SN2″-Selective and Enantioselective Substitution with Unsaturated Organoboron Compounds and Catalyzed by a Sulfonate-Containing NHC-Cu Complex

Article abstract of DOI:10.1021/jacs.8b10885

The first broadly applicable strategy for S_N2″-selective and enantioselective catalytic substitution is disclosed. Transformations are promoted by 5.0 mol% of a sulfonate-containing NHC-Cu complex (NHC = N-heterocyclic carbene), and are carried

Full text of DOI:10.1021/jacs.8b10885

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
SN2″-Selective and Enantioselective Substitution with Unsaturated
Organoboron Compounds and Catalyzed by a Sulfonate-Containing
NHC-Cu Complex
Yuebiao Zhou, Ying Shi, Sebastian Torker,* and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
S
* Supporting Information
ABSTRACT: The first broadly applicable strategy for SN2″-
selective and enantioselective catalytic substitution is disclosed.
Transformations are promoted by 5.0 mol% of a sulfonate-
containing NHC-Cu complex (NHC = N-heterocyclic carbene),
and are carried out in the presence of commercially available
allenyl-B(pin) (pin = pinacolato) or a readily accessible silyl-
protected propargyl-B(pin). Acyclic, or aryl-, heteroaryl-,
and alkyl-substituted penta-2,4-dienyl phosphates, as well
as those bearing either only 1,2-disubstituted olefins or a 1,
2-disubstituted and a trisubstituted alkene were found to be
suitable starting materials. Cyclic dienyl phosphates may also
serve as substrates. The products containing, in addition to a
1,3-dienyl group, a readily functionalizable propargyl moiety
(from reactions with allenyl-B(pin)) were obtained in 51−82% yield, 84−97% SN2″ selectivity, 89:11−97:3 E:Z ratio, and
86:14−98:2 enantiomeric ratio (er). Reactions with a silyl-protected propargyl-B(pin) compound led to the formation of the
corresponding silyl-allenyl products in 53−89% yield, 69−96% SN2″ selectivity, 98:2 to >98:2 E:Z ratio, and 94:6−98:2 er.
Insight regarding several of the unique mechanistic attributes of the catalytic process was obtained on the basis of kinetic
isotope effect measurements and DFT studies. These investigations indicate that cationic π-allyl-Cu complexes are likely inter-
mediates, clarifying the role of the s-cis and s-trans conformers of the intermediate organocopper species and their impact on
E:Z selectivity and enantioselectivity. The utility of the approach is demonstrated by chemoselective functionalization of various
product types, through which the propargyl, allenyl, or 1,3-dienyl sites within the products have been converted catalytically and
chemoselectively to several useful derivatives.
via I, and II7 (vs allene-containing derivatives by SN2′ and SN2
1. INTRODUCTION
pathways). The propargyl and the 1,3-dienyl groups would
Catalytic enantioselective allylic substitutions, transform an
render the expected products of considerable utility, especially
alkenyl substrate to a new unsaturated compound that bears an
when containing a stereochemically defined trisubstituted
allylic stereogenic center and are widely used in organic synthe-
sis (Scheme 1a).1 The majority of these SN2′-selective reac-
alkene. Equally useful compounds containing an easily alterable
tions allow for the addition of a methyl or a simple alkyl group.1,2
silyl-substituted allenyl moiety could be similarly generated
Strategies for incorporation of a readily modifiable alkenyl,3
through the use of 2, a readily accessible organoboron
species14,15 (Scheme 1b). Such 1,5-additions (i.e., SN2″-
selective) would be mechanistically distinct from the more
widely utilized SN2′-selective substitutions largely due to
involvement of organocopper intermediates that contain an
extended π system (cf. II, Scheme 1b). Involvement of the
derived s-cis and s-trans conformers would pose key questions
allyl,4 allenyl,5 alkynyl,6 or a propargyl7 have been introduced
only recently. In contrast, catalytic SN2″-selective and enantio-
selective substitutions, regardless of the moiety being intro-
duced, are relatively uncommon.8−10 The one case of which we
are aware involves reaction of a “soft” nucleophile (derived
from CH(NHAc)(CO2Et)2) with a 2-bromo-1,3,5-triene to gen-
erate a vinylallene (up to 90.5:9.5 enantiomeric ratio (er)).11
We envisioned that it might be possible to develop catalytic
enantioselective SN2″ additions by exploiting a key isomer-
ization (akin to a 3,3′-reductive elimination) that was recently
used in designing 1,6-conjugate additions.12 We imagined a
process (Scheme 1b) through which a dienyl phosphate and
commercially available allenyl-B(pin) 113 (pin = pinacolato)
would participate in an SN2″- and enantioselective substitution
̀
vis-a-vis their relative rates of interconversion and reaction,
factors that impact E:Z selectivity and/or enantioselectivity.
