Chiral N-phosphonyl imine chemistry: asymmetric additions of malonate-derived enolates to chiral N-phosphonyl imines for the synthesis of β-aminomalonates

Article abstract of DOI:10.1016/j.tetlet.2008.12.093

Chiral N-phosphonyl imines attached by 1-naphthyl group were found to react with lithium malonate enolates smoothly to give chiral β-aminomalonates. Good yields and excellent diastereoselectivity were achieved for sixteen examples. The chiral auxiliary ca

Full text of DOI:10.1016/j.tetlet.2008.12.093

Tetrahedron Letters 50 (2009) 1079–1081
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Tetrahedron Letters
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Chiral N-phosphonyl imine chemistry: asymmetric additions
of malonate-derived enolates to chiral N-phosphonyl imines
for the synthesis of b-aminomalonates
*
Zhong-Xiu Chen , Teng Ai, Parminder Kaur, Guigen Li
Department of Chemistry and Biochemistry, Texas Tech University Lubbock, TX 79409-1061, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral N-phosphonyl imines attached by 1-naphthyl group were found to react with lithium malonate
enolates smoothly to give chiral b-aminomalonates. Good yields and excellent diastereoselectivity were
achieved for sixteen examples. The chiral auxiliary can be readily removed by treating with trifluoroace-
tic acid (TFA) to give free amino malonates. The absolute structure has been unambiguously determined
by converting one of the products into an authentic sample.
Received 29 November 2008
Revised 16 December 2008
Accepted 17 December 2008
Available online 24 December 2008
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Phosphoramide
N-Phosphonyl imines
Dimethyl malonate
b-Aminomalonates
b-Aminomalonates and b-amino acids belong to important
building blocks for the study of natural products, pharmaceuticals
and peptides, and copolymers.1–6 They serve as direct precursors to
chiral amino alcohols that are also chemically and biologically
important.7,8 In recent years, there has been a continuing interest
in asymmetric synthesis of b-amino acids and their derivatives in
organic and medicinal chemistry, among them the asymmetric
Mannich reaction has become a powerful and practical protocol
for this purpose.9 Although a significant progress has been made
in the development of asymmetric Mannich reactions using eno-
late nucleophiles derived from enolsilane,10 b-ketoesters,11a–c and
1,3-diketones,11 a practical Mannich reaction of dialkyl malonate-
derived enolates with simple imines remains less explored. Re-
cently, Marigo et al.12 reported the Mannich reaction of malonates
with N-tosyl-imino esters that showed enantioselectivity of 39–
87% ee. Deng and co-workers have developed an efficient enantio-
selective direct Mannich reactions of N-Boc-protected imines with
malonates under mild conditions by using bifunctional cinchona
alkaloids as catalysts.13
tions provided an easy access to chiral aziridines, vicinal amino
nitroalkanes, b-aminoketones, and b-amino esters. As a continuing
effort on this chiral N-phosphonyl imine chemistry, herein we
would like to report the asymmetric addition of alkyl malonates
onto chiral phosphonyl imines for the synthesis of chiral b-amino
malonates (Scheme 1).
In our previous studies,16,17 N-phosphonyl imines attached with
1-naphthylmethyl group had been proven to show higher diastere-
oselectivity as compared with their benzyl counterparts due to a
larger steric effect on asymmetric induction process. Sometimes,
they are even more effective than iso-propyl group attached N-
phosphonyl imines.16 In the present Letter, the 1-naphthyl group
attached N-phosphonyl imine 1a was thus chosen for the model
reaction to react with dialkyl malonate enolates. The reaction pro-
cedure is similar to those we reported earlier14–17 in that N-phos-
phonyl imines (1a, 1.0 equiv) were added into preprepared lithium
dialkyl malonate enolate (2.0 equiv) in THF solution at ꢀ78 °C. The
resulting mixture was stirred for 1 h at this temperature and then
raised to ꢀ30 °C and stirred for additional 6 h to furnish the
reaction.
