Short total synthesis of aspartyl protease inhibitors L-685,434, L-682,679 and L-685,458

Article abstract of DOI:10.1055/s-2002-34891

Hydroxyethylene dipeptide isosteres L-685,434, L-682,679 and L-685,458 were synthesized in a few steps by a sequence involving an allyltrichlorostannane coupling with an α-aminoaldehyde followed by hydroboration of the corresponding 1,2-syn and 1,2-anti a

Full text of DOI:10.1055/s-2002-34891

LETTER
1845
Short Total Synthesis of Aspartyl Protease Inhibitors L-685,434, L-682,679
and L-685,458
S
hor
t
Total Syn
u
thesis of
A
sp
i
artyl
P
z
rotease
I
nhibitorsC. Dias,* Andrea A. Ferreira, Gaspar Diaz
Instituto de Química, Universidade Estadual de Campinas/UNICAMP, C.P. 6154, CEP: 13083-970, Campinas, SP, Brazil
Fax +55(19)37883023; E-mail: ldias@iqm.unicamp.br
Received 30 August 2002
This paper is dedicated to the Brazilian Chemical Society (SBQ).
and selective inhibitor of HIV-1 protease (IC50 = 0.42 nM,
Abstract: Hydroxyethylene dipeptide isosteres L-685,434, L-
Figure 1).10
682,679 and L-685,458 were synthesized in a few steps by a se-
quence involving an allyltrichlorostannane coupling with an -ami-
noaldehyde followed by hydroboration of the corresponding 1,2-
syn and 1,2-anti aminoalcohols to give the diols, lactonization under
TPAP conditions, lactone opening and peptide coupling with the
desired amine or dipeptide amide.
Inhibitor L-685,458 (3) is a potent inhibitor of -secretase
(IC50 = 17 nM) and is of potential therapeutic benefit in
the treatment of Alzheimer’s disease and other neurologi-
cal disorders (Figure 1).11–18 Attracted by the HIV inhibi-
tory potency of 1 and 2 as well as by the highly potent
inhibition of A PP -secretase activity of L-685,458 (3),
we initiated a project directed towards their total syn-
thesis. The approach described here to L-685,434 (1),
L-682,679 (2) and L-685,458 (3) might also give access
to additional derivatives with potential relevance for bio-
logical evaluation.
Key words: amino aldehydes, HIV, peptides, total synthesis,
lactones
The acquired immunodeficiency syndrome (AIDS) re-
mains a serious public problem, especially in the develop-
ing world where it has now reached tragic dimensions and
treatment is affordable only for a small percentage of in-
fected people.1–3 Success in the development of HIV-Pr
inhibitors as drugs was based upon early recognition of
the central role of this enzyme in viral maturation and an
intensive effort toward gaining an understanding of its
structure and function.4,5 L-685,434 (1), a potent HIV-1
protease inhibitor (IC50 = 0.23 nM) containing 1-(S)-ami-
no-2-(R)-hydroxyindan P2 ligand, was found to block the
spread of HIV-1 in T-lymphoid cells (Figure 1).6–9 The
pseudo pentapeptide L-682,679 (2) is also a highly potent
We recently communicated that allylsilanes react with N-
Boc- -aminoaldehydes in the presence of SnCl4 to give
1,2-syn N-Boc- -aminoalcohols that are key intermedi-
ates for the preparation of hydroxyethylene dipeptide
isosteres.19–23 The stereoselectivity of these tin(IV) chlor-
ide-promoted reactions is consistent with a mechanism in-
volving transmetallation of the allylsilanes to give an
intermediate allyltintrichloride.21 Our approach to aspar-
tyl protease inhibitors 1, 2 and 3 began with N-Boc-phe-
nyl-alaninal 4, a very useful synthetic intermediate, that
OH
O
OH
OH
H
H
N
NH2
N
N
H
NHBoc
O
O
NHBoc
O
Me
1
L-682,679
L-685,434
IC50= 0,23 nM
2
Me
IC50= 0.42 nM
OH
O
H
N
NH2
N
H
L-685,458
NHBoc
O
O
IC50= 17 nM
Me
3
Me
Figure 1 Chemical structures of the aspartyl protease inhibitors L-685,434, L-682,679 and L-685,458
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1845,1849,ftx,en;D17602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1846
L. C. Dias et al.
LETTER
O
CH2Cl2, –78 °C
96%
H
+
Cl3Sn
4
NHBoc
5
OH
Me
BocN
Me
O
Me2C(OMe)2
6
p-TsOH, 91%
NHBoc
diastereoselection = 95:05
25 °C
Ha Hb
7
Scheme 1 Coupling between aldehyde 4 and allyltrichlorostannane 5
could be easily prepared from -phenylalanine ethyl ester Attempts to obtain more of the desired trans-lactone 10 by
by Boc protection followed by DIBALH reduction.24–26 a deprotonation and reprotonation sequence of cis-lactone
Addition of the aldehyde 4 to a CH2Cl2 solution of allyl- 11 led to a 70:30 mixture of lactones 10:11 in good yields
trichlorostannane 5 at _78 °C gave the 1,2-syn aminoalco- (Scheme 2).9
hol 6 in 96% yield and 95:5 diastereoselectivity
Basic hydrolysis of desired trans-lactone 10, silylation of
(Scheme 1).22,23,27 In order to prove the relative stere-
the resulting carboxylate, and selective desilylation of the
ochemistry, the next step involved treatment of aminoal-
cohol 6 with Me2C(OMe)2 in the presence of catalytic
amounts of p-TsOH to give trans-oxazolidine 7 in 91%
yield after purification by SiO2 column chromatography
(Scheme 1).22
acylsiloxy moiety cleanly provided 12 in excellent yield
(Scheme 3).
TBS
O
The observed coupling constant (JHa/Hb = 4.0 Hz, upon ir-
radiation of the hydrogens adjacent to Ha and Hb) indicat-
ed that hydrogens Ha and Hb are on opposite faces of the
heterocyclic ring and, therefore, the oxazolidine is derived
from 1,2-syn adduct (Scheme 1).22,26
O
O
1. LiOH, DME
OH
2. i.TBSCl, DMF
imidazole
10
NHBoc
NHBoc
O
ii. MeOH, 94%
12
1. HOBt, DCC
NaHCO3
The double bond in homoallylic alcohol 6 was oxidatively
hydroborated at 0 °C with BH3 DMS to give diols 8 and 9
as a 56:44 mixture, respectively, in 93% overall yield
(Scheme 2).27 After treatment with TPAP and NMO in
CH2Cl2 at room temperature these diols were smoothly
converted to trans- and cis-lactones, 10 (51%) and 11
(43%), respectively, which were separated by flash chro-
matography on silica gel.9,28,29
HO
13
= °C– rt
H2N
2. TBAF, THF, 25 °C
70% (2 steps)
OH
OH
H
N
NHBoc
O
1
L-685,434
OH
OH
Scheme 3 Synthesis of L-685,434 (1)
NHBoc
OH
8
9
This carboxylic acid, prepared in only 4 steps from 6, is a
versatile intermediate for the introduction of different
functional groups in intermediates aiming at the synthesis
of hydroxyethylene isosteres. Compound L-685,434 (1) is
readily prepared from 12 by a simple peptide coupling re-
action with 1(S)-amino-2(R)-hydroxyindan 13, followed
by TBS removal with TBAF, in 70% yield for the two-
step sequence (Scheme 3).33
OH
BH3 DMS
+
OH
THF, 0 °C
93%
NHBoc
6
NHBoc
O
O
1. NaHMDS
THF, –78 °C
2. NH4Claq.
97%
TPAP, NMO
25 °C
NHBoc
O
10 (51%)
In order to prepare inhibitors 2 and 3 we first obtained
dipeptide amide NH2Leu-PheNH2 17 (Scheme 4). N-Boc
protection of -phenylalanine, peptidic type coupling
with a 25% solution of ammonium hydroxide followed by
Boc deprotection with MeOH/CH3COCl gave amide 15 in
50% overall yield.
