CN1220686C - Beta-hydroxy-alpha-amino acid and its derivatives and synthesizing method for preparing template - Google Patents
Beta-hydroxy-alpha-amino acid and its derivatives and synthesizing method for preparing template Download PDFInfo
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Abstract
The present invention relates to a method for preparing heterocyclic compounds, particularly to a method in which two chiral templates-tricyclic imine lactone and trans-tricyclic imine lactone which are composed of hexatomic cyclic compounds containing nitrogen-oxygen atoms and used for synthesizing beta-hydroxy-alpha-amino acid and derivatives thereof are used for synthesizing beta-hydroxy-alpha-amino acid derivatives, and the derivatives are used for preparing beta-hydroxy-alpha-amino acid.
Description
Technical field
The present invention relates to a kind of method for preparing heterocyclic compound, particularly the two kinds of chiral template-three epimino lactones and the trans three epimino lactones that are used for synthetic beta-hydroxy-a-amino acid and derivative thereof that constitute by the six-membered ring compounds that contains the nitrogen Sauerstoffatom; And the derivative that synthesizes beta-hydroxy-a-amino acid with three epimino lactones and these two kinds of chiral templates of trans three epimino lactones; Then the method for preparing beta-hydroxy-a-amino acid again with this derivative.The present invention synthesizes the chiral template preparation method of beta-hydroxy-a-amino acid and derivative thereof, is to change camphor into the camphor diketone, and again with the reduction of camphor diketone, esterification is closed ring at last and obtained two kind of three epimino lactone chiral template.
Background technology
Amino acid has multiple biological activity as peptide and proteinic structural unit, and plays an important role in origin of life and evolutionary process.Natural and alpha-non-natural amino acid are as constituting and closely-related polypeptide of vital movement and proteinic unit, playing the part of extremely important role in biology, biological chemistry, medicine and natural product research, this mainly is because its configuration has determined the configuration of the peptide that generates.Particularly in recent years, the rise of polypeptide drugs, amino acid whose asymmetric synthesis has caused more and more organic synthesis workers' great interest, it synthesizes and studies since the rise of the later stage 1980s, and is in the ascendant always.
About amino acid whose synthetic existing many reports, classical synthetic method has the Stryker method, drop cloth riel method, Hull-Wu Erha-Marian Zielinski-α-bromination method, malonic ester method etc.It is with the solid control synthetic method of chiral template as inducible factor that the up-to-date chirality of amino acid is synthesized, as: a) Ferraris, D.Young, BCox, CDudding, T.Drury, W.J.Ryzhkov, L.Taaggi, A.E.Lectka, T.J.Am.Chem.Soc.2002,124.67; B) Heyes, J.A.Niculescu, D.D.Cooper, R.G.Springer, C.J.J.Med.Chem.2002,45,99; C) Xiong, C.-Y.Wang, W.Cai, C-Z.Hruby, V.j.J.Org.Chem.2002,67,1399; D) Warmuth, R.munsch, T.E.Stalker, R.A.Li, Beatty, A.Teraheddron2001,57,6383; E) Ding, K.Ma, D.-W, Teraheddron 2001,57, and 6361; F) hang, J.-F.Tian, S.-K.Tang, Li Deng, Li J.Am.Chem.Soc.2001,123,12696; G) Chinchilla, R.Falvello, L.R, Galindo, N.Najera, C.J.Org.Chem.2000,65,3034; H) Najera, C.Abellan, T.Sansano, J.M.Eur.J.Org.Chem.2000.15,2809.
But carry out in the asymmetric synthesis report of a-amino acid in known employing chiral template method, the synthetic chiral template nearly all is from the chirality L-Ala, so just inevitably obtain α, α '-two replacement-a-amino acids, and also alpha-position has methyl.Because there is active proton in the alpha site of carboxyl group of α-list replacement-a-amino acid, the template reaction of existing bibliographical information is meeting racemization mostly in hydrolysis, thereby be difficult to obtain single a-amino acid that replaces of high optical activity, can only synthesize α, α '--two replacement-a-amino acids, and because the unicity of resulting chiral template makes by its control synthetic configuration natural and non-natural a-amino acid single, can not optionally synthesize the a-amino acid of other configuration as required.
The contriver is once by the chirality of natural camphor and the rigidity of molecule, auxiliary basic with it as chirality, circularize into three epimino lactones with the CBZ-glycine, successfully synthesize two kinds of complementary chiral template compound three epimino lactone iminolactone and trans three epimino lactone anti-iminolactone with two kinds of different methods.At low temperatures, be alkali with LDA and in the presence of HMPA, they carried out alkylation that its product is mainly the endo product, and the stereoselectivity of product good (ee%＞98).This foundation for the configuration of thereafter the amino acid whose alpha-position amino of hydrolysate is laid a good foundation.As: the alkylate hydrolysis of three epimino lactone iminolactone will obtain the a-amino acid of R-configuration certainly, and the alkylate hydrolysis of trans three epimino lactone anti-iminolactone will obtain the a-amino acid of S-configuration certainly.This makes us become possibility by the a-amino acid of synthetic required configuration to the synthetic of complementary chiral template.These work are published in J.Org.Chem.2002 successively, and 67 (7), 2309; J.Org.Chem.2003,68 (3), 658.But be earlier camphor to be oxidized to the camphor diketone in the aforesaid work of contriver; then the camphor diketone is adopted diverse ways selective protection; reduction; obtain 2-oxycamphor ketone and 3-oxycamphor ketone respectively; again with them and CBZ-glycine esterification condensation; last hydrogen reducing closes ring, obtains three epimino lactone iminolactone and trans three epimino lactone anti-iminolactone respectively.Its whole reactions steps is long, and control is comparatively difficult.On the other hand, two kinds of complementary chiral templates must obtain by different operations.Simultaneously from document noted earlier also as can be known, its template is just reacted with haloalkane.
Summary of the invention
The present invention discloses and a kind ofly can produce two kinds of chiral templates that are used for synthetic beta-hydroxy-a-amino acid and derivative thereof simultaneously with more simple method, i.e. three epimino lactones and trans three epimino lactones, provide simultaneously with three epimino lactones and trans three epimino lactones this two kinds of chiral templates and aldehyde reaction, generate the method for the derivative of beta-hydroxy-a-amino acid, and the method that obtains beta-hydroxy-a-amino acid with beta-hydroxy-alpha-amino acid derivatives.
