Isothiocyanate Strategy for the Synthesis of Quaternary α-Amino Acids Bearing a Spirocyclic Ring System

Article abstract of DOI:10.1002/adsc.201701642

This study demonstrates that isothiocyanates derived from α-substituted α-amino acids are useful building blocks in the heteroannulation reactions with electron-deficient olefins. The developed strategy proceeds in a cascade manner and involves Michael addition followed by a cyclization via nucleophilic addition. Target, spirocyclic heterocycles bearing either a quaternary α-amino acid moiety or α-aminophosphonate group have been efficiently synthesized in very high yield (up to 99%) and with excellent stereocontrol. The usefulness of heterocycles obtained has been demonstrated in selected transformations. (Figure presented.).

Full text of DOI:10.1002/adsc.201701642

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DOI: 10.1002/adsc.201701642
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Isothiocyanate Strategy for the Synthesis of Quaternary a-Amino
Acids Bearing a Spirocyclic Ring System
a
a
a,
Sebastian Frankowski, Tadeusz Gajda, and Łukasz Albrecht *
a
Institute of Organic Chemistry, Department of Chemistry, Lodz University of Technology, Zeromskiego 116, 90–924 Ł o´ d z´ ,
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Poland
Tel. +48426313157www.a-teamlab.p.lodz.pl
E-mail: lukasz.albrecht@p.lodz.pl
Received: December 28, 2017; Revised: March 15, 2018; Published online: &&&, &&&&
Dedicated to the memory of Professor Henryk Krawczyk, our friend and mentor, who passed away too soon
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201701642
Abstract: This study demonstrates that isothiocyanates derived from a-substituted a-amino acids are useful
building blocks in the heteroannulation reactions with electron-deficient olefins. The developed strategy
proceeds in a cascade manner and involves Michael addition followed by a cyclization via nucleophilic
addition. Target, spirocyclic heterocycles bearing either a quaternary a-amino acid moiety or a-amino-
phosphonate group have been efficiently synthesized in very high yield (up to 99%) and with excellent
stereocontrol. The usefulness of heterocycles obtained has been demonstrated in selected transformations.
Keywords: Asymmetric synthesis; Bifunctional catalysis; Isothiocyanates; Quaternary a-amino acids;
Pyrrolidine
1 Introduction
acid motif into a target molecule results in increased
resistance to enzymatic and chemical degradation and,
Quaternary a-amino acids are an important group of in many cases, enhanced biological properties. Nota-
[
1]
biologically relevant molecules. Such a structural bly, the biological activity of such systems is directly
motif is present in various natural products and correlated with the absolute stereochemistry of the
compounds relevant for the life-science industry (with quaternary stereogenic center. For this reason, the
[
2]
representative examples I–III shown in the Figure 1).
development of methods for their preparation in an
Furthermore, the incorporation of quaternary a-amino enantioselective fashion is of particular importance.
Barbituric acid constitutes another structural motif
widely distributed in nature that is highly relevant in
the contemporary medicinal and organic chemistry.
Compounds containing that scaffold possess strong
and diverse biological activity (Figure 1, compounds
[
3]
IV,V). In this context, the spirocyclic architecture
present in the biologically relevant barbituric acid
derivatives is worth noticing. Surprisingly, the enantio-
selective methods for their preparation remain lim-
[
4]
ited.
Target-oriented-synthesis of privileged structural
motifs is the ultimate goal of the contemporary
[
5]
organic chemistry. This field of research has been
recently dominated by the enantioselective ap-
proaches with the chiral catalysts used to achieve
chiral discrimination. In particular, biomimetic cas-
cade reactivities have recently emerged as a conven-
[
6]
Figure 1. Examples of biologically relevant quaternary a-
amino acid and barbituric acid derivatives.
Adv. Synth. Catal. 2018, 360, 1–12
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ient tool to build chemical and stereochemical diver-
Given the biological and chemical importance of
sity from simple and readily available starting materi- quaternary a-amino acids and their analogues, the
[7,8]
als. Within this field of research asymmetric organo- task of development of a new approach to this class of
catalysis has revealed its great potential for the compounds was undertaken. We became particularly
construction of biologically relevant molecules in a interested in 2-pyrrolidinethione derivatives contain-
single chemical transformation proceeding in a cas- ing additional barbiturate or Meldrum’s acid moiety
[8]
cade manner. In this context, the immense progress in a spirocyclic alignment. In this context it is worth to
in the development of biomimetic asymmetric strat- note that the introduction of two bio-relevant core
egies leading to a-amino acids and their derivatives is structures (such as barbituric acid and quaternary
[1,9]
1
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2
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worth noticing.
Over the years various organo- amino acid moieties) into one molecule should lead to
catalytic, stereocontrolled approaches for the prepara- hybrid molecules with intriguing biological properties.
tion of quaternary a-amino acids have been intro- Herein, we present our studies on the application of
[9]
duced. Among them one particularly visible trend isothiocyanates derived either from a-substituted a-
involves the usage of alkyl isothiocyanates bearing an amino acids or a-aminophosphonates for the synthesis
electron-withdrawing moiety in the a-position of 2-pyrrolidinethione derivatives bearing spirocyclic
[
9b,10–13]
(Scheme 1, top).
They readily participate in ring system (Scheme 1, bottom).
cascade reactions with various electron-poor C=X and
C=C double bonds resulting in the annulation of
various heterocyclic systems. Isothiocyanates based on
2
Results and Discussion
[
10]
[11]
the oxindole scaffold or derived from glycine are Optimization studies were performed using dimethyl
commonly employed in such strategies (Scheme 1, 5-(benzylidene)barbiturate 1a and phenylglycine-de-
middle). Surprisingly, the application of simple iso- rived isothiocyanate 2a as model starting materials
thiocyanates derived from a-substituted a-amino acids (Table 1). Initial experiment was performed in di-
in organocatalytic heteroannulations is limited and chloromethane in the presence of quinine 4a as the
focuses mainly on their reactions with aldehydes or catalyst (Table 1, entry 1). We were pleased to observe
[12,13]
imines.
that under these conditions the annulation of five-
membered heterocycle occurred. Disappointingly, the
reaction was not stereoselective as 3aa was formed as
almost a racemic mixture of two diastereomers in a
close to 1:1 ratio. Therefore, the catalyst screening was
initiated (Table 1, entries 1–3). We anticipated that the
use of catalysts bearing stronger H-bonding donors
such as thiourea or squaramide moieties should be
beneficial for the stereochemical reaction outcome.
Surprisingly, while the use of thiourea catalyst 4b
(Table 1, entry 2) resulted in similar result when
compared to quinine 4a, the application of squara-
mide catalyst 4c (Table 1, entry 3) led to significant
improvement in terms of both enantio- and diaster-
eoselectivity. Subsequent solvent screening (Table 1,
entries 3–9) indicated that the diastereoselectivity of
the elaborated cascade was increased by a simple
change of solvent with the reaction performed in
toluene providing the best results (Table 1, entry 9).
However, longer reaction time was required to
achieve full conversion in this case. Notably, the
reaction proceeded efficiently with pseudoenantiomer-
ic catalyst 4d providing access to opposite enantiomer
of the product ent-3aa with comparable results
(Table 1, entry 10).
With the optimized reaction conditions in hand,
studies on the scope and limitations of the developed
heteroannulation reaction were undertaken. Initially,
various dimethyl 5-(alkylidene)barbiturates 1 were
employed in the developed reaction using 2a as a
model isothiocyanate component (Table 2). To our
delight, the reaction proved unbiased towards both
Scheme 1. Iso(thio)cyanate strategy in the synthesis of het-
erocycles and the synthetic objectives of our study.
Adv. Synth. Catal. 2018, 360, 1–12
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Table 1. Isothiocyanate strategy in the enantioselective syn-
thesis of quaternary a-amino acids 3 – optimization studies.