O
+
ratio 10:11 = 70:30
11 (43%)
NHBoc
separated by SiO2 column chromatography
Scheme 2 Hydroboration of homoallylic alcohol 6 followed by
lactonization
Synlett 2002, No. 11, 1845–1849 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Short Total Synthesis of Aspartyl Protease Inhibitors
1847
A sequence of Dess–Martin30 oxidation of 6 at 0 °C fol-
lowed by LiBH4 reduction of the intermediate aminoke-
tone in THF at –50 °C gave the desired 1,2-anti
homoallylic alcohol 18 in 76% yield (94:6 diastereoselec-
tivity) for the two-step sequence (Scheme 6). Direct hy-
droboration of 1,2-anti homoallylic alcohol 18 with
BH3 DMS gave a 50:50 mixture of diols 19:20 in 95%
overall yield (Scheme 6). These diols were not separated
but were converted directly to a mixture of lactones 21
and 22 by treatment with TPAP and NMO in the presence
of molecular sieves at room temperature.31
1. (Boc)2O, NaHCO3
MeOH
O
O
NH2
OH
2. HOBt, EDC
DMF, NH4OH
3. MeOH, CH3COCl
NH2
NH2
15
14
50% overall yield
O
BocHN
OH
Me
16
O
Me
H2N
N
NH2
H
After separation by SiO2 column chromatography, a two-
step sequence involving the desired cis-lactone 21 open-
ing with lithium hydroxide (5 equiv) in aqueous 1,2-
dimethoxyethane, treatment of the resulting carboxylate
with TBSCl and imidazole, in DMF at room temperature,
followed by MeOH, gave the desired TBS-protected acid
23 in 74% overall yield (Scheme 7).18 Compound 3 is pre-
pared in 75% yield (2 steps) from 23 and NH2Leu-
PheNH2 17 by a peptide coupling reaction followed by
deprotection of the resulting silyl ether with TBAF in
THF at room temperature.18,32,33
1. HOBt, DCC
NaHCO3
O
Me
17
Me
CH2Cl2
2. MeOH, CH3COCl
85% (2 steps)
Scheme 4 Preparation of NH2Leu-PheNH2 17
Peptidic coupling between carboxylic acid 16 and amide
15 followed by Boc deprotection gave NH2Leu-PheNH2
17 in 85% yield overall yield (Scheme 4). Compound L-
682,679 (2) is prepared from carboxylic acid 12 by a sim-
ple peptide coupling reaction with NH2Leu-PheNH2 17
followed by TBS deprotection with TBAF, in 76% overall
yield (Scheme 5).33
This convergent asymmetric approach to aspartyl pro-
tease inhibitors L-685,434 (1), L-682,679 (2) and L-
685,458 (3) relies on the use of aminoalcohol 6 as a key
intermediate. The route described here might easily pro-
vide access to additional analogues with potential rele-
vance in biological studies. Further optimization of these
syntheses, especially in order to improve the selectivity in
Our approach to the synthesis of L-685-458 (3) is based
on the use of the corresponding 1,2-anti aminoalcohol 18.
1. HOBt, EDC
DMF, Et3N
TBS
OH
O
O
N
H
NH2
OH H2N-Leu-Phe-NH2 (17)
N
H
NHBoc
O
O
NHBoc
O
Me
2. TBAF, THF, 25 °C
76% (2-steps)
L-682,679
2
12
Me
Scheme 5 Synthesis of L-682,679 (2)
1. Dess-Martin
CH2Cl2, 0 °C
OH
OH
2. LiBH4
THF, –50 °C
18
6
NHBoc
NHBoc
76% (2 steps)
diastereoselection = 94:06
OH
OH
OH
OH
BH3 DMS
THF, 95%
+
20
19
NHBoc
NHBoc
ratio 19:20 = 50:50
O
O
O
O
+
TPAP, NMO
25 °C
NHBoc
21 (45%)
NHBoc
22 (47%)
separated by SiO2 column chromatography
Scheme 6 Preparation of cis-lactone 21
Synlett 2002, No. 11, 1845–1849 ISSN 0936-5214 © Thieme Stuttgart · New York

1848
L. C. Dias et al.
LETTER
O
TBS
1. LiOH, DME
O
O
OH
2.i.TBSCl, DMF
imidazole
ii. MeOH, 74%
NHBoc
21
NHBoc
23
O
1.HOBt, EDC
DMF, Et3N
OH
O
H
N
NH2
H2NLeu-PheNH2
N
H
Me
NHBoc
O
O
17
2. TBAF, THF, 25 °C
75% (2 stps)
3
L-685,458
Me
Scheme 7 Synthesis of L-685,458 (3)
Nunberg, J.; Springer, J. P.; Huff, J. R. J. Med. Chem. 1992,
35, 1685.
the hydroboration reactions from aminoalcohols 6 and 18
to diols 8 and 19, respectively, as well as the direct trans-
formation from 2 to 3 by an oxidation/reduction sequence
is underway, and the results will be described in a full
account of this work.
