Bifunctional catalyst promotes highly enantioselective bromolactonizations to generate stereogenic C-Br bonds

Article abstract of DOI:10.1021/ja305117m

A novel bifunctional catalyst derived from BINOL has been developed that promotes the highly enantioselective bromolactonizations of a number of structurally distinct unsaturated acids. Like some known catalysts, this catalyst promotes highly enantioselec

Full text of DOI:10.1021/ja305117m

Communication
pubs.acs.org/JACS
Bifunctional Catalyst Promotes Highly Enantioselective
Bromolactonizations To Generate Stereogenic C−Br Bonds
Daniel H. Paull, Chao Fang, James R. Donald, Andrew D. Pansick, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
intermediates than the corresponding lactones. For example,
ABSTRACT: A novel bifunctional catalyst derived from
BINOL has been developed that promotes the highly
enantioselective bromolactonizations of a number of
structurally distinct unsaturated acids. Like some known
catalysts, this catalyst promotes highly enantioselective
bromolactonizations of 4- and 5-aryl-4-pentenoic acids, but
it also catalyzes the highly enantioselective bromolactoni-
zations of 5-alkyl-4(Z)-pentenoic acids. These reactions
represent the first catalytic bromolactonizations of alkyl-
substituted olefinic acids that proceed via 5-exo mode
cyclizations to give lactones in which new carbon−
bromine bonds are formed at a stereogenic center with
high enantioselectivity. We also disclose the first catalytic
desymmetrization of a prochiral dienoic acid by
enantioselective bromolactonization.
halolactones may be readily converted into halohydrins and
epoxides. Finally, we are aware of no examples of catalytic,
enantioselective halolactonizations involving prochiral dienes.
In the context of several ongoing projects in natural product
synthesis, we encountered a requirement to induce the
enantioselective bromolactonizations of a number of structur-
ally different alkenes. We thus sought to address the existing
problems in the field with a novel approach to bifunctional
catalyst design.7 Mechanistic considerations suggest that a
Lewis base can mediate proton transfer and/or stabilize the
intermediate bromonium ion,5c and a Lewis or Brønsted acid
can activate the brominating agent.4b These catalytic elements
must then be incorporated on a suitable chiral scaffold. There
are a number of possibilities, but we decided to use the
binaphthyl backbone, which has been widely used as a chiral
template for catalyst design.8 Although BINOL-derived
catalysts have been used to promote enantioselective iodo−
diene cyclizations9 and haloetherifications,6 binaphthyl-derived
ligands do not appear to have been used in halolactonizations.
Accordingly, we envisioned that 5, employing a bifunctional
partnership of an amidine moiety3e,k and a phenolic −OH
group,10 might be an effective catalyst. Bulky groups at the 3-
and/or 3′-position of binaphthyl ligands can enhance stereo-
selectivity, so a 3-phenyl group was incorporated in the first
generation catalyst. Catalyst 5 can be readily made on
multigram scale in seven steps and 41% overall yield from
commercially available material (Scheme 1). Monotriflation of
alolactonization of unsaturated carboxylic acids is an
H
important reaction that has been widely used in organic
synthesis, especially for the preparation of molecules of
biological relevance.1,2 Accordingly, the development of
methods for inducing catalytic, enantioselective halolactoniza-
tions in general has become of great interest, and some notable
successes have been recorded.3,4 Despite considerable effort,
there remain some significant gaps in the area that arise, in part,
from the propensity of iodonium and bromonium ions to
undergo facile racemization via exchange with olefins prior to
cyclization with an internal nucleophile.5 In particular, we are
aware of no examples of catalytic halolactonizations of
unsaturated, alkyl-substituted carboxylic acids 1 (n = 1, 2;
R1−R3 = H, alkyl) that proceed via 5- or 6-exo modes of ring
closure to give lactones 2 in which new carbon−halogen bonds
are created at stereogenic centers with high enantioselectivity
(eq 1);3h however, enantioselective bromolactonizations of 1 (n
a
Scheme 1. Catalyst Synthesis
a
Reagents and conditions: (a) EtN(i-Pr)2, Tf2O, CH2Cl2, −78 °C;
91%. (b) KCN, Ni(PPh3)4, CH3CN, 70 °C; 86%. (c) BH3·THF, 0 °C,
Δ; HCl(aq), THF, Δ; 92%. (d) CH3C(OMe)2NMe2, CH3CN; 78%.