Table 2. Isothiocyanate strategy in the enantioselective syn-
thesis of quaternary a-amino acids 3 – dimethyl 5-(alkyli-
dene)barbiturate 1 scope.
[a]
[a]
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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2
3
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3
3
3
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5
5
5
5
5
5
5
5
1
[b]
[c]
[d]
R
yield [%]
dr
er
1
2
3
4
5
6
7
8
9
1
1
1
Ph (3aa)
90
77
79
62
20:1
20:1
>20:1 95:5
>20:1 98.5:1.5
20:1
20:1
>20:1 99:1
10:1 98:2
>20:1 99:1
>20:1 96:4
6:1
15:1
97:3
97:3
4-ClC H (3ba)
6
4
3-ClC H (3ca)
6
4
[b]
[c]
[d]
solvent
CH Cl
cat. conv. (yield)
dr
er
2-ClC H (3da)
6
4
4-NO C H (3ea) 52
82.5:17.5
97.5:2.5
2
6
4
1
2
3
4
5
6
7
8
9
1
4a
4b
4c
4c
4c
4c
4c
4c
96
97
57
81
97
93
96
82
1:1.2 60:40
1.3:1 51:49
5.6:1 94:6
6.7:1 95:5
5.3:1 94:6
5.0:1 92.5:7.5
1.2:1 73:27
9.7:1 96:4
2
2
2
2
4-MeOC
H
(3fa) 98
6
4
CH Cl
2
2,4-Cl C H (3ga) 93
2
6
3
CH Cl
2
1-naphthyl (3ha)
2-furyl (3ia)
i-Pr (3ja)
(E)-b-styryl (3ka) 79
Ph (3aa) 86
56
88
40
CHCl3
AcOEt
THF
MeCN
Et O
2
0
1
2
94:6
99:1
[e]
e)
e)
toluene 4c
toluene 4d
>95(90)
>95(80)
20:1
20:1
97:3
6:94
[a]
Reactions performed on 0.05 mmol scale using 1 (1 equiv.)
and 2a (1 equiv.) in 0.2 mL of the toluene.
Isolated yields are given.
0
[
[
[
[
b]
c]
d]
e]
[
a]
Reactions performed on 0.05 mmol scale using 1a
(1 equiv.) and 2a (1 equiv.) in 0.2 mL of the CH Cl .
As determined by H NMR of a crude reaction mixture
1
As determined by H NMR of a crude reaction mixture.
2
2
[
[
b]
1
Determined by a chiral stationary phase HPLC.
Reaction performed on 3 mmol scale for 72 h. Isolated
yield of a single diastereomer is given.
after 24 h (in parenthesis isolated yield is given).
c]
1
As determined by H NMR of a crude reaction mixture
after 24 h.
[
[
d]
e]
Determined by a chiral stationary phase HPLC.
Reaction carried out for 48 h.
Further scope studies were devoted towards the
application of isothiocyanates 2 in which the ester
moiety was replaced with diphenylphosphonate group.
the position (Table 2, entries 2–4) and electronic Such a strategy was highly appealing as it provided a
properties (Table 2, entries 2, 5 vs. 6) of substituents facile entry to biologically relevant a-aminophospho-
present on the aromatic ring in 1. Target products 3 nates. However, initial experiment showed that re-
were obtained in high yields and in a highly stereo- optimization of reaction conditions was necessary
selective fashion in all of the cases. Furthermore, (Table 3). The application of the aforementioned
disubstituted aromatic rings and heteroaromatic moi- conditions gave unsatisfactory results (Table 3, en-
eties were also well-tolerated as demonstrated in the try 1). Therefore, the solvent screening was performed
synthesis of 3ga, 3ha and 3ia (Table 2, entries 7–9). (Table 3, entries 1–4) indicating THF as the best suited
Interestingly, the reaction proceeded for barbiturates solvent for the cascade in terms of diastereoselectivity.
1j and 1k substituted with alkyl and alkenyl groups To our delight, a substantial increase of the chemical
(Table 2, entries 10, 11). However, in the case of 3ja efficiency of the studied reaction was observed when
(R=i-Pr) synthesis, lower yield was observed. Nota- the reaction concentration was increased (Table 3,
bly, the developed cascade was also efficiently realized entry 5). Notably, under these conditions the reaction
on a 60-fold larger scale further increasing the proceeded with excellent stereocontrol. Unfortu-
usability of the elaborated protocol (Table 2, en- nately, alkyl-substituted isothiocyanates 3 were not
try 12).
Adv. Synth. Catal. 2018, 360, 1–12
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reactive enough under the optimized reaction con- Table 4. Isothiocyanate strategy in the enantioselective syn-
[a]
ditions.
thesis of quaternary a-aminophosphonates 3 – scope studies.
Table 3. Isothiocyanate strategy in the enantioselective syn-
thesis of quaternary a-aminophosphonates 3 – optimization
[
a]
studies.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
1
2
[b]
[c]
[d]
R
R
yield [%]
dr
er
1
2
3
4
5
6
7
Ph
4-ClC H
3-ClC H
2-ClC H
4-MeOC H Ph
Ph
Ph
Ph
Ph
Ph
Ph
3ab: 99
3bb: 79
3cb: 84
3db: 60
3fb: 85
3ac: 97
>20:1 99:1
10:1
15:1
20:1
97:3
96:4
98:2
6
4
4
4
6
[b]
[c]
[d]
R
conv. (yield)
dr
er
6
>20:1 99:1
>20:1 98:2
6
4
1
2
3
4
toluene
MeCN
1,4-dioxane
THF
20
72
17
40
10:1
4:1
10:1
>20:1
>20:1
n.d.
n.d.
n.d.
n.d.
99:1
4-ClC H
4-MeOC H 3ad: 73
6 4
7:1
97:3
6
4
[a]
Reactions performed on 0.1 mmol scale using 1 (1 equiv.)
and 2 (1 equiv.) in 0.2 mL of THF.
Isolated yields are given.
As determined by H NMR of a crude reaction mixture.
Determined by a chiral stationary phase HPLC.
[
e]
5
THF
100 (99)
[b]
[c]
[d]
[
a]
Reactions performed on 0.05 mmol scale using 1 a
(1 equiv.) and 2b (1 equiv.) in 0.2 mL of the toluene.
As determined by H NMR of a crude reaction mixture (in
1
[
b]
1
parenthesis isolated yield is given).
As determined by H NMR of a crude reaction mixture.
Determined by a chiral stationary phase HPLC.
Reaction performed in 0.1 mL of the solvent.
[
[
[
c]
d]
e]
1
To our delight, the reaction of 2b with selected
barbiturates 1a,b–d,f proceeded efficiently (Table 4).
Both the position (Table 4, entries 2–4) and the
electronic properties of substituents on the aromatic
ring in 1 (Table 4, entry 2 vs. 5) had no pronounced
effect on the reaction outcome. Furthermore, it was
2
found that the nature of R substituent in 2 can be
modified as demonstrated in the synthesis of 3ac and
3ad (Table 4, entries 6, 7).
In the final part of scope studies the possibility to
introduce a different electron-withdrawing group at
the double bond in 1 was evaluated (Scheme 2). The
reaction with Meldrum’s-acid-derived olefin 1l, per-
formed under un-optimized conditions, proceeded
Scheme 2. Isothiocyanate strategy in the enantioselective
synthesis of quaternary a-amino acids 3 – Meldrumꢁs acid
derivative case.
efficiently providing 3la with high diastereoselectivity, pyrrolidinone 5aa in high 90% yield. Furthermore, S-
albeit with lower enantioselectivity compared to methylation of 3aa was readily performed under basic
barbiturate counterpart 1f.
conditions yielding 6aa in almost quantitative yield.
