Allyltrichlorostannane additions to α-amino aldehydes: Application to the total synthesis of the aspartyl protease inhibitors L-682,679, L-684,414, L-685,434, and L-685,458

Article abstract of DOI:10.1055/s-2003-37649

The hydroxyethylene dipeptide isosteres L-682,679, L-684,414, L-685,434, and L-685,458 were synthesized in a few steps by a sequence involving an allyltrichlorostannane coupling with an α-amino aldehyde, followed by hydroboration of the corresponding 1,2-

Full text of DOI:10.1055/s-2003-37649

FEATURE ARTICLE
603
Allyltrichlorostannane Additions to -Amino Aldehydes: Application to the
Total Synthesis of the Aspartyl Protease Inhibitors L-682,679, L-684,414,
L-685,434, and L-685,458
Total
Synthesis
u
of
A
spartyl
P
roteas
z
e
Inhibitors C. Dias,* Gaspar Diaz, Andrea A. Ferreira, Paulo R. R. Meira, Edílson Ferreira
Instituto de Química - Universidade Estadual de Campinas, UNICAMP, C.P. 6154, 13084-971, Campinas, SP, Brazil
Fax +55(193)7883023; E-mail: ldias@iqm.unicamp.br
Received 16 October 2002
This paper is dedicated to Prof. Albert Kascheres on the occasion of his 60th birthday and also to the Brazilian Chemical Society (SBQ).
rovirus family Retroviriadae, whose genome is encoded
Abstract: The hydroxyethylene dipeptide isosteres L-682,679, L-
in RNA. Success in the development of HIV-Protease in-
684,414, L-685,434, and L-685,458 were synthesized in a few steps
hibitors as drugs was based upon early recognition of the
central role of this enzyme in viral maturation and an in-
by a sequence involving an allyltrichlorostannane coupling with an
α-amino aldehyde, followed by hydroboration of the corresponding
1,2-syn and 1,2-anti amino alcohols to give the diols, lactonization tensive effort toward gaining an understanding of its
structure and function.1–7 L-685,434 (1) is a potent HIV-1
protease inhibitor (IC50 = 0.23 nM) containing (1S,2R)-1-
under TPAP conditions, lactone opening, and peptide coupling with
the desired amine or dipeptide amide. The present synthetic ap-
proach represents a practical entry to a large range of other dipep-
amino-2-hydroxyindan P2′ ligand (Figure 2).8,9 This in-
tide isosteres.
hibitor was found to block the spread of HIV-1 in T-lym-
phoid cells, being a highly potent and selective HIV
protease inhibitor.
Key words: amino aldehydes, HIV, peptides, total synthesis, lac-
tones
The pseudo pentapeptide L-682,679 (2) is a highly potent
and selective inhibitor of HIV-1 protease (IC50 = 0.42 nM,
Figure 2).10 Structural manipulations of various portions
of this molecule provided compounds with enhanced po-
tency, selectivity, and solubility.
Introduction
In the last several years there have been major research ef-
forts towards the development of clinically useful inhibi-
tors of aspartyl proteases.1–7 This worldwide search has
led to various peptide isosteres, wherein the scissile pep-
tide bond is replaced by a hydrolytically more stable isos-
teric functional group. In this context, the hydroxy amino
acid framework B (Figure 1), where the peptide linkage of
the sequence in structure A is replaced by a CH(OH)CH2
group, constitutes a useful class of aspartyl protease inhib-
itors.1–7
-Secretase Inhibitors
Alzheimer’s disease (AD), a physical disease which at-
tacks brain cells, nerves and transmitters, is the most com-
mon cause of dementia.11–15 New drugs are being
developed which seek to slow down the rate of mental de-
cline, but they are promising only in the early stages of the
disease. β-Secretase inhibitors are already under develop-
ment and inhibition of amyloid β-peptide (Aβ) production
is the desired goal. Compounds that would inhibit either
β- or γ-secretase could potentially block Aβ production
and be useful in treating Alzheimer’s disease.11–15 L-
685,458 (3) is a potent inhibitor of γ-secretase
(IC50 = 17nM) and is of potential therapeutic benefit in the
treatment of Alzheimer’s disease and other neurological
disorders (Figure 2).16–18 This compound, originally de-
veloped as an HIV protease inhibitor, was found to be a
poor inhibitor of HIV protease, but a potent inhibitor of γ-
secretase. L-685,458 (3) is a novel inhibitor of AβPP-γ-
secretase activity, with a similar potency for inhibition of
Aβ(42) and Aβ(40) peptides. Elevated levels of Aβ(42)
peptide formation have been linked to early onset of fa-
miliar AD-causing gene mutations in the amyloid β-pro-
tein precursor (AβPP) and the presenilins. Sequential
cleavage of AβPP by β- and γ-secretase generates the N-
and C- termini of the Aβ peptide, making both the β- and
γ-secretase enzymes potential therapeutic targets for
AD.16–18 L-685,458 (3) contains a hydroxyethylene dipep-
tide isostere that should serve as a transition state
Figure 1 Core units of HIV protease inhibitors
HIV-1 Protease Inhibitors
The acquired immunodeficiency syndrome (AIDS) re-
mains a serious public problem, especially in developing
countries where it has now reached tragic dimensions and
treatment is affordable only for a small percentage of in-
fected people. The HIV virus, the causative agent of
AIDS, is a highly mutable lentivirus, a member of the ret-
Synthesis 2003, No. 4, Print: 18 03 2003.
Art Id.1437-210X,E;2003,0,04,0603,0622,ftx,en;M04502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

604
L. C. Dias et al.
FEATURE ARTICLE
Biographical Sketches
logically important compounds
like HIV-1 inhibitors, immunos-
suppressant agents, plant toxins,
herpes virus inhibitors, antibiot-
ics, antitumor agents and neu-
rotransmitters are being devel-
oped in his laboratory.
In 1999, Prof. Dias received the
Journal of the Brazilian Chemi-
cal Society Medal (http://
jbcs.sbq.org.br/) and since 2000
he is the General Secretary of the
Brazilian Chemical Society
(SBQ). Most of the rest of his
time is spent with his wife Luci-
ana and two daughters, Luana
and Luiza.
Luiz Carlos Dias was born in
1964, in Balneário Camboriú, SC
(Brazil). He received his under-
graduate degree from the Federal
University of Santa Catarina
(UFSC), Florianópolis, SC, in
1988. He received his PhD, in
1993 with a thesis on alkaloid
chemistry developed under the
supervision of Prof. R. A. Pilli, at
the State University of Campinas
(UNICAMP). In 1992 he joined
the faculty at the Department of
Chemistry at UNICAMP as an
Instructor. In 1993 he was pro-
moted to Assistant Professor and
in 1999 to Associate Professor.
He spent two years as a postdoc-
toral fellow with Prof. David A.
Evans at Harvard University,
USA (1994–1995) where he
worked on the total synthesis of
spongistatin A.
His research interests lie in the
study of the control elements that
influence the stereochemical out-
come of double stereodifferenti-
ating chiral allylsilane, allyl-
stannane and methyl ketone ad-
ditions to chiral aldehydes and
imines. These methodological
studies are being applied to the
asymmetric synthesis of a wide
variety of important natural and
synthetic products of biological
significance. Short, efficient and
flexible synthetic routes to bio-
(Further informations: http://pc-
server.iqm.unicamp.br/~ldias)
Gaspar Diaz Muñoz was born
in 1964 in Iquitos (Peru) and re-
ceived his undergraduate degree
in chemical engineering in 1989
from the National University of
Peruvian Amazon (UNAP). He
then moved to Brazil and ob-
tained his Masters degree in
1997 at the Federal University of
Pará (UFPA) under the supervi-
sion of Prof. Alberto C. Arruda.
He obtained a PhD in chemistry
from the State University of
Campinas (UNICAMP) in 2001,
under the supervision of Prof.
Fernando A. S. Coelho, working
on the synthesis of (+/-)-Pathy-
lactone A, a nor-sesquiterpene
lactone isolated from marine
sources. In 2002 he joined the re-
search group of Prof. Dias as a
postdoctoral fellow. Gaspar now
resides with his wife Marisa, and
their son Flávio, in Cascavel,
(Brazil).
Andréa A. Ferreira was born in
1975 in São Paulo, SP (Brazil)
and received her undergraduate
degree in chemistry at the State
University of Campinas (UNI-
CAMP) in 1998. As an under-
graduate she carried out research
in the group of Prof. Dias and
then obtained her Masters de-
gree, in 2002, from the State Uni-
versity of Campinas under the
supervision of Prof. Dias. An-
drea and her husband, Wagner,
are now expecting their first
daughter, Beatriz, which should
be born in March, 2003.
Paulo R. R. Meira was born in
1966 in Goiânia, GO (Brazil) and
obtained a Bachelor’s degree in
chemistry at the Federal Univer-
sity of Goiás (1993). In 1997,
Paulo and his wife Gêmia,
moved to Campinas and Paulo
joined the research group of Prof.
Dias at the State University of
Campinas (UNICAMP). He fin-
ished his Masters degree in 1999
and he is currently pursuing his
PhD under the direction of Prof.
Dias. His research focuses on
studies towards the total synthe-
sis of callystatin A, a potent anti-
tumor polyketide isolated from
the marine sponge Callyspongia
truncata.
Edílson Ferreira was born in
1974 in Elói Mendes, MG (Bra-
zil) and obtained his undergradu-
ate degree in chemistry at the
State University of Campinas
(UNICAMP) in 1998. As an un-
dergraduate student he joined the
research group of Prof. Dias at
the State University of Campinas
and finished his Masters degree
in 2001. Edílson now resides
with his wife Adriana and their
son Davi, in Elói Mendes, MG.
He is currently teaching organic
chemistry at the University of
Alfenas (UNIFENAS) and cen-
tro Universitário do Sul de Minas
(UNIS), Minas Gerais State, Bra-
zil.
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FEATURE ARTICLE
Total Synthesis of Aspartyl Protease Inhibitors
605
analogue mimic to direct the inhibitor to the active site of
an aspartyl protease target (Figure 2). L-684,414 (4), the
ketone derivative, was also found to be active (IC50 = 181
nM) but less so than L-685,458 (3), as expected if the hy-
droxyethylene dipeptide is serving as a transition state
mimic. The observations that the inhibitory potency of L-
685,458 (3) is sensitive to the configuration of the hydrox-
ylic carbon atom and that the substrate analogue L-
682,679 (2) is processed by γ-secretase (IC50 >10000 nM)
and binds to the enzyme much less tightly than L-685,458
(3) provide strong evidence that L-685,458 (3) is an active
site directed transition state analogue inhibitor for an as-
partyl protease. This supports the conclusion that γ-secre-
tase is an aspartyl protease and agrees with previous
studies showing that other aspartyl protease transition
state analogues inhibit γ-secretase activity in cells.11–18
1. TMSCH2MgCl
CeCl3, THF
-78 0C
TMS
O
MeO
2. Amberlyst 15
n-hexane, 97%
5
6
1. TMSCH2MgCl
CeCl3, THF
-78 0C
TMS
O
OBn
OBn
MeO
2. SiO2
n-hexane, 93%
7
Me
8
Me
Scheme 1 Preparation of allylsilanes 6 and 8
The next step involved a spectroscopic study (1H, 13C, and
119Sn NMR) of the reactions of allylsilanes 6, 8 and 9 with
SnCl4 (Scheme 2). Allylsilanes 6, 8 and 9 and SnCl4 (0.5
M solution in CDCl3) were mixed in order to promote
ligand exchange, leading to the corresponding allyl-
trichlorostannanes.22 For allyltrimethylsilane (9) (0.5 M in
CDCl3) the ligand exchange producing allyltrichlorostan-
nane (10) and Me3SiCl is complete after 120 minutes at
room temperature (Scheme 2). For allylsilane 6 (0.5 M in
CDCl3) the metathesis to give 11 and Me3SiCl is faster, as
expected for a 1,1-disubstituted olefin, being complete af-
ter 60 minutes at room temperature.22 Upon addition of
SnCl4 to a solution of chiral allylsilane 8 in CDCl3, at
–60 °C, as well as at 25 °C, a slightly yellow homoge-
neous solution was obtained. The resulting NMR spectra
at –60 °C showed the formation of Me3SiCl and complete
consumption of the allylsilane 8 within 1 minute to give
allyltrichlorostannane 12. It appears that the oxygen func-
tionality is responsible for the rapid ligand exchange reac-
tion observed even at low temperatures for this particular
allylsilane and SnCl4. The ligand exchange reaction is
probably facilitated by coordination of tin to this oxygen
followed by cleavage of the carbon–silicon bond by a free
chloride ion.
Based on our initial results on allyltrichlorostannane addi-
tions to N-Boc-α-amino aldehydes and attracted by the
highly potent inhibition of AβPP γ-secretase activity of L-
685,458 (3), as well as by the HIV inhibitory potency of
1, 2 and 4, we initiated a project directed towards their to-
tal synthesis. An efficient and flexible synthesis is essen-
tial to provide material for more extensive biological
studies, along with access to novel analogues. The ap-
proach described here to L685,434 (1), L-682,679 (2), L-
685,458 (3), and L-684,414 (4) might also give access to
additional derivatives with potential relevance for biolog-
ical evaluation.
Results and Discussion
Allylsilane Additions to N-Boc- -amino Aldehydes
We began this work a few years ago, and observed that al-
lylsilanes react with N-Boc-α-amino aldehydes in the
presence of SnCl4 to give 1,2-syn N-Boc-α-amino alco-
hols that are key intermediates (molecules of type C,
Figure 1) for the preparation of hydroxyethylene dipep-
tide isosteres.19–25 We have also reported the first success-
ful examples of allylsilane additions to chiral dipeptide
aldehydes.24 This synthetic methodology allows com-
pounds with programmed variations of substituents to be
synthesized and is particularly important in the screening
of the pharmacological activity and in the study of struc-
ture-activity relationships directed toward the design of
the best substituents for positions 1 and 4 in structure C
(R1 and R groups, Figure 1).
TMS
SnCl4
Cl3Sn
+
Me3SiCl
10
9
CH2Cl2, 25oC
120 min.
TMS
SnCl4
Cl3Sn
+
Me3SiCl
Me3SiCl
CH2Cl2, 25oC
60 min.
6
11
Cl
Cl
Cl
TMS
SnCl4
Sn
OBn
OBn
In order to prepare these allylsilanes, the cerium reagent
generated from cerium(III) chloride and trimethylsilylm-
ethylmagnesium chloride was reacted with methyl ester 5
to give an intermediate bis(trimethylsilylmethyl)carbinol
which, after treatment with amberlyst 15® in n-hexane,
gave allylsilane 6 in 97% yield for the two-step sequence
(Scheme 1).26,27 Treatment of methyl ester 7 under the
same conditions gave an intermediate carbinol that was
treated with silica gel in hexane to give allylsilane 8 in
93% yield for the two-step sequence.19
8
+
CH2Cl2, -60oC
12
Me
Me
Scheme 2 Metathesis of allylsilanes 6, 8 and 9
We have observed 119Sn resonance signals at –27 ppm for
allylstannanes 10 and 11. The tin chemical shift for allyl-
stannane 12 appeared at –187 ppm. We believe that tin
chemical shifts are highly sensitive to oxygen bonding,
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L. C. Dias et al.
