Catalytic Enantioselective Addition of an Allyl Group to Ketones Containing a Tri-, a Di-, or a Monohalomethyl Moiety. Stereochemical Control Based on Distinctive Electronic and Steric Attributes of C-Cl, C-Br, and C-F Bonds

Article abstract of DOI:10.1021/jacs.9b08443

We disclose the results of an investigation designed to generate insight regarding the differences in the electronic and steric attributes of C-F, C-Cl, and C-Br bonds. Mechanistic insight has been gleaned by analysis of variations in enantioselectivity, regarding the ability of electrostatic contact between a halomethyl moiety and a catalyst's ammonium group as opposed to factors lowering steric repulsion and/or dipole minimization. In the process, catalytic and enantioselective methods have been developed for transforming a wide range of trihalomethyl (halogen = Cl or Br), dihalomethyl, or monohalomethyl (halogen = F, Cl, or Br) ketones to the corresponding tertiary homoallylic alcohols. By exploiting electrostatic attraction between a halomethyl moiety and the catalyst's ammonium moiety and steric factors, high enantioselectivity was attained in many instances. Reactions can be performed with 0.5-5.0 mol % of an in situ generated boryl-ammonium catalyst, affording products in 42-99% yield and up to >99:1 enantiomeric ratio. Not only are there no existing protocols for accessing the great majority of the resulting products enantioselectively but also in some cases there are hardly any instances of a catalytic enantioselective addition of a carbon-based nucleophile (e.g., one enzyme-catalyzed aldol addition involving trichloromethyl ketones, and none with dichloromethyl, tribromomethyl, or dibromomethyl ketones). The approach is scalable and offers an expeditious route to the enantioselective synthesis of versatile and otherwise difficult to access aldehydes that bear an α-halo-substituted quaternary carbon stereogenic center as well as an assortment of 2,2-disubstituted epoxides that contain an easily modifiable alkene. Tertiary homoallylic alcohols containing a triazole and a halomethyl moiety, structural units relevant to drug development, may also be accessed efficiently with exceptional enantioselectivity.

Full text of DOI:10.1021/jacs.9b08443

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Catalytic Enantioselective Addition of an Allyl Group to Ketones
Containing a Tri‑, a Di‑, or a Monohalomethyl Moiety.
Stereochemical Control Based on Distinctive Electronic and Steric
Attributes of C−Cl, C−Br, and C−F Bonds
Diana C. Fager,† KyungA Lee,† and Amir H. Hoveyda*,†,‡
†Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
‡Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, 67000 Strasbourg, France
S
* Supporting Information
ABSTRACT: We disclose the results of an investigation
designed to generate insight regarding the differences in the
electronic and steric attributes of C−F, C−Cl, and C−Br
bonds. Mechanistic insight has been gleaned by analysis of
variations in enantioselectivity, regarding the ability of
electrostatic contact between a halomethyl moiety and a
catalyst’s ammonium group as opposed to factors lowering
steric repulsion and/or dipole minimization. In the process,
catalytic and enantioselective methods have been developed
for transforming a wide range of trihalomethyl (halogen = Cl
or Br), dihalomethyl, or monohalomethyl (halogen = F, Cl, or Br) ketones to the corresponding tertiary homoallylic alcohols.
By exploiting electrostatic attraction between a halomethyl moiety and the catalyst’s ammonium moiety and steric factors, high
enantioselectivity was attained in many instances. Reactions can be performed with 0.5−5.0 mol % of an in situ generated
boryl−ammonium catalyst, affording products in 42−99% yield and up to >99:1 enantiomeric ratio. Not only are there no
existing protocols for accessing the great majority of the resulting products enantioselectively but also in some cases there are
hardly any instances of a catalytic enantioselective addition of a carbon-based nucleophile (e.g., one enzyme-catalyzed aldol
addition involving trichloromethyl ketones, and none with dichloromethyl, tribromomethyl, or dibromomethyl ketones). The
approach is scalable and offers an expeditious route to the enantioselective synthesis of versatile and otherwise difficult to access
aldehydes that bear an α-halo-substituted quaternary carbon stereogenic center as well as an assortment of 2,2-disubstituted
epoxides that contain an easily modifiable alkene. Tertiary homoallylic alcohols containing a triazole and a halomethyl moiety,
structural units relevant to drug development, may also be accessed efficiently with exceptional enantioselectivity.
might be expected on the basis of width (B1) Sterimol
parameters7 (Ph, 1.71; CH3, 1.52; CF3, 1.97),8 but the er
differences would probably be significantly less. Length (L)
Sterimol values (Ph, 6.28; CH3, 3.00; CF3, 3.328) would
predict a high er in both instances and with the same sense of
enantioselectivity. We have proposed stereochemical models,
on the basis of experimental as well as DFT studies, where
electrostatic attraction between the trifluoromethyl group and
the ammonium proton attenuates electron−electron repulsion
(I, Scheme 1a).5a We have posited a rationale for several
selectivity variations. For instance, the reason reactions with 2-
furyl and 2-thienyl trifluoromethyl ketones are less enantiose-
lective, in comparison to the 3-furyl and 3-thienyl derivatives,
seems to be due to competitive electrostatic attraction in the
former (III, Scheme 1a).
