A stereodivergent synthesis of hydroxyethylene dipeptide isostere via highly diastereoselective epoxidation

Article abstract of DOI:10.1055/s-2005-921907

Epoxidation of δ-amino-β,γ-unsaturated ester with trifluoroperacetic acid afforded its epoxide in a highly diastereoselective manner. Subsequent stereodivergent epoxide opening reactions provided synthetic routes towards both the threo and erythro hydroxy

Full text of DOI:10.1055/s-2005-921907

3136
LETTER
A Stereodivergent Synthesis of Hydroxyethylene Dipeptide Isostere via Highly
Diastereoselective Epoxidation
H
ydroxyethylene
D
y
ipeptide
I
so
u
stere via Highly
D
i
W
astereoselective
E
poxid
o
ation ong Lee, Hyeong-wook Choi, Byung Han Lee, Bo Seung Choi, Jay Hyok Chang, Young Keun Kim,
Jae Hoon Lee, Taeho Heo, Do Hyun Nam, Hyunik Shin*
Chemical Development Division, LG Life Sciences Ltd. R&D, 104-1, Moonji-dong, Yusong-gu, Daejon 305-380, Korea
Fax +82(42)8665754; E-mail: hisin@lgls.co.kr
Received 26 September 2005
R1
Abstract: Epoxidation of d-amino-b,g-unsaturated ester with tri-
fluoroperacetic acid afforded its epoxide in a highly diastereo-
R1
O
H2N
selective manner. Subsequent stereodivergent epoxide opening
reactions provided synthetic routes towards both the threo and
erythro hydroxyethylene peptide isostere.
OH
H2N
O
OH R2
O
2
1
Key words: hydroxyethylene isostere, diastereoselective epoxida-
tion, stereodivergent, epoxide ring opening
Scheme 1
d-amino-(Z)-b,g-unsaturated amide fragment,20 a more
electron-deficient peracid enhanced the diastereoselectiv-
ity through synergistic combination of the directing effect
of the carbamate group and A1,3-strain: use of permaleic
acid increased the selectivity to 10:1 and the most electron
deficient trifluoroperacetic acid21 led to better than 150:1
selectivity (Table 1). Moreover, simple recrystallization
of the crude product in methyl tert-butylether (MTBE)
provided highly pure 4a in better than 99% ee.22
As a transition state surrogate of the scissile amide bond
with enhanced metabolic stability, hydroxyethylene
dipeptide isostere 1 containing g-hydroxy-d-amino acid
functionality has been exploited extensively as a key
structural unit of many inhibitors of aspartyl proteases
such as renin,1 HIV,2 and g-secretase3 (Scheme 1). There-
fore, numerous synthetic routes have been devised partic-
ularly for the preparation of the common intermediate
lactone 2 that was efficiently transformed to 1 via well-es-
tablished enolate alkylation process.4 The most common
approach is based upon the reaction of an indium,5 zinc,6
titanium,7 or magnesium8 homoenolate equivalent with
N-protected amino-aldehyde or amino acid derivatives as
a key reaction. Other strategies include the use of an
epoxide intermediate9 prepared from N-protected amino-
aldehyde; a radical intermediate;10 a thiazolyl ketone in-
termediate;11 a chiron approach starting from mannose12
or glutamic acid;13 asymmetric reactions such as
Sharpless epoxidation,14 dihydroxylation,15 or aminohy-
droxylation;16 and finally, strategically interesting olefin
metathesis reaction17 for the construction of the lactone
ring. In addition to these approaches, many diverse syn-
