A Stereoselective Route to Hydroxyethylamine Dipeptide Isosteres

Article abstract of DOI:10.1021/jo001072b

An efficient synthesis of stereodefined hydroxyethylamine dipeptide isosteres has been developed, utilizing a syn-selective Grignard addition and reductive amination as the key reactions.

Full text of DOI:10.1021/jo001072b

J . Org. Chem. 2000, 65, 7609-7611
7609
A Ster eoselective Rou te to Hyd r oxyeth yla m in e Dip ep tid e
Isoster es†
Apurba Datta*,‡,§ and Gududuru Veeresa‡,§
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, and
Organic Division III, Indian Institute of Chemical Technology, Hyderabad - 500 007, India
adutta@rx.pharm.ukans.edu
Received J uly 17, 2000
An efficient synthesis of stereodefined hydroxyethylamine dipeptide isosteres has been developed,
utilizing a syn-selective Grignard addition and reductive amination as the key reactions.
Extensive research toward finding potent enzyme
inhibitors active against HIV protease has led to the
development of various peptide isosteres, wherein the
scissile peptide bond is replaced by hydrolytically more
stable isosteric functional groups.1 A useful approach in
this regard has been the incorporation of a transition-
state isostere, mimicking the tetrahedral transition-state
of amide bond hydrolysis, into the designed inhibitors.
In this context, hydroxyethylamine (HEA) dipeptide iso-
F igu r e 1. Hydrolytically stable hydroxyethylamine (HEA)
steres (Figure 1) constitute a useful class of HIV protease
inhibitors.2,3 Interestingly, studies regarding the effect
of the absolute configuration of the structurally critical
hydroxy group of these class of compounds have revealed
that (i) the hydroxy configuration necessary for maximal
protease inhibitory activity depends on the peptide frame-
work and (ii) inhibitors may bind to the protease with
either of the two possible configurations.4 It appears that,
in these inhibitors where binding interactions involve
several sub-sites, substituents present in P4-P3 and P3′
positions exert significant influence on the P1-P1′ binding
interactions. Consequently, a number of methods have
been reported for the synthesis of HEA peptide isosteres
with either of the two possible hydroxy group configura-
tions. Interestingly, in all the above methods, the key
HEA peptide isostere structural core has been assembled
via initial synthesis of a chiral R-aminoalkyl epoxide and
subsequent opening of the epoxide with suitable amine
nucleophiles.4-10 We report herein an alternative ap-
proach toward building up the HEA dipeptide framework
dipeptide isosteric replacement for the scissile peptide bond.
via a stereoselective Grignard addition and a reductive
amination as the key reaction steps.
Recent work from our laboratory has demonstrated the
utility of chelation-controlled, syn-selective addition of
Grignard reagents to chiral R-amino aldehydes for the
stereoselective formation of structurally important 1,2-
amino alcohol units.11 In continuation of the above
studies, we envisaged that (i) addition of vinylmagnesium
bromide to phenylalaninal (derived from L-phenylalanine)
forming the syn-â-amino alcohol fragment 4, followed by
(ii) utilization of the vinyl group as an aldehyde precursor
and subsequent reductive amination with various amino
acids 3 will provide a direct route to stereodefined
hydroxyethylamine peptide isosteres 1 (Scheme 1). Re-
sults of the studies thus undertaken are described below.
In a one-pot reaction, L-phenylalanine was converted
to the known N-Boc-phenylalaninol (5)12 (Scheme 2) by
sequential carboxylic acid reduction and Boc-protection
of the amino group. Following a reported protocol,13
Swern oxidation of the alcohol 5 to the corresponding
aldehyde and its in-situ reaction with vinylmagnesium
bromide afforded the syn-amino alcohol 4 as the major
product (syn:anti ) 87:13, diastereoisomers separated by
column chromatography). The pivotal intermediate 4,
having the required stereodefined â-amino alcohol func-
tionality and the strategic terminal alkene moiety,
represents an ideal precursor for the proposed synthesis
of the hydroxyethylamine isosteres. Subsequent ac-
etonide protection of the amino alcohol functionality
provided the oxazolidine derivative 6, for which the
* Corresponding author. Tel: 785 864 4117. FAX: 785 864 5836.
