Catalytic 1,3-difunctionalisation of organic backbones through a highly stereoselective, one-pot, boron conjugate-addition/reduction/oxidation process

Article abstract of DOI:10.1002/chem.201102081

A simple one-pot, three-step synthetic route to chiral 1,3-amino alcohols and 1,3-diols has been established. Considering the overall stereocontrol of the synthetic protocol, the first and key step is an enantioselective β-boration of α,β-unsaturated imin

Full text of DOI:10.1002/chem.201102081

DOI: 10.1002/chem.201102081
Catalytic 1,3-Difunctionalisation of Organic Backbones through a Highly
Stereoselective, One-Pot, Boron Conjugate-Addition/Reduction/Oxidation
Process
Cristina Solꢀ,[a] Amolak Tatla,[a] Jose A. Mata,[b] Andrew Whiting,[c]
Henrik Gulyꢁs,*[a] and Elena Fernꢁndez*[a]
Abstract: A simple one-pot, three-step
synthetic route to chiral 1,3-amino al-
cohols and 1,3-diols has been estab-
lished. Considering the overall stereo-
control of the synthetic protocol, the
first and key step is an enantioselective
b-boration of a,b-unsaturated imines
and ketones, respectively. The enantio-
selectivity provided by the CuI catalyst
modified with Josiphos- and Mandy-
phos-type ligands has been examined.
The oxidative substitution of the boryl
unit with a hydroxyl group proceeds
with complete retention of configura-
tion at the Cb-atom. In parallel, the sto-
ichiometric reduction of the imino or
carbonyl group provides a second ste-
reogenic centre. Depending on the
nature of the reducing reagent, excep-
tionally high diastereoselectivity is ach-
ieved, especially for syn-1,3-amino al-
cohols and 1,3-diols.
Keywords: amino alcohols
· bo-
rates · copper · diastereoselectivity ·
enantioselectivity
Introduction
fins, enantiocontrol is usually achieved by the use of chiral
transition-metal complexes as catalysts,[2] although efficient
chiral organocatalytic systems have also been developed.[3a]
Of the various chiral catalysts, chiral copper(I)-complexes
stand out as the most economical, versatile, active and selec-
tive systems for performing the catalytic asymmetric b-bora-
tion of activated olefins at room temperature (Scheme 1,
Path a).
Over the course of the last few decades, control of stereo-
chemistry has become very important and, more recently, is
a common requirement in organic synthesis. The number of
stereoselective reactions is steadily increasing, providing
newer and more effective tools to control the formation of
new stereogenic elements in organic target molecules. One
of the most recently developed and fascinating synthetic
tools is the asymmetric boron conjugate addition reaction,[1]
which allows the functionalisation of electron-deficient ole-
fins through a Michael type boron addition. In these reac-
tions, the boron nucleophile is generated from common di-
boron reagents, such as bis(pinacolato)diboron (B2pin2,
pin=OCACHTUNGTRENNUNG(CH3)2CACHTUNGTRENNUNG(CH3)2O), whereas the proton electrophile
usually derives from an alcohol. In the case of prochiral ole-
[a] C. Solꢀ, A. Tatla, Dr. H. Gulyꢁs, Dr. E. Fernꢁndez
Departament Quꢂmica Fꢂsica i Inorgꢃnica
University Rovira i Virgili
Scheme 1. Straightforward routes to a-chiral b-functionalised organobor-
anes.
C/Marcel.lꢂ Domingo s/n 43007 Tarragona (Spain)
Fax : (+34)977-559563
E-mail: mariaelena.fernandez@urv.cat
henrik.gulyas@urv.cat
Alternatively, Hall and co-workers[3b] have developed an
interesting asymmetric route to a-chiral boranes by a
copper-mediated enantioselective 1,4-addition of Grignard
reagents to b-boron-substituted a,b-unsaturated esters and
thioesters, with high yields and enantioselectivities up to
98% (Scheme 1, Path b).
[b] Dr. J. A. Mata
Departament de Quꢂmica Inorgꢃnica i Orgꢃnica
Universitat Jaume I, Sos Banyat, s/n, 12080 Castellꢄ (Spain)
[c] Dr. A. Whiting
Centre for Sustainable Chemical Processes
Department of Chemistry, Science Laboratories
Durham University, South Road, Durham, DH1 3LE (UK)
Importantly, taking into account the well-established
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102081.
