Stereoselective synthesis of protected threo-β-hydroxy-L-glutamic acid using a chiral aziridine

Article abstract of DOI:10.1016/S0957-4166(00)00311-6

Threo-β-hydroxy-L-glutamic acid derivatives with different carboxylic acid protecting groups were stereoselectively prepared from a chiral aziridine-2-carboxylate using an aldol reaction, stereoselective ketone reduction, and aziridine ring transformation. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00311-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3283–3292
Stereoselective synthesis of protected
threo-b-hydroxy- -glutamic acid using a chiral aziridine
L
Chan Sun Park,a Hawn Geun Choi,a Hyunjoo Lee,a,† Won Koo Leea,* and
Hyun-Joon Hab,*
aDepartment of Chemistry, Sogang University, Seoul 121-742, South Korea
bDepartment of Chemistry, Hankuk University of Foreign Studies, Yongin 449-791, South Korea
Received 17 May 2000; accepted 8 August 2000
Abstract
Threo-b-hydroxy-
L
-glutamic acid derivatives with different carboxylic acid protecting groups were
stereoselectively prepared from a chiral aziridine-2-carboxylate using an aldol reaction, stereoselective
ketone reduction, and aziridine ring transformation. © 2000 Published by Elsevier Science Ltd.
1. Introduction
It is well known that
L
-glutamic acid plays important roles in living organisms as an
excitatory neurotransmitter acting on many kinds of subclasses of the glutamate receptor1 and
a precursor in a wide variety of metabolic processes.2 Owing to such biological importance,
many scientists have shown their interest in the modification of the structure of this amino acid
and also studied analogues of
-glutamic acid to modulate its biological activity.3,4 In particular,
L
threo-b-hydroxyglutamic acid5,10a has significant biological activities as an enzyme inhibitor due
to the presence of the a,b-amino-hydroxy system. As for its structure, two stereogenic centers
and three different functional groups make it useful as a chiral synthon6 (Fig. 1).
Figure 1.
* Corresponding authors. Fax: (+82)-2-7010967; e-mail: wonkoo@ccs.sogang.ac.kr
†
CFC Alternative Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul
136-791, South Korea.
0957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00311-6

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2. Results and discussion
Recently, we reported that enantiomerically pure aziridine-2-carboxylates were prepared from
the reaction of enantiomerically pure a-methylbenzylamine and dibromopropionate ester7 and a
variety of 2-amino-1,3-propanediols were obtained from regiospecific ring opening of the
aziridine-2-methanols from organometallic addition to the corresponding aziridine-2-carbox-
aldehyde 2 (Scheme 1).8,9
Scheme 1.
The aldol reaction to the enantiomerically pure aziridine 2-carboxaldehyde 2, which is a
configurationally stable a-amino aldehyde, provides a mixture of two diastereomers 4a and 4b
almost quantitatively in the diastereomeric ratio of 1:2. However, the precursor of the threo-b-
hydroxy- -glutamic acid compound was obtained as the minor product 4a. We found that the
L
diastereomeric ratio of the aldol products could be controlled by stereoselective reduction10 of
the b-keto ester 3, which was prepared from the chiral aziridine 2-carboxylate 1 using the same
aldol conditions in good yield (Scheme 2).
Scheme 2.
We varied the reduction conditions to obtain high stereoselectivity with numerous hydride
reducing reagents, reaction solvents, and reaction temperatures. Of the various conditions,
sodium borohydride in IPA at −40°C (Entry 6)11 provided the best result in terms of selectivity
and yield (Scheme 3).
The absolute configuration at C-3 of the aldol products 4a and 4b was established by
transformation of the aldol products to 2,3-disubstituted chiral aziridines 11a and 11b. Treat-
ment of the amino alcohols 10a and 10b, which were obtained by an AcOH ring opening
reaction, with MsCl and Et3N in CH2Cl2 at −78°C provided the corresponding 2,3-disubstituted
chiral aziridines 11a and 11b (Scheme 4).12 It is well known that cis-2,3-disubstituted aziridines
are thermodynamically more stable than trans-2,3-disubstituted aziridines.13 The aldol product
4a was readily transformed to cis-2,3-disubstituted chiral aziridine 11a but 4b provided the

C. S. Park et al. / Tetrahedron: Asymmetry 11 (2000) 3283–3292
3285
Scheme 3.
diastereomeric mixture 11b of trans- and cis-2,3-disubstituted chiral aziridines in poor yield. The
mesylation of the erythro isomer 10b seems to be followed by elimination due to the presence of
Et3N to provide the a,b-unsaturated ester to which amine adds conjugatively to form the
mixture of cis- and trans-2,3-disubstituted aziridines.
