Enantioselective Synthesis of Trisubstituted Allenyl-B(pin) Compounds by Phosphine-Cu-Catalyzed 1,3-Enyne Hydroboration. Insights Regarding Stereochemical Integrity of Cu-Allenyl Intermediates

Article abstract of DOI:10.1021/jacs.7b13296

Catalytic enantioselective boron-hydride additions to 1,3-enynes, which afford allenyl-B(pin) (pin = pinacolato) products, are disclosed. Transformations are promoted by a readily accessible bis-phosphine-Cu complex and involve commercially available HB(pin). The method is applicable to aryl- and alkyl-substituted 1,3-enynes. Trisubstituted allenyl-B(pin) products were generated in 52-80% yield and, in most cases, in >98:2 allenyl:propargyl and 92:8-99:1 enantiomeric ratio. Utility is highlighted through a highly diastereoselective addition to an aldehyde, and a stereospecific catalytic cross-coupling process that delivers an enantiomerically enriched allene with three carbon-based substituents. The following key mechanistic attributes are elucidated: (1) Spectroscopic and computational investigations indicate that low enantioselectivity can arise from loss of kinetic stereoselectivity, which, as suggested by experimental evidence, may occur by formation of a propargylic anion generated by heterolytic Cu-C cleavage. This is particularly a problem when trapping of the Cu-allenyl intermediate is slow, namely, when an electron deficient 1,3-enyne or a less reactive boron-hydride reagent (e.g., HB(dan) (dan = naphthalene-1,8-diaminato)) is used or under non-optimal conditions (e.g., lower boron-hydride concentration causing slower trapping). (2) With enynes that contain a sterically demanding o-aryl substituent considerable amounts of the propargyl-B(pin) isomer may be generated (25-96%) because a less sterically demanding transition state for Cu/B exchange becomes favorable. (3) The phosphine ligand can promote isomerization of the enantiomerically enriched allenyl-B(pin) product; accordingly, lower ligand loading might at times be optimal. (4) Catalytic cross-coupling with an enantiomerically enriched allenyl-B(pin) compound might proceed with high stereospecificity (e.g., phosphine-Pd-catalyzed cross-coupling) or lead to considerable racemization (e.g., phosphine-Cu-catalyzed allylic substitution).

Full text of DOI:10.1021/jacs.7b13296

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Enantioselective Synthesis of Trisubstituted Allenyl−B(pin)
Compounds by Phosphine−Cu-Catalyzed 1,3-Enyne Hydroboration.
Insights Regarding Stereochemical Integrity of Cu−Allenyl
Intermediates
Youming Huang, Juan del Pozo, Sebastian Torker,* and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: Catalytic enantioselective boron−hydride addi-
tions to 1,3-enynes, which afford allenyl−B(pin) (pin =
pinacolato) products, are disclosed. Transformations are
promoted by a readily accessible bis-phosphine−Cu complex
and involve commercially available HB(pin). The method is
applicable to aryl- and alkyl-substituted 1,3-enynes. Trisub-
stituted allenyl−B(pin) products were generated in 52−80%
yield and, in most cases, in >98:2 allenyl:propargyl and 92:8−
99:1 enantiomeric ratio. Utility is highlighted through a highly
diastereoselective addition to an aldehyde, and a stereospecific
catalytic cross-coupling process that delivers an enantiomeri-
cally enriched allene with three carbon-based substituents. The following key mechanistic attributes are elucidated: (1)
Spectroscopic and computational investigations indicate that low enantioselectivity can arise from loss of kinetic stereoselectivity,
which, as suggested by experimental evidence, may occur by formation of a propargylic anion generated by heterolytic Cu−C
cleavage. This is particularly a problem when trapping of the Cu−allenyl intermediate is slow, namely, when an electron deficient
1,3-enyne or a less reactive boron−hydride reagent (e.g., HB(dan) (dan = naphthalene-1,8-diaminato)) is used or under non-
optimal conditions (e.g., lower boron−hydride concentration causing slower trapping). (2) With enynes that contain a sterically
demanding o-aryl substituent considerable amounts of the propargyl−B(pin) isomer may be generated (25−96%) because a less
sterically demanding transition state for Cu/B exchange becomes favorable. (3) The phosphine ligand can promote isomerization
of the enantiomerically enriched allenyl−B(pin) product; accordingly, lower ligand loading might at times be optimal. (4)
Catalytic cross-coupling with an enantiomerically enriched allenyl−B(pin) compound might proceed with high stereospecificity
(e.g., phosphine−Pd-catalyzed cross-coupling) or lead to considerable racemization (e.g., phosphine−Cu-catalyzed allylic
substitution).
selectivity was minimized under conditions that allow for faster
trapping of a Cu−alkyl intermediate.
1. INTRODUCTION
A central advance in organic synthesis relates to catalytic
transformations through which an organocopper intermediate is
formed enantioselectively by the addition of a Cu−B(pin) (pin =
pinacolato) or a Cu−H complex to an alkene. Typically, this is
followed by reaction of the resulting Cu−alkyl species with an
electrophile (e.g., a proton,1 a hydroxylamine,2 an allylic
electrophile,3 an enoate,4 or an acyl halide5). A key mechanistic
issue is whether kinetic selectivity is partially or entirely lost
before the organocopper entity is trapped by an electrophile.3g
Deeper understanding of factors that impact the stereochemical
integrity of the Cu-based intermediates is therefore crucial to the
success of future efforts in this emerging area. We recently
showed3g that in reactions via Cu−alkyl entity i (Scheme 1a)
differences in steric and electronic attributes of the aryl
substituent (Ar) and/or the electrophile (E) may engender
major differences in product enantiopurity. In transformations
involving the less nucleophilic organocopper intermediates or
more congested allyl electrophiles, loss of kinetic enantio-
The focus of the present study is a set of reactions that proceed
through a Cu−allenyl complex (iv, Scheme 1b); such entities
may arise from addition of a Cu complex to a 1,3-enyne to afford
a Cu−propargyl species (iii), which would likely be rapidly
converted to the lower energy allenyl isomer.6 We have
previously demonstrated that the latter sequence may be utilized
in catalytic site- and enantioselective Cu−B(pin) additions to
1,3-enynes followed by a γ-selective reaction with aldehydes
(affording v, Scheme 1b).7 More recently, in a noteworthy
disclosure,8 Buchwald and co-workers have shown that a similar
process may involve a Cu−H complex9 and a ketone (but not an
aldehyde, as will be discussed below).
Trisubstituted allenes are valuable axially chiral molecules10 for
which only a limited number of catalytic enantioselective
Received: December 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
favor of the propargyl−B(pin) compound (ix), and precisely
what factors can influence this selectivity.
Scheme 1. Relevant Previous Investigations
A more direct, efficient and enantioselective method for
synthesizing trisubstituted allenyl−B(pin) compounds, one that
is distinct from the notable procedures outlined by Ito,
Sawamura, and Szabo,15
which require enantiomerically enriched
́
propargyl carbonates or phosphates. Moreover, Cu−H com-
plexes react too fast with aldehydes (i.e., rapid reduction of
aldehyde substrates is problematic) such that, unlike when the
less reactive ketones are involved, the corresponding multi-
component CuH-catalyzed processes8 are low yielding. Allenyl−
B(pin) products may be converted by catalytic cross-coupling to
other desirable enantiomerically enriched trisubstituted allenes10
(i.e., x → xii, Scheme 2b).