À
À
À
À
methods for converting C B bond into C C, C O, C N
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FULL PAPER
[4]
À
and C F bonds with complete retention of configuration,
(Scheme 3). However, probably all these types of strategies
involving b-amino ketones were eclipsed by an efficient,
two-step procedure combining organo-, organometallic and
the products of the asymmetric boron conjugate addition
seem to be highly versatile intermediates, from which dense-
ly functionalised organic molecules can be obtained. For in-
stance, Yun and co-workers were able to apply b-boration to
cinnamic acid N-methylamide in 99% ee with a CuI–Josi-
phos complex.[2e] Oxidation of the C B carbon atom to C
O, with complete retention of configuration, afforded a suit-
able intermediate for the synthesis of (S)-fluoxetine.[5] As
another example of practical applications of the enantiose-
lective conjugate boron additions, we have recently shown
that these reactions can also be used in the synthesis of
enantioenriched g-amino alcohols.[6] To demonstrate this
synthetic method, we have optimised the copper-catalysed
asymmetric b-boration of three imine derivatives of benzyli-
deneacetone, screening a relatively small, yet diverse library
of chiral phosphorus ligands. The chiral copper(I)-complexes
provided the b-boryl imines in up to 99% ee. A highly dia-
stereoselective, stoichiometric reduction of the C=N bond,
followed by oxidative substitution of the boryl functionality
with OH, provided the corresponding enantioenriched syn-
and anti-g-amino alcohols in good to excellent isolated
yields (Scheme 2).
Our described methodology can be considered to be an
efficient alternative to currently reported methods. For ex-
ample, Zhang and co-workers[7] found that rhodium com-
plexes could efficiently be used to perform the enantioselec-
tive reduction of b-secondary amino ketones, and Troung
and co-workers[8] also described the directed reduction of b-
amino ketones to syn- or anti-1,3-amino alcohols in the pres-
ence of Sm complexes. Both methodologies were based on
the use of b-secondary amino-ketones as substrates. Alterna-
tively, Rudolph and co-workers[9] reported a directed reduc-
tive amination of b-hydroxy-ketones as a convergent assem-
bly towards syn-1,3-amino alcohols. In this work, the imino
functionality is formed “in situ” in the presence of a primary
amine and the intermediate imino alcohol was proposed to
À
À
Scheme 3. Directed reductive amination of b-hydroxy-ketones postulated
by Rudolph and co-workers.
enzymatic catalysis described by Bꢆckvall and co-workers.[10]
By using this methodology, an elegant enantioselective syn-
thesis of syn- and anti-1,3-amino alcohols followed by a sub-
sequent reduction/dynamic kinetic asymmetric transforma-
tion was achieved. Alternatively, Palmieri and co-workers[11]
also described an interesting stereoselective synthesis of
enantiopure g-amino alcohols by reduction of chiral b-enam-
ino ketones. Although the substrate was already chiral, the
authors described important mechanistic aspects to justify
the preference for formation of the syn- or the anti-diaste-
reomer, in the presence of AcOH.[12]
In a different context, White and co-workers[13] reported
À
an elegant palladium-mediated allylic C H amination pro-
cedure to synthesise exclusively syn-1,3-amino alcohols.
Most recently, Ellman and co-workers[14] used a chiral auxili-
ary substituted on the imino group to control the asymmet-
ric addition of a nucleophile to N-sulfinyl imines through a
metalloenamine. Reduction of the resulting a-hydroxysulfin-
yl imines with catecholborane and LiBHEt3 provided syn-
and anti-1,3-amino alcohols, respectively, with very high dia-
stereoisomeric ratios. It is also noteworthy that the syn-dia-
À
stereoisomer was suggested to be formed due to a B N in-
teraction between the substrate and catecholborane
(Scheme 4), as we have suggested in the present work (see
below).
strongly coordinate to [TiACTHNUTRGNE(UGN OiPr)4], and, therefore, the reduc-
tion could proceed through a Zimmerman–Traxler type
transition state, leading to the desired 1,3-syn product
Scheme 2. Synthesis of enantioenriched syn- and anti-g-amino alcohols from 1-phenyl-N-(4-phenylbut-3-en-2-ylidene)methanamine through a one-pot b-
boration/reduction/oxidation process.
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H. Gulyꢁs, E. Fernꢁndez et al.
Table 1. Substrate scope: a,b-unsaturated ketones and the corresponding
synthesised a,b-unsaturated imines.[a]
Ketone
Imine
Isolated
yield [%]
1
2
1a
1a
1b 73[11]
1c 89[11]
Scheme 4. Asymmetric synthesis of syn- and anti-1,3-amino alcohols from
chiral N-sulfinyl imines.
3
1a
1d 78[11]
Considering the importance in pharmaceutical applica-
tions of chiral g-amino alcohols (for example, nikkomycin,
negamycin, ritonavir and lopinavir)[15] and their notable role
as chiral synthons,[16] chiral auxiliaries[17] and chiral ligands
in transition-metal catalysis,[18] we decided to survey the pos-
sibility of extending the range of a,b-unsaturated imines em-
ployed, and compare the results of this study with those ob-
tained from the analogous transformations of the corre-
sponding a,b-unsaturated ketones into chiral 1,3-diols. In
this paper we give a full account of this work.
4[b]
5[b]
6[b]
7[b]
2a
2a
3a
3a
2b 95
2c 91
3b 73
3c 73
Results and Discussion
8[c]
4a
4c 43
Synthesis of a,b-unsaturated imines: Non-functionalised ke-
tones and aldehydes readily react with primary amines to
afford the corresponding imines. The equilibrium can be
shifted towards imine formation, for example, by using de-
hydrating agents, or by azeotropic distillation or crystallisa-
tion of the imine from the reaction mixture. In early work,
we prepared a series of a,b-unsaturated imines and oximes
with different electronic and steric properties.[19] The ke-
tones reacted with substituted amines and hydroxylamine in
the presence of montmorillonite clay K-10 (MK10), and the
rate of condensation of these reactants in the presence of
MK10[20] was found to be comparable to the conversion
when molecular sieves were used as dehydrating agent.[21]
The yields of the isolated a,b-unsaturated imines were high
(Table 1, entries 1–3) and comparable to the yields obtained
from other synthetic procedures described in the litera-
ture.[22,23]
Examining the substrate scope of the present approach in-
volved the synthesis of a series of a,b-unsaturated imines
with variations of electronic properties on the structure. The
imines N-[4-(p-methoxyphenyl)but-3-en-2-ylidene]butan-1-
amine (2b) and 1-phenyl-N-[4-(p-methoxyphenyl)but-3-en-
2-ylidene]methanamine (2c) were prepared and isolated in
high yields by condensation of the corresponding ketones
[a] Standard conditions for the imine synthesis: ketone (1 mmol), amine
(1.1 mmol), MK-10 (100 mg), CH3CN (2.5 mL), RT, 15 h. [b] Solvent:
MeOH. [c] Solvent: hexane, T=708C.
and amines in the presence of MK-10 (Table 1, entries 4 and
5). Similarly, the imines N-[4-(p-chlorophenyl)but-3-en-2-yli-
dene]butan-1-amine (3b) and phenyl-N-[4-(p-chlorophenyl)-
but-3-en-2-ylidene]methanamine (3c) were synthesised;
however, the isolated yields in these cases were only moder-
ate (Table 1, entries 6 and 7). To analyse the influence of
bulkier substituents on the imine functionality, the benzyli-
mine 4c of benzylideneacetophenone was prepared and iso-
lated in 43% yield (Table 1, entry 8). Figure 1 shows the mo-
lecular structure of imine 4c determined by X-ray crystallo-
À
graphic analysis. The C(1) N(1) distance is 1.285 ꢇ, indicat-
ing the double bond character of the imino group. The
À
À
À
C(1) C(2) C(3) C(4) dihedral angle of 179.58 confirms the
E-geometry around the C=C bond. The co-planarity found
À
À
for the imine N(1) C(1) and alkene C(2) C(3) atoms, and
À
the short distance for a single bond between C(1) C(2), in-
À
dicates some degree of conjugation along the N(1)=C(1)
C(2)=C(3) p-electron system. We have found that, to obtain
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1,3-Difunctionalisation of Organic Backbones
FULL PAPER
Scheme 5. Synthesis of 1,3-diols and 1,3-amino alcohols from a,b-unsatu-
rated ketones and imines through a one-pot catalytic b-boration/reduc-
tion/oxidation process.
Figure 1. Molecular diagram of benzylimine 4c. Ellipsoids at 50% proba-
bility level. Hydrogen atoms have been omitted for clarity. Selected bond
À
À
lengths (ꢇ) and angles (8): C(1) N(1) 1.285(3), C(1) C(2) 1.465(3),
À
À
À
À
C(1) C(10) 1.501(3), N(1) C(16) 1.462(3), C(2) C(3) 1.322(3), C(3)
C(4) 1.472(3), N(1)-C(1)-C(2) 117.12(19), N(1)-C(1)-C(10) 124.87(19),
C(2)-C(1)-C(10) 118.00(19), C(1)-N(1)-C(16) 119.92(19). C(1)-C(2)-C(3)
125.9(2).
tones 2-cyclohexen-1-one and trans-3-nonen-2-one, resulting
in complete conversion into the desired organoboranes.
The isolated b-boryl products 7–12 have very different
boron signals in their 11B{1H}-NMR spectra, depending on
the nature of the C=E functionality (Table 2). Whereas b-
boryl ketones show boron signals between d=33.0–37.0 ppm
(Table 2, entries 1, 5, 8 and 11), the corresponding boron sig-
nals for b-boryl imines appear between d=18.1–21.7 ppm
(Table 2, entries 2–4, 6, 7, 9, 10 and 12). The shift to higher
fields of the boron signals in b-boryl imines is diagnostic of
the intramolecular interaction between N and B.[24] For the
analogous b-boryl ketones, there is no evidence of any intra-
sufficient chemoselectivity towards imine formation, an aryl
substituent on the b-carbon of the ketones is a crucial struc-
tural feature. In the case of aliphatic ketones 2-cyclohexen-
1-one (5) and trans-3-nonen-2-one (6), the aza-Michael addi-
tion dominated, irrespective of the reaction conditions.
Copper/PPh3-catalysed b-boration of a,b-unsaturated ke-
tones and imines, followed by in situ reduction/oxidation;
the origin of the diastereoselectivity: The stereoselectivity of
the b-boration/reduction/oxidation process is determined by
two independent factors, that is, the enantioselectivity of the
boron conjugate addition reaction, and the diastereoselectiv-
ity of the stoichiometric reduction of the C=O and C=N
double bond. We decided to address the two issues separate-
ly. Firstly, we examined the diastereoselectivity of the forma-
tion of the 1,3-diols and 1,3-aminoalcohols in a one-pot re-
action sequence, whereby the b-boration of substrates 1–6
was carried out by using achiral CuI catalysts, and the race-
mic organoboranes were converted in situ into the corre-
sponding products through stoichiometric reduction of the
carbon–heteroatom double bond, followed by oxidative sub-
stitution of the Bpin moiety, as outlined in Scheme 5.
À
molecular B O interaction in solution phase, which is con-
firmed by solid phase structures of organoboranes 7a and
À
10a (Figures 2 and 3). The B(1) O(1) distance in compound
7a is 2.706 ꢇ, which is significantly higher than the sum of
the covalent radii of boron and oxygen, indicating negligible
interaction between the boron and oxygen centres. The
same situation is observed in the case of compound 10a,
À
however, in this case, the B(1) O(1) distance is 2.854 ꢇ,
which is even higher than in compound 7a.
From our previous study on the synthesis of enantioen-
riched g-amino alcohols,[6] we identified selective reducing
agents for the C=N reduction, which, when coupled with the
À
stereospecific oxidation reaction of the B C bond, provided
exclusively the syn- or anti-g-amino alcohols. The reducing
The catalyst system CuCl/PPh3 efficiently b-borated the
a,b-unsaturated ketones and imines 1–6 into the organobor-
onate intermediates 7–12, in the presence of 1.1 equivalents
of bis(pinacolato)diboron (B2pin2) at room temperature
(Table 2). The addition of base (NaOtBu) was crucial for
the quantitative transformation of the substrates into the de-
sired products.[11]
Quantitative conversions were observed for all the sub-
strates (Table 2), except for the b-boration of (E)-N-(4-phe-
nylbut-3-en-2-ylidene)aniline (1d; Table 2, entry 4), which is
probably due to the steric hindrance around the imine func-
tionality. We also explored the b-boration of aliphatic ke-
agents
studied
were:
BH3·THF,
NaBH4·EtOH,
NaBH4·MeOH, NaBH4·THF (2% H2O), DIBAL-H·THF
and DIBAL-H/ZnCl2·THF (DIBAL-H=diisobutylalumini-
um hydride). A pronounced tendency to obtain the syn-dia-
stereoisomer was observed in the reduction/oxidation se-
quence of b-boryl benzylimine 7c and b-boryl phenylimine
7d with BH3·THF. However, selective formation of the syn-
diastereoisomer of b-boryl butylimine 7b was only achieved
for the reduction/oxidation sequence with DIBAL-H·THF,
DIBAL-H/ZnCl2·THF and NaBH4·MeOH.[6] In this work,
the reagent BH3·THF was chosen for the reduction step,
À
whereas the oxidative cleavage of the C B bond was carried
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H. Gulyꢁs, E. Fernꢁndez et al.
Table 2. CuCl/PPh3 catalysed b-boration of a,b-unsaturated ketones and
a,b-unsaturated imines.[a]
Table 2. (Continued)
Organoborane
Conv. Isolated
[%][b] yield [%] d [ppm]
11B{1H}-NMR
Organoborane
Conv. Isolated
[%][b] yield [%] d [ppm]
11B{1H}-NMR
13
14
11a 100
12a 100
88
52
33.4
38.1
1
2
3
4
7a
7b
7c
7d
99
99
99
40
42
70
82
29
37.0
21.7
21.1
21.4
[a] Standard conditions for the b-boration: substrate (0.25 mmol), CuCl
(2 mol%), PPh3 (4 mol%), B2pin2 (1.1 equiv), NaOtBu (3 mol%),
MeOH (2 equiv), THF (2.5 mL), RT, 6 h. [b] Conversion calculated on
1
the basis of H NMR spectroscopic analysis. [c] 12 h.
5
6
8a
8b
8c
9a
9b
9c
90
99
99
98
99
99
82
97
85
91
89
85
33.6
20.2
19.2
33.1
19.0
18.9
Figure 2. Molecular diagram of b-boryl imine 7a. Ellipsoids at 50% prob-
ability level. Hydrogen atoms have been omitted for clarity except H(4).
7
À
À
Selected bond lengths (ꢇ) and angles (8): B(1) O(1) 2.706, O(1) C(2)
À
À
À
1.204(2), B(1) O(3) 1.3580(18), B(1) O(2) 1.3594(18), B(1) C(4)
À
À
À
1.567(2), C(1) C(2) 1.493(3), C(2) C(3) 1.493(2), C(3) C(4) 1.517(2),
O(3)-B(1)-O(2) 113.37(13), O(2)-B(1)-C(4) 123.21(13), O(1)-C(2)-C(3)
121.31(15).
8
9
10
11
12
10a
10c
99[c]
57
78
34.1
18.1
Figure 3. Molecular diagram of b-boryl imine 10a. Ellipsoids at 50%
probability level. Hydrogen atoms have been omitted for clarity. Selected
99[c]
À
À
bond lengths (ꢇ) and angles (8): B(1) O(1) 2.854, O(1) C(2) 1.206(6),
À
À
À
À
B(1) O(3) 1.354(5), B(1) O(2) 1.357(5), B(1) C(3) 1.565(6), C(1) C(2)
À
À
1.491(7), C(2) C(3) 1.518(6), C(3) C(4) 1.521(6), O(3)-B(1)-O(2)
112.8(3), O(1)-C(1)-C(10) 120.3(5), O(2)-B(1)-C(3) 122.3(4), C(1)-C(2)-
C(3) 112.9(4), C(4)-C(5)-C(6) 120.6(5).
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1,3-Difunctionalisation of Organic Backbones
FULL PAPER
out in the presence of alkaline hydrogen peroxide. With
these model reagents for reduction/oxidation, we intended
to identify those structural features of the substrates that in-
fluence the diastereoselectivity of the reduction/oxidation of
organoboranes 7–12 (Table 3) to the greatest extent. The
diastereoselectivity of the reactions was determined by
1H NMR spectroscopic analysis of the crude and isolated
1,3-diols and 1,3-amino alcohols 13–18. We found that, in
most cases, the stoichiometric reduction/oxidation of orga-
noborane intermediates indeed takes place with good to ex-
cellent syn-selectivity (Table 3, entries 1, 3, 4, 7, 11 and 12).
It is worth mentioning that, in addition to H NMR spectro-
scopic evidence, the formation of the syn-products was also
confirmed by X-ray studies on 16a (Figure 4). Notable ex-
1
Table 3. Diastereoselective reduction/oxidation of b-boryl ketones and b-
boryl imines with BH3·THF and H2O2/NaOH.[a]
Difunctionalised
product[b]
syn/anti
ratio
Isolated
yield [%]
syn/anti
product
1[6]
13a
13b
95:5
85
–
99:1
–
2[6]
53:47
Figure 4. Molecular diagram of 1,3-diol 16a. Ellipsoids at 50% probabili-
ty level. Hydrogen atoms have been omitted for clarity except H(3) and
3[6]
13c
13d
95:5
99:1
82
95
99:1
99:1
À
H(8). Selected bond lengths (ꢇ) and angles (8): O(1) C(3) 1.432(3),
À
À
À
À
C(1) C(8) 1.516(3), O(2) C(8) 1.434(3), C(2) C(3) 1.512(3), C(3) C(4)
À
À
1.522(4), C(4) C(8) 1.524(3), O(1) C(3) 1.432(3), O(1)-C(3)-C(2)
111.66(19), C(2)-C(3)-C(4) 113.14(19), C(2)-C(3)-C(4) 113.14(19).
4
ceptions are the reduction/oxidation of b-boryl n-butyli-
mines, which afforded 1,3-amino alcohols with comparable
amounts of both the syn- and anti-diastereoisomers (Table 3,
entries 2, 6 and 9). To improve the diastereoselectivity of
the syn-1,3-amino alcohol, we turned our attention to the al-
ternative reducing reagent, DIBAL-H·THF, which provided
high syn-diastereoselection on the b-boryl n-butylimine
(Table 4, entry 1).[6] When b-boryl-n-butylimines 8b and 9b
were reduced and oxidised with DIBAL-H·THF and H2O2/
NaOH, respectively, the formation of the syn- versus the
anti-diastereoisomer increased, although no exclusive forma-
tion of either syn-14b or syn-15b products could be ach-
ieved. In contrast to the case of acyclic substrates, the reduc-
tion/oxidation of 3-boryl-cyclohexen-1-one (11a) with
BH3·THF and H2O2/NaOH, gave the anti-diastereoisomer as
the major product (Table 3, entry 13).
5
6
14a
14b
83:17
54:46
71
–
99:1
–
7
14c
77:23
80
98:2
8
9
15a
15b
86:14
60:40
82
–
99:1
–
10
15c
16a
16c
87:13
99:1
99:1
73
95
90
98:2
99:1
99:1
Table 4. Diastereoselective reduction/oxidation of b-boryl n-butylimines
11
12
with DIBAL-H·THF and H2O2/NaOH.[a]
Difunctionalised
product
Conv.
[%][b]
syn/anti
Isolated
yield [%]
syn/anti ratio
of pure product
1
2
3
13b
14b
15b
90
99
99
99:1
77:23
82:18
84
47
52
99:1
99:1
99:1
13
14
17a
18a
30:70
80:20
60
63
1:99
99:1
[a] Standard conditions for the reduction: b-boryl n-butylimines
(0.5 mmol), DIBAL-H·THF (3 eq), THF (2 mL), À788C to 258C, 15 h.
Standard conditions for the oxidation: NaOH (aq.) (1.0m, 10 mL,
10 mmol), H2O2 (aq.) (30% v/v, 750 mL, 7.6 mmol), RT, 3 h. [b] Conver-
[a] Standard conditions for the reduction: b-boryl ketone or imine
(0.5 mmol), BH3·THF (1m, 1.5 mL, 1.5 mmol), THF (2 mL), 08C to 258C,
15 h. Standard conditions for the oxidation: NaOH (aq.) (1.0m, 10 mL,
10 mmol), H2O2 (aq.) (30% v/v, 750 mL, 7.6 mmol), RT, 3 h. [b] Conver-
1
sion calculated on the basis of H NMR spectroscopic analysis.
1
To explain the pronounced syn-selectivity of the reaction
sion calculated on the basis of H NMR spectroscopic analysis were more
than 99% in all the examples, in at least two reproducible reactions.
sequence (Scheme 5), we suggest a model based on the
Chem. Eur. J. 2011, 17, 14248 – 14257
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14253

H. Gulyꢁs, E. Fernꢁndez et al.
close proximity of the Lewis acidic boryl group and the
Lewis basic ketone/imine functionalities in the organobor-
ane intermediates 7–12. If we consider an intramolecular
Lewis acid/Lewis base interaction between the two function-
pected with 3-substituted cyclohexanones, hydride reduction
occurs to give predominantly 1,3-anti-stereocontrol, as ex-
plained elsewhere.[27] However, the origin of the reduced
syn-diastereocontrol upon formation of the N-n-butyl amino
alcohols 13–15b (see Table 3) is less clear. In these cases,
the syn-diastereocontrol remains in place to some extent,
À
al groups (i.e., A; Scheme 6), the cyclic B N chelate struc-
À
perhaps by intramolecular B N complex 7b–9b, as outlined
in Scheme 6. However, a more likely explanation is that in
the presence of BH3·THF, there is the competing effect of
À
intermolecular N B complexation with the reducing agent
BH3·THF due to the more electron-rich n-butyl imine (see
Scheme 7). This would have the effect of allowing acylic
Scheme 6. Predicted intramolecular Lewis acid complex involved in orga-
noboronates 7–12 resulting in the formation of the syn-diastereoisomers
13–18.
tures formed upon such an interaction have two sterically
different diastereotopic faces. The primary factor that cre-
ates the facial differentiation is the substituent on the b-
carbon, as shown in Scheme 6. Other steric features of the
molecules (such as the large boronate ester group) are ex-
pected to exert a similar steric influence on both sides of the
C=E functionality, however, they could contribute by ampli-
fying or reducing the effect of the b-substituent. It is impor-
tant to note that the existence of such interactions are
widely accepted in the literature,[25] even on ketone and al-
dehyde systems;[26] however, to the best of our knowledge,
direct proof has never been presented.
For the reasons outlined above, we have made a consider-
able effort to find structural and spectroscopic evidence for
the internal Lewis acid–Lewis base interaction shown sche-
matically in Scheme 6 by structure A. Despite the lack of
solid-state structural evidence, there is a clear spectroscopic
À
indication of intramolecular B N interaction as shown in
Scheme 7. Proposed origin of the competing anti-diastereoselection in the
BH3-mediated reduction to derive amino alcohols 13–15b.
Table 2. The observed Dd between the 11B{1H}-NMR chemi-
cal shifts of the b-boryl ketones and the corresponding b-
boryl imines are consistent with partial rehybridisation of
the boron atom from pure sp2 towards sp3 in the case of the
b-boryl imines upon the formation of the intramolecular
Lewis adducts. We can presume, therefore, that the control-
ling element in the formal hydride addition that results in
high syn-diastereocontrol is indeed a complex of type A
(Scheme 6). In cases where E is NR’, the evidence for the
chelates is strong (especially from 11B NMR spectroscopic
analysis). In the case of ketones, the explanation forwarded
by previous workers in this area,[24] that a transient activated
intramolecular complex is likely to be involved, seems to be
a sound hypothesis because such complexes can effect
remote asymmetric induction processes.[24,25]
stereoselection processes to occur, which are likely to be
governed by the types of effects used to explain additions to
chiral ketone systems.[28] Hence, n-butyl-BH3 activated com-
plexes of type B could undergo additions as outlined in
Scheme 5 to derive both syn- and anti-products via reactive
conformations C1 and C2. In these types of models, we pre-
dict that the Ar group behaves as the larger group, leaving
the Bpin moiety to stabilise or destabilise either of the pos-
sible reactive conformations. In fact, there may be little to
choose between conformations C1 and C2, with the former
having possible stereoelectronic repulsion between the elec-
tropositive formal imminium ion, and the latter having
steric repulsion between the R-group and Bpin. The net
result would be approximately equal amounts of both the
syn- and anti-diastereoisomers being formed, as is indeed
observed.
In contrast to the highly syn-diastereocontrolled reduction
reaction, the origin of the dominant anti-selectivity in the re-
duction/oxidation of 3-boryl-cyclohexen-1-one (11a) can be
explained by the lack of intramolecular Lewis acid–Lewis
base interactions between the B and O centres, due to the
cyclic conformational restrictions of the molecule. As ex-
14254
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Chem. Eur. J. 2011, 17, 14248 – 14257

1,3-Difunctionalisation of Organic Backbones
FULL PAPER
Copper–chiral-ligand-catalysed b-boration of a,b-unsaturat-
ed ketones and imines, followed by in situ reduction/oxida-
tion—the origin of the enantioselectivity: The overall ste-
reoselectivity of the b-boration/reduction/oxidation reaction
was next addressed through the enantioselective b-boration
of the a,b-unsaturated ketones and imines 1–3, in the pres-
ence of copper(I) modified with chiral bidentate ligands, fol-
lowed by in situ reduction/oxidation with the appropriate re-
ducing reagent (BH3·THF or DIBAL-H·THF) and H2O2/
NaOH. The chiral ligands explored were Josiphos diphos-
phanes 19 and 20 and Mandyphos diphosphanes 21–22.[29]
Most of the reactions were complete within 6 h at room
temperature (Table 5).
were involved in the asymmetric b-boration, it is worth men-
tioning that the catalytic system CuCl/ligand 19 provided
the best results (Table 5, entries 5–7, 12, 13, 17 and 18).
Electron-rich substrates could be transformed into the cor-
responding g-amino alcohols with ee values of between 93
and 99% (Table 5, entries 6 and 13). Substituents on the ni-
trogen atom of the imines had an influence on the enantio-
selectivity of the b-boration, as shown in Table 5 and
Figure 5. The electronic and steric properties of the imino
benzyl group also had a beneficial effect on the enantiose-
lectivity of the asymmetric b-boration.
Table 5. Enantio- and diastereo-selective b-boration/reduction/oxidation
of a,b-unsaturated imines and ketones with Cu-chiral ligands.[a]
Product
Chiral ligand
NMR yield [%][b]
syn/anti
ee
1
2
3
4
13a
13a
13a
13a
13b
13c
13d
14a
14a
14a
14a
14b
14c
15a
15a
15a
15a
15b
15c
16a
16a
16a
16a
16c
19
20
21
22
19
19
19
19
20
21
22
19
19
19
20
21
22
19
19
19
20
21
22
19
99
99
99
99
94
99
99
99
99
44
71
99
99
99
99
90
96
99
99
99
99
90
96
99
92:8
90:10
95:5
90:10
99:1
91:9
8
66
75
52
80
99
52
3
65
10
42
79
93
5
42
61
65
56
61
2
42
73
84
65
5[c][6]
6[6]
7[6]
8
99:1
83:17
82:18
83:17
83:17
54:46
71:29
88:12
84:16
86:14
84:16
57:43
82:18
99:1
9
10
11
12[c]
13
14
15
16
Figure 5. Relative values of enantiomeric excesses on the catalytic b-bo-
ration/reduction/oxidation of a,b-unsaturated ketones and imines.
17
18[c]
19
The benefits of our methodology with respect to the re-
ported methodologies is based on the use of simple, achiral,
activated ketones or imines and the use of inexpensive
copper catalyst for the b-boration. The asymmetric b-bora-
tion is achieved by the use of catalytic amounts of chiral di-
phosphanes, and the reduction/oxidation procedure can be
performed with appropriate reducing agents to obtain the
syn-diastereoisomer with retention of configuration, in a
one-pot sequence.
21[d]
22[d]
23[d]
24[d]
25[d]
99:1
99:1
99:1
99:1
[a] Standard conditions for the reduction: b-boryl ketone or imine
(0.5 mmol), BH3·THF (1m, 1.5 mL, 1.5 mmol), THF (2 mL), 08C to 258C,
15 h. Standard conditions for the oxidation: NaOH (aq.) (1.0m, 10 mL,
10 mmol), H2O2 (aq.) (30% v/v, 750 mL, 7.6 mmol), RT, 3 h. [b] Calculat-
ed on the basis of 1H NMR spectroscopic analysis. [c] Standard condi-
tions for the reduction: b-boryl n-butylimines (0.5 mmol), DIBAL-
H·THF (3 equiv), THF (2 mL), À788C to 258C, 15 h. [d] 12 h.
Conclusion
The enantiomeric excess of 1a was variable, ranging from
8% with the catalytic system CuCl/ligand 19, to 75% with
CuCl/ligand 21 (Table 5, entries 1–4). The asymmetric induc-
tion observed is in agreement with related reports.[2] Ligand
20 and the two Mandiphos type ligands 21 and 22 had a pos-
itive influence on the asymmetric b-boration of the analo-
gous substrates 2a and 3a, whereas the chiral ligand 19 was
quite inefficient (ee<10%; Table 5, entries 8–11 and 14–17).