Also, SN2″-selective substitutions would be mechanistically
dissimilar to 1,6-conjugate additions12 in that C−C bond
formation would be occurring within an intermediate that
Received: October 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b10885
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Scheme 1. Relevant Previous Advances
a
Table 1. Examination of Different Types of Cu-Based Complexes
b
b
b
c
d
entry
ligand
solvent
conv (%)
SN2″:SN2′:SN2 (4a:5a:6a)
E:Z (4a)
yield 4a (%)
er
1
2
3
4
5
−
phos-1
phos-2
phos-3
thf
thf
thf
thf
thf
>95
87
>95
79
95:<2:5
88:<2:12
92:<2:8
93:<2:7
90:<2:10
81:19
79:21
81:19
83:17
80:20
71
55
65
58
82
−
50:50
50:50
50:50
50:50
imid(O)-1
>95
B
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Table 1. continued
b
b
b
c
d
entry
ligand
solvent
conv (%)
SN2″:SN2′:SN2 (4a:5a:6a)
E:Z (4a)
yield 4a (%)
er
6
7
8
9
imid(S)-1
imid(S)-2
imid(S)-3
imid(S)-2
imid(S)-3
thf
thf
thf
CH2Cl2
CH2Cl2
>98
>95
>95
>98
>98
80:18:2
86:10:4
74:19:7
93:4:3
86:14
93:7
85:15
95:5
76
69
72
75
75
39:61
85:15
73:27
85:15
90:10
10
88:7:5
90:10
a
b
Performed under N2 atm. Conversion and SN2″:SN2′:SN2 ratios were determined by analysis of 1H NMR spectra of unpurified mixtures; conv
c
d
( 2%) refers to disappearance of the 3a. Yields are for isolated and purified 4a (E and Z isomers; 5%). Enantioselectivity was determined by
HPLC or GC ( 1%). See the Supporting Information for experimental and analytical details. Abbreviations: Mes, 2,4,6-(Me)3C6H2.
Scheme 2. SN2″-Selective and Enantioselective Substitutions
present (entry 1), and the product was again generated in up to
83:17 E:Z ratio without any enantioselectivity.
with Dialkenyl Phosphates That Contain Only
a
Disubstituted Alkenes
Particularly disconcerting was that with imid(O)-1, optimal
for enantioselective 1,6-conjugate additions with the same
allenyl-B(pin) compound,12 4a was generated in 80:20 E:Z selec-
tivity and in the racemic form (entry 5). Enantioselectivity was
first detected when sulfonate-containing imidazolinium salt
imid(S)-117 was utilized (39:61 er, entry 6). The low er was
accompanied by an improvement in the E:Z ratio (86:14), which
came at the expense of diminished regioselectivity (80:18:2
SN2″:SN2′:SN2). We then examined imid(S)-2, which bears a
3,5-disubstituted NAr unit (vs a 2,4,6-trisubstituted NAr group),
and is the precursor to a catalyst proved to be optimal in several
previous studies2,3e,5,7,18 (entry 7). There was a modest increase
in SN2″ selectivity, a larger increase in E selectivity (93:7 E:Z),
and an even greater boost in er (85:15). In the reaction involv-
ing imid(S)-3, containing an NAr group with C2 and C5 sub-
stituents (entry 8), selectivity suffered in comparison to
imid(S)-2 (74% SN2″, 85% E, 73:27 er). Finally, we evaluated
the performance of the NHC-Cu complexes derived from
imid(S)-2 and imid(S)-3 in a similarly polar but non-
coordinating solvent (CH2Cl2; entries 9−10), leading us to
establish that under the latter conditions, imid(S)-3 is overall
the most effective chiral ligand (88% SN2″, 90% E, 90:10 er;
entry 10).
