Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination of Allylic Alcohols

Article abstract of DOI:10.1021/jacs.5b01384

Herein we describe a highly chemo-, regio-, and enantioselective bromochlorination reaction of allylic alcohols, employing readily available halogen sources and a simple Schiff base as the chiral catalyst. The application of this interhalogenation reaction to a variety of substrates, the rapid enantioselective synthesis of a bromochlorinated natural product, and preliminary extension of this chemistry to dibromination and dichlorination are reported.

Full text of DOI:10.1021/jacs.5b01384

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Communication
Catalytic Chemo-, Regio-, and Enantioselective
Bromochlorination of Allylic Alcohols
Dennis X Hu, Frederick J. Seidl, Cyril Bucher, and Noah Z. Burns
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 Mar 2015
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Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination
of Allylic Alcohols
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Dennis X. Hu,† Frederick J. Seidl,† Cyril Bucher, and Noah Z. Burns*
Department of Chemistry, Stanford University, Stanford, California 94305, United States
Supporting Information Placeholder
of unsaturated terpenes (1–6, Fig. 1B).19 The cytotox-
ABSTRACT: Herein we describe a highly chemo-, re-
ic17 secondary metabolite bromochloromyrcene (7),
gio-, and enantioselective bromochlorination reac-
tion of allylic alcohols, employing readily available
for example, is proposed19,20 to derive biosynthetical-
ly from myrcene via electrophilic bromination and
Markovnikov delivery of chloride across one of three
double bonds (Fig. 1C). This would represent a re-
markable example of selectivity that has yet to be
achieved in the laboratory. To this end, we report the
development of a catalytic chemo-, regio-, and enan-
tioselective bromochlorination reaction of allylic al-
cohols. This method provides access to a wide range
of interhalogenated compounds that were previously
inaccessible, even in racemic form. Furthermore,
preliminary results suggest that this strategy will be
generalizable to enantioselective dichlorination and
dibromination.
halogen sources and a simple Schiff base as the chiral
catalyst. The application of this interhalogenation
reaction to a variety of substrates, the rapid enanti-
oselective synthesis of a bromochlorinated natural
product, and preliminary extension of this chemistry
to dibromination and dichlorination are reported.
Alkene dihalogenation is
a
classic anti-
difunctionalization reaction of carbon–carbon dou-
ble bonds with few enantioselective variants.1 De-
spite impressive recent work in the stereoselective
synthesis of vicinal dichlorides and polychlorinated
natural products,2–7 no general methods exist for the
enantio- and regioselective addition of two halogen
atoms across non-conjugated olefins.8–10 Additional-
ly, catalyst control over the regioselective addition of
two different halogens (heterodihalogenation or
interhalogenation) to an alkene is unprecedented
(Fig. 1A). This lack of a general enantioselective
method for alkene dihalogenation represents a sig-
nificant gap in regio- and stereoselective methodolo-
gy that remains unsolved, despite the prevalence of
chiral bioactive poly- and interhalogenated com-
pounds in nature11,12 and the widespread use of alkyl
halides as intermediates in organic synthesis.
FIGURE 1. Alkene bromochlorination is an
interhalogenation reaction used by nature with no
synthetic regio- and/or enantioselective equiva-
lent.
Nearly 2,000 halogenated natural products that
contain either a chlorine- or a bromine-bearing ste-
reocenter have been identified from natural
sources.11,12 Many of these natural products demon-
strate potent and selective biological activities,11–17
which have remained underexplored at times explic-
itly due to a lack of isolable material.16,17 The enzy-
matic machinery responsible for dihalogenation is
not yet known,18 but many polyhalogenated second-
ary metabolites appear to arise from the selective
dibromination, dichlorination, or bromochlorination
Recently, we reported a titanium-based enantiose-
lective dibromination of allylic alcohols wherein high
enantioselectivity was obtained only for substrates in
which the regioselectivity of halide delivery was elec-
tronically biased (e.g. cinnamyl alcohols).21 This limi-
tation in substrate scope is attributed to a unique
mechanistic challenge inherent to enantioselective
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alkene dihalogenation: each enantiomer of the cyclic ternal regiocontrol over halogenation provides access
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halonium intermediate can be opened by halide ion
to form two possible constitutional isomers.2,8,21
When the electrophilic and nucleophilic halogen
atoms are the same element, the two products of re-
gioisomeric opening are enantiomers. When the
electrophilic and nucleophilic halogen atoms are dif-
ferent, four distinct products can be formed. Inter-
ested in exploring this interplay between regioselec-
tivity and enantioselectivity and cognizant of the fact
that catalyst-controlled interhalogenation of carbon–
carbon double bonds did not exist, we directed our
efforts to designing a system capable of selective
bromochlorination of allylic alcohols. It was antici-
pated that the development of such chemistry would
enable access to a broad range of interhalogenated
natural product motifs while providing mechanistic
insight by allowing independent quantification of
enantioselectivity and regioselectivity.
to compounds for which separation or resolution of
isomers would otherwise be non-trivial.