Several different bases, such as LDA, LiHMDS, (Me3Si)2NK, and
n-BuLi, were utilized for generation of metal enolates. As shown
in Table 1, among these bases, LDA was found to be the best choice
for the present reaction. Other bases gave either poor diastereose-
lectivity or low chemical yields. (Me3Si)2NK gave a slightly higher
diastereoselectivity (91:9) but in a lower yield of 70%. Surprisingly,
n-BuLi resulted in a diastereoselectivity of 93:7, but in a poor yield
of 25%.
Very recently, we have established novel phosphoramide and
chiral N-phosphonyl imine chemistry and have been successful in
utilizing N-phosphonyl imines for asymmetric aza-Darzens reac-
tion,14 aza-Henry reaction,15 asymmetric Mannich reaction with
ketone enolates,16 and ester enolates.17 These asymmetric reac-
* Corresponding author. Tel.: +1 806 742 3015; fax +1 806 742 1289.
E-mail address: Guigen.li@ttu.edu (G. Li).
Visiting scholar from Zhejiang Gongshang University, Hangzhou, PR China.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.093

1080
Z.-X. Chen et al. / Tetrahedron Letters 50 (2009) 1079–1081
H
H
H
H
N
N
O
N
O
N
LDA/THF
P
P
OCH3
O
NH
H3CO
O
N
-78 to -30 ºC, 7 h
COOCH3
Ph
Ph
1a
Scheme 1. Addition of dimethyl malonate enolate to N-phosphonyl imine.
COOCH3
2a
Table 1
diastereoselectivity and good to high chemical yields have been
achieved after purification via flash column chromatography or
recrystallization. For entries 3, 5, 6, and 14, their crude products
were even determined to show excellent diastereoselectivity. In
fact, a single diastereoisomer was observed for each of these cases
as revealed by crude 31P NMR. For the rest of the examples, except
for entries 1 and 14, high diastereoselectivities ranging from 94:4
to 97:3 were obtained. Obviously, for the present reaction, the
most phosphonyl imines displayed higher diastereoselectivity than
those of ester enolate-based reactions.17
The alkyl group of dialkyl malonates was found to have a sub-
stantial effect on chemical yields. As showed by cases 4, 6, 8, and
15, diethyl malonate-derived enolate resulted in significant yield
enhancement up to 36%, at the same time, to retain diastereoselec-
tivity at the same level as those when using dimethyl malonate-de-
rived enolate. Surprisingly, when di-tert-butyl malonate-derived
lithium enolate was employed for the reaction, good to excellent
yield (75–93%) can still be obtained. However, diastereoselectivity
was diminished to a range of 52/48–62/38. This phenomenon is
similar to the observations of Michael addition of di-tert-butyl
malonate esters to nitroolefins18 and to chalcone derivatives in
the presence of a chiral phase-transfer catalysts.19
Effects of solvents and bases on the reaction outcomesa
Entry
Base
Solvent
Yield (%)
drb
1
2
3
4
5
6
7
LDA
THF
88
54
70
25
79
55
84
90:10
87:13
91:9
LiHMDS
(Me3Si)2NK
n-BuLi
LDA
LDA
LDA
THF
THF
THF
Toluene
CHCl3
Et2O
93:7
88:12
90:10
83:17
a
Reaction condition: 0.1 mmol of imine, 0.3 mmol of ester, 0.2 mmol of base in
3.5 mL of solvent.
b
Determined by 31P NMR of crude products.
The solvent effect was also examined for this reaction. It was
found that the two polar and Lewis base solvents, THF and ethyl
ether, resulted in higher chemical yields than other two less polar
solvents, toluene and CHCl3. THF was thus chosen as the solvent for
this reaction.
Under the above optimized conditions, a series of substrates
were examined to find the scope of generality. As shown in
Table 2, a variety of phosphonyl imines derived from benzaldehyde
derivatives attached with electron-withdrawing groups or elec-
tron-donating groups on their aromatic rings and 1-naphthalde-
hyde are all suitable for this reaction. For all cases, excellent
It is noteworthy that in the present reaction, almost all products
can be readily purified by flash column chromatography or recrys-
tallization from ethanol solution to give single isomers.
Table 2
Results of asymmetric additions of alkyl malonates to chiral N-phosphonyl iminesa
H
H
H
H
N
O
N
O
N
N
LDA/THF
P
P
OR
RO
O
NH
O
N
-78 to -30 ºC, 7 h
COOR
Ar
Ar
COOR
Entry
Imine
Ar
R
Prod.
Yieldb (%)
drc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1c
1d
1d
1e
1e
1f
Ph
CH3
2a
2b
88
54
50
67
62
80
55
76
62
67
68
66
73
47
83
90
>99:1e (90:10)
97:3
2-OCH3–Ph
4-OCH3–Ph
4-OCH3–Ph
2-CH3–Ph
2-CH3–Ph
2-F–Ph
2-F–Ph
4-F–Ph
2-Br–Ph
4-Br–Ph
2-NO2–Ph
4-Ph–Ph
4-OBn–Ph
4-OBn–Ph
2-Naphthyl
CH3
CH3
Et
CH3
Et
2ca
2cb
2da
2db
2ea
2eb
2f
2g
2h
2i
2j
>99:1
>99:1d (96:4)
>99:1
>99:1
97:3
>99:1
CH3
Et
CH3
CH3
CH3
CH3
CH3
CH3
Et
>99:1e (94:6)
>99:1d (93:7)
>99:1e (93:7)
97:3e (94:6)
99:1e 93:7
>99:1
1g
1h
1i
1j
1k
1k
1l
2ka
2kb
2l
(>99:1)d 94:6
(>99:1)d 88:12
CH3
a
Reaction conditions:21 0.4 mmol imine, 0.12 mmol ester, 0.8 mmol base, 7 mL solvent, ꢀ78 to ꢀ30 °C.
b
c
Isolated yields after column.
dr in bracket was determined by 31P NMR spectra of crude samples; Otherwise, purified dr is the same as crude dr; >99:1 means only one isomer observed.
Diastereoselectivities in the bracket were determined by 31P NMR after purified by column.
d
e
Diastereoselectivity was determined by 31P NMR after purified by recrystallization.

Z.-X. Chen et al. / Tetrahedron Letters 50 (2009) 1079–1081
1081
Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566–1568; (c) Josephsohn, N. S.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734–3735; (d)
Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am.
Chem. Soc. 2003, 125, 2507–2515.
The absolute stereochemistry of this reaction has been deter-
mined by converting a product to a known sample.22 In this proce-
dure, 2a was subjected to deprotection reaction with TFA/MeOH–
H2O at room temperature followed by protection using (Boc)2O
in the presence of NaHCO3. The in situ procedure resulted in
2-(tert-butoxycarbonylamino-phenyl-methyl)-malonic acid di-
methyl ester.20 An overall yield of 80% was obtained under these
convenient conditions; the effectiveness of this procedure enables
the present method an efficient approach to b-aminomalonates.
The resulting stereochemistry revealed that the asymmetric
induction of this reaction is similar to that of the previous asym-
metric reactions as we reported,14–17 that is, the enolates approach
the electrophilic center of N-phosphonyl imines from their Si faces
to give b-S amino products.
11. (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127,
11256–11257; (b) Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.;
Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005, 44, 1525–1529; (c)
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356–5357.
12. Marigo, M.; Kjaersgaard, A.; Juhl, K.; Gathergood, N.; Jorgensen, K. A. Chem. Eur.
J. 2003, 9, 2359–2367.
13. Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048–6049.
14. Kattuboina, A.; Li, G. Tetrahedron Lett. 2008, 49, 1573–1577.
15. Kattuboina, A.; Kaur, P.; Ai, T.; Li, G. Chem. Biol. Drug Des. 2008, 71, 216–223.
16. Han, J. l.; Ai, T.; Li, G. Synthesis 2008, 16, 2519–2526.
17. Han, J. L.; Ai, T.; Nguyen, T.; Li, G. Chem. Biol. Drug Des. 2008, 72, 120–126.
18. Lattanzi, A. Tetrahedron: Asymmetry 2006, 17, 837–841.
19. Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka, K. Org. Lett. 2005, 15, 3195–3197.