a
Reactions were carried out under N2 atm. Conversion was
1
2.1.2. Further Optimization and Exploration of the Scope.
We subsequently found that results could be improved when
the reaction was carried out with imid(S)-3 at −30 °C in
CH2Cl2: 4a was isolated in 71% yield, 96% SN2″ selectivity,
92:8 er, and 94:6 E:Z selectivity (Scheme 2). Transformations
with substrates with an o-, m-, or p-substituted aryl halide
delivered 4b−d in 69−76% yield, 90−94% SN2″ selectivity,
91−92% E selectivity, and 89:11−91:9 er (Scheme 2). Reac-
tion of p-nitro-substituted dienyl phosphate afforded 4e with
comparable regio- and stereoselectivity, but higher catalyst
loading (7.5 mol%) was needed for >80% conversion. Synthe-
sis of alkyl-substituted 4f was similarly regio- and stereo-
selective, but the yield was lower (51%) probably due to dimin-
ished electrophilicity of the alkyl-substituted substrate. In every
instance that a comparative experiment was carried out, trans-
formations were less enantioselective with imid(S)-2 (e.g., 82%
and 50% yield, >98:<2:<2 and 95:5:<2 SN2″:SN2′:SN2, 97% and
95% E, 89:11 and 80:20 er for 4a and 4f, Scheme 2, respectively).
While the reactions in Scheme 2 were highly SN2″ selective,
and E:Z ratios ranged from 91:9 to 94:6, we were concerned
about the moderate enantioselectivity, which dipped to as low
as 86:14 er. These considerations led us to investigate pro-
cesses where C−C bond formation takes place at a trisub-
stituted alkene; our hope was that the additional substituent
would translate to more effective differentiation between
the competing transition states (Scheme 3). We found such
determined by analysis of H NMR spectra of unpurified product
mixtures ( 2%). Yields are for purified products ( 5%) and
correspond to E and Z olefin mixtures. Enantioselectivities were
determined by HPLC or GC analysis ( 1%). Experiments were run
in duplicate or more. Performed with 7.5 mol % imid(S)-3 and
7.5 mol% CuCl. See the Supporting Information for details.
b
no longer carries an electron-withdrawing moiety. One must
therefore contend with less substituted π systems, which are
conformationally more flexible and electronically less activated.
2. RESULTS AND DISCUSSION
2.1. Catalytic SN2″-Selective and Enantioselective
Substitutions Involving an Allenyl-B(pin) Reagent.
2.1.1. Identification of an Effective Catalyst. To explore feasi-
bility, we chose to examine the reaction of 1 with dienyl phos-
phate 3a in the presence of 5.5 mol% of a ligand and 5.0 mol%
CuCl in thf and at room temperature (22 °C). Representative
data regarding the different types of Cu complexes are shown
in Table 1.16 Without a ligand (entry 1), the reaction was effi-
cient and highly SN2″-selective (>95% conv, 95% SN2″), but 4a
was formed as an 81:19 mixture of E and Z alkene isomers.
We then probed the effectiveness of a number of different
chiral bisphosphine ligands. The transformations carried out
with phos-1−3 (Table 1, entries 2−4) were similarly efficient
and regioselective (88−93% SN2″) as when there was no ligand
C
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Scheme 3. SN2″-Selective and Enantioselective Substitutions with Dialkenyl Phosphates That Contain a Trisubstituted
a
Alkene
a
1
Reactions were carried out under N2 atm. Conversion was determined by analysis of H NMR spectra of unpurified product mixtures ( 2%).
Yields are for purified products ( 5%). Enantioselectivities were determined by HPLC or GC analysis ( 1%). Experiments were run in duplicate
or more. See the Supporting Information for details.
a
Scheme 4. SN2″-Selective and Enantioselective Substitutions with Allenyl-B(pin) and Involving Cyclic Substrates
a
1
Reactions were carried out under N2 atm. Conversion was determined by analysis of H NMR spectra of unpurified product mixtures ( 2%).
Yields for purified products ( 5%). Enantioselectivities were determined by HPLC or GC analysis ( 1%). Experiments were run in duplicate or
more. See the Supporting Information for details.
an approach attractive for two additional reasons: (1) the
stereoselectively by alternative catalytic methods,19 and (2) the
possible application to synthesis of fasicularin20 (see Scheme 11).
relative difficulty of accessing the more highly substituted olefins
D
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Scheme 5. SN2″-Selective and Enantioselective Substitutions Leading to Transfer of a Silyl-Substituted Allenyl
a
Moiety
a
1
Reactions were carried out under N2 atm. Conversion was determined by analysis of H NMR spectra of unpurified product mixtures ( 2%).
