A convenient route to enantiopure 3-aryl-2,3-diaminopropanoic acids by diastereoselective Mannich reaction of camphor-based tricyclic iminolactone with imines

Article abstract of DOI:10.1021/jo8001408

(Chemical Equation Presented) A novel and convenient route to the asymmetric synthesis of 2,3-diamino acids via Mannich reaction of iminolactones 1a and 1b with N-protected imines has been achieved in good yields (up to 95%) and high diastereoselectivity (dr: >99:1). Hydrolysis of the Mannich adducts under acidic conditions furnished the desired 3-aryl-2,3-diaminopropanoic acids in good yields (up to 85%) with excellent enantiomeric excesses (99% ee).

Full text of DOI:10.1021/jo8001408

carbon-carbon bond-forming reactions for the synthesis of
nitrogenous molecules, such as diamino acid derivatives6 and
amino alcohols, which can lead to the generation of two
contiguous nitrogen-bearing stereogenic centers. Thus, we report
a novel and convenient approach to generate optically pure 2,3-
diamino acids in high yields with excellent diastereoselectivity
via asymmetric Mannich reaction of N-protected imines with
zinc enolates of tricyclic iminolactones 1a and 1b7 derived from
natural (1R)-(+)-camphor.
A Convenient Route to Enantiopure
3-Aryl-2,3-diaminopropanoic Acids by
Diastereoselective Mannich Reaction of
Camphor-Based Tricyclic Iminolactone with
Imines
Huan-Huan Zhang, Xiu-Qin Hu, Xiao Wang,
Yong-Chun Luo, and Peng-Fei Xu*
Our investigation began with the reaction of iminolactone
1a with various N-aryl-substituted imines, but no Mannich
adducts were detected. Given the low reactivity of imines in
this nucleophilic addition, a strong electron-withdrawing group,
such as sulfonyl, was introduced on the nitrogen atom of the
imine in order to activate the CdN bond. Fortunately, we found
that N-tosyl-C-phenyl imine 2a reacted smoothly with imino-
lactone 1a at -78 °C in THF using LDA as the base to afford
a mixture of diastereomeric adducts. The result suggested that
the electron-withdrawing imine-protecting group played an
important role in this nucleophilic addition. Thus, we chose the
N-tosyl-C-phenyl imine 2a as a substrate for further investigation.
In an attempt to improve the yield and the diastereoselec-
tivity, we carried out a series of experiments varying the
additives and bases used. Representative results are listed in
Table 1. Commonly used additives, such as LiCl, DMPU, or
Et2AlCl, either failed to promote the reaction (entry 1) or
gave the addition adducts in low yields with poor diastereo-
State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou UniVersity,
Lanzhou, Gansu 730000, People’s Republic of China
xupf@lzu.edu.cn
ReceiVed January 20, 2008
A novel and convenient route to the asymmetric synthesis
of 2,3-diamino acids via Mannich reaction of iminolactones
1a and 1b with N-protected imines has been achieved in good
yields (up to 95%) and high diastereoselectivity (dr: >99:1).
Hydrolysis of the Mannich adducts under acidic conditions
furnished the desired 3-aryl-2,3-diaminopropanoic acids in
good yields (up to 85%) with excellent enantiomeric excesses
(99% ee).
(3) For summaries of the existing literature of the synthesis of 2,3-diamino
acids, see: (a) Han, H.; Yoon, J.; Janda, K. D. J. Org. Chem. 1998, 63, 2045.
(b) Lee, S.-H.; Yoon, J.; Chung, S.-H.; Lee, Y.-S. Tetrahedron 2001, 57, 2139.
(c) Zhou, X.-T.; Lin, Y.-R.; Dai, L.-X. Tetrahedron: Asymmetry 1999, 10, 855.
(d) Capone, S.; Guaragna, A.; Palumbo, G.; Pedatella, S. Tetrahedron 2005, 61,
6575. (e) Nadir, U. K.; Krishna, R. V.; Singh, A. Tetrahedron Lett. 2005, 46,
479. (f) Durham, T. B.; Miller, M. J. J. Org. Chem. 2003, 68, 35. (g) Robinson,
A. J.; Stanislawski, P.; Mulholland, D.; He, L.; Li, H.-Y. J. Org. Chem. 2001,
66, 4148. (h) Li, B.-F.; Yuan, K.; Zhang, M.-J.; Wu, H.; Dai, L.-X.; Wang,
Q.-R.; Hou, X.-L. J. Org. Chem. 2003, 68, 6264. (i) Viso, A.; Fernández de la
Pradilla, R.; López-Rodríguez, M. L.; García, A.; Flores, A.; Alonso, M. J. Org.