thetic routes18 are also available. Herein, we disclose an
alternative stereodivergent synthetic route towards a
hydroxyethylene peptide isostere featuring the use of a
highly diastereoselective epoxidation and subsequent
stereodivergent ring-opening reactions as key transforma-
tions.
Table 1 Influence of Epoxidation Reagents on the Diastereoselec-
tivity
NHCbz
NHCbz
CO2R
CO2Me
O
3a R = H
3b R = Me
4a α-epoxide
4b β-epoxide
Entry
Peracid
Selectivity (4a/4b)
1
2
3
MCPBA
3:1
Permaleic acida
Trifluoroperacetic acida
10:1
>150:1
a Epoxidation of 3b was performed by peracid generated in situ by
slow addition of the anhydride to the stirred mixture of urea hydrogen
peroxide complex and Na2HPO4 (2 equiv) in CH2Cl2.
Treatment of the epoxide 4a with DBU smoothly opened
the epoxide ring to give 5, a common intermediate for
both hydroxyethylene and (E)-alkene dipeptide iso-
steres,23 respectively. Chemoselective reduction of the
a,b-unsaturated double bond of 5 by Ni2B,24 generated in
situ, resulted in a mixture of lactone 6 and its open
hydroxy-ester compound, which was exposed to p-TsOH
in toluene at reflux resulting in only lactone 6. Simple
trituration of the crude product with hexane resulted in
solidification and gave pure (1S,2¢S)-625 in 80% overall
yield (Scheme 2).
Ene-acid 3a19 was converted to its methyl ester 3b in
methanol in the presence of trimethylsilyl chloride in
quantitative yield. Epoxidation of 3b with MCPBA
provided a-epoxide 4a and b-epoxide 4b in moderate 3:1
selectivity. As observed in the epoxidation of a similar
SYNLETT 2005, No. 20, pp 3136–3138
1
9
.1
2
.2
0
0
5
Advanced online publication: 04.11.2005
DOI: 10.1055/s-2005-921907; Art ID: U28005ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hydroxyethylene Dipeptide Isostere via Highly Diastereoselective Epoxidation
3137
formation of the same class of lactam side-product.28 Hy-
drolysis of the oxazolidinone moiety of 9, protection by
the Cbz group, and final lactonization afforded (1S,2¢R)-
10 in 90% yield (Scheme 3).29
NHCbz
NHCbz
i)
CO2Me
CO2Me
O
OH
4a
5
In conclusion, we have developed efficient and stereo-
divergent synthetic routes towards diastereomeric 6 or 10
via the common intermediate 4a. Particularly noteworthy
are the highly diastereoselective epoxidation and subse-
quent stereodivergent ring-opening of the epoxide group
of 4a.
ii)
NHCbz
O
O
6
References
Scheme 2 Reagents and conditions: i) DBU, CH2Cl2; ii) (a) NaBH4,
NiCl2·6H2O, MeOH; (b) p-TsOH, toluene, reflux.
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10
Scheme 3 Reagents and conditions: i) ZrCl4 (2.5 equiv), CH2Cl2,
reflux; ii) MsCl, Et3N, CH2Cl2; iii) H2, Pd/C, EtOAc; iv) (a) NaOH,
EtOH–H2O, CbzCl; (b) AcOH, toluene, reflux.
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accomplished by the internal participation of the carbam-
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One-pot mesylation of 7 and subsequent elimination gave
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reaction solvent led to significant contamination (ca.
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Synlett 2005, No. 20, 3136–3138 © Thieme Stuttgart · New York

