Catalytic Regio- and Enantioselective Haloazidation of Allylic Alcohols

Article abstract of DOI:10.1021/jacs.8b10799

Herein we report a highly regio- and stereoselective haloazidation of allylic alcohols. This enantioselective reaction uses readily available materials and can be performed on a variety of alkyl-substituted alkenes and can incorporate either bromine or chlorine as the electrophilic halogen component. Both halide and azido groups of the resulting products can be transformed into valuable building blocks with complete stereospecificity. The first example of an enantioselective 1,4-haloazidation of a conjugated diene is reported as well as its application to a concise synthesis of an aza-sugar.

Full text of DOI:10.1021/jacs.8b10799

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Catalytic Regio- and Enantioselective Haloazidation of Allylic Alcohols
Frederick J. Seidl, Chang Min, Jovan A. Lopez, and Noah Z. Burns
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 07 Nov 2018
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Catalytic Regio- and Enantioselective Haloazidation of Allylic
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‡
‡
Frederick J. Seidl , Chang Min , Jovan A. Lopez, and Noah Z. Burns*
Department of Chemistry, Stanford University, Stanford, California 94305, United States
Supporting Information Placeholder
ABSTRACT: Herein we report a highly regio- and
stereoselective haloazidation of allylic alcohols. This
enantioselective reaction uses readily available materials
and can be performed on a variety of alkyl-substituted
alkenes and can incorporate either bromine or chlorine as
the electrophilic halogen component. Both halide and
azido groups of the resulting products can be transformed
into valuable building blocks with complete
stereospecificity. The first example of an enantioselective
halogen electrophiles with a titanium-bound nitrogen
nucleophile to render this a more general platform for the
selective 1,2-difunctionalization of allylic alcohols.
Herein we describe the enantioselective haloazidation of
allylic alcohols as an illustration of this process.
Figure 1. Selective Haloazidation and Aminochloride
Natural Products
1
,4-haloazidation of a conjugated diene is reported as
well as its application to a concise synthesis of an aza-
sugar.
Vicinal difunctionalization of alkenes is a powerful
way to rapidly build complexity into small molecules
1
from readily available starting materials. However,
adding two functional groups across alkenes with regio-,
diastereo-, and enantiocontrol is a challenging task.
Taking advantage of the inherent reactivity of olefins,
2
,3
halofunctionalization is among the most direct ways to
react unactivated alkenes without resorting to -bond
1
b,1c,1g
activation by late-transition metals.
Nevertheless,
due to the highly reactive nature of most commonly
employed halogen sources and the potential issue of
4
configurational instability of haliranium ions, successful
enantioselective halofunctionalizations have largely
relied on the intramolecular capture of haliranium ion
intermediates; this substantially limits their substrate
scope and synthetic utility. Our group has recently
developed an enantioselective titanium-mediated
dihalogenation of allylic alcohols. Selectivity is achieved
through the addition of substoichiometric amounts of
simple chiral Schiff base (R,S)-1 that is available in one
Since the first preparation of iodine azide by Hantsch6b
in 1900, alkene haloazidation has seen use in synthetic
7
8
chemistry. Given the utility of organic azides and alkyl
5
9
step from commercial materials (Figure 1A). This
halides, the haloazide motif serves as an obvious
method has been used strategically to achieve
enantioselective total syntheses of over 11 structurally
precursor to valuable chiral amines and potentially to a
handful of aminochlorinated natural products (Figure
1B). For electron-deficient alkenes, conjugate 1,4-
5
h
10
diverse halogenated natural products.
Due to the
importance of nonracemic chiral amines in small
molecules, we next sought to extend this system to C–N
bond formation. For this, we envisioned a combination of
addition of azide followed by trapping with electrophilic
6
a
halogen
sources
provides
substrate-controlled
regioselective access to -halo--azides (Figure 1C).
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Using this strategy to control regioselectivity, Feng11
dichlorinated alkene; f. See Supporting Information for X-
ray structures of ferrocene triazole derivatives.
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recently reported a highly enantioselective Lewis acid-
catalyzed haloazidation of enones as the first and only
enantioselective example of such a reaction. The
haloazidation of electron-neutral or rich olefins typically
uses preformed or in situ generated haloazide reagents,
however, enantioselective variants are still unknown,
presumably because these highly reactive and unstable
To apply our titanium-based system to selective alkene
haloazidation, we posited that a titanium azide species
would be Lewis acidic enough to activate an electrophilic
halogen source (bracketed intermediate, Table 1) for
+
+
intramolecular transfer of Br or Cl to form a transient
bromonium or chloronium ion. Azide could then add to
the transient halonium to deliver a haloazide product. In
accord with the seminal work of Sharpless and others on
the ring opening of epoxides by Ti(N ) (Oi-Pr) and
reagents render the control of selectivity challenging. In
7b,7d,7r,7s
addition, free radical
and ionic addition pathways
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have been proposed under different conditions, further
complicating the design of a system for asymmetric
catalysis. We thus set out to determine if our titanium–
Schiff base combination would be amenable to such a
selective alkene functionalization.