FEATURE ARTICLE
OH
O
OH
OH
H
N
H
NH2
N
N
H
Me
NHBoc
O
O
NHBoc
O
1
2
L-685,434
L-682,679
Me
IC50 = 0.23 nM
IC50 = 0.42 nM
OH
H
O
O
O
H
N
N
NH2
NH2
N
H
Me
N
H
Me
NHBoc
O
O
NHBoc
O
O
L-685,458
4
3
L-684,414
Me
Me
IC50 = 17 ± 8 nM
(Merck compound)
IC50 = 181 ± 1 nM
Figure 2 Chemical structures of the inhibitors L-685,434, L-682,679, L-685,458 and L-684,414
and this is an observation in favor of the complexed inter- tack).28,29 The increased steric bulk of the R group gives
mediate.
better diastereoselection.1d,28–31
We next moved to investigate the allyltrichlorostannane Under the same conditions, chiral allyltrichlorostannane
additions to chiral aldehydes 13a–c. In order to confirm 12 reacted with (S)-α-amino aldehydes 13a–c to give a
the facial selectivities of the (S)-N-Boc-α-amino alde- mixture of 1,2-syn (16a–c) and 1,2-anti (17a–c) diastere-
hydes 13a–c, we reacted them with allyltrichlorostannane omers with useful diastereoselectivities, favoring the 1,2-
10 (Scheme 3, Table 1).19–25
syn-isomer with anti-Felkin addition and aldehyde Si face
attack (Scheme 4). Results of reactions of 12 with (S)-al-
dehydes 13a–c are summarized in Table 2.19–25
SnCl3
OH
OH
10
CH2Cl2
-78 °C
R
R
+
O
+
O
15a-c
14a-c
R
OH
OBn
OH
OBn
NHBoc
NHBoc
1,2-syn
R
H
NHBoc
CH2Cl2
-78 °C
MS 4Å
H
1,2-anti
R
+
R
NHBoc
(S)-13a-c
NHBoc
Me
NHBoc
Me
MS 4Å
(S)-13a, R = Me
(S)-13b, R = Bn
(S)-13c, R = iPr
+
Cl3
Sn
1,2-anti (17a-c
Felkin addition
)
1,2-syn (16a-c)
anti-Felkin addition
OBn
12
Scheme 3 Allyltrichlorostannane addition to α-amino aldehydes
13a–c
Me
Scheme 4 Chiral allyltrichlorostannane addition to α-amino alde-
hydes 13a–c
In all cases, the major product results from a chelation-
controlled reaction that mainly gives the 1,2-syn-isomers
14a–c, showing that the (S)-α-amino aldehydes 13a–c
have a preference for anti-Felkin addition (Si face at-
As we know from previous work that the chiral allyl-
trichlorostannane 12 has a preference for Si face ap-
Table 1 Allyltrichlorostannane Addition to (S)-N-Boc-α-amino Aldehydes 13a–c
13a (R = Me)a,b
1,2-syn : 1,2-anti
88:12
Yield
(%)c
85
13b (R = Bn)a,b
1,2-syn : 1,2-anti
90:10
Yield
(%)c
86
13c (R = i-Pr)a,b
1,2-syn : 1,2-anti
90:10
Yield
(%)c
85
a The ratios were determined by 1H and 13C NMR spectroscopic analysis of the purified product mixture. The 1,2-syn- and anti-products could
not be separated and were characterized as mixtures.
b Averages of at least three runs with ratios ±3%.
c Combined yields of products isolated chromatographically (silica gel), after 2 steps (reduction to the aldehyde and coupling with allyltrichlo-
rostannane).
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FEATURE ARTICLE
Total Synthesis of Aspartyl Protease Inhibitors
607
Table 2 Tin(IV) Chloride-Promoted Additions of Chiral Allyltrichlorostannane 12 to (S)-N-Boc-α-Amino Aldehydes
13a (R = Me)a,b
1,2-syn:1,2-anti
95:05
Yield
(%)c
88
13b (R = Bn)a,b
1,2-syn:1,2-anti
95:05
Yield
(%)c
84
13c (R = i-Pr)a,b
1,2-syn:1,2-anti
95:05
Yield
(%)c
85
a The ratios were determined by 1H and 13C NMR spectroscopic analysis of the purified product mixture. The 1,4-syn and anti-products could
not be separated and were characterized as mixtures.
bAverages of at least three runs with ratios ±3%.
c Combined yields of products isolated chromatographically (silica gel), after 2 steps (reduction to the aldehyde and coupling with allyltrichlor-
ostannane).
H
O
H
R
O
H
Boc N
H
Boc
HN
(Cl)n
Sn
BocHN
R
O
R
H
Nu
Nu
E
D
H
R
H
F
R = H, Bn, (S)-CHMeCH2Obn
1,2-syn
Figure 3 Transition state model
1,2-anti
proach, this is an example of a matched reaction.19 It vored, whereas the prevalence of the E-like conformer
should be noted that this reaction gives a very important (smaller R groups) leads to the anti-isomer. The nucleo-
subunit with a double bond and a benzyl protected prima- phile selects the less hindered Si-face, forming a six mem-
ry alcohol that can be further manipulated.32,33
bered transition state F where the chiral residue of the
aldehyde occupies a pseudo-equatorial position.
The 1,2-syn relative stereochemistry of the major products
was unambiguously established by spectroscopic analysis
of the corresponding trans-oxazolidines 18a–c (upon irra-
diation of the hydrogens adjacents to Ha and Hb). Ob-
served average coupling constants (3J = 1.0 to 4.6 Hz)
indicate that protons Ha and Hb are on opposite faces of the
heterocyclic ring, and therefore, the oxazolidines are de-
rived from 1,2-syn adducts (Scheme 5).34
Total Synthesis of Aspartyl Protease Inhibitors L-
682,679, L-684,414, L-685,434, and L-685,458
Our disconnection for the synthesis of compounds 2–4 is
illustrated for inhibitor 3, summarized in Scheme 6. Not
surprisingly, compound 3 is viewed as arising from 2 by
either alcohol oxidation followed by selective 1,2-anti
reduction37 or by using the Mitsunobu inversion proto-
col.38 Further analysis involved cleavage of the C–N pep-
tide bond to give fragments 19 and 20. Carboxylic acid 19,
the core unit common for the synthesis of compounds 1–
4, is viewed as arising from α-amino aldehyde 13b by se-
lective allyltrichlorostannane addition followed by hy-
droboration of the double bond and oxidation of the
resulting primary alcohol. Dipeptide 20 may be dissected
in a straightforward manner to give carboxylic acid 21 and
amide 22.
Me
Me2C(OMe)2
PPTS
Me
OH
O
Hb
BocHN
CH2Cl2
N
Ha
R
Boc
R
R2
14b, R = H, R2 = Bn
16a, R = CH(Me)CH2OBn, R2 = Me
16c, R = CH(Me)CH2OBn, R2 = iPr
R2
80-85 %
18a-c
JHa/Hb trans
JHa/Hb cis
Literature: 1.1-4.9 Hz 4.6-6.0 Hz
Observed: 1.0 to 4.6 Hz
Our approach to aspartyl protease inhibitors 1–4 began
with N-Boc-phenylalaninal (13b), a useful synthetic inter-
mediate, easily prepared from α-phenylalanine ethyl ester
by Boc protection followed by DIBALH reduction.28–33
Scheme 5 Coupling constant analysis
The stereoselectivity of these reactions is consistent with
a mechanism involving transmetalation of the allylsilanes
to give an intermediate allyltin trichloride.22,35 We expect
such reactions to be dominated by the stereogenic center
next to the aldehyde function. We believe that the ob-
served selectivity can be explained by an equilibrium be-
tween the intramolecular hydrogen bond conformer D and
the non-bonded conformer E (Figure 3).36 When the form
D predominates (bulkier R groups), the syn-isomer is fa-
According to a previously established experimental pro-
cedure, allylsilane 6 and SnCl4 (0.5 M solution in CH2Cl2)
were mixed before the addition of a solution of the alde-
hyde in order to promote in situ ligand exchange, leading
to the corresponding allyltrichlorostannane 11
(Scheme 2).19–25 Addition of the aldehyde 13b to a CH2Cl2
solution of allyltrichlorostannane 11 at –78 °C gave the
1,2-syn amino alcohol 23 in 94% yield for the two-step se-
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608
L. C. Dias et al.
FEATURE ARTICLE
OH
O
OH
O
H
H
N
NH2
N
NH2
O
N
H
Me
N
H
Me
NHBoc
O
O
NHBoc
O
L-685,458
3
Me
2
Me
L-682,679
TBS
O
O
+
H2N
NH2
OH
N
H
Me
O
NHBoc
O
20
19
Me
O
O
BocHN
OH
Me
+
+
H
11
NH2
NHBoc
13b
H2N
22
21
SnCl3
Me
O
Scheme 6 Retrosynthetic analysis
quence (DIBALH reduction of α-phenylalanine ethyl es- we have observed loss of the Boc protecting group with
ter and coupling with allyltrichlorostannane) and 95:5 the corresponding deprotected homoallylic alcohol 24 be-
diastereoselectivity (Scheme 7).28–33
ing isolated in 82% yield and having essentially the same
selectivity.
1
The ratio was determined by H and 13C NMR spectro-
scopic analysis of the crude mixture, with averages of at The next step involved treatment of amino alcohol 23 with
least three runs with ±3% accuracy.
Me2C(OMe)2 in the presence of catalytic amounts of p-
TsOH to give trans oxazolidine 25 in 91% yield after pu-
rification by silica gel column chromatography.39,40 The
1,2-syn relative stereochemistry was unambiguously es-
tablished by spectroscopic analysis of trans oxazolidine
25 (upon irradiation of the hydrogens adjacent to Ha and
Hb). The observed coupling constant (JHa/Hb = 4.0 Hz) in-
It is essential to promote the ligand exchange reaction be-
fore addition of the aldehyde in order to get good yields
and selectivities. This reaction benefits from the fact that
the real nucleophile is the allyltrichlorostannane and not
the allylsilane itself. If the allyltrichlorostannane addition
reaction is carried out from –78 °C to room temperature,
O
CH2Cl2, -78 °C
H
+
Cl3Sn
94%
(2 steps)
NHBoc
13b
11
OH
Me
BocN
Me
O
Me2C(OMe)2
p-TsOH, 91%
NHR
25 °C
diastereoselection = 95:05
Ha Hb
Ha/Hb = 4.0 Hz
25
23, R = Boc
24, R = H
J
1. CF3CO2H, CH2Cl2
2. Triphosgene, 70%
O
O
HN
JHa/Hb = 5.1Hz
Hb 26
Ha
Scheme 7 Coupling between allyltrichlorostannane 11 and aldehyde 13b
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FEATURE ARTICLE
Total Synthesis of Aspartyl Protease Inhibitors
609
dicated that hydrogens Ha and Hb are on opposite faces of ica gel column chromatography) in 94% overall yield
the heterocyclic ring and, therefore, the oxazolidine is de- (Scheme 8). A better approach to these diols involved di-
rived from 1,2-syn adduct (Scheme 7).34,39,40 Alternative- rect hydroboration of the unprotected homoallylic alcohol
ly, amino alcohol 24 was transformed to the 23 with BH3 SMe2 in THF at 0 °C to give a mixture of di-
1
corresponding oxazolidinone 26 (70%), followed by H ols 30 and 31 in 93% yield (Scheme 10).
NMR coupling constant analysis. The observed coupling
These diols were not separated but were converted direct-
constant (JHa/Hb = 5.1 Hz) indicates that hydrogens Ha and
ly to a mixture of lactones 32 and 33 (95% yield) by treat-
Hb are on opposite faces of the heterocyclic ring
ment with tetrapropylammonium perruthenate (TPAP)
(Scheme 7).
and N-methylmorpholino N-oxide (NMO) in the presence
The double bond in acetonide 25 was oxidatively hydrob- of molecular sieves at room temperature.42,43 These lac-
orated at 0 °C with BH3 SMe2 to give primary alcohols 27 tones were readily separated by flash column chromatog-
and 28 in 93% overall yield (Scheme 8).6,39–41 The use of raphy. Although these lactones have been prepared earlier
the more hindered 9-BBN gave essentially the same re- by others, the relative stereochemistry for cis-lactone 33
sult, although in lower yields (65%). Although these two was ascertained by NOESY experiments (observed inter-
isomers are not easily separated, we were able to get pure action between Ha and Hb). Attempts to obtain more of the
isolated compounds after careful silica gel flash column desired trans-lactone 32 by a deprotonation and reproto-
chromatography. A coupling constant of 4.0 Hz between nation sequence of cis-lactone 33 led to a 70:30 mixture
Ha and Hb is again observed for alcohols 27 and 28.6,39–41
of lactones 32:33 in 96% yield (Scheme 10). It is interest-
ing to point out that cis-lactone 33 is also an important in-
termediate for the synthesis of other potent HIV-1
protease inhibitors.43b
The relative stereochemistry for undesired primary alco-
hol 28 was ascertained by conversion to the piperidine de-
rivative 29 after a two-step sequence involving reaction
with Ph3P, I2 and imidazole, and treatment of the interme- Basic hydrolysis of desired trans-lactone 32 (LiOH, 1,2-
diate iodide with 4 M HCl in MeOH followed by K2CO3 dimethoxyethane), silylation (TBSCl, imidazole, DMF,
in DMF (Scheme 9). The illustrated NOESY interactions r.t., 12h) of the resulting carboxylate, and selective desily-
confirmed the proposed relative stereochemistry for cy- lation of the acylsiloxy moiety (MeOH) cleanly provided
clic amino alcohol 29.
19 in excellent yield after purification by silica gel flash
chromatography (Scheme 11).
Selective acetonide deprotection in alcohols 27 and 28
was achieved by using the complex BF3 2AcOH at room The carboxylic acid 19 is a versatile intermediate for the
temperature to give diols 30 and 31 (not separated by sil- introduction of different functional groups in intermedi-
Scheme 8 Hydroboration of compound 25
Me
BocN
Me
O
1. PPh3, I2
imidazole
OH
29
NH
2. 4 M HCl, MeOH
3. K2CO3, DMF
HO
28
63% (over 3-steps)
OH
H
H
H
H
H
N
H
29
H
H
Scheme 9 Preparation of piperidine derivative 29
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FEATURE ARTICLE
Scheme 10 Direct hydroboration of homoallylic alcohol 23
O
TBS
O
OH
O
O
1. LiOH, DME
2. i.TBSCl, DMF
imidazole
32
NHBoc
NHBoc
19
ii. MeOH, 94%
1. HOBt, DCC
NaHCO3
HO
34
H2N
0 °C- rt
2. TBAF, THF, 25 °C
70% (2 steps)
OH
OH
H
N
NHBoc
O
1
L-685,434
Scheme 11 Synthesis of L-685,434
ates aiming at the synthesis of hydroxyethylene isosteres Peptide coupling between carboxylic acid 21 and amide
and is prepared in 4 steps and 24% overall yield from 23, 22, followed by Boc deprotection, gave NH2Leu-PheNH2
being amenable to a gram scale-up.
35 in 85% overall yield (Scheme 13).
Compound L-685,434 (1) is readily prepared from carbox- Compound L-682,679 (2) is readily prepared from carbox-
ylic acid 19 by a simple peptide coupling reaction with ylic acid 19 and dipeptidic amine 35 by a simple peptide
(1S,2R)-1-amino-2-hydroxyindane (34) followed by TBS coupling reaction followed by TBS deprotection with
removal with TBAF in 70% yield for the two-step se- TBAF in 86% overall yield (Scheme 13).10
quence (Scheme 11).6–8
Oxidation of the hydroxyl function in 2 with pyridinium
Compounds 2–4 are also prepared from the same carbox- dichromate (PDC) in DMF gave inhibitor L-684,414 (4) in
ylic acid precursor 19. In order to prepare inhibitors 2 and 85% isolated yield. Selective reduction of L-684,414 (4)
3 we first obtained the dipeptide amide NH2Leu-PheNH2 with LiBH4 gave γ-secretase inhibitor L-685,458 (3) in
(35) (Scheme 12). Peptide type coupling of N-Boc-pheny- 93% yield and 95:5 diastereoselection (Scheme 13).37
lalanine (36) with a 25% solution of ammonium hydrox-
ide followed by Boc deprotection with MeOH/AcCl gave
amide 22 in 71% overall yield.
Another approach to the synthesis of L-685-458 (3) is by
using the corresponding 1,2-anti amino alcohol 39 pre-
pared from 23. Of the available options to promote the in-
version of the hydroxyl stereochemistry of 23 in order to
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FEATURE ARTICLE
Total Synthesis of Aspartyl Protease Inhibitors
611
The 1,2-anti relative stereochemistry for 39 was tentative-
ly assigned by spectroscopic analysis of the cis-oxazoli-
dine 41 (JHa-Hb = 4.7 Hz), (Scheme 14).23–25,34 As the
observed coupling constants for oxazolidines 25 (4.0 Hz)
and 41 (4.7 Hz) were very close, we decided to check the
differences in chemical shifts in compounds 23 and 39.
The relative stereochemistry for compounds 23 and 39
was confirmed using Heathcock’s model for β-hydroxy
carbonyl compounds (Scheme 15 and Table 3).45 Consid-
ering an intramolecular hydrogen bond in CDCl3 solution
between NH and OH in both compounds, and after analy-
sis of 1H and 13C NMR chemical shifts we observed that:
O
O
1. HOBt, EDC
DMF, NH4OH
NH2
OH
NH2
NHBoc
2. MeOH, CH3COCl
71% overall yield
22
36
O
BocHN
21
OH
Me
O
Me
H2N
NH2
N
H
Me
1. HOBt, DCC
O
NaHCO3, CH2Cl2, 86%
35
- C1 and C4 in 23 are more deshielded than C1′ and C4′ in
39;
Me
2. MeOH, CH3COCl
85% (2 steps)
- C2 and C3 in 23 are more shielded than C2′ and C3′ in 39;
and
Scheme 12 Preparation of NH2Leu-PheNH2 35
- Ha and Hb in 23 are more shielded than Hc and Hd in 39.
prepare L-685,458 (3) we tested the Mitsunobu reaction
using 4-nitrobenzoic acid, Ph3P and DBAD
(Scheme 14).38 The p-nitrobenzoate ester 37 was isolated
in 60% yield together with about 10% of elimination
product 38 and 20% of recovered starting material.
It is also interesting to observe the difference in the melt-
ing points of compounds 23 and 39 (Scheme 15). The 1,2-
syn amino alcohol 23, where an intramolecular hydrogen
bond between NH and OH is expected, leading to a trans
relationship between the two substituents, has a melting
point of 95.5–97.8 °C. The 1,2-anti amino alcohol 39,
where an intramolecular hydrogen bond in the solid state
is not expected to be favored over intermolecular interac-
tion, has a higher melting point (mp 141.5–142.3 °C).
These results are consistent with the proposed stere-
ochemistry for 23 and 39.
Hydrolysis of the 4-nitrobenzoate 37 with lithium hydrox-
ide gave the desired 1,2-anti amino alcohol 39 in 98%
yield (Scheme 14). Another approach for the preparation
of 39 involved Dess–Martin44 oxidation of 23 at 0 °C to
37
give ketone 40 (77% yield) followed by LiBH4 reduc-
tion in THF at –60 °C (Scheme 14). Although we were
able to isolate the amino alcohol 39 in good yields and
with 94:6 diastereoselectivity, this protocol is sometimes
hard to reproduce since a lot of care must be taken in order
to avoid rearrangement to the conjugated ketone 40.
The next step involved a direct hydroboration of 1,2-anti
homoallylic alcohol 39 with BH3 SMe2 to give a 55:45
mixture of diols 42 and 43 in 93% overall yield
1. HOBt, EDC
DMF, Et3N
TBS
OH
O
O
H
N
NH2
H2N-Leu-Phe-NH2 (35)
OH
N
H
Me
91%
NHBoc
O
O
NHBoc
O
2. TBAF, THF
r.t., 94%
L-682,679
2
19
Me
PDC, DMF
r.t., 85%
O
O
H
LiBH4
N
NH2
N
H
Me
EtOH, -60 °C
93%
NHBoc
O
O
4
Me
L-684,414
OH
O
H
N
NH2
N
H
Me
NHBoc
L-685,458
Scheme 13 Total synthesis of inhibitors 2, 3 and 4
O
O
diastereoselection 95:05
3
Me
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612
L. C. Dias et al.
FEATURE ARTICLE
38
10%
NHBoc
NO2
+
O
O
OH
p-NO2C6H4CO2H
Ph3P, DBAD
23
37
NHBoc
NHBoc
THF, 0 °C, 60%
LiOH
EtOH/ H2O/THF
98%
Dess-Martin
CH2Cl2, 0 °C
77%
O
OH
LiBH4
THF, -60oC
39
40
NHBoc
NHBoc
79%
diastereoselection = 94:06
Me
BocN
Me
Me2C(OMe)2
CSA , 77%
O
Ha Hb
JHa-Hb= 4.7 Hz
41
Scheme 14 Preparation of 1,2-anti amino alcohol 39
Boc
H
(Scheme 16). These diols were not separated but were
most conveniently treated with TPAP to give a mixture of
lactones 44 and 45 (97% overall yield), which were then
separated by silica gel column chromatography.18
N
OH
4
2
3
6
1
Ha Hb
1,2-syn 23
m.p.: 95.5-97.8 °C
A two-step sequence involving opening lactone 44 with
lithium hydroxide (5 equiv) in aqueous 1,2-dimethoxy-
ethane followed by treatment of the resulting hydroxy
acid with TBSCl and imidazole, in DMF at room temper-
ature, followed by MeOH, gave the desired TBS-protect-
ed acid 46 in 73% overall yield (Scheme 17).18 At this
stage, all that remained was to carry out the necessary
peptide coupling between 46 and 35 and remove the TBS
protecting group.
Boc
H
N
OH
4'
3'
2'
1'
6'
Hc Hd
1,2-anti 39
m.p.: 141.5-142.3 °C
Scheme 15 Spectroscopic data for compounds 23 and 39
Compound 3 is thus prepared in 75% yield from 46 and
NH2Leu-PheNH2 (35) by a simple peptide coupling reac-
tion followed by deprotection of the resulting silyl ether
with TBAF in THF at room temperature.17,18,46 The spec-
troscopic and physical data [IR, 1H and 13C NMR; mp and
Rf] for inhibitor 3 were identical in all respects with the
Table 3 Spectroscopic Data for Compounds 23 and 39
1,2-syn 23, δ
1,2-anti 39, δ
25
C1
C2
C3
C4
C6
Ha
Hb
38.9
55.2
68.1
40.9
42.7
3.67
3.67
C1′
C2′
C3′
C4′
C6′
Hc
35.5
published data. The observed optical rotation, [α ]D
–27.5 (c = 0.5, CHCl3) agrees satisfactorily with the re-
56.1
71.1
39.9
42.8
3.80
3.80
ported value {[α]D25 –27.9 (c = 0.5, CHCl3)}.18,46,47
Conclusions
This convergent asymmetric approach to aspartyl pro-
tease inhibitors L-685,434 (1), L-682,679 (2), L-685,458
(3) and L-684,414 (4) relies on the use of amino alcohol
23 as a key intermediate. The route described here might
Hd
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FEATURE ARTICLE
Total Synthesis of Aspartyl Protease Inhibitors
613
OH
OH
NHBoc
OH
42 (51%)
OH
BH3 SMe2
THF, 93%
+
OH
NHBoc
39
NHBoc
O
43 (42%)
O
TPAP, NMO
25 °C
NHBoc
O
44 (53%)
separated by column
chromatography
O
+
NHBoc
45 (44%)
Scheme 16 Hydroboration of 39 followed by lactonization
O
TBS
O
1. LiOH, DME
O
OH
2.i.TBSCl, DMF
imidazole
ii. MeOH, 74%
NHBoc
44
NHBoc
46
O
1.HOBt, DCC
DMF, Et3N
OH
O
H
N
NH2
H2NLeu-PheNH2 35
N
H
Me
NHBoc
O
O
2. TBAF, THF, 25 oC
75% (2 steps)
3
L-685,458
Me
Scheme 17 Synthesis of L-685,458
br = broad, br s = broad singlet, br d = broad doublet, dq = doublet
of quartets, dt = doublet of triplets, td = triplet of doublets, ap
qt = apparent quintet, ap dt = apparent doublet of triplets, number of
hydrogens, coupling constant(s) in Hz). Proton-decoupled 13C
NMR spectra were recorded on either a Varian Gemini 300 (75
MHz) or Bruker AC 300/P (75 MHz) spectrometers and are record-
ed in ppm using solvent as an internal standard (CDCl3 at 77.0 ppm
or C6D6 at 128 ppm), unless otherwise indicated. IR spectra were re-
corded on a Perkin-Elmer 1600 FTIR spectrophotometer. Mass
spectra were recorded on a HP-5988-A GC-MS spectrometer. Opti-
cal rotations were measured on a Polamat A polarimeter from Carl
Zeiss, using a 1 mL quartz cell, with mercury or sodium lamps, and
easily provide access to additional analogues with poten-
tial relevance in biological studies.
All reactions were carried out under argon or N2 in flame-dried
glassware with magnetic stirring. CH2Cl2, Et3N, cyclohexane, and
DMF were distilled from CaH2. SnCl4 was distilled from CaH2 and
stored in a Schlenk flask. DMSO was distilled under reduced pres-
sure from CaH2 and stored over molecular sieves. THF, Et2O, and
toluene were distilled from sodium/benzophenone ketyl. Oxalyl
chloride, dimethoxypropane, isobutyraldehyde, trimethylsilylmeth-
yl chloride and (c-Hex)2BCl were distilled immediately prior to use.
MeOH was distilled from Mg(OMe)2. TLC plates were silica gel 60
(GF 5–40 µm). Visualization was accomplished with either a UV
lamp or I2 staining. Chromatography on silica gel (230–400 mesh)
was performed using forced-flow of the indicated solvent system
(flash chromatography). Visualization was accomplished with UV
light and an anisaldehyde, ceric ammonium nitrate stain, a heated
phosphomolybdic acid or by I2 staining. 1H NMR spectra were re-
corded on either a Varian Gemini 300 (300 MHz) or a Varian Inova
500 (500 MHz) spectrometer and are reported in ppm using residual
undeuterated solvent as an internal standard (CDCl3 at 7.26 ppm or
C6D6 at 7.15 ppm), unless otherwise indicated. Data are reported as
(ap = apparent, s = singlet, d = doublet, t = triplet, q = quartet,
qt = quintet, st = sextet, ap t = apparent triplet, m = multiplet,
t
are reported as follows: [α]λ , (c = g/100 mL, solvent).
Benzylallyl(trimethyl)silane (6)
In a 3-necked 500 mL round bottomed flask was heated powdered
CeCl3 7H2O (15.44 g, 41.4 mmol) under vacuum (1 Torr) at 160 °C
for 12 h with vigorous stirring, resulting in the formation of a mo-
bile white solid. The reaction flask was flushed with argon and al-
lowed to cool to r.t. when anhyd THF (65 mL) was added to the
vigorously stirred anhyd cerium(III) chloride forming a uniform
white suspension, which was kept under stirring for 2 h. During this
time, a separate three-necked 100 mL flask, fitted with a condenser
and a pressure-equalizing dropping funnel, was charged with Mg
turnings (1 g, 41.4 mmol), and the whole apparatus was flame dried
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614
L. C. Dias et al.
FEATURE ARTICLE
under a flow of argon. To this flask was added dropwise a solution
of ClCH2SiMe3 (5.8 mL, 41.4 mmol) in anhyd THF (27 mL). This
mixture was stirred for 3 h until almost all of the Mg had dissolved.
The anhyd CeCl3 suspension was now cooled to –78 °C. To this sus-
pension was added dropwise the previously prepared Grignard re-
agent, forming an off-white suspension, and was stirred at –78 °C
for 2 h. At this time, a solution of ester 5 (2.07 g, 13.8 mmol) in an-
hyd THF (8 mL) was added to the Grignard-cerium chloride com-
plex dropwise over 5 min, and the resulting mixture was warmed
gradually to r.t. When consumption of the starting ester was com-
plete, as determined by TLC (3 h), the resulting grey solution was
cooled to 0 °C and quenched by the addition of a sat. aq solution of
NH4Cl (30 mL). The organic layer was separated, and the aqueous
layer was extracted with Et2O (2 × 50 mL). The combined organic
layers were washed with brine (2 × 50 mL) and dried (MgSO4). The
solvent was removed under reduced pressure to give a slightly yel-
low liquid that was dissolved in CH2Cl2 (100 mL). To this flask was
added Amberlyst 15 (1.0 g) and this mixture was stirred at r.t. until
complete consumption of starting material. The resin was then re-
moved by filtration and washed with CH2Cl2 (100 mL). The solvent
was removed under reduced pressure to give allylsilane 6 as a col-
orless liquid; yield: 2.73 g (97%); Rf 0.60 (hexane).
IR (neat): 3430, 3064, 3026, 2978, 2931, 2248, 1689, 1641, 1604,
1562, 1496, 1453, 1392, 1366, 1283, 1250, 1169, 1051, 1022, 915,
867, 734, 700, 647, 547 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.41 (s, 9 H), 2.10 (d, 1 H, J = 3.7
Hz), 2.25 (d, 2 H, J = 6.9 Hz), 2.94 (m, 2 H), 3.60 (br s, 1 H), 3.79
(dd, 1 H, J = 8.6, 7.5 Hz), 4.87 (d, 1 H, J = 8.6 Hz), 5.10 (s, 1 H),
5.15 (s, 1 H), 5.76 (m, 1 H), 7.25 (m, 5 H).
13C NMR (CDCl3, 75 MHz): δ = 28.1, 38.6, 39.1, 55.1, 70.0, 79.3,
118.7, 126.5, 128.6, 129.5, 134.0, 138.4, 156.3.
HRMS: m/z calcd for C17H25NO3: 291.1834; found: 200.0505
(M+ – 91).
tert-Butyl(1S,2S)-2-Hydroxy-1-isopropylpent-4-enylcarbamate
(14c)
Yield: 85%; Rf 0.38 (20% EtOAc–hexane).
IR (neat): 3422, 2976, 2932, 1684, 1508, 1456, 1391, 1366, 1248,
1169, 1097, 1045, 1027, 990, 914, 865, 781 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.95 (d, 3 H, J = 6.6 Hz), 0.97 (d,
3 H, J = 5.5 Hz), 1.45 (s, 9 H), 1.85 (m, 1 H), 1.90 (br d, 1 H), 2.26
(m, 2 H), 3.21 (br t, 1 H, J = 8.0 Hz,), 3.82 (br s, 1 H), 4.80 (br s, 1
H), 5.18 (s, 1 H), 5.21 (br s, 1 H), 5.84 (m, 1 H).
IR (neat): 3065, 3028, 2958, 2916, 1716, 1632, 1064, 1491, 1457,
1416, 1244, 1162, 1073, 1026, 856, 744, 697 cm–1.
13C NMR (CDCl3, 75 MHz): δ = 19.1, 19.7, 28.3, 30.3, 39.6, 59.3,
69.9, 79.0, 118.5, 134.7, 156.7.
1H NMR (CDCl3, 300 MHz): δ = 0.0 (s, 9 H), 1.44 (s, 2 H), 3.23 (s,
2 H), 4.53 (br s, 1 H), 4.58 (br s, 1 H), 7.10–7.25 (m, 5 H).
13C NMR (CDCl3, 75 MHz): δ = –1.0, 26.1, 45.1, 109.5, 126.0,
128.2, 129.1, 138.9, 146.7.
