Stereoselective Synthesis of $\beta$-Hydroxy-$\alpha$-Amino Acid : Synthesis of 4(R)-4-((E)-2-Butenyl)-4,N-Dimethyl-L-Threonine

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Journal of the Korean Chemical Society 1995, Vol. 39, No. 2

Printed in the Republic of Korea 디. 人 |

p-Hydroxy-a-Amino Add 의 입체선택적인 합성 : 4(/?)-4-((E)-2-Butenyl)-4,N-Dimethyl-L-Threonine2| ^합성

李相

灵

* •金榮權•金聖圭•尹容

鎮

•朴基動

경상대학교 자연과학대학 화학과 (1994. 7. 27 접수)

Stereoselective Synthesis of p-Hydroxy-a-Amino Acid : Synthesis of 4(7?)-4-((E)-2-Butenyl)-4,N-Dimethyl-L-Threonine

**Sang Gyeong Lee*, Young Kwen Kim, Sung Kyu Kim, Yong-Jin Yoon, and Ki Hun Park** Department of Chemistry, Gyeongsang National University, Chinju 660-701, Korea

(Received July 27, 1994)

The unusual amino acid 4(l?)-4-((£)-2-butenyl)-4,N-dimethyl-L-threonine (MeBmt 1), found in the immunosuppressive peptide cyclosporine?

is essential for biological activity of this chemothe

rapeutic agent. Since the first reported synthesis of MeBmt,2 the various synthetic routes have been developed to get this valuable compound.3 Al

though they have proven to be useful methods, but it is necessary to improve their stereoselecti

vities. Our Objective was to develop a synthetic route to enantiomerically pure 1 from sugar. As our chiral educt we chose 2-deoxy-D-ribose which has two stereocenters in abs사ute stereochemistry as required for C3 and C4 in MeBmt 1. Key trans

formations included Wittig reaction, methylation with cuperate and selective acetonide formation

(Scheme 1).

The acetonide 2 was prepared from 2-deoxy-D- ribose as described.4 Subsequent Wittig reaction of the aldehyde with ethyltriphenylphosphonium bromide and w-butylithium in THF/ether (3 : 5, v/v) under the Schlosser's condition5 gave 3 in 86% yi이d・ The removal of actonide 3 with Dowex- 50W resin (H+ form) in methanol at room tempe

rature gave 4 in qualitative yield.6 The regioselec

tive protection of triol 4 at 1,2-position was pro

ceeded with various normal acidic conditions.7 We used the Dowex-50W as an acid catalyst and ob

tained desirable selectivity (the ratio of 5 ： 6=9 ： 1). According to this result, heterogeneous acid catalyst Dowex-50W is more selective for 1,2-position protecting in 1,2,3-triol than normal acids such as HC1, HBr, AcOH and TFA. These two iso-

a. PhjPXHjCHsBr； n-BuU, THF/Et?O. -78-(rC; b. Dowex-50W, MeOH. rt;

c. acetone, Dowex-50W, rt： d. Dowex-50W, MeOH, rt; e. CX4. CHjCIj..

0*C; f. 1) PhjP. DEAD, AcOH, benzene 2) UAlHx.EtjO, 0BC 3) XCt, DMAP.

<TC; g) Cui, MeU, -40-0°C; h.1) Dowex-50W , 2) PhCOCI

Scheme 1.

-123-

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124 ^李相灵-金榮權-金聖圭•尹容鎭•朴基勳

Table 1. Cuprate reaction for compound 7a, 7b, 8a,

and

8b

X RLi Solvent Temp. Yield (%)

7a

CH3Li Et2O -40 — 01 75

7b

CH3Li Et2O -40 »°C 40 〜50

8a

CH3Li EtQ -4dO°C 5-10

8b

CH3Li Et2O 一40t0°C trace

mers were seperated chromatographic지ly and

6

was recycled. The hydroxy of compound

5

was transformed to halides gave

7a

and

7b

in 83%

and 80% yi이d, respectiv이y. And also the isomer of compound

5

was prepared using Mitsunobu reaction9 and corresponding alcohol was treated with tosyl chloride or mesyl chloride to give

8a

and

8b

in 85% and 83% yields, respectively. Com

pound

7a, 7b, 8a

and

8b

were used for the cuprate reaction in the next step (Table 1).

