A selective transformation of enals into chiral γ-amino alcohols

Article abstract of DOI:10.1021/ol4022029

A one-pot synthesis of chiral amino alcohols from α,β- unsaturated aldehydes is reported which circumvents competitive 1,2- versus 1,4-boryl addition, by means of using a sterically hindered amine-derived imine. In addition to the complete chemoselectivit

Full text of DOI:10.1021/ol4022029

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
A Selective Transformation of Enals into
Chiral γ‑Amino Alcohols
†
†
‡
,‡
ꢀ ‡
ꢀ
Adam D. J. Calow, Andrei S. Batsanov, Alba Pujol, Cristina Sole, Elena Fernandez,*
and Andrew Whiting*,†
Centre for Sustainable Chemical Processes, Department of Chemistry,
Durham University, South Road, Durham DH1 3LE, U.K., and Departamento de
´ ´
ꢁ
Quımica Fısica i Inorganica, Universitat Rovira i Virgili, 43007 Tarragona, Spain
andy.whiting@durham.ac.uk; mariaelena.fernandez@urv.cat
Received August 2, 2013
ABSTRACT
A one-pot synthesis of chiral amino alcohols from R,β-unsaturated aldehydes is reported which circumvents competitive 1,2- versus 1,4-boryl
addition, by means of using a sterically hindered amine-derived imine. In addition to the complete chemoselectivity, modification of the Cu(I)
catalyst with readily available chiral diphosphines, such as (R)-DM-BINAP, gave the 1,4-boryl addition products with high levels of asymmetric
induction.
Metal and organocatalytic activation of diboron com-
pounds provides the ideal platform to add boryl moieties
to R,β-unsaturated carbonyl compounds in a 1,4-fashion
(Scheme 1a).1,2 However, R,β-unsaturated aldehydes suf-
fer from competitive 1,2-boryl addition and, therefore, the
synthesis of β-boryl aldehydes is a challenge3 (Scheme 1b).
Copper(I) alkoxides have proven to interact efficiently
with B2pin2 (bis(pinacolato)diboron) via σ-bond metath-
esis to enhance the chemoselective β-boration of R,β-
unsaturated aldehydes.4 However, the asymmetric induc-
tion on the CβÀB bond formation was originally afforded
in modest ee values when chiral N-heterocyclic carbenes
(NHCs) modified Cu(I) salts. The direct activation of
B2pin2 with chiral NHCs favored the formation of enan-
tioenriched mixtures of β-boryl aldehydes with ee’s up to
90% despite large amounts of base and MeOH (30 mol %
and 60 equiv respectively) being required.5 Moreover, this
method was limited to β-aryl substituted R,β-unsaturated
aldehydes. Alternative approaches to promote the chemo-
selective 1,4-boryl addition to enals were postulated on the
basis of iminium intermediates, in both copper mediated
reactions6 and organocatalytic reactions.7
Alternative approaches topromote 1,4-boryladdition to
enals were proposed on the basis of using iminium inter-
mediates, in both copper-mediated6 and organocatalytic
reactions.7 However, only when CuOTf/PPh3 catalyzed
the reaction in the presence of a chiral proline-derived
cocatalyst could the resulting β-borated product be
formed with moderate to high ee (up to 95%) as proved
by conversion of the β-boryl aldehyde intermediates into
enantioenriched mixtures of homoallylboronates (through
Wittig chemistry). However, the use of an organic acid as
† Durham University.
‡ Universitat Rovira i Virgili.
(1) For reviews in metal mediated β-boration, see: (a) Schiffner, J. A.;
€
Muther, K.; Oestreich, M. Angew. Chem., Int. Ed. 2010, 49, 1194. (b)
Hartmann, E.; Vyas, D. J.; Oestreich, M. Chem. Commun. 2011, 7917. (c)
ꢀ
Lillo, V.; Bonet, A.; Fernandez, E. Dalton Trans. 2009, 2899. (d) Dang,
L.; Lin, Z.; Marder, T. B. Chem. Commun. 2009, 3987. (e) Mantilli, L.;
Mazet, C. ChemCatChem 2010, 2, 501. (f) Calow, A. D. J.; Whiting, A.
Org. Biomol. Chem. 2012, 29, 5485.
(2) (a) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8, 4887. (b) Lee,
J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145.
(3) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006,
128, 11036.
(5) Wu, H.; Radomkit, S.; O’Brien, J. M.; Hoveyda, A. H. J. Am.
Chem. Soc. 2012, 134, 8277.
ꢀ
(6) Ibrahem, I.; Breistein, P.; Cordova, A. Angew. Chem., Int. Ed.
ꢀ
´
(4) (a) Bonet, A.; Lillo, V.; Ramırez, J.; Diaz-Requejo, M.; Fernandez,
2011, 50, 12036.
E. Org. Biomol. Chem. 2009, 7, 1533. (b) Lillo, V.; Prieto, A.; Bonet, A.;
ꢀ
rez, J.; Perez, P. J.; Fernandez, E. Organome-
ꢀ
ꢀ
Dı
´
az-Requejo, M.; Ramı
´
(7) Ibrahem, I.; Breistein, P.; Cordova, A. Chem.;Eur. J. 2012, 18,
5175.
tallics 2009, 28, 659.
r
10.1021/ol4022029
XXXX American Chemical Society

