Val-Ala dipeptide isosteres by hydrocyanation of α′-amino α,β-unsaturated ketones - Control of stereoselectivity by the N-protecting group

Article abstract of DOI:10.1002/ejoc.200200626

Three diastereoisomeric hydroxyethylene isosters of the Val-Ala dipeptide were synthesized from α,β-unsaturated ketones 1 derived from N-Boc- and N,N-dibenzyl-L-valine. The enones were hydrocyanated with diethylaluminum cyanide to give the corresponding β-cyano ketones with the stereoselectivity depending on the protecting group. N-Boc protected enone 1a gave a 1:1 mixture of anti and syn adducts 4a, 5a while the corresponding N,N-dibenzyl compound 1c gave a 6:1 mixture of anti, syn adducts 4c, 5c. Borohydride reduction of the resulting cyano ketones is also controlled by the protecting group, resulting in opposite stereoselectivities for N-Boc and N,N-dibenzyl compounds. The cyano alcohols thus obtained were converted, in several steps, into two series of enantiomerically pure hydroxyethylene isosters of the Val-Ala dipeptide. In the first series the hydroxy group and the N-terminal of the isoster are internally protected through the formation of an oxazolidine; in the second series the hydroxy group and the C-terminal are protected as lactone. Two oxazolidines (28, 29), corresponding to syn,syn and syn,anti 4-hydroxy-5-amino acid isosters, and three lactones (23-25), corresponding to syn,syn, syn,anti, and anti,anti isosters were obtained by this approach. Wiley-VCH Verlag GmbH & Co KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200200626

FULL PAPER
Val-Ala Dipeptide Isosteres by Hydrocyanation of αЈ-Amino α,β-Unsaturated
Ketones ؊ Control of Stereoselectivity by the N-Protecting Group
Fabio Benedetti,*[a] Federico Berti,[a] Gianpiero Garau,[a] Ivan Martinuzzi,[a] and
Stefano Norbedo[a]
Keywords: Aluminum / Cyanides / Nucleophilic addition / Asymmetric synthesis / Dipeptide isosters
Three diastereoisomeric hydroxyethylene isosters of the Val-
Ala dipeptide were synthesized from α,β-unsaturated keto-
thus obtained were converted, in several steps, into two se-
ries of enantiomerically pure hydroxyethylene isosters of the
nes 1 derived from N-Boc- and N,N-dibenzyl-L-valine. The Val-Ala dipeptide. In the first series the hydroxy group and
enones were hydrocyanated with diethylaluminum cyanide
the N-terminal of the isoster are internally protected through
to give the corresponding β-cyano ketones with the stereo-
the formation of an oxazolidine; in the second series the hy-
selectivity depending on the protecting group. N-Boc pro- droxy group and the C-terminal are protected as lactone.
tected enone 1a gave a 1:1 mixture of anti and syn adducts
4a, 5a while the corresponding N,N-dibenzyl compound 1c
gave a 6:1 mixture of anti, syn adducts 4c, 5c. Borohydride
reduction of the resulting cyano ketones is also controlled by
Two oxazolidines (28, 29), corresponding to syn,syn and
syn,anti 4-hydroxy-5-amino acid isosters, and three lactones
(23−25), corresponding to syn,syn, syn,anti, and anti,anti iso-
sters were obtained by this approach.
the protecting group, resulting in opposite stereoselectivities ( Wiley-VCH Verlag GmbH & Co KGaA, 69451 Weinheim,
for N-Boc and N,N-dibenzyl compounds. The cyano alcohols Germany, 2003)
Peptidomimetics of general structure PnϪP1ϪXϪ with corresponding subsites on the enzyme.[1,2] Hydroxyeth-
YϪP1ЈϪPnЈ, in which non-hydrolizable isoster ylene and dihydroxyethylene isosters have proved particu-
a
P1ϪXϪYϪP1Ј replaces the scissile dipeptide P1ϪP1Ј in a larly useful as dipeptide replacements in the design of po-
short peptide chain PnϪP1ϪP1ЈϪPnЈ, are efficient inhibi- tent inhibitors of HIV-1 PR[6Ϫ10] and other aspartic pro-
tors of aspartic proteases.[1] Enzymes of this class play an teases,[2] as the hydroxy groups can make favorable polar
important role in many biological processes and are in- interactions with the catalytic aspartates, while R1 and R1Ј
volved in a variety of pathologies. Thus, extensive investi- groups interact with the hydrophobic S1, S1Ј subsites.[11]
gations have been devoted to the discovery of peptidomi-
metic inhibitors potentially useful in therapy.[2] Renin in-
hibitors, for example, have long been recognized for their
potential in the control of hypertension[3] and inhibitors of
HIV-1 protease (HIV-PR) are currently in clinical use for
the treatment of acquired immunodeficiency syndrome
(AIDS).[4,5] More recently, other aspartic proteases, such as
A number of studies have shown that the configuration
candidapepsins, involved in fungal invasiveness, plasmep-
of the isoster can affect both the in vitro and the in vivo
sins from malaria parasites and human cathepsin D, in-
activity of peptidomimetic inhibitors[9,12,13] and the import-
volved in Alzheimer’s disease, have emerged as new targets
ance of synthesizing and evaluating stereoisomers of a given
inhibitor clearly emerges from these studies. Synthetic
for peptidomimetic inhibitors.[2]
Peptidomimetic inhibitors of aspartyl proteases displace
routes that give access to stereoisomeric dipeptide isosters
the substrate from the enzyme’s active site, interacting with
in enantiomerically pure form are thus highly valuable in
the protease through a network of hydrogen bonds, electro-
the search for new inhibitors. Recently, we have described a
static and hydrophobic interactions. In particular, the
novel approach to enantiomerically pure 4-hydroxy-5-
P1ϪXϪYϪP1Ј isoster interacts with the aspartate catalytic
residues and with S1, S1Ј subsites in close proximity with
the active site, while the flanking residues make contact
amino acids following the retrosynthetic analysis shown in
Scheme 1.[14] Here we present a full account of that work
and describe how the selectivity can be controlled by choice
of the N-protecting group, resulting in the synthesis of dif-
ferent diastereoisomers of the same isoster.
The synthesis is based on the conjugate addition of a
suitable precursor of the carboxylate group (X) to the αЈ-
[a]
Department of Chemistry, University of Trieste,
via Giorgieri 1, 34127 Trieste, Italy
Fax: (internat.) ϩ 39-040/5582402
E-mail: benedett@units.it
Eur. J. Org. Chem. 2003, 1973Ϫ1982
DOI: 10.1002/ejoc.200200626
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1973

F. Benedetti, F. Berti, G. Garau, I. Martinuzzi, S. Norbedo
FULL PAPER
known that this reagent adds to α,β-unsaturated ketones in
a complete 1,4 fashion,[20] providing a nitrile ready for
further manipulation. When 1a was treated with excess di-
ethylaluminum cyanide, in toluene at room temperature, a
mixture of diastereoisomeric cyano ketones 4a and 5a was
obtained, in a 1:1 ratio (Scheme 2). The same reaction was
also carried out with bis(2,6-di-tert-butyl-4-methylphenoxy)-
aluminum cyanide, obtained in situ from diethylaluminum
cyanide and 2,6-di-tert-butyl-4-methylphenol,[21] but even
this bulky reagent failed to display any appreciable dia-
stereofacial selectivity. A moderate stereoselectivity, favor-
ing 5a, was observed at lower temperature and a 2:1 mixture
of 5a and 4a was obtained at Ϫ70 °C. The results are con-
sistent with the hypothesis that, under these conditions, the
conjugate hydrocyanation of unsaturated ketone 1 is revers-
ible resulting, at room temperature, in a fast equilibration
of the adducts via the corresponding aluminium enolates,
as suggested by Nagata.[20] The moderate stereoselectivity
observed at Ϫ70 °C indicates that equilibration is slower at
this temperature; unfortunately, the reaction was sluggish
and these conditions were not further pursued.
If diethylaluminum cyanide is replaced by a trialkylalu-
minum and hydrogen cyanide, hydrocyanation of α,β-un-
saturated ketones becomes irreversible because the enolate
is rapidly protonated thus preventing equilibration.[22] We
modified these conditions by carrying out the hydrocyan-
ation of enone 1a with diethylaluminum cyanide and ace-
tone cyanohydrin as proton donor to decompose the alu-
minium enolate (Scheme 2, Table 1). This resulted in
shorter reaction time (6 h vs. 48 h) and better yield (96% vs.
70%), if compared with Et2AlCN alone (Table 1), but did
not lead to any appreciable diastereomeric excess, indicating
an insufficient facial discrimination by the nucleophile.
Even if the lack of stereoselectivity was disappointing, pure
anti 4a could be obtained by crystallization and further
steps (see Scheme 5) allowed us to assign the configuration
of the newly formed chiral center which is S in 4a and R
in 5a.
Scheme 1. Retrosynthetic analysis of hydroxyethylene dipeptide iso-
sters
amino α,β-unsaturated ketone 1. This intermediate is read-
ily obtained from α-amino acids and has been recently used
by us as precursor of epoxy alcohols, in the synthesis of
dihydroxyethylene dipeptide isosters.[15,16] In view of the
well-known preference of aspartic proteases for hydro-
phobic residues at the scissile bond,[1,2] aliphatic residues R1
and R1Ј were chosen for this study and the approach de-
scribed in Scheme 1 was demonstrated with the synthesis of
three enantiomerically pure diastereoisomeric analogs of
the Val-Ala dipeptide.
Results and Discussion
The N-Boc protected α,β-unsaturated ketone 1a was ob-
tained in two steps from the methyl ester of N-Boc -valine
2a (Scheme 2). This was initially converted into the phos-
phonate 3a[17] following the procedure (dimethyl methyl-
phosphonate, nBuLi, Ϫ78 to Ϫ30 °C) described by Chakra-
varty.[18] HornerϪEmmons olefination of 3a with acetalde-
hyde was carried out in ethanol, in the presence of potas-
sium carbonate,[19] giving 1a. The trans geometry of the
enone was confirmed by the NMR spectrum showing a
15 Hz coupling constant between the vinyl protons.
Table 1. Addition of Et2AlCN to enones 1
Enone
R
RЈ
Acetone
cyanohydrin
anti (4)/syn (5)[a]
Yield%
1a
1a
1b
1c
Boc
Boc
Tr
H
H
H
Bn
No
Yes
Yes
Yes
1:1
70
96
94
75
1:1
n. d.[b]
6:1
Bn
[a] By NMR spectroscopy. [b] A 2:1 mixture of diastereoisomers was
detected by NMR spectroscopy.
Scheme 2. Synthesis of cyano ketones 4, 5: a) (CH3O)2P(O)CH3,
nBuLi, THF, Ϫ78 °C, 69Ϫ92%; b) CH3CHO, K2CO3, EtOH, 25
°C, 81Ϫ97%; c) Et2AlCN, toluene, 25 °C, 75Ϫ96%
Hoping for a better stereoselectivity, the addition to 1a of
other precursors of the carboxylate group was investigated
under non-equilibrating conditions. The addition of vinyl-
Addition of the carboxylate precursor to 1a is the crucial magnesium bromide to enone 1a was carried out in THF,
step in the synthesis and much effort was devoted to optim- in the presence of DMAP and of several CuI, CuII, TiIV
ize this reaction. The initial reagent chosen for the conju- and AlIII catalysts to favor 1,4-addition, but only 2:1 dia-
gate addition was Et2AlCN (Nagata’s reagent), for it is stereomeric mixtures of anti and syn adducts were obtained
1974
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Eur. J. Org. Chem. 2003, 1973Ϫ1982

Val-Ala Dipeptide Isosteres by Hydrocyanation
FULL PAPER
in the best cases. Diethyl-2-phenylethinylalane, obtained in
situ from diethylaluminum chloride and lithiated phenyl-
acetylene, was also tested as a nucleophile, carrying out the
reaction at room temperature in toluene/diethyl ether in the
presence of catalytic CuBr. When applied to enone 1a, this
reagent gave again a 2:1 mixture of adducts prompting us
to consider other factors to control the selectivity of the re-
action.
To this end we reverted to using diethylaluminum cyanide
and investigated whether a change in the N-protecting
group on the remote asymmetric center of the enone 1 had
any effect on the stereoselectivity of the addition. The en-
ones 1b and 1c (Table 1) were thus prepared by the same
route followed for the synthesis of 1a, starting from N-trityl
and N,N-dibenzyl--Val (Scheme 2). Replacement of the
Boc protecting group of 1a with the more hindered trityl
group (1b) resulted in a modest 2:1 selectivity. However, by
Scheme 3. Chelated and nonchelated models for 1,4-addition to αЈ-
N,N-dibenzylamino α,β-unsaturated ketones
It was now possible to proceed to the next step in the
switching to the dibenzyl derivative 1c the selectivity in- synthesis of the isosters, namely the reduction of the car-
creased to 6:1 in favor of the anti adduct 4c; the configura- bonyl with sodium borohydride in methanol, at 0 °C
tion of the latter was established by the X-ray crystal struc- (Scheme 4). Again, as in the hydrocyanation of the enones
ture of lactone 22 (Figure 1), derived from 4c (Scheme 5).
1, the stereochemical course of the reaction is determined
by the nature of the protecting groups on nitrogen. Thus,
the reduction of N-Boc α-amino ketone 4a gives a 4:1 mix-
ture of 4R and 4S alcohols 8 and 9; similarly, 5a (an insep-
arable 3:2 mixture with 4a) gave the 4R and 4S alcohols 10
and 11 in 16:1 ratio (together with the corresponding
amounts of 8 and 9). However, the reduction of the N,N-
dibenzyl protected enone 4c proceeds with the opposite
stereoselectivity, giving the 4S amino alcohol 12 with 90%
diastereoselectivity.
The stereochemistry of the newly formed asymmetric
center was confirmed by converting the N-Boc amino al-
cohols 8؊10 into the corresponding 2,2-dimethyl oxazol-
idines 13؊15 (Scheme 4). In CDCl3 solution these com-
pounds are present as 1:1 mixtures of rotamers around the
amide bond with a coalescence temperature above 70 °C;
NOE experiments, in which transfer of saturation between
rotamers was observed upon irradiating the oxazolidine
ring protons, reveal 11% and 10% enhancements between
H-4 and H-5 in oxazolidines 13 and 15, consistent with a cis
relationship between these protons. The H-4, H-5 coupling
Figure 1. X-ray crystal structure of lactone 22 showing crystallo-
graphic numbering scheme
The high 1,4-asymmetric induction displayed by 1c is re- constant (4.9, 5.1 Hz for 13 and 15 respectively) is also con-
markable, and can be explained with a model (Scheme 3) in sistent with a cis structure for these oxazolidines.[15] Since
which the unsaturated system adopts a s-cis conformation in both compounds the configuration of C-4 is S, as in the
with the metal chelated between the carbonyl and the starting amino ester, it follows that the configuration of C-
amino group. In this conformation the re face of the double 5 must be R. In the oxazolidine 14, derived from the minor
bond is shielded by the isopropyl group and the nucleophile reduction product 9, only 2% NOE enhancement is ob-
attacks preferentially the si face (backside attack). Alterna- served between H-4 and H-5, consistent with a trans re-
tively, the stereoselectivity would be also consistent with a lationship between these protons, thus confirming the S
nonchelated model (Scheme ) and topside attack of the nu- configuration for C-5. In the case of the N,N-diprotected
cleophile on the s-trans enone. The latter conformation, amino alcohol 12, the S configuration of the newly estab-
however, involves an unfavorable interaction between the lished stereocenter was assigned from the X-ray crystal
vinyl and dibenzylamino groups: we thus favor the chelated structure of its derivative 22 (Figure 1).
model. This hypothesis is also consistent with the results
The selectivity of the reduction of N-Boc amino ketones
obtained with the N-Boc enone 1a, as replacement of the 4a, 5a is in agreement with previous results,[15,24,25] and is
dibenzylaminogroup of 1c with the less basic carbamate of consistent with the Cram model assuming that NHBoc is
1a may prevent chelation resulting thus in the loss of stereo- the medium-size group.[15] The inversion of stereoselectivity
selectivity.
observed in the reduction of 4c is consistent with the non-
Eur. J. Org. Chem. 2003, 1973Ϫ1982
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1975

F. Benedetti, F. Berti, G. Garau, I. Martinuzzi, S. Norbedo
FULL PAPER
Scheme 4. Reduction of cyano ketones 4,5: a) NaBH4, MeOH, 0 °C, 82Ϫ90%; b) 2,2-dimethoxypropane, cat. pTsOH, 60Ϫ62%
chelated Cram model proposed for N,N-dibenzylamino ke-
tones (Bn2N ϭ Large).[23,26] The different selectivities ob-
served in the reduction of ketones 4a and 5a indicate that
the remote asymmetric center also has some influence on
the stereochemistry of the reaction. In the cyano ketone 4a
the approach of the nucleophile to the preferred si face of
the carbonyl is hindered by the syn cyano group when the
chain adopts the extended conformation represented in
Scheme 4. In the reduction of 5a the approach is unhin-
dered by the substituent on C-2 and the selectivity is the
same (16:1) as that observed in the reduction of enone
1a.[27]
Having established the configuration of the stereocenter
resulting from the reduction of the carbonyl, it was now
possible to proceed with the synthesis of the Val-Ala iso-
sters; en route to these, it was also possible to demonstrate
the configuration of the third stereocenter, resulting from
the hydrocyanation of enones 1a and 1c. To this end, nitriles
8,10 (as a 7:3 mixture with 8) and 12 were hydrated with
hydrogen peroxide in dimethyl sulfoxide[28] to give the cor-
responding amides 16؊18 (Scheme 5). In the hydration of
nitrile 12 partial (20%) epimerization at the carbon atom
vicinal to the amide was observed, probably due to longer
reaction times required by this substrate. This problem was
overcome by inverting the order of carbonyl reduction and
nitrile hydration, and the amide 18 could be obtained, with-
out any detectable epimerization, from 4c via ketone 19 and
stereoselective reduction of the latter (Scheme 5). Amides
Scheme 5. Synthesis of lactones 20؊25: a) H2O2, K2CO3, DMSO,
80Ϫ96%; b) 1  HCl, H2O/dioxane, 25 °C, 83%; c) TFA, CH2Cl2,
95%; d) NaBH4, MeOH, 0 °C, 94%; e) 1 Atm H2, Pd(OH)2/C, 93%
16؊18 readily cyclize to lactones 20؊22 in aqueous diox-
ane at pH ϭ 2. An analysis of the NOE spectra of the
lactones (Scheme 5) allowed to assign the configuration of
the chiral center adjacent to the carbonyl. In lactone 20 5 are on opposite sides with respect to the plane of the ring.
enhancements are observed between H-3 and HЈ-4 (8%) In lactones 21 (obtained as a 7:3 mixture with 20 from
and between H-5 and H-4 (6%), indicating that H-3 and H- which it was separated by chromatography) and 22, on the
1976
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Val-Ala Dipeptide Isosteres by Hydrocyanation
FULL PAPER
contrary, protons H-3 and H-5 correlate with the same pro-
ton H-4 (6% and 7% enhancements, respectively) indicating
that these protons are on the same side with respect to the
mid-plane of the lactone ring. Since the configuration of C-
5 is R in lactones 20 and 21 and S in lactone 22 it follows
that the configuration of C-3 is S in 20, R in 21 and S in
22, as shown in Scheme 5. The stereochemical assignment
was unanmbiguously confirmed, for lactone 22, by the X-
ray crystal structure (Figure 1) showing that all three stereo-
centers possess the same S configuration, as predicted by
NMR spectroscopy.
Finally, removal of the tert-butoxycarbonyl protection
(Scheme 5) gave enantiomerically pure amino lactones 23
and 24 in 77% and 80% yield from the corresponding cyano
alcohols 8 and 10, respectively. Similarly, reductive de-
benzylation of 22 gave amino lactone 25 in 58% overall
yield from the cyano ketone 4c. Aminolactones 23؊25 are
masked hydroxyethylene dipeptide isosters in which the
hydroxy group and C-terminal are internally protected; as
Scheme 6. Synthesis of acids 28, 29: a) DIBALH, toluene, 25 °C,
then H3Oϩ, 77Ϫ80%; b) KMnO4, tBuOH, phosphate buffer, pH ϭ
7, 95%
such they are potentially useful for the synthesis of more hydrocyanation and the reduction. Replacing the N,N-di-
complex peptidomimetics by direct amide coupling, while benzyl protection with N-Boc results in a complete loss of
also the lactone can be directly converted into hydroxy selectivity in the addition step, while in the following re-
amide under Weinreb’s conditions.[29Ϫ31]
duction of the α-amino ketone the selectivity is reversed as
A second series of N,O-protected hydroxyethylene iso- a consequence of the smaller size of the protecting group.
sters was readily available by simple elaboration of By applying the concept of protecting group controlled
oxazolidines 13 and 15, as shown in Scheme 6. Direct con- stereoselectivity to the synthesis of isosters of the Val-Ala
version of the oxazolidine-protected nitriles 13 and 15 into dipeptide we have synthesized enantiomerically pure
acids by basic hydrolysis (30% KOH in refluxing methanol) syn,syn isosters 28, 23 and syn,anti isosters 29, 24 from the
resulted in epimerization at the chiral center adjacent to the N-Boc enone 1a and the anti,anti isoster 25 from the N,N-
nitrile group. The conversion was thus performed stepwise dibenzyl enone 1c.
(Scheme 6): diisobutylaluminum hydride reduction was car-
ried out first and gave the aldehydes 26 and 27. In order to
prevent epimerization on the side chain, it is essential to
avoid an excess of DIBALH in this step. If one equivalent
of reducing agent is used, no epimerization is detected and
the products are formed as single diastereoisomers. Alde-
hydes 26, 27 were then oxidized with potassium permanga-
nate in buffered aqueous tert-butyl alcohol.[32] By this pro-
cedure, the acids 28, 29 were obtained in 45% and 39%
yields from the corresponding cyanoalcohols 8, 10. 1,3-Ox-
azolidines can be hydrolyzed to amino alcohols under mild
conditions; thus acids 28 and 29 correspond to masked
hydroxyethylene isosters. Similar compounds have been
used for the synthesis of pseudopeptide inhibitors by coup-
ling the free carboxylate group with an amino acid or a pep-
tide.[33]
Conclusion
We have described a novel approach to the synthesis of
masked hydroxyethylene dipeptide isosters based on the
The availability, by the same route, of stereoisomeric iso-
hydrocyanation of αЈ-amino α,β-unsaturated ketones de- sters protected either at the amino group (28, 29) or at the
rived from valine. The stereochemistry of both cyanide ad- carboxy group (23؊25) is another feature of this approach
dition to the enone and the reduction of the resulting α- and should be particularly useful for the flexible synthesis
amino ketone can be controlled by the choice of the pro- of pseudopeptide inhibitors of aspartic proteases contain-
tecting group on nitrogen. In particular, N,N-dibenzyl pro- ing a 5-amino-4-hydroxypentanoate core as non-hydroliz-
tected substrates give excellent selectivities in both the able dipeptide replacement.
Eur. J. Org. Chem. 2003, 1973Ϫ1982
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F. Benedetti, F. Berti, G. Garau, I. Martinuzzi, S. Norbedo
FULL PAPER
3.0, 9.5 Hz, 1 H), 3.63 (d, J ϭ 11.1 Hz, 3 H), 3.65 (d, J ϭ 11.1 Hz,
3 H), 7.29 (m, 10 H), 7.51 (m, 5 H). 13C NMR: δ ϭ 18.2, 19.3,
31.3, 38.6 (d, J ϭ 138 Hz), 52.5 (d, J ϭ 6.8 Hz), 67.1, 70.7, 126.5,
127.8, 129.1, 146.3, 204.6 (d, J ϭ 8.4 Hz). ESI-MS: m/z ϭ 466
[MH]ϩ, 243, 224.
Experimental Section
General Remarks: Moisture-sensitive reactions were carried out in
oven-dried vessels under a positive argon pressure. Tetrahydrofuran
and toluene were distilled from sodium-benzophenone prior to use.
Flash column chromatography was performed on Merck silica gel
60 (230Ϫ400 mesh); Merck silica gel 60F254 coated plastic sheets
(0.25 mm) were used for TLC and developed with iodine and/or
permanganate. Melting points were determined with a Büchi 510
open capillary apparatus and are uncorrected. Optical rotations
were measured at 589 nm in methanol with a PerkinϪElmer 261
polarimeter fitted with a 10 cm cell. IR spectra were recorded as
Nujol mulls, unless otherwise noted, on a JASCO 200 FT/IR spec-
trophotometer. 1H NMR spectra (400 MHz) and 13C NMR spectra
(100.4 MHz) were recorded for CDCl3 solutions containing Me4Si
as an internal standard, unless otherwise noted, on a Jeol EX 400
spectrometer. Electrospray ionization mass spectra (ESI-MS) were
obtained on a SCIEX PerkinϪElmer API1 spectrometer at the
interdepartmental center for mass spectrometry of the University
of Trieste. CHN analyses were obtained on a Carlo Erba 1106 ele-
mental analyzer. Diastereomeric ratios were measured by NMR
spectroscopy. Compounds 2a, 2c and 3a were obtained as de-
scribed.[15,34] Full characterization for known compound 1a[35] is
given.
Dimethyl (3S)-[3-(Dibenzylamino)-4-methyl-2-oxopentyl]phosphon-
ate (3c): Following the same procedure, 2c (3.0 g, 7.75 mmol), 2.5
 BuLi (9.3 mL, 23.2 mmol) and dimethyl methylphosphonate
(2.52 mL, 23.2 mmol), gave an oil, which was purified by flash
chromatography (10% MeOH in diethyl ether) to give 2.13 g of 3c
(5.28 mmol, 69%). [α]2D5 ϭ Ϫ181 (c ϭ 0.3). IR (neat): ν˜ ϭ 1706,
1257 cmϪ1. 1H NMR (CD3CN): δ ϭ 0.81 (d, J ϭ 6.0 Hz, 3 H), 1.15
(d, J ϭ 6.0 Hz, 3 H), 2.32 (m, 1 H), 2.90 (dd, J ϭ 14.5, 21.5 Hz, 1
H), 3.07 (dd, J ϭ 14.5, 21.8 Hz, 1 H), 3.17 (d, J ϭ 10.4 Hz, 1 H),
3.62 (d, J ϭ 11.3 Hz, 3 H), 3.69 (d, J ϭ 11.3 Hz, 3 H), 3.70 (d, J ϭ
13.7 Hz, 2 H), 3.87 (d, J ϭ 13.7 Hz, 2 H), 7.28 (m, 10 H). 13C
NMR (CD3CN): δ ϭ 20.2, 20.6, 27.0, 41.2 (d, J ϭ 129 Hz), 52.5,
54.4, 72.0, 128.1, 129.3, 130.1, 140.6, 201.8 (d, J ϭ 5.4 Hz). ESI-
MS: m/z ϭ 404 [MH]ϩ.
tert-Butyl (1S,3E)-1-Isopropyl-2-oxopent-3-enylcarbamate (1a):
Oven dried K2CO3 (5.78 g, 41.8 mmol) was added portionwise over
15 min, with vigorous stirring, to a solution of phosphonate 3a
(13.5 g, 41.8 mmol) and acetaldehyde (10 mL, 179 mmol) in
150 mL absolute ethanol. After 2 h at 25 °C the solid was filtered
off and the solution neutralized with glacial acetic acid. The solvent
was removed under reduced pressure and the residue was par-
titioned between 250 mL ethyl acetate and 100 mL saturated aque-
ous NaHCO3. The aqueous layer was extracted with 100 mL ethyl
acetate; the combined organic phases were washed with brine and
dried over anhydrous Na2SO4. The solvent was removed under re-
duced pressure and the crude product 1a was purified by flash chro-
matography on silica gel (diethyl ether/petroleum ether, 1:1) to give
9.80 g (40.7 mmol, 97%) of a colorless oil. [α]2D5 ϭ ϩ14.3 (c ϭ 0.23).
L-N-Trityl-valine Methyl Ester (2b): Finely powdered potassium
carbonate (2.00 g, 20 mmol) was added to a suspension of -valine
methyl ester hydrochloride (1.50 g, 8.85 mmol) in 15 mL dichloro-
methane with stirring at room temperature. After 15 min the mix-
ture was filtered and the solvent was evaporated to obtain the free
amine as an oil (1.1 g, 8.4 mmol, 92%). To a solution of this oil
(1.0 g, 7.6 mmol) in anhydrous dichloromethane (15 mL) were
added, under argon and with stirring, triethylamine (1.0 mL,
7.6 mmol) and trityl chloride (2.1 g, 7.6 mmol). After 15 h at room
temperature, 20 mL of water were added and stirring was continued
for 15 min. The organic layer was dried over anhydrous Na2SO4
and the solvents evaporated to give a residue that was crystallized
from n-pentane to give 2.1 g (5.6 mmol, 75%) of a white solid.
m. p. 88 °C Ϫ [α]2D5 ϭ ϩ2.9 (c ϭ 0.3). IR (KBr): ν˜ ϭ 3472, 3302,
1
IR (film): ν˜ ϭ 3430, 3340, 1714, 1694, 1630 cmϪ1. H NMR: δ ϭ
0.78 (d, J ϭ 6.8 Hz, 3 H), 1.00 (d, J ϭ 6.8 Hz, 3 H), 1.44 (s, 9 H),
1.93 (dd, 3 H, J ϭ 1.6, 6.8 Hz), 2.13 (m, 1 H), 4.50 (dd, J ϭ 4.2,
8.8 Hz, 1 H), 5.29 (d, NH, J ϭ 8.8 Hz), 6.24 (d, J ϭ 15.6 Hz, 1 H),
7.00 (dq, J ϭ 6.8, 15.6 Hz, 1 H). 13C NMR: δ ϭ 16.6, 18.4, 19.8,
28.2, 30.7, 61.8, 79.3, 129.2, 144.4, 155.8, 198.1. ESI-MS: m/z ϭ
242 [MH]ϩ, 186, 142.
1
1733, 1595 cmϪ1. H NMR: δ ϭ 0.94 (d, J ϭ 7.0 Hz, 3 H), 1.00
(d, J ϭ 7.0 Hz, 3 H), 2.18 (m, 1 H), 2.66 (d, NH, J ϭ 11.0 Hz),
3.10 (s, 3 H), 3.25 (dd, J ϭ 4.9, 11.0 Hz, 1 H), 7.29 (m, 10 H), 7.51
(m, 5 H). 13C NMR: δ ϭ 17.9, 19.6, 33.7, 50.9, 60.7, 70.9, 126.3,
127.7, 128.9, 146.1, 173.9. ESI-MS: m/z ϭ 374 [MH]ϩ, 243.
C25H27NO2 (373.50): calcd. C 80.4, H 7.24, N 3.75; found C 80.2,
H 7.40, N 3.69.
(2E,3S)-6-Methyl-5-(tritylamino)hept-2-en-4-one (1b): Following
the procedure described above and starting from 3b (2.15 g,
4.62 mmol), acetaldehyde (2 mL, 35.6 mmol) and dry K2CO3
(640 mg, 4.6 mmol), an oil was obtained. Purification by flash chro-
matography (diethyl ether/petroleum ether, 1:1) gave 1.51 g
(3.93 mmol, 85%) of 1b. [α]2D5 ϭ ϩ90 (c ϭ 0.24). IR (film): ν˜ ϭ
Dimethyl (3S)-[4-Methyl-2-oxo-3-(tritylamino)pentyl]phosphonate
(3b): A 2.5  BuLi solution in hexanes (12.9 mL, 32.2 mmol) was
added portionwise to a stirred solution of dimethyl methylphos-
phonate (3.4 mL, 32.2 mmol) in anhydrous tetrahydrofuran
(50 mL) under Argon and cooling at Ϫ78 °C. After additional stir-
ring for 15 min , a solution of 2b (2.00 g, 5.36 mmol) in 10 mL
anhydrous THF was added portionwise and the mixture was stirred
at Ϫ78 °C for 2 h and then at Ϫ30 °C for 1 h. The mixture was
poured into 200 mL of 10% citric acid solution and the aqueous
layer extracted twice with ethyl acetate. The combined organic lay-
1
3308, 1689, 1627 cmϪ1. H NMR: δ ϭ 0.94 (d, J ϭ 6.9 Hz, 3 H),
1.00 (d, J ϭ 6.9 Hz, 3 H), 1.64 (dd, 3 H, J ϭ 1.5, 7.0 Hz), 2.10 (m,
1 H), 3.17 (d, NH, J ϭ 11.0 Hz), 3.55 (dd, J ϭ 4.0, 11.0 Hz, 1 H),
5.62 (dq, J ϭ 1.5, 15.4 Hz, 1 H), 6.23 (dq, J ϭ 7.0, 15.4 Hz, 1 H),
7.25Ϫ7.51 (m, 15 H). 13C NMR: δ ϭ 17.8, 18.7, 19.6, 33.2, 63.8,
71.1, 126.3, 127.8, 129.0, 130.4, 140.4, 146.7, 201.6. ESI-MS:
m/z ϭ 384 [MH]ϩ, 243.
(2E,5S)-5-(Dibenzylamino)-6-methylhept-2-en-4-one (1c): Following
ers were washed with saturated NaHCO3 solution and with brine, the procedure described above and starting from 3c (2.00 g,
then dried over Na2SO4 and the solvents evaporated to give crude
4.96 mmol), acetaldehyde (2 mL, 35.6 mmol) and dry K2CO3
(690 mg, 4.96 mmol), an oil was obtained. Purification by flash
3b (2.04 g, 4.55 mmol, 85%) which was used without further purifi-
cation. [α]2D5 ϭ ϩ49 (c ϭ 0.2). IR (neat): 3400, 3317, 1708, 1255 chromatography (diethyl ether/petroleum ether, 1:1) gave 1.30 g
cmϪ1. 1H NMR: δ ϭ 0.94 (d, J ϭ 7.0 Hz, 3 H), 1.10 (d, J ϭ 7.0 Hz,
(4.05 mmol, 81%) of 1c. [α]2D5 ϭ Ϫ170 (c ϭ 0.3). IR (film): ν˜ ϭ
3 H), 2.05 (dd, J ϭ 16.7, 22.4 Hz, 1 H), 2.12 (m, 1 H), 2.57 (dd, 1687, 1660, 1621 cmϪ1. H NMR: δ ϭ 0.73 (d, J ϭ 6.6 Hz, 3 H),
1
J ϭ 16.7, 16.7 Hz, 1 H), 3.06 (d, NH, J ϭ 9.5 Hz), 3.40 (dd, J ϭ 1.14 (d, J ϭ 6.6 Hz, 3 H), 1.86 (dd, 3 H, J ϭ 1.5, 6.6 Hz), 2.26 (m,
1978
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1973Ϫ1982

Val-Ala Dipeptide Isosteres by Hydrocyanation
FULL PAPER
1 H), 3.29 (d, J ϭ 10.6 Hz, 1 H), 3.39 (d, J ϭ 14.3 Hz, 2 H), 4.00 8: Oil. [α]2D5 ϭ ϩ18 (c ϭ 0.22). IR (film): ν˜ ϭ 3455, 2250, 1690
(d, J ϭ 14.3 Hz, 2 H), 6.10 (dq, J ϭ 1.5, 15.6 Hz, 1 H), 6.56 (dq, cmϪ1. 1H NMR: δ ϭ 0.94 (d, J ϭ 6.7 Hz, 3 H), 0.98 (d, J ϭ 6.7 Hz,
J ϭ 6.6, 15.6 Hz, 1 H), 7.21Ϫ7.38 (m, 10 H). 13C NMR: δ ϭ 18.3,
3 H), 1.35 (d, J ϭ 7.2 Hz, 3 H), 1.45 (s, 9 H), 1.53 (m, 1 H), 1.73
20.13, 20.16, 27.1, 54.3, 67.9, 126.8, 128.2, 128.6, 134.0, 139.9, (m, 1 H), 1.90 (m, 1 H), 3.03 (m, 1 H), 3.23 (br. s, OH), 3.50 (m,
143.1, 201.8. ESI-MS: m/z ϭ 322 [MH]ϩ, 232.