Yields are for purified products ( 5%). Enantioselectivities were determined by HPLC or GC analysis ( 1%). Experiments were run in duplicate
or more. See the Supporting Information for details.
In the event, reactions with the more substituted dienyl phos-
phates 8a−l (Scheme 3) proceeded from 78% to >98% con-
version under the same conditions as before (Scheme 2).21
Not only were the SN2″ selectivities equally high (84−97%),
products were obtained with better E selectivity (93:7−97:3
vs 91:9−94:6 in Scheme 2) and er (95:5−98:2 vs 86:14−
92:8, Scheme 2). We were unable to obtain the pure SN2″
addition product in just one instance (8d). An assortment of
aryl-substituted substrates (8a−i, Scheme 3), regardless of the
position and electronic attributes of their substituent, heteroaryl-
containing dienyl phosphates (8j,k), and one bearing an aliphatic
moiety (8l), reacted efficiently and selectively.
Cyclic phosphates afforded products with similarly high
yields and selectivities. Dienynes 12a−c (Scheme 4) were
obtained in 71−82% yield, with a strong preference for the
SN2″ mode of addition (94 to >95%), and in 96:4−97:3 er.
In the case of cyclic dienes E selectivity was slightly lower
(89:11−92:8 E:Z); this could be improved at lower temperature,
but at the expense of product yield (e.g., for 12b at −30 °C for
24 h: 90% conv, 61% yield, >95:<5:<2 SN2″:SN2′:SN2
selectivity, 94:6 E:Z, and 98:2 er).
2.2. Catalytic SN2″- and Enantioselective Substitutions
with a Propargyl-B(pin) Reagent. With silyl-substituted
propargyl-B(pin) compound 2 as the reagent (Scheme 5),
processes involving dienyl allylic phosphates with only 1,2-
disubstituted alkenes (Scheme 5a) or those containing a
trisubstituted olefin (Scheme 5b) proceeded to completion
under similar conditions as before (Schemes 2−4). Acyclic aryl-
(cf. 15a−c,e,f) and alkyl-substituted (cf. 15d,g) dienyl phos-
phates and the corresponding cyclic systems (cf. 18) proved to
be effective substrates.
Several additional points merit note: (1) Transformations
with phosphates that contain only disubstituted alkenes
(Scheme 5a) were generally more enantioselective than those
E
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Scheme 6. Mechanistic Analysis on the Basis of Deuterium-Labeling Experiments
with allenyl-B(pin) (compare to data in Scheme 2). (2)
Particularly with imid(S)-3, SN2″ selectivities were lower for
reactions with silyl-protected propargyl-B(pin) reagent (2;
69−96% vs 84−97%). This difference might arise from
increased steric pressure for C−C bond formation in the
proximity of a larger substituent when the silyl-containing
organoboron compound is involved. (3) In general, while SN2″
selectivities were lower with imid(S)-3 and dienylphosphates
containing disubstituted alkenes (Scheme 5a), the er was
higher; formation of 15a with imid(S)-2 (Scheme 5c) is a case
in point (94% vs 82% SN2″ and 87:13 vs 95:5 er with imid(S)-
2 and imid(S)-3, respectively). Thus, if product yield happens
to be more critical than its enantiomeric purity, then imid(S)-2
might be the more suitable catalyst precursor. (4) The
situation is more straightforward with substrates that contain a
trisubstituted olefin (Scheme 5b). As the data for 15e indicate
(Scheme 5c), although enantioselectivity was similar (95:5
and 97:3 er for imid(S)-2 and imid(S)-3, respectively),
SN2″ selectivity was higher with imid(S)-2 (94% vs 83% for
imid(S)-3).
2.3. Mechanistic Investigations. We have previously
shown that sulfonate-bearing NHC-Cu complexes are espe-
cially effective in promoting allylic substitutions with high SN2′
selectivity and enantioselectivity.2,3a−e,5,6a,b,7 The catalyst’s
ability to accommodate a metal bridge between its sulfonate
moiety and the electrophile’s phosphate unit appears to be cen-
tral to high regio- and stereocontrol.2,7,22 Nonetheless, as noted
earlier, the SN2″-selective substitutions are mechanistically dis-
tinct, mainly because of the involvement of stereoisomeric
organocopper complexes that contain an extended π system.