an additive (2-fluorobenzoic acid) was required to accel-
erate the catalytic cycle of the iminium ion formation and
to provide the chemoselective 1,4-addition.
Table 1. Comparative β-Boration of R,β-Unsaturated 2-Hexenal
and the Corresponding Aldiminesa
Scheme 1. Illustrative Copper-Mediated Bpin Addition to
R,β-Unsaturated Ketones, Aldehydes, and Aldimines
conv
(%)b
β-borated 3-
entry
L
amine
(%)
1
2
3
4
5
PPh3
À
99
99
99
99
99
63
99
99
99
75
“
“
“
“
NH2CH2Ph
NH2CH2p-C6H4OMe
NH2CHPh2
NH2C4H9
a A 0.25 mmol scale reaction: 2.00 mmol (1:1, amine/enal) were
stirred in THF (8 mL) and 3 A-MS (2.0 g) for 16 h, after which a
1 mL aliquot was transferred to a Schlenk tube (under Ar) containing
Cu(I) salt (3 mol %), PPh3 (6 mol %), NaOt-Bu (9 mol %), and B2pin2
(1.1 equiv). After 5 min, MeOH (2.5 equiv) was added to the solution and
the reaction was stirred for 6 h. b Determined by 1H NMR.
In our ongoing research to establish new methods to
reach γ-amino alcohols using one-pot protocols, through
organoboron intermediates,8 we recently established a
highly chemoselective Cu-catalyzed β-boration of in situ
formed enone and enal-derived imines, with subsequent
CdN reduction and CÀB oxidation.9 Furthermore, the
four steps were efficiently carried out without isolation of
intermediates, and the substrate scope was open to β-alkyl
and β-aryl substituted R,β-unsaturated aldehydes. We
focus now on the enantioselective version of this straight-
forward method to establish a new protocol to induce
enantioselectivity through the use ofchiralphosphinesthat
modify the Cu(I) catalytic system (see Scheme 1c).
The advantage of using R,β-unsaturated aldimines as
substrates to be borylated is based on complete chemo-
selectivity on the 1,4-addition as a result of steric hindrance
ofthe CdNRbond versus CdO (Table1). Weperformeda
comparative study of chemoselective β-boration of 2-hexenal
1d and the β-boration of the corresponding imines,
formed in situ by condensation with benzhydrylamine,
benzylamine, p-MeO-benzylamine, and n-butylamine.
Subsequent hydrolysis of the β-borated imines (Scheme 2)
thus provided the β-borated aldehyde with higher che-
moselectivity than the direct β-boration of 2-hexenal.
In the β-boration of the R,β-unsaturated imine formed
from n-butylamine, the chemoselectivity dropped signifi-
cantly, probably due to the reduced steric hindrance
around the CdN bond (Table 1, entry 5).
We found that benzhydrylamine provided sufficient
steric hindrance to guarantee the complete chemoselective
β-boration of 2-hexenal. For that reason, we moved to
β-aryl substituted enals to explore the viability of this
method, and indeed, we could follow the in situ formation
of imine 2a derived from cinnamaldehyde 1a and benzhy-
drylamine, using ReactIR (see Figure 1).
Figure 1. ReactIR plot of the in situ reaction of cinnamaldehyde
and benzhydrylamine to give the corresponding R,β-unsaturated
imine.
Imine 2a was formed in situ, and without isolation, we
conducted the Cu/PPh3 mediated β-boration. This again
proved that the competitive 1,2 boryl addition was no
longer observed (Table 2, entry 1) and the β-borated imine
was then subjected to reduction and oxidation in situ to
give the corresponding γ-amino alcohol 4a. With these
results in hand, we subjected the model substrate 1a to the
one-pot enantioselective β-boration through the inter-
mediate imine 2a. When BINAP L1 (Figure 2) or Tol-
BINAP L2 were used, high conversions into the desired
product 4a were observed (85 and 95% yields, respectively)
with moderate enantioselectivity (ee’s 72 and 71%, respec-
tively, Table 2, entries 2 and 3). Furthermore, when (R)-
DM-BINAP L3 was employed, the corresponding
γ-amino alcohol (R)-4a was formed in excellent conver-
sion (95%) and ee (97%, Table 2, entry 4). The abso-
lute configuration was determined by X-ray crystallogra-
phy of the corresponding 1,3-oxazine derived from 4a
ꢀ
(8) Sole, A.; Gulyas, H.; Whiting, A.; Fernandez, E. Adv. Synth.
Catal. 2011, 353, 376–384.
(9) Calow, A. D. J.; Batsanov, A. S.; Fernandez, E.; Sole, C.;
ꢀ
ꢀ
Whiting, A. Chem. Commun. 2012, 48, 11401–1403.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Enantioselective β-Boration of Cinnamaldehyde 2