The chiral template preparation method of synthetic beta-hydroxy-a-amino acid of the present invention and derivative thereof is: at first camphor and tin anhydride are refluxed in acetic anhydride; camphor is oxidized to the camphor diketone; again in the mixed liquid of ether that the camphor diketone is dissolved in and methyl alcohol; under condition of ice bath, add sodium borohydride; solvent evaporated behind the stirring reaction; add a small amount of cold water extracted with diethyl ether; organic phase is washed with the full salt solution that closes; drying, solvent evaporated, column chromatography gets 2-oxycamphor and 3-oxycamphor; afterwards 2-oxycamphor ketone and 3-oxycamphor ketone are mixed with the glycine of chloroformic acid benzyl ester protection; with solution concentration, column chromatography obtains glycinate, and glycinate is dissolved in the exsiccant dehydrated alcohol; add palladium carbon; then reaction vessels is found time to feed hydrogen, under hydrogen atmosphere and room temperature condition, react, remove hydrogen; continue reaction at room temperature; remove by filter palladium carbon, solvent evaporated obtains three epimino lactones and two chiral templates of trans three epimino lactones respectively with column chromatography.
Also can be among the present invention with 2-oxycamphor ketone and 3-oxycamphor ketone with after the glycine of chloroformic acid benzyl ester protection mixes; after adding the 4-Dimethylamino pyridine; system adds the tetrahydrofuran solution of dicyclohexylcarbodiimide (DCC) under 0 ℃ of agitation condition; continue reaction for some time; reaction at room temperature again; remove by filter dicyclohexyl urea; with solution concentration; column chromatography obtains glycinate; glycinate is dissolved in the exsiccant dehydrated alcohol, adds palladium carbon, then reaction vessels is found time to feed hydrogen; under hydrogen atmosphere and room temperature condition, react; remove hydrogen, continue reaction at room temperature, remove by filter palladium carbon; solvent evaporated obtains three epimino lactones and two chiral templates of trans three epimino lactones respectively with column chromatography.The tetrahydrofuran solution that adds dicyclohexylcarbodiimide (DCC) reacts, and can promote reaction to carry out, and can obtain higher reaction product yield.
In the present invention the method for preparing beta-hydroxy-alpha-amino acid derivatives with the resultant chiral template in front be with three epimino lactones or trans three epimino lactones respectively with aldehyde reaction, obtain corresponding aldol adduct---beta-hydroxy-alpha-amino acid derivatives.
A kind of implementation method for preparing beta-hydroxy-alpha-amino acid derivatives with described chiral template among the present invention is under-30 ℃; Diisopropylamine joined use in argon shield and the exsiccant container; add anhydrous tetrahydro furan; add n-Butyl Lithium again; after stirring, will be dissolved in three epimino lactones in the anhydrous tetrahydro furan again; perhaps trans three epimino lactones slowly add in the reaction system and react; temperature is reduced to gradually-78 ℃; the tetrahydrofuran (THF) saturated solution that adds Lithium chloride (anhydrous); to be dissolved with the tetrahydrofuran solution of aldehyde again, and join reaction system slowly, system continues reaction down at-78 ℃; use the hydrochloric acid cancellation; allow its temperature rise to room temperature naturally,, organic layer is carried out drying with saturated lithium chloride solution washing; concentrate, get beta-hydroxy-alpha-amino acid derivatives crude product.Beta-hydroxy-alpha-amino acid derivatives purifying crude can be obtained the pure product of beta-hydroxy-alpha-amino acid derivatives by column chromatography again.
The method that the present invention synthesizes beta-hydroxy-a-amino acid is to be hydrolyzed with beta-hydroxy-alpha-amino acid derivatives of stating the method gained, to obtain beta-hydroxy-a-amino acid.
Starting raw material natural camphor required for the present invention is cheap and easy to get.Compared with prior art its synthesis flow is shorter, and simple to operate relatively, production cost is low, and is economical and practical, and can obtain two kinds of complementary chiral templates simultaneously.The present invention and aldehyde reaction selectivity are good, and the productive rate height can obtain the specific amino acids of any required configuration.
Description of drawings
Accompanying drawing 1 prepare for the present invention three epimino lactones and trans three epimino lactones chiral template reacting flow chart.
Accompanying drawing 2 prepares the reacting flow chart of beta-hydroxy-alpha-amino acid derivatives for the present invention.
Accompanying drawing 3 prepares the reacting flow chart of beta-hydroxy-a-amino acid for the present invention.
Embodiment
Provide most preferred embodiment of the present invention below in conjunction with accompanying drawing
1. camphor diketone (1) is synthetic:
Camphor (100mmol) is dissolved in acetic anhydride, and (in 30～40mL), dissolving back fully adds tin anhydride (2.0～2.5eqv.).Reaction system is cooled to room temperature 170 ℃ of stirring and refluxing 17 hours, removes by filter the selenium of black, adds cold water (50mL) in filtrate, and the ice bath cooling produces yellow mercury oxide, and restir 5 minutes filters out this precipitation and uses a small amount of cold water washing.Filtrate in saturated sodium hydroxide and after, use ethyl acetate extraction, organic phase saturated common salt water washing, drying, evaporate to dryness obtains yellow solid, it and fore portion is merged promptly get required compound camphor diketone (productive rate 98%).Its actual measurement spectral data is as follows:
Camphor diketone (1): IR (NaCl, CHCl
3): 3040 (m), 2980 (m), 1775 (m), 1760 (s) cm
-1 1H NMR (400MHz, CDCl
3): δ 2.64 (d, J=5.6Hz, 1H), 2.08～2.28 (m, 1H), 1.99～1.82 (m, 1H), 1.71～1.56 (m, 2H), 1.11 (s, 3H), 1.07 (s, 3H), 0.94 (s, 3H).
2.2-oxycamphor ketone (2) and 3-oxycamphor ketone (3) is synthetic:
(50～70mL), system is as cold as 0 ℃ in ice bath after, added sodium borohydride in 10 minutes (0.25～0.30eqv.), ice bath stirred 3.5 hours in batches with camphor diketone (25mmol) be dissolved in 1: 1 ether of (V/V) and the mixed liquid of methyl alcohol.Solvent evaporated adds a small amount of cold water, extracted with diethyl ether, organic phase saturated common salt water washing then, drying, solvent evaporated, column chromatography (EtOAc: Hexane=1: 8) get white solid 2-oxycamphor and 3-oxycamphor (productive rate 94%).