3-phenyl-BINOL (3), which was prepared by the protocol of
Shi,11 followed by nickel(0)-catalyzed cyanation provided 4 in
78% yield (two steps). Reduction of nitrile 4 to the amine and
subsequent amidine formation delivered the catalyst 5 in 71%
yield (two steps).
= 2, R1 = aryl and R2 or R3 = alkyl) via 6-exo closures have been
recently disclosed.3k The 5-exo cyclizations of unsaturated
alcohols to generate stereogenic carbon−halogen bonds by
haloetherification are known,6 but the products, which are
cyclic ethers, are arguably less versatile as synthetic
Received: May 25, 2012
Published: June 25, 2012
© 2012 American Chemical Society
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The validity of this new catalyst design was quickly
confirmed in preliminary experiments. At the low temperatures
required to minimize the background reaction, commonly used
“Br+” sources N-bromosuccinimide (NBS) and N,N′-dibromo-
dimethyl hydantoin (DBDMH) gave only trace amounts of
product. However, we found that bromolactonizations of a
series of 5-alkyl-4(Z)-pentenoic acids 6a−e using 2,4,4,6-
tetrabromocyclohexadienone (TBCO) (1.2 equiv) as the
brominating agent and 10 mol % of the catalyst 5 proceeded
with high regioselectivity to deliver the corresponding γ-
lactones 7a−e in excellent yields (eq 2), with enantiomeric
ratios (er) between 95:5 and 98:2 for branched alkyl substrates
6b−e and 85:15 for the n-alkyl substrate 6a (Table 1, entries
a−e).12 The observation that TBCO is superior to NBS and
DBDMH is surprising, as in other reports TBCO has been
shown to be less efficacious than NBS and DBDMH as a source
of electrophilic bromine.3h,j
Table 2. Exo Mode Enantioselective Bromolactonizations of
Acids 9a−f (Eq 3)
a
b
entry product
X
R1
R2
% yield
er
a
b
c
d
e
f
10a
10b
10c
10d
11e
11f
−CH2−
−CH2−
−CH2−
−CH2−
−CH2O−
−CH2O−
H
Ph
99
89
92
89
98
93
86:14
91:9
H
m-CN-Ph
p-CN-Ph
Me
H
94:6
Me
H
71:29
86:14
85:15
Ph
Me
Me
a
Isolated yield from the reaction of 1.0 equiv of olefinic acid, 1.2 equiv
of TBCO, and 0.1 equiv of catalyst 5 in 1:2 CH2Cl2/tol at −50 °C for
b
14 h. er determined by chiral phase HPLC; the absolute
stereochemistry of 10a is based on comparison of its optical rotation
with that previously reported,3f and other assignments are based upon
analogy.
electronic nature of aryl substituents plays an important role in
these reactions; greater electron-withdrawing power enhances
the enantioselectivity.13 When the 5-substituted-5-eneoic acids
9e,f are used as substrates, the bromolactonization proceeds via
a 6-exo mode to give δ-lactones 11e,f (Table 2, entries e,f).3d,e
To our knowledge, the exo cyclizations of 9d,f are the first
examples of a catalytic, enantioselective halolactonization of
trialkyl-substituted olefinic acids to give lactones in which a
stereogenic carbon−bromine bond is formed (Table 2, entries
d,f), although a related bromolactonization of an aryl-
substituted unsaturated acid was recently reported.3k It is
noteworthy that the enantioselectivity for the 6-exo cyclization
of 9f is somewhat higher than that for the 5-exo cyclization of
9d.