1. INTRODUCTION
Organohalides are central to research in chemistry. Fluoro-
organic molecules are important in medicine,1 and, aside from
being common electrophiles, chloro- and bromoalkyl moieties
can be found in bioactive compounds.2 Catalytic strategies for
enantioselective synthesis of organohalides are thus highly
desirable. And yet, there are only a small number of catalytic
methods for generating halogen-containing organic molecules
in high enantiomeric purity. One notable study appeared more
than three decades ago by Corey in regard to enantioselective
reductions of halo-substituted ketones.3,4
We have previously reported catalytic reactions between
trifluoromethyl ketones and allylic boronates5,6 where the
enantioselectivity was an indicator of the extent of electrostatic
attraction between an ammonium moiety and a C−F bond.
We showed that, whereas additions to methyl ketones proceed
with low selectivity (e.g., 68:32 enantiomeric ratio (er),
Scheme 1a), transformations with trifluoromethyl ketones are
much more enantioselective, affording the alternative stereo-
isomer preferentially (e.g., 4:96 er, Scheme 1a). This reversal
Reactions with difluoromethyl or monofluoromethyl ke-
tones, on the other hand, are hardly enantioselective (≤65:35
Received: August 8, 2019
© XXXX American Chemical Society
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Scheme 1. Previous Findings
2.87 (4.018)), and steric factors could well exert a
greater influence on efficiency and/or enantioselectivity.
er, Scheme 1b), as might be expected on the basis of Sterimol
B1 or L differences (Scheme 1b). The lower er for
difluoromethyl and monofluoromethyl ketones is likely a
consequence of dipole minimization (cf. IV and V, Scheme
1b), which is not applicable to trifluoromethyl groups.
Accordingly, we found that addition to a cyclic difluoroalkane,
where the C−F bonds cannot orient anti to the carbonyl
group, is highly selective (94:6 er, Scheme 1b). We were later
able to achieve considerable enantioselectivity in reactions with
mono- and difluoromethyl ketones by using (Z)-crotyl−B(pin)
as the reagent;5b however, an additional Me (or any other)
substituent was required. Achieving the same with allyl−
B(pin) via a considerably more flexible transition state would
be considerably more challenging.
(2) Would additions to dichloromethyl and dibromomethyl
ketones or monochloromethyl and monobromomethyl
ketones be much less enantioselective in comparison to
their trihalomethyl derivatives, as was the case with the
F-substituted variants (Scheme 1b)? If the er were to be
high with monohalomethyl or dihalomethyl ketones,
considering the larger size of Cl and Br, it would mean
that electrostatic interactions play an even more
important role (favoring reaction via the chloro or
bromo derivative of IV). If steric factors were to be
dominant, the smaller difference in size between the
mono- or dihalomethyl moieties and other ketone
substituents would render enantiotopic differentiation
more challenging.
The following key questions subsequently arose and are the
subject of the present report:
(3) Considering that electronic factors do not play a major
role with mono- and difluoromethyl ketones, and the
importance of organofluorine compounds, might a
strategy be developed for accessing the corresponding
tertiary homoallylic alcohols in high er?
(4) The products of many of the above transformations
would be synthetically versatile due to the higher
reactivity of the C−Cl and C−Br bonds (vs C−F).
What valuable and otherwise difficult to synthesize
enantiomerically enriched organic molecules would
become readily available through functionalization of
(1) Would additions to trichloromethyl and tribromomethyl
ketones be governed by electrostatic forces similar to
those observed with trifluoromethyl variants, or do steric
factors dominate (Scheme 2)? Although Cl and Br are
much less electronegative than F (Pauling scale: F, 3.98;
Cl, 3.16; Br, 2.96), C−Cl and C−Br bonds are longer
and more polarized, implying that electrostatic attraction
might be important (bond moments: C−F, 1.39 D; C−
Cl, 1.47 D; C−Br, 1.42 D).9 Still, CCl3 and CBr3 are
significantly larger than CF3 (Sterimol B1 (L) values: Ph,
1.71 (6.28); CF3. 1.97 (3.32); CCl3, 2.64 (3.83); CBr3,
B
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Scheme 2. Main Objectives of This Study
a
Scheme 3. Allyl−B(pin) Addition to Trichloromethyl Ketones
a
1
Reactions were run under an N2 atmosphere. Conversion (>98% in all cases) was determined by analysis of H NMR spectra of unpurified
product mixtures ( 2%). Yields are for the purified products ( 5%). Enantioselecivity was determined by HPLC analysis ( 1%). Experiments
were run at least in triplicate. See the Supporting Information for details.
substituent are more similar and therefore steric differentiation
is more difficult. Furthermore, in the case of dihalomethyl and
monohalomethyl ketones, where the halogen is a chlorine or
bromine atom, the strongly basic conditions needed for
protocols that involve organometallic species can lead to
undesirable pathways (e.g., enolization and self-condensation).