Chem. 2004, 69, 1542. (j) Wang, D.; Zhang, P.-F.; Yu, B. HelV. Chim. Acta
2007, 90, 938. (k) Viso, A.; Fernández de la Pradilla, R.; García, A.; Guerrero-
Strachan, C.; Alonso, M.; Tortosa, M.; Flores, A.; Martínez-Ripoll, M.; Fonseca,
I.; André, I.; Rodríguez, A. Chem. Eur. J. 2003, 9, 2867. (l) Tranchant, M.-J.;
Dalla, V. Tetrahedron 2006, 62, 10255. (m) Knudsen, K. R.; Risgaard, T.;
Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123,
5843. (n) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc.
2007, 129, 3466. (o) Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2008, 130, 2170.
Optically active 2,3-diamino acids are an important class of
compounds due to their presence in a variety of peptide
antibiotics, antifungal dipeptides, and other biologically active
compounds.1 One example is (2R,3S)-2,3-diamino-3-phenyl-
propanoic acid, which is an alternative side chain of taxol to
improve its water solubility.2 As a consequence, a range of
methods to synthesize optically active 2,3-diamino acid deriva-
tives have been reported so far.3 However, almost all of them
suffer from one or more drawbacks including lack of generality,
low-yielding, or complex procedures. Furthermore, to the best
of our knowledge, there have been only a few reports for the
synthesis of free 2,3-diamino acids.3b,4 The Mannich reaction5
was discovered in 1912 and is one of the most important
(4) (a) Alker, D.; Harwood, L. M.; Williams, C. E. Tetrahedron Lett. 1998,
39, 475. (b) Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Millican, N. L.;
Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2003, 1,
3708.
(5) Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647.
(6) For recent examples of the asymmetric Mannich reaction to synthesize
2,3-diamino acid derivatives, see: (a) Nishiwaki, N.; Knudsen, K. R.; Gothelf,
K. V.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992. (b) Bernardi,
L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68,
2583. (c) Davis, F. A.; Deng, J. Org. Lett. 2004, 6, 2789. (d) Ooi, T.; Kameda,
M.; Fujii, J.-i.; Maruoka, K. Org. Lett. 2004, 6, 2397. (e) Salter, M. M.;
Kobayashi, J.; Shimizu, Y.; Kobayashi, S. Org. Lett. 2006, 8, 3533. (f) Davis,
F. A.; Zhang, Y.; Qiu, H. Org. Lett. 2007, 9, 833. (g) Cutting, G. A.; Stainforth,
N. E.; John, M. P.; Kociok-Kohn, G.; Willis, M. C. J. Am. Chem. Soc. 2007,
129, 10632. (h) DeMong, D. E.; Williams, R. M. J. Am. Chem. Soc. 2003, 125,
8561. (i) DeMong, D. E.; Williams, R. M. Tetrahedron Lett. 2001, 42, 3529.
(7) (a) Xu, P.-F.; Chen, Y.-S.; Lin, S.-I.; Lu, T.-J. J. Org. Chem. 2002, 67,
2309. (b) Xu, P.-F.; Lu, T.-J. J. Org. Chem. 2003, 68, 658. (c) Li, S.; Hui,
X.-P.; Yang, S.-B.; Jia, Z.-J.; Xu, P.-F.; Lu, T.-J. Tetrahedron: Asymmetry 2005,
16, 1729. (d) Xu, P.-F.; Li, S.; Lu, T.-J.; Wu, C.-C.; Fan, B.; Golfis, G. J. Org.
Chem. 2006, 71, 4364.
(1) For a comprehensive summary of biologically active 2,3-diamino acids,
see: (a) Dunn, P. J.; Häner, R.; Rapoport, H. J. Org. Chem. 1990, 55, 5017. (b)
Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
(c) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151. (d) Wang, M.; Gould,
S. J. J. Org. Chem. 1993, 58, 5176. (e) Webber, S. E.; Okano, K.; Little, T. L.;
Reich, S. H.; Xin, Y.; Worland, S. T.; Fuhrman, S. A.; Matthews, D. A.; Love,
R. A.; Hendrickson, T. F.; Patick, A. K.; Meador, J. W.; Ferre, R. A.; Brown,
E. L.; Ford, C. E.; Binford, S. L. J. Med. Chem. 1998, 41, 2786. (f) Viso, A.;
Fernández de la Pradilla, R.; García, A.; Flores, A. Chem. ReV. 2005, 105, 3167.
and references cited therein.