MS (70 ev): m/z (%) = 204 (M+, 12), 189 (2), 173 (5), 147 (40), 134
Homoallylic Alcohols 16a–c; General Procedure
To a solution of allylsilane 8 (1.5 mmol) in CH2Cl2 (5 mL) at 0 °C
was added SnCl4 (1.5 mmol). The resulting solution was stirred at
0 °C for 5 min and then cooled to –78 °C when a solution of alde-
hyde 13a–c (1.5 mmol) in CH2Cl2 (2 mL) was added. This mixture
was stirred for 2 h at –78 °C and quenched by the slow addition of
a sat. aq solution of NaHCO3 (5 mL) followed by CH2Cl2 (10 mL).
The layers were separated and the aqueous layer was extracted with
CH2Cl2 (2 × 5 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. Purification by flash
chromatography on silica gel (30% EtOAc–hexane) gave the corre-
sponding homoallylic alcohols 16a–c.
(21), 115 (24), 104 (7), 91 (87), 73 (100).
HRMS: m/z calcd for C13H20Si: 204.1334, found: 204.1354.
Anal. Calcd for C13H20Si: C, 76.40; H, 9.86; Si, 13.74. Found: C,
76.32; H, 9.81.
Homoallylic Alcohols 14a–c; General Procedure
To a solution of allylsilane 9 (1.5 mmol) in CH2Cl2 (5 mL) at r.t. was
added SnCl4 (1.4 mmol). The resulting solution was stirred at r.t. for
2 h and then cooled to –78 °C when a solution of aldehyde 13a–c
(1.4 mmol) in CH2Cl2 (2 mL) was added. This mixture was stirred
for 2 h at –78 °C and quenched by the slow addition of a sat. aq so-
lution of NaHCO3 (5 mL) followed by CH2Cl2 (5 mL). The layers
were separated and the aqueous layer was extracted with CH2Cl2
(2 × 5 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated in vacuo. Purification by flash chromato-
graphy on silica gel (30% EtOAc–hexane) gave the corresponding
homoallylic alcohols 14a–c.
tert-Butyl (1S,2S)-4-[(1S)-2-Benzyloxy-1-methylethyl]-2-hy-
droxy-1-methylpent-4-enylcarbamte (16a)
Yield: 88%; [α]D20 +27.48 (c = 1.6, CHCl3); Rf 0.30 (20% EtOAc–
hexane).
IR (neat): 3442, 3065, 3029, 2963, 2871, 1713, 1643, 1497, 1453,
1390, 1365, 1246, 1171, 1094, 1019, 876, 735, 697 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.01 (d, 3 H, J = 6.8 Hz), 1.21 (d,
3 H, J = 6.8 Hz), 1.45 (s, 9 H), 2.21 (m, 1 H), 2.49 (m, 2 H), 2.82 (br
s, 1 H), 3.37 (dd, 1 H, J = 9.0, 5.7 Hz), 3.46 (t, 2 H, J = 9.0 Hz), 3.69
(m, 2 H), 4.50 (s, 2 H), 4.97 (s, 2 H), 7.32 (m, 5 H).
tert-Butyl (1S,2S)-2-Hydroxy-1-methylpent-4-enylcarbamate
(14a)
Yield: 85%; Rf 0.38 (20% EtOAc–Hexane).
13C NMR (75 MHz, CDCl3): δ = 17.5, 18.9, 28.3, 38.8, 40.8, 71.4,
73.0, 74.4, 79.5, 112.6, 127.6, 128.3, 137.8, 148.6, 155.9, 199.7.
IR (neat): 3422, 2976, 2932, 1684, 1508, 1456, 1391, 1366, 1248,
1169, 1097, 1045, 1027, 990, 914, 865, 781 cm–1.
HRMS: m/z calcd for C21H33NO4: 363.2409; found: 219.0860
(M+ – 144).
1H NMR (CDCl3, 300 MHz): δ = 1.19 (d, 3 H, J = 6.9 Hz), 1.44 (s,
9 H), 2.22 (m, 2 H), 2.32 (m, 1 H), 3.55 (m, 1 H), 3.67 (br s, 1 H),
4.74 (br s, 1 H), 5.12 (s, 1 H), 5.13 (s, 1 H), 5.16 (s, 1 H), 5.83 (m,
1 H).
Anal. Calcd for C21H33NO4: C, 69.39; H, 9.15; N, 3.85. Found: C,
68.47; H, 8.91; N, 4.0.
tert-Butyl (1S,2S)-1-Benzyl-4-[(1S)-2-benzyloxy-1-methyleth-
yl]-2-hydroxypent-4-enylcarbamate (16b)
Yield: 84%; [α]D20 +10.8 (c = 1.18, CHCl3); Rf 0.29 (20% EtOAc–
hexane).
HRMS: m/z calcd for C11H21NO3: 215.1521; found: 170.0526
(M+ – 45).
tert-Butyl (1S,2S)-1-Benzyl-2-hydroxypent-4-enylcarbamate
(14b)
Yield: 86%; Rf 0.33 (20% EtOAc–hexane).
IR (neat): 3375, 3091, 3063, 3030, 2963, 2924, 2857, 1949, 1682,
1643, 1604, 1520, 1453, 1393, 1364, 1314, 1253, 1170, 1087, 1002,
891, 735, 696 cm–1.
Synthesis 2003, No. 4, 603–622 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of Aspartyl Protease Inhibitors
615
1H NMR (CDCl3, 300 MHz): δ = 0.93 (d, 3 H, J = 6.9 Hz), 1.40 (s,
9 H), 2.24 (d, 1 H, J = 10.2 Hz), 2.32 (dd, 2 H, J = 6.9, 5.8 Hz), 2.91
(m, 3 H), 3.35 (dd, 1 H, J = 8.8, 5.5 Hz), 3.41 (t, 1 H, J = 5.5 Hz),
3.75 (m, 2 H), 4.45 (s, 2 H), 4.94 (m, 3 H), 7.27 (m, 10 H).
13C NMR (CDCl3, 75 MHz): δ = 17.5, 28.3, 38.5, 39.2, 40.9, 55.4,
67.7, 73.0, 74.6, 112.7, 127.8, 128.5, 137.8, 138.7, 148.7, 155.9,
199.6.
13C NMR (CDCl3, 75 MHz): δ = 17.5, 28.4, 38.8, 59.5, 67.6, 73.0,
78.7, 112.6, 127.7, 137.8, 148.8, 153.5.
HRMS: m/z calcd for C24H37NO4: 403.2722; found: 388.1632
(M+ – 15).
tert-Butyl (4S,5S)-5-Allyl-4-benzyl-2,2-dimethyl-1,3-oxazoli-
dine-3-carboxylate (18b)
Yield: 84%; Rf 0.29 (20% EtOAc–hexane).
HRMS: m/z calcd for C27H37NO4: 439.2722; found: 291.6855
(M+ – 147).
IR (neat): 3426, 3068, 2974, 2930, 1699, 1460, 1387, 1253, 1175,
708 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.25 (br s, 3 H), 1.53 (s, 12 H),
2.19 (m, 2 H), 2.85 (m, 1 H), 3.23 (dd, 1 H, J = 12.8, 2.9 Hz), 3.80
(br s, 1 H), 3.96 (dt, 2 H, J = 4.4, 1.8 Hz), 4.9 (br d, 2 H, J = 9.1 Hz),
5.50 (br s, 1 H), 7.24 (m, 5 H).
Anal. Calcd for C27H37NO4: C, 73.77; H, 8.48; N, 3.19. Found: C,
73.26; H, 8.45; N, 3.65.
tert-Butyl (1S,2S)-4-[(1S)-2-Benzyloxy-1-methylethyl]-2-hy-
droxy-1-isopropylpent-4-enylcarbamate (16c)
Yield: 85%; [α]D20 +56.8 (c = 1.04, CHCl3); Rf 0.29 (20% EtOAc–
hexane).
13C NMR (CDCl3, 75 MHz): δ = 26.9, 28.5, 37.5, 38.0, 62.6, 79.9,
117.4, 126.4, 128.4, 129.4, 129.8, 133.7, 137.7, 151.8.
IR (neat): 3442, 3065, 3029, 2963, 2871, 1713, 1643, 1497, 1453,
1390, 1365, 1246, 1171, 1094, 1019, 876, 735, 697 cm–1.
HRMS: m/z calcd for C20H29NO3: 331.2147; found: 331.2142.
1H NMR (CDCl3, 300 MHz): δ = 0.94 (d, 3 H, J = 6.6 Hz), 0.95 (d,
3 H, J = 6.6 Hz), 1.03 (d, 3 H, J = 6.6 Hz), 1.43 (s, 9 H), 1.82 (m, 2
H), 2.19 (d, 2 H, J = 7.3 Hz), 2.46 (m, 1 H), 3.19 (t, 1 H, J = 8.6 Hz),
3.43 (m, 2 H), 3.97 (m, 1 H), 4.55 (s, 2 H), 4.87 (d, 1 H, J = 10.2
Hz), 4.98 (br s, 2 H), 7.30 (m, 5 H).
13C NMR (CDCl3, 75 MHz): δ = 17.6, 19.5, 19.8, 28.4, 30.9, 38.9,
41.3, 59.6, 67.7, 73.1, 76.7, 78.7, 112.7, 127.7, 128.4, 137.8, 148.9,
156.5 199.6.
tert-Butyl (4R,5R)-5-{2-[(1R)-2-Benzyloxy-1-methylethyl]allyl}-
4-isopropyl-2,2-dimethyl-1,3-oxazolane-3-carboxylate (18c)
Yield: 80%; Rf 0.29 (20% EtOAc–hexane).
1H NMR (CDCl3, 300 MHz): δ = 0.88 (br s, 3 H), 0.95 (br s, 3 H),
1.11 (d, 3 H, J = 6.8 Hz), 1.48 (s, 9 H), 1.78 (m, 1 H), 1.95 (m, 1 H),
2.38 (dd, 1 H, J = 7.8, 6.5 Hz), 2.48 (dd, 1 H, J = 6.8, 6.1 Hz), 2.56
(dd, 1 H, J = 7.6, 6.8 Hz), 3.25 (dd, 1 H, J = 7.5, 6.1 Hz), 3.51 (m,
2 H), 4.06 (m, 2 H), 4.58 (d, 2 H, J = 6.6 Hz), 4.92 (br s, 2 H), 5.02
(s, 1 H), 7.34 (m, 5 H).
HRMS: m/z calcd for C23H37NO4: 391.2722; found: 301.7508
(M+ – 90).
13C NMR (CDCl3, 75 MHz): δ = 17.0, 22.6, 28.5, 39.6, 51.9, 73.0,
74.6, 80.1, 111.5, 127.4, 128.3, 138.5, 148.1, 152.1.
Anal. Calcd for C23H37NO4: C, 70.55; H, 9.52; N, 3.58. Found: C,
70.87; H, 9.65; N, 3.65.
(4S,5S)-2-Benzyl-5-[(tert-butoxycarbonyl)amino]-6-phenylhex-
1-en-4-ol (23)
Allyltrichlorostannane (12)
To a solution of allylsilane 6 (2.86 g, 14 mmol) in CH2Cl2 (50 mL)
at 0 °C was added SnCl4 (1.7 mL, 14 mmol). The resulting solution
was stirred at 0 °C for 2 h and then cooled to –78 °C when a solution
of aldehyde 13b (2.7 g, 11 mmol) in CH2Cl2 (20 mL) was added.
This mixture was stirred for 2 h at –78 °C and quenched by the slow
addition of a sat. aq solution of NaHCO3 (50 mL) followed by
CH2Cl2 (100 mL). The layers were separated and the aqueous layer
was extracted with CH2Cl2 (2 × 25 mL). The combined organic lay-
ers were dried (MgSO4), filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography on silica gel (30% EtOAc–hexane)
gave the corresponding homoallylic alcohol 23 as a white solid.
1H NMR (CDCl3, 300 MHz): δ = 0.95 (d, 3 H, J = 6.9 Hz), 2.48 (m,
1 H), 3.19 (d, 1 H, J = 10.9 Hz), 3.36 (d, 1 H, J = 11.3 Hz), 3.53 (dd,
1 H, J = 9.8, 6.9 Hz), 3.70 (dd, 1 H, J = 9.8, 4.4 Hz), 4.71 (d, 1 H,
J = 13.2 Hz), 4.77 (d, 1 H, J = 5.8 Hz), 5.04 (s, 1 H), 5.18 (s, 1 H),
7.36 (s, 5 H).
13C NMR (CDCl3, 75 MHz): δ = 15.6, 39.9, 42.6, 73.0, 74.5, 114.6,
144.0, 127.5, 128.3, 128.6, 138.7.
119Sn NMR (CDCl3, 111.92 MHz): δ = –186.87 (tt, JSn-H = 136.78
Hz, JSn-H = 78 Hz).
Acetonides 18a–c; General Procedure
Yield: 3.95 g (94%); Rf 0.35 (20% EtOAc–hexane); mp 95.5–
97.8 °C; [α]D20 –15.0 (c = 2.84, CH2Cl2).
To a stirred solution of the corresponding amino alcohols 16a, 14b,
16c (1.4 mmol) in 2,2-dimethoxypropane (2 mL) at r.t. was added
p-toluenesulfonic acid (2 mg), and the mixture was stirred for 46 h
at r.t. Et2O (2 mL) was added, and the organic layer was washed
with 10% NaHCO3 (1 mL) and brine (1 mL). The organic layer was
dried (MgSO4), filtered, and concentrated in vacuo. Purification by
flash chromatography on silica gel (10% EtOAc–hexane) afforded
products 18a–c.
IR (neat): 3422, 3351, 3066, 3030, 2977, 2929, 1685, 1644, 1507,
1455, 1365, 1252, 1170, 1015, 967, 868, 743, 701, 530 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.39 (s, 9 H), 1.98 (br s, 1 H),
2.08–2.15 (m, 2 H), 2.82–2.93 (m, 2 H), 3.23 (br s, 2 H), 3.65–3.70
(m, 2 H), 4.83 (m, 1 H), 4.88 (br s, 2 H), 7.02 (d, 2 H, J = 7.0 Hz),
7.16–7.31 (m, 8 H).
13C NMR (CDCl3, 75 MHz): δ = 28.4, 38.9, 40.9, 42.8, 55.2, 68.1,
79.2, 114.7, 126.1, 128.3, 128.7, 128.8, 129.2, 138.3, 138.7, 145.1,
155.7.
MS (70 eV): m/z (%) = 290 (M+ – 91, 20), 234 (16), 190 (26), 164
(31), 120 (45), 91 (41), 57 (100).
tert-Butyl (4R,5R)-5-{2-[(1R)-2-Benzyloxy-1-methylethyl]allyl}-
2,2,4-trimethyl-1,3-oxazolane-3-carboxylate (18a)
Yield: 85%; Rf 0.29 (20% EtOAc–hexane).
IR (neat): 3413, 3068, 2980, 2934, 1874, 1699, 1453, 1387, 1258,
1097 cm–1.
HRMS: m/z calcd for C24H31NO3: 381.2304, found: 290.1804
1H NMR (CDCl3, 300 MHz): δ = 0.86 (s, 3 H), 0.88 (d, 3 H, J = 6.6
Hz), 1.18 (d, 3 H, J = 6.8 Hz), 1.48 (s, 9 H), 2.38 (dd, 1 H, J = 7.6,
6.8 Hz), 2.48 (dd, 1 H, J = 6.8, 6.1 Hz), 2.56 (dd, 1 H, J = 7.6, 6.8
Hz), 3.25 (dd, 1 H, J = 7.6, 6.1 Hz), 3.51 (m, 1 H), 4.06 (m, 1 H),
4.58 (d, 2 H, J = 6.6 Hz), 4.92 (br s, 1 H), 5.02 (s, 1 H), 7.34 (m, 5
H).
