conditions in the presence of a variety of functional groups.

Full text of DOI:10.1021/jacs.7b07792

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Article
Enantiospecific Solvolytic Functionalization of Bromochlorides
Alexander J. Burckle, Bálint Gál, Frederick J. Seidl, Vasil H. Vasilev, and Noah Z. Burns
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07792 • Publication Date (Web): 31 Aug 2017
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Enantiospecific Solvolytic Functionalization of Bromochloꢀ
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Alexander J. Burckle, Bálint Gál, Frederick J. Seidl, Vasil H. Vasilev, and Noah Z. Burns*
Department of Chemistry, Stanford University, Stanford, California 94305, United States
Supporting Information Placeholder
ABSTRACT: Herein we report that under mild solvolytic conditions, enantioenriched bromochlorides can be ionized, stereospecifꢀ
ically cyclized to an array of complex bromocyclic scaffolds, or intermolecularly trapped by exogenous nucleophiles. Mechanistic
investigations support an ionic mechanism wherein the bromochloride serves as an enantioenriched bromonium surrogate. Several
natural productꢀrelevant motifs are accessed in enantioenriched form for the first time with high levels of stereocontrol, and this
technology is applied to the scalable synthesis of a polycyclic brominated natural product. An array of nucleophiles including oleꢀ
fins, alkynes, heterocycles, and epoxides are competent traps in the bromoniumꢀinduced cyclizations, leading to the formation of
enantioenriched monoꢀ, biꢀ, and tricyclic products. This strategy is further amenable to intermolecular coupling between cinnamyl
bromochlorides and a diverse set of commercially available nucleophiles. Collectively this work demonstrates that enantioenriched
bromonium chlorides are configurationally stable under solvolytic conditions in the presence of a variety of functional groups.
INTRODUCTION: The number of known halogenated
natural products has increased dramatically since the early
1970’s; to date over 2,000 secondary metabolites containing
either a chlorineꢀ or bromineꢀbearing stereocenter have been
isolated and structurally characterized.1 Of these, approximateꢀ
ly 500 contain a brominated fiveꢀ, sixꢀ, or sevenꢀmembered
cyclic scaffold that is commonly embedded within a larger
polycyclic framework (1–9, Figure 1A).1 Promising biological
activity has been demonstrated for brominated cyclic terpenes,
with noteworthy examples including dactylone (1) as a cancer
preventative agent,2 callophycoic acid G (6) as an antibiotic
against resistant Staphylococci and Enterococci strains,3 and
thyrsiferyl 23ꢀacetate (7) which exhibits subꢀnanomolar activiꢀ
ty against a Pꢀ388 leukemia cell line.4
nate in an arene or a phenol, significantly limiting its potential
utility in the context of natural product synthesis. Although
some formal bromopolyene cyclizations (multistep cyclization
sequences or cyclizations from a bromohydrin derivative)
provide access to natural productꢀrelevant scaffolds, these
reactions are generally limited by narrow substrate scopes,
moderate selectivities, or the use of stoichiometric toxic heavy
metals.10
To address these shortcomings, we anticipated that enantiꢀ
oenriched vicinal dihalides could be deployed under solvolytic
conditions to effect bromopolyene cyclizations across a broad
range of substrates. Recently our laboratory disclosed a stereoꢀ
specific solvolytic cyclization of an enantioenriched bromoꢀ
chloride en route to the synthesis of four distinct members of
the brominated chamigrene sesquiterpenes, including the highꢀ
ly strained aplydactone (2) (Figure 1A).11 We hypothesized
this solvolytic approach could be a useful platform for the
generation of an enantiopure bromonium ion (10, Figure 1C)
which could then be captured in an intraꢀ or intermolecular
sense. Herein, we describe our investigation into mechanistic
aspects of this cyclization, a full exploration of the substrate
scope with various enantioenriched bromochloride motifs in
conjunction with a range of pendant nucleophiles, application
to a scalable enantioselective synthesis, and an extension of
this solvolytic reaction manifold to intermolecular couplings.
Biosynthetically, these compounds are thought to arise from
the carbocationic cyclization of an isoprenoid initiated by an
electrophilic source of bromine (Br+) (Figure 1B) followed by
discrete steps including: cyclohexane formation (Figure 1B,
path a), decalin formation (path a,b), and/or heteroatom trapꢀ
ping (e.g. paths b, c, d).5 Recapitulating this reactivity with
high levels of chemoꢀ, diastereoꢀ, and enantioselectivity in a
laboratory setting has long eluded chemists. The first report of
a racemic bromopolyene cyclization was published more than
50 years ago by van Tamelen and Hessler.6 Since this seminal
report, a variety of reactive brominating reagents have been
used to initiate polyene cyclizations, albeit in generally low
yields.7 In fact, a high yielding protocol did not emerge until
the popularization of more reactive sulfoniumꢀbased brominatꢀ
ing agents by the Snyder laboratoy.8 The work recently pubꢀ
lished by Yamamoto and coꢀworkers stands as the only examꢀ
ple of a catalytic enantioselective bromopolyene cyclization.9a
While selectivities for this reaction are generally impressive,
the scope of this reaction is limited to cyclizations that termiꢀ
DEVELOPMENT AND MECHANISM OF
A
SOLVOLYTIC CYCLIZATION: The bromonium ion, a
reactive intermediate universally taught in undergraduate orꢀ
ganic chemistry, has a rich history in chemical synthesis. This
intermediate can be readily accessed from olefins in racemic
fashion. However, forming an enantiopure bromonium ion has
remained a longstanding challenge for synthetic chemists.
Studies on the nature and reactivity of racemic bromonium
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Figure 1. (A) Representative bromocyclic natural products. (B) Putative biosynthetic pathway for the biosynthesis of two related natural
products involving several discrete bromocyclization steps. (C) Our previous work on a stereospecific bromopolyene cyclization and that
accomplished in this report.
ions date back to the pioneering work by Winstein in the
1940’s.12 It was not until 2010 when Denmark and coꢀworkers
investigated the configurational stability of enantiopure broꢀ
monium ions;13 in that report, the stereochemical integrity of a
bromonium ion was observed to be highly dependent on the
nature of the trapping nucleophile and presence of alkene in
ionizing media. However, the Braddock group has demonꢀ
strated that a configurationally stable enantiopure bromonium
ion can be generated and captured in the presence of an alkene
nucleophile and an oxophilic Lewis acid in dichloroꢀ
methane.10d Together, these reports highlight a rather incomꢀ
plete understanding of the configurational stability of a broꢀ
monium ion in varied reaction settings. With our recent total
synthesis of aplydactone notwithstanding, there have been no
investigations into the stereochemical nature of a bromonium
ion derived from an enantioenriched dihalide.
no observed racemization of the starting material, with slow
equilibration to the isomeric bromochloride over extended
reaction times (entries 3 and 4). When the temperature of the
reaction was elevated to 50 °C cyclization was observed
(10%) with no loss in enantiopurity of the cyclized product or
starting material (entry 5). We next sought to improve the
yield of the solvolytic cyclization and hypothesized that the
presence of the alcohol used to direct the dihalogenation was
impeding ionization and/or subsequent cyclization. Indeed,
when deoxygenated furyl bromochloride 15 was subjected to
the solvolysis at room temperature facile equilibration of the
bromochloride regioisomers was observed with concomitant
production of bromocycle 16 in synthetically viable yields
(40%) and high enantiospecificity (entry 6).
A mechanistic rationale explaining the observed trends (Taꢀ
ble 1B) involves the initial formation of bromonium intermeꢀ
diate 18 from all dihalide starting materials (11, 14, 15). In the
case of bromochlorides 14 and 15, recapture by chloride anion
could lead to the observed mixture of constitutional isomers
(X = Cl, 17 and 19). In the case of dibromide 11, such ionizaꢀ
tion and recapture by bromide anion would lead to dibromide
racemization (via 18 or 20). Bromochlorides 14 and 15 thus
serve as non-racemizing, enantioenriched bromonium surro-
gates under these conditions.
Our laboratory previously disclosed a chemoꢀ, regioꢀ, and
enantioselective Schiff baseꢀcatalyzed dihalogenation reaction
of allylic alcohols, providing access to highly enantioenriched
bromochlorides, dibromides, and dichlorides.14 We initially
hypothesized that subjecting these species to ionizing condiꢀ
tions could facilitate the generation of an enantioenriched
halonium ion that could be captured intramolecularly for
productive cyclization (Figure 1C). To test our hypothesis we
first subjected enantioenriched dibrominated furan alcohol 11
to common ionizing conditions of 1,1,1,3,3,3ꢀhexafluoroꢀ2ꢀ
propanol (HFIP)15 hopeful that an enantioenriched bromonium
ion 12 could be generated and captured by the nucleophilic
furan, ultimately leading to carbocycle 13 (Table 1A). Unforꢀ
tunately, facile dibromide racemization (i.e. 11 to ent-11) was
found to occur at room temperature (entry 1), with only trace
racemic cyclization product 13 being observed after 96 hours
(entry 2). Fortunately, subjecting the analogous enantioenꢀ
riched bromochloroalcohol 14 to the ionizing conditions led to
Seeking to better understand the mechanism of bromochloꢀ
ride solvolysis and to distinguish it from the closely related
dyotropic rearrangement of dihalides,16 we computationally
investigated the interconversion between isomeric bromochloꢀ
rides of 2ꢀmethylꢀ2ꢀbutene (Figure 2). We hypothesized that
solvent dielectric plays an important role in stabilizing interꢀ
mediates or transition states that have high charge separation.
Calculations were performed at the M06ꢀ2X/6ꢀ31G+(d) level
of theory with the IEFPCM implicit solvation model using
either toluene or 2,2,2ꢀtrifluoroethanol (TFE) as solvent (see
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Table 1. Timepoint analysis for the solvolytic cyclization of enantioenriched dihalides.
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a
(A) Prepared as a >20:1 mixture of constitutional bromochloride isomers. b1.5 equiv. K2CO3, 0.05 M in HFIP. cBased on 1H NMR analyꢀ
sis using 1,4ꢀdinitrobenzene as an internal standard. dAccording to chiral stationary phase HPLC analysis. eRatio of constitutional isomers
according to H NMR analysis. HPLC integration was complicated by the presence of the corresponding constitutional isomer. (B) Proꢀ
posed mechanism for equilibration of bromochloride constitutional isomers and racemization of dibromides.
1
f
Supporting information and references therein for details). In
the nonpolar solvent model with implicit toluene, a dyotropic
rearrangement transition state structure was identified, but no
ground state structure corresponding to an ion pair was found.
Conversely, in the polar solvent model with implicit TFE, two
transition state structures corresponding to ionization of each
isomer were found, along with an intermediate bromonium
chloride ion pair ground state. Overall, implicit polar solvation
lowers the calculated barrier to rearrangement by 8 kcal/mol.
Inclusion of a single explicit HFIP molecule hydrogenꢀbonded
to chloride further lowers this barrier by an additional 5.7
kcal/mol (see Supporting Information). These results suggest
that both solvent dielectric and hydrogen bonding play a role
in activating vicinal bromochlorides toward ionization under
our solvolytic conditions, and establish the bromonium chloꢀ
ride tight ion pair as a viable intermediate in the mechanism of
these solvolytic reactions.
SUBSTRATE SCOPE AND APPLICATIONS: With opꢀ
timal conditions in hand, a wide variety of substrates were
synthesized and investigated. We discovered that the condiꢀ
tions for solvolysis were readily applicable to a diverse set of
bromochlorides synthesized from the corresponding trisubstiꢀ
tuted allylic alcohol via our reported dihalogenationꢀ
deoxygenation sequence10,14 with the exception of substrate
24a. The varied nature of nucleophiles used to trap the bromoꢀ
nium ions generated from the corresponding bromochlorides is
shown in Table 2 and includes trisubstituted olefins, free alcoꢀ
hols, alkynes, carbamates, esters, phenols, and a furan heteroꢀ
cycle. As previously described in Table 1, furyl bromochloride
15 is cyclized with perfect enantiospecificity. Enantioenriched
bromochlorides derived from geraniol are effectively cyclized
with various terminating groups (21a, 22a, 23a, and 26a) and
were isolated as single diastereomers. The cyclization of 21a
was performed on gramꢀscale and proceeded with 96% enantiꢀ
ospecificity, producing the simple bromoꢀcyclohexane motif
which we utilized in our recently disclosed total synthesis of
the chamigrene sesquiterpenes.11 The bicyclic bromolactone
23b derived from diꢀtertꢀbutyl malonate 23a, whose absolute
stereochemistry was determined by Xꢀray crystallography,
confirmed that the cyclization proceeded with complete retenꢀ
tion of the bromide stereocenter. Cyclization of internal broꢀ
mochloride 24a proceeded in good yield and high enantiospecꢀ
ificity (91% es), but was isolated as a mixture of epimeric
tertiary ethers. This result is particularly intriguing as it sugꢀ
gests that the intermediate bromonium exists as, or in equilibꢀ
rium with an open βꢀbromo carbocation; nonꢀstereoselective
nucleophilic attack then accounts for the formation of both
‡
PCM = toluene
PCM = TFE
‡
‡
dyotropic
rearrangement
40.6
32.6
32.6
32.4
bromonium/chloride
ion-pair
1.5
0.0
Figure 2. Computational investigation of the interconversion of
bromochloride constitutional isomers at the M06ꢀ2X/6ꢀ31G+(d)
level of theory; uncorrected electronic energies are listed in
kcal/mol (PCM = polarizable continuum model).
