Enantioselective synthesis of functionalized α-amino acids via a chiral guanidine catalyzed Michael addition reaction

Article abstract of DOI:10.1016/S0957-4166(99)00038-5

Several chiral guanidines were evaluated as catalysts for the Michael reaction of glycine derivatives 7 with acrylic esters 8. The best result (30.4% ee) was obtained when 7b was reacted with 8b under the catalysis of guanidine 1 in THF.

Full text of DOI:10.1016/S0957-4166(99)00038-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 713–719
Enantioselective synthesis of functionalized α-amino acids via a
chiral guanidine catalyzed Michael addition reaction
Dawei Ma ∗ and Kejun Cheng
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received 15 December 1998; accepted 25 January 1999
Abstract
Several chiral guanidines were evaluated as catalysts for the Michael reaction of glycine derivatives7 with acrylic
esters 8. The best result (30.4% ee) was obtained when 7b was reacted with 8b under the catalysis of guanidine 1
in THF. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
As a strong organic base, tetramethylguanidine (TMG) has been used as a catalyst for carbon–carbon
bond formation,1–3 and known reactions catalyzed by TMG include Michael additions2 and aldol
condensations.3 Thus, the use of chiral guanidines as catalysts could open a new avenue for the
asymmetric formation of a carbon–carbon bond. Recently, successful asymmetric inductions have been
achieved in the nitroaldol reaction4 and Strecker reaction5 by using enantiomerically pure guanidines
as catalysts. The chiral guanidines have also shown the ability to induce enantioselective alkylative
esterification.6 Herein, we wish to report the first example of an asymmetric Michael addition reaction
catalyzed by a chiral guanidine.
2. Results and discussion
Two methods were used for preparation of our chiral guanidine catalysts, which are illustrated by the
syntheses of catalysts 1, 2 and 3. The catalyst 1 ([α]D25=−57.6 (c 0.65, H2O)) was synthesized from
(S)-α-methylbenzylamine by the reaction sequence shown in Scheme 1 according to a similar procedure
reported by Poss and coworkers.7
∗
Corresponding author. E-mail: madw@pub.sioc.ac.cn
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00038-5

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D. Ma, K. Cheng / Tetrahedron: Asymmetry 10 (1999) 713–719
Scheme 1.
As outlined in Scheme 2, the other two catalysts were prepared by treatment of the corresponding
amine with cyanogen bromide in ethanol.8 From the secondary amine 5 prepared from (1R,2S,5R)-
menthol the catalyst 2 ([α]D25=+56.9 (c 1, CHCl3)) was obtained, while the cyclic guanidine 3
([α]D25=+78.5 (c 1, CHCl3)) was synthesized by the reaction of diamine 6 with cyanogen bromide.
In addition, the known guanidine 44 was also prepared for comparison.
Scheme 2.
The Michael addition reaction of glycine derivatives9 to acrylic esters was chosen as our model
reaction to check the asymmetric induction of guanidines 1–4 as chiral catalysts. It is obvious that
success in this reaction will lead to a new methodology for preparing synthetically useful α-amino
acid derivatives. The reaction was carried out simply by stirring a mixture of imine 7, excess acrylic
ester 8 and a catalytic amount of chiral guanidine in a suitable solvent at room temperature. The
enantiomeric purity of the resultant α-amino acid derivative was determined by chiral HPLC analysis
using a Chiralpak AD column with 1% isopropyl alcohol in hexane for elution at 25°C. The configuration
of each product was assigned by its transformation to glutamic acid and determination of the sign of
its optical rotation. As shown in Table 1, the reaction proceeded with high chemical yield and modest
enantioselectivity. Among the glycine derivatives examined, tert-butyl glycinate benzophenone imine
7b gave higher enantioselectivity than ethyl glycinate benzophenone imine 7a (compare entries 1 and
3), which implied that an imine–guanidine complex might form in the course of the reaction thereby
determining the outcome of the enantioselectivity. As in many other asymmetric catalytic reactions,
the enantioselectivity of the present reaction was highly dependent on the nature of solvent. Among
the solvents examined, THF was the best solvent for this reaction (compare entries 3 and 5–7). As
catalysts, guanidines derived from (S)-α-methylbenzylamine gave better results than those of (1R,2S,5R)-
menthol-derived guanidines (compare entries 3 and 9–11), while the cyclic guanidine delivered poorer
enantioselectivity in comparison with acyclic guanidine (entries 3 and 11). In addition, lowering the
reaction temperatures was found not to improve the enantioselectivity of this reaction (entries 3 and 12).

