Facile way to synthesize Nα-Boc-Nβ-Cbz-2, 3-diaminopropionic acid derivatives via 5-oxazolidinone

Article abstract of DOI:10.1080/00397910600948039

An economical and facile synthesis of N^α-Boc-N ^β-Cbz-2,3-diaminopropionic acid derivatives is reported. The key aspect of this method is employment of N-Boc-5-oxazolidinone moiety to simultaneously provide proper protection of α-amid

Full text of DOI:10.1080/00397910600948039

Synthetic Communicationsw, 36: 3803–3807, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600948039
Facile Way to Synthesize Na-Boc-Nb-Cbz-2,3-
Diaminopropionic Acid Derivatives
via 5-Oxazolidinone
Hanbing Teng, Zhengguo Jiang, Lamei Wu, Jiangtao Su,
Xichun Feng, Guofu Qiu, Shucai Liang, and Xianming Hu
State Key Laboratory of Virology, College of Pharmacy,
Wuhan University, Wuhan, China
Abstract: An economical and facile synthesis of Na-Boc-Nb-Cbz-2,3-diaminopropio-
nic acid derivatives is reported. The key aspect of this method is employment of
N-Boc-5-oxazolidinone moiety to simultaneously provide proper protection of
a-amido and a-carboxyl functional groups and affords the desired isocyanate 5 suc-
cessfully by a Curtius rearrangement. The obtained intermediate 6 can be readily
converted to various derivatives of Na-Boc-Nb-Cbz-2,3-diaminopropionic acid by con-
ventional procedure.
Keywords: Curtius rearrangement, 2,3-diaminopropionic acid, isocyanate,
5-oxazolidinone
L-2,3-Diaminopropanoic acid (Dap), a nonproteinogenic amino acid occuring
in nature both in its free form and as a constituent of peptides,[1] has been
widely used in the construction of medicinally important entities.[2] Thus,
much effort has been directed toward the synthesis of it and its derivatives
in recent years, and several new synthetic methodologies have been
developed.[3]
The most common synthesis of Dap involves Hoffman[4] or modified
Curtius[5] rearrangements of asparagines derivatives and various N-protecting
groups (such as Cbz, Ts, Boc) are used. However, these methods, in
Received in ROC October 8, 2005
Address correspondence to Xianming Hu, State Key Laboratory of Virology,
College of Pharmacy, Wuhan University, Wuhan 430072, China. E-mail: xmhu@
whu.edu.cn
3803

3804
H. Teng et al.
preparation of the derivatives of Na-Boc-Dap, often suffer from low yields[6]
or require expensive reagents such as bis-[trifluoroacetoxy]-iodo benzene[5,6]
or diphenyl phosphorazidate (DPPA).[7a]
Here, we report an economical and facile way to synthesize the deriva-
tives of Na-Boc-Dap from Boc-L-aspartic acid. Synthetic analysis suggests
that the isocyanate 2 from the L-aspartic acid derivative would provide
efficient access to Na-Boc-b-aminoalanine alkyl ester. But Boc-Asp-OR
cannot afford the expected isocyanate 2; it directly gives cyclic urea after a
Curtius rearrangement (Scheme 1).[7]
To prevent the intermolecular trapping of the isocyanate after the Curtius
rearrangement, the strategy of dual Boc-protection of the reactive nitrogen has
been put forward, and the desired isocyanate was obtained successfully. This
approach, without using bis-[trifluoroacetoxy]-iodo benzene or DPPA,
provides a promising synthesis of the Nb-Cbz, Na-Boc-Dap.[7b] However, it
involves tedious protection and deprotection steps both in the a-carboxyl
and a-amino groups. We thought that employment of N-Boc-5-oxazolidinone
moiety could provide not only the protection of the a-carboxyl functional
group but also the complete protection of the a-amino group. This protection
strategy would also avoid the intermolecular trapping and afford the desired
isocyanate. Moreover, it would shortern the route greatly.
Starting with Boc-L-aspartic acid, the 5-oxazolidinone 4 was prepared in
good yield in benzene by a modification of the literature procedure.[8] We
found that if toluene was used a very lower yield was obtained. The
procedure for the preparation of compound 4 is as follows: Boc-L-aspartic
acid (25 mmol) was dissolved in EtOAc (10 mL); benzene (200 mL) was
added. The powder paraformaldehyde (50 mmol) and p-TsOH (1.5 mmol)
were added slowly at about 608C. Then the mixture was refluxed 2 h with
removal of water by a Dean–Stark trap. EtOAc (100 mL) was added; the
solution was washed with 0.3 M K2CO3 (2.5 mL) and brine (2 ꢀ 10 mL)
and dried with Na2SO4. The solvent was evaporated to give a light yellow
solid (4.4 g) in 72% yield. Recrystallization from anhydrous ether provided
a sample for analytical characterization. Mp ¼ 132–1348C; [a]2D0 þ153.1
1
(c ¼ 1, CH3OH); H NMR (300 MHz, CDCl3): d ¼ 1.49 (s, 9H), 3.03–3.27
(m, 2H), 4.31 (s, 1H), 5.24 (d, 2H, J ¼ 3), 5.45 (br, 1H). 13C NMR
(150 MHz, CDCl3): d ¼ 28.59, 34.70, 51.68, 78.84, 82.92, 152.24, 172.12,
175.26. MS: m/z ¼ 284 [M þ K]þ. Anal. calcd. for C10H15NO6: C, 48.98;
H, 6.17; N, 5.71. Found: C, 49.14; H, 6.39; N, 5.48.
Scheme 1.

Na-Boc-Nb-Cbz-2,3-Diaminopropionic Acid Derivatives
3805
The 4-carboxylic acid was activated with ethyl chloroformate and
N-methylmorpholine (NMM) in dry THF, followed by addition of aqueous
sodium azide to afford the acyl azide (strong absorption at 2145 cm21 in
IR). Then the acyl azide was converted to isocyanate 5 (strong absorption at
2223–2255 cm21 in IR) successfully in toluene at 758C.[9] The procedure
for the preparation of isocyanate 5:is as follows: 4 (10 mmol) was dissolved
in dry THF (30 mL) and cooled to 2158S. After addition of EtOCOCl
(11 mmol) and NMM (12 mmol), the mixture was stirred for 20 min. A
solution of NaN3 (25 mmol) in H2O (5 mL) was added, and stirring
continued for 1 h at 2108S. The solution was then diluted with water and
extracted with EtOAc (150 mL). The organic layers were washed with brine
(2 ꢀ 10 mL), dried over Na2SO4 and concentrated under reduced pressure
to give crude acyl azide. This crude acyl azide can be further purified by a
flash-column chromatography (petroleum ether/EtOAc, 2:1, Rf ¼ 0.7).
Purified acyl azide was dissolved in toluene (30 mL), and the resulting
solution was heated to 758S under stirring. After the gas evolution had
stopped, the toluene was removed under reduced pressure to afford isocyanate
5 as clear oil.
This isocyanate 5 was directly used in the next step without further puri-
fication. This isocyanate reacted with benzyl alcohol in the presence of CuCl
in dry DMF to lead to the important intermediate 6[10] (Scheme 2). The
procedure for the preparation of compound 6. To a stirred green mixture of
benzyl alcohol (9 mmol) CuCl (9 mmol), is as follows: and dry DMF
(6 mL) at room temperature, a solution of isocyanate 5 in dry DMF (4 mL)
was added. The solution was diluted with 1 N HCl (20 mL) after stirring for
3 h, then it was extracted with EtOAc (4 ꢀ 40 mL), washed with brine
(3 ꢀ 20 mL), dried (Na2SO4), concentrated, and purified by column chrom-
atography (petroleum ether/EtOAc, 4:1, Rf ¼ 0.3) to afford a white solid
(2.4 g) in 68% yield from compound 4. Mp ¼ 83–848C; [a]2D0 þ92.2
1
(c ¼ 1, CH3OH); H NMR (300 MHz, CDCl3): d ¼ 1.57 (s, 9H), 3.75–3.88
(m, 2H), 4.31 (s, 1H), 5.11–5.21 (m, 4H), 5.42 (br, 1H), 7.39 (s, 5H). 13C
NMR (150 MHz, CDCl3): d ¼ 29.10, 41.94, 55.98, 67.60, 78.73, 83.01,
128.23, 128.56, 136.19, 151.80, 156.13, 170.93. MS: m/z ¼ 350 [Mþ].
Anal. calcd. for C17H22N2O6: C, 58.28; H, 6.33; N, 8.00. Found: C, 58.46;
H, 6.59; N, 8.24.
Directly reacting 5 with water in THF at room temperature did not give
free b-amino 7; 1H NMR and electrospary MS indicated the isolated
product was a symmetrical urea 8 (Scheme 3).
Scheme 2.