Scheme 4.

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For the selective oxidation of the primary alcohol, the secondary alcohol of 4a was protected
with a TBDMS group. The protected aldol product 5a was treated with AcOH in CH2Cl2 to
provide the 1-substituted 2-amino-1,3-propandiol 6a in high yield.9 The a-methylbenzyl group
was replaced with the Boc group by catalytic hydrogenation in the presence of (Boc)2O to
provide the N-Boc derivative 7a quantitatively.8 The acetyl group in 7a was readily hydrolyzed
by KOH in ethanol to give the amino alcohol 8a, which was oxidized to the corresponding
14
carboxylic acid using RuCl3 and NaIO4 and the crude carboxylic acid was converted to its
methyl ester 9a using MeI in the presence of potassium hydrogen carbonate in DMF at room
temperature in 79% yield15 (Scheme 5). Sequential treatments of 9a including ester hydrolysis
with KOH in ethanol, dimethylation with MeI and KHCO3, and desilylation with TBAF
afforded the known 2(S)-tert-butoxycarbonylamino-3(S)-hydroxypentanedioic acid 1,5-dimethyl
ester {[h]3D0=+32.9 (c 1.0, CHCl3); lit.3k [h]D20=+28.9 (CHCl3)} in 21% yield. We also prepared
the C-3 diastereomer of 9a using the same procedure from the aldol product 4b in comparable
yield.
Scheme 5.
3. Conclusion
In summary, we have developed a methodology to prepare the threo-b-hydroxy- -glutamic
L
acid derivative with different acid protecting groups from chiral aziridine-2-carboxylate through
an aldol reaction, stereoselective ketone reduction, and aziridine ring transformation. The two
different acid protecting groups allow selective functionalization of the carboxylic acid groups.
We can also prepare threo-b-hydroxy-
D
-glutamic acid derivatives by the same protocol if the
enantiomer of chiral aziridine-2-carboxylate 1 is used as the starting material.

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4. Experimental
4.1. General
Flash chromatography was performed on a Tokyo Rikagikai EF-10 with Merck 230ꢀ400
mesh silica gel. Melting points were determined on a Thomas–Hoover capillary melting point
1
apparatus and all melting points were not corrected. H NMR spectra were obtained on a
Varian Gemini 200 (200 MHz), Varian Gemini 300 (300 MHz) and Varian Gemini 500 (500
MHz) spectrometers. NMR spectra were recorded in ppm (l) related to tetramethylsilane
(l=0.00) as an internal standard unless stated otherwise and are reported as follows: chemical
shift, multiplicity (br=broad, s=singlet, t=triplet, q=quartet, m=multiplet), coupling con-
stant and integration. Elemental analysis was performed by a Carlo Erba EA 1180 elemental
analyzer. Optical rotations were obtained on a Rudolph Autopol III. digital polarimeter. Data
are reported as follows: [h]2D5 (concentration g/100 mL, solvent). Solvents and liquid reagents
were transferred using hypodermic syringes. All other reagents and solvents used were reagent
grade. All glassware was dried in an oven at 150°C prior to use. Methylene chloride and
triethylamine were dried from calcium hydride prior to use. Small and medium scale purifica-
tions were performed by flash chromatography.