With the scope study accomplished the usefulness Finally, reductive desulfuration of 3aa was accom-
of the compounds obtained for the synthesis of various plished using Nickel Raney to give 7aa in 48% yield.
pyrrolidine derivatives was demonstrated (Scheme 3). In all cases, stereochemical composition of the starting
Oxidative desulfuration of 3aa realized under material 3aa was fully preserved as 5aa, 6aa and 7aa
standard conditions proceeded efficiently affording were obtained as single diastereomers.
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Scheme 3. Chemoselective transformations of 3aa.
The absolute configuration of the products 3 was
unequivocally determined by the single crystal X-ray
analysis of the products 3aa and 3ab (Figure 2).
[
14]
Scheme 4. Mechanistic considerations.
3
Conclusion
In conclusion, we demonstrated that isothiocyanates 1
derived from a-substituted a-amino acids served as
useful building blocks for the synthesis of pyrrolidine-
based heterocycles. Their cascade reaction with ole-
finic barbiturates or Meldrum’s acid derivative pro-
ceeding in a sequence Michael addition followed by
nucleophilic addition resulted in the heteroannulation
of 2-pyrrolidinethione ring with spirocyclic architec-
ture. The developed reactivity was expanded for the
synthesis of a,a-disubstituted a-aminophosphonates
and benefited from excellent chemical and stereo-
chemical efficiency as well as broad substrate scope.
Furthermore, usefulness of the products obtained was
confirmed in selected transformations.
Figure 2. Determination of absolute configuration.
Based on these assignments, a plausible reaction
mechanism was proposed (Scheme 4). The elaborated
cascade reaction was initiated by two independent NMR spectra were acquired on a Bruker Ultra Shield 700
Experimental Section
1
13
instrument, running at 700 MHz for H, 176 MHz for C and
processes. Isothiocyanate 2 was deprotonated by 4c to
give anion 8. Simultaneously, electron-deficient olefin
1 was recognized through the H-bonding interaction
with squaramide moiety of the catalyst 4c. Such a
recognition profile of both reactants positioned them
correctly in space and forced the enolate 8 to
approach 1 in a stereocontrolled fashion. Michael
adduct 9 thus obtained underwent intramolecular
nucleophilic addition to give 10. In such a manner, the
annulation of five-membered heterocyclic ring was
31
2
83 MHz for P, respectively. Chemical shifts (d) are
reported in ppm relative to residual solvent signals (CDCl :
3
1
13
31
7
.26 ppm for H NMR, 77.16 ppm for C NMR). P NMR
spectra were recorded using 85% H PO as external
standard. Mass spectra were recorded on a Bruker Maxis
Impact spectrometer using electrospray (ES+) ionization
3
4
(referenced to the mass of the charged species). Optical
rotations were measured on a Perkin-Elmer 241 polarimeter
À1
À1
and [a] values are given in deg·cm·g ·dm ; concentration c
D
À1
is listed in g·(100 mL) . Melting points were determined in
accomplished and the catalyst was liberated. Tautome- open capillaries and are uncorrected. Analytical thin layer
rization of 10 furnished the cascade yielding 3.
chromatography (TLC) was performed using pre-coated
aluminum-backed plates (Merck Kieselgel 60 F254) and
visualized by ultraviolet irradiation or KMnO . The enantio-
meric ratio (er) of the products was determined by chiral
4
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stationary phase HPLC (Daicel Chiralpak IA, IC, ID and
IG). Unless otherwise noted, analytical grade solvents and
commercially available reagents were used without further
purification. For flash chromatography (FC) silica gel (Silica
gel 60, 230–400 mesh, Fluka) was used. Electron-deficient
1H), 7.32 (dd, J=11.6, 4.4 Hz, 2H), 7.19 (ddd, J=8.0, 2.0,
1.0 Hz, 1H), 7.17 (d, J=7.4 Hz, 2H), 7.00 (dd, J=11.8,
4.1 Hz, 1H), 6.63–6.61 (m, 2H), 5.34 (s, 1H), 3.79 (s, 3H), 3.33
13
(s, 3H), 3.02 (s, 3H). C NMR (176 MHz, CDCl ) d196.6,
3
170.3, 167.2, 164.8, 150.0, 134.4, 133.9, 133.1, 132.0, 130.1,
129.4, 129.3, 129.2, 128.2 (2C), 127.5 (2C), 77.6, 74.9, 58.7,
[
15a]
[15b]
[15b–d]
olefins 1
and isothiocyanates 2a
and 2b–d
were
+
prepared according to literature procedures.
54.0, 29.8, 29.1. HRMS calculated for [C H ClN O S+H ]:
2
3
20
3
5
23
4
86.0885; found: 486.0881 [a]D =À36.6 (c=1.0, CHCl ).
3
Isothiocyanate strategy in the enantioselective synthesis of
quaternary a-amino acids 3 – general procedure
The er was determined by HPLC using a chiral Chiralpack
IG column [hexane:i-PrOH, 90:10]; column temperature
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
In an ordinary 4 mL glass vial, equipped with a Teflon-coated
magnetic stirring bar and a screw cap, catalyst 4c (0.2 equiv.,
308C; flow rate 1.0 mL/min;
tmajor =13.8 min.,
t =
minor
11.4 min., (95:5 er).
0.01 mmol, 6.3 mg), corresponding electron-poor olefin 1
3
da (3R,4R)-Methyl 4-(2-chlorophenyl)-7,9-dimethyl-6,8,10-
trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decane-3-car-
boxylate. Following the general procedure (reaction time
8 h, >20:1 dr) 3da was isolated by FC on silica gel (eluent:
CH Cl ) in 62% yield (15.0 mg) as a white amorphous solid.
(1.0 equiv., 0.05 mmol) and isothiocyanate 2a (1.0 equiv.,
0.05 mmol) were dissolved in toluene (0.2 mL) and stirring
was maintained for 48 h at ambient temperature. Pure
product 3 was isolated by flash chromatography on silica gel
4
2
2
(
eluent: CH Cl ).
1
2
2
H NMR (700 MHz, CDCl ) d 8.91 (bs, 1H), 7.32 (dd, J=8.1,
3
3
aa (3R,4S)-Methyl 7,9-dimethyl-6,8,10-trioxo-3,4-diphenyl-
1.3 Hz, 2H), 7.31–7.27 (m, 4H), 7.07 (ddd, J=8.1, 7.4, 1.6 Hz,
1H), 6.72–6.69 (m, 1H), 6.12 (dd, J=8.1, 1.6 Hz, 1H), 6.04 (s,
1-thioxo-2,7,9-triazaspiro[4.5]decane-3-carboxylate. Follow-
ing the general procedure (reaction time 48 h, 20:1 dr), 3aa
was isolated by FC on silica gel (eluent: CH Cl ) in 90%
13
1H), 3.81 (s, 3H), 3.34 (s, 3H), 2.82 (s, 3H). C NMR
(176 MHz, CDCl ) d197.2, 170.3, 167.2, 165.0, 150.1, 135.8,
34.7, 133.1, 130.0, 129.7, 129.4, 129.0, 128.6, 127.1 (2C),
125.5, 78.0, 73.9, 54.4, 54.1, 29.6, 28.8, 28.8. HRMS calculated
2
2
3
1
yield (20.3 mg) as a white solid (mp=230–2318C). H NMR
700 MHz, CDCl ) d 8.96 (bs, 1H), 7.35–7.32 (m, 1H), 7.30–
1
(
3
+
23
7.27 (m, 2H), 7.21–7.18 (m, 3H), 7.06–7.04 (m, 2H), 6.65 (dd,
for [C23
À23.5 (c=1.0, CHCl
using a chiral Chiralpack ID column [hexane:i-PrOH, 80:20];
H
20ClN
3
O
5
S+H ]: 486.0885; found: 486.0894 [a]
D
=
J=8.2, 0.9 Hz, 2H), 5.30 (s, 1H), 3.77 (s, 3H), 3.30 (s, 3H),
3
). The er was determined by HPLC
1
3
2
1
1
2
.94 (s, 3H). C NMR (176 MHz, CDCl ) d 197.0, 170.5,
3
67.6, 165.2, 150.0, 134.7, 131.7 (2C), 131.0, 129.2, 129.1,
28.1 (2C), 128.1 (2C), 127.5 (2C), 77.8, 75.2, 60.0, 53.9, 29.6,
9.0. HRMS calculated for [C H N O S+H ]: 452.1275;
column temperature 308C; flow rate 1.0 mL/min; tmajor
22.3 min., tminor =20.7 min., (98.5:1.5 er).