Product actual measurement spectral data is as follows:
2-oxycamphor ketone (2): m.p.209～212 ℃; IR (NaCl, CHCl
3): 3444 (br), 2959 (m), 1746 (s) cm
-1 1H NMR (400MHz, CDCl
3): δ 3.54 (d, J=2.8Hz, 1H), 2.32 (d, J=2.8Hz, 1H), 2.17 (d, J=4.4Hz, 1H), 1.96～1.82 (m, 2H), 1.47～l.35 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H), 0.94 (s, 3H);
13C NMR (100MHz, CDCl
3); δ 79.5,58.6, and 49.2,46.5,33.9,21.1,20.3,18.8,10.2; MS:m/z 210 (M
+, 6.9), 182 (61.0), 113 (72.4), 99 (100).
3-oxycamphor ketone (3): m.p.166～168 ℃; IR (NaCl, CHCl
3): 3442 (br), 2957 (s), 1744 (s) cm
-1 1H NMR (400MHz, CDCl
3); δ 3.74 (s, 1H), 2.10 (d, J=4.4Hz, 1H), 2.06～1.97 (m, 1H), 1.70～1.63 (m, 1H), 1.49～1.35 (m, 2H), 0.99 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H); MS:m/z 168 (M
+, 53.8), 153 (3.0), 140 (12.0), 125 (31.6), 107 (7.3), 100 (11.7), 83 (100.0), 69 (23.4), 55 (25.4), 53 (3.8).
Glycinate (1R, 2S, 4S)-Benzyloxycarbonylamino-acetic acid
1,7,7-trimethyl-3-oxo-bicyclo[2.2.1] hept-2-yl ester (4) and
(1S，2R，4R)-Benzyloxycarbonylamino-acetic acid
4,7,7-trimethyl-3-oxo-bicyclo[2.2.1] hept-2-yl ester (5) synthetic:
With 2-oxycamphor ketone and 3-oxycamphor ketone (10mmol); glycine Cbz-glycine (1.0～1.5eqv.) with the chloroformic acid benzyl ester protection; 4-Dimethylamino pyridine (4-N; N-dimethylaminopydine; 0.3～0.8eqv.); be dissolved in tetrahydrofuran (THF) (35～45mL); system stirred 15 minutes at 0 ℃; then to wherein slowly dripping dicyclohexylcarbodiimide (DCC; 1.0～2.0eqv.) tetrahydrofuran solution (10mL); mixture stirred 2 hours at 0 ℃, again room temperature reaction 14～16 hours.Remove by filter dicyclohexyl urea (DCU), solution concentration, column chromatography (EtOAc: Hexane=1: 8) obtain colourless heavy-gravity ester (productive rate 98%).
Product actual measurement spectral data is as follows:
The glycinate of S configuration (1R, 2S, 4S)-and Benzyloxycarbonylamino-acetic acid1,7,7-trimethyl-3-oxo-bicyclo[2.2.1] hept-2-yl ester (4): [α]
D 22=-94.6 ° of (c=2.04, CHCl
3); M.p.72～74 ℃; IR (NaCl, CHCl
3): 3360 (br), 2961 (m), 1758 (s), 1750 (s) cm
-1 1H NMR (400MHz, CDCl
3): δ 7.36～7.35 (m, 5H), 5.24 (s, 1H), 5.12 (s, 1H), 4.90 (s, 1H), 4.15～4.02 (m, 2H), 2.21～2.20 (d, J=4.0Hz, 2H), 2.10～1.84 (m, 2H), 1.62～1.44 (m, 2H), 0.97 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 212.4,169.7, and 156.5,136.4,128.8,128.4,79.4,67.3,58.9,49.7,46.8,42.9,33.7,21.0,20.6,18.7,10.6; HRMS:calcd for C
20H
25NO
5: 359.1735; Found:359.1733.
The glycinate of R configuration (1S, 2R, 4R)-and Benzyloxycarbonylamino-acetic acid4,7,7-trimethyl-3-oxo-bicyclo[2.2.1] hept-2-yl ester (5): IR (NaCl, CHCl
3): 3366 (br), 3033 (m), 1754 (s), 1746 (s) cm
-1 1H NMR (400MHz, CDCl
3): δ 7.36～7.34 (m, 5H), 5.24 (b, 1H), 5.12 (s, 2H), 4.84 (s, 1H), 4.02 (d, J=5.6Hz, 2H), 2.13 (d, J=4.4Hz, 1H), 1.79～1.62 (m, 2H), 1.58～1.43 (m, 2H), 0.95 (s, 6H), 0.92 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 213.6,169.3, and 156.2,136.1,128.4,1283,128.1,128.0,67.0,57.2,48.2,46.5,42.7,28.4,24.7,20.6,19.5,9.0; MS:m/z 359 (M
+, 23.1), 316 (1.2), 258 (2.8), 224 (6.6), 192 (15.2), 152 (32.3), 139 (66.2), 108 (52.0), 91 (100.0), 83 (25.4), 55 (20.2); HRMS:calcdfor C
20H
25NO
5: 359.1738; Found:359.1733.
4. three epimino lactones (6) and trans three epimino lactones (7) (chiral template) is synthetic:
Palladium carbon (0.24～the 0.33g of adding 5% in glycinate (10mmol), 0.12～0.16eqv.), then reaction vessels is found time to feed hydrogen, 3 times repeatedly, add exsiccant ethanol (25～40mL), room temperature reaction is 3.5～4.5 hours under the hydrogen of 1atm, remove hydrogen, room temperature reaction 12～16 hours removes by filter palladium carbon, solvent evaporated, column chromatography (EtOAc: Hexane=1: 4) obtain colorless solid three epimino lactones and trans three epimino lactones (productive rate 76%) respectively.