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see SI. gAfter subsequent decarboxylation step. hdr shown for two
isolated diastereomers; see SI for structures.
diastereomers in 24b. At this time we cannot rule out competꢀ
ing participation of the styrene,
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Table 2. Substrate Scope of the Solvolytic Cyclization.
or subtle hydrogen bonding effects with the free alcohol, as a
rationale for the lower levels of diastereoselectivity. It is worth
noting that accessing and effectively capturing the bromonium
from bromochloride 24a would be difficult or impossible with
other protocols given the polyunsaturated nature of the subꢀ
strate. Cyclization of alkynyl bromochloride 25a interestingly
provided cyclopentyl bromide 25b. To our knowledge, this is
the only example of a bromoniumꢀinduced cyclization affordꢀ
ing a bromocyclopentaneꢀ a motif found in bromocyclic natuꢀ
ral products (e.g. 5, Figure 1A).
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Expanding on successful cyclizations with geraniolꢀderived
bromochlorides, we subjected bromochlorofarnesyl acetate
27a to the solvolytic cyclization conditions. We were able to
isolate the bicyclic bromodecalin 27b and a corresponding
diastereomer in a combined 30% yield. Also isolated were
small amounts (ca. 5%) of additional minor diastereomer conꢀ
tent and significant amounts of partially cyclized material (ca.
40%). Mechanistically, these results implicate a stepwise polꢀ
yolefin cyclization being operative under these reaction condiꢀ
tions; however, we cannot rule out a concerted cyclization at
this time. This bromodecalin has been previously used in variꢀ
ous racemic natural product syntheses17 but has never been
accessed in enantioenriched form.
We were particularly intrigued by trying to access bromopyꢀ
ran 29 (Scheme 1), a motif that is found in close to 100 natural
products (e.g. 7, Figure 1), however synthetic technologies
enabling enantioꢀ and diastereoselective access to this motif
are largely deficient.18 To date, only one approach utilizing an
epoxide opening kinetic resolution with a bromohydrin has
been successful in accessing this motif with regioꢀ and enantiꢀ
ocontrol.19 We were confident that we could access this chalꢀ
lenging motif using our dihalide solvolysis, and to test this
strategy, we constructed epoxidized bromochlorogeraniol deꢀ
rivative 28 and subjected this substrate to standard solvolysis
conditions. Unfortunately, the reaction produced a complex
mixture of products. However, when this crude mixture was
treated with wet HCl in ether, we observed formation of 29 as
the major reaction product. Our working hypothesis is that
when substrate 28 is subjected to the solvolysis conditions
oxonium ion 30 is initially formed and nonselectively trapped,
either intramolecularly via the carbamate or intermolecularly
by adventitious water, leading to a mixture of bromopyran 29
and the corresponding 7ꢀmembered bromoether (i.e. from the
trapping of 30 at Cꢀ6). We believe that subjecting the crude
mixture to acidic aqueous ether leads to reformation of 30, but
is selectively trapped by water at Cꢀ7 to 30a under these conꢀ
ditions leading to formation of pyran 29.
While we previously demonstrated the utility of this solꢀ
volytic methodology in the total synthesis of the brominated
chamigrene sesquiterpenes, we sought to demonstrate that this
methodology could be applied towards the scalable synthesis
of a brominated polycyclic natural product (Scheme 2). We
targeted the bicyclic, brominated ether 3420 which we believed
could be accessed in a straightforward fashion from bromolacꢀ
tone ent-23b. Solvolysis of diꢀtertꢀbutyl malonate bromochloꢀ
ride entꢀ23a on 5.7 gramꢀscale proceeded smoothly, and a
subsequent decarboxylation step on the crude material cleanly
afforded bicyclic bromolactone entꢀ23b in 75% yield as a sinꢀ
gle isolated diasteromer, with complete enantiospecificity,
over two steps. Our strategy called for conversion of lactone
aBased on chiral stationary phase HPLC analysis of the correꢀ
sponding bromochloroalcohol. bYields shown are of the major
isolated diastereomer; d.r. given is for combined diastereomer
content unless otherwise noted. cBased on chiral HPLC analysis of
the cyclization product or derivative; es (enantiospecificity) =
d
((%ee s/m)/(%ee product)) x 100%. Reaction conducted at 4 ºC;
NMR yield for 16. eSee ref. 11. fAfter subsequent hydrolysis step;
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entꢀ23b to allylic diol 33, which required conversion to the rapid (<5 mins) conversion of the starting material to bicyclic
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acyclic Weinreb amide 31, and was then converted to methyl
ketone 32 on gramꢀscale. This intermediate proved to be unꢀ
stable, where upon exposure to acidic media or silica gel the
material was observed to rapidly dehydrate to a cyclic enol
ether. Bypassing a purification step, crude keto alcohol 32 was
treated with vinylmagnesium chloride on gramꢀscale to afford
diol 33 in 73% yield over two steps.