3
2
2
1
2
TiN (Oi-Pr) , we observed formation of solid TiN (Oi-
Pr) by IR (2076 cm ) upon combining stoichiometric
3
3
3
–
1
3
amounts of TMSN and Ti(Oi-Pr) . A mild exotherm was
3
4
observed in combining these two reagents (see
Supporting Information). We obtained
calorimetry/thermogravimetric analysis data on TiN (Oi-
Table 1. Haloazidation Substrate Scope
3
Pr) and observed an onset temperature of decomposition
3
of 230 ˚C (see Supporting Information). The resulting
TiN (Oi-Pr) can then be dissolved in hexanes and
3
3
directly employed in enantioselective haloazidations.
With N-bromosuccinimide (NBS) as the halogen source,
the bromoazidation is highly selective for a variety of
allylic alcohols. Cinnamyl alcohol (Table 1, entry 1),
geminal disubstituted alkenes (entries 2, 3 and 4), 1,2-
disubstituted allylic alkenes (entries 5 and 6), linear
trisubstituted alkene (entry 7) and cyclic alkenes (entry 8)
are all suitable substrates, and the resulting vicinal bromo
azides can be obtained in good yields, excellent
enantioselectivities, and good to moderate constitutional
isomer ratios (cr). C-3 disubstitution, including
tetrasubstitution, is not tolerated. Evidence for a similar
reaction pathway with our dihalogenation is provided by
5
c
identical observed regioselectivities. With the exception
of cinnamyl alcohols (entry 1) and trans-disubstituted
allylic alcohols (entry 5), C-2 azide products are obtained
as the major isomer. High chemoselectivity for allylic
alcohol haloazidition is demonstrated on a doubly
unsaturated substrate (entry 4). When substituting NBS
with t-BuOCl, the corresponding vicinal chloroazides are
produced with similarly high selectivities. A collection
of allylic alcohols is well tolerated (entries 9 to 13),
although higher Schiff base loadings are necessary, likely
due to the more reactive nature of t-BuOCl and
intermediate chloronium ions. Density functional theory
calculations (M06-2X/6-31g(d), pcm
= n-hexane)
comparing N-1 with N-3 azide addition show an energetic
preference for the distal N-3 serving as the nucleophile
(Figure 2).
In order to further demonstrate the utility and
stereointegrity of the product haloazides, several
derivatizations were investigated. All derivatizations
occur with complete stereospecifity (Scheme 1). LiAlH4
is known to reduce haloazides to the corresponding
aminohalides which spontaneously collapse to
Conditions unless otherwise noted: 1.0 mmol allylic
alcohol, 1.3 equiv of NBS or 2.0 equiv of t-BuOCl, 1.2 equiv
Ti(Oi-Pr) , 1.1 equiv TMSN , 10–30 mol % (R,S)-1,
4 3
hexanes, –20 °C, 12–18 h; a. reported isolated yields are for
the sum of constitutional isomers; b. cr = constitutional
isomer ratio; c. reaction run at 0 °C; d. 10:1 ratio of product
to dichlorinated alkene; e. 5:1 ratio of product to
7g
aziridines, and this proceeded smoothly in 82% yield to
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give hydroxy N-H aziridine 2. Selective reduction of the
rise to selective formation of unsaturated 1,4-bromoazide
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azide to the primary amine without aziridine formation
9 (Scheme 2). This method represents the first example of
was also achieved. It was found that a combination of
an
enantioselective
intermolecular
1,4-
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17
Ac O, tri-n-butylphosphonium tetrafluoroborate, and
halofunctionalization of a conjugated diene and sets two
remote stereocenters. Here it is likely that the N-3
nitrogen of the azide serves as the nucleophilic atom,
however we propose that this pathway involves diene 1,2-
addition followed by [3,3] allylic azide rearrangement
2
base was capable of reducing the azide and trapping the
incipient iminophosphorane to provide diacyl
bromoaminoalcohol 3 in 70% yield. Bromides can be
selectively substituted by pyrrolidine, piperidine, or
sodium azide to provide 4, 5, and 6/8, respectively,
18
(Scheme 2, top). Such rearrangements are known to
5
-1 18a
demonstrating efficiency in simple nucleophilic
have a first order rate constant of at least 4.9x10 sec .
Seeing potential for such products in the construction of
highly substituted chiral pyrrolidines we targeted aza-
sugar 11 (Scheme 2); such monosaccharide mimics have
served as therapeutic agents in a variety of diseases
including diabetes and viral infection as glycosidase
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displacements.