1 H), 3.83 (m, 1 H), 4.49 (d, NH, J ϭ 8.9 Hz). 13C NMR: δ ϭ
17.8, 18.5, 19.9, 22.5, 28.3, 28.5, 37.5, 60.5, 70.2, 79.9, 122.9, 157.1.
ESI-MS: m/z ϭ 271 [MH]ϩ, 215, 171.
tert-Butyl (1S,4S)- and (1S,4R)-4-Cyano-1-isopropyl-2-oxopentyl-
carbamate (4a, 5a): Diethylaluminium cyanide (49.8 mL of 1 
solution in toluene) and acetone cyanohydrin (2.2 mL, 24.9 mmol)
were added, under an argon atmosphere, to enone 1a (6.00 g,
24.9 mmol) in 100 mL dry toluene. After 6 h at 25 °C, the reaction
mixture was cooled to 0 °C and NaF (14.6 g, 342 mmol) and water
(6.30 mL, 342 mmol) were carefully added (CAUTION: HCN can
be formed!) (Workup with aqueous NaHCO3 resulted in poor re-
covery). The mixture was stirred for 30 min at 25 °C, then filtered
through a short pad of anhydrous Na2SO4. The solvent was re-
moved under reduced pressure and the crude product was purified
by flash chromatography on silica gel (diethyl ether/petroleum
ether, 1:1) to give 6.40 g (23.9 mmol, 96%) of a 1:1 mixture of cyano
ketones 4a and 5a. Crystallization from diisopropyl ether/petro-
leum ether gave 1.59 g (5.94 mmol, 23%) of pure 4a: m. p. 73 °C.
[α]2D5 ϭ ϩ33.6 (c ϭ 0.22). IR: ν˜ ϭ 3360, 2240, 1714, 1694 cmϪ1. 1H
NMR: δ ϭ 0.84 (d, J ϭ 6.8 Hz, 3 H), 1.01 (d, J ϭ 6.8 Hz, 3 H),
1.33 (d, J ϭ 7.2 Hz, 3 H), 1.45 (s, 9 H), 2.15 (m, 1 H), 2.78 (dd,
J ϭ 7.2, 18.3 Hz, 1 H), 2.94 (dd, J ϭ 6.1, 18.3 Hz, 1 H), 3.16 (m,
1 H), 4.17 (dd, J ϭ 5.0, 7.9 Hz, 1 H), 5.06 (d, NH, J ϭ 7.9 Hz).
13C NMR: δ ϭ 17.0, 17.6, 19.6, 20.0, 28.2, 29.9, 44.0, 64.0, 80.1,
122.1, 155.8, 205.6. ESI-MS: m/z ϭ 269 [MH]ϩ, 213, 169.
C14H24N2O3 (268.36): calcd. C 62.7, H 8.95, N 10.4; found C 62.3,
H 9.05, N 10.2.
9: Oil. [α]2D5 ϭ Ϫ33 (c ϭ 0.25). IR (neat): 3455, 3350, 2250, 1690
cmϪ1. 1H NMR: δ ϭ 0.89 (d, J ϭ 6.8 Hz, 3 H), 0.93 (d, J ϭ 6.8 Hz,
3 H), 1.26 (d, J ϭ 7.0 Hz, 3 H), 1.37 (s, 9 H), 1.57 (m, 1 H), 1.78
(m, 2 H), 2.71 (m, 1 H), 3.07 (m, 1 H), 3.15 (br. s, OH), 3.89 (m,
1 H), 4.78 (d, NH, J ϭ 9.9 Hz). 13C NMR: δ ϭ 17.9, 19.3, 19.7,
21.9, 28.2, 29.6, 38.6, 59.4, 68.1, 79.3, 123.1, 156.7. ESI-MS: m/z ϭ
271 [MH]ϩ, 215, 171.
tert-Butyl (1S,2R,4R)- and (1S,2S,4R)-4-Cyano-2-hydroxy-1-isopro-
pylpentylcarbamate (10, 11): NaBH4 (282 mg, 7.5 mmol) reduction
of a 3:2 mixture of ketones 5a and 4a (2.0 g, 7.5 mmol) gave, after
chromatography, alcohols 9 (170 mg, 8%), 11 (50 mg, 2%) and an
1
inseparable 7:3 mixture of alcohols 10 and 8 (1.49 g, 74%). 10: H
NMR: δ ϭ 0.95 (m, 6 H), 1.34 (d, J ϭ 7.1 Hz, 3 H), 1.45 (s, 9 H),
1.45 (m, 1 H), 1.63 (m, 1 H), 1.83 (m, 1 H), 2.94 (m, 1 H), 3.32
(m, OH), 3.50 (m, 1 H), 3.73 (m, 1 H), 4.54 (d, NH, J ϭ 8.8 Hz).
13C NMR: δ ϭ 16.9, 18.4, 20.0, 21.6, 28.3, 28.7, 36.1, 60.8, 69.0,
80.1, 123.7, 157.3.
11: [α]2D5 ϭ ϩ19 (c ϭ 0.25). IR (film): ν˜ ϭ 3450, 2250, 1690 cmϪ1
.
1H NMR: δ ϭ 0.95 (d, J ϭ 6.8 Hz, 3 H), 1.00 (d, J ϭ 6.6 Hz, 3
H), 1.35 (d, J ϭ 7.1 Hz, 3 H), 1.44 (s, 9 H), 1.65 (m, 1 H), 1.85 (m,
2 H), 2.94 (m, 2 H), 3.12 (m, 1 H), 3.98 (m, 1 H), 4.83 (d, NH,
J ϭ 9.2 Hz). 13C NMR: δ ϭ 14.0, 18.2, 18.9, 21.4, 28.0, 28.2, 39.1,
60.4, 68.2, 79.3, 122.9, 156.7. ESI-MS: m/z ϭ 271 [MH]ϩ, 215, 171.
1
5a: H NMR: δ ϭ 0.85 (d, J ϭ 6.9 Hz, 3 H), 1.02 (d, J ϭ 6.9 Hz,
3 H), 1.34 (d, J ϭ 7.1 Hz, 3 H), 1.44 (s, 9 H), 2.15 (m, 1 H), 2.74
(dd, J ϭ 6.3, 18.2 Hz, 1 H), 2.96 (dd, J ϭ 7.4, 18.2 Hz, 1 H), 3.16
(m, 1 H), 4.20 (dd, J ϭ 5.0, 8.2 Hz, 1 H), 5.08 (d, NH, J ϭ 8.2 Hz).
13C NMR: δ ϭ 16.9, 17.6, 19.7, 20.0, 28.2, 29.9, 44.5, 63.9, 80.0,
122.1, 155.9, 205.6.
(5S)-5-(Dibenzylamino)-4-hydroxy-2,6-dimethylheptanenitrile (12):
NaBH4 (426 mg, 11.4 mmol) reduction of 4c (800 mg, 2.28 mmol)
gave, after flash chromatography (diethyl ether/petroleum ether,
1:1), 636 mg (1.82 mmol, 86%) of oily 12 as a single diastereoiso-
mer. [α]2D5 ϭ Ϫ31 (c ϭ 0.2). IR (neat): ν˜ ϭ 2244, 1602, 1586 cmϪ1
.
(5S)-5-(Dibenzylamino)-2,6-dimethyl-4-oxoheptanenitrile (4c): With
the same procedure, 1c (100 mg, 0.31 mmol), 1  Et2AlCN
(0.47 mL) and acetone cyanohydrin (0.057 mL, 0.62 mmol) gave a
6:1 mixture of diastereoisomers (4c was the major diastereoisomer),
which was purified by flash chromatography (diethyl ether/petro-
leum ether, 1:1) to give 80 mg (0.23 mmol, 75%) of oil, still con-
sisting of a diastereomeric mixture in the same ratio. IR (neat): ν˜ ϭ
1H NMR: δ ϭ 1.05 (m, 6 H), 1.32 (d, J ϭ 6.8 Hz, 3 H), 1.51 (m,
1 H), 1.67 (m, 1 H), 2.30 (m, 2 H), 2.83 (m, 1 H), 3.45 (d, J ϭ
14.2 Hz, 2 H), 3.74 (m, 1 H), 3.90 (d, J ϭ 14.2 Hz, 2 H), 4.51 (br.
s, OH), 7.30 (m, 10 H). 13C NMR: δ ϭ 16.7, 19.2, 21.6, 23.8, 25.0,
39.2, 53.9, 63.6, 123.6, 127.3, 128.4, 129.1, 138.5. ESI-MS: m/z ϭ
352 [MH]ϩ.
1
3360, 2242, 1712, 1662 cmϪ1. H NMR: δ ϭ 0.75 (d, J ϭ 6.2 Hz,
tert-Butyl (4S,5R,2ЈS)-5-(2-Cyanopropyl)-4-isopropyl-2,2-dimethyl-
3 H), 1.13 (d, J ϭ 6.2 Hz, 3 H), 1.28 (d, J ϭ 7.0 Hz, 3 H), 2.26 (m,
1 H), 2.34 (dd, J ϭ 6.6, 18.7 Hz, 1 H), 2.74 (dd, J ϭ 6.6, 18.7 Hz,
1 H), 3.01 (d, J ϭ 10.6 Hz, 1 H), 3.14 (m, 1 H), 3.55 (d, J ϭ
14.3 Hz, 2 H), 3.98 (d, J ϭ 14.3 Hz, 2 H), 7.25Ϫ7.35 (m, 10 H).
13C NMR: δ ϭ 17.7, 19.6, 20.1, 20.3, 27.3, 48.9, 54.4, 70.4, 122.5,
127.1, 128.4, 128.6, 139.2, 207.5. ESI-MS: m/z ϭ 349 [MH]ϩ.
1,3-oxazolidine-3-carboxylate (13): Amino alcohol
8 (400 mg,
1.48 mmol) was heated at reflux for 15 h in 5 mL 2,2-dimeth-
oxypropane containing a catalytic amount of p-toluensulfonic acid
(8 mg, 0.04 mmol). The solvent was removed under reduced pres-
sure and the residue partitioned between diethyl ether and satu-
rated aqueous NaHCO3. The organic phase was separated, washed
with brine and dried over anhydrous Na2SO4. The solvent was
tert-Butyl (1S,2R,4S)- and (1S,2S,4S)-4-Cyano-2-hydroxy-1-isopro-
pylpentylcarbamate (8, 9): NaBH4 (99 mg, 2.6 mmol) was added rotary evaporated and the crude product was purified by flash
portionwise to cyano ketone 4a (700 mg, 2.61 mmol) in 20 mL chromatography on silica gel (diethyl ether/petroleum ether, 7:3)
methanol at 0 °C and stirring was continued for 1 h. The mixture
was neutralized with glacial acetic acid, the solvent was removed
under reduced pressure and the residue was partitioned between
30 mL ethyl acetate and saturated aqueous NaHCO3. The aqueous
layer was extracted with 30 mL ethyl acetate and the combined
organic layers were washed with brine and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and
flash chromatography of the residue on silica gel (diethyl ether/
petroleum ether, 7:3) gave pure alcohols 8 (505 mg, 72%) and 9
(127 mg, 18%).
giving 13 (275 mg, 60%) as a white solid. m. p. 63 °C. [α]2D5 ϭ ϩ14.5
1
(c ϭ 0.2). IR: ν˜ ϭ 2240, 1685 cmϪ1. H NMR (45 °C): δ ϭ 0.97
(m, 6 H), 1.38 (d, J ϭ 7.1 Hz, 3 H), 1.47 (s, 9 H), 1.47 (m, 1 H),
1.56 (s, 6 H), 1.83 (m, 1 H), 1.85 (m, 1 H), 2.91 (m, 1 H), 3.78 (m,
1 H), 4.26 (ddd, J ϭ 2.8, 5.1, 10.8 Hz, 1 H). 13C NMR (25 °C, two
rotamers): δ ϭ 18.5, 19.0, 19.4, 21.6, 22.0, 23.4, 24.9, 23.5, 26.3,
26.9, 28.3, 28.5, 28.8, 34.1, 34.2, 63.6, 63.7, 74.1, 74.3, 79.7, 79.9,
92.5, 93.1, 122.1, 122.2, 152.6, 153.2. ESI-MS: m/z ϭ 311 [MH]ϩ,
255, 211. C17H30N2O3 (310.44): calcd. C 65.8, H 9.68, N 9.03;
found C 66.1, H 9.64, N 9.06.
Eur. J. Org. Chem. 2003, 1973Ϫ1982
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1979

F. Benedetti, F. Berti, G. Garau, I. Martinuzzi, S. Norbedo
FULL PAPER
tert-Butyl (4S,5S,2ЈS)-5-(2-Cyanopropyl)-4-isopropyl-2,2-dimethyl-
2.6 mmol) was added dropwise to a vigorously stirred mixture of
1,3-oxazolidine-3-carboxylate (14): From amino alcohol 9 (300 mg, K2CO3·1.5H2O (38 mg, 0.23 mmol) and nitrile
8
(200 mg,
1.11 mmol), with the same procedure, were obtained 206 mg of ox-
0.74 mmol) in 1 mL dimethyl sulfoxide. The reaction mixture was
stirred at 25 °C for 3 h, poured into 10 mL water and extracted
azolidine 14 as a white solid (60%), m. p. 80Ϫ83 °C. [α]2D5 ϭ Ϫ6.0
1
(c ϭ 0.28). IR: ν˜ ϭ 2240, 1685 cmϪ1. H NMR (45 °C): δ ϭ 0.92 with ethyl acetate (2 ϫ 30 mL). The combined organic phases were
(d, J ϭ 7.0 Hz, 6 H), 1.37 (d, J ϭ 7.0 Hz, 3 H), 1.48 (s, 9 H), 1.51 washed with water and brine, dried over anhydrous Na2SO4 and
(s, 3 H), 1.60 (s, 3 H), 1.69 (ddd, 1 H, J ϭ 4.9, 8.3, 14 Hz), 2.06
(ddd, J ϭ 6.0, 9.1, 14.0 Hz, 1 H), 2.18 (m, 1 H), 2.80 (m, 1 H),
rotary evaporated to give the oily amide 16 (200 mg). IR (neat):
1
ν˜ ϭ 3420, 3370, 1670 cmϪ1. H NMR: δ ϭ 0.89 (d, J ϭ 6.8 Hz, 3
3.55 (m, 1 H), 4.01 (ddd, J ϭ 3.1, 4.9, 9.1 Hz, 1 H). 13C NMR (45 H), 0.92 (d, J ϭ 6.8 Hz, 3 H), 1.20 (d, J ϭ 7 Hz, 3 H), 1.44 (s, 9
°C): δ ϭ 17.3, 17.8, 19.1, 22.0, 23.5, 27.8, 28.4, 30.3, 40.4, 67.6,
H), 1.45 (m, 1 H), 1.78 (m, 1 H), 1.86 (m, 1 H), 2.71 (m, 1 H), 3.45
74.1, 80.1, 94.6, 122.7, 152.5. ESI-MS: m/z ϭ 311 [MH]ϩ, 255, 211. (m, 1 H), 3.66 (m, 1 H), 3.93 (br. s, OH), 4.62 (d, NH, J ϭ 9.5 Hz),
C17H30N2O3 (310.44): calcd. C 65.8, H 9.68, N 9.03; found C 65.4,
H 9.70, N 8.95.
5.89 (s, 1 H, NH2), 6.43 (s, 1 H, NH2). 13C NMR: δ ϭ 18.0, 18.6,
19.9, 28.3, 28.7, 36.3, 36.4, 60.6, 69.9, 79.7, 157.2, 179.7. ESI-MS:
m/z ϭ 289 [MH]ϩ, 233, 216, 189. The crude amide 16 (200 mg) was
hydrolyzed in 5 mL dioxane and 0.57 mL 1  HCl for 4 days at 25
°C. The reaction mixture was poured into 20 mL water and ex-
tracted twice with 20 mL ethyl acetate. The combined extracts were
washed with saturated aqueous NaHCO3 and brine and dried over
anhydrous Na2SO4. The solvent was removed in vacuo to give lac-
tone 20 as a white solid (163 mg, 81% for the two steps), m. p. 60
°C. [α]2D5 ϭ Ϫ27.5 (c ϭ 0.24). IR (nujol): ν˜ ϭ 3375, 1760, 1715
cmϪ1. 1H NMR: δ ϭ 0.89 (d, J ϭ 6.8 Hz, 3 H), 0.95 (d, J ϭ 6.8 Hz,
3 H), 1.28 (d, J ϭ 7.1 Hz, 3 H), 1.45 (s, 9 H), 1.95 (m, 1 H), 2.38
(m, 1 H), 2.13 (m, 1 H), 2.77 (m, 1 H), 3.61 (m, 1 H), 4.29 (m, 1
H), 4.41 (d, NH, J ϭ 10.1 Hz). 13C NMR: δ ϭ 15.3, 15.7, 19.8,
27.7, 28.3, 32.7, 33.2, 56.9, 77.2, 79.9, 156.1, 179.8. ESI-MS: m/z ϭ
272 [MH]ϩ, 216, 172. C14H25NO4 (271.36): calcd. C 62.0, H 9.22,
N 5.17; found C 62.2, H 9.15, N 5.12.
tert-Butyl (4S,5R,2ЈR)-5-(2-Cyanopropyl)-4-isopropyl-2,2-dimethyl-
1,3-oxazolidine-3-carboxylate (15): With the same procedure, from
a 7:3 mixture of amino alcohols 10 and 8 (1.50 g, 5.55 mmol) a 7:3
mixture of oxazolidines 15 and 13 was obtained (1.07 g, 62%).