As such, at least in certain cases, electronic factors that can
the above halomethyl-substituted tertiary homoallylic
alcohols?
It should be emphasized that while catalytic enantioselective
additions of allyl moieties to ketones have been widely
investigated,10 those involving the above set of halogen-
substituted ketones (Scheme 2) are uncommon. This is likely
because the sizes of a halomethyl group and the other ketone
C
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a
promote stereodifferentiation are required. While there is just a
single report regarding enzyme-catalyzed aldol addition to a
trichloromethyl ketone,11 there are, to the best of our
knowledge, no examples that involve a dichloromethyl, a
tribromomethyl, or a dibromomethyl derivative. Moreover,
although there are reported instances of catalytic enantiose-
lective reactions between a C-based nucleophile and a
monochloromethyl, a monobromomethyl, a monofluorometh-
yl, or a difluoromethyl ketone,12,13 other than the two isolated
examples of allyl additions to phenyl monochloromethyl
ketone (i.e., a single substrate), no other corresponds to
formation of a tertiary homoallylic alcohol.14,15
Scheme 5. Competition with an Organofluorine Group
2. RESULTS AND DISCUSSION
2.1. Trichloromethyl and Tribromomethyl Ketones.
We began with the question of whether or not catalytic allyl
addition to trichloromethyl or tribromomethyl ketones can be
efficient and highly enantioselective and, if so, whether the
sense of selectivity is the same as that observed with
trifluoromethyl analogues (i.e., electronic factors play a
significant role).
2.1.1. Trichloromethyl Ketones. With ap-1a and NaO-t-Bu,
there was <2% reaction with trichloroacetophenone (Scheme
3a), but with the more Lewis acidic Zn(OMe)216 we were able
to isolate homoallylic alcohol 1a in 91% yield and 95:5 er. The
high er is noteworthy considering that, without ap-1a, there
was ∼70% conversion to rac-1a. Equally important, the major
isomer arises from addition to the same enantiotopic face as a
trifluoromethyl ketone (I, Scheme 1a), indicating that
electronic factors remain dominant. The minor role of steric
strain17 is underscored by the low er for tert-butylphenyl
ketone (70:30 er; Sterimol B1 (L) values: t-Bu, 2.6 (4.11); Ph,
1.71 (6.28); Cl3C, 2.64 (3.83)).
Aryl-substituted trichloromethyl ketones reacted efficiently
and enantioselectively (Scheme 3b), including those with an
electron-donating (1b), electron-withdrawing (1c), or a
hindered moiety (1d−f). The reduced er for 1d and
particularly 1f, which contain relatively hindered aryl
substituents, may be attributed to increased steric pressure
involving the catalyst’s t-Bu group (see Scheme 2). Additions
to 3-furyl- and 3-thienyltrichloromethyl ketones afforded 1g,h
in 94% and 95% yield and 96:4 and 97:3 er, respectively. As
expected, and likely for the reasons noted above (III, Scheme
1a), 1i,j were formed with lower enantioselectivity (90:10 vs
a
Reactions were run under an N2 atmosphere. Conversion (>98% in
all cases) were determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields are for the purified
products ( 5%). Enantioselectivity was determined by HPLC analysis
( 1%). Experiments were run at least in triplicate. See the Supporting
Information for details.
96:4 er for the 2-furyl and 3-furyl cases, respectively, and
86.5:13.5 vs 97:3 er for the 2-thienyl and 3-thienyl cases,
respectively). These cases confirm that, despite its much larger
size (vs a CF3), a CCl3 group can engage in electrostatic
interaction with the catalyst’s ammonium unit, especially
considering that selectivities were similar to those of
trifluoromethyl ketones.5a Higher polarization of a C−Cl
bond (vs C−F) thus fully compensates for the increase in
steric requirements. Efficient synthesis of allylic alcohol 1k
highlights the advantage of a non-transition metal catalyst,18
where competitive conjugate addition can be a complication.
The lower er for phenethyl-substituted 1l (86:14 er), in
comparison to the tertiary benzylic alcohols and especially 1k
(97.5:2.5 er), might be because there is greater steric pressure
with a more extended alkyl moiety (see VI; Scheme 4), a
proposal that is supported by the large Sterimol L value
calculated for a phenethyl moiety (8.47 vs 6.28 for Ph).8
Hence, 1l was formed in 71:29 er when the larger
triphenylsilyl-substituted ap-1b was used (vs 86:14 with ap-
1a).