The associated s-cis and s-trans conformers and the relative
rates of their interconversion (vs C−C bond formation) and/
or reactivity can impact E:Z selectivity and/or enantioselectivity.
Mindful of such issues and considering the data presented
above, we set out to establish the identity of the stereochemistry-
determining step and, with the support of DFT studies, to gather
insight regarding the origins of the stereoselectivity differences.
2.3.1. Identifying the Stereochemistry-Determining Step.
We evaluated two mechanistic possibilities, which typically involve
anti displacement23−25 of the leaving group, and are commonly
invoked in allylic substitution processes (Scheme 6).26 One route
(path a) entails the formation of π-allyl complex III by initial
cleavage of the C−Ophosphate bond, followed by the collapse of
the relatively high-energy π-allyl intermediate IV and forma-
tion of a C−C bond.27 Alternatively, the C−C bond generation
in path b might occur prior to elimination of the phosphate
moiety from the Cu-alkyl species (II → V → VI).
Based on the results of competition experiments involving
equal amounts of labeled (i.e., 3a-d2 and 3a-d) and non-labeled
substrate (3a) we were able to identify the more likely sequence
of events (Scheme 7). Through the reaction with 3a-d2 (R1 = D,
R2 = H, Scheme 7a) we measured a secondary kinetic isotope
effect of 1.11 0.01, which suggested that there is sp3→sp2
hybridization change at the carbon bearing the phosphate
group during the stereochemistry-determining step. When 3a-d
(R1 = H, R2 = D, Scheme 7b) was used, we did not detect any
secondary kinetic isotope effect (0.99 0.01), implying that
C−C bond formation probably is energetically more favorable
and occurs at a subsequent stage (IV → product).28
F
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a
Scheme 7. Kinetic Isotope Effect Measurements
a
Conditions: 5.5 mol% imid(S)-3, 5.0 mol% CuCl, 1.5 equiv NaOMe, CH2Cl2, −30 °C, 24 h. See the Supporting Information for details.
Scheme 8. Mechanistic Model: Origin of Enantioselectivity
2.3.2. Regarding the Enantioselectivity Variations. The
results of DFT calculations (Scheme 8) allow us to formulate a
rationale as to why reactions were more enantioselective with
the Cu-based complex derived from imid(S)-3 compared to
when imid(S)-2 was used (90:10 vs 85:15 er, respectively).
Comparison of the transition states leading to the E isomer of
the major enantiomer in processes involving imid(S)-3 (cf. VII)
and imid(S)-2 (cf. VIII) reveals that the NHC ligands possess
distinct conformational preferences (see top panel, Scheme 8).
This may be appreciated more easily if while holding the
position of the allenyl ligand constant, the NHC ligands derived
from imid(S)-3 and imid(S)-2 are rotated in a clockwise and
counterclockwise manner, respectively. In VII and VIII the
dienyl phosphate can approach the allenyl-Cu complex so that
its phosphate unit can establish the key sodium cation bridge
with the NHC ligand’s sulfonate group.7 In the lowest energy
conformer of VII, the allenyl moiety can therefore be placed
within the vacant quadrant. Because there is no large meta
substituent in the Cu complex derived from imid(S)-3, there
is little steric repulsion between the ligand’s NAr moiety
G
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a
Scheme 9. Mechanistic Model: Differences in E Selectivity as a Function of NHC Ligand
a
See the Supporting Information for details.
(highlighted in blue; VII) and the allenyl unit. The proximity
of a triisopropylphenyl moiety and the allenyl group in VIII
(in red), on the other hand, gives rise to steric pressure, which
can be countered by counterclockwise rotation around the
Cu−CNHC bond. These factors impact the relative energies of
the transition states leading to the minor product enantiomer
(IX and X, lower panel, Scheme 8). In IX rotation around the
N−CAr bond can help minimize the steric strain generated by
the nearness of the ligand’s o-phenyl substituent and the allenyl
moiety. However, this conformational adjustment induces the
corresponding m-triisopropylphenyl moiety to be positioned
closer to the tail end of the dienyl phosphate, exacerbating an
unfavorable interaction. Such considerations provide a basis for
the higher energy of IX and the attendant increase in er. In X,
the triisopropylphenyl group, which points to the rear of the
complex, can move further away from the dienyl phosphate.