Herein, we detail our studies aimed at addressing the above
questions and the realization of related objectives, including the
development of the first catalytic method for enantioselective
hydroboration16,17 of 1,3-enynes.
2. RESULTS AND DISCUSSION
2.1. The Method and Its Scope. 2.1.1. Reactions with
Aryl-Substituted 1,3-Enynes. We began by examining the ability
of Cu complexes derived from phosphine or N-heterocyclic
carbene (NHC) ligands to promote hydroboration of 1,3-enyne
1a (Scheme 3). We found that (1,2-bis(2,5-
diphenylphospholano)ethane (phenyl-bpe),18 either enantiomer
of which is commercially available, and Cu(OAc)2 is the optimal
combination.19 Allenyl−B(pin) 2a was thus isolated exclusively
(i.e., >98:2 viii:ix, Scheme 2a) in 63% yield and 96:4
enantiomeric ratio (er). The same ligand/Cu salt system was
employed in the aforementioned transformations involving 1,3-
enynes, ketones, and a silyl hydride;8 the stereochemical model
proposed in this latter report is applicable here as well.
In mostbut not allinstances, reactions of aryl-substituted
enynes afforded the allenyl−B(pin) with reasonable efficiency
(2a−j, 51−80% yield; Scheme 3), without observable amounts of
the propargyl isomer formation (<2%), and in up to 98:2 er. This
included enynes that contain 1,2-disubstituted alkenyl moiety
(2k,l; Scheme 3), although longer reaction times were necessary.
Processes leading to p-trifluoromethylphenyl-substituted 2e
and o-fluorophenyl-substituted 2i were less enantioselective
methods exist.11,12 To the best of our knowledge, there is no
extant catalytic protocol for preparation of enantiomerically
enriched trisubstituted allenyl boronates (i.e., α-addition to
furnish vi, Scheme 1b).13 An attractive way to synthesize
trisubstituted allenyl boronates (viii, Scheme 2a) enantio-
selectively would be by 1,3-enyne hydroboration,14 which
might proceed via Cu−allenyl species vii. We wished to
investigate whether, despite the relative robustness of a Cu−
allenyl bond (vs the formerly studied Cu−alkyl bonds3g), there
might be cases where the stereochemical integrity of a Cu−
allenyl intermediate might be jeopardized, and whether
conditions may be modified for achieving high enantioselectivity.
It remained to be determined the extent to which Cu−B(pin)
exchange would be α-selective, affording allenyl product (viii) in
Scheme 2. Goals of This Study
B
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Scheme 3. Synthesis of Trisubstituted Allenyl Boronates. Scope I: Aryl-Substituted 1,3-Enynes as Substrates
a
1
Reactions were carried out under N2 atmosphere. Conversion >98% in all cases, determined by analysis of H spectra of unpurified product
b
mixtures ( 2%). Yields are given for purified allenyl products ( 5%). Enantioselectivities were determined by HPLC analysis. Reaction time was 40
h. Experiments were run in duplicate or more. See the Supporting Information for details. pin = pinacolato.
a
Scheme 4. Synthesis of Trisubstituted Allenyl Boronates. Scope II: Alkyl-Substituted 1,3-Enynes as Substrates
a
1
Reactions were carried out under N2 atmosphere. Conversion >98% in all cases except for 4f (67%), determined by analysis of H spectra of
b
unpurified product mixtures ( 2%). Yields for purified products ( 5%). Enantioselectivities were determined by HPLC analysis. Reaction time was
40 h. Experiments were run in duplicate or more. See the Supporting Information for details.
C
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(80:20 and 90:10 er, respectively). This is in contrast to
transformations of the corresponding meta-substituted isomers:
2g and 2h were generated in 93:7 and 94:6 er, respectively.
Reactions that generate p-bromo- or m-trifluoromethyl-sub-
stituted 2d and 2g (93:7−95:5 er) were less enantioselective than
those delivering p-tolyl-, p-methoxyphenyl-, or m-tolyl-substi-
tuted 2b, 2c, and 2f (97:3−98:2 er). Thus, although less
pronounced, these data further indicate that enantioselectivity
can be lower with electron-deficient enynes. We note that in the
previously reported catalytic Cu−H addition/ketone trapping
study,8 there were no examples regarding reactions with enynes
that bear an electron withdrawing or an ortho-substituted aryl
group. Another key finding is that only in the transformation
leading to o-fluorophenyl-substituted 2i was the propargyl
addition byproduct formed (25%; see below for further
discussion).
Scheme 5. Efficient and Diastereoselective Addition to an
Aldehyde
a
2.1.2. Reactions with Alkyl-Substituted Enynes. Trans-
formations with alkyl-substituted enynes were for the most
part efficient and exceptionally enantioselective (4a−i, 48−80%
yield and 95:5−99:1 er; Scheme 4). Among suitable substrates
were those containing a relatively bulky cyclohexyl group (e.g.,
4h, in 65% yield and 98:2 er). A carboxylic ester or an alkene unit
was tolerated, as these moieties were not subject to competitive
reduction or hydroboration, respectively. Nevertheless, methyl
ketone 4f was formed less efficiently (67% conversion, 22%
recovered 3f, 48% yield).20 Based on a previous hypothesis,
presented in connection to a set of NHC−Cu-catalyzed allylic
substitutions,21 internal Cu−carbonyl chelation might lead to
reduced reaction rates. Consistent with the suggested scenario,
4g, containing a larger isopropyl ketone unit, was obtained in
higher yield (67% vs 48%, Scheme 4).
2.2. Utility. 2.2.1. Efficiency of Allenyl−B(pin) Synthesis.
1,3-Enynes may be prepared by catalytic Sonogashira cross-
coupling22 between a terminal alkyne and an alkenyl bromide.
This compares favorably with the alternative multistep sequence
needed for synthesis of trisubstituted allenylboronates, where the
following steps are required: deprotonation of the alkyne
substrate with a strong base (e.g., n-BuLi), addition to an
aldehyde, oxidation to the ynone, enantioselective reduction,
alcohol activation (i.e., carbonate generation), and phosphine−
Cu-catalyzed boryl allylic substitution.15 Enantiomerically
enriched propargyl alcohols can be prepared by the addition of
a terminal alkyne to an aldehyde.23 Nonetheless, reactions with
acetaldehyde, which afford especially important building blocks,
proceed with low enantioselectivity,24 and carbonate formation
and an ensuing boryl addition must still be carried out.
2.2.2. Diastereoselective Addition to Aldehydes. As noted
earlier, a key advantage of the present approach is that it allows
for diastereoselective additions to aldehydes and formation of
valuable propargylic alcohol fragments. A representative case,
entailing catalytic enantioselective synthesis of trisubstituted
allenyl−B(pin) 4j and its conversion to alkyne 5,25 is presented
in Scheme 5. As expertly demonstrated by Roush and Chen, who
originally developed this widely applicable addition reaction, use
of the other phosphoric acid enantiomer will lead to the
formation of the alternative diastereomer with high selectivity.25a
The reaction leading to the formation of 4j, obtained in 68% yield
and 95:5 er, was carried out on 0.5 g of the enyne 3j at reduced
catalyst loading (2.5 mol%). This approach complements that of
Krische and co-workers26 in regard to efficient and enantio-
selective segphos−Ir-catalyzed coupling of alcohols and 1,3-
enynes, which must bear a specific protecting group. The
a
Carried out under N2 atmosphere. Conversion (>98% in all cases)
1
determined by analysis of H spectra of unpurified product mixtures
( 2%). Yields for purified products ( 5%). Enantioselectivities were
determined by HPLC analysis. Experiments were run in duplicate or
more. See the Supporting Information for details.
protocol is also applicable to a wider range of aryl- and alkyl-
substituted substrates (Schemes 3 and 4).