A major challenge to any catalytic, enantioselective trans-
formation is its application to the desymmetrization of prochiral
substrates. It is thus significant that 5 catalyzes the
bromolactonization of prochiral dienoic acids as exemplified
by the conversion of 12 into 13, the absolute stereochemistry of
which was established by X-ray analysis, with high regiose-
lectivity and 73:27 er (eq 4). It is noteworthy that similar
bromolactonizations to give racemic products have been used
as key steps in the syntheses of several naturally occurring
compounds.14
Table 1. Enantioselective Bromolactonizations of 5-
Substituted-4-Pentenoic Acids 6 (Eq 2)
a
b
entry
product
R1
R2
Et
% yield
er
a
b
c
d
e
f
7a
7b
7c
7d
7e
8f
H
H
H
H
H
Ph
90
87
94
94
97
85:15
95:5
i-Bu
i-Pr
Cy
t-Bu
H
97:3
98.5:1.5
97:3
c
94
98:2
g
h
8g
8h
1-Np
H
97
92
96:4
2-thienyl
H
94:6
a
Isolated yield from the reaction of 1.0 equiv of olefinic acid, 1.2 equiv
of TBCO, and 0.1 equiv of catalyst 5 in 1:2 CH2Cl2/tol at −50 °C for
b
14 h. er determined by chiral phase HPLC; absolute stereochemistry
for 7e was determined by X-ray crystallography, and 7a−d are assigned
by analogy; 8f−h are assigned based upon correlations of optical
c
rotations with those previously reported.3g Reaction executed at −60
°C to maximize δ:γ-lactone ratio (20:1).
These reactions represent the first examples of catalytic
bromolactonizations of alkyl-substituted olefinic acids that
proceed via a 5-exo mode of ring closure to give products in
which stereogenic carbon−bromine bonds have been formed
with high enantioselectivity. The enantioselectivity for the
bromolactonizations of Z-olefins was significantly higher than
those for the corresponding E-olefins. For example, E-6c (R1 =
i-Pr, R2 = H) underwent cyclization to give the diastereomer of
7c in 98% yield but in 71:29 er. Similar to the findings of
Yeung,3g 5-aryl-4(E)-pentenoic acids 6f−h underwent bromo-
lactonization via a 6-endo cyclization mode to give the
corresponding δ-lactones 8f−h in uniformly high yield and
enantioselectivity (Table 1, entries f−h).
The basic mechanistic features of bromonium ion-initiated
cyclizations are reasonably well established.4b,5c Catalyst 5 is
unusual in that it contains relatively acidic phenolic and highly
basic amidine functions, so determining the identities of the
Brønsted acid and the Lewis base is somewhat problematic.
With this caveat in mind, one tentative working model that is
consistent with the stereochemical outcome of bromolactoniza-
tions catalyzed by 5 is shown in Figure 1. We assume that
hydrogen bonding between the phenolic −OH and the
Enantioselective halolactonizations of 4-aryl-4-enoic acid
substrates via a 5-exo cyclization mode are well precedented
(eq 3),3b,d−f and we found that 5 also catalyzes the cyclizations
of 9a−c in the presence of TBCO to furnish the γ-lactones
10a−c in high yield and er (Table 2, entries a−c). The
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Journal of the American Chemical Society
Communication
5 offers numerous opportunities for structural modification to
improve enantioselectivities and to extend the utility of this
class of catalysts to other electrophile-initiated cyclizations,
including iodo- and chlorolactonizations. These developments
as well as the use of catalysts related to 5 in key steps in
complex molecule synthesis will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthesis of catalyst 5, experimental procedures, character-
ization of new compounds, and X-ray crystal data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sfmartin@mail.utexas.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM31077) and
the Robert A. Welch Foundation (F-0652) for generous
support of this research. D.H.P. thanks the NIH for a
postdoctoral fellowship (GM096557). We are also grateful to
Dr. Vincent Lynch (The University of Texas) for X-ray
crystallography and Shawn Blumberg (The University of
Texas) for helpful discussions.
Figure 1. Tentative stereochemical model for enantioselective
bromolactonizations catalyzed by 5. (A) Preferred mode for
cyclizations of 6a−e. (B) Preferred mode for cyclizations of 6f−h.
(C) Preferred mode for cyclizations of 9a−c; model for 6-exo
cyclizations of 9e,f is similar.
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