Neither electron-donating nor electron-releasing substitu-
ents on the phenyl group in the b-position of the substrate
had a significant influence on the asymmetric b-boration.
However, when the corresponding a,b-unsaturated imines
This comparative study on the catalytic b-boration/reduc-
tion/oxidation of a,b-unsaturated ketones and imines has
highlighted two important features. The asymmetric induc-
tion of the b-boration of a,b-unsaturated imines has been
performed with more success than in the case of the corre-
sponding a,b-unsaturated ketones, when the catalytic system
is CuCl modified with Josiphos type ligand 19. The imine
group itself and the aryl and alkyl substituents on the imino
group seem to provide a beneficial effect on the enantiose-
lection of the reaction, and configuration is maintained
along the subsequent reduction and oxidation, which allows
the reaction to proceed in a one pot system. As far as the
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14255

H. Gulyꢁs, E. Fernꢁndez et al.
reduction protocol is concerned, it has also been observed
that when BH3·THF is used as reducing reagent, the syn-dia-
stereoisomer is favoured, probably due to an intramolecular
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À
B N interaction. This hypothesis has also been supported
11
1
À
by B{ H}-NMR studies that confirm intramolecular B N
chelation. The lack of this intramolecular interaction for the
corresponding b-boryl ketones (supported by 11B{1H}-NMR
spectroscopic analysis and by X-ray diffraction studies),
could also explain why the diastereoselectivity of the syn-
isomer is lower. However, when n-butyl groups are the sub-
stituents of the imino group, the ratio of syn- versus anti-
diastereoisomer decreases to close to 1/1. In this case, a
plausible explanation is the presence of competitive inter-
and intra-molecular interactions of the imine nitrogen atom
with both the BH3·THF and the Bpin, respectively, which
could explain the lack of diastereoselectivity. n-Butyl amino
alcohols with improved syn-diastereomer selectivity can be
obtained using DIBAL-H·THF as the reducing reagent. The
one-pot reaction sequence b-boration/reduction/oxidation of
activated ketones and imines offers a convenient method for
the direct synthesis of enantioenriched 1,3-diols and 1,3-
amino alcohols. Experimental and theoretical efforts to elu-
cidate the intrinsic mechanism of the asymmetric induction
are being developed in our laboratories.
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Experimental Section
General method for one-pot copper-catalysed asymmetric b-boration/re-
duction/oxidation of a,b-unsaturated imines and ketones: CuCl
(0.01 mmol), phosphorus bidentate ligand (0.01 mmol) and tBuONa
(0.045 mmol) were transferred into a Schlenk tube and dissolved in THF
(1.5 mL) under nitrogen. The suspension was stirred for 30 min and bis(-
pinacolato)diboron (140 mg, 0.55 mmol) was added. The suspension was
stirred for 10 min. Afterwards, a solution of the corresponding a,b-unsa-
turated imine or ketone (0.5 mmol) was added in THF (1 mL). Finally,
MeOH (40 mL, 2 equiv) was added, and the mixture was allowed to stir
at RT for 6 h. The reaction mixture was cooled to low temperatures (08C
and À788C, and the reducing agent (1.5 mmol) was added “in situ” ac-
cording to the reduction procedures (see the Supporting Information).
The solution was treated with NaOH (aq.) (1.0m, 5 mL, 5 mmol) and
H2O2 (aq.) (30% w/v, 500 mL, ca. 4 mmol) and stirred for 3 h at RT to
give a colourless solution, which was partitioned between dichlorome-
thane and saturated NaCl (aq.). The organic phase was dried over
MgSO4 and the organic solvents were evaporated to yield the crude prod-
ucts as cloudy oils, which were purified by column chromatography.
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We thank MEC for funding (CTQ2010–16226 and Consolider-Ingenio
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for our ongoing research program. We also thank Bancaja (P1.1B2008–
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Chem. Eur. J. 2011, 17, 14248 – 14257

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hexylphosphine ethanol adduct; ligand 20: (R)-1-[(S)-2-(diphenyl-
phosphino)ferrocenyl]ethyldi(3,5-xylyl)phosphine;
(aR,aR)-2,2’-bis(a-N,N-dimethylaminophenylmethyl]-(S,S)-1,1’-bis(-
diphenylphosphino)feroocene; ligand 22: (aR,aR)-2,2’-Bis(a-N,N-
(dimethylamino)benzyl)((S,S)-1,1ꢉ-bis[di(3,5-dimethyl-4-methoxy
phenyl)phosphino]ferrocene.
ligand
21:
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[24] C. M. Vogels, P. E. O’Connor, T. E. Phillips, K. J. Watson, M. P.
Shaver, P. G. Hayes, S. A. Westcott, Can. J. Chem. 2001, 79, 1898.
Received: July 6, 2011
Published online: November 10, 2011
Chem. Eur. J. 2011, 17, 14248 – 14257
ꢅ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14257