Diastereo- A nd Enantioselective Synthesis of Homoallylic Amines Bearing Quaternary Carbon Centers

Article abstract of DOI:10.1021/jacs.9b11529

A Cu-catalyzed method for the efficient enantio- A nd diastereoselective synthesis of chiral homoallylic amines bearing a quaternary carbon and an alkenylboron is disclosed. Transformations are promoted by a readily prepared (phosphoramidite)-Cu complex and involve bench-stable ?,?-disubstituted allyldiborons and benzyl imines; products are obtained in up to 82% yield, >20:1 dr, and >99:1 er. Reactions proceed via stereodefined boron-stabilized allylic Cu species formed by an enantioselective transmetalation. Utility of the 1-amino-3-alkenylboronate products is highlighted by a variety of synthetic transformations.

Full text of DOI:10.1021/jacs.9b11529

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Communication
Diastereo- and Enantioselective Synthesis of
Homoallylic Amines Bearing Quaternary Carbon Centers
Jacob C. Green, Joseph M. Zanghi, and Simon J. Meek
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Jan 2020
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Diastereo- and Enantioselective Synthesis of Homoallylic Amines
Bearing Quaternary Carbon Centers.
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Jacob C. Green, Joseph M. Zanghi, and Simon J. Meek*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290.
Supporting Information Placeholder
boronic acids to cyclic imines in high stereoselectivity
(Scheme 1C).9 Nevertheless, both catalytic protocols
present limitations related to the requirement of either
pre-formed
ABSTRACT: A Cu-catalyzed method for the efficient
enantio- and diastereoselective synthesis of chiral
homoallylic amines bearing a quaternary carbon and an
alkenylboron is disclosed. Transformations are promoted
by a readily prepared (phosphoramidite)–Cu complex,
and involve bench-stable -disubstituted allyldiborons
and benzyl imines; products are obtained in up to 82%
yield, >20:1 dr, and >99:1 er. Reactions proceed via
stereodefined boron-stabilized allylic Cu species formed
by an enantioselective transmetalation. Utility of the 1-
amino-3-alkenylboronate products is highlighted by a
variety of synthetic transformations.
Scheme 1. Enantio- and Diastereoselective Additions
to Imines with ,-Disubstituted Allyl Reagents
Development of catalytic enantioselective methods for
the synthesis of chiral amines and all-carbon quaternary
stereocenters are both critical objectives in organic
synthesis.1,2 In this regard, the enantioselective allyl
addition to imines with appropriately substituted C-based
nucleophiles represents a direct route for the concomitant
generation of both of these important chemical motifs.3
While a number of catalytic methods have been reported
for the enantio- and diastereoselective additions of -
substituted allyl reagents (e.g., crotyl) to imines that
afford secondary homoallylic amines bearing a vicinal
tertiary stereocenter,4,5 the corresponding quaternary
enantioenriched -disubstituted allylboron reagents or
unstable achiral allyl boronic acids. To-date, metal-free
catalytic methods have proven to be most effective for the
enantioselective synthesis of quaternary carbon
stereogenic centers in allylic nucleophile additions to
imines. Such catalytic protocols possess mechanistic
characteristics that maintain the E or Z alkene isomer of
6
stereocenter variants remain lacking. One example
involves the diastereoselective and enantiospecific
addition of chiral allylborons to TMS-aldimines via the
borinic ester recently reported by Aggarwal (Scheme
1A).7 In contrast, only two catalytic protocols have been
introduced for the enantio- and diastereoselective
synthesis of homoallylamines bearing quaternary carbon
stereocenters. First, chiral amino alcohols have been
shown to catalyze an efficient enantio- and
diastereoselective addition of a chiral allyl-B(pin) to
aldimines that proceeds by stereospecific allyl transfer to
the catalyst (Scheme 1B).8 Secondly, chiral binaphthyl
diols have been shown to catalyze the enantio- and
diastereoselective additions of -disubstituted allyl
the allyl reagent.8,9
In contrast, due to their
configurational instability, reactions of most -allylmetal
complexes lead to poor diastereoselectivity or are limited
to the synthesis of one stereoisomer.10,11,12
An emerging strategy for the construction of contiguous
stereogenic centers via allylic nucleophile additions to
C=O and C=N electrophiles involves the use of allylic
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gem-diboronate esters. Murakami reported the in situ
groups (2g–h). Moreover, ethyl-substituted variants 2d,
2f, and E/Z-2i can be prepared efficiently.