(M+ – 91).
Anal. Calcd for C24H31NO3: C, 75.56; H, 8.19; N, 3.67. Found: C,
75.30; H, 8.20; N, 3.63.
Synthesis 2003, No. 4, 603–622 ISSN 0039-7881 © Thieme Stuttgart · New York

616
L. C. Dias et al.
FEATURE ARTICLE
(2S,3S)-2-Amino-5-benzyl-1-phenylhex-5-en-3-ol (24)
After stirring at –78 °C for 2 h, the above reaction was allowed to
warm to r.t. before it was quenched by the addition of an aq sat. so-
lution of NH4Cl. This procedure led to the isolation of amino alco-
hol 24 in 82% yield from α-amino aldehyde 13b.
Hz), 4.86 (s, 1 H), 4.89 (s, 1 H), 5.98 (br s, 1 H), 7.08–7.33 (m, 10
H).
13C NMR (CDCl3, 75 MHz): δ = 40.1, 41.4, 43.0, 58.5, 79.9, 115.4,
126.3, 127.1, 128.3, 128.8, 128.9, 135.7, 138.5, 142.9, 158.5.
Yield: 2.52 g (82%); Rf 0.24 (50% EtOAc–hexane) .
Hydroboration of Acetonide 25
To a solution of acetonide 25 (0.59 g, 1.4 mmol) in THF (10 mL)
cooled to 0 °C was added the BH3 SMe2 complex (0.9 mL of a 2 M
solution in THF, 1.8 mmol). This mixture was stirred at 0 °C until
complete consumption of starting material, as determined by TLC
(ca. 24 h). EtOH (2 mL) was added followed by an aq 3 M solution
of NaOH (6 mL) and 30% H2O2 (6 mL). The mixture was stirred 10
h at r.t. EtOAc (10 mL) was added, and the organic layer was sep-
arated and washed with aq 10% Na2SO3 (10 mL) and brine (10 mL).
The combined organic layer was dried (MgSO4), filtered, and con-
centrated in vacuo. Purification by flash chromatography on silica
gel (30% Et2O–hexane) produced the desired product (2′R,4S,5S)-
27 (0.34 g, 55%) and its isomer (2′S,4S,5S)-28 (0.23 g, 38%) as col-
orless oils.
IR (KBr): 3383, 3063, 3030, 2952, 2912, 1945, 1878, 1799, 1632,
1605, 1497, 1453, 1364, 1252, 1061, 894, 843, 742, 704 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 0.93–1.20 (m, 3 H), 2.05 (dd, 1 H,
J = 13.8, 6.1 Hz), 2.27 (dd, 1 H, J = 13.8, 7.5 Hz), 2.41 (dd, 1 H,
J = 13.4, 9.2 Hz), 2.64 (dd, 1 H, J = 13.4, 5.0 Hz), 2.82 (ddd, 1 H,
J = 9.1, 5.3, 2.9 Hz), 3.17 (d, 1 H, J = 15.0 Hz), 3.24 (d, 1 H,
J = 15.0 Hz), 3.64 (ddd, 1 H, J = 7.4, 6.3, 2.7 Hz), 4.78 (s, 1 H),
4.83 (s, 1 H), 7.03 (d, 2 H, J = 7.0 Hz), 7.10–7.30 (m, 8 H).
13C NMR (CDCl3, 75 MHz): δ = 40.1, 41.4, 43.2, 55.4, 73.0, 114.5,
126.0, 126.1, 128.2, 128.3, 128.9, 129.1, 139.0, 139.8, 145.3.
(4S,5S)-4-Benzyl-5-(2-benzylprop-3-enyl)-3-(tert-butoxycarbo-
nyl)-2,2-dimethyl-1,3-oxazolidine (25)
(4S,5S)-4-Benzyl-5-[(2R)- 2-benzyl-3-hydroxypropyl]-3-(tert-
To a stirred solution of the amino alcohol 23 (0.53 g, 1.4 mmol) in
2,2-dimethoxypropane (20 mL) at r.t. was added p-toluenesulfonic
acid (13 mg), and the mixture was stirred for 46 h at r.t. Et2O (20
mL) was added and the organic layer was washed with 10% aq
NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried
(MgSO4), filtered, and concentrated in vacuo. Purification by flash
chromatography on silica gel (10% EtOAc–hexane) gave product
25 as a colorless oil.
butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidine (27)
20
Yield: 0.32 g (55%); [α]D +4.1 (c = 2.44, CHCl3); Rf 0.35 (70%
Et2O–hexane).
IR (neat): 3452, 3027, 2978, 2931, 1696, 1496, 1455, 1392, 1367,
1255, 1174, 1075 cm–1.
1H NMR (C6D6, 300 MHz, 65 °C): δ = 1.38 (m, 6 H), 1.45 (s, 9 H),
1.67 (br s, 3 H), 1.73–1.78 (m, 1 H), 2.38 (dd, 1 H, J = 12.9, 6.8 Hz),
2,47 (dd, 1 H, J = 12.9, 7.3 Hz), 2.72–2.92 (m, 1 H), 3.19–3.35 (m,
3 H), 3.68–3.79 (m, 1 H), 3.99 (ddd, 1 H, J = 9.2, 5.4, 3.8 Hz), 6.97–
7.13 (m, 10 H).
1H NMR (CDCl3, 300 MHz, 60 °C): δ = 1.25–1.33 (m, 2 H), 1.45
(br s, 3 H), 1.52 (s, 9 H), 1.57 (br s, 3 H), 1.70–1.73 (m, 1 H), 1.83–
2.14 (m, 1 H), 2.40 (dd, 1 H, J = 13.7, 6.8 Hz), 2.51 (dd, 1 H,
J = 13.7, 7.3 Hz), 2.75–2.91 (m, 1 H), 3.15 (dd, 1 H, J = 13.1, 3.3
Hz), 3.34–3.38 (m, 1 H), 3.42–3.47 (m, 1 H), 3.54–3.75 (m, 1 H),
3.92 (ddd, 1 H, J = 8.9, 5.3, 3.7 Hz), 7.02 (br d, 2 H, J = 6.6 Hz),
7.08 (d, 2 H, J = 7.2 Hz), 7.18–7.25 (m, 6 H).
13C NMR (C6D6, 75 MHz, 65 °C): δ = 27.3, 28.7, 28.8, 30.8, 37.2,
38.3, 41.0, 64.7, 65.3, 78.3, 79.7, 94.6, 126.1, 126.7, 128.5, 128.7,
129.5, 130.0, 138.4, 140.8, 152.1.
13C NMR (CDCl3, 75 MHz, 60 °C): δ = 26.7, 28.4, 28.5, 29.6, 36.8,
38.1, 40.8, 63.9, 65.3, 77.9, 80.0, 94.4, 125.9, 126.7, 128.3, 128.4,
129.1, 129.7, 137.7, 140.2, 152.0.
20
Yield: 0.54 g (91%); Rf 0.51 (30% EtOAc–hexane); [α]D –6.4
(c = 1.33, CHCl3).
IR (neat): 3066, 3028, 2972, 2924, 2856, 1945, 1876, 1808, 1702,
1645, 1604, 1491, 1453, 1385, 1256, 1175, 1076, 1032, 896, 741,
699 cm–1.
1H NMR (CDCl3, 300 MHz, 60 °C): δ = 1.50 (br s, 3 H), 1.64 (s, 9
H), 1.69 (s, 3 H), 2.06 (dd, 1 H, J = 14.3, 5.9 Hz), 2.22 (dd, 1 H,
J = 14.3, 7.3 Hz), 2.84–2.92 (m, 1 H), 3.22 (br s, 2 H), 3.30 (dd, 1
H, J = 12.9, 3.1 Hz), 3.91–3.97 (m, 1 H), 4.18 (ddd, 1 H, J = 7.3,
5.9, 4.0 Hz), 4.80 (s, 2 H), 7.11 (d, 2 H, J = 6.6 Hz), 7.25–7.39 (m,
8 H).
13C NMR (CDCl3, 75 MHz, 60 °C): δ = 27.2, 28.4, 28.6, 35.1, 40.9,
42.8, 63.3, 77.8, 80.0, 94.3, 114.2, 126.2, 126.6, 128.4, 128.6,
129.1, 129.8, 138.2, 139.5, 145.3, 152.3.
HRMS: m/z calcd for C27H35NO3: 421.2617, found: 421.1827.
Anal. Calcd for C27H35NO3: C, 76.92; H, 8.37; N, 3.32. Found: C,
77.28; H, 8.17; N, 3.45.
HRMS: m/z calcd for C27H37NO4: 439.2723, found: 324.1949
(M+ – 105).
(4S,5S)-4-Benzyl-5-(2-benzylprop-2-enyl)-1,3-oxazolidin-2-one
(26)
Anal. Calcd for C27H37NO4: C, 73.77; H, 8.48; N, 3.19: Found: C,
73.70; H, 8.41; N, 3.17.
To a solution of amino alcohol 24 (60 mg, 0.213 mmol) in CH2Cl2
(1.2 mL) at 0 °C was added slowly a solution of triphosgene (76 mg,
0.256 mmol) in CH2Cl2 (1.2 mL). The mixture was stirred for 3 h at
r.t., diluted with CH2Cl2 (10 mL), and washed with aq sat. NaHCO3
(5 mL). The aqueous phase was extracted with CH2Cl2 (2 × 10 mL)
and the organic layer dried (MgSO4) and concentrated to provide
the crude product, which was purified by flash chromatography
(20% EtOAc–hexane).
(4S,5S)-4-Benzyl-5-[(2S)-2-benzyl-3-hydroxypropyl]-3-(tert-bu-
toxycarbonyl)-2,2-dimethyl-1,3-oxazolidine (28)
20
Yield: 0.23 g (38%); [α]D +5.3 (c = 1.89, CHCl3); Rf 0.40 (70%
Et2O–hexane).
IR (film): 3469, 3062, 3027, 2979, 2933, 1695, 1604, 1496, 1478,
1455, 1392, 1367, 1256, 1208, 1174, 1077, 1031, 868, 770, 740,
701, 516 cm–1.
1H NMR (C6D6, 300 MHz, 65 °C): δ = 1.35 (br s, 2 H), 1.46–1.49
(m, 1 H), 1.53 (br s, 12 H), 1.82–1.88 (m, 2 H), 2.42 (dd, 1 H,
J = 13.6, 6.8 Hz), 2.58 (dd, 1 H, J = 13.6, 7.9 Hz), 2.77–2.84 (m, 1
H), 3.20 (dd, 1 H, J = 13.2, 2.9 Hz), 3.39 (dd, 1 H, J = 10.8, 5.1 Hz),
3.46 (dd, 1 H, J = 10.8, 4.4 Hz), 3.73–3.79 (m, 1 H), 4.07 (ap dt, 1
H, J = 13.0, 4.2 Hz), 7.02 (d, 2 H, J = 7.0 Hz), 7.15–7.31 (m, 8 H).
Yield: 46 mg (70%); Rf 0.52 (50% EtOAc–hexane).
IR (film): 3278, 3068, 3028, 2917, 2852, 1754, 1644, 1600, 1494,
1456, 1389, 1246, 1096, 1013, 902, 735, 703 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 2.10 (dd, 1 H, J = 14.6, 6.0 Hz),
2.33 (dd, 1 H, J = 14.6, 7.3 Hz), 2.72 (dd, 1 H, J = 13.4, 6.3 Hz),
2.81 (dd, 1 H, J = 13.4, 7.0 Hz), 3.20 (d, 1 H, J = 15.4 Hz), 3.26 (d,
1 H, J = 15.4 Hz), 3.63 (q, 1 H, J = 6.0 Hz), 4.37 (q, 1 H, J = 6.0
Synthesis 2003, No. 4, 603–622 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of Aspartyl Protease Inhibitors
617
1H NMR (CDCl3, 300 MHz, 60 °C): δ = 1.35 (br s, 4 H), 1.46–1.49
(m, 1 H), 1.53 (s, 12 H), 1.82–1.88 (m, 1 H), 2.42 (dd, 1 H, J = 13.7,
6.8 Hz), 2.58 (dd, 1 H, J = 13.7, 7.9 Hz), 2.77–2.84 (m, 1 H), 3.21
(dd, 1 H, J = 13.2, 2.9 Hz), 3.39 (dd, 1 H, J = 11.0, 5.1 Hz), 3.46
(dd, 1 H, J = 11.0, 4.6 Hz), 3.73–3.82 (m, 1 H), 4.07 (ap dt, 1 H,
J = 8.8, 4.4 Hz), 7.02 (br d, 2 H, J = 7.0 Hz), 7.17–7.27 (m, 8 H).
13C NMR (C6D6, 75 MHz, 65 °C): δ = 27.3, 28.5, 28.8, 30.1, 36.2,
38.3, 40.0, 64.3, 64.5, 77.4, 79.7, 94.6, 126.1, 126.7, 128.5, 128.7,
129.5, 130.1, 138.5, 140.8, 152.1.
(1.92 g, 16.5 mmol) and activated powdered molecular sieves (2.74
g) in CH2Cl2 (6 mL) was added at r.t. under argon. On completion
of the reaction, the mixture was filtered through a pad of silica gel,
eluting with 7% EtOAc–hexane. The filtrate was evaporated and the
residue was purified by column chromatography on silica gel using
7% EtOAc–hexane to give lactones 32 and 33, respectively, in 95%
overall yield.
(3R,5S)-3-Benzyl-5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-
phenylethyl}dihydrofuran-2-(3H)-one (32)
Yield: 1.15 g (53%); Rf 0.60 (30% EtOAc–hexane).
13C NMR (CDCl3, 75 MHz, 60 °C): δ = 26.9, 28.1, 28.6, 29.7, 36.6,
37.7, 39.4, 63.7, 64.4, 77.2, 80.0, 94.3, 125.9, 126.6, 128.3, 128.5,
129.1, 129.7, 137.9, 140.3, 152.1.
IR (film): 3340, 3027, 2975, 2927, 2848, 1769, 1706, 1493, 1457,
1367, 1245, 1166, 1028, 965, 747, 700 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.35 (s, 9 H), 1.96 (m, 1 H), 2.22
(m, 1 H), 2.76 (dd, 1 H, J = 13.5, 8.8 Hz), 2.85 (m, 2 H), 2.97 (m, 1
H), 3.10 (dd, 1 H, J = 13.5, 4.4 Hz), 3.93 (br q, 1 H, J = 8.4 Hz),
4.20 (m, 1 H), 4.57 (br d, 1 H, J = 9.5 Hz), 7.20 (m, 10 H).
HRMS: m/z calcd for C27H37NO4: 439.2723, found: 324.1955
(M+ – 105).
Anal. Calcd for C27H37NO4: C, 73.77; H, 8.48; N, 3.19. Found: C,
73.69; H, 8.42; N, 3.16.
13C NMR (CDCl3, 75 MHz): δ = 28.3, 29.4, 36.9, 39.1, 41.4, 54.5,
78.3, 79.9, 126.5, 126.7, 128.4, 128.5, 128.7, 129.1, 136.9, 137.7,
155.6, 178.9.