2.2.3. Catalytic Cross-Coupling and Fluctuations in er.
Another important mode of functionalization for trisubstituted
allenyl−B(pin) compounds involves catalytic cross-coupling.27
A
key issue here is that loss of enantiopurity of the metal−allenyl
intermediate must not be competitive with C−C bond
formation. The examples in Scheme 6 reveal that the initial
enantiomeric purity may be retained or vanished, depending on
the coupling process. The dppe−Pd-catalyzed reaction of 4d
with phenyl iodide delivered 6 in 70% yield without any
detectable alteration in enantiomeric purity (95:5 er). In
contrast, attempts to carry out enantioselective allylic sub-
stitution under conditions developed by us for NHC−Cu-
catalyzed allylic substitutions involving monosubstituted allen-
yl−B(pin) and allylic phosphate28 led only to formation of a
mixture of unidentifiable byproducts. Additionally, (phenyl)-
bpe−Cu-catalyzed multicomponent allylic substitution with
allylphosphate afforded 7 in 70% yield, but only in the racemic
form (see below for analysis).
2.3. Influence of Reaction Conditions and Enyne
Structure on Allenyl:Propargyl Selectivity and Enantio-
selectivity. To gain further insight as to why, depending on
electronic and/or steric attributes of an enyne substrate or
reaction conditions, there might be significant variations in
allenyl:propargyl ratio or er, the following investigations were
performed.
2.3.1. Influence of Enyne Structure on Differences in
Allenyl:Propargyl Selectivity. As was noted and illustrated in
entries 1 and 2 of Table 1, unlike other aryl- or alkyl-substituted
enynes, significant amounts of the propargyl−B(pin) isomer was
generated during the reaction of an o-fluorophenyl-substituted
enyne. Moreover, in the transformation involving o-bromophen-
yl-substituted 1m (entry 3, Table 1) propargyl−B(pin) 8m was
formed preferentially (20:80 allenyl:propargyl ratio),29 and
D
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Scheme 6. Retention/Loss of Kinetic Selectivity Depends on the Type of Reaction
a
1
Carried out under N2 atmosphere. Conversion >98% in both cases (determined by analysis of H spectra of unpurified product mixtures; 2%).
Yields are for purified products ( 5%). Enantioselectivity was determined by HPLC analysis. Experiments were run in duplicate or more. See the
Supporting Information for details.
Table 1. Effect of ortho-Substituted Aryl Enyne Group on
a
Allenyl:Propargyl Selectivity
a
Reactions were carried out under N2 atmosphere. Conversion (>98%
1
in all cases) was determined by analysis of H NMR spectra of the
unpurified product mixtures ( 2%). Determined by analysis of H
NMR spectra of unpurified product mixtures. Yields are for isolated
and purified allenyl boronate products ( 5%). Er was determined by
HPLC analysis ( 1%). Based on analysis of the H NMR spectra of
the unpurified product mixture with diphenylmethane as the internal
standard. See the Supporting Information for details. nd = not
determined.
b
1
c
d
e
1
propargyl−B(pin) 8n was generated with 4:96 allenyl:propargyl
selectivity, in 48% yield and 92:8 er (entry 4).
2.3.2. Fluctuations in er Based on Boron−Hydride Identity
and Concentration. The lower er for reactions of enynes
containing a relatively electron-deficient aryl group might be
because of the slower reaction between the Cu−allenyl complex
and the boron−hydride. Indeed, er decreased as H−B(pin)
concentration was diminished and/or when the less reactive H−
B(dan) was used (Figure 1). Whereas enyne 1a was converted to
allenyl−B(pin) 2a in 91:9 er with 0.5 equiv of HB(pin) (square
symbol, Figure 1), er improved significantly (96:4 er) with 1.0
equiv of the hydride; further increase in boron−hydride
concentration was inconsequential. In transformation of 1a
with the less reactive HB(dan) (dan = naphthalene-1,8-
diaminato; diamond symbol, Figure 1), as the hydride amount
was increased from 0.5 to 1.0 to 2.0 to 4.0 equiv, so did the er
(from 77:23 to 81:19 to 89:11 to 92:8). With the more electron-
deficient p-trifluoromethylphenyl-substituted enyne 1e (triangle
symbol) and o-fluorophenyl-substituted enyne 1i (circle
symbol), enantioselectivity improved when the amount of
HB(pin) was increased from 0.5 to 4.0 equiv (from 52:48 and
Figure 1. Influence of electrophile concentration and/or identity on er.
Reactions were carried out under N2 1atmosphere; >98% conversion in
all cases (determined by analysis of H spectra of unpurified product
mixtures; 2%). Yields (in parentheses) are for isolated and purified
allenyl boronate products and are based on the limiting reagent ( 5%).
Enantioselectivity was determined through HPLC analysis ( 1%). See
the Supporting Information for details. dan = naphthalene-1,8-
diaminato.
70:30 er to 81:19 and 91:9 er, respectively). Faster trapping of
the enantiomerically enriched Cu−allenyl intermediates seems
to allow for more effective preservation of kinetic selectivity. The
fact that a plateau is reached with >2.0 equiv HB(pin) may be
attributed to the lower kinetic selectivity of reactions involving
the boron−hydride reagent (vs PMHS).30 Similar to what was
observed in a recently disclosed study,3g er values are higher at
E
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
lower alkene concentration; this suggests that, when HB(pin) is
used as the reagent, a Cu−H complex that reacts with 1,3-enyne
with lower enantioselectivity may be formed. For instance, when
the amount of 1e is reduced from 1.0 to 0.25 equiv, while
maintaining constant HB(pin) concentration, er increases from
62:38 (Figure 1) to 75:25 er.
2.3.3. Influence of Bis-phosphine:Cu Salt Ratio on er. We
carried out selected transformations with different amounts of
the bis-phosphine ligand (5.0 mol% Cu(OAc)2; Table 2). For 2e
Recent advances in computational chemistry have rendered
high-level ab initio CCSD(T) calculations significantly more
affordable, while maintaining high accuracy, through the use of
localized orbitals (DLPNO−CCSD(T)).45 These latter calcu-
lations are intended to serve as the internal standard in the
present investigation, rather than relying solely on density
functionals, which have been calibrated against external data-
bases. Density functional MN1546 showed the best overall
agreement with the reference and, accordingly, the correspond-
ing values were used.
Specifically, we set out to address the following questions:
Table 2. Effect of Bis-phosphine Amount on
Enantioselectivity
a
(a) What might be the mechanism of unimolecular
racemization (i.e., interconversion of Cu−allenyl diaster-
eomers), and how might these processes compare
energetically to the more frequently invoked π-allyl
isomerization?
(b) How facile is the bimolecular trapping of Cu−allenyl
intermediates with boron−hydride in comparison to
unimolecular isomerization, which leads to diminished
er?
(c) What electronic factors govern the racemization process,
and is there more than one pathway that leads to lowering
of er?