The cuprate reaction10 of 7a with copper iodide/methyl lithium in ether at — 40^-01 gave methylated product

9

in 75% yi이d, but

7b, 8a

and

8b

gave very poor yields in the similar condition.

This result appeared the Gilman-type reagent, R2 CuLi, well undergo substitution reaction at secon

dary position at halide than tosylate or mesylate.

Removal of acetal with Dowex-50W resin in me

thanol followed by protection with benzoyl chloride at primary position gave

10

in 83% yield. Chemical structures of the compounds

3~9

were identified by the NMR, IR, and analytical data. The trans

formation of

10

ta-

1

were conducted according to the literature2 to obtain the final product

1.

The physical data (NMR, mp and optical rot가ion value) of 1 were in full agreement with the reported va

lues in the literature.2

In summary, we have achieved efficient synthe

sis of MeBmt 1 from 2-deoxy-D-ribose, which provides two chiral centers among three one of

1. We have also reported improved selective ace

tonide formation.

EXPERIMENTAL

Genera].

All reactions were conducted under atomosphere of dry nitrogen unless otherwise no

ted. Tetrahydrofurane (THF) and Et2O were distil

led from Na/benzophenone. EtOAc and CH2C12 were distilled from CaH2. Melting points were de

termined with a Fisher-Johns apparatus and are uncorrected.NMR spectra were recorded on a Varian 200 (200 MHz) or a Brucker ARX-300 (300 MHz) spectrometer using tetramethylsilane as an internal standard.

(2/?,35)-3,4-O-Isopropylidene hept-5-en-l-ol (3).

To (ethyl)triphenylphosphonium bromide (5.6 g, 15 mmol) in 100 mL of THF/EtQ (3 : 5) under N2 at — 7811 w-BuLi (11.6 mLf 18.6 mol, 1.6 mol in hexane) was added and the temperature was not allowed to increase to — 301 during the ad

dition. After the mixture turns red, stirring was continued for additional 0.5 h before addition ace

tal 2 (1.3 g, 7.5 mmol) in ether (7 mL) was added.

The mixture wa then stirred an additional 3 mL of w-BuLi was added. The resulting red mixture was 아irred for 0.5 h at — 78t： and allowed to warm —301 at which Z-BuOH (3 mL dropwise) followed by Z BuOK (2.0 g) were added. The reac

tion mixture was allowed to attain room tempera

ture and stirred for 1.5 h and poured into water.

The two layers were separated, aqueous pha않e was extracted with ether. The combined organic phase were dried (Na2SO4) and concentrated. The resi

due was chromatoraphed on silica gel column with acetone/w - hexane (1:1) as eluent to give 3 (1.2 g) in 86% yield, [a]須)=+14.6° (c 25, CH2C12), IR (neat), 3600-3200, 3010, 2950 cm1; *H NMR (CDCl3f 300 MHz) 8 1.36 (s, 3H), 1.43 (s, 3H)( 1.65 (d, J=7.4, 3H), 2.05 (m, 1 H)( 2.30 (m, 2 H), 3.62 (m, 2 H), 4.17 (m, 2 H), 5.47 (m, 1H), 5.57 (m, 1 H).