D. Ma, K. Cheng / Tetrahedron: Asymmetry 10 (1999) 713–719
715
Table 1
Chiral guanidine catalyzed Michael addition reaction of glycine derivatives to acrylic estersa
To check if enones could be suitable Michael addition acceptors under the present reaction conditions
we attempted the reaction of 7b with vinyl methyl ketone using catalyst 1. It was found that the reaction
was complete in 12 h to give the addition product 10 in 98% yield. However, the enantioselectivity
(16.5% ee) was poor.
It is known that guanidines could be used for molecular recognition of carboxylate anions because
of their ability to form strong zwitterionic hydrogen bonds.10 Based on these results we propose the
possible mechanism of the present reaction as follows. After deprotonation of 7 under the action of the
chiral guanidine 1, a complex A might form, which could react with acrylic ester 8 to deliver the addition
product 9. It might be possible to obtain better enantioselectivity by using a bulkier R1 group or by
replacement of the phenyl group in the guanidine 1 with a larger group.

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In conclusion, we have found that some chiral guanidines can catalyze the Michael addition of glycine
derivatives to acrylic esters or enones to provide the addition products with low enantioselectivity.11
Although the enantioselectivity was poor, these results demonstrate the ability of chiral guanidines as
asymmetric catalysts in the Michael addition reaction. Optimization of the reaction conditions together
with the application of these chiral guanidines to other systems are presently under study in our
laboratory.
3. Experimental
3.1. (R)-N-Benzoyl-N0-(1-phenylethyl)thiourea 12
To a solution of ammonium thiocyanate (3.80 g, 50 mmol) in 20 mL of anhydrous acetone under a
nitrogen atmosphere, was added dropwise benzoyl chloride (7.10 g, 50 mmol) at 60°C. The mixture was
stirred for 15 min and then a solution of (R)-α-methylbenzylamine (6.05 g, 50 mmol) in 10 mL of acetone
was added dropwise. After the reaction mixture was stirred for 2 h at 65°C, it was poured into 100 mL
of water and extracted with methylene chloride (3×50 mL). The combined organic layers were dried
over Na2SO4 and evaporated to dryness under reduced pressure. Purification of the residue by column
chromatography (using 1:10 ethyl acetate:petroleum ether as an eluent) afforded 12.8 g (90%) of 12 as
1
a light-yellow oil. [α]D20=+8.9 (c 1, CHCl3); IR (KBr) 1671, 1539, 1376 cm−1; H NMR (300 MHz,
CDCl3) δ 1.65 (d, J=7.2 Hz, 3H), 1.85 (s, 1H), 5.65 (q, J=7.2 Hz, 1H), 7.41–7.92 (m, 10H), 9.10 (s, 1H);
MS m/z 284 (M+), 120, 105, 77; HRMS calcd for C16H16N2OS: 284.0983; found: 284.0976.
3.2. (R)-N-(1-Phenylethyl)thiourea 13
A solution of 12 (10.99 g, 38.7 mmol), potassium carbonate (10.68 g, 77.0 mmol) and water (10 mL)
in methanol (100 mL) was stirred at rt for 3 h. The mixture was evaporated and the residue was extracted
with ethyl ether (2×50 mL). The combined organic layers were dried over MgSO4 and evaporated to
dryness. The residual oil was purified by column chromatography (using 1:1 ethyl acetate:petroleum
ether as an eluent) afforded 6.97 g (90%) of 13 as colorless prisms. [α]D20=−51.3 (c 1.0, CHCl3); IR
(KBr): 3274, 1538, 1274 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.50 (d, J=7.1 Hz, 3H), 2.05 (s, 1H), 4.50
(q, J=7.2 Hz, 1H), 6.10 (br s, 2H), 7.20–7.50 (m, 5H); MS m/z 180 (M+), 120, 105, 77; HRMS calcd for
C9H12N2S: 180.0721; found: 108.0706.
3.3. (R)-N0-(tert-Butoxycarboxyl)-N-(1-phenylethyl)thiourea 14
To a suspension of NaH (65% in mineral oil, 1.80 g, 47 mmol) and 13 (5.96 g, 33 mmol) in THF (150
mL) under a nitrogen atmosphere, was added portionwise a solution of di-tert-butyl dicarbonate (7.22
g, 33 mmol) in THF (10 mL) which was then stirred at room temperature overnight. After evaporation
of THF, the mixture was poured into water, and then extracted with ethyl acetate (2×100 mL). The