4.2. 3-Oxo-3-[1-(1%(S)-h-methylbenzyl)-aziridin-2(R)-yl]-propionic acid tert-butyl ester 3
To a solution of LHMDS (1.46 mL, 1.46 mmol) in 2.90 mL of THF under a nitrogen
atmosphere at −78°C was added t-BuOAc (0.20 mL, 1.459 mmol). The reaction mixture was
stirred for 30 minutes at −78°C and then treated with 1 (160 mg, 0.730 mmol) in 0.80 mL of
THF at −78°C. The mixture was stirred for 30 minutes at −78°C and then quenched with 2 mL
of water at −78°C then warmed to room temperature. The organic layer was separated and the
aqueous layer was extracted with EtOAc (5×5 mL). The combined organic extracts were washed
with 2 mL of brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
Purification by silica gel flash chromatography (EtOAc/n-hexane/TEA, 10:90:0.01) gave 186 mg
1
(88%) of 3 as yellow oil. [h]2D7=+70.8 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) l 7.34–7.24
(m, 5H), 3.35 (d, J=15.7 Hz, 1H), 3.22 (d, J=15.7 Hz, 1H), 2.59 (q, J=6.6 Hz, 1H), 2.33 (d,
J=2.7 Hz, 1H), 2.20 (dd, J=6.9, 3.0 Hz, 1H), 1.85 (d, J=6.9 Hz, 1H), 1.44 (d, J=6.6 Hz, 3H),
1.41 (s, 9H). 13C NMR (75 MHz, CDCl3) l 201.24, 166.43, 143.62, 128.54, 127.35, 126.45, 81.73,
69.63, 45.96, 44.13, 35.19, 27.91, 23.52. Anal. calcd for C17H23NO3: C, 74.69; H, 8.48; N, 5.12.
Found: C, 74.62; H, 8.54; N, 5.17.
4.3. 3(R)-Hydroxy-3-[1-(1%(S)-h-methylbenzyl)-aziridin-2(R)-yl]-propionic acid tert-butyl ester
4a and 3(S)-hydroxy-3-[1-(1%(S)-h-methylbenzyl)-aziridin-2(R)-yl]-propionic acid tert-butyl
ester 4b
To a solution of NaBH4 (34.2 mg, 0.905 mmol) in 2.30 mL of IPA at −40°C was added 3 (130
mg, 0.452 mmol). The reaction mixture was stirred for 1 hour at −40°C and then quenched with
2 mL of water at −40°C. The organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (5×5 mL). The combined organic extracts were washed with 2 mL of brine, dried

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over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel flash
chromatography (EtOAc/n-hexane, 30:70) gave 106 mg (80%) of 4a and 10 mg (8%) of 4b as a
1
yellow oil. 4a: [h]2D7=−46.7 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) l 7.37–7.24 (m, 5H),
3.71 (m, 1H), 2.49 (q, J=6.6 Hz, 1H), 2.26 (br, OH), 2.15 (dd, J=15.4, 7.7 Hz, 1H), 1.98 (dd,
J=9.9, 5.5 Hz, 1H), 1.95 (d, J=3.3 Hz, 1H), 1.65–1.60 (m, 1H), 1.49 (d, J=6.6 Hz, 1H), 1.44
(d, J=6.6 Hz, 3H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3) l 170.59, 144.21, 128.46, 127.36,
126.81, 80.38, 69.47, 67.31, 41.61, 41.36, 31.10, 27.90, 22.41. Anal. calcd for C17H25NO3: C,
1
70.07; H, 8.65; N, 4.81. Found: C, 70.03; H, 8.71; N, 4.86. 4b: [h]2D6=−23.4 (c 1.0, CHCl3). H
NMR (300 MHz, CDCl3) l 7.36–7.23 (m, 5H), 3.72 (m, 1H), 3.02 (br, OH), 2.53 (q, J=6.6 Hz,
1H), 2.18 (dd, J=16.2, 4.9 Hz, 1H), 2.11 (dd, J=16.2, 7.4 Hz, 1H), 1.96 (d, J=3.3 Hz, 1H),
1.66–1.60 (m, 1H), 1.47 (d, J=3.8 Hz, 1H), 1.42 (d, J=6.3 Hz, 3H), 1.39 (s, 9H). 13C NMR (75
MHz, CDCl3) l 171.33, 144.28, 128.47, 127.28, 126.78, 80.85, 69.55, 67.30, 41.33, 40.35, 30.84,
28.05, 22.80. Anal. calcd for C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 70.02; H, 8.72;
N, 4.87.