Scheme 4. Factors Controlling Addition to Alkyl-
Substituted Trichloromethyl Ketones
Despite the major difference in size between a CF3 and a
CCl3 group (Sterimol B1 = 1.97 and 2.64, respectively), the
addition to trifluoromethyl-substituted trichloromethyl ketone
is minimally selective (1m, 60:40 er). This is revealing and
lends credence to the ability of a CCl3 unit to associate
electrostatically with an ammonium group. Equally informative
D
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a
Scheme 6. Reactions with a C2-Substituted Allylboronate
Table 1. Influence of Aminophenol Structure on Additions
to Dichloromethyl and Dibromomethyl Ketones
a
b
c
entry
X
aminophenol
yield (%)
er
1
2
3
4
Cl
Cl
Br
Br
ap-1a
ap-1b
ap-1a
ap-1b
96
98
89
93
86:14
76:24
91:9
84:16
a
Reactions run were run under an N2 atmosphere. Conversions
1
(>98% in all cases) were determined by analysis of H NMR spectra
of unpurified product mixtures ( 2%). Yields are for purified
products ( 5%). Enantioselectivity was determined by HPLC
b
c
analysis ( 1%). See the Supporting Information for details.
Scheme 8. Possible Reason for Lower Enantioselectivity of
Reactions with Dichloromethyl and Dibromomethyl
Ketones
a
Reactions were run under an N2 atmosphere. Conversions (>98% in
all cases) were determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields are for the purified
products ( 5%). Enantioselectivity was determined by HPLC analysis
( 1%). Experiments were run at least in triplicate. See the Supporting
Information for details.
Scheme 7. Influence of a Tribromomethyl Group in
Comparison to a Difluorochloromethyl and a
a
Difluorobromomethyl Unit
similar electrostatic attractions and steric repulsions in VIII
and IX.
A C2-methyl substituent within the allyl boronate thus
causes the er to be higher (e.g., 98:2 vs 95:5 er for 1o vs 1a and
97:3 vs 92.5:7.5 er for 1p vs 1e; see Scheme 6 and Scheme 3);
the alternative addition mode (X vs XI, Scheme 6) is
destabilized because of more severe repulsion. Considering
the repulsion between the naphthyl substituent and the
catalyst’s t-Bu moiety,14 the high er for 1p underscores the
influence of electrostatic forces on enantioselectivity.
2.1.2. Other Trihalomethyl Ketones. Tribromomethyl-
substituted tertiary alcohol 3 was obtained in 96% yield and
96:4 er after 2 h at 4 °C (Scheme 7; at 22 °C, 38% yield,19
87:13 er). The efficiency of addition to this significantly
congested carbonyl group is especially noteworthy, as is the
sense of enantioselectivity, which is the same as for
trifluoromethyl and trichloromethyl ketones. In light of the
much larger size of a CBr3 group (Sterimol B1 (L) values:
CCl3, 2.64 (3.83); CBr3, 2.87 (4.01)]) and lower polarization
in a C−Br bond (bond moments: C−Cl, 1.47 D; C−Br, 1.42
D), the high er more likely originates from steric factors, as the
sizable trihalomethyl group is probably situated equatorially
a
Reactions were run under an N2 atmosphere. Conversions (>98% in
all cases) were determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields are for purified products
( 5%). Enantioselectivity was determined by HPLC analysis ( 1%).
All experiments were run at least in triplicate. See the Supporting
Information for details.
is the low er for 2,6-difluorophenyl-substituted 1n (64.5:35.5
er; Scheme 5) in comparison to the more enantioselective case
of a 2,6-difluorophenyl-substituted ketone (2a, 98.5:1.5 er).5a
There is probably analogous steric repulsion between the
catalyst’s t-Bu unit and a CCl3 or a 2,6-difluorophenyl unit
(VIII and IX, respectively, Scheme 5). However, unlike 2a, a
product derived from a methyl ketone for which VIII′
represents the more favorable mode of addition, there are
E
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a
Scheme 9. Additions to Dichloromethyl and Dibromomethyl Ketones
a
1
Reactions were run under an N2 atmosphere. Conversions (>98% in all cases) were determined by analysis of H NMR spectra of unpurified
product mixtures ( 2%). Yields are for purified products ( 5%). Enantioselectivity was determined by HPLC analysis ( 1%). Experiments were
run at least in triplicate. See the Supporting Information for details.
Scheme 10. Impact of Electrostatic Interactions and
Stereoelectronic Effects on Enantioselectivity
Scheme 11. Synthesis of α-Halo-γ,δ-Unsaturated
Aldehydes
a
(cf. X, Scheme 6). This is consistent with dominant steric
effects, affording products in ≥95:5 er with methyl ketones that
have a large aryl moiety (e.g., 1-naphthyl substituted), or those
performed with aminophenol-based catalysts with a triphe-
nylsilyl moiety instead of a t-Bu-aryl unit (e.g., ap-1b; see
Scheme 4).14 Formation of 4 and 5 (Scheme 7) in lower er in
comparison to 3 shows that electrostatic attraction involving
the C−F bonds is less controlling than the release of steric
pressure resulting from the positioning of a CBr3 moiety
pseudoequatorially (cf. IV, Scheme 1b).