TABLE 1. Development of an enantio- and regioselec-
tive bromochlorination of allylic alcohols.
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Table 1 summarizes the optimization of this selec-
tive bromochlorination reaction. When allylic alco-
hol 8 was treated with pyridinium chloride and N-
bromosuccinimide (NBS),
a
convenient non-
disproportionating equivalent to bromine mono-
chloride,22,23 a constitutional isomer ratio (cr) of 1:4
was obtained for 9A and 9B, favoring chloride addi-
tion to C3 (Table 1, entry 1). This is consistent with
the electronic preference for nucleophiles to add to
non-symmetric halonium intermediates in a Mar-
kovnikov fashion.24 With chlorotitanium triiso-
propoxide and NBS, the inherent sense of regioselec-
tivity was maintained, albeit in a lower ratio (entry
2). Diol 10 exerted a small influence on selectivity
(entry 3), but further ligand investigations (11–13,
entries 4–6) identified tridentate Schiff base 1325 as
being particularly promising. When 50 mol % 13 was
added to the reaction mixture, equal amounts of the
two constitutional isomers were formed, but signifi-
cant enantiomeric excess (ee) was observed only for
the isomer arising from delivery of chloride to C2
(entry 6). This difference in enantioselectivity be-
tween constitutional isomers could have been de-
convolved only through studying interhalogenation.
A crucial finding was that in nonpolar solvents, such
as hexanes, the regioselectivity of this Schiff base-
Reactions were conducted on 0.1 mmol scale; consti-
tutional isomers assigned based on observation of C-
NMR chlorine isotopic shifts; absolute configuration of
9A assigned by X-ray crystallography; absolute config-
uration of 9B not determined.
13
Under the optimized conditions, five prevalent di-
halogenated terpenoid motifs could be produced on
preparative scale in high yields and with high levels
of selectivity (Table 2, entries 1–5). Substrates with
multiple olefins are halogenated with high chemose-
lectivity at the less nucleophilic allylic alcohol alkene
(entries 6–9, and 13). Ester (entry 9), ketone (entry
10), and silyl ether (entries 8 and 16) functionalities
are also well tolerated. 1,1-Disubstituted (entries 1, 11,
13, and 14), trisubstituted (entries 2–10, and 12), and
cis-disubstituted alkene (entries 15 and 16) substrates
are bromochlorinated selectively under these condi-
tions. trans-Disubstituted alkenes react with poor
regioselectivity, and significant enantio- and regiose-
lectivity have not yet been observed for alkenes lack-
ing allylic hydroxyl functionality. Absolute configura-
tion was assigned for several products or derivatives
(entries 1, 3, 6, and 10) by X-ray crystallography. A
proposed intermediate for this reaction is shown at
the top of Table 2 that invokes a ligand- and sub-
strate-bound titanium complex (14) wherein the hal-
ide is delivered to the nearest olefinic carbon.
catalyzed
bromochlorination
favors
anti-
Markovnikov halide addition to C2, with a concomi-
tant improvement in enantioselectivity (entry 7).
Optimal selectivities were observed at lower temper-
atures (–20 ˚C), conditions that allow for a reduction
in catalyst loading (entries 8 and 9). Here, nearly
exclusive formation of anti-Markovnikov product 9A
was observed, demonstrating that this system is ca-
pable of overriding inherent substrate bias. Such ex-
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TABLE 2. Substrate scope.
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Journal of the American Chemical Society
Using tert-butyl hypochlorite and chlorotitanium
triisopropoxide (entry 17) or NBS and bromotitanium
triisopropoxide (entries 18 and 19), enriched dichlo-
rides or dibromides are produced that map directly
onto known dihalogenated natural product motifs (3
and 4, Figure 1).
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Scheme 1. Applications of selective bromochlo-
rination.
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Reagents and conditions: a. NBS (1.05 equiv),
ClTi(Oi-Pr)3 (1.10 equiv), 10 mol % (R,S)-13, hexanes, –
20 ˚C; b. Dess–Martin periodinane (DMP) (1.5 equiv),
NaHCO3 (10.0 equiv), CH2Cl2, r.t.; c. methyltri-
phenylphosphonium bromide (1.8 equiv), sodium hex-
amethyldisilazide (NaHMDS) (1.4 equiv), toluene, –78
˚C to 0 ˚C, 60% over two steps.