4.4. 3(R)-(tert-Butyldimethylsilanyloxy)-3-[1-(1%(S)-h-methylbenzyl)-aziridin-2(R)-yl]-propionic
acid tert-butyl ester 5a
To a solution of TBDMSCl (358 mg, 2.38 mmol) in 4.00 mL of CH2Cl2 under a nitrogen
atmosphere at room temperature was added DMAP (151 mg, 1.19 mmol) and TEA (0.58 mL,
4.16 mmol). The mixture was stirred for 5 minutes and then treated with 4a (346 mg, 1.19 mmol)
in 2.00 mL of CH2Cl2. The mixture was stirred for 17 hours at room temperature and was
treated with 4 mL of saturated NaHCO3 solution. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (5×7 mL). The combined organic extracts were washed
with 5 mL of brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
Purification by silica gel flash chromatography (EtOAc/n-hexane, 10:90) gave 438 mg (91%) of
1
5a as a colorless oil. [h]2D6=+1.85 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) l 7.34–7.20 (m,
5H), 3.90 (dd, J=11.5, 6.0 Hz, 1H), 2.43 (q, J=6.6 Hz, 1H), 2.30 (dd, J=15.1, 6.0 Hz, 1H), 2.21
(dd, J=14.8, 6.0 Hz, 1H), 1.83 (d, J=3.6 Hz, 1H), 1.73–1.68 (m, 1H), 1.40 (s, 9H), 1.37 (d,
J=6.6 Hz, 3H), 1.35 (d, J=6.9 Hz, 1H), 0.79 (s, 9H), −0.05 (s, 3H), −0.15 (s, 3H). 13C NMR
(75 MHz, CDCl3) l 170.59, 144.21, 128.29, 127.17, 127.04, 80.16, 70.14, 69.77, 43.43, 41.56,
30.58, 28.07, 25.78, 22.64, 17.95, −4.65, −4.99. Anal. calcd for C23H39NO3Si: C, 68.10; H, 9.69;
N, 3.45. Found: C, 68.11; H, 9.83; N, 3.53.
4.5. 3(S)-(tert-Butyldimethylsilanyloxy)-3-[1-(1%(S)-h-methylbenzyl)-aziridin-2(R)-yl]-propionic
acid tert-butyl ester 5b
90% yield (colorless oil), [h]2D7=−32.0 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) l 7.32–7.22
(m, 5H), 3.48 (td, J=7.7, 3.3 Hz, 1H), 2.39 (q, J=6.6 Hz, 1H), 1.96 (dd, J=15.4, 3.3 Hz, 1H),
1.86 (dd, J=15.4, 8.2 Hz, 1H), 1.84 (d, J=3.6 Hz, 1H), 1.64–1.58 (m, 1H), 1.49 (d, J=6.9 Hz,
1H), 1.41 (d, J=6.6 Hz, 3H), 1.35 (s, 9H), 0.82 (s, 9H), 0.03 (s, 3H), −0.02 (s, 3H). 13C NMR
(125 MHz, CDCl3) l 170.44, 143.95, 128.34, 127.40, 127.23, 79.87, 71.88, 70.11, 42.92, 42.33,
34.33, 28.11, 25.80, 22.21, 17.98, −4.06, −4.96. Anal. calcd for C23H39NO3Si: C, 68.10; H, 9.69;
N, 3.45. Found: C, 68.15; H, 9.66; N, 3.43.

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4.6. 5-Acetoxy-3(R)-(tert-butyldimethylsilanyloxy)-4(R)-(1%(S)-h-methylbenzylamino)-pentanoic
acid tert-butyl ester 6a
To a solution of 5a (191 mg, 0.471 mmol) in 2.36 mL of CH2Cl2 under a nitrogen atmosphere
at room temperature was added AcOH (0.14 mL, 2.354 mmol). The mixture was stirred for 10
hours and then quenched with 1 mL of saturated NaHCO3 solution. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (5×8 mL). The combined organic
extracts were washed with 5 mL of brine, dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. Purification by silica gel flash chromatography (EtOAc/n-hexane, 10:90) gave
1
215 mg (98%) of 6a as a colorless oil. [h]2D7=−26.2 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3)
l 7.35–7.22 (m, 5H), 4.22 (dd, J=11.2, 5.4 Hz, 1H), 4.12 (dd, J=5.9, 2.9 Hz, 1H), 4.05 (dd,
J=11.2, 6.8 Hz, 1H), 3.95 (q, J=6.8 Hz, 1H), 2.71 (dd, J=16.1, 6.3 Hz, 1H), 2.64 (m, 1H), 2.30
(dd, J=16.1, 8.7 Hz, 1H), 2.07 (s, 3H), 1.38 (s, 9H), 1.30 (d, J=6.8 Hz, 3H), 0.85 (s, 9H), −0.01
(s, 3H), −0.06 (s, 3H). 13C NMR (125 MHz, CDCl3) l 170.90, 170.87, 145.54, 128.36, 126.92,
126.82, 80.21, 69.17, 63.41, 56.69, 55.69, 37.70, 28.03, 25.79, 25.28, 20.93, 17.92, −4.74, −5.17.
