Racemic Vinylallenes in Catalytic Enantioselective Multicomponent Processes: Rapid Generation of Complexity through 1,6-Conjugate Additions

Article abstract of DOI:10.1002/anie.201812535

Racemic vinylallenes are shown to be effective substrates for catalytic multicomponent diastereo- and enantioselective 1,6-conjugate addition of multifunctional allyl moieties to easily accessible α,β,γ,δ-unsaturated diesters. Reactions may be catalyzed by 5.0 mol % of a readily accessible NHC-Cu complex at ambient temperature, and other than a vinylallene, involve B₂(pin)₂ and an α,β,γ,δ-unsaturated diester. A variety of vinylallenes were converted to products bearing a Z-trisubstituted alkenyl-B(pin) moiety, a vinyl group, a β,γ-unsaturated diester unit, and vicinal stereogenic centers in up to 67 % yield, 87:13 Z/E ratio, >98:2 d.r., and 98:2 e.r. Chemoselective modifications involving the alkenyl-B(pin), the vinyl, or the 1,2-disubstituted olefin moieties were carried out to demonstrate versatility and utility. Stereochemical models, based on mechanistic and DFT studies, demonstrate the dynamic behavior of intermediated Cu-allyl species and account for various selectivity profiles.

Full text of DOI:10.1002/anie.201812535

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Accepted Article
Title: Racemic Vinylallenes in Catalytic Enantioselective
Multicomponent Processes. Rapid Generation of Complexity
through 1,6-Conjugate Additions
Authors: Amir H. Hoveyda, Youming J. Huang, Sebastian J. Torker,
Xinghan J. Li, and Juan J. del Pozo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812535
Angew. Chem. 10.1002/ange.201812535
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10.1002/anie.201812535
Angewandte Chemie International Edition
Racemic Vinylallenes in Catalytic Enantioselective Multicomponent Processes.
Rapid Generation of Complexity through 1,6-Conjugate Additions
Youming Huang, Sebastian Torker, Xinghan Li, Juan del Pozo, and Amir H. Hoveyda*
Prof. A. H. Hoveyda, Dr. Y. Huang, Dr. S. Torker, X. Li, Dr. Juan del Pozo
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
Abstract: Racemic vinylallenes are shown to be attractive substrates for catalytic
multicomponent diastereo-, and enantioselective 1,6-conjugate addition of multifunctional allyl moieties
to easily accessible ,,,unsaturated diesters. Reactions may be catalyzed by 5.0 mol % of a readily
accessible NHC–Cu complex at ambient temperature, and other than a vinylallene, involve B2(pin)2, and
an ,,,-unsaturated diester. By just one operation, a variety of vinylallenes were converted to
products bearing a Z-trisubstituted alkenyl–B(pin) moiety, a vinyl group, a ,-unsaturated diester unit,
and vicinal stereogenic centers in up to 67% yield, 87:13 Z:E ratio, >98:2 d.r., and 98:2 e.r. A variety of
chemoselective modifications involving the alkenyl–B(pin), vinyl, or the 1,2-disubstituted olefin moieties
were carried out to demonstrate versatility and utility. Stereochemical models, based on mechanistic and
DFT studies, demonstrate the dynamic behavior of intermediated Cu–allyl species and account for
various selectivity profiles. These studies foreshadow the use of vinylallenes as starting materials in a
wide range of multicomponent reactions, those catalyzed by Cu–H or Cu–B(pin) complexes.
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Various methods have emerged for catalytic enantioselective union of an unsaturated
organic molecule, bis(pinacolato)diboron [B2(pin)2], and an electrophile,[1,2,3,4,5] which afford
difficult-to-access multifunctional entities. Early advances involved achiral monosubstituted[1]
or 1,1-disubstituted allenes,[1g] where an initial regio- and stereoselective addition of an in situ
generated Cu–B(pin) complex to the less substituted C=C bond afforded a boryl-substituted Cu–
allyl species; this was followed by an - or -selective addition to an electrophile. With a 1,3-
diene,[2] different Cu–allyl regioisomers may be generated. With 1,3-enynes,[3] the Cu–B(pin)
complex was also shown to add first to the less substituted vinyl moiety, and, depending on the
process, the energetically more favorable Cu–allenyl intermediate[6] (vs. Cu–propargyl) may
react with an electrophile to furnish the - or the -addition isomer.
Vinylallenes are readily accessible[7] but have not been previously utilized in catalytic
multicomponent processes. The expected products would be of high value, as they would
contain a versatile vinyl and a stereochemically defined trisubstituted alkenyl–B(pin) units
(Scheme 1), and thus, such entities represent an attractive possibility. Nonetheless, two key
questions must be addressed: 1) Would Cu–B addition occur selectively at the allene or the
vinyl site? 2) As 1,3-disubstituted allenes are chiral, would enantiomerically enriched substrates
be needed?