Substantial catalyst influence has also been ob-
served with enantioenriched (S)-perillyl alcohol (15,
Scheme 1, top). When 15 was subjected to bromo-
chlorination conditions employing (S,R)-13, bromo-
chloride 16 was formed as the major product. When
enantiomeric (R,S)-13 was used, constitutional iso-
mer 17 was produced almost exclusively. The unusual
preference for chloride delivery to the distal olefinic
carbon in the former case (16) is rationalized as a
combination of catalyst facial control of alkene halo-
genation with the requirement for trans-diaxial de-
livery of halogens to a conformationally restricted
cyclohexene.26 Both isomeric bromochlorocyclohex-
Conditions unless otherwise noted: ≥ 1 mmol scale,
1.05 equiv NBS, 1.10 equiv ClTi(Oi-Pr)3, 10–30 mol %
(S,R)-13, hexanes, –20 ˚C, 4–12 hours; constitutional
isomers assigned based on observation of 13C-NMR
chlorine isotopic shifts; reported isolated yields are for
the sum of constitutional isomers; a. solvent = 3:1 hex-
anes/CCl4; b. 1.05 equiv tert-butyl hypochlorite used in
place of NBS; c. 1.10 equiv BrTi(Oi-Pr)3 used in place of
ClTi(Oi-Pr)3.
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(1) (a) Carreira, E. M.; Kvaerno, L. Classics in Stereoselective
ane motifs in 16 and 17 can be found within several
natural products including obtusol27 (18) and prein-
tricatol28 (19).
1
2
Synthesis; Wiley-VCH: Weinheim, 2009. (b) Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis;
Springer: New York, 1999.
3
4
5
6
7
8
9
(2) (a) Nicolaou, K. C.; Simmons, N. L.; Ying, Y.; Heretsch, P.
M.; Chen, J. S. J. Am. Chem. Soc. 2011, 133, 8134–8137. (b) Monaco,
M. R.; Bella, M. Angew. Chem. Int. Ed. 2011, 50, 11044–11046.
(3) (a) Nilewski, C.; Deprez, N. R.; Fessard, T. C.; Li, D. B.;
Geisser, R. W.; Carreira, E. M. Angew. Chem. Int. Ed. 2011, 50,
7940–7943. (b) Nilewski, C.; Geisser, R. W.; Carreira, E. M. Na-
ture 2009, 457, 573–576. (c) Nilewski, C.; Carreira, E. M. Eur. J.
Org. Chem. 2012, 9, 1685–1698.
(4) (a) Snyder, S. A.; Tang, Z.-Y.; Gupta, R. J. Am. Chem. Soc.
2009, 131, 5744−5745. (b) Brucks, A. P.; Treitler, D. S.; Liu, S.-A.;
Snyder, S. A. Synthesis 2013, 45, 1886–1898.
(5) (a) Chung, W.-J.; Carlson, J. S.; Vanderwal, C. D. J. Org.
Chem. 2014, 79, 2226–2241. (b) Chung, W. J.; Vanderwal, C. D.
Acc. Chem. Res. 2014, 47, 718–728.
(6) (a) Yoshimitsu, T.; Fukumoto, N.; Nakatani, R.; Kojima, N.;
Tanaka, T. J. Org. Chem. 2010, 75, 5425–5437. (b) Umezawa, T.;
Shibata, M.; Kaneko, K.; Okino, T.; Matsuda, F. Org. Lett. 2011,
13, 904–907. (c) Yoshimitsu, T.; Nakatani, R.; Kobayashi, A.;
Tanaka, T. Org. Lett. 2011, 13, 908–911. (d) Umezawa, T.; Matsu-
da, F. Tetrahedron Lett. 2014, 55, 3003–3012.
(7) Recently a catalytic, stereospecific, syn-dichlorination of
alkenes was reported: Cresswell, A. J.; Eey, S. T.-C.; Denmark, S.
E.; Nature Chem. 2015, 7, 146–152.
(8) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem.
Int. Ed. 2012, 51, 10938–10953.
(9) Chen, J.; Zhou, L. Synthesis 2014, 46, 586–595.
(10) Cheng, Y. A.; Yu, W. Z.; Yeung, Y.-Y. Org. Biomol. Chem.
2014, 12, 2333–2343.
(11) Gribble, G. W. Naturally Occurring Organohalogen Com-
pounds – A Comprehensive Survey; Springer-Verlag: Wien, 1996.
(12) Gribble, G. W. Naturally Occurring Organohalogen Com-
pounds – A Comprehensive Update; Springer-Verlag: Wien,
2010.