Anal. calcd for C25H43NO5Si: C, 64.48; H, 9.31; N, 3.01. Found: C, 64.46; H, 9.36; N, 3.08.
4.7. 5-Acetoxy-3(S)-(tert-butyldimethylsilanyloxy)-4(R)-(1%(S)-h-methylbenzylamino)-pentanoic
acid tert-butyl ester 6b
1
94% yield (colorless oil), [h]2D5=−30.8 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3) l7.39–7.24
(m, 5H), 4.35 (dd, J=11.4, 4.0 Hz, 1H), 4.15 (td, J=7.0, 4.5 Hz, 1H), 4.07 (dd, J=11.5, 3.1 Hz,
1H), 3.94 (q, J=6.4 Hz, 1H), 2.26–2.49 (m, 2H), 2.38 (dd, J=16.1, 4.5 Hz, 1H), 2.11 (s, 3H),
1.47 (s, 9H), 1.28 (d, J=6.5 Hz, 3H), 0.84 (s, 9H), 0.07 (s, 3H), 0.02 (s, 3H). 13C NMR (125
MHz, CDCl3) l 171.03, 171.02, 145.31, 128.35, 126.97, 126.94, 80.16, 69.41, 61.00, 58.32, 54.75,
42.00, 28.10, 25.72, 25.40, 20.93, 17.86, −4.67, −5.12. Anal. calcd for C25H43NO5Si: C, 64.48; H,
9.31; N, 3.01. Found: C, 64.52; H, 9.29; N, 3.08.
4.8. 5-Acetoxy-4(R)-tert-butoxycarbonylamino-3(R)-(tert-butyldimethylsilanyloxy)-pentanoic
acid tert-butyl ester 7a
To a solution of 6a (123 mg, 0.264 mmol) in 1.30 mL of MeOH was added Pd(OH)2 (25 mg,
20 wt%) and (Boc)2O (115 mg, 0.528 mmol). The mixture was stirred at a balloon pressure of
hydrogen for 3 hours at room temperature. The reaction mixture was filtered and concentrated
in vacuo. Purification by silica gel flash chromatography (EtOAc/n-hexane, 10:90) gave 119 mg
1
(99%) of 7a as a colorless oil. [h]2D6=+0.60 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) l 4.70
(d, J=8.8 Hz, NHBoc), 4.32 (br, 1H), 4.10 (br, 1H), 3.99–3.93 (m, 2H), 2.51 (dd, J=16.1, 7.3
Hz, 1H), 2.40 (dd, J=16.1, 5.4 Hz, 1H), 2.06 (s, 3H), 1.46 (s, 18H), 0.89 (s, 9H), 0.08 (s, 6H).
13C NMR (125 MHz, CDCl3) l 170.59, 169.97, 155.42, 80.92, 79.47, 67.49, 63.36, 52.45, 40.57,
28.26, 28.01, 25.78, 20.73, 17.93, −4.76, −5.19. Anal. calcd for C22H43NO7Si: C, 57.24; H, 9.39;
N, 3.03. Found: C, 57.25; H, 9.48; N, 3.07.
4.9. 5-Acetoxy-4(R)-tert-butoxycarbonylamino-3(S)-(tert-butyldimethylsilanyloxy)-pentanoic
acid tert-butyl ester 7b
1
97% yield (colorless oil), [h]2D7=−3.95 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) l 4.74
(d, J=8.2 Hz, NHBoc), 4.27–4.21 (m, 3H), 3.87 (br, 1H), 2.521 (dd, J=16.5, 6.3 Hz, 1H),
2.43 (dd,

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J=16.5, 5.8 Hz, 1H), 2.07 (s, 3H), 1.46 (s, 9H), 1.44 (s, 9H), 0.88 (s, 9H), 0.087 (s, 3H), 0.074
(s, 3H). 13C NMR (75 MHz, CDCl3) l 170.85, 170.33, 55.26, 80.95, 79.55, 68.95, 63.11, 54.02,
41.25, 28.32, 28.09, 25.74, 20.83, 17.94, −4.58, −5.15. Anal. calcd for C22H43NO7Si: C, 57.24; H,
9.39; N, 3.03. Found: C, 57.24; H, 9.61; N, 3.13.