(2) (a) Rossi, F. M.; Powers, E. T.; Yoon, R.; Rosenberg, L.; Meinwald, J.
Tetrahedron 1996, 52, 10279. (b) Moyna, G.; Williams, H. J.; Scott, A. I. Synth.
Commun. 1997, 27, 1561.
3634 J. Org. Chem. 2008, 73, 3634–3637
10.1021/jo8001408 CCC: $40.75 2008 American Chemical Society
Published on Web 03/26/2008

TABLE 1. Mannich Reaction of Iminolactone 1a with N-Tosyl-C-phenyl Imine 2a
entry
base (equiv)
additive (equiv)
dra
yield (%)
1
2
3
4
5
6
LDA(1.2)
LDA(1.2)
LDA(1.2)
LDA(1.2)
LHMDS(1.2)
KHMDS(1.2)
LiCl(6)
complex
100:37:26:13
100:67:24:0
>99/1
DMPU(3)
Et2AlCl(2.2)
ZnCl2(1.2)
ZnCl2(1.2)
ZnCl2(1.2)
58b
32b
91c
91c
90c
>99/1
>99/1
a The ratios were estimated by 1H NMR integrations of the crude reaction mixtures. b Yield of the inseparable diastereomeric mixture after silica gel
column chromatography. c Isolated yield.
TABLE 2. Mannich Reaction of Tricyclic Iminolactones 1a and 1b with N-tosyl Imines 2a-h
entry
substrate
PG
R
product
dra
yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ph
3a
3b
3c
3d
3e
3f
3g
3h
4a
4b
4c
4d
4e
4f
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
91
94
87
86
95
91
93
91
95
91
82
87
85
83
84
92
p-CH3Ph
o-CH3Ph
m-CH3Ph
p-CH3OPh
o-CH3OPh
p-ClPh
2-furyl
Ph
9
10
11
12
13
14
15
16
p-CH3Ph
o-CH3Ph
m-CH3Ph
p-CH3OPh
o-CH3OPh
p-ClPh
4g
4h
2-furyl
a The ratios were estimated by 1H NMR integrations, we cannot find other isomers from crude reaction mixtures. b Yield of the major products after
silica gel column chromatography.
selectivity (entries 2 and 3). However, addition of 1.2 equiv
of zinc chloride (ZnCl2)8 dramatically improved both the yield
(91%) and the diastereoselectivity (dr: >99:1) affording a
complete conversion of the starting materials to the product
3a as a single isomer in less than 30 min (entry 4). Other
bases, such as lithium hexamethyldisilazide (LHMDS) and
potassium hexamethyldisilazide (KHMDS), could also give
the same results as LDA (entries 5 and 6).
SCHEME 1. Proposed Mechanism of Mannich Reaction of
1b with Imines
Encouraged by these results, we next examined the scope of
the reaction under the optimized conditions. Results obtained
in the addition of tricyclic iminolactones 1a and 1b to a variety
of N-tosyl imines 2a-h are summarized in Table 2. All reactions
were conducted in THF at -78 °C in the presence of ZnCl2
with LDA as the base.
As revealed in Table 2, high yields (82–95%) and excellent
diastereoselectivities (dr: >99:1) were obtained with all the
substrates. The high diastereoselectivity, which is consistent with
our previous results,7 suggests that the Mannich reaction should
take place from the endo face of the enolate to give the endo-
isomer as the predominant product. The extremely high endo/
exo ratio for the Mannich products is presumably due to the
steric hindrance of C12-methyl, which effectively blocks the
reaction approach from the exo-face and thus favors the reaction
of the electrophile from the endo-face of the enolate.
Although the NMR spectroscopic data support the formation
of the Mannich adducts, the absolute and relative configurations
J. Org. Chem. Vol. 73, No. 9, 2008 3635

TABLE 3. Mannich Reaction of Tricyclic Iminolactones 1a and 1b
to N-Boc imines as an electrophile because of the fact that a
Boc protecting group can be readily removed under acidic
conditions.
with N-Boc Imines 2i-k
entry substrate
PG
R
products
dra
yield (%)b
Thus, a series of Mannich reactions with N-Boc imines 2i-k
were then conducted as summarized in Table 3. It is noteworthy
that two diastereoisomers generated in the case of N-Boc imines
cannot be separated and the diastereomeric ratios were estimated
by 1H NMR integrations. The predominant endo configurations
were the same as those of N-tosyl imines. The structure was
also assigned by X-ray crystallographic analysis of compound
3j (see the Supporting Information).9
1
2
3
4
5
6
1a
1a
1a
1b
1b
1b
Boc Ph
Boc p-CH3Ph
Boc m-CH3Ph 3k+3k′
Boc Ph
Boc p-CH3Ph
Boc m-CH3Ph 4k+4k′
3i+ 3i′
3j+ 3j′
50:1
33:1
30:1
50:1
22:1
20:1
82
81
71
86
81
79
4i+ 4i′
4j+ 4j′
a The ratios were estimated by 1H NMR integrations after silica gel
column chromatography. b Isolated yield of the two isomers.