(d) Why do catalytic cross-coupling reactions involving a Pd−
allenyl complex proceed with minimal loss of enantio-
selectivity but not in the case of phosphine−Cu-catalyzed
allylic substitution reactions (see Scheme 6)?
a
Reactions were carried out under N2 atmosphere; >98% conversion
in all cases (determined by analysis of 1H spectra of unpurified product
mixtures; 2%). Yields are for isolated and purified allenyl boronate
products ( 5%). Enantioselectivity was determined through HPLC
analysis ( 1%). See the Supporting Information for details.
2.4.1. Fluxional Processes with Cu−Allenyl Intermediates.
Computational studies indicate that Cu−H addition leading to
generation of the major Cu−allenyl diastereomer (Cu-amajor) via
ts(CuHa)major (29.0 kcal/mol; Figure 2) is exergonic by 21.3
kcal/mol (i.e., largely irreversible Cu−H addition; Cu(I) is likely
generated by facile in situ reduction9). The barrier to formation
of the minor diastereomer (Cu-aminor) is predicted to be 6.2 kcal/
mol higher in energy, which is in agreement with a previous
study.8 The initial Cu−propargyl species (Cu-pmajor and Cu-
b
c
and 2i, er was higher at lower catalyst loading, and there was no
additional improvement when less than 2.5 mol% ligand was
present. Moreover, when equal amounts of the chiral ligand and
Cu salt were used, er values remained constant throughout the
transformation (e.g., with 1e, 80:20 er after 0.5 and 15 h), further
suggesting that diminished enantioselectivity likely originates a
less kinetically selective Cu−H addition. The diminution in er
was not observed with electron-neutral or electron-rich enynes.
This implies that, with electron-deficient allenes, free phosphine
can lead to lowering of er. If so, er could be improved by properly
adjusting ligand concentration (see below for discussion).
2.4. DFT Studies. The er fluctuations might be a
consequence of the fluxional attributes of the metal−allenyl
intermediates,31 a possibility which, despite some available
evidence,32 has not been rigorously investigated.33,34 Similar
considerations have been applied to metal−alkenyl complexes
involved in alkyne hydroboration35 (or hydrosilylation36 or
hydrogenation37), where unimolecular rearrangements via
metallacyclopropenes38 or zwitterionic metal carbenes39,40
have been proposed to cause selectivity variations. However, it
seems unlikely that such resonance contributions are strong
enough to cause the same type of process to occur with
organocopper compounds.41 As several transition metal
complexes (e.g., Cu-, Au-, or Pd-based) have been reported to
promote isomerization of chiral allenes,42,43 we chose to use
density functional theory (DFT) and high level ab initio
DLPNO−CCSD(T)44 calculations as the means to investigate
these mechanistic issues.
p
minor) were found to reside in a shallow minimum on the
potential energy surface (e.g., 5.5 kcal/mol for Cu-pmajor), readily
transforming to allenyl isomers (e.g., via ts(iso)major; free energy
= 6.6 kcal/mol).6,31 In contrast, we find that the transition state
for interconversion of the Cu−allenyl diastereomers (Cu-amajor
and Cu-aminor) is energetically more demanding (17.0 kcal/mol
for ts(rac)). This barrier is sufficiently high for the initial
stereochemistry to be preserved if subsequent trapping following
Cu−H addition is competitive, yet fast enough for ts(rac) to be
accessible (i.e., low reactivity and/or concentration of electro-
phile). The transition state (ts(rac)) is best described as a Cu−
propargyl anion complex, wherein the alkynyl π-system,
orthogonal to the extended π cloud, is transition metal bound.
The C1−C2 bond contraction from 1.313 Å in Cu-amajor to 1.297
Å in ts(rac) and elongation of the C2−C3 bond from 1.325 to
1.359 Å support this proposal. The geometric parameters for
ts(rac) are similar to bond lengths in the corresponding free
propargyl anion (1.259 and 1.356 Å for C1−C2 and C2−C3,
respectively), but considerably different compared to the ones in
the neutral alkyne after protonation at C3 (1.220 and 1.453 Å,
respectively). The latter comparison underscores the importance
of resonance contributions in stabilizing the negative charge.
Furthermore, the Cu−C1 bond in ts(rac) is relatively ionic, and
natural bond orbital (NBO) analysis indicates 84% contribution
from C1 (vs 16% from Cu; more on this below).
F
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 2. Fluxional nature of Cu−allenyl complexes (enantioselective Cu−H addition, propargyl-to-allenyl isomerization and racemization). Free
energy values were obtained at the MN15/Def2TZVPPthf(SMD)//M06L/DF-Def2SVPthf(PCM) level; pc, π-complex; ts(CuHa), transition state for
copper hydride addition; ts(rac), transition state for racemization; ts(iso), transition state for π-allyl isomerization; Cu-p, Cu−propargyl intermediate;
Cu-a, Cu−allenyl intermediate. See the Supporting Information for details.
Figure 3. Competition between racemization and trapping with H−B(pin); free energy values were obtained at the MN15/Def2TZVPPthf(SMD)//
M06L/DF-Def2SVPthf(PCM) level. Abbreviations: ts(rac), transition state for racemization; Cu-a, Cu−allenyl intermediate; tsα, transition state for α-
addition to H−B(pin); tsγ, transition state for γ-addition to H−B(pin); BHa, borohydride adduct. See the Supporting Information for details.
G
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 4. Comparison of various modes of racemization; free energy values were obtained at the MN15/Def2TZVPPthf(SMD)//M06L/DF-
Def2SVPthf(PCM) level. Abbreviations: ts(rac), transition state for racemization; Cu-a, Cu−allenyl intermediate; a-B(pin), allenyl−B(pin) product;
phos-a, phosphine adduct with allenyl−B(pin) product; Ar = p-F3CC6H4; uncat = uncatalyzed. See the Supporting Information for details.
2.4.2. Competition between Unimolecular Isomerization
and Bimolecular Trapping: Impact of Bulky Substituents on
Allenyl:Propargyl Ratios. We calculated the relative barriers
between ts(rac) and tsα/tsγ, leading to allenyl (2a and 2n) and
propargyl products (8a and 8n) via intermediates BHaα and
BHaγ (Figure 3). Transition states ts(rac), tsα, and tsγ were
found to be similar in energy when functionals that account for
dispersion were applied (e.g., MN15). Furthermore, in agree-
ment with the experimental data, with a phenyl-substituted
substrate, tsα (15.7 kcal/mol) was found to be favored over tsγ
(18.2 kcal/mol).47 The finding that the computed relationship
between tsα and tsγ is reversed in the case of an o-tolyl-
substituted enyne (18.8 vs 16.6 kcal/mol, respectively) is
congruent with the experimental observation (Table 1). That
ts(rac) (16.4 kcal/mol; cf. Figure 3) is predicted to be slightly
lower in energy than tsγ (by 0.2 kcal/mol) still supports the
observed high enantioselectivity and is consistent with expected
uncertainties in DFT energies.48 The energy needed to reach tsα
in the case of the p-trifluoromethylphenyl-substituted substrate is
16.1 kcal/mol (not shown in Figure 3; see the Supporting
Information), whereas it is 15.7 kcal/mol for the phenyl-
substituted species (cf. Figure 3). Although the difference
between these latter values is smaller than the error bar in
computational accuracy, it is consistent with the scenario that a
Cu−allenyl species bearing an electron-withdrawing moiety is
likely less nucleophilic.3g
2.4.3. Transition States Leading to Isomerization and
Impact of Excess Phosphine. We then investigated the influence
of electronic modification on the barrier to loss of kinetic
enantioselectivity (e.g., effect of an electron-withdrawing unit;
Figure 4). Based on our calculations, a p-trifluoromethylphenyl
group can stabilize the propargyl anion en route to ts(rac) (15.8
kcal/mol vs 17.0 kcal/mol for a phenyl moiety), and the
corresponding barrier is higher for the methyl-substituted
intermediate (21.1 kcal/mol). The decrease in resonance
stabilization is reflected in the contraction of the C1−C2 bond
in the methyl-substituted complex (1.291 Å) compared to the
one that contains a p-trifluoromethylphenyl group (1.300 Å).