(10) For synthesis of analogues of L-682,679, see: deSolms, S. J.;
Giuliani, E. A.; Guare, J. P.; Vacca, J. P.; Sanders, W. M.;
Graham, S. L.; Wiggins, J. M.; Darke, P. L.; Sigal, I. S.;
Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Quintero, J. C.;
Anderson, P. S.; Huff, J. R. J. Med. Chem. 1991, 34, 2852.
(11) Evans, J. Chem. Brit. 2001, April, 47.
(12) Pesti, J. A.; Chorvat, R. J.; Huhn, G. F. Chem. Innovation
2000, October, 29.
(13) de Clerq, E. Pure Appl. Chem. 2001, 73, 55.
(14) Ghosh, A. K.; Shin, D.; Mathivanan, P. Chem. Commun.
1999, 1025.
Acknowledgement
We are grateful to FAPESP and CNPq for financial support. We
thank also Prof. Carol H. Collins, from IQ-UNICAMP, for helpful
suggestions about English grammar and style.
(15) Li, Y. M.; Xu, M.; Lai, M. T.; Huang, Q.; Castro, J. L.;
DiMuzio-Mower, J.; Harrison, T.; Lellis, C.; Nadin, A.;
Neduvelil, J. G.; Register, R. B.; Sardana, M. K.; Shearman,
M. S.; Smith, A. L.; Shi, X. P.; Yin, K. C.; Shafer, J. A.;
Gardell, S. J. Nature (London) 2000, 405, 689.
(16) Li, Y. M.; Lai, M. T.; Xu, M.; Huang, Q.; DiMuzio-Mower,
J.; Sardana, M. K.; Shi, X. P.; Yin, K. C.; Shafer, J. A.;
Gardell, S. J. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 6138.
(17) Shearman, M. S.; Beher, D.; Clarke, E. E.; Lewis, H. D.;
Harrison, T.; Hunt, P.; Nadin, A.; Smith, A. L.; Stevenson,
G.; Castro, J. L. Biochemistry 2000, 39, 8698.
(18) Nadin, A.; López, J. M. S.; Neduvelil, J. G.; Thomas, S. R.
Tetrahedron 2001, 57, 1861.
(19) Dias, L. C.; Giacomini, R. J. Braz. Chem. Soc. 1998, 9, 357.
(20) Dias, L. C.; Giacomini, R. Tetrahedron Lett. 1998, 39, 5343.
(21) Dias, L. C.; Meira, P. R. R.; Ferreira, E. Org. Lett. 1999, 1,
1335.
(22) Dias, L. C.; Meira, P. R. R. Synlett 2000, 37.
(23) Dias, L. C.; Ferreira, E. Tetrahedron Lett. 2001, 42, 7159.
(24) (a) Fehrentz, J. A.; Castro, B. Synthesis 1983, 676.
(b) Saari, W. S.; Fisher, T. E. Synthesis 1990, 453.
(25) For optical stability studies of N-protected -amino
aldehydes, see: (a) Jurczak, J.; Golebiowski, A. Chem. Rev.
1989, 89, 149. (b) Myers, A. G.; Zhong, B. Y.; Movassaghi,
M.; Kung, D. W.; Lanman, B. A.; Kwon, S. Tetrahedron
Lett. 2000, 41, 1359.
(26) Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.;
Zlatoidzky, P. J. Org. Chem. 1997, 62, 9348.
(27) (a) D’Aniello, F.; Mann, A.; Mattii, D.; Taddei, M. J. Org.
Chem. 1994, 59, 3762. (b) Ciapetti, P.; Falorni, M.; Taddei,
M. Tetrahedron 1996, 52, 7379.
References
(1) (a) Vacca, J. P.; Condra, J. H. Drug Discovery Today 1997,
2, 261. (b) Steele, F. R. Nature Med. 1996, 2, 257.
(2) Wlodawer, A.; Vondrasek, J. Annu. Rev. Biophys. Biomol.