=
+
2
3
21
3
5
3
ea (3R,4S)-Methyl 7,9-dimethyl-4-(4-nitrophenyl)-6,8,10-tri-
22
found: 452.1281. [a]D =À38.1 (c=1.0, CHCl ). The er was
3
oxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decane-3-carbox-
ylate. Following the general procedure (reaction time 48 h,
determined by HPLC using a chiral Chiralpack IG column
[
hexane:i-PrOH, 90:10]; column temperature 308C; flow rate
2
0:1 dr) 3ea was isolated by FC on silica gel (eluent: CH Cl )
2 2
1
1.0 mL/min; tmajor =16.4 min., tminor =14.1 min., (97:3 er). The
reaction was also performed on 0.5 mmol scale providing 3aa
in 90% yield, 20:1 dr, 96:4 er.
in 52% yield (12.9 mg) as a white amorphous solid. H NMR
700 MHz, CDCl ) d 8.70 (s, 1H), 7.93–7.87 (m, 2H), 7.42–
(
3
7
.38 (m, 1H), 7.36–7.30 (m, 2H), 7.17–7.13 (m, 2H), 6.97–6.94
3
ba (3R,4S)-Methyl 4-(4-chlorophenyl)-7,9-dimethyl-6,8,10-
(m, 2H), 5.65 (s, 1H), 3.80 (s, 3H), 3.35 (s, 3H), 3.06 (s, 3H).
13
trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decane-3-car-
boxylate. Following the general procedure (reaction time
C NMR (176 MHz, CDCl ) d 195.7, 170.3, 166.5, 164.2,
3
149.9, 148.1, 138.6, 134.3, 133.4 (2C), 129.7, 128.4 (2C), 127.4
(2C), 122.9 (2C), 77.5, 74.9, 57.4, 54.1, 30.0, 29.3.HRMS
48 h, 20:1 dr), 3ba was isolated by FC on silica gel (eluent:
+
CH Cl ) in 77% yield (18.7 mg) as an off-white amorphous
calculated for [C H N O S+H ]: 497.1125; found:
23 21
4
7
2
2
1
24
D
solid. H NMR (700 MHz, CDCl ) d 8.81 (bs, 1H), 7.38–7.35
497.1131. [a]
mined by HPLC using a chiral Chiralpack IG column
hexane:i-PrOH, 90:10]; column temperature 308C; flow rate
1.0 mL/min; tmajor =24.1 min., tminor =21.3 min., (82.5:17.5 er).
=À35.9 (c=1.0, CHCl
3
). The er was deter-
3
(m, 1H), 7.32–7.30 (t, J=7.7 Hz, 2H), 7.17–7.16 (m, 2H),
7.04–7.03 (m, 2H), 6.64–6.62 (m, 2H),5.39 (s, 1H), 3.77 (s,
[
1
3
3
1
1
5
H), 3.32 (s, 3H), 3.01 (s, 3H). C NMR (176 MHz, CDCl ) d
3
96.5, 170.4, 167.2, 164.8, 150.0, 135.4, 134.5, 133.3 (2C),
29.7, 129.3, 128.3 (2C), 128.2 (2C), 127.5 (2C), 77.0, 75.0,
8.4, 53.9, 29.7, 29.1. HRMS calculated for [C H ClN O S+
3
fa (3R,4S)-Methyl 4-(4-methoxyphenyl)-7,9-dimethyl-
6,8,10-trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decane-
3-carboxylate. Following the general procedure (reaction
time 48 h, 20:1 dr) 3fa was isolated by FC on silica gel
2
3
20
3
5
+
21
H ]: 486.0885; found: 486.0888. [a]D =À60.1 (c=1.0,
CHCl ). The er was determined by HPLC using a chiral
3
(
eluent: CH Cl ) in 98% yield (23.6 mg) as a pale yellow
2 2
1
Chiralpack IG column [hexane:i-PrOH, 90:10]; column
temperature 308C; flow rate 1.0 mL/min; tmajor =12.9 min.,
tminor =10.9 min., (97:3 er).
amorphous solid. H NMR (700 MHz, CDCl ) d8.86 (bs, 1H),
3
7
7
.36–7.33 (m, 1H), 7.28 (dd, J=11.6, 4.4 Hz, 2H), 7.18 (d, J=
.4 Hz, 2H), 6.56 (s, 4H), 5.27 (s, 1H), 3.76 (s, 3H), 3.72 (s,
13
3
ca (3R,4S)-Methyl 4-(3-chlorophenyl)-7,9-dimethyl-6,8,10-
3H), 3.30 (s, 3H), 2.97 (s, 3H). C NMR (176 MHz, CDCl ) d
3
trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decane-3-car-
boxylate. Following the general procedure (reaction time
197.1, 170.5, 167.7, 165.3, 160.0, 150.1, 134.7, 132.9 (2C),
129.1, 128.1 (2C), 127.5 (2C), 122.8, 113.4 (2C), 77.7, 75.2,
59.5, 55.2, 53.8, 29.6, 29.0. HRMS calculated for
48 h, >20:1 dr) 3ca was isolated by FC on silica gel (eluent:
+
23
D
CH Cl ) in 79% yield (19.0 mg) as a white amorphous solid.
[C24
H
23
N
3
O
6
S+H ]: 482.1380; found: 482.1376. [a]
=
2
2
1
H NMR (700 MHz, CDCl ) d 8.68 (bs, 1H), 7.39–7.37 (m,
À56.0 (c=1.0, CHCl ). The er was determined by HPLC
3
3
Adv. Synth. Catal. 2018, 360, 1–12
6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
1
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
using a chiral Chiralpack IG column [hexane: i-PrOH,
0:10]; column temperature 308C; flow rate 1.0 mL/min;
tmajor =23.5 min., tminor =20.2 min., (97.5:2.5 er).
40% yield (8.4 mg) as an off-white amorphous solid. H
9
NMR (700 MHz, CDCl ) d 8.17 (s, 1H), 7.57–7.53 (m, 2H),
7.45–7.40 (m, 3H), 4.32 (d, J=11.0 Hz, 1H), 3.90 (s, 3H), 3.40
s, 3H), 3.37 (s, 3H), 1.84–1.78 (m, 1H), 0.89 (d, J=6.4 Hz,
H), 0.60 (d, J=6.5 Hz, 3H). C NMR (176 MHz, CDCl ) d
94.1, 171.1, 167.4, 165.2, 150.9, 135.2, 129.3, 128.6 (2C),
28.2 (2C), 78.5, 73.6, 57.5, 53.7, 30.0, 29.5, 26.3, 22.1,
2.1.HRMS calculated for [C H N O S+H ]: 418.1431;
3
(
3
ga (3R,4R)-Methyl 4-(2,4-dichlorophenyl)-7,9-dimethyl-
13
3
1
1
2
3
6,8,10-trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decane-
3-carboxylate. Following the general procedure (reaction
time 48 h, >20:1 dr) 3ga was isolated by FC on silica gel
+
2
0
23
3
5
(eluent: CH
Cl
) in 93% yield (24.2 mg) as a pale yellow
22
2
2
found: 418.1427. [a]D =À11.5 (c=1.0, CHCl ). The er was
1
3
amorphous solid. H NMR (700 MHz, CDCl ) d 9.02 (s, 1H),
3
determined by HPLC using a chiral Chiralpack IC column
7
8
3
1
1
.38–7.27 (m, 6H), 6.69 (dd, J=8.7, 2.2 Hz, 1H), 6.08 (d, J=
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
[
hexane:i-PrOH, 80:10]; column temperature 308C; flow rate
.7 Hz, 1H), 6.02 (s, 1H), 3.81 (s, 3H), 3.35 (s, 3H), 2.90 (s,
1
.0 mL/min; tmajor =15.1 min., tminor =14.0 min., (96:4 er).