(2R,3S)-Hept-5-enT,2,3-tri ( H (4). The reac

tion mixture was stirred for 8 h at room tempera

ture, then was filtered, the filterate was evapora

ted. The crude residue was chromatographed on silica gel (hexane/EtOAc, 1/1 and then 1/8) to give 0.96 g, 97%) as white solide. [a]j°=+L6° (c L4, CH2C12, variable), mp 69~7(此:,IR (KBr), 3600~

3200 (broad), 3010, 1650, 1070 cm1;NMR (CDC13, 200 MHz) 8 1.64 (d, J=7.6 Hz, 3H), 2.30 (dd, /=6.8, 6.7 Hz, 2 H), 2.75 (s, 1 H, OH), 3.40 (m, 1H), 3.63〜3.80 (bs, 2H, 2OH), 3.75 (m, 2H), 3.99 (m, 1 H), 5.46 (m, 1 H), 5.63 (m, 1 H).

Joumal of the Korean Chemical Society

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p-Hydroxy-a-Amino Acid^{의 입체선백적인}합성 125

(2J?,35)- 1,2-O-Isopropylidene hept-5-en-3-ol (5).

To a mixture of compound

4

(0.92 gf 6.3 mmol), Dowex-50W (0.8 g) and acetone (20 mL) was stirred for 8 h at room temperature. Dowex- 50W resin was filtered through a small pad of cellite, acetone and water evaporated. The residue was chromatographed on silica gel column with n-hexane/ethyl acetate (4 :1) as eluent to give

6

(0.96 g) in 82% yield. [a]*= + 12.2° (c 1.3, CH2- Cl2), IR (neat), 3600-3200, 3010, 2900, 1380 cm1;

】H NMR (CDC13, 200 MHz) 8 1.37 (s, 3H), 1.43 (s, 3H), 1.64 (d,/=6.7Hz, 3H), 1.99 (s, 1 H( OH), 2.64 (dd, /-=6.8 Hz, 2 H), 3.77 (m, 1 H), 3.96 (m, 1 H), 3.99 (m, 2 H)t 5.47 (m, 1 H), 5.65 (m, 1 H).

(2JJ,3<V)-l,2-O-Isopropylidene-3-bromohept-5- ene (7a).

A mixture of

5

(0.7 g, 3.7 mmol), triphe

nylphosphine (1.9 g, 7.2 mmol) and carbonatetrab- romide (2.4 g, 7.2 mmol) in dry CH2C12 (40 mL) were stirred for 4 h and the solvent evaporated with rotary evaporator to give crude mixture. The crude mixture applied to the open bed silica gel column chromatography and eluted with n-hexane/ethyl acetate (4 :1) to give

7a

(0.76 g) in 83%

yi시d. [a]*°=+12.5° (c 0.5, CH2CI2)； IR (neat), 2010, 1650, 1070 cm1;NMR (CDCI3, 300 MHz) 8 1.24 (s, 3H), 1.39 (s, 3 H), 1.52 (d"=8.2Hz, 3 H)( 2.25 (m, 2 H), 3.42 (m, 2 H), 4.01 (m, 1 H), 4.35 (m, 1 H), 5.44 (m, 1 H), 5.61 (m, 1 H).

(2/J,3»y ) -l,2-O-Isopropylidene-3-chlorohept-5- ene (7b).

The same procedure as

7a

only used carbontetrachloride instead of carbontetrabromide.

The spectral data well agreed.

(2^?,351)-1,2-O-Isopropylidene hept-5-en-3-ol (8a).

To a benzene (10 mL) solution of

5

(0.6 g, 3.2 mmol) and triphenylphosphine (1.67 g, 6.4 mmol) were added succesively a solution of acetic acid (0.38 g, 6.4 mmol) in benzene (3 mL) and a solution of diethylazodicarboxylate (1.11 g, 6.4 mmol) in benzene (5 mL). The mixture was reflu

xed for 12 h, then was filtered, filterate was evapo

rated. The crude residue was chromatographed on silica gel column with n-hexane/ethylacetate (8 :1) as eluent to give acetylated 8a (0.37 g, 51%).

And then to colled (0°) slurry of LiAlH4 (62 mg, 1.6 mmol) in EtQ (10 mL) was added a solution of acetylated

8a

in Et2O (3 mL). After being stirred

1995, Vol. 39, No. 2

for 1 h at rt, the mixture was filtered and rinsed with EtQ and combined solvent was evaporated.