Struct. 1998, 27, 249.
(3) Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359.
(4) Tomasselli, A. G.; Heinrikson, R. L. Biochim. Biophys. Acta
2000, 189.
(5) For comparative quantitative structure-activity relationship
studies on anti-HIV drugs, see: Garg, R.; Gupta, S. P.; Gao,
H.; Babu, M. S.; Debnath, A. K.; Hansch, C. Chem. Rev.
1999, 99, 3525.
(6) Lyle, T. A.; Wiscount, C. M.; Guare, J. P.; Thompson, W. J.;
Anderson, P. S.; Darke, P. L.; Zugay, J. A.; Emini, E. A.;
Schleif, W. A.; Quintero, J. C.; Dixion, R. A. F.; Sigal, I. S.;
Huff, J. R. J. Med. Chem. 1991, 34, 1228.
(7) Panchagnula, R.; Thomas, N. S. Int. J. Pharm. 2000, 201,
131.
(8) For the synthesis of analogues of L-685,434, see: (a)Litera,
J.; Budesinsky, M.; Urban, J.; Soucek, M. Collect. Czech.
Chem. Commun. 1998, 63, 231. (b) Litera, J.; Weber, J.;
Krizova, I.; Pichova, I.; Konvaluka, J.; Fusek, M.; Soucek,
M. Collect. Czech. Chem. Commun. 1998, 63, 541.
(c) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J.
P.; Hirshfield, J.; Veber, D. F. J. Org. Chem. 1985, 50, 4615.
(9) (a) cis-Lactone 11 is also an important intermediate for the
synthesis of potent HIV-1 protease inhibitors: Ghosh, A. K.;
McKee, S. P.; Thompson, W. J.; Darke, P. L.; Zugay, J. C. J.
Org. Chem. 1993, 58, 1025. (b) Thompson, W. J.;
Fitzgerald, P. M. D.; Holloway, M. K.; Emini, E. A.; Darke,
P. L.; McKeever, B. M.; Schleif, W. A.; Quintero, J. C.;
Zugay, J. A.; Tucker, T. J.; Schwering, J. E.; Homnick, C. F.;
(28) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
Synlett 2002, No. 11, 1845–1849 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Short Total Synthesis of Aspartyl Protease Inhibitors
1849
(29) For other synthesis of these lactones, see: (a) Ghosh, A. K.;
Fidanze, S. J. Org. Chem. 1998, 63, 6146. (b) Pégorier, L.;
Larchevêque, M. Tetrahedron Lett. 1995, 36, 2753; see also
ref. 9a.
(30) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58,
2899.
(31) Hoffman, R. V.; Maslouch, N.; Cervantes-Lee, F. J. Org.
Chem. 2002, 67, 1045.
(32) New compounds and the additional isolatable intermediates
gave satisfactory 1H and 13C NMR, IR, HRMS and analytical
data. Yields refer to chromatographically and
1273, 1250, 1172, 1080, 743, 698 cm–1. 1H NMR (500 MHz,
DMSO): = 0.77 (d, J = 6.4 Hz, 3 H), 0.84 (d, J = 6.4 Hz,
3 H), 1.28 (s, 9 H), 1.20–1.35 (m, 2 H), 1.49 (m, 1 H), 1.60
(m, 2 H), 2.45 (dd, J = 8.2, 13.4 Hz, 1 H), 2.53 (dd, J = 9.5,
13.7 Hz, 1 H), 2.70 (dd, J = 5.0, 13.6 Hz, 1 H), 2.78–2.87 (m,
3 H), 3.00 (dd, J = 5.2, 3.7 Hz, 1 H), 3.51–3.57 (m, 1 H), 4.21
(q, J = 6.7 Hz, 1 H), 4.42 (q, J = 5.5 Hz, 1 H), 4.48 (d, J = 6.1
Hz, 1 H), 6.36 (d, J = 9.0 Hz, 1 H), 7.09 (brs, 1 H), 7.12–7.25
(m, 15 H), 7.34 (brs, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.93 (d,
J = 8.0 Hz, 1 H). 13C NMR (125 MHz, DMSO): = 23.1,
24.2, 28.0, 28.4, 35.1, 36.3, 37.7, 38.9, 40.9, 43.7, 51.5, 53.5,
56.5, 69.4, 77.6, 125.9, 126.0, 126.4, 128.1, 128.2, 128.3,
129.1, 129.2, 129.4, 137.9, 139.8, 140.0, 155.5, 171.8,
172.8, 174.7. TLC: Rf = 0.18 (70% EtOAc:hexanes).