Nonetheless, the ease with which ts(rac) can be accessed
supports the notion that isomerization of metal−alkenyl species
via the aforementioned zwitterionic metal carbene intermediates
is more challenging.41
́
In search of additional evidence vis-a-vis the proposed
unimolecular racemization (Figure 4), we synthesized Cu−
allenyl complex Cu-amajor diastereoselectively and monitored its
conversion to the corresponding minor isomer (Cu-aminor) by
1
low-temperature H NMR spectroscopy. Addition of enyne 3c
(at −50 °C) to a sample of the bis-phosphine−Cu−H complex,
generated from a mixture of CuOt-Bu, bisphosphine, and a silyl
hydride (tetramethyldisiloxane), led to the formation of 1:99
ratio of diastereomers (Figure 5a). The alternative route to access
the major Cu-allenyl diastereomer through transmetalation of
enantiomerically enriched allenyl−B(pin) products to a bi-
sphosphine CuOt-Bu complex was not stereospecific and
inapplicable.50 After 2.75 h (at −50 °C) the ratio was reduced
to 4.5:95.5 (Figure 5b). Accordingly, a free energy of activation
(ΔG⧧) of 18.5 kcal/mol was measured (at −50 °C),50 which is in
agreement with the value calculated for the model system
(ts(rac)Me = 21.1 kcal/mol; Figure 4). When equilibration was
Structural analysis offers a clue for the reversal in
allenyl:propargyl product selectivity. The short CMe···Cβ
distance of 2.98 Å in tsα for o-tolyl-substituted enynes points
to destabilizing A(1,3) strain, which is absent in the case of
phenyl-substituted substrates. In tsγ the aryl ring is able to rotate
such that it is in conjugation with the Cu−C1 bond and A(1,3)
strain49 can be avoided (CMe···Cβ distance = 3.61 Å).
H
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
which is markedly higher than those that correspond to a Cu−
allenyl species (see Figure 4). In addition, we find that reductive
elimination, also a unimolecular process, can outcompete
racemization (22.7 kcal/mol for ts(re)major,Pd). We have
previously shown that allylic substitution involving Cu-alkyl
intermediates bearing a bis-phosphine ligand can be energetically
demanding,3g rendering isomerization problematic. Comparison
of the electronic features of Pd−allenyl species (Pd-amajor) with
those of the corresponding organocopper entities (Cu-amajor, see
Figure 2) offers further support for the increased configurational
stability of the former four-coordinate systems. While the Cu−
C1 bond is relatively polar (84% C1, 16% Cu), NBO analysis
predicts a greater degree of covalent character for the Pd−C1
bond (65% C1, 35% Pd), implying that more energy is required
for formation of the corresponding propargyl anion transition
state in the case of an organopalladium complex.
CONCLUSIONS
■
We have developed the first enantioselective method for
preparation of trisubstituted allenyl−B(pin) compounds,
obtained by catalytic hydroboration of 1,3-enynes; the method
is efficient and broadly applicable. We demonstrate that
processes involving the use of an allenyl−B(pin) compound
complement the related multicomponent transformations where
the enantiomerically enriched Cu−allenyl intermediate reacts in
situ with an electrophile. For example, in cases where the
electrophile might react competitively with a Cu−H complex
(e.g., an aldehyde; Scheme 5), or if certain subsequent cross-
coupling reactions are desired, it is preferable to utilize an
allenyl−B(pin) compound.
Figure 5. Low-temperature 31P NMR experiment to investigate the
isomerization of Cu-amajor to Cu-aminor; all measurements were
performed at −50 °C in thf-d8. See the Supporting Information for
details.
allowed to be established at 22 °C, followed by cooling to −50
°C, the diastereomeric ratio plummeted (52:48; Figure 5c).
Subsequent trapping with HB(pin) afforded racemic allenyl−
B(pin), ruling out an event other than Cu−H addition as the
stereochemistry-determining step.51
For further insight regarding a possible adverse influence of
free phosphine on enantioselectivity (see Table 2), we probed
the feasibility of a mechanism that is reminiscent of what has
formerly been proposed for Morita−Baylis−Hillman trans-
formations.52 Indeed, when an enantiomerically enriched sample
of 2i (90:10 er) was subjected to 5.0 mol% of the bis-phosphine
ligand (22 °C, thf, 15 h to emulate the reaction conditions), the
enantiomeric purity of recovered 2i was found to be measurably
lower (83:17 er; eq 1). The same experiment with allenyl−
The present studies shed light on factors that impact
allenyl:propargyl ratios and/or enantioselectivity:
(a) With enynes bearing an electron-deficient substituent,
where the Cu−allenyl intermediates are more stabilized
(i.e., are less reactive), loss of er might arise from
competitive racemization. This can be minimized by the
use of larger amounts of and/or more reactive boron−
hydride reagents (i.e., HB(pin)).
(b) Particularly with enynes bearing an electron-deficient
substituent, a Lewis basic phosphine ligand can promote
isomerization of an enantiomerically enriched allenyl−
B(pin) product.
(c) Depending on the type of transformation, functionaliza-
tion of a trisubstituted allenyl−B(pin) compound might
take place with high stereospecificity or lead to major loss
of enantiomeric purity.
B(pin) compounds that lack an electron-withdrawing aryl unit
(e.g., 2a) did not lead to any observable change in er.
Calculations suggest that reversible addition of phosphine53 to
the central/sp-hybridized carbon of the chiral allenyl B(pin)
product might lead to racemization (right panel, Figure 4). The
26.6 2.0 kcal/mol estimate for ts(rac)Phos is a reasonable value
for a process at ambient temperature.
2.4.4. Variations in Loss of er in Different Catalytic
Reactions of Allenyl−B(pin) Products. The above consider-
ations raise another intriguing question: Why is there complete
retention of stereochemistry during phosphine−Pd-catalyzed
cross-coupling, whereas with a phosphine−Cu-catalyzed allylic
substitution it is entirely lost (see Scheme 6)? DFT studies show
that the barrier for unimolecular transition state for racemization
of a Pd−allenyl complex ts(rac)Pd (Figure 6) is 26.8 kcal/mol,
The insights provided by the present investigations are
applicable to other sets of transformations. The examples
provided in Scheme 7 are illustrative. It can now be more easily
understood why whereas 9a and 9b were obtained in 97% and
99% enantiomeric excess (ee; ≥98.5:15 er), respectively,8
synthesis of p-trifluoromethylphenyl-substituted 9c, formed via
a less nucleophilic Cu−allenyl intermediate, is notably less
enantioselective [84% ee (92:8 er)]. It is probably for similar
reasons that enantioselectivity for 9c decreases further to 80% ee
(90:10 er) when the concentration of the enyne is increased (3:1
enyne:acetophenone, lower kinetic selectivity), but improves to
88% ee (94:6 er) with excess ketone (1:3 enyne:acetophenone,
faster trapping).