Scheme 1. General strategy pursued in this study. G, R, carbon-based substituents; pin, pinacolato; L, ligand.
We selected catalytic multicomponent 1,6-conjugate additions with vinylallene as our
initial foray for several reasons. Unlike catalytic 1,4-conjugate additions, for which there are
many enantioselective methods,[8] 1,6-conjugate additions involving carbon-based nucleophiles
are rare,[9] especially with C4 not fully substituted. The only known instances are those of
Feringa,[10] Hayashi,[11–12] Alexakis.[13] These advances, while notable, were confined to
magnesium-,[10] Al-, or Zn-based[13] entities containing a simple alkyl unit. Reactions with a silyl-
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protected alkyne[11] or an aryl moiety broadened the scope, but just one aryl group in a (ArBO)3
compound could be transferred.[12]
We surmised that the Cu–B(pin) complex would add regioselectively to a vinylallene to
generate II via I (Scheme 1). Although the vinyl site is less hindered, interaction between an
allene bond, bearing an sp- and an sp2-hybridized carbon (vs. two sp2-hybridized vinyl carbons),
and the Cu–B(pin) bond, where probably the HOMO is centered,[14] would be preferred. The
Cu–allyl species II could isomerize to III, the reaction of which with an ,,,-unsaturated
diester would afford IV. The intermediacy of III would mean that racemic vinylallene may be
used (i.e., enantioselective synthesis vs. kinetic resolution).
We began by probing reactions involving 1a, B2(pin)2 and vinylallene 2a (Scheme 2).
With chiral phosphine ligands there was complete consumption of 1a but no 3a was
detected.[15] With imid-1a,[16] optimal for previously reported reactions with monosubstituted
allenes,[1e] 1,4-conjugate boryl addition was the main competing pathway;[17] 3a was isolated in
just 21% yield and with 75:25 Z:E selectivity, >98:2 diastereomeric ratio (d.r.), and 83:17
enantiomeric ratio (e.r.). These early findings underscored the distinct nature of the processes
with a vinyl-containing 1,3-disubstituted allene (vs. monosubstituted variants [1e]).
Scheme 2. Identification of an effective NHC–Cu complex. [a] Conv. (2%; loss of 1a), Z:E ratio, and d.r. (2%) determined by analysis of 1H
NMR spectra of unpurified mixtures. [b] Yield (5%, average of at least three runs) is for purified product (Z/E mixture). [c] E.r. determined by HPLC
analysis. See the Supporting Information for details.
Reactions with other imidazolinium salts were evaluated (Scheme 2).[15] With imid-1b,
d.r. remained high (>98:2), and efficiency (56% yield) and e.r. (94:6) were enhanced
considerably, but there was little change in the Z:E ratio (75:25). We then examined N-
adamantyl-substituted imid-1c, a lesser-known member of this ligand class,[18] the use of which
had led to relatively low e.r. (~80:20) in the NHC–Cu-catalyzed 1,6-conjugate additions with
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monosubstituted allenes (Scheme 1a).[1e] Here, somewhat surprisingly, while the reaction was
slightly less efficient (52% yield), d.r. and e.r. remained high (>98:2 and 95:5, respectively), and
the Z:E ratio improved (85:15).
After further optimization [i.e., 1.1 equiv. B2(pin)2 and NaOtBu], we explored the scope
of aryl-substituted dienoates (Table 1). 1,6-Addition was exclusive throughout, and a single
disubstituted alkene isomer and diastereomer was detected in every case (>98% ,-alkene and
>98:2 d.r., respectively). Reactions of bulky o-tolyl-substituted 1b and 1-naphthyl-containing 1c,
which afforded 3b and 3c in 58% and 59% yield, 87:13 Z:E selectivity, and 96:4 and 95:5 e.r.,
respectively, (entries 2–3). Additions to electron-rich (entries 4–6) or electron-deficient (entry
7–8) dienoates were efficient and selective, as were the heterocyclic variants (entries 9–10).
[a] Reactions were performed under N2 atm. Conv. was >98% in all cases (2%; loss of allene). [b] Yield (5%, average of at least three runs)
corresponds to purified products (Z/E mixture). [c] Z:E ratios as well as d.r. (2%) were determined by analysis of 1H NMR spectra of unpurified
mixtures. [d] E.r. was determined by HPLC analysis. See the Supporting Information for details.
Alkyl-substituted dienoates (Scheme 3a) were converted 5a-c with similar efficiency and
selectivity; 1,6:1,4, and selectivity remained exceptional. However, diastereoselectivity levels
do depend on the size of the alkyl group: 5a, containing a smaller methyl group, was generated
in 81:19 d.r., increasing with a larger alkyl moiety (5b-c, 87:13 and >98:2 d.r., respectively).