(2S,3S,5S)-2,5-Dibenzylpiperidin-3-ol (29)
To a solution of imidazole (34.4 mg, 0.51 mmol) and Ph3P (48.6
mg, 0.185 mmol) in CH2Cl2 (2 mL) at 0 °C was added I2 (47 mg,
0.19 mmol). This mixture was stirred at 0 °C for 15 min and then a
solution of the alcohol (2′S,4S,5S)-28 (74 mg, 0.17 mmol) in
CH2Cl2 (1 mL) was added. The resulting mixture was stirred at 0 °C
for 15 min and then at r.t. for 12 h. The mixture was diluted with a
sat. aq solution of Na2S2O3 (1 mL) followed by addition of H2O (5
mL). The aqueous phase was extracted with CH2Cl2 (3 × 10 mL),
the combined organic layers were dried (MgSO4) and concentrated
to provide the crude product, which was purified by flash chroma-
tography (5% EtOAc–hexane) to give 63 mg (68%) of the interme-
diate iodide. To a solution of this iodide (63 mg, 0.115 mmol) in a
50:50 mixture of EtOAc–DMF (2 mL) was added aq 4 M HCl (1.8
mL). This mixture was stirred at r.t. for 3 h, quenched by the addi-
tion of K2CO3 (0.5 g) and H2O (5 mL) and allowed to stir at r.t. for
2 h. The volatiles were removed under reduced pressure and the re-
maining solvent was removed in vacuo (2 Torr). The product was
purified by flash cromatography (5% MeOH–CH2Cl2).
(3S,5S)-3-Benzyl-5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-
phenylethyl}dihydrofuran-2-(3H)-one (33)
Yield: 0.911 g (42%); Rf 0.56 (30% EtOAc–hexane).
IR (film): 3347, 3065, 3030, 2978, 2927, 2855, 1774, 1703, 1602,
1497, 1451, 1365, 1247, 1170, 1042, 740, 705 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.40 (s, 9 H), 1.79 (br q, 1 H,
J = 12.0 Hz), 2.06 (m, 1 H), 2.68 (dd, 1 H, J = 13.7, 10.0 Hz), 2.81–
3.0 (m, 3 H), 3.25 (dd, 1 H, J = 13.5, 3.7 Hz), 3.93 (br q, 1 H, J = 8.4
Hz), 4.3 (dd, 1 H, J = 9.2, 6.2 Hz), 4.61 (br d, 1 H, J = 10.0 Hz),
7.11–7.30 (m, 10 H).
13C NMR (CDCl3, 75 MHz): δ = 28.3, 30.5, 36.2, 39.4, 42.6, 53.2,
77.7, 79.8, 126.6, 128.5, 128.8, 129.2, 137.0, 138.2, 155.7, 177.7.
(2R,4S,5S)-2-Benzyl-5-[(tert-butoxycarbonyl)amino]-4-hy-
droxy-N-[(1S,2R)-2-hydroxy-1-indanyl]-6-phenylhexanamide
(1)
Yield: 30 mg (63%); Rf 0.29 (70% MeOH–CH2Cl2).
IR (film): 3470, 3061, 3025, 2960, 2930, 1497, 1475, 1450, 1390,
1365, 1252, 1206, 1170, 1030, 865, 770 cm–1.
A solution of 32 (982 mg, 2.4 mmol) in 1,4-dioxane (14 mL) was
treated with a solution of LiOH in H2O (1 M, 2.6 mL, 2.6 mmol) and
stirred at r.t. for 3 h. The reaction mixture was carefully acidified to
pH 4 with citric acid and then extracted with EtOAc. The organic
extracts were combined and washed with brine, dried (MgSO4), fil-
tered and evaporated in vacuo. The crude hydroxy acid was dis-
solved in DMF (30 mL), treated with tert-butyldimethylsilyl
chloride (3.63 g, 24 mmol) and imidazole (1.95 g, 28.6 mol), and
stirred for 24 h. MeOH (20 mL) was added to the mixture and it was
stirred for 3 h, evaporated in vacuo, and then partitioned between
10% aq citric acid (50 mL) and EtOAc (200 mL). The organic layer
was washed with brine, dried (MgSO4), filtered and evaporated in
vacuo. Purification by flash column chromatography (3% MeOH–
CH2Cl2) gave 19 (1.19 g, 94%) as a white foam. A solution of 19
(100 mg, 0.188 mmol), (1S,2R)-1-amino-2-hydroxyindan (34; 34.7
mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (51 mg, 0.27 mmol) and 1-hydroxybenzotriazole (31
mg, 0.26 mmol) in DMF (5 mL) was stirred at r.t. for 15 h. The re-
action mixture was diluted with EtOAc (25 mL) and the organic
phase was washed with aq citric acid (pH 4), aq NaHCO3, and brine,
dried (MgSO4), filtered, and evaporated in vacuo. Purification by
flash column chromatography (20% EtOAc–hexane) gave the cor-
responding silylated product.
1H NMR (CDCl3, 500 MHz): δ = 1.76 (ddd, 1 H, J = 12.7, 7.4, 5.5
Hz), 1.87 (dt, 1 H, J = 12.2, 7.6 Hz), 1.92 (br s, 2 H), 2.49 (dd, 1 H,
J = 13.4, 9.5 Hz), 2.57 (m, 1 H), 2.69 (d, 2 H, J = 7.6 Hz), 2.80 (dd,
1 H, J = 13.4, 4.0 Hz), 2.89 (m, 1 H), 3.49 (dd, 1 H, J = 8.54, 6.1
Hz), 3.89 (q, 1 H, J = 6.7 Hz), 3.92 (dd, 1 H, J = 8.4, 6.3 Hz), 7.16–
7.30 (m, 10 H).
13C NMR (CDCl3, 75 MHz): δ = 34.6, 39.3, 40.8, 41.2, 56.8, 73.0,
81.8, 125.9, 126.1, 128.3, 128.4, 128.6, 129.1, 138.8, 140.4.
HRMS: m/z calcd for C19H23NO4: 281.1780, found: 281.1824.
Lactones 32 and 33
To a solution of amino alcohol 23 (2.25 g, 5.90 mmol) in THF (70
mL) cooled to 0 °C was added the BH3 SMe2 complex (15.8 mL of
a 2 M solution in THF, 29.5 mmol). This mixture was stirred at 0 °C
until complete consumption of starting material, as determined by
TLC ( ca.24 h). EtOH (36 mL) was added followed by an aq 3 M
solution of NaOH (74 mL) plus 30% H2O2 (56 mL). The mixture
was stirred at r.t. for 10 h. EtOAc (20 mL) was added and the organ-
ic layer was separated and washed with aq 10% Na2SO3 (20 mL)
and brine (20 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. Purification by flash
chromatography on silica gel (50% EtOAc–hexane) gave a mixture
of diols 30 and 31 (2.19 g, 93% yield) as a colorless oil. Solid TPAP
(192 mg, 0.59 mmol) was added in one portion to a stirred mixture
of diols 30 and 31 (2.18 g, 5.60 mmol), then a mixture of NMO
Yield: 100 mg (80%); Rf 0.32 (30% EtOAc–hexane).
Silylated Product
IR (film): 3322, 2957, 2856, 2796, 1710, 1655, 1500, 1462, 1362,
1251, 1173, 1091, 841, 780, 702 cm–1.
Synthesis 2003, No. 4, 603–622 ISSN 0039-7881 © Thieme Stuttgart · New York

618
L. C. Dias et al.
FEATURE ARTICLE
1H NMR (CDCl3, 500 MHz): δ = 0.11 (s, 3 H), 0.15 (s, 3 H), 0.96
(s, 9 H), 1.26 (s, 9 H), 1.75–1.79 (m, 2 H), 1.96–2.01 (m, 2 H), 2.56–
2.62 (m, 2 H), 2.76–2.84 (m, 4 H), 3.0 (dd, 1 H, J = 16.6, 5.0 Hz),
3.85 (br dd, 1 H, J = 8.5, 4.0 Hz), 3.99 (br q, 1 H, J = 8.8 Hz), 4.23
(br t, 1 H, J = 4.9 Hz), 4.83 (d, 1 H, J = 9.5 Hz), 5.25 (dd, 1 H,
J = 8.7, 4.8 Hz), 5.96 (d, 1 H, J = 8.8 Hz), 7.12–7.32 (m, 14 H).
13C NMR (CDCl3, 125 MHz): δ = –4.4, –3.9, 18.1, 25.9, 28.2, 37.3,
38.4, 38.9, 39.1, 46.7, 54.1, 57.4, 70.7, 73.1, 79.5, 124.2, 124.9,
126.4, 126.5, 126.7, 127.8, 128.5, 128.6, 129.0, 129.1, 138.5, 139.8,
140.1, 140.2, 156.0, 174.5.
IR (film): 3415, 3351, 3060, 3031, 2974, 2928, 2854, 1945, 1882,
1704, 1602, 1487, 1453, 1367, 1253, 1167, 1018, 967, 893, 802,
732, 699 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.42 (s, 9 H), 2.78 (br s, 2 H), 3.52
(s, 2 H), 4.35–4.50 (m, 2 H), 4.92 (s, 1 H), 5.12 (s, 1 H), 5.60 (ap dt,
1 H, J = 15.8, 2.7 Hz), 6.14 (d, 1 H, J = 15.8 Hz), 6,96 (br d, 2 H,
J = 7.7 Hz), 7.14–7.34 (m, 8 H).
(4R,5S)-2-Benzyl-5-[(tert-butoxycarbonyl)amino]-6-phenylhex-
1-en-4-ol (39)
To a solution of ester 37 (557 mg, 1.05 mmol) in a mixture of
EtOH–H2O–THF (75 mL, 2:1:2) was added LiOH (150 mg, 0.60
mmol). After 1 h, the reaction mixture had turned yellow and to it
was added Et2O (75 mL) and sat. aq NH4Cl (75 mL). After separa-
tion, the organic phase was dried (MgSO4) and concentrated in vac-
uo. The residue was purified by recrystallization (5% EtOAc–
hexane) to give 392 mg of 39 as a white solid in 98% yield.
This material was dissolved in a solution of Bu4NF in THF (1 M,
1.25 mL) and stirred at r.t. for 12 h. The reaction mixture was dilut-
ed with citric acid in Et2O (pH 4) and the resulting precipitate was
collected by filtration, washed and dried in vacuo. Further purifica-
tion by flash column chromatography (6% MeOH/CH2Cl2) gave L-
685-434 (1) as a white solid.
L-685,434 (1)
Method B: To a stirred solution of alcohol 23 (103 mg, 0.27 mmol)
in CH2Cl2 (5 mL) at 0 °C under argon was added Dess–Martin pe-
riodinane (229 mg, 0.54 mmol) and the stirring was continued for 1
h. Sat. aq NaHCO3 (5 mL), aq Na2S2O3 (1.5 M, 4 mL) and Et2O
were added and stirring was continued for 15 min at r.t. The aqueous
layer was further extracted with Et2O and the combined organic lay-
ers were dried, filtered and concentrated. To a solution of the crude
ketone 40 in THF (3 mL) at 0 °C was added dropwise a 1 M solution
of LiBH4 in THF (0.5 mL, 0.5 mmol). After 24 h, the solution was
quenched with H2O (2 mL) and extracted with EtOAc (2 × 50 mL).
The combined organic extracts were washed with H2O (20 mL) and
brine (20 mL), dried (MgSO4), and concentrated in vacuo. The res-
idue was purified by recrystallization (5% EtOAc–hexane) to give
39 (62.8 mg) as a white solid.
Yield: 90 mg (88%); Rf 0.21 (60% EtOAc–hexane); [α]D25 +16.7
(c = 0.28, MeOH); mp 194.3–197.5 °C.
IR (KBr) 3447, 3365, 3061, 3022, 2917, 2849, 1665, 1645, 1537,
1392, 1278, 1158, 1058, 899, 862, 733, 703, 649 cm–1.
1H NMR (DMSO-d6, 500 MHz): δ = 1.37 (s, 9 H), 1.80–1.96 (m, 2
H), 2.72–2.95 (m, 6 H), 3.02 (dd, 1 H, J = 16.8, 5.1 Hz), 3.45 (m, 1
H), 3.68 (m, 1 H), 3.81 (m, 1 H), 4.22 (t, 1 H, J = 4.8 Hz), 4.81 (d,
1 H, J = 9.5 Hz), 5.23 (dd, 1 H, J = 8.4, 5.1 Hz), 5.87 (d, 1 H, J = 8.4
Hz), 7.05 (br s, 1 H), 7.05–7.30 (m, 14 H).
13C NMR (DMSO-d6, 125 MHz,): δ = 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.
Yield: 61% overall; mp 141.5–142.3 °C; Rf 0.32 (30% EtOAc–hex-
ane).
HRMS: m/z calcd for C33H40N2O5: 544.2937, found: 544.2888.
IR (KBr): 3365, 3065, 3028, 2928, 2852, 1685, 1644, 1528, 1450,
1369, 1316, 1269, 1169, 1073, 1015, 909, 873, 732, 697, 644, 537
cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.34 (br s, 9 H), 2.16 (dd, 2 H,
J = 14.3, 9.2 Hz), 2,29 (m, 1 H), 2,77 (m, 1 H), 2.89 (dd, 1 H,
J = 14.3, 4.0 Hz), 3.36 (d, 1 H, J = 15.0 Hz), 3.42 (d, 1 H, J = 15.0
Hz), 3.80 (m, 2 H), 4.56 (br d, 1 H, J = 7.7 Hz), 4.95 (br s, 1 H), 5.00
(br s, 1 H), 7.15–7.34 (m, 10 H).
(1R)-3-Benzyl-1-{(1S)-1-[(tert-Butoxycarbonyl)amino]-2-phe-
nylethyl}but-3-enyl 4-Nitrobenzoate (37)
Method A: To a stirred solution of alcohol 23 (1.14 g, 3 mmol), Ph3P
(6.2 g, 24 mmol) and p-nitrobenzoic acid (3.9 g, 24 mmol) in THF
(50 mL) at r.t. was added di-tert-butyl azodicarboxylate (5.4 g) in
THF (10 mL). The solution was then stirred at r.t. for 18 h, where-
upon the volatile components were removed in vacuo and the resi-
due purified by flash chromatography on silica gel (15% EtOAc–
hexane) to give 37 as a white crystalline solid and 38 as a colorless
oil.
13C NMR (CDCl3, 75 MHz): δ = 28.2, 35.5, 39.9, 42.8, 56.1, 71.1,
79.5, 114.8, 126.3, 128.3, 128.4, 128.6, 129.0, 129.4, 135.7, 138.1,
145.6, 156.0.
Yield: 955 mg (60%); Rf 0.47 (30% EtOAc–hexane); mp 137.1–
138.8 °C; [α]D25 +10.0 (c = 1.0, CHCl3).
MS: m/z (%) = 290 (M+ – 91, 11), 216 (7), 190 (16), 164 (45), 120
(74), 91 (46), 57 (100).
IR (KBr): 3375, 3065, 3032, 2984, 2926, 2852, 1953, 1715, 1691,
1609,1520, 1454, 1331, 1265, 1176, 1127, 995, 874, 742, 717 cm–1.
HRMS: m/z calcd for C24H31NO3: 381.2304; found: 290.0425
(M+ – 91).
1H NMR (CDCl3, 300 MHz): δ = 1.24 (s, 9 H), 2.37 (m, 2 H), 2.62
(br d, 1 H, J = 13.8, 9.2 Hz), 2.84 (dd, 1 H, J = 13.8, 4.9 Hz), 3.29
(d, 1 H, J = 15.2 Hz), 3.36 (d, 1 H, J = 15.2 Hz), 4.14–4.28 (m, 1 H),
4.44 (d, 1 H, J = 9.2 Hz), 4.74 (br s, 1 H), 4.84 (br s, 1 H), 5.34–5.37
(m, 1 H), 7.07–7.22 (m, 10 H), 8.05 (d, 2 H, J = 8.6 Hz), 8.19 (d, 2
H, J = 8.6 Hz).