Development of additional catalytic enantioselective methods,
the associated mechanistic investigations, and applications to
I
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 6. Relevance of metal−allenyl racemization to bis-phosphine−Pd-catalyzed cross-coupling; free energy values have been obtained at the MN15/
Def2TZVPPthf(SMD)//M06L/DF-Def2SVPthf(PCM) level. Abbreviations: P2 = (phenyl)bpe; ts(rac), transition state for racemization; ts(iso), transition
state for π-allyl isomerization; Pd-p, Pd−propargyl intermediate; Pd-a, Pd−allenyl intermediate; ts(re), transition state for reductive elimination; pc, π-
complex. See the Supporting Information for details.
a
Scheme 7. Relevance to a Previously Reported Method
a
1
Reactions were carried out under N2 atmosphere. Conversion >98% in both cases (determined by analysis of H spectra of unpurified product
mixtures; 2%). Yields are for purified products ( 5%). Enantioselectivity was determined by HPLC analysis. Experiments were run in duplicate or
more. See the Supporting Information for details.
synthesis of biologically active molecules continue to be
investigated in these laboratories.
functionals M06, M06L, wB97XD, PBE0−D3BJ, and
PBE0, as well as coordinates of computed structures.
(PDF)
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b13296.
■
S
AUTHOR INFORMATION
■
Corresponding Authors
*sebastian.torker@bc.edu
*amir.hoveyda@bc.edu
Experimental details for all reactions and analytic details
for all products; free energy surfaces with density
J
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(9) For a review on CuH-catalyzed reactions, see: Deutsch, C.; Krause,
N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916−2927.
ORCID
Amir H. Hoveyda: 0000-0002-1470-6456
(10) For a review on preparation of trisubstituted allenes, see: Ye, J.;
Ma, S. Org. Chem. Front. 2014, 1, 1210−1224.
Notes
(11) (a) Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305−
307. (b) Li, C.-Y.; Wang, X.-B.; Sun, X.-L.; Tang, Y.; Zheng, J.-C.; Xu, Z.-
H.; Zhou, Y.-G.; Dai, L.-X. J. Am. Chem. Soc. 2007, 129, 1494−1495.
(c) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang, W. J.
Am. Chem. Soc. 2010, 132, 3664−3665. (d) Nishimura, T.; Makino, H.;
Nagaosa, M.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 12865−12867.
(e) Wang, Y.; Zhang, W.; Ma, S. J. Am. Chem. Soc. 2013, 135, 11517−
11520. (f) Qian, H.; Yu, X.; Zhang, J.; Sun, J. J. Am. Chem. Soc. 2013, 135,
18020−18023. (g) Wang, M.; Liu, Z.-L.; Zhang, X.; Tian, P.-P.; Xu, Y.-
H.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 14830−14833. (h) Chu, W.-
D.; Zhang, L.; Zhang, Z.; Zhou, Q.; Mo, F.; Zhang, Y.; Wang, J. J. Am.
Chem. Soc. 2016, 138, 14558−14561. (i) Yao, Q.; Liao, Y.; Lin, L.; Lin,
X.; Ji, J.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2016, 55, 1859−1863.
(12) For additional examples (also see ref 10) of trisubstituted allenes
prepared through modification of enantiomerically enriched substrates,
see: (a) Hung, S.-C.; Wen, Y.-F.; Chang, J.-W.; Liao, C.-C.; Uang, B.-J. J.
Org. Chem. 2002, 67, 1308−1313. (b) Molander, G. A.; Sommers, E. M.;
Baker, S. R. J. Org. Chem. 2006, 71, 1563−1568. (c) Dieter, R. K.; Chen,
N.; Gore, V. K. J. Org. Chem. 2006, 71, 8755−8760. (d) Liu, Z.;
Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 10352−
10353. (e) Kobayashi, K.; Naka, H.; Wheatley, A. E. H.; Kondo, Y. Org.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by a grant from the NIH (GM-
47480) and postdoctoral fellowships to Y.H. by the Shanghai
Institute of Organic Chemistry, Zhejiang Medicine Co., and
Pharmaron, and to J.d.P. by Alfonso Martin Escudero
Foundation.
REFERENCES
■
(1) For representative reports, see: (a) Lee, Y.; Hoveyda, A. H. J. Am.
Chem. Soc. 2009, 131, 3160−3161. (b) Lee, Y.; Jang, H.; Hoveyda, A. H.
J. Am. Chem. Soc. 2009, 131, 18234−18235. (c) Sasaki, Y.; Zhong, C.;
Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226−1227.
(d) Jang, H.; Zhugralin, A. R.; Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc.
́
2011, 133, 7859−7871. (e) Corberan, R.; Mszar, N. W.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2011, 50, 7079−7082. (f) Sasaki, Y.; Horita, Y.;
Zhong, C.; Sawamura, M.; Ito, H. Angew. Chem., Int. Ed. 2011, 50,
2778−2782. (g) Meng, F.; Jang, H.; Hoveyda, A. H. Chem. - Eur. J. 2013,
19, 3204−3214. (h) Kubota, K.; Yamamoto, E.; Ito, H. Adv. Synth. Catal.
2013, 355, 3527−3531. (i) Jang, H.; Jung, B.; Hoveyda, A. H. Org. Lett.
2014, 16, 4658−4661. (j) Wang, Z.; He, X.; Zhang, R.; Zhang, G.; Xu,
G.; Zhang, Q.; Xiong, T.; Zhang, Q. Org. Lett. 2017, 19, 3067−3070.
(2) For representative reports, see: (a) Matsuda, N.; Hirano, K.; Satoh,
T.; Miura, M. J. Am. Chem. Soc. 2013, 135, 4934−4937. (b) Zhu, S.;
Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 15746−
15749. (c) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int.
Ed. 2013, 52, 10830−10834. (d) Zhu, S.; Buchwald, S. L. J. Am. Chem.
Soc. 2014, 136, 15913−15916. (e) Shi, S.-L.; Buchwald, S. L. Nat. Chem.
2015, 7, 38−44. (f) Sakae, R.; Hirano, K.; Satoh, T.; Miura, M. Angew.
Chem., Int. Ed. 2015, 54, 613−617. (g) Niljianskul, N.; Zhu, S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2015, 54, 1638−1641. (h) Yang,
Y.; Shi, S.-L.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62−66.
(i) Niu, D.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 9716−9721.
(j) Nishikawa, D.; Hirano, K.; Miura, M. J. Am. Chem. Soc. 2015, 137,
15620−15623. (k) Pirnot, M. T.; Wang, Y.-M.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2016, 55, 48−57. (l) Kato, K.; Hirano, K.; Miura, M.
Angew. Chem., Int. Ed. 2016, 55, 14400−14404. (m) Zhu, S.; Niljianskul,
N.; Buchwald, S. L. Nat. Chem. 2016, 8, 144−150. (n) Shi, S.-L.; Wong,
Z. L.; Buchwald, S. L. Nature 2016, 532, 353−356. (o) Wang, H.; Yang,
J. C.; Buchwald, S. L. J. Am. Chem. Soc. 2017, 139, 8428−8431.
(3) For representative reports, see: (a) Jia, T.; Cao, P.; Wang, B.; Lou,
Y.; Yin, X.; Wang, M.; Liao, J. J. Am. Chem. Soc. 2015, 137, 13760−
13763. (b) Wang, Y.-M.; Buchwald, S. L. J. Am. Chem. Soc. 2016, 138,
5024−5027. (c) Han, J. T.; Jang, W. J.; Kim, N.; Yun, J. J. Am. Chem. Soc.
