Chiral diamines for asymmetric synthesis: An efficient RCM construction of the ligand core of (-)- and (+)-sparteine

Article abstract of DOI:10.1016/j.tetlet.2005.08.106

An efficient RCM-based approach was applied to the total asymmetric synthesis of a tricyclic diamine and, formally, of its enantiomer, widely known as efficient and versatile chiral ligands of the sparteine-like type.

Full text of DOI:10.1016/j.tetlet.2005.08.106

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7121–7123
Chiral diamines for asymmetric synthesis: an efficient
RCM construction of the ligand core of (ꢀ)- and (+)-sparteine
Bruno Danieli, Giordano Lesma,* Daniele Passarella,
Alessandro Sacchetti and Alessandra Silvani
Dipartimento di Chimica Organica e Industriale e Centro Interdisciplinare Studi biomolecolari e applicazioni Industriali (CISI),
`
Universita degli Studi di Milano, via G. Venezian 21, 20133 Milano, Italy
Received 12 July 2005; revised 12 August 2005; accepted 22 August 2005
Abstract—An efficient RCM-based approach was applied to the total asymmetric synthesis of a tricyclic diamine and, formally, of
its enantiomer, widely known as efficient and versatile chiral ligands of the sparteine-like type.
Ó 2005 Elsevier Ltd. All rights reserved.
The quinolizidine alkaloid (ꢀ)-sparteine 11 (Fig. 1) is a
chiral bidentate ligand with broad applicability. Of par-
ticular interest has been its complex with sec-butyl-
lithium, which Hoppe and Hense2 first showed could
induce high enantioenrichments in lithiation–electro-
philic quench reactions.3 After pioneering applications
in very effective asymmetric deprotonation of N-Boc
pyrrolidine,4 this diamine was used for dynamic resolu-
tions5 and deprotonations6 of phosphine–boranes,
asymmetric additions of alkyllithiums to imines,7 asym-
metric carbometallations8 and enantioselective a-lithia-
tions of achiral epoxides.9
The impact of sparteine as a chiral ligand in organoli-
thium chemistry has been incredible and, more recently,
the use has been extended to magnesium, for desymmet-
rization of anhydrides with carbon nucleophiles such as
Grignard reagents,10 and to palladium, for palladium-
catalyzed oxidative kinetic resolutions of secondary
alcohols.11
Due to the lack of ready availability of (+)-sparteine
from natural sources, there is a need to develop ligands
that behave in an enantiocomplementary fashion to (ꢀ)-
sparteine. Our efforts in this field allowed to achieve the
synthesis of various chiral bicyclic and tricyclic diamines
embodying the bispidine (3,7-diazabicyclo[3.3.1]nonane)
framework.12 In particular, in a previous report,13 we
recently described the synthesis of enantiopure diamine
ligands 2 and 3, which constitute the ABC and BCD tri-
cyclic portions of (ꢀ)-sparteine, via imino Diels–Alder
reactions mediated by a catalytic amount of scandium
triflate. The synthesis of 2 and 3 and their examination
as ligands in the enantioselective deprotonation of N-
Boc pyrrolidine provided insight into the important fea-
tures relevant to the stereoselectivity by means of sparte-
ine surrogates. The capacity of bidentate coordination
of a cation is retained in the ABC ring system of 2, while
ring D does not allow a favourable conformation for
coordination in the BCD ring system of 3.
H
N
A
B
D
C
N
H
(-)-Sparteine (1)
H
N
CH3
N
N
H
N
H3C
2
3
Figure 1.
After these preliminary results, OÕBrien et al. fully dem-
onstrated the efficiency of diamine ent-2 as a (+)-sparte-
ine equivalent in a wide range of test reactions and
provided a rapid access to this ligand from the natural
Keywords: RCM reactions; Asymmetric synthesis; Chiral ligands;
Sparteine.
*
Corresponding author. Tel.: +39 02 50314079; fax: +39 02
50314078; e-mail: giordano.lesma@unimi.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.106

7122
B. Danieli et al. / Tetrahedron Letters 46 (2005) 7121–7123
occurring alkaloid (ꢀ)-cytisine.14 Quite recently, Kann
et al. still further expanded the field of applicability of
ent-2 to the desymmetrization of prochiral phosphine
boranes.15
N3
OAc
OAc
H
H
OHC
4
N
Cbz
N
Ref. 16
Cbz
In connection with our recent results on the asymmetric
synthesis of quinolizidine alkaloids,16 we devised an
innovative strategy for the preparation of 2 in both
enantiomeric forms, relied on a RCM reaction as the
key step. We report here our approach to ent-2.
8
7
Scheme 2.
N3
In order to ensure a formal access to both the enantio-
mers of the target compound, our retrosynthetic plan
(Scheme 1) features the chiral cis-piperidine-3,5-dimeth-
anol monoacetate 4 as a suitable starting material. In
fact, this compound, together with its enantiomer, is
readily available by means of biocatalytic asymmetriza-
tion of appropriate CS-symmetric forms.17 The first dis-
section of ring B (N1–C10 bond) in ent-2 yields to the
decahydro-[2,30]-bipyridine derivative 5, which in turn
could be accessed from the key intermediate 6. In fact,
the cleavage of the C3–C4 bond (dissection of ring A)
in the retrosynthetic pathway reveals that 5 would in
principle be obtained by a ring closing metathesis reac-
tion on the N-allyl-(but-3-enyl)-carbamate moiety of 6.
Finally, intermediate 6 could in turn be fashioned by
selective functional group modification of the chiral
cis-piperidine-3,5-dimethanol monoacetate 4.
Boc
H
OAc
N
OAc
H
H
H
d
a, b, c
N
N
Cbz
7
Cbz
6
Boc
H
NH
OAc
OX
H
N
H
H
e, f
N
Cbz
N
Cbz
9 X = H
10 X = Ms
5
g
N
i, j
h
ent-2
H
H
H
It should be noted that slight modifications of the syn-
thetic sequence affording the precursor of RCM key
step, would make this approach amenable for the syn-
thesis of related compounds differing for the size of ring
A.
N
Cbz
11
Scheme 3. Reagents and conditions: (a) Ph3P, THF, then H2O (75%);
(b) (Boc)2O, TEA, CH2Cl2 (78%); (c) 80% NaH, allyl bromide, DMF
(66%); (d) first generation GrubbsÕ catalyst, CH2Cl2, rt (89%); (e) 10%
TFA, CH2Cl2 (98%); (f) NaOH 0.5 M, THF (98%); (g) mesyl chloride,
TEA, CH2Cl2 (62%); (h) TEA, CH2Cl2, reflux (67%); (i) H2, Pd/C,
10%, AcOEt (96%); (j) NaCNBH3, CH2Oaq, THF (66%).
We recently reported16 a concise entry to azide 7, starting
from 4, by means of an highly diastereoselective allyl-
ation of intermediate aldehyde 8 with (+)-allyldiisopino-
campheylborane, as the key step (Scheme 2).
allyl bromide, to afford 6 in 47% overall yield from 7.
Ring closing metathesis on 6 was performed with first-
generation GrubbsÕ ruthenium catalyst (benzylidene-
Conversion of azide 7 to ent-2 was straightforward
(Scheme 3). Reduction of azide with PPh3–H2O afforded
the corresponding amine, which was directly protected
as Boc carbamate and allowed to react with NaH and
bis(tricyclohexylphosphine)dichlororuthenium)
and
gave the decahydro-[2,30]-bipyridine derivative 5 almost
quantitatively.
A
3
2
N1
8
4
2
Closure of ring B was performed by a standard three
steps sequence, involving Boc deprotection, hydrolysis
of acetate (5 ! 9) and cyclization upon mesylate activa-
tion (9 ! 10 ! 11). Finally, ent-2 was achieved from 11,
by means of hydrogenation of the C3–C4 double bond
with concomitant Cbz deprotection, followed by a
reductive methylation at the N12 atom, in the presence
of NaBH3CN and formaldehyde.18 Pure ent-2 was
found to have identical physical and spectroscopic prop-
erties to those reported in the literature.14 {[a]D +25.4 (c
0.5, EtOH), lit. [a]D +26.5 (c 1, EtOH)}.
Boc
H
3
OAc
N
5
10
9
H
B
4
H
H
6
7
H
N
13
11
12 N
Me
ent-2
Cbz
C
5
Boc
H
OH
OAc
OAc
N
H
N
Cbz
N
Cbz
The efficiency of diamine ent-2 as chiral ligand is by now
quite established for many different kinds of reactions.
Since the recovery and reuse of a chiral ligand or cata-
lyst is an important feature in asymmetric reactions,
4
6
Scheme 1. Retrosynthetic pathway.

B. Danieli et al. / Tetrahedron Letters 46 (2005) 7121–7123
7123
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1057.
studies are in progress towards the synthesis of a poly-
mer anchored version of 2 and ent-2 and the evaluation
of the supported ligandsÕ retained activity.
References and notes
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Silvani, A. Tetrahedron: Asymmetry 2003, 14, 2453–2458;
(b) Asymmetric Synthesis of Molecules Containing the
Bispidine Core, Lesma, G.; Sacchetti, A.; Silvani, A.;
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of Nitrogen Heterocycles, Research Signpost Ed., 2005,
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