20. Tillman, A. L.; Ye, J. Chem. Commun. 2006, 1191–1193.
21. Typical procedure for the synthesis of chiral amino malonates: Into an oven-dried
vial flushed with N2 were loaded dialkyl malonates (1.2 mmol) and 3.0 mL of
dry THF. The loaded vial was cooled to ꢀ78 °C and 0.4 mL of 2 LDA solution in
THF (2.0 M) was added dropwise with stirring over 10 min, and the resulting
solution was stirred at ꢀ78 °C for additional 30 min. Into the resulting mixture
was added dropwise 4.0 mL of THF of phosphonyl imine 1 (0.4 mmol) and was
stirred at ꢀ78 °C for 1 h. The reaction temperature was then raised to ꢀ30 °C.
After the reaction mixture has been stirred for 6 h at this temperature, 1.0 mL
of saturated NH4Cl solution was added and followed by 5.0 mL water to quench
the reaction. The mixture was transferred into a separation funnel, and the
aqueous layer was extracted with 2 ꢁ 20 mL of ethyl acetate. Combined
organic layers were dried on anhydrous sodium sulfate. Sodium sulfate was
filtered off and evaporated the organic solvent. Purification by column
chromatography obtained adducts 2.Selected data of 2a: White solid, mp
In summary, chiral N-phosphonyl imines were found to react
with lithium dialkyl malonate enolates smoothly to give chiral b-
amino malonates in excellent diastereoselectivity and good chem-
ical yields. The reaction shows good substrate scope in that aro-
matic phosphonyl imines with both electron-withdrawing and
electron-donating groups on their rings can be utilized. The result-
ing products can be readily purified by both flash column chroma-
tography and recrystallization. The resulting products will be
converted into other important building blocks in due course.
147–150 °C. ½a 2D5
ꢂ
ꢀ18.7 (c 0.475, CHCl3); 1H NMR (CDCl3, 300 MHz): d 8.04–
Acknowledgment
8.02 (m, 1H), 7.94–7.68 (m, 7H), 7.57–7.42 (m, 6H), 7.32–7.25 (m, 2H), 7.11–
7.04 (m, 3H), 5.08–4.98 (m, 1H), 4.80–4.69 (dd, J = 13.2 Hz, 16.5 Hz, 1H), 4.47–
4.30 (m, 3H), 3.50 (s, 3H), 3.59–3.54 (m, 1H), 3.42 (s, 3H), 3.41–3.89 (m, 1H),
3.14–2.88 (m, 2H), 1.74–0.90 (m, 8H).13C NMR (CDCl3, 125 MHz): d 168.09,
167.42, 141.53, 135.39, 135.34, 134.27, 134.23, 133.51, 133.34, 131.06, 130.63,
128.67, 128.53, 128.26, 127.62, 127.27, 127.24, 127.02, 125.91, 125.55, 125.48,
125.41, 125.40, 125.25, 125.12, 124.74, 122.76, 122.71, 64.75, 64.67, 63.47,
63.40, 58.23, 58.17, 55.19, 52.36, 52.29, 44.11, 44.07, 43.92, 43.89, 29.80, 29.74,
29.58, 29.50, 24.22, 24.19. 31P NMR: (CDCl3, 202 MHz): d 26.27.
Financial assistance from Robert A. Welch Foundation (D-1361)
is gratefully acknowledged.
References and notes
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0.5 mmol), methanol (15.0 mL), and H2O (5.0 mL). To the resulting mixture was
added 10 equiv of trifluoroacetic acid; the reaction was stirred at rt for 24 h.
The reaction was monitored by TLC. Volatiles were removed to give a yellow
oil, to which were added MeOH (15.0 mL), H2O (5.0 mL), and NaHCO3
(5.0 mmol) at room temperature. To the resulting mixture was added di-tert-
butyl dicarbonate (0.654 g, 3.0 mmol) and stirred at room temperature
overnight. The crude reaction mixture obtained after standard aqueous
work-up was purified by using silica gel column chromatography with 10%
ethyl acetate in hexanes as the eluent. N-Boc b-amino malonate was obtained
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as a white solid in 80% yield (114 mg). ½a D25
ꢂ
ꢀ47.0 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.33–7.22 (m, 5H), 6.13 (s, br, 1H), 5.49 (s, br, 1H), 3.93 (d,
J = 4.2 Hz, 1H), 3.75 (s, 3H), 3.64 (s, 3H), 1.42 (s, 9H).