1
3
H). C NMR (176 MHz, CDCl ) d 197.0, 170.2, 167.0, 164.8,
3
50.0, 136.5, 135.4, 134.5, 134.0, 129.5, 129.4, 128.7 (2C),
3ka (3R,4S)-Methyl 7,9-dimethyl-6,8,10-trioxo-3-phenyl-4-
((E)-styryl)-1-thioxo-2,7,9-triazaspiro[4.5]decane-3-carboxy-
late. Following the general procedure (reaction time 48 h, 6:1
dr) 3ka was isolated by FC on silica gel (eluent: CH Cl ) in
27.7, 127.1 (2C), 125.9, 78.0, 73.8, 54.1, 53.6, 29.7, 28.9.
+
HRMS calculated for [C H Cl N O S+H ]: 520.0495;
2
3
19
2
3
5
25
found: 520.0490.[a]D =À50.3 (c=1.0, CHCl ). The er was
3
2
2
1
determined by HPLC using a chiral Chiralpack IG column
79% yield (18.9 mg) as a pale yellow amorphous solid. H
[
hexane:i-PrOH, 90:10]; column temperature 308C; flow rate
NMR (700 MHz, CDCl ) d 8.57 (s, 1H), 7.42 (dd, J=4.2,
2.4 Hz, 3H), 7.39–7.36 (m, 2H), 7.24 (ddd, J=8.7, 6.1, 3.0 Hz,
3H), 7.16–7.12 (m, 2H), 6.67 (d, J=15.7 Hz, 1H), 5.61 (dd,
3
1.0 mL/min; tmajor =15.5 min., tminor =13.8 min., (99:1 er).
3
ha (3R,4S)-Methyl 7,9-dimethyl-4-(naphthalen-1-yl)-6,8,10-
J=15.7, 10.1 Hz, 1H), 5.11 (d, J=10.1 Hz, 1H), 3.82 (s, 3H),
trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decane-3-car-
boxylate. Following the general procedure (reaction time
13
3.39 (s, 3H), 3.20 (s, 3H). C NMR (176 MHz, CDCl
) d
3
1
1
7
95.8, 170.3, 166.5, 163.8, 150.7, 136.7, 136.1, 134.8, 129.2,
48 h, 10:1 dr) 3ha was isolated by FC on silica gel (eluent:
28.8 (2C), 128.5, 128.4 (2C), 126.9 (2C), 126.7 (2C), 121.9,
6.9, 74.6, 54.6, 53.9, 29.9, 29.3. HRMS calculated for
CH Cl ) in 56% yield (14.0 mg) as a pale yellow amorphous
2
2
1
solid. H NMR (700 MHz, CDCl ) d 8.92 (s, 1H), 8.13 (d, J=
+
22
3
[
C H N O S+H ]: 478.1431; found: 478.1438. [a]D =
25 23 3 5
8.7 Hz, 1H), 7.84–7.80 (m, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.60
(ddd, J=8.5, 6.8, 1.3 Hz, 1H), 7.52–7.47 (m, 1H), 7.37 (dd,
J=11.4, 4.2 Hz, 1H), 7.36–7.17 (m, 4H), 6.93 (t, J=7.8 Hz,
1H), 6.40 (s, 1H), 6.18 (dd, J=7.5, 1.0 Hz, 1H), 3.75 (s, 3H),
À46.4 (c=1.0, CHCl ). The er was determined by HPLC
3
using a chiral Chiralpack IC column [hexane:i-PrOH, 80:20];
column temperature 308C; flow rate 1.0 mL/min; tmajor
.4 min., tminor =8.7 min., (94:6 er).
=
7
1
3
3
1
1
1
.08 (s, 3H), 2.76 (s, 3H). C NMR (176 MHz, CDCl ) d
3
97.3, 170.7, 167.9, 165.6, 149.7, 135.0, 133.9, 132.6, 130.6,
29.7, 129.6, 129.3, 128.3, 127.7, 127.4, 126.1, 126.0, 123.7,
21.9, 78.5, 75.2, 54.0, 54.0, 52.3, 29.8, 29.4, 28.7. HRMS
3la (3R,4S)-Methyl 4-(4-methoxyphenyl)-8,8-dimethyl-6,10-
dioxo-3-phenyl-1-thioxo-7,9-dioxa-2-azaspiro[4.5]decane-3-
carboxylate. Following the general procedure (reaction time
48 h, 12:1 dr) 3la was isolated by FC on silica gel (eluent:
CH Cl ) in 75% yield (17.6 mg) as a pale yellow amorphous
solid. H NMR (700 MHz, CDCl ) d 8.78 (s, 1H), 7.34–7.31
(m, 1H), 7.29–7.26 (m, 2H), 7.17 (s, 2H), 6.66 (d, J=8.5 Hz,
2H), 6.63–6.58 (m, 2H), 5.32 (s, 1H), 3.78 (s, 3H), 3.72 (s,
H), 1.76 (s, 3H), 0.98 (s, 3H). C NMR (176 MHz, CDCl ) d
+
calculated for [C H N O S+H ]: 502.1431; found:
2
7
23
3
5
2
3
5
02.1420. [a]D = +38.5 (c=1.0, CHCl ). The er was deter-
3
2
2
1
mined by HPLC using a chiral Chiralpack IG column
hexane:i-PrOH, 90:10]; column temperature 308C; flow rate
3
[
1.0 mL/min; tmajor =18.7 min., tminor =23.6 min., (98:2 er).
13
3
3
3
ia (3R,4S)-Methyl 4-(furan-2-yl)-7,9-dimethyl-6,8,10-trioxo-
196.7, 170.4, 166.9, 163.1, 160.1, 134.4, 133.4 (2C), 129.2,
128.1 (2C), 127.5 (2C), 122.9, 113.7 (2C), 107.0, 77.8, 73.6,
59.1, 55.3, 53.9, 29.6, 29.1. HRMS calculated for
3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decane-3-carboxylate.
Following the general procedure (reaction time 48 h, >20:1
dr) 3ia was isolated by FC on silica gel (eluent: CH Cl ) in
2
2
+
22
D
[C24H23NO
S+H ]: 470.1268; found: 470.1273.[a]
c=1.0, CHCl ). The er was determined by HPLC using a
=À30.3
1
7
88% yield (19.5 mg) as an off-white amorphous solid. H
(
3
NMR (700 MHz, CDCl ) d 8.82 (bs, 1H), 7.37–7.34 (m, 1H),
3
chiral Chiralpack IC column [hexane:i-PrOH, 80:10]; column
temperature 308C; flow rate 1.0 mL/min; tmajor =23.0 min.,
tminor =16.4 min., (84:16 er).
7.33–7.30 (m, 2H), 7.22 (ddd, J=7.1, 3.2, 1.9 Hz, 2H), 7.17
(
dd, J=1.8, 0.8 Hz, 1H), 6.13–6.11 (m, 1H), 5.65 (s, 1H), 5.59
13
(d, J=3.4 Hz, 1H), 3.81 (s, 3H), 3.35 (s, 3H), 3.11 (s, 3H).