Product actual measurement wave spectrum is:
Three epimino lactones (6): [α]
D 22=-265.6 ° of (c=2.34, CHCl
3), m.p.63～64 ℃; IR (NaCl, CHCl
3): 2962 (m), 1751 (s), 1695 (m) cm
-1 1H NMR (400MHz, CDCl
3): δ 4.52 (d, J=18Hz, 1H), 4.32 (d, J=1.6Hz), 3.90 (dd, J=1.6,18Hz, 1H), 2.45 (d, J=4.4Hz, 1H), 2.05～1.98 (m, 1H), 1.95～1.88 (m, 1H), 1.59～1.52 (m, 1H), 1.43～1.36 (m, 1H), 1.09 (s, 3H), 0.98 (s, 3H), 0.86 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 181.8,168.8, and 81.7,53.2,52.5,49.4,48.9,34.0,21.6,20.0,19.3,9.8.Trans three epimino lactones (7): [α]
D 22=+266.3 ° of (c=1.35, CHCl
3); M.p.103～104 ℃; IR (NaCl, CHCl
3): 2972 (m), 1758 (s), 1685 (m) cm
-1 1H NMR (400MHz, CDCl
3): δ 4.56 (d, J=18Hz, 1H), 4.49 (d, J=1.6Hz, 1H), 3.95～3.90 (dd, J=18Hz, 1.6Hz), 2.28 (d, J=4.8Hz), 2.13～2.06 (m, 1H), 1.83～1.75 (m, 1H), 1.62～1.55 (m, 1H), 1.41～1.34 (m, 1H), 1.07 (s, 3H), 0.98 (s, 3H), 0.81 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 184.0,169.2, and 79.9,52.9,49.3,47.7,29.7,25.6,20.2,19.9,10.1; MS:m/z 207 (M
+, 64.0), 192 (5.1), 179 (100.0), 164 (13.7), 150 (32.0), 136 (31.9), 111 (51.2), 110 (22.7), 82 (44.0), 69 (54.7), 55 (15.4), 53 (10.7); HRMS:calcd for C
12H
17NO
2: 207.1268; Found:207.1259.
More than reaction is referring to accompanying drawing 1.
5. the reaction (compound 8,9) of three epimino lactones or trans three epimino lactones and aldehyde:
Under-30 ℃; with 156 microlitres (density=0.713～0.718g/mL; 1.1mmol) Diisopropylamine join and use in argon shield and 50 milliliters of Chang Cervical round-bottomed flasks of exsiccant; add 1 milliliter of anhydrous tetrahydro furan; after 2 minutes; add 500 microlitre (2.2mol/L; 1.1mmol) n-Butyl Lithium; continue reaction 30 minutes; 207 milligrams of (1.0mmol) three epiminos (or trans three epiminos) that are dissolved in 10 milliliters of anhydrous tetrahydro furans slowly are added drop-wise in the reaction system along the bottle wall with syringe, the temperature of reaction of system are reduced to-78 ℃ then.The tetrahydrofuran (THF) saturated solution of 15 milliliters of Lithium chloride (anhydrous)s (is contained Lithium chloride (anhydrous) 0.2～0.3g) and splashes into reaction system with syringe along the bottle wall; After 5 minutes,, quickening in 10 minutes, to be added drop-wise to reaction system with syringe slowly along the bottle wall under the condition of stirring again with 10 milliliters of tetrahydrofuran solutions that are dissolved with 1.3～1.5 mmole aldehyde.Reaction system continues down reaction after 12 hours at-78 ℃, will react cancellation with the hydrochloric acid of 2 milliliter of 2 mol.Allow its temperature rise to room temperature naturally, it is inferior to give a baby a bath on the third day after its birth with the saturated lithium chloride aqueous solution, with the organic layer anhydrous magnesium sulfate drying, concentrates, and gets crude product; By column chromatography (sherwood oil: ethyl acetate, 8: 1～4: 1) purifying, promptly obtain the derivative of beta-hydroxy-a-amino acid.Table 1 is three epimino lactones and the relevant data of several representative different aldehyde reactions, and table 2 is the situation of trans three epimino lactones and several representative aldehyde reaction.
The reaction (compound 8) of table 1. three epimino lactones and aldehyde
| Sequence number | Aldehyde (RCHO) | Productive rate (%) | Product | Diastereomeric excess (%) |
| 1 2 3 4 5 6 7 8 | PhCHO p-Cl-PhCHO o-Cl-PhCHO m-Cl-PhCHO o-F-PhCHO o-MeO-PhCHO PhCH＝CHCHO CH 3CH＝CHCHO | 90 85 92 87 84 92 83 81 | 8a 8b 8c 8d 8e 8f 8g 8h | 96 80 90 71 90 80 85 80 |
The reaction (compound 9) of trans three epimino lactones of table 2. and aldehyde
| Sequence number | Aldehyde (RCHO) | Productive rate (%) | Product | Diastereomeric excess .% |
| 1 2 3 4 5 6 7 8 | CH 3CHO CH 3CH 2CH 2CHO (CH3) 2CHCHO cyclo-HexylCHO o-Cl-PhCHO PhCHO o-F-PhCHO o-MeO-PhCHO | 85 80 82 84 75 73 80 78 | 9a 9b 9c 9d 9e 9f 9g 9h | ＞98 ＞98 ＞98 ＞98 71 78 60 85 |
Each product relevant test data is as follows:
A series of products (8) of three epimino lactones and aldehyde reaction:
(1R，2S，5R，8S)-5-(1’-hydroxybenzyl)-1，11，11-Tetramethyl-3-oxa-6-azatricyclo-[6.2.1.02，7]undec-6-en-4-one(8a)：[α]
D 20＝+93(c＝2.52 CH
2C
l2)；
1HNMR(300MHz，CDCl
3)：δ779-7.226(m，4H)，5.195(d，J＝3.6Hz，1H)，4.675(d，J＝4.2Hz，1H)，3.646(s，1H)，2.296(d，J＝4.8Hz，1H)，1.954-0.965(m，4H)，0.836(s，3H)，0.780(s，3H)，0.657(s，3H)；
13CNMR：δ181.80，170.70，139.78，128.39，126.29，126.03，81.66，75.06，67.09，53.80，49.08，48.00，34.46，21.23，19.82，19.09，9.49.
(1R，2S，5R，8S)-5-(1’-hydroxy-p-chlorobenzyl)-1，11，11-Tetramethyl-3-oxa-6-azatricyclo-[6.2.1.02，7]undec-6-en-4-one(8b)：[α]
D 20＝+77(c＝1.276 CH
2Cl
2)；Rf＝0.55(PE∶EA＝1∶1)；mp：147-149；
1HNMR(300MHz，CDCl
3)：δ7.295-7.168(m，4H)，5.227(d，J＝2.4Hz，1H)，4.580(s，1H)，4.111(s，1H)，2.320(d，J＝4.2Hz，1H)，1.968-1.766(m，2H)，1.571-1.483(m，1H)，1.266-1.184(m，1H)，0.973(s，3H)，0.903(s，3H)，0.694(s，3H)；
13CNMR：182.30，170.565，138.436，133.963，128.469，127.522，81.945，74.604，66.972，53.799，49.205，48.045，34.522，21.334，19.808，19.121，9.551.