Facile deprotection of the N-Boc group and removal of the
chiral auxiliary could be achieved under acidic conditions. It is
exciting that the racemization was not detected and both 3-aryl-
(2S,3R)-2,3-diaminopropanoic acids and 3-aryl-(2R,3S)-2,3-
diaminopropanoic acids were obtained in very high diastereo-
selectivies with predominantly >99% ee (Table 4).
TABLE 4. Hydrolysis of Mannich Products
In conclusion, we have developed a simple and efficient
method for the preparation of both free 3-aryl-(2S,3R)-2,3-
diaminopropanoic acids and its enantiomers in high yield via
Mannich reaction of N-protected imines with zinc chelated
enolates derived from tricyclic iminolactones. Diastereo- and
enantioselectivies obtained in this manner are very high
compared with those obtained by previously reported methods.
Detailed mechanistic studies of the reaction, especially to clarify
the high diastereoselectivity, are ongoing.
entry
substrate
product
yield (%)
dra
ee (%)a
1
2
3
4
3i + 3i′
3j + 3j′
4i + 4i′
4j + 4j′
5i
5j
6i
6j
78
75
85
79
95.1/4.9
97.3/2.7
96/4
>99
>99
>99
>99
97/3
Experimental Section
a Determined by HPLC analysis on a CR(+) column.
General Procedure for Mannich Reaction of Iminolactone
and N-Protected Imines. Preparation of iminolactones 1a and 1b
was described in ref 7. N-Tosyl imines 2a-h and N-Boc imines
2i-k were synthesized according to the reported procedure.11,12
Diisopropylamine (0.17 mL, 1.20 mmol) was added to dry THF
(8.0 mL) in a long-neck flask under argon. After the solution was
cooled to -78 °C, n-BuLi (2.163 M, 0.56 mL, 1.20 mmol) was
added dropwise. The reaction mixture was stirred at -78 °C
for 15 min. Iminolactone (207 mg, 1.0 mmol) in dry THF (8.0
mL) was added to the above freshly prepared LDA solution at -78
°C and the solution was stirred for 20 min. Then a solution of
anhydrous ZnCl2 (163 mg, 1.2 mmol) in dry Et2O (2.0 mL) was
added and stirring was continued for 30 min followed by the
addition of imine (1.2 mmol) in dry THF (5.0 mL), then the reaction
mixture was stirred for another 30 min at -78 °C and saturated
NH4Cl solution (1.0 mL) was added to quench the reaction. The
solvent was removed under reduced pressure and the residue was
diluted with diethyl ether (3 × 15 mL). The resulting mixture was
washed with water (3 × 3.0 mL) and brine (3 × 3.0 mL), dried
over anhydrous MgSO4, and then concentrated to give the crude
product. The crude product was purified by flash column chroma-
tography to yield the desired compound.
(1S,2R,5S,8R,1′R)-5-(1′-p-Tolylsulfinylaminobenzyl)-8,11,11-tri-
methyl-3-oxa-6-azatricyclo[6.2.1.02,7]undec-6-en-4-one (4a). 4a was
purified by chromatography (EtOAc/petroleum ) 1/5) as a white
solid: yield 95%; [R]26D -15 (c 1.0, CH2Cl2); mp 140–142 °C; IR
(KBr) 2960, 1733, 1334, 1161, 703, 666 cm-1; 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.63 (d, J ) 8.0 Hz, 2H), 7.29–7.26 (m, 1H),
7.22–7.15 (m, 4H), 7.03 (d, J ) 8.8 Hz, 2H), 6.21 (d, J ) 8.4 Hz,
1H), 4.84 (dd, J ) 8.4, 4.4 Hz, 1H), 4.70 (d, J ) 4.4 Hz, 1H), 2.36
(s, 3H), 2.19 (s, 1H), 1.81 (d, J ) 4.8 Hz, 1H), 1.78–1.71 (m, 1H),
1.60–1.53 (m, 1H), 1.30–1.23 (m, 1H), 0.99 (s, 3H), 0.81 (s, 3H),
0.65 (s, 3H), 0.60–0.54 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 183.6, 170.2, 143.3, 137.5, 136.5, 129.4, 128.5, 128.4, 127.4,
were unambiguously confirmed through X-ray crystal structure
analysis of compounds 3d and 4c (see the Supporting Informa-
tion).9
The high diastereoselectivity led us to propose the mechanism
to account for the stereochemical induction of the reaction. The
zinc enolate of tricyclic iminolactone 1b is formed in situ from
the corresponding lithium enolate via transmetalation with 1
equiv of zinc chloride. As shown in Scheme 1, two possible
pathways for the reaction are depicted. Obviously, the coordina-
tion of the imine via the lone pair of electrons on the nitrogen
with the zinc center enables a six-membered cyclic transition
state in pathway 1. This model can account for both the endo
configuration and the high diastereoselectivity. By contrast, in
pathway 2, the bulky sulfonyl group within the imine would
not allow for efficient interaction with the zinc center.