D. Ma, K. Cheng / Tetrahedron: Asymmetry 10 (1999) 713–719
717
organic solution was washed with water and brine, respectively, dried over MgSO4, and evaporated to
dryness. The residue was purified by column chromatography (using 1:7 ethyl acetate:petroleum ether as
an eluent) affording 6.95 g (75%) of 14 as colorless prisms. [α]D21=+33.8 (c 1.0, CHCl3); 1H NMR (300
MHz, CDCl3) δ 1.50 (s, 9H), 1.60 (d, J=7.2 Hz, 3H), 5.60 (q, J=7.2 Hz, 1H), 7.20–7.40 (m, 5H), 7.90
(s, 1H), 10.0 (br s, 1H); MS m/z 280 (M+), 224, 120, 105, 77. Anal. calcd for C14H20N2O2S: C, 59.63;
H, 7.19; N, 9.90; found: C, 59.97; H, 7.19; N, 9.99.
3.4. (R,R)-N,N0-Bis(1-phenylethyl)-N00 -tert-butoxycarbonyl guanidine 15
To a solution of 14 (0.28 g, 1.0 mmol), Et3N (0.12 mL) and DCC (0.21 g, 1.0 mmol) in DMF (4
mL) under a nitrogen atmosphere, was added dropwise (R)-α-methylbenzylamine (0.13 g, 1.1 mmol) at
40°C. After the mixture had been stirred at 70°C overnight, 10 mL of water was added. The resultant
mixture was extracted with ethyl acetate (2×20 mL), and dried over Na2SO4. After removal of solvent,
the residual oil was purified by column chromatography (using 1:7 ethyl acetate:petroleum ether as an
eluent) affording 0.22 g (66%) of 15 as colorless prisms. [α]D23=−143.9 (c 1.0, CHCl3); IR (KBr) 3268,
1
1598 cm−1; H NMR (300 MHz, CDCl3) δ 1.50 (s, 9H), 1.60 (d, J=7.2 Hz, 6H), 4.60 (q, J=7.2 Hz,
2H), 7.10 (br s, 2H), 7.20–7.40 (m, 10H); MS m/z: 367 (M+), 267, 206, 120, 105, 77; HRMS calcd for
C22H29N3O2: 367.2260; found: 367.2297.
3.5. (R,R)-N,N0-Bis(1-phenylethyl)guanidine 1
A solution of 15 (0.58 g, 1.58 mmol) and TFA (5 mL) in methylene chloride (5 mL) was stirred at rt
for 1 h. After the excess of TFA was evaporated, the residue was basified with 5 mL of 50% aqueous
NaOH, and extracted with methylene chloride (3×10 mL). The combined organic layers were dried over
Na2SO4 and evaporated to dryness to yield 0.42 g (100%) of 1 as a light-yellow solid. [α]D23=−54.8 (c
1.0, CHCl3); IR (KBr) 3294, 3028, 1621 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.50 (d, J=7.0 Hz, 6H),
4.50 (q, J=7.1 Hz, 2H), 7.00–7.20 (br s, 3H), 7.20–7.40 (m, 10H); MS m/z 267 (M+), 252, 162, 120, 105,
77; HRMS calcd for C17H21N3: 267.1735; found: 267.1744.
3.6. N,N0-Bis(2-isopropyl-5-methylcyclohexyl)guanidine 2
To a stirring solution of 5 (1.55 g, 10 mmol) in 3 mL of ethanol was carefully added a solution of
cyanogen bromide (1.16 g, 11 mmol) in 1 mL of ethanol at 0°C. After the addition, the reaction mixture
was allowed to warm to 25°C in 10 min and then heated at 150°C for 30 min, while N2 was swept through
the flask to completely remove the boiling solvent. The fused reaction mixture was allowed to cool to
rt, and the resulting glassy solid was taken up in hot EtOH (15 mL). The resultant solution was treated
with decolorizing charcoal (60 mg) and filtered through Celite. The filtrate was diluted with aqueous 1
N NaOH (20 mL), and the precipitate guanidine free base was filtered off to afford 1.17 g (35%) of 2 as
colorless prisms in 35% yield. [α]D28=+56.9 (c 1.0, CHCl3); IR (KBr): 3288, 3171, 2952, 1629, 1556
1
cm−1; H NMR (300 MHz, CDCl3) δ 0.85 (d, J=7.2 Hz, 6H), 0.90 (d, J=7.1 Hz, 12H), 0.95–1.10 (m,
10H), 1.50 (m, 4H), 1.80 (m, 4H), 3.30 (m, 1H), 7.30 (br s, 3H); MS m/z 335 (M+), 320, 292, 250, 224,
154, 70; HRMS calcd for C21H41N3: 335.3300; found: 335.3275.