ether 34 and its corresponding C8ꢀepimer (ca. 1:1 dr). Over
time, the diastereomeric ratio of the desired natural product
increased with slight erosion in overall yield, which was conꢀ
comitant with formation of an isomeric, bicyclic tetrahydrofuꢀ
ran. This suggests that 34 and its epimer are initially formed
with low diastereoselectivity (ca. 1:1 dr) and rapidly and reꢀ
versibly interconvert as the reaction progresses. Each diastereꢀ
omer is then irreversibly funneled to undesired byproduct at a
different rate, giving rise to the enrichment in the desired epiꢀ
mer of 34. Allowing this reaction to run for extended periods
resulted in exclusive formation of the undesired isomer, sugꢀ
gesting it is the thermodynamic product in this setting. The
consequence of this mechanistic scenario is that the reaction
must be run for an amount of time such that good levels of
diastereoselectivity are obtained while the amount of isomeric
byproduct formed is minimized, thereby maximizing the yield
of desired 34. Allowing the cyclization to run for a period of 1
hour at 4 ºC proved to be optimal conditions on scale, and we
obtained the natural product in 50% yield and 6:1 dr. Having
produced a total amount of 233 mg, we have demonstrated the
use of this methodology toward the scalable enantioselective
synthesis of a brominated natural product.
Scheme 1. Solvolytic epoxide opening cascade for the syn-
thesis of a brominated pyrana
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EXTENSION TO INTERMOLECULAR COUPLING:
Having demonstrated the utility of this approach in an intra-
molecular sense, as well as its utility in total synthesis, we set
out to see if this methodology could be extended to intermo-
lecular solvolytic couplings. Given the extensive use of alkyl
halides as versatile building blocks in chemical synthesis, we
believed that developing a strategy for providing access to a
diverse set of highly enantioenriched antiꢀfunctionalized alkyl
bromides would be an enabling technology.
aReagents and conditions: (i) K2CO3 (1.5 equiv), 1,1,1,3,3,3ꢀ
hexafluoroisopropanol (0.05 M), rt; (ii) HCl (concentrated aq., 5
equiv), wet Et2O, rt, 34% over two steps.
Treatment of diol 33 with boron trifluoride diethyl etherate
readily afforded target natural product 34 as a mixture of diaꢀ
stereomers (ca. 4:1 dr at C8) on small scale. However, atꢀ
tempts to scale this reaction gave inconsistent results. Specifiꢀ
cally, variable amounts of the natural product and its epimer
were produced, in addition to an isomeric byproduct. These
findings prompted us to investigate the nature of this cyclizaꢀ
tion and after extensive experimentation on this system (see
Supporting Information for details), we were able to develop a
mechanistic hypothesis consistent with our data. Treating 33
with a slight excess of boron trifluoride diethyl etherate led to
After investigating an array of enantioenriched dihalides, we
identified cinnamyl bromochloride 35 as an optimal substrate
which was observed to engage with a diverse set of exogenous
nucleophiles in an intermolecular coupling reaction. Our solꢀ
volysis conditions employed in the intramolecular cyclization
were general for intermolecular coupling with some minor
modifications. Running the reactions at a concentration of 0.1
M (cyclizations are run at 0.05 M) at room temperature and
employing 5 equivalents of a commercially available nucleoꢀ
Scheme 2. Application of the dihalide solvolysis to a scalable, enantioselective synthesis of a brominated natural producta
aReagents and conditions: (a) K2CO3 (1.5 equiv), 1,1,1,3,3,3ꢀhexafluoroisopropanol (0.05 M), rt; (b) trifluoroacetic acid, CH2Cl2, rt;
PhMe, 110 ºC, 75% over two steps; (c) trimethylaluminum (3.0 equiv), N,Oꢀdimethylhydroxylamine hydrochloride (3.0 equiv), CH2Cl2, 0
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ºC to rt; (d) methyllithium lithium bromide complex (3.5 equiv), THF, –78 ºC; (e) vinylmagnesium chloride, Et2O, 0 ºC, 73% over two
1
steps; (f) BF3— OEt2 (1.5 equiv), CH2Cl2, 4 ºC, 50% (6:1 dr).