C
NMR (176 MHz, CDCl ) d 196.1, 170.1, 167.0, 164.3, 150.4,
Isothiocyanate strategy in the enantioselective synthesis of a-
3
145.5, 142.9, 135.0, 129.2, 128.0 (2C), 126.9 (2C), 113.1, 110.8,
aminophosphonates 3 – general procedure
7
6.9, 73.5, 54.0, 52.4, 29.8, 29.2. HRMS calculated for
+
2
2
In an ordinary 4 mL glass vial, equipped with a Teflon-coated
magnetic stirring bar and a screw cap, catalyst 4c (0.2 equiv.,
.02 mmol, 6.3 mg), the corresponding dimethyl 5-(alkyli-
dene)barbiturate 1 (1.0 equiv., 0.1 mmol) and isothiocyanate
2 (1.0 equiv., 0.1 mmol) were dissolved in freshly distilled
THF (0.2 mL) and stirring was maintained for 24–48 h at
ambient temperature. Pure product 3 was isolated by flash
chromatography on silica gel (eluent: hexanes:acetone 4:1).
[
C H N O S+H ]: 442.1067; found: 442.1063. [a] = +
21 19 2 6 D
1
9.8 (c=1.0, CHCl ). The er was determined by HPLC using
3
0
a chiral Chiralpack IG column [hexane:i-PrOH, 90:10];
column temperature 308C; flow rate 1.0 mL/min; tmajor
6.2 min., tminor =18.7 min., (99:1 er).
=
1
3ja (3R,4S)-Methyl 4-isopropyl-7,9-dimethyl-6,8,10-trioxo-3-
phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decane-3-carboxylate.
Following the general procedure (reaction time 48 h, >20:1
dr) 3ja was isolated by FC on silica gel (eluent: CH Cl ) in
2
2
Adv. Synth. Catal. 2018, 360, 1–12
7
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
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7
3ab Diphenyl ((3S,4S)-7,9-dimethyl-6,8,10-trioxo-3,4-diphen-
yl-1-thioxo-2,7,9-triazaspiro[4.5]decan-3-yl)phosphonate. Fol-
lowing the general procedure (reaction time 24 h, >20:1 dr)
chiral Chiralpack IA column [hexane:i-PrOH, 80:20]; column
temperature 308C; flow rate 1.0 mL/min; tmajor =9.2 min.,
tminor =12.9 min., (96:4 er).
3
4
2
1
ab was isolated by FC on silica gel (eluent: hexanes:acetone
3
db Diphenyl ((3S,4R)-4-(2-chlorophenyl)-7,9-dimethyl-
:1) in 99% yield (61.9 mg) as an off-white solid (mp=227–
1
6,8,10-trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decan-3-
yl)phosphonate. Following the general procedure (reaction
time 48 h, 20:1 dr) 3db was isolated by FC on silica gel
288C). H NMR (700 MHz, CDCl ) d 11.00–10.88 (m, 1H),
3
0.04 (s, 1H), 7.31–7.24 (m, 9H), 7.19–7.15 (m, 3H), 7.11–7.09
(
2
m, 2H), 7.07–7.04 (m, 2H), 6.99–6.97 (m, 1H), 6.81–6.76 (m,
13
(eluent: hexanes:acetone 4:1) in 60% yield (39.7 mg) as a
H), 5.74 (d, J=20.9 Hz, 1H), 3.31 (s, 3H), 3.04 (s, 3H).
C
1
yellow amorphous solid. H NMR (700 MHz, CDCl ) d 9.83
3
NMR (176 MHz, CDCl ) d 197.5 (d, J=8.1 Hz), 167.1, 165.1,
3
(
s, 1H), 7.90 (d, J=26.3 Hz, 1H), 7.51–7.41 (m, 1H), 7.38 (dd,
J=8.0, 1.3 Hz, 1H), 7.33–7.28 (m, 5H), 7.20–7.16 (m, 1H),
.14 (tt, J=11.2, 2.7 Hz, 1H), 7.12–7.08 (m, 2H), 7.00–6.98
m, 1H), 6.98–6.90 (m, 2H), 6.87–6.84 (m, 2H), 6.77–6.71 (m,
1H), 6.49 (d, J=20.6 Hz, 1H), 6.01 (dd, J=8.1, 1.6 Hz, 1H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
1
1
50.6 (d, J=10.0 Hz), 150.3 (d, J=11.5 Hz), 150.1, 132.2,
30.3, 130.0 (2C), 129.5 (3C), 129.5, 129.3 (d, J=5.4 Hz, 2C),
7
(
128.9, 128.2 (2C), 127.6 (2C), 125.7, 125.3, 120.6 (d, J=
4.4 Hz, 2C), 120.4 (d, J=4.0 Hz, 2C), 75.3 (d, J=8.1 Hz),
3
1
74.6, 73.7, 58.4, 29.6, 29.1. P NMR (283 MHz, CDCl
) d
3
13
+
3.33 (s, 3H), 2.90 (s, 3H). C NMR (176 MHz, CDCl
198.0, 166.9, 165.6, 150.7 (d, J=10.1 Hz), 150.1 (d, J=
1.5 Hz), 149.9, 136.5, 133.4, 132.3, 130.5, 130.1 (2C), 130.0
3C), 129.6 (3C), 129.3, 127.8, 125.7, 125.4 (d, J=4.9 Hz)
3
) d
1
0.1. HRMS calculated for [C H N O PS+H ]: 626.1509;
33 28
3
6
2
0
found: 626.1517 [a]D =À49.0 (c=1.0, CHCl ). The er was
3
1
(
determined by HPLC using a chiral Chiralpack IA column
[
hexane:i-PrOH, 80:20]; column temperature 308C; flow rate
(2C), 120.8 (d, J=4.4 Hz) (2C), 120.6 (d, J=4.0 Hz) (2C),
1.0 mL/min; tmajor =12.0 min., tminor =10.2 min., (99:1 er).
31
74.6, 74.3 (d, J=7.8 Hz), 73.7, 52.5, 29.7, 28.9. P NMR
3bb Diphenyl ((3S,4S)-4-(4-chlorophenyl)-7,9-dimethyl-
6,8,10-trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decan-3-
yl)phosphonate. Following the general procedure (reaction
time 24 h, 10:1 dr) 3bb was isolated by FC on silica gel
(101 MHz, Chloroform-d) d 9.92. HRMS calculated for
+
24
[C33
H27 ClN O PS+H ]: 660.1119; found: 660.1127. [a] =-
3
6
D
20.7 (c=1.0, CHCl ). The er was determined by HPLC using
3
a chiral Chiralpack IA column [hexane:i-PrOH, 80:20];
(
eluent: hexanes:acetone 4:1) in 79% yield (52.1 mg) as a
column temperature 308C; flow rate 1.0 mL/min; tmajor
14.5 min., tminor =10.7 min., (98:2 er).