4.10. 4(R)-tert-Butoxycarbonylamino-3(R)-(tert-butyldimethylsilanyloxy)-5-hydroxy-pentanoic
acid tert-butyl ester 8a
To a solution of 7a (92 mg, 0.199 mmol) in 1.00 mL of EtOH at 0°C was added KOH (13.4
mg, 0.239 mmol). The mixture was stirred for 10 minutes at 0°C and then quenched with 1 mL
of water. The product was extracted with CH2Cl2 (7×7 mL) and the combined organic extracts
were washed with 4 mL of brine, dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. Purification by silica gel flash chromatography (EtOAc/n-hexane, 20:80) gave 70 mg
1
(84%) of 8a as a colorless oil. [h]2D7=−6.45 (c 1.0, CHCl3). H NMR (500 MHz, CDCl3) l 4.90
(d, J=7.8 Hz, NHBoc), 4.34–4.32 (m, 1H), 3.73–3.62 (m, 3H), 2.53 (dd, J=16.1, 7.8 Hz, 1H),
2.41 (dd, J=16.1, 5.4 Hz, 1H), 1.46 (s, 9H), 1.45 (s, 9H), 0.89 (s, 9H), 0.115 (s, 3H), 0.096 (s,
3H). 13C NMR (125 MHz, CDCl3) l 170.35, 156.45, 80.97, 79.61, 70.61, 63.57, 55.61, 40.69,
28.34, 28.06, 25.81, 17.95, −4.57, −5.00. Anal. calcd for C20H41NO6Si: C, 57.24; H, 9.85; N, 3.34.
Found: C, 57.28; H, 9.82; N, 3.39.
4.11. 4(R)-tert-Butoxycarbonylamino-3(S)-(tert-butyldimethylsilanyloxy)-5-hydroxy-pentanoic
acid tert-butyl ester 8b
1
87% yield (colorless oil), [h]2D7=−0.90 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) l 5.21 (br,
NHBoc), 4.39 (m, 1H), 3.92 (dd, J=11.3, 8.0 Hz, 1H), 3.67–3.58 (m, 2H), 2.96 (br, OH), 2.48
(d, J=6.0, 2H), 1.46 (s, 18H), 0.88 (s, 9H), 0.14 (s, 3H), 0.098 (s, 3H). 13C NMR (75 MHz,
CDCl3) l 169.94, 155.78, 81.01, 79.50, 70.91, 62.36, 55.22, 41.04, 28.34, 28.06, 25.75, 17.90,
−4.82, −5.08. Anal. calcd for C20H41NO6Si: C, 57.24; H, 9.85; N, 3.34. Found: C, 57.24; H, 9.82;
N, 3.33.