† Dedicated to Professor Richard R. Schmidt on the occasion of his
65th birthday.
‡ University of Kansas.
§ Indian Institute of Chemical Technology.
(1) Huff, J . R. J . Med. Chem. 1991, 34, 2305.
(2) Leung, D.; Abbenante, G.; Fairlie, D. P. J . Med. Chem. 2000,
43, 305.
(3) Dutta, A. S. Small Peptides: Chemistry, Biology, and Clinical
Studies; Elsevier: Amsterdam, 1993; pp 482-523.
(4) Rich, D. H.; Sun, C.-Q.; Vara Prasad, J . V. N.; Pathiasseril, A.;
Toth, M. V.; Marshall, G. R.; Clare, M.; Mueller, R. A.; Housman, K.
J . Med. Chem. 1991, 34, 1222, and references cited therein.
(5) For synthesis of aminoalkyl epoxides, see: Beier, C.; Schaumann,
E.; Adiwidjaja, G. Synlett 1998, 41, and references therein.
(6) J anetka, J . W.; Raman, P.; Satyshur, K.; Flentke, G. R.; Rich,
D. H. J . Am. Chem. Soc. 1997, 119, 441.
(7) Ghosh, A. K.; Hussain, A. K.; Fidanze, S. J . Org. Chem. 1997,
62, 6080-6082.
(11) Kumar, K. K.; Datta, A. Tetrahedron 1999, 55, 13899, and
references therein. For an efficient approach to anti-1,2-amino alcohols,
via nonchelation controlled addition of organometallic reagents to
chiral R-amino aldehydes, see: Reetz, M. T. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1531.
(12) Veeresa, G.; Datta, A. Tetrahedron 1998, 54, 15673.
(13) Denis, J .-N.; Correa, A.; Greene, A. E. J . Org. Chem. 1991, 56,
6939.
(8) Noteberg, D.; Branalt, I.; Kvarnstrom, I.; Classon, B.; Samuels-
son, B.; Nillroth, U.; Danielson, H.; Karlen, A.; Hallberg, A. Tetrahe-
dron 1997, 53, 7975.
(9) Ojima, I.; Wang, H.; Wang, T.; Ng, E. W. Tetrahedron Lett. 1998,
39, 923, and references cited therein.
(10) Inaba, T.; Yamada, Y.; Abe, H.; Sagawa, S.; Cho, H. J . Org.
Chem. 2000, 65, 1623.
10.1021/jo001072b CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/07/2000

7610 J . Org. Chem., Vol. 65, No. 22, 2000
Datta and Veeresa
Sch em e 1
Sch em e 2
stereoselective route to biologically important hydroxy-
ethylamine dipeptide isosteres, has been developed fol-
lowing a relatively short and simple reaction sequence.
The strategy and the approach described is of general
applicability and can be easily extended to synthesize a
large number of possible structural variants, utilizing
different amino acid combinations to form the HEA
dipeptide skeleton. It is hoped that the described method
will be a useful addition to existing methodologies for
synthesizing hydroxyethylamine peptide isosteres of
potential biological importance.
Exp er im en ta l Section 14
(3S,4S)-5-[(ter t-Bu t oxyca r b on yl)a m in o]-3-h yd r oxy-5-
p h en yl-1-p en ten e (4). To a stirred solution of oxalyl chloride
(2.4 mL, 27.88 mmol) and CH2Cl2 (50 mL) at -78 °C under
nitrogen atmosphere was added DMSO (2.26 mL, 31.86 mmol)
dropwise. After stirring for 30 min, a solution of the amino
alcohol 512 (4 g, 15.93 mmol) in CH2Cl2 (100 mL) was added
over 30 min. The mixture was warmed to -35 °C and stirred
for 30 min at this temperature, followed by addition of di-
isopropylethylamine (19 mL, 111.55 mmol) over 5 min. The
reaction mixture was then warmed to 0 °C in 15 min and
transferred through a cannula to a room-temperature solution
of vinylmagnesium bromide (1 M soln in THF, 100 mL, 100
mmol) over 30 min. After stirring for 2 h at room temperature,
the reaction mixture was poured into aqueous saturated NH4-
Cl solution (100 mL) and acidified to pH 4 by adding 10%
aqueous HCl solution. The organic layer was separated, the
aqueous layer extracted with CHCl3 (3 × 100 mL), and the
combined organic extracts were washed sequentially with wa-
ter and brine. After drying over Na2SO4, solvent was removed
under vacuum and the residual oil purified by flash column
chromatography (ethyl acetate/hexane ) 1/12) to yield the
amino alcohol 4 (2.7 g, 62%) as a viscous semisolid: [R]22
)
D
coupling constant between the two protons in the ring
(J 4,5 ) 6.3 Hz) is consistent with their trans-relationship,
thereby also confirming the assigned stereochemistry.