=
1
pale yellow amorphous solid. H NMR (700 MHz, CDCl ) d
3
1
7
0.02 (bs, 1H), 7.31–7.27 (m, 4H), 7.25–7.24 (m, 3H), 7.20–
.16 (m, 3H), 7.08–7.06 (m, 2H), 7.05–7.03 (m, 2H), 6.99–6.97
3fb Diphenyl ((3S,4S)-4-(4-methoxyphenyl)-7,9-dimethyl-
6,8,10-trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decan-3-
yl)phosphonate. Following the general procedure (reaction
time 24 h, >20:1 dr) 3fb was isolated by FC on silica gel
(
m, 1H), 6.78–6.74 (m, 2H), 6.68 (d, J=8.4 Hz, 2H), 5.81 (d,
13
J=21.0 Hz, 1H), 3.33 (s, 3H), 3.09 (s, 3H). C NMR
(
(
176 MHz, CDCl ) d 197.0 (d, J=7.9 Hz), 166.7, 164.7, 150.5
d, J=10.2 Hz), 150.2 (d, J=11.2 Hz), 150.0, 135.7, 133.8
3
(
eluent: hexanes:acetone 4:1) in 85% yield (55.8 mg) as a
1
pale yellow amorphous solid. H NMR (700 MHz, CDCl ) d
3
(2C), 132.1 (d, J=4.3 Hz), 130.1 (2C), 129.5 (2C), 129.3 (d,
J=5.5 Hz, 2C), 129.1, 129.0, 128.4 (2C), 127.7, 125.8, 125.4,
120.6 (d, J=4.4 Hz, 2C), 120.4 (d, J=3.9 Hz, 2C), 75.2 (d, J=
9
.96 (s, 1H), 7.38–7.24 (m, 8H), 7.21–7.14 (m, 3H), 7.07–7.02
m, 2H), 6.98 (t, J=7.4 Hz, 1H), 6.70–6.69 (m, 4H), 6.62–6.61
(m, 2H), 5.70 (d, J=21.0 Hz, 1H), 3.73 (s, 3H), 3.31 (s, 3H),
(
3
1
8.0 Hz), 74.4, 73.5, 56.9, 29.8, 29.2. P NMR (283 MHz,
13
+
3.05 (s, 3H). C NMR (176 MHz, CDCl
) d 197.7 (d, J=
3
CDCl ) d 10.1. HRMS calculated for [C H ClN O PS+H
3
33 27
3
6
2
0
8.1 Hz), 165.2, 160.3, 150.6 (d, J=10.0 Hz), 150.3 (d, J=
]
: 660.1119; found: 660.1129. [a]D =À59.6 (c=1.0, CHCl ).
3
1
1
1.3 Hz), 150.1, 133.4 (2C), 132.3 (d, J=4.2 Hz), 130.0 (2C),
29.5 (2C), 129.3 (d, J=5.3 Hz, 2C), 128.9, 127.6(2C), 125.7,
The er was determined by HPLC using a chiral Chiralpack
IA column [hexane:i-PrOH, 80:20]; column temperature
125.3, 122.0, 120.6 (d, J=4.3 Hz, 2C), 120.4 (d, J=3.8 Hz,
2C), 113.5 (2C), 75.3 (d, J=8.3 Hz), 74.5, 73.6, 57.9, 55.2,
308C; flow rate 1.0 mL/min; tmajor =14.7 min., tminor =
10.0 min., (97:3 er).
3
1
29.6, 29.1. P NMR (283 MHz, CDCl
) d 10.1. HRMS
3
+
3cb Diphenyl ((3S,4S)-4-(3-chlorophenyl)-7,9-dimethyl-
,8,10-trioxo-3-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decan-3-
calculated for [C34
H
30
N
3
O PS+H ]: 656.1615; found:
7
20
6
656.1610. [a]D =À62.0 (c=1.0, CHCl ). The er was deter-
3
yl)phosphonate. Following the general procedure (reaction
time 48 h, 15:1 dr) 3cb was isolated by FC on silica gel
mined by HPLC using a chiral Chiralpack IA column
[hexane:i-PrOH, 80:20]; column temperature 308C; flow rate
1.0 mL/min; tmajor =15.4 min, tminor =11.9 min, (99:1 er).
(
eluent: hexanes:acetone 4:1) in 84% yield (55.4 mg) as a
1
yellow amorphous solid. H NMR (700 MHz, CDCl ) d 10.13
3
3ac Diphenyl ((3S,4S)-3-(4-chlorophenyl)-7,9-dimethyl-
6,8,10-trioxo-4-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decan-3-
yl)phosphonate. Following the general procedure (reaction
time 24 h, >20:1 dr) 3ac was isolated by FC on silica gel
(
s, 1H), 7.32–7.27 (m, 5H), 7.25–7.22 (m, 3H), 7.18–7.16 (m,
3
1
3
1
H), 7.08–7.04 (m, 3H), 7.00–6.96 (m, 1H), 6.80–6.76 (m,
H), 6.74–6.68 (m, 3H), 5.76 (d, J=20.8 Hz, 1H), 3.34 (s,
13
H), 3.09 (s, 3H). C NMR (176 MHz, CDCl ) d 196.9, 166.7,
3
(
eluent: hexanes:acetone, 4:1) in 97% yield (64.0 mg) as an
64.7, 150.5 (d, J=10.2 Hz), 150.2 (d, J=11.4 Hz), 150.0,
1
off-white amorphous solid. H NMR (700 MHz, CDCl ) d
3
133.9, 132.4, 131.9, 130.7, 130.0 (2C), 129.6, 129.6 (2C), 129.4,
129.2 (d, J=5.5 Hz) (2C), 129.2, 127.6 (2C), 125.8, 125.4,
120.5 (d, J=4.3 Hz) (2C), 120.4 (d, J=3.9 Hz) (2C), 75.1 (d,
1
7
0.38 (s, 1H), 7.32–7.26 (m, 3H), 7.25–7.17 (m, 5H), 7.15–
.13(dtm, 2H), 7.12–7.07 (m, 4H), 7.01–6.99 (m, 1H), 6.82–
3
1
6.80 (m, 4H), 5.73 (d, J=20.8 Hz, 1H), 3.31 (s, 3H), 3.08 (s,
J=8.0 Hz), 74.5, 73.6, 57.1, 29.8, 29.1. P NMR (101 MHz,
Chloroform-d) 10.24. HRMS calculated for [C H
13
3
H). C NMR (176 MHz, CDCl ) d 197.6 (d, J=8.4 Hz),
3
d
33 27
+
24
D
167.0, 165.2, 150.5 (d, J=10.2 Hz), 150.2 (d, J=11.3 Hz),
ClN O PS+H ]: 660.1119; found: 660.1125. [a] =À35.0
3
6
1
50.0, 135.2 (d, J=2.6 Hz), 132.2 (2C), 131.0 (d, J=3.9 Hz),
(
c=1.0, CHCl ). The er was determined by HPLC using a
3
Adv. Synth. Catal. 2018, 360, 1–12
8
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
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0
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8
9
0
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2
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8
9
0
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6
7
130.8 (d, J=5.5 Hz, 2C), 130.1 (2C), 129.7, 129.6 (2C), 128.4
ature reaction mixture was filtered through syringe filter and
evaporated giving without any further purification product
(
(
2
2C), 127.7 (2C), 125.8, 125.5, 120.5 (d, J=4.4 Hz, 2C), 120.4
d, J=3.9 Hz, 2C), 75.2 (d, J=8.1 Hz), 74.2, 73.3, 58.1, 29.7,
6aa (20:1 dr) in 95% yield (44.2 mg) as an off-white
3
1
1
9.1. P NMR (283 MHz, CDCl ) d 9.7. HRMS calculated
amorphous solid. H NMR (700 MHz, CDCl ) d 7.19–7.11
3
3
+
for [C H ClN O PS+H ]: 660.1119; found: 660.1111.
(m, 5H), 7.11–7.07 (m, 1H), 6.98 (dd, J=8.2, 7.5 Hz, 2H),
6.53 (dd, J=8.2, 1.0 Hz, 2H), 5.15 (s, 1H), 3.72 (s, 3H), 3.30
3
3
27
3
6
2
0
[
a]D =À67.2 (c=1.0, CHCl ). The er was determined by
3
13
HPLC using a chiral Chiralpack ID column [hexane:i-PrOH,
(s, 3H), 2.81 (s, 3H), 2.74 (s, 3H). C NMR (176 MHz,
80:20]; column temperature 308C; flow rate 1.0 mL/min;
CDCl ) d 172.8, 169.5, 167.5, 165.3, 150.3, 137.4, 132.6, 131.1
3
tmajor =11.3 min., tminor =15.9 min., (98:2 er).