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3.7. (R,R)-N,N0-(1-Phenylethyl)-ethylenediamine 6
A mixture of (R)-α-methylbenzylamine (2.42 g, 20 mmol), 1,2-dibromoethane (1.88 g, 10 mmol) and
sodium hydroxide (0.16 g, 40 mmol) in 5 mL of DMSO was stirred at 70°C for 24 h. The mixture was
poured into water (20 mL) and then extracted with ethyl ether (2×20 mL). The combined organic layers
were washed with water and brine, respectively, dried over MgSO4, and concentrated via rotavapor.
The residual oil was chromatographed (using 0.05:1:3 triethyl amine:ethyl acetate:petroleum ether as an
eluent) to afford 1.88 g (70%) of 6 as a colorless oil. [α]D23=+73.3 (c 1.0, CHCl3); IR (KBr) 3311, 1452,
1
1124 cm−1; H NMR (300 MHz, CDCl3) δ 1.35 (d, J=7.1 Hz, 6H), 2.30 (br s, 2H), 2.55 (t, J=6.9 Hz,
4H), 3.70 (q, J=7.1 Hz, 2H), 7.20–7.40 (m, 10H); MS m/z 269 (M++H+), 163, 149, 134, 120, 105, 91,
77; HRMS calcd for C18H24N2: 268.1939; found: 268.1911.
3.8. (R,R)-N,N0-Bis(1-phenylethyl)-2-imidazolidine 3
Following the procedure for preparing 2 from 5, the cyclic guanidine 3 was prepared from 6 in 40%
yield as colorless prisms. [α]D25=+78.5 (c 1.0, CHCl3); IR (KBr) 3344, 3030, 1618, 1289 cm−1; 1H NMR
(300 MHz, CDCl3) δ 1.55 (d, J=7.0 Hz, 6H), 2.95 (m, 2H), 3.15 (m, 2H), 5.15 (q, J=7.0 Hz, 2H), 7.25
(br s, 1H), 7.30–7.40 (m, 10H); MS 292 (M+−H+), 278, 188, 148, 105, 84; HRMS calcd for C19H22N3:
292.1814; found: 292.1798.
3.9. Typical procedure for asymmetric Michael addition reactions catalyzed by chiral guanidine
To a mixture of glycine derivative 7 (0.125 mmol) and guanidine 1 (7 mg, 0.025 mmol) in THF (0.5
mL) was added a suitable acrylic ester (or vinyl methyl ketone) (0.46 mmol) dropwise at −78°C. The
resulting reaction mixture was stirred for 2 h at −78°C and then warmed to −10°C. The stirring was
continued until no more 7 existed as monitored by TLC. The mixture was concentrated under reduced
pressure followed by purification by column chromatography (using 1:10 ethyl acetate:petroleum ether
as an eluent) to afford the corresponding addition product.
3.9.1. 2-Benzhydrylideneamino-1,5-pentanedioic acid diethyl ester 9a
98% yield, 6.4% ee. [α]D25=+8.3 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 1.15 (t, J=7.1 Hz,
1
3H), 1.20 (t, J=7.1 Hz, 3H), 2.10–2.20 (m, 4H), 3.90 (dd, J=7.0, 5.8 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H),
4.10 (q, J=7.1 Hz, 2H), 7.10–7.60 (m, 10H); MS m/z 367 (M+−H+), 338, 294, 220, 206, 165, 117; HRMS
calcd for C22H25NO4: 367.1784 [M+−H+]; found: 367.1681.
3.9.2. 2-Benzhydrylideneamino-1,5-pentanedioic acid, 1-tert-butylester 5-methyl ester 9b
1
95% yield, 15.7% ee. [α]D25=+14.6 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H),
2.10–2.20 (m, 2H), 2.30–2.40 (m, 2H), 3.50 (s, 3H), 3.95 (dd, J=7.1, 5.8 Hz, 1H), 7.10–7.60 (m, 10H);
MS m/z 381 (M+), 366, 326, 294, 280, 248, 165, 57; HRMS calcd for C23H27NO4: 381.1940; found:
381.1941.
3.9.3. 2-Benzhydrylideneamino-1,5-pentanedioic acid 1-tert-butylester 5-ethyl ester 9c
99% yield, 30.4% ee. [α]D25=+28.5 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.20 (t, J=7.1 Hz,
3H), 1.45 (s, 9H), 2.00–2.10 (m, 2H), 2.10–2.20 (m, 2H), 3.85 (dd, J=7.0, 5.8 Hz, 1H), 4.10 (q, J=7.1 Hz,
2H), 7.05–7.60 (m, 10H); MS m/z 396 (M++H+), 338, 294, 220, 165, 57; HRMS calcd for C24H29NO4:
395.2097; found: 395.2104.

