Novel 1,3,2-diazaphospholidines with pseudodipeptide substituents

Article abstract of DOI:10.1080/10426507.2018.1540484

Chiral 1,3,2-diazaphospholidine with pseudodipeptide substituents was prepared. This asymmetric inducer provided up to 84% ee in the Pd-catalyzed asymmetric allylic alkylation of (E)-1,3-diphenylallyl acetate with dimethyl malonate, and up to 53% ee in the Rh-catalyzed asymmetric hydrogenation of (Z)-methyl 2-acetamido-3-phenylacrylate.

Full text of DOI:10.1080/10426507.2018.1540484

Phosphorus, Sulfur, and Silicon and the Related Elements
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Novel 1,3,2-diazaphospholidines with
pseudodipeptide substituents
I. V. Chuchelkin, V. K. Gavrilov, I. D. Firsin, V. S. Zimarev, I. M. Novikov, M. G.
Maksimova, A. A. Shiryaev, S. V. Zheglov, V. A. Tafeenko, V. V. Chernyshev & K.
N. Gavrilov
To cite this article: I. V. Chuchelkin, V. K. Gavrilov, I. D. Firsin, V. S. Zimarev, I. M. Novikov, M.
G. Maksimova, A. A. Shiryaev, S. V. Zheglov, V. A. Tafeenko, V. V. Chernyshev & K. N. Gavrilov
(2018): Novel 1,3,2-diazaphospholidines with pseudodipeptide substituents, Phosphorus, Sulfur,
and Silicon and the Related Elements, DOI: 10.1080/10426507.2018.1540484
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1540484
Novel 1,3,2-diazaphospholidines with pseudodipeptide substituents
I. V. Chuchelkina , V. K. Gavrilova, I. D. Firsina, V. S. Zimareva, I. M. Novikova, M. G. Maksimovaa, A. A. Shiryaeva,
S. V. Zheglova, V. A. Tafeenkob, V. V. Chernyshevb, and K. N. Gavrilova
b
aChemistry Department, Ryazan State University, Ryazan, Russian Federation; Department of Chemistry, Lomonosov Moscow State
University, Leninskie Gory, GSP-1, Moscow, 119991, Russian Federation
ABSTRACT
ARTICLE HISTORY
Received 13 September 2018
Accepted 3 October 2018
Chiral 1,3,2-diazaphospholidine with pseudodipeptide substituents was prepared. This asymmetric
inducer provided up to 84% ee in the Pd-catalyzed asymmetric allylic alkylation of (E)-1,3-dipheny-
lallyl acetate with dimethyl malonate, and up to 53% ee in the Rh-catalyzed asymmetric hydrogen-
ation of (Z)-methyl 2-acetamido-3-phenylacrylate.
KEYWORDS
Chiral 1,3,2-
diazaphospholidine;
pseudodipeptide;
GRAPHICAL ABSTRACT
Pd-catalyzed asymmetric
allylation; Rh-catalyzed
asymmetric hydrogenation
1. Introduction
the phosphorus atom into the 1,3,2-diazophospholidine cycle
increases oxidation and hydrolytic stability of the ligand. On
the other hand, the possibility to widely vary the phosphorus
and/or nitrogen substituents allows the fine-tuning of its steric
and electronic properties.[8–12] The presence of an asymmetric
donor phosphorus atom significantly facilitates the chirality
transfer from the chiral catalyst to the product.[13–16]
It should be noted that the presence of the pseudodipep-
tide fragments in the phosphorus containing stereo inducers
structure makes it possible to form supramolecular assem-
blies based on them, in which two ligands are bound by
hydrogen bonds. Currently, there are examples of successive
application of supramolecular systems based on porphyrin
and amide derivatives in the asymmetric metal complex
catalysis.[17–23]
This work describes the preparation of a chiral diamido-
phosphite based on a pseudodipeptide bearing a stereogenic
phosphorus atom in the 1,3,2-diazophospholidine cycle and
its application in the enantioselective Pd-catalyzed allylic sub-
stitution and Rh-catalyzed hydrogenation reactions. Such
reactions are widely used for estimation of the catalytic per-
formance of new chiral inducers and for asymmetric synthesis
of valuable organic and natural compounds.[1 , 6, 13, 15, 24–32]
Asymmetric metal complex catalysis is an efficient tool for the
synthesis of enantiopure and, in general, enantioenriched
organic and organoelement compounds. Such products are
used in the preparation of pharmaceutical drugs, vitamins,
chemical plant-protecting agents, perfume compounds, and
food additives, as well as ferroelectric liquid crystals and chiral
polymers with nonlinear optical properties. The activity and
stereoselectivity of metal complex catalysts is governed to a
considerable degree by an adequate strategy for the design and
synthesis of corresponding chiral ligands, primarily, phos-
phorus-containing ones thousands representatives of which
have been used in various asymmetric transformations.[1–5]
Among numerous phosphorus-containing stereo inducers,
phosphite-type ligands are of particular interest. They are charac-
terized by the oxidative stability, considerable p-acidity, ease of
preparation by simple condensation (including techniques of par-
allel and solid-phase synthesis), and a low cost. These key benefits
allow one to build up a wide library of ligands and to select the
most efficient asymmetric inducers for each catalytic process.[4–7]
Very attractive are diamidophosphites, which, on the one
hand, have balanced electronic properties and involvement of
CONTACT I. V. Chuchelkin
chuchelkin1989@gmail.com
Chemistry Department, Ryazan State University, 46 Svoboda street, Ryazan, 390000,
Russian Federation.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
ß 2018 Taylor & Francis Group, LLC

2
I. V. CHUCHELKIN ET AL.
Scheme 1. Synthesis of the pseudodipeptide 4.
phenylacrylate 9 in the presence of [Rh(cod)2]BF4 as a pre-
catalyst (up to 53% ee of the product 10) (Scheme 4).[34]
2. Results and discussion
2.1. Synthesis of organic compounds
The compound 4 was obtained by a three-step synthesis from
(S)-tert-leucine 1 using optimized known techniques:[33] the
N-Boc (S)-derivative 2 was synthesized by the reaction (S)-
tert-leucine 1 with Boc2O in the presence of K2CO3 in an i-
PrOH–H2O mixture; the (S)-1,2-amino alcohol 3 was pre-
pared by reduction of the amino acid 1 with LiAlH4 in THF;
the pseudodipeptide 4 was obtained by the reaction between
the resulting compounds 2 and 3 in CH2Cl2 with the addition
of isobutyl chloroformate and Et3N (Scheme 1).
3. Conclusions
In conclusion, diazaphospholidine 6 with pseudodipeptide
substituent was prepared from (S)-tert-leucine. This ligand
was tested in the asymmetric reactions of Pd-catalyzed allylic
substitution and Rh-catalyzed ahydrogenation. In general,
the ligand has a moderate asymmetric ability.
Our next task is to expand the library of the 1,3,2-diaza-
phospholidines based on pseudodipeptides and study the
coordination behavior of these ligands, as well as their catalytic
testing. An attempt to obtain supramolecular catalytic materi-
als based on metal complexes of the 1,3,2-diazaphospholidines
with pseudodipeptide substituents is also of interest.
2.2. Synthesis and study of the structure of
diamidophosphites
The 1,3,2-diazaphospholidine 6 was prepared by condensa-
tion of the pseudodipeptide 4 with (5S)-2-chloro-3-phenyl-
1,3-diaza-2-phosphabicyclo[3.3.0]octane 5 in toluene in the
presence of an excess of Et3N as a base (Scheme 2).[34] The
phosphorylating reagent 5 was synthesized[35] analogously to
4. Experimental
Synthesis of (2R,5S)-2-[(S)-2-{(S)-2-[(tert-butoxycarbonyl)
amino]-3,3-dimethyl-butanamido}-3,3-dimethylbutyl]-3-phe-
nyl-1,3-diaza-2-phosphabicyclo[3.3.0]octane 6. To a vigor-
ously stirred solution of phosphorylating agent 5 (0.48 g,
2 mmol) and Et3N (0.56 mL, 4 mmol) in toluene (15 mL),
compound 4 (0.66 g, 2 mmol) was added in one portion at
20 ꢀC. The reaction mixture was stirred at 20 ꢀC for 24 h
and passed through a short column filled with SiO2/Al2O3.
The filtrate was concentrated in vacuo (40 Torr). The residue
was dried in vacuo (1 Torr) and crystallized from heptane to
afford compound 6.[34]
Asymmetric alkylation of (E)-1,3-diphenylallyl acetate 7
with dimethyl malonate. A solution of either [Pd(allyl)Cl]2
(0.0037 g, 0.01 mmol and ligand 6 (0.0107 g, 0.02 mmol or
0.0214 g, 0.04 mmol) in CH2Cl2 or THF (5 mL) was stirred
for 40 min. Then (E)-1,3-diphenylallyl acetate (0.1 mL,
0.5 mmol) was added, the mixture was stirred for 15 min,
and treated with dimethyl malonate (0.1 mL, 0.87 mmol),
BSA (0.22 mL, 0.87 mmol), and KOAc (0.002 g). The reac-
tion mixture was stirred for 48 h, diluted with hexane
(5 mL), and filtered through a short SiO2 layer. The solvents
known procedures from (S)-glutamic acid and anilide.[36 ,37
]
The chemical and enantiomeric purity, as well as the
composition, structure and stereochemical features of the
diamidophosphite 6 are determined using NMR spectros-
1
copy of 31P, H and 13C (including using homo- and heter-
onuclear correlation APT, DEPT, 1H,1H-COSY, 13C,1H-
HSQC, 13C,1H-HMBC). The results of X-ray diffraction
analysis of 6 show that this ligand crystallizes into supra-
molecular assemblies consisting of two molecules connected
by hydrogen bonds (Figure 1).
2.3. Pd- and Rh-catalyzed asymmetric reactions
The asymmetric inducer 6 was tested in the Pd-catalysed
reaction of asymmetric allylic alkylation of (E)-1,3-dipheny-
lallyl acetate 7 with dimethyl malonate, [Pd(allyl)Cl]2 was
used as a precatalyst. (up to 84% ee of the product 8)
(Scheme 3) The ligandas 6 was also used in the Rh-catalyzed
asymmetric hydrogenation of (Z)-methyl 2-acetamido-3- were removed in vacuo (40 Torr) and the residue was dried

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 2. Synthesis of the diamidophosphite 6.
Figure 1. Supramolecular assembly consisting of two molecules 6 according to X-ray diffraction data.
Scheme 3. Pd-catalysed reaction of asymmetric allylic alkylation of (E)-1,3-diphenylallyl acetate 7 with dimethyl malonate.
Funding
This work was financially supported by the Russian Science
Foundation (Grant @ 17-73-10356).
ORCID
Scheme 4. Rh-catalyzed asymmetric hydrogenation of (Z)-methyl 2-acetamido-
3-phenylacrylate 9.
I. V. Chuchelkin
http://orcid.org/0000-0002-3656-468X
in vacuo (10 Torr). Conversion of the substrate 7 and
enantiomeric excesses of the product 8 were determined by
HPLC on a Daicel Chiralcel OD-H chiral column.[34]
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