(1R，2S，5R，8S)-5-(1’-hydroxy-o-chlorobenzyl)-1，11，11-Tetramethyl-3-oxa-6-azatricyclo-[6.2.1.02，7]undec-6-en-4-one(8c)：R
f＝0.63(PE∶EA＝2∶1)；
1HNMR(300MHz，CDCl
3)：δ7.469-7.257(m，4H)，5.227(d，J＝2.4Hz，1H)，5.792(d，J＝3.6Hz，1H)，4.876(d，J＝3.3Hz，1H)，4.522(s，1H)，2.339(d，J＝4.8Hz，1H)，2.038-1.860(m，2H)，1.411-1.250(m，2H)，1.041(s，3H)，0.926(s，3H)，0.776(s，3H)；
13CNMR(CDCl
3，DMSO-d
6)：180.40，169.93，137.89，130.15，128.81，128.53，126.34，81.28，71.11，63.82，53.12，48.46，47.18，33.86，20.87，19.34，18.69，9.25.
(1R，2S，5R，8S)-5-(1’-hydroxy-m-chlorobenzyl)-1，11，11-Tetramethyl-3-oxa-6-azatricyclo-[6.2.1.02，7]undec-6-en-4-one(8d)∶R
f＝0.23(PE∶EA＝2∶1)；IR：1748，2954，2931，1073，1011，3326；
1HNMR(300MHz，CDCl
3)：δ7.318-7.259(m，4H)，5.327(s，1H)，4.780(d，J＝3.3Hz，1H)，3.814(s，1H)，2.823(d，J＝4.5Hz 1H)，2.038-1.579(m，2H)，1.579(m，1H)，1.200-1.170(m，1H)，0.977(s，3H)，0.924(s，3H)，0.795(s，3H)；
13CNMR：δ182.33，170.53，142.24，134.13，129.70，128.41，126.43，124.00，81.94，74.46，66.926，53.80，49.08，48.00，34.46，21.23，19.82，19.09，9.49.
(1R，2S，5R，8S)-5-(1’-hydroxy-o-fluorobenzyl)-1，11，11-Tetramethyl-3-oxa-6-azatricyclo-[6.2.1.02，7]undec-6-en-4-one(8e)：R
f＝0.44(PE∶EA＝1∶1)；
20＝+64(c＝1.05CH
2Cl
2)；IR：3324，2958，2931，1745，1219，1082，758；
1HNMR(300MHz，CDCl
3)：δ7.457-7.009(m，4H)，5.682(s，1H)，4.812(d，J＝4.2Hz，1H)，4.283(s，1H)，2.734(s，1H)，2.377(d，J＝4.2Hz 2H)，2.001-1.248(m，4H)，1.022(s，3H)，0.930(s，3H)，0.799(s，3H)；
13CNMR：182.28，170.604，130.155，128.202，124.615，115.701，82.091，69.956，66.552，54.174，49.579，48.267，34.820，21.647，20.121，19.449，9.910.
(1R，2S，5R，8S)-5-(1’-hydroxy-o-methoxybenzyl)-1，11，11-Tetramethyl-3-oxa-6-azatricyclo-[6.2.1.02，7]undec-6-en-4-one(8f)：R
f＝0.34(PE∶EA＝2∶1)；mp：171-173；
1HNMR(300MHz，CDCl
3)：δ7.351-7.259(m，2H)，7.000-6.951(t，J＝6.9Hz，1H)，6.871(d，J＝7.5Hz，1H)，5.521(d，J＝4.2Hz，1H)，4.855(d，J＝4.2Hz，1H)，4.291(s，1H)，3.867(s，3H)，2.375(d，J＝4.2Hz，1H)，1.972-1.211(m，4H)，1.020(s，3H)，0.803(s，3H)，0.754(s，3H)；
13CNMR：181.494，170.443，156.202，129.247，127.553，120.699，110.427，81.625，72.345，66.697，55.143，53.845，49.251，47.954，34.583，21.471，19.869，19.212，9.718.
(1R，2S，5R，8S)-5-(1’-hydroxy-3’-benzylallyl)-1，11，11-Tetramethyl-3-oxa-6-azatricyclo-[6.2.1.02，7]undec-6-en-4-one(8g)：
1HNMR(300MHz，CDCl
3)：δ7.418-7.263(m，4H)，6.674(d，J＝4.2 15.8Hz 1H)，4.812(dd，J＝15.8，7.2Hz，1H)，4.980(m，1H)，4.679(d，J＝3.2Hz 1H)，4.622(s 1H)，2.458(d，J＝4.2Hz 4H)，2.011-1.127(m，8H)，1.051(s，3H)，0.967(s，3H)，0.864(s，3H)；
13CNMR：δ181.92，169.00，135.90，132.24，128.61，128.13，127.87，126.71，82.22，74.37，67.00，53.89，49.43，48.26，34.51，21.41，19.98，19.23，9.64.
(1R，2S，5R，8S)-5-(1’-hydroxy-3’-methylallyl)-1，11，11-Tetramethyl-3-oxa-6-azatricyclo-[6.2.1.02，7]undec-6-en-4-one(8h)：mp：137-139℃；
1HNMR(CDCl
3，300MHz)；δ5.761-5.647(m，1H)，5.604-5.530(m，1H)，4.676-4.641(dd，J＝4.2Hz，J＝3.6，6.9Hz，1H)，4.582(s，1H)，4.421(d，J＝3.6Hz，1H)，2.371(d，J＝4.2Hz 1H)，1.975-1.268(m，7H)，1.006(s，3H)，0.885(s，3H)，0.721(s，3H)；
13CNMR：δ181.64，170.78，129.69，128.85，81.90，75.12，66.85，53.86，49.13，47.95，34.35，21.24，19.78，19.07，17.45，9.25.