Steric repulsion can thus be diminished and greater amounts of
the minor enantiomer generated (i.e., lower er).
Scheme 10. Mechanistic Model: Variations in SN2″/SN2′
The proposed model offers an explanation for other enantio-
selectivity trends as well. For example, as shown in XI, the
additional substituent of the trisubstituted alkene destabilizes
the intermediates leading to the minor enantiomer and
er values improve (compared to dienyl phosphates that have
only disubstituted olefins; compare the data in Schemes 2
and 3).
The conformational mobility of the NHC ligands discussed
above (i.e., clockwise or counterclockwise rotation around the
Cu−CNHC bonds, Scheme 8) offers hints as to why E selec-
tivities are higher with the complex derived from imid(S)-2.
The imid(S)-3-derived NHC in XII (Scheme 9)an s-cis
conformercan rotate (clockwise, as shown) without incur-
ring significant steric pressure (see above). The sulfonate unit
can therefore be placed, with little or no cost in energy, at a site
that is more distal from the dienyl phosphate. The situation is
2.3.3. Regarding the E Selectivity Variations. Another ques-
tion arises: Why does the less enantioselective catalyst derived
from imid(S)-2 afford products with higher E/Z selectivity
(95:5 vs 90:10 for imid(S)-2 and imid(S)-3, respectively)?
The answer hinges on the geometry of the extended π-allyl
intermediate complex (cf. III and IV, Scheme 6), where an
s-trans conformer likely leads to the E-alkene.
H
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a
Scheme 11. Chemo- and Stereoselective Functionalization of Products and Demonstration of Utility
a
Carried out under N2 atm. Conversion (>98% in all cases) was determined by analysis of 1H spectra of unpurified product mixtures ( 2%). Yields
are for purified products ( 5%). Enantioselectivities were determined by HPLC or GC analysis ( 1%). Experiments were run in duplicate or more.
b
Samples contained 5−10% of the isomerized alkene. See the Supporting Information for details.
different for the s-cis conformer corresponding to imid(S)-2
(XIII) where counterclockwise turning of the NHC ligand
positions the sulfonate group nearer to the dienyl phosphate.
This causes XIII to be higher in energy and lesser amounts of
the Z-alkene to be generated (i.e., higher E:Z ratio).
DFT studies suggest that s-cis geometry is in all likelihood
established during C−O bond cleavage (cf. Scheme 6). This
implies that s-cis to s-trans isomerization in the cationic π-allyl
intermediate is energetically more demanding than the C−C
bond formation event.26 Consequently, reaction via XII delivers
the Z alkene of the S enantiomer, whereas transformation through
VII leads to the E-alkene of the R enantiomer. This scenario is
supported by the observation that hydrogenation of a derivative of
4a (90:10 E:Z, 90:10 er (E), 92:8 er (Z)) afforded the alkane
with diminished enantiomeric purity (79:21 er).29
imid(S)-2 and imid(S)-3, respectively). We propose that in the
transition state for C−C bond formation (XIV; Scheme 10) the
allenyl nucleophile likely adopts a conformation that engenders
steric repulsion between the nucleophile’s Cα−H and phenyl
moiety of the NHC ligand in imid(S)-3. This interaction can be
avoided in XV, resulting in greater amounts of the SN2′ product
isomer to be generated.
2.4. Utility. A notable attribute of the method is that it
delivers products bearing a 1,3-diene and a terminal alkyne or a
silyl-substituted allene. The transformations in Scheme 11 demon-
strate several distinct ways by which further structural modifi-
cations may be implemented.
Catalytic coupling30 of 4a to commercially available Z-alkenyl
iodide 19 afforded enyne 20 with complete retention of stereo-
chemical identity in quantitative yield (Scheme 11a). Analo-
gously, zirconocene-catalyzed hydroboration31 of 8a afforded
alkenyl-B(pin) 21 in 72% yield and >98:2 E:Z selectivity
(Scheme 11a). The same procedure followed by oxidative
treatment furnished the corresponding aldehyde 22 in 80% yield.
