Highly efficient asymmetric mannich reaction of dialkyl α-diazomethylphosphonates with N -carbamoyl imines catalyzed by chiral bronsted acids

Article abstract of DOI:10.1021/ol300664d

An efficient method involving the first use of chiral phosphoric acids as catalysts in the asymmetric Mannich reaction of dialkyl diazomethylphosphonates and N-carbamoyl imines is developed. With only 0.1 mol % catalyst 1f, the reaction proceeded smoothly and produced the corresponding β-amino-α- diazophosphonate with up to 97% yield and >99% ee.

Full text of DOI:10.1021/ol300664d

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2126–2129
Highly Efficient Asymmetric
Mannich Reaction of Dialkyl
r-Diazomethylphosphonates with
N-Carbamoyl Imines Catalyzed by
Chiral Brønsted Acids
Hui Zhang, Xiaojing Wen, Lihua Gan, and Yungui Peng*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
P. R. China
pengyungui@hotmail.com
Received March 15, 2012
ABSTRACT
An efficient method involving the first use of chiral phosphoric acids as catalysts in the asymmetric Mannich reaction of dialkyl
diazomethylphosphonates and N-carbamoyl imines is developed. With only 0.1 mol % catalyst 1f, the reaction proceeded smoothly and
produced the corresponding β-amino-R-diazophosphonate with up to 97% yield and >99% ee.
R-Diazocarbonyl compounds are valuable synthons,
and they have been investigated as nucleophiles in asym-
metric transformations,1 such as addition reactions with
carbonyl compounds2 and imines.3 Recent advances in
the asymmetric reactions of diazoacetates and imines
catalyzed by chiral Brønsted acids3aꢀe,4 or chiral Lewis
acids3h,5 have produced the corresponding enantiopure
R-amino-β-diazo carbonyl compounds or developed
aziridine derivatives. These derivatives can be further
transformed into β-amino acid, β-amino-R-hydroxy acid,
and other common synthetic intermediates.6 Surprisingly,
R-diazomethylphosphonates as isosteric analogs of their
(3) (a) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129,
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Jiang, L. Q.; Prajapati, D.; Hu, W. H. J. Org. Chem. 2010, 75, 7483. (h) Lu,
Z. J.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185. (i)
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r
10.1021/ol300664d
Published on Web 03/30/2012
2012 American Chemical Society

R-diazoacetate counterparts have seldom been used as
nucleophiles in the asymmetric Mannich reaction with
imines3aꢀc,f to give the corresponding β-amino-R-diazo-
phosphonate products. These products could be easily
transformed to a variety of β-amino phosphoric acid7
and β-amino-R-hydroxyphosphoric acid8 derivatives via
simple reduction or oxidation of the diazo moiety alter-
natively. The β-amino phosphoric acid derivatives are
interesting and potentially useful in the synthesis of in-
hibitors of human renin, calpain I, and anti-HIV agents.6c
Most of the reported methods for the synthesis of optically
pure β-amino phosphoric acid derivatives start from chiral
sources, such as proteinogenic amino acids or amino
aldehydes thereof.7c,e There are only a few methods avail-
able for catalytic asymmetric hydrogenation or amino-
hydroxylation.7fꢀi,8a β-Amino-R-diazophosphonate could
provide an alternative facile access to important β-amino
phosphoric acid derivatives that cannot be obtained by
derivatization of proteinogenic amino acids. Although
enantiopure β-amino-R-diazophosphonates are important
in organic synthesis, there are few reports on the asym-
metric Mannich reaction of R-diazomethylphosphonate
with imines. This is presumably because of the bulky and
tetrahedral phosphonate moiety, which will lower the
reactivity. To date, only one group has investigated the
catalysis of the asymmetric transformation by axially
chiral dicarboxylic acid. They have resulted in the
β-amino-R-diazophosphonate derivatives with good ee,
but the studiesuseda5%catalystloading, and thecatalytic
efficiency and applicability of the imine substrates require
improvement.3a,b
Table 1. Optimization of Catalysts and Reaction Conditionsa
(5) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099.
(b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518. (c)
Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675. (d) Zhang, Y.; Lu,
Z. J.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10, 5429. (e) Mukherjee,
M.; Gupta, A. K.; Lu, Z. J.; Zhang, Y.; Wulff, W. D. J. Org. Chem. 2010,
75, 5643. (f) Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010, 132,
13100. (g) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett. 2011,
13, 5866.