2.2. Dichloromethyl and Dibromomethyl Ketones.
Reactions with dichloromethyl and dibromomethyl ketones
(Table 1) were efficient (89−98% yield), revealing several key
attributes. (1) The major enantiomer is derived from addition
to the same enantiotopic face of the carbonyl group as with the
trihalomethyl ketones. (2) Tertiary homoallylic alcohols 6a
and 7a were generated in higher er (86:14 and 91:9 with ap-
1a, entries 1 and 3) in comparison to their difluoromethyl
derivative (58:42 er, Scheme 1b). (3) Enantioselectivities were
lower than those when trihalomethyl ketones were used, not
exceeding 91:9 er. (4) With silyl-substituted ap-1b the er was
lower (entries 2 and 4 vs entries 1 and 2, Table 1).
a
Reactions were run under an N2 atmosphere. Conversions (>98% in
all cases) were determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields are for purified products
( 5%). Enantioselectivity was determined by HPLC analysis ( 1%).
Experiments were run at least in triplicate. es = enantiospecificity
((product er)/(substrate er) × 100). See the Supporting Information
for details.
Stereochemical models XII and XIII (Scheme 8) offer a
plausible rationale for these findings. Reaction via XII should
be preferred due to electrostatic attraction between the
dihalomethyl group and the ammonium moiety. However,
unlike for the reactions of trihalomethyl ketones, addition via
XIII can be more competitive because, although ammonium/
X−C association is lost, dipolar repulsion is minimized. With
the larger ap-1b, reaction via XII becomes less preferred
because of steric repulsion between the silyl moiety and the
ketone’s aryl group. The lower er for the dichloromethyl and
dibromomethyl ketones is probably a consequence of the
diminished steric repulsion between these moieties and the t-
Bu group in XIII, as reflected by the Sterimol L (but not B1)
F
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minimization favoring the latter (i.e., XIV vs XV, Scheme 10),
there would be little difference in the activation energies.
Direct synthesis of tertiary homoallylic alcohols with an
adjacent dihalomethylene is a convenient way of synthesizing
valuable but otherwise difficult to access compounds. For
example, treatment of 6a or 7a (Scheme 11) with NaHMDS
(3 h, 22 °C), probably affording epoxides 8a,b,20 was followed
by the addition of CeCl3·7H2O21 (5 h, 50 °C). We thus
isolated 9a,b in 76% yield and 90:10 er and 58% yield and 93:7
er, respectively. The α-halo-γ,δ-unsaturated aldehydes were
accordingly synthesized with exceptional enantiospecificity
(es). Although there are catalytic methods for the enantiose-
lective synthesis of such entities, which have been used to
prepare bioactive compounds,22 a protocol for the synthesis of
a fully substituted variant is uncommon.23
Scheme 12. Steric Effects and Dipole Minimization in
Reactions with Monohalomethyl Ketones
2.3. Monochloromethyl and Monobromomethyl
Ketones. In light of the enantioselectivity trends for additions
to trihalomethyl versus dihalomethyl ketones, and the weaker
impact of electrostatic factors in the latter, we wondered
whether steric factors might play a greater role with
monohalomethyl variants (Scheme 12). With a C−halogen
bond anti to the CO (XVII vs XVI, Scheme 12),
electrostatic attraction can be countered by dipolar forces,
which has two consequences: additions would occur on the
opposite enantiotopic carbonyl face preferentially and steric
factors would be more dominant. Experimental data indicate
that this is the case (Table 2), as 10a and 11a, derived from
addition to the re face, were obtained in 97:3 (96% yield) and
98:2 er (98% yield), respectively.24 The central role of steric
factors is underscored by the higher enantioselectivity with the
more sizable ap-1b (vs ap-1a; Table 2).
After a mild basic workup (3.0 equiv of dbu, 30 min−3 h, 22
°C), various 2,2-substituted epoxides, including aryl-, hetero-
aryl-, alkynyl-, and alkyl-substituted variants, were isolated in
42−94% yield and 92:8 to >99:1 er (Scheme 13; lower yields
due to product volatility).25 Either a chloride or a bromide
product may be used as the substrate for epoxide formation. It
would be difficult to access this class of epoxides in high er by
another protocol (catalytic or otherwise), whether it involves
an olefin26 or a ketone27 substrate (i.e., due to chemoselectivity
issues or sensitivity of α,β-unsaturated ketones). For the most
part, enantioselectivities are consistent with the proposed
stereochemical model presented in Scheme 12. However, at
times, notably in the case of adamantyl-substituted 12o, it is
unclear why, despite the use of a more sterically hindered
aminophenol, the enantioselectivity is lower than expected
(89:11 and 92:8 er with ap-2 and ap-4, respectively).