2.3.4. Regarding the SN2″/SN2′ Selectivity Variations.
Another notable difference between the imid(S)-2 and
imid(S)-3-derived NHC ligands relates to the SN2″/SN2′
ratios (see Scheme 5; e.g., 94:4 vs 82:14 for 15a with
I
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The transformations in Scheme 11b represent the type of
chemoselective modification that is possible with a silyl-allenyl
product. The 1,3-dienyl fragment in 15a was selectively
functionalized by bisphosphine-Cu-catalyzed regioselective 1,
4-proto-boryl addition,32 affording 23 in 83% yield, and 96:4 Z:E
ratio. Only the primary C−B bond was formed, and none of
the side product derived from reaction at the allenyl site was
detected.33
These studies underscore the need for development of
chemoselective methods. With the emergence of increasingly
sophisticated strategies, products with multiple functionalities
are becoming more easily available. Without reliable protocols
for site-selective modification of multiple reactive sites within a
multifunctional molecule, however, the full potential of such
advances can only be partially fulfilled.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b10885.
The allenyl moiety could be modified chemoselectively as
well, as represented by conversion of 15a to tetrasubstituted
alkenyl-B(pin) 24 by regio- and stereoselective hydroboration
■
S
promoted by a Pd-based catalyst. This process, performed
34
̈
according to a method by Backvall and co-workers, has the
Experimental details for all reactions and analytic details
for all products (PDF)
X-ray crystallographic data for p-nitrobezoate derivative
of 26 (CIF)
distinction of likely being directed by a dienyl unit (vs an alkene).
Chemoselective catalytic cross-coupling involving the C−B bond
might be used to access various tetrasubstituted alkenylsilane
derivatives.35 Another case relates to chemoselective NHC-Cu-
catalyzed proto-boryl addition5,36 to the monosubstituted
allene derived from 15e, affording 25 in 72% yield and >98%
β selectivity.
AUTHOR INFORMATION
■
Corresponding Authors
*sebastian.torker@bc.edu
*amir.hoveyda@bc.edu
Applicability is further highlighted by phosphine−Ni-catalyzed
cyclization37 of 22 to afford bicyclic alcohol 26 (Scheme 11c),
which was obtained in 62% yield and 94:6 diastereomeric ratio
(dr). The X-ray structure of the p-nitrobenzoate derivative of
26 confirmed the constitutional and stereochemical identity of
the products. Cross-metathesis with 22 and alkene 27 was
most effectively with complex Ru-1, affording 28 in 75% yield
and 89% E selectivity. This latter product is an intermediate
that was prepared in the racemic form in a reported total
synthesis of fasicularin.38
ORCID
Amir H. Hoveyda: 0000-0002-1470-6456
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH (GM-47480).
We thank M. S. Mikus for assistance in obtaining the X-ray
structure for p-nitrobezoate derivative of 26. We are grateful to
Dr. J. del Pozo and Dr. F. W. W. Hartrampf for helpful
discussions.
3. CONCLUSIONS
The investigations described herein introduce methods that are
notable for several reasons. These are the first examples of
catalytic SN2″-selective and enantioselective substitutions that
allow for incorporation of versatile and easily modifiable pro-
pargyl or allenyl moieties. While there is just a single report
corresponding to catalytic SN2′-selective enantioselective allylic
substitution of an allenyl unit5 and one dealing with incor-
poration of a silyl-protected propargyl moiety,7 to the best of
our knowledge, there are none involving the addition of an
unprotected propargyl group or a silyl-allenyl group. It has
formerly been shown,15c and the findings presented here fur-
ther substantiate, that different product types can be used for
generation of valuable compounds. The present advances fur-
nish access to a variety of useful, polyfunctional, and otherwise
difficult-to-access organic molecule building blocks in high er.
A combination of deuterium labeling experiments (KIE) and
DFT studies were used to establish that a cationic π-allyl-Cu
intermediate is probably generated prior to C−C bond forma-
tion, and that the process likely does not involve migratory
insertion of an alkene into a Cu−C bond (unlike a Cu−H or a
Cu−B bond). The pre-activation of the electrophile before
C−C bond formation, formerly proposed on the basis of
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(28) If phosphate elimination (VI product) were stereochemistry-
determining (i.e., is higher in energy) in path b (as opposed to C−C
bond formation, V), then an equilibrium isotope effect (EIE), and not
a kinetic isotope effect (KIE), would be observed. Such a scenario
would also require that the initial C−C bond formation is reversible,
which is unlikely. What is more, the greater likelihood that reactions
proceed through path a is supported by DFT studies.
(29) See the Supporting Information for details.
M
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