3806
H. Teng et al.
Scheme 3.
Compound 6, containing the 5-oxazolidinone moiety, can undergo a ring-
opening reaction in different alkaline conditions to afford corresponding Na-
Boc-Nb-Cbz-Dap derivatives in high yields. For example, when it was treated
with NaOMe in MeOH at 2108S,[8a] methyl ester 9 was obtained in 86%
yield. Direct saponification of it with 1 N NaOH in MeOH at room tempera-
ture[11] afforded carboxylic acid 10; opening the ring by aqueous ammonia[12]
in THF provided carboxamide 11 (Scheme 4).
The procedure for the preparation of compound 9 is as follows: Na
(80 mg) was added to anhydrous MeOH (32 mL) at 2108S with stirring.
Compounds 6 (1.5 mmol) was added when Na was disappeared. After
stirring for 1.5 h at this temperature, the solution was diluted with EtOAc
(80 mL), 1 N HCl (5 mL), and brine (20 mL). The organic layer was
washed with brine (2 ꢀ 10 mL), dried (Na2SO4), concentrated, and purified
by column chromatography (petroleum ether/EtOAc, 2 : 1, Rf ¼ 0.4) to
1
afford a clear oil (0.45 g) in 86% yield. [a]2D0 29.0 (c ¼ 1, CH3OH); H
NMR (300 MHz, CDCl3): d ¼ 1.41 (s, 9H), 3.52–3.58 (m, 2H), 3.69
(s, 3H), 4.34 (s, 1H), 5.05 (s, 2H), 5.43 (br, 1H), 5.60 (br, 1H), 7.29 (s, 5H).
13C NMR (150 MHz, CDCl3): d ¼ 29.13, 43.45, 53.21, 54.74, 67.39, 80.50,
128.09, 128.47, 136.26, 155.36, 156.66, 171.00. MS: m/z ¼ 352 [Mþ].
Anal. calcd. for C17H24N2O6: C, 57.94; H, 6.86; N, 7.95. Found: C, 57.71;
H, 7.02; N, 8.07.
Selective removal of Cbz-protecting group of compounds 9–11 via
hydrogenolysis (H2-Pd/C) can afford the corresponding free b-amino in quan-
titative yield.[4,7b]
In conclusion, we have developed an economical and facile way to
prepare the derivatives of Na-Boc-Dap. The key aspect of this method is
Scheme 4.

Na-Boc-Nb-Cbz-2,3-Diaminopropionic Acid Derivatives
3807
employment of N-Boc-5-oxazolidinone moiety to provide a proper protection
of the a-amino group and successfully affords the desired isocyanate by a
Curtius rearrangement. The advantages over previous approaches are a
shorter route by choosing the proper protection strategy, no costly reagents,
a conventional procedure, and of good yields.
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