Table 2. Reversal of Enantioselectivity and Greater
Influence of Steric Factors in Additions to
Monochloromethyl and Monobromomethyl Ketones
a
b
c
entry
X
aminophenol
yield (%)
er
1
2
3
4
Cl
Cl
Br
Br
ap-1a
ap-1b
ap-1a
ap-1b
83
96
91
98
81:19
97:3
87:13
98:2
a
Reactions were run under an N2 atmosphere. Conversions (>98% in
all cases) were determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields are for purified products
( 5%). Enantioselectivity was determined by HPLC analysis ( 1%).
b
c
See the Supporting Information for details.
values (Sterimol B1 (L) values: phenyl, 1.71 (6.28); Cl2HC,
1.65 (3.85); Br2HC, 1.64 (4.04);8 see below for further
analysis).
Enantioselectivities increased at −40 °C, and 6a and 7a were
isolated in 90:10 to 94:6 er (Scheme 9). Reactions with
dihalomethyl ketones bearing an electron-deficient (e.g., 6c,
Scheme 9a; 7c, Scheme 9b) or electron-donating aryl group
(e.g., 7d, Scheme 9b) or those with a heterocyclic moiety (e.g.,
6d, Scheme 9a, and 7f, Scheme 9b) afforded the desired
tertiary alcohols in up to 98% yield and 97.5:2.5 er. Control
experiments indicate that the lower er for 7d probably
originates from an increase in competitive uncatalyzed
addition, which in turn might be because of stronger
association of the more electron rich carbonyl with allyl−
B(pin). Addition of a 2-substituted allyl−B(pin) gave 6e in
98% yield and 98:2 er (Scheme 9a).
The epoxides derived from an electron-rich aryl ketone are
unstable28 and thus difficult to isolate and purify (Scheme 14).
Unlike an epoxide derived from an ynone (e.g., 12n, Scheme
13), we could not isolate that which is derived from an α-
halogenated enone (10e, Scheme 14). Otherwise, all processes
were efficient and highly enantioselective. Two additional
points are worth mentioning. (1) Alkyl-substituted mono-
halomethyl products, which may be readily converted to
Like trichloromethyl ketones, reactions with alkyl-substi-
tuted substrates were efficient but less enantioselective (e.g.,
7g, Scheme 9b), which is in line with the aforementioned
̀
proposal vis-a-vis the diminished er for reactions of an alkyl-
substituted trichloromethyl ketone (see Scheme 4). The
factors described above notwithstanding, it seems that, with
the competition between electrostatic attraction and dipolar
G
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Scheme 13. Enantioselective Conversion of Monochloromethyl and Monobromomethyl Ketones to 2,2-Disubstituted
a
Epoxides
a
1
Reactions were run under an N2 atmosphere. Conversions (>98% in all cases) were determined by analysis of H NMR spectra of unpurified
mixtures ( 2%). Yields are for purified products ( 5%). Enantioselectivity was determined by HPLC analysis ( 1%). All experiments were run at
b
c
least in triplicate. With ap-4 (Scheme 17); 89:11 er with ap-2. With 1.0 mol % ap-2. See the Supporting Information for details.
epoxides, can also be isolated in high yield (e.g., 11e, Scheme
14). (2) Similar to the aforementioned reactions with a
trichloromethyl ketone (see Scheme 2), there is substantial
transformation without an aminophenol (e.g., ∼70% in the
case of 12a (X = Cl or Br)), and yet with only 0.5 mol %
loading and within 3 h the catalytic process dominates.
The transformation with ketone 13 (eq 1), bearing a
trifluoromethyl and a bromomethyl substituent, is noteworthy.
The fact that 14 was generated in 98:2 er21 suggests that,
despite the involvement of ap-2, which probably places the
bromomethyl moiety in the proximity of the catalyst’s
triphenylsilyl group, the transformation proceeds enantiose-
lectively by the virtue of the electrostatic attraction between
the trifluoromethyl group and ammonium ion imbedded
within the catalyst structure.
prepared enoate 15 in 74% yield and 94.5:5.5 er by catalytic
cross-metathesis between 11f and benzyl acrylate.
2.4. Monofluoromethyl and Difluoromethyl Ketones.
The dominance of steric factors in reactions of monochlor-
omethyl and monobromomethyl ketones implies that, with an
appropriate catalyst, the corresponding fluoro-substituted
products might be synthesized in high er. In view of the
importance of monofluoromethyl and difluoromethyl groups in
medicine,30 we chose to pursue this objective. In the event,
whereas we obtained 16a in 87% yield and 65:35 er with t-Bu-
substituted ap-1a (eq 2), with Ph3Si-substituted ap-1b, the
tertiary alcohol was isolated in 90% yield and 91:9 er. There
was 40−50% conversion without an aminophenol present.