A series of products (9) of trans three epimino lactones and aldehyde reaction:
(1S，2R，5S，8R，1’R)-5-(1’-hydroxyethyl)-8，11，11-Trimethyl-3-oxa-6-azatricyclo[6.2.1.0
2，7]undec-6-en-4-one(9a)：White solid，[α]
D 20＝+52°(c＝1.61，CHCl
3)；mp139～141℃；IR(KBr)：3354(s)，2990(m)，1745(S)，1702(s)cm
-1；
1H NMR(400MHz，CDCl
3)：δ4.78(s，1H)，δ4.43(d，J＝4.4Hz，1H)，4.18(m，1H)，2.20(d，J＝4.8Hz，1H)，2.08～2.01(m，1H)，1.81～1.75(m，1H)，1.66～1.60(m，1H)，1.48～1.35(m，4H)，1.07(s，3H)，0.97(s，3H)，0.61(s，3H)；
13C NMR(300MHz，CDCl
3)：δ182.8，169.8，80.1，69.4，68.2，52.9，48.4，47.7，29.3，25.9 21.8，20.1，19.5，10.1；HRMS(calcd for C
14H
22NO
3)252.1594，found 252.1594(MH
+).
(1S，2R，5S，8R，1’S)-5-(1’-hydroxybutyl)-8，11，11-Trimethyl-3-oxa-6-azatricyclo[6.2.1.0
2，7]undec-6-en-4-one(9b)：White solid，[α]
D 20＝+37°(c＝1.15，CHCl
3)；mp 99～101℃；IR(KBr)：3438(s)，2959(m)，1740(S)，1691(s)cm
-1；
1H NMR(400MHz，CDCl
3)：δ4.79(s，1H)，δ4.46(d，J＝3.3Hz，1H)，3.97(m，1H)，2.17(d，J＝4.8Hz，1H)，2.05～2.01(m，1H)，1.79～1.36(m，7H)，1.05(s，3H)，0.95(m，6H)，0.79(s，3H)；
13C NMR(300MHz，CDCl
3)：δ182.7，169.9，80.2，73.4，67.0，52.9，48.3，47.7，37.4，29.3，25.9，20.1，19.5，19.0，13.7，10.1；HRMS(calcd for C
16H
26NO
3)280.1907，found 280.1907(MH
+).
(1S，2R，5S，8R，1’S)-5-(1’-hydroxyisobutyl)-8，11，11-Trimethyl-3-oxa-6-azatricyclo[6.2.1.0
2，7]undec-6-en-4-one(9c)：White solid，[α]
D 20＝+38°(c＝1.17，CHCl
3)；mp102～104℃；IR(KBr)：3422(s)，2962(m)，1717(S)，1693(s)cm
-1；
1H NMR(400MHz，CDCl
3)：δ4.79(s，1H)，δ4.66(d，J＝3.9Hz，1H)，3.58(m，1H)，2.18(d，J＝4.8Hz，1H)，2.07～1.98(m，2H)，1.79～1.56(m，2H)，1.41～1.35(m，1H)，1.09～1.00(m，9H)，0.95(s，3H)，0.79(s，3H)；
13C NMR(300MHz，CDCl
3)：δ182.7，170.0，80.2，79.2，64.8，52.9，48.3，47.7，31.7，29.3，25.9，20.1，19.6，19.5，17.9，10.1；HRMS(calcd for C
16H
26NO
3)280.1907，found 280.1908(MH
+).
(1S，2R，5S，8R，1’S)-5-(1’-hydroxy-2’-cyclohexylethyl)-8，11，11-Trimethyl-3-oxa-6-azatricyclo[6.2.1.0
2，7]undec-6-en-4-one(9d)：White solid，[α]
D 20＝+33°(c＝1.22，CHCl
3)；mp 154～156℃；IR(KBr)：3583(s)，2927(s)，1726(s)，1699(s)，1038(s)cm
-1；
1HNMR(400MHz，CDCl
3)：δ4.79(s，1H)，δ4.68(d，4.2Hz，1H)，3.62(dd，J＝7.2Hz，J＝3.6Hz，1H)，δ2.18(d，4.8Hz，1H)，2.07～1.93(m，3H)，1.79～1.56(m，6H)，1.41～1.11(m，6H)，1.08(s，3H)，0.91(s，3H)，0.80(s，3H)；
13C NMR(300MHz，CDCl
3)：δ183.0，170.1，80.2，78.6，64.2，52.9，48.3，47.7，40.9，29.5，29.3，28.3，26.1，25.9，25.7，25.6，20.1，19.5，10.2；HRMS(calcd for C
19H
30NO
3)320.2220，found320.2223(MH
+).
(1S，2R，5S，8R，1’S)-5-(1’-hydroxy-o-chlorobenzyl)-8，11，11-Trimethyl-3-oxa-6-azatricyclo[6.2.1.0
2，7]undec-6-en-4-one(9e)：White solid，[α]
D 20＝-27°(c＝1.19，CHCl
3)；mp124～126℃；IR(KBr)：3375(br)，2960(s)，1743(s)，1691(s)cm
-1；
1H NMR(400MHz，CDCl
3)：δ7.52～7.27(m，4H)，δ5.79(dd，J＝8.4Hz，4.2Hz，1H)，δ4.90(d，J＝4.2Hz，1H)，δ4.48(s，1H)，2.68(d，J＝4.0Hz，1H)，2.17(d，J＝4.8Hz，1H)，2.05～2.01(m，1H)，1.77～1.74(m，1H)，1.68～1.60(m，1H)，1.34～1.24(m，1H)，1.01(s，3H)，0.95(s，3H)，0.77(s，3H)；
13C NMR(300MHz，CDCl
3)：δ183.2，170.3，129.3，127.9，127.3，120 7，110.5，79.5，72.3，67.5，52.9，48.1，47.6，29.3，25.9，20.0，19.5，10.1；HRMS(calcd forC
19H
23ClNO
3)348.1361，found 348.1371(MH
+).
(1S，2R，5S，8R，1’S)-5-(1’-hydroxybenzyl)-8，11，11-Trimethyl-3-oxa-6-azatricyclo[6.2.1.0
2,7]undec-6-en-4-one(9f)：White solid，[α]
D 20＝-3°(c＝1.27，CHCl
3)；mp141～143℃；IR(KBr)：3467(s)，2960(s)，1747(s)，1624(s)cm
-1；
1H NMR(400MHz，CDCl
3)：δ7.38～7.26(m，5H)，δ5.26(d，J＝4Hz，1H)，δ4.89(d，J＝12Hz，1H)，3.33(s，1H)，3.01(s，1H)，2.00(d，J＝4.8Hz，1H)，1.88～1.92(m，1H)，1.65～1.72(m，1H)，1.46～1.52(m，1H)，1.11～1.26(m，1H)，1.04(s，3H)，0.90(s，3H)，0.75(s，3H)；
13C NMR(300MHz，CDCl
3)：δ183.3，170.8，139.6，128.4，126.5，79.6，74.8，67.3，52.9，48.2，47.3，29.1，25.9，19.9，19.4，10.1；HRMS(calcd for C
19H
24NO
3)314.1751，found 314.1754(MH
+).