Introduction of the second amino acid fragment via
functionalization of the terminal double bond of oxazo-
lidine 6 was next investigated. Thus, oxidative degrada-
tion of the alkene under standard conditions afforded the
corresponding aldehyde 2, which was then subjected to
reductive amination with various amino acid esters 3,
affording uneventfully the expected diamino alcohol
derivatives 7 in good overall yield. Enantiomeric purity
of the products thus formed were verified by HPLC
analysis. Finally, deprotection of the acetonide linkage
resulted in the target hydroxyethylamine dipeptide isos-
teres 8 in good yields.
-43.4 (c)1, CHCl3); IR (neat) 3364, 1698 cm-1; 1H NMR (200
MHz, CDCl3) δ 1.38 (br s, 9H), 2.88 (d, J ) 7.3 Hz, 2H), 3.76
(m, 1H), 4.07 (br s, 1H), 4.75 (d, J ) 8.9 Hz, 1H), 5.22 (m, 2H),
5.89 (m, 1H), 7.23 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 156.1,
138.4, 129.3, 128.4, 128.3, 126.3, 116.0, 79.4, 72.8, 56.2, 38.1,
28.3; FABMS 278 (MH+). Anal. Calcd for C16H23NO3 (277.36):
C, 69.29; H, 8.36; N, 5.05. Found: C, 69.61; H, 8.28; N, 4.78.
(4S,5S)-2,2-Dim eth yl-3-(ter t-bu toxyca r bon yl)-4-ben zyl-
5-(1-eth yn yl)-1,3-oxa zolid in e (6). A solution of the amino
alcohol 4 (3 g, 10.8 mmol), 2,2-dimethoxypropane (19.5 mL,
123.7 mmol), and a catalytic amount of pyridinium p-toluene-
sulfonate (50 mg) in toluene (35 mL) was stirred at 80 °C for
4 h. Removal of the solvent under vacuum and purification of
the resulting residue by column chromatography (ethyl acetate/
hexane ) 1/19) afforded the pure oxazolidine derivative 6 (2.9
(14) For general experimental details, see, Mohapatra, D. K.; Datta,
In conclusion, a new method, resulting in an efficient,
A. J . Org. Chem. 1998, 63, 642.

Hydroxyethylamine Dipeptide Isosteres
J . Org. Chem., Vol. 65, No. 22, 2000 7611
g, 85%) as a light yellow viscous liquid: [R]22D ) 11.5 (c ) 1.1,
δ 1.23 (d, J ) 6.38 Hz, 3H), 1.58 (br s, 15H), 2.14 (br s, 1H),
2.63-2.78 (m, 2H), 3.22 (m, 2H), 3.69 (s, 3H), 3.82 (m, 2H),
4.03 (m, 1H), 7.22 (m, 5H); FABMS 407 (MH+). Anal. Calcd
for C22H34N2O5 (406.52): C, 65.00; H, 8.43; N, 6.89. Found: C,
65.27; H, 8.70; N, 7.12.
CHCl3); IR (neat) 1697 cm-1 1H NMR (200 MHz, CDCl3) δ
;
1.52 and 1.55 (2s, 15Η), 3.13 (br s, 2H), 3.89 (m, 1H), 4.30 (dd,
J ) 4.04 and 6.3 Hz, 1H), 5.18 (m, 2H), 5.74 (m, 1H), 7.25 (m,
5H); FABMS 318 (MH+). Anal. Calcd for C19H27NO3 (317.42):
C, 71.89; H, 8.57; N, 4.41. Found: C, 71.51; H, 8.57; N, 4.59.