The crude residue was chromatographed on silica gel column with n - hexane/ethylacetate (4 :1) as eluent to give 8a (0.26 g, 84%) as colorless oil.

[a]^須)=+8.5° (c 1.27, CH2Cl2)t IR (neat), 3600〜

3200t 3010, 2900, 1380 cm1; lH NMR (CDCI3, 200 MHz)) 8 1.39 (s, 3 H), 1.46 (s, 3 H), 1.46 (s, 3 H), 1.64 (d, J-7.2 Hz, 3H), 1.96 (s, 1 H, OH), 2.64 (m, 2 H)t 3.77 (m, 1 H), 3.98 (m, 1 H), 4.01 (m, 2 H), 5.47 (m, 1 H), 5.65 (m, 1H).

(2/?,3S)-l,2-O-Isopropylidene-3-(p-toluenesul- fonyl)oxyhept-5-ene (8b).

To a stirred mixture of 5 (0.7 g, 3.7 mmol) and 4-dimethylaminopyrine (0.59 g, 4.9 mmol) in dry CH2C12 (30 mL), />-tolue- nesulfonyl chloride (0.92 g, 4.9 mmol) was added at Ot： and allowed to stand at ambient tempera

ture for 3 days. Reaction mixture was treated with citric acid (3%, 20 mL) and extracted with ethyl acetate (25 mLX4). Organic pha돊e was subsequen

tly washed with water, brine and dried Na2SO4.

Evaporation of the solvent and chromatography of the residue over silica gel using w~hexane/ethyl acetate (4 :1) as eluent furnished tosylate 8 (1.14 g) in 88% yi이d. [a]*=+12.8 (c 1.3, CH2Cl2)t IR (neat), 3010, 1980, 1600 cm1;NMR (CDC13, 300 MHz) 8 1.30 (s, 3H), 1.32 (s, 3H), 1.54 (d,J=87.9 Hz, 3 H), 2.39 (m, 2 H), 2.44 (s, 3 H), 3.78 (m, 1 H), 3.97 (m, 1H), 4.12 (m, 1H), 4.63 (m, 1H), 5.29 (m, 1H), 5.53 (m, 1 H), 7.34 (d,/=6.5Hz, 2 H), 7.79 (d, /=6.5Hz, 2 H).

(2R,3S)~ 1,2- O-Isopropylidene-3-(methanesulfo- nyl)oxyhept-5-ene (8c).

The same procedure as

8a

only used methanesulfonyl chloride instead of y)-toluenesulfonylchloride. The spectral data well

agreed.

(2/J,35)-l,2-O'Isopropylidene-3-methylhept-5- ene (9).

The cuprate reactions of

7a, 7b, 8a

and

8b

were examined with the same method. Stan

dard method for cuprate reactions discribed as fol

low. To a suspended solution of copper (I) iodide in ether was added droppwised methyl lithium at

—20M and stirred for 20 minute. After turned to the homogenious solution, reaction mixture tra

nsferee] to the — 40M bath and added

7a, 7b, 8a

and

8b

and temperature increased to 0° slowly

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126 李相灵•金榮權-金聖圭•尹容鎭•朴基勳

for 5 h. The reaction mixture quenched with satu

rated ammonium chloride. The two layer were se

parated, aqueous phase was extracted with ether.

The combined organic phase were dried (Na2SO4) and concentrated. The residue was chromatogra

phed on silica gel column with ethyl acetate/w-he

xane (1: 8) as eluent to give 9 in variable yield (0~75%) according to substrate."订【*=+10.6°

(c 0.5, CH2CL2); IR (KBr) 2980, 1600 cm NMR (CDCk 200 MHz) 8 01.95 (d,/=7.4 Hz, 3 H), 1.24 (s, 3H), 1.38 (s, 3H), 1.40 (d,/=8.5Hz, 3H), 2.20 (m, 2 H), 3.32 (m, 2 H), 4.00 (m, 1 H)( 5.36 (m, 1H), 5.41 (m, 1H).