4.12. 2(S)-tert-Butoxycarbonylamino-3(R)-(tert-butyldimethylsilanyloxy)-pentanedioic acid
5-tert-butyl ester 1-methyl ester 9a
To a vigorously stirred mixture of 8a (70 mg, 0.167 mmol) and 0.84 mL of a 1/1/1.5
CCl4/H2O/CH3CN mixture at room temperature was added RuCl3 (0.69 mg, 0.0033 mmol) and
NaIO4 (146 mg, 0.684 mmol). The reaction mixture was stirred for 7 hours and then quenched
with 2 mL of water at room temperature. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (10×7 mL). The combined organic extracts were washed with 2 mL
of brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. To a solution of the
crude acid in 0.84 mL of DMF were added KHCO3 (50 mg, 0.498 mmol) and MeI (0.021 mL,
0.334 mmol). The reaction mixture was stirred for 5 hours at room temperature and then
quenched with 2 mL of water. The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (5×7 mL). Purification by silica gel flash chromatography (EtOAc/n-hex-
1
ane, 20:80) gave 59 mg (79%) of 9a as a colorless oil. [h]2D7=+10.7 (c 1.0, CHCl3). H NMR (300

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3291
MHz, CDCl3) l 5.11 (d, J=9.9 Hz, NHBoc), 4.67 (m, 1H), 4.44 (dd, J=9.9, 1.4 Hz, 1H), 3.72
(s, 3H), 2.54 (dd, J=16.5, 7.7 Hz, 1H), 2.38 (dd, J=16.5, 5.5 Hz, 1H), 1.45 (s, 9H), 1.44 (s, 9H),
0.82 (s, 9H), 0.038 (s, 3H), −0.003 (s, 3H). 13C NMR (75 MHz, CDCl3) l 171.29, 169.81, 155.89,
81.04, 79.83, 69.49, 57.61, 52.13, 40.44, 28.28, 28.04, 25.64, 17.84, −4.64, −5.34. Anal. calcd for
C21H41NO7Si: C, 56.35; H, 9.23; N, 3.13. Found: C, 56.16; H, 9.26; N, 3.23.
4.13. 2(S)-tert-Butoxycarbonylamino-3(S)-(tert-butyldimethylsilanyloxy)-pentanedioic acid
5-tert-butyl ester 1-methyl ester 9b
1
84% yield (colorless oil), [h]2D7=+99.3 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) l 5.29 (br,
NHBoc), 4.42 (m, 2H), 3.75 (s, 3H), 2.56 (dd, J=17.0, 6.0 Hz, 1H), 2.48 (dd, J=16.8, 7.1 Hz,
1H), 1.46 (s, 9H), 1.44 (s, 9H), 0.86 (s, 9H), 0.112 (s, 3H), 0.059 (s, 3H). 13C NMR (75 MHz,
CDCl3) l 170.36, 169.97, 154.87, 80.80, 79.73, 70.10, 58.48, 52.03, 40.78, 28.25, 28.06, 25.62,
17.91, −4.80, −5.12. Anal. calcd for C21H41NO7Si: C, 56.35; H, 9.23; N, 3.13. Found: C, 56.31;
H, 9.25; N, 3.16.
4.14. [3(S)-Acetoxymethyl-1-(1%(S)-h-methylbenzyl)-aziridin-2(S)-yl]-acetic acid tert-butyl ester
11a
To a solution of 10a (114 mg, 0.324 mmol) in 16.00 mL of CH2Cl2 under a nitrogen
atmosphere at −78°C was added TEA (0.45 mL, 3.244 mmol). The mixture was stirred for 15
minutes at −78°C and treated with MsCl (0.126 ml, 1.480 mmol). The reaction mixture was
warmed to room temperature and quenched with 1 mL of saturated NaHCO3 solution. The
organic layer was separated and the aqueous layer was extracted with CH2Cl2 (5×9 mL). The
combined organic extracts were washed with 7 mL of brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc/n-
1
hexane, 20:80) gave 87 mg (81%) of 11a as a colorless oil. [h]2D7=−8.2 (c 1.0, CHCl3). H NMR
(500 MHz, CDCl3) l 7.34–7.22 (m, 5H), 4.23 (dd, J=11.7, 4.9 Hz, 1H), 4.05 (dd, J=11.7, 7.3
Hz, 1H), 2.63 (q, J=6.8 Hz, 1H), 2.47 (dd, J=16.6, 4.9 Hz, 1H), 2.21 (dd, J=16.6, 6.8 Hz, 1H),
2.09 (s, 3H), 1.93 (m, 2H), 1.39 (d, J=6.8 Hz, 3H), 1.33 (s, 9H). 13C NMR (75 MHz, CDCl3)
l 170.83, 170.40, 144.22, 128.27, 126.94, 126.62, 80.62, 69.20, 63.69, 40.73, 38.81, 35.36, 27.89,
23.22, 20.83. Anal. calcd for C17H23NO3: C, 68.44; H, 8.16; N, 4.20. Found: C, 68.42; H, 8.17;
N, 4.23.
Acknowledgements
Financial support from the KOSEF (1999-1-123-001-5), HUFS and the Korean Research
Foundation Grant (KRF-99-042-D00079-D3004) is gratefully acknowledged.
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