(4S,5S)-2,2-Dim eth yl-3-(ter t-bu toxyca r bon yl)-4-ben zyl-
5-for m yl-1,3-oxa zolid in e (2). To a stirred solution of the vi-
nyl oxazolidine 6 (2.5 g, 7.88 mmol) and N-methylmorpholine
N-oxide (NMO) (4.61 g, 39.4 mmol) in acetone (15 mL) and
water (3 mL) at room temperature was added a catalytic am-
ount of OsO4 solution in toluene (5% solution, 5 mol %). After
stirring for 8 h, a saturated aqueous solution of Na2SO3 (5 mL)
was added to the mixture and the resulting solution extracted
with ethyl acetate (4 × 50 mL). The combined extracts were
dried over Na2SO4, and the solvent was removed thoroughly
under vacuum affording the crude dihydroxylated compound
(2.7 g), which was dissolved in CH2Cl2 (40 mL) and added in
one lot to a vigorously stirred suspension of NaIO4 supported
in silica gel (16 g, 20% NaIO4)15 in CH2Cl2 (25 mL) maintained
at 0 °C. After stirring at the same temperature for 1 h, the
solid was removed by filtration and washed with CHCl3 (3 ×
25 mL), and the combined filtrate was concentrated under
vacuum. The resulting residue was filtered through a pad of
silica gel yielding the pure aldehyde 2 (2.31 g, 92% two steps)
as a viscous liquid: [R]22D ) 6 (c ) 1.0, CHCl3); IR (neat) 1728,
7d : colorless oil; 72% yield; [R]22D ) -25.2 (c ) 1.20, CHCl3);
1
IR (neat) 3353, 1746, 1693 cm-1; H NMR (200 MHz, CDCl3)
δ 0.87 (d, J ) 6.3 Hz, 6H), 1.50 (br s, 15H), 1.8 (m, 1H), 2.17
(br s, 1H), 2.58-2.71 (m, 2H), 2.89-3.20 (m, 2H), 3.67 (s, 3H),
3.73 (m, 2H), 4.07 (m, 1H), 7.17 (m, 5H); FABMS 435 (MH+).
Anal. Calcd for C24H38N2O5 (434.57): C, 66.33; H, 8.81; N, 6.45.
Found: C, 66.49; H, 8.53; N, 6.80.
7e: colorless oil; 79% yield; [R]22D ) -28.7 (c ) 1.22, CHCl3);
1
IR (neat) 3448, 1752, 1698 cm-1; H NMR (200 MHz, CDCl3)
δ 0.88 (2d, 6H), 1.36 (m, 3H), 1.52 (br s, 15H), 2.56-2.74 (m,
2H), 3.01-3.33 (m, 2H), 3.65 (s, 3H), 3.82 (m, 2H), 3.99 (m,
1H), 7.20 (m, 5H); FABMS 449 (MH+); Anal. Calcd for
C25H40N2O5 (448.60): C, 66.94; H, 8.99; N, 6.24. Found: C,
67.23; H, 8.68; N, 6.57.
Gen er a l P r oced u r e for th e Syn th esis of 8a-e. To a well-
stirred solution of 7 (1 mmol) in CH2Cl2 (5 mL) at 0 °C was
added 96% formic acid (10 mL) dropwise. After 30 min. the
cooling bath was removed and stirring continued at room
temperature for another 30 min. The reaction mixture was
then concentrated under vacuum (below 40 °C), and the
resulting residue was dissolved in CHCl3 (20 mL), washed
sequentially with saturated NaHCO3 solution and brine, dried
over anhydrous Na2SO4, and concentrated under vacuum. The
residual liquid was purified by column chromatography (ethyl
acetate/hexane ) 1/3), affording the product.
1
1691 cm-1; H NMR δ 1.5 (br s, 15H), 2.8 and 3.22 (2m, 2H),
4.12 (m, 1H), 4.40 (m, 1H), 7.23 (m, 5H), 9.62 (br s, 1H); MS
(FAB+) 320 (MH+). The aldehyde 2 was found to decompose
on storage and was used immediately for the next reaction.