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With inylallenes that contain a relatively hindered substituent, transformations proceeded with
similar efficiency, d.r., Z:E ratio, and e.r. (6c-d vs. 6a-b). We were unable to identify conditions
that would allow the isolation of the expected products from the corresponding reaction with
an aryl-substituted vinylallene (unidentifiable mixtures).
Scheme 3. Transformations with different alkyl-substituted dienoates and vinylallenes. See the Supporting Information for details.
A general point regarding the present approach merits note. A transformation that
delivers products in 50–70% yield, as is the case here, while useful in chemical synthesis, is
typically not considered as highly efficient. Nonetheless, multicomponent processes may be
performed with readily accessible catalysts and starting materials, entail formation of multiple
bonds, and address more than one selectivity issue, and should therefore be considered in a
different light. The greater amount of waste notwithstanding, an alternative multi-step route,
were it feasible, and if each step were higher yielding, may still not be as high yielding overall.
For the present approach to achieve its maximum potential, it is imperative that the
different functional units within a product structure can be modified with high site-, regio-,
and/or stereoselectivity. In this context, we were able to transform 3a (Scheme 4a) to E-
trisubstituted ester 7 (>98% E), which retains its Z-trisubstituted alkenyl boronate in two steps
and 51% overall yield (Scheme 4a). This is a more direct and milder approach compared to a
reported two-step procedure (68% vs. 70% yield for 2 steps).[19]
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Scheme 4. Exploration of the utility of the catalytic multicomponent method. See the Supporting Information for details. dbu, 1,8-
diazabicyclo[5.4.0]undec-7-ene;TBS, t-butyldimethyl silyl; MOM, methoxymethyl.
Nonetheless, the sterically congested trisubstituted alkenyl–B(pin) compounds exposes
an existing deficiency in the state-of-the-art in catalytic cross-coupling, as repeated attempts to
effect such a transformation resulted in <5% conversion to the desired product (see below for
an alternative (non-catalytic) set of conditions). Furthermore, we carried out the sequence of
transformations leading to 12 (Scheme 4b), formerly used to synthesize vitamin D3.[20] We
prepared 2.1 g of 6e in similar yield and selectivity as the smaller scale reactions (Scheme 3b).
Conversion to 8 under mild basic conditions[1e] was followed by cross-metathesis involving the
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vinyl moiety and readily available Z-alkene 9. After Wittig reaction, the disubstituted alkenes
were site selectively reduced to afford 10. To obtain E-trisubstituted olefin 11, we used a one-
vessel operation entailing treatment with MeLi, followed by PhSeCl[21] and trifluoroethanol.
Removal of the silyl group afforded alcohol 11 in 49% overall yield (for 2 steps) and 96:4 Z:E
ratio. Formation of the derived tosyl ester, removal of the methoxymethyl (MOM) group, and
base-induced tosylate elimination afforded 12 in 38% overall yield (for 3 steps).
The above findings pose several key mechanistic issues. One question is: why does the
catalyst derived from imid-1c deliver higher Z:E selectivity (vs. imid-1a-b; Scheme 2)? This is
likely because the boryl moiety of a Cu–B(pin) complex can be deposited at the sp-hybridized
carbon by two different modes of addition, namely, those leading to intermediates V and VI
(Scheme 5a). The latter organocopper entities can then be transformed to Zprod via VII, wherein
the sizeable Cu(NHC) is attached to the least hindered primary carbon. However, Eprod can also
be formed through VI via higher energy VIII and IX. There are therefore two ways by which Z:E
selectivity might be influenced. Either the kinetic selectivity established by the initial CuB
addition is maintained and is reflected in the final Z:E ratio, requiring relatively slow Z-to-E
interconversion, or there is a certain degree of stereoisomerization and the selectivity is
determined by the relative rates of reactions with the dienoate (i.e., Curtin-Hammett kinetics).
To gain insight, we carried out the following experiments.
We monitored the reaction with stoichiometric amounts of NHC–Cu-1, B2(pin)2 and rac-
2a (1H NMR, thf-d8, 4022 °C; Scheme 5b), observing two sets of peaks. These signals which
exchanged rapidly at 22 °C but resolved at –40 °C (94:6 ratio), probably originate from (E,Z)-Cu–
allyl-1 and (E,E)-Cu–allyl-1 (Scheme 5b).[15] An X-ray structure for (E,Z)-Cu–allyl-1 was secured
(CCDC number, 1874716).