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generation of these reagents via Pd- or Ru-catalyzed
olefin isomerization, followed by enantio- and
diastereoselective addition to aldehydes promoted by a
chiral phosphoric acid.13 Subsequently, Cho reported the
diastereoselective addition of isolated allyldiboron ester 5
to a variety of cyclic sulfonyl imines, although, the report
is limited to the E-crotyl reagent (Eq 1).14
Next, we began by identifying catalytic conditions for
the enantioselective reaction of phosphinoylimine 9 with
2a (Table 1). Investigation of a variety of bidentate and
monodentate phosphine ligands (L1–L5, entries 1–5)
revealed monodentate phosphoramidite L4 to be the most
effective, delivering 11 in 77% conv. and 85:15 er (entry
Table 1. Reaction Optimization of Enantio- and
Diastereoselective Cu-Catalyzed Additions to Iminesa
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At this juncture, based on our previous work with 1,1-
diborylalkanes,15,16 we postulated that stereodefined -
disubstituted allyldiboron (e.g., 2) would result in
increased reagent stability, and their participation in
enantioselective Cu-catalyzed additions to imines would
result in the enantioselective synthesis of secondary
homoallylic amines bearing
a quaternary carbon
stereogenic center (e.g., 3) (Scheme 1D). A key aspect of
this strategy requires reactions to proceed by
enantioselective transmetalation through a chiral -
boryl–Cu–allyl nucleophile.
Scheme
2.
Synthesis
of
,-Disubstituted
Allyldiboronate Esters a
aReactions performed under N2 atmosphere. bYield and diastereomeric
ratios (dr) determined by analysis of 400, 500, or 600 MHz H NMR
1
spectra of crude reactions with hexamethyldisiloxane as internal
standard. cEnantiomeric ratios (er) determined by HPLC or SFC
d
analysis; see the SI for details. 15% proto-deboration of 2b. e55%
proto-deboration of 2a. f<2% proto-deboration of 2a or 2b.
aSee SI for details.
4). Similar low enantio- and diastereoselectivity was
observed in reactions with Me/n-Bu reagent 2b (entries
6–8), with L5 affording 12 in 94% 1H NMR yield, 1.1:1.0
dr, and 90:10 and 91:9 er (entry 8). In addition,
phosphoramidite ligands L6 and L7 bearing 3,3’ mesityl
and 3,5-xylyl groups, delivered 12 in low dr but with an
Successful implementation of our plan required the
development of a general method for the synthesis of
allylic gem-diboronate esters (e.g., 2). To accomplish this
goal, we hypothesized that the direct Pd-catalyzed cross
coupling of lithiated organodiboron 7, which can be
prepared by deprotonation of diborylmethane with bulky
lithium amide bases (LDA or LTMP) on gram-scale with
readily available stereodefined vinyl halides would
provide the most direct strategy for the synthesis of a
variety of stereodefined bis-allylic 1,1-diborons.
Building on work by Feringa, 17 we found a wide variety
of stereodefined alkenyl halides undergo Pd-catalyzed
cross coupling with organolithium 7, to afford
chromatographically stable stereodefined allyldiborons
2a–i isolated in 32–75% yield (Scheme 2); for example,
n-butyl 2b is often isolated in up to 75% yield on a
multigram-scale. As the synthesis of 2c and 2e illustrate,
the presence of silyl ethers and aryl groups result in
equally efficient coupling. The method can also be
extended to alkenyl iodides containing -branched alkyl
increase in enantioselectivity.
At this point we
hypothesized that the high enantioselectivity of each
diastereoisomer of 12 afforded with L7 is a result of a
chiral (L7)-Cu-allyl formed in high er by an
enantioselective transmetalation, but reacts with both
prochiral faces of 9 with limited bias. Such an outcome
would be consistent with the poor enantioselectivity
observed in reverse prenyl additions (entries 1–5), and
likely the result of non-selective binding of imine 9 to the
Cu-allyl species. Changing the imine activating group to
p-MeO-benzyl (PMB) 10, which results in a less
electrophilic imine but more Lewis basic nitrogen,
resulted in marked improvement in dr. Treatment of 10
and 2b with 5 mol % Cu-OtBu, 10 mol % L7, and 1
equivalent of MeOH at -40 °C for 18 h delivered 14 in
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77% yield, >20:1 dr, and 99:1 er (entry 11). Furthermore,
pyridyl groups, results in equally efficient and
enantioselective reactions.19
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reaction of 2a with PMB imine 10 under identical
conditions resulted in 13 in 36% yield and 99:1 er (entry
12). In reactions of PMB imine 10 with both 2a and 2b it
was noted that significant quantities (15–55%) of
protodeborated allyldiboron is formed through
competitive reaction of the allylic Cu with methanol. To
suppress protonation
The catalytic method is equally effective for reactions
of non-symmetric allyldiboron reagents 2b–j with aryl
imines (Scheme 4), providing stereoselective access to a
range of complex homoallylic amines bearing a vicinal
quaternary carbon stereogenic center, and a pendant
alkenylboron group. Reaction of E-allyldiboron reagents
that contain n-alkyl groups (14a-b), a pendant silyl ether
(14c-d) or a homobenzyl unit (14e-f) react smoothly to
furnish secondary amines bearing quaternary carbon
stereogenic centers in good yield, dr, and er. Notably,
Scheme 3. Enantioselective Cu-Catalyzed Reverse
Prenyl Addition to Aldiminesa–d
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Scheme 4. Enantio- and Diastereoselective Cu-
Catalyzed Synthesis of Quaternary Carbon
Stereogenic Centersa–d
aReactions performed under N2 atmosphere.
bConversion
1
determined by analysis of 400, 500, or 600 MHz H NMR spectra of
crude reactions with hexamethyldisiloxane as internal standard.
cEnantiomeric ratios (er) determined by HPLC or SFC analysis; see the
d
SI for details. Yields of isolated product after SiO2 chromatography
and represent an average of at least two runs.
aReactions performed under N2 atmosphere. bConversion and
diastereomeric ratios (dr) determined by analysis of 400, 500, or 600
MHz 1H NMR spectra of crude reactions with hexamethyldisiloxane as
internal standard. cEnantiomeric ratios (er) determined by HPLC or
of the Cu-allyl species, we employed CD3OD to utilize a
deuterium isotope effect.18 As illustrated in entries 13
and 14, reaction in the presence of CD3OD results in an
increase in yield, furnishing 14 in 84% yield (>20:1 dr,
and 99:1 er), and 13 in 65% yield (99:1 er).
d
SFC analysis; see the SI for details. Yields of isolated product after
SiO2 chromatography and represent an average of at least two runs.
reaction of smaller 2-furyl derived-imine with 2e, affords
14e with excellent stereocontrol (>20:1 dr, and 97:3 er).
Stereoselective synthesis of ethyl-substituted quaternary
stereocenters can be achieved with high selectivity
through the application of ethyl-derived E-allyldiborons
2d-f; for example, secondary amines 14d and 14f are both
isolated as single enantio- and diastereomers.
Allyldiboron reagents containing more sterically
congested -branched alkyl groups participate under the
reaction conditions, although, with mixed results.
Cyclohexyl-substituted organodiboron reagent 2g affords
14g in 64% yield and >20:1 dr but 93:7 er. In comparison,
a smaller cyclopropyl group (e.g., 2h) results in a
To investigate substrate scope of the allylic nucleophile
addition reaction, we first focused on enantioselective
reverse prenyl addition to aryl imines with allyldiboron
2a (Scheme 4). The catalytic method can be used to
prepare a wide array of secondary amines bearing an
alkenylboron in good yield (>55%) and high selectivity
(>98:2 er). Parent phenyl imine (13a), as well as aryl
imines bearing electron-donating (13c), electron-
withdrawing substituents (13b, d–f), and halogens (13b,
h–i) in various positions are suitable substrates.
Naphthyl-derived imines also undergo efficient and
selective reverse prenyl addition (13g). As the synthesis
of 13j–l illustrates, use of heteroaryl imines, including
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restoration in selectivity (14h: 74% yield, >20:1 dr, and
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98:2 er).
The efficient transfer of E and Z alkene stereochemistry
from the allyldiboron to the product, indicated that the
catalytic method could provide an effective strategy for
the stereoselective synthesis of Me/Et quaternary carbon
stereogenic centers. Potential diminution in selectivity
could arise from poor enantioselective transmetalation
and/or stereochemical isomerization of the transient
allylic Cu species prior to C–C bond formation. As
shown in Scheme 5, reactions of both E- and Z-2i were
found to proceed stereospecifically with naphthyl imine
10m to access both diastereoisomers in high dr and er.
For example, Cu-catalyzed reaction of E-2i delivers R,S-
14i in 63% yield, >20:1 dr, and 97.5:2.5 er, whereas,
transformation of Z-2i results in R,R-14j in 59% yield,
>20:1 dr, and 97.5:2.5 er. These results indicate that the
reaction proceeds by an enantioselective transmetalation,
followed by Cu-allyl addition to the imine, which is either
faster than isomerization or nucleophilic addition via a
diastereomeric Cu-allyl isomer. The same mechanism
must also be operative for the reverse prenyl addition
(Scheme 3).
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The secondary amines prepared through the Cu-
catalyzed protocol are amenable to a range of subsequent
chemical transformations (Scheme 7). For example,
homoallylic amine 14e undergoes efficient Suzuki-
Miyaura cross coupling with p-CF3-C6H4Br to afford
alkenylarene 15 in 66% isolated yield. Allylboronic ester
16 can be efficiently prepared in 72% yield via the one
carbon
homologation
of
14f.
Additionally,
protodeboration of alkenylboronate 13a proceeds
smoothly in the
Scheme 7. Synthetic Utility of Products
Scheme 5. Cu-Catalyzed Stereospecific Additions with
E- and Z-Methyl/Ethyl AllylDiboronsa
aSee SI for details.
A proposed catalytic cycle and stereochemical model
for the enantio- and diastereoselective synthesis of
complex homoallylic amines is depicted in Scheme 6. In
situ
generated
(L)-Cu–OMe
(I)
undergoes
enantioselective transmetalation with allyldiboron II via
III to generate enantioenriched allylic Cu species IV.
The orientation of the B(pin) units will be positioned to
minimize A(1,3)-strain. Isomerization to less congested
and boron-stabilized allylic Cu E-V is followed by
reaction with the E-PMB imine via 6-membered cyclic
transition state VI. Coordination of the E-imine to (L)-Cu
places both the aryl substituent and the PMB groups
axial.20 Furthermore, to minimize additional 1,3-diaxial
interactions, the B(pin) unit is placed in the equatorial
aSee SI for details. bContains ~10% by-product that cannot be removed.
presence of AgF to furnish terminal olefin 17 in 67%
yield.21 Of note, this two-step process represents an
example of a formal enantioselective reverse prenylation
of an acyclic imine.22 Finally, the secondary amines can
be transformed into pyrrolidines by a two-step sequence.
Treatment of alkenylboronates 13b, 14b-c with
NaBO3•4H2O, results in conversion to the corresponding
cyclic hemiaminal, which can be reduced with NaBH3CN
position.
Following allyl transfer in a highly
diastereoselective manner, CD3OD (or MeOH) then
releases the homoallylic amine VIII and regenerates (L)-
Cu-OCD3.
Scheme 6. Proposed Catalytic Cycle and
Stereochemical Model
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to afford functionalized pyrrolidines 18, 19 and 20 in
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49%, 57%, and 47% yield, respectively over two steps
(Scheme 7D). Absolute stereochemistry of the products
was determined through X-Ray crystallographic analysis
of dimethyl-substituted pyrrolidine 18, which revealed
the stereochemical orientation of the secondary amine to
be R (Scheme 7D). Furthermore, examination of
pyrrolidine 19 by 1D-NOESY confirmed a cis-
relationship between the benzylic methine and adjacent
methyl group.
(1) For representative reviews that cover the
stereoselective synthesis of amines, see: (a) Enders, D.;
Reinhold, U. Asymmetric Synthesis of Amines by
Nucleophilic 1,2-Addition of Organometallic Reagents to
the CN-Double Bond. Tetrahedron: Asymmetry 1997, 8,
1895–1946. (b) Bloch, R. Additions of Organometallic
Reagents to C=N Bonds: Reactivity and Selectivity. Chem.
Rev. 1998, 98, 1407–1438. (c) Kobayashi, S.; Ishitani, H.
Catalytic Enantioselective Addition to Imines. Chem. Rev.
1999, 99, 1069–1094. (d) Ding, H.; Friestad, G. K.
Asymmetric Addition of Allylic Nucleophiles to Imino
Compounds. Synthesis 2005, 17, 2815–2829. (e) Friestad, G.
K.; Mathies, A. K. Recent Developments in Asymmetric
Catalytic Addition to CN Bonds. Tetrahedron 2007, 63,
2541–2569. (f) Shibasaki, M.; Kanai, M. Asymmetric
Synthesis of Tertiary Alcohols and α-Tertiary Amines via
Cu-Catalyzed C−C Bond Formation to Ketones and
Ketimines. Chem. Rev. 2008, 108 (8), 2853–2873. (g)
Robak, M. T.; Herbage, M. A.; Ellman, J. A. Synthesis and
Applications of tert-Butanesulfinamide. Chem. Rev. 2010,
110, 3600–3740.
