Highly Diastereoselective Synthesis of Cyclic α-Aminophosphonic and α-Aminophosphinic Acids from Glycyl-l-Proline 2,5-Diketopiperazine

Article abstract of DOI:10.1002/ejoc.201901439

This paper describes the first diastereoselective synthesis of cyclic α-aminophosphonic and α-amino phosphonic acids from glycyl-l-proline 2,5-diketopiperazine (S)-6 prepared according to the usual peptide coupling procedures. The highlights of this contribution is the chemoselective reduction of the carbamate-imide activated carbonyl group in the N-Boc 2,5-diketopiperazine (S)-11 to generate the unstable hemiaminals (1R,8aS)-12 and (1S,8aS)-13, followed by the highly diastereoselective nucleophilic addition of trimethyl phosphite or dimethyl phenylphosphonite to the chiral carbenium ion (S)-5. Acid hydrolysis of the phosphonate and phosphinate functionalities with simultaneous cleavage of the tert-butyl carbamate protecting group led to the target compounds. The high diastereoselectivity in the nucleophilic addition of trivalent phosphorus to the chiral carbenium ion (S)-5 is in agreement with our precedent reports.

Full text of DOI:10.1002/ejoc.201901439

A Journal of
Accepted Article
Title: Highly diastereoselective synthesis of cyclic α-aminophosphonic
and α-aminophosphinic acids from glycyl-L-proline 2,5-
diketopiperazine
Authors: Mario Ordonez, Fernando Torres-Hernández, and José Luis
Viveros-Ceballos
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901439
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10.1002/ejoc.201901439
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Highly diastereoselective synthesis of cyclic α-aminophosphonic
and α-aminophosphinic acids from glycyl-L-proline 2,5-
diketopiperazine
Mario Ordóñez*, Fernando Torres-Hernández and José Luis Viveros-Ceballos
Abstract: This paper describes the first diastereoselective synthesis
of cyclic α-aminophosphonic and α-aminophosphinic acids from
glycyl-L-proline 2,5-diketopiperazine (S)-6 prepared according to the
usual peptide coupling procedures. The highlights of this contribution
is the chemoselective reduction of the carbamate-imide activated
carbonyl group in the N-Boc 2,5-diketopiperazine (S)-11 to generate
the unstable hemiaminals (1R,8aS)-12 and (1S,8aS)-13, followed by
the highly diastereoselective nucleophilic addition of trimethyl
phosphite or dimethyl phenylphosphonite to the chiral carbenium ion
(S)-5. Acid hydrolysis of the phosphonate and phosphinate
functionalities with simultaneous cleavage of the tert-butyl carbamate
protecting group led to the target compounds. The high
diastereoselectivity in the nucleophilic addition of trivalent phosphorus
to the chiral carbenium ion (S)-5 is in agreement with our precedent
reports.
nucleophiles to chiral carbenium ions readily obtained from cyclic
amides has proven to be one of the most suitable methods.5
On the other hand, 2,5-diketopiperazines (2,5-DKP) are optically
active cyclodipeptides abundantly distributed in the nature and
are easily synthesized from available α-amino acids, which
represent privileged structures as templates for the preparation
of structurally diverse bioactive heterocycles.6 Among different
methods developed for the selective functionalization of 2,5-DKP
precursors,7 the generation of endocyclic carbenium ions derived
from the C-2 carbonyl group has been widely employed for the
intramolecular construction of the 2,6-bridged piperazine-3-one
scaffold present in tetrahydroisoquinoline alkaloids;8 however,
the stereoselective addition of external nucleophiles to these
intermediates has remained virtually unexplored.
Introduction
α-Aminophosphonic and phosphinic acids represent an
important class of organophosphorus compounds widely used as
inhibitors or false substrates of therapeutically valuable
protesases,1 which is attributable to the well-known capacity of
phosphonic and phosphinic groups to simulate the tetrahedral
transition state of enzymatic peptide bond hydrolysis.2
Particularly, a large number of azaheterocyclic derivatives have
been prepared and incorporated into small peptides as
conformationally restricted bioisosteres of natural amino acids.3
Although the synthesis of these compounds has been
approached by different strategies,4 the addition of P-
Figure 1. Relevant 2,5-diketopiperazines derivatives and target molecules.
Taking into account the high potential of conformationally
constrained phosphorus α-amino acid analogs,1 the relevance of
2,5-diketopiperazines bearing the phosphonate moiety group
like the compound 19 as well as the importance of the
stereochemistry in the drug-receptor interactions,10 we here
describe the stereoselective synthesis of the novel cyclic α-
aminophosphonic acid (1R,8aS)-3 and cyclic α-aminophosphinic
acid (1R,8aS)-4 analogs of the corresponding methyl ester
(1S,8aS)-2 (Figure 1),11 from the glycyl-L-proline 2,5-
diketopiperazine (S)-6 [cyclo(Gly-L-Pro), cGP], through the
diastereoselective phosphonylation of the cyclic chiral
carbenium ion (S)-5 as a key step.
Centro de Investigaciones Químicas – IICBA,
Universidad Autónoma del Estado de Morelos,
Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico
E-mail: palacios@uaem.mx
fernando.torresher@uaem.edu.mx
jlvc@uaem.mx
https://www.ciquaem.mx/ordonez-palacios-jose-mario
https://www.ciquaem.mx/torres-hernandez-fernando
https://www.ciquaem.mx/viveros-ceballos-jose-luis
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201901439
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making use of this methodology, the coupling reaction of N-Boc
protected glycine with L-proline methyl ester hydrochloride (S)-7
easily obtained, in dichloromethane using isobutyl chloroformate
(IBCF) as a coupling reagent and triethylamine at room
temperature, afforded the dipeptide (S)-8 in 72% yield. Cleavage
of the N-Boc bond in (S)-8 with formic acid, followed by
intramolecular cyclization under thermal conditions, provided the
key starting material 2,5-diketopiperazine (S)-6 in 96% yield
[64% overall yield from L-proline]. Additionally, was also possible
to invert the order of the peptide coupling to obtain the 2,5-
diketopiperazine (S)-6. In this context, the reaction of N-Boc-L-
proline (S)-9 obtained in excellent yield from L-proline, with
glycine methyl ester hydrochloride, isobutyl chloroformate and N-
methylmorpholine in dichloromethane at room temperature,
gave the dipeptide (S)-10 in 93% yield, which by cleavage of the
N-Boc protective group with TFA followed by treatment with Et3N
in methanol under thermal conditions, produced the 2,5-
diketopiperazine (S)-6 in 78% yield [71% overall yield from L-
proline] (Scheme 2).
Results and Discussion
For the synthesis of the novel cyclic α-aminophosphonic and α-
aminophosphinic acids (1R,8aS)-3 and (1R,8aS)-4, we
proposed the chiral 2,5-diketopiperazine (S)-6 easily obtained
from L-proline as a key starting material, considering that one of
the methodologies for the synthesis of cyclic α-
aminophosphonate derivatives is the addition of trialkyl
phosphites to cyclic carbenium ions, which can be obtained from
the corresponding cyclic amides (Scheme 1).
In the next stage, selective activation of one of the carbonyl
groups in the 2,5-diketopiperazine (S)-6 was performed by its
transformation into a carbamate-imide derivative that would
allow its reduction into an hemiaminal using mild reducing agents,
since the tert-butoxycarbonyl protecting group acts as an
electron acceptor, enhancing the electrophilicity of otherwise
less electrophilic C-2 carbonyl group. Thus, the 2,5-
diketopiperazine (S)-6 was reacted with (Boc)2O, triethylamine
and 4-(dimethylamino)pyridine (DMAP) in dichloromethane at
room temperature, to obtain the N-Boc 2,5-diketopiperazine (S)-
11 in 92% yield (Scheme 3).
Scheme 1. Retrosynthetic analysis of (1R,8aS)-3 and (1R,8aS)-4.
Taking into account the previous analysis, we first addressed the
preparation of the glycyl-L-proline 2,5-diketopiperazine (S)-6.
Various methods have been reported for the synthesis of 2,5-
DKPs7 and one of the most common involves the coupling of an
N-protected α-amino acid with an α-amino acid ester, followed
by removal of the N-protecting group and cyclization. Therefore,
Scheme 2. Synthesis of the glycyl-L-proline 2,5-diketopiperazine (S)-6.
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10.1002/ejoc.201901439
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hemiaminals,14 we carried out the reduction of the carbamate-
imide function in the N-Boc protected 2,5-diketopiperazine (S)-11
with Et3BHLi in dichloromethane at -78 ºC, obtaining the
corresponding hemiaminals (1R,8aS)-12 and (1S,8aS)-13, which
without further purification were reacted with the appropriate
phosphorus nucleophile in the presence of BF3·OEt2 in
dichloromethane at -78 ºC, obtaining the corresponding cyclic
organophosphorus compounds (1R,8aS)-16 or (1R,8aS,RP)-17
and (1R,8aS,SP)-18 in 40 and 47% overall yield from (S)-11,
respectively, with identical diastereoselectivities (Scheme 4,
Method B).
Scheme 3. Preparation of the N-Boc 2,5-diketopiperazine (S)-11.
Once the 2,5-diketopiperazine with the appropriate imide system
(S)-11 was prepared, we undertook its transformation into the α-
aminophosphonate and phosphinate functionalities by a three-
step process without isolation of the intermediates. Thus, the
selective reduction of carbamate-imide function in the N-Boc 2,5-
diketopiperazine (S)-11 with lithium triethyl borohydride (Et3BHLi)
in dichloromethane at -78 ºC, gave the diastereoisomeric mixture
of unstable hemiaminals (1R,8aS)-12 and (1S,8aS)-13.
Considering the well-known hemiaminal derivatization to its
methyl ether as carbenium ion precursor in the synthesis of α-
amino acid derivatives,12 we carried out the treatment of the
unisolated hemiaminals (1R,8aS)-12 and (1S,8aS)-13 with
methanol and catalytic amounts of pyridinium p-toluenesulfonate
(PPTS), to obtain the corresponding hemiaminal methyl ethers
(1R,8aS)-14 and (1S,8aS)-15, which by reaction with trimethyl
phosphite in the presence of boron trifluoride diethyl ether
(BF3·OEt2) in dichloromethane at -78 ºC, afforded the cyclic N-
Boc α-aminophosphonate (1R,8aS)-16 in 46% overall yield from
(S)-11 and 98:2 diastereoisomeric ratio, presumably through the
phosphonylation of the carbenium ion (S)-5. On the other hand,
when dimethyl phenylphosphonite was used as trivalent
phosphorus nucleophile in this last step, the cyclic N-Boc α-
aminophosphinates (1R,8aS,RP)-17 and (1R,8aS,SP)-18 were
obtained in 33% overall yield from (S)-11 and 4:1 cis:trans
diastereoisomeric ratio (Scheme 4, Method A). It is noteworthy to
mention that although the reduction of C-2 carbonyl group
proceeds with low diastereoselectivity probably due to the
reduced nucleophile size (hydride), the diastereoselectivity of this
stage does not affect the stereochemical outcome of the global
route, since the stereochemistry of this center is lost during Lewis
acid mediated elimination (Scheme 4).
The diastereoisomeric ratio was determined by 31P NMR
spectroscopy at 202 MHz, and the absolute configuration of the
α-aminophosphonate (1R,8aS)-16 was established by X-ray
diffraction (Figure 2).13
Scheme 4. Synthesis of (1R,8aS)-16, (1R,8aS,RP)-17 and (1R,8aS,SP)-18 via
the carbenium ion intermediate (S)-5.
Despite what was expected, the preferred formation of cis
diastereoisomers (Schemes 4) can be explained by depicting a
carbenium ion intermediate (S)-5a15 as indicated in Figure 3, in
which the tert-butoxycarbonyl protecting group adopts a trans
Additionally, aiming to reduce the number of steps of the
procedure and taking into account reports that describe that Lewis
acids can mediate the direct addition of nucleophiles to
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10.1002/ejoc.201901439
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orientation with respect to the pyrrolidine ring. Thus, cis products
arise from a kinetically controlled process where nucleophiles
prefer to approach the carbenium carbon center from the Re face
(less hindered face).
Finally, the cleavage of tert-butoxycarbonyl protecting group in
(1R,8aS)-16 with simultaneous hydrolysis of phosphonic ester
moiety was accomplished by reaction with a 33% solution of
hydrogen bromide in acetic acid, followed by the treatment with
propylene oxide in ethanol, obtaining the cyclic α-
aminophosphonic acid (1R,8aS)-3 in quantitative yield as a single
diastereoisomer. Surprisingly, these conditions did not work to
meet the hydrolysis of the N-Boc α-aminophosphinates
(1R,8aS,RP)-17 and (1R,8aS,SP)-18. In this regard,
bromotrimethylsilane is known as a selective reagent to prepare
trimethylsilyl derivatives from phosphinate alkyl esters, thus
making the corresponding phosphinic acids readily available via
hydrolysis with neutral H2O. Indeed, deprotection of compounds
(1R,8aS,RP)-17 and (1R,8aS,SP)-18 with bromotrimethylsilane in
dichloromethane followed by the methanolysis and subsequent
treatment with propylene oxide in methanol, produced the cyclic
α-aminophosphinic acid (1R,8aS)-4 in 93% yield and 81:19
diastereoisomeric ratio (Scheme 5).
Figure 2. Single-crystal X-Ray analysis structure of (1R,8aS)-16.
Scheme 5. Preparation of target compounds (1R,8aS)-3 and (1R,8aS)-4.
Conclusions
In conclusion, we have developed the first highly
diastereoselective synthesis of cyclic α-aminophosphonic acid
(1R,8aS)-3 and phosphinic acid (1R,8aS)-4 starting from the
glycyl-L-proline 2,5-diketopiperazine (S)-6 involving the high
diastereoselective addition of trimetyl phosphite and dimethyl
phenylphosphonite to the chiral carbenium ion (S)-5a as the key
step. These results show the utility of the 2,5-diketopiperazines
as valuable chiral intermediates in the synthesis of
organophosphorus compounds with potential application in
medicinal and organic chemistry.
Figure 3. Proposed mechanism for the addition of phosphorus nucleophiles to
chiral carbenium ion (S)-5a.
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stirred vigorously for 15 min and then extracted with CH2Cl2 (3 x 5 mL).
The organic layers were washed with brine (5 mL), dried over anhydrous
Na2SO4, filtered and evaporated under reduced pressure to obtain the
mixture of unstable hemiaminals (1R,8aS)-12 and (1S,8aS)-13, which was
dissolved in anhydrous CH2Cl2 (3 mL) and kept under nitrogen. The
corresponding phosphorus nucleophile (trimethyl phosphite or dimethyl
phenylphosphonite) (0.38 mmol) was added and the resulting solution was
cooled at 0 °C. Boron trifluoride-diethyl ether (0.38 mmol) was added
dropwise and the reaction mixture was stirred for 15 min at 0 °C and 3.0 h
at room temperature. The reaction was then quenched with water (1 mL)
and extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered and evaporated under reduced
pressure. Finally, the crude product was purified by flash column
chromatography.
Experimental Section
All commercial materials were used as received unless otherwise noted.
Flash chromatography was performed with 230-400 mesh Silica Flash 60®.
Thin layer chromatography was performed with pre-coated TLC sheets of
silica gel (60 F254, Merck) and the plates were visualized with iodine, UV-
light and solutions of ninhydrin and KMnO4. Melting points were
determined with a Fisher–Johns apparatus and are uncorrected. NMR
spectra were recorded on a Bruker Avance III HD instrument (500 MHz for
1H, 126 MHz for 13C and 202 MHz for 31P) and calibrated using the TMS,
P(O)Ph3 and the residual solvent signal as internal standards; chemical
shifts (δ) are expressed in parts per million (ppm) and coupling constants
(J) in Hertz and an asterisk (*) indicates a duplicate signal corresponding
to the minor rotamer. Abbreviations used for NMR characterization: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; bs, unresolved broad
signal. High resolution FAB+ and ESI mass spectra (HRMS) were obtained
on a JEOL MStation MS-700. 1H and 13C NMR data for the compounds
(S)-616 and (S)-1117 were identical to those described in the literature.
4.1.1. Dimethyl (1R,8aS)-N-(tert-butoxycarbonyl)-4-oxohexahydro
pyrrolo[1,2-a]pyrazine-2-phosphonate 16. White solid, 46% (method A),
40% (method B); m.p. = 116-119 °C. [α]20 = -21.06 (c 1.0, MeOH). 1H NMR
(DMSO-d6): δ = 1.43* (s, 9H, (CH3)3C), 1,46 (s, 9H, (CH3)3C), 1.69-1.79
(m, 1H, CH2), 1.89-1.99 (m, 1H, CH2), 2.07-2.12 (m, 2H, CH2), 3.35-3.39
(m, 2H, CH2N), 3.59 (bs, 1H, CHN), 3.65 (d, J = 10.8, 3H, (CH3O)2P), 3.67
(d, J = 10.7, 3H, (CH3O)2P), 3.72* (d, J = 10.6, 3H, (CH3O)2P), 3.73* (d, J
= 10.6, 3H, (CH3O)2P), 3.89-4.01 (m, 1H, CHP), 4.10 (d, J = 17.7, 1H,
CH2CO). 13C NMR (DMSO-d6): δ = 21.9 (CH2), 22.0* (CH2), 27.8 ((CH3)3C),
28.0 (CH2), 44.9* (CH2N), 45.0 (CH2N), 45.6* (CH2CO), 46.1 (CH2CO),
48.0 (d, J = 150.0, CHP), 49.6* (d, J = 149.4, CHP), 52.6* (d, J = 5.1,
(CH3O)2P), 52.7 (d, J = 6.8, (CH3O)2P), 52.8* (d, J = 6.9, (CH3O)2P), 56.8
(CHN), 57.1* (CHN), 80.6* (C(CH3)3), 80.7 (C(CH3)3), 152.6* (C=O), 153.1
(C=O), 162.7 (C=O), 162.8* (C=O). 31P NMR (DMSO-d6): δ = 22.9*, 23.1.
HRMS (FAB+): calcd. for C14H26N2O6P [M+H]+, m/z 349.1528; found for
[M+H]+, m/z 349.1490.
4.1. General procedure for the preparation of N-Boc α-
aminophosphonate (1R,8aS)-16 and N-Boc α-aminophosphinates
(1R,8aS,RP)-17 and (1R,8aS,SP)-18.
Method A: To a stirred solution of 2,5-diketopiperazine (S)-11 (0.19 mmol)
in anhydrous CH2Cl2 (2 mL) at -78 °C and under nitrogen was dropwise
added 1.0 M solution of Et3BHLi in THF (0.29 mmol). The reaction mixture
was stirred at -78 °C for 1.0 h and then quenched with water (1 mL) and
H2O2 (1 mL) and warmed at room temperature. The resulting mixture was
stirred vigorously for 15 min and then extracted with CH2Cl2 (3 x 5 mL).
The organic layers were washed with brine (5 mL), dried over anhydrous
Na2SO4, filtered and evaporated under reduced pressure to obtain the
mixture of unstable hemiaminals (1R,8aS)-12 and (1S,8aS)-13, which was
dissolved in MeOH (2 mL) and catalytic PPTS (0.019 mmol) was added.
The mixture was allowed to reach at room temperature and stirred for an
additional 12.0 h. The reaction was quenched with Et3N (0.13 mmol) and
the solvent was evaporated under reduced pressure, to give the
hemiaminal methyl ethers (1R,8aS)-14 and (1S,8aS)-15, which were
dissolved in anhydrous CH2Cl2 (3 mL) and kept under nitrogen. The
corresponding phosphorus nucleophile (trimethyl phosphite or dimethyl
phenylphosphonite) (0.38 mmol) was added and the resulting solution was
cooled at 0 °C. Boron trifluoride-diethyl ether (0.38 mmol) was added
dropwise and the reaction mixture was stirred for 15 min at 0 °C and 3.0 h
at room temperature. The reaction was then quenched with water (1 mL)
and extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered and evaporated under reduced
pressure. Finally, the crude product was purified by flash column
chromatography.
4.1.2. Methyl (1R,8aS,RP)-N-(tert-butoxycarbonyl)-4-oxohexahydro
pyrrolo[1,2-a]pyrazine-2-phenylphosphinate 17 and (1R,8aS,SP)-18.