For insight regarding the dynamic behavior of such Cu–allyl species, we carried out
proto-boryl additions with the NHC–Cu complex derived from imid-1d with MeOH or tBuOH
(Scheme 5c). Whereas 13 was formed in >98:2 Z:E ratio with MeOH, selectivity decreased to
94:6 with tBuOH. These data suggest the following: 1) Initially, a Z-allyl– Cu isomer (VII, Scheme
5a) is generated exclusively, as, otherwise, the E product isomer (Eprod) would be formed by fast
trapping with MeOH. 2) There is probably some Z-to-E isomerization prior to trapping of the
kinetically formed Z-allyl–Cu when the slower reacting tBuOH is involved. In another set of
experiments, we carried out a pair of reactions with enantiomerically enriched 2a (81:19 e.r.) in
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the presence of Cu complexes derived from (R)- and (S)-imid-1d (Scheme 5d). In both instances
3a was formed with identical Z:E selectivity (85:15), suggesting that the organocopper
intermediate is in equilibrium and trapping with 1a is slower. Finally, DFT calculations involving
a model NHC (Scheme 5e) indicate that -allyl isomerization is facile (Grel = 3.5 kcal/mol; only
the highest of two sequential transition states shown), and that single bond rotation that lead
Scheme 5. Studies regarding pathways that cause lower Z:E selectivity. Abbreviations: ts = transition state.
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to s-ciss-trans isomerization, while slower (Grel = 12.7 kcal/mol), are energetically feasible.
Other questions relate to the origin of higher Z selectivity with imid-1d, and the reason
for high e.r. and the lower d.r. with dienoates that bear a smaller substituent (cf. Scheme 3).
Scheme 6. Stereochemical models accounting for the various stereoselectivity issues.
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Considering that Curtin-Hammett kinetics is likely (cf. Scheme 5b), DFT studies (MN15/def2-
TZVPP//M06-L/def2-SVP level)[15] point to two coordination geometries involving a Na+ bridge
(A-D, Scheme 6a); A and B lead to the Z isomer, whereas the E isomer would result from C and
D.[22] In A and C, in which alkoxide oxygen O1 points to the right, there is steric repulsion
between the bound dienoate and the NHC substituent G; there is no such interaction in B and
D, wherein O1 is oriented in the opposite direction. The smaller energy difference separating A
and C (vs. B and D) means that reaction via these complexes favors an E trisubstituted alkene
(namely, lower Z:E ratios), probably because G and Me are more proximal in A than in B (i.e.,
kC/kA > kD/kB). It is worth noting that a larger N-Ar unit is involved in the actual system (vs. N-Me
group). Moreover, with an N-Ad moiety (i.e., with imid-1d), there is a wider energy gap
between A/C and B/D (Erel between A and B = 6.4  2.0 kcal/mol), rendering A/C significantly
less accessible. In contrast, in the case of complexes with an NAr-substituted NHC (i.e., derived
from imid-1b), A/C and B/D probably contribute more similarly (Erel between A and B = 1.8 
2.0 kcal/mol), and more of the E isomer is formed with imid-1b (vs. when imid-1d is used). In
line with the experimental results is the relatively large energy difference between the
transition states leading to the major (B) and minor enantiomer (E, Scheme 6b, Erel = 4.4
kcal/mol). This difference arises from repulsion between the N-Ad and the B(pin) moieties in E.
As noted,[1e] such steric pressure weakens Na+–substrate coordination, resulting in longer
average Na……O distance (2.204 Å in B to 2.223 Å in E). Diastereoselectivity is lower with
dienoates with a smaller substituent probably due to reduced steric pressure in F (Scheme 6c),
which leads to the formation of the minor isomer, when 4a (R = Me) is involved (Erel = 2.8
kcal/mol); in comparison, d.r. is higher with 1a (R = Ph) as the substrate (Erel = 4.5 kcal/mol).
In brief, we show that vinylallenes are promising substrates for catalytic
multicomponent processes (with Cu–H[23] or Cu–B(pin) complexes) and can provide direct
access to structurally complex compounds. The above findings are a notable addition to two
important and under-developed areas: broadly applicable catalytic enantioselective conjugate
additions of allyl moieties,[24] and catalytic regio-, diastereo- and enantioselective 1,6-conjugate
1
9
additions of C-based nucleophiles.[ e, ]
Acknowledgements. This research was funded by the NIH (GM-47480). Y.H. was partially supported by a
postdoctoral fellowship from the Shanghai Institute of Organic Chemistry and Zhejiang Medicine Co., Pharmaron. J.
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d. P. was supported in the form of a postdoctoral fellowship by Alfonso Martin Escudero Foundation. We are
grateful to Dr. Bo Li for his invaluable assistance in securing the X-ray structure for compound (E,Z)-Cu–allyl-1.
Keywords: boron, 1,6-conjugate additions, copper, enantioselective catalysis, vinylallenes
References & Footnotes
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