(2C), 128.5, 127.9, 127.8 (2C), 127.8 (4C), 88.7, 75.4, 65.4,
5
3.6, 29.4, 28.7, 15.1.HRMS calculated for [C H N O S+
24 23 3 5
+ 19
3
ad Diphenyl ((3S,4S)-3-(4-methoxyphenyl)-7,9-dimethyl-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
H ]: 466.1431; found: 466.1433. [a]D =À50.9 (c=1.0,
6,8,10-trioxo-4-phenyl-1-thioxo-2,7,9-triazaspiro[4.5]decan-3-
acetone).
yl)phosphonate. Following the general procedure (reaction
time 48 h, 7:1 dr) 3ad was isolated by FC on silica gel
Synthesis of (3R,4S)-methyl 7,9-dimethyl-6,8,10-trioxo-3,4-
diphenyl-2,7,9-triazaspiro[4.5]decane-3-carboxylate (7aa)
(
eluent: hexanes:acetone 4:1) in 73% yield (47.9 mg) as a
1
pale yellow amorphous solid. H NMR (700 MHz, CDCl ) d
3
In an ordinary screw-cap vial equipped with magnetic stirring
9
7
.64 (s, 1H), 7.33–7.29 (m, 2H), 7.29–7.23 (m, 4H), 7.19 (t, J=
.3 Hz, 1H), 7.13–7.08 (m, 5H), 7.02 (t, J=7.4 Hz, 1H), 6.77
bar, the 3aa (90.2 mg, 0.2 mmol) was suspended in EtOH,
o
cooled to 0 C and excess Raney Nickel was added. After
(
dd, J=19.2, 7.9 Hz, 4H), 6.72 (d, J=8.5 Hz, 2H), 6.51 (d, J=
stirring for 2 h at 08C, mixture was filtered through a short
17.6 Hz, 1H), 5.67 (d, J=20.5 Hz, 1H), 3.76 (s, 3H), 3.31 (s,
13
pad of Celite and washed with CHCl and concentrated
3
3H), 3.04 (s, 3H). C NMR (176 MHz, CDCl ) d 197.6 (d,
3
under reduced pressure. Crude product was purified by
column chromatography (hexanes:acetone 3:2) affording
J=8.4 Hz), 167.2, 165.3, 160.1, 150.6 (d, J=10.0 Hz), 150.3
(d, J=11.4 Hz), 150.1, 132.2 (2C), 130.7 (d, J=5.5 Hz, 2C),
desired amine 7aa (20:1 dr) in 48% yield (40.4 mg) as white
1
1
7
30.3, 130.1 (2C), 129.6 (2C), 129.5, 128.2 (2C), 125.7, 125.4,
1
amorphous solid. H NMR (700 MHz, CDCl ) d 7.27–7.24
3
20.6 (d, J=4.4 Hz, 2C), 120.5 (d, J=3.9 Hz, 2C), 113.1(2C),
31
(m, 2H), 7.06–7.03 (m, 2H), 7.02–6.97 (m, 4H), 6.95–6.92 (m,
5.3 (d, J=8.6 Hz), 74.3, 73.4, 58.5, 55.3, 29.6, 29.1. P NMR
10.2. HRMS calculated for
2
H), 4.76 (s, 1H), 4.00 (d, J=10.7 Hz, 1H), 3.95 (d, J=
(
283 MHz, CDCl )
d
3
+
13
20
D
10.7 Hz, 1H), 3.74 (s, 3H), 3.39 (s, 2H), 2.57 (s, 3H).
C
[
C H N O PS+H ]: 656.1615; found: 656.1608. [a]
=
34
30
3
7
NMR (176 MHz, CDCl ) d 175.0, 170.8, 168.2, 151.3, 138.4,
3
À49.1 (c=1.0, CHCl ). The er was determined by HPLC
3
134.8, 130.8 (2C), 127.9 (2C), 127.8, 127.7 (2C), 127.4, 127.2
(2C), 76.8, 64.5, 64.4, 53.5, 47.5, 29.6, 28.7. HRMS calculated
using a chiral Chiralpack IA column [hexane:i-PrOH, 80:20];
column temperature 308C; flow rate 1.0 mL/min; tmajor
=
+
24
D
for [C H N O +H ]: 422.1710; found: 422.1717. [a] =
23 23
3
5
13.6 min., tminor =11.0 min., (97:3 er).
À62.9 (c=1.0, CHCl ).
3
Synthesis of (3R,4S)-methyl 7,9-dimethyl-1,6,8,10-tetraoxo-
3,4-diphenyl-2,7,9-triazaspiro[4.5]decane-3-carboxylate (5aa)
Acknowledgements
In an ordinary 4 mL glass vial, equipped with a Teflon-coated
magnetic stirring bar and a screw cap solution of 3aa
This project was financially supported by the Ministry of
Science and Higher Education, Poland within the “Iuventus
Plus” programme realized in the period 2015–2017, project
number: 0008/IP3/2015/73. ŁA acknowledges Lodz Univer-
sity of Technology for a scholarship (Własny Fundusz
Stypendialny PŁ programme). Thanks are expressed to Dr.
Jakub Wojciechowski (Faculty of Chemistry, Lodz University
of Technology) for performing X-ray analysis.
(1 equiv., 0.1 mmol, 45 mg) in dry CH
Cl (2 mL) was placed.
2
2
After cooling in an ice-bath mCPBA (4 equiv., 0.4 mmol,
6
2
9 mg) was added. After stirring in room temperature for
0 h, reaction mixture was directly subjected to flash
chromatography on silica gel (eluent: hexanes:acetone 7:3)
giving product 5aa (20:1 dr) in 90% yield (39.2 mg) as an off-
1
white amorphous solid. H NMR (700 MHz, CDCl ) d 8.16
3
(
s, 1H), 7.22–7.12 (m, 5H), 7.11–7.06 (m, 1H), 6.99–6.91 (m,
2
3
1
H), 6.58 (dd, J=8.2, 0.9 Hz, 2H), 5.00 (s, 1H), 3.68 (s, 3H),
13
.20 (s, 3H), 2.76 (s, 3H). C NMR (176 MHz, CDCl ) d References
3
71.8, 168.6, 167.6, 165.3, 150.2, 135.3, 131.7, 131.2 (2C),
128.9, 128.8, 128.1 (2C), 127.9 (2C), 127.2 (2C), 70.9, 67.0,
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+
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2
3
21
3
6
2
1
]: 436.1503; found: 436.1509. [a]
=-90.88 (c=1.0, CHCl ).
D
3
Synthesis of (3R,4S)-methyl 7,9-dimethyl-1-(methylthio)-
6,8,10-trioxo-3,4-diphenyl-2,7,9-triazaspiro[4.5]dec-1-ene-3-
carboxylate (6aa)
In an ordinary 4 mL glass vial, equipped with a Teflon-coated
magnetic stirring bar and a screw cap solution of 3aa
(
1 equiv., 0.1 mmol, 45.0 mg) in dry acetone (2 mL) was
placed. After cooling in an ice-bath, K CO (1.1 equiv.,
2
3
0
1
.11 mmol, 15.2 mg) and MeI (1.1 equiv., 0.11 mmol,
5.6 mg) were added. After 20 h of stirring in room temper-
Adv. Synth. Catal. 2018, 360, 1–12
9
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
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FULL PAPER
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ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Isothiocyanate Strategy for the Synthesis of Quaternary
a-Amino Acids Bearing a Spirocyclic Ring System
Adv. Synth. Catal. 2018, 360, 1–12
S. Frankowski, T. Gajda, Ł. Albrecht*
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