through the Imine Intermediate 2aa
Table 3. Substrate Scope of the Enantioselective β-Boration of
R,β-Unsaturated Aldehydes in Situ Condensed with Benzhy-
drylaminea
conv (%)b
IY(%)
ee
(%)c
entry
L
4a
4a
1
2
3
4
5
6
7
PPh3
L1
99
85
95
95
95
95
27
62
53
64
50
45
86
À
À
72 (R)
71 (R)
97 (R)
80 (R)
58 (R)
97 (R)
L2
L3
L4
L5
L6
a A 0.50 mmol scale reaction: 2.00 mmol (1:1, amine/enal) were
stirred in THF (8 mL) and 3 A-MS (2.0 g) for 3À9 h (see Supporting
Information for imine formation), after which a 2 mL aliquot was
transferred to a Schlenk tube (under Ar) containing Cu(I) salt (3 mol %),
PPh3 (6 mol %) or diphosphine (3 mol %), NaOt-Bu (9 mol %), and
B2pin2 (1.1 equiv). After 5 min, MeOH (2.5 equiv) was added to the
solution, and the reaction was stirred for 16 h. NaBH4 (1.50 mmol) was
added, followed by the dropwise addition of MeOH (1 mL). The mixture
was stirred for 3 h, followed by the removal of solvent under reduced
pressure. THF (3 mL) was added to the resulting residue, followed by
NaOH (0.30 mL, w/v 20%) and H2O2 (0.13 mL, w/v 35%), and the
solution was heated to reflux for 1 h. The product was obtained after
SiO2 column chromatography. b Determined by 1H NMR, with some
percentage of substrate not transformed. c Determined by chiral HPLC
on the resulting O/N diacetate (see Supporting Information).
a Same reaction conditions as those shown in Table 2. b Determined
by 1H NMR, with some percentage of substrate not transformed.
c Determined by chiral HPLC on the resulting O/N diacetate (see
Supporting Information).
Scheme 2. Access to Enantioenriched β-Boryl Aldehyde 5d via
Imine Hydrolysis
afforded a high ee (97%), but with low conversion (27%,
Table 2, entry 7).
Due to the low cost and ready availability of the (R)-
DM-BINAP L3, we applied the optimized one-pot reac-
tion to a variety of enals with varying β-substituents (alkyl
and aryl), as shown in Table 3. To our delight, substrates
1aÀf were transformed into the analogous γ-amino alco-
hols 4aÀf in excellent conversion and ee’s, which were
all readily determined by derivatization to the analogous
O/N-diacetates.
Figure 2. Chiral phosphine ligands, L1À6.
(see Figure 3). The use of a similar bidentate ligand (R)-
DM-SEGPHOS L4 with the CuCl catalyst also accom-
plished the formation of 4a with high conversion but lower
enantioselectivity (80% ee, Table 2, entry 5).
Chiral Et-DuPHOS L5 and Pr-DuPHOS L6 gave a
spread of results depending on the bulky substituents,
while the Cu(I)/Et-DuPHOS L5 system provided high
conversion but with the lowest ee (58%, Table 2, entry 6).
In contrast, the Cu(I)/i-Pr-DuPHOS L6 catalytic system
In summary, we have reported an efficient and highly
enantioselective route for the one-pot conversion of enals
to γ-amino alcohols in up to 97% ee. The key to the success
of this procedure is an in situ imine formation using a
sufficiently sterically demanding amine to ensure complete
Org. Lett., Vol. XX, No. XX, XXXX
C

the nucleophilic copper-boryl species. While this approach
allows the subsequent transformation of the borylation
products to γ-amino alcohols, this protocol also opens up
the way for asymmetric borylation of unsaturated alde-
hydes by simple hydrolysis of the corresponding borylated
aldimines. Further studies in this area will be reported in
due course.
Acknowledgment. We thank the EPSRC for Doctoral
Training Account funding to A.D.J.C., the MEC for
funding (CTQ2010-16226), and FPU for a grant to C.S.
We also thank AllyChem, Solvias, and Dr. Reddy for gifts
of diboron reagents and chiral ligands.
Figure 3. X-ray structure of the analogous 1,3-oxazine of 4a
used to determine the absolute stereochemistry.
Supporting Information Available. Full experimental
details, characterization data for all products, ReactIR
and X-ray crystallographic and CIF information. This
material is available free of charge via the Internet at
http://pubs.acs.org.
chemoselectivity in the subsequent β-boration step. This
novel and straightforward approach enables the use of
enal-derived aldimines that had previously only undergone
1,2-boryl addition tonow undergo selective 1,4-addition of
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX