Allyltrichlorostannane additions to chiral dipeptide aldehydes

Article abstract of DOI:10.1016/S0040-4039(01)01502-7

The first examples of successful allylsilane additions to chiral dipeptide aldehydes are described. Treatment of allylsilanes with tin tetrachloride at room temperature affords allyltrichlorostannane intermediates that reacts with dipeptide aldehydes to give 1,2-syn-homoallylic alcohols, potential intermediates for the synthesis of hydroxyethylene dipeptide isosteres.

Full text of DOI:10.1016/S0040-4039(01)01502-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7159–7162
Allyltrichlorostannane additions to chiral dipeptide aldehydes†
Luiz C. Dias* and Ed´ılson Ferreira
Instituto de Qu´ımica-Universidade Estadual de Campinas/UNICAMP, CP 6154, CEP 13083-970, Campinas, SP, Brazil
Received 15 August 2001; accepted 16 August 2001
Abstract—The first examples of successful allylsilane additions to chiral dipeptide aldehydes are described. Treatment of
allylsilanes with tin tetrachloride at room temperature affords allyltrichlorostannane intermediates that reacts with dipeptide
aldehydes to give 1,2-syn-homoallylic alcohols, potential intermediates for the synthesis of hydroxyethylene dipeptide isosteres.
© 2001 Elsevier Science Ltd. All rights reserved.
In the last several years there has been a major research
effort towards the development of clinically useful
inhibitors of HIV-1 protease.1 This world-wide search
has led to various peptide isosteres, wherein the scissile
peptide bond is replaced by a hydrolytically more stable
isosteric functional group. In this context, the hydroxy
amino acid framework B in Fig. 1, where the peptidic
linkage of the sequence in structure A is replaced by a
CH(OH)CH2 group, constitute a useful class of HIV
protease inhibitors.1–3
directed toward the design of the best substituents for
positions 1 and 4 in structure C (R and R1 groups).
Taddei and co-workers reported that allylchro-
mium(III) organometallics react with dipeptide alde-
hydes to give the corresponding homoallylic alcohols
with predominantly syn-selectivity.5 They observed that
any attempt to react allylsilanes, trialkylstannanes and
allylcuprates with dipeptide aldehydes in the presence
of Lewis acids or fluoride ions failed, mainly giving the
product of protodesilylation, poor yields and a complex
mixture of products.5
We recently communicated that a chiral allylsilane
reacts with N-Boc-a-aminoaldehydes in the presence of
SnCl4 to give 1,2-syn N-Boc-a-aminoalcohols that are
key intermediates (molecules of type C) for the prepara-
tion of hydroxyethylene dipeptide isosteres.4 The
stereoselectivity of these tin(IV) chloride-promoted
reactions is consistent with a mechanism involving
transmetallation of the chiral allylsilane to give an
intermediate allyltintrichloride which is stabilized by
We wish to report here our initial results towards the
synthesis of more complex dipeptide isosteres by reac-
tion of allylsilanes with dipeptide aldehydes in the
presence of SnCl4. The present methodology is useful
for the preparation of molecules of type C and consists,
in the first step, of the preparation of molecules of type
B (Fig. 1). To the best of our knowledge, these are the
first examples of successful allylsilane additions to chi-
ral dipeptide aldehydes.
tin–oxygen interaction.4
A synthetic methodology
which allows compounds with programmed variations
of substituents to be synthesized is particularly impor-
tant in the screening of the pharmacological activity
and in a study of structure–activity relationships
The corresponding dipeptide amides 7a–e were
obtained in excellent yields by treatment of N-Boc-L-
amino acids 1 and 2 and N-deprotected-L-Weinreb
amides 3–6 with HOBt, DCC and NaHCO3 in CH2Cl2
OH
O
CONH
OH CONH
(Scheme 1).
1
1
R1
R1
R1
2
4
R
4
N
R
R
2
H
NH
NH
NH
The dipeptide aldehydes 8a–e were obtained in good
isolated yields for the two-step sequence by LiAlH4
reduction of the corresponding Weinreb amides 7a–e
(Scheme 1).5–10
A
B
C
Figure 1. Core units of HIV protease inhibitors.
* Corresponding author. Fax: +55-019-3788-3023; e-mail: ldias@
The dipeptide aldehyde 8f was obtained after the fol-
lowing sequence: coupling between N-Boc-phenylala-
iqm.unicamp.br
†
This paper is dedicated to the Brazilian Chemical Society (SBQ).
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01502-7

7160
L. C. Dias, E. Ferreira / Tetrahedron Letters 42 (2001) 7159–7162
HOBt, DCC
Boc
R1
Boc
R1
Boc
R1
O
NaHCO3
NH
O
NH
NH
O
H
N
H
N
R2
LiAlH4
THF
OH
NOMe
+
H
NOMe
R2 Me
CH2Cl2
0 0C to 25oC
NH3 Me
Cl
O
O
O
R2
0 0C to 25oC
1, R1 = Bn
2, R1 = iPr
7a-e
5, R2 = iBu
(2 steps)
3, R2 = Me
4, R2 = iPr
6, R2 = Bn
8a, R1 = Bn, R2 = Me, 72%
8b, R1 = Bn, R2 = iPr, 80%
8c, R1 = Bn, R2 = iBu, 81%
8d, R1 = Bn, R2 = Bn, 70%
8e, R1 = iPr, R2 = Bn, 69%
Scheme 1. Dipeptide aldehydes 8a–e.
nine 1 and hydrochloride 9 (74%), protection of 10 with
TBSCl (95%), reduction with 2 M LiBH4 in THF to
produce 11 (100%), followed by Dess–Martin oxidation
(88%) (Scheme 2).6–10
hyde in order to obtain good yields and selectivities.
This reaction benefits from the fact that the real nucleo-
phile is the allyltrichlorostannane and not the allylsilane
itself.11 It is interesting to point out that, if the allyl-
trichlorostannane addition reaction is carried out from
−78°C to room temperature, we have observed loss of
the Boc protecting group with the corresponding depro-
tected homoallylic alcohols being isolated in very good
yields and having essentially the same selectivities.
The next step is allyltrichlorostannane addition to these
dipeptide aldehydes. According to a previously estab-
lished experimental procedure, allylsilanes 12 and 14
and SnCl4 (0.5 M solution in CH2Cl2) were mixed
before the addition of a solution of the aldehyde in
order to promote ligand exchange, leading to the corre-
sponding allyltrichlorostannanes.4b For allyltrimethylsi-
lane 12 (0.5 M in CH2Cl2) the ligand exchange
affording allyltrichlorostannane 13 is complete after
120 min (Scheme 3). For allylsilane 14 (0.5 M in
CH2Cl2) the metathesis is faster, as expected for a
1,1-disubstituted olefin, being complete after 60 min at
room temperature, furnishing 15.
The 1,2-syn relative stereochemistry of the major prod-
ucts was unambiguously established by spectroscopic
analysis of the corresponding trans oxazolidines (upon
irradiation of the hydrogens adjacent to Ha and Hb).
Observed average coupling constants (3J=1.0 Hz) indi-
cate that protons Ha and Hb are on opposite faces of
the heterocyclic ring and, therefore, the oxazolidines are
derived from 1,2-syn adducts (Scheme 4).12
Although the remote stereogenic center may influence
the stereochemical course of CꢀC bond formation, we
The results of allyltrichlorostannane additions to dipep-
tide aldehydes 8a–f are shown in Table 1. In all cases,
the major product results from a chelation controlled
reaction that mainly gives the 1,2-syn isomer, showing
that the (S)-a-amino dipeptide aldehydes have a prefer-
ence for anti-Felkin addition (Si-face attack). Increased
TMS
Cl3Sn
SnCl4
CH2Cl2, 25oC
120 min.
13
12
i
steric bulk of the R2 group (R2=iPr, Bu) in the alde-
hydes gives better diastereoselection.
TMS
Cl3Sn
SnCl4
CH2Cl2, 25oC
60 min.
With small R2 groups (R2=CH3, Bn, CH2OTBS) the
diastereoselectivity is poor, although the reaction
occurs in very good yields. It is essential to promote the
ligand-exchange reaction before addition of the alde-
14
15
Scheme 3. Metathesis of allylsilanes 12 and 14.
Boc
NH
OH
Boc
1. TBSCl, imidazole
CH2Cl2, 0 0C, 95%
Boc
1
HOBt, DCC
NaHCO3
O
NH
O
NH
O
+
H
N
H
N
OH
O
OMe
CH2Cl2
74%
H
2. 2M LiBH4
O
8f
10
O
THF, 0 oC, 100%
3. Dess-Martin, 88%
OMe
OH
OTBS
9
NH2.HCl
Scheme 2. Dipeptide aldehyde 8f.

L. C. Dias, E. Ferreira / Tetrahedron Letters 42 (2001) 7159–7162
Table 1. Allyltrichlorostannane additions to dipeptide aldehydesa,b
7161
Boc
NH
O
H
N
Boc
R1
Boc
NH
OH
NH
OH
H
N
H
N
R1
H
+
R
R1
R
8 a-f O
R2
CH2Cl2
O
R2
1,2-syn
O
R2
1,2-anti
+
-78 0C to- 25oC
(Cl)3Sn
R
16a-f, R = H
18a-f, R = Bn
17a-f, R = H
19a-f, R = Bn
13, R = H
15, R = Bn
Dipeptide aldehydes 8
R=H
R=Bn
Yield (%)d
R1
R2
16:17b,c
Yield (%)d
18:19b,c
a
b
c
d
e
f
Bn
Bn
Bn
Bn
iPr
Bn
Me
78:22
95:5
90:10
60:40
53:47
66:34
87
89
83
79
74
86
68:32
95:5
90:10
60:40
60:40
60:40
80
89
83
70
75
74
iPr
iBu
Bn
Bn
CH2OTBS
a Reactions were carried out in dichloromethane from −78 to −25°C using molar equivalents of allylsilane, SnCl4 and aldehyde in the presence
,
of MS 4 A.
b The ratios were determined by 1H and 13C NMR spectroscopic analysis of the crude mixtures of syn and anti products.
c Averages of at least three runs with ratios 3%.
d Combined yields of products isolated chromatographically (SiO2), after two steps (preparation of the aldehyde and coupling with allyl-
trichlorostannane).
Me
Boc
Me2C(OMe)2
PPTS
CH2Cl2
Boc
Me
NH
OH
H
N
NH
O
Hb
N
R
R
Ha
O
R2
80-85 %
O
R2
16d, R2 = Bn, R = H
16b, R2 = iPr, R = H
18b, R2 = iPr, R = Bn
20, R2 = Bn, R = H
21, R2 = iPr, R = H
22,, R2 = iPr, R = Bn
JHa/Hb trans
JHa/Hb cis
Literature: 1.1 to 4.9 Hz
Observed: 1.0 to 1.1 Hz
4.6-6.0 Hz
Scheme 4. Coupling constants analysis.
expect such reactions to be dominated by the stereo-
genic center next to the aldehyde function. We believe
that the observed selectivity can be explained by an
equilibrium between the intramolecular hydrogen bond
conformer D and a non-bonded conformer E (Fig. 2).13
When the form D predominates (bulkier R groups), the
syn isomer is favored, whereas the prevalence of the
E-like conformer (smaller R groups) leads to the anti
isomer. The nucleophile selects the less hindered Si-
face, forming a six-membered transition state F where
the chiral residue of the aldehyde occupies a pseudo-
equatorial position.
We have reported herein the first examples of allylsilane
additions to chiral dipeptide aldehydes. Treatment of
allylsilanes with tin tetrachloride at room temperature
affords allyltrichlorostannane intermediates that react
with dipeptide aldehydes to give 1,2-syn-homoallylic
H
R
O
H
O
H
R'OC N
H
COR'
(Cl)n
Sn
HN
R'OCHN
R
O
R
H
Nu
Nu
E
D
H
H
F
R
1,2-syn
1,2-anti
Figure 2. Transition state model.

7162
L. C. Dias, E. Ferreira / Tetrahedron Letters 42 (2001) 7159–7162
alcohols, potential intermediates for the synthesis of
hydroxyethylene dipeptide isosteres, with little or no
undesired a-epimerization at the stereogenic center next
to the aldehyde function.14
NMR spectra (DMSO-d6), which proves the absence of
appreciable epimerization.