(M3^5£)-3-Methyl-5-heptene-l,2-diol (10).

A mixture of 9 (1.58 g, 8.5 mmol), Dowex-50W re

sin (1.2 g), and water (0.3 mL) in methanol (40 mL) was stirred for 8 h. Dowex-50W resin was filtered through a small pad of cellite, methanol and water evaporated to give deacetalized 9 (2.5 g) as pure without purification in quentative yield. To a solu

tion of 9.0 g (62.5 mmol) of deacetalized 9 in 90 mL of pyridine are added PhCOCl (9.66 g, 68.71 mol).

The mixture is stirred for 40 min at rt, diluted with 60 mL of CH2C12 and washed 600 (3X200) mL of sat. CuSQ*. The aqueous phase are extrac

ted with CH2CI2, the combined organic phase are dried over Na2SO4, evaporated, and filtered th

rough 500 g silica gel using 1% MeOH/CH2Cl2:

14.0 g (90%) of

10,

colorless oil. The phsical data were in full agreement with reported values.2

REFERENCES

1. Aebi, J. D.; Dey。，D. T.; Sun, C. Q.; Guillaume,

D.; Dunlap, B.; Rich, D. H. / Med. Chetn,

1990, 33, 999.

2. Wenger, R. M. Helv. Chim. Acta

1983,

66, 2308.

3. (a) Tung, R. D.; Rich, D. H. Tetrahedron Lett.

1987, 28, 1139. (b) Sun, C. Q.; Rich, D. H. Tetrahedron Lett. 198& 29, 5205. (c) Rao, A. V. R.; Dhar, T.

G. M.; Chakraborty, T. K.; Gurjar, M. K. Tetrahed

ron Lett. 198& 29, 2069. (d) Evans, D. A.; Weber,

A. E. J. Am. Chem. Soc.

198& 108, 6757. (e) Sch

midt, U.; Siegel,

W. Tetrahedron Lett. 1987, 28,

2849. (f) Aebi, J. D.; Dhaon, M. K.; Rich, D. H.

J- Org. Chem. 1987, 52, 2881. (g) Togni, A.; Pastor,

S. D.; Rihs, G. Helv. Chim. Acta

1989, 72, 1471.

(h) Lubell, W. D.; Jamison, T. F.; Rapoport, H.

J. Org. Chem. 199Q 55, 3511.

4. Corey, E. J.; Snider, B. B./ Am. Chem. Soc.

1980, 94, 2549.

5. 父hlosser, M.; Christmann, K. F. Justus Liebigs

Ann. Chem. 1967, 708, 1.

6. Ho, P. 0. Tetrahedron Lett.

1978,

1623.

7. (a) Gelas, J.; Horton, D. Heterocycles

1981, 16,

1578. (b) Evans, E.; Parrish, F. W.; Long, L. Jr.

Carbohydr. Res. 1967, 3, 435. (c) Singh, P. P.; Gha

na, M. M.; Dasgupta, F.; Srivastava, H. C. Tetra

hedron Lett. 1977,

439. (d) Schmidt, O. T. Methods

Carbohydr. Chem. II, 1965,

318. (e) Beider, A. B.

D. Adv. Carbohydr. Chem.

1965 20, 219.

8. Rf values of

5

and

6

were 0.4 and 0.5 in hexane/ethyl acetate = 3 ： 7 respectably.

9. Mitsunobu, 0. Synthesis

1981,

1.

10. (a) Johnson, C. R.; Dutra, G. A. / Am. Chem, Soc.

1973, 95, 7777. (b) Marfat, A.; P. R. McGuirk, P.

R.; Helquist, P. J. Org. Chem.

197잇 44, 3888. (c)

Lipshutz, B. C.; Willalm, R. S. / Am. Chem.

1981, 102, 7672.