(1S，2R，5S，8R，1’S)-5-(1’-hydroxy-o-fluorobenzyl)-8，11，11-Trimethyl-3-oxa-6-azatricyclo[6.2.1.0
2，7]undec-6-en-4-one(9g)：White solid，[α]
D 20＝-17°(c＝1.24，CHCl
3)；mp138～141℃；IR(KBr)：3 194(br)，2990(m)，1740(s)，1690(s)cm
-1；
1H NMR(400MHz，CDCl
3)：δ7.46～6.98(m，4H)，δ5.61(dd，J＝9.6，5.4Hz，1H)，δ4.80(d，J＝4.2Hz，1H)，δ4.29(s，1H)，δ3.12(s，1H)δ2.13(d，J＝4.8Hz，1H)，2.06～1.94(m，1H)，1.78～1.66(m，1H)，1.62～1.53(m，1H)，1.31～1.19(m，1H)，0.98(s，3H)，0.92(s，3H)，0.71(s，3H)；
13C NMR(300MHz，CDCl
3)：δ183.5，170.4，129.9，129.8，128.1，124.4，115.5，115.2，79.8，69.3，66.9，53.0，48.1，47.6，29.2，25.9，20.0，19.4，10.0；HRMS(calcd for C
19H
23FNO
3)332.1656，found 332.1660(MH
+).
(1S，2R，5S，8R，1’S)-5-(1’-hydroxy-o-methoxybenzyl)-8，11，11-Trimethyl-3-oxa-6-azatricyclo[6.2.1.0
2，7]undec-6-en-4-one(9h)：White solid，[α]
D 20＝-2°(c＝1.15，CHCl
3)；mp138～140℃；IR(KBr)：3632(s)，2960(s)，1746(S)，1693(s)，1240(S)cm
-1；
1HNMR(400MHz，CDCl
3)：δ7.25～6.67(m，4H)，δ5.43(dd，J＝10.4，5.2Hz，1H)，δ4.67(d，J＝5.2Hz，1H)，δ4.27(s，1H)，δ3.63(s，1H)，3.31(d，J＝4.0Hz，1H)，2.13(d，J＝4.8Hz，1H)，2.05～1.97(m，1H)，1.77～1.70(m，1H)，1.57～1.50(m，1H)，1.26～1.17(m，1H)，1.03(s，3H)，0.93(s，3H)，0.77(s，3H)；
13C NMR(300MHz，CDCl
3)：δ182.8，170.3，155.6，128.6，127.5，127.3，120.1，109.8，79.2，70.8，66.8，54.6，52.5，47.7，47.2，29.0，25.5，19.6，19.1，9.8；HRMS(calcd for C
20H
26NO
4)344.1856，found 344.1861(MH
+).
More than reaction is referring to accompanying drawing 2.
6. the asymmetric synthesis of beta-hydroxy-a-amino acid (compound 10,11):
The derivative (1.0mmol) of top resultant beta-hydroxy-a-amino acid is transferred in the tube sealing, added the hydrochloric acid of 2 milliliter of 8 mol, reacted 3 hours down at 95 ℃.Be chilled to room temperature, add 2 ml waters, use ethyl acetate extraction three times,, get crude extract the water layer evaporated under reduced pressure.With the absolute anhydrous alcohol solution of crude extract with 2 milliliters, add 1.5 milliliters propylene oxide again, at room temperature stirred 30 minutes, the adularescent throw out generates.Filter, with cold dehydrated alcohol and anhydrous diethyl ether washing, drying gets beta-hydroxy-a-amino acid successively.
Table 3 and table 4 are three epimino lactones and trans three epimino lactones and the amino acid whose situation of aldehyde reaction product hydrolysis gained (compound 10, compound 11)
Table 3
| Sequence number | R | Product | Productive rate (%) | Molten point (℃) |
| 1 2 3 4 | Ph o-Cl-Ph m-Cl-Ph o-F-Ph | 11a 11e 11f 11g | 70 80 76 87 | ＞280 ＞280 200 ＞280 |
Table 4
| Sequence number | R | Product | Productive rate (%) | Molten point (℃) | Optically-active |
| 1 2 3 4 5 6 7 | CH 3 CH 3CH 2CH 2 (CH3) 2CH cyclo-Hexyl o-Cl-Ph Ph o-F-Ph | 11a 11b 11c 11d 11e 11f 11g | 77 72 80 74 76 65 70 | 264～266 230～231 224～226 208～210 206～208 184～186 204～206 | +8 a-6 a+20 a+33 b-34 a-29 a-20 a |
A) optically-active records in the aqueous solution; B) optically-active records in 2N hydrochloric acid
Each product measured data is as follows:
Beta-hydroxy-a-amino acid (compound 10,11):
2-Amino-3-hydroxy-3-phenylpropanoic acid(10a)：mp：＞280；
1HNMR(300MHz，D
2O)：δ7.326-7.254(m，5H)，5.155(d，J＝4.2Hz，1H)，3.771(d，J＝4.8Hz，1H).
2-Amino-3-hydroxy-3-(o-chlorophenyl)propanoic acid(10b)：mp：＞280；
1HNMR(300MHz，D
2O)δ7.516(d，J＝7.5Hz，1H)，7.381～7.228(m，3H)，5.553(d，J＝2.7Hz，1H)，3.975(d，J＝3.3Hz，1H).
2-Amino-3-hydroxy-3-(m-chlorophenyl)propanoic acid(10c)：mp：200；IR：3516，2924，1646，1599，1529，1412
1HNMR(300MHz，D
2O)：δ7.332(s，1H)，7.254-7.205(m，3H)，5.107(d，J＝4.2Hz，1H)，3.730(m，1H).
2-Amino-3-hydroxy-3-(o-fluorophenyl)propanoic acid(10d)：mp：＞280；IR：3547，3323，3082，1664，1598，1484，1399，764；
1HNMR(300MHz，D
2O)：δ7.235-6.856(m，4H)，5.192(d，J＝5.4Hz，1H)，3.675(d，J＝4.8Hz，1H).