3138
K. W. Lee et al.
LETTER
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J = 17.5, 8.7 Hz), 2.98 (1 H, dd, J = 13.3, 6.9 Hz), 2.90 (1 H,
dd, J = 13.3, 8.7 Hz), 2.48 (dd, 2 H, J = 9.7, 7.4 Hz), 2.16–
2.03 (2 H, m); 13C NMR (CDCl3,125 MHz): d = 177.2,
156.7, 137.1, 136.4, 129.4, 128.8, 128.6, 128.2, 128.0,
126.9, 79.9, 54.9, 39.3, 28.7, 24.1; MS: m/z = 340 [M + H].
(26) Casado-Bellver, F. J.; Gonzalez-Rosende, M. E.; Asensio,
A.; Jorda-Gregori, J. M.; Alvarez-Sorolla, A.; Sepulveda-
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(19) Ene-acid 3a is available in multi-kg quantities (Z/E
selectivity, 24:1; 83% ee); see ref. 20.
(27) Amino-ester side-product (Figure 1): 1H NMR (CDCl3,
400 MHz): d = 7.34–7.28 (5 H, m), 3.57 (3 H, s), 3.51 (1 H,
m), 3.24 (1 H, dd, J = 13.6, 5.6 Hz), 2.95 (1 H, dd, J = 13.6,
8.8 Hz), 2.32 (2 H, m), 1.95–1.69 (4 H, m); MS: m/z = 222
[M + H].
(20) Lee, K. W.; Hwang, S. Y.; Kim, C. R.; Nam, D. H.; Chang,
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W.; Shin, H. Org. Process Res. Dev. 2003, 7, 839.
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(22) Preparation of 4a: To a stirred mixture of 3b (660 mg, 1.87
mmol), urea hydrogen peroxide (790 mg, 8.40 mmol), and
Na2HPO4 (1.12 g, 7.89 mmol) in CH2Cl2 (10 mL) was added
(CF3CO)2O (784 mg, 3.73 mmol) at 0 °C. The mixture was
allowed to warm to r.t. and stirred for 4 h. The reaction
mixture was washed with a sat. aq solution of NaHCO3, a 5%
solution of NaHSO3, and finally H2O. The separated organic
layer was concentrated and MTBE (15 mL) was added to the
residue. The mixture was stirred for 5 h. The solid formed
was filtered and washed with MTBE (2 mL). The cake was
dried over a stream of nitrogen to give 4a (615 mg, 86.1%)
as a white solid; 4a tR 31.4 min, ent-4a tR 40.8 min
(Chiralpak® AD-H; 35 °C; 10% i-PrOH–hexane; 1 mL/min;
250 nm); ee of isolated 4a ≥99.9%, while the ee of the filtrate
was 50%, which reflects highly selective recrystallization.
1H NMR (CDCl3, 400 MHz): d = 7.38–7.18 (10 H, m), 5.12
(1 H, d, J = 12.4 Hz), 5.09 (1 H, d, J = 12.4 Hz), 4.95 (1 H,
br), 3.71 (1 H, m), 3.67 (3 H, s), 3.32 (1 H, m), 3.07 (1 H, m),
3.01 (1 H, dd, J = 8.0, 4.4 Hz), 2.85 (1 H, dd, J = 13.2, 8.0
Hz), 2.38 (1 H, dd, J = 16.8, 7.6 Hz), 2.03 (1 H, dd, J = 17.2,
4.8 Hz); 13C NMR (CDCl3, 125 MHz): d = 170.8, 155.8,
136.6, 136.5, 129.6, 128.7, 128.6, 128.2, 128.1, 127.0, 67.0,
57.6, 53.6, 52.0, 51.8, 39.5, 33.3.
O
H2N
OMe
Figure 1
(28) Lactam side-product (Figure 2): 1H NMR (CDCl3, 400
MHz): d = 7.35–7.17 (5 H, m), 5.65 (1 H, br), 3.61 (1 H, m),
2.88 (1 H, dd, J = 13.6, 5.2 Hz), 2.62 (1 H, dd, J = 13.6, 9.2
Hz), 2.43–2.29 (2 H, m), 1.94 (2 H, m), 1.68 (1 H, m), 1.47
(1 H, m); MS: m/z = 190 [M + H] .
HN
O
Figure 2
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1991, 56, 4370.
(24) Brown, H. C.; Brown, C. A. J. Am. Chem. Soc. 1963, 85,
1003.
(25) Benzyl (1S)-1-[(2¢S)-5¢-oxotetrahydrofuran-2¢-yl]-2-
phenylethylcarbamate (6): [a]D25 = –9.6 (CHCl3, c 1); 1H
NMR (CDCl3, 500 MHz): d = 7.34–7.25 (10 H, m), 5.09 (1
H, d, J = 12.4 Hz), 5.05 (1 H, d, J = 12.4 Hz), 4.87 (d, 1 H,
J = 10.0Hz), 4.48 (1 H, t, J = 7.8 Hz), 4.07 (dd, 1 H,
(29) Benzyl (1S)-1-[(2¢R)-5¢-oxotetrahydrofuran-2¢-yl]-2-
phenylethylcarbamate (10): [a]D25 = –8.6 (CHCl3, c 0.02);
1H NMR (CDCl3, 400 MHz): d = 7.37–7.18 (10 H, m), 5.04
(2 H, s), 4.66 (1 H, br), 4.40 (1 H, m), 4.05 (1 H, m), 3.03 (1
H, dd, J = 14.4, 4.4 Hz), 2.90 (1 H, m), 2.52 (2 H, m), 2.25
(1 H, m), 2.11 (1 H, m); 13C NMR (CDCl3, 100 MHz): d =
176.6, 165.9, 136.1, 132.7, 129.5, 128.8, 128.6, 128.3,
128.0, 127.0, 80.4, 60.4, 50.0, 30.9, 28.2, 24.7; MS: m/z =
340 [M + H] .
Synlett 2005, No. 20, 3136–3138 © Thieme Stuttgart · New York