Flash chromatography of this mixture gave 629 mg (2.03 mmol,
53% from 10) of pure 15 as a white solid, m. p. 98Ϫ100 °C. [α]2D5
ϭ
Ϫ29 (c ϭ 0.43). IR: ν˜ ϭ 2240, 1685 cmϪ1. 1H NMR (two rotamers):
δ ϭ 0.97 (m, 6 H), 1.37 (d, J ϭ 7 Hz, 3 H), 1.46Ϫ1.57 (m, 15 H),
1.85 (m, 1 H), 1.85 (m, 1 H), 2.08 (ddd, J ϭ 5.2, 10.5, 15.7 Hz, 1
H), 2.86 (m, 1 H), 3.62 (m, 0.5 H), 3.77 (m, 0.5 H), 4.10 (m, 1 H).
13C NMR (two rotamers): δ ϭ 16.8, 16.9, 19.0, 19.4, 21.7, 22.0,
22.5, 23.4, 25.0, 26.2, 26.8, 28.3, 28.6, 32.9, 33.0, 63.0, 63.6, 73.1,
73.3, 79.7, 79.9, 92.5, 93.0, 122.8, 152.6, 153.2. ESI-MS: m/z ϭ 311
[MH]ϩ, 255, 211. C17H30N2O3 (310.44): calcd. C 65.8, H 9.68, N
9.03; found C 65.6, H 9.91, N 9.09.
tert-Butyl
ran-2-yl)propylcarbamate (21): A 7:3 mixture of nitriles 10 (350 mg,
1.30 mmol) and (150 mg) in 1 mL DMSO containing
(1S,2ЈR,4ЈR)-2-Methyl-1-(4-methyl-5-oxotetrahydrofu-
(5S)-5-(Dibenzylamino)-4-hydroxy-2,6-dimethylheptaneamide (18):
Reduction of ketone 19 (1.00 g, 2.73 mmol) with NaBH4 as de-
scribed for the synthesis of 12 gave the crude product which was
crystallized from diisopropyl ether and petroleum ether yielding
945 mg (2.57 mmol, 94%) of alcohol 18 as a single diastereoisomer.
White solid, m. p. 93 °C. [α]2D5 ϭ Ϫ29 (c ϭ 0.4). IR: ν˜ ϭ 3359,
1668, 1602 cmϪ1. 1H NMR: δ ϭ 1.06 (m, 6 H), 1.16 (d, J ϭ 7.0 Hz,
3 H), 1.41 (m, 1 H), 1.55 (m, 1 H), 2.28 (m, 2 H), 2.58 (m, 1 H),
3.45 (d, J ϭ 13 Hz, 2 H), 3.80 (m, 1 H), 3.92 (d, J ϭ 13 Hz, 2 H),
4.72 (br. s, OH), 5.32 (br. s, 1 H, NH2), 5.82 (br. s, 1 H, NH2),
7.22Ϭ7.32 (m, 10 H). 13C NMR: δ ϭ 16.6, 19.2, 24.0, 24.9, 37.0,
39.7, 53.8, 65.1, 66.3, 127.3, 128.3, 128.5, 138.8, 179.5. ESI-MS:
m/z ϭ 369 [MH]ϩ. C23H32N2O2 (368.52): calcd. C 74.96, H 8.75,
N 7.60; found C 75.0, H 8.81, N 7.47.
8
K2CO3·1.5H2O (70 mg, 0.42 mmol) was hydrated with 0.26 mL
30% hydrogen peroxide. Workup as described gave a 7:3 mixture of
amides 17 and 16. IR (neat): ν˜ ϭ 3430, 3370, 1670 cmϪ1. 1H NMR:
δ ϭ 0.84 (m, 6 H), 1.09 (d, J ϭ 6.6 Hz, 3 H), 1.36 (s, 9 H), 1.45
(m, 1 H), 1.85 (m, 1 H), 1.68 (m, 1 H), 2.50 (m, 1 H), 3.36 (m, 1
H), 3.59 (m, 1H ϩ OH), 4.8 (d, NH, J ϭ 9.9 Hz), 6.17 and 6.51 (2
br. s, 2 H, NH2). 13C NMR: δ ϭ 17.3, 17.8, 20.1, 28.3, 28.5, 36.7,
37.2, 60.4, 69.7, 79.4, 157.0, 180.6. ESI-MS: m/z ϭ 289 [MH]ϩ,
233, 216, 189. Hydrolysis of the 7:3 mixture of crude amides 17
and 16 was carried out as described for 16 and gave the correspond-
ing lactones 21 and 20, from which 21 was isolated by flash chro-
matography (ethyl ether/petroleum ether, 1:1) as a white solid
(296 mg, 84% from 10), m. p. 94 °C. [α]2D5 ϭ Ϫ11.5 (c ϭ 0.22). IR:
(5S)-5-(Dibenzylamino)-2,6-dimethyl-4-oxoheptaneamide (19):
K2CO3 (1.54 g, 11.2 mmol) and 30% H2O2 (0.65 mL) were added
to 4c (1.30 g, 3.73 mmol) in 5 mL DMSO. The mixture was stirred
overnight at room temperature, poured into 20 mL of water and
extracted with 3 ϫ 30 mL ethyl acetate. The combined organic lay-
ers were washed with water and brine, dried over Na2SO4 and the
solvents evaporated to give a crude oil which was purified by flash
chromatography (diethyl ether), giving 1.10 g (2.98 mmol, 80%) of
oily amide 19 as a single diastereoisomer. [α]2D5 ϭ Ϫ154 (c ϭ 0.6).
1
ν˜ ϭ 3370, 1750, 1710 cmϪ1. H NMR: δ ϭ 0.89 (d, J ϭ 7 Hz, 3
H); 0.96 (d, J ϭ 7 Hz, 3 H), 1.29 (d, J ϭ 7 Hz, 3 H), 1.45 (s, 9 H),
1.78 (m, 1 H), 2.48 (m, 1 H), 2.16 (m, 1 H), 2.64 (m, 1 H), 3.67
(m, 1 H), 4.20 (m, 1 H), 4.39 (d, NH, J ϭ 9.5 Hz). 13C NMR: δ ϭ
15.1, 15.6, 19.7, 28.1, 28.3, 34.8, 35.5, 54.8, 77.6, 79.7, 155.9, 179.1.
ESI-MS: m/z ϭ 272 [MH]ϩ, 216, 172. C14H25NO4 (271.36): calcd.
C 62.0, H 9.22, N 5.17; found C 61.7, H 9.18, N 5.17.
5-[(1S,2S,3S)-1-(Dibenzylamino)-2-methylpropyl]-3-methyldihydro-
furan-2(3H)-one (22): 2.73 mL of a 1  HCl solution (2.73 mmol)
were added to a solution of 18 (500 mg, 1.59 mmol) in 10 mL
dioxane. After stirring at room temperature for 4 days, the mixture
was neutralized with saturated NaHCO3 solution. The aqueous
layer was extracted with 2 ϫ 30 mL ethyl acetate; the combined
organic layers were washed with brine, dried over Na2SO4 and the
solvents evaporated. The residue was crystallized from dichloro-
methane/petroleum ether to give 440 mg (1.32 mmol, 83%) of 22 as
colorless crystals. m. p. 112 °C. [α]2D5 ϭ ϩ90 (c ϭ 0.1). IR (KBr):
1
IR (neat): ν˜ ϭ 3436, 1738, 1674 cmϪ1. H NMR: δ ϭ 0.74 (d, J ϭ
6.2 Hz, 3 H), 1.10 (d, J ϭ 6.2 Hz, 3 H), 1.16 (d, J ϭ 7.0 Hz, 3 H),
2.19 (m, 1 H), 2.26 (dd, J ϭ 3.7, 18.7 Hz, 1 H), 2.89 (m, 1 H), 3.00
(dd, J ϭ 9.2, 18.7 Hz, 1 H), 3.04 (d, J ϭ 10.3 Hz, 1 H), 3.52 (d,
J ϭ 14.3 Hz, 2 H), 4.00 (d, J ϭ 14.3 Hz, 2 H), 6.17 (br. s, 1 H,
NH2), 6.24 (br. s, 1 H, NH2), 7.22Ϫ7.43 (m, 10 H). 13C NMR: δ ϭ
17.8, 20.0, 20.2, 27.4, 34.4, 50.8, 54.6, 70.4, 127.0, 127.5, 128.6,
139.6, 178.1, 212.2. ESI-MS: m/z ϭ 367 [MH]ϩ.