2016, 138, 15146−15149. (d) Lee, J.; Torker, S.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2017, 56, 821−826. (e) Radomkit, S.; Liu, Z.; Closs, A.;
Mikus, M. S.; Hoveyda, A. H. Tetrahedron 2017, 73, 5011−5017. (f) Xu,
G.; Zhao, H.; Fu, B.; Cang, A.; Zhang, G.; Zhang, Q.; Xiong, T.; Zhang,
Q. Angew. Chem., Int. Ed. 2017, 56, 13130−13134. (g) Lee, J.; Radomkit,
S.; Torker, S.; del Pozo, J.; Hoveyda, A. H. Nat. Chem. 2018, 10, 99−108.
(h) Kim, N.; Han, J. T.; Ryu, D. H.; Yun, J. Org. Lett. 2017, 19, 6144−
6147.
́
Lett. 2008, 10, 3375−3377. (f) Cerat, P.; Gritsch, P. J.; Goudreau, S. R.;
Charette, A. B. Org. Lett. 2010, 12, 564−567. (g) Dabrowski, J. A.;
Haeffner, F.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2013, 52, 7694−
7699.
(13) For a recent report that includes synthesis of a racemic
trisubstituted allenyl−B(pin), see: Zhao, J.; Szabo,
́
K. J. Angew. Chem.,
Int. Ed. 2016, 55, 1502−1506.
(14) For hydroboration of enynes by Pd-based complexes, see:
Matsumoto, Y.; Naito, M.; Hayashi, T. Organometallics 1992, 11, 2732−
2734.
(15) (a) Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008, 130,
15774−15775. (b) Sasaki, Y.; Sawamura, M.; Ito, H. Chem. Lett. 2011,
́
40, 1044−1046. (c) Zhao, T. S. N.; Yang, Y.; Lessing, T.; Szabo, K. J. J.
Am. Chem. Soc. 2014, 136, 7563−7566.
(16) For selected reports on catalytic enantioselective hydroboration
of acyclic alkenes, see: (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am.
Chem. Soc. 1989, 111, 3426−3428. (b) Moteki, S. A.; Takacs, J. M.
Angew. Chem., Int. Ed. 2008, 47, 894−897. (c) Noh, D.; Chea, H.; Ju, J.;
Yun, J. Angew. Chem., Int. Ed. 2009, 48, 6062−6064. (d) Mazet, C.;
́
Gerard, D. Chem. Commun. 2011, 47, 298−300. (e) Feng, X.; Jeon, H.;
Yun, J. Angew. Chem., Int. Ed. 2013, 52, 3989−3992. (f) Chen, J.; Xi, T.;
Lu, Z. Org. Lett. 2014, 16, 6452−6455. (g) Zhang, L.; Zuo, Z.; Wan, X.;
Huang, Z. J. Am. Chem. Soc. 2014, 136, 15501−15504. (h) Zhang, H.;
Lu, Z. ACS Catal. 2016, 6, 6596−6600. For reviews on catalytic
enantioselective hydroboration, see: (i) Crudden, C.; Edwards, D. Eur. J.
Org. Chem. 2003, 2003, 4695−4712. (j) Carroll, A.-M.; O’Sullivan, T. P.;
Guiry, P. J. Adv. Synth. Catal. 2005, 347, 609−631.
(17) For catalytic enantioselective proto-boryl additions to alkenes and
allenes, see refs 1a, b, e−h.
(18) Pilkington, C. J.; Zanotti-Gerosa, A. Org. Lett. 2003, 5, 1273−
1275.
(19) See the Supporting Information for data regarding ligand
screening.
(20) None of the byproduct derived from reduction of the methyl
ketone group could be detected (1H NMR analysis), and extended
reaction times (e.g., 40 h) result in the formation of a complex mixture of
unidentifiable compounds.
(4) For example, see: Zhou, Y.; Bandar, J. S.; Buchwald, S. L. J. Am.
Chem. Soc. 2017, 139, 8126−8129.
(5) For example, see: Huang, Y.; Smith, K. B.; Brown, M. K. Angew.
Chem., Int. Ed. 2017, 56, 13314−13318.
(21) Meng, F.; McGrath, K. P.; Hoveyda, A. H. Nature 2014, 513,
367−374.
(6) Mszar, N. W.; Haeffner, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2014,
136, 3362−3365.
(22) For a recent review on Sonogashira cross-coupling, see: Thomas,
A. M.; Sujatha, A.; Anilkumar, G. RSC Adv. 2014, 4, 21688−21698.
(7) Meng, F.; Haeffner, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2014, 136,
11304−11307.
(23) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
̈
(8) Yang, Y.; Perry, I. B.; Lu, G.; Liu, P.; Buchwald, S. L. Science 2016,
353, 144−150.
́
2000, 122, 1806−1807. (b) Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D.
E.; Carreira, E. M. Org. Lett. 2000, 2, 4233−4236. (c) Anand, N. K.;
K
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687−9688. (d) Molina, Y.
S.; Ruchti, J.; Carreira, E. M. Org. Lett. 2017, 19, 743−745.
(24) Dominguez, B. Int. Patent WO 2004/092098 (Great Britain),
2004.
(40) For a recent mechanistic investigation regarding hydroboration of
terminal alkynes promoted by Co-based complexes, see: Obligacion, J.
V.; Neely, J. M.; Yazdani, A. N.; Pappas, I.; Chirik, P. J. J. Am. Chem. Soc.
(25) For studies regarding the use of chiral phosphoric acids in
diastereo- and enantioselective synthesis of propargyl alcohols, involving
allenyl−B(pin) compounds prepared by an alternative approach, see:
(a) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2012, 134, 10947−10952.
For related studies, see: (b) Sasaki, Y.; Sawamura, M.; Ito, H. Chem. Lett.
2011, 40, 1044−1046.
2015, 137, 5855−5858.
(41) Preliminary calculations imply that isomerization of a Cu-alkenyl
intermediate, as proposed previously (ref 39; see scheme below) is less
likely. With MN15/def2-TZVPPthf(SMD) the barrier is estimated to be
approximately 36−38 kcal/mol (see the Supporting Information for
details). The following scheme is illustrative of how isomerization has
been proposed to take place via a zwitterionic metal carbene complex:
(26) Geary, L. M.; Woo, S. K.; Leung, J. C.; Krische, M. J. Angew. Chem.,
Int. Ed. 2012, 51, 2972−2976.
(27) Metal-Catalyzed Cross-Coupling Reactions and More; de Meijre, A.,
Brase, S., Oestreich, M., Eds.; Wiley-VCH: Weinheim, Germany, 2014.
(28) Jung, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 1490−1493.
(29) Repeated attempts to measure er for inseparable mixtures of 2j
and 8j were not successful.
(30) The phenomenon of er plateau also applies to reactions with
phenyl- (→2a) and p-trifluoromethylphenyl-substituted (→2e) enynes.
With PHMS, enantioselectivity for Cu−H addition to the above-
mentioned 1,3-enynes is 99.5:0.5 and 94:6 er, respectively, as judged by
in situ trapping with acetophenone (see ref 8 and Scheme 7). However,
when a boron−hydride is involved, selectivities range from 96:4 to 81:19
er (see Figure 1).
(31) For a review on η3-allenyl/propargyl transition metal complexes,
see: (a) Chen, J. T. Coord. Chem. Rev. 1999, 190−192, 1143−1168. For
early reports on allenyl-to-propargyl isomerization, see: (b) Chen, M.-
C.; Keng, R.-S.; Lin, Y.-C.; Wang, Y.; Cheng, M.-C.; Lee, G.-H. J. Chem.