(2S，3S)-2-Amino-3-hydroxybutanoic acid(11a)：White solid，mp：264-266℃；[α]
D 20＝+8°(c＝1.04，H
2O)；
1H NMR(300MHz，D
2O)：δ4.21(ad，J＝6.6Hz，J＝3.9Hz，1H)，δ3.69(d，J＝3.9Hz，1H)，δ1.05(d，J＝6.6Hz，3H).
(2S，3S)-2-Amino-3-hydroxyhexanoic aid(11b)：White solid，mp：230-231℃；[α]
D 20＝-6°(c＝1.20，H
2O)；
1H NMR(300MHz，D
2O)：δ4.035(m，1H)，δ3.736(d，J＝3.6Hz，1H)，δ1.364(m，4H)，δ0.821(t，3H).
(2S，3S)-3-Hydroxyleucine(11c)：White solid，mp：224-226℃；[α]
D 20＝+20°(c＝1.14，H
2O)；
1H NMR(300MHz，D
2O)：δ3.840(d，J＝3.0Hz，1H)，δ3.461(dd，J＝8.7Hz，J＝3.0Hz 1H)，δ1.858(m，1H)，δ0.893(m，6H).
(2S，3S)-2-Amino-3-cyclohexyl-3-hydroxypropanoic acid(11d)：mp：208-210℃；[α]
D 20＝+33°(c＝1.07，H
2O)；
1H NMR(300MHz，D
2O)：83.81(d，J＝3.0Hz，1H)，δ3.50(dd，J＝9.6，3.0Hz，1H)，δ1.83～0.83(m，11H).
(2S，3S)-2-Amino-3-hydroxy-3-(o-chlorophenyl)propanoic acid(11e)：mp：206-208℃；[α]
D 20＝-34°(c＝0.60，H
2O)；
1H NMR(300MHz，D
2O)：δ7.52～7.22(m，4H)，δ5.55(d，J＝3.6Hz，1H)，δ3.97(d，J＝3.6Hz，1H).
(2S，3R)-2-Amino-3-hydroxy-3-phenylpropanoic acid(11f)：mp：184-186℃；[α]
D 20＝-29°(c＝0.84，H
2O)；
1H NMR(300MHz，D
2O)：δ7.34～7.27(m，4H)，δ5.18(d，J＝4.5Hz，1H)，δ3.81(d，J＝4.5Hz，1H).
(2S，3R)-2-Amino-3-hydroxy-3-(o-fluorophenyl)propanoic acid(11g)：mp：204-206℃；[α]
D 20＝-20°(c＝1.22，H
2O)；
1H NMR(300MHz，D
2O)：δ7.44～7.00(m，4H)，δ5.36(d，J＝4.8Hz，1H)，δ3.85(d，J＝4.8Hz，1H)。
More than reaction is referring to accompanying drawing 3.
Can adopt the three epimino lactones or the trans three epimino lactones of method preparation provided by the present invention when preparing beta-hydroxy-a-amino acid and derivative thereof among the present invention who needs to specify, three epimino lactones that the method that also can adopt prior art to provide prepares or trans three ring imido lactones, as be published in J.Org.Chem.2002,67 (7), 2309; J.Org.Chem.2003, the method in 68 (3), 658.
Claims (3)
1; the preparation method of the chiral template of synthetic beta-hydroxy-a-amino acid and derivative thereof; camphor is oxidized to the camphor diketone; again the camphor diketone is reduced; esterification; close ring at last and obtain three epimino lactone chiral templates; it is characterized in that at first camphor and tin anhydride being refluxed in acetic anhydride; camphor is oxidized to the camphor diketone; again the camphor diketone is dissolved in the mixed liquid of ether and methyl alcohol; under condition of ice bath, add sodium borohydride; solvent evaporated behind the stirring reaction; add a small amount of cold water extracted with diethyl ether; organic phase is washed with the full salt solution that closes; dry; solvent evaporated; column chromatography gets 2-oxycamphor ketone and 3-oxycamphor ketone, afterwards 2-oxycamphor ketone and 3-oxycamphor ketone is mixed with the glycine of chloroformic acid benzyl ester protection, with solution concentration; column chromatography obtains glycinate; glycinate is dissolved in the exsiccant dehydrated alcohol, adds palladium carbon, then reaction vessels is found time to feed hydrogen; under hydrogen atmosphere and room temperature condition, react; remove hydrogen, continue reaction at room temperature, remove by filter palladium carbon; solvent evaporated obtains three epimino lactones and two chiral templates of trans three epimino lactones respectively with column chromatography.
2; the preparation method of the chiral template of synthetic beta-hydroxy-a-amino acid and derivative thereof; camphor is oxidized to the camphor diketone; again the camphor diketone is reduced; esterification; close ring at last and obtain three epimino lactone chiral templates; it is characterized in that at first camphor and tin anhydride being refluxed in acetic anhydride; camphor is oxidized to the camphor diketone; again the camphor diketone is dissolved in the mixed liquid of ether and methyl alcohol; under condition of ice bath, add sodium borohydride; solvent evaporated behind the stirring reaction; add a small amount of cold water extracted with diethyl ether; organic phase is washed with the full salt solution that closes; dry; solvent evaporated; column chromatography gets 2-oxycamphor ketone and 3-oxycamphor ketone; 2-oxycamphor ketone and 3-oxycamphor ketone are mixed with the glycine of chloroformic acid benzyl ester protection; after adding the 4-Dimethylamino pyridine; system adds the tetrahydrofuran solution of dicyclohexylcarbodiimide (DCC) under 0 ℃ of agitation condition, continue reaction for some time, again reaction at room temperature; remove by filter dicyclohexyl urea; with solution concentration, column chromatography obtains glycinate, and glycinate is dissolved in the exsiccant dehydrated alcohol; add palladium carbon; then reaction vessels is found time to feed hydrogen, under hydrogen atmosphere and room temperature condition, react, remove hydrogen; continue reaction at room temperature; remove by filter palladium carbon, solvent evaporated obtains three epimino lactones and two chiral templates of trans three epimino lactones respectively with column chromatography.
3, the method for preparing beta-hydroxy-a-amino acid, it is characterized in that and to be hydrolyzed with the beta-hydroxy-alpha-amino acid derivatives of the chiral template preparation of three epimino lactones of the method for claim 1 or 2 preparation or trans three epimino lactones, obtain beta-hydroxy-a-amino acid.
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