Phosphoramidite ligands for the enantioselective iridium-catalyzed asymmetric hydroboration of meso-bicyclic hydrazines

Article abstract of DOI:10.1016/j.tetasy.2005.09.023

Twenty phosphoramidites or phosphite ligands have been screened in the iridium-catalyzed hydroboration of a meso-bicyclic hydrazine. Enantiomeric excesses of up to 67% could be obtained with moderate to good yields. Although bidentate ligands are believed to be more efficient in transition metal-catalyzed asymmetric hydroboration, this study shows that monodentate ligands have to be investigated for further development of this type of reaction.

Full text of DOI:10.1016/j.tetasy.2005.09.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3672–3675
Phosphoramidite ligands for the enantioselective
iridium-catalyzed asymmetric hydroboration
of meso-bicyclic hydrazines
a,
a
b
*
Alexandre Alexakis, Damien Polet, Chlo e´ e Bournaud,
b
b,
*
Martine Bonin and Laurent Micouin
a
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland
Laboratoire de Chimie Th e´ rapeutique, UMR 8638 associ e´ e au CNRS et a` l’Universit e´ Ren e´ Descartes, Facult e´ des Sciences,
Pharmaceutiques et Biologiques 4, av de l’Observatoire, 75270 Paris cedex 06, France
b
Received 30 July 2005; revised 14 September 2005; accepted 19 September 2005
Available online 9 November 2005
Abstract—Twenty phosphoramidites or phosphite ligands have been screened in the iridium-catalyzed hydroboration of a meso-
bicyclic hydrazine. Enantiomeric excesses of up to 67% could be obtained with moderate to good yields. Although bidentate ligands
are believed to be more efficient in transition metal-catalyzed asymmetric hydroboration, this study shows that monodentate ligands
have to be investigated for further development of this type of reaction.
ꢀ
2005 Elsevier Ltd. All rights reserved.
1
. Introduction
1) CatBH,
% [IrCODCl]2
L, THF, 0 ºC
1
HO
The transition metal-catalyzed asymmetric hydrobora-
tion reaction has been intensively studied over the last
two decades. Excellent regio- and enantioselectivities
have been achieved, mainly on styrene or substituted
styrenes, and more recently on prochiral cycloprop-
NCO2Bn
NCO2Bn
N
N
2
) H2O2
CO2Bn
1
CO2Bn
1
2
PPh2
1
L =
N
2
enes. Despite numerous studies on the use of different
ee = 71%
yield = 76%
metallic precatalysts and ligands, the best results are
generally obtained with rhodium as the metal of choice,
associated with P,P or P,N ligands. However, the scope
of this asymmetric transformation is still very substrate
dependent, and new reactions conditions have yet to be
investigated.
Scheme 1. Asymmetric hydroboration of bicyclic hydrazines.
Ir-catalyzed reactions can occur with interesting enantio-
selectivities with this class of ligands. Since the use of
5
monodentate ligands in asymmetric hydroboration is
poorly documented, we investigated the potential of
chiral phosphoramidite ligands in inducing asymmetry
in such a transformation. We herein report our investi-
gations on this topic.
We have recently described the iridium-catalyzed
hydroboration of various bicyclic meso-hydrazines 1
with several bidentate ligands, leading to alcohol 2 with
6
3
enantiomeric excesses up to 71% (Scheme 1).
Phosphoramidites are now well established ligands for
4
numerous asymmetric transformations. Among them,
2. Results and discussion
Preliminary experiments were conducted with binaph-
thol-based phosphoramidites L1–L3 (Table 1). As most
previous studies have shown that one full equivalent of a
bidentate ligand is needed, we started our investigations
*
Corresponding authors. Tel.: +41 22 37 96522; fax: +41 22 37 93215
A.A.); tel.: +33 1 53 73 97 51; fax: +33 1 43 29 14 03 (L.M.); e-mail
addresses: alexandre.alexakis@chiorg.unige.ch; laurent.micouin@
univ-paris5.fr
(
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.09.023

A. Alexakis et al. / Tetrahedron: Asymmetry 16 (2005) 3672–3675
Table 2. Screening in the biphenol series
3673
Table 1. Screening in the binaphthol series
) CatBH,
% [IrCODCl]2
1
1
1) CatBH,
1% [IrCODCl]2
L, THF, 0 ºC, 7 h
HO
HO
L, THF, 0 ºC, 7 h
NCO2Bn
NCO2Bn
NCO2Bn
NCO2Bn
N
N
N
N
2
) H O
CO Bn
2) H O
2
2
CO Bn
CO2Bn
2
2
2
CO2Bn
2
1
2
1
2
R1
P N
R1
1
2
R2
R = H, R = H, (S)-BINOL : L1
O
O
1
2
R = Ph, R = Me, (R)-BINOL : L2
R2
R1
R4
R2
R1
R2
1
2
R = Ph, R = Me, (S)-BINOL : L3
R3
O
O
O
P N
P N
a
b
c
O
R1
3
Entry
Ligand
L/Ir
ee (%)
Yield (%)
3
R
1
2
3
L1
L2
L3
2
2
2
2
57
25
32
R2
R2
R1
4
d
R
À9
18
1
2
4
R = R = R = R = H, : L4
R = R = R = H, R = Et : L5
R = R =Me, R = R = H : L6
a
b
c
1
2
3
4
Experimental conditions: see Section 4.
Determined by chiral HPLC.
Isolated yield of pure compound.
ent-2 was the major enantiomer.
1
2
3
4
1
2
R = R = Cl : L12
1
2
3
4
1
2
R = R = R = H, R = OMe : L7
R = R = Me : L13
1
2
3
4
d
R = OMe, R = Me, R = R = H : L8
1 2 3 4
1
R = R = Cl, R = R = H : L9
2
3
4
R = TMS, R = H, R = R = H : L10
1
2
3
4
R = R =Br, R = R = H : L11
a
b
c
with 2 equiv of a monodentate ligand. In all cases, good
conversion was obtained, although with little, if any,
enantioselectivity. A small match–mismatch effect could
be observed with ligands bearing two stereogenic ele-
ments (entries 2 and 3).
Entry
Ligand
L/Ir
ee (%)
Yield (%)
d
1
2
3
4
5
6
7
8
9
L4
L4
1
2
3
2
1
2
1
2
1
2
3
2
2
2
2
À4
55
53
54
46
24
17
62
41
42
48
40
17
45
75
41
36
48
31
7
L4
L5
L6
L6
We then turned our attention to biphenol-based ligands
25
34
0
12
50
59
20
46
55
40
7
L4–L13 (Table 2). The first experiments, conducted
L7
L7
7
a
with ligand L4, clearly showed the influence of the chi-
rality of the amine part of the ligand in the enantioselec-
tivity of the hydroboration, since ees up to 48% could be
obtained with these phosphoramidites devoid of axial
chirality. Changing the ligand/metal ratio (entries 1–3)
had a strong influence on the enantioselectivity. As
expected, the best results were usually obtained with
L8
L9
10
11
12
13
14
15
L9
L10
L11
L12
L13
8
two ligands for every metallic center. The only
a
b
c
Experimental conditions: see Experimental.
Determined by chiral HPLC.
Isolated yield of pure compound.
ent-2 was the major enantiomer.
exception is L7, which could be considered as a biden-
tate ligand (entries 7 and 8). The other potential biden-
tate ligand L8 also led to low selectivity (entry 9). The
introduction of larger alkyl groups on the amine part
d
(
L5, entry 4) or increasing the steric hindrance of the
biphenol moiety (L6, entries 5 and 6) did not lead to a
significant improvement on enantioselectivity. However,
the electronic properties seemed to play an important
role, since a dramatic improvement was observed with
the hydrazine-alcohol in 64% yield with a 67% enantio-
1
0
meric excess (entry 7). Changing to a cationic iri-
dium precatalyst led to similar results (entry 8), whereas
no reaction occurred at lower temperature or with
7
b
chloro-substituted biphenols (L9, entries 10 and 11).
[Rh(COD)Cl] as a rhodium precatalyst.
2
The replacement of the usual bis (1-phenyl-ethyl)-amine
7
c
by the corresponding 2-naphthalenyl derivatives also
had some positive effect on the enantioselectivity (L12
and L13, entries 14, 15).
3. Conclusion
We have shown in this work that various chiral non-
racemic phosphoramidites or phosphite ligands are effi-
cient in the Ir-catalyzed asymmetric hydroboration of
meso-hydrazines. Although promising ees up to 67%
could be obtained with bidentate amino-phosphinites
ligands, the use of phosphoramidite ligands in such a
transformation can deliver the final compound with
enantiomeric excesses between 50% and 60% with chemi-
cal yields up to 75%. These results clearly indicate that
chiral non-racemic monodentate ligands have to be
Since the best enantioselectivities were generally
obtained with 2 equiv of ligand per metallic center, other
potentially bidentate ligands were investigated (Table 3).
Once again, very different results were obtained when
varying the substitution pattern of the amine moiety.
1
The nature of the R group seems to greatly influence
the enantioselectivity of the hydroboration (L18 and
L19, entries 5 and 6). Finally, interesting results were
9
obtained with amino-phosphite ligand L20, leading to

3674
A. Alexakis et al. / Tetrahedron: Asymmetry 16 (2005) 3672–3675
Table 3. Screening of bidentate ligands
) CatBH,
% [IrCODCl]2
chromatography (cyclohexane/ethyl acetate = 50:50)
afforded 2 as a colorless oil. 5-Hydroxy-2,3-diaza-bicy-
1
1
clo[2.2.1]heptane-2,3-dicarboxylic acid dibenzyl ester 2.
HO
1
H NMR (300 MHz, DMSO-d , 70 ꢁC) d 1.46 (dt,
L, THF, 0 ºC, 7 h
NCO2Bn
6
NCO2Bn
N
J = 13.7, 2.5 Hz, 1H), 1.54 (d, J = 10.5 Hz, 1H), 1.98
N
2
) H2O2
CO Bn
CO2Bn
2
(d, J = 10.5 Hz, 1H), 1.98–2.04 (m, 1H), 4.28 (s, 1H),
1
2
4
.52 (s, 1H), 4.68 (s, 1H), 5.16 (m, 4H), 7.35 (m, 10H)
1
3
C NMR (75 MHz, CDCl ) d 34.0, 38.0 (br), 59.6,
3
6
4.3, 68.1, 68.2, 70.4, 128.0, 128.3, 135.8, 135.9, 155.0
Ph Ph
(br) IR (neat) 3453, 3063, 3032, 2952, 1760, 1633,
1
O
O
+
R
N
O
O
O
1496. MS: 400 (M+18), 383 (MH ), 339, 249.
Anal. Calcd for C H N O : C 65.96; H 5.80; N 7.33.
2
P
O
P
N R
O
21 22
2
5
Ph Ph
N
Found C 65.79, H 5.96, N 7.33. [a] = À7.55 (c 1.06,
D
CH Cl ).
2
2
1
2
R = R = Me : L14
L20
Enantioselectivities were determined by chiral HPLC:
Chiralpack AD column (0.46 cm I.D. · 25 cm),
equipped with a Chiralpack AD pre-column (0.46 cm
1
2
R = Me, R = Bn : L15
1
2
R = Bn, R = Me : L16
1
2
R = cHex, R = Me : L17
À1
1
Ph
Ph
2
I.D. · 5 cm). Flow: 0.8 mL min , detection: k = 220 nm.
R =
R = Me : L18
À1
Samples were injected at a 0.1 g L concentration with
a 20 lL inlet. hexane/iPrOH = 80/20, retention time-
s = 15.98 min (1S,4R,5R), 17.82 min (1R,4S,5S).
1
2
R =
R = Me : L19
a
b
c
Entry
Ligand L/Ir
ee (%)
Yield (%)
1
2
3
4
5
6
7
8
L14
L15
L16
L17
L18
L19
L20
L20
1
1
1
1
1
1
1
1
18
1
23
62
7
54
31
68
11
8
11
64
71
Acknowledgements
This work was supported by a French-Swiss ÔGermaine
de StaelsÕ program. C.B. thanks the MRT for a grant,
and A.A. and D.P. thank the Swiss National Science
Foundation (grant No. 200020-105368) for financial
support.
55
67
d
64
a
b
c
Experimental conditions: see Section 4.
Determined by chiral HPLC.
Isolated yield of pure compound.
Ir(COD)BF was used in this study.
4
d
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3
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7
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5
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2
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A. Alexakis et al. / Tetrahedron: Asymmetry 16 (2005) 3672–3675
3675
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9