(6) (a) Zhao, Y. H.; Ma, Z. H.; Zhang, X. M.; Zou, Y. P.; Jin, X. L.;
Wang, J. B. Angew. Chem., Int. Ed. 2004, 43, 5977. (b) Zhao, Y. H.;
Jiang, N.; Chen, S. F.; Peng, C.; Zhang, X. M.; Zou, Y. P.; Zhang, S. W.;
Wang, J. B. Tetrahedron 2005, 61, 6546. (c) Park, H.; Cho, C. W.;
Krische, M. J. J. Org. Chem. 2006, 71, 7892.
a Reactions were performed with benzaldehyde N-Boc imine (0.15
mmol) and R-diazomethylphosphonate (0.10 mmol) in the presence of
phosphoric acid 1 and 4 A MS (50 mg) in toluene (1 mL). b Isolated yield.
˚
c Determined by chiral HPLC analysis.
(7) (a) Palacios, F.; Alonso, C.; De Los Santos, J. M. Enantioselective
Synthesis of β-amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.;
John Wiley & Sons, Inc.: Hoboken, NJ, 2005. (b) Palacios, F.; Alonso, C.; de
los Santos, J. M. Chem. Rev. 2005, 105, 899. (c) Mikolajczyk, M.; Lyzwa,
P.; Drabowicz, J.; Wieczorek, M. W.; Blaszcyk, J. Chem. Commun. 1996,
1503. (d) Xu, C. F.; Yuan, C. Y. Eur. J. Org. Chem. 2004, 4410. (e)
Zhang, D. H.; Yuan, C. Y. Chem.;Eur. J. 2009, 15, 4088. (f) Zhang,
J. Z.; Li, Y.; Wang, Z.; Ding, K. L. Angew. Chem., Int. Ed. 2011, 50,
11743. (g) Ryglowski, A.; Kafarski, P. Tetrahedron 1996, 52, 10685. (h)
Kadyrov, R.; Holz, J.; Schaffner, B.; Zayas, O.; Almena, J.; Borner, A.
Tetrahedron: Asymmetry 2008, 19, 1189. (i) Doherty, S.; Knight, J. G.;
Bell, A. L.; El-Menabawey, S.; Vogels, C. M.; Decken, A.; Westcott,
S. A. Tetrahedron: Asymmetry 2009, 20, 1437. (j) Wang, J.; Heikkinen,
L. D.; Li, H.; Zu, L. S.; Jiang, W.; Xie, H.-X.; Wang, W. Adv. Synth.
Catal. 2007, 349, 1052.
Binaphthylphosphates have been extensively used as
chiral catalysts in a wide range of asymmetric organic
transformations.9 For example, pioneering work by Terada
and co-workers demonstrated that chiral phosphoric
acid could catalyze the asymmetric Mannich reaction of
N-acylimines and tert-butyl diazoacetate with high effi-
ciency and excellent enantioselectivity.3e The chiral phos-
phoric acids performed well in those asymmetric transfor-
mations prompted us toinvestigate their use in the reaction
of N-carbamoyl imines with R-diazomethylphosphonate.
Our aim was to develop an efficient catalytic methodology
for the synthesis of β-amino-R-diazophosphonate with
€
€
(8) (a) Thomas, A. A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379.
(b) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C. A.; Rogers,
W. L.; Smith, S. A.; DeForrest, J. M.; Oehl, R. S.; Petrillo, E. W. Jr.
J. Med. Chem. 1995, 38, 4557. (c) Zygmunt, J.; Gancarz, R.; Lejczak, B.;
Wieczorek, P.; Kafarski, P. Bioorg. Med. Chem. Lett. 1996, 6, 2989. (d)
(9) (a) Cheon, C. H.; Yamamoto, H. Chem. Commun. 2011, 3043. (b)
Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org. Biomol.
Chem. 2010, 8, 5262. (c) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007,
107, 5713. (d) Akiyama, T. Chem. Rev. 2007, 107, 5744. (e) Akiyama, T.;
Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999. (f) Connon, S. J.
Angew. Chem., Int. Ed. 2006, 45, 3909. (g) Adair, G.; Mukherjee, S.; List,
B. Aldrichimica Acta 2008, 41, 31. (h) Terada, M. Bull. Chem. Soc. Jpn.
2010, 83, 101. (i) Kampen, D.; Reisinger, C. M.; List, B. Top. Curr.
Chem. 2010, 291, 395.