White solid, 33% (method A), 47% (method B). 1H NMR (CDCl3): δ = 1.04
(s, 9H, (CH3)3C), 1.15 (s, 9H, (CH3)3C), 1.20 (s, 9H, (CH3)3C), 1.22 (s, 9H,
(CH3)3C), 1.29 (s, 9H, (CH3)3C), 1.71-1.83 (m, 1H, CH2), 2.05-2.15 (m, 1H,
CH2), 2.14-2.27 (m, 1H, CH2), 2.42-2.53 (m, 1H, CH2), 2.52-2.64 (m, 1H,
CH2), 2.68-2.82 (m, 1H, CH2), 3.52-3.60 (m, 1H, CH2N), 3.62 (d, J = 11.0,
3H, CH3OP), 3.66 (d, J = 10.7, 3H, CH3OP), 3.72 (d, J = 10.8, 3H, CH3OP),
3.89 (d, J = 18.2, 1H, CH2CO), 3.92 (d, J = 17.7, 1H, CH2CO), 3.97-4.06
(m, 1H, CH2N), 4.03-4.11 (m, 1H, CH2N), 4.16 (d, J = 18.1, 1H, CH2CO),
4.26 (d, J = 17.9, 1H, CH2CO), 4.32 (d, J = 18.4, 1H, CH2CO), 4.41 (d, J =
18.2, 1H, CH2CO), 4.71 (dd, J = 8.7, 4.8, 1H, CHP), 4.78 (dd, J = 12.3, 4.6,
1H, CHP), 4.96 (dd, J = 8.2, 4.8, 1H, CHP), 5.04 (dd, J = 11.0, 4.6, 1H,
CHP), 7.41-7.65 (m, 5H, Harom), 7.66-7.89 (m, 5H, Harom). 31P NMR
(CDCl3): δ = 39.1, 40.0, 40.6, 42.1, 42.4. HRMS (FAB+): calcd. for
C19H28N2O5P [M+H]+, m/z 395.1736; found for [M+H]+, m/z 395.1727.
Method B: To a stirred solution of 2,5-diketopiperazine (S)-11 (0.19 mmol)
in anhydrous CH2Cl2 (2 mL) at -78 °C and under nitrogen was dropwise
added 1.0 M solution of Et3BHLi in THF (0.29 mmol). The reaction mixture
was stirred at -78 °C for 1.0 h and then quenched with water (1 mL) and
H2O2 (1 mL) and warmed at room temperature. The resulting mixture was
4.2. ((1R,8aS)-4-Oxooctahydropyrrolo[1,2-a]pyrazin-1-yl)phosphonic
acid 3. The cyclic α-aminophosphonate (1R,8aS)-16 (0.06 g, 0.17 mmol)
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10.1002/ejoc.201901439
European Journal of Organic Chemistry
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was treated with a 33% solution of hydrogen bromide in acetic acid (3 mL).
The reaction mixture was stirred at room temperature for 6.0 h, and the
volatiles were evaporated under reduced pressure. The crude product was
dissolved in ethanol (2 mL), and the resulting solution was treated with
propylene oxide (3 mL) and stirred at room temperature for 12.0 h. The
precipitate formed was filtered, washed successively with CH2Cl2 and
AcOEt and dried under reduced pressure to give 36 mg (>98%) of
(1R,8aS)-3 in >98:2 d.r. as a white solid; m.p. = 245-248 °C. [α]20 = -21.1
(c 1.0, H2O). 1H NMR (D2O): δ = 1.77-1.96 (m, 1H, CH2), 2.03-2.36 (m, 3H,
CH2CH2), 3.46-3.52 (m, 1H, CH2N), 3.58-3.62 (m, 1H, CH2N), 3.89 (d, J =
17.5, 1H, CH2CO), 3.94 (d, J = 17.5, 1H, CH2CO), 4.04 (dd, J = 14.0, 3.7,
1H, CHP), 4.12 (ddd, J = 26.9, 10.3, 4.8, 1H, CHN). 13C NMR (D2O): δ =
21.7 (CH2), 28.6 (CH2), 42.2 (CH2N), 46.0 (CH2CO), 50.8 (d, J = 139.2,
CHP), 55.9 (CHN), 162.7 (C=O). 31P NMR (D2O): δ = 5.6. HRMS (ESI):
calcd. for C7H14N2O4P [M+H]+, m/z 221.0691; found for [M+H]+, m/z
221.0686.
Keywords: Chiral carbenium ions • cyclic α-aminophosphonic
acids • cyclic α-aminophosphinic acids • 2,5-diketopiperazines
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((1R,8aS)-4-Oxooctahydropyrrolo[1,2-a]pyrazin-1-yl)(phenyl)
phosphinic acid 4. To a stirred solution of the α-aminophosphinates
(1R,8aS,RP)-17 and (1R,8aS,SP)-18 (0.10 g, 0.25 mmol) in dry
dichloromethane (7 mL) at room temperature, bromotrimethylsilane (0.4
mL, 3.04 mmol) was added. Stirring was continued for 24.0 h. After
evaporation of solvent, the solid residue was washed with dry methanol (5
x 5 mL). Then, propylene oxide (5 mL) was added to the resulting residue
and the mixture was kept under stirring for 2.0 h. Then the excess of
propylene oxide was removed under reduced pressure, the residue was
redissolved in MeOH (2 mL) and precipitated with the addition of Et2O. The
precipitate formed was filtered, washed successively with Et2O and AcOEt
and dried under reduced pressure to give 65 mg (93%) of (1R,8aS)-4 in
81:19 d.r. as a light brown solid; m.p. = 162-165 °C. [α]20 = -23.6 (c 1.0,
CHCl3). 1H NMR (D2O): δ = 1.71-1.86 (m, 1H, CH2), 1.94-2.13 (m, 2H, CH2),
2.15-2.31 (m, 1H, CH2), 2.94-3.16 (m, 1H, CH2N), 3.34-3.56 (m, 1H, CH2N),
3.87 (d, J = 17.2, 1H, CH2CO), 3.95 (d, J = 17.2, 1H, CH2CO), 4.02-4.16
(m, 1H, CHN), 4.22 (dd, J = 10.5, 4.6, 1H, CHP), 7.48-7.71 (m, 3H, Harom),
7.74-7.97 (m, 2H, Harom). 13C NMR (D2O): δ = 21.8 (CH2), 28.5 (CH2), 30.9*
(CH2), 42.8 (CH2N), 44.9* (d, J = 6.9, CH2N), 45.6* (CH2CO), 46.1
(CH2CO), 53.7 (d, J = 91.7, CHP), 56.2 (CHN), 56.6* (CHN), 57.3* (d, J =
89.3, CHP), 129.1 (d, J = 12.6, Carom), 131.9 (d, J = 10.1, Carom), 132.1* (d,
J = 9.8, Carom), 132.7 (Carom), 132.9* (Carom), 133.4* (Carom), 134.5 (Carom),
162.3 (C=O), 162.5* (C=O). 31P NMR (D2O): δ = 17.9, 18.2*. HRMS (ESI):
calcd. for C13H18N2O3P [M+H]+, m/z 281.1055; found for [M+H]+, m/z
281.1049.
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Acknowledgments
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The authors thank the Consejo Nacional de Ciencia y Tecnología
(CONACYT) for financial support through projects 286614 and
256985. We also thank Victoria Labastida and Jorge Guillermo
Domínguez-Chávez for their valuable technical support in
obtaining MS spectra and X-ray structure. F.T.H. also wish to
thank CONACYT for Graduate Scholarships 626420.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901439
European Journal of Organic Chemistry
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Diastereoselective synthesis
Mario Ordóñez*, Fernando Torres-
Hernández and José Luis Viveros-
Ceballos
Page No. – Page No.
This paper describes the first diastereoselective synthesis of cyclic α-
aminophosphonic and α-aminophosphinic acids (1R,8aS)-3 and (1R,8aS)-4 from
glycyl-L-proline 2,5-diketopiperazine (S)-6, through the highly diastereoselective
nucleophilic addition of trimethyl phosphite or dimethyl phenylphosphonite to the
chiral carbenium ion (S)-5.
Highly diastereoselective synthesis
of cyclic α-aminophosphonic and α-
aminophosphinic acids from glycyl-L-
proline 2,5-diketopiperazine
This article is protected by copyright. All rights reserved.