Gen er a l P r oced u r e for th e Syn th esis of 7a -e. To a
stirred mixture of the aldehyde 2 (1 mmol) and anhydrous Na2-
SO4 (50 mg) in CH2Cl2 (15 mL) at 0 °C was added a solution
of the commercially available amino acid methyl ester 3 (1
mmol) in CH2Cl2 (5 mL) and stirring continued for 1 h while
allowing the reaction mixture to warm to room temperature.
The mixture was filtered, the solid residue washed with CH2-
Cl2 (2 × 5 mL), and the combined filtrate concentrated under
reduced pressure. The syrupy residue thus obtained was dis-
solved in MeOH (15 mL) and cooled to - 15 °C, and NaBH4
(1.2 mmol) was added to the solution in portions. After stirring
the reaction mixture for 2 h at room temperature, water (15
mL) was added to the reaction mixture, and the resulting so-
lution was extracted with ethyl acetate (4 × 25 mL). The com-
bined extract was washed with brine, dried over anhydrous
Na2SO4, and concentrated under vacuum. The residual liquid
was purified by column chromatography (ethyl acetate/hexane
) 1/9) affording the product. Enantiomeric purity of the pro-
ducts formed were confirmed by HPLC analysis. HPLC condi-
tions; column: CHIRALCEL (ODS); mobile phase: 90% aceto-
nitrile + 10% water; flow rate: 1 mL/min; UV detection at 225
nm.
8a : light yellow oil; 79% yield; [R]22 ) -35.9 (c ) 0.80,
D
CHCl3); IR (neat) 3453, 1736, 1688 cm-1; 1H NMR (200 MHz,
CDCl3) δ 1.39 (br s, 9H), 1.90 (m, 2H), 2.07 (s, 3H), 2.31 (br s,
1H), 2.53 (m, 4H), 2.88 (br d, J ) 7.4 Hz, 2H), 3.33 (dd, J )
4.5 and 7.7 Hz, 1H), 3.52 (m, 1H), 3.69 (br s, 4H), 4.89 (d, J )
9.4 Hz,1H), 7.21 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 174.7,
155.5, 138.3, 129.4, 128.6, 128.4, 126.7, 79.2, 68.5, 59.4, 53.7,
52.0, 50.6, 45.3, 39.1, 32.2, 30.5, 29.6, 28.3, 15.4; FABMS 427
(MH+). Anal. Calcd for C21H34N2O5S (426.57): C, 59.13; H,
8.03; N, 6.57, S, 7.52. Found: C, 59.43; H, 8.16; N, 6.93; S,
7.18.
8b: light yellow oil; 73% yield; [R]22 ) -19.8 (c ) 0.70,
D
CHCl3); IR (neat) 3440, 1752, 1692 cm-1; 1H NMR (200 MHz,
CDCl3) δ 1.36 (br s, 9H), 2.48 (m, 3H, 1H exchangeable with
D2O), 2.72 (d, J ) 6.6 Hz, 2H), 2.98 (dd, J ) 5.5 and 13.3 Hz,
2H), 3.40 (m, 2H), 3.62 (m, 1H), 3.68 (s, 3H), 4.83 (d, J ) 9.9
Hz, 1H), 7.19 (m, 10H); FABMS 443 (MH+). Anal. Calcd for
C
25H34N2O5 (442.55): C, 67.85; H, 7.74; N, 6.33. Found: C,
67.63; H, 8.07; N, 6.65.
8c: colorless oil; 72% yield; [R]22D ) -13.3 (c ) 0.73, CHCl3);
1
IR (neat) 3411, 1743, 1683 cm-1; H NMR (200 MHz, CDCl3)
7a : colorless oil; 70% yield; [R]22D ) -30.6 (c)1.10, CHCl3);
δ 1.22 (d, J ) 6.7 Hz, 3H), 1.38 (s, 9H), 2.33 (m, 1H), 2.83 (m,
2H), 3.28 (m, 2H), 3.63 (m, 2H), 3.71 (s, 3H), 3.98 (m, 1H),
4.97 (m,1H), 7.22 (m, 5H); FABMS 367 (MH+). Anal. Calcd
for C19H30N2O5 (366.45): C, 62.27; H, 8.25; N, 7.64. Found: C,
62.12; H, 8.58; N, 7.91.