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Piotrowska, D. G.; Wroblewski, A. E. Tetrahedron 2009, 65, 4310. (e)
ꢀ
Wroblewski, A. E.; Piotrowska, D. G. Tetrahedron: Asymmetry 2000,
11, 2615. (f) Cravotto, G.; Giovenzana, G. B.; Pagliarin, R.; Palmisano,
G.; Sisti, M. Tetrahedron: Asymmetry 1998, 9, 745. (g) Yokomatsu, T.;
Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry 1993, 4, 1401. (h)
Barco, A.; Benetti, S.; Bergamini, P.; De Risi, C.; Marchetti, P.; Pollini,
G. P.; Zanirato, V. Tetrahedron Lett. 1999, 40, 7705. (i) Patel, D. V.;
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Org. Lett., Vol. 14, No. 8, 2012
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high enantioselectivity and broad substrate scope. Herein,
we described that binapthylphosphates are capable of an
even higher ee and excellent yield and can operate at a
0.1%catalyst loading in the asymmetric Mannich reaction.
The reaction of benzaldehyde N-Boc imine 2a with
dimethyl R-diazomethylphosphonate 3a was investigated
first as a model reaction. Chiral phosphoric acids 1aꢀ1f
Table 2. Catalytic Asymmetric Mannich Reactions of N-Car-
bamoyl Imines with Di-tert-butyl R-Diazomethylphosphonatea
˚
were used as catalysts. Molecular sieves (4 A) were used to
scavenge water. With a 10 mol % catalyst load in toluene
at 0 °C the reaction proceeded smoothly, with moderate
yields (31ꢀ73%) and low to good enantioselectivities
(ꢀ11% ee to 94% ee) (Table 1, entries 1ꢀ6). When the
reaction was catalyzed by chiral phosphoric acid 1a, the
product was racemic (Table 1, entry 1). Introduction of
phenyl groups to the structure of catalyst 1a at the 3- and
30-positions (catalyst 1b) decreased the reactivity (31%
yield, 36 h) and increased the enantioselectivity to 38%
ee (Table 1, entry 2). With electron-deficient aryl groups
at the 3- and 30-positions (catalyst 1c), the product with
the opposite configuration was obtained with a low ee
(Table 1, entry 3). Further changes of the substituents at
the 3- and 30-positions to ꢀSiPh3 (catalyst 1d), 9-anthyl
(catalyst 1e), and 2,4,6-(iPr)3C6H2 (catalyst 1f) were in-
vestigated. Among these, 1f showed good catalytic effi-
ciency and stereocontrol, with a reaction yield of 73% and
94% ee in 15 min (Table 1, entry 6).
Using 1f as the catalyst, we investigated decreasing the
catalyst loads from 10% to 5% and then 2%. To maintain
the yield and enantioselectivity, the reaction time had to be
increased to 1 h (5% catalyst load, 73% yield, 94% ee) and
2 h (2% catalyst load, 70% yield, 94% ee) (Table 1, entries
6ꢀ8). Lowering the reaction temperature toꢀ20orꢀ40°C
increased the enantioselectivity to 97% ee (Table 1, entries
9 and 10). Under these reaction conditions (2% catalyst
load, ꢀ40 °C, toluene), we investigated changing R1 from
a Reactions were performed with arylaldehyde N-carbamoyl imine
(0.15 mmol) and di-tert-butyl R-diazomethylphosphonate (0.10 mmol)
in the presence of (R)-1f (0.1%) and 4 A MS (50 mg) in toluene (1 mL).
˚
b Isolated yield. c Determined by chiral HPLC analysis. d With 1%
catalyst load. e With 5% catalyst load. f With 0.1% (S)-1f as the catalyst.
diazomethylphosphonates and N-carbamoyl imines was
investigated (Table 2). The reaction had a broad substrate
scope, with good yields and excellent enantioselectivities
achieved irrespective of the presence of electronic donating
or withdrawing substituents on the aromatic ring of the
imine (Table 2, entries 2ꢀ9, 11ꢀ13, and 15ꢀ16).
i
t
Me (3a) to Et (3b), Pr (3c), and Bu (3e). With these
changes, a large increase in the reactivity was observed
as the steric hindrance of R1 increased (Table 1, entries
10ꢀ14). This could be attributed to the change in the
negative charge of the R-carbon in R-diazomethylpho-
sphonate caused by variation of R1, which would alter
thenucleophilicity tothe phenylN-Boc imine. Withdi-tert-
butyl R-diazomethylphosphonate as the nucleophile, and
a decreased reaction temperature (ꢀ60 °C), the reaction
was complete within 20 min with excellent yield (91%)
and enantioselectivity (>99% ee) (Table 1, entry 16). At
ꢀ40 °C, further reductions in the catalyst load to 1%,
0.5%, 0.2%, and 0.1% were investigated. With these
loadings, the reaction time had to be increased to 30 min
(1%), 1 h (0.5%), 2.5 h (0.2%), and 4 h (0.1%), but the
yield (91%) and enantioselectivity (>99% ee) remained
the same (Table 1, entries 17ꢀ20). Even with reduction of
thecatalystloadto0.05%, thereaction could be performed
in 22 h with 93% yield and >99% ee (Table 1, entry 21).