tert-Butyl (1S,2ЈR,4ЈS)-2-Methyl-1-(4-methyl-5-oxotetrahydrofuran-
2-yl)propylcarbamate (20): 30% hydrogen peroxide (0.30 mL,
1
ν˜ ϭ 1773 cmϪ1. H NMR: δ ϭ 0.85 (d, J ϭ 7.0 Hz, 3 H), 1.02 (d,
1980
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1973Ϫ1982

Val-Ala Dipeptide Isosteres by Hydrocyanation
J ϭ 7.0 Hz, 3 H), 1.24 (d, J ϭ 7.0 Hz, 1 H), 1.81 (m, 1 H), 1.97 (2S,4ЈS,5ЈR)-3-[3-(tert-Butoxycarbonyl)-4-isopropyl-2,2-dimethyl-
FULL PAPER
(m, 1 H), 2.15 (m, 1 H), 2.49 (m, 1 H), 2.66 (m, 1 H), 3.83 (d, J ϭ
13.2 Hz, 2 H), 3.87 (d, J ϭ 13.2 Hz, 2 H), 4.69 (m, 1 H), 7.22Ϭ7.35
1,3-oxazolidin-5-yl]-2-methylpropanoic Acid (28): 3 mL of 1 
KMnO4 were added dropwise, with stirring, to a solution of alde-
(m, 10 H). 13C NMR: δ ϭ 15.0, 20.4, 21.2, 28.38, 28.42, 35.4, 56.3, hyde 26 (100 mg, 0.32 mmol) in 3 mL of tert-butyl alcohol and
64.2, 79.4, 126.9, 128.1, 129.4, 140.1, 179.4. ESI-MS: m/z ϭ 352
2 mL of 5% aqueous KH2PO4. After 10 min saturated Na2SO3 was
[MH]ϩ Ϫ C23H29NO2 (351.49): calcd. C 78.63, H 8.26, N 3.99; added and the resulting solution was acidified to pH ϭ 3 with
found C 79.0, H 8.38, N 4.23.
dilute HCl and extracted with ethyl acetate (3 ϫ 20 mL). The or-
ganic phases were washed with brine and dried over anhydrous
Na2SO4 and the solvent was removed under reduced pressure to
give the acid 28[14] as an oil (99 mg, 0.30 mmol, 94%). IR: ν˜ ϭ
3500Ϫ3000, 1690 cmϪ1. ESI-MS: m/z ϭ 330 [MH]ϩ, 274, 230.
(3S,5R,1ЈS)-5-(1-Amino-2-methylpropyl)-3-methyldihydrofuran-
2(3H)-one (23) and (3R,5R,1ЈS)-5-(1-amino-2-methylpropyl)-3-
methyldihydrofuran-2(3H)-one (24): Trifluoroacetic acid (0.5 mL)
was added to the lactone 20 or 21, respectively, (50 mg, 0.18 mmol)
in 1 mL dichloromethane and the solution was kept at 25 °C for
10 min. The solvent was evaporated in vacuo and the residue was
partitioned between 15 mL dichloromethane and 15 mL of satu-
rated NaHCO3 solution. The aqueous layer was extracted twice
with 5 mL dichloromethane and the combined organic phases were
washed with brine and dried over anhydrous Na2SO4. The solvent
(2S,4ЈS,5ЈR)-3-[3-(tert-Butoxycarbonyl)-4-isopropyl-2,2-dimethyl-
1,3-oxazolidin-5-yl]-2-methylpropanoic Acid (29): Permanganate
oxidation of aldehyde 27 (100 mg, 0.32 mmol), as described, gave
the corresponding acid 29[14] as an oil (100 mg, 0.30 mmol, 95%),
IR (neat): 3500Ϫ3000, 1690 cmϪ1. ESI-MS: m/z ϭ 330 [MH]ϩ,
274, 230.
was removed under reduced pressure to give the oily free amines
Crystal Data for 22: C23H54NO2, M ϭ 376.67 g molϪ1, crystal di-
mensions 0.30 ϫ 0.20 ϫ 0.05 mm, orthorhombic, space group
[14]
23, 24
(30 mg, 95%). 23: IR (neat): ν˜ ϭ 1768 cmϪ1. 24: IR
(neat): ν˜ ϭ 1770 cmϪ1
.
˚
P212121, a ϭ 7.690(3), b ϭ 9.542(9), c ϭ 26.882(5) A, V ϭ 1973(2)
3
A , Z ϭ 4, ρcalcd. ϭ 1.268 g cmϪ3, µ ϭ 0.08 mmϪ1, R ϭ 0.0746,
˚
(3S,5S,1ЈS)-5-(1-Amino-2-methylpropyl)-3-methyldihydrofuran-
2(3H)-one (25): 50 mg of 22 (0.14 mmol) in 5 mL methanol were
stirred, in the presence of 10 mg of Pd(OH)2/C and under 1 Atm
of hydrogen, for 24 h. The suspension was filtered through celite
and the solvents evaporated in vacuo to give 23 mg (0.13 mmol,
Rw ϭ 0.1721 for 2690 reflections with I Ͼ 3σ(I) and 238 param-
eters. Data were collected at 293 K with a Nonius-DIP1030 dif-
fractometer equipped with a Nonius R590 X-ray generator using a
˚
graphite-monochromated Mo-Kα radiation (λ ϭ 0.7107 A). The
1
93%) of an oil. IR (neat): ν˜ ϭ 1772 cmϪ1. H NMR: δ ϭ 0.93 (d,
structure was solved by direct methods and refined by full-matrix
methods (SHELX-97).
J ϭ 6.8 Hz, 3 H), 1.01 (d, J ϭ 6.8 Hz, 3 H), 1.29 (d, J ϭ 7.0 Hz,
3 H), 1.59 (br. s, 2 H, NH2), 1.79 (m, 2 H), 2.39 (m, 1 H), 2.56 (dd,
1 H, J ϭ 5.1 Hz), 2.70 (m, 1 H), 4.34 (m, 1 H). 13C NMR: δ ϭ
15.0, 16.6, 20.2, 30.2, 34.1, 35.8, 59.8, 80.8, 179.4.
CCDC-197056 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at www.
ccdc. cam. ac. uk/conts/retrieving. html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
tert-Butyl (4S,5R,2ЈS)-4-Isopropyl-5-(2-methyl-3-oxopropyl)-2,2-di-
methyl-1,3-oxazolidine-3-carboxylate (26): 0.90 mL of a 1  solu-
tion of diisobutylaluminium hydride in toluene were added drop-
wise to the cyano-oxazolidine 13 (280 mg, 0.90 mmol) in 10 mL dry
toluene, under an argon atmosphere. The solution was kept for 15 h
at 25 °C, then 10 mL aqueous 5% tartaric acid were added and the
mixture was stirred for further 4 h and filtered through celite. The
filtrate was washed with brine, dried over anhydrous Na2SO4, and
the solvent was removed under reduced pressure. The crude prod-
uct was purified by flash chromatography on silica gel (diethyl
ether/petroleum ether, 1:1) to give the aldehyde 26 (225 mg, 80%)
as a colorless oil. [α]2D5 ϭ Ϫ20.5 (c ϭ 0.20). IR (neat): ν˜ ϭ 1720,
CB2 1EZ, UK; Fax: (internat.)
deposit@ccdc. cam. ac. uk].
ϩ 44-1223/336-033; E-mail:
Acknowledgments
`
Support by Istituto Superiore di Sanita, FIRB (Programma Stra-
tegico Post Genoma, grant RBNE017F8N) and the CNR (Agenzia
2000, progetto giovani) is gratefully acknowledged. We thank C. E.
B. for a postdoctoral grant to S. N. and Dr. Fabio Hollan for the
mass spectra.
1
1685 cmϪ1. H NMR (two rotamers): δ ϭ 0.96 (m, 6 H), 1.19 (m,
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(ddd, J ϭ 2.9, 4.9, 10.6 Hz, 1 H), 9.66 (s, 1 H). 13C NMR (two
rotamers): δ ϭ 13.7, 14.0, 19.1, 19.5, 21.8, 22.2, 23.3, 24.9, 26.2,
26.8, 28.3, 28.5, 30.1, 43.7, 63.8, 63.9, 74.2, 74.7, 79.5, 79.7, 92.3,
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methyl-1,3-oxazolidine-3-carboxylate (27): Reduction of nitrile 15
(350 mg, 1.13 mmol) with diethylaluminium hydride, as described,
gave aldehyde 27 as a white solid (272 mg, 77% after chromatogra-
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1
1685 cmϪ1. H NMR (two rotamers): δ ϭ 0.97 (m, 6 H), 1.14 (m,
Emini, P. L. Darke, B. M. McKeever, W. A. Schleif, J. C. Quin-
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3 H), 1.48 (s, 9 H), 1.53 (m, 7 H), 1.91 (m, 1 H), 2.09 (m, 1 H),
2.59 (m, 1 H), 3.64 (m, 0.5 H), 3.80 (m, 0.5 H), 4.08 (m, 1 H), 9.67
(s, 1 H). 13C NMR (two rotamers): δ ϭ 13.3, 13.4, 19.1, 19.5, 21.8,
22.2, 23.4, 25.0, 26.2, 26.9, 28.4, 28.7, 30.0, 30.3, 44.1, 44.3, 63.9,
64.1, 74.4, 74.6, 79.5, 79.8, 92.3, 92.8, 152.7, 153.4, 204.2, 204.4.
ESI-MS: m/z ϭ 314 [MH]ϩ, 258, 214.
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Eur. J. Org. Chem. 2003, 1973Ϫ1982
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1981

F. Benedetti, F. Berti, G. Garau, I. Martinuzzi, S. Norbedo
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Received November 11, 2002
1982
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1973Ϫ1982