The ease with which 12q can be prepared highlights the
utility of the approach (Scheme 15). This 2,2-disubstituted
epoxide was recently prepared in three steps, in 53% yield and
96:4 er, from an allylic alcohol (including operations that
require −25 to −78 °C) for an enantioselective synthesis of
boscartin F.29 By a single-vessel operation, 1 g of the readily
accessible α-bromoketone was converted to 11f and then 12q
(0.76 g; >98% conversion, >98% yield, and 94.5:5.5 er). We
H
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a
Scheme 14. Monochloromethyl and Monobromomethyl
Tertiary Alcohol Products
Scheme 15. Representative Functionalizations
a
a
Reactions were run under an N2 atmosphere, under the same
conditions as in Scheme 12 but without basic workup. Conversions
1
were >98% in all cases and were determined by analysis of H NMR
a
spectra of unpurified product mixtures ( 2%). Yields are of purified
products ( 5%). Enantioselectivity was determined by HPLC analysis
( 1%). All experiments were run in duplicate or more. See the
Supporting Information for details.
Reactions were run under an N2 atmosphere. Conversions (>98% in
all cases) were determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields are of purified products
( 5%). Enantioselectivity was determined by HPLC analysis ( 1%).
b
All experiments were run at least in triplicate. Owing to product
volatility, the yield was determined by analysis of the 1H NMR
spectra. See the Supporting Information for details.
Optimization studies led us to identify conditions for the
preparation of 16a in 92.5:7.5 er (Scheme 16). Other aryl
ketones (16b−e), including one with a hindered o-tolyl group
(16e), were converted to tertiary alcohols in 82−96% yield and
88.5:11.5−98:2 er. The 95:5 er for 2-thienyl-substituted 16f
was a surprise, as it is in contrast to lower values (vs 3-thienyl
derivatives) associated with reactions of trifluoromethyl
ketones (see Scheme 1a); a rationale for this finding is
provided below.
On a related front, we have previously shown that additions
to difluoromethyl ketones proceed with low er.5 This is likely
because the conformations that represent minimal dipole−
dipole repulsion between the CO and C−F bonds do not
allow for electrostatic attraction between the difluoromethyl
and ammonium moieties. The question here was to what
extent might we improve er by exploiting steric factors.
Screening studies indicated that ap-4 (Scheme 17), bearing a
much larger trinaphthylsilyl moiety (vs t-Bu), is optimal,
reflecting the more challenging differentiation between the
enantiotopic faces of a difluoromethyl ketone (vs monofluor-
omethyl) (Sterimol B1 (L) values: Ph, 1.71 (6.28); FH2C, 1.52
(3.31); F2HC, 1.63 (3.29)). For instance, 17a was obtained in
71% and 80% yield and 76:24 and 85.5:14.5 er with ap-3 and
ap-4, respectively. Also revealing is that, as with monofluor-
omethyl product 16f (Scheme 16), 2-thienyl-substituted 17c
was obtained in 96:4 er, which is far more enantioselective in
comparison to 3-thienyl variant 17d (79:21 er). It bears
emphasizing that this trend is opposite to that found for
trichloromethyl-, dichloromethyl-, or dibromomethyl-substi-
tuted derivatives.
A possible reason for 16f and 17c being formed in higher er
(in stark contrast to trihalomethyl derivatives) is that
electrostatic attraction is weaker with a difluoromethyl group
(vs a CF3) and, as a result, steric factors are more dominant. It
follows that for the sterically less hindered mode of addition
(XVIII, Scheme 18) electrostatic attraction can serve a
supporting role. In the case of a 3-thienyl substituent, the
latter type of interaction is not feasible (XIX), and the
enantioselectivity should be lower. This model is supported by
the exceptionally high er for the Boc-protected31 indole 17e
(>99:1 er) and the fact that the major enantiomer derived
from the trifluoromethyl analogue is the alternative enantiomer
(see Scheme 1). It should also be noted that these selectivity
patterns point to the significance of electrostatic attraction
between a trihalomethyl and an ammonium group. The
inherent steric bias can thus be overcome, as supported by the
much lower er when a smaller aminophenol was used (e.g., 17a
in 58:42 vs 85.5:14.5 er with ap-1a and ap-4, respectively).