Anal. Calcd for C24H31NO3: C 75.56, H 8.19, N 3.67; found: C
75.41, H 8.13, N 3.62.
(4S,5R)-4-Benzyl-5-(2-benzylprop-3-enyl)-3-(tert-butoxycarbo-
nyl)-2,2-dimethyl-1,3-oxazolidine (41)
To a stirred solution of the amino alcohol 39 (76 mg, 0.2 mmol) in
2,2-dimethoxypropane (1 mL) at r.t., was added p-toluenesulfonic
acid (1.5 mg), and the mixture was stirred for 46 h at r.t. Et2O (5 mL)
was added, and the organic layer was washed with 10% NaHCO3 (3
mL) and a sat. aq solution of NaCl (2 mL). The organic layer was
dried (MgSO4), filtered, and concentrated in vacuo. Purification by
flash chromatography on silica gel (10% EtOAc–hexane) gave
product 41 as a colorless oil.
13C NMR (CDCl3, 75 MHz): δ = 28.1, 36.5, 36.6, 42.4, 53.3, 75.0,
79.6, 115.3, 123.5, 126.4, 126.7, 128.5, 128.6, 129.1, 130.8, 135.7,
137.2, 138.9, 144.1, 150.6, 155.3, 164.2.
MS: m/z (%) = 530 (M+, 55), 225 (67), 91 (32), 57 (100).
HRMS: m/z calcd for C31H34N2O6: 530.2417; found: 530.9723.
tert-Butyl (1S,2E)-1,4-Dibenzylpenta-2,4-dienylcarbamate (38)
Yield: 109 mg (10%); Rf 0.64 (20% EtOAc–hexane).
20
Yield: 65 mg (77%); Rf 0.56 (20% EtOAc–hexane); [α]D +5.6
(c = 1.8, CHCl3).
Synthesis 2003, No. 4, 603–622 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of Aspartyl Protease Inhibitors
619
IR (neat): 3440, 3063, 3027, 2979, 2933, 1696, 1647, 1604, 1496,
1455, 1386, 1355, 1251, 1087, 1029 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 0.88 (d, 3 H, J = 6.4 Hz), 0.91 (d,
3 H, J = 6.4 Hz), 1.38 (s, 9 H), 1.45–1.62 (m, 3 H), 3.09 (d, 1 H,
J = 6.6 Hz), 3.10–3.20 (m, 1 H), 4.06 (br s, 1 H), 4.74 (dd, 1 H,
J = 15.0, 6.6 Hz), 5.13 (br s, 1 H), 6.02 (br s, 1 H), 6.65 (br s, 1 H),
7.05 (br s, 1 H), 7.19–7.31 (m, 5 H).
13C NMR (CDCl3, 75 MHz): δ = 22.9, 24.7, 28.3, 37.6, 41.0, 53.6,
53.8, 80.4, 126.8, 128.4, 129.1, 136.4, 155.7, 172.4, 173.4.
1H NMR (CDCl3, 300 MHz, 60 °C): δ = 1.34 (br s, 9 H), 1.51 (s, 3
H), 1.58 (s, 3 H), 2.02 (dd, 1 H, J = 15.9, 4.0 Hz), 2.29 (dd, 1 H,
J = 15.9, 8.2 Hz), 2.78 (br d, 1 H, J = 6.6 Hz), 3.28 (s, 2 H), 4.03–
4.16 (m, 1 H), 4.21 (ddd, 1 H, J = 8.2, 4.8, 4.0 Hz), 4.79 (s, 1 H),
4.84 (s, 1 H), 7.09–7.26 (m, 10 H).
13C NMR (CDCl3, 75 MHz, 60 °C): δ = 24.1, 37.8, 28.5, 35.2, 36.5,
44.0, 60.8, 75.8, 79.6, 92.7, 112.5, 125.9, 126.1, 127.0, 128.2,
129.0, 129.4, 139.0, 139.3, 145.5, 151.8.
(1S,2S,4R)-{1-Benzyl-4-[1-(1S)-carbamoyl-2-phenylethylcarba-
moyl)-(1S)-3-methylbutylcarbamoyl]-2-hydroxy-5-phenylpent-
yl}carbamic Acid tert-Butyl Ester (2)
HRMS: m/z Calcd for C27H35NO3: 421.2617, found: 330.2040
To a solution of Boc-Leu-Phe-NH2 (90 mg, 0.24 mmol) in EtOAc–
MeOH (50:50, 3 mL) was added AcCl (1 mL) at 0 °C. The resulting
mixture was stirred for 30 min at 0 °C and the solvent was removed
in vacuo (2 Torr, 45 °C) to give NH2-Leu-Phe-NH2 (35) in quanti-
tative yield. A solution of 19 (62 mg, 0.117 mmol), NH2-Leu-Phe-
NH2 (35; 63 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide hydrochloride (34 mg, 0.176 mmol), 1-hydroxyben-
zotriazole (21 mg, 0.176 mmol) and Et3N (50 µL) in DMF (3 mL)
was stirred at r.t. for 15 h. The reaction mixture was diluted with
EtOAc (10 mL), and the organic phase was washed with aq citric
acid (pH 4), aq NaHCO3 and brine, dried (MgSO4), filtered, and
evaporated in vacuo. Purification by flash column chromatography
(5% MeOH–CH2Cl2) gave the corresponding silylated product.
(M+ – 91).
Anal. Calcd for C27H35NO3: C, 76.92; H, 8.37; N, 3.32. Found: C,
77.02; H, 8.21; N, 3.35.
tert-Butyl (1S)-2-Amino-1-benzyl-2-oxoethylcarbamate
A solution of N-Boc-Phe 36 (1.35 g, 5.1 mmol), 1-(3-dimethylami-
nopropyl)-3-ethylcarbodiimide hydrochloride (1.06 g, 5.61 mmol)
and 1-hydroxybenzotriazole (669 mg, 5.61 mmol) in a mixture of
DMF (10 mL) and CH2Cl2 (20 mL) was stirred at r.t. for 1 h. To the
resulting suspension was aq (0.78 mL, 10.2 mmol) at 0 °C and the
mixture was stirred for 2 h at 0 °C and 18 h at r.t. The mixture was
diluted with EtOAc (25 mL) and the organic phase was washed with
aq citric acid (pH 4), aq NaHCO3 (2 × 10 mL) and brine (10 mL),
dried (MgSO4), filtered, and evaporated in vacuo.
Yield: 83 mg (91%); [α]D25 –32.6 (c = 0.57, MeOH); Rf 0.28 (60%
EtOAc–hexane); mp 189.3–192.2 °C.
Boc-Protected 22
Silylated Product
IR (KBr): 3453, 3297, 3077, 3033, 2964, 2935, 2867, 1689, 1650,
1548, 1494, 1455, 1382, 1259, 1176, 1074, 844, 781, 703.
Yield: 1.12 g (90%); mp 148.2–151.5 °C; Rf 0.34 (60% EtOAc–
hexane); [α]D20 +12.3 (c = 0.82, MeOH).
1H NMR (CDCl3, 500 MHz): δ = 0.09 (s, 6 H), 0.70 (d, 3 H, J = 6.4
Hz), 0.78 (d, 3 H, J = 6.4 Hz), 0.94 (s, 9 H), 1.18–1.31 (m, 3 H),
1.33 (s, 9 H), 1.63 (m, 1 H), 1.75 (br t, 1 H, J = 11.0 Hz), 2.50 (dd,
1 H, J = 13.6, 4.0 Hz), 2.61–2.69 (m, 3 H), 2.72–2.81 (m, 2 H), 3.20
(dd, 1 H, J = 14.3, 5.5 Hz), 3.68 (dd, 1 H, J = 10.2, 3.82 Hz), 3.97
(dd, 1 H, J = 17.0, 7.63 Hz), 4.05 (dd, 1 H, J = 12.7, 7.63 Hz), 4.56
(m, 1 H), 4.75 (d, 1 H, J = 10.0 Hz), 5.65 (br s, 1 H), 5.92 (d, 1 H,
J = 8.2 Hz), 6.31 (d, 1 H, J = 5.2 Hz), 6.45 (br s, 1 H), 7.04–7.10 (m,
4 H), 7.11–7.33 (m, 11 H).
IR (KBr): 3390, 3347, 3194, 2986, 2930, 1660, 1520, 1446, 1368,
1328, 1251, 1168, 1046, 756 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.40 (s, 9 H), 3.06 (br s, 2 H),
4.39–4.41 (m, 1 H), 5.21 (br d, 1 H, J = 8.0 Hz), 5.72–5.84 (m, 1
H), 5.96–6.10 (m, 1 H), 7.17–7.33 (m, 5 H).
13C NMR (CDCl3, 75 MHz): δ = 28.3, 38.5, 55.3, 80.1, 126.8,
128.5, 129.2, 136.6, 155.3, 173.9.
MS: m/z (%) = 264 (M+, 3), 230 (29), 191 (4), 164 (18), 147 (13),
120 (43), 91 (23), 73 (12), 57 (100).
13C NMR (CDCl3, 125 MHz): δ = –4.5, –3.8, 18.0, 22.2, 22.3, 24.4,
25.9, 28.4, 36.8, 36.9, 37.2, 39.2, 40.5, 44.6, 53.1, 53.3, 53.6, 70.4,
79.6, 126.5, 126.6, 126.7, 128.5, 128.5, 128.7, 128.8, 128.9, 130.0,
137.0, 138.2, 139.4, 156.5, 171.2, 173.1, 175.7.
HRMS: m/z calcd for C9H12N2O: 264.1474; found: 264.1479.
To a solution of this product in EtOAc–MeOH (50:50, 6 mL) at
0 °C was added AcCl (2 mL). The resulting mixture was stirred for
30 min at 0 °C and the solvent was removed in vacuo (2 Torr,
45 °C) to give PheNH2. Purification by flash column chromatogra-
phy (40% EtOAc–hexane) gave product 22 (0.594 g, 71% overall
yield).
L-682,458 (2)
This material was dissolved in a solution of Bu4NF in THF (1 M, 2
mL) and stirred at r.t. for 48 h. The reaction mixture was diluted
with citric acid in Et2O (pH 4) and the resulting precipitate was col-
lected by filtration, washed, and dried in vacuo to give L-682,679
(2). Further purification by flash column chromatography (6%
MeOH–CH2Cl2) gave L-682,679 (2) as a white solid.
(2S)-N-[(1S)-2-Amino-1-benzyl-2-oxoethyl]-2-[(tert-butoxycar-
bonyl)amino]-4-methylpentanamide (Boc-Leu-Phe-NH2)
A solution of N-Boc-Leu 21 (0.948 g, 4.1 mmol), 1-(3-dimethy-
laminopropyl)-3-ethylcarbodiimide hydrochloride (3.92 mmol), 1-
hydroxybenzotriazole (467 mg, 3.92 mmol) and NaHCO3 (598 mg)
in DMF (15 mL) was stirred at r.t. for 1 h. To the resulting suspen-
sion was added amide 22 (638 mg, 3.92 mmol) at 0 °C and the mix-
ture was stirred for 2 h at 0 °C and 18 h at r.t. The reaction mixture
was diluted with EtOAc (25 mL) and the organic phase was washed
with aq citric acid (pH 4), aq NaHCO3 (2 × 10 mL) and brine (10
mL), dried (MgSO4), filtered, and evaporated in vacuo. Purification
by flash column chromatography (40% EtOAc–hexane) gave the
product.
Yield: 67 mg (94%); [α]D25 –32.6 (c = 0.57, MeOH); mp 189.3–
192.2 °C; Rf 0.43 (80% EtOAc–hexane).
IR (KBr): 3377, 3341, 3190, 2955, 2924, 2872, 2853, 1667, 1649,
1621, 1531, 1451, 1365, 1273, 1250, 1172, 1080, 743, 698 cm–1.
1H NMR (DMSO-d6, 500 MHz): δ = 0.77 (d, 3 H, J = 6.4 Hz), 0.84
(d, 3 H, J = 6.4 Hz), 1.28 (s, 9 H), 1.20–1.35 (m, 2 H), 1.49 (m, 1
H), 1.60 (m, 1 H), 2.45 (dd, 1 H, J = 13.4, 8.2 Hz), 2.53 (dd, 1 H,
J = 13.7, 9.5 Hz), 2.70 (dd, 1 H, J = 13.6, 5.0 Hz), 2.78–2.87 (m, 3
H), 3.00 (dd, 1 H, J = 5.2, 3.7 Hz), 3.51–3.57 (m, 1 H), 4.21 (q, 1 H,
J = 6.7 Hz), 4.42 (q, 1 H, J = 5.5 Hz), 4.48 (d, 1 H, J = 6.1 Hz), 6.36
(d, 1 H, J = 9.0 Hz), 7.09 (br s, 1 H), 7.12–7.25 (m, 15 H), 7.34 (br
s, 1 H), 7.70 (d, 1 H, J = 8.0 Hz), 7.93 (d, 1 H, J = 8.0 Hz).
Yield: 1.33 mg (86%); Rf 0.39 (70% EtOAc–hexane).
IR (KBr): 3063, 2957, 2922, 1935, 1502, 1453, 1367, 1253, 1168,
1099, 1042, 921, 870, 730 cm–1.
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L. C. Dias et al.
FEATURE ARTICLE
13C NMR (DMSO-d6, 125 MHz): δ = 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.
13C NMR (CDCl3, 75 MHz): δ = 28.2, 29.7, 31.4, 36.1, 45.5, 54.3,
78.9, 79.8, 126.6, 128.4, 128.5, 128.6, 129.3, 136.4, 138.2, 155.0,
177.4.
(2R,4R,5S)-2-Benzyl-5-tert-butoxycarbonylamino-4-(tert-butyl-
dimethylsilyloxy)-6-phenylhexanoic Acid (46)
(1S,4R){(1)-Benzyl-4-[1-(1S)-carbamoyl-2-phenylethylcarba-
moyl)-(1S)-3-methylbutylcarbamoyl]-2-oxo-5-phenylpentyl}-
carbamic Acid tert-Butyl Ester (4)
A solution of 44 (0.21 g, 5.3 mmol) in 1,2-dimethoxyethane (36
mL) was treated with a solution of LiOH in H2O (1 M, 36 mL, 36
mmol) and stirred at r.t. for 6 h. The reaction mixture was carefully
acidified to pH 4 with aq citric acid, and then extracted with EtOAc.
The organic extracts were combined and washed with brine, dried
(MgSO4), filtered, and evaporated in vacuo. The crude hydroxy acid
(0.216 g) was dissolved in DMF (30 mL), treated with tert-bu-
tyldimethylsilyl chloride (7.98 g, 52.8 mmol) and imidazole (4.26
g, 0.06 mol). The solution was stirred for 15 h. The mixture was di-
luted with MeOH (6 mL), stirred for 3 h, and then evaporated in
vacuo. The mixture was partitioned between aq citric acid and
EtOAc. The organic layer was washed with brine, dried (MgSO4),
filtered, and evaporated in vacuo. Purification by flash column
chromatography (3% MeOH–CH2Cl2) gave 46 (204 mg, 73%) as a
white foam.
To a stirred solution of alcohol 2 (40 mg, 0.06 mmol) in DMF (1.5
mL) was added PDC (112 mg, 0.3 mmol) in one portion. The result-
ing reaction mixture was allowed to stirr at r.t. for 24 h. It was
quenched with H2O (10 mL), and extracted with EtOAc (2 × 15
mL). The organic layers were combined and dried (MgSO4), filtered
and concentrated in vacuo. The crude product was purified by flash
cromatography on silica gel (50% EtOAc–hexane) to provide the
desired inhibitor L-684,414 (4) as a white solid.