Subsequently, we attempted to hydrolyze the Mannich adducts
under acidic conditions, but the procedure has suffered from a
few problems: (1) removal of the p-toluenesulfonate (tosyl)
group was difficult under mild conditions10 and (2) racemization
could occur under acidic conditions and reducing the acidity or
lowering the reaction temperature from 80 to 45 °C could not
suppress the racemization. The best result was achieved in
moderate diastereoselectivity (dr: 15:1) by treatment with 6 N
HCl at 45 °C. In view of these problems, we turned our attention
(8) It is very important to use dry ZnCl2, otherwise the yields and
diastereoselectivity will be lower. Therefore, ZnCl2 was dried with a heat gun
under vacuum.
(9) Crystal data for 3d, 3j, and 4c have been deposited in CCDC as deposition
numbers 672090, 672091, and 672092, respectively. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via www.
ccdc.com.
(11) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561.
(10) Jefford, C. W.; MeNulty, J. HelV. Chim. Acta 1994, 77, 2142.
(12) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
3636 J. Org. Chem. Vol. 73, No. 9, 2008

126.9, 79.2, 65.4, 57.5, 52.9, 48.3, 47.0, 28.6, 25.8, 21.4, 19.8, 19.3,
10.0; HRMS (calcd for C26H31N2O4S) 467.1999, found 467.1995
(M + H+).
) 11.2 Hz, 1H), 4.26 (d, J ) 11.2 Hz, 1H); 13C NMR (100 MHz,
D2O) δ (ppm) 171.0, 131.5, 131.1, 130.3, 128.1, 54.6, 54.4; HRMS
(calcd for C9H13N2O2) 181.0972, found 181.0972 (M + H+).
Diastereomeric ratio 96/4, enantiomeric excess >99%, determined
by HPLC.
General Procedure for Hydrolysis of Mannich Products. The
Mannich product (80 mg) was dissolved in 6 N HCl (3 mL) in a
sealed tube with a Teflon screw cap and heated at 45 °C for 3 h.
After it was cooled to room temperature, water (5 mL) was added
and the mixture was extracted with diethyl ether (3 × 5 mL). The
separated aqueous layer was evaporated under reduced pressure
and the residue was dissolved in EtOH (5 mL). Propylene oxide (2
mL) was then added to the above solution and the mixture was
stirred at room temperature for 30 min. The white solid started to
precipitate, which was collected by filtration under reduced pressure
and washed with cold EtOH (2 × 2 mL) and Et2O (1 × 4 mL) to
give the desired 2,3-diamino acid.
Acknowledgment. We are grateful for the financial support
of the National Natural Science Foundation of China (NSFC,
20772051, 20572039), the Program for NCET-05-0880, and the
Doctoral Funds from the Chinese Ministry of Education of the
People’s Republic of China.
Supporting Information Available: Crystallographic data
1
for products 3d, 4c, and 3j (CIF), copies of H and 13C NMR
spectra, characterization data for all new compounds, and HPLC
results. This material is available free of charge via the Internet
at http://pubs.acs.org.
3-Phenyl-(2S,3R)-2,3-diaminopropanoic acid (6i). 6i was
obtained as a white solid: yield 85%; [R]26 +39 (c 0.52, H2O);
D
mp 189–191 °C; IR (KBr) 3419, 2920, 1650, 1531, 768, 703 cm-1
;
1H NMR (400 MHz, D2O) δ (ppm) 7.54–7.49 (m, 5H), 4.65 (d, J
JO8001408
J. Org. Chem. Vol. 73, No. 9, 2008 3637