7. For optical stability studies of N-protected a-amino alde-
hydes, 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. Chem. Rev. 1989, 89, 149; (d) Myers, A. G.; Zhong, B.
Y.; Movassaghi, M.; Kung, D. W.; Lannan, B. A.;
Kwon, S. Tetrahedron Lett. 2000, 41, 1359.
8. For an interesting paper dealing with the question of
configurational stability at the stereogenic center next to
the aldehyde function in dipeptide aldehydes, see: Reetz,
M. T.; Griebenow, N. Liebgs Ann. 1996, 335.
These resulting homoallylic alcohols are versatile inter-
mediates for the introduction of different functional
groups in intermediates aimed at the synthesis of
hydroxyethylene isosteres. The examples show that the
levels of p-facial selection depend on the substituents of
the dipeptide aldehydes. We believe that this chemistry
is truly significant in the context of acyclic diastereo-
selection and will prove to be exceptionally useful in the
synthesis of more complex hydroxyethylene isosteres.
Further exploration of these reagents and their applica-
tions is now underway in our laboratory.14,15
9. When aldehydes 8d and 8e (R2=Bn) were prepared from
Swern oxidation of the corresponding peptide alcohols
and used in coupling reactions with allyltrichlorostan-
nanes 13 and 15, we observed the formation of all four
possible diastereomers. We have not observed this a-
epimerization at the aldehyde stage when the correspond-
ing primary alcohols derived from amides 7a–c were
submitted to Swern conditions, in agreement with the
observations by Reetz and Griebenow. See Ref. 8.
10. We believe that partial epimerization of these dipeptide
aldehydes does not occur in the allyltrichlorostannane
Acknowledgements
We are grateful to FAPESP and CNPq for financial
support. We also thank Professor Carol H. Collins,
from IQ-UNICAMP, for helpful suggestions about
English grammar and style.
1
addition reactions, since we have observed very clean H
and 13C NMR spectra for all the corresponding products
with signals for only two products.
11. Attempts to use allylsilanes 12 and 14 with other Lewis
acids (TiCl4, BF3·OEt2) as well as attempts at mixing
allylsilanes and dipeptide aldehydes before addition of
SnCl4 lead to poor yields, loss of the Boc protecting
group and recovered starting material.
12. Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.; Zla-
toidzky, P. J. Org. Chem. 1997, 62, 9348.
13. The influence of an intramolecular hydrogen bond in the
stereoselection of a-amino carbonyl compounds has been
described. See: Pace, R. D.; Kabalka, G. W. J. Org.
Chem. 1995, 60, 4838.
14. All new compounds were isolated as chromatographically
pure materials and exhibited acceptable 1H and 13C
NMR, IR, MS, and HRMS spectral data.
References
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15. General procedure for the allyltrichlorostannane additions:
To a solution of 2.5 mmol of the corresponding allylsi-
lane in 5 mL of dry CH2Cl2 at 25°C suspended with
,
powdered molecular sieves 4 A (50 mg) was added 2.5
mmol of SnCl4. The resulting solution was stirred at 25°C
for 1 h, then cooled to −78°C and 2.5 mmol of aldehyde
in 2.5 mL of CH2Cl2 were added. This mixture was
stirred for 30 min (−78 to −25°C) and quenched by the
slow addition of 0.2 mL of Et3N, followed by 10 mL of
saturated NH4Cl solution. The layers were separated and
the aqueous layer was extracted with CH2Cl2 (2×5 mL).
The combined organic layer was dried (MgSO4), filtered,
and concentrated in vacuo. Purification by flash chro-
matography on silica gel (40% EtOAc/hexanes) afforded
the corresponding homoallylic alcohols.
6. (a) Fehrentz, J.-A.; Castro, B. Synthesis 1983, 676; (b)
Saari, W. S.; Fisher, T. E. Synthesis 1990, 453. These
aldehydes should be used freshly prepared. Attempts to
purify dipeptide aldehydes 8a–f by silica-gel chromato-
graphy resulted in partial epimerization. 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. All the freshly prepared dipeptide aldehydes
show single sets of signals in their respective H and 13C
1