Various solvents, including DCM, CHCl3, THF, Et2O,
CH3CN, m-xylene, and toluene, were screened for the
reaction, and toluene performed the best.
The substituent pattern influenced the reactivity, with
ortho substitution decreasing the reactivity dramatically
(Table 2, entries 2, 6, 10, 12, and 14). This was particularly
apparent with electronic withdrawing substituents Cl and
NO2 at the ortho position. In these cases, even with a 5%
catalyst load, only moderate yields (55% and 52%) were
obtained with excellent enantioselectivity (>97% ee)
(Table 2, entries 10 and 14). Imines substituted with
naphthalene and heteroaromatics were also tested, and
these were suitable for the asymmetric Mannich reactions
(Table 2, entries 17ꢀ19). The furyl imine showed slightly
lower reactivity, and a 1% catalyst load was required to
promote the reaction (Table 2, entry 18). Benzyloxycar-
bonyl (Cbz) is a useful orthogonal N-protecting group in
organic synthesis, and we investigated N-Cbz imines in-
stead of N-Boc imines in the reaction under the same
conditions. These reactions gave the desired asymmetric
Mannich products in good yields and enantioselectivities
(Table 2, entries 20ꢀ22). The reactivities of the N-Cbz
After establishing the optimized reaction conditions, the
scope of the asymmetric Mannich reaction of di-tert-butyl
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Org. Lett., Vol. 14, No. 8, 2012

imines were lower than those of the corresponding N-Boc
imines, and the reaction times needed to be increased
(Table 2, entries 1, 4, and 9 vs 20ꢀ22). When (S)-1f was
used as the catalyst, enantiomeric products were produced
with excellent yields and enantioselectivities (Table 2,
entries 23ꢀ25).
hydroxyl, produced the β-N-Boc amino-R-hydroxyl di-tert-
butyl phosphonate ester with good yield, diastereoselectiv-
ity, and enantioselectivity.6a,b This methodology provides
an efficient alternative route to β-amino phosphoric acid
derivatives with high optical purity and is especially impor-
tant for those that cannot be derived from proteinogenic
amino acids.
The absolute configuration of N-Boc-protected 4aa was
determined to be S by comparison of its HPLC retention
time and optical rotation with literature data reported.3a,b
To account for the observed outcome, the mechanism
is supposed to be similar to that of the enantioselective
R-substitution reaction of diazoacetate with imine cata-
lyzed by chiral phosphoric acid proposed by Terada.9h
A transition state model is proposed as Scheme 1. The
phosphoric acid acts as a dual function catalyst with both
Brønsted acid and Brønsted basic sites, the acid proton
captures the nitrogen of imine through hydrogen-bonding
interactions to activate it, and then the negative carbon
of diazomethylphosphonate nucleophile attacks from the
Si-face of imine; subsequently, the phosphoryl oxygen
would function as a Brønsted basic site for deprotonation
via intracomplex and give the Mannich product.
Scheme 2. Synthetic Utility of β-Amino-R-diazophosphonate
Scheme 1. Proposed a Transition State Model
In conclusion, we demonstrated that chiral phosphoric
acids can be used in the catalysis of the asymmetric
Mannich reaction of N-carbamoyl imines with dialkyl
diazomethylphosphonates. A highly efficient method for
the synthesis of various chiral β-amino-R-diazophospho-
nates and their derivatives was established. Further use of
these β-amino phosphoric acid derivatives in peptide
mimetics is underway.
Acknowledgment. We are grateful for financial support
from the National Science Foundation of China (Grant
Nos. 20872120 and 21172180) and the Municipal Science
Foundation of Chongqing City (Grant No. 2009BB5110).
To demonstrate the potential utility of β-amino-R-diazo-
phosphonate products in organic synthesis (Scheme 2), the
diazo moiety of adduct 4ae was subjected to hydrogena-
tion catalysis by PtO2 under a hydrogen atmosphere. The
β-N-Boc amino di-tert-butyl phosphonate ester was ob-
tained almost without loss of enantiomeric excess. Addi-
tional deprotection of the Boc and di-tert-butyl ester under
mildly acidic conditions gave the β-amino phosphoric acid.7
The oxidation of the diazo moiety by oxone, and subsequent
diastereoselective reduction of the carbonyl with NaBH4 to
Supporting Information Available. Experimental pro-
cedures, spectral and analytical data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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