L-685,458(3): {(1S)-benzyl-(4R)-[1-((1S)-carbamoyl-2-
phenyl-ethylcarbamoyl)-(1S)-3-methyl-butyl-carba-
spectroscopically homogeneous materials.
(33) L-685,434(1): N-[(2R)-Hydroxy-(1S)-indanyl]-(5S)-
{[tert-butoxycarbonyl]-amino-(4S)-hydroxy-6-phenyl-
(2R)-benzyl}-hexanamide: IR (KBr) 3447, 3365, 3061,
3022, 2917, 2849, 1665, 1645, 1537, 1392, 1278, 1158,
1058, 899, 862, 733, 703, 649 cm–1. 1H NMR (500 MHz,
DMSO): = 1.37 (s, 9 H), 1.80–1.96 (m, 2 H), 2.72–2.95 (m,
6 H), 3.02 (dd, J = 5.1, 16.8 Hz, 1 H), 3.45 (m, 1 H), 3.68 (m,
1 H), 3.81 (m, 1 H), 4.22 (t, J = 4.8 Hz, 1 H), 4.81 (d, J = 9.5
Hz, 1 H), 5.23 (dd, J = 6.1, 8.4 Hz, 1 H), 5.87 (d, J = 8.4 Hz,
1 H), 7.05 (brs, 1 H), 7.05–7.30 (m, 14 H). 13C NMR (125
MHz, DMSO): = 28.5, 37.5, 39.0, 39.1, 39.6, 47.1, 57.4,
57.6, 69.3, 73.1, 79.6, 124.1, 125.1, 126.4, 126.5, 127.0,
128.0, 128.4, 128.5, 129.0, 129.3, 138.4, 139.8, 140.1,
140.3, 156.2, 175.4. TLC: Rf = 0.21 (60% EtOAc:hexanes).
L-682,679(2): {(1S)-benzyl-4R-[1-((1S)-carbamoyl-2-
phenyl-ethylcarbamoyl)-(1S)-3-methyl-butyl-
moyl]-(2R)-hydroxy-5-phenyl-pentyl} Carbamic Acid
25
tert-Butyl Ester: White solid. Mp 212–213 °C. [ ]D
=
–26.8 (c 0.5, CHCl3). IR (KBr): 3375, 3338, 3197, 2960,
2930, 2872, 2856, 1666, 1647, 16231, 1535, 1451, 13675,
1271, 1251, 1174, 1086, 743, 698 cm–1. 1H NMR (500 MHz,
DMSO): = 0.74 (d, J = 6.6 Hz, 3 H), 0.81 (d, J = 6.6 Hz,
3 H), 1.24 (s, 9 H), 1.25–1.40 (m, 2 H), 144–1.70 (m, 3 H),
2.40–3.00 (m, 7 H), 3.42 (m, 2 H), 4.16 (m, 1 H), 4.40 (m,
1 H), 4.70 (brs, 1 H), 6.48 (d, J = 9.0 Hz, 1 H), 7.05–7.27
(m, 17 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1
H). 13C NMR (125 MHz, DMSO): = 23.9, 25.4, 26.1, 30.4,
37.6, 38.0, 39.8, 39.9, 42.8, 46.6, 53.7, 55.8, 58.9, 73.5, 79.7,
127.9, 128.0, 128.6, 130.0, 130.2, 130.4, 131.1, 131.4,
140.0, 142.0, 142.3, 157.4, 174.0, 174.8, 175.2. TLC:
Rf = 0.21 (60% EtOAc:hexanes).
carbamoyl]-(2S)-hydroxy-5-phenyl-pentyl} Carbamic
Acid tert-Butyl Ester: IR (KBr) 3377, 3341, 3190, 2955,
2924, 2872, 2853, 1667, 1649, 1621, 1531, 1451, 1365,
Synlett 2002, No. 11, 1845–1849 ISSN 0936-5214 © Thieme Stuttgart · New York