Halogen-substituted tertiary alcohols connected to a triazole
ring, an amide bond isostere,32 are another important set of
compounds. These haloacetyl substituted triazoles indeed are
central features of several biaoactive entities,33 an example
being leukotriene biosynthesis inhibitor (Scheme 19a).34 The
only relevant published case entails the reaction of organo-
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a
Scheme 16. Additions to Monofluoromethyl Ketones
Scheme 18. When and Why Steric or Electronic Factors
Dominate
bonding between the triazole moiety and the ammonium
proton within the catalyst. Accordingly, we expected that the
reactions with a monohalomethyl or a dihalomethyl ketone
would be more enantioselective. Unexpectedly, there was only
a slight improvement (e.g., 22 → 23, 69.5:30.5 er). Subsequent
control studies showed that this is largely a consequence of
exceptionally facile non-catalytic addition to the electronically
more activated and less hindered carbonyl unit (≥74%
conversion, same conditions but no aminophenol).
We therefore developed a catalytic one-pot strategy,
entailing initial allyl addition to an ynone followed by triazole
ring36 formation (Scheme 19c). Treatment of 24 or 27 to
allyl−B(pin) addition conditions (with 3.0 mol % amino-
phenol) and subjection of the mixture to 20 mol % CuSO4·
2H2O, benzyl azide 25, and 40 mol % L-ascorbic acid (2.0
equiv K2CO3, 1/1 MeOH/H2O, 22 °C, 12 h) afforded 26 and
28 in 86% and 89% yield and ≥99:1 er.37 This approach is
suitable for enantioselective late-stage incorporation of a
fluoro-substituted tertiary alcohol moiety within a complex
molecule.
a
Reactions were run under an N2 atmosphere. Conversions (>98% in
all cases) were determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields are for purified products
( 5%). Enantioselectivity was determined by HPLC analysis ( 1%).
Experiments were run at least in triplicate. See the Supporting
Information for details.
a
Scheme 17. Additions to Difluoromethyl Ketones
3. CONCLUSIONS
These investigations shed new light on several key, but scarcely
explored, properties of tri-, di-, and monochloromethyl and tri-,
di-, and monobromomethyl, as well as di- and monofluor-
omethyl, moieties. We show how differences in polarizability,
the ability of a halogen atom to establish electrostatic
association with an ammonium group, and variations in size
and the length and polarity of the corresponding C−halogen
bond can strongly impact reactivity and/or enantioselectivity.
Along the way, we have developed the first broadly
applicable catalytic and enantioselective strategies for con-
version of a wide range of halomethyl ketones to the
corresponding tertiary homoallylic alcohols. The method can
be used to transform many trihalomethyl (halogen = Cl or Br),
dihalomethyl (halogen = F, Cl, or Br), and monohalomethyl
(halogen = F, Cl, or Br) ketones. Our studies reveal that,
whereas electrostatic interaction between a trihalomethyl, a
dichloromethyl, or a dibromomethyl group and a catalyst’s
ammonium moiety is the overriding factor (Scheme 20), with
monochloromethyl, monobromomethyl, difluoromethyl, and
monofluoromethyl substituents steric effects take control,
leading to products generated from addition to the opposite
carbonyl enantiotopic face. In these latter cases, steric
differentiation is maximized by utilizing an aminophenol that
contains a sizable silyl substituent (e.g., SiPh3 in ap-1b).
Another outcome of the above studies is that direct and
practical routes have been made available for the synthesis of a
number of desirable derivatives, such as α-halo-aldehydes and
2,2-disubstituted epoxides, many of which are difficult to
a
Reactions were run under an N2 atmosphere. Conversions (>98% in
all cases) were determined by analysis of 1H NMR spectra of
unpurified product mixtures ( 2%). Yields are for purified products
( 5%). Enantioselectivity was determined by HPLC analysis ( 1%).
Experiments were run at least in triplicate. See the Supporting
Information for details.
aluminum reagents (non-enantioselective) with a trifluoro-
methyl or trichloromethyl ketone precursor of the antiseizure
medication Banzel.35
We first studied allyl additions to ketones 18 and 19, which
are structurally related to Banzel (Scheme 19b). To our
surprise, however, enantioselectivity was minimal (20 and 21
in 56.5:43.5 and 52:48 er). We attributed this to competitive H
J
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a
Scheme 19. Triazole-Containing Products
Scheme 20. Electrostatic versus Steric Effects, Depending
on the Halomethyl Substituent
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b08443.
■
S
Experimental details for all reactions and analytic details
for all products (PDF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail for A.H.H.: amir.hoveyda@bc.edu or ahoveyda@
unistra.fr.
■
ORCID
Amir H. Hoveyda: 0000-0002-1470-6456
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Institutes of
Health (GM-130395). We are grateful to R. J. Morrison, J. del
Pozo, and S. Torker for helpful discussions.
a
Reactions were carried out under an N2 atm. Conversions were
REFERENCES
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Supporting Information for details.
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M
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Journal of the American Chemical Society
Article
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out DFT calculations, but these studies proved to be inconclusive, as
the energy differences between the competing diastereomeric
transition structures remained the same (∼3 kcal/mol). At the
present we do not have a plausible rationale for this unexpected
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