D. Ma, K. Cheng / Tetrahedron: Asymmetry 10 (1999) 713–719
719
3.9.4. 2-Benzhydrylideneamino-1,5-pentanedioic acid di-tert-butylester 9d
99% yield, 30.1% ee. [α]D25=+20.2 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.35 (s, 9H), 1.45
(s, 9H), 2.05–2.10 (m, 2H), 2.10–2.20 (m, 2H), 3.90 (dd, J=6.4, 5.8 Hz, 1H), 7.10–7.60 (m, 10H); MS
m/z 424 (M++H+), 368, 350, 294, 266, 194, 165, 91, 57; HRMS calcd for C26H33NO4: 423.2410; found:
423.2416.
3.9.5. 2-Benzhydrylideneamino-5-oxo-1-hexanoic acid tert-butylester 10
1
99% yield, 16.5% ee. [α]D25=+17.1 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 1.40 (s, 9H),
2.00–2.10 (m, 2H), 2.10–2.20 (m, 2H), 2.25 (s, 3H), 3.90 (dd, J=7.0, J=5.8 Hz, 1H), 7.10–7.60 (m,
10H); MS 365 (M++H+), 308, 264, 206, 182, 165, 57; HRMS calcd for C24H29NO4: 365.1991; found:
365.1993.
Acknowledgements
The authors are grateful to the Chinese Academy of Sciences and National Natural Science Foundation
of China (grant 29725205) for their financial support.
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