1
IR (neat) 3315, 1748, 1697 cm-1; H NMR (200 MHz, CDCl3)
δ 1.52 (br s, 15H), 1.75 (m, 2H), 2.05 (s, 3H), 2.11 (br s, 1H),
2.49 (t, J ) 7.3 Hz, 2H), 2.59 (m, 3H), 3.20 (m, 2H), 3.59 (s,
3H), 3.62 (m, 1H), 3.98 (m, 1H), 7.23 (m, 5H); 13C NMR (50
MHz, CDCl3) δ 174.9, 160.0, 137.7, 129.5, 128.5, 126.6, 91.3,
80.5, 78.4, 61.8, 60.2, 51.7, 51.5, 32.6, 30.4, 28.5, 27.3, 15.3;
FABMS 467 (MH+). Anal. Calcd for C24H38N2O5S (466.63): C,
61.77; H, 8.21; N, 6.00; S, 6.87. Found: C, 61.61; H, 8.28; N,
6.38; S, 6.49.
8d : colorless oil; 74% yield; [R]22D ) -26.9 (c ) 1.20, CHCl3);
1
IR (neat) 3401, 1744, 1691 cm-1; H NMR (200 MHz, CDCl3)
δ 0.92 (br d, 6H), 1.41 (br s, 9H), 1.9 (m, 1H), 2.44 (dd, J ) 4.4
and 13.3 Hz, 1H), 2.64 (m, 1H), 2.93 (m, 2H), 3.51 (m, 1H),
3.66 (br s, 1H), 3.72 (s, 4H), 4.88 (d, J ) 9.0 Hz,1H), 7.24 (m,
5H); FABMS 395 (MH+). Anal. Calcd for C21H34N2O5
(394.25): C, 63.93; H, 8.69; N, 7.10. Found: C, 64.21; H, 8.63;
N, 7.42.
7b: colorless oil; 74% yield; [R]22D ) -12.9 (c ) 1.51, CHCl3);
1
IR (neat) 3402, 1742, 1686 cm-1; H NMR (200 MHz, CDCl3)
δ 1.49 (br s, 15H), 2.18 (br s, 1H), 2.45-2.78 (m, 2H), 2.48 (m,
2H), 3.22-3.35 (m, 2H), 3.54 (s, 3H), 3.70-3.91 (m, 2H), 3.95
(m, 1H), 7.18 (m, 10H); 13C NMR (50 MHz, CDCl3) δ 174.4,
161.0, 137.6, 137.1,129.3, 129.0, 128.3, 128.1, 126.5, 126.4,
91.8, 79.8, 78.3, 62.8, 61.5, 51.3, 39.6, 28.4, 27.1; FABMS 483
(MH+). Anal. Calcd for C28H38N2O5 (482.61): C, 69.68; H, 7.94;
N, 5.80. Found: C, 70.03; H, 8.15; N, 5.67.
8e: colorless oil; 78% yield; [R]22D ) -31.8 (c ) 2.20, CHCl3);
1
IR (neat) 3348, 1746, 1682 cm-1; H NMR (200 MHz, CDCl3)
δ 0.92 (t, J ) 6.8 Hz, 6H), 1.38 (br s, 10H), 1.69 (m, 2H), 2.43
(dd, J ) 4.0 and 12.7 Hz, 1H), 2.5-2.63 (m, 1H), 2.88 (d, J )
7.6 Hz, 2H), 3.18 (br t, J ) 7.4 Hz, 1H), 3.49 (m, 1H), 3.62 br
(s, 1H), 3.67 (s, 3H), 4.83 (d, J ) 9.3 Hz,1H), 7.23 (m, 5H);
FABMS 409 (MH+). Anal. Calcd for C22H36N2O5 (408.53): C,
64.68; H, 8.88; N, 6.86. Found: C, 64.85; H, 8.91; N, 7.07.
7c: colorless oil; 69% yield; [R]22D ) -27.8 (c ) 1.20, CHCl3);
1
IR (neat) 3353, 1751, 1692 cm-1; H NMR (200 MHz, CDCl3)
(15) Zhang, Y. L.; Shing, T. K. M. J . Org. Chem. 1997, 62, 2622.
J O001072B