Application of allylic amine formation from aziridine-2-ol under Appel reaction condition: Synthesis of N-(tert-butoxycarbonyl)-D-vinyl glycine methyl ester

Article abstract of DOI:10.1016/j.tetlet.2021.153119

PPh₃/I₂/imidazolde mediated allyl amine formation from aziridine-2-alcohol was explored for the synthesis of N-(tert-butoxycarbonyl)-D-vinyl glycine methyl ester.

Full text of DOI:10.1016/j.tetlet.2021.153119

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Application of allylic amine formation from aziridine-2-ol under Appel
reaction condition: Synthesis of N-(tert-butoxycarbonyl)-D-vinyl glycine
methyl ester
Subhash P. Chavan a,b, , Sanket A. Kawale a,b, Niteen B. Patil a,b, Dinesh B. Kalbhor a,b
⇑
a Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411008, India
b Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
PPh3/I2/imidazolde mediated allyl amine formation from aziridine-2-alcohol was explored for the synthe-
sis of N-(tert-butoxycarbonyl)-D-vinyl glycine methyl ester.
Received 9 February 2021
Revised 17 April 2021
Accepted 20 April 2021
Available online xxxx
Ó 2021 Published by Elsevier Ltd.
Keywords:
Aziridine-2-alcohol
Allyl amine
Ring opening
Birch reaction
Aziridinium ion
Nature is the primary source of millions of bio-important mole-
cules. The -vinyl amino acid is a class of naturally occurring
amino acids which contain the vinyl group as a substituent. The
Considering the structural properties of the vinyl glycine, which
is known as a ‘‘broad spectrum inactivator” and as a key synthon
for the synthesis of alkaloids, novel amino acids and azasugars,
the organic chemists have paid a lot of attention for the synthesis
of racemate as well as both chiral antipodes of VG as valuable syn-
thetic intermediates [11].
As a continuation of our efforts to explore the new synthetic
methods for biologically active compounds [12], we have exploited
aziridine-2-carboxylate as a chiral synthon [13] and report herein a
simple and efficient protocol for the transformation of chiral
hydroxy aziridines into chiral allylic amines under Appel reaction
condition (Scheme 1) [14]. Due to the versatility of the above men-
tioned protocol developed in our lab, it was envisioned that it
could be utilized for the synthesis of a variety of chiral vinyl glycine
derivatives. In the present work, we have explored it for the syn-
thesis of D-VG, the simplest member of the VG family.
a
vinyl glycine is the smallest and most important family member
of
a-vinyl amino acid class and exists in three different forms,
DL-vinyl glycine 1 (DL-VG), D-vinyl glycine 2 (D-VG) and L-vinyl
glycine 3 (L-VG) (Fig. 1). D-Antipode is produced by Rhodophyllus
nidorosus mushroom species [1] whereas L-vinyl glycine is inter-
mediate found in different pyridoxal phosphate enzymatic reac-
tions [2].
All the three antipodes of vinyl glycine act as pyridoxal phos-
phate enzyme inhibitor for enzymes such as aspartate amino-
transaminase [3], D-amino acid transaminase [4], kynurenine
aminotransferase [5], rat hepatic alanine aminotransferase [6], cys-
tathionine
antiepileptic drug vigabatrin was considered to be designed on
the basis of anti- -aminobutyric acid aminotransferase movement
c-synthase [7] etc. The structurally comparable
c
A synthetic plan for the preparation of N-(tert-butoxycarbonyl)-
D-vinyl glycine methyl ester 9 is shown in Scheme 2. The
trans-Aziridine-2-carboxylate 6 could be converted to trans-aziri-
dine-2-alcohols 7 and 8 which could be converted to N-(tert-
of vinyl glycine [8]. All the three antipodes of vinyl glycine are used
as chiral building blocks or as key intermediates for the synthesis
of many alkaloids, novel amino acids and azasugars [9]. Vinyl gly-
cine and its derivatives also show a wide range of antibacterial
activity [10].
butoxycarbonyl)-D-vinyl glycine methyl ester
mentioned protocol developed in our laboratory.
9 using above
Accordingly, the required enantiomerically pure trans-aziri-
dine-2-carboxylate 6 was synthesized from D-mannitol diace-
tonide by following the literature procedure [15]. It was
envisioned that the use of aziridine-2-alcohol 7 for the synthesis
⇑
Corresponding author at: Division of Organic Chemistry, CSIR-NCL
(National Chemical Laboratory), Pune 411008, India.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
https://doi.org/10.1016/j.tetlet.2021.153119
0040-4039/Ó 2021 Published by Elsevier Ltd.
Please cite this article as: S.P. Chavan, S.A. Kawale, N.B. Patil et al., Application of allylic amine formation from aziridine-2-ol under Appel reaction con-
dition: Synthesis of N-(tert-butoxycarbonyl)-D-vinyl glycine methyl ester, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153119

S.P. Chavan, S.A. Kawale, N.B. Patil et al.
Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Vinyl glycine isomers.
Scheme 1. Allyl amine formation from aziridine-2-alcohol.
Scheme 2. Synthetic Plan.
of 9 would be superior to aziridine-2-alcohol 8 as it directly gives
oxidized carbon of D-vinyl glycine. Hence, aziridine 6 was sub-
jected to the acetonide deprotection using TMSOTf/DCM condition
to afford the diol 10.13a Oxidative cleavage of diol 10 using NaIO4
followed by reduction of the resulting aldehyde using sodium
borohydride provided required aziridine alcohol 7. Surprisingly,
aziridine alcohol 7 under Appel reaction condition (I2, PPh3 and
imidazole) gave unsaturated ester 12 instead of expected chiral
allylic amine 11 essential for the synthesis of 9 (Scheme 3).
Possible mechanistic pathway to explain the formation of
unsaturated ester 12 is depicted in Scheme 4 [16]. It seems likely
that under Appel reaction condition, aziridine-2-alcohol 7 reacts
to form a bicyclic aziridinium ion 14 which in turn opens by iodide
ion as nucleophile from a position becomes more activated due to
electron withdrawing substituent (EWG) ester group. Instead of
opening from sterically less hindered side to form rearranged azir-
Scheme 4. A plausible mechanism for the formation of 12.
idine iodide 16 which in-situ undergoes reductive elimination with
iodide ion to form unsaturated ester 12.
It may be noted that interestingly the formation of chiral allylic
amines 5 under Appel reaction condition from aziridine alcohols 4
takes place only when R1 is an electron donating substituent (EDG)
[17] (Scheme 1).
Due to unpredicted behaviour of aziridine-2-alcohol 7 under
Appel reaction condition, we explored second plan for the synthe-
sis of 9 as shown in Scheme 2. Accordingly, ester functionality of
trans-aziridine-2-carboxylate 6 was reduced by using LiAlH4 to
obtain hydroxy aziridine 8 in 90% yield (Scheme 5). Hydroxy ester
8 was subjected to Appel reaction condition (I2, PPh3, imidazole) to
obtain allyl amine 17 in 87% yield [14]. For N-debenzylation of
amine 17, it was first protected as its Boc derivative and subjected
to chemoselective N-debenzylation using Birch reaction condition
led to N-debenzylated compound 19 in 30% yield [18]. The poor
yield of N-debenzylation was attributed to side reaction in which
the carbon–nitrogen bond of compound 18 was cleaved under
Birch reaction condition to obtain compound 20. Replacing the sol-
vent from THF to diethyl ether and Li to Na as metal was ineffective
to improve the yield of this transformation. Also reducing the tem-
perature from À78 °C to À30 °C did not improve the yield of Birch
reduction. The yield of N-debenzylated compound 17 was
improved by its chlorination using NCS, dehydrochlorination using
KOt-Bu followed by SiO2 mediated imine hydrolysis to amine
Scheme 3. Route 1.
2

S.P. Chavan, S.A. Kawale, N.B. Patil et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 5. Route 2.
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21 in 66% overall yield in four steps [19]. Exposure of Boc-pro-
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[20] which was converted to its methyl ester derivative 9 using
an ethereal solution of diazomethane. Spectral and optical data
of N-(tert-butoxycarbonyl)-D-vinyl glycine methyl ester 9 was
found to be in well agreement with its opposite antipode [21]
(Scheme 5).
In conclusion, allylamine formation from aziridine-2-alcohol
under Appel reaction condition (I2/PPh3/Imidazole) was extended
for the synthesis of N-(tert-butoxycarbonyl)-D-vinyl glycine
methyl ester. Present work could be useful for the synthesis of a
variety of vinyl glycine derivatives useful as chiral building blocks
for the synthesis of complex bioactive compounds.
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Declaration of Competing Interest
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Acknowledgements
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Appendix A. Supplementary data
Supplementary material that may be helpful in the review pro-
cess should be prepared and provided as a separate electronic file.
That file can then be transformed into PDF format and submitted
along with the manuscript and graphic files to the appropriate.
Supplementary data to this article can be found online at
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