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In conclusion, we have developed the first catalytic
enantio- and diastereoselective process for the synthesis
of complex homoallylic amines via the reaction of
allyldiboronates with aldimines. A (phosphoramidite)-
Cu catalyst promotes enantioselective transmetalation,
generating a highly reactive -boryl-Cu-allyl species.
This nucleophile reacts efficiently with a variety of aryl
aldimines to generate enantioenriched homoallylic
amines in excellent dr and er, bearing either gem-
dimethyl substitution or a quaternary carbon stereogenic
center. Significantly, both product diastereoisomers are
rendered accessible by choice of E- and Z-allyldiboron
stereochemistry. Furthermore, utility of the products is
highlighted through representative transformations that
included cross coupling, homologation, and conversion to
(2) For recent reviews on the enantioselective synthesis of
quaternary carbon stereogenic centers, see: (a) Das, J. P.;
Marek, I. Enantioselective Synthesis of All-Carbon
Quaternary Stereogenic Centers in Acyclic Systems. Chem.
Commun. 2011, 47, 4593–4623. (b) Minko, Y.; Marek, I.
Stereodefined Acyclic Trisubstituted Metal Enolates
Towards the Asymmetric Formation of Quaternary Carbon
Stereocentres. Chem. Commun. 2014, 50, 12597–12611. (c)
Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa, N.;
Chechik, H.; Das, J. P. All-Carbon Quaternary Stereogenic
Centers in Acyclic Systems through the Creation of Several
C−C Bonds per Chemical Step. J. Am. Chem. Soc. 2014,
136, 2682–2694. (d) Quasdorf, K. W.; Overman, L. E.
Catalytic Enantioselective Synthesis of Quaternary Carbon
Stereocentres. Nature 2014, 516, 181–191. (e) Liu, Y.; Han,
S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective
Construction of Quaternary Stereocenters: Assembly of Key
Building Blocks for the Synthesis of Biologically Active
Molecules. Acc. Chem. Res. 2015, 48, 740–751. (f) Zeng,
X.-P.; Cao, Z.-Y.; Wang, Y.-H.; Zhou, F.; Zhou, J. Catalytic
Enantioselective Desymmetrization Reactions to All-
Carbon Quaternary Stereocenters. Chem. Rev. 2016, 116,
7330–7396. (g) Feng, J.; Holmes, M.; Krische, M. J. Acyclic
Quaternary Carbon Stereocenters via Enantioselective
Transition Metal Catalysis. Chem. Rev. 2017, 117, 12564–
12580.
functionalized pyrrolidines.
stereoselective reactions of allyldiborons are ongoing.
Further catalytic
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and spectral
and analytical data for all products. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sjmeek@unc.edu
ORCID
Simon J. Meek: 0000-0001-7537-9420
Notes
Authors declare no competing financial interests.
ACKNOWLEDGMENT
(3) (a) Marek, I.; Sklute, G. Creation of quaternary
stereocenters in carbonyl allylation reactions. Chem.
Commun. 2007, 1683–1691. (b) Kolodney, G.; Sklute, G.;
Perrone, S.; Knochel, P.; Marek, I. Diastereodivergent
Synthesis of Enantiomerically Pure Homoallylic Amine
Derivatives Containing Quaternary Carbon Stereocenters.
Angew. Chem. Int. Ed. 2007, 46, 9291–9294.
(4) Yus, M.; González-Gómez, J. C.; Foubelo, F. Catalytic
Enantioselective Allylation of Carbonyl Compounds and
Imines. Chem. Rev. 2011, 111, 7774–7854.
Financial support was provided by the United States National
Institutes of Health, Institute of General Medical Sciences
(R01GM116987) and the University of North Carolina at Chapel
Hill. Mass spectrometry facilities in the Department of Chemistry
at University of North Carolina are supported by the National
Science Foundation (CHE1726291). We thank Blane Zavesky of
UNC for X-ray structure elucidation of 18. AllyChem is
acknowledged for donations of B2(pin)2.
(5) For recent examples of enantioselective Cu-catalyzed
allyl additions to imines and ketimines that do not generate
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(17) Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L.
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(19) Under the current catalytic protocol, reactions of
aliphatic and -unsaturated imines are not efficient; for
example, reaction of cinnamaldehyde-derived N-Bn imine
with 2a results in 15% conversion and 63:37 er.
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(21) Nave, S.; Sonawane, R. P.; Elford, T. G.; Aggarwal,
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