N-Methylative aziridine ring opening and asymmetric synthesis of MeBmt

Article abstract of DOI:10.1016/j.tetlet.2011.08.048

Asymmetric synthesis of MeBmt, an unusual amino acid constituent of cyclosporine A, was achieved from aziridine-(2R)-carboxaldehyde through the highly stereoselective addition of (E)-crotylboronate and the subsequent N-methylative aziridine ring opening as key steps.

Full text of DOI:10.1016/j.tetlet.2011.08.048

Tetrahedron Letters 52 (2011) 5918–5920
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N-Methylative aziridine ring opening and asymmetric synthesis of MeBmt
Yongeun Kim a, Doo-Ha Yoon a, Hyun-Joon Ha a, , Kyung Yeon Kang b, Won Koo Lee b,
⇑
⇑
a Department of Chemistry and Protein Research Center for Bio-Industry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-719, Republic of Korea
b Department of Chemistry, Sogang University, Seoul 121-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2011
Revised 4 August 2011
Accepted 8 August 2011
Available online 7 September 2011
Asymmetric synthesis of MeBmt, an unusual amino acid constituent of cyclosporine A, was achieved from
aziridine-(2R)-carboxaldehyde through highly stereoselective addition of (E)-crotylboronate and the sub-
sequent N-methylative aziridine ring opening as key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
MeBmt
Asymmetric synthesis
Aziridine
Ring opening
Crotylation
MeBmt (1) was isolated from the fungus Tolypocladium inflatium
with a cyclic undecapeptide cyclosporine possessing immunosup-
pressive activity.1 The structure of MeBmt as a nonproteogenic
Garner’s aldehyde.7 Thereby chiral aziridine-2-carboxaldehyde,5
readily available from commercial source, was used as a starting
substrate. Addition of (E)-crotylboronate was planned to put three
more carbons to the aziridine-2-carboxaldehyde with the hydroxyl
group and the methyl branch formed at C3 and C4 in MeBmt with
the expectation of high stereoselectivity. Another key reaction, N-
methylative aziridine ring opening, from 3 to 4 at a certain stage
may generate N-methyl amino alcohol which are essential func-
tional groups toward the target molecule.4 The synthetic plan
including those two key reactions would afford us a facile route
for the preparation of MeBmt not only as in its naked but as in
its orthogonally protected form.
unusual amino acid features
c-alkyl-b-hydroxy-a-methylamino
acid with three contiguous stereocenters and a
e
,f- trans double
bond. Though MeBmt itself does not have biological activity, struc-
tural modification of MeBmt in cyclosporine affects its immuno-
suppressant activity to a great extend.2 There is rich literature
detailing the synthesis of MeBmt based on asymmetric reactions
and chiral building blocks including sugars and amino acid.3 How-
ever all synthetic methods except one3b required monomethyla-
tion of amine at a certain stage. Recently we have developed the
N-methylative aziridine ring opening reaction with various nucle-
ophiles to afford N-methylated a
- or b-amino compounds.4 Apply-
ing this methodology allows us to give an easy access for the
asymmetric synthesis of MeBmt including orthogonally protected
MeBmt as a synthetic intermediate which is valuable for the fur-
ther biological studies.
Our synthetic plan stems from two key reactions (Scheme 1);
the addition of crotylboronate of aziridine-2-carboxaldehyde to
OP
OH
HO2C
AcO
Me
Me
N
Me
Me
NH Me
Me
Ph
1
4
give rise to the methyl groups at c-position with the extension of
the backbone and the subsequent N-methylative aziridine ring
opening reaction. Aziridine-2-carboxaldehyde5 (2) considered as
a synthetic surrogate of aminoaldehyde shows better stereoselec-
tivity in most of nucleophilic carbonyl addition reactions with bet-
ter stability under strong base compared to the most of other
aminoaldehydes and their synthetic surrogates6 including the
Me
Me
O
OP
Ph
N
Ph
N
H
H
H
Me
2
3
⇑
Corresponding authors. Tel.: +82 31 330 4369 (H.-J.H.); +82 2 705 8449 (W.K.L.).
E-mail addresses: hjha@hufs.ac.kr (H.-J. Ha), wonkoo@sogang.ac.kr (W.K. Lee).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.048

Y. Kim et al. / Tetrahedron Letters 52 (2011) 5918–5920
5919
CO2i-Pr
Me
Me
O
B
OH
O
CO2i-Pr
Ph
N
Ph
N
O
H
H
Me
H
3
2
OAc Me
OBn
Me
OBn
AcO
Me
a
b
Ph
N
Me
N
OBn
Me
N
Me
Me
H
Me
Ph
Ph
6
4
5
OBn
OBn
c
e
HO
Me
Me
AcO
Me
R
f
1
N
Me
Me
N
Me
Me
Ph
Ph
7
R = CH2OH
9
d
8 R = CHO
Scheme 2. Reagents and conditions: (a) NaH, BnBr, THF, 0 °C (0.5 h) then rt (3 h) 88%; (b) MeOTf, CsOAc, CH3CN, rt, 69% (87:13); (c) (Ph3P)3RhCl, catecholborane, THF, rt then
NaOH (2 M), H2O2 (30%), 78%; (d) DMSO, (ClCO)2, CH2Cl2. 90% (e) 5-(ethylsulfonyl)-1-phenyl-1H-tetrazole, KHMDS, THF, 89%; (f) PDC, DMF, rt then Na in liq. NH3 À78 °C, 61%.
This synthesis was initiated from the addition reaction of cro-
tylboronate to aziridine-2-carboxaldehyde (2). The reaction of
(S,S)-diisopropyl tartrate (E)-crotylboronate8 with (2R)-aziridine-
2-carboxaldehyde (2) provided anti-favored crotylation product,
(1R,2R)-2-methyl-1-{(R)-1-[(R)-1-phenylethyl]aziridin-2-yl}but-3-
en-1-ol (3), without detection of any other isomers in 87% yield
(Scheme 2).
The secondary alcohol in 3 was protected with benzylbromide
and sodium hydride to provide 1-benzyloxy-2-methyl-3-buteny-
laziridine (4) in 88% yield. The next key step is the N-methylative
aziridine ring opening with an acetate nucleophile to get the
90% yield. The reaction of aldehyde 8 with 5-(ethylsulfonyl)-1-
phenyl-1H-tetrazole10 in the presence KHMDS in THF provided
the (E)-olefin 9 with the removal of acetate in 89% yield. The
enantiomerically pure amino acid protected by two benzyl groups
at the nitrogen and oxygen was prepared from the primary alcohol
9 through oxidation with pyridinium dichromate (PDC) in dimeth-
ylformamide (DMF). Subsequent removal of two benzyl groups was
accomplished in the presence of sodium and liquid ammonia in THF
to afford the target molecule MeBmt (1) in 61% yield (Scheme 2).
In conclusion an asymmetric synthesis of MeBmt, an unusual
amino acid constituent of cyclosporine A, was achieved from aziri-
dine-(2R)-carboxaldehyde through seven chemical steps including
highly stereoselective addition of (E)-crotylboronate and N-methy-
lative aziridine-ring opening in 20% overall yield.
1-acetyloxy-2-(N-methyl) amino compound.
A regioselective
N-methylative ring opening reaction of the unactivated aziridine
proceeded with methyl trifluoromethansulfonate and an acetate
nucleophile. After the successful formation of N-methyl aziridnium
ion by N-methylation with methyl trifluoromethansulfonate we
tried (n-Bu)4NOAc as an acetate source with an advantage of good
solubility in organic solvent to yield two regioisomers of the ring-
opened products (5) and (6) with the ratio of 71:29 in 51% yield,
which were readily separable by silica gel chromatography
(Scheme 2). We tried to improve the regioselectivity and the reac-
tion yield by changing the sources of acetate nucleophiles includ-
ing NaOAc, CsOAc, and AgOAc. Eventually, we found that CsOAc
was the best to show the selectivity as 87:13 in favor of the ex-
pected product 5 in 69% yield.
Acknowledgments
This work was supported by National Research Foundation
(NRF) (Basic Science Research Program, 2010-0008424 and the
Center for Bioactive Molecular Hybrides to H.-J.H.) and the HUFS
Grant (2011). W.K.L. also acknowledges the financial support from
KRF-2010-0005538 and KRF-2009-0081956.
Supplementary data
The successful introduction of all three stereocenters with the N-
methyl group is followed by the extension of two more carbons
with (E)-olefin between C6 and C7 of backbone and the oxidation
of the primary alcohol to the corresponding carboxylic acid. Exten-
sion of the backbone chain by two more carbons from the ring-
opened product 5 was achieved by the olefination of the aldehyde
(8) which was acquired from hydration of the olefin to the primary
alcohol (7) followed by oxidation. To furnish 7 from 5 through hyd-
roboration and oxidation protocol, Wilkinson’ catalyst procedure
with catecholborane9 and oxidative workup was the best in a 78%
yield. The Swern oxidation of the resulting primary alcohol 7 with
dimethyl sulfoxide and oxalyl chloride afforded the aldehyde 8 in
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.048.
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