(13) Fuller, R. W.; Cardellina, J. H., II; Kato, Y.; Brinen, L. S.;
Clardy, J.; Snader, K. M.; Boyd, M. R. J. Med. Chem. 1992, 35,
3007–3011.
(14) Andrianasolo, E. H.; France, D.; Cornell-Kennon, S.;
Gerwick, W. H. J. Nat. Prod. 2006, 69, 576–579.
(15) Kladi, M.; Vagias, C.; Roussis, V. Phytochem. Rev. 2014, 3,
337–366.
The utility of the bromochloroalcohol motif is il-
lustrated by a short chemo-, regio-, and enantiose-
lective synthesis of (+)-bromochloromyrcene (7).
Selective bromochlorination of known alcohol 20 on
multigram scale provided 21, which was readily con-
verted into (+)-(7) in two steps via aldehyde 22
(Scheme 1, bottom). This natural product was pre-
pared previously in racemic form in 9 steps.29 An op-
tical rotation taken at the same concentration (c =
147 mg/mL) as the original isolation20 suggests that
natural bromochloromyrcene is produced in only ca.
35% ee, raising an intriguing question about the level
of enantiocontrol in its biosynthesis. The present
methodology should facilitate future investigations
into the degree of enantiopurity of similar natural
products.
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External enantio- and regiocontrol in alkene
interhalogenation has been demonstrated. The de-
veloped method is practical and scalable given the
trivial cost of reagents and the ease of preparation of
the chiral ligand. Multiple organohalogen building
blocks can now be readily accessed in isomerically
enriched form. We anticipate that this chemistry will
enable enantioselective syntheses of a wide variety of
polyhalogenated natural products. Such investiga-
tions are ongoing and will be reported in due course.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures,
characterizations, and spectral data. This material is
available free of charge via the Internet at
http://pubs.acs.org.
(16) Vogel, C. V.; Pietraszkiewicz, H.; Sabry, O. M.; Gerwick,
W. H.; Valeriote, F. A.; Vanderwal, C. D. Angew. Chem. Int. Ed.
2014, 53, 12205–12209.
AUTHOR INFORMATION
Corresponding Author
(17) Fuller, R. W.; Cardellina, J. H.; Jurek, J.; Scheuer, P. J.; Al-
varado-Lindner, B.; McGuire, M.; Gray, G. N.; Steiner, J. R.;
Clardy, J.; Menez, E.; Shoemaker, R. H.; Newman, D. J.; Snader,
K. M.; Boyd, M. R. J. Med. Chem. 1994, 37, 4407–4411.
(18) Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-
Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364–3378.
(19) Burreson, J. B.; Woolard, F. X.; Moore, R. E. Chem. Lett.
1975, 4, 1111–1114.
(20) Woolard, F. X.; Moore, R. E.; Mahendran, M.; Sivapalan,
A. Phytochemistry 1976, 15, 1069–1070.
(21) Hu, D. X.; Shibuya, G. M.; Burns, N. Z. J. Am. Chem. Soc.
2013, 135, 12960–12963.
(22) Popov, A. I.; Mannion, J. J. J. Am. Chem. Soc. 1952, 74,
222–224.
(23) Buckles, R. E.; Long, J. W. J. Am. Chem. Soc. 1951, 73, 998–
1000.
(24) De la Mare, P. D. B. Electrophilic Halogenation; Cam-
bridge Univ. Press: Cambridge, 1976.
nburns@stanford.edu
Author Contributions
†These authors contributed equally.
Funding Sources
This work was supported by Stanford University and
the NSF (GRF to DXH, DGE-114747).
ACKNOWLEDGMENT
We are grateful to Dr. A. Oliver (University of Notre
Dame) for X-ray crystallographic analysis and Dr. S.
Lynch (Stanford University) for assistance with NMR
spectroscopy.
REFERENCES
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(25) (a) Jiang, Y.; Zhou, X.; Hu, W.; Wu, L.; Mi, A. Tetrahe-
1
2
3
4
5
6
7
8
dron: Asymmetry 1995, 6, 405–408. (b) Li, Z.; Fernández, M.;
Jacobsen, E. N. Org. Lett. 1999, 1, 1611–1613.
(26) (a) Hageman, H. J.; Havinga, E. Rec. Trav. Chim. 1966, 85,
1141–1150. (b) Fürst, A.; Plattner, P. A. Helv. Chim. Acta. 1949, 32,
275–283.
(27) Perales, A.; Martínez-Ripoll, M.; Fayos, J. Acta Cryst. B
1979, 35, 2771–2773.
(28) König, G. M.; Wright, A. D. J. Nat. Prod. 1994, 57, 477–
485.
9
(29) Jung, M. E.; Parker, M. H. J. Org. Chem. 1997, 62, 7094–
7095.
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