Design and solid-phase synthesis of chiral acyclic and cyclic diamine ligands

Article abstract of DOI:10.1016/j.tetasy.2005.03.029

A model resin-bound oligoamide functionalized with a rationally designed non-interfering diamine spacer was reduced with borane-THF to provide the corresponding diamine derivative. The latter was transformed using an efficient orthogonal sequence of trans

Full text of DOI:10.1016/j.tetasy.2005.03.029

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1733–1736
Design and solid-phase synthesis of chiral acyclic
and cyclic diamine ligands
Dehe Li and Dennis G. Hall*
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
Received 4 March 2005; accepted 24 March 2005
Abstract—A model resin-bound oligoamide functionalized with a rationally designed non-interfering diamine spacer was reduced
with borane–THF to provide the corresponding diamine derivative. The latter was transformed using an efficient orthogonal
sequence of transformations into two acyclic chiral model diamines 19 and 22 and two cyclic diamine ligands 23 and 24.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Unfortunately, there does not appear to be a universal
structural type of chiral diamine that can accommodate
a wide scope of reactions and substrates. Consequently,
there is great interest in the development of a general ap-
proach for quickly generating highly diverse chiral di-
amine derivatives that could be rapidly evaluated using
parallel combinatorial chemistry techniques.8 Ideally,
such an approach would employ readily available chiral
building blocks, and would be modular and flexible for
accessing several different structural types (e.g., acyclic,
cyclic, N-substitution). To this end, we believed that a
solid-phase approach based on the reduction of chiral
oligoamides and peptides derived from amino acids
would be most advantageous. Our laboratory9,10 and
others11 have optimized a solid-phase synthesis of
polyamines based on the exhaustive reduction of poly-
peptides with diborane followed by an appropriate
work-up (Fig. 2). Very importantly, the stereochemical
integrity of the a-amino acid residues is preserved in this
process. Herein, we report the solid-phase synthesis of
Chiral oligoamine derivatives have been employed as
bases, additives, ligands, and catalysts in a wide variety
of useful synthetic transformations. In particular, a
number of chiral 1,2-diamines of diverse structural types
have been used in several asymmetric reactions.1 Nota-
ble examples of such reactions include enantioselective
enolization with lithiated diamine 1,2 the asymmetric
desymmetrization of meso epoxides with lithiated 2,3
kinetic resolution by palladium-catalyzed aerobic oxid-
ation of secondary alcohols with sparteine 3 as ligand,4
the Noyori ruthenium-catalyzed transfer hydrogenation
using ligands of type 4,5 the allylation of hydrazones
using diamine ligand 5,6 and the organocatalytic aldol
reaction employing 6 (Fig. 1).7
X
Ph
NH
N
R
N
N
N
N
H
n
O
( )n
H
N
1 X = CH2 or NMe
3
2 n = 1 or 2
N
H
SPACER N
R'
H
Ph
Ph
NHR'
R
i. BH3-THF, 65 ˚C
ii. piperidine, 65 ˚C
or I2, AcOH/i-PrEt2N/THF
RHN
N
N
H
4 R = H, R' = SO2Ar
5 R, R' = o-methoxybenzyl
6
n
H
Figure 1. Examples of chiral diamines used in asymmetric synthesis.
N
N
H
SPACER N
R'
H
R
*
Corresponding author. Tel.: +1 780 492 3141; fax: +1 780 492
8231; e-mail: dennis.hall@ualberta.ca
Figure 2. General solid-phase synthesis of polyamines from peptides.
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.029

1734
D. Li, D. G. Hall / Tetrahedron: Asymmetry 16 (2005) 1733–1736
four model chiral diamine ligands, two acyclic ones and
two cyclic derivatives.
desired reaction, and neither acts as a coordinating
group in the desired metal complex. Our design of
diamines 7 is centered on the use of a 4-aminomethyl
piperidine linker, and involves post-cleavage neutraliza-
tion of the piperidinyl anchor as a pivalic amide (Fig. 3).
2. Results and discussion
The harsh conditions for the solid-phase borane-pro-
moted reduction of peptides were found to be compati-
ble with only very few resin linkers.9 Fortunately, trityl
resin-linked amines are particularly reliable substrates,
which can be cleaved easily with a mild acid at the end
of the sequence. Application of this solid-phase strategy
to the synthesis of diamine ligands however, requires
post-cleavage removal or some modification of the
anchoring amine so that it does not interfere with the
It was anticipated that a non-enolizable hindered ter-
tiary amide would be tolerant to a wide range of reac-
tion conditions, such as the use of strong bases and
most oxidants and reductants. Furthermore, the piperid-
inyl spacer would make internal coordination of the
amide carbonyl to a metal unfavorable. For this to hap-
pen, the piperidinyl ring would need to adopt a boatlike
conformation, with a twisted amide and a pseudo-axial
aminomethyl substituent. These unfavorable require-
ments make it rather improbable for the pivaloyl amide
of putative complex 8 to interfere as an internal ligand
and form the tricoordinate complex 9.
O
R1
(CH3)3C
N
N
R2
The preparation of the requisite piperidinyl diamine
linker and its attachment to chlorotrityl polystyrene
are exemplified with the preparation of acyclic
secondary diamine 19 (Scheme 1). Thus, the selective
monoprotection of 10 as bis-N-[1-(4,4-dimethyl-2,6-
dioxocyclohexylidene) ethyl] (Dde) derivative12 11 is fol-
lowed by attachment of the latter to chlorotrityl resin.
Removal of the protecting group using dilute meth-
anolic hydrazine afforded primary amine 13. Amino
acid coupling using Fmoc-Phe-OH, followed by Fmoc
removal and coupling with ortho-toluic acid provided
common diamide precursor 14. Reduction using the
borane-promoted protocol afforded diamine 15. At this
stage, temporary protection of the thus formed amines
as trifluoroacetamides is required in order to allow
orthogonal derivatization of the anchoring secondary
amine. Thus, treatment of 16 with TFA/CH2Cl2 affor-
ded cleaved amine 17. Its acylation as a pivaloyl amide
followed by selective basic hydrolysis of the trifluoro-
N
N
R4
7
8
R3
MLn
O
R1
(CH3)3C
R2
N
N
R4
M
R3
Ln
R4 R2
N
LnM
R1
O
N
R3
(CH3)3C
N
9
Figure 3. Design of chiral diamine ligands with a non-interfering
spacer.
trityl
d, e, f
NH2
NHDde
c
NH2
NHDde
b
a
N
N
HN
HN
12
13
10
11
O
Bn
O
N
Bn
Bn
F3C
N
NH
NH
O
HN
i
HN
g, h
N
F3C
16
N
N
O
15
14
Bn
NH HN
CF3CO2
H2N
Bn
O
Bn
O
F3C
N
F3C
N
l
N
O
O
N
O
k
j
N
F3C
N
F3C
O
t-Bu
t-Bu
18
19
17
Scheme 1. Reaction conditions: (a) 4-(aminomethyl)piperidine (1 equiv), Dde-OH (1.05 equiv), THF, rt, 1 h; (b) trityl chloride resin (1 equiv),
4-(Dde-aminomethyl) piperidine (4 equiv), DIPEA (4 equiv), DCM, rt, 3 h; (c) 2% NH2NH2/DMF, rt, 30 min; (d) HBTU, HOBt, DIPEA, Fmoc-
L-phenylalanine; (e) 20% piperidine/DMF; (f) HBTU, HOBt, DIPEA, o-toluic acid; (g) BH3/THF, 65 ꢁC, 2 days; (h) piperidine, 65 ꢁC, 16 h;
(i) (CF3CO)2O (10 equiv), pyridine (10 equiv), rt, 3 h; (j) 5% TFA/DCM, 30 min; (k) (t-BuCO)2O (3 equiv), Et3N (3 equiv), THF, rt, 6 h; (l) 7%
K2CO3 in MeOH/H2O (v/v 5:2), rt, 24 h.

D. Li, D. G. Hall / Tetrahedron: Asymmetry 16 (2005) 1733–1736
1735
acetamide groups led to the crude diamine ligand 19,
which was purified by acid–base extractions or flash
chromatography (MeOH/CH2Cl2). Acyclic secondary
diamine 19 was obtained in >95% purity (HPLC–UV–
ESMS) and 70% overall yield from chlorotrityl resin.13
were formed. Then, cleavage of the product from the
resin and pivaloylation of the anchoring amine as
described above provided cyclic diamine ligand 23 in
32% overall yield (flash-chromatography, >95% purity
by HPLC–UV–ESMS).13 The seven-membered cyclic
diamine 24 was synthesized using the same approach
with propane 1,3-ditriflate as reagent (22% yield from
chlorotrityl resin, flash-chromatography purification,
>95% purity by HPLC–UV–ESMS).13
Access to acyclic tertiary diamines from the common
precursor 15 was best accomplished by the acylation
of the two secondary amines followed by borane reduc-
tion, as opposed to a direct alkylation approach using
alkyl halides. Thus, double benzoylation and reduction
of 15 to give 20 were followed by resin cleavage and
pivaloylation to afford tertiary diamine ligand 22
(Scheme 2). This product was obtained in 35% overall
yield from chlorotrityl resin after flash-chromatography
purification (>95% purity by HPLC–UV–ESMS).13
3. Conclusion
Herein, we have reported the design and successful eval-
uation of a solid-phase synthetic route for the prepara-
tion of diverse structural types of chiral diamine
ligands. Key to this approach is the use of a non-inter-
fering spacer, and an efficient orthogonal amine protec-
tion scheme. The wide scope of a-amino acids
compatible with the borane-promoted peptide reduction
protocol has already been demonstrated.9 Thus, the use
of functionalized a-aminoacids, coupled with the differ-
ent structural types of diamines accessible using the
approach shown herein, could greatly facilitate the syn-
thesis of parallel libraries of chiral diamine ligands.
These diamines could be rapidly screened in a wide vari-
ety of asymmetric reactions. Work in this direction is in
progress.
Bn
Bn
N
d
N
a, b, c
Bn
N
15
20
Bn
N
Bn
CF3CO2
N
Bn
N
N
Bn
Bn
e
Bn
N
H2N
O
21
t-Bu
22
References
Scheme 2. Reaction conditions: (a) benzoyl chloride (10 equiv),
DIPEA (10 equiv), THF, rt, 16 h; (b) 1 M BH3–THF (20 equiv),
THF, 65 ꢁC, 3 days; (c) piperidine, 65 ꢁC, 16 h; (d) 5% TFA/DCM,
30 min; (e) (t-BuCO)2O (3 equiv), Et3N (3 equiv), THF, rt, 6 h.
1. Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int.
Ed. 1998, 37, 2580–2627.
2. Aoki, K.; Noguchi, H.; Tomioka, K.; Koga, K. Tetra-
hedron Lett. 1993, 34, 5105–5108.
3. Bertilsson, S. K.; So¨dergren, M. S.; Andersson, P. G.
J. Org. Chem. 2002, 67, 1567–1573.
4. Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem.
Soc. 2001, 123, 7475–7476.
5. Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–
102.
6. Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2003, 42, 3927–3930.
Next, two model cyclic diamines, 23 and 24, were tar-
geted from the common resin-bound precursor 15
(Scheme 3). Chiral piperazinyl diamine 23 was synthe-
sized by the slow addition of ethane 1,2-ditriflate to resin
15 in the presence of HunigÕs base. Analysis of the
cleaved product by HPLC–ESMS confirmed that no
cross-linked derivatives, nor any other side-products,
7. Mase, N.; Tanaka, F.; Barbas, C. F. Angew. Chem., Int.
Ed. 2004, 43, 2420–2423.
Bn
8. For a review, see: Lavastre, O.; Bonnette, F.; Gallard, L.
Curr. Opin. Chem. Biol. 2004, 8, 311–318.
9. Manku, S.; Laplante, C.; Kopac, D.; Chan, T.; Hall, D. G.
J. Org. Chem. 2001, 66, 874–885.
N
N
a, b, c
15
N
10. Application to macrocyclic amine ligands: Kopac, D.;
Hall, D. G. J. Comb. Chem. 2002, 4, 251–254.
11. Nefzi, A.; Giulianetti, M. A.; Houghten, R. A. Tetrahe-
dron 2000, 56, 3319–3326, and references cited therein.
12. Bycroft, B. W.; Chan, W. C.; Chhabra, S. R.; Hone, N. D.
J. Chem. Soc., Chem. Commun. 1993, 778–779.
13. Characterization of model diamine ligands. Compound
19: TLC: Rf = 0.42 (CH2Cl2–MeOH = 8:1). IR (CH2Cl2
O
t-Bu
23
Bn
N
d, b, c
N
15
O
N
.