In addition, an azide-alkyne
16
cycloaddition proceeds under mild conditions in the
presence of a copper catalyst without interference of the
secondary alkyl bromide to produce triazole 7 in 84%
yield.
19
inhibitors. Following TBS protection of alcohol 9, the
Figure 2. Computed isomeric transition state structures for
N-1 versus N-3 nucleophilic addition; M06-2X/6-31g(d)
level of theory (PCM = n-hexane); relative uncorrected
electronic energies.
internal alkene undergoes a stereoselective Sharpless
dihydroxylation to give diol 10. Without the
2
(DHQ) PHAL ligand, a 1:1 mixture of diastereomers was
observed. The diol is subsequently protected as the
acetonide, and the azide can then be be reduced by
LiAlH4 to give the primary amine. After global
deprotection with HCl, clean cyclization is achieved
under basic conditions at elevated temperatures to
provide target 11. This application paves the way for the
synthesis of other enantioenriched pyrrolidines utilizing
this haloazidation technology.
‡
‡
N-1
N-3
TS N-1
+3.2 kcal/mol
TS N-3
0.0 kcal/mol
Scheme 2. Diene 1,4-Bromoazidation and Application to the
Synthesis of Aza-Sugars
Scheme 1. Bromoazide Derivatizations
Conditions: a. 10.0 mmol allylic alcohol, 1.3 equiv of
NBS, 1.2 equiv Ti(Oi-Pr)
4
, 1.1 equiv TMSN
3
, 10 mol %
(R,S)-1, hexanes, –20 °C, 74%, 90% ee; b. TBSCl (2 equiv),
Et
3
N (1.5 equiv), DMAP (0.5 equiv), DCM, RT, 90%; c.
(2 mol %), (DHQ) PHAL (6 mol %), NMO (2 equiv),
acetone/pH 7 buffer, 0 °C to RT, 68%; d. TsOHH O (10 mol
), 2,2-dimethoxypropane/acetone, RT, 92%; e. LiAlH
equiv), THF, –78 °C to RT, 72%; f. 6N HCl, MeOH, H
then K CO (14 equiv), 120 °C (µw), 6 h, 87%.
OsO
4
2
2
%
4
(3
2
O,
2
3
In summary, we have developed a highly practical
method for the catalytic enantioselective haloazidation of
electronically-unbiased alkenes with catalyst-controlled
Lastly, in an interesting display of regiochemistry, 2,4-
hexadien-1-ol is functionalized in a 1,4-manner, giving
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Jacobsen, E. N. Tertiary aminourea-catalyzed enantioselective
regio- and enantioselectivity. We have also used this
system in the first example of an enantioselective 1,4-
haloazidation of a 1,3-conjugated diene. The obtained
products have been demonstrated as precursors to chiral
nitrogen-containing small molecules including an aza-
sugar. The continuing development of our titanium-based
catalytic system in other difunctionalizations of -
systems is ongoing in our lab.
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ASSOCIATED CONTENT
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Experimental procedures, characterizations, spectral data,
and CIF files. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*nburns@stanford.edu
Author Contributions
‡
These authors contributed equally.
Funding Sources
This work was supported by Stanford University and the
National Institutes of Health (R01 GM114061).
(4) Denmark, S. E.; Burk, M. T.; Hoover, A. J. On the absolute
configurational stability of bromonium and chloronium ions. J. Am. Chem.
Soc. 2010, 132, 1232.
ACKNOWLEDGMENT
(5) (a) Hu, D. X.; Shibuya, G. M.; Burns, N. Z. Catalytic enantioselective
dibromination of allylic alcohols. J. Am. Chem. Soc. 2013, 135, 12960. (b)
Bucher, C.; Deans, R. M.; Burns, N. Z. Highly selective synthesis of
halomon, plocamenone, and isoplocamenone. J. Am. Chem. Soc. 2015, 137,
We are grateful to Dr. A. Oliver (University of Notre Dame)
for X-ray crystallographic analysis, Dr. S. Lynch (Stanford
University) for assistance with NMR spectroscopy, and Prof.
Stefan Bräse (Karlsruher Institut für Technologie) for
helpful discussion.
1
2784. (c) Hu, D. X.; Seidl, F. J.; Bucher, C.; Burns, N. Z. Catalytic chemo-,
regio-, and enantioselective bromochlorination of allylic alcohols. J. Am.
Chem. Soc. 2015, 137, 3795. (d) Burckle, A. J.; Vasilev, V. H.; Burns, N.
Z. A unified approach for the enantioselective synthesis of the brominated
chamigrene sesquiterpenes. Angew. Chem. Int. Ed. 2016, 55, 11476. (e)
Landry, M. L.; Hu, D. X.; McKenna, G. M.; Burns, N. Z. Catalytic
enantioselective dihalogenation and the selective synthesis of (-)-
deschloromytilipin A and (-)-danicalipin A. J. Am. Chem. Soc. 2016, 138,
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