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Table 3. Scope of the intermolecular solvolytic coupling.
Simple nucleophiles can be readily deployed to effect carꢀ
bon–nitrogen, carbon–fluorine, carbon–sulfur, and carbon–
oxygen bond formation in good yield, high levels of diastereꢀ
oselectivity, and with excellent enantiospecificity (all >90%;
37–42). Triethylsilane can be employed to effect stereospecific
reduction of the bromochloride (36). This method can be exꢀ
tended to carbon–carbon formation using allyltrimethylsilane
as nucleophile (43 and 46). Triethylsilylꢀprotected cinnamyl
bromochloride can be allylated in excellent yield producing
the product (43) in 12:1 dr with near perfect enantiospecificity.
Simple arenes also serve as competent nucleophiles in this
reaction for productive carbon–carbon bond formation (44).
Deoxygenated cinnamyl bromochlorides were observed to be
considerably more reactive than their alcoholꢀbearing counterꢀ
parts, presumably due to an increase in the rate of solvolysis,
capture, or both. These underwent clean reactions with several
distinct nucleophiles (45–47). A current limitation of this
method is the requirement of an arene to stabilize the bromoꢀ
nium resulting from the solvolysis of the bromochloride. Curꢀ
rently, most alkylꢀderived bromochlorides do not engage in
the solvolytic coupling, however citronellyl bromochloride 48
can be diastereospecifically converted to its corresponding
bromohydrin (49), a common motif found in halogenated natꢀ
ural products (e.g. 8), under these conditions. We are actively
engaged in further exploring the substrate scope of this reacꢀ
tion, specifically with regard to nonꢀbenzylic substrates.
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CONCLUSION: We have demonstrated that under mild
solvolytic conditions enantioenriched bromochlorides can be
efficiently cyclized to a diverse array of natural productꢀ
relevant motifs, and coupled to exogenous nucelophiles in an
intermolecular sense, with high levels of enantiospecificity.
Bromochlorides were demonstrated to be superior to their
dibromide counterparts, which were observed to rapidly and
competitively racemize under the cyclization conditions. A
variety of enantioenriched antiꢀfunctionalized brominated
compounds can be constructed from their corresponding broꢀ
mochloride precursor, which we anticipate will serve as valuꢀ
able building blocks in chemical synthesis. This solvolytic
approach provides scaffolds that have seen use in racemic total
syntheses and are herein accessed in highly enantioenriched
form for the first time.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, full characterization, spectral data, and
computational details. This material is available free of charge on
the ACS Publications website.
AUTHOR INFORMATION
aIsolated as a 4:1 mixture of thiocyanate and isothiocyanate. bTriꢀ
Corresponding Author
c
ethylsilyl protected 35 was used in this reaction. Isolated as a
*nburns@stanford.edu
12:1 mixture of diastereomers. dIsolated as a 2.5:1 mixture of
e
Funding Sources
ortho,para- to ortho,orthoꢀisomers. Isolated as a 9:1 mixture of
f
diastereomers. HPLC integration was complicated by the presꢀ
This work was supported by Stanford University, the National
Institutes of Health (R01 GM114061), and the National Science
Foundation (DGEꢀ114747 GRF to AJB).
ence of a trace impurity.
phile proved optimal. Under these conditions, a variety of
carbon–heteroatom bond formations can be effected and the
scope of this reaction is highlighted in Table 3.
Notes
The authors declare no competing financial interests
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bromonium ion is generated from a dihalide, a halohydrin, or a deꢀ
ACKNOWLEDGMENT
rivative thereof. For a summary of key findings, see part XIII of this
series: Winstein, S.; Grunwald, E. J. Am. Chem. Soc. 1948, 70, 828–
837.
(13) Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc.
2010, 132, 1232–1233.
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We are grateful to Dr. A. Oliver (University of Notre Dame) for
Xꢀray crystallographic analysis and Dr. S. Lynch (Stanford Uniꢀ
versity) for assistance with NMR spectroscopy.
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