Soc., Chem. Commun. 1990, 1138−1140. (c) Ogoshi, S.; Fukunishi, Y.;
Tsutsumi, K.; Kurosawa, H. Inorg. Chim. Acta 1997, 265, 9−15.
(32) For a review regarding transfer and/or loss of stereochemical
purity during propargylic substitution, see ref 10. For selected reports
invoking the fluxional nature of Pd-allenyl intermediates, see: (a) Ref
12b. (b) Yoshida, M.; Hayashi, M.; Shishido, K. Org. Lett. 2007, 9,
1643−1646. (c) Yoshida, M.; Okada, T.; Shishido, K. Tetrahedron 2007,
63, 6996−7002. (d) Wang, Y.; Zhang, W.; Ma, S. J. Am. Chem. Soc. 2013,
135, 11517−11520. (e) Wang, Y.; Zhang, W.; Ma, S. Org. Chem. Front.
2014, 1, 807−811.
(42) For racemization of enantiomerically enriched allenes by
organometallic complexes, see the following.Cu-based complexes:
(a) Claesson, A.; Olsson, L.-I. J. Chem. Soc., Chem. Commun. 1979,
́
524−525. (b) Pd-based complexes: Horvath, A.; Backvall, J.-E. Chem.
̈
Commun. 2004, 964−965. (c) Au-based complexes: Li, H.; Harris, R. J.;
Nakafuku, K.; Widenhoefer, R. A. Organometallics 2016, 35, 2242−
2248.
(43) For cases where facile racemization has been utilized in the
stereoconvergent transformations with racemic allenes, see: (a) Zhang,
Z.; Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 129,
14148−14149. (b) Wang, Y. M.; Kuzniewski, C. N.; Rauniyar, V.;
Hoong, C.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 12972−12975.
(c) Butler, K. L.; Tragni, M.; Widenhoefer, R. A. Angew. Chem., Int. Ed.
2012, 51, 5175−5178. (d) Khrakovsky, D. A.; Tao, C.; Johnson, M. W.;
Thornbury, R. T.; Shevick, S. L.; Toste, F. D. Angew. Chem., Int. Ed.
(33) For an experimental study regarding racemization of an
enantiomerically enriched Pd−allenyl complex, see: Ogoshi, S.;
Nishida, T.; Shinagawa, T.; Kurosawa, H. J. Am. Chem. Soc. 2001, 123,
7164−7165.
(34) For a computational study on propargylic substitution promoted
by a Pd-based catalyst, see: Vaz, B.; Pereira, R.; Per
Lera, A. R. J. Org. Chem. 2008, 73, 6534−6541.
(35) For trans-selective hydroboration of internal alkynes, see:
́
ez, M.; Alvarez, R.; de
(a) Sundararaju, B.; Furstner, A. Angew. Chem., Int. Ed. 2013, 52,
̈
2016, 55, 6079−6083.
14050−14054. For a related example involving a Pd complex, see:
(b) Xu, S.; Zhang, Y.; Li, B.; Liu, S. Y. J. Am. Chem. Soc. 2016, 138,
14566−14569.
(44) Liakos, D. G.; Neese, F. J. Chem. Theory Comput. 2015, 11, 4054−
4063.
(45) DLPNO-CCSD(T)/def2-TZVPPthf(SMD) calculations under the
(36) For trans-selective hydrosilylation or hydrosilylation/desilylation
sequences through the use of cationic Ru complexes, see: (a) Trost, B.
M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726−12727. (b) Trost, B.
NormalPNO setting have been performed for a selected set of
geometries, which seem to support the MN15 values (see diagram
below). Other investigated density functionals (M06, M06L, ωB97XD,
and PBE0-D3BJ) have been found to exhibit larger errors (see the
Supporting Information for further details). These predictions are valid
only if the M06L/def2-SVP-optimized structures are an appropriate
representation of the geometry in solution. (Abbreviations: MSD, mean
signed deviation; MUD, mean unsigned deviation; energy values are
given in kcal/mol.)
M.; Ball, Z. T.; Joge, T. J. Am. Chem. Soc. 2002, 124, 7922−7923.
̈
(c) Furstner, A.; Radkowski, K. Chem. Commun. 2002, 2182−2183.
̈
(37) For trans-selective hydrogenation of internal alkynes catalyzed by
cationic Ru complexes, see: (a) Radkowski, K.; Sundararaju, B.;
Furstner, A. Angew. Chem., Int. Ed. 2013, 52, 355−360. For a related
̈
report involving reactions promoted by Ru-based olefin metathesis
catalysts, proceeding through a mechanistically distinct reduction/
isomerization sequence, see: (b) Kusy, R.; Grela, K. Org. Lett. 2016, 18,
6196−6199.
(38) (a) Chung, L. W.; Wu, Y.-O.; Trost, B. M.; Ball, Z. T. J. Am. Chem.
Soc. 2003, 125, 11578−11582. (b) Song, L.-J.; Wang, T.; Zhang, X.;
Chung, L. W.; Wu, Y. D. ACS Catal. 2017, 7, 1361−1368. (c) Rosca, D.
A.; Radkowski, K.; Wolf, L. M.; Wagh, M.; Goddard, R.; Thiel, W.;
Furstner, A. J. Am. Chem. Soc. 2017, 139, 2443−2455.
̈
(39) Jang, W. J.; Lee, W. L.; Moon, J. H.; Lee, J. Y.; Yun, J. Org. Lett.
2016, 18, 1390−1393.
L
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(46) Yu, H. S.; He, X.; Li, S. L.; Truhlar, D. G. Chem. Sci. 2016, 7,
5032−5051.
(47) Barriers of comparable magnitude were calculated with M06,
M06L, ωB97XD, and PBE0-D3BJ functionals, but not when those that
do not account for dispersion were used (i.e., PBE0). For example, PBE0
predicted a value of 16.0 kcal/mol for ts(rac), with tsα having an energy
of 27.7 kcal/mol. Dispersion effects, therefore, seem to be crucial when
modeling unimolecular processes that compete with bimolecular events.
Moreover, we find that only MN15 predicts tsα to be lower in energy
than tsγ (Figure 3), a fact that is also supported by the DLPNO-
CCSD(T) values. In contrast, the transition states are similar in energy
with the other investigated density functionals. See the Supporting
Information for details.
(48) Even the most accurate density functionals available show mean
absolute deviations >2.0 kcal/mol in reasonably large benchmark studies
(for example, see ref 46). Nonetheless, the MN15 energies are
significantly more accurate compared to the values obtained with
PBE0, which predict tsγ (27.3 kcal/mol) at significantly higher energy
compared to ts(rac) (14.6 kcal/mol).
(49) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841−1860.
(50) See the Supporting Information for details.
(51) Computational uncertainties preclude a more definitive answer.
However, we did not identify obvious structural reasons that would
support high er if trapping with HB(pin) was stereochemistry-
determining.
(52) For a recent review on Morita−Baylis−Hillman reactions, see:
Pellissier, H. Tetrahedron 2017, 73, 2831−2861.
(53) For a summary of related observations (phosphine conjugate
addition/elimination), see: Yu, S.; Ma, S. Angew. Chem., Int. Ed. 2012,
51, 3074−3112.
M
DOI: 10.1021/jacs.7b13296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX