Synthesis of syn-vicinal diamines via the stereoselective allylation of acyclic chiral α-amino aldimines

Article abstract of DOI:10.1016/j.tetlet.2018.12.021

The stereoselective allylation of acyclic chiral α-amino aldimines affording vicinal diamines, mediated by various Lewis acids (TiCl₄, SnCl₄, MgBr₂·OEt₂, BF₃·OEt₂, ZnCl₂), is des

Full text of DOI:10.1016/j.tetlet.2018.12.021

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of syn-vicinal diamines via the stereoselective allylation of
acyclic chiral a-amino aldimines
In-Soo Myeong a,1, Changyoung Jung a,1, Won-Hun Ham a,b,
⇑
a School of Pharmacy, Sungkyunkwan University, Seobu-ro 2066, Suwon-si, Gyeonggi-do 16419, Republic of Korea
b Yonsung Fine Chemicals Co., Ltd., Sujeong-ro 207, Jangan-myeon, Hwaseong-si, Gyeonggi-do 18581, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective allylation of acyclic chiral a-amino aldimines affording vicinal diamines, mediated by
Received 27 October 2018
Revised 7 December 2018
Accepted 10 December 2018
Available online xxxx
various Lewis acids (TiCl4, SnCl4, MgBr2ÁOEt2, BF3ÁOEt2, ZnCl2), is described. The TiCl4-mediated allylation
of an -N-Boc aldimine afforded the allylation product with syn-selectivity, which in turn was used for
the synthesis of an intermediate of an oseltamivir derivative.
a
Ó 2018 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective allylations
Vicinal diamine
TiCl4
Aldimine
Oseltamivir derivative
Introduction
In order to obtain chiral 1,2-diamino compounds, the develop-
ment of stereoselective diamination methods is necessary. General
synthetic approaches to syn-vicinal diamines are illustrated in
Fig. 2.
1,2-Diamino functionalities are prevalent structural motifs in
natural products. Due to their potent biological activities, several
vicinal diamine compounds have been employed as medicinal
agents (Fig. 1) [1]. It is believed that the amine functionality plays
an important role in hydrogen bonding and enzyme folding [2].
Biotin (or vitamin H), which features a 1,2-diamino functionality
in an imidazolidinone ring, is an important cofactor for carboxylase
enzymes. Penicillins and cephalosporins are well-known antibi-
Classic methods, including reductive coupling and aziridine
opening reactions, have been extensively studied and applied to
the synthesis of various 1,2-diamino compounds [1b,4b]. Two
methods are available for obtaining syn-vicinal diamines via the
direct diamination of alkenes. One reliable method is asymmetric
hydroxylation followed by displacement of the oxygen atoms by
amines. In particular, osmium-based catalyzed reactions have
been well-established by the Sharpless group [1b,5]. The other
method, which is recently developed, involves a metal-catalyzed
stereoselective diamination. Since the direct diamination can be
regarded as the most straightforward and environmentally
benign route, articles reviewing this methodology have
frequently appeared [5,4] The diaza-Cope rearrangement [6] and
aza-Michael addition [1b] are good alternatives to synthesize 1,2-
diamine functionalities. Moreover, nitro-Mannich reactions, also
known as aza-Henry reactions, are widely researched methods
[7]. The stereoselectivity in such nitro-Mannich reactions strongly
depends on the choice of chiral bulky ligands. On the other hand,
otics possessing
Oxaliplatin is a cancer medication that features a Pt(II) center
and bidentate 1,2-diaminocyclohexane. Oseltamivir and
a 2,3-diamino carboxylic acid moiety [1b].
a
zanamivir, which also bear 1,2-diamino functionalities, are
neuraminidase inhibitor antiviral agents used for the treatment
and prevention of influenza [2,3]. Vicinal diamine functionalities
can also be found in various natural alkaloids, ranging from small
and simple molecules to large and structurally intriguing ones
[4]. They have become important synthetic targets not only
because of their structural complexities but also due to their signif-
icant biological activities.
the nucleophilic addition of
a-amino aldimines has remained lar-
gely unexplored. The nucleophilic addition of
a-amino aldimines
derived from Garner’s aldehyde has been reported by Fujisawa
[8] and Chattopadhyay [9], while the nucleophilic addition of acyc-
⇑
Corresponding author at: School of Pharmacy, Sungkyunkwan University,
Seobu-ro 2066, Suwon-si, Gyeonggi-do 16419, Republic of Korea.
E-mail address: whham@skku.edu (W.-H. Ham).
Both authors contributed equally to this work.
lic
a-amino aldimines has been described by Reetz [10]. Despite
1
https://doi.org/10.1016/j.tetlet.2018.12.021
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: I.-S. Myeong, C. Jung and W. H. Ham, Synthesis of syn-vicinal diamines via the stereoselective allylation of acyclic chiral a-amino
aldimines, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.021

2
I.-S. Myeong et al. / Tetrahedron Letters xxx (xxxx) xxx
SnCl4
AllylSnBu3
NPMP
H
NHPMP
CH2Cl2
OBn
OBn
8:1 dr
Scheme 1. Previous work [11].
NPMP
a
a
TBSO
TBSO
OH
NHCbz
TBSO
TBSO
H
NHCbz
1
2
NPMP
OH
NHBoc
H
NHBoc
3
4
Fig. 1. Various medicinal compounds containing vicinal diamino functionality.
Scheme 2. Preparation of a-NHCbz-aldimine 2 and a-NHBoc-aldimine 4. Reagents
and conditions: (a) i. Dess-Martin Periodinane, CH2Cl2, rt; ii. p-anisidine, Ti(OiPr)4,
CH2Cl2, rt, 87–90%.
the utility and efficiency of these reactions, only a few examples
have been demonstrated.
We have previously reported the stereoselective allylation of N-
p-methoxyphenyl
(PMP)-substituted
a-hydroxy
aldimines
Results and discussion
(Scheme 1) [11], where the addition of an allyl group generates a
new stereocenter and affords a syn-vicinal amino alcohol. Nucle-
ophilic addition to aldimines requires particular conditions due
to their lower reactivity compared to that of carbonyl compounds
[12]. In the case of less reactive aldimines, an electron-donating
group can strengthen the coordination between the Lewis acid
and the imino nitrogen [10a]. Diastereoselective nucleophilic
additions to aldimines are stereocontrolled according to the
Felkin-Anh model and chelation [13] mediated by Lewis acids
[14]. As part of our ongoing research, herein we report a new
approach to syn-vicinal diamines via stereoselective allylations of
Enantiomerically pure N-Cbz-protected
N-Boc-protected -amino alcohol 3 were prepared using a previ-
ously reported method [15]. Primary alcohols 1 and 3 were con-
verted to the corresponding N-PMP-protected -amino aldimines
a-amino alcohol 1 and
a
a
2 and 4 using a previously reported method (Scheme 2) [11].
The results of the allylation reactions with different allyl
reagents using various Lewis acids are shown in Table 1. The ally-
lation mediated by SnCl4 gave syn-compound 5a with a 6:1 ratio in
66% yield (Entry 1). In the presence of TiCl4, the ratio was
decreased (Entry 2). In the presence of MgBr2ÁOEt2 the reaction
did not occur (Entry 3). The allylation mediated by BF3ÁOEt2
acyclic chiral
a-amino aldimines, and its application to the synthe-
sis of an intermediate of an oseltamivir derivative.
Fig. 2. General synthetic approaches to syn-vicinal diamines.
Please cite this article as: I.-S. Myeong, C. Jung and W. H. Ham, Synthesis of syn-vicinal diamines via the stereoselective allylation of acyclic chiral
aldimines, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.021
a-amino

I.-S. Myeong et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 1
Lewis-acid-mediated allyl addition reactions of
a-N-Cbz aldimine 2.
Lewis acid,
M
NPMP
H
NHPMP
NHPMP
+
TBSO
TBSO
TBSO
CH2Cl2
Temp.
NHCbz
NHCbz
5a
NHCbz
5b
2
Entry
Lewis acid
Allyl reagent
Temp.
Ratio (syn:anti)a
Yield (%)b
1
2
3
4
5
6
7
SnCl4
TiCl4
MgBr2ÁOEt2
BF3ÁOEt2
–
AllylSnBu3
AllylSnBu3
AllylSnBu3
AllylSnBu3
AllylMgBr
AllylMgBr
AllylSiMe3
À78 °C
À78 °C
0 °C
6:1
2:1
N.R.
1:2
2:1
66
69
N.R.
68
44
À78 °C
0 °C
ZnCl2
SnCl4
0 °C
À78 °C
1.2:1
N.R.
29
N.R.
a
Ratio determined by integrating the relevant 1H NMR resonances.
Yields refer to isolated mixture of products over two-steps from the aldehyde derived from 1.
b
Table 2
Lewis-acid-mediated allyl addition reactions of
a-N-Boc aldimine 4.
Lewis acid,
M
NPMP
NHPMP
NHPMP
+
TBSO
TBSO
H
TBSO
CH2Cl2
Temp.
NHBoc
NHBoc
6a
NHBoc
6b
4
Entry
Lewis acid
Allyl reagent
Temp.
Ratio (syn:anti)a
Yield (%)b
1
2
3
4
5
6
7
SnCl4
TiCl4
MgBr2ÁOEt2
BF3ÁOEt2
–
AllylSnBu3
AllylSnBu3
AllylSnBu3
AllylSnBu3
AllylMgBr
AllylMgBr
AllylSiMe3
À78 °C
À78 °C
0 °C
5:1
8:1
N.R.
1:2
1:1
54
77
N.R.
51
81
À78 °C
0 °C
ZnCl2
SnCl4
0 °C
À78 °C
1.2:1
N.R.
24
N.R.
a
Ratio determined by integrating the relevant 1H NMR resonances.
Yields refer to isolated mixture of products over two-steps from the aldehyde derived from 3.
b
afforded 5a and 5b with a 1:2 ratio (Entry 4). The Grignard reac-
tions, with or without Lewis acid, were not stereoselective (Entries
5 and 6). The reaction using a silyl allyl reagent mediated by SnCl4
did not proceed (Entry 7); this result is in accordance with our pre-
vious work [11].
methyl, ethyl, and benzyl containing substrates, the reaction only
afforded syn/anti-products with a 2:1 ratio and little
a-chelation
was observed.
The observed syn-selectivity in the allylation of
aldimines (Table 1, entry 2 and Table 2, entry 2) can be explained
by -chelation between the amido group and the aldimine nitro-
a-N-protected-
The Lewis-acid-mediated allylation of
a-N-Boc aldimine 4 was
a
similarly investigated (Table 2). The allylation mediated by SnCl4
proceeded to give syn-product 6a as the major compound (Entry
1). In the presence of TiCl4, the syn-selectivity dramatically
gen (Fig. 3A or B). Instead, the slightly anti-selective results
(Table 1, entry 4 and Table 2, entry 4) can be accounted for by
the Felkin–Anh model (Fig. 3C). To confirm the syn-configuration
increased compared with the
a-N-Cbz aldimine system (Entry 2).
The reaction did not proceed in the presence of MgBrÁOEt2 (Entry
3). The allylation mediated by BF3ÁOEt2 afforded anti-product 6b
as the major stereoisomer with a 1:2 syn:anti ratio, which is in
accordance with the a-N-Cbz aldimine system (Entry 4). The Grig-
nard reactions proceeded to give non-selective products (Entries 5
and 6). When allyltrimethylsilane was employed as nucleophile,
the SnCl4-mediated reaction did not proceed (Entry 7).
Additionally, compounds with methyl, ethyl, phenyl, and benzyl
groups instead of CH2OTBS were examined under TiCl4 and
allylSnBu3 conditions. When the phenyl containing substrate was
used as a reactant, the reaction did not proceed. In the case of
Fig. 3. Proposed mechanism for allylation.
Please cite this article as: I.-S. Myeong, C. Jung and W. H. Ham, Synthesis of syn-vicinal diamines via the stereoselective allylation of acyclic chiral
aldimines, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.021
a-amino

4
I.-S. Myeong et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 3. Retrosynthetic analysis.
NHCbz
NHPMP
NHPMP
b
c
a
HO
HO
O
TBSO
NHBoc
NHBoc
NHBoc
6a
9
10
OH
OH
OTBDPS
OH
NHCbz
CbzHN
CbzHN
e
d
O
O
NBoc
NBoc
NBoc
11
8
12
OTBDPS
HO
AcHN
CO2Et
CbzHN
NBoc
ref. 17
f
O
NH2
Oseltamivir derivative
7
Scheme 4. Synthesis of 7. Reagents and conditions: (a) 70% HF/Pyridine, Pyridine, THF, 0 °C to rt, 90%; (b) cerium(IV) ammonium nitrate, CH3CN/H2O, 0 °C then 0.6 M
NaHCO3, CH2Cl2, CbzCl, 30 °C, 56%; (c) PTSA, 2,2-dimethoxypropane, CH2Cl2, 40 °C, 80%; (d) OsO4 (0.05 equiv.), NMO, acetone/H2O, rt, 85%; (e) TBDPSCl, imidazole, CH2Cl2, 0 °C
to rt, 91%; (f) i. Dess-Martin periodinane, CH2Cl2, 82%; ii. Ph3PCH3Br, n-BuLi, THF, À78 °C to rt, 80%.
of the 1,2-diamine in 6a, an intermediate of an oseltamivir deriva-
tive was synthesized.
uct. A method for formation of the syn-vicinal diamines motif was
developed, and its application was demonstrated by the synthesis
of an intermediate of an oseltamivir derivative. Further experi-
ments and the application of this methodology to total synthesis
are in progress.
The retrosynthetic analysis for oxazolidine 7, which was
reported in Yao’s synthesis of an oseltamivir derivative [16], is
shown in Scheme 3. The desired compound 7 can be prepared by
Wittig olefination of diol 8, which can be obtained from alkene 9
by dihydroxylation. Compound 9 can be obtained by selective
deprotection and exchange of the amine protecting group in com-
pound 6a.
The synthesis of 7 is shown in Scheme 4. The silyl protecting
group on 6a was removed using Olah’s reagent to afford primary
alcohol 10. Deprotection of the p-methoxyphenyl group was
achieved using cerium(IV) ammonium nitrate and the carboxyben-
zyl protecting group was installed to give 9 in a one-pot procedure.
Acetonide protection of 9 afforded compound 11, and dihydroxyla-
tion with osmium tetroxide provided diol 8. TBDPS protection gave
alcohol 12. Dess-Martin oxidation afforded the corresponding
ketone, which was transformed into olefin 7 by Wittig olefination.
The synthesis of the desired compound 7 was accomplished from
amino alcohol 3 in 14% overall yield over 10 steps. The stereochem-
istry of the allylation product 6a was confirmed by the synthesis of
known compounds 8, 12, and 7, whose data were in good agree-
ment with the reported data in the literature [16].
Acknowledgements
This work was supported by the Yonsung Fine Chemicals Co.,
Ltd. We thank Yonsung R&D center for the NMR measurements.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2018.12.021.
References
[1] (a) E.T. Michalson, J. Szmuszkovicz, in: Progress in Drug Research, Springer,
1989, pp. 135–149;
(b) D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem. Int. Ed. 37 (1998) 2580–
2627.
[2] S. Saibabu Kotti, C. Timmons, G. Li, Chem. Biol. Drug Des. 67 (2006) 101–114.
[3] A. Viso, R. Fernández de la Pradilla, M. Tortosa, A. García, A. Flores, Chem. Rev.
111 (2011) PR1-PR42.
Conclusion
[4] (a) S. De Jong, D.G. Nosal, D.J. Wardrop, Tetrahedron 68 (2012) 4067;
(b) Y. Zhu, R.G. Cornwall, H. Du, B. Zhao, Y. Shi, Acc. Chem. Res. 47 (2014)
3665–3678.
[5] F. Cardona, A. Goti, Nat. Chem. 1 (2009) 269–275.
[6] H. Kim, S.M. So, J. Chin, B.M. Kim, Aldrichim. Acta 41 (2008) 77–88.
In summary, we have developed a Lewis-acid-mediated, stere-
oselective allylation of
a-amino aldimines. The reaction of an a-
N-Boc aldimine mediated by TiCl4 afforded the syn-selective prod-
Please cite this article as: I.-S. Myeong, C. Jung and W. H. Ham, Synthesis of syn-vicinal diamines via the stereoselective allylation of acyclic chiral
aldimines, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.021
a-amino

I.-S. Myeong et al. / Tetrahedron Letters xxx (xxxx) xxx
5
[7] (a) E. Marqués-López, P. Merino, T. Tejero, R.P. Herrera, Eur. J. Org. Chem. 2009
[12] R. Bloch, Chem. Rev. 98 (1998) 1407–1438.
(2009) 2401–2420;
[13] (a) J.A. Marshall, Chem. Rev. 96 (1996) 31–48;
(b) M.T. Reetz, Angew. Chem. Int. Ed. 23 (1984) 556–569;
(c) M.T. Reetz, Acc. Chem. Res. 26 (1993) 462–468;
(d) Y. Yamamoto, N. Asao, Chem. Rev. 93 (1993) 2207–2293;
(e) A. Mengel, O. Reiser, Chem. Rev. 99 (1999) 1191–1224;
(b) A. Noble, J.C. Anderson, Chem. Rev. 113 (2013) 2887–2939.
[8] T. Fujisawa, M. Nagai, Y. Koike, M. Shimizu, J. Org. Chem. 59 (1994) 5865–5867.
[9] (a) S.K. Chattopadhyay, K. Sarkar, L. Thander, S.P. Roy, Tetrahedron lett. 48
(2007) 6113–6116;
(b) N. Saha, B. Chatterjee, S.K. Chattopadhyay, J. Org. Chem. 80 (2015) 1896–
1904.
(f) M. Yus, J.C. González-Gómez, F. Foubelo, Chem. Rev. 113 (2013) 5595–
5698.
[10] (a) M.T. Reetz, R. Jaeger, R. Drewlies, M. Hübel, Angew. Chem. Int. Ed. 30
(1991) 103–106;
[14] B.W. Gung, Additions of allyl, allenyl, and propargylstannanes to aldehydes
and mines, in: L.E. Overman (Ed.), Organic Reactions, John Wiley & Sons, New
Jersey, 2004, p. 1, Chap. 1.
[15] I.-S. Myeong, Y.-T. Lee, S.-H. Lee, C. Jung, J.-S. Kim, S.-H. Park, J. Kang, S.-J. Lee,
I.-H. Ye, W.-H. Ham, Tetrahedron: Asymmetry 28 (2017) 1053–1060.
[16] X. Cong, Z.-J. Yao, J. Org. Chem. 71 (2006) 5365–5368.
(b) M.T. Reetz, M. Hübel, R. Jaeger, R. Schwickardi, R. Goddard, Synthesis 1994
(1994) 733–738;
(c) M.T. Reetz, Angew. Chem. Int. Ed. 30 (1991) 1531–1546;
(d) M.T. Reetz, Chem. Rev. 99 (1999) 1121–1162.
[11] Y.-T. Lee, C. Jung, I.-S. Myeong, S.-H. Lee, J.-S. Kim, W.-H. Ham, Tetrahedron 74
(2018) 506–511.
Please cite this article as: I.-S. Myeong, C. Jung and W. H. Ham, Synthesis of syn-vicinal diamines via the stereoselective allylation of acyclic chiral a-amino
aldimines, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.021