cast film): 1626, 2920, 3024, 3311 cmꢀ1 1H NMR
t-Bu
(500 MHz, CD3OD) d (ppm): 0.95–1.05 (m, 2H), 1.25 (s,
9H), 1.58–1.70 (m, 3H), 2.25 (s, 3H), 2.27 (dd, J = 6.5,
11.8 Hz, 1H), 2.31 (dd, J = 6.6, 11.8 Hz, 1H), 2.46 (dd,
J = 7.9, 12.0 Hz, 1H), 2.58 (dd, J = 3.9, 12.0 Hz, 1H), 2.65
(dd, J = 9.4, 15.7 Hz, 1H), 2.77 (app. t, J = 11.7 Hz, 2H),
2.88–2.95 (m, 2H), 3.68 (d, J = 12.9 Hz, 1H), 3.79 (d,
J = 12.9 Hz, 1H), 4.32 (br s, 1H), 4.35 (br s, 1H), 7.10–7.14
24
Scheme 3. Reaction conditions: (a) TfOCH2CH2OTf (5 equiv),
DIPEA (8 equiv), DCM, 0 ꢁC, 5 h, then rt, 10 h; (b) 5% TFA/DCM,
30 min; (c) (t-BuCO)2O (3 equiv), Et3N (3 equiv), THF, rt, 6 h; (d)
TfO(CH2)3OTf (5 equiv), DIPEA (8 equiv), DCM, 0 ꢁC, 5 h, then rt,
10 h.

1736
D. Li, D. G. Hall / Tetrahedron: Asymmetry 16 (2005) 1733–1736
(m, 3H), 7.17–7.22 (m, 4H), 7.25–7.30 (m, 2H). 13C NMR
(100 MHz, CD3OD) d (ppm): 19.1 (CH3), 28.8 (CH3),
31.80 (CH2), 31.82 (CH2), 37.4 (CH), 39.8 (C), 40.3 (CH2),
46.5 (CH2), 46.6 (CH2), 50.0 (CH2), 53.9 (CH2), 56.1
(CH2), 59.2 (CH), 126.9 (CH), 127.4 (CH), 128.4 (CH),
130.31 (CH), 130.33 (CH), 131.4 (CH), 137.6 (C), 139.1
(C), 140.5 (C), 178.3 (CO). LC–MS: Zorbax SB-C8
reverse-phase column (4.6 · 50 mm, 3.5 lm), solvent:
CH3CN (0.1% TFA)/water (0.1% TFA) 5:95–85:15 over
5 min then held for 7 min, flow rate: 0.5 mL/min, 25 ꢁC,
UV-DAD (210 and 254 nm) and ESMS. Rt = 9.669 min,
Compound 23: TLC: Rf = 0.30 (hexanes–EtOAc = 4:1).
1
IR (CH2Cl2 cast film): 1628, 2924, 3023 cmꢀ1. H NMR
(500 MHz, CDCl3) d (ppm): 1.02–1.11 (m, 2H), 1.28 (s,
9H), 1.58–1.69 (m, 1H), 1.76 (d, J = 13.0 Hz, 1H), 1.82 (d,
J = 13.0 Hz, 1H), 2.02 (dd, J = 7.0, 12.2 Hz, 1H), 2.09 (dd,
J = 7.5, 12.2 Hz, 1H), 2.14–2.26 (m, 2H), 2.26–2.33 (m,
1H), 2.38 (s, 3H), 2.33–2.48 (m, 2H), 2.68–2.82 (m, 4H),
2.83–2.92 (br t, 1H), 3.06 (d, J = 11.7 Hz, 1H), 3.50 (d,
J = 12.0 Hz, 1H), 3.94 (d, J = 12.5 Hz, 1H), 4.39 (br s,
2H), 7.10–7.35 (m, 9H). 13C NMR (125 MHz, CDCl3) d
(ppm): 19.3 (CH3), 28.5 (CH3), 31.1 (CH2), 31.3 (CH2),
33.8 (CH), 38.7 (C), 45.28 (CH2), 45.36 (CH2), 45.39
(CH2), 53.7 (CH2), 56.7 (CH2), 60.3 (CH), 64.5 (CH2),
125.5 (CH), 125.8 (CH), 126.9 (CH), 128.3 (CH), 129.2
(CH), 129.6 (CH), 130.3 (C), 137.1 (C), 137.5 (C),
140.5 (C), 176.1 (CO). LC–MS: see diamine 19 for condi-
tions, Rt = 13.780 min, % purity >98%. m/z (M+1)+ =
462.3. HR-MS for C30H43N3O: m/z (M+H)+ calcd
%
purity >99%. m/z (M+1)+ = 436.3. HR-MS for
C28H42N3O: m/z (M+H)+ calcd 436.3328 found
25
436.3323. ½aꢁD ¼ þ17:3 (c 0.070, CHCl3).
Compound 22: TLC: Rf = 0.37 (hexanes–EtOAc = 2:1).
IR (CH2Cl2 cast film): 1627, 2849, 2925, 3025 cmꢀ1 1H
.
NMR (500 MHz, CDCl3) d (ppm): 0.72 (ddd, J = 3.4,
12.2, 12.2 Hz, 1H), 0.89 (ddd, J = 3.4, 12.2, 12.2 Hz, 1H),
1.29 (s, 9H), 1.48–1.58 (m, 1H), 1.63 (d, J = 12.2 Hz, 1H),
1.72 (d, J = 12.3 Hz, 1H), 2.10 (s, 3H), 2.10 (dd, J = 5.0,
12.8 Hz, 1H), 2.16 (dd, J = 5.7, 12.8 Hz, 1H), 2.49 (dd,
J = 8.2, 12.6 Hz, 1H), 2.61–2.71 (m, 2H), 2.75 (dd, J = 4.1,
12.7 Hz, 1H), 2.77 (dd, J = 8.7, 13.9 Hz, 1H), 2.92 (dd,
J = 5.5, 13.9 Hz, 1H), 3.07 (m, 1H), 3.35 (d,J = 13.6 Hz,
1H), 3.62 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.5 Hz, 1H),
3.65 (s, 2H), 3.73 (d, J = 13.7 Hz, 1H), 4.19 (br d,
J = 12.0 Hz, 1H), 4.28 (br d, J = 12.8 Hz, 1H), 7.02–7.32
(m, 19H). 13C NMR (125 MHz, CDCl3) d (ppm): 19.3
(CH3), 28.4 (CH3), 30.8 (CH2), 31.0 (CH2), 34.5 (CH),
35.9 (CH2), 38.7 (C), 45.0 (CH2), 45.2 (CH2), 51.1 (CH2),
54.0 (CH2), 55.4 (CH2), 58.3 (CH), 60.5 (CH2), 61.1
(CH2), 125.6 (CH), 125.8 (CH), 126.6 (CH), 126.8 (CH),
126.9 (CH), 128.0 (CH), 128.1 (CH), 128.9 (CH), 129.0
(CH), 129.1 (CH), 129.6 (CH), 130.1 (CH), 136.8 (C),
137.3 (C), 139.7 (C), 139.9 (C), 141.1 (C), 176.0 (CO). LC–
MS: see diamine 19 for conditions, Rt = 13.155 min,
25
462.3479, found 462.3476. ½aꢁD ¼ þ49:5 (c 0.012, CHCl3).
Compound 24: TLC: Rf = 0.24 (hexanes–EtOAc = 1:1).
IR (CH2Cl2 cast film): 1628, 2924, 3023, 3059 cmꢀ1 1H
.
NMR (400 MHz, CDCl3) d (ppm): 0.98–1.10 (m, 2H), 1.29
(s, 9H), 1.44–1.54 (m, 1H), 1.55–1.65 (m, 1H), 1.69 (d,
J = 13.1 Hz, 1H), 1.75–1.90 (m, 2H), 2.20 (dd, J = 8.1,
12.4 Hz, 1H), 2.26 (dd, J = 6.4, 12.4 Hz, 1H), 2.31 (s, 3H),
2.45 (dd, J = 7.2, 13.8 Hz, 1H), 2.52–2.78 (m, 7H), 2.85
(dd, J = 5.3, 13.4 Hz, 1H), 2.90–3.04 (m, 2H), 3.78 (d,
J = 12.2 Hz, 1H), 3.86 (d, J = 12.2 Hz, 1H), 4.36 (br s,
1H), 4.39 (br s, 1H), 7.06–7.34 (m, 9H). 13C NMR
(125 MHz, CDCl3) d (ppm): 19.2 (CH3), 28.5 (CH3), 27.0
(CH2), 31.10 (CH2), 31.14 (CH2), 35.2 (CH), 38.6 (CH2),
38.7 (C), 45.3 (CH2), 45.4 (CH2), 48.8 (CH2), 55.9 (CH2),
56.6 (CH2), 58.5 (CH2), 64.5 (CH), 65.1 (CH2), 125.4
(CH), 125.7 (CH), 126.7 (CH), 128.1 (CH), 129.2 (CH),
129.5 (CH), 130.2 (CH), 137.2 (C), 138.2 (C), 140.8 (C),
176.1 (CO). LC–MS: see diamine 19 for conditions,
Rt = 9.170 min, % purity >98%, m/z (M+H)+ = 476.4.
HR-MS for C31H45N3O: m/z (M+H)+ calcd 476.3635,
%
purity >95%. m/z (M+1)+ = 616.4. HR-MS for
C42H54N3O m/z (M+H)+ calcd 616.4261, found
25
25
616.4265. ½aꢁD ¼ ꢀ47:3 (c 0.012, CHCl3).
found: 476.3635. ½aꢁD ¼ ꢀ21:1 (c 0.013, CHCl3).