Journal of the Korean Chemical Society

Stereoselective Synthesis of $\beta$-Hydroxy-$\alpha$-Amino Acid : Synthesis of 4(R)-4-((E)-2-Butenyl)-4,N-Dimethyl-L-Threonine

p-Hydroxy-a-Amino Add 의 입체선택적인 합성 : 4(/?)-4-((E)-2-Butenyl)-4,N-Dimethyl-L-Threonine2| 합성

灵

鎮

Stereoselective Synthesis of p-Hydroxy-a-Amino Acid : Synthesis of 4(7?)-4-((E)-2-Butenyl)-4,N-Dimethyl-L-Threonine

Sang Gyeong Lee*, Young Kwen Kim, Sung Kyu Kim, Yong-Jin Yoon, and Ki Hun Park Department of Chemistry, Gyeongsang National University, Chinju 660-701, Korea

(Scheme 1).

Scheme 1.

Table 1. Cuprate reaction for compound 7a, 7b, 8a,

8b

7a

7b

8a

8b

6

5

7a

7b

5

8a

8b

7a, 7b, 8a

8b

9

7b, 8a

8b

10

3~9

10

1

1.

EXPERIMENTAL

Genera].

(2/?,35)-3,4-O-Isopropylidene hept-5-en-l-ol (3).

(2R,3S)-Hept-5-enT,2,3-tri ( H (4). The reac­

(2J?,35)- 1,2-O-Isopropylidene hept-5-en-3-ol (5).

4

6

(2JJ,3<V)-l,2-O-Isopropylidene-3-bromohept-5- ene (7a).

5

7a

(2/J,3»y ) -l,2-O-Isopropylidene-3-chlorohept-5- ene (7b).

7a

(2^?,351)-1,2-O-Isopropylidene hept-5-en-3-ol (8a).

5

8a

(2/?,3S)-l,2-O-Isopropylidene-3-(p-toluenesul- fonyl)oxyhept-5-ene (8b).

(2R,3S)~ 1,2- O-Isopropylidene-3-(methanesulfo- nyl)oxyhept-5-ene (8c).

8a

(2/J,35)-l,2-O'Isopropylidene-3-methylhept-5- ene (9).

7a, 7b, 8a

8b

7a, 7b, 8a

8b

(M3^5£)-3-Methyl-5-heptene-l,2-diol (10).

10,

REFERENCES

1990, 33, 999.

1983,

1987, 28, 1139. (b) Sun, C. Q.; Rich, D. H. Tetrahedron Lett. 198& 29, 5205. (c) Rao, A. V. R.; Dhar, T.

ron Lett. 198& 29, 2069. (d) Evans, D. A.; Weber,

198& 108, 6757. (e) Sch­

W. Tetrahedron Lett. 1987, 28,

J- Org. Chem. 1987, 52, 2881. (g) Togni, A.; Pastor,

1989, 72, 1471.

J. Org. Chem. 199Q 55, 3511.

1980, 94, 2549.

Ann. Chem. 1967, 708, 1.

1978,

1981, 16,

Carbohydr. Res. 1967, 3, 435. (c) Singh, P. P.; Gha­

hedron Lett. 1977,

Carbohydr. Chem. II, 1965,

1965 20, 219.

5

6

1981,

197잇 44, 3888. (c)

1981, 102, 7672.

p-Hydroxy-a-Amino Add 의 입체선택적인 합성 : 4(/?)-4-((E)-2-Butenyl)-4,N-Dimethyl-L-Threonine2| ^합성

**Sang Gyeong Lee*, Young Kwen Kim, Sung Kyu Kim, Yong-Jin Yoon, and Ki Hun Park** Department of Chemistry, Gyeongsang National University, Chinju 660-701, Korea

(2R,3S)-Hept-5-enT,2,3-tri ( H (4). The reac

198& 108, 6757. (e) Sch

Carbohydr. Res. 1967, 3, 435. (c) Singh, P. P.; Gha