Yield: 34 mg (85%); mp 173–176.8 °C; [α]D25 –30.8 (c = 0.54,
MeOH); Rf 0.41 (70% EtOAc–hexane).
IR (KBr): 3315, 3192, 3029, 2954, 1725, 1684, 1643, 1528, 1452,
1359, 1290, 1173, 1128, 826, 744, 697 cm–1.
1H NMR (DMSO-d6, 500 MHz): δ = 0.80 (d, 3 H, J = 6.4 Hz), 0.88
(d, 3 H, J = 6.4 Hz), 1.27 (s, 9 H), 1.39 (m, 2 H), 1.57 (m, 1 H), 2.29
(dd, 1 H, J = 17.8, 4.1 Hz), 2.41 (dd, 1 H, J = 13.4, 9.4 Hz), 2.50 (br
s, 1 H), 2.54 (dd, 1 H, J = 14.0, 11.0 Hz), 2.80–2.88 (m, 2 H), 2.91
(dd, 1 H, J = 13.6, 4.7 Hz), 2.96–3.07 (m, 2 H), 4.00 (m, 1 H), 4.20
(m, 1 H), 4.43 (m, 1 H), 7.08 (br s, 1 H), 7.12–7.28 (m, 16 H), 7.34
(br s, 1 H), 7.66 (d, 1 H, J = 7.6 Hz), 8.15 (d, 1 H, J = 7.9 Hz).
13C NMR (DMSO-d6, 125 MHz): δ = 21.6, 23.1, 24.1, 27.7, 28.2,
34.6, 37.6, 37.9, 40.7, 41.8, 51.4, 53.4, 61.0, 78.3, 126.2, 126.3,
128.1, 128.2, 128.3, 129.0, 129.1, 129.2, 129.3, 137.7, 138.4, 139.4,
155.5, 171.8, 172.7, 173.9, 208.5.
Yield: 204 mg (73%); [α]D25 –12.8 (c 1.03, CHCl3); Rf 0.54 (30%
EtOAc–hexane).
1H NMR (DMSO-d6, 500 MHz): δ = 0.05 (s, 3 H), 0.07 (s, 3 H),
0.81 (s, 9 H), 1.23 (s, 9 H), 1.51–1.80 (m, 2 H), 2.51–2.75 (m, 5 H),
3.54–3.75 (m, 2 H), 6.44 (d, 1 H, J = 8.8 Hz), 7.05–7.25 (m, 10 H),
12.06 (m, 1 H).
13C NMR (DMSO-d6, 125 MHz): δ = –2.4, 20.1, 28.2, 30.4, 39.9,
41.1, 45.5, 58.6, 74.0, 79.8, 128.0, 128.5, 130.4, 130.6, 131.0,
131.2, 141.8, 147.8, 157.4, 178.4;
(1S,2R,4R)-{1-Benzyl-4-[1-(1S)-carbamoyl-2-phenylethylcar-
bamoyl)-(1S)-3-methylbutylcarbamoyl]-2-hydroxy-5-phenyl-
pentyl}carbamic Acid tert-Butyl Ester (3)
HRMS: m/z calcd for C39H50N4O6: 670.3730, found: 670.3718.
(3R,5R)-3-Benzyl-5-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-
phenylethyl}dihydrofuran-2-(3H)-one (44)
To a solution of Boc-Leu-Phe-NH2 (91.3 mg, 0.24 mmol) in
EtOAc–MeOH (50:50, 3 mL) at 0 °C was added AcCl (1 mL). The
resulting mixture was stirred for 30 min at 0 °C and the solvent was
removed in vacuo (2 Torr, 45 °C) to give NH2-Leu-Phe-NH2 (35) in
quantitative yield. A solution of 46 (100 mg, 0.19 mmol), H2NLeu-
Phe-NH2 (35) (63 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (51 mg, 0.27 mmol) and 1-hy-
droxybenzotriazole (36 mg, 0.26 mmol) in DMF (5 mL) was stirred
at r.t. for 15 h. The reaction mixture was diluted with EtOAc (10
mL), and the organic phase was washed with aq citric acid (pH 4),
aq NaHCO3 and brine, dried (MgSO4), filtered, and evaporated in
vacuo. Purification by flash column chromatography (5% MeOH–
CH2Cl2) gave the the corresponding silylated product.
To a solution of amino alcohol 39 (0.560 g, 1.47 mmol) in THF (20
mL) cooled to 0 °C was added BH3 SMe2 complex (4 mL of a 2 M
solution in THF, 8 mmol). This mixture was stirred at 0 °C until
complete consumption of starting material, as determined by TLC
(ca. 24 h). EtOH (19 mL) was added followed by a 3 M solution of
NaOH (20 mL) and 30% H2O2 (15 mL). The mixture was stirred at
r.t. for 10 h. EtOAc (50 mL) was added and the organic layer was
separated and washed with aq 10% Na2SO3 (50 mL) and brine (5
mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated in vacuo. Purification by flash chromatography on
silica gel (50% EtOAc–hexane) gave a mixture of diols 42 and 43
(545 mg, 93%) as a colorless oil. Solid TPAP (46.5 mg, 0.14 mmol)
was added in one portion to a stirred mixture of the diols 42 and 43
(545 mg, 1.36 mmol), followed by a suspension of NMO (465 mg,
4.3 mmol) and activated powdered molecular sieves (665 mg) in
CH2Cl2 (15 mL) at r.t. under argon. On completion, the mixture was
filtered through a pad of silica gel, eluting with hexane–EtOAc
(93:07). The filtrate was evaporated and the residue was purified by
column chromatography on silica gel using 7% EtOAc–hexane to
give 308 mg and 227 mg of lactones 44 and 45, respectively, in 97%
overall yield.
Yield: 135 mg (91%); Rf 0.5 (70% EtOAc–hexane).
Silylated Product
IR (KBr): 3453, 3386, 3303, 3065, 2960, 2926, 2861, 1647, 1496,
1458, 1370, 1252, 1164, 1097, 743 cm–1.
1H NMR (CDCl3, 500 MHz): δ = –0.05 (s, 3 H), –0.03 (s, 3 H), 0.69
(d, 3 H, J = 6.4 Hz), 0.74 (d, 3 H, J = 6.4 Hz), 0.83 (s, 9 H), 1.18–
1.36 (m, 3 H), 1.26 (s, 9 H), 1.57 (m, 1 H), 1.76 (m, 1 H), 2.39 (dd,
1 H, J = 14.8, 9.92 Hz), 2.45 (m, 1 H), 2.57–2.65 (m, 1 H), 2.67 (dd,
1 H J = 8.85, 6.7 Hz), 2.77 (dd, 1 H, J = 14.3, 8.2 Hz), 3.04 (m, 1
H), 3.10 (dd, 1 H, J = 14.2, 5.6 Hz), 3.63 (m, 1 H), 3.72 (m, 1 H),
4.07 (m, 1 H), 4.56 (m, 2 H), 5.41 (br s, 1 H), 5.95 (d, 1 H, J = 8.2
Hz), 6.37 (br s, 1 H), 6.68 (br d, 1 H, J = 4.6 Hz), 6.92 (d, 1 H,
J = 7.3 Hz), 7.05–7.26 (m, 15 H).
Yield: 0.308 g (53%); mp 123–124.5 °C; [α]D25 –70.0 (c = 1.0,
CHCl3); Rf 0.60 (30% EtOAc–hexane).
IR (KBr): 3397, 3025, 2996, 2930, 1785, 1696, 1608, 1513, 1336,
1259, 1172, 1101 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 1.34 (s, 9 H), 1.72–1.84 (m, 1 H),
2.17–2.27 (m, 1 H), 2.66–2.95 (m, 4 H), 3.26 (dd, 1 H, J = 13.6, 4.0
Hz,), 3.88 (br s, 1 H), 4.26 (br s, 1 H), 4.42 (br d, 1 H, J = 7.3 Hz),
7.15–7.32 (m, 10 H).
13C NMR (CDCl3, 125 MHz): δ = –5.0, –4.5, 18.0, 22.3, 22.4, 24.5,
25.8, 28.4, 36.7, 36.8, 38.1, 38.7, 40.3, 44.8, 53.3, 53.5, 54.2, 71.8,
79.6, 126.3, 126.7, 126.9, 127.3, 128.4, 128.6, 128.7, 128.9, 129.0,
136.9, 138.6, 139.0, 155.8, 171.4, 173.1, 176.0.
Synthesis 2003, No. 4, 603–622 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of Aspartyl Protease Inhibitors
621
This material was dissolved in a solution of Bu4NF in THF (1 M,
1.25 mL) and the solution was stirred at r.t. for 12 h. The reaction
mixture was diluted with citric acid in Et2O (pH 4) and the resulting
precipitate was collected by filtration, and dried in vacuo to give L-
685,458 (3). Further purification by flash column chromatography
(6% MeOH–CH2Cl2) gave L-685,458 (3) as a white solid.47
(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.; Konvalinka, 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) 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.; Nunberg, J.; Springer, J. P.; Huff, J. R. J.
Med. Chem. 1992, 35, 1685.
(10) For the synthesis of analogues of L-682,679, see: de Solms,
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.
Yield: 96 mg (75%); mp 212–213 °C; [α]D25 –27.5 (c = 0.5,
CHCl3); Rf 0.43 (80% EtOAc–hexane).
L-685,458 (3)
1H NMR (DMSO-d6, 500 MHz): δ = 0.76 (d, 3 H, J = 6.9 Hz), 0.82
(d, 3 H, J = 6.6 Hz), 1.24 (s, 9 H), 1.26–1.41 (m, 2 H), 1.47–1.67
(m, 3 H), 2.43 (dd, 1 H, J = 13.4, 10.7 Hz), 2.54 (dd, 1 H, J = 13.6,
6.5 Hz), 2.64–2.85 (m, 4 H), 3.00 (dd, 1 H, J = 13.7, 5.2 Hz), 3.39–
3.42 (m, 2 H), 4.14–4.19 (m, 1 H), 4.38–4.40 (m, 1 H), 4.74 (d, 1 H,
J = 5.8 Hz), 6.49 (d, 1 H, J = 9.2 Hz), 7.07–7.24 (m, 16 H), 7.31 (br
s, 1 H), 7.65 (d, 1 H, J = 8.5 Hz), 7.91 (d, 1 H, J = 8.0 Hz).
13C NMR (DMSO-d6, 125 MHz): δ = 19.1, 21.8, 23.2, 24.1, 28.4,
35.5, 35.9, 37.7, 40.8, 44.6, 51.6, 53.6, 56.7, 71.4, 77.5, 125.7,
126.0, 126.3, 128.0, 128.15, 128.2, 129.0, 129.2, 129.3, 137.9,
139.9, 140.2, 155.3, 171.9, 172.8, 175.06.47
(12) Pesti, J. A.; Chorvat, R. J.; Huhn, G. F. Chem. Innovation
2000, October, 28.
(13) de Clercq, E. Pure Appl. Chem. 2001, 73, 55.
(14) Ghosh, A. K.; Shin, D.; Mathivanan, P. Chem. Commun.
1999, 1025.
(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;
Chem. Abstr. 1999, 130, 66177.
(20) (a) Evans, D. A.; Coleman, P. J.; Dias, L. C. Angew Chem.,
Int. Ed. Engl. 1997, 36, 2738. (b) Evans, D. A.; Trotter, B.
W.; Cote, B.; Coleman, P. J.; Dias, L. C.; Tyler, A. N. Angew
Chem., Int. Ed. Engl. 1997, 36, 2744.
Compound 3 From Ketone 4
LiBH4 (127 mg, 0.50 mmol) was dissolved in EtOH (4 mL) at –5 °C
under N2, and then a solution of ketone 4 (0.25 mmol) in EtOH (3
mL) was added dropwise. After 24 h, the solution was quenched
with H2O (2 mL) and extracted with EtOAc (2 × 10 mL). The com-
bined organic extracts were washed with H2O (10 mL) and brine (20
mL), dried (MgSO4), and concentrated under vacuum. The residue
was purified by flash column chromatography (6% MeOH–CH2Cl2)
to give L-685,458 (3) as a white solid.
Yield: 93%.18,46,47
Acknowledgments
We are grateful to FAPESP and CNPq for financial support. We
also thank Prof. Carol H. Collins, from IQ-UNICAMP, for helpful
suggestions about English grammar and style. We thank also Dr.
Alan Nadin, from Merck Sharp & Dohme (Harlow, Essex, UK) for
sharing information and for a copy of the 13C NMR spectra of L-
685,458.
(21) Dias, L. C.; Giacomini, R. Tetrahedron Lett. 1998, 39, 5343.
(22) Dias, L. C.; Meira, P. R. R.; Ferreira, E. Org. Lett. 1999, 1,
1335.
(23) Dias, L. C.; Meira, P. R. R. Synlett 2000, 37.
(24) Dias, L. C.; Ferreira, E. Tetrahedron Lett. 2001, 42, 7159.
(25) Dias, L. C.; Ferreira, A. A.; Diaz, G. Synlett 2002, 1845.
(26) Liu, H. J.; Shia, K. S.; Shang, X.; Zhu, B. Y. Tetrahedron
1999, 55, 3803.
References
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(28) (a) Fehrentz, J. A.; Castro, B. Synthesis 1983, 676. (b)
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(5) For a comparative quantitative structure-activity
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S. P.; Gao, H.; Babu, M. S.; Debnath, A. K.; Hansch, C.
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(29) These aldehydes should be freshly prepared before use.
Attempts to purify aldehydes 13a–c by silica gel
chromatography resulted in partial racemization. Since the
diastereoselectivity of the reactions of these aldehydes with
allylsilanes depends on their diastereomeric purity, crude
aldehydes were used in all of the studies described in the
text.
Synthesis 2003, No. 4, 603–622 ISSN 0039-7881 © Thieme Stuttgart · New York

622
L. C. Dias et al.
FEATURE ARTICLE
(30) For optical stability studies of N-protected α-amino
aldehydes, see: (a) Ito, A.; Takahashi, R.; Baba, Y. Chem
Pharm. Bull. 1975, 23, 3081. (b) Garner, P.; Park, J. M. J.
Org. Chem. 1987, 52, 2361. (c) Jurczak, J.; Golebiowski, A.
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(31) For a review of the synthesis of vicinal amino alcohols, see:
Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(32) For a review about recent advances in the synthesis of
peptides, see: Nájera, C. Synlett 2002, 1388.
(40) This compound has been prepared earlier by Taddei and co-
workers. The 1H NMR data for our compound is consistent
with the described 1H NMR data reported by Taddei et al.,
but the 13C NMR data are not. According to Taddei et al.,
there are no chemical shifts between 60 and 80 ppm, and we
observed 2 signals, at 65 and 75 ppm, attributed to CHN and
CHOH, respectively, as expected: D’Aniello, F.; Taddei, M.
J. Org. Chem. 1992, 57, 5247.
(41) Alcohols 27 and 28 have been prepared previously by
Taddei and co-workers, but our 13C NMR data are not
consistent with the described data reported in that work,
although consistent with the expected structure. See Ref.40
(42) (a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639. (b) Bloch, R.; Brillet, C. Synlett 1991,
829.
(33) For an interesting paper dealing with the question of
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(47) After re-examining our original 13C NMR spectrum of L-
685-458 (3) we observed that in our first publication in
Synlett (see Ref.25 of this manuscript) we had mistakenly
referenced the central line of the residual DMSO peak at
41.9 and not 39.7, as expected.
Synthesis 2003, No. 4, 603–622